ES2363188T3 - CONDENSED IMIDAZOLS FOR THE TREATMENT OF CANCER. - Google Patents

Abstract

Compound of formula (I) in which ring B and the imidazole with which it is condensed form a ring system selected from which R1 is hydrogen, C1-4 alkyl, halogen, amino, -SR2, trifluoromethyl, cyano, C3-7 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-7 cycloalkoxy, mono or C1-4 dialkylamino, mono or C1-4 dialkylaminocarbonyl, -C (NH) NH2, -C (O ) NH2 or -C (O) OR10 R2 is hydrogen, C1-4 alkyl or C3-7 cycloalkyl, R3 is hydrogen, C1-4 alkyl or halogen, R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl, thiazolyl or oxazolyl unsubstituted, R5 is C1-4 alkyl, halogen or C1-4 alkoxy, R6 is hydrogen or C1-4 alkyl, R7 is -WY, W is a 5-membered monocyclic heteroarylene comprising 1 nitrogen atom and optionally 1 or 2 additional heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein the heteroarylene is optionally substituted with R8, R8 is C1-4 alkyl or cycloalkyl C3-7, Y is phenyl or a 5 or 6 membered monocyclic heteroaryl comprising 1 nitrogen atom and optionally 1 or 2 additional heteroatoms independently selected from oxygen, nitrogen, sulfur and in which the heteroaryl is optionally substituted with R9, R9 it is C1-4 alkyl, C1-4 alkoxy or halogen, R10 is hydrogen or C1-4 alkyl; or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

Description

Field of application of the invention

The invention relates to condensed imidazole compounds, which are used in the pharmaceutical industry for the manufacture of pharmaceutical compositions.

Known Technical Background

Cancer is the second most prevalent cause of death in the United States, causing 450,000 deaths a year. Although substantial progress has been made in the identification of some of the probable environmental and inherited causes of cancer, there is a need for additional therapeutic modalities that target cancer and related diseases. In particular, there is a need for therapeutic methods to treat diseases associated with deregulated proliferation / growth.

Cancer is a complex disease that arises after a process of selecting cells with acquired functional abilities such as enhanced survival / resistance to apoptosis and unlimited proliferative potential. Therefore, it is preferred to develop drugs for cancer therapy that address different characteristics of established tumors.

A route that has been shown to mediate important survival signals for mammalian cells comprises tyrosine kinase receptors such as the platelet-derived growth factor receptor (PDGFR), the human epidermal growth factor 2/3 receptor (HER2 / 3 ), or insulin-like growth factor 1 receptor (IGF-1R). Upon activation thereof by the ligand, these receptors activate the phosphatidylinositol 3-kinase (Pi3K) / Akt pathway. The phosphatidylinositol 3-kinase (Pi3K) / Akt protein kinase pathway is essential for the control of cell growth, proliferation and survival, driving tumor evolution. Therefore, within the specific signaling serine-threonine kinase class, Akt (protein kinase B; PKB) with the isozymes Akt1 (PKB ), Akt2 (PKB ) and Akt3 (PKB y) is of great interest for the intervention therapy. Akt is activated primarily in a Pi3-kinase-dependent manner and activation is regulated by the PTEN tumor suppressor (phosphatase and tensin homolog), which essentially functions as the functional antagonist of Pi3K.

The Pi3K / Akt pathway regulates fundamental cellular functions (eg transcription, translation, growth and survival), and is involved in human diseases including diabetes and cancer. The route is frequently overactivated in a wide range of tumor entities such as breast and prostate carcinomas. Increase regulation may be due to overexpression or constitutively activating tyrosine kinase receptors (eg EGFR, HER2 / 3), which are in the 5 'direction and are involved in their direct activation, or gain or loss mutants of function of some of the components such as loss of PTEN. The route is the target of genomic alterations including mutation, amplification and redisposition more frequently than any other route in human cancer, with the possible exception of the p53 and retinoblastoma routes. The alterations of the Pi3K / Akt path trigger a cascade of biological events, which drive evolution, survival, angiogenesis and tumor metastases.

Activation of Akt kinases promotes increased nutrient uptake, transforming cells to a glucose-dependent metabolism that redirects lipid and amino acid precursors to anabolic processes that support cell growth and proliferation. This metabolic phenotype with overactive Akt leads to malignant tumors that show a metabolic transformation to aerobic glycolysis (the Warburg effect). In this sense, it is commented that the Pi3K / Akt route is essential for survival despite unfavorable growth conditions such as glucose depletion or hypoxia.

An additional aspect of the activated P13K / Akt pathway is to protect cells from programmed cell death ("apoptosis") and is therefore considered to transduce a survival signal. Acting as a modulator of antiapoptotic signaling in tumor cells, the Pi3K / Akt pathway, in particular Akt itself is a target for cancer therapy. Akt activated phosphorylates and regulates several targets, for example BAD, GSK3 or FKHRL1, which affect different signaling pathways such as cell survival, protein synthesis or cell movement. This route of Pi3K / Akt also plays an important part in the resistance of tumor cells to conventional anticancer therapies. The blocking of the Pi3K / Akt pathway could therefore simultaneously inhibit the proliferation of tumor cells (for example by inhibiting the metabolic effect) and sensitize towards proapoptotic agents.

Akt inhibition selectively sensitized tumor cells against apoptotic stimuli such as Trail, camptothecin and doxorubicin. Depending on the genetic background / molecular occurrences of tumors, Akt inhibitors could induce apoptotic cell death alone as well.

In European patent EP1268478, phenyl substituted imidazopyridines are known as H3 antagonists

to treat diseases in the central nervous system. In the international patent application W02005014598

disclose substituted imidazopyrimidines for the treatment of cancer. In the international patent application

W02007025090 substituted imidazopyridazines for the treatment of cancer are disclosed. In the documents

EP 1 277 754 (WO 01/083481) and WO 01/74815 are substituted imidazopyridines, the first for

Cancer treatment, the last for the treatment of disorders of the central nervous system. From WO document

2006/125101 Imidazopyrazines are known for the treatment of cancer. In WO 2007/095588 are given

namely imidazopyridines and imidazopyridazines as inhibitors of Pi3K. In patent applications

International W02004096131, W02005100344, WO2006036395, WO2006065601, W02006091395 and 10 W02006135627 Akt inhibitors are described.

Description of the invention

It has been found that the condensed imidazole compounds, which are described in detail below, have advantageous and surprising properties.

According to a first aspect, the invention relates to compounds of formula (I)

image 1

wherein the ring B and the imidazole with which it is condensed form a ring system selected from

image2

in which

30

R1

is hydrogen, C1-4 alkyl, halogen, amino, -SR2, trifluoromethyl, cyano, C3-7 cycloalkyl, C2-4 alkenyl,

C2-4 alkynyl, C1-4 alkoxy, C3-7 cycloalkoxy, mono or C1-4 dialkylamino, mono or dialkylaminocarbonyl

C1-4, C (NH) NH2, -C (O) NH2 or -C (O) OR10

35

R2 is hydrogen, C1-4 alkyl or C3-7 cycloalkyl,

R3

is hydrogen, C1-4 alkyl or halogen,

R4

it is phenyl substituted with R5, phenyl, thienyl, pyridinyl, thiazolyl or unsubstituted oxazolyl,

40

R5

is C1-4 alkyl, halogen or C1-4 alkoxy,

R6

is hydrogen or C1-4 alkyl,

R7 is -W-Y, W is a 5-membered monocyclic heteroarylene comprising 1 nitrogen atom and optionally 1 or 2 additional heteroatoms independently selected from oxygen, nitrogen and sulfur, and in which

The heteroarylene is optionally substituted with R8, R8 is C1-4 alkyl or C3-7 cycloalkyl, Y is phenyl or a 5 or 6 membered monocyclic heteroaryl comprising 1 nitrogen atom and

Optionally 1 or 2 additional heteroatoms independently selected from oxygen, nitrogen, sulfur and in which the heteroaryl is optionally substituted with R9, R9 is C1-4 alkyl, C1-4 alkoxy or halogen, R10 is hydrogen or C1-4 alkyl ,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

According to a second aspect, the invention relates to compounds of formula (I)

image 1

25 in which ring B and the imidazole with which it is condensed form a ring system selected from

image 1

30 in which

R1 is hydrogen, C1-4 alkyl, halogen, amino, -SR2, trifluoromethyl, cyano, C3-7 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-7 cycloalkoxy, mono or C1- dialkylamino 4, mono or dialkylaminocarbonyl C1-4-4, -C (NH) NH2, -C (O) NH2 or -C (O) OR10

R2 is hydrogen, C1-4 alkyl or C3-7 cycloalkyl,

R3 is hydrogen, C1-4 alkyl or halogen, R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl, thiazolyl or unsubstituted oxazolyl,

R5 is C1-4 alkyl, halogen or C1-4 alkoxy,

R6 is hydrogen or C1-4 alkyl,

R7 is -W-Y,

W is a 5-membered monocyclic heteroarylene comprising 1 nitrogen atom and optionally 1 or

2 additional heteroatoms independently selected from oxygen, nitrogen and sulfur, and in which

heteroarylene is optionally substituted with R8,

R8 is C1-4 alkyl or C3-7 cycloalkyl,

Y is a 5 or 6 membered monocyclic heteroaryl comprising 1 nitrogen atom and optionally 1 or

2 additional heteroatoms independently selected from oxygen, nitrogen, sulfur and in which the

heteroaryl is optionally substituted with R9,

R9 is C1-4 alkyl, C1-4 alkoxy or halogen,

R10 is hydrogen or C1-4 alkyl,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

C1-4 alkyl is a branched or straight chain alkyl group having 1 to 4 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

The mono or C1-4 dialkylamino radicals contain in addition to the nitrogen atom, one or two of the abovementioned C1-4 alkyl radicals. Examples are the methylamino radical, ethylamino, isopropylamino, dimethylamino, diethylamino and diisopropylamino.

The C1-4 mono or dialkylaminocarbonyl radicals contain in addition to the carbonyl group one of the mono radicals

or C1-4 dialkylamino mentioned above. Examples are N-methylaminocarbonyl, N, N-dimethylaminocarbonyl, N-ethylaminocarbonyl, N-propylaminocarbonyl, N, N-diethylaminocarbonyl and Nisopropylaminocarbonyl.

Halogen within the meaning of the present invention is iodine, or particularly bromine, chlorine and fluorine.

C1-4 alkoxy represents radicals, which in addition to the oxygen atom, contain a branched or straight chain alkyl radical having 1 to 4 carbon atoms. Examples that may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.

C3-7 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

C3-7 cycloalkyloxy means cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy.

C2-4 alkenyl is a branched or straight chain alkenyl radical having 2 to 4 carbon atoms. Examples are the but-2-enyl, but-3-enyl (homoalyl), prop-1-enyl, prop-2-enyl (allyl) and ethenyl (vinyl) radicals.

C2-4 alkynyl is a branched or straight chain alkynyl radical having from 2 to 4 carbon atoms. Examples are the but-2-inyl, but-3-inyl (homopropargyl), prop-1-inyl, 1-methylprop-2-inyl (1-methylpropargyl), prop-2inyl (propargyl) and ethynyl radicals.

The term "5 or 6-membered monocyclic heteroaryl" includes, without restriction thereof, the 5-membered heteroaryl radicals furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl (1,2,4- triazolyl, 1,3,4-triazolyl or 1,2,3-triazolyl), thiadiazolyl (1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3thiadiazolyl or 1,2,4-thiadiazolyl ) and oxadiazolyl (1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl or 1,2,4oxadiazolyl), as well as the 6-membered heteroaryl radicals pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl Preferred 5- or 6-membered heteroaryl radicals are furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrimidinyl, pyrazinyl or pyridazinyl. More preferred 5 or 6-membered heteroaryl radicals are furan-2-yl, thien-2-yl, pyrrol-2-yl, thiazolyl, oxazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, pyridine- 2-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl or pyridazin-3-yl.

The term "5-membered monocyclic heteroarylene" is a divalent radical in which an arbitrary hydrogen atom is removed from the "heteroaryl" described above and may include, without restricting them, the 5-membered heteroaryl radicals furylene, thienylene, pyrrolylene , oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, imidazolylene, pyrazolylene, triazolylene (1,2,4-triazolylene, 1,3,4-triazolylene or 1,2,3-triazolylene),

5 thiadiazolylene (1,3,4-thiadiazolylene, 1,2,5-thiadiazolylene, 1,2,3-thiadiazolylene or 1,2,4-thiadiazolylene) and oxadiazolylene (1,3,4-oxadiazolylene, 1,2, 5-oxadiazolylene, 1,2,3-oxadiazolylene or 1,2,4-oxadiazolylene). Preferred 5-membered heteroaryl radicals are triazolylene, pyrazolylene, oxadiazolylene or imidazolylene. More preferred 5-membered heteroaryl radicals are 1,2,4-triazolylene, pyrazolylene, 1,2,4-oxadiazolylene or imidazolylene.

In general, and unless otherwise mentioned, heteroaryl or heteroarylene radicals include all possible isomeric forms thereof, for example the positional isomers thereof. Thus, for some illustrative non-restrictive example, the term pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylne, pyridin-3yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.

The constituents that are optionally substituted as set forth herein may be substituted, unless otherwise indicated, in any possible position. Similarly, it is understood that it is possible for any heteroaryl group if it is chemically suitable that said heteroaryl group can be attached to the rest of the molecule by any suitable atom.

The heteroaryl or heteroarylene groups mentioned herein may be substituted with their given substituents or original molecular groups, unless otherwise indicated, in any possible position, such as for example in any ring nitrogen atom or carbon of replaceable ring

Unless otherwise indicated, rings containing quaternizable imino or amino ring nitrogen atoms (-N =) may preferably not be quaternized in these imino or amino ring nitrogen atoms by the above-mentioned substitutes or groups original molecular.

Unless otherwise indicated, any heteroatom of a heteroaryl ring or

The heteroarylene with unsatisfied valences mentioned herein has the hydrogen atom (s) to satisfy the valences.

When any variable appears more than once in any constituent, each definition is independent.

In another embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), in which

ring B and the imidazole with which it is condensed form a ring system selected from

image3

in which 45

R1 is hydrogen, C1-4 alkyl, halogen, amino, -SR2, trifluoromethyl, cyano, C3-7 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-7 cycloalkoxy, mono or C1- dialkylamino 4, C1-4 mono or dialkylaminocarbonyl, -C (NH) NH2, -C (O) NH2 or

R2 is hydrogen, C1-4 alkyl or C3-7 cycloalkyl,

R3 is hydrogen, C1-4 alkyl or halogen,

R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl, thiazolyl or unsubstituted oxazolyl,

R5 is C1-4 alkyl, halogen or C1-4 alkoxy,

R6 is hydrogen or C1-4 alkyl,

R7 is -W-Y,

10 W is a 5-membered monocyclic heteroarylene comprising 1 nitrogen atom and optionally 1 or 2 additional heteroatoms independently selected from oxygen, nitrogen and sulfur, and in which the heteroarylene is optionally substituted with R8,

R 8 is C 1-4 alkyl or C 3-7 cycloalkyl,

Y is a 5 or 6 membered monocyclic heteroaryl comprising 1 nitrogen atom and optionally 1 or 2 additional heteroatoms independently selected from oxygen, nitrogen, sulfur and in which the heteroaryl is optionally substituted with R9,

R9 is C1-4 alkyl or halogen,

or a salt, as well as the stereoisomer and the stereoisomer salt thereof. In a further embodiment, the invention relates to compounds of formula (I),

in which ring B and the imidazole with which it is condensed form a ring system selected from

image4

in which

35

R1

is hydrogen, C1-4 alkyl, halogen, amino, -SR2, trifluoromethyl, cyano, C3-7 cycloalkyl, C2-4 alkenyl,

C2-4 alkynyl, C1-4 alkoxy, C3-7 cycloalkoxy, C1-4 mono or dialkylamino, mono or dialkylaminocabonyl

C1-4, -C (NH) NH2 or -C (O) NH2,

40

R2 is hydrogen, C1-4 alkyl or C3-7 cycloalkyl,

R3

it's hydrogen

R4

it is phenyl substituted with R5, phenyl, thienyl, pyridinyl or unsubstituted thiazolyl,

Four. Five

R5

is C1-4 alkyl, halogen or C1-4 alkoxy,

R6

it's hydrogen or methyl,

R7 is -W-Y, W is triazolylene, pyrazolylene, oxadiazolylene or imidazolylene, each of which is substituted

5 optionally with R 8, R 8 is C 1-4 alkyl or C 3-7 cycloalkyl, Y is thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of the

10 which is optionally substituted with R9, R9 is C1-4 alkyl or halogen,

or a salt, as well as the stereoisomer and the stereoisomer salt thereof.

In another embodiment, the invention relates to compounds of formula (I),

in which

20 ring B and the imidazole with which it is condensed form a ring system selected from

image 1

25 in which

R1 is hydrogen, C1-4 alkyl, halogen, amino, -SR2, trifluoromethyl, cyano, C3-7 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-7 cycloalkoxy, mono or C1- dialkylamino 4, mono or dialkylaminocarbonyl C1-4-4, -C (NH) NH2 or -C (O) NH2,

R2 is hydrogen, C1-4 alkyl or C3-7 cycloalkyl,

R3 is hydrogen, R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl or unsubstituted thiazolyl,

R5 is C1-4 alkyl, halogen or C1-4 alkoxy,

R6 is hydrogen or methyl,

R7 is -W-Y,

W is 1,2,4-triazolylene, pyrazolylene, 1,2,4-oxadiazolylene or imidazolylene, 45 Y is thiazol-2-yl, thiazol-4-yl, oxazol-2-yl, oxazol-4-yl, 1 , 3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl or pyridazin-3 -ilo,

or a salt as well as the stereoisomer and the stereoisomer salt thereof.

In a further preferred embodiment, the invention relates to compounds of formula (I), in which the ring B and the imidazole with which it is fused form a ring system selected from

image5

wherein R1 is hydrogen, C1-4 alkyl, halogen, amino, trifluoromethyl, cyano, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, mono or C1-4 dialkylamino, mono or C1-4 dialkylaminocarbonyl, -C (NH) NH2 or -C (O) NH2, R3 is hydrogen,

R4 is phenyl or unsubstituted thienyl, R6 is hydrogen, R7 is -W-Y,

20 W is 1,2,4-triazolylene, pyrazolylene, 1,2,4-oxadiazolylene or imidazolylene, Y is pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl or pyridazin -3-yl, 25 or a salt thereof. In a further preferred embodiment, the invention relates to compounds of formula (I), in which the ring B and the imidazole with which it is fused form a ring system selected from 30

image 1

in which 35

R1 is hydrogen, C1-4 alkyl, halogen, amino, trifluoromethyl, cyano, C1-4 alkoxy, -C (NH) NH2 or -C (O) NH2,

R3 is hydrogen,

R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl or unsubstituted thiazolyl,

R5 is C1-4 alkyl, halogen or C1-4 alkoxy,

R6 is hydrogen,

45 R7 is -W-Y,

W is 1,2,4-triazolylene, 1,2,4-oxadiazolylene or pyrazolylene, And it is pyridin-2-yl or pyrazin-2-yl,

5

and the salts, as well as the stereoisomers and the salts of the stereoisomers thereof. In a further preferred embodiment, the invention relates to compounds of formula (I), wherein the ring B and the imidazole with which it is fused form a ring system selected from

image 1

fifteen

in which

R1 is hydrogen, C1-4 alkyl, halogen, amino, trifluoromethyl, cyano, C1-4 alkoxy, -C (NH) NH2 or -C (O) NH2, R3 is hydrogen,

R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl or unsubstituted thiazolyl,

R5 is C1-4 alkyl, halogen or C1-4 alkoxy, 25

R6 is hydrogen,

R7 is -W-Y, 30 W is 1,2,4-triazolylene, 1,2,4-oxadiazolylene or pyrazolylene,

And it is pyridin-2-yl or pyrazin-2-yl,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said

Compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment, the invention relates to compounds of formula (I), in which

40 ring B and the imidazole with which it is condensed form a ring system selected from

image 1

in which R1 is hydrogen, methyl, halogen, trifluoromethyl, cyano, methoxy, -C (NH) NH2 or -C (O) NH2,

5 R3 is hydrogen, R4 is unsubstituted phenyl, R6 is hydrogen,

10

R7 is -W-Y, W is 1,2,4-triazolylene,

15 And it is pyridin-2-yl, and the salts, as well as the stereoisomers and the salts of the stereoisomers thereof. In a further preferred embodiment, the invention relates to compounds of formula (I), in which

twenty

ring B and the imidazole with which it is condensed form a ring system selected from

image 1

Wherein R1 is hydrogen, methyl, halogen, trifluoromethyl, cyano, methoxy, -C (NH) NH2 or -C (O) NH2, 30 R3 is hydrogen, R4 is unsubstituted phenyl, R6 is hydrogen, R7 is -WY, W is 1,2,4-triazolylene, 40 and is pyridin-2-yl,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further embodiment, the invention relates to compounds of formula (I), in which

ring B and the imidazole with which it is condensed form a ring system selected from

image 1

in which

R1 is hydrogen, C1-4 alkyl, halogen, amino, -SR2, trifluoromethyl, cyano, C3-7 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-7 cycloalkoxy, mono or C1- dialkylamino 4, mono or dialkylaminocarbonyl

C1-4, -C (NH) NH2, -C (O) NH2 or -C (O) OR10

R2 is hydrogen, C1-4 alkyl or C3-7 cycloalkyl,

R3 is hydrogen, C1-4 alkyl or halogen,

R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl, oxazolyl or unsubstituted thiazolyl,

R5 is C1-4 alkyl, halogen or C1-4 alkoxy,

R6 is hydrogen or methyl,

R7 is -W-Y,

W is triazolylene, pyrazolylene, oxadiazolylene or imidazolylene, each of which is substituted

optionally with R8,

R8 is C1-4 alkyl or C3-7 cycloalkyl,

Y is phenyl, furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl

or pyridazinyl, each of which is optionally substituted with R9, R9 is C1-4 alkyl, C1-4 alkoxy or halogen, R10 is hydrogen or C1-4 alkyl,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In another embodiment, the invention relates to compounds of formula (I), in which

ring B and the imidazole with which it is condensed form a ring system selected from

image 1

image 1

in which 5

R1 is hydrogen, C1-4 alkyl, halogen, amino, -SR2, trifluoromethyl, cyano, C3-7 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-7 cycloalkoxy, mono or C1- dialkylamino 4, C1-4 mono or dialkylaminocarbonyl, -C (NH) NH2, -C (O) NH2 or -C (O) OR10

R 2 is hydrogen, C 1-4 alkyl or C 3-7 cycloalkyl, R 3 is hydrogen, C 1-4 alkyl or halogen, R 4 is phenyl substituted with R 5, phenyl, thienyl, pyridinyl, oxazolyl or unsubstituted thiazolyl,

R5 is C1-4 alkyl, halogen or C1-4 alkoxy, R6 is hydrogen or methyl, R7 is -WY, W is 1,2,4-triazolylene, pyrazolylene, 1,2,4-oxadiazolylene or imidazolylene, Y it is phenyl, furan-2-yl, tien-2-yl, pyrrole-2-yl, pyridin-4-yl, thiazol-2-yl, thiazol-4-yl, oxazol-2-yl, oxazol-4-yl , 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl or pyridazin-3-yl, each of which is optionally substituted with R9, R9 is C1-4 alkyl, C1-4 alkoxy or halogen, R10 is hydrogen or C1-4 alkyl,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment, the invention relates to compounds of formula (I), in which

ring B and the imidazole with which it is condensed form a ring system selected from

image3

wherein R1 is hydrogen, C1-4 alkyl, halogen, -SR2, amino, trifluoromethyl, cyano, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, mono or C1-4 dialkylamino, mono or C1- dialkylaminocarbonyl 4, -C (NH) NH2, -C (O) NH2 or -C (O) OR10

R2 is C1-4 alkyl, 5 R3 is hydrogen or halogen,

R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl, oxazolyl or unsubstituted thiazolyl,

10 R6 is hydrogen,

R7 is -W-Y,

W is 1,2,4-triazolylene, pyrazolylene or 1,2,4-oxadiazolylene, 15 Y is phenyl, furan-2-yl, thien-2-yl, pyrrol-2-yl, pyridin-4-yl, thiazole -2-yl, pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl or pyridazin-3-yl, each of which is optionally substituted with R9,

R10 is hydrogen or C1-4 alkyl, 20

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment the invention relates to compounds of formula (I), in which the ring B and the imidazole with which it is fused form a ring system selected from

image4

in which

R1

is hydrogen, C1-4 alkyl, halogen, amino, -SR2, trifluoromethyl, cyano, C3-7 cycloalkyl, C2-4 alkenyl,

35

C2-4 alkynyl, C1-4 alkoxy, C3-7 cycloalkoxy, mono or C1-4 dialkylamino, mono or dialkylaminocarbonyl

C1-4, -C (NH) NH2, -C (O) NH2 or -C (O) OR10

R2

is hydrogen, C1-4 alkyl or C3-7 cycloalkyl,

40

R3 is hydrogen, C1-4 alkyl or halogen,

R4

it is phenyl substituted with R5, phenyl, thienyl, pyridinyl, oxazolyl or unsubstituted thiazolyl,

R5

is C1-4 alkyl, halogen or C1-4 alkoxy,

Four. Five

R6

it's hydrogen or methyl,

R7

it's -W-Y,

W is triazolylene, pyrazolylene, oxadiazolylene or imidazolylene, each of which is optionally substituted with R8,

R 8 is C 1-4 alkyl or C 3-7 cycloalkyl. Y is furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is optionally substituted with R 9,

R9 is C1-4 alkyl, C1-4 alkoxy or halogen, R10 is hydrogen or C1-4 alkyl,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said

compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the second aspect, the invention relates to compounds of formula (I), in which the B ring and the imidazole with which it is fused form a ring system selected from

image6

in which 25

R1 is hydrogen, C1-4 alkyl, halogen, amino, -SR2, trifluoromethyl, cyano, C3-7 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-7 cycloalkoxy, mono or C1- dialkylamino 4, C1-4 mono or dialkylaminocarbonyl, -C (NH) NH2, -C (O) NH2 or -C (O) OR10

R2 is hydrogen, C1-4 alkyl or C3-7 cycloalkyl,

R3 is hydrogen, C1-4 alkyl or halogen,

R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl, oxazolyl or unsubstituted thiazolyl, R5 is C1-4 alkyl, halogen or C1-4 alkoxy,

R6 is hydrogen or methyl,

40 R7 is -W-Y,

W is 1,2,4-triazolylene, pyrazolylene, 1,2,4-oxadiazolylene or imidazolylene,

Y is furan-2-yl, thien-2-yl, pyrrol-2-yl, pyridin-4-yl, thiazol-2-yl, thiazol-4-yl, oxazol-2-yl, oxazol-4-yl, 1,3,445 thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl or pyridazin-3-yl , each of which is optionally substituted with R9,

R9 is C1-4 alkyl, C1-4 alkoxy or halogen, R10 is hydrogen or C1-4 alkyl,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the second aspect, the invention relates to compounds of formula (I), in which the B ring and the imidazole with which it is fused form a ring system selected from

image7

in which

R1 is hydrogen, C1-4 alkyl, halogen, -SR2, amino, trifluoromethyl, cyano, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, mono or C1-4 dialkylamino, mono or C1-4 dialkylaminocarbonyl, -C (NH) NH2, -C (O) NH2 or -C (O) OR10

R2 is C1-4 alkyl, R3 is hydrogen or halogen,

R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl, oxazolyl or unsubstituted thiazolyl,

25 R6 is hydrogen,

R7 is -W-Y,

W is 1,2,4-triazolylene, pyrazolylene or 1,2,4-oxadiazolylene, 30 Y is furan-2-yl, thien-2-yl, pyrrol-2-yl, pyridin-4-yl, thiazol-2 -yl, pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl or pyridazin-3-yl, each of which is optionally substituted with R9,

R9 is C1-4 alkyl, C1-4 alkoxy or halogen, R10 is hydrogen or C1-4 alkyl,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said

compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment, the invention relates to compounds of formula (I), in which the ring B and the imidazole with which it is fused form a ring system selected from

image8

image 1

in which 5 R1 is hydrogen, C1-4 alkyl, halogen, -SR2, amino, trifluoromethyl, cyano, C1-4 alkoxy, -C (NH) NH2, -C (O) NH2 or -C (O) OR10, R2 is C1-4 alkyl,

R3 is hydrogen or halogen, R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl or unsubstituted thiazolyl, R5 is C1-4 alkyl, halogen or C1-4 alkoxy,

R6 is hydrogen, R7 is -WY, 20 W is 1,2,4-triazolylene, 1,2,4-oxadiazolylene or pyrazolylene, and is pyridin-2-yl or pyrazin-2-yl, each of which is optionally substituted with R9, R9 is C1-4 alkyl, C1-4 alkoxy or halogen, R10 is hydrogen or C1-4 alkyl,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said

compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment, the invention relates to compounds of formula (I), in which the ring B and the imidazole with which it is fused form a ring system selected from

image9

in which

R1 is hydrogen, methyl, halogen, -SR2, trifluoromethyl, cyano, methoxy, -C (NH) NH2, -C (O) NH2 or -C (O) OR10, R2 is C1-4 alkyl, R3 is hydrogen or halogen,

Four. Five

R4 is unsubstituted phenyl,

R6 is hydrogen, R7 is -W-Y,

5 W is 1,2,4-triazolylene, And it is pyridin-2-yl which is optionally substituted with R9, R9 is C1-4 alkyl, C1-4 alkoxy or halogen,

R10 is hydrogen or C1-4 alkyl,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said

compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), in which

20 ring B and the imidazole with which it is condensed form a ring system selected from

image 1

In which R1 is hydrogen, methyl, halogen, -SR2, trifluoromethyl, cyano, methoxy, -C (NH) NH2, -C (O) NH2 or -C (O) OR10, R2 is C1-4 alkyl,

R3 is hydrogen, R4 is unsubstituted phenyl, R6 is hydrogen, R7 is -W-Y, W is 1,2,4-triazolylene, 40 Y is pyridin-2-yl, R10 is hydrogen or C1-4 alkyl,

Or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), in which ring B and the imidazole with which it is fused form the following ring system

image 1

R3 is hydrogen, R6 is hydrogen and R1, R2, R4, R5, R7, R8, R9, W and Y are as described above,

5 or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention is

10 refers to compounds of formula (I), in which ring B and the imidazole with which it is condensed form the following ring system

image 1

R3 is hydrogen, R6 is hydrogen and R1, R2, R4, R5, R7, R8, R9, W and Y are as described above,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), in which ring B and the imidazole with which it is fused form the following ring system

image 1

R3 is hydrogen, R6 is hydrogen and R1, R2, R4, R5, R7, R8, R9, W and Y are as described above,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), in which ring B and the imidazole with which it is fused form the following ring system

image 1

35

R3 is hydrogen, R6 is hydrogen and R1, R2, R4, R5, R7, R8, R9, W and Y are as described above,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said

compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), in which ring B and the imidazole with which it is fused form the following ring system

image 1

5

R3 is hydrogen, R6 is hydrogen and R1, R2, R4, R5, R7, R8, R9, W and Y are as described above,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said

compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), in which ring B and the imidazole with which it is fused form the following ring system

fifteen

image 1

R6 is hydrogen and R1, R2, R4, R5, R7, R8, R9, W and Y are as described above, or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a

20 salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), in which ring B and the imidazole with which it is fused form the following ring system

25

image 1

R3 is hydrogen, R6 is hydrogen, R4 is phenyl and R1, R2, R7, R8, R9, W and Y are as described above, or a salt, particularly a pharmaceutically acceptable salt, a tautomer, or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), wherein ring B and the imidazole with which it is fused form the following ring system

image 1

R3 is hydrogen, R6 is hydrogen, R4 is phenyl and R1, R2, R7, R8, R9, W and Y are as described

40 above, or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), in which ring B and the imidazole with which it is fused form the following ring system

image 1

5

R3 is hydrogen, R6 is hydrogen, R4 is phenyl and R1, R2, R7, R8, R9, W and Y are as described above, or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound , or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said

10 stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), in which ring B and the imidazole with which it is fused form the following ring system

fifteen

image 1

R3 is hydrogen, R6 is hydrogen, R4 is phenyl and R1, R2, R7, R8, R9, W and Y are as described above, or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer 20 of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), in which ring B and the imidazole with which it is fused form the following ring system

image 1

R3 is hydrogen, R6 is hydrogen, R4 is phenyl and R1, R2, R7, R8, R9, W and Y are as described

30 above, or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention is

35 refers to compounds of formula (I), in which ring B and the imidazole with which it is condensed form the following ring system

image 1

R6 is hydrogen, R4 is phenyl and R1, R2, R7, R8, R9, W and Y are as described above, or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), wherein ring B and the imidazole with which it is condensed is

image 1

R3 is hydrogen, R6 is hydrogen, R4 is phenyl, R7 is -W-Y, W is 1,2,4-triazolylene, Y is pyridin-2-yl and R1 and R2 are as described above,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said

The compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), wherein ring B and the imidazole with which it is condensed is

fifteen

image 1

R3 is hydrogen, R6 is hydrogen, R4 is phenyl, R7 is -W-Y, W is 1,2,4-triazolylene, Y is pyridin-2-yl and R1 and R2 are as described above,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), wherein ring B and the imidazole with which it is condensed is

image 1

R3 is hydrogen, R6 is hydrogen, R4 is phenyl, R7 is -W-Y, W is 1,2,4-triazolylene, Y is pyridin-2-yl and R1 and R2 are as described above,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said

compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), wherein ring B and the imidazole with which it is condensed is

image 1

R3 is hydrogen, R6 is hydrogen, R4 is phenyl, R7 is -W-Y, W is 1,2,4-triazolylene, Y is pyridin-2-yl and R1 and R2 are as described above,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), wherein ring B and the imidazole with which it is condensed is

image 1

R3 is hydrogen, R6 is hydrogen, R4 is phenyl, R7 is -W-Y, W is 1,2,4-triazolylene, Y is pyridin-2-yl and R1 and R2 are as described above,

or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said

compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

In a further preferred embodiment of the first or second aspect mentioned above, the invention relates to compounds of formula (I), wherein ring B and the imidazole with which it is condensed is

image 1

twenty

R6 is hydrogen, R4 is phenyl, R7 is -WY, W is 1,2,4-triazolylene, Y is pyridin-2-yl and R1 and R2 are as described above, or a salt, particularly a pharmaceutically acceptable salt , a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said

Tautomer or said stereoisomer.

The salts of the compounds according to the invention include all inorganic and organic acid addition salts and base salts, especially all inorganic and organic acid addition salts and pharmaceutically acceptable base salts, particularly all acid addition salts. inorganic and organic and

30 salts with pharmaceutically acceptable bases commonly used in pharmacy.

Examples of acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, sulfamic acid salts, formates, acetates, propionates, citrates, D-gluconates, benzoates, 2- (4-hydroxybenzoyl) -benzoates, butyrates, salicylates, sulphosalicylates, lactates, maleates, laurates, malate, smokers,

35 succinates, oxalates, malonates, pyruvates, acetoacetates, tartarates, stearates, benzenesulfonates, toluenesulfonates, methanesulfonates, trifluoromethanesulfonates, 3-hydroxy-2-naphthoates, benzenesulfonates, naphthalene disulfonates and trifluoroacetates.

Examples of salts with bases include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, salts.

40 mg, titanium, meglumine, ammonium optionally derived from NH3 or organic amines having from 1 to 16 C atoms such as, for example, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylamine dibethane, procaine, ethanol , Nmethylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperindine and guanidinium salts.

The salts include water insoluble salts and, particularly, water soluble salts.

According to the person skilled in the art, the compounds of formula (I) according to this invention as well as their salts may contain, for example when crystalline forms are isolated, varying amounts of solvents. Therefore, all solvates and in particular all hydrates of the compounds are included within the scope of the invention

50 of formula (I) according to this invention as well as all solvates and in particular all hydrates of the salts of the compounds of formula (I) according to this invention.

The compounds according to the invention and their salts may exist in the form of tautomers. In particular, those compounds of the invention that contain a pyrazole residue, for example, may exist as a 1H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole residue, by

For example, it can exist as a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1H, 2H and 4H tautomers:

image 1

The compounds according to the invention and the salts thereof include stereoisomers. Each of the stereogenic centers present in said stereoisomers can have the absolute configuration R or the absolute configuration S (according to the rules of Cahn, Ingold and Prelog). Therefore, the stereoisomers (1S) and (1R) in the case of a compound of formula (Ia *)

10

image 1

and the salts thereof are part of the invention.

The invention further includes all mixtures of the stereoisomers mentioned above independently of the ratio, including racemates.

Some of the compounds and salts according to the invention may exist in different crystalline forms (polymorphs) that are within the scope of the invention.

In addition, the invention covers derivatives of the compounds of formula (I) and salts thereof which are converted into a compound of formula (I) or a salt thereof in a biological system (bioprecursors or prodrugs). Said biological system is for example a mammalian organism, particularly a human subject. The bioprecursor is converted, for example, into the compound of formula (I) or a salt thereof by metabolic processes.

The intermediates used for the synthesis of the compounds of claims 1-5 as described below as well as their use for the synthesis of the compounds of claims 1-5 are a further aspect of the present invention.

The compounds according to the invention can be prepared as follows:

As shown in reaction scheme 1, the compounds of formula (I), in which the ring B and the imidazole with which it is fused, R4 and R7, have the meanings mentioned above and R6 is hydrogen or C1 alkyl -4, can be obtained by a reductive amination reaction of a corresponding compound of

Formula (III), in which R has the meaning -C (O) R6, with a piperidine derivative of formula (II), in which R7 has the meanings mentioned above. The reductive amination can be carried out according to conventional procedures, for example by using NaBH (OAc) 3 or NaBH3CN in a suitable solvent exemplified by dimethylformamide (DMF) or methanol or mixtures of methanol and DMF.

The piperidine derivatives of formula (II), in which R7 has the meanings mentioned above, are known or can be prepared according to known procedures (may contain protective group (s) in certain cases to protect other functionalities such as but not limited to NH functions).

The use of the compounds of formula (II) for the synthesis of the compounds of claims 1-5 is an aspect of the present invention.

Compounds of formula (III), in which R has the meaning -C (O) H, can be obtained from corresponding compounds of formula (III), in which R has the meaning -C (O) O (C1-alkyl) -4), in a procedure of one

or two stages. The ester group is selectively reduced to the aldehyde group by methods known to the skilled person, for example by using DIBALH at low temperature, for example from -80 to -60 ° C in the one-step process. Alternatively, the ester group is reduced to the alcohol group (-CH2OH) according to known procedures, for example by the use of LiAlH4 or NaBH4, and then, the resulting alcohol is selectively oxidized to the group -C (O) H by methods known by the expert, for example with SO3-pyridine complex

or Dess-Martin's periodical, in the two-stage procedure.

Alternatively to the reaction sequence described above, the compounds of formula (I), in which the ring B and the imidazole with which it is condensed, R4 and R7, have the meanings mentioned above and R6 is hydrogen or C1-4 alkyl , can be obtained by reacting a corresponding compound of formula (IIIa), in which X is a suitable leaving group, such as for example a halogen atom or a sulphoester, with piperidine derivatives of formula (II), in which R7 has the meanings mentioned above. The reaction is preferably carried out in an inert solvent, such as for example DMF, at a temperature of from 60 to 100 ° C in the presence of a base, such as for example triethylamine.

Compounds of formula (IIIa), in which X is a suitable leaving group, for example a halogen atom, can be obtained from corresponding compounds of formula (III), in which R is -CH (R6) OH and R6 it's hydrogen

or C1-4 alkyl, by a halogenation reaction. Such a halogenation reaction can be achieved, for example, by the use of PBr3 in dichloromethane.

Alternatively, compounds of formula (IIIa), in which X is a suitable leaving group, for example a halogen atom, can be obtained from corresponding compounds of formula (III), in which R is -CH2R6 and R6 is hydrogen or C1-4 alkyl, by benzyl halogenation. The benzyl halogenation can be achieved, for example, by the use of N-bromosuccinimide (NBS).

Compounds of formula (III), wherein R is -CH (R6) OH and R6 is hydrogen or C1-4 alkyl, can be obtained, for example, from corresponding compounds of formula (III), wherein R is - C (O) R6, by methods known to those skilled in the art, for example by reduction with NaBH4 or LiAlH4.

Alternatively, compounds of formula (III), wherein R is -CH (R6) OH and R6 is hydrogen or C1-4 alkyl, can be obtained from corresponding compounds of formula (III), wherein R is - CH2R6, by benzyl oxidation, which can be achieved, for example, by the use of catalytic or equimolar amounts of SeO2.

In a further alternative, compounds of formula (III), in which R is -CH (C1-4 alkyl) OH can be obtained from corresponding compounds of formula (III), in which R is -C (O) H by the addition of a suitable organic metal reagent, such as, but not limited to Gringnard or lithium reagents.

If necessary for the reactions in reaction scheme 1, for the synthesis of compounds of formula (III), in which ring B and the imidazole with which it is condensed and R4 have the meanings mentioned above and R is -C (O) R6 or -CH (R6) OH, these groups can be protected in some or all of the precursors by suitable protecting groups known to those skilled in the art. Compounds of formula (III) can be deprotected, wherein the ring B and the imidazole with which it is condensed and R4 have the meanings mentioned above and R is a ketone, aldehyde or protected alcohol group, by elimination known in the art of protecting groups to generate the corresponding unprotected compounds.

Compounds of formula (III) can be obtained, in which R has the meanings -C (O) O (C1-4 alkyl), -C (O) R6, -CH (R6) OH or -CH2R6 and R6 is hydrogen or C1-4 alkyl, as shown in reaction scheme 1 by the cyclocondensation of compounds of formula (IV) with compounds of formula (V), wherein R4 has the meanings provided above, R has the meanings -C ( O) O (C1-4 alkyl), -C (O) R6, -CH (R6) OH or -CH2R6 and R6 is hydrogen or C1-4 alkyl and X1 is a suitable leaving group, such as for example a halogen or a sulphonate This reaction can be carried out, for example, in DMF at a temperature of from 80 to 140 ° C.

Reaction scheme 1: In the case where the substituent of ring B and the imidazole with which it is condensed, which was previously described as R1 or R3, is a halogen, preferably CI, Br or I, these halogens can be transformed into other functionalities in this or a later phase of the global synthesis. This transformation can be achieved, for example, by catalyzed or uncatalyzed halogen substitution by certain exemplified reagents but not limited to boronic acids, tin reagents, Gringnard reagents, cyanide salts, alcohols or amines. Certain Cu or Pd complexes are examples of catalysts, which can be used for these transformations.

image 1

As further shown in reaction scheme 1, compounds of formula (V) can be obtained, in which R4 has the meanings provided above, R has the meanings -C (O) O (C1-4 alkyl), -C (O) R6, -CH (R6) OH or -CH2R6 and R6 is hydrogen or C1-4 alkyl and X1 is an appropriate leaving group, such as for example a halogen or a sulfonate, from the corresponding compounds of formula ( VI) by procedures known to the skilled person, for example by alpha-halogenation reaction of ketones for example using CuBr in suitable solvents such as a mixture of chloroform and ethyl acetate. This may also lead to concomitant cleavage of certain protecting groups, which are a part of R, for example acetal protection groups.

Compounds of formula (VI) can be synthesized, in which R4 has the meanings provided above and R has the meanings -C (O) O (C1-4 alkyl), -C (O) R6, -CH (R6) OH or -CH2R6 and R6 is hydrogen or C1-4 alkyl, for example starting from nitriles of formula (VII), wherein R has the meanings -C (O) O (C1-4 alkyl), -C (O) R6, -CH (R6) OH or -CH2R6 and R6 is hydrogen or C1-4 alkyl, by the addition of an organic metal reagent of formula (VIII), in which R4 has the meanings described above.

Alternatively, compounds of formula (VI) can be synthesized, in which R4 has the meanings described above and R has the meanings -C (O) O (C1-4 alkyl), -C (O) R6, -CH (R6) OH or -CH2R6 and R6 is hydrogen or C1-4 alkyl, starting from compounds of formula (Xa), in which R4 has the meanings mentioned above, by adding an organic metal reagent of formula (IX), in the that R has the meanings -C (O) O (C1-4 alkyl), -C (O) R6, -CH (R6) OH or -CH2R6 and R6 is hydrogen or C1-4 alkyl. The organic metal reagent of formula (IX) may be a Grignard or lithium reagent; If necessary, the addition of the organic metal reagent is followed by an oxidation reaction.

The oxidation reaction can be carried out by the use of reagents known to those skilled in the art, for example the Dess-Martin pyridine-SO3 or periodic complex.

The compounds of formulas (VII), (VIII), (IX) and (Xa) are either commercially available or can be prepared from commercially available compounds by methods known to those skilled in the art.

An alternative synthesis route for compounds of formula (III) is described in reaction scheme 2.

Compounds of formula (III) can be obtained, in which the ring B and the imidazole with which it is condensed and R4 have the meanings mentioned above and R is -C (O) O (C1-4 alkyl), -C (O ) R6, -CH (R6) OH or -CH2R6 and R6 is hydrogen or C1-4 alkyl, by reacting a corresponding compound of formula (XI) with compounds of formula (XIII), wherein X3 has the meaning of Cl , Br, I or -OS (O2) CF3. This reaction can be carried out, for example, with palladium acetate, triphenylphosphine and triethylamine in dioxane.

The compounds of formula (XIII) are either commercially available or can be prepared from commercially available compounds by methods known to those skilled in the art.

Alternatively, compounds of formula (III) can be obtained, in which the ring B and the imidazole with which it is condensed and R4 have the meanings mentioned above and R is -C (O) O (C1-4 alkyl), -C (O) R6, -CH (R6) OH or -CH2R6 and R6 is hydrogen or C1-4 alkyl, by the formation of transition metal catalyzed CC bonds of a corresponding compound of formula (XII), wherein X2 is Cl, Br or I, with a corresponding compound of formula (XIV), wherein R4-A is R4-B (OH) 2, R4-B (O-C1-4 alkyl) 2,

image 1

R4ZnCl, R4ZnBr, R4Znl or (C1-4 alkyl) 3SnR4

and R4 has the meaning mentioned above. This reaction can be carried out, for example, by the use of palladium tetrakis triphenylphosphine in suitable solvent exemplified by dioxane or mixtures of ethanol in water at a temperature of from 60 to 100 ° C.

The compounds of formula (XIV) are either commercially available or can be prepared from commercially available compounds by methods known to those skilled in the art.

Compounds of formula (XII) can be obtained, in which the ring B and the imidazole with which it is condensed have the aforementioned meaning and R is -C (O) O (C1-4 alkyl), -C (O) R6 , -CH (R6) OH or -CH2R6 and R6 is hydrogen or C1-4 alkyl and X2 is Cl, Br or I, by a halogenation reaction of a corresponding compound of formula (XI) with, for example, N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS).

Compounds of formula (XI) can be obtained, in which the ring B and the imidazole with which it is condensed and R is -C (O) O (C1-4 alkyl), -C (O) R6, -CH (R6 ) OH or -CH2R6 and R6 is hydrogen or C1-4 alkyl, by cyclocondensation of corresponding compounds of formula (IV) with a corresponding compound of formula (XV), wherein X4 has the meaning of a halogen or tosylate. This reaction can be carried out, for example, in DMF at a temperature of from 80 to 140 ° C.

Compounds of formula (XV) may be prepared, wherein R is -C (O) O (C1-4 alkyl), -C (O) R6, -CH (R6) OH or -CH2R6 and R6 is hydrogen or C1 alkyl -4 and X4 is mesylate or tosylate, with a corresponding compound of formula

(XVII) by treatment with appropriate reagents such as, but not limited to, sulfonyl chlorides.

Compounds of the formula (XV) may be prepared, wherein R is -C (O) O (C1-4 alkyl), -C (O) R6, -CH (R6) OH or -CH2R6 and R6 is hydrogen or alkyl C1-4 and X4 is halogen, by a halogenation reaction of a corresponding compound of formula (XVI) with, for example, Br2 or NBS in case the halogen is Br.

The compounds of formulas (XVI) or (XVII) are either commercially available or can be prepared from commercially available compounds by methods known to those skilled in the art.

Compounds of formula (III) can be transformed in reaction scheme 2, in which ring B and the imidazole with which it is condensed and R4 have the meaning mentioned above and R is -C (O) O (C1-4 alkyl ), -C (O) R6, -CH (R6) OH or -CH2R6 and R6 is hydrogen or C1-4 alkyl, in compounds of formula (I) or in compounds of formula (IIIa) and then in compounds of formula ( I), as described above in the reaction scheme

one.

If necessary for the reactions in reaction scheme 2, for the synthesis of compounds of formula (III), in which the ring B and the imidazole with which it is condensed have the meaning mentioned above and R is -C (O ) R6 or -CH (R6) OH and R6 is hydrogen or C1-4 alkyl, these groups can be protected in some or all of the precursors by means of suitable protecting groups known to those skilled in the art. Compounds of formula (III), wherein R is a ketone, aldehyde or protected alcohol group, can be deprotected by elimination known in the art from the protecting groups to generate the corresponding unprotected compounds.

Reaction Scheme 2

image 1

A preferred aspect of the invention is the process for the preparation of the compounds of the claims 1-5 according to the examples.

Optionally, compounds of formula (I) can be converted into their salts, or, optionally, salts of compounds of formula (I) can be converted into free compounds. The corresponding procedures are common for the expert.

The person skilled in the art knows that, if there are several reactive centers in a starting or intermediate compound, it may be necessary to block one or more reactive centers temporarily by protecting groups in order to allow the reaction to proceed specifically in the reaction center. wanted. A detailed description is found for the use of a large number of tested protecting groups, for example, in T. W. Greene, Protective

20 Groups in Organic Synthesis, John Wiley & Sons, 1999, 3rd Ed., Or in P. Kocienski, Protecting Groups, Thieme Medical Publishers, 2000.

The compounds according to the invention are isolated and purified in a manner known per se, for example by removal by distillation of the solvent in vacuo and recrystallization of the residue obtained in an appropriate solvent or by subjecting it to one of the usual purification methods, such as chromatography. in column in an appropriate support material.

The salts of the compounds of formula (I) according to the invention can be obtained by dissolving the free compound in an appropriate solvent (for example a ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) containing the desired acid or base, or to which the desired acid or base is then added. The acid or base can be used in the preparation of salts, depending on whether it refers to a mono or polybasic acid or base and depending on which salt is desired, in an equimolar quantitative ratio or one that differs from it. The salts are obtained by filtering, re-precipitating, precipitating with a non-solvent for the salt or evaporating the solvent. The salts obtained can be converted into free compounds which, in turn, can be converted into salts. In this way, they can

converting pharmaceutically unacceptable salts, which can be obtained, for example, as process products in manufacturing on an industrial scale, into pharmaceutically acceptable salts by methods known to those skilled in the art.

Pure diastereomers and pure enantiomers of the compounds and salts according to the invention can be obtained for example by asymmetric synthesis, using chiral starting compounds in synthesis and by separating enantiomeric and diasteriomeric mixtures obtained in synthesis.

Enantiomeric and diastereomeric mixtures can be separated into pure enantiomers and pure diastereomers by methods known to one skilled in the art. Preferably, the diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. The enantiomeric mixtures can be separated, for example, by forming diastereomers with a chiral auxiliary agent, resolving the obtained diastereomers and eliminating the chiral auxiliary agent. As chiral auxiliary agents, for example, chiral acids can be used to separate enantiomeric bases such as, for example, mandelic acid and chiral bases can be used to separate enantiomeric acids through the formation of diastereomeric salts. In addition, diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids or chiral alcohols, respectively, as chiral auxiliary agents. Additionally, diastereomeric complexes or diastereomeric clathrates can be used to separate enantiomeric mixtures. Alternatively, enantiomeric mixtures can be separated using chiral separator columns in chromatography. Another suitable method for the isolation of enantiomers is enzymatic separation.

As those skilled in the art will appreciate, the invention is not limited to the particular embodiments described herein, but covers all modifications of said embodiments that are within the scope of the invention as defined by the appended claims.

The following examples illustrate the invention in greater detail. Additional compounds according to the invention, of which the preparation is not explicitly described, can be prepared in an analogous manner.

The compounds, which are mentioned in the examples and the salts thereof, represent preferred embodiments of the invention as well as a claim that covers all sub-combinations of the residues of the compound of formula (I) as disclosed by the examples. specific.

The term "according" within the experimental section is used in the sense that the procedure to which it refers is to be used "analogously to".

Examples

The following abbreviations are used in the examples: p.f. means melting point, h hour (s), min. minutes, conc. concentrated, calc. calculated, enc. found, FE elementary formula, EM mass spectrometry, molecular ion in mass spectrometry, CCF: thin layer chromatography, HPLC high resolution liquid chromatography, 1H-NMR 1H nuclear magnetic resonance spectroscopy (chemical shifts are reported as ppm versus tetramethylsilane as internal standard, coupling constants J are reported in Hz), w / w weight by weight, TA room temperature (20-25 ° C), DCM dichloromethane, THF tetrahydrofuran, DMSO dimethylsulfoxide, DBU 1.8- diazabicyclo [5.4.0] undec-7-ene, EtOAc ethyl acetate, DIBAL diisobutylaluminum hydride, DCM dichloromethane, ACN acetonitrile and other abbreviations have their usual meanings per se for the person skilled in the art.

Intermediate A: 2- [3- (piperidin-4-yl) -1H-1,2,4-triazol-5-yl] pyridine dihydrochloride (procedure described in US4011218 or W02005100344)

Stage-I: pyridin-2-carbohydrazonamide

A solution of pyridin-2-carbonitrile, 20 g, (192 mM), hydrazine hydrate (3 eq.) In ethanol (50 ml) is stirred at room temperature for 18 h. The reaction mass is then diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo to provide the desired compound.

MS (M + 1): 137.28

1H NMR (300MHZ, CDCl3): 

8.53 (d, 1H, J = 8 & 2.3 Hz), 8.02 (d, 1H, J = 7.8 & 2.1 Hz), 7.72 (t, 1H, J = 8, 2 & 2Hz), 7.29 (t, 1 H, J = 8.4 & 2.1 Hz), 5.42 (sa, 2H), 4.60 (sa, 2H).

Step-II: 4-({(2Z) -2- [amino (pyridin-2-yl) methylidene] hydrazinyl} carbonyl) piperidine-1-carboxylic acid tert-butyl ester

To a solution of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid, 37 g, (167 mM) in dichloromethane (300 ml) is added carbonyldiimidazole (1 eq.) In a small part over a period 30 min Then pyridine-2-carbohydrazonamide is added to the reaction mixture and stirred at room temperature for 3 h. The dichloromethane is evaporated and the reaction mass is then stirred in water for 30 min. The solid precipitate is filtered and dried to provide the desired compound.

MS (M + 1): 348.07

1H NMR (300MHZ, CDCl3): 10.75 (s, 1H), 8.56 (d, 1 H, J = 4.5Hz), 8.10 (d, 1 H, J = 8.3Hz), 7.75 (dt, 1H, J = 8.2 & 1.3Hz), 7.34 (dt, 1H, J = 7.9 & 1.5Hz), 4.18 (sa, 2H), 3.46 (s, 1H), 2.88 (t, 2H), 1.91 (m, 2H), 1.72 (m, 4H), 1.47 (s, 9H).

Stage-III: tert-butyl 4- [5- (pyridin-2-yl) -1 H-1,2,4-triazol-3-yl] piperidin-1-carboxylate

The tert-butyl 4 - ({(2Z) -2- [amino (pyridin-2-yl) methylidene] hydrazinyl} carbonyl) piperidine-1-carboxylate, 45 g, (129 mM) obtained in step II is melted at 220 ° C under nitrogen atmosphere for 1 h. The reaction is then cooled to 150 ° C and ethanol is added until the solid dissolves. The ethanol is then evaporated to obtain the desired compound.

MS (M + 1): 330.5

1H NMR (300MHZ, DMSO): 

9.11 (s, 1 H), 8.74 (dd, 1 H, J = 4.8 & 1.3 Hz), 8.17 (dt, 2H, J = 8.2 & 2.1 Hz) , 7.66 (dt, 1H, J = 8.0 & 1.3 Hz), 3.34 (m, 2H), 3.18 (m, 1 H), 3.06 (m, 2H), 2 , 20 (m, 2H), 1.99 (m, 2H), 1.28 (s, 9H).

Stage-IV: 2- [3- (piperidin-4-yl) -1H-1,2,4-triazol-5-yl] pyridine dihydrochloride

To a solution of tert-butyl 4- [5- (pyridin-2-yl) -1 H-1,2,4-triazol-3-yl] piperidin-1-carboxylate, 39 g, (111 mM) in methanol 50 ml of HCl solution in dioxane are added and stirred at room temperature for 3 h. The precipitate is then filtered and washed with cold acetonitrile to obtain 2- [3- (piperidin-4-yl) -1H-1,2,4-triazol-5-yl] pyridine dihydrochloride as a white solid.

1 H NMR (300 MHz, DMSO): ,19.11 (s, 1 H), 8.97 (s, 1 H), 8.74 (dd, 1 H, J = 4.8 & 1.3 Hz) , 8.17 (dt, 2H, J = 8.2 & 2.1 Hz), 7.66 (dt, 1H, J = 8.0 & 1.3 Hz), 3.34 (m, 2H), 3.18 (m, 1 H), 3.06 (m, 2H), 2.20 (m, 2H), 1.99 (m, 2H)

Intermediate B: 4- [3- (piperidin-4-yl) -1H-1,2,4-triazol-5-yl] pyridine

Prepared according to intermediate product A.

Intermediate product C: 2-methyl-6- [3- (piperidin-4-yl) -1H-1,2,4-triazol-5-yl] pyridine

Prepared according to intermediate product A.

Intermediate product D: 5-methyl-2- [3- (piperidin-4-yl) -1H-1,2,4-triazol-5-yl] pyridine

Prepared according to intermediate product A.

Intermediate product E: 5-chloro-2- [3- (piperidin-4-yl) -1H-1,2,4-triazol-5-yl] pyridine

Prepared according to intermediate product A.

Intermediate product F: 2- [3- (piperidin-4-yl) -1H-1,2,4-triazol-5-yl] pyrimidine

Prepared according to intermediate product A.

Intermediate G: 4- [5- (1,3-thiazol-2-yl) -1H-1,2,4-triazol-3-yl] piperidine

Prepared according to intermediate product A.

Intermediate product H: 4- [5- (furan-2-yl) -1H-1,2,4-triazol-3-yl] piperidine

Prepared according to intermediate product A.

Intermediate product I: 4- [5- (thiophen-2-yl) -1H-1,2,4-triazol-3-yl] piperidine

Prepared according to intermediate product A.

Intermediate J: 4- [5- (1H-Pyrrol-2-yl) -1H-1,2,4-triazol-3-yl] piperidine Stage-I: 1H-pyrrole-2-carbohydrazonamide

A solution of 1H-pyrrole-2-carbonitrile, 10 g, (108 mM) and sodium methoxide (1 eq.) In ethanol (20 ml) is stirred for 10 min. Hydrazine hydrate (3 eq.) Is then added and the resulting reaction mixture is stirred at room temperature for 18 h. The reaction mass is then diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo to provide the desired compound.

Stages II, III, IV are similar to intermediate A.

Intermediate product K: 2- [3- (piperidin-4-yl) -1H-pyrazol-5-yl] pyridine

Prepared according to intermediate product A.

Intermediate product L: 2- [3- (piperidin-4-yl) -1,2,4-oxadiazol-5-yl] pyridine

Intermediate L is prepared according to intermediate A.

Intermediate M: 4- (5-phenyl-1H-1,2,4-triazol-3-yl) piperidine

Intermediate M is prepared according to intermediate J.

Example 1: 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1 , 2-a] pyrimidine

Stage 1: 1- [4- (dimethoxymethyl) phenyl] -2-phenylethanol

A mixture of 2.4 g of Mg shavings (0.1 mol) and 2 ml of 1-bromo-4- (dimethoxymethyl) benzene (0.012 mol) in THF (10 ml) is heated under nitrogen atmosphere until it begins the reaction. Subsequently, 14.71 ml of additional 1-bromo-4- (dimethoxymethyl) benzene (0.088 mol) dissolved in 30 ml of THF are slowly added and the reaction is refluxed for 1 h to complete the formation of the Gringnard reagent. A solution of 11.70 ml of phenylacetaldehyde (0.1 mol) in 100 ml of THF is added at 0 ° C and the reaction is refluxed for 2 h until the addition is complete. The mixture is subjected to final treatment by pouring it into saturated aqueous NH4Cl and extracting with ethyl acetate. The combined organic phases are washed with brine, dried over MgSO4 and the solvent is evaporated under reduced pressure. The blackish brown oily product is used for the next stage without purification.

Stage 2: 1- [4- (dimethoxymethyl) phenyl] -2-phenylethanone

29.16 g of the sulfur trioxide-pyridine complex (0.183 mol) are added in portions to a solution of 33 g of 1- [4- (dimethoxymethyl) phenyl] -2-phenylethanol in dichloromethane (540 ml), DMSO ( 140 ml) and triethylamine (25.5 ml) at 10 ° C. The mixture is slowly heated to room temperature and stirred for 2 h. Water is added and the organic phase is separated, washed with 1 mol / l HCl, 3 times with a 5% w / w sodium thiosulfate solution and saturated NaCl. The combined organic phases are dried over sodium sulfate and the solvents are evaporated. The residue is purified by chromatography on a silica gel column chromatography (n-hexane / EtOAc). MS (M + 1): 271

1 H NMR signals (300 MHz, dDMSO) characteristics: 8.1 ppm (d, 2 H); 7.6 ppm (d, 2H); 5.4 ppm (s, 1H), 4.3 (s, 2H)

Stage 3: 4- [bromine (phenyl) acetyl] benzaldehyde

A solution of 3.0 g of 1- [4- (dimethoxymethyl) phenyl] -2-phenylethanone (0.011 mol) in 60 ml of ethyl acetate and 60 ml of chloroform is heated to reflux. 4.96 g of powdered cupric bromide (0.022 mol) are added over a period of 2 h in small portions under nitrogen atmosphere. Reflux is continued for 1 h until the green color and dark cupric bromide disappear, then the reaction mixture is cooled to room temperature and filtered through celite. The solvents are evaporated and the residue is purified on silica gel (nhexane / EtOAc).

MS (M + -Br): 223

1 H NMR signals (300 MHz, dDMSO) characteristics: 10.0 ppm (s, 1 H); 8.3 ppm (d, 2H); 8.0 ppm (d, 2H); 7.2 ppm (s, 1 H)

Stage 4: 4- (3-phenylimidazo [1,2-a] pyrimidin-2-yl) benzaldehyde

4.6 g of 4- [bromine (phenyl) acetyl] benzaldehyde and 1.64 g of pyrimidin-2-amine in 140 ml of DMF are stirred at 90 ° C for 4 h. The DMF is evaporated and the residue is suspended in ethyl acetate overnight, collected by filtration.

MS (M + 1): 300 1H NMR signals (400MHz, dDMSO) characteristics: 10 ppm (s, 1H), 7.0 ppm (1H)

Step 5: 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyrimidine

0.14 ml of triethylamine are added to a solution of 156 mg of 4- (3-phenylimidazo [1,2-a] pyrimidin-2-yl) benzaldehyde in 10 ml of methanol. To this solution is added a solution of 140 mg of 2- (5-piperidin-1,2,4] triazol-3-yl) pyridine * 2HCl (intermediate product A prepared from 4- (hydrazinocarbonyl) piperidin-1 tert-butyl and pyridine-2-carbonitrile carboxylate according to a procedure described in US4011218 or WO2005100344), followed by 0.07 ml of glacial acetic acid and 198 mg of NaBH (OAc) 3. The resulting mixture is stirred at room temperature. Three additional 198 mg portions of NaBH (OAc) 3 are added after 2, 4 and 20 hours. The solvents are removed by evaporation after 24 h and the residue is purified by chromatography on silica gel (dichloromethane / methanol).

MS (M + 1): 513

1 H NMR signals (400 MHz, dDMSO) characteristics: 8.6 ppm (1 H); 7 ppm (1H); 3.5 ppm (s, 2H)

Example 2: 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridine

Example 2 is prepared in a manner according to example 1 using pyridin-2-amine in step 4. MS (M + 1): 512 1 H NMR signals (400 MHz, dDMSO) characteristics: 8.7 ppm (1 H); 6.9 ppm (1H); 3.5 ppm (s, 2H)

Example 3: 7-phenyl-6- (4 - {[4- (5-pyridin-2-yl-1H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-b] [1,2,4] triazine

Example 3 is prepared in a manner according to example 1 using 1,2,4-triazin-3-amine in step 4. MS (M + 1): 514 1 H NMR signals (400 MHz, dDMSO) characteristics: 8.0 ppm (1 H); 7.9 ppm (1H); 3.5 ppm (s, 2H)

Example 4: 3-phenyl-2- (4 - {[4- (3-pyrazin-2-yl-1,2,4-oxadiazol-5-yl) piperidin-1-yl] methyl} phenyl) imidazo [1 , 2-a] pyrimidine

This example is prepared in a manner similar to 1 using 2- (5-piperidin-4-yl-1,2,4-oxadiazol-3-yl) pyrazine commercially available in the last stage. Analytical data MS (M + 1): 515 1H NMR signals (400Hz, dDMSO) characteristics: 9.2 ppm (s, 1H); 7.1 ppm (dd, 1 H); 3.5 ppm (s, 2H).

Example 5: 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1 , 2-a] pyridin-8-carbonitrile

This example is prepared in a manner according to Example 12 using 2-aminonicotinonitrile in the first stage. MS (M + 1): 537.23 1H NMR (CD3OD): 

8.675 (dd, J = 7.2 Hz, 1.2 Hz, 1H), 8.073 (d, J = 7.8 Hz, 1H), 7.945-7.87 (m, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.60-7.56 (m, 2H), 7.49-7.46 (m, 3H), 7.444-7.419 (m, 3H), 7.345 (d, J = 8.4 Hz, 2 H), 7.010 (t, 1H), 3.75 (s, 2H), 3.16-3.12 (m, 2H), 3.01-2.91 (m, 1H ), 2.48-2.41 (m, 2H), 2.15-1.96 (m, 3H).

Example 6: 6-Bromo-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyridine

Stage 1: 4- (6-Bromo-3-phenylimidazo [1,2-a] pyridin-2-yl) benzaldehyde

3.3 mmol of (2-bromo-2-phenyl-ethanoyl) -benzaldehyde and 1.2 equivalents of 5-bromo-pyridin-2-ylamine are dissolved in 10 ml of DMF. The reaction mixture is heated at 100 ° C for 18 hours. The reaction mixture is cooled and water is added. Then it is extracted with ethyl acetate. The organic phase is dried and concentrated. The crude product is purified by column chromatography to provide the desired compound.

MS (M + 1): 377.27, 379.27.

1H NMR (CDCl3): δ

9,950 (s, 1H), 8.1 (dd, J = 1.8Hz, 0.9Hz, 1H), 7.86-7.76 (m, 4H), 7.72 (dd, J = 9.3Hz , 0.6Hz, 1H), 7.6-7.54 (m, 5H), 7.5 (dd, J = 9.3Hz, 1.8Hz, 1H).

Stage 2: [4- (6-Bromo-3-phenylimidazo [1,2-a] pyridin-2-yl) phenyl] methanol

To the stirred solution of 4- (6-bromo-3-phenylimidazo [1,2-a] pyridin-2-yl) benzaldehyde (0.795 mM) in 15 ml of methanol is added NaBH4 (1.5 eq) at 0 ° C and the reaction is allowed to stir at room temperature for 1 h. The reaction is concentrated and quenched with water. The precipitated solid is filtered and dried to provide the desired product.

MS (M + 1): 379.27, 381.27.

1 H NMR (DMSO-d6): δ =

8.1 (dd, J = 1.8Hz, 0.6Hz, 1H). 7.7-7.525 (m, 8H), 7.5 (dd, J 8.4Hz, 1.8Hz, 1H), 7.2 (d, J = 8.4Hz, 2H), 5.4 (sa, 1H), 4.5 (s, 2H).

Stage 3: 6-Bromo-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyridine

To the stirred solution of 0.52 mM of [4- (6-bromo-3-phenylimidazo [1,2-a] pyridin-2-yl) phenyl] methanol in 15 ml of dichloromethane is added methanesulfonyl chloride (1 , 1 eq.) At 0 ° C followed by triethylamine (1.5 eq). The reaction mixture is allowed to stir at room temperature for 3 h. The reaction is quenched with water and extracted with DCM. The organic phase is dried and concentrated. Then it is taken in the next reaction without further purification. The crude product is dissolved in 5 ml of DMF. To this solution of 2- (5-piperidin- [1,2,4] triazol-3-yl) -pyridine * 2HCl (1 eq.), Triethylamine (4 eq) is added. The reaction mixture is heated at 80 ° C for 3 h. The reaction mixture is quenched with water and extracted with ethyl acetate. The organic phase is dried and concentrated. The crude product obtained is crushed with pentane to obtain the desired compound.

MS (M + 1): 590.13, 592.07.

1 H NMR (DMSO-d6): δ

14.2-14.0 (sa, 1H), 8.7 (d, J = 4.2Hz 1H), 8.1-7.9 (m, 3H), 7.7-7.5 (m, 8H), 7.4 (dd, J = 9.3Hz, 1.8Hz, 2H), 7.2 (d, J = 8.4Hz, 2H), 3.5 (s, 2H), 2.8 ( d, 2H) 2.8-2.7 (m, 1H), 2.1 (t, 2H), 2.0 (t, 2H), 1.8 (t, 2H).

Example 7: 6-Chloro-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl } phenyl) imidazo [1,2, a] pyridine

This compound is prepared according to example 6 using 5-chloropyridin-2-amine in step 1.

MS (M + 1): 546.20, 548.20.

1H NMR (CDCl3): δ

8.7 (s, 1 H). 8.2 (d, J = 7.5Hz, 1H), 8.0 (d, J = 1.2Hz, 1H), 7.8 (t, J = 7.5Hz, 1H), 7.6-7 , 5 (m, 6H), 7.5 (dd, J = 7.8Hz, 2.1Hz, 2H), 7.2 (d, J = 8.1Hz, 2H), 7.3 (s, 1H) , 7.2 (dd, J = 9.3Hz, 1.8Hz, 1H), 3.5 (s, 2H), 3.0-2.8 (m, 3H), 2.1-1.9 ( m, 6H)

Example 8: 8-methyl-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyridine

This compound is prepared according to example 6 using 3-methylpyridin-2-amine in step 1.

MS (M + 1): 526.27.

1H NMR (CDCl3): δ

8.7 (d, J = 3.3Hz, 1H), 8.2 (d, J = 7.8Hz, 1H), 7.9-7.7 (m, 2H), 2.2-1.9 (m, 7H), 7.6 (d, J = 8.1Hz, 1H), 7.5-7.5 (m, 5H), 7.3 (t, J = 5.7Hz, 1H), 7 , 2 (d, J = 8.1Hz, 3H), 7.0 (d, J = 6.9Hz, 1H), 6.7 (t, J = 6.9Hz, 1H), 3.5 (s, 2H), 3.0-2.8 (m, 2H), 2.7 (s, 3H)

Example 9: 3- (4-fluorophenyl) -2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2a] pyridine

Stage 1: 4- [3- (4-fluorophenyl) imidazo [1,2-a] pyridin-2-yl] benzaldehyde

0.46 g of 4- (3-bromoimidazo [1,2-a] pyridin-2-yl) benzaldehyde (1.5 mM) (prepared as described by Sundberg et al .; J. Heterociclic Chem. , 25, 129, 1988) in 5 ml of toluene. To this mixture is added 4fluorophenylboronic acid (1.5 eq) followed by 10% by weight tetrakis-triphenylphosphine-palladium (0), K2CO3 (3 eq) and ethanol-water mixture (4 ml). The reaction mixture is heated at 90 ° C for 4-6 h. The reaction is cooled to room temperature and 20 ml of water are added and the reaction mixture is extracted with ethyl acetate. The organic phase is dried and concentrated. The crude product is purified by flash column chromatography to obtain the desired compound.

MS (M + 1): 317.33.

1H NMR (DMSO-d6): δ = = 6.6Hz, 2H), 7.8 (d, J = 8.4Hz, 2H), 7.45 (d, J =

9.9 (s, 1H), 8.0 (d, J 6.9Hz, 1H), 7.85 (d, J9.3Hz, 1H), 7.6 (m, 2H), 7.45 (m , 2H), 7.35 (m, 1H), 6.9 (dt, J = 6.9Hz, 1.2Hz, 1H).

Stage 2: 3- (4-fluorophenyl) -2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyridine

To a solution of 0.1 g of 4- [3- (4-fluorophenyl) imidazo [1,2-a] pyridin-2-yl] benzaldehyde (0.31 mM) in 5 ml of THF is added triethylamine ( 2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 2- (5piperidin- [1,2,4] triazol-3-yl) -pyridine * 2HCl (1.5 eq) followed by acetic acid (2.5 eq.). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq) over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 530.27.

1 H NMR (CD3OD): δ

8.7 (d, 1H), 8.1 (m, 2H), 7.9 (dt, J = 1.8Hz, 7.8Hz, 1H), 7.6-7.7 (m, 3H), 7.2-7.5 (m, 8H), 6.9 (dt, J = 6.9Hz, 1.2Hz, 1H), 3.9 (s, 2H), 3.0 (m, 1H), 2.7 (t, 2H), 2.1 (m, 4H), 2.0 (m, 2H).

Example 10: 5-phenyl-6- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2 , 1-b] [1,3] thiazole

Stage 1: 4- (methyl phenylacetyl) benzoate:

33 g of methyl 4- (1-hydroxy-2-phenylethyl) benzoate are dissolved (prepared as described by Berk et al .; J. Org. Chem. 1988, 53, 5791) in 200 ml of dichloromethane. The solution is cooled to 0-10 ° C. To this is added DMSO (10 eq) and triethylamine (1.5 eq) followed by the addition of 1.5 eq. of pyridine-sulfur trioxide complex. The reaction is stirred overnight at RT, 200 ml of Water. Then ethyl acetate is added and the organic phase is separated, dried and concentrated to obtain the gross compound It is purified by column chromatography to obtain the desired compound.

1H NMR (DMSO-d6) δ8.15 (d, J = 8.4Hz, 2H), 8.06 (d, J = 8.4Hz, 2H), 7.40-7.19 (m, 5H ), 4.44 (s, 2H), 3.87 (s, 3H).

Stage 2: 4- [methyl bromine (phenyl) acetyl] benzoate:

Methyl 4- (phenylacetyl) benzoate (3.8 g, 14.9 mM) is dissolved in 300 ml of a mixture of ethyl acetate / chloroform. The reaction mixture is refluxed and cupric bromide (2 eq.) Is added in portions over a period of 2 h while constantly purging with nitrogen. The reaction mixture is refluxed for 4 h. The reaction mixture is cooled, filtered and evaporated. The crude product is purified by column chromatography.

1H NMR (DMSO-d6) δ8.18 (d, J = 8.1Hz, 2H), 8.05 (d, J = 7.5Hz, 2H), 7.6-7.3 (m, 5H ), 7.21 (s, 1H), 3.87 (s, 3H).

Stage 3: methyl 4- (5-phenylimidazo [2,1-b] [1,3] thiazol-6-yl) benzoate

0.7 g (2.1 mM) of methyl 4- [bromine (phenyl) acetyl] benzoate and 2-aminothiazole (2.5 eq.) In 20 ml of DMF are stirred at 90 ° C for 6 h. The DMF is evaporated and the crude product is purified by column chromatography.

MS (M + 1): 335.27.

1 H NMR (DMSO-d6): δ

7.9 (d, J = 8.4Hz, 2H), 7.7 (d, J = 4.5Hz, 1 H), 7.6 (d, J = 8.7Hz, 2H), 7.4- 7.6 (m, 5H), 7.3 (d, J = 4.5Hz, 1H), 3.8 (s, 3H).

Stage 4: [4- (5-phenylimidazo [2,1-b] [1,3] thiazol-6-yl) phenyl] methanol:

0.12 g (0.36 mM) of methyl 4- (5-phenylimidazo [2,1-b] [1,3] thiazol-6-yl) benzoate are dissolved in 8 ml of dry THF. To this is added lithium aluminum hydride (5 eq.) At 0 ° C. The reaction mixture is brought to RT and stirred for 2 h. Then it is extinguished with a sat solution. of sodium sulfate and filtered. The filtrate is evaporated and extracted in ethyl acetate. The organic phase is dried and concentrated to obtain the desired compound.

MS (M + 1): 307.27.

1 H NMR (DMSO-d6) δ

7.7 (d, J = 4.5Hz, 1H), 7.5-7.4 (m, 7H), 7.3 (d, J = 4.5Hz, 1H), 7.2 (d, J = 8.1Hz, 2H), 5.2 (t, J = 5.7Hz, 1H), 4.5 (d, J = 5.7Hz, 2H).

Stage 5: 5-phenyl-6- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2 , 1-b] [1,3] thiazole

At the stirred solution of 0.12 g (0.39 mM) of [4- (5-phenylimidazo [2,1-b] [1,3] thiazol-6-yl) phenyl] methanol in 5 ml of dichloromethane is Add methanesulfonyl chloride (1.5 eq.) at 0 ° C followed by triethylamine (2.5 eq). The reaction mixture is allowed to stir at room temperature for 3 h. The reaction is quenched with water and extracted with DCM. The organic phase is dried and concentrated. Then it is taken in the next reaction without further purification. The crude product is dissolved in 4 ml of DMF. To this is added 2- (5-piperidin- [1,2,4] triazol-3-yl) -pyridine * 2HCl (1.2 eq.), NaHCO3 (4 eq.). The reaction mixture is stirred at RT for 12 h and then heated at 80 ° C for 3 h. The reaction mixture is quenched with water and extracted with ethyl acetate. The organic phase is dried and concentrated. The crude product obtained in its HCl salt is converted by the addition of ethereal HCl. The solid obtained is washed with acetone / methanol to obtain the desired compound.

MS (M + 1): 518.2.

1 H NMR (D2O): δ

8.7 (d, J = 5.7Hz, 1H), 8.5 (t, J = 8.1Hz, 1H), 8.4 (d, J = 7.8Hz, 1H), 8.0-7 , 9 (m, 1H), 7.8 (d, J = 4.5Hz, 1H), 4.3 (s, 2H), 3.6 (da, J = 12Hz, 2H), 7.6-7 , 40 (m, 10H), 3.4-3.2 (m, 1H), 3.2-3.1 (m, 2H), 2.1-1.9 (m, 2H), 2.3 (da, J = 12.6, 2H).

Example 11: 5-phenyl-6 (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2, 1-b] [1,3,4] thiadiazole

Stage 1: methyl 4- (5-phenylimidazo [2,1-b] [1,3,4] thiadiazol-6-yl) benzoate

0.7 g (2.1 mM) of methyl 4- [bromine (phenyl) acetyl] benzoate (prepared as described in example 10) and 2-aminothiadiazole (2 eq.) In 15 ml of DMF are stirred. at 90 ° C for 6 h. The DMF is evaporated and the residue is suspended in ethyl acetate overnight. The desired product is collected by filtration.

MS (M + 1): 336.20.

1H NMR (DMSO-d6): δ9.2 (s, 1H), 7.91 (d, 2H, J = 7.2Hz), 7.7 (d, 2H, J = 6.9 Hz), 7.5-7.4 (m, 5H), 3.8 (s, 3H).

Stage 2: [4- (5-phenylimidazo [2,1-b] [1,3,4] thiadiazol-6-yl) phenyl] methanol:

Methyl 4- (5-phenylimidazo [2,1-b] [1,3,4] thiadiazol-6-yl) benzoate (0.25 g, 0.77 mM) is dissolved in 25 ml of DCM. To this DIBAL (5 eq) is added to TA. The reaction mixture is stirred for 20 min. The reaction mixture is diluted with DCM and the organic phase is washed with water. The organic phase is dried and concentrated to obtain the desired compound as a white solid.

MS (M + 1): 308.20.

1HRMN (CD3OD): δ

9.02 (s, 1H), 7.58-7.50 (m, 4H), 7.43-7.38 (m, 3H), 7.32 (d, 2H, J = 9Hz), 4, 6 (s, 2H).

Stage 3: 5-phenyl-6- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2 , 1-b] [1,3,4] thiadiazole:

At the stirred solution of 0.21 g (0.684 mM) of [4- (5-phenylimidazo [2,1-b] [1,3,4] thiadiazol-6-yl) phenyl] methanol in 15 ml of dichloromethane is Add methanesulfonyl chloride (1.5 eq.) at 0 ° C followed by triethylamine (2.0 eq). The reaction mixture is allowed to stir at room temperature for 3 h. The reaction is concentrated. Then it is taken in the next reaction without further purification.

The crude product is dissolved in 10 ml of DMF. To this are added 2- (5-piperidin- [1,2,4] triazol-3-yl) -pyridine * 2HCl (2.5 eq), triethylamine (3 eq). The reaction mixture is heated at 80 ° C for 8 h. The reaction mixture is quenched with water and extracted with ethyl acetate. The organic phase is dried and concentrated. The crude product is purified by cc to obtain the desired compound.

MS (M + 1): 519.27.

1HNMR (CDCl3): δ

8.67 (d, 1H, J = 4.2Hz), 8.5 (s, 1H), 8.1 (d, 1H, J = 7.8Hz), 7.8 (dt, 1H, J = 7 , 8, 8.1Hz), 7.66-7.62 (m, 4H), 7.4-7.2 (m, 6H), 3.59 (s, 2H), 3.0 (d, 2H ), 2.9 (t, 1H), 2.1-1.9 (m, 6H).

Example 12: 6-Bromo-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) i midazo [1,2-a] pyrimidine

Stage 1: 4- (6-Bromo-3-phenylimidazo [1,2-a] pyrimidin-2-yl) benzaldehyde

0.15 g (0.5 mM) of 4- [bromine (phenyl) acetyl] benzaldehyde and 2.0 equivalents of 5-bromopyrimidin-2-amine are dissolved in 6 ml of DMF. The reaction mixture is heated at 90 ° C overnight. The reaction mixture is cooled and water is added. Then it is extracted with ethyl acetate. The organic phase is dried and concentrated. The crude product is purified by column chromatography to obtain the desired compound.

MS (M + 1): 378.27, 380.27.

1 H NMR (DMSO-d6): δ

10.0 (s, 1H), 8.7 (d, 1H, J = 2.4Hz), 8.6 (d, 1H, J = 2.4Hz), 7.9 (d, 2H, J = 8 , 7Hz), 7.8 (d, 2H, J = 8.4Hz), 7.5-7.6 (m, 5H).

Stage 2: 6-Bromo-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2a] pyrimidine

To a solution of 0.044 g (0.116 mM) of 4- (6-bromo-3-phenylimidazo [1,2-a] pyrimidin-2-yl) benzaldehyde in 3 ml of THF is added triethylamine (2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 2- (5-piperidin- [1,2,4] triazol-3-yl) -pyridine * 2HCl (1.5 eq.) Followed by acetic acid (2.5 eq.). The reaction mixture is stirred for 10 minutes, NaBH (OAc) 3 (6 eq) is added over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 591.27, 593.13.

1H NMR (CDCl3): δ

8.63 (d, 1H, J = 4.8Hz), 8.61 (d, 1H, J = 2.4Hz), 8.57 (d, 1H, J = 2.4Hz), 8.1 (d , 1H, J = 7.8Hz), 7.9 (t, 1H, J = 7.5Hz, 1.9 Hz), 7.59-7.61 (m, 5H), 7.49-7.52 (m, 2H), 7.4 (t, 1H), 7.3 (d, 2H, J = 8.4Hz), 3.7 (s, 2H), 3.1 (d, 2H), 2, 9 (t, 1H), 2.4 (t, 2H), 2.1 (d, 2H), 2.0 (t, 2H).

Example 13: 8-methoxy-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyridine

Example 13 is prepared according to example 12.

MS (M + 1): 542.20.

1 H NMR (CD3OD): 

8.64 (d, 1H, J = 4.2 Hz), 8.06 (d, 1H, J = 8.1Hz), 7.91 (dt, 1H, J = 7.8, 7.5Hz), 7.5-7.7 (m, 6H), 7.42-7.44 (m, 3H), 7.33 (d, 2H, J = 8.1Hz), 6.82 (t, 1H), 6.75 (d, 1H, J = 7.5Hz), 4.06 (s, 3H), 3.83 (s, 2H), 3.1 (q, 2H), 3.03 (m, 1H) , 2.57 (t, 2H), 2.12 (d, 2H), 2.02 (t, 2H).

Example 14: 3- (3-fluorophenyl) -2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyridine

Example 14 is prepared according to example 9.

MS (M + 1): 530.20.

1 H NMR (DMSO-d6): 

8.7 (s, 1H), 8.07 (d, J = 6.9Hz, 1H), 8.0 (d, J = 7.2Hz, 1H), 8.0 (m, 1H) 7.7 -7.6 (m, 2H), 7.5 (d, J = 8.1Hz, 2H), 7.4-7.2 (m, 7H), 6.9 (t, 1H), 3.5 (s, 2H), 2.9 (d, 2H), 2.6 (m, 1H), 2.1 (t, 2H), 1.9 (d, 2H), 1.8 (t, 2H) .

Example 15: 3- (4-methoxyphenyl) -2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyridine

Example 15 is prepared according to example 9 using 4-methoxyphenylboronic acid in step 1.

MS (M + 1): 542.27.

1 H NMR (CD3OD): 

8.7 (d, 1H), 8.1 (m, 2H), 7.9 (dt, J = 1.8Hz, 7.8Hz, 1H), 7.6-7.7 (m, 3H), 7.2-7.5 (m, 8H), 6.9 (dt, J = 6.9Hz, 1.2Hz, 1H), 4.1 (s, 2H), 3.9 (s, 3H), 3 (m, 1H), 2.7 (t, 2H), 2.1 (m, 4H), 2.0 (m, 2H).

Example 16: 3-pyridin-4-yl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyridine

Stage 1: 4- (3-pyridin-4-unlimiteddazo [1,2-a] pyridin-2-yl) benzaldehyde

0.2 g (0.9 mM) of 4-imidazo [1,2-a] pyridin-2-ylbenzaldehyde (prepared as described by Sundberg et al .; J. Heterocyclic Chem., 25, 129, are dissolved. 1988) in 5 ml of dioxane. To this is added CsCO3 (1.1 eq.), Palladium acetate (8 mol%), triphenylphosphine (16 mol%), triethylamine (2 eq.) And 4-bromo-pyridine (1.4 eq. ). The reaction mixture (microwave) is heated for 45 min. at 100 ° C. The reaction mixture is cooled to RT, diluted with DCM. The organic phase is washed with water, dried and concentrated. The crude product is purified by column chromatography to obtain the desired compound.

MS (M + 1): 300.33.

1 H NMR (DMSO-d6): δ

10 (s, 1H), 8.8 (d, J = 4.2Hz, 2H), 8.3 (d, J = 6.9Hz, 1H), 7.9 (d, J = 8.4Hz, 2H ), 7.7 (d, J = 8.1Hz, 2H), 7.6 (d, J = 5.7Hz, 2H), 7.73 (s, 1H), 7.4 (m, 1H) , 7 (dt, J = 6.9Hz, 1.2Hz, 1H).

Stage 2: 3-pyridin-4-yl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyridine

To a solution of 0.05 g (0.16 mM) of 4- (3-pyridin-4-unlimitedidazo [1,2-a] pyridin-2-yl) benzaldehyde in 5 ml of THF is added triethylamine (2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 2- (5piperidin- [1,2,4] triazol-3-yl) -pyridine * 2HCl (1.5 eq.) Followed by acetic acid (2.5 eq.). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq.) Over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 513.33.

1 H NMR (CD3OD): δ

8.7 (d, J = 1.5Hz, 2H), 8.65 (d, J = 4.8Hz, 1H), 8.1 (d, J = 6.9Hz, 1H), 8.1 (d , J = 7.8Hz, 1H), 7.93 (dd, J = 1.8Hz, J = 7.8Hz, 1H), 7.9 (s, 1H), 7.7 (d, J = 9Hz, 1H), 7.3-7.7 (m, 8H), 7.0 (dt, J = 6.9Hz, 1.2Hz, 1H), 3.9 (s, 2H), 3 (m, 1H) , 2.7 (t, 2H), 2.1 (m, 4H), 2 (m, 2H).

Example 17: 2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) -3- (2-thienyl ) imidazo [1,2-a] pyridine

Example 17 is prepared according to example 9 using 2-thienylboronic acid in the step.

MS (M + 1): 518.20.

1 H NMR (CD3OD): δ

8.65 (d, J = 4.2Hz, 1H), 8.1 (t, J = 6.9Hz, 2H), 7.9 (m, 1H), 7.8 (dd J = 2.1Hz, 4.5Hz, 1H), 7.7 (d, J = 8.1Hz, 2H), 7.6 (d, J = 9.3Hz, 1H), 7.4 (m, 4H), 7.3 ( m, 2H), 7 (dt, J = 6.9Hz, 1.2Hz, 1H), 3.9 (s, 2H), 3 (m, 1H), 2.7 (t, 2H), 2.1 (m, 4H), 2 (m, 2H).

Example 18: 3- (4-fluorophenyl) -2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyrimidine

Stage 1: 1- [4- (1,3-dioxolan-2-yl) phenyl] ethanone

To the stirred solution of methyl magnesium chloride in ether is added 4- (1,3-dioxolan-2-yl) benzonitrile (15 g, 85.6 mM, 0.2 eq.) In dry ether along a period of 15 min. The reaction mixture is stirred overnight. The reaction mixture is cooled to 0 ° C and slowly quenched with a sat. of ammonium chloride. Ether is added and the separated organic phase is dried and concentrated. The crude product is purified by column chromatography to obtain the desired compound as a white solid.

1H NMR (CDCl3): δ2.622 (s, 3H), 4.165-4.04 (m, 4H), 5.875 (s, 1H), 7.588 (d, J = 8.1Hz, 2H), 7.987 (d, J = 8.4 Hz, 2H).

Stage 2: 4- (bromoacetyl) benzaldehyde

5.5 g (28.6 mM) of 1- [4- (1,3-dioxolan-2-yl) phenyl] ethanone are dissolved in a mixture of acetone and water (200 ml). A catalytic amount of 4-methylbenzenesulfonic acid is added and the reaction mixture is refluxed for 4 h. The organic solvent is evaporated and the crude product is extracted in ethyl acetate. The organic phase is dried and concentrated to obtain the crude product, which is dissolved in a mixture of ethyl acetate and chloroform (100 ml). The reaction mixture is refluxed. To this is added cupric bromide (2 eq.) In portions while purging in N2 gas. The reaction mixture is refluxed for 8 h. It is then filtered, concentrated and the crude product is purified by cc to obtain the desired compound.

1 H NMR (DMSO-d6): δ

10.12 (s, 1H), 8.18 (d, J = 8.1Hz, 2H), 8.06 (d, J = 6.6Hz, 2H), 5.09 (s, 2H).

Stage 3: 4-imidazo [1,2-a] pyrimidin-2-ylbenzaldehyde.

4- (Bromoacetyl) benzaldehyde is dissolved in acetone. To this is added pyrimidin-2-amine (1 eq). The reaction mixture is stirred overnight. The precipitated solid is separated by filtration and dried to obtain the desired compound as a white solid.

MS (M + 1): 224.13.

1 H NMR (DMSO-d6): δ

10 (s, 1H), 9 (dd, J = 6.6Hz, 1.5Hz, 1H), 8.57 (dd, J = 2.1Hz, 4.2Hz, 1H), 8.5 (s, 1H ), 8.3 (d, J = 8.4Hz, 2H), 8.0 (d, J = 8.4Hz, 2H), 7.1 (dd, J = 6.6Hz, 3.9Hz, 1H) .

Stage 4: 4- (3-Bromoimidazo [1,2-a] pyrimidin-2-yl) benzaldehyde:

This compound 13 is prepared according to the procedure reported by Sundberg et al. (J. Heterociclic Chem., 25, 129, 1988).

Stage 5: 4- [3- (4-fluorophenyl) imidazo [1,2-a] pyrimidin-2-yl] benzaldehyde

0.225 g (0.74 mM) of 4- (3-bromoimidazo [1,2-a] pyrimidin-2-yl) benzaldehyde are dissolved in 5 ml of toluene. To this mixture is added 4-fluorophenylboronic acid (1.5 eq) followed by 10% by weight tetrakis-triphenylphosphine-palladium (0), K2CO3 (3 eq.) And a mixture of ethanol and water (4 ml). The reaction mixture is heated at 90 ° C for 4-6 h. The reaction is cooled to room temperature and 20 ml of water are added and the reaction mixture is extracted with ethyl acetate. The organic phase is dried and concentrated. The crude product is purified by flash column chromatography to provide the desired compound.

MS (M + 1): 318.33.

1 H NMR (DMSO-d6): δ

10.07 (s, 1H), 8.89 (dd, J = 2.1Hz, 6.9Hz, 1H), 8.68 (dd, J = 1.Hz, 4.2Hz, 1H), 8.36 (d, J = 8.1Hz, 2H), 8.08 (d, J = 8.4Hz, 2H), 7.26 (dd, J = 4.2Hz, 6.9Hz, 1H).

Step 6: 3- (4-fluorophenyl) -2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyrimidine

To a solution of 0.23 g (0.72 mM) of 4- [3- (4-fluorophenyl) imidazo [1,2-a] pyrimidin-2-yl] benzaldehyde in 5 ml of THF is added triethylamine ( 2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 2- (5piperidin- [1,2,4] triazol-3-yl) -pyridine * 2HCl (1.5 eq.) Followed by acetic acid (2.5 eq.). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq.) Over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 531.27.

1 H NMR (CD3OD): δ

8.7 (m, 2H), 8.5 (d, 1H), 8.1 (d, 1H), 7.9 (dt, J = 1.8Hz, 7.8Hz, 1H), 7.7- 7.6 (m, 3H), 7.2-7.5 (m, 8H), 6.9 (dt, J = 6.9Hz, 1.2Hz, 1H), 3.9 (s, 2H), 3 (m, 1H), 2.7 (t, 2H), 2.1 (m, 4H), 2.0 (m, 2H).

Example 19: 7-methyl-3-phenyl-2 (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyrimidine

This example is prepared according to compound 12 using 4-methylpyrimidin-2-amine in step 1. MS (M + 1): 527.13. 1H NMR (CD3OD): δ8.7 (s, 1H), 8.35 (d, J = 6.9Hz, 1H), 8.1 (d, J = 8.1Hz, 1H), 7.6 -7.5 (m, 6H), 7.5-7.4 (m, 3H), 7.3 (d, J

= 7.8Hz, 2H), 6.9 (d, J = 6.9Hz, 1H), 3.7 (s, 2H), 3.1 (m, 2H), 2.9 (m, 1H), 2.6 (s, 3H), 2.3 (m, 2H), 2.1-1.9 (m, 4H).

Example 20: 3- (4-methoxyphenyl) -2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyrimidine

This example is prepared in a manner according to Example 18 using 4-methoxyphenylboronic acid in step 5. MS (M + 1): 543.27. 1 H NMR (CD3OD): δ

8.65 (d, J = 4.2Hz, 1H), 8.61 (dd, J = 2.1Hz, 4.2Hz, 1H), 8.4 (dd, J = 1.9Hz, 6.9Hz, 1H), 8.05 (d, J = 7.8Hz, 1H), 7.92 (t, 1H), 7.73 (d, J = 8.1Hz, 2H).

Example 21: 6-Chloro-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyrimidine

This example is prepared in a manner according to Example 12 using 5-chloropyrimidin-2-amine in step 1. MS (M + 1): 547.20, 549.20.

1 H NMR (CD3OD): δ

8.65 (d, J = 3.6Hz, 1H), 8.60 (d, J = 2.4Hz, 1H), 8.54 (d, J = 2.4Hz, 1H), 8.06 (d , J = 7.8Hz 1H), 7.97-7.89 (m, 1H), 7.70 (d, J = 8.4Hz, 2H) 7.65-7.57 (m, 3H), 7 , 55-7.42 (m, 5H), 4.20 (s, 2H), 3.46 (da, J = 10.2Hz, 2H), 3.4-3.35 (m, 1H), 3 , 1-2.95 (m, 2H), 2.28 (da, 2H), 2.2-2.0 (m, 2H).

Example 22: 6-fluoro-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyridine

This example is prepared in a manner according to Example 12 using 5-fluoropyridin-2-amine in the first stage. MS (M + 1): 530.27. 1 H NMR (CD3OD): δ

8.65 (da, J = 4.2Hz, 1H), 8.10-8.02 (m, 2H), 7.96-7.88 (m, 1H), 7.71-7.55 (m , 5H), 7.49-7.40 (m, 5H), 7.40-7.32 (m, 1H), 7.24-7.12 (m, 1H) 4.08 (s, 2H) , 3.44-3.32 (m, 2H), 3.15-3.05 (m, 1H), 3.00-2.8 (m, 2H), 2,302.19 (m, 2H), 2 , 19-2.00 (m, 2H).

Example 23: 6-iodo-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyrimidine

This example is prepared in a manner according to Example 12 using 5-iodopyrimidin-2-amine in the first stage. MS (M + 1): 639.13. 1 H NMR (CD3OD): δ

8.67 (d, J = 2.4Hz, 1H), 8.64 (d, J = 4.5Hz, 1H), 8.58 (d, J = 2.1Hz, 1H), 8.07 (d , J = 7.8Hz, 1H), 7.91 (dt, J = 1.8.7.5Hz, 1H), 7.68-7.57 (m, 5H), 7.51-7.47 ( m, 2H), 7.44 (t, 1H), 7.34 (d, J = 8.1Hz, 2H), 3.8 (s, 2H), 3.11 (d, 2H), 2.90 (m, 1H), 2.42 (t, 2H), 2.15 (d, 2H), 1.96 (t, 2H).

Example 24: 7-methoxy-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyrimidine

This example is prepared in a manner according to Example 12 using 4-methoxy-2-amine in the first stage. MS (M + 1): 543.13. 1 H NMR (CD3OD): δ

8.64 (d, J = 4.5Hz, 1H), 8.21 (d, J = 7.2Hz, 1H), 8.07 (d, J = 8.1Hz, 1H), 7.89 (dt , J = 2,1,7,8Hz, 1H), 7.59-7.52 (m, 5H), 7.49-7.44 (m, 3H), 7.28 (d, J = 8, 4Hz, 2H), 6.54 (d, J = 7.2Hz, 1H), 4.07 (s, 3H), 3.73 (s, 2H), 3.12 (d, 2H), 2.92 (m, 1H), 2.44 (t, 2H), 2.14 (d, 2H), 2.0 (t, 2H).

Example 25: 8-Bromo-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyridine

This example is prepared in a manner according to Example 12 using 3-bromopyridin-2-amine in the first stage. MS (M + 1): 590.07, 592.07. 1 H NMR (CD3OD): δ

8.64 (d, J = 4.5Hz, 1H), 8.07 (d, J = 6.6Hz, 2H), 7.92 (dt, J = 1.Hz, 7.8Hz, 1H), 7 , 65-7.54 (m, 6H), 7.48-7.42 (m, 3H), 7.34 (d, J = 8.1Hz, 2H), 6.81 (t, 1H), 3 , 84 (s, 2H), 3.20 (d, 2H), 2.98 (m, 1H), 2.57 (t, 2H), 2.14 (d, 2H), 2.06 (t, 2H).

Example 26: 8-Chloro-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyrazine

This example is prepared in a manner according to Example 12 using 3-chloropyrazine-2-amine in the first stage. MS (M + 1): 547.20, 549.20. 1 H NMR (CD3OD): δ

8.64 (d, J = 4.8Hz, 1H), 8.08 (t, 1H), 8.06 (s, 1H), 7.92 (dt, J = 1.8, 7.8Hz, 1H ), 7.68 (t, 3H), 7.62-7.59 (m, 3H), 7.56-7.46 (m, 2H), 7.44-7.57 (m, 3H), 3.83 (s, 2H), 3.18 (d, 2H), 2.98 (m, 1H), 2.58 (t, 2H), 2.16 (d, 2H), 2.01 (t , 2H).

Example 27: 8-methoxy-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyrazine

This example is prepared in a manner according to Example 12 using 3-methoxypyrazin-2-amine in the first stage. MS (M + 1): 543.07.

1 H NMR (CD3OD): 

8.26 (d, J = 3.9Hz, 1H), 8.06 (d, J = 7.8Hz, 1H), 7.90 (t, 1H), 7.65 (d, J = 4.8Hz , 1H), 7.55-7.53 (m, 5H), 7.45-7.38 (m, 4H), 7.29 (d, J = 8.1Hz, 2H), 4.16 (s , 3H), 3.59 (s, 2H), 3.0 (s, 2H), 2.85 (m, 1H), 2.28 (t, 2H), 2.08 (d, 2H), 1 , 90 (d, 2H).

Example 28: 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) -7- (trifluoromethyl) imidazo [1,2-a] pyrimidine

This example is prepared in a manner according to Example 12 using 4- (trifluoromethyl) pyrimidin-2-amine in the first stage. MS (M + 1): 581.13. 1 H NMR (CD3OD): δ

8.73 (d, J = 7.2Hz, 1H), 8.65 (da, J = 3.6Hz, 1H), 8.12-8.05 (m, 1H), 7.97-7.89 (m, 2H), 7.73-7.53 (m, 5H), 7.49-7.38 (m, 4H), 7.37-7.30 (m, 1H) 3.86 (s, 2H), 3.2-2.9 (m, 3H), 2.7-2.5 (m, 2H), 2.2-1.95 (m, 4H).

Example 29: 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1 , 2-a] pyridin-7-carbonitrile

This example is prepared in a manner according to Example 12 using 2-aminoisonicotinonitrile in the first stage. MS (M + 1): 537.23 1H NMR (CDCl3): 

8.675 (d, J = 6.5 Hz, 1H), 8.177 (d, J = 8.1Hz, 1H), 8.16 (s, 1H), 8.019 (d, J = 7.2 Hz, 1H) 7.858 (t, J = 7.2Hz, 1H) 7.664 (d, J = 8.1Hz, 2H) 7.608-7.457 (m, 5H) 7.36 (d, 8.1Hz, 2H) 7.285 (m, 3H) , 6,907 (dd, J = 7.2 Hz, 1.5 Hz, 1H), 3,714 (s, 2H), 3,185-2,155 (m, 9H).

(2E) -But-2-3-phenyl-2- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin- 1-yl} methyl) phenyl] imidazo [1,2-a] pyridin-7-carbonitrile

To 3.0 g of 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridin-7-carbonitrile (prepared as described in example 29) in 50 ml of acetone is added a solution of 0.714 g of fumaric acid. The reaction mixture is stirred at room temperature for 3 d. The desired compound is collected by filtration and dried.

Signals of 1H NMR (dDMSO, 300MHz) characteristics: 8.66 (d, 1H); 8.43 (s, 1H), 8.13 (d, 1H), 8.01 (d, 1H), 7.93 (t, 1H), 7.61 (m, 5H), 7.41 (t , 1H), 7.33 (d, 2H), 7.16 (d, 1H), 6.6 (2H)

Example 30: 3-phenyl-2- (4 - {[4- (3-pyridin-2-yl-pyrazol-5-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyrimidine

This example is prepared in a manner similar to 1 using 2- (5-piperidin-4-ylpyrazol-3-yl) pyridine in the last stage that was prepared as described in Bioorg. Med. Chem. Lett .; IN; 12; 3; 2002; 383-386. Analytical data EM (M + 1): 510 Signals of 1 H NMR (400 Hz, dDMSO) characteristics: 8.4 ppm (d, 1 H); 7.1 ppm (dd, 1 H);

Example 31: 6-Chloro-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-b] pyridazine.

This example is prepared in a manner according to Example 12 using 6-chloropyridazin-3-amine in the first stage. MS (M + 1): 547.13. 1 H NMR (300 MHz, DMSO-d6): δ

8.65 (d, 1H), 8.278 (d, J = 9.6Hz, 1H), 8.014 (d, J = 7.8Hz, 1H), 7.92 (s, 1H), 7.597.51 (m, 7H), 7.41 (d, J = 9.3Hz, 3H), 7.3 (d, J = 7.5Hz, 2H), 3.49 (s, 1H), 2.86-2.73 ( m, 3H), 2.07 (s, 2H) 1.97-1.76 (m, 5H).

Example 32: 6-methoxy-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-b] pyridazine.

To a suspension of example 31 (0.2 g, 0.366 mM) in 15 ml of methanol is added NaOCH3 (10 eq.) And the reaction mixture is refluxed for 6 h. The reaction mixture is concentrated and quenched with water. The resulting solid is filtered and dried to obtain the desired compound.

MS (M + 1): 543.13.

1 H NMR (300 MHz, CD3OD) δ

8.65 (d, J = 4.2Hz, 1H), 8.1 (d, J = 8.1Hz, 1H), 7.94-7.9 (m, 2H), 7.6-7.5 (m, 4H), 7.57.4 (m, 4H), 7.32 (d, J = 8.1Hz, 2H), 6.9 (d, J = 9.6Hz, 1H), 3.9 (s, 3H), 3.6 (s, 2H), 3.04-3.0 (m, 2H) 2.88-2.87 (m, 1H), 2.25-2.18 (m, 2H), 2.07-1.88 (m, 4H).

Example 33: 3-phenyl-2-4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1, 2-a] pyridine-8carboximidamide.

To a solution of hydroxylamine hydrochloride (10 eq) in 5 ml of anhydrous DMSO, KtBuO (10 eq.) Is added at 5 ° C in portions. To this is added Example 5 (0.15 g, 0.28 mM). The reaction is stirred overnight. The reaction mixture is quenched with water and the resulting ppt is filtered to obtain 170 mg of crude hydroxyamidine. This is dissolved in 3 ml of acetic acid and acetic anhydride (0.1 ml) is added. The reaction mixture is stirred overnight at RT. The reaction mixture is concentrated and triturated with ether to obtain acetylated hydroxyamidine. This crude product is dissolved in methanol and 10% Pd / C is added thereto, and the reaction mixture is stirred under a hydrogen atmosphere for 2 h. After the final treatment, the crude product is purified by prep HPLC. to obtain the desired compound.

MS (M + 1): 554.2.

1H NMR (300 MHz, CD3OD) 8: 8.75 (d, J = 3.3Hz, 1H), 8.50 (s, 1H), 8.37 (d, J = 6.9Hz, 1H), 8 , 22 (d, J = 6.6Hz, 1H), 8.076 (d, J = 7.8Hz, 1H), 7.95-7.89 (m, 2H), 7.71-7.50 (m, 5H), 7.44 (t, 1H), 7.35 (d, J = 7.8Hz, 2H), 7.14 (t, 1H) 4.87 (s, 2H), 3.24-3, 23 (d, 2H), 3.13-3.1 (d, 2H), 2.9 (m, 1H), 2.13-1.96 (m, 2H).

Example 34: 2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) -3- (3-thienyl ) imidazo [1,2, a] pyrimidine

This example is prepared according to Example 18 using 3-thienylboronic acid in step 5.

MS (M + 1): 519.13.

1 H NMR (CD3OD): δ

8.7 (d, J = 4.8Hz, 1H), 8.6 (m, 1H), 8.5 (dd, J = 1.8, 6.9Hz, 1H), 8.1 (d, J = 8.1Hz, 1H), 7.9 (m, 1H), 7.7 (m, 4H), 7.5 (m, 1H), 7.4 (d, J = 8.1Hz, 1H), 7.2 (dd, J = 1.5, 5.1Hz, 1H), 7 (m, 1H), 3.8 (s, 2H), 3.2 (m, 2H), 3 (m, 1H) , 2.5 (m, 2H), 2.2 (m, 2H), 2 (m, 2H).

Example 35: 2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) -3- (2-thienyl ) imidazo [1,2-a] pyrimidine

This example is prepared according to Example 18 using 2-thienylboronic acid in step 5.

MS (M + 1): 519.13.

1 H NMR (CD3OD): δ

8.7 (dd, J = 4.2, 2.1Hz, 2H), 8.5 (dd, J = 1.8, 6.6Hz, 1H), 8.1 (d, J = 8.1, 1H), 7.95 (m, 1H), 7.8 (m, 3H), 7.5 (m, 3H), 7.4 (m, 2H), 7.1 (m, 1H), 4, 1 (s, 2H), 3.4 (m, 2H), 3.1 (m, 2H), 2.9 (m, 1H), 2.3 (m, 2H), 2.1 (m, 2H ).

Example 36: 3-pyridin-4-yl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2-a] pyrimidine

This example is prepared in a manner according to example 18 (first 3 steps). The final 2 stages are performed in a manner according to steps 1 and 2 of Example 16.

MS (M + 1): 514.2.

1H NMR (CD3OD): δ, 8-8.6 (m, 5H), 8.1 (d, J = 7.8Hz, 1H), 7.9 (m, 1H), 7.7 (d, J = 8.1Hz, 2H), 7.6 (m, 4H), 7.4 (m, 1H), 7.2 (m, 1H), 4.25 (s, 2H), 3.6 (m, 2H), 3.2 (m, 2H), 3.1 (m, 1H), 2.3 (m, 2H), 2.2 (m, 2H).

Example 37: 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1 , 2-a] pyrazine

To a solution of example 26 (0.1 g, 0.18 mM) in 10 ml of methanol is added 40 mg of Pd / C (10%). The reaction mixture is stirred at RT under hydrogen atmosphere overnight. The reaction mixture is filtered through celite and concentrated. It is then purified by column chromatography and washed with water to obtain the desired compound.

MS (M + 1): 513.20.

1 H NMR (CD3OD): δ

9.05 (d, J = 1.5Hz, 1H), 8.64 (d, J = 3.9Hz, 1H), 8.14 (dd, J = 4.8Hz, 1.5Hz, 1H) , 8.07 (d, J = 7.8Hz, 1H), 7.94-7.87 (m, 2H), 7.68 (d, J = 8.4Hz, 2H), 7.63-7, 56 (m, 3H), 7.52-7.46 (m, 3H), 7.38 (d, J = 8.1Hz, 2H), 3.81 (s, 2H), 3.19 (d, 2H), 2.98 (m, 1H), 2.51 (t, 2H), 2.21-1.92 (m, 4H).

Example 38: 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1 , 2-a] pyridine-7carboxamide.

Example 29 (0.1 g, 0.018 mM) is dissolved in 3 ml conc. H2SO4. It is stirred overnight and quenched with water and basified with a 20% w / w NaOH solution. The precipitated solid is filtered and dried. It is then purified by column chromatography to obtain the desired compound.

MS (M + 1): 555.13.

1H NMR (CDCl3): δ

8.64 (d, J = 4.5 Hz, 1H), 8.18 (s, 1H), 8.13 (d, J = 7.2 Hz, 1H), 8.08 (d, J = 7 , 8 Hz, 1H) 7.94 (dd, J = 7.8Hz, 1.Hz, 2H) 7.64-7.54 (m, 5H) 7.50-7.42 (m, 3H) 7, 38-7.36 (m, 3 H) 7.33 (s, 2H), 3.30 (sa, 2H), 3.18 (d, 2H), 2.95 (m, 1H), 2.40 (m, 2H), 2.15-1.93 (m, 4H)

Example 39: 2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) -3- (1,3 -thiazol-2-yl) imidazo [1,2-a] pyrimidine

This example is prepared in a manner according to Example 18 except step 5 in which the Stille coupling using 2- (tributilestanil) -1,3-thiazole is performed instead of the Suzuki coupling. Stage 6 is according to the example

18.

Stage 5: 4- [3- (1,3-thiazol-2-yl) imidazo [1,2-a] pyrimidin-2-yl] benzaldehyde

0.5 g (1.65 mM) of 4- (3-bromoimidazo [1,2-a] pyrimidin-2-yl) benzaldehyde is dissolved in 15 ml of 1,4-dioxane. To this solution is added tetrakis-triphenylphosphine-palladium (200 mg) at 40%. The reaction mixture is heated at 100 ° C for 10 min. and 2- (tributylstanyl) -1,3-thiazole (681 mg, 1.81 mM) is added. The reaction (oil bath or microwave) is heated at the same temp for 5 h. The reaction is cooled to room temperature and 50 ml of water is added and the reaction mixture is extracted with ethyl acetate. The organic phase is dried and concentrated. The crude product is purified by flash column chromatography to provide the desired product.

MS (M + 1): 307.20.

1 H NMR (DMSO-d6): δ

10.16 (s, 1H), 9.72 (dd, J = 1.8, 6.9 Hz, 1H), 8.7 (dd, J = 1.8, 4.2 Hz, 1H), 8 , 08 (d, J = 3.3 Hz, 1H), 8.06 (d, J = 8.1Hz, 2H), 7.94 (d, J = 8.1Hz, 2H), 7.81 (d , J = 3.3 Hz, 1H), 7.35 (m, 1H).

Step 6: 2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) -3- (1,3 -thiazol-2-yl) imidazo [1,2-a] pyrimidine

MS (M + 1): 520.13

1 H NMR (CD3OD): δ

9.93 (d, J = 5.1Hz, 1H), 8.72 (dd, J = 4.2, 2.1Hz, 1H), 8.63 (d, J = 4.2, 1H), 8.092 (d, J = 8.1, 1H), 7.98 (d, J = 3.3Hz, 1H), 7.92 (t, 1H), 7.71 (d, J = 8.1, 2H) , 7.58 (d, J = 8.1Hz, 2H), 7.54 (d, J = 3.3, 1H), 7.44 (t, 1H), 7.26 (dd, J = 4, 5, 7.2 Hz, 1H) 3.92 (s, 2H), 3.21 (m, 2H), 3.18 (m, 1H), 2.55 (m, 2H), 2.15 (m , 2H), 2.14 (m, 2H).

Example 40: 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1 , 2-a] pyridine-8-carboxamide.

This example is prepared from example 5 in a manner according to example 38.

MS (M + 1): 555.13.

1 H NMR (CD3OD): δ

8.63 (d, J = 5 Hz, 1H), 8.19-8.13 (m, 2H), 8.07 (d, J = 7.8Hz, 1H), 7.93-7.87 ( m, 1H), 7.65 (d, J = 8.4Hz, 2H), 7.62-7.56 (m, 3H), 7.51-7.48 (m, 2H), 7.44- 7.40 (m, 1H), 7.29 (d, J = 8.4Hz, 2H), 7.01 (t, 1H) 3.56 (s, 2H) 3.05-2.98 (da, 1H), 2.91-2.78 (m, 1H), 2.23-2.11 (m, 2H), 2,070-1,950 (m, 3H), 1,950-1,911 (m, 2H).

Example 41: 3- (2-fluorophenyl) -2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [1,2a] pyrimidine

This example is prepared according to Example 9 using 2-fluorophenylboronic acid in step 1.

MS (M + 1): 531.13.

1 H NMR (CD3OD): δ

8.64 (dd, J = 4.2, 1.2 Hz, 2H), 8.39 (dd, J = 6.9, 2.1Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.93 (dt, J = 7.8, 1.8 Hz, 1H), 7.6-7.7 (m, 3H), 7.2-7.5 (m, 6H) , 7.02 (dd, J = 6.9, 1.2 Hz, 1H), 3.65 (s, 2H), 3.18 (d, 2H), 2.9 (m, 1H), 2, 06 (t, 2H), 1.9 (d, 2H), 1.8 (d, 2H)

Example 42: 6- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) -5- (1,3 -thiazol-2-yl) imidazo [2,1b] [1,3] thiazole

Stage 1: 4-imidazo [2,1-b] thiazol-6-yl-benzaldehyde

0.7 g (2.1 mM) of 4- (2-bromo-acetyl) -benzaldehyde and 2-aminothiazole (2 eq.) In 15 ml DMF are stirred at 90 ° C for 6

h. The DMF is evaporated and the residue is suspended in ethyl acetate overnight. The desired product is collected by filtration.

MS (M + 1): 229.13

1 H NMR (DMSO-d6): d 10.0 (s, 1 H), 8.51 (s, 1 H), 8.06 (d, J = 8.2 Hz, 2 H), 8.04 (d, J = 4.5 Hz, 1H), 7.9 (d, J = 8.4 Hz, 2H), 7.40 (d, 1J = 4.5 Hz, 1H).

Stage 2: 4- (5-Bromo-imidazo [2,1-b] thiazol-6-yl) -benzaldehyde

4-Imidazo [2,1-b] thiazol-6-yl-benzaldehyde (3.8 g, 14.9 mM) is dissolved in 30 ml of acetic acid. A solution of bromine (1.1 eq) in acetic acid (15 ml) is added to the reaction mixture. The reaction mixture is stirred for 3 h at room temperature. The solid obtained is collected by filtration and dissolved again in water (100 ml) and the solution is neutralized with aqueous ammonia. The solid obtained is collected by filtration and dried.

MS (M + 1): 307.13, 309.1

1H NMR (DMSO-d6): d 10.03 (s, 1H), 8.2 (d, J = 8.4 Hz, 2H), 8.0 (d, J = 8.4Hz, 2H), 7 , 95 (d, J = 4.5 Hz, 1H), 7.48 (d, J = 4.5 Hz, 1H).

Stage 3: (5-Thiazol-2-yl-imidazo [2,1-b] thiazol-6-yl) -benzaldehyde

0.09 g (0.37 mM) of 4- (5-bromo-imidazo [2,1-b] thiazol-6-yl) -benzaldehyde are dissolved in 5 ml of 1,4 dioxane and 0.5 are added eq of Pd (PPh3) 4 followed by the addition of 2- (tributilestanyl) -1,3-thiazole (1.1 eq) and the reaction mixture is heated to reflux for 24 h. The reaction mixture is cooled to room temperature and diluted with 10 ml of methylene chloride and 15 ml of water. The separated organic phase is washed with water and dried over Na2SO4. The crude reaction mixture is used in the next step.

MS (M + 1): 312.1

Stage 4: 6- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) -5- (1,3 -thiazol-2-yl) imidazo [2,1-b] [1,3] thiazole

To a solution of 0.1 g (0.31 mM) of 4- (5-thiazol-2-yl-imidazo [2,1-b] thiazol-6-yl) -benzaldehyde in 5 ml of THF is added triethylamine (2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 2- (5piperidin- [1,2,4] triazol-3-yl) -pyridine * 2HCl (1.5 eq.) Followed by acetic acid (2.5 eq.). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq.) Over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on an ultrafast column to obtain the desired compound.

Mass (M + 1): 525.13

1H NMR (CD3OD): d 8.64 (s, 1H), 8.55 (d, J = 4.5 Hz, 1H), 8.08 (d, J = 9.6 Hz, 1H), 9, 92 (t, J = 9.3, 9.2 Hz, 1H), 7.84 (d, J = 3.3 Hz, 1H), 7.66 (d, J = 6.6 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.4 (d, J = 3.3Hz, 2H), 7.30 (d, J = 4.5 Hz, 1H), 3.8 (s, 2H), 3.2 (d, 2H), 3.0 (m, 1H), 2.5 (t, 2H), 2.14 (d, 2H), 2.00 (d, 2H) .

Example 43: 5- (1,3-oxazol-2-yl) -6- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin -1-yl] methyl} phenyl) imidazo [2,1b] [1,3] thiazole

This example is prepared according to Example 42 using 2- (tributilestanil) -1,3-oxazolo in step 3.

MS (M + 1): 509.13.

1 H NMR (CD3OD): δ

8.62 (d, J = 4.5 Hz, 1H), 8.41 (d, J = 4.5 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7, 9 (m, 2H), 7.81 (d, 2H, J = 8.1Hz), 7.49-7.41 (m, 3H), 7.34 (d, J = 4.2 Hz, 2H) , 3.7 (s, 2H), 3.19 (d, 2H), 3.0 (m, 1H), 2.4 (t, 2H), 2.1 (d, 2H), 2.0 ( d, 2H).

Example 44: 6,8-Difluoro-3-phenyl-2- {4- [4- (5-pyridin-2-yl-4H- [1,2,4] triazol-3-yl) -piperidin-1- ilmethyl] -phenyl} imidazo [1,2-a] pyridine

Example 44 is prepared according to example 12. MS (M + 1): 548.20 1 H NMR (300 MHz, CD3OD): δ

8.64 (dd, J = 4.2, 1.2 Hz, 2H), 8.39 (dd, J = 6.9, 2.1Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.93 (dt, J = 7.8, 1.8 Hz, 1H), 7.6-7.7 (m, 3H), 7.2-7.5 (m, 6H) , 7.02 (dd, J = 6.9, 1.2 Hz, 1H), 3.65 (s, 2H), 3.18 (d, 2H), 2.9 (m, 1H), 2, 06 (t, 2H), 1.9 (d, 2H), 1.8 (d, 2H)

Example 45: 2-methyl-5-phenyl-6- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl } methyl) phenyl] imidazo [2,1b] [1,3,4] thiadiazole

Example 45 is prepared according to example 12. MS (M + 1): 533.13 1H NMR (300MHz, CDCl3) δ

8.67 (d, J = 3Hz, 1H), 8.17 (d, J = 6Hz, 1H), 7.9-7.2 (m, 12H), 3.6 (s, 2H), 3, 1-2.8 (m, 3H), 2.71 (s, 3H), 2.4-1.9 (m, 6H).

Example 46: 2-methyl-5-phenyl-6- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl } methyl) phenyl] imidazo [2,1b] [1,3] thiazole

Example 46 is prepared according to example 12. MS (M + 1): 532.13 1H NMR (300MHz, CDCl3) δ

8.651 (d, 1H), 8.089 (d, J = 7.8, Hz 1H), 7.954 (t, J = 1.5 Hz 1H), 7.523-7.456 (m, 7H), 7.377-7.217 (m, 4H ), 3,760 (s, 2H), 3,082 (d, J = 7.8Hz, 2H), 2,981-2,943 (m, 1H), 2,457 (s, 2H), 2.45 (s, 3H) 2.2432, 125 (m, 4H).

Example 47: 2- (methylsulfanyl) -5-phenyl-6- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1 -yl} methyl) phenyl] imidazo [2,1-b] [1,3,4] thiadiazole

Example 47 is prepared according to example 12. MS (M + 1): 565.07 1 H NMR (300 MHz, CDCl 3): - δ

8.672 (d, J = 3.9 Hz, 1H), 8.163 (d, J = 7.8Hz, 1H), 7.828 (t, J = 1.2 Hz 1H), 7.637-7.561 (m, 4H), 7.448 -7,338 (m, 4H), 7,288 (d, J = 8.4Hz, 2H), 3,552 (s, 2H), 3,012 (d, J = 11.1Hz, 2H), 2,873 (m, 1H), 2, 73 (s, 3H), 2,195-1,970 (m, 6H).

Example 48: 5-phenyl-6- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl ] -2- (trifluoromethyl) imidazo [2,1-b] [1,3,4] thiadiazole

Example 48 is prepared according to Example 12 MS (M + 1): 587.05 1 H NMR (300 MHz, CDCl 3): - δ

8.683 (d, J = 4.5 Hz, 1H), 8.177 (d, J = 7.8 Hz, 1H), 7.852 (t, J = 1.5 Hz 1H), 7.643 (s, 2H), 7.616 ( s, 2H), 7,511-7,439 (m, 3H), 7,402-7.32 (m, 3H), 3,637 (s, 2H), 3,065 (d, J = 11,1Hz, 1H), 2,928 (sa, 1H ), 2,243-2,067 (m, 6H).

Example 49: 3-Phenyl-2- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl) (2Z) -but-2-enodioate ] piperidin-1yl} methyl) phenyl] imidazo [1,2-a] pyridin-7-carbonitrile

To 3.0 g of 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridin-7-carbonitrile (prepared as described in example 29) in 50 ml of acetone is added a solution of 0.714 g of malonic acid in 10 ml of acetone dropwise. The reaction mixture is stirred at room temperature for 18

h. The desired compound is collected by filtration and dried.

Signals of 1H NMR (dDMSO, 300MHz) characteristics: 8.68 (d, 1H); 8.44 (s, 1H), 8.15 (d, 1H), 8.01 (d, 1H), 7.90 (t, 1H), 7.70 (m, 5H), 7.63 (t , 1H), 7.47 (d, 2H), 7.18 (d, 1H), 6.0 (2H)

Example 50: 7-methyl-3-phenyl-2- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl } methyl) phenyl] imidazo [1,2a] pyridine

Example 50 is prepared according to example 12. MS (M + 1): 526.13 1 H NMR (300 MHz, CDCl 3): - δ

8.65 (sa, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.9 (d, J = 7.2 Hz, 1H), 7.46-7.60 (m , 7H), 7.42 (s, 1H), 7.22 (d, J = 8.1Hz, 2H), 3.45 (s, 2H), 2.9 (d, 2H), 2.37 ( s, 3H), 1.71-2.07 (m, 6H)

Example 51: 2-ethyl-5-phenyl-6 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1b] [1,3,4] thiadiazole

Example 51 is prepared according to example 12. MS (M + 1): 547.07 1 H NMR (300 MHz, CDCl 3): - δ

8.67 (s, 1H), 8.18 (d, J = 7.5 Hz, 1H), 7.9-7.25 (m, 12H), 3.56 (s, 2H), 3.1 -2.8 (m, 3H), 2.3-1.9 (m, 6H), 1.43 (t, J = 7.5 Hz, 3H), 0.9 (m, 2H)

Example 52: '6-Bromo-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2a] pyridin-7-carbonitrile

Example 52 is prepared according to example 12. MS (M + 1): 417.07 1H NMR (300 MHz, CDCl3): - δ

8.7 (s, 1H), 8.0-8.2 (m, 4H), 7.8 (m, 1H), 7.5-7.7 (m, 4H), 7.2-7, 4 (m, 5H), 3.9 (s, 2H), 3 - 3.3 (m, 3H), 2-2.6 (m, 6H).

Example 53: '6-methyl-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2b] pyridazine

Example 53 is prepared according to Example 12 MS (M + 1): 527.13 1H NMR (300 MHz, CDCl3): - δ8.6 (m, 1H), 8.1 (m, 1H), 7 , 8-7.9 (m, 2H), 7.7 (d, 2H), 7.6 (d, 2H), 7.3-7.5 (m, 6H), 6.9 (d,

1H), 3.9 (s, 2H), 3.0-3.3 (m, 3H), 2.5 (s, 3H), 2.0-2.3 (m, 6H). Example 54: '7-Chloro-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridine

Example 54 is prepared according to Example 12 MS (M + 1): 546.13 1 H NMR (300 MHz, CDCl 3): - δ

8.7 (d, J = 4.5Hz, 1H), 8.1 (d, J = 8.1Hz, 1H), 7.8-7.9 (m, 2H), 7.6-7.7 (m, 3H), 7.5-7.6 (m, 3H), 7.3-7.5 (m, 5H), 6.7 (d, 1H), 3.9 (s, 2H), 3.0-3.3 (m, 3H), 2.1-2.8 (m, 6H)

Example 55: '3-phenyl-2- (4 - {[4- (5-pyridin-4-yl-1H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyrimidine.

To a solution of 0.094 g (0.314 mM) of 4- (3-phenylimidazo [1,2-a] pyrimidin-2-yl) benzaldehyde in 3 ml of THF is added triethylamine (2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 4- [3 (piperidin-4-yl) -1H-1,2,4-triazol-5-yl] pyridine 2HCl (1.5 eq) (intermediate B) followed by acetic acid ( 2.5 eq.). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq.) Over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 513.2 1H NMR (300 MHz, CDCl3): - δ

8.66 (d, J = 5.7 Hz, 2H), 8.576 (s, 1H), 8.28 (dd, J = 6.6.1.5 Hz 1H), 7.98 (d, J = 6Hz, 2H), 7.65 (d, J = 8.1Hz 2H), 7.54 (d, J = 6.3Hz, 3H), 7.457-7.431 (m, 2H), 7.265-7.216 (m, 2H ), 6,880-6,843 (m, 1H) 3.57 (s, 2H), 2.97 (d, J = 10.8Hz, 3H) 2,182-2,094 (m, 2H), 1,992-1,910 (m, 4H) .

Example 56: '5-phenyl-6- (4 - {[4- (5-pyridin-4-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1-b] [1,3] thiazole

Example 56 is prepared according to Example 55 MS (M + 1): 518.0 1H NMR (300MHz, DMSO-d6) δ

8.63 (d, J = 6Hz, 2H), 7.88 (d, J = 4.5Hz, 2H), 7.70 (d, J = 4.5Hz, 1H), 7.55-7.15 (m, 11H), 3.46 (s, 2H), 3.0-2.7 (m, 3H), 2.2-1.7 (m, 6H).

Example 57: '3-phenyl-2- (4 - {[4- (3-pyridin-4-yl-1H-1,2,4-triazol-5-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridine-7carbonitrile

Example 57 is prepared according to Example 55 MS (M + 1): 537.13 1 H NMR (300 MHz, CDCl 3): - δ

8.69 (dd, J = 4.5 Hz, 1.2 Hz, 2H), 8.123 (s, 1H), 8.011 (dd, J = 7.2 Hz, 0.9 Hz, 1H), 7.95 (dd, J = 4.5 Hz, 1.5Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.60-7.52 (m, 2H), 7.46- 7.4 (m, 2H), 7.30 (d, J = 8.4 Hz, 2H) 6.90 (dd, J = 6.9Hz, 1.5Hz, 1H), 3.60 (m, 3H ), 2.44-1.91 (m, 7H)

Example 58: '3-phenyl-2- (4 - {[4- (5-pyridin-4-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridine

Example 58 is prepared according to Example 55 MS (M + 1): 512.07 1H NMR (300 MHz, CDCl3): - δ

8.7 (d, 2H), 8 (m, 3H), 7.7 (d, 1H), 7.4 to 7.6 (m, 7H), 7.1 to 7.3 (m, 3H), 6.8 (t, 1H), 3.6 (s, 2H), 2.7 to 2.9 (m, 3H), 1.7 to 2.2 (m, 6H).

Example 59: '3-phenyl-2- (4 - {[4- (5-pyridin-4-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridine-8carbonitrile

Example 59 is prepared according to Example 55 MS (M + 1): 537.13 1 H NMR (300 MHz, CDCl 3): - δ

8.7 (d, 2H), 8.2 (d, 1H), 8 (d, 1H), 7.2-7.7 (m, 10H), 6.8 (t, 1H), 3.5 (s, 2H), 2.8-3.1 (m, 3H), 1.8-2.3 (m, 6H).

Example 60: '5-phenyl-6- (4 - {[4- (5-pyridin-4-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1-b] [1,3,4] thiadiazole

Example 60 is prepared according to Example 55 MS (M + 1): 519.0 1H NMR (300MHz, DMSO-d6) δ

9.22 (s, 1H), 8.65 (d, J = 4.5Hz, 2H), 7.87 (d, J = 4.5Hz, 2H), 7.6-7.3 (m, 7H ), 7.26 (d, J = 8.1Hz, 2H), 3.47 (s, 2H), 2.95-2.75 (m, 3H), 2.15-1.7 (m, 6H )

Example 61: 2- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] - 3-phenylimidazo [1,2, a] pyridin-7-carbonitrile

Triethylamine (2 eq.) Is added to a solution of 0.150 g (0.444 mM) of 2- (4-formylphenyl) -3-phenylimidazo [1,2-a] pyridin-7-carbonitrile in 3 ml of THF. The reaction mixture is stirred for 5 minutes. To this solution is added 2-methyl-4- [3- (piperidin-4-yl) -1H-1,2,4-triazol-5-yl] pyridine dihydrochloride (intermediate C) (1.5 eq .) followed by acetic acid (2.5 eq.). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq.) Over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 551.2 1H NMR (300 MHz, CDCl3): - δ

8.15 (s, 1 H), 7.9 (m, 2H), 7.7 (m, 3H), 7.55 (m, 3H), 7.45 (m, 2H), 7.3 ( d, J = 8.1 Hz, 2H), 7.2 (d, J = 7.5Hz, 1 H), 6.9 (d, 1 H), 3.6 (s, 2H), 3 (d , 2H), 2.9 (m, 1H), 2.5 (s, 3H), from 2 to 2.6 (m, 6H).

Example 62: 2- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] - 3-phenylimidazo [1,2a] pyridin-8-carbonitrile

Example 62 is prepared according to example 61 MS (M + 1): 551.2 1 H NMR (300 MHz, CDCl 3): - δ

8.15 (d, J = 7.2Hz, 1H), 7.9 (d, J = 7.8Hz, 1H), 7.7 (m, 4H), 7.55 (m, 3H), 7, 45 (m, 2H), 7.3 (d, J = 8.1Hz, 2H), 7.2 (d, J = 7.5Hz, 1H), 6.8 (t, 1H), 3.7 ( s, 2H), 3.1 (m, 2H), 2.9 (m, 1H), 2.6 (s, 3H), from 2 to 2.6 (m, 6H).

Example 63: 2- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] - 3-phenylimidazo [1,2-a] pyrimidine

Example 63 is prepared according to example 61 MS (M + 1): 527.2 1 H NMR (300 MHz, CDCl 3): - δ =

8.237 (dd, J 6.6.1.8 Hz, 1H), 7.938 (d, J = 7.5Hz, 1H), 7.751-7.668 (m, 3H), 7.5987.525 (m, 3H), 7.47-7.439 (m, 2H), 7.30 (d, J = 8.1Hz, 2H), 7.193 (d, J = 7.5 Hz, 1H), 6.835-6.799 (m, 1H), 3.665 (s, 2H) 3,088-2,938 (m, 3H), 2,583 (s, 3H), 2,351 (t, J = 7.8 Hz, 2H), 2,121-2,025 (m, 4H).

Example 64: 2- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] - 3-phenylimidazo [1,2a] pyridine

Example 64 is prepared according to example 61 MS (M + 1): 526.1 1 H NMR (300 MHz, CDCl 3): - δ

8 (m, 2H), 7, 6 to 7.8 (m, 4H), 7.4 to 7.6 (m, 5H), 7.1 to 7.4 (m, 4H), 6 , 7 (t, 1H), 3.6 (s, 2H), 2.8 to 3.1 (m, 3H), 2.5 (s, 3H), 1.8 to 2.4 (m , 6H).

Example 65: '8-methoxy-2- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2-a] pyrazine

Example 65 is prepared according to example 61 MS (M + 1): 557.13 1 H NMR (300 MHz, CDCl 3): - δ

8 (d, J = 7.8Hz, 1 H), 7.65-7.75 (m, 3H), 7.49-7.57 (m, 4H), 7.4-7.48 (m, 2H), 7.277.35 (m, 2H), 7.2 (d, J = 7.8Hz, 1H), 4.2 (s, 2H), 3.7 (s, 2H), 2.8-3 , 2 (m, 3H), 2.6 (s, 3H), 2-2.3 (m, 4H).

Example 66: '6- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -5-phenylimidazo [2,1b] [1,3] thiazole

Example 66 is prepared according to example 61 MS (M + 1): 532.07 1 H NMR (300 MHz, CDCl 3): - δ

7.94 (d, J = 7.5Hz, 1H), 7.75-7.15 (m, 13H), 6.81 (d, J = 4.2Hz, 1H), 3.52 (s, 2H ), 3.05-2.75 (m, 3H), 2.58 (s, 3H), 2.2-1.8 (m, 6H).

Example 67: '6- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -5-phenylimidazo [2,1b] [1,3,4] thiadiazole

Example 67 is prepared according to example 61 MS (M + 1): 533.13 1H NMR (300 MHz, CDCl3): -  8.54 (s, 1H), 7.94 (d, J = 7.5Hz , 1H), 7.75-7.55 (m, 4H), 7.5-7.15 (m, 8H), 3.58 (s, 2H),

3.1-2.8 (m, 3H), 2.58 (s, 3H), 2.4-1.9 (m, 6H).

Example 68: '7-methoxy-2- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3phenylimidazo [1,2-a] pyridine

Example 68 is prepared according to example 61 MS (M + 1): 557.3 1 H NMR (300 MHz, CDCl 3): - δ

8 (m, 2H), 7.65 to 7.75 (m, 3H), 7.4 to 7.6 (m, 5H), 7.1 to 7.3 (m, 3H), 6 , 4 (d, 1H), 4.1 (s, 3H), 3.6 (s, 2H), 2.8 to 3.1 (m, 3H), 2.5 (s, 3H), of 1.9 to 2.4 (m, 6H).

Example 69: 6-methyl-2- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl ) phenyl] -3phenylimidazo [1,2-b] pyridazine (467395)

Example 69 is prepared according to example 61 MS (M + 1): 541.13 1 H NMR (300 MHz, CDCl 3): - δ

from 7.85 to 7.95 (m, 2H), from 7.55 to 7.75 (m, 5H), from 7.4 to 7.5 (m, 3H), from 7.3 to 7.4 (m, 2H), 7.2 (d, 1H), 6.9 (d, 1H), 3.7 (s, 2H), 2.9 to 3.1 (m, 3H), 2.6 (s, 3H), 2.5 (s, 3H), from 2 to 2.3 (m, 6H).

Example 70: '2- [4 - ({4- [5- (5-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2a] pyrimidine

Triethylamine (2 eq.) Is added to a solution of 0.115 g (0.367 mM) of 4- (3-phenylimidazo [1,2-a] pyrimidin-2-yl) benzaldehyde in 3 ml of THF. The reaction mixture is stirred for 5 minutes. To this solution is added 5-methyl-2- [3- (piperidin-4-yl) -1H-1,2,4-triazol-5-yl] pyridine dihydrochloride (intermediate D) (1.5 eq .) followed by acetic acid (2.5 eq). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq) over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 527.13

1H NMR (300 MHz, CDCl3): - δ

8.57-8.55 (q, 1H), 8.43 (sa, 1H), 8.23 (dd, J = 6.9.1.8Hz, 1H), 8.04 (d, J = 8 , 1Hz, 2H), 7.64-7.59 (m, 1H), 7.58-7.52 (m, 3H), 7.49-7.47 (m, 2H), 7.30 (d , J = 8.4Hz 2H), 6.83-6.79 (q, 1H). 3.63 (s, 2H), 3.06 (d, 2H), 2.91 (sa, 1H), 2.39 (s, 3H), 2.72 (sa, 1H), 2.10-1 , 87 (m, 4H).

Example 71: '2- [4 - ({4- [5- (5-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2a] pyridin-8-carbonitrile

Example 71 is prepared according to Example 70 MS (M + 1): 551.2 1 H NMR (300 MHz, CDCl 3): - δ

8.5 (s, 1H), 8.1 (d, J = 6.9Hz, 1H), 8 (d, J = 8.1Hz, 1H), 7.6 to 7.7 (m, 4H) , 7.5 to 7.6 (m, 3H), 7.4 to 7.5 (m, 2H), 7.3 (m, 2H), 6.8 (d, 1H), 3.6 (s, 2H), 2.8 to 3.1 (m, 3H), 2.4 (s, 3H), 1.9 to 2.2 (m, 6H)

Example 72: '2- [4 - ({4- [5- (5-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2a] pyridin-7-carbonitrile

Example 72 is prepared according to Example 70 MS (M + 1): 551.27 1 H NMR (300 MHz, DMSO-d6) δ

8.50 (sa, 1H), 8.45 (s, 1H), 8.13 (dd, J = 7.2Hz, 0.9Hz, 1H), 7.92 (d, J = 8.1Hz, 1H ), 7.75 (sa, 1H), 7.67-7.53 (m, 7H), 7.28 (d, J = 8.4Hz, 2H), 7.17 (dd, J = 7.2Hz , 1.Hz, 1H) 3.47- (s, 2H), 2.87-2.72 (m, 3H), 2.11-1.74 (m, 6H)

Example 73: '6- [4 - ({4- [5- (5-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -5-phenylimidazo [2,1b] [1,3] thiazole

Example 73 is prepared according to example 70

MS (M + 1): 532.07 1H NMR (300 MHz, CDCl3): - δ

8.47 (s, 1H), 8.04 (d, J = 7.8Hz, 1H), 7.65-7.2 (m, 12H), 6.81 (d, J = 4.5Hz, 1H ), 3.58 (s, 2H), 3.1-2.8 (m, 3H), 2.39 (s, 3H), 2.3-1.9 (m, 6H)

Example 74: '6- [4 - ({4- [5- (5-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -5-phenylimidazo [2,1b] [1,3,4] thiadiazole

Example 74 is prepared according to example 70

MS (M + 1): 533.07 1

1H NMR (300 MHz, CDCl3): - δ

8.53 (s, 1H), 8.47 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.68-7.25 (m, 11H), 3.57 (s, 2H), 3.12.8 (m, 3H), 2.39 (s, 3H), 2.3-1.9 (m, 6H)

Example 75: '2- [4 - ({4- [5- (5-chloropyridin-2-yl) -1H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2a] pyridin-8-carbonitrile

To a solution of 0.230 g (0.712 mM) of 2- (4-formylphenyl) -3-phenylimidazo [1,2-a] pyridin-8-carbonitrile in 5 ml of THF is added triethylamine (2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 5-chloro-2- [3- (piperidin-4-yl) -1H-1,2,4-triazol-5-yl] pyridine dihydrochloride (intermediate E) (1.5 eq .) followed by acetic acid (2.5 eq.). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq.) Over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 571.2

1H NMR (300 MHz, CDCl3): - δ

8.61 (sa, 1H), 8.11 (t, 2H), 7.78-7.58 (m, 2H), 7.71-7.7.43 (m, 6H), 7.28-7, 17 (m, 4 H), 6.85 (t, 1H), 4.88 (sa, 1H), 3.55 (s, 2H), 2.97 (, 3H), 2.21-1.7 (m, 5H).

Example 76: '2- [4 - ({4- [5- (5-chloropyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2a] pyrimidine

Example 76 is prepared according to example 75

MS (M + 1): 547.07

1H NMR (300 MHz, CDCl3): - δ

8.612 (sa, 1H), 8.55 (q, 1H), 8.24 (dd, J = 2.1Hz, 6.9Hz, 1H), 8.10 (d, J = 8.4Hz, 1H), 7.75 (dd, J = 2.1.8.4Hz, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.58-7.52 (m, 3H), 7, 48-7,431 (m, 2H), 7.26-7.22 (m, 2 H), 6.82 (q, 1H), 3.52 (s, 2H), 2.98-2.86 (m , 3H), 2,157-1.95 (m, 6H).

Example 77: 3-phenyl-2- [4 - ({4- [5- (pyrimidin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl ] imidazo [1,2-a] pyridin8-carbonitrile

To a solution of 0.125 g (0.582 mM) of 2- (4-formylphenyl) -3-phenylimidazo [1,2-a] pyridin-8-carbonitrile in 4 ml of THF is added triethylamine (2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 2- [3- (piperidin-4-yl) -1H-1,2,4-triazol-5-yl] pyrimidine dihydrochloride (intermediate F) (1.5 eq.) Followed by acetic acid (2.5 eq.). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq.) Over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 538.2

1H NMR (300 MHz, CDCl3): - δ

8.15 (s, 1H), 7.9 (m, 2H), 7.7 (m, 3H), 7.55 (m, 3H), 7.45 (m, 2H), 7.3 (d , J = 8.1Hz, 2H), 7.2 (d, J = 7.5Hz, 1H), 6.9 (d, 1H), 3.6 (s, 2H), 3 (d, 2H), 2.9 (m, 1H), 2.5 (s, 3H), 2-2.6 (m, 6H).

Example 78: 3-phenyl-2- [4 - ({4- [5- (pyrimidin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl ] imidazo [1,2-a] pyridin7-carbonitrile

Example 78 is prepared according to example 77

MS (M + 1): 538.2 1H NMR (300 MHz, CDCl3): - δ

8.92 (d, J = 4.5 Hz, 1H), 8.45 (s, 1H), 8.13 (d, J = 7.2 Hz, 1H), 7.53-7.66 (m , 9H), 7.29 (d, J = 7.8 Hz, 2H), 7.15-7.18 (dd, J = 1.5 Hz, 6.9 Hz, 2H), 3.49 (s , 2H), 2.85 (sa, 2H), 1,755-2,101 (m, 5H)

Example 79: '3-phenyl-2- (4 - {[4- (5-pyrimidin-2-yl-1H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2a] pyrimidine

Example 79 is prepared according to example 77 MS (M + 1): 514.13 1 H NMR (300 MHz, CDCl 3): - δ

8.88 (d, J = 4.2 Hz, 2H), 8.564 (s, 1H), 8.24 (dd, J = 7.5.1.8 Hz 1H), 7.70 (d, J = 8.1Hz, 2H), 7.611-7.516 (m, 3H), 7.467-7.435 (m, 2H), 7.326 (m, 1H), 7.282-7.255 (m, 2H), 6.835-6.799 (m, 1H), 3.604 (s, 2H), 3.01 (d, J = 11.1Hz, 3H) 2,356-2,063 (m, 6H).

Example 80: '3-phenyl-2- (4 - {[4- (5-pyrimidin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridine

Example 80 is prepared according to example 77 MS (M + 1): 513.13 1 H NMR (300 MHz, DMSO-d6) �

9.0 (s, 2H), 8 (d, 1H), 7.4-7.7 (m, 9H), 7.1 to 7.3 (m, 3H), 6.9 (t, 1H) , 3.5 (s, 2H), 2.6-3.2 (m, 3H), 1.7-2.3 (m, 6H).

Example 81: '5-phenyl-6- (4 - {[4- (5-pyrimidin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1-b] [1,3] thiazole

Example 81 is prepared according to example 77 MS (M + 1): 519.07 1 H NMR (300 MHz, DMSO-d6) δ

8.91 (d, J = 4.2Hz, 2H), 7.7 (d, J = 4.5Hz, 1H), 7.6-7.18 (m, 12H), 3.46 (s, 2H ), 2.88-2.63 (m, 3H), 2.22-1.74 (m, 6H).

Example 82: '5-phenyl-6- (4 - {[4- (5-pyrimidin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1b] [1,3,4] thiadiazole

Example 82 is prepared according to example 77 MS (M + 1): 520.13 1 H NMR (300 MHz, CDCl 3): - δ

8.90 (d, J = 4.8Hz, 2H), 8.54 (s, 1H), 7.65-7.25 (m, 11H), 3.58 (s, 2H), 3.1- 2.9 (m, 3H), 2.25-1.95 (m, 6H)

Example 83: '6-methyl-3-phenyl-2- (4 - {[4- (5-pyrimidin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2b] pyridazine

Example 83 is prepared according to example 77 MS (M + 1): 528.2 1 H NMR (300 MHz, CDCl 3): - δ

9.0 (s, 1H), 7.9 (d, 1H), 7.7 (d, 2H), 7.3 to 7.6 (m, 8H), 6.9 (d, 1H), 4.1 (s, 2H), 3.13.4 (m, 3H), 2.8 (m, 3H), 2.5 (s, 1H), 2.2-2.4 (m, 3H) .

Example 84: '3-phenyl-2- [4 - ({4- [5- (1,3-thiazol-2-yl) -1H-1,2,4-triazol-3-yl] piperidin-1- il} methyl) phenyl] imidazo [1,2-a] pyrimidine

To a solution of 0.340 g (1,137 mM) of 4- (3-phenylimidazo [1,2-a] pyrimidin-2-yl) benzaldehyde in 7 ml of THF is added triethylamine (2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 4- [5- (1,3-thiazol-2-yl) -1H-1,2,4-triazol-3-yl] piperidine dihydrochloride (intermediate G) (1.5 eq .) followed by acetic acid (2.5 eq.). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq.) Over a period of 60 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 519.07 1H NMR (300 MHz, CDCl3): - δ

8.567 (s, 1H), 8.26 (d, J = 6Hz 1H), 7.92 (d, J = 3 Hz 1H), 7.67 (d, J = 8.1Hz, 2H), 7.5497 , 364 (m, 6H), 7,227 (s, 2H), 6,852-6,816 (m, 1H), 3,585 (s, 2H), 2.99 (d, 3H) 2,211-1,971 (m, 6H).

Example 85: '3-phenyl-2- [4 - ({4- [5- (1,3-thiazol-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1- il} methyl) phenyl] imidazo [1,2a] pyridine

Example 85 is prepared according to example 84 MS (M + 1): 518.07 1 H NMR (300 MHz, CDCl 3): - δ

7.9-8.1 (m, 2H), 7.7 (d, 1H), 7.4-7.7 (m, 8H), 7.1-7.3 (m, 3H), 6, 8 (t, 1H), 3.6 (s, 2H), 2.73.1 (m, 3H), 1.8-2.3 (m, 6H).

Example 86: '3-phenyl-2- [4 - ({4- [5- (1,3-thiazol-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1- il} methyl) phenyl] imidazo [1,2a] pyridin-8-carbonitrile

Example 86 is prepared according to example 84 MS (M + 1): 543.07 1 H NMR (300 MHz, CDCl 3): -  8.2 (d, 1 H), 8 (s, 1 H), 7.6- 7.7 (m, 3H), 7.4-7.6 (m, 6H), 7.2-7.4 (m, 2H), 6.8 (t, 1H),

3.6 (s, 2H), 2.8-3.1 (m, 3H), 1.9-2.3 (m, 6H).

Example 87: '5-phenyl-6- [4 - ({4- [5- (1,3-thiazol-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1- il} methyl) phenyl] imidazo [2,1-b] [1,3] thiazole

Example 87 is prepared according to example 84 MS (M + 1): 524.07 1H NMR (300 MHz, CDCl3): - ,957.95 (d, J = 3.3Hz, 1H), 7.6- 7.2 (m, 12H), 6.84 (d, J = 4.8Hz, 1H), 3.59 (s, 2H), 3.05-2.85

(m, 3H), 2.3-1.9 (m, 6H).

Example 88: '5-phenyl-6- [4 - ({4- [5- (1,3-thiazol-2-yl) -1H-1,2,4-triazol-3-yl] piperidin-1- il} methyl) phenyl] imidazo [2,1b] [1,3,4] thiadiazole

Example 88 is prepared according to example 84 MS (M + 1): 525.07 1H NMR (300 MHz, CDCl3): - ,58.55 (s, 1H), 7.94 (d, J = 3Hz, 1H), 7.65-7.25 (m, 11H), 3.58 (s, 2H), 3.1-2.8 (m, 3H), 2.3

1.8 (m, 6H)

Example 89: '3-phenyl-2- [4 - ({4- [5- (1,3-thiazol-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1- il} methyl) phenyl] imidazo [1,2a] pyridin-7-carbonitrile

Example 89 is prepared according to example 84 MS (M + 1): 543.13 1 H NMR (300 MHz, CDCl3): - 

8.101 (s 1H), 8.023 (dd J = 7.2 Hz, 0.9 Hz, 1H), 7.966 (d, J = 3.3 Hz, 1H), 7.64 (d, J = 8.1Hz, 2H), 7,611-7,559 (m, 3H), 7,479-7,448 (m, 3H), 7.31 (d, J = 8.4 Hz, 2H), 6,908 (dd, J = 7.2Hz, J = 1 , 8 Hz, 1H) 3,615 (s, 2H), 3,053-2,915 (m, 4H), 2.24-1,993 (m, 7H)

Example 90: '2- [4 - ({4- [5- (2-furyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2-a] pyridine-8carbonitrile

To a solution of 0.188 g (0.557 mM) of 2- (4-formylphenyl) -3-phenylimidazo [1,2-a] pyridin-8-carbonitrile in 5 ml of THF is added triethylamine (2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 4- [5- (furan-2-yl) -1H-1,2,4-triazol-3-yl] piperidine dihydrochloride (intermediate H) (1.5 eq.) Followed by acetic acid (2.5 eq.). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq.) Over a period of 60 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 526.13

1H NMR (300 MHz, CDCl3): - ,28.2 (d, 1H), 7.6-7.7 (m, 3H), 7.5-7.6 (m, 3H), 7.5 (m, 1H), 7.4-7.5 (m, 2H), 7.2-7.3 (m, 2H), 7 (d, 1H), 6.8 (t, 1H), 6, 5 (q, 1H), 3.6 (s, 2H), 2.8-3.1 (m, 3H), 1.8-2.3 (m, 6H).

Example 91: '2- [4 - ({4- [5- (2-furyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2-a] pyridine

Example 91 is prepared according to example 90 MS (M + 1): 501.13 1 H NMR (300 MHz, CDCl 3): - 8 (d, 1 H), 7.7 (d, 1 H), 7.4 -7.7 (m, 9H), 7.2-7.3 (m, 3H), 7 (d, 1H), 6.8 (t, 1H), 6.5 (q, 1H), 3, 6

(s, 2H), 2.8-3 (m, 3H), 1.8-2.2 (m, 6H).

Example 92: '2- [4 - ({4- [5- (2-furyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -6-methyl -3-phenylimidazo [1,2b] pyridazine

Example 92 is prepared according to example 90 MS (M + 1): 516.13 1 H NMR (300 MHz, CDCl 3): - 

7.9 (d, 1H), 7.6 (m, 4H), 7.4 to 7.5 (m, 4H), 7.2 to 7.3 (m, 2H), 6.9 at 7 (m, 2H), 6.5 (q, 1H), 3.6 (s, 2H), 2.8 to 3.1 (m, 3H), 2.5 (s, 3H), of 1.9 to 2.2 (m, 6H).

Example 93: '6- [4 - ({4- [5- (2-furyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -5-phenylimidazo [2,1-b] [1,3] thiazole

Example 93 is prepared according to example 90 MS (M + 1): 507.07 1H NMR (300 MHz, CDCl3): - ,58.55 (s, 1H), 7.65-7.2 (m, 12H), 6.98 (d, J = 3.3Hz, 1H), 6.55-6.45 (m, 1H), 3.56 (s, 2H),

3.1-2.8 (m, 3H), 2.3-1.8 (m, 6H)

Example 94: '6- [4 - ({4- [5- (2-furyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -5-phenylimidazo [2,1b] [1,3,4] thiadiazole

Example 94 is prepared according to example 90 MS (M + 1): 508.07 1 H NMR (300 MHz, CDCl 3): - 

7.6-7.15 (m, 11H), 6.97 (d, J = 3Hz, 1H), 6.82 (d, J = 4.5Hz, 1H), 6.55-6.45 (m , 1H), 3.51 (s, 2H), 3.0-2.8 (m, 3H), 2.2-1.8 (m, 6H).

Example 95: '2- [4 - ({4- [5- (2-furyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2-a] pyrimidine

Example 95 is prepared according to example 90

MS (M + 1): 502.2

1H NMR (300 MHz, CDCl3): - ,58.57-8.55 (m, 1H), 8.25 (dd, J = 6.6.1.8Hz, 1H), 7.69 (d, J = 8.4 Hz 2H), 7.56-7.43 (m, 6H), 7.24 (s, 2H), 6.98 (d, J = 3.3Hz, 1H), 6.84- 6.81 (m, 1H), 6.50-6.48 (m, 1H), 3,581 (s, 2H), 3.02-2.91 (m, 3H) 2.18 (t, 2H), 2,085-1.93 (m, 4H).

Example 96: '2- [4 - ({4- [5- (2-furyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2-a] pyridine-7carbonitrile

Example 96 is prepared according to example 90

MS (M + 1): 526.13

1H NMR (300 MHz, CDCl3): - ,08.07 (s, 1H), 7.51 (d, J = 5.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.58-7.43 (m 6H), 7.29 (d, J = 8.1Hz, 2H), 7.98 (d, J = 3.3Hz, 1H), 6.89 (dd , J = 6.9 Hz, 4.5 Hz, 1H), 6.51 (dd, J = 3.3 Hz, 1.8Hz, 1H) 3.6 (s, 2H), 3.042.91 (m, 3H), 2.4-1.94 (m, 8H)

Example 97: '3-phenyl-2- [4 - ({4- [5- (2-thienyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-a] pyridine

To a solution of 0,120 g (0.402 mM) of 4- (3-phenylimidazo [1,2-a] pyridin-2-yl) benzaldehyde in 5 ml of THF is added triethylamine (2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 4- [5- (thiophen-2-yl) -1 H-1,2,4-triazol-3-yl] piperidine dihydrochloride (intermediate I) (1.5 eq.) Followed by acetic acid (2.5 eq.). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq.) Over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 517.13

1H NMR (300 MHz, CDCl3): - 8 (d, 1H), 7.4-7.7 (m, 9H), 7.2-7.4 (m, 4H), 7.1 (m , 1H), 6.8 (t, 1H), 3.6 (s, 2H), 2.8-3.1 (m, 3H), 1.8-2.2 (m, 6H).

Example 98: '3-phenyl-2- [4 - ({4- [5- (2-thienyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-a] pyridine-8carbonitrile

Example 98 is prepared according to example 97 MS (M + 1): 542.13 1 H NMR (300 MHz, CDCl 3): - ,18.1 (d, 1 H), 7.6-7.7 (m, 4H), 7.5-7.6 (m, 3H), 7.4-7.5 (m, 2H), 7.2-7.4 (m, 3H), 7.1 (m, 1H) ,

6.8 (t, 1H), 3.6 (s, 2H), 2.8-3.1 (m, 3H), 1.8-2.3 (m, 6H).

Example 99: '6-methyl-3-phenyl-2- [4 - ({4- [5- (2-thienyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2b] pyridazine

Example 99 is prepared according to example 97 MS (M + 1): 532.13 1H NMR (300 MHz, CDCl3): - ,97.9 (d, J = 9.3Hz, 1H), 7.5- 7.7 (m, 5H), 7.4-7.5 (m, 3H), 7.3-7.35 (d, J = 5.1Hz, 1H), 7.2-7.3 (m

, 2H), 3.6 (s, 2H), 2.8-3 (m, 3H), 2.5 (s, 3H), 1.8-2.2 (m, 6H).

Example 100: '5-phenyl-6- [4 - ({4- [5- (2-thienyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [2,1-b] [1,3] thiazole

Example 100 is prepared according to example 97 MS (M + 1): 523.07 1H NMR (300 MHz, CDCl3): - ,67.66-7.0 (m, 14H), 6.825 (d, J = 4.5Hz, 1H), 3.61 (s, 2H), 3.15-2.85 (m, 3H), 2.3-1.9 (m,

6H).

Example 101: '5-phenyl-6- [4 - ({4- [5- (2-thienyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [2,1-b] [1,3,4] thiadiazole

Example 101 is prepared according to example 97 MS (M + 1): 524.07 1H NMR (300 MHz, CDCl3): - ,58.57 (s, 1H), 7.7-7.05 (m, 13H), 3.61 (s, 2H), 3.14-2.85 (m, 3H), 2.3-1.9 (m, 6H).

Example 102: '3-phenyl-2- [4 - ({4- [5- (2-thienyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-a] pyridine-7carbonitrile

Example 102 is prepared according to example 97 MS (M + 1): 542.13 1 H NMR (300 MHz, DMSO-d6) 

8.44 (s, 1H), 8.13 (d, J = 7.2 Hz, 1H), 7.64 = 7.5 (m, 10H), 7.28 (d, J = 5.4Hz, 2H), 7,727.12 (m, 2H), 3.51 (sa, 3H), 2.89-2.78 (m 3H), 2.1-1.74 (m, 6H)

Example 103: '7-Chloro-3-phenyl-2- [4 - ({4- [5- (2-thienyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2a] pyridine

Example 103 is prepared according to example 97 MS (M + 1): 551.07 1H NMR (300 MHz, CDCl3): - ,97.9 (d, J = 7.5Hz, 1H), 7.7 ( d, J = 2.1Hz, 1H), 7.5-7.67 (m, 5H), 7.4-7.5 (m, 2H), 7.18-7.35 (m,

3H), 7.09 (q, 1H), 6.7 (q, 1H), 3.5 (s, 2H), 2.8-3 (m, 3H), 1.7-2.2 (m , 6H)

Example 104: '6-methyl-3-phenyl-2- [4 - ({4- [5- (1H-pyrrole-2-yl) -4H-1,2,4-triazol-3-yl] piperidin- 1-yl} methyl) phenyl] imidazo [1,2b] pyridazine

To a solution of 0.125 g (0.479 mM) of 4- (6-methyl-3-phenylimidazo [1,2-b] pyridazin-2-yl) benzaldehyde in 6 ml of THF is added triethylamine (2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 4- [5- (1H-pyrrol-2-yl) -1H-1,2,4-triazol-3-yl] piperidine dihydrochloride (intermediate J) (1.5 eq.) followed by acetic acid (2.5 eq). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq.) Over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 515.13

1H NMR (300 MHz, CDCl3): - ,59.5 (s, 1H), 7.9 (d, J = 9Hz, 1H), 7.55-7.65 (m, 4H), 7.4 -7.5 (m, 3H), 7.2-7.3 (m, 2H), 6.8-7 (m, 2H), 6.7 (s, 1H), 6.2-6.3 (s, 1H), 3.5 (s, 2H), 2.8-3 (m, 3H), 2.5 (s, 3H) 1.7-2.2 (m, 6H)

Example 105: '3-phenyl-2- [4 - ({4- [5- (1H-pyrrole-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2a] pyridin-8-carbonitrile

Example 105 is prepared according to example 104 MS (M + 1): 525.13 1H NMR (300 MHz, CDCl3): - ,59.5 (s, 1H), 8.1 (d, J = 6, 9Hz, 1H), 7.6-7.7 (m, 3H), 7.5-7.6 (m, 3H), 7.4-7.5 (m, 2H), 7.2

7.3 (m, 2H), 6.5-7 (m, 3H), 6.3 (m, 1H), 3.5 (s, 2H), 2.8-3 (m, 3H), 1 , 7-2.2 (m, 6H).

Example 106: '3-phenyl-2- [4 - ({4- [5- (1H-pyrrol-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2a] pyrimidine

Example 106 is prepared according to example 104 MS (M + 1): 501.13 1 H NMR (300 MHz, CDCl 3): - 

8.56 (q, J = 2.1Hz, 1H), 8.25 (dd, J = 6.9.2.1Hz, 1H), 7.68 (d, J = 8.1Hz, 2H), 7 , 60-7.51 (m, 3H), 7.45-7.428 (m, 2H), 7.24 (s, 2H), 6.91-6.76 (m, 3H), 6.24 (q , J = 3.3Hz, 1H), 3.56 (s, 2H), 2.98 (d, J = 11.1Hz, 2H), 2.88-2.81 (m, 1H), 2.18 -1.93 (m, 6H),

Example 107: '7-Chloro-3-phenyl-2- [4 - ({4- [5- (1H-pyrrol-2-yl) -4H-1,2,4-triazol-3-yl] piperidin- 1-yl} methyl) phenyl] and midazo [1,2-a] pyridine

Example 107 is prepared according to example 104 MS (M + 1): 534.13 1 H NMR (300 MHz, CDCl 3): - 

8.56 (q, J = 2.1Hz, 1H), 8.25 (dd, J = 6.9.2.1Hz, 1H), 7.68 (d, J 9.5 (s, 1H)) 7.9 (d, J = 7.5Hz, 1H) 7.4-7.7 (m, 8H), 7.2-7.3 (m, 2H), 6.9 (m, 1H), 6.7-6.8 (m, 2H), 6.3 (q, 1H), 3.5 (s, 2H), 2.8-3 (m, 3H), 1.8-2.2 ( m, 6H).

Example 108: '5-phenyl-6- [4 - ({4- [5- (1H-pyrrole-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [2,1b] [1,3,4] thiadiazole

Example 108 is prepared according to example 104 MS (M + 1): 507.13 1 H NMR (300 MHz, CDCl 3): - 

9.7 (s, 1H), 8.54 (s, 1H), 7.66-7.24 (m, 10H), 6.87 (sa, 1H), 6.73 (sa, 1H), 6 , 26 (m, 1H), 3.57 (s, 2H), 3.1-2.6 (m, 3H), 2.25-1.85 (m, 6H).

Example 109: '5-phenyl-6- [4 - ({4- [5- (1H-pyrrole-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [2,1b] [1,3] thiazole

Example 109 is prepared according to example 104 MS (M + 1): 506.13 1 H NMR (300 MHz, CDCl 3): - 9.93 (s, 1 H), 7.6-7.2 (m, 10H), 6.9-6.7 (m, 3H), 6.3-6.2 (m, 1H), 3.59 (s, 2H), 3.0-2.8 (m,

3H), 2.3-1.8 (m, 7H)

Example 110: '3-phenyl-2- [4 - ({4- [5- (1H-pyrrole-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2a] pyridin-7-carbonitrile

Example 110 is prepared according to example 104

MS (M + 1): 525.2

1H NMR (300 MHz, CDCl3): - ,08.06 (s, 1H), 8.8 (d, J = 7.2 Hz, 1H), 7.614 (d, J = 4.2 Hz, 2H) , 7.59-7.57 (m 3H), 7.46-7.43 (m, 2H), 7.26 (s, 2H), 6.91-6.87 (m, 2H), 6.725 ( s, 1H) 6.28 (dd, J = 6Hz, 2.7 Hz, 1H), 3,515 (s, 1H), 2.96 (d, 2H), 2.82 (m, 1H), 2.15 -1.71 (m, 7H)

Example 111: '3-phenyl-2- (4 - {[4- (3-pyridin-2-yl-1H-pyrazol-5-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2, a] pyridine

To a solution of 0.250 g (0.838 mM) of 4- (3-phenylimidazo [1,2-a] pyridin-2-yl) benzaldehyde in 6 ml of THF is added triethylamine (2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 2- [3- (piperidin-4-yl) -1 H -pyrazol-5-yl] pyridine dihydrochloride (intermediate K) (1.5 eq.) Followed by acetic acid (2.5 eq.). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq.) Over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 511.13

1H NMR (300 MHz, CDCl3): - 

8.6 (d, 1H), 7.9 (d, 1H), 7.6-7.8 (m, 5H), 7.4-7.6 (m, 5H), 7.15-7, 4 (m, 4H), 6.8 (t, 1H), 6.6 (s, 1H), 3.7 (s, 2H), 3.1 (m, 2H), 2.8 (m, 1H ), 1.8-2.4 (m, 6H).

Example 112: '5-phenyl-6- (4 - {[4- (5-pyridin-2-yl-1H-pyrazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1- b] [1,3,4] thiadiazole

Example 112 is prepared according to example 111 MS (M + 1): 518.07 1 H NMR (300 MHz, CDCl 3): - 

9.22 (s, 1H), 8.53 (s, 1H), 7.9-7.75 (m, 2H), 7.6-7.2 (m, 10H), 6.61 (s, 1H), 3.49 (s, 2H), 3.0-2.5 (m, 3H), 2.2-1.6 (m, 6H)

Example 113: '5-phenyl-6- (4 - {[4- (5-pyridin-2-yl) -1 H -pyrazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1 -b] [1,3] thiazole

Example 113 is prepared according to example 111 MS (M + 1): 517.07 1H NMR (300 MHz, CDCl3): - 12.75 (s, 1H), 8.53 (d, J = 4, 8Hz, 1H), 7.92-7.18 (m, 14H), 6.6 (s, 1H), 3.45 (s, 2H), 2.95

2.55 (m, 3H), 2.2-1.55 (m, 5H).

Example 114: '3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridine-7carbonitrile

Example 114 is prepared according to example 111 MS (M + 1): 536.2

1H NMR (300 MHz, CDCl3): - ,58.57 (d, J = 4.8 Hz, 1H), 8.06 (s, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.73-7.44 (m, 9H), 7.30 (d, J = 8.1Hz, 2H), 7.23-7.19 (m, 1H), 6.89 (dd, J = 7.2 Hz, 1.8 Hz, 1H), 6.59 (s, 1H), 3.56 (s, 2H), 2.50 (d, 2H), 2.74 (m, 1H) , 2.15-1.82 (m, 14H)

Example 115: '3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-oxadiazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyridine-7carbonitrile

To a solution of 0.250 g (0.838 mM) of 2- (4-formylphenyl) -3-phenylimidazo [1,2-a] pyridin-7-carbonitrile in 6 ml of THF is added triethylamine (2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 2- [3- (piperidin-4-yl) -1,2,4-oxadiazol-5-yl] pyridine dihydrochloride (intermediate L) (1.5 eq.) Followed by acetic acid ( 2.5 eq.). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq.) Over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 537.6

1H NMR (300 MHz, DMSO-d6) 

8.74 (d, J = 4.8 Hz, 1H), 8.43 (s, 1H), 8.113 (d, J = 7.2Hz, 1H), 8.061-7.99 (m, 2H), 7.647 , 51 (m, 8H), 7.3 (d, J = 8.1Hz, 2H), 7.15 (dd, J = 6.9 Hz 1.5 Hz, 1H), 3.47- (s, 2H), 2.84-2.80 (m, 2H), 2.17-2.05 (m, 4H), 1.83-1.79 (m, 2H)

Example 116: '3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-oxadiazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyrimidine

Example 116 is prepared according to example 115

MS (M + 1): 514.13

1H NMR (300 MHz, DMSO-d6) �

8.75 (d, J = 4.8Hz, 1H), 8.59 (q, 1H), 8.55-8.44 (m, 1H), 8.07-7.98 (m, 2H), 7.64-7.47 (m, 8H), 7.03 (q, 1H), 7.31 (m, 2H), 3.49 (s, 2H), 3.19-3.14 (m, 1 H), 2.91-2.82 (m, 2H), 2.24-2.06 (m, 4H), 1,891.81 (m, 2H).

Example 117: 3-phenyl-2- (4 - {[4- (5-phenyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2 -a] pyridin-8-carbonitrile

To a solution of 0.250 g (0.838 mM) of 2- (4-formylphenyl) -3-phenylimidazo [1,2-a] pyridine-8-carbonitrile in 6 ml of THF is added triethylamine (2 eq.). The reaction mixture is stirred for 5 minutes. To this solution is added 4- (5-phenyl-1H-1, 2,4-triazol-3-yl) piperidine (intermediate product M) (1.5 eq.) Followed by acetic acid (2.5 eq.). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH (OAc) 3 (6 eq.) Over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained in chloroform is taken and washed with water, dried and concentrated. The crude product is purified on flash column chromatography to obtain the desired compound.

MS (M + 1): 536.2

1H NMR (300 MHz, CDCl3): - 8.1 (d, 1H), 8.0 (m, 2H), 7.6-7.7 (m, 3H), 7.5-7.6 (m, 3H), 7.4-7.5 (m, 5H), 7.2-7.3 (m, 2H), 6.8 (t, 1H), 3.6 (s, 2H), 2.8-3.1 (m, 3H), 1.9-2.3 (m, 6H).

Example 118: 3-phenyl-2- (4 - {[4- (5-phenyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2 -a] pyridine-7carbonitrile

Example 118 is prepared according to example 117

MS (M + 1): 536.2

1HNMR (300 MHz, CDCl3): - 8.1 (s, 1H), 8.03-7.9 (m, 3H), 7.62 (d, J = 8.4Hz, 2H), 7, 57-7.54 (m, 3H), 7.46-7.39 (m, 5H), 7.3 (d, J = 9.6Hz, 2H), 6.9 (dd, J = 4.2Hz , 0.6Hz, 1H), 3.54 (s, 2H), 3.02-2.91 (m, 3H), 2.185-1.87 (m, 6H)

Example 119: 6-methyl-3-phenyl-2- (4 - {[4- (5-phenyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2b] pyridazine

Example 119 is prepared according to example 117

MS (M + 1): 526.13 1H NMR (300 MHz, CDCl3): - ,18.1 (d, J = 8.1Hz, 2H), 7.9 (d, J = 9.3Hz, 1H ), 7.6 (m, 4H), 7.4 to 7.5 (m, 6H), 7.2 to 7.3 (m, 2H), 6.9 (d, J = 9Hz, 1H) , 3.6 (s, 2H), from 2.8 to 3.1 (m, 3H), 2.5 (s, 3H), from 1.8 to 2.2 (m, 6H).

Example 120: 7-Chloro-3-phenyl-2- (4 - {[4- (5-phenyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridine

Example 120 is prepared according to example 117 MS (M + 1): 445.2 1 H NMR (300 MHz, CDCl 3): - ,18.1 (d, 2H), 7.9 (d, J = 7, 5Hz, 1H), 7.7 (d, 1H), 7.6 to 7.65 (m, 2H), 7.4 to 7.6 (m, 7H),

from 7.2 to 7.3 (m, 2H), 6.8 (dd, J = 7.2Hz, 1H), 3.6 (s, 2H), from 2.8 to 3.1 (m, 3H ), from 1.6 to 2.2 (m, 6H).

Example 121: 3-phenyl-2- (4 - {[4- (5-henyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2 -a] pyrimidine.

Example 121 is prepared according to example 117 MS (M + 1): 512.27 1 H NMR (DMSO d6): - 

8.59 (q, J = 2.4Hz, 1H), 8.476 (dd, J = 6.9.1.8Hz, 1H), 7.975 (d, J = 7.2 Hz 2H), 7.646-7.529 (m , 7H), 7,437-7,411 (m, 3H), 7,281 (d, J = 7,8Hz, 2H), 7,034 (q, 1H), 3,485 (s, 2H), 2,873 (d J = 9,9Hz, 2H ), 2,729 (t, 1H) 2,087 (t, 2H), 1,925 (t, 2H), 1,799 (t, 2H).

Example 122: 5-phenyl-6- (4 - {[4- (5-phenyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1 -b] [1,3] thiazole

Example 122 is prepared according to example 117 MS (M + 1): 517.07 1H NMR (300 MHz, CDCl3): - ,08.05-8.00 (m, 2H), 7.6-7, 21 (m, 13H), 6.82 (d, J = 4.5Hz, 1H), 3.58 (s, 2H), 3.1-2.85 (m,

3H), 2.3-1.9 (m, 6H).

Example 123: 5-phenyl-6- (4 - {[4- (5-phenyl-4H-1, 2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1 -b] [1,3,4] thiadiazole

Example 123 is prepared according to example 117 MS (M + 1): 518.13 1H NMR (300 MHz, CDCl3): - ,58.54 (s, 1H), 8.07-7.98 (m, 2H), 7.68-7.22 (m, 12H), 3.56 (s, 2H), 3.1-2.8 (m, 3H), 2.25

1.8 (m, 6H).

Example 124: 3-phenyl-2- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl ] imidazo [1,2-a] methyl pyridine-7-carboxylate

Example 124 is prepared according to example 12

MS (M + 1); 570.1

1H NMR (300 MHz, CDCl3): - ,68.67 (d, J = 4.2 Hz, 1H), 8.414 (s, 1H), 8.161 (d, J = 7.8 Hz 1H), 7.967 ( d, J = 6.6Hz, 1H), 7.825 (t, J = 1.5Hz 1H), 7.621 (d, J = 8.1Hz, 2H), 7.564-7.517 (m, 3H), 7.373-7.319 (m , 2H), 7,295 (s, 2H) 3.97 (s, 3H), 3,535 (s, 2H), 2.98 (d, J = 11.4Hz, 2H), 2,175-1,948 (m, 6H).

Example 125: 3-phenyl-2- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2a] pyridine-7-carboxylic

To a solution of example 124 (0.100 g, 0.175 mM) in methanol (3 ml) is added 1N NaOH (1 ml). The resulting reaction mixture is stirred at room temperature overnight. The reaction mass is then concentrated to remove methanol, diluted with 4 ml of water and neutralized (pH �

7). The precipitated solid is filtered and dried to provide the desired compound. MS (M + 1): 556.13 1 H NMR (DMSO-d6): - 

8.653 (sa, 1H), 8.32 (s, 1H), 8.174 (s, 1H), 8.079-8.015 (m, 2H), 7.93 (sa, 1H), 7.65-7.532 (m, 7H ), 7,462 (sa, 1H), 7,337-7,263 (m, 3H), 3,5 (s, 3H), 2,877 (d, J = 10,8Hz, 2H) 2,729 (m, 21H), 2,118 (t, J = 11.1Hz, 2H), 1,953 (d, 2H), 1.80 (t, J = 10.5Hz, 2H).

Example 126: Methoxy [5-phenyl-6- (4 - {[4- (5-pyridin-2-yl-1H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [2,1b] [1,3] thiazol-2-yl] methanol

Example 126 is prepared according to example 12

MS (M + 1): 573.13

1H NMR (300 MHz, CDCl3): - ,68.675 (d, J = 4.5Hz, 1H), 8.175 (d, J = 7.8 Hz, 1H), 8.09 (s, 1H), 7.844 ( td, J = 7.8 Hz, 1.Hz, 1H), 7.60 (d, J = 8.1Hz, 2H), 7.511-7.46 (m, 5H), 7.395-7.349 (m, 1H) , 7.292 (d, J = 6.3Hz, 1H) 3.934 (s, 3H), 3.55 (s, 2H), 3.011 (d, J = 11.4 Hz, 2H), 2.88 (m, 2H ), 2,257-1,975 (m, 8H)

Example 127: '5-phenyl-6- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl ) imidazo [2,1b] [1,3] thiazol-2-carboxylic

To a solution of example 126 (0.125 g 0.219 mM) in 3 ml of methanol and 2 ml of water is added potassium carbonate (3 eq.). The resulting reaction mixture is stirred at room temperature overnight. The reaction mass is then concentrated to remove methanol, diluted with 4 ml of water and neutralized (pH �

7). The precipitated solid is filtered and dried to provide the desired compound.

MS (M + 1): 562.07

1H NMR (300 MHz, DMSO-d6) 

14.44 (sa, 1H), 8.67 (d, J = 3 Hz, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.57-7.44 (m, 8H), 7.34 (d, J = 7.5Hz, 2H), 3.83-3.75 (sa, 2H) 3.17- 2.89 (m, 4H), 2.18-1.69 (m, 4H)

Commercial utility

The compounds of formula (I) and the stereoisomers of the compounds of formula (I) according to the invention are hereinafter referred to as compounds of the invention. In particular, the compounds of the invention are pharmaceutically acceptable. The compounds according to the invention have valuable pharmaceutical properties, which make them commercially usable. In particular, they inhibit the Pi3K / Akt pathway and show cellular activity. It is expected that they can be applied commercially in the therapy of diseases (for example diseases dependent on overactivated Pi3K / Akt).

Cellular activity and analogous terms in the present invention are used as known to those skilled in the art, as an example, induction of apoptosis or chemosensitization.

Chemosensitization and similar terms in the present invention are used as known to those skilled in the art. These stimuli include, for example, effectors of death receptors and survival pathways as well as cytotoxic / chemotherapeutic and directed agents and finally radiotherapy. Induction of apoptosis and similar terms according to the present invention are used to identify a compound that produces programmed cell death in cells in contact with that compound or in combination with other compounds routinely used for therapy. Apoptosis in the present invention is used as known to those skilled in the art. The induction of apoptosis in cells in contact with the compound of this invention may not necessarily be coupled with the inhibition of cell proliferation. Preferably, inhibition of proliferation and / or induction of apoptosis are specific for cells with aberrant cell growth.

In addition, the compounds according to the present invention inhibit protein kinase activity in cells and tissues, causing a shift towards dephosphorylated substrate proteins and as a functional consequence, for example, the induction of apoptosis, cell cycle arrest and / or sensitization towards chemotherapeutic drugs and against target specific cancer. In a preferred embodiment, inhibition of the Pi3K / Akt pathway induces cellular effects as mentioned herein alone or in combination with conventional directed cytotoxic or directed anti-cancer drugs.

The compounds according to the present invention show antiproliferative and / or proapoptotic and / or chemosensitization properties. Accordingly, the compounds of the present invention are useful for the treatment of hyperproliferative disorders, in particular cancer. Therefore, the compounds of the present invention are used in the production of an antiproliferative and / or proapoptotic and / or chemosensitization effect in mammals such as humans suffering from hyperproliferative disorders, such as cancer.

The compounds according to the present invention show antiproliferative and / or proapoptotic properties in mammals such as humans due to inhibition of the metabolic activity of cancer cells that can survive despite unfavorable growth conditions such as glucose depletion, hypoxia or other stresses. chemical

Therefore, the compounds according to the present invention are for treating, improving or preventing diseases of benign or malignant behavior as described herein, such as for example to inhibit cell neoplasia.

Neoplasia in the present invention is used as known to those skilled in the art. A benign neoplasm is described by hyperproliferation of cells, which cannot form an aggressive tumor, that produces metastases in vivo. In contrast, a malignant neoplasm is described by cells with multiple biochemical and cellular abnormalities, which can form a systemic disease, for example forming tumor metastases in distant organs.

The compounds according to the present invention can preferably be used for the treatment of malignant neoplasia. Examples of malignant neoplasia that can be treated with the compounds according to the present invention include solid and hematologic tumors. Solid tumors can be exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands (for example thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney, liver , lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissues, testicles, stomach, skin, ureter, vagina and vulva. Malignant neoplasms include inherited cancers exemplified by retinoblastoma and Wilms tumor. In addition, malignant neoplasms include primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases"). Hematologic tumors can be exemplified by indolent and aggressive forms of leukemia and lymphoma, specifically non-Hodgkin's disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkin's disease, multiple myeloma and T-cell lymphoma Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes and cancers of unknown primary site as well as AIDS-related malignant tumors.

It is observed that a malignant neoplasm does not necessarily require the formation of metastases in distant organs. Certain tumors exert devastating effects on the primary organ itself through its aggressive growth properties. These can lead to the destruction of the structure of the organ and tissue resulting in the insufficiency of the assigned organic function and death.

Drug resistance is of particular importance for the frequent failure of conventional therapeutic agents against cancer. This drug resistance is caused by various cellular and molecular mechanisms. One aspect of drug resistance is caused by the constitutive activation of antiapoptotic survival signals with PKB / Akt as a key signaling kinase. Inhibition of the Pi3K / Akt pathway leads to resensitization towards conventional chemotherapeutic agents or target specific cancer therapeutic agents. As a consequence, the commercial applicability of the compounds according to the present invention is not limited to the treatment of 1st line of cancer patients. In a preferred embodiment, cancer patients with resistance to cancer chemotherapeutic agents or target specific anticancer drugs can also be used for treatment with these compounds for, for example, 2nd or 3rd line treatment cycles. In particular, the compounds according to the present invention could be used in combination with conventional targeted drugs or chemotherapeutics to resensitize tumors towards these agents.

In the context of their properties, functions and utilities mentioned herein, the compounds according to the present invention are distinguished by unexpected desirable and valuable effects related thereto, such as for example superior therapeutic window, superior bioavailability (such as for example good oral absorption), low toxicity and / or additional beneficial effects related to its therapeutic and pharmaceutical qualities.

The compounds according to the present invention are for the treatment, prevention or amelioration of the benign and malignant diseases described above, such as for example benign or malignant neoplasia, particularly cancer, especially a cancer that is sensitive to the inhibition of Pi3K / Akt route.

The present invention further includes the use of the compounds for treating, preventing or improving mammals, including human beings, suffering from one of the conditions, ailments, disorders or diseases mentioned above. The use is characterized in that a tolerable and therapeutically effective and pharmacologically active amount of one or more of the compounds according to the present invention is administered to the subject in need of such treatment.

The present invention further includes the use of the compounds to treat, prevent or ameliorate diseases that respond to the inhibition of the Pi3K / Akt pathway, in a mammal, including a human being, which comprises administering a tolerable and therapeutically effective and pharmacologically effective amount. activates one or more of the compounds according to the present invention to said mammal.

The present invention further includes the use of the compounds for treating hyperproliferative diseases of benign or malignant behavior and / or disorders that respond to the induction of apoptosis, such as for example cancer, particularly any of the cancerous diseases described above, in a mammal, which comprises administering a tolerable and therapeutically effective and pharmacologically active amount of one or more of the compounds according to the present invention to said mammal.

The present invention further includes the use of the compounds to inhibit cell hyperproliferation or stop aberrant cell growth in a mammal, which comprises administering a tolerable and therapeutically effective and pharmacologically active amount of one or more of the compounds according to the present invention to said mammal.

The present invention further includes the use of the compounds to induce apoptosis in the therapy of benign or malignant neoplasia, particularly cancer, which comprises administering a tolerable and therapeutically effective and pharmacologically active amount of one or more of the compounds according to the present invention to a Subject who needs such therapy.

The present invention further includes the use of the compounds to inhibit protein kinase activity in cells comprising administering a tolerable and therapeutically effective and pharmacologically active amount of one or more of the compounds according to the present invention to a patient in need of such therapy.

The present invention further includes the use of the compounds to sensitize chemotherapeutic agents or anti-cancer agents specific to the target in a mammal, which comprises administering a tolerable and therapeutically effective and pharmacologically active amount of one or more of the compounds according to the present invention to said mammal.

The present invention further includes the use of the compounds for treating benign and / or malignant neoplasia, particularly cancer, in a mammal, including a human being, comprising administering a tolerable and therapeutically effective and pharmacologically active amount of one or more of the compounds. according to the present invention said mammal.

The present invention further relates to the use of the compounds for the production of pharmaceutical compositions, which are used for the treatment, prophylaxis and / or improvement of one or more of the aforementioned conditions. The present invention further relates to the use of the compounds for the manufacture of pharmaceutical compositions for treating, preventing or improving hyperproliferative diseases and / or disorders that respond to the induction of apoptosis, such as for example benign or malignant neoplasia, in particular cancer.

The present invention further relates to the use of the compounds according to this invention for the production of pharmaceutical compositions for treating, preventing or improving benign or malignant neoplasia, particularly cancer, such as for example any of the cancerous diseases described above.

The invention further relates to a compound according to the invention or a pharmaceutically acceptable salt thereof, for the treatment and / or prophylaxis of (hyper) proliferative diseases and / or disorders that respond to the induction of apoptosis, including benign neoplasia and malignancy, including cancer.

The invention further relates to a pharmaceutical composition, which comprises a compound according to the invention.

or a pharmaceutically acceptable salt thereof, for the treatment and / or prophylaxis of (hyper) proliferative diseases and / or disorders that respond to the induction of apoptosis, which include benign neoplasia and malignant neoplasia, including cancer.

The present invention further relates to the use of pharmaceutically acceptable compounds and salts according to the present invention for the manufacture of pharmaceutical compositions, which can be used to sensitize chemotherapeutic agents or anti-cancer agents specific to the target.

The present invention further relates to the use of compounds according to the present invention for the manufacture of pharmaceutical compositions, which can be used to sensitize radiotherapy of the diseases mentioned herein, particularly cancer.

The present invention further relates to the use of the compounds according to the present invention for the manufacture of pharmaceutical compositions, which can be used in the treatment of diseases sensitive to protein kinase inhibitor therapy and other than cell neoplasia. These non-malignant diseases include, but are not limited to, benign prostatic hyperplasia, neurofibromatosis, dermatosis and myelodysplastic syndromes.

The present invention further relates to pharmaceutical compositions comprising one or more of the compounds according to this invention and a pharmaceutically acceptable carrier or diluent.

The present invention further relates to pharmaceutical compositions comprising one or more of the compounds according to this invention and pharmaceutically acceptable auxiliary compounds and / or excipients.

The pharmaceutical compositions according to this invention are prepared by methods known per se and are familiar to the person skilled in the art. As pharmaceutical compositions, the compounds of the invention (= active compounds) are either employed as such, or preferably in combination with appropriate auxiliary compounds and / or pharmaceutical excipients, for example in the form of tablets, coated tablets, sugar-coated tablets. , pills, cachets, granules, capsules, oblong tablets, suppositories, patches (for example as TTS), emulsions (such as for example microemulsions or lipid emulsions), suspensions (such as for example nanosuspensions), gels, solubilized or solutions (for sterile solutions, for example), or encapsulated in liposomes or as inclusion complexes of beta-cyclodextrin or beta-cyclodextrin derivatives or the like, the content of the active compound being advantageously between 0.1 and 95% and in which, by the appropriate choice of auxiliary compounds and / or excipients, a form of pharmaceutical administration can be achieved (by example a delayed release form or an enteric form) exactly suitable for the active compound and / or for the desired start of the action.

The person skilled in the art is familiar with auxiliary compounds, vehicles, excipients, diluents, carriers.

or adjuvants that are suitable for the desired pharmaceutical formulations, preparations or compositions taking into account their expert knowledge. In addition to solvents, gel formers, ointment bases and other excipients of the active compound, for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers (such as, for example, polyoxyethylene glyceroltryricinoleate 35, PEG 400, Tween 80, Captisol, Solutol HS15 or similar), colorants, complexing agents, permeation promoters, stabilizers, fillers, binders, thickeners, disintegrating agents, buffers, pH regulators (for example to obtain neutral, alkaline or acidic formulations), polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, flavorings, sweeteners or dyes.

In particular, auxiliary compounds and / or excipients of a type suitable for the desired formulation and the desired mode of administration are used.

The administration of the compounds, pharmaceutical compositions or combinations according to the invention can be carried out in any of the generally accepted modes of administration available in the art. Illustrative examples of suitable modes of administration include intravenous, oral, nasal, parenteral, topical, transdermal and rectal administration. Oral and intravenous administrations are preferred.

Generally, the pharmaceutical compositions according to the invention can be administered so that the dose of the active compound is in the usual range for inhibitors of the Pi3K / Akt pathway. In particular, a dose in the range of from 0.01 to 4000 mg of the active compound per day is preferred for an average adult patient having a body weight of 70 kg. In this regard, it should be noted that the dose depends, for example, on the specific compound used, the species treated, the age, body weight, general health, sex and diet of the treated subject, the mode and time of administration, the rate of excretion, the severity of the disease to be treated and the combination of drugs.

The pharmaceutical composition can be administered in a single dose per day or in multiple sub-doses, for example, from 2 to 4 doses per day. A single dose unit of the pharmaceutical composition may contain for example from 0.01 mg to 4000 mg, preferably from 0.1 mg to 2000 mg, more preferably from 0.5 to 1000 mg, most preferably from 1 to 500 mg. , of the active compound. In addition, the pharmaceutical composition can be adapted to a weekly, monthly or even more infrequent administration, for example using an implant, for example a subcutaneous or intramuscular implant, using the active compound in the form of a moderately soluble salt or using the active compound coupled to a polymer

The choice of the optimal dosage regimen and the duration of the medication, particularly the optimal dose and manner of administration of the necessary active compounds in each case can be determined by one skilled in the art.

The present invention further relates to combinations comprising one or more first active ingredients selected from the compounds of the invention and one or more second active ingredients selected from chemotherapeutic anticancer agents and target specific anticancer agents for example to treat, prevent or ameliorate diseases that respond or are sensitive to inhibition of the Pi3K / Akt pathway, such as hyperproliferative diseases of benign or malignant behavior and / or disorders that respond to the induction of apoptosis, particularly cancer, such as for example any of the cancerous diseases described previously.

The invention further relates to the use of a pharmaceutical composition comprising one or more of the compounds according to this invention as the sole active ingredient (s) and a pharmaceutically acceptable carrier or diluent in the manufacture of pharmaceutical products for the treatment and / or prophylaxis of the ailments mentioned above.

Depending on the particular disease, to be treated or prevented, additional therapeutic active agents, which are normally administered to treat or prevent that disease, may optionally be co-administered with the compounds according to this invention. As used herein, additional therapeutic agents are known that are normally administered to treat or prevent a particular disease as appropriate for the disease being treated.

The second active ingredient mentioned above, which is a chemotherapeutic anticancer agent, includes but is not limited to (i) alkylating / carbamilating agents such as cyclophosphamide (Endoxan®), ifosfamide (Holoxan®), thiotepa (Thiotepa Lederle®), melphalan ( Alkeran®), or chloroethylnitrosourea (BCNU); (ii) platinum derivatives such as cisplatin (Platinex® BMS), oxaliplatin (Eloxatin®), satraplatin or carboplatin (Cabroplat® BMS); (iii) tubulin antimitotic agents / inhibitors such as vinca alkaloids (vincristine, vinblastine, vinorelbine), taxanes such as paclitaxel (Taxol®), docetaxel (Taxotere®) and the like as well as new formulations and conjugates thereof ( such as the formulation of Abraxane® nanoparticles with paclitaxel bound to albumine), epothilones such as epothilone B (Patupilone®), azaepotilone (Ixabe pilone®) or ZK-EPO, a completely synthetic epothilone B analogue; (iv) topoisomerase inhibitors such as anthracyclines (exemplified by doxorubicin / Adriblastin®), epipodophyllotoxins (exemplified by estopósido / Etopophos®) and camptothecin and camptothecin analogs (exemplified by irinotecan / Camptosar® or Topotecan / Hytecan); (v) pyrimidine antagonists such as 5-fluorouracil (5-FU), capecitabine (Xeloda®), arabinosylcytosine / cytarabine (Alexan®) or gemcitabine (Gemzar®); (vi) purine antagonists such as 6-mercaptopurine (Puri-Nethol®), 6-thioguanine or fludarabine (Fludara®) and (vii) folic acid antagonists such as methotrexate (Farmitrexat®) or premetrexed (Alimta®).

The second active ingredient mentioned above, which is a target specific anticancer agent, includes but is not limited to (i) kinase inhibitors such as imatinib (Glivec®), ZD-1839 / gefitinib (Iressa®), Bay43- 9006 (sorafenib, Nexavar®), SU11248 / sunitinib (Sutent®), OSI-774 / erlotinib (Tarceva®), dasatinib (Sprycel®), lapatinib (Tykerb®), or, see also below, vatalanib, vandetanib (Zactima ®) or pazopanib; (ii) proteasome inhibitors such as PS-341 / bortezumib (Velcade®); (iii) histone deacitalase inhibitors such as SAHA (Zolinza®), PXD101, MS275, MGCD0103, depsipeptide / FK228, NVP-LBH589, valproic acid (VPA), CRA / PCI 24781, ITF2357, SB939 and butyrates (iv) inhibitors heat shock protein 90 such as 17-allylaminogeldanamicin (17-AAG) or 17-dimethylaminogeldanamicin (17-DMAG); (v) vascular targeting agents (VTA) such as combretastine A4 phosphate or AVE8062 / AC7700 and antiangiogenic drugs such as antibodies against VEGF, such as bevacizumab (Avastin®), or KDR tyrosine kinase inhibitors such as PTK787 / ZK222584 (Vatalanib® ) or vandetanib (Zactima®) or pazopanib; (vi) monoclonal antibodies such as trastuzumab (Herceptin®), rituximab (MabThera / Rituxan®), alemtuzumab (Campath®), Tositumomab (Bexxar®), C225 / cetuximab (Erbitux®), avastine (see above) or panitumumab (Vectibix ®) as well as monoclonal antibody mutants and conjugates, for example gemtuzumab ozogamicin (Milotarg®) or ibritumomab tiuxetan (Zevalin®), and antibody fragments; (vii) oligonucleotide-based therapeutic compounds such as G-3139 / oblimersen (Genasense®) or the MG98 DNMT1 inhibitor; (viii) Toll / TLR 9 receptor agonists such as Promune®, TLR 7 agonists such as imiquimod (Aldara®) or isatoribine and analogs thereof, or TLR 7/8 agonists as resiquimod as well as immunostimulatory RNA as agonists TLR 7/8; (ix) protease inhibitors; (x) hormonal therapeutic compounds such as antiestrogens (for example tamoxifen or raloxifene), antiandrogens (for example flutamide or casodex), LHRH analogs (for example leuprolide, goserelin or triptorelin) and aromatase inhibitors (for example Femara, Arimedex or Aromasin ).

Other target-specific anticancer agents include bleomycin, retinoids such as all-trans retinoic acid (ATRA), DNA methyltransferase inhibitors such as 5-aza-2'-deoxycytidine (decitabine, Dacogen®) and 5azacitidine (Vidaza®), alanosine, cytokines such as interleukin-2, interferons such as interferon 2 or interferon-, bcl2 antagonists (for example ABT-737 or the like), death receptor agonists, such as TRAIL agonist antibodies, DR4 / 5, FasL agonists and TNF-R (for example TRAIL receptor agonists such as mapatumumab or lexatumumab).

Specific examples of the second active ingredient include, but are not limited to 5 FU, actinomycin D, ABARELIX, ABCIXIMAB, ACLARUBYCIN, ADAPALENE, ALEMTUZUMAB, ALTRETAMINE, AMINOGLUTETIMIDE, AMIPRILOSE, AMRUBYCIN, ANASTROZOL, ANCITAINBINBIN, BINYLIMINABINBIN bevacizumab, Bexxar, bicalutamide, bleomycin, bortezomib, broxuridine, busulfan, CAMPATH, capecitabine, carboplatin, carboquone, carmustine, cetrorelix, chlorambucil, mechlorethamine, cisplatin, cladribine, clomiphene, cyclophosphamide, dacarbazine, daclizumab dactinomycin, dasatinib, daunorubicin, decitabine, deslorelin, dexrazoxane, docetaxel, doxifluridine, doxorubicin, droloxifene, drostanolone, edelfosine, eflornithine, emitefur, epirubicin, epitiostanol, eptaplatin, ERBITUX, erlotinib, estramustine, etoposide, exemestane, fadrozole, finasteride, floxuridine, flucytosine, fludarabine, fluorouracil, flutamide, FORMESTANE, FOSCARNET, FOSFESTROL, PHOTEMUSTINE, FULVESTRANT, GEFITINIB, GEN ASense, gemcitabine, Glivec, goserelin, gusperimus, herceptin, idarubicin, idoxuridine, ifosfamide, imatinib, improsulfan, infliximab, irinotecan, ixabepilone, lanreotide, lapatinib, letrozole, leuprolide, lobaplatin, lomustine, luprolide, melphalan, mercaptopurine, methotrexate, meturedepa, MIBOPLATINO, mifepristone, miltefosine mirimostim, mitoguazone, mitolactol, mitomycin, mitoxantrone, mizoribine, motexafin, Mylotarg, nartograstim, NEBAZUMAB, nedaplatin, nilutamide, nimustine, octreotide, ORMELOXIFENO, oxaliplatin, paclitaxel, palivizumab panitumumab, PATUPILONA, pazopanib, pegaspargase, pegfilgrastim , pEMETREXED, pentetreotide, pentostatin, perfosfamide, piposulfan, pirarubicin, plicamycin, prednimustine, procarbazine, propagermanium CHLORIDE PROSPIDIO, raloxifene, raltitrexed, ranimustine, ranpirnase, RASBURICASE, razoxane, rITUXIMAB, rIFAMPICIN, RITROSULFÁN, romurtide, ruboxistaurin, sARGRAMOSTIM, satraplatin , SIROLIMUS, SOBUZOXANO, SORAFENIB, ESPIROMUSTINA , Streptozocin, sunitinib, tamoxifen, tasonermin, tegafur, temoporfin, temozolomide, teniposide, testolactone, thiotepa, thymalfasin, thiamiprine, topotecan, toremifene, TRAIL, trastuzumab, treosulfan, triaziquone, trimetrexate, triptorelin, trofosfamide, uredepa, valrubicin, vatalanib, vandetanib , VERTEPORFINA, VINBLASTINA, VINCRISTINA, VINDESINA, VINORELBINA, VOROZOL, ZEVALINA and ZOLINZA.

The anticancer agents mentioned herein as combination pairs of the compounds according to this invention are intended to include pharmaceutically acceptable derivatives thereof, such as, for example, their pharmaceutically acceptable salts.

The person skilled in the art is aware of the total daily dosage (s) and dosage (s) and the administration method (s) of the additional therapeutic agent (s). co-administered (s). Said dosage (s) / total daily dose (s) may vary within a wide range.

In the practice of the present invention, the compounds according to this invention can be administered in combination therapy separately, sequentially, simultaneously, concurrently or chronologically staggered (such as for example as combined unit dosage forms, as separate unit dosage forms, such as adjacent differentiated unit dosage forms, as fixed or non-fixed combinations, as kit of parts or as mixtures) with one or more conventional therapeutic compounds (chemotherapeutic agents and / or target specific anticancer agents), in particular anticancer agents known in the art, such as any of for example those mentioned above.

In this context, the present invention further relates to a combination comprising a first active principle, which is at least one compound according to this invention, and a second active principle, which is at least one anticancer agent known in the art, such as for example one or more of those mentioned hereinbefore, for use separately, sequentially, simultaneously, concurrently or chronologically staggered in therapy, such as for example in therapy of any of the diseases mentioned herein.

The term "combination" in the present invention is used as known to those skilled in the art and may be presented as a fixed combination, a non-fixed combination or kit of parts.

A "fixed combination" in the present invention is used as known to those skilled in the art and is defined as a combination in which said first active principle and said second active principle are present together in a unit dosage or in an individual entity. An example of a "fixed combination" is a pharmaceutical composition in which said first active principle and said second active principle are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination in which said first active principle and said second active principle are present in a unit without being mixed.

A non-fixed combination or "kit of parts" in the present invention is used as known to those skilled in the art and is defined as a combination in which said first active principle and said second active principle are present in more than one unit. An example of a non-fixed combination or kit of parts is a combination in which said first active principle and said second active principle are present separately. The components of the non-fixed combination or parts kit can be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

The present invention further relates to a pharmaceutical composition comprising a first active ingredient, which is at least one compound according to this invention, and a second active ingredient, which is at least one anti-cancer agent known in the art, such as for example one or more than those mentioned herein above, and, optionally, a pharmaceutically acceptable carrier or diluent, for separate, sequential, simultaneous, concurrent or chronologically staggered use in therapy.

The present invention further relates to a combination product comprising

a.) at least one compound according to this invention formulated with a pharmaceutically acceptable carrier or diluent, and

b.) at least one anticancer agent known in the art, such as for example one or more of those mentioned hereinbefore, formulated with a pharmaceutically acceptable carrier or diluent.

The present invention further relates to a kit of parts comprising a preparation of a first active ingredient, which is a compound according to this invention, and a pharmaceutically acceptable carrier or diluent; a preparation of a second active ingredient, which is an anticancer agent known in the art, such as one of those mentioned above, and a pharmaceutically acceptable carrier or diluent; for simultaneous, concurrent, sequential, separate or chronologically staggered use in therapy. Optionally, said kit comprises instructions for use in therapy, for example to treat hyperproliferative diseases and diseases that respond or sensitive to inhibition of the Pi3K / Akt pathway, such as for example benign or malignant neoplasia, particularly cancer, more precisely , any of the cancerous diseases described above.

The present invention further relates to a combined preparation comprising at least one compound according to this invention and at least one anticancer agent known in the art for simultaneous, concurrent, sequential or separate administration.

The present invention further relates to combinations, compositions, formulations, preparations or kits according to the present invention that have inhibitory activity of the Pi3K / Akt pathway.

In addition, the present invention further relates to a method of treating hyperproliferative diseases and / or disorders that respond to induction of apoptosis, such as cancer, in combination therapy in a patient comprising administering a combination, composition, formulation. , preparation

or kit as described herein to said patient in need.

In addition, the present invention further relates to a method for treating hyperproliferative diseases of benign or malignant behavior and / or disorders that respond to induction of apoptosis, such as cancer, in a patient comprising administering in combination therapy by simultaneously, concurrently, concurrently, sequentially or chronologically staggered a tolerable and therapeutically effective and pharmaceutically active amount of a pharmaceutical composition, comprising a compound according to this invention and a pharmaceutically acceptable carrier or diluent, and a tolerable and therapeutically effective and pharmaceutically effective amount. activates one or more anti-cancer agents known in the art, such as, for example, one or more of those mentioned herein, to said patient in need thereof.

Additionally, the present invention relates to a method for treating, preventing or improving hyperproliferative diseases and / or disorders that respond to the induction of apoptosis, such as for example benign or malignant neoplasia, for example cancer, particularly any of the cancerous diseases. mentioned herein, in a patient comprising administering separately, concurrently, concurrently, sequentially or chronologically staggered to said patient in need thereof an amount of a first active compound, which is a compound according to the present invention, and a amount of at least a second active compound, said at least one second active compound being a conventional therapeutic agent, particularly at least one anticancer agent known in the art, such as for example one or more of the chemotherapeutic and target specific anticancer agents mentioned in this document, in which the ca The first active compound and said second active compound result in a therapeutic effect.

Still further, the present invention relates to a method for treating, preventing or ameliorating hyperproliferative diseases and / or disorders that respond to the induction of apoptosis, such as for example benign or malignant neoplasia, for example cancer, particularly any of the diseases. cancers mentioned herein, in a patient comprising administering a combination according to the present invention.

Furthermore, the present invention further relates to the use of a composition, combination, formulation, preparation or kit according to this invention in the manufacture of a pharmaceutical product, such as for example a commercial container or medicament, for treating, preventing or ameliorating diseases. hyperproliferatives, such as for example cancer, and / or disorders that respond to the induction of apoptosis, particularly the diseases mentioned herein, such as for example malignant or benign neoplasia.

The present invention further relates to a commercial package comprising one or more compounds of the present invention together with instructions for simultaneous, concurrent, sequential or separate use with one or more chemotherapeutic and / or target specific anti-cancer agents, such as by example any of those mentioned in this document.

The present invention further relates to a commercial package consisting essentially of one or more compounds of the present invention as the sole active ingredient together with instructions for simultaneous, concurrent, sequential or separate use with one or more chemotherapeutic and / or specific anti-cancer agents. of target, such as for example any of those mentioned herein.

The present invention further relates to a commercial package comprising one or more chemotherapeutic and / or target specific anticancer agents, such as for example any of those mentioned herein, together with instructions for simultaneous, concurrent, sequential or separated with one or more compounds according to the present invention.

The compositions, combinations, preparations, formulations, kits or packages mentioned in the context of the combination therapy according to this invention may also include more than one of the compounds according to this invention and / or more than one the anti-cancer agents known in the art mentioned .

The first and second active principle of a combination or kit of parts according to this invention can be provided as separate formulations (i.e. independently of each other), which are subsequently combined for simultaneous, concurrent, sequential, separate or chronologically staggered use in therapy. of combination; or packaged and presented together as separate components of a combination package for simultaneous, concurrent, sequential, separate or chronologically staggered use in combination therapy.

The type of pharmaceutical formulation of the first and the second active ingredient of a combination or kit of parts according to this invention may coincide, that is, both components are formulated into separate tablets or capsules, or may be different, that is, suitable for different forms. for administration, as for example an active ingredient is formulated as a tablet or capsule and the other one is formulated for for example intravenous administration.

The amounts of the first and second active ingredients of the combinations, compositions or kits according to this invention may together comprise a therapeutically effective amount for the treatment, prophylaxis or improvement of a hyperproliferative disease and / or a disorder that responds to the induction of Apoptosis, particularly one of the diseases mentioned herein, such as for example malignant or benign neoplasia, especially cancer, as any of the cancerous diseases mentioned herein.

In addition, compounds according to the present invention can be used in the pre or post-surgical treatment of cancer.

Additionally, compounds of the present invention can be used in combination with radiotherapy.

A combination according to this invention may refer to a composition comprising both the compound (s) according to this invention and the other active anticancer agent (s) in a fixed combination (pharmaceutical form) fixed unit), or a package of medicine comprising the two or more active ingredients as separate separate dosage forms (non-fixed combination). In the case of a medicine package comprising the two or more active ingredients, the active ingredients are preferably packaged in blister cards, which are suitable for improving compliance.

Each blister card preferably contains the medications to be taken on a day of treatment. If the medications are to be taken at different times of the day, the medications can be arranged in different sections on the blister card according to the different time intervals of the day in which the medications are to be taken (for example, morning and night or tomorrow, noon and night). The blister cavities for medications to be taken at a particular time of day are accommodated in the respective range of times of day. Of course, the various moments of the day are also placed in the blister in a clearly visible way. It is also possible, of course, for example to indicate a period in which the medications are to be taken, for example by setting the times.

The daily sections may represent a blister card line, and then the times of day are identified in chronological sequence in this column.

Medications that must be taken together at a particular time of day are placed together at the appropriate time on the blister card, preferably separated a narrow distance, allowing them to be easily removed from the blister, and have the effect of not forget to extract the pharmaceutical form of the blister.

Biological research

P13K / Akt cell path assay

In order to study the cellular activity of the compounds according to the present invention, an assay based on enzyme-linked immunosorbent assay (ELISA) specific for phospho-AKT has been used. The assay is based on a sandwich ELISA kit (PathScan phospho-Akt1 (Ser473); Cell Signaling, USA; No. 7160). The ELISA kit detects endogenous levels of phosphorylated Akt protein. An antibody against phospho-Akt (Ser473) (Cell Signaling, USA; # 9271) has been coated on the microwells. After incubation with cell lysates, the coated antibody captures the phosphorylated Akt protein. After thorough washing, the monoclonal antibody against Akt1 (Cell Signaling, USA; # 2967) is added to detect the captured phospho-Akt1 protein. Then anti-mouse antibody bound to HRP (HRP: horseradish peroxidase; Cell Signaling, USA; # 7076) is used to recognize the bound detection antibody. The HRP substrate (= 3.3 ’, 5.5’-tetramethylbenzidine (TMB); Cell Signaling, USA; # 7160) is added to develop the color. The magnitude of the optical density for this developed color is proportional to the amount of phosphorylated Akt protein. MCF7 cells (ATCC HTB-22) are seeded in 96-well flat bottom plates at a density of 10,000 cells / well. 24 hours after sowing, cells are deprived of serum using low serum medium (IMEM media including FCS treated with 0.1% carbon (FCS: fetal calf serum)). After 24 hours, 1 µl of each of the compound dilutions is added (the test compounds were dissolved as 10 mM solutions in dimethylsulfoxide (DMSO) and subsequently diluted) to each well of the 96-well plates and incubated for 48 h at 37 ° C in a humidified atmosphere containing 5% CO2. To stimulate the phosphorylation of Akt, here-heregulin (-HRG 20 ng / ml) is added in parallel to the compounds. Wells containing unstimulated control cells (without stimulation with here-heregulin) are incubated with or without the diluted compound. Wells containing untreated control cells (without compound) are filled with medium containing 0.5% v: v DMSO and stimulated or not with -heregulin. The cells are collected and lysed with brief sonification in 1x cell lysis buffer (20 mM Tris (pH 7.5), 150 mM NaCl, 1 mM ethylenediaminetetraacetate (EDTA), ethylene glycolbis (2-aminoethyl) -N acid, 1 mM N, N ', N'-tetraacetic acid (EGTA), 1% Triton X-100, 2.5 mM sodium pyrophosphate, 1 mM g-glycerophosphate, 1 mM Na3VO4, 1 g / ml leupeptin) . The lysate is centrifuged for 10 min. at 4 ° C and the supernatant is transferred to a new tube. 100 µl of sample diluent (0.1% Tween 20 by volume, 0.1% volume sodium azide in phosphate buffered saline (PBS)) is added to a microcentrifuge tube and 100 µl is transferred cell lysate to the tube and vortexed. 100 µl of each diluted cell lysate is added to the appropriate ELISA well, and incubated overnight at 4 ° C. The plates are washed 4 times with 1x wash buffer (1% tween 20 by volume, thymol 0.33% by volume, in PBS). Next, 100 µl of detection antibody (monoclonal detection antibody against Akt1 (2H10); Cell Signaling, USA; # 2967) is added to each well and incubation is continued for 1 h at 37 ° C. The washing procedure is repeated between each stage. 100 µl of secondary antibody (anti-mouse IgG antibody bound to HRP; Cell Signaling, USA; No. 7076) is added to each well and incubated for 30 min. at 37 ° C. Then, 100 µl of TMB substrate (3,3 ', 5,5'-tetramethylbenzidine 0.05%, 0.1% hydrogen peroxide, complex polypeptides in a buffered solution are added; Cell Signaling, USA .; No. 7160) to each well and incubate for 30 min. at 25 ° C. Finally, 100 µl of stop solution (carbonyl compound  and 0.05% unsaturated by volume) is added to each well and the plate is gently shaken. Absorbance at 450 nm (Wallac Victor2; Perkin Elmer, USA) is measured within 30 min. after adding the stop solution. Data analysis is performed using a statistical program (Excel; Microsoft, USA). Preferred compounds show an inhibitory activity towards Akt phosphorylation below 10 µM.

Cellular pGSK3 assay:

In order to study the cellular activity of the compounds according to the present invention, an ELISA based assay for phosphorylated glycogen synthetase kinase 3 (GSK3) protein has been established. The assay is based on a solid phase sandwich ELISA that detects endogenous levels of phosphorylated GSK3 using specific antibodies against phospho-GSK3 (Ser9) (BioSource International, Inc .; catalog No. KH00461). After incubation with cell lysates, the coated antibody captures the phosphorylated GSK3 protein. After thorough washing, polyclonal antibody against GSK3 is added to detect the captured phospho-GSK3 protein. The secondary antibody (rabbit anti-rabbit IgG-HRP) is then used to recognize the bound detection antibody. After the second incubation and washing to remove all excess rabbit anti-rabbit IgG-HRP antibody, a substrate solution is added, which acts on the bound enzyme to produce color. The intensity of the colored product is directly proportional to the concentration of GSK-3

[pS9] present in the original sample. MCF7 cells (ATCC HTB-22) were seeded in 96-well flat bottom plates at a density of 10,000 cells / well. After 24 h, 1 µl of each of the compound dilutions was added (test compounds were dissolved as 10 mM solutions in dimethylsulfoxide (DMSO) and subsequently diluted) to each well of the 96-well plates and incubated for 48 h at 37 ° C in a humidified atmosphere containing 5% CO2.

The cells were collected and lysed in cell extraction buffer (10 mM Tris, pH 7.4, 100 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM NaF, 20 mM Na4P2O7, 2 mM Na3VO4, Triton X-100 1%, glycerol 10% by volume, SDS 0.1% by volume, deoxycholate 0.5% by volume, phenylmethylsulfonyl fluoride (PMSF) 1 mM). The lysates were centrifuged for 10 min. at 4 ° C and the supernatants were transferred to a new tube. 50 µl of sample diluent (conventional diluent buffer, Biosource) was added and 100 µl of cell lysate was transferred to the tube and vortexed. 100 µl of each diluted cell lysate was added to the plate with appropriate ELISA wells and incubated for 3 h at room temperature. The plates were washed 4 times with 1x wash buffer (Biosource). 50 µl of detection antibody (detection antibody against GSK3 (Ser9); BioSource) was added to each well and incubated for 30 min. at room temperature. The washing procedure was repeated between each stage. 100 µl of secondary antibody bound to HRP (anti-mouse IgG antibody) was added

bound to HRP) to each well and incubated for 30 min. at room temperature. 100 µl of TMB substrate (3,3 ', 5,5'-tetramethylbenzidine by volume, 0.1% hydrogen peroxide by volume, complex polypeptides in a buffered solution; Biosource) were added to each well and incubated for 30 min. at room temperature. Finally, 100 µl of stop solution (carbonyl compound  and 0.05% unsaturated by volume) was added to each well and the plate was gently shaken for a few seconds. Absorbance at 450 nm (Wallac Victor2; Perkin Elmer, USA) was measured within 30 min. after adding the stop solution. Data analysis was performed using a statistical program (Excel; Microsoft, USA) and the IC50 of pGSK3 inhibition was determined.

10 Table:

Assay of cellular pGSK3 / inhibition of the path of PI3K / cellular Akt

Example No.

Pi3K / Akt cell path assay PGSK3 cell path assay

one

 +++ ++

2

 +++ ++

3

+++ +++

4

++

5

+++ +++

6

+++ ++

7

+++ ++

8

+++ ++

9

 ++ ++

10

+++ +++

eleven

+++ ++

12

+++ +++

13

+++ ++

14

 +++ ++

fifteen

+ ++

16

 ++ ++

17

 +++ ++

18

 ++ ++

19

 +++ +++

twenty

 + +

twenty-one

 +++ ++

22

 +++ ++

2. 3

 +++ ++

24

 +++ +++

25

 +++ +++

26

++

27

 +++ ++

28

++

29

 +++ +++

30

 ++ +++

Example No.

Pi3K / Akt cell path assay PGSK3 cell path assay

43

++

44

+++ ++

Four. Five

46

+++ ++

47

48

49

fifty

51

52

53

54

55

56

57

58

59

+++

60

61

+++

62

+++

63

64

65

+++

66

+++

67

68

+++

69

70

71

+++

72

Example No.

Pi3K / Akt cell path assay PGSK3 cell path assay

85

86

87

88

89

90

91

92

93

+++

94

95

96

97

98

+++

99

100

101

102

103

104

105

+++

106

+++

107

108

109

110

111

112

113

114

31

 +++ +++

32

 +++ ++

33

 ++ +

3. 4

 +++ +++

35

++

36

++

37

 +++ ++

38

 +++ +++

39

 +++ ++

40

 +++ +++

41

 +++ ++

42

 +++ +

73

74

75

76

77

+++

78

79

80

81

82

83

84

115

116

117

+++

118

119

120

121

122

123

125

124

+++

126

127

IC50> 10 M + 10 M> IC50> 1 M ++ 1 M> IC50 +++

5 Cytotoxicity / cell proliferation assay:

The antiproliferative activity of the compounds is evaluated as described herein, using the OvCAR3, HCT116 and A549 cell lines and the alamar blue cell viability assay (resazurine) (O'Brien et al. Eur J Biochem 267 , 5421-5426, 2000). Resazurin is reduced to fluorescent resofurin by 10 cell dehydrogenase activity, which correlates with viable proliferating cells. The test compounds are dissolved as 10 mM solutions in DMSO and subsequently diluted. Cells were seeded as HCT116 or A549 cells in 96-well flat bottom plates at a density of 10,000 cells / well (OvCAR3 cells), 1000 cells / well (HCT116 cells) or 2000 cells / well (A549 cells) in a volume of 200 µl / well. 24 hours after sowing, 1 µl of each of the compound dilutions is added to each well 15 of the 96 well plates. Each dilution of the compound is tested at least as duplicates. Wells containing untreated control cells were filled with 200 µl of DMEM (Eagle medium modified by Dulbecco) containing 0.5% DMSO in volume v: v. The cells are then incubated with the substances for 72 h at 37 ° C in a humidified atmosphere containing 5% CO2 by volume. To determine the viability of the cells, 20 µl of a resazurin solution (90 mg / l) is added. After 4 h of incubation at 37 ° C, fluorescence is measured by extinction at A = 544 nm and an emission of A = 590 nm (Wallac Victor2; Perkin Elmer, USA). For the calculation of cell viability, the emission value of untreated cells is established as 100% viability and the fluorescence intensity of treated cells is established in relation to the values of untreated cells. The viabilities are expressed as values in%. The corresponding IC50 values of the compounds are determined to determine the cytotoxic activity from the concentration-effect curves by means of

25 nonlinear regression. Data analysis is performed using a biostatistical program (GraphPad Prism, USA).

Representative IC50 values for the antiproliferative / cytotoxic potency determined in the aforementioned test are deduced from the following table, in which the compound numbers correspond to

30 the numbers of the examples.

Table:

Antiproliferative / cytotoxic activity (OvCAR3 and A549 cells)

35

Activity

Activity

Example No.

antiproliferative / cytotoxic antiproliferative / cytotoxic

(A549 cells)

(OVCAR3 cells)

one

+ ++

2

++ ++

Example No.

Antiproliferative / cytotoxic activity (A549 cells) Antiproliferative / cytotoxic activity (OVCAR3 cells)

43

44

 + ++

Example No.

Antiproliferative / cytotoxic activity (A549 cells) Antiproliferative / cytotoxic activity (OVCAR3 cells)

85

+

86

 +

3

++

4

+ +

++

++

6

++ ++

7

++ ++

8

 ++ ++

9

++ +

++

++

eleven

 ++ ++

12

++ ++

13

 ++ ++

14

 ++ ++

++

+

16

+ ++

17

++ ++

18

+ ++

19

 ++ ++

+

+

twenty-one

 ++ ++

22

 + ++

2. 3

+ ++

24

++ ++

++

++

26

+ ++

27

++ ++

28

+ ++

29

+ ++

+

++

31

 + ++

32

++ ++

33

++ ++

3. 4

+ ++

+

++

36

+ +

37

 + ++

38

 + ++

39

 + ++

+

++

41

+ ++

42

++ ++

Four. Five

+

46

 ++

47

+

48

 +

49

fifty

+

51

 ++

52

+

53

++

54

 ++

55

+

56

++

57

 ++

58

++

59

++

60

++

61

+

62

+

63

+

64

++

65

++

66

++

67

++

68

++

69

++

70

++

71

++

72

++

73

++

74

++

75

+

76

++

77

+

78

++

79

+

80

+

81

+

82

++

83

+

84

+

87

++

88

 ++

89

++

90

 +

91

++

92

++

93

 ++

94

++

95

+

96

 ++

97

++

98

+

99

 ++

100

++

101

++

102

++

103

++

104

++

105

++

106

+

107

++

108

++

109

++

110

++

111

++

112

++

113

++

114

++

115

+

116

++

117

+

118

++

119

++

120

++

121

++

122

++

123

++

125

+

124

+

127

+

126

++

Chemosensitization test:

The compounds disclosed herein are evaluated to determine the ability to sensitize cancer cells towards apoptotic stimuli. Akt inhibitors are tested alone and in combination with targeted cancer therapeutic agents and chemotherapeutic agents to determine the effect on the induction of apoptosis. Cancer cells are seeded in 96-well plates at concentrations ranging from 2 x 103 to 1 x 104 cells per well in their respective growth media. 48-72 hours later, the apoptosis assay is established as follows:

For combination assays with a particularly preferred chemotherapeutic agent, topoisomerase inhibitors (such as doxorubicin, etoposide, camptothecin or mitoxantrone) or antifungal agents / tubulin inhibitors (such as vincristine), the compounds are added at the respective indicated concentrations and incubate the plates at 37 ° C in a CO2 incubator for 18 hours. For conventional combination assays that use chemotherapeutic agent treatment, they are added at the same time to the respective concentrations indicated. For assays of combinations that involve the addition of targeted proapoptotic agents such as the TRAIL / Apo2L death receptor ligand (Research Diagnostics), the compounds are added for 1.5 hours prior to the addition of TRAIL and the plates are incubated for another 3 4 hours after the addition of TRAIL. In the case of time, the plates are incubated for 2, 3, 4 and 6 hours with TRAIL ligand before the end of the test. For both procedures, the total final volumes do not exceed 250 μl. At the end of the incubation time, the cells are pelleted by centrifugation (200 x g; 10 min. At RT) and the supernatant is discarded. The cells are resuspended and incubated using lysis buffer for 30 min. a TA (ELISAPLUS cell death detection, Roche, cat. no. 11774425001). After centrifugation is repeated (200 x g; 10 min at RT), an aliquot of the supernatant is transferred to a streptavidin coated well of a microplate. This is followed by incubation (2 h, TA) and the binding of nucleosomes in the supernatant with antihistone antibody (biotin labeled) and anti-DNA antibody (peroxidase conjugate; ELISAPLUS cell death detection, Roche, no. from cat. 11774425 001). The antibody-nucleosome complexes bind to the microplate. The immobilized antibody-histone complexes are washed three times at RT to remove cellular components that are not immunoreactive. The substrate solution (2,2'-AZINO-bis [3-ethylbenciazoline-6-sulfonic acid (ABTS); ELISAPLUS cell death detection, Roche, cat. 11,774,425,001) was added and incubated shows them for 15 min., TA. The amount of colored product is determined spectrophotometrically (absorbance at



= 405 nm). Data are expressed as a percentage of control activity with cisplatin used as a positive control. The induction of apoptosis by 50 cisM cisplatin is arbitrarily defined as 100 cisplatin units (100 CPU).

Claims (13)

1. Compound of formula (I) image 1 wherein the ring B and the imidazole with which it is condensed form a ring system selected from image 1

10

in which

fifteen

R1 is hydrogen, C1-4 alkyl, halogen, amino, -SR2, trifluoromethyl, cyano, C3-7 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-7 cycloalkoxy, mono or C1- dialkylamino 4, C1-4 mono or dialkylaminocarbonyl, -C (NH) NH2, -C (O) NH2 or -C (O) OR10

R2 is hydrogen, C1-4 alkyl or C3-7 cycloalkyl,

twenty

R3 is hydrogen, C1-4 alkyl or halogen, R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl, thiazolyl or unsubstituted oxazolyl,

R5 is C1-4 alkyl, halogen or C1-4 alkoxy,

25

R6 is hydrogen or C1-4 alkyl,

R7 is -W-Y,

30

W is a 5-membered monocyclic heteroarylene comprising 1 nitrogen atom and optionally 1 or 2 additional heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein the heteroarylene is optionally substituted with R8,

R8 is C1-4 alkyl or C3-7 cycloalkyl,

35

Y is phenyl or a 5 or 6 membered monocyclic heteroaryl comprising 1 nitrogen atom and optionally 1 or 2 additional heteroatoms independently selected from oxygen, nitrogen, sulfur and in which the heteroaryl is optionally substituted with R9,

R9 is C1-4 alkyl, C1-4 alkoxy or halogen,

R10 is hydrogen or C1-4 alkyl; or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said 5 compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer. 2. A compound according to claim 1, wherein the ring B and the imidazole with which it is fused form a ring system selected from 10 image 1 15 in which R1 is hydrogen, C1-4 alkyl, halogen, amino, -SR2, trifluoromethyl, cyano, C3-7 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-7 cycloalkoxy, mono or C1- dialkylamino 4, C1-4 mono or dialkylaminocarbonyl, -C (NH) NH2, -C (O) NH2 or -C (O) OR10 R2 is hydrogen, C1-4 alkyl or C3-7 cycloalkyl, R3 is hydrogen, C1-4 alkyl or halogen, R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl, oxazolyl or unsubstituted thiazolyl, R5 is C1-4 alkyl, halogen or C1-4 alkoxy, R6 is hydrogen or methyl, R7 is -W-Y, W is triazolylene, pyrazolylene, oxadiazolylene or imidazolylene, each of which is optionally substituted with R 8, R 8 is C 1-4 alkyl or C 3-7 cycloalkyl, Y is phenyl, furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is optionally substituted with R9, R9 is C1-4alkyl, C1-4alkoxy or halogen, R10 is hydrogen or C1-4 alkyl; Or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer. 3. A compound according to claim 1 or 2, wherein the ring B and the imidazole with which it is fused form a ring system selected from image 1 wherein R1 is hydrogen, C1-4 alkyl, halogen, amino, -SR2, trifluoromethyl, cyano, C3-7 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-7 cycloalkoxy, mono or C1-4 dialkylamino, mono or C1-4 dialkylaminocarbonyl, -C (NH) NH2, -C (O) NH2 or -C (O) OR10 R2 is hydrogen, C1-4 alkyl or C3-7 cycloalkyl, R3 is hydrogen, C1-4 alkyl or halogen, R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl, oxazolyl or unsubstituted thiazolyl, R5 is C1-4 alkyl, halogen or C1-4 alkoxy, R6 is hydrogen or methyl, R7 is -W-Y, W is 1,2,4-triazolylene, pyrazolylene, 1,2,4-oxadiazolylene or imidazolylene, Y is phenyl, furan-2-yl, thien-2-yl, pyrrol-2-yl, pyridin-4-yl, thiazol-2-yl, thiazol-4-yl, oxazol-2-yl, oxazole 4-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2- ilo or pyridazin-3-yl, each of which is optionally substituted with R9, R9 is C1-4 alkyl, C1-4 alkoxy or halogen, R10 is hydrogen or C1-4 alkyl, or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer. 4. A compound according to claim 1, 2 or 3 wherein the ring B and the imidazole with which it is fused form a ring system selected from image 1 image 1 wherein R1 is hydrogen, C1-4 alkyl, halogen, -SR2, amino, trifluoromethyl, cyano, C2-4 alkenyl, alkynyl C2-4, C1-4 alkoxy, C1-4 mono or dialkylamino, C1-4 mono or dialkylaminocarbonyl, -C (NH) NH2, -C (O) NH2 or -C (O) OR10 R2 is C1-4 alkyl, R3 is hydrogen or halogen, R4 is phenyl substituted with R5, phenyl, thienyl, pyridinyl, oxazolyl or unsubstituted thiazolyl, R6 is hydrogen, R7 is -W-Y, W is 1,2,4-triazolylene, pyrazolylene or 1,2,4-oxadiazolylene, Y is phenyl, furan-2-yl, thien-2-yl, pyrrol-2-yl, pyridin-4-yl, thiazol-2-yl, pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl or pyridazin-3-yl, each of which is optionally substituted with R9, R9 is C1-4 alkyl, C1-4 alkoxy or halogen, R10 is hydrogen or C1-4 alkyl, or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer. 5. Compound according to claim 1, 2, 3 or 4 selected from the group consisting of 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3- il) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyrimidine; 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1, 2-a] pyridine; 7-phenyl-6- (4 - {[4- (5-pyridin-2-yl-1H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1, 2-b] [1,2,4] triazine; 3-phenyl-2- (4 - {[4- (3-pyrazin-2-yl-1,2,4-oxadiazol-5-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2- a] pyrimidine; 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2- a] pyridin-8-carbonitrile; 6-Bromo-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyridine; 6-Chloro-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridine; 8-methyl-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyridine; 3- (4-fluorophenyl) -2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyridine; 5-phenyl-6- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1- b] [1,3] thiazole; 5-phenyl-6- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1- b] [1,3,4] thiadiazole; 6-Bromo-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyrimidine; 8-methoxy-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyridine; 3- (3-fluorophenyl) -2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyridine; 3- (4-methoxyphenyl) -2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyridine; 3-pyridin-4-yl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyridine; 2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) -3- (2-thienyl) imidazo [ 1,2-a] pyridine; 3- (4-fluorophenyl) -2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyrimidine; 7-methyl-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyrimidine; 3- (4-methoxyphenyl) -2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyrimidine; 6-Chloro-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyrimidine; 6-fluoro-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyridine; 6-iodo-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyrimidine; 7-methoxy-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyrimidine; 8-Bromo-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyridine; 8-Chloro-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyrazine; 8-methoxy-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyrazine; 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) -7- (trifluoromethyl) imidazo [1,2 a] pyrimidine; 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2- a] pyridin-7-carbonitrile; 3-Phenyl-2- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidine- (2E) -but-2-enodioate) one il} methyl) phenyl] imidazo [1,2-a] pyridin-7-carbonitrile 3-phenyl-2- (4 - {[4- (3-pyridin-2-yl-pyrazol-5-yl) piperidin-1 -yl] methyl} phenyl) imidazo [1,2-a] pyrimidine; 6-Chloro-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-b] pyridazine; 6-methoxy-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-b] pyridazine; 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2- a] pyridin-8 carboximidamide; 2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) -3- (3-thienyl) imidazo [ 1,2-a] pyrimidine; 2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) -3- (2-thienyl) imidazo [ 1,2-a] pyrimidine; 3-pyridin-4-yl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyrimidine; 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2- a] pyrazine; 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2- a] pyridin-7-carboxamide; 2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) -3- (1,3-thiazol- 2-yl) imidazo [1,2-a] pyrimidine; 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2- a] pyridin-8-carboxamide; 3- (2-fluorophenyl) -2- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 1,2-a] pyrimidine 6- (4 - {[4- (5-pyridin-2-yl-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) -5- (1,3-thiazol-2-yl) imidazo [2,1-b] [1,3] thiazole; 5- (1,3-oxazol-2-yl) -6- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1- il] methyl} phenyl) imidazo [2,1-b] [1,3] thiazole; 6,8-difluoro-3-phenyl-2- {4- [4- (5-pyridin-2-yl-4H- [1,2,4] triazol-3-yl) -piperidin-1-ylmethyl] - phenyl} -imidazo [1,2-a] pyridine; 2-methyl-5-phenyl-6- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [2,1b] [1,3,4] thiadiazole; 2-methyl-5-phenyl-6- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [2,1-b] [1,3] thiazole; 2- (methylsulfanyl) -5-phenyl-6- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [2,1 b] [1,3,4] thiadiazole; 5-phenyl-6- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -2 - (trifluoromethyl) imidazo [2,1b] [1,3,4] thiadiazole; (2Z) -but-2-3-phenyl-2- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-) one il} methyl) phenyl] imidazo [1,2-a] pyridin-7-carbonitrile; 7-methyl-3-phenyl-2- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-a] pyridine; 2-ethyl-5-phenyl-6- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1-b] [1,3,4] thiadiazole; 6-Bromo-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridin-7 carbonitrile; 6-methyl-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-b] pyridazine; 7-Chloro-3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridine; 3-phenyl-2- (4 - {[4- (5-pyridin-4-yl-1H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1, 2-a] pyrimidine; 5-phenyl-6- (4 - {[4- (5-pyridin-4-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2, 1-b] [1,3] thiazole; 3-phenyl-2- (4 - {[4- (3-pyridin-4-yl-1H-1,2,4-triazol-5-yl) piperidin-1-yl] methyl} phenyl) imidazo [1, 2-a] pyridin-7-carbonitrile; 3-phenyl-2- (4 - {[4- (5-pyridin-4-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1, 2-a] pyridine; 3-phenyl-2- (4 - {[4- (5-pyridin-4-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1, 2-a] pyridin-8-carbonitrile; 5-phenyl-6- (4 - {[4- (5-pyridin-4-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2, 1-b] [1,3,4] thiadiazole; 2- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2-a] pyridin-7 carbonitrile; 2- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2-a] pyridine-8carbonitrile; 2- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2-a] pyrimidine; 2- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2-a] pyridine; 8-methoxy-2- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2 a] pyrazine; 6- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -5-phenylimidazo [2,1-b] [1,3] thiazole; 6- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -5-phenylimidazo [2.1 b] [1,3,4] thiadiazole; 7-methoxy-2- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2a] pyridine; 6-methyl-2- [4 - ({4- [5- (6-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2 b] pyridazine; 2- [4 - ({4- [5- (5-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2-a] pyrimidine; 2- [4 - ({4- [5- (5-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2-a] pyridin-8 carbonitrile; 2- [4 - ({4- [5- (5-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2-a] pyridine-7carbonitrile; 6- [4 - ({4- [5- (5-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -5-phenyl -imidazo [2,1-b] [1,3] thiazole; 6- [4 - ({4- [5- (5-methylpyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -5-phenylimidazo [2,1b] [1,3,4] thiadiazole; 2- [4 - ({4- [5- (5-chloropyridin-2-yl) -1H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2-a] pyridin-8 carbonitrile; 2- [4 - ({4- [5- (5-chloropyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2-a] pyrimidine; 3-phenyl-2- [4 - ({4- [5- (pyrimidin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [ 1,2-a] pyridin-8 carbonitrile; 3-phenyl-2- [4 - ({4- [5- (pyrimidin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [ 1,2-a] pyridine-7carbonitrile; 3-phenyl-2- (4 - {[4- (5-pyrimidin-2-yl-1H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1, 2-a] pyrimidine; 3-phenyl-2- (4 - {[4- (5-pyrimidin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1, 2-a] pyridine; 5-phenyl-6- (4 - {[4- (5-pyrimidin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2, 1-b] [1,3] thiazole; 5-phenyl-6- (4 - {[4- (5-pyrimidin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2, 1-b] [1,3,4] thiadiazole; 6-methyl-3-phenyl-2- (4 - {[4- (5-pyrimidin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-b] pyridazine; 3-phenyl-2- [4 - ({4- [5- (1,3-thiazol-2-yl) -1H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-a] pyrimidine; 3-phenyl-2- [4 - ({4- [5- (1,3-thiazol-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-a] pyridine; 3-phenyl-2- [4 - ({4- [5- (1,3-thiazol-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-a] pyridin-8 carbonitrile; 5-phenyl-6- [4 - ({4- [5- (1,3-thiazol-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [2,1-b] [1,3] thiazole; 5-phenyl-6- [4 - ({4- [5- (1,3-thiazol-2-yl) -1H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [2,1-b] [1,3,4] thiadiazole; 3-phenyl-2- [4 - ({4- [5- (1,3-thiazol-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-a] pyridin-7 carbonitrile; 2- [4 - ({4- [5- (2-furyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2 -a] pyridin-8-carbonitrile; 2- [4 - ({4- [5- (2-furyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2 -a] pyridine; 2- [4 - ({4- [5- (2-furyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -6-methyl-3-phenylimidazo [1,2-b] pyridazine; 6- [4 - ({4- [5- (2-furyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -5-phenylimidazo [2,1 -b] [1,3] thiazole; 6- [4 - ({4- [5- (2-furyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -5-phenylimidazo [2,1 -b] [1,3,4] thiadiazole; 2- [4 - ({4- [5- (2-furyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2 -a] pyrimidine; 2- [4 - ({4- [5- (2-furyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] -3-phenylimidazo [1,2 -a] pyridin-7-carbonitrile; 3-phenyl-2- [4 - ({4- [5- (2-thienyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1, 2-a] pyridine; 3-phenyl-2- [4 - ({4- [5- (2-thienyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1, 2-a] pyridin-8-carbonitrile; 6-methyl-3-phenyl-2- [4 - ({4- [5- (2-thienyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-b] pyridazine; 5-phenyl-6- [4 - ({4- [5- (2-thienyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [2, 1-b] [1,3] thiazole; 5-phenyl-6- [4 - ({4- [5- (2-thienyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [2, 1-b] [1,3,4] thiadiazole; 3-phenyl-2- [4 - ({4- [5- (2-thienyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1, 2-a] pyridin-7-carbonitrile; 7-Chloro-3-phenyl-2- [4 - ({4- [5- (2-thienyl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-a] pyridine; 6-methyl-3-phenyl-2- [4 - ({4- [5- (1H-pyrrole-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-b] pyridazine; 3-phenyl-2- [4 - ({4- [5- (1H-pyrrol-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-a] pyridin-8 carbonitrile; 3-phenyl-2- [4 - ({4- [5- (1H-pyrrol-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-a] pyrimidine; 7-Chloro-3-phenyl-2- [4 - ({4- [5- (1H-pyrrol-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-a] pyridine; 5-phenyl-6- [4 - ({4- [5- (1H-pyrrole-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [2,1-b] [1,3,4] thiadiazole; 5-phenyl-6- [4 - ({4- [5- (1H-pyrrole-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [2,1-b] [1,3] thiazole; 3-phenyl-2- [4 - ({4- [5- (1H-pyrrol-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [1,2-a] pyridin-7 carbonitrile; 3-phenyl-2- (4 - {[4- (3-pyridin-2-yl-1H-pyrazol-5-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridine; 5-phenyl-6- (4 - {[4- (5-pyridin-2-yl-1H-pyrazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1-b] [1 , 3,4] thiadiazole; 5-phenyl-6- (4 - {[4- (5-pyridin-2-yl-1H-pyrazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1-b] [1 , 3] thiazole; 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1, 2-a] pyridin-7-carbonitrile; 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-oxadiazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2- a] pyridin-7-carbonitrile; 3-phenyl-2- (4 - {[4- (5-pyridin-2-yl-1,2,4-oxadiazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2- a] pyrimidine; 3-phenyl-2- (4 - {[4- (5-phenyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridin-8-carbonitrile; 3-phenyl-2- (4 - {[4- (5-phenyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyridin-7-carbonitrile; 6-methyl-3-phenyl-2- (4 - {[4- (5-phenyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1, 2-b] pyridazine; 7-Chloro-3-phenyl-2- (4 - {[4- (5-phenyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1, 2-a] pyridine; 3-phenyl-2- (4 - {[4- (5-phenyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [1,2-a] pyrimidine; 5-phenyl-6- (4 - {[4- (5-phenyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1-b] [1,3] thiazole; 5-phenyl-6- (4 - {[4- (5-phenyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [2,1-b] [1,3,4] thiadiazole; 3-phenyl-2- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo [ 1,2-a] pyridine-7-carboxylate of methyl; 3-phenyl-2- [4 - ({4- [5- (pyridin-2-yl) -4H-1,2,4-triazol-3-yl] piperidin-1-yl} methyl) phenyl] imidazo acid [1,2-a] pyridine-7 carboxylic; methoxy [5-phenyl-6- (4 - {[4- (5-pyridin-2-yl-1H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 2,1-b] [1,3] thiazol-2 il] methanol; and 5-phenyl-6- (4 - {[4- (5-pyridin-2-yl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] methyl} phenyl) imidazo [ 2,1-b] [1,3] thiazol-2-carboxylic; or a salt, particularly a pharmaceutically acceptable salt, a tautomer or a stereoisomer of said compound, or a salt, particularly a pharmaceutically acceptable salt, of said tautomer or said stereoisomer.

6.

 Compound, tautomer thereof or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, tautomer or stereoisomer according to any one of claims 1 to 5 for use in the treatment or prophylaxis of diseases.

7.

 Compound, tautomer thereof or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, tautomer or stereoisomer according to any one of claims 1 to 5, or a pharmaceutical composition comprising a compound, a tautomer of said compound or a stereoisomer of said compound. compound, or a pharmaceutically acceptable salt of said compound, tautomer or stereoisomer according to any one of claims 1 to 5, for the treatment and / or prophylaxis of hyperproliferative diseases and / or disorders that respond to the induction of apoptosis.

8.

 Compound, tautomer thereof or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, tautomer or stereoisomer according to any one of claims 1 to 5, or a pharmaceutical composition comprising a compound, a tautomer of said compound or a stereoisomer of said compound. compound, or a pharmaceutically acceptable salt of said compound, tautomer or stereoisomer according to any one of claims 1 to 5, for the treatment of cancer.

9.

 Pharmaceutical composition comprising at least one compound, tautomer of said compound or stereoisomer of said compound, or a pharmaceutically acceptable salt of said compound, tautomer or stereoisomer according to any one of claims 1 to 5, together with at least one pharmaceutically acceptable auxiliary compound.

10.

 Combination comprising one or more first active ingredients selected from the compounds, tautomers of said compounds, or stereoisomers of said compounds, or pharmaceutically acceptable salts of said compounds, tautomers or stereoisomers according to any one of claims 1 to 5, and one or more seconds. active ingredients selected from chemotherapeutic anticancer agents and target specific anticancer agents.

eleven.

 Use of a compound, or tautomer of said compound, or a stereoisomer of said compound or a pharmaceutically acceptable salt of said compound, tautomer or stereoisomer according to any one of claims 1 to 5 for the production of a pharmaceutical composition for treatment, the prevention or improvement of benign or malignant neoplasia.

12.

 Use of a compound, or tautomer of said compound, or a stereoisomer of said compound or a pharmaceutically acceptable salt of said compound, tautomer or stereoisomer according to any one of claims 1 to 5 for the production of a pharmaceutical composition for the treatment of neoplasia. benign and / or malignant.

13.

 Use of a compound, or tautomer of said compound, or a stereoisomer of said compound or a pharmaceutically acceptable salt of said compound, tautomer or stereoisomer according to any one of claims 1 to 5 for the production of a pharmaceutical composition for the treatment of cancer. .