(19)
(11)EP 3 359 537 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
25.03.2020 Bulletin 2020/13

(21)Application number: 16774955.5

(22)Date of filing:  04.10.2016
(51)International Patent Classification (IPC): 
C07D 409/12(2006.01)
A61K 31/41(2006.01)
C07D 249/02(2006.01)
A61P 25/00(2006.01)
(86)International application number:
PCT/EP2016/073589
(87)International publication number:
WO 2017/060202 (13.04.2017 Gazette  2017/15)

(54)

TRIAZOLE DERIVATIVES

TRIAZOLDERIVATE

DÉRIVÉS DE TRIAZOLE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 06.10.2015 EP 15188567

(43)Date of publication of application:
15.08.2018 Bulletin 2018/33

(73)Proprietor: F. Hoffmann-La Roche AG
4070 Basel (CH)

(72)Inventors:
  • HOENER, Marius
    4058 Basel (CH)
  • WICHMANN, Juergen
    79585 Steinen (DE)

(74)Representative: Salud, Carlos E. 
F. Hoffmann-La Roche AG Patent Department Grenzacherstrasse 124
4070 Basel
4070 Basel (CH)


(56)References cited: : 
WO-A1-2008/000645
WO-A1-2009/077366
WO-A1-2009/043780
WO-A1-2016/169902
  
  • BRIDGES R J ET AL: "The excitatory amino acid transporters: Pharmacological insights on substrate and inhibitor specificity of the EAAT subtypes", PHARMACOLOGY AND THERAPEUTICS, ELSEVIER, GB, vol. 107, no. 3, 1 September 2005 (2005-09-01), pages 271-285, XP027636200, ISSN: 0163-7258 [retrieved on 2005-09-01]
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description


[0001] The present invention relates to compounds of formula I

wherein
R1'
is CH3
R1
is methyl, ethyl, CF3, CH2OH, cyclopropyl or cyano, or
R1' and R1 may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring;
R2
is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol;
R3
is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;
R4
is hydrogen, methyl, F or Cl;
or to a pharmaceutically acceptable salt or acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

[0002] The compounds of formula I may be used in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder.

[0003] It has been surprisingly been found that the compounds of general formula I are EAAT3 inhibitors.

[0004] The excitatory amino acid transporter 3 (EAAT3), also referred to in human studies as solute carrier family 1, member 1 (systematic gene name: SLC1A1) and in rodents as excitatory amino acid carrier 1 (EAAC1), is a high-affinity anionic amino acid transporter found in neurons throughout the cortex and in the hippocampus, basal ganglia (striatum, thalamus), and the olfactory bulb. EAAT3 functions to buffer local glutamate concentrations at excitatory synapses, for example in the hippocampus, and modulates the differential recruitment of glutamate receptor subtypes at extrasynaptic sites. Furthermore, EAAT3 is thought to be involved in facilitating GABA and glutathione biosynthesis. EAAT3 is a member of the EAAT family that mediates the uptake of glutamate into neuronal and glial cells of the mammalian CNS. Two transporters expressed primarily in glia, EAAT1 and EAAT2, are crucial for glutamate homeostasis in the adult mammalian brain and for rapid clearance of glutamate from the synaptic cleft. Three neuronal transporters (EAAT3, EAAT4, and EAAT5) appear to have additional functions in regulating and processing cellular excitability with EAAT3 being abundantly expressed throughout the CNS (EAAT4 is unique to Purkinje cells of the cerebellum and EAAT5 is expressed in rod photoreceptor and bipolar cells of the retina).
EAATs are assembled as trimers, and the existence of multiple isoforms raises the question of whether certain isoforms can form hetero-oligomers. In the mammalian brain, the specificity of excitatory synaptic transmission depends on rapid diffusion of glutamate away from active synapses and the powerful uptake capacity of glutamate transporters in astrocytes. The extent to which neuronal glutamate transporters influence the lifetime of glutamate in the extracellular space remains unclear, but it is thought to be minor. EAAT3, the predominant neuronal glutamate transporter at excitatory synapses in hippocampal area CA1, buffers glutamate released during synaptic events and prolongs the time course of its clearance by astrocytes. EAAT3 does not significantly alter activation of receptors in the synaptic cleft. Instead, it reduces recruitment of perisynaptic/ extrasynaptic NR2B-containing NMDARs, thereby facilitating induction of long-term potentiation by short bursts of high-frequency stimulation. Specific EAAT3 inhibitors may have the potential to locally and specifically strengthen particular synapses.

[0005] Obsessive-compulsive disorder (OCD) is among the most common mental disorders (prevalence 1-3%), and is at least as prevalent as schizophrenia and bipolar disorder. In the United States, one in 50 adults suffers from OCD. OCD affects children and adolescents as well as adults. Roughly one third to one half of adults with OCD reports a childhood onset of the disorder, and the disorder is typically chronic in nature. Treatment consists of predominantly serotonergic TCAs (clomipramine) or SSRIs in combination with cognitive-behavioral therapy (CBT). Overall, response to these interventions is of some but still limited benefit (approximately comparable to antidepressant response in MDD), and given the chronicity of OCD, the unmet medical need remains very high. OCD has been linked to serotonin and glutamate abnormalities. The hypothesis of glutamate signaling dysfunction in OCD is based on findings from neuroimaging, animal models, positional cloning and treatment studies.

[0006] The obsessive-compulsive symptomatology in OCD has considerable phenomenological, epidemiological and possibly (aetio)-pathophysiological overlap with a core autism spectrum disorder criterion: "restricted, repetitive patterns of behavior, interests, or activities" (taken from proposed DSM-5 revision). In support of this notion, human genetics studies have linked both the serotonin transporter and EAAT3 (SLC1A1) genes to autism spectrum disorder (ASD) or rigid-compulsive behavior in ASD and to OCD.

[0007] In addition, obsessive-compulsive symptoms induced by antipsychotics in schizophrenic bipolar disorder patients have been linked to EAAT3 (SLC1A1) gene variants. Post-mortem brain studies have shown that both classic and atypical antipsychotics reduce EAAT3, suggesting an involvement of this transporter in neuroleptic mechanisms beyond dopamine and serotonin modulation. Moreover, genetic variation in the human gene EAAT3 (SLC1A1) has been associated with antipsychotic drug response.

[0008] There is converging evidence from neurobiological data, human genetics, imaging studies and experimental treatments that EAAT3 is a key pathophysiological element in OCD and rigid-compulsive behavior in autism and in schizophrenia.

[0009] Compounds of formula I are distinguished by having valuable therapeutic properties. They can be used in the treatment or prevention of disorders, relating to EAAT3 inhibitors.
The most preferred indications for compounds which are EAAT3 inhibitors are psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder.

[0010] The present invention relates to compounds of formula I and to their pharmaceutically acceptable salts, to their use in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder, to compounds of formulas I, IA, IB, IC, ID, IE, IF and IG as pharmaceutically active substances, to the processes for their production as well as to their use in the treatment or prevention of disorders, relating to EAAT3 inhibitors, such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder and to pharmaceutical compositions containing the compounds of formula IA

[0011] A further object of the present invention is a compound of formula I for use in a method for the treatment or prophylaxis of psychiatric disorder such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder, which method comprises administering an effective amount of a compound of formula I to a mammal in need.

[0012] Furthermore, the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers, or analogues containing isotopes of hydrogen, fluorine, carbon, oxygen or nitrogen.

[0013] One object of the present invention are novel compounds of formula IA,

wherein
R2
is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol;
R3
is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;
R4
is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof,
for example the following compounds:

N-tert-Butyl-3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-fluorophenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-chlorophenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(3-methyl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-fluorophenyl)-benzamide

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-chlorophenyl)-benzamide

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

N-tert-Butyl-3-(4-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-chlorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

N-tert-Buty1-3-(4-chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamide

N-tert-Butyl-3-(4-chlorophenyl)-5-[3-(2-hydroxypropan-2-yl)-1,2,4-triazol-4-yl]-benzamide

N-tert-Butyl-3-(3,4-difluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-methoxyphenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-chloro-3-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-fluoro-3-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(3-fluoro-4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-cyano-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide or

N-tert-Butyl-3-(4-cyclopropyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide.



[0014] One further object of the present invention are novel compounds of formula IB,

wherein
R2
is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol;
R3
is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;
R4
is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof,
for example the following compounds:

3-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-5-(1,2,4-triazol-4-yl)-benzamide

N-(2-Methylbutan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

3-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide or

3-(4-Chlorophenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide.



[0015] One object of the present invention are novel compounds of formula IC,

wherein
R2
is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol;
R3
is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;
R4
is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof,
for example the following compound:
3-(4-Fluorophenyl)-5-(1,2,4-triazol-4-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide.

[0016] One further object of the present invention are novel compounds of formula ID,

wherein
R2
is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol;
R3
is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;
R4
is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof,
for example the following compounds:

3-(4-Fluorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

3-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide or

N-(1-hydroxy-2-methylpropan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide.



[0017] One object of the present invention are novel compounds of formula IE,

wherein
R2
is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol;
R3
is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;
R4
is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof,
for example the following compounds:

N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzamide

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-benzamide

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-5-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-benzamide

N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

3-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-(2-Cyclopropyl-propan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide or

3-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamide.



[0018] One further object of the invention are compounds of formula IF,

wherein
R2
is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol;
R3
is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;
R4
is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

[0019] One further object of the invention are compounds of formula IG,

R2
is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol;
R3
is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;
R4
is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof,
for example the following compound:
(RS)-3-(4-Chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide.

[0020] The preparation of compounds of formulas IA, IB, IC, ID, IE, IF and IG of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes 1 to 6. The skills required for carrying out the reaction and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before.

[0021] The compounds of formulas IA, IB, IC, ID, IE, IF and IG can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.

[0022] The present compounds of IA, IB, IC, ID, IE, IF and IG and their pharmaceutically acceptable salts may be prepared by methods, known in the art, for example by the process variant described below, which process comprises
  1. a) reacting a compound of formula II

    with N,N-dimethylformamide-dimethylacetal

    and a compound of formula

    to a compound of formula I

  2. b) reacting a compound of formula V

    with a compound of formula III

    to a compound of formula I

    wherein the substituents are as described above, or
    if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts, or
  3. c) reacting a compound of formula VII

    with a compound of formula VIII

    to a compound of formula I

    wherein the substituents are described above, or
    if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.


[0023] The preparation of compounds of formulas IA, IB, IC, ID, IE, IF and IG is further described in more detail in schemes below and in examples 1 -37.

[0024] In general the triazole derivatives I can either be prepared from the intermediate aniline derivatives II by well-known trizole formation with N,N-dimthylformamide-dimethylacetal III and commercially available acyl-hydrazides IV,

or by coupling reaction of the bromo derivatives V with commercially available boronic acid derivatives VI,

or by amide formation using the acid derivatives VII and the commercially available amines VIII.



[0025] The aniline derivatives II can be prepared starting from commercially available 3-iodo-5-nitrobenzoic acid IX. Amide formation with the commercially available amines VIII using standard conditions leads to the amides X which can coupled with commercially available boronic acid derivatives VI to yield the nitro compounds XI which can be reduced with tin(II)chloride to yield the aniline building blocks II.



[0026] The synthesis of the bromo derivatives V can start from the commercially available 3-amino-5-bromobenzoic acid XII. Triazole formation by reaction with the N-[(E)-dimethylamino-methylidene-amino]-acylamides XIII prepared from commercially available acyl-hydrazides IV and N,N-dimthylformamide-dimethylacetal III yields the triazole derivatives XIV. Amide formation with the commercially available amines VIII led to the building blocks V.



[0027] An alternative route for the synthesis of the triazole derivatives I can start from the commercially available 3-amino-5-bromobenzoic acid XII. Triazole formation using N,N-dimthylformamide-dimethylacetal III and commercially available acyl-hydrazides IV, yields the ester derivatives XV. Coupling reaction with commercially available boronic acid derivatives VI and subsequent ester hydrolysis led to the acid building blocks VII.



[0028] An alternative route to the tetrazole building block XIV-1 (R2 = H) is the condensation of the commercially available 3-amino-5-bromobenzoic acid XII with commercially available 1,2-diformylhydrazine XVI.



[0029] Generally speaking, the sequence of steps used to synthesize the compounds of formula I can also be modified in certain cases.

[0030] The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmaceutical properties. Specifically, it has been found that the compounds of the present invention are EAAT3 inhibitors for use in the treatment of schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorders.

[0031] The compounds were investigated in accordance with the test given hereinafter.

Biological Assay and Data:


The FLIPR Membrane Potential (FMP) assay



[0032] HEK-293 cells stably expressing human EAAT3 were seeded at 55 000 cells/ well in growth medium (DMEM glutamate free (Invitrogen 11960-044), 1% Pen Strep (10 ml/l GIBCO BRL N°15140-023), 10% FCS non dialysed heat inactivated, 5 mg/l puromycin) in poly-D-lysine treated 96-well black microtiter plates with clear-bottom. After 24 h, the growth medium was removed and 100 µl/well of Krebs buffer (140 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.2 mM MgCl2, 11 mM HEPES, 10 mM D-glucose, pH=7.4) added. The cells were then loaded by adding 100 µl/well FMP assay dye (FLIPR Membrane Potential assay reagent, Molecular Devices). The 96-well plates were then incubated at 37 °C for 1 h. The depolarization of the cells will cause more dye to enter in the cells, where it will bind to intracellular proteins and lipids and cause an increase in the fluorescence signal. Antagonist potency at human EAAT3 was determined by using L-glutamate as agonist at a concentration which gives 80% of the maximum response. The antagonists were applied 15 min before the application of the agonist L-glutamate. The assays were performed at room temperature and measurements done by using a Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices) and filter #2. Responses were measured as peak increase in fluorescence minus basal (i.e. fluorescence without addition of L-glutamate). Kb was determined using the Cheng-Prusoff equation Kb = IC50/[1 + (A/EC50)], where IC50 is the concentration of the antagonist producing 50% inhibition, A is the concentration of the agonist against which the IC50 is being determined (at EC80) and EC50 is the concentration of the agonist producing 50% inhibition.
List of Examples and data:
 StructureCompound nameEAAT3 Kb [uM]
1

3-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-5-(1,2,4-triazol-4-yl)-benzamide 0.088
2

N-tert-Butyl-3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzamide 0.29
3

N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzamide 0.39
4

3-(4-Fluorophenyl)-5-(1,2,4-triazol-4-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide 0.25
5

N-tert-Butyl-3-(4-fluorophenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide 0.16
6

N-tert-Butyl-3-(4-chlorophenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide 0.076
7

N-tert-Butyl-3-(3-methyl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide 0.13
8

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-fluorophenyl)-benzamide 0.19
9

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-chlorophenyl)-benzamide 0.18
10

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide 0.16
11

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide 0.18
12

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-benzamide 0.15
13

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-5-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-benzamide 0.29
14

N-tert-Butyl-3-(4-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.075
15

N-tert-Butyl-3-(4-chlorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.075
16

N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.1
17

3-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.19
18

N-tert-Butyl-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide 0.13
19

N-(2-Cyclopropyl-propan-2-yl)-3-(3-propan-2-yl-l,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl] -benzamide 0.22
20

3-(4-Fluorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.39
21

3-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.23
22

N-(1-hydroxy-2-methylpropan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl] -benzamide 0.33
23

N-(2-Methylbutan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide 0.094
24

3-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.054
25

3-(4-Chlorophenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.12
26

N-tert-Butyl-3-(4-chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamide 0.145
27

N-tert-Butyl-3-(4-chlorophenyl)-5-[3-(2-hydroxypropan-2-yl)-1,2,4-triazol-4-yl]-benzamide 0.064
28

N-tert-Butyl-3-(3,4-difluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.16
29

N-tert-Butyl-3-(4-methoxyphenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.29
30

N-tert-Butyl-3-(4-chloro-3-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.1
31

N-tert-Butyl-3-(4-fluoro-3-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.098
32

N-tert-Butyl-3-(3-fluoro-4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.12
33

N-tert-Butyl-3-(4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.1
34

N-tert-Butyl-3-(4-cyano-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.22
35

N-tert-Butyl-3-(4-cyclopropyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide 0.13
36

(RS)-3-(4-Chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl] -N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide 1.57
37

3-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamide 0.15


[0033] The compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

[0034] The compounds of formula (I) and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula (I), but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[0035] In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

[0036] As mentioned earlier, medicaments containing a compound of formula (I) or pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.

[0037] As further mentioned earlier, the use of the compounds of formula (I) for the preparation of medicaments useful in the prevention and/or the treatment of the above recited diseases is also an object of the present invention.

[0038] The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/ kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.

Preparation of pharmaceutical compositions comprising compounds of the invention:



[0039] Tablets of the following composition are manufactured in the usual manner:
ingredientmg/tablet
525100500
Compound of formula I 5 25 100 500
Lactose Anhydrous DTG 125 105 30 150
Sta-Rx 1500 6 6 6 60
Microcrystalline Cellulose 30 30 30 450
Magnesium Stearate 1 1 1 1
Total 167 167 167 831

Manufacturing Procedure



[0040] 
  1. 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.
  2. 2. Dry the granules at 50°C.
  3. 3. Pass the granules through suitable milling equipment.
  4. 4. Add ingredient 5 and mix for three minutes; compress on a suitable press.


[0041] Capsules of the following composition are manufactured:
ingredientmg/capsule
525100500
Compound of formula I 5 25 100 500
Hydrous Lactose 159 123 148 -
Corn Starch 25 35 40 70
Talk 10 15 10 25
Magnesium Stearate 1 2 2 5
Total 200 200 300 600

Manufacturing Procedure



[0042] 
  1. 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.
  2. 2. Add ingredients 4 and 5 and mix for 3 minutes.
  3. 3. Fill into a suitable capsule.


[0043] A compound of formula I, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer; the talc is added thereto and mixed thoroughly. The mixture is filled by machine into suitable capsules, e.g. hard gelatin capsules.

[0044] Injection solutions of the following composition are manufactured:
ingredientmg/injection solution.
Compound of formula I 3
Polyethylene Glycol 400 150
acetic acid q.s. ad pH 5.0
water for injection solutions ad 1.0 ml

Manufacturing Procedure



[0045] A compound of formula I is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Experimental Section:


Intermediates


Intermediate 1: 3-(4-Fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzoic acid



[0046] 


Step A



[0047] To a stirred mixture of commercially available 3-amino-5-bromobenzoic acid (0.50 g, 2.31 mmol), commercially available 1,2-diformylhydrazine (611 mg, 6.94 mmol) and pyridine (2.5 ml) was added dropwise at room temperature chlorotrimethylsilane (5.03 g, 5.87 ml, 46.3 mmol) and triethylamine (1.64 g, 2.26 ml, 16.2 mmol). The mixture was alloed to stir for 5h at 100°C, cooled to room temperature, diluted with water (50 ml) and the precipitate collected by filtration to yield 3-bromo-5-(1,2,4-triazol-4-yl)-benzoic acid (0.61 g, 98%) as a light brown solid, MS (ISP) m/z = 268.0 [(M+H)+], mp 281.5°C.

Step B



[0048] A mixture of 3-bromo-5-(1,2,4-triazol-4-yl)-benzoic acid (0.30 g, 1.13 mmol) and (4-fluorophenyl)boronic acid (206 mg, 1.47 mmol), 1,2-dimethoxyethane (7.55 ml) and 2M sodium carbonate solution (1.89 ml, 3.78 mmol) was purged with argon in an ultrasonic bath for 5 min, triphenylphosphine (59.5 mg, 227 µmol) and palladium(II)acetate (25.5 mg, 113 µmol) were added and the reaction mixture was allowed to stir for 5h under reflux conditions. The reaction mixture was cooled to room temperature, 2N NaOH (2 ml) was added, and the reaction mixture was allowed to stir for 30 min at room temperature. The organic phase was separated, the inorganic layer was adjusted to pH = 2 with concentrated HCl solution, and the resulting precipitate was collected by filtration to yield the tile compound (0.24 g, 75%) as a light brown solid, MS (ISP) m/z = 284.1 [(M+H)+], mp 329°C.

Intermediate 2: 3-Bromo-N-tert-butyl-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide



[0049] 


Step A



[0050] A solution of commercially available acetohydrazide (1 g, 13.5 mmol) and commercially available 1,1-dimethoxy-N,N-dimethylmethan-amine (1.61 g, 1.79 ml, 13.5 mmol) in dichloromethane (9 ml) was allowed to stir for 30 min under reflux conditions, and was evaporated to yield N-[(E)-dimethylamino-methylidene-amino]-acetamide (1.72 g, 99%) as a light yellow solid, MS (ISP) m/z = 130.1 [(M+H)+].

Step B



[0051] In a sealed tube a mixture of commercially available 3-amino-5-bromobenzoic acid (1.99 g, 9.21 mmol), N-[(E)-dimethylamino-methylidene-amino]-acetamide (1.27 g, 9.85 mmol) and acetic acid (5 ml) was irradiated in a microwave oven for 15 min at 160°C. To the solution was added water (10 ml), the mixture was allowed to stir for 30 min at room temperature and the precipitate was collected by filtration. Reverse phase chromatography (acetonitrile/ formic acid 48:52) yielded 3-bromo-5-(3-methyl-1,2,4-triazol-4-yl)-benzoic acid (0.24 g, 75%) as an off-white solid, MS (ISP) m/z = 284.0 [(M+H)+], mp 290.5°C.

Step C



[0052] To a stirred solution of 3-bromo-5-(3-methyl-1,2,4-triazol-4-yl)-benzoic acid (0.5 g, 1.77 mmol) in THF (13 ml) was added N,N-diisopropylethylamine (573 mg, 774 µl, 4.43 mmol), 2-methylpropan-2-amine (159 mg, 228 µl, 2.13 mmol) and TBTU (911 mg, 2.84 mmol). The reaction mixture was allowed to stir at room temperature for 17h, evaporated and purified by flash chromatography [heptane/ ethyl acetate (20-100%)] to yield the title compound (0.30 g, 50%) as a white solid, MS (ISP) m/z = 337.1 [(M+H)+], mp 224.5°C.

Intermediate 3: 3-Bromo-N-tert-butyl-5-(3-tert-butyl-1,2,4-triazol-4-yl)-benzamide



[0053] 


Step A



[0054] N-[(E)-Dimethylamino-methylideneamino]-2,2-dimethylpropanamide, white solid (2.12 g, 92%), MS (ISP) m/z = 172.1 [(M+H)+], mp 131°C, was prepared in accordance with the general method of intermediate 2, step A, from commercially available pivalohydrazide (1.57 g, 13.5 mmol) and commercially available 1,1-dimethoxy-N,N-dimethylmethan-amine (1.61 g, 1.79 ml, 13.5 mmol).

Step B



[0055] 3-Bromo-5-(3-tert-butyl-1,2,4-triazol-4-yl)-benzoic acid, white solid (0.63 g, 17%), MS (ISP) m/z = 324.0 [(M+H)+], mp 302.5°C, was prepared in accordance with the general method of intermediate 2, step B, from commercially available 3-amino-5-bromobenzoic acid (2.48 g, 11.5 mmol) and N-[(E)-dimethylamino-methylideneamino]-2,2-dimethylpropanamide (2.10 g, 12.3 mmol).

Step C



[0056] The title compound, white solid (0.36 g, 98%), MS (ISP) m/z = 381.1 [(M+H)+], mp 189°C, was prepared in accordance with the general method of intermediate 2, step C, from 3-bromo-5-(3-tert-butyl-1,2,4-triazol-4-yl)-benzoic acid (314 mg, 0.97 mmol) and 2-methyl-propan-2-amine (84.8 mg, 1.16 mmol).

Intermediate 4: 3-Bromo-5-(3-tert-butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-benzamide



[0057] 



[0058] The title compound, light yellow foam (0.39 g, 99%), MS (ISP) m/z = 407.2 [(M+H)+], mp 60.5°C, was prepared in accordance with the general method of intermediate 2, step C, from 3-bromo-5-(3-tert-butyl-1,2,4-triazol-4-yl)-benzoic acid (intermediate 3, step B) (314 mg, 0.97 mmol) and 2-cyclopropylpropan-2-amine hydrochloride (158 mg, 1.16 mmol).

Intermediate 5: 3-Bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0059] 


Step A



[0060] N-[(E)-Dimethylamino-methylideneamino]-2-methylpropanamide, white solid (2.11 g, 99%), MS (ISP) m/z = 158.1 [(M+H)+], mp 131°C, was prepared in accordance with the general method of intermediate 2, step A, from commercially available isobutyrohydrazide (1.38 g, 13.5 mmol) and commercially available 1,1-dimethoxy-N,N-dimethylmethan-amine (1.61 g, 1.79 ml, 13.5 mmol).

Step B



[0061] 3-Bromo-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzoic acid, off-white solid (1.26 g, 33%), MS (ISP) m/z = 310.1 [(M+H)+], mp 261°C, was prepared in accordance with the general method of intermediate 2, step B, from commercially available 3-amino-5-bromobenzoic acid (2.70 g, 12.5 mmol) and N-[(E)-dimethylamino-methylideneamino]-2,2-dimethylpropanamide (2.10 g, 13.4 mmol).

Step C



[0062] The title compound, off-white foam (0.25 g, 71%), MS (ISP) m/z = 365.2 [(M+H)+], mp 198°C, was prepared in accordance with the general method of intermediate 2, step C, from 3-bromo-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzoic acid (301 mg, 0.97 mmol) and 2-methyl-propan-2-amine (84.8 mg, 1.16 mmol).

Intermediate 6: 3-Bromo-N-(2-cyclopropylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0063] 



[0064] The title compound, off-white foam (0.23 g, 61%), MS (ISP) m/z = 393.2 [(M+H)+], mp 137°C, was prepared in accordance with the general method of intermediate 2, step C, from 3-bromo-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzoic acid (intermediate 5, step B) (301 mg, 0.97 mmol) and 2-cyclopropylpropan-2-amine hydrochloride (158 mg, 1.16 mmol).

Intermediate 7: 3-Bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0065] 



[0066] The title compound, white foam (0.33 g, 90%), MS (ISP) m/z = 381.1 [(M+H)+], mp 85°C, was prepared in accordance with the general method of intermediate 2, step C, from 3-bromo-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzoic acid (intermediate 5, step B) (301 mg, 0.97 mmol) and 2-amino-2-methylpropan-1-ol (103 mg, 1.16 mmol).

Intermediate 8: 3-Bromo-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0067] 



[0068] The title compound, off-white foam (0.31 g, 85%), MS (ISP) m/z = 381.1 [(M+H)+], mp 184°C, was prepared in accordance with the general method of intermediate 2, step C, from 3-bromo-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzoic acid (intermediate 5, step B) (301 mg, 0.97 mmol) and 2-methylbutan-2-amine (101 mg, 1.16 mmol).

Intermediate 9: 3-(4-Chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzoic acid



[0069] 


Step A



[0070] A stirred mixture of commercially available 3-amino-5-bromobenzoic acid (500 mg, 2.31 mmol), toluene (7.6 ml) and 1,1-dimethoxy-N,N-dimethylmethanamine (1.56 g, 1.75 ml, 13.1 mmol was allowed to stir under reflux conditions for 2h, evaporated and purified by flash chromatography on silica gel [dichloromethane/dichloromethane:methanol 9:1 (0-50%)] to yield methyl 3-bromo-5-[(E)-dimethylaminomethylideneamino]-benzoate (0.65 g, 99%) as a light yellow oil, MS (ISP) m/z = 287.1 [(M+H)+].

Step B



[0071] To a solution of methyl 3-bromo-5-[(E)-dimethylaminomethylideneamino]-benzoate (0.44 g, 1.54 mmol) in acetic acid (772 µl), commercially available 2-hydroxyacetohydrazide (219 mg, 2.31 mmol) was added. The reaction mixture was irradiated in a microwave oven at 160°C for 15 min in a sealed tube. The reaction mixture was poured into water (30 ml) and extracted with dichloromethane (2 x 30 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product (0.51 g) was purified by flash chromatography on silica gel [dichloromethane/dichloromethane:methanol 9:1 (0-50%)] to yield methyl 3-bromo-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzoate (0.22 g, 46%) as a white solid, MS (ISP) m/z = 314.1 [(M+H)+], mp 160°C.

Step C



[0072] Methyl 3-(4-chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzoate, off-white solid (0.14 g, 71%), MS (ISP) m/z = 344.2 [(M+H)+], mp 203.5°C, was prepared in accordance with the general method of intermediate 1, step B, from methyl 3-bromo-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzoate (180 mg, 0.58 mmol) and (4-chlorophenyl)-boronic acid (117 mg, 0.75 mmol).

Step D



[0073] A mixture of methyl 3-(4-chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzoate (130 mg, 378 µmol), THF (628 µl), MeOH (628 µl), water (628 µl) and lithium hydroxide monohydrate (20.6 mg, 491 µmol) was allowed to stir for 3h at room temperature. The reaction mixture was evaporated to one third, 2N HCl solution (727 ml) was added, the precipitate collected by filtration, washed with water and dried to yield the title compound (0.14 g, %) as a white solid (0.12 g, 96%), MS (ISP) m/z = 330.2 [(M+H)+], mp 200.5°C.

Intermediate 10: 3-Amino-N-tert-butyl-5-(4-chlorophenyl)-benzamide



[0074] 


Step A



[0075] To a stirred solution of commercially available 3-iodo-5-nitrobenzoic acid (2 g, 6.83 mmol) in THF (49.1 ml) was added at room temperature N,N-diisopropylethylamine (2.21 g, 2.98 ml, 17.1 mmol), 2-methylpropan-2-amine (611 mg, 878 µl, 8.19 mmol) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (3.51 g, 10.9 mmol). The reaction mixture was stirred at room temperature for 4 h, evaporated and the residue purified by flash chromatography on silica gel [heptane/ethyl acetate (0-50%)] to yield N-tert-butyl-3-iodo-5-nitrobenzamide (2.31 g, 97%) as an off-white solid, MS (ISP) m/z = 349.0 [(M+H)+], mp 166°C.

Step B



[0076] A mixture of N-tert-butyl-3-iodo-5-nitrobenzamide (2.3 g, 6.61 mmol) and (4-chlorophenyl)boronic acid (1.34 g, 8.59 mmol) in 1,2-dimethoxyethane (44 ml) and 2M Na2CO3 (11 ml, 22 mmol) was purged with argon in an ultrasonic bath for 5 min, triphenylphosphine (347 mg, 1.32 mmol) and palladium(II)acetate (148 mg, 661 µmol) were added and the reaction mixture was stirred for 3h under reflux conditions. The reaction mixture poured into water (50 ml) and extracted with ethylacetate (2 x 50 ml).The combined organic layers were washed with brine (40 ml),dried (MgSO4) and evaporated to give the crude product (3.09 g) as brown solid, which was purified by flash chromatography on silica gel [heptane/ethyl acetate (0-50%)] to yield N-tert-butyl-3-(4-chlorophenyl)-5-nitrobenzamide (2.38 g, 92%) as a brown solid, MS (ISP) m/z = 333.1 [(M+H)+], mp 186°C.

Step C



[0077] To a stirred solution of N-tert-butyl-3-(4-chlorophenyl)-5-nitrobenzamide (2.38 g, 6.58 mmol) in MeOH (49.8 ml) was added at room temperature tin(II)chloride dihydrate (5.94 g, 26.3 mmol) and the reaction mixture was stirred under reflux conditions for 2h, evaporated, water (50 ml) and 2N NaOH (50ml) were added and the mixture was extracted with ethyl acetate (2 x 75 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated. The crude product (brown solid, 2.08 g) was purified by flash chromatography on silica gel [dichloromethane/MeOH (1-5%)] to yield the title compound (1.90 g, 95%) as a light brown solid, MS (ISP) m/z = 303.1 [(M+H)+], mp 231°C.

Example 1


3-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-5-(1,2,4-triazol-4-yl)-benzamide



[0078] 



[0079] A stirred mixture of 3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzoic acid (intermediate 1) (70.8 mg, 0.25 mmol) and oxalyl chloride (723 mg, 499 µl, 5.7 mmol) was cooled to 0 °C, DMF (10 µl) was added, the reaction mixture was allowed to stir for 2h at room temperature, was evaporated to dryness, THF (2 ml), commercially available 2-methylbutan-2-amine (26.2 mg, 300 µmol) and N,N-diisopropylethylamine (113 mg, 150 µl, 875 µmol) were added and the reaction mixture was allowed to stir room temperature for 17h. The crude mixture was purified by flash chromatography on silica [dichloromethane/ dichloromethane: MeOH 9:1 (20-80%)] and a second time [dichloromethane/ dichloromethane: MeOH 9:1 (0-50%)] to yield the title compound as a light yellow solid (29 mg, 33%), MS (ISP) m/z = 353.2 [(M+H)+], mp 212°C.

Example 2


N-tert-Butyl-3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzamide



[0080] 



[0081] The title compound, light yellow solid (30 mg, 35%), MS (ISP) m/z = 339.2 [(M+H)+], mp 204°C, was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzoic acid (intermediate 1) (70.8 mg, 0.25 mmol) and 2-methylbutan-2-amine (21.9 mg, 0.30 mmol).

Example 3


N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzamide



[0082] 



[0083] The title compound, light yellow foam (80 mg, 88%), MS (ISP) m/z = 365.2 [(M+H)+], mp 135.5°C, was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzoic acid (intermediate 1) (70.8 mg, 0.25 mmol) and 2-cyclopropylpropan-2-amine hydrochloride (40.7 mg, 0.30 mmol).

Example 4


3-(4-Fluorophenyl)-5-(1,2,4-triazol-4-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide



[0084] 



[0085] The title compound, white foam (20 mg, 20%), MS (ISP) m/z = 393.1 [(M+H)+], mp 147°C, was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzoic acid (intermediate 1) (70.8 mg, 0.25 mmol) and 1,1,1-trifluoro-2-methylpropan-2-amine (38.1 mg, 0.30 mmol).

Example 5


N-tert-Butyl-3-(4-fluorophenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide



[0086] 



[0087] A mixture of 3-bromo-N-tert-butyl-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide (intermediate 2) (84.3 mg, 0.25 mmol), commercially available (4-fluorophenyl)boronic acid (45.5 mg, 325 µmol), 1,2-dimethoxyethane (1.67 ml) and 2M sodium carbonate solution (416 µl, 833 µmol) was purged with argon in an ultrasonic bath for 5 min, triphenylphosphine (13.1 mg, 50 µmol) and palladium(II)acetate (5.61 mg, 25 µmol) were added, the reaction mixture was stirred for 3h under reflux conditions, and was evaporated. After filtration the crude reaction mixture was purified by flash chromatography on silica gel [dichloromethane/ dichloromethane: MeOH 9:1 (20-100%)] to yield the title compound as a light grey solid (80 mg, 91%), MS (ISP) m/z = 353.1 [(M+H)+], mp 235.5°C.

Example 6


N-tert-Butyl-3-(4-chlorophenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide



[0088] 



[0089] The title compound, off-white solid (90 mg, 98%), MS (ISP) m/z = 369.2 [(M+H)+], mp 241°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide (intermediate 2) (84.3 mg, 0.25 mmol) and (4-chlorophenyl)boronic acid (50.8 mg, 325 µmol).

Example 7


N-tert-Butyl-3-(3-methyl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide



[0090] 



[0091] The title compound, off-white solid (90 mg, 90%), MS (ISP) m/z = 403.2 [(M+H)+], mp 225.5°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide (intermediate 2) (84.3 mg, 0.25 mmol) and (4-trifluoromethyl-phenyl)boronic acid (61.7 mg, 325 µmol).

Example 8


N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-fluorophenyl)-benzamide



[0092] 



[0093] The title compound, white solid (98 mg, 99%), MS (ISP) m/z = 395.3 [(M+H)+], mp 279°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-tert-butyl-1,2,4-triazol-4-yl)-benzamide (intermediate 3) (94.8 mg, 0.25 mmol) and (4-fluorophenyl)boronic acid (45.5 mg, 325 µmol).

Example 9


N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-chlorophenyl)-benzamide



[0094] 



[0095] The title compound, white solid (100 mg, 97%), MS (ISP) m/z = 411.2 [(M+H)+], mp 292.5°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-tert-butyl-1,2,4-triazol-4-yl)-benzamide (intermediate 3) (94.8 mg, 0.25 mmol) and (4-chlorophenyl)boronic acid (50.8 mg, 325 µmol).

Example 10


N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide



[0096] 



[0097] The title compound, white solid (110 mg, 99%), MS (ISP) m/z = 445.3 [(M+H)+], mp 280.5°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-tert-butyl-1,2,4-triazol-4-yl)-benzamide (intermediate 3) (94.8 mg, 0.25 mmol) and (4-trifluoromethyl-phenyl)boronic acid (61.7 mg, 325 µmol).

Example 11


3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide



[0098] 



[0099] The title compound, white solid (110 mg, 94%), MS (ISP) m/z = 471.3 [(M+H)+], mp 242.5°C, was prepared in accordance with the general method of example 5 from 3-bromo-5-(3-tert-butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-benzamide (intermediate 4) (101 mg, 0.25 mmol) and (4-trifluoromethyl-phenyl)boronic acid (61.7 mg, 325 µmol).

Example 12


3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-benzamide



[0100] 



[0101] The title compound, white foam (90 mg, 86%), MS (ISP) m/z = 421.3 [(M+H)+], mp 111°C, was prepared in accordance with the general method of example 5 from 3-bromo-5-(3-tert-butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-benzamide (intermediate 4) (101 mg, 0.25 mmol) and (4-fluorophenyl)boronic acid (45.5 mg, 325 µmol).

Example 13


3-(3-tert-Butyl-1,2,4-triazol-4-yl)-5-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-benzamide



[0102] 



[0103] The title compound, white foam (90 mg, 82%), MS (ISP) m/z = 437.3 [(M+H)+], mp 136.5°C, was prepared in accordance with the general method of example 5 from 3-bromo-5-(3-tert-butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-benzamide (intermediate 4) (101 mg, 0.25 mmol) and (4-chlorophenyl)boronic acid (50.8 mg, 325 µmol).

Example 14


N-tert-Butyl-3-(4-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0104] 



[0105] The title compound, white solid (90 mg, 95%), MS (ISP) m/z = 381.2 [(M+H)+], mp 240.5°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 0.25 mmol) and (4-fluorophenyl)boronic acid (45.5 mg, 325 µmol).

Example 15


N-tert-Butyl-3-(4-chlorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0106] 



[0107] The title compound, white solid (99 mg, 100%), MS (ISP) m/z = 397.2 [(M+H)+], mp 239.5°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 0.25 mmol) and (4-chlorophenyl)boronic acid (50.8 mg, 325 µmol).

Example 16


N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0108] 



[0109] The title compound, off-white foam (100 mg, 98%), MS (ISP) m/z = 407.3 [(M+H)+], mp 101°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-(2-cyclopropylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 6) (97.8 mg, 0.25 mmol) and (4-fluorophenyl)boronic acid (45.5 mg, 325 µmol).

Example 17


3-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0110] 



[0111] The title compound, white foam (100 mg, 95%), MS (ISP) m/z = 423.3 [(M+H)+], mp 105°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-(2-cyclopropylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 6) (97.8 mg, 0.25 mmol) and (4-chlorophenyl)boronic acid (50.8 mg, 325 µmol).

Example 18


N-tert-Butyl-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide



[0112] 



[0113] The title compound, white foam (70 mg, 99%), MS (ISP) m/z = 431.3 [(M+H)+], mp 126°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (60.0 mg, 164 µmol) and (4-trifluoromethyl-phenyl)boronic acid (40.6 mg, 214 µmol).

Example 19


N-(2-Cyclopropyl-propan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide



[0114] 



[0115] The title compound, white foam (50 mg, 86%), MS (ISP) m/z = 457.3 [(M+H)+], mp 100°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-(2-cyclopropylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 6) (50.0 mg, 128 µmol) and (4-trifluoromethyl-phenyl)boronic acid (31.5 mg, 166 µmol).

Example 20


3-(4-Fluorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0116] 



[0117] The title compound, white foam (90 mg, 91%), MS (ISP) m/z = 397.3 [(M+H)+], mp 171.5°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 7) (95.3 mg, 0.25 mmol) and (4-fluorophenyl)boronic acid (45.5 mg, 325 µmol).

Example 21


3-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0118] 



[0119] The title compound, off-white foam (80 mg, 78%), MS (ISP) m/z = 413.3 [(M+H)+], mp 180°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 7) (95.3 mg, 0.25 mmol) and (4-chlorophenyl)boronic acid (50.8 mg, 325 µmol).

Example 22


N-(1-hydroxy-2-methylpropan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide



[0120] 



[0121] The title compound, light yellow foam (100 mg, 90%), MS (ISP) m/z = 447.4 [(M+H)+], mp 214°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 7) (95.3 mg, 0.25 mmol) and (4-trifluoromethyl-phenyl)boronic acid (61.7 mg, 325 µmol).

Example 23


N-(2-Methylbutan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide



[0122] 



[0123] The title compound, light yellow foam (110 mg, 99%), MS (ISP) m/z = 445.4 [(M+H)+], mp 104°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 8) (94.8 mg, 0.25 mmol) and (4-trifluoromethyl-phenyl)boronic acid (61.7 mg, 325 µmol).

Example 24


3-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0124] 



[0125] The title compound, off-white foam (98 mg, 99%), MS (ISP) m/z = 395.3 [(M+H)+], mp 95°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 8) (94.8 mg, 0.25 mmol) and (4-fluorophenyl)boronic acid (45.5 mg, 325 µmol).

Example 25


3-(4-Chlorophenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0126] 



[0127] The title compound, light yellow foam (100 mg, 97%), MS (ISP) m/z = 411.3 [(M+H)+], mp 103°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 8) (94.8 mg, 0.25 mmol) and (4-chlorophenyl)boronic acid (50.8 mg, 325 µmol).

Example 26


N-tert-Butyl-3-(4-chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamide



[0128] 



[0129] The title compound, white solid (60 mg, 43%), MS (ISP) m/z = 385.3 [(M+H)+], mp 210°C, was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzoic acid (intermediate 9) (120 mg, 0.36 mmol) and 2-methylbutan-2-amine (32.2 mg, 0.44 mmol).

Example 27


N-tert-Butyl-3-(4-chlorophenyl)-5-[3-(2-hydroxypropan-2-yl)-1,2,4-triazol-4-yl]-benzamide



[0130] 


Step A



[0131] A mixture of 3-amino-N-tert-butyl-5-(4-chlorophenyl)-benzamide (intermediate 10) (0.32 g, 1.06 mmol), 1,1-dimethoxy-N,N-dimethylmethanamine (714 mg, 799 µl, 5.99 mmol) and toluene (3.5 ml) was allowed to stir for 2h under reflux conditions, evaporated and purified by flash chromatography on silica gel [dichloromethane/dichloromethane:methanol 9:1 (0-50%)] to yield N-tert-butyl-3-(4-chlorophenyl)-5-[(E)-dimethylaminomethylideneamino]-benzamide (0.31 g, 82%) as an off-white foam, MS (ISP) m/z = 358.3 [(M+H)+], mp 79.5°C.

Step B



[0132] A mixture of N-tert-butyl-3-(4-chlorophenyl)-5-[(E)-dimethylaminomethylideneamino]-benzamide (0.31 g, 866 µmol), commercially available 2-hydroxy-2-methylpropanehydrazide (162 mg, 1.3 mmol, Eq: 1.5) and acetic acid (434 µl) was irradiated in a microwave oven at 140°C for 15 min in a sealed tube. The mixture was poured into water (10 ml) and extracted with ethyl acetate (3 x 10 ml). The combined organic layers were washed with brine (15 ml), dried (MgSO4) and evaporated. The crude product (0.4 g) was purified by flash chromatography on silica gel [dichloromethane/dichloromethane:methanol 9:1 (0-50%)] to yield the title compound (50 mg, 14%) as white foam, MS (ISP) m/z = 413.3 [(M+H)+], mp 163°C.

Example 28


N-tert-Butyl-3-(3,4-difluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0133] 



[0134] The title compound, off-white foam (70 mg, 70%), MS (ISP) m/z = 399.3 [(M+H)+], mp 115°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 µmol) and commercially available (3,4-difluoro-phenyl)boronic acid (51.3 mg, 325 µmol).

Example 29


N-tert-Butyl-3-(4-methoxyphenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0135] 



[0136] The title compound, off-white foam (80 mg, 82%), MS (ISP) m/z = 393.3 [(M+H)+], mp 107°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 µmol) and commercially available (4-methoxy-phenyl)boronic acid (49.4 mg, 325 µmol).

Example 30


N-tert-Butyl-3-(4-chloro-3-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0137] 



[0138] The title compound, white foam (70 mg, 68%), MS (ISP) m/z = 415.2 [(M+H)+], mp 135°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 µmol) and commercially available (4-chloro-3-fluoro-phenyl)boronic acid (56.7 mg, 325 µmol).

Example 31


N-tert-Butyl-3-(4-fluoro-3-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0139] 



[0140] The title compound, white foam (60 mg, 61%), MS (ISP) m/z = 395.3 [(M+H)+], mp 106°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 µmol) and commercially available (4-fluoro-3-methyl-phenyl)boronic acid (50.0 mg, 325 µmol).

Example 32


N-tert-Butyl-3-(3-fluoro-4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0141] 



[0142] The title compound, white foam (60 mg, 61%), MS (ISP) m/z = 395.4 [(M+H)+], mp 109°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 µmol) and commercially available (3-fluoro-4-methyl-phenyl)boronic acid (50.0 mg, 325 µmol).

Example 33


N-tert-Butyl-3-(4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0143] 



[0144] The title compound, off-white foam (60 mg, 64%), MS (ISP) m/z = 377.4 [(M+H)+], mp 100°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 µmol) and commercially available (4-methyl-phenyl)boronic acid (44.2 mg, 325 µmol).

Example 34


N-tert-Butyl-3-(4-cyano-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0145] 



[0146] The title compound, off-white solid (50 mg, 52%), MS (ISP) m/z = 388.3 [(M+H)+], mp 290°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 µmol) and commercially available (4-cyano-phenyl)boronic acid (47.8 mg, 325 µmol).

Example 35


N-tert-Butyl-3-(4-cyclopropyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide



[0147] 



[0148] The title compound, off-white foam (40 mg, 40%), MS (ISP) m/z = 403.4 [(M+H)+], mp 120°C, was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 µmol) and commercially available (4-cyclopropyl-phenyl)boronic acid (52.6 mg, 325 µmol).

Example 36


(RS)-3-(4-Chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide



[0149] 



[0150] The title compound, white solid (50 mg, 43%), MS (ISP) m/z = 461.2 [(M+H)+], mp 161.5°C, was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzoic acid (intermediate 9) (82.4 mg, 0.25 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (55.7 mg, 0.30 mmol).

Example 37


3-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamide



[0151] 



[0152] The title compound, white foam (70 mg, 56%), MS (ISP) m/z = 411.3 [(M+H)+], mp 120°C, was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzoic acid (intermediate 9) (100 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine hydrochloride (49.4 mg, 0.36 mmol).


Claims

1. A compound of formula I

wherein

R1' is CH3

R1 is methyl, ethyl, CF3, CH2OH, cyclopropyl or cyano, or
R1' and R1 may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring;

R2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxymethyl, or 2-propyl-2-ol;

R3 is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;

R4 is hydrogen, methyl, F or Cl;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
 
2. A compound of formula IA according to claim 1,

wherein

R2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxymethyl, or 2-propyl-2-ol;

R3 is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;

R4 is hydrogen, methyl, F or Cl;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
 
3. A compound of formula IB according to claim 1

wherein

R2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxymethyl, or 2-propyl-2-ol;

R3 is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;

R4 is hydrogen, methyl, F or Cl;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
 
4. A compound of formula IC according to claim 1

wherein

R2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxymethyl, or 2-propyl-2-ol;

R3 is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;

R4 is hydrogen, methyl, F or Cl;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
 
5. A compound of formula ID according to claim 1

wherein

R2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxymethyl, or 2-propyl-2-ol;

R3 is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;

R4 is hydrogen, methyl, F or Cl;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
 
6. A compound of formula IE according to claim 1

wherein

R2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxymethyl, or 2-propyl-2-ol;

R3 is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;

R4 is hydrogen, methyl, F or Cl;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
 
7. A compound of formula IF according to claim 1

wherein

R2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxymethyl, or 2-propyl-2-ol;

R3 is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;

R4 is hydrogen, methyl, F or Cl;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof
 
8. A compound of formula IG according to claim 1

wherein

R2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxymethyl, or 2-propyl-2-ol;

R3 is Cl, F, CF3, cyano, methyl, methoxy, isopropyl, or cyclopropyl;

R4 is hydrogen, methyl, F or Cl;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
 
9. A compound of formula I according to claim 1, which compound is

(RS)-3-(4-Chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide

N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzamide

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-benzamide

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-5-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-benzamide

N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

3-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-(2-Cyclopropyl-propan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

3-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamide

3-(4-Fluorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

3-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-(1-hydroxy-2-methylpropan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

3-(4-Fluorophenyl)-5-(1,2,4-triazol-4-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide

3-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-5-(1,2,4-triazol-4-yl)-benzamide

N-(2-Methylbutan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

3-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

3-(4-Chlorophenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-fluorophenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-chlorophenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(3-methyl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-fluorophenyl)-benzamide

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-chlorophenyl)-benzamide

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

N-tert-Butyl-3-(4-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-chlorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

N-tert-Butyl-3-(4-chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamide

N-tert-Butyl-3-(4-chlorophenyl)-5-[3-(2-hydroxypropan-2-yl)-1,2,4-triazol-4-yl]-benzamide

N-tert-Butyl-3-(3,4-difluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-methoxyphenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-chloro-3-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-fluoro-3-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(3-fluoro-4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

N-tert-Butyl-3-(4-cyano-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide or

N-tert-Butyl-3-(4-cyclopropyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide.


 
10. A process for the manufacture of a compound of formula I as defined in any one of
claims 1 to 9, which process comprises

a) reacting a compound of formula II

with N,N-dimethylformamide-dimethylacetal

and a compound of formula

to a compound of formula I

b) reacting a compound of formula V

with a compound of formula VI

to a compound of formula I

wherein the substituents are as described above, or
if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts, or

c) reacting a compound of formula VII

with a compound of formula VIII

to a compound of formula I

wherein the substituents are described above, or

if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
 
11. A compound of formula I according to any one of claims 1 - 9 for use as therapeutically active substances.
 
12. A compound of formula I according to any one of claims 1 - 9 for use in the treatment of schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder.
 
13. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 - 9 and pharmaceutically acceptable excipients.
 


Ansprüche

1. Verbindung der Formel I

wobei

R1' CH3 ist

R1 Methyl, Ethyl, CF3, CH2OH, Cyclopropyl oder Cyano ist, oder
R1' und R1 zusammen einen 1,1-Dioxo-tetrahydro-thiophen-3-yl-Ring bilden können;

R2 Wasserstoff, Methyl, Ethyl, Isopropyl, tert-Butyl, Cyclopropyl, Hydroxymethyl oder 2-Propyl-2-ol ist;

R3 Cl, F, CF3, Cyano, Methyl, Methoxy, Isopropyl oder Cyclopropyl ist;

R4 Wasserstoff, Methyl, F oder Cl ist;

oder ein pharmazeutisch unbedenkliches Salz oder Säureadditionssalz, eine racemische Mischung oder ihr entsprechendes Enantiomer und/oder optisches Isomer und/oder Stereoisomer davon.
 
2. Verbindung der Formel IA nach Anspruch 1,

wobei

R2 Wasserstoff, Methyl, Ethyl, Isopropyl, tert-Butyl, Cyclopropyl, Hydroxymethyl oder 2-Propyl-2-ol ist;

R3 Cl, F, CF3, Cyano, Methyl, Methoxy, Isopropyl oder Cyclopropyl ist;

R4 Wasserstoff, Methyl, F oder Cl ist;

oder ein pharmazeutisch unbedenkliches Salz oder Säureadditionssalz, eine racemische Mischung oder ihr entsprechendes Enantiomer und/oder optisches Isomer und/oder Stereoisomer davon.
 
3. Verbindung der Formel IB nach Anspruch 1

wobei

R2 Wasserstoff, Methyl, Ethyl, Isopropyl, tert-Butyl, Cyclopropyl, Hydroxymethyl oder 2-Propyl-2-ol ist;

R3 Cl, F, CF3, Cyano, Methyl, Methoxy, Isopropyl oder Cyclopropyl ist;

R4 Wasserstoff, Methyl, F oder Cl ist;

oder ein pharmazeutisch unbedenkliches Salz oder Säureadditionssalz, eine racemische Mischung oder ihr entsprechendes Enantiomer und/oder optisches Isomer und/oder Stereoisomer davon.
 
4. Verbindung der Formel IC nach Anspruch 1

wobei

R2 Wasserstoff, Methyl, Ethyl, Isopropyl, tert-Butyl, Cyclopropyl, Hydroxymethyl oder 2-Propyl-2-ol ist;

R3 Cl, F, CF3, Cyano, Methyl, Methoxy, Isopropyl oder Cyclopropyl ist;

R4 Wasserstoff, Methyl, F oder Cl ist;

oder ein pharmazeutisch unbedenkliches Salz oder Säureadditionssalz, eine racemische Mischung oder ihr entsprechendes Enantiomer und/oder optisches Isomer und/oder Stereoisomer davon.
 
5. Verbindung der Formel ID nach Anspruch 1

wobei

R2 Wasserstoff, Methyl, Ethyl, Isopropyl, tert-Butyl, Cyclopropyl, Hydroxymethyl oder 2-Propyl-2-ol ist;

R3 Cl, F, CF3, Cyano, Methyl, Methoxy, Isopropyl oder Cyclopropyl ist;

R4 Wasserstoff, Methyl, F oder Cl ist;

oder ein pharmazeutisch unbedenkliches Salz oder Säureadditionssalz, eine racemische Mischung oder ihr entsprechendes Enantiomer und/oder optisches Isomer und/oder Stereoisomer davon.
 
6. Verbindung der Formel IE nach Anspruch 1

wobei

R2 Wasserstoff, Methyl, Ethyl, Isopropyl, tert-Butyl, Cyclopropyl, Hydroxymethyl oder 2-Propyl-2-ol ist;

R3 Cl, F, CF3, Cyano, Methyl, Methoxy, Isopropyl oder Cyclopropyl ist;

R4 Wasserstoff, Methyl, F oder Cl ist;

oder ein pharmazeutisch unbedenkliches Salz oder Säureadditionssalz, eine racemische Mischung oder ihr entsprechendes Enantiomer und/oder optisches Isomer und/oder Stereoisomer davon.
 
7. Verbindung der Formel IF nach Anspruch 1

wobei

R2 Wasserstoff, Methyl, Ethyl, Isopropyl, tert-Butyl, Cyclopropyl, Hydroxymethyl oder 2-Propyl-2-ol ist;

R3 Cl, F, CF3, Cyano, Methyl, Methoxy, Isopropyl oder Cyclopropyl ist;

R4 Wasserstoff, Methyl, F oder Cl ist;

oder ein pharmazeutisch unbedenkliches Salz oder Säureadditionssalz, eine racemische Mischung oder ihr entsprechendes Enantiomer und/oder optisches Isomer und/oder Stereoisomer davon.
 
8. Verbindung der Formel IG nach Anspruch 1

wobei

R2 Wasserstoff, Methyl, Ethyl, Isopropyl, tert-Butyl, Cyclopropyl, Hydroxymethyl oder 2-Propyl-2-ol ist;

R3 Cl, F, CF3, Cyano, Methyl, Methoxy, Isopropyl oder Cyclopropyl ist;

R4 Wasserstoff, Methyl, F oder Cl ist;

oder ein pharmazeutisch unbedenkliches Salz oder Säureadditionssalz, eine racemische Mischung oder ihr entsprechendes Enantiomer und/oder optisches Isomer und/oder Stereoisomer davon.
 
9. Verbindung der Formel I nach Anspruch 1, wobei es sich um folgende Verbindung handelt

(RS)-3-(4-Chlorphenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-N-(3-methyl-1,1-dioxothiolan-3 -yl)-benzamid

N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorphenyl)-5-(1,2,4-triazol-4-yl)-benzamid

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-[4-(trifluormethyl)-phenyl]-benzamid

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorphenyl)-benzamid

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-5-(4-chlorphenyl)-N-(2-cyclopropylpropan-2-yl)-benzamid

N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorphenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid

3-(4-Chlorphenyl)-N-(2-cyclopropyl-propan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid

N-(2-Cyclopropyl-propan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluormethyl)-phenyl]-benzamid

3-(4-Chlorphenyl)-N-(2-cyclopropyl-propan-2-yl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamid

3-(4-Fluorphenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid

3-(4-Chlorphenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid

N-(1-Hydroxy-2-methylpropan-2-yl)-3-(3-propan-2-yl-1,2,4- triazol-4-yl)-5-[4-(trifluormethyl)-phenyl]-benzamid

3-(4-Fluorphenyl)-5-(1,2,4-triazol-4-yl)-N-(1,1,1-trifluor-2-methylpropan-2-yl)-benzamid

3-(4-Fluorphenyl)-N-(2-methylbutan-2-yl)-5-(1,2,4-triazol-4-yl)-benzamid

N-(2-Methylbutan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluormethyl)-phenyl]-benzamid

3-(4-Fluorphenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid

3-(4-Chlorphenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid

N-tert-Butyl-3-(4-fluorphenyl)-5-(1,2,4-triazol-4-yl)-benzamid

N-tert-Butyl-3-(4-fluorphenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamid

N-tert-Butyl-3-(4-chlorphenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamid

N-tert-Butyl-3-(3-methyl-1,2,4-triazol-4-yl)-5-[4-(trifluormethyl)-phenyl]-benzamid

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-fluorphenyl)-benzamid

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-chlorphenyl)-benzamid

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-[4-(trifluormethyl)-phenyl]-benzamid

N-tert-Butyl-3-(4-fluorphenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid

N-tert-Butyl-3-(4-chlorphenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid

N-tert-Butyl-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluormethyl)-phenyl]-benzamid

N-tert-Butyl-3-(4-chlorphenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamid

N-tert-Butyl-3-(4-chlorphenyl)-5-[3-(2-hydroxypropan-2-yl)-1,2,4-triazol-4-yl]-benzamid

N-tert-Butyl-3-(3,4-difluorphenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid

N-tert-Butyl-3-(4-methoxyphenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid

N-tert-Butyl-3-(4-chlor-3-fluorphenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid

N-tert-Butyl-3-(4-fluor-3-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid

N-tert-Butyl-3-(3-fluor-4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid

N-tert-Butyl-3-(4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid

N-tert-Butyl-3-(4-cyano-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid oder

N-tert-Butyl-3-(4-cyclopropyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamid.


 
10. Verfahren zur Herstellung einer Verbindung der Formel I, wie in einem der Ansprüche 1 bis 9 definiert, wobei das Verfahren Folgendes umfasst

a) Reagieren einer Verbindung der Formel II

mit N,N-Dimethylformamid-dimethylacetal

und einer Verbindung der Formel

zu einer Verbindung der Formel I

b) Reagieren einer Verbindung der Formel V

mit einer Verbindung der Formel VI

zu einer Verbindung der Formel I

wobei die Substituenten wie oben beschrieben sind, oder
falls erwünscht, Umwandeln der erhaltenen Verbindungen in pharmazeutisch unbedenkliche Säureadditionssalze, oder

c) Reagieren einer Verbindung der Formel VII

mit einer Verbindung der Formel VIII

zu einer Verbindung der Formel I

wobei die Substituenten wie oben beschrieben sind, oder

falls erwünscht, Umwandeln der erhaltenen Verbindungen in pharmazeutisch unbedenkliche Säureadditionssalze.
 
11. Verbindung der Formel I nach einem der Ansprüche 1-9 zur Verwendung als therapeutisch wirksame Substanzen.
 
12. Verbindung der Formel I nach einem der Ansprüche 1-9 zur Verwendung bei der Behandlung von Schizophrenie, bipolarer Störung, Zwangsstörung oder Autismus-Spektrum-Störung.
 
13. Pharmazeutische Zusammensetzung, umfassend eine Verbindung der Formel I nach einem der Ansprüche 1-9, und pharmazeutisch unbedenkliche Hilfsstoffe.
 


Revendications

1. Composé de formule I

dans laquelle

R1' représente CH3

R1 représente un méthyle, un éthyle, CF3, CH2OH, un cyclopropyle ou un cyano, ou
R1' et R1 peuvent former conjointement un cycle 1,1-dioxo-tétrahydro-thiophén-3-yle ;

R2 représente un hydrogène, un méthyle, un éthyle, un isopropyle, un tert-butyle, un cyclopropyle, un hydroxyméthyle ou un 2-propyl-2-ol ;

R3 représente Cl, F, CF3, un cyano, un méthyle, un méthoxy, un isopropyle ou un cyclopropyle ;

R4 représente un hydrogène, un méthyle, F ou Cl ;

ou un sel ou sel d'addition acide pharmaceutiquement acceptable, un mélange racémique, ou son énantiomère et/ou isomère optique et/ou stéréoisomère correspondant.
 
2. Composé de formule IA selon la revendication 1,

dans laquelle

R2 représente un hydrogène, un méthyle, un éthyle, un isopropyle, un tert-butyle, un cyclopropyle, un hydroxyméthyle ou un 2-propyl-2-ol ;

R3 représente Cl, F, CF3, un cyano, un méthyle, un méthoxy, un isopropyle ou un cyclopropyle ;

R4 représente un hydrogène, un méthyle, F ou Cl ;

ou un sel ou sel d'addition acide pharmaceutiquement acceptable, un mélange racémique, ou son énantiomère et/ou isomère optique et/ou stéréoisomère correspondant.
 
3. Composé de formule IB selon la revendication 1

dans laquelle

R2 représente un hydrogène, un méthyle, un éthyle, un isopropyle, un tert-butyle, un cyclopropyle, un hydroxyméthyle ou un 2-propyl-2-ol ;

R3 représente Cl, F, CF3, un cyano, un méthyle, un méthoxy, un isopropyle ou un cyclopropyle ;

R4 représente un hydrogène, un méthyle, F ou Cl ;

ou un sel ou sel d'addition acide pharmaceutiquement acceptable, un mélange racémique, ou son énantiomère et/ou isomère optique et/ou stéréoisomère correspondant.
 
4. Composé de formule IC selon la revendication 1

dans laquelle

R2 représente un hydrogène, un méthyle, un éthyle, un isopropyle, un tert-butyle, un cyclopropyle, un hydroxyméthyle ou un 2-propyl-2-ol ;

R3 représente Cl, F, CF3, un cyano, un méthyle, un méthoxy, un isopropyle ou un cyclopropyle ;

R4 représente un hydrogène, un méthyle, F ou Cl ;

ou un sel ou sel d'addition acide pharmaceutiquement acceptable, un mélange racémique, ou son énantiomère et/ou isomère optique et/ou stéréoisomère correspondant.
 
5. Composé de formule ID selon la revendication 1

dans laquelle

R2 représente un hydrogène, un méthyle, un éthyle, un isopropyle, un tert-butyle, un cyclopropyle, un hydroxyméthyle ou un 2-propyl-2-ol ;

R3 représente Cl, F, CF3, un cyano, un méthyle, un méthoxy, un isopropyle ou un cyclopropyle ;

R4 représente un hydrogène, un méthyle, F ou Cl ;

ou un sel ou sel d'addition acide pharmaceutiquement acceptable, un mélange racémique, ou son énantiomère et/ou isomère optique et/ou stéréoisomère correspondant.
 
6. Composé de formule IE selon la revendication 1

dans laquelle

R2 représente un hydrogène, un méthyle, un éthyle, un isopropyle, un tert-butyle, un cyclopropyle, un hydroxyméthyle ou un 2-propyl-2-ol ;

R3 représente Cl, F, CF3, un cyano, un méthyle, un méthoxy, un isopropyle ou un cyclopropyle ;

R4 représente un hydrogène, un méthyle, F ou Cl ;

ou un sel ou sel d'addition acide pharmaceutiquement acceptable, un mélange racémique, ou son énantiomère et/ou isomère optique et/ou stéréoisomère correspondant.
 
7. Composé de formule IF selon la revendication 1

dans laquelle

R2 représente un hydrogène, un méthyle, un éthyle, un isopropyle, un tert-butyle, un cyclopropyle, un hydroxyméthyle ou un 2-propyl-2-ol ;

R3 représente Cl, F, CF3, un cyano, un méthyle, un méthoxy, un isopropyle ou un cyclopropyle ;

R4 représente un hydrogène, un méthyle, F ou Cl ;

ou un sel ou sel d'addition acide pharmaceutiquement acceptable, un mélange racémique, ou son énantiomère et/ou isomère optique et/ou stéréoisomère correspondant.
 
8. Composé de formule IG selon la revendication 1

dans laquelle

R2 représente un hydrogène, un méthyle, un éthyle, un isopropyle, un tert-butyle, un cyclopropyle, un hydroxyméthyle ou un 2-propyl-2-ol ;

R3 représente Cl, F, CF3, un cyano, un méthyle, un méthoxy, un isopropyle ou un cyclopropyle ;

R4 représente un hydrogène, un méthyle, F ou Cl ;

ou un sel ou sel d'addition acide pharmaceutiquement acceptable, un mélange racémique, ou son énantiomère et/ou isomère optique et/ou stéréoisomère correspondant.
 
9. Composé de formule I selon la revendication 1, lequel composé est

le (RS)-3-(4-chlorophényl)-5-[3-(hydroxyméthyl)-1,2,4-triazol-4-yl]-N-(3-méthyl-1,1-dioxothiolan-3-yl)-benzamide

le N-(2-cyclopropylpropan-2-yl)-3-(4-fluorophényl)-5-(1,2,4-triazol-4-yl)-benzamide

le 3-(3-tert-butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-[4-(trifluorométhyl)-phényl]-benzamide

le 3-(3-tert-butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorophényl)-benzamide

le 3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-chlorophényl)-N-(2-cyclopropylpropan-2-yl)-benzamide

le N-(2-cyclopropylpropan-2-yl)-3-(4-fluorophényl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

le 3-(4-chlorophényl)-N-(2-cyclopropyl-propan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

le N-(2-cyclopropyl-propan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluorométhyl)-phényl]-benzamide

le 3-(4-chlorophényl)-N-(2-cyclopropyl-propan-2-yl)-5-[3-(hydroxyméthyl)-1,2,4-triazol-4-yl]-benzamide

le 3-(4-fluorophényl)-N-(1-hydroxy-2-méthylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

le 3-(4-chlorophényl)-N-(1-hydroxy-2-méthylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

le N-(1-hydroxy-2-méthylpropan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluorométhyl)-phényl]-benzamide

le 3-(4-fluorophényl)-5-(1,2,4-triazol-4-yl)-N-(1,1,1-trifluoro-2-méthylpropan-2-yl)-benzamide

le 3-(4-fluorophényl)-N-(2-méthylbutan-2-yl)-5-(1,2,4-triazol-4-yl)-benzamide

le N-(2-méthylbutan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluorométhyl)-phényl]-benzamide

le 3-(4-fluorophényl)-N-(2-méthylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

le 3-(4-chlorophényl)-N-(2-méthylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

le N-tert-butyl-3-(4-fluorophényl)-5-(1,2,4-triazol-4-yl)-benzamide

le N-tert-butyl-3-(4-fluorophényl)-5-(3-méthyl-1,2,4-triazol-4-yl)-benzamide

le N-tert-butyl-3-(4-chlorophényl)-5-(3-méthyl-1,2,4-triazol-4-yl)-benzamide

le N-tert-butyl-3-(3-méthyl-1,2,4-triazol-4-yl)-5-[4-(trifluorométhyl)-phényl]-benzamide

le N-tert-butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-fluorophényl)-benzamide

le N-tert-butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-chlorophényl)-benzamide

le N-tert-butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-[4-(trifluorométhyl)-phényl]-benzamide

le N-tert-butyl-3-(4-fluorophényl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

le N-tert-butyl-3-(4-chlorophényl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

le N-tert-butyl-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluorométhyl)-phényl]-benzamide

le N-tert-butyl-3-(4-chlorophényl)-5-[3-(hydroxyméthyl)-1,2,4-triazol-4-yl]-benzamide

le N-tert-butyl-3-(4-chlorophényl)-5-[3-(2-hydroxypropan-2-yl)-1,2,4-triazol-4-yl]-benzamide

le N-tert-butyl-3-(3,4-difluorophényl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

le N-tert-butyl-3-(4-méthoxyphényl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

le N-tert-butyl-3-(4-chloro-3-fluorophényl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

le N-tert-butyl-3-(4-fluoro-3-méthyl-phényl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

le N-tert-butyl-3-(3-fluoro-4-méthyl-phényl)-5-(3-propan-2-yl-1,2,4-tnazol-4-yl)-benzamide

le N-tert-butyl-3-(4-méthyl-phényl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

le N-tert-butyl-3-(4-cyano-phényl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide ou

le N-tert-butyl-3-(4-cyclopropyl-phényl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide.


 
10. Procédé de fabrication d'un composé de formule I tel que défini dans l'une quelconque des revendications 1 à 9, lequel procédé comprend

a) la réaction d'un composé de formule II

avec du N,N-diméthylformamide-diméthylacétal

et un composé de formule

afin d'obtenir un composé de formule I

b) la réaction d'un composé de formule V

avec un composé de formule VI

afin d'obtenir un composé de formule I

dans lesquelles les substituants sont tels que décrits ci-dessus, ou
si souhaité, la conversion des composés obtenus en des sels d'addition acide pharmaceutiquement acceptables, ou

c) la réaction d'un composé de formule VII

avec un composé de formule VIII

afin d'obtenir un composé de formule I

dans lesquelles les substituants sont décrits ci-dessus, ou

si souhaité, la conversion des composés obtenus en des sels d'addition acide pharmaceutiquement acceptables.
 
11. Composé de formule I selon l'une quelconque des revendications 1 à 9 pour une utilisation comme substances thérapeutiquement actives.
 
12. Composé de formule I selon l'une quelconque des revendications 1 à 9 pour une utilisation dans le traitement de la schizophrénie, d'un trouble bipolaire, d'un trouble obsessionnel compulsif ou d'un trouble du spectre de l'autisme.
 
13. Composition pharmaceutique comprenant un composé de formule I selon l'une quelconque des revendications 1 à 9 et des excipients pharmaceutiquement acceptables.
 






Cited references

REFERENCES CITED IN THE DESCRIPTION



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Non-patent literature cited in the description