TW201524972A - Imidazole derivatives - Google Patents

Abstract

The present invention relates to compounds of formula (I), wherein A, B, R1 and R2 are as defined herein before.

Description

Imidazole derivative

The present invention relates to a compound of formula (I)

Wherein A is selected from the group consisting of:

B is a C ₁ -C ₄ -alkylene group, a C ₂ -C ₄ -alkenyl group, a C ₂ -C ₄ -exetylene group, and the R ¹ group is selected from the group consisting of hydrogen, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxyalkyl, C ₁ -C ₇ -haloalkyl, -(CH ₂ ) _0,1,2- C ₃ -C ₅ -cycloalkyl, optionally halogen, C ₁ -C ₇ -alkyl or C ₁ -C ₇ alkoxy substituted -(CH ₂ ) _0,1,2- (hetero-)aryl, R ² is selected from 1 to 3, optionally selected from the following Heteroaryl substituted by a substituent: halogen, hydroxy, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -hydroxyalkyl, C ₁ -C ₇ -haloalkoxy, C ₁ -C ₇ -halide Alkyl, C ₃ -C ₅ -cycloalkyl, cyano, amine, nitro, -OR ⁶ -C(O)-R ⁷ , heteroaryl, heterocycloalkyl, -SO ₂ R ¹² -C (O) NR'R ", NR'R" , wherein R 'and R "are independently selected hydrogen, C ₁ -C ₇ - alkyl or R' and R" appended thereto together form a hetero nitrogen atom of contact a cycloalkyl group, or R ² is selected from C ₁ -C ₂ -alkoxy optionally substituted by halogen, R ⁶ and R ¹² are independently selected from C ₁ -C ₇ -alkyl, and R ⁷ is selected from Heterocycloalkyl, X-based NR ³ or CR ³ , Y-based (CH ₂ ) _n , n-system 1, 2, ³ , 4, and R ³ is selected from hydrogen and C ₁ -C ₇ -alkyl.

Further, the present invention relates to a process for producing the above-mentioned compounds, a pharmaceutical preparation containing the same, and the use of the compounds in the manufacture of a pharmaceutical preparation.

Schizophrenia is a progressive and destructive neurological disorder characterized by paroxysmal positive symptoms (such as delusions, hallucinations, thought disorders, and psychosis) and persistent negative symptoms (such as indifference, impaired attention, and social withdrawal). And cognitive impairment) (Lewis DA and Lieberman JA, Neuron, 28:325-33, 2000 ). For decades, people have been working on the hypothesis of dopaminergic hyperactivity that leads to therapeutic interventions involving dopaminergic system blockade (Vandenberg RJ and Aubrey KR., Exp . Opin . Ther . Targets , 5 ( 4): 507-518, 2001 ; Nakazato A and Okuyama S et al, Exp . Opin . Ther . Patents , 10(1): 75-98, 2000 ). In addition to improving the positive symptoms of patients with schizophrenia, this pharmacological approach does not adequately address negative and cognitive symptoms, which are the best predictors of functional outcomes (Sharma T., Br . J. Psychiatry , 174) (Supplement 28): 44-51, 1999 ). In addition, current antipsychotic treatments can cause adverse effects such as weight gain, extrapyramidal symptoms or effects of glucose and lipid metabolism, which are associated with their non-specific pharmacology.

In summary, there is still a need to develop novel antipsychotic drugs with improved efficacy and safety properties. In the mid-1960s, it was triggered by a compound such as phencyclidine (PCP) and a related agent (ketamine) that is a non-competitive NMDA receptor antagonist due to the glutamate system. Psychotic behavior proposes a complementary model of schizophrenia. Interestingly, in healthy volunteers, PCP induced Psychotic behaviors include positive and negative symptoms and cognitive dysfunction and are therefore very similar to patients with schizophrenia (Javitt DC et al, Biol. Psychiatry, 45: 668-679, 1999).

Cyclic Nucleotide Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are ubiquitous second messengers that regulate the biological responses of a variety of extracellular signals, including neurotransmitters, light and hormones. . cAPM and cGMP regulate a variety of intracellular processes by activating cAMP- and cGMP-dependent kinases, followed by phosphorylation of these kinases involved in the regulation of synaptic transmission, neuronal differentiation and survival (especially in neurons of the central nervous system) ).

An important mechanism for controlling the intracellular cyclic nucleotide content and thus the circular nucleotide signaling is by hydrolysis of the 3',5'-phosphodiester linkage by phosphodiesterase. Phosphodiesterase (PDE) is a family of enzymes that are widely expressed in humans and are encoded by 21 different genes, each of which encodes several splice variants (Beavo, J., Physiol. Rev. 1995, 75, 725- 748; Conti, M., Jin, SL, Prog. Nucleic Acid Res. Mol. Biol. 1999, 63, 1-38; Soderling, SH, Beavo, JA, Curr. Opin. Cell Biol. 2000, 12, 174-179; Manallack, DT et al, J. Med. Chem. 2005, 48(10), 3449-3462).

The PDE family differs in the nature of the cyclic nucleotides, the regulatory mechanisms, and the sensitivity to inhibitors. In addition, there are differences in the distribution in organisms, between organ cells and even within cells. These differences lead to a distinct involvement of the PDE family in various physiological functions.

As reported by three separate research groups in 1999, PDE10A is a dual-enhanced PDE encoded by a single gene (Fujishige K. et al., Eur J Biochem (1999) 266(3): 1118-1127; Soderling SH et al. ProcNatl Acad Sci USA (1999) 96(12): 7071-7076; Loughney K. et al., Gene (1999) 234(1): 109-117). PDE10A differs from other multigene family members in the following aspects: amino acid sequence (779 aa), tissue-specific expression pattern, affinity for cAMP and cGMP, and specificity And the effect of general inhibitors on PDE activity.

PDE10A is one of the most restricted families of any PDE family, which is mainly expressed in the brain, especially in the nucleus accumbens and caudate putamen. In addition, the thalamus, olfactory bulb, hippocampus, and frontal cortex showed moderate PDE10A performance. It has been shown that all of these brain regions are associated with pathophysiological abnormalities of schizophrenia and psychosis, suggesting that PDE10A plays an important role in this devastating mental disorder. In addition to the central nervous system, PDE10A transcripts were also observed in peripheral tissues such as thyroid, pituitary, insulin-secreting pancreatic cells, and testis (Fujishige, K. et al., J. Biol. Chem. 1999, 274, 18438). -18445; Sweet, L. (2005) WO 2005/012485). On the other hand, the expression of the PDE10A protein was observed only in the intestinal ganglion, the testis and the spermatozoa (Coskran T. M et al., J. Histochem. Cytochem. 2006, 54(11), 1205-1213).

In the striatum, both mRNA and protein are only expressed in medium-sized spiny projection neurons containing GABA (γ-aminobutyric acid), making it an attractive target for the treatment of central nervous system diseases ( Fujishige, K. et al., Eur. J. Biochem. 1999, 266, 1118-1127; Seeger, TF et al., Brain Res. 2003, 985, 113-126). The striatum medium spine neuron is the main input site in the basal ganglion circuit of the mammalian brain and the primary site for information integration. Basal ganglia A series of interconnected subcortical nucleus that integrates widely distributed cortical inputs with dopaminergic signaling to deploy and perform related activities and cognitive patterns while suppressing undesired or unrelated patterns (Graybiel , AM Curr. Biol. 2000, 10, R509-R511 (2000).

Papaverine (a relatively specific PDE10A inhibitor) and PDE10A knockout mice have been used to explore the physiological functions of this enzyme and the possible therapeutic uses of PDE10A inhibition. Inhibition of this enzyme in a pharmacological manner or via genetic disruption results in reduced activity and reduced response to psychomotor stimulants. Inhibition also reduces the conditional avoidance response, a behavioral response that predicts clinical antipsychotic activity (Siuciak, J.A. et al., Neuropharmacology 2006, 51(2), 386-396; Siuciak, J.A., et al. Neuropharmacology 2006, 51(2), 374-385).

In addition, PDE10A inhibits the potential to improve negative and cognitive symptoms associated with schizophrenia. In fact, papaverine has been shown to attenuate the extra-dimensional shift learning deficit in rats induced by PCP subchronic therapy (An animal paradigm of NMDA receptor dysfunction) (Rodefer, J, S. et al. , Eur. J. Neuroscience 2005, 2,: 1070-1076). In addition, an increase in social interaction in PDE10A2-deficient mice has been observed (Sano, H.J. Neurochem. 2008, 105, 546-556).

Diseases that can be treated with a PDE10A inhibitor include, but are not limited to, diseases that are believed to be mediated, in part, by dysfunction of the basal ganglia, other parts of the central nervous system, and other PDE10A-expressing tissues. Specifically, a disease which inhibits the therapeutic effect of PDE10A can be treated.

Such diseases include, but are not limited to, certain psychiatric conditions such as schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusions or substance-induced psychiatric disorders; anxiety disorders such as panic , obsessive-compulsive disorder, acute stress disorder or generalized anxiety disorder; obsessive/compulsive disorder; drug addiction; motor disorder, such as Parkinson's disease or restlessness Leg syndrome; cognitive deficit disorders such as Alzheimer's disease or multiple infarct dementia; mood disorders such as depression or two-way affective disorders; or neuropsychiatric conditions such as psychosis, attention deficit/hyperactivity disorder ( ADHD) or related attention disorders.

The compounds of the invention are also suitable for the treatment of diabetes and related conditions (e.g., obesity) by modulating the cAMP signaling system.

PDE10A inhibitors can also be used to prevent neuronals from undergoing apoptosis by increasing cAMP and cGMP levels, and thus may have anti-inflammatory properties. Neurodegenerative disorders treatable with PDE10A inhibitors include, but are not limited to, Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, stroke, or spinal cord injury.

cAMP and cGMP inhibit the growth of cancer cells. Therefore, by increasing cAMP and cGMP, PDE10A inhibitors can also be used to treat different solid tumors and hematological malignancies, such as renal cell carcinoma or breast cancer.

definition

Unless otherwise stated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention.

The term "compound of formula (I)", "compound of formula (I)", "compound of the invention" or "compound of the invention" means any compound selected from the group consisting of compounds as defined by formula (I), including Stereoisomers, tautomers, solvates and salts thereof (e.g., pharmaceutically acceptable salts).

It must be noted that the singular forms "a", "an", "the"

When indicating the number of substituents, the term "one or more" means one substituent to the highest possible substitution number, i.e., replacing one hydrogen with a substituent up to all hydrogens.

The term "optional" or "as appropriate" means that the subsequently described event or circumstance may, but does not necessarily, occur, and that the description includes the circumstances in which the event or circumstance occurred and the circumstances in which the event or circumstance did not occur.

The term "substituent" means a group of atoms or atoms that replace a hydrogen atom on a parent molecule.

The term "alkenyl" denotes a monovalent straight or branched hydrocarbon group having from 2 to 7 carbon atoms of at least one double bond. In a particular embodiment, an alkenyl group has 2 to 4 carbon atoms and at least one double bond. Examples of alkenyl groups include ethenyl, propenyl, prop-2-enyl, isopropene Base, n-butenyl, isobutenyl and third butenyl.

The term "alkenyl group" means a linear divalent hydrocarbon chain of 2 to 7 carbon atoms having at least one double bond or a branched divalent hydrocarbon chain of 3 to 7 carbon atoms. Exemplary alkenyl groups include vinyl, 2,2-dimethylvinyl, propenyl, 2-methylpropenyl, butenyl and pentenyl.

The term "alkoxy" denotes a radical of the formula -O-R' wherein R' is alkyl. Examples of the alkoxy moiety include a methoxy group, an ethoxy group, an isopropoxy group, and a third butoxy group.

The term "alkyl" denotes a monovalent straight or branched saturated hydrocarbon group of 1 to 12 carbon atoms. In a particular embodiment, the alkyl group has from 1 to 7 carbon atoms, and in more specific embodiments from 1 to 4 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a second butyl group or a tert-butyl group.

The term "alkylene" means a linear saturated divalent hydrocarbon group of 1 to 7 carbon atoms or a divalent branched saturated divalent hydrocarbon group of 3 to 7 carbon atoms. Examples of alkylene groups include methylene, ethyl, propyl, 2-methylpropyl, butyl, 2-ethylbutyl, pentyl, and hexyl.

The term "extended alkynyl" means a straight-chain divalent hydrocarbon chain of 2 to 6 carbon atoms having at least one triple bond or a branched divalent hydrocarbon chain of 3 to 6 carbon atoms. Exemplary alkynyl groups include ethynyl, 2,2-dimethylexetylene, propynyl, 2-methylpropynyl, butynyl and pentynyl.

The term "aromatic" refers to the conventional concept of aroma, as defined in the literature, specifically IUPAC-Compendium of Chemical Terminology, 2nd ed., ADMcNaught and A. Wilkinson (ed.), Blackwell Scientific Publications, Oxford (1997). .

The term "aryl" means a monovalent aromatic carbocyclic monocyclic or bicyclic ring system containing from 6 to 10 carbon ring atoms. Examples of the aryl moiety include a phenyl group and a naphthyl group.

The term "bicyclic system" means via a shared single or double bond (additional ring system) Two rings fused to each other by a sequence of three or more shared atoms (bridged bicyclic system) or via a shared single atom (spirobicyclic system). The bicyclic system can be a saturated, partially unsaturated, unsaturated or aromatic system. The bicyclic system may comprise a heteroatom selected from the group consisting of N, O and S.

The term "cyanoalkyl" denotes an alkyl group wherein at least one hydrogen atom of the alkyl group is replaced by a cyano group. Examples of the cyanoalkyl group include a cyanomethyl group, a cyanoethyl group, a cyanopropyl group, a cyano-isopropyl group, a cyano-isobutyl group, a cyano-second butyl group, and a cyano-third butyl group. Base, cyanopentyl or cyanohexyl.

The term "cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In a particular embodiment, a cycloalkyl group represents a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbon rings having one or more shared carbon atoms. The specific cycloalkyl group is a single ring. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicyclic cycloalkyl groups are bicyclo [2.2.1] heptyl or bicyclo [2.2.2] octyl.

The term "haloalkoxy" denotes an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by the same or different halogen atom, especially a fluorine atom. Examples of haloalkoxy groups include monofluoro-, difluoro- or trifluoro-methoxy, -ethoxy or -propoxy, such as 3,3,3-trifluoropropoxy, 2-fluoroethoxy Base, 2,2,2-trifluoroethoxy, fluoromethoxy or trifluoromethoxy. The term "perhaloalkoxy" denotes an alkoxy group wherein all of the hydrogen atoms of the alkoxy group are replaced by the same or different halogen atoms.

The term "haloalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by the same or a different halogen atom, especially a fluorine atom. Examples of haloalkyl groups include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2, 2-Trifluoroethyl, fluoromethyl or trifluoromethyl. The term "perhaloalkyl" means an alkyl group wherein all of the hydrogen atoms of the alkyl group are replaced by the same or different halogen atoms.

The term "heteroaryl" means a monovalent aromatic heterocyclic ring having 5 to 12 ring atoms, containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Single or two ring system. Examples of heteroaryl moieties include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridyl Base, pyrazolyl, anthracene Base, pyrimidinyl, three Base, aziridine, diazenium, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, fluorenyl, isodecyl, isobenzofuranyl, benzimidazolyl, Benzooxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, fluorenyl, quinolyl , isoquinolyl, quinazolinyl or quinoxalinyl.

The term "heterocycloalkyl" denotes a monovalent or partial moiety having from 3 to 9 ring atoms, containing 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Saturated monocyclic or bicyclic ring systems. In a particular embodiment, the heterocycloalkyl group has from 4 to 7 ring atoms, contains one, two or three ring heteroatoms selected from N, O and S, and the remaining ring atoms are all monovalent saturated carbons. Ring system. Examples of monocyclic saturated heterocycloalkyl groups are aziridine, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl. , imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, hexahydropyridyl, tetrahydropyranyl, tetrahydrothiopyranyl, hexahydropyridyl , morpholinyl, thiomorpholinyl, 1,1-di-oxy-thiomorpholin-4-yl, azepanyl, diazepine, homohexahydropyridyl Or oxazepanyl. Examples of bicyclic saturated heterocycloalkyl groups are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]fluorenyl, 3-oxa-9-aza-bicyclo[3.3.1]fluorenyl or 3-thia-9-aza-bicyclo[3.3. 1] 壬基. Examples of partially unsaturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridyl or dihydropyranyl.

The term "hydroxyalkyl" denotes an alkyl group wherein at least one hydrogen atom of the alkyl group is replaced by a hydroxy group. Examples of the hydroxyalkyl group include a hydroxymethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 1-(hydroxymethyl)-2-methylpropyl group, a 2-hydroxybutyl group, and 3 -hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl or 2-(hydroxymethyl)-3-hydroxypropyl.

The term "pharmaceutically acceptable" means an attribute of a material that can be used in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and acceptable for veterinary and human medical use.

The terms "pharmaceutically acceptable excipient" and "therapeutic inert excipient" are used interchangeably and mean any pharmaceutically acceptable ingredient in a pharmaceutical composition that is not therapeutically active and non-toxic to the individual to whom it is administered, for example A disintegrant, a binder, a filler, a solvent, a buffer, a tonicity agent, a stabilizer, an antioxidant, a surfactant, a carrier, a diluent or a lubricant for formulating a pharmaceutical product.

The term "buffer" means a pharmaceutically acceptable excipient that stabilizes the pH of a pharmaceutical preparation. Suitable buffers are well known in the art and can be found in the literature. Particular pharmaceutically acceptable buffers include histidine buffers, arginine buffers, citrate buffers, succinate buffers, acetate buffers, and phosphate buffers. Independent of the buffer used, the pH can be adjusted using acids or bases known in the art such as hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid and citric acid, sodium hydroxide and potassium hydroxide.

The definitions described herein apply regardless of whether the terms in question are used alone or in combination. It is contemplated that the definitions described herein may be appended to form chemically relevant combinations, such as "heterocycloalkylaryl", "haloalkylheteroaryl", "arylalkylheterocycloalkyl" or "alkoxyalkyl" base". The last member of the combination is the group that binds to the rest of the molecule. Other members of the combination are attached to the binding group in the reverse order of the literal sequence, for example, a combined arylalkylheterocycloalkyl group refers to a heterocycloalkyl group substituted by an aryl group-substituted alkyl group.

The present invention relates to a compound of formula (I)

Wherein A is selected from the group consisting of:

B is a C ₁ -C ₄ -alkylene group, a C ₂ -C ₄ -alkenyl group, a C ₂ -C ₄ -exetylene group, and the R ¹ group is selected from the group consisting of hydrogen, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxyalkyl, C ₁ -C ₇ -haloalkyl, -(CH ₂ ) _0,1,2- C ₃ -C ₅ -cycloalkyl, optionally halogen, C ₁ -C ₇ -alkyl or C ₁ -C ₇ alkoxy substituted -(CH ₂ ) _0,1,2- (hetero-)aryl, R ² is selected from 1 to 3, optionally selected from the following Heteroaryl substituted by a substituent: halogen, hydroxy, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -hydroxyalkyl, C ₁ -C ₇ -haloalkoxy, C ₁ -C ₇ -halide Alkyl, C ₃ -C ₅ -cycloalkyl, cyano, amine, nitro, -OR ⁶ -C(O)-R ⁷ , heteroaryl, heterocycloalkyl, -SO ₂ R ¹² -C (O) NR'R ", NR'R" , wherein R 'and R "are independently selected hydrogen, C ₁ -C ₇ - alkyl or R' and R" appended thereto together form a hetero nitrogen atom of contact a cycloalkyl group, or R ² is selected from C ₁ -C ₂ -alkoxy optionally substituted by halogen, R ⁶ and R ¹² are independently selected from C ₁ -C ₇ -alkyl, and R ⁷ is selected from Heterocycloalkyl, X-based NR ³ or CR ³ , Y-based (CH ₂ ) _n , n-system 1, 2, ³ , 4, and R ³ is selected from hydrogen and C ₁ -C ₇ -alkyl.

In a particular embodiment, the invention relates to a compound of formula (I), wherein R ² is selected from heteroaryl substituted with 1 to 3 substituents selected from the group consisting of halogen, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -haloalkyl, optionally substituted by halogen, C ₁ -C ₂ -alkoxy, C ₃ -C ₅ -cycloalkyl, cyano; in a specific embodiment, The invention relates to a compound of formula (I), wherein A is a

In a particular embodiment, the invention relates to a compound of formula (I), wherein A is

In a particular embodiment, the invention relates to a compound of formula (I), wherein R ² is selected from the group consisting of:

One or more of R ⁵ are selected from the group consisting of hydrogen, halogen, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -hydroxyalkyl, C ₁ -C ₇ -haloalkoxy, C ₁ -C ₇ - haloalkyl, C ₃ -C ₅ - cycloalkyl, cyano, amino, ^{nitro, -OR 6 -C (O) -R} 7, -SO 2 R 8, optionally substituted by halogen of C ₁ - C ₂ -alkoxy, C ₁ -C ₂ -alkoxy or heterocycloalkyl, R ⁶ and R ⁸ are independently selected from C ₁ -C ₇ -alkyl, and R ⁷ is selected from heterocycloalkyl .

R ⁸ and R ⁹ are independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -haloalkyl, C ₁ -C ₇ -hydroxyalkyl, cyano, or R ⁸ R ⁹ together form a C ₃ -C ₈ cycloalkyl group; R ¹⁰ is selected from the group consisting of hydrogen, C ₁ -C ₇ -haloalkoxy, C ₃ -C ₈ cycloalkyl, C ₁ -C ₇ alkoxy, hydroxy Halogen, S(O) ₂ -C ₁ -C ₇ -alkyl, -C(O)NR'R", NR'R", wherein R' and R" are independently selected from hydrogen, C ₁ -C ₇ -alkyl or R' and R" together with the nitrogen atom to which they are attached form a heterocycloalkyl group, or R ¹⁰ and R ⁴ together form a C ₃ -C ₈ cycloalkyl group, R ¹¹ is selected from heteroaryl or Heterocycloalkyl, preferably 5 or 6 membered heteroaryl or 5 or 6 membered heterocycloalkyl, X ₁ is N or CR ⁴ wherein R ⁴ is selected from hydrogen, C ₁ -C ₇ -alkyl , C ₁ -C ₇ alkoxy, C ₁ -C ₇ -haloalkyl, C ₃ -C ₈ cycloalkyl; -C(O)NR'R", wherein R' and R" are independently selected from Hydrogen and C ₁ -C ₇ -alkyl.

In a particular embodiment, the invention relates to a compound of formula (I), wherein R ² is selected from the group consisting of:

Wherein R ⁵ is independently selected from the group consisting of hydrogen, halogen, C _1-7 alkyl, C ₁ -C ₇ -haloalkyl, and R ⁸ and R ⁹ are independently selected from C _1-7 alkyl, C ₁ -C _7-- haloalkyl, and R ¹⁰ is selected from hydrogen and -C (O) NR'R ", wherein R 'and R" are independently selected hydrogen and C ₁ -C ₇ - alkyl.

In a particular embodiment, the invention is directed to a compound of formula (I) wherein B is selected from the group consisting of exoethyl, vinyl and ethynyl.

In a particular embodiment, the invention relates to a compound of formula (I), wherein X is CR ³ and Y is CH ₂ , wherein R ³ is hydrogen.

In a particular embodiment, the invention relates to compounds of formula (I), wherein X is NR ³ and Y is CH ₂ , wherein R ³ is C _1-7 alkyl.

In a particular embodiment, the invention relates to a compound of formula (I), wherein R ¹ is selected from the group consisting of C ₁ -C ₇ -alkyl, C ₁ -C ₇ -haloalkyl, -(CH ₂ ) _{0,1, 2} -C ₃ -C ₅ -cycloalkyl, phenyl.

In a particular embodiment, the invention relates to a compound of formula (I) selected from the group consisting of:

1-(2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl)-1-methyl-1H -imidazol-4-yl)pyrrolidin-2-one

1-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) -2-yl)ethyl)-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one

1-[2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)vinyl]-1-phenylimidazol-4-yl]pyrrolidin-2-one

1-(1-(cyclopropylmethyl)-2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) -2-yl)ethyl)-1H-imidazol-4-yl)pyridine-2(1H)-one

1-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) -2-yl)ethyl)-1-methyl-1H-imidazol-4-yl)pyridine-2(1H)-one

1-[1-cyclopropyl-2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)vinyl]imidazol-4-yl]pyrrolidin-2-one

1-(1-cyclopropyl-2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) -2-yl)ethyl)-1H-imidazol-4-yl)pyrrolidin-2-one

1-[2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)vinyl]-1-methyl-imidazol-4-yl]-3-methyl-imidazolidin-2-one

1-(2-((4,8-dimethylquinazolin-2-yl)ethynyl)-1-methyl-1H-imidazol-4-yl)pyrrolidin-2-one

1-{2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-methyl-1H-imidazol-4-yl}pyrrolidin-2-one

1-[2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1-methyl-1H-imidazol-4-yl]pyrrolidin-2-one

1-[1-(cyclopropylmethyl)-2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

1-[2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

1-[1-(2,2-difluoroethyl)-2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

1-[2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethynyl)-1-methyl-1H-imidazol-4-yl]pyrrolidin-2-one

1-[1-(cyclopropylmethyl)-2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl} Ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

1-[2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl]-1-phenyl-imidazole -4-yl]pyrrolidin-2-one

1-[2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}ethyl)-1-(2,2 ,2-trifluoroethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

1-[1-(2,2-difluoroethyl)-2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine-2 -yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

1-{2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-phenyl-1H-imidazol-4-yl}pyrrolidin-2-one

1-[2-(2-{5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}ethyl)-1-methyl-1H -imidazol-4-yl]pyrrolidin-2-one

1-(2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethyl}-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one

1-(1-methyl-2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethynyl}-1H-imidazol-4-yl)pyrrolidin-2-one

1-(2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethynyl}-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one

N,3-Dimethyl-6-{2-[1-methyl-4-(2-o-oxypyrrolidin-1-yl)-1H-imidazol-2-yl]ethyl}-2-tri Fluoromethyl)imidazo[1,2-b]indole -8-carbamamine

N,3-Dimethyl-6-{2-[4-(2-o-oxypyrrolidin-1-yl)-1-phenyl-1H-imidazol-2-yl]ethyl}-2-( Trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine

The present invention relates to a process for the manufacture of a compound of formula (I) comprising:

a) making a compound of formula (II)

b) reacting with a compound of formula (III) or (IV) (III) or (IV)

The compound of formula (I) is hydrogenated as appropriate, wherein R ¹ , R ² , X and Y are as defined above.

10. A process for the manufacture of a compound of formula I, wherein B is an ethynyl group, the process comprising:

a) making the compound of formula (V)

b) reacting with a compound of formula (III) or (IV) (III) or (IV)

Compounds of formula (I) wherein R ¹ , R ² , X and Y are as defined above.

In another aspect, the invention relates to the use of a compound of the invention for the treatment or prevention of a psychiatric disorder, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusions, Substance-induced psychiatric disorders, anxiety disorders, panic disorder, obsessive-compulsive disorder, acute stress disorder, generalized anxiety disorder, drug addiction, motor disorder, Parkinson's disease, restless leg syndrome, cognitive deficit disorder, Alzheimer's Disease, multiple infarct dementia, mood disorders, depression, two-way affective disorder, neuropsychiatric condition, psychosis, attention deficit/hyperactivity disorder, attention disorder, diabetes and related disorders, type 2 diabetes Disease, neurodegenerative disorder, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumor, hematological malignancy, renal cell carcinoma or breast cancer.

In another aspect, the invention relates to the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a psychiatric disorder, schizophrenia, positive, negative and/or cognitive related to schizophrenia Symptoms, delusions, substance-induced psychosis, anxiety, panic disorder, obsessive-compulsive disorder, acute stress disorder, generalized anxiety disorder, drug addiction, motor disorder, Parkinson's disease, restless leg syndrome, cognitive deficit disorder, Alzheimer's disease, multiple infarct dementia, mood disorders, depression, two-way affective disorder, neuropsychiatric condition, psychosis, attention deficit/hyperactivity disorder, attention disorder, diabetes and related disorders, type 2 diabetes, neurodegenerative disorders , Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumors, hematological malignancies, renal cell carcinoma or breast cancer.

In another aspect, the invention relates to a compound of the invention for use in the treatment or prevention of a psychiatric disorder, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusions, Substance-induced psychiatric disorders, anxiety disorders, panic disorder, obsessive-compulsive disorder, acute stress disorder, generalized anxiety disorder, drug addiction, motor disorder, Parkinson's disease, restless leg syndrome, cognitive deficit disorder, Alzheimer's Disease, multiple infarct dementia, mood disorders, depression, two-way affective disorder, neuropsychiatric condition, psychosis, attention deficit/hyperactivity disorder, attention disorder, diabetes and related disorders, type 2 diabetes, neurodegenerative disorders, Huntington's disease, Multiple sclerosis, stroke, spinal cord injury, solid tumor, hematological malignancy, renal cell carcinoma or breast cancer.

In another aspect, the invention relates to methods for treating or preventing: psychotic disorders, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusions, substance induction Mental illness, anxiety, panic disorder, obsessive-compulsive disorder, acute stress disorder, generalized anxiety disorder, drug addiction, motor disorder, Parkinson's disease, restless leg syndrome, cognitive deficit disorder, Alzheimer's disease, Multiple infarction dementia, emotional disorders, depression, two-way emotional disorders, neuropsychiatric conditions, mental illness, attention Force defect/hyperactivity disorder, attention disorder, diabetes and related disorders, type 2 diabetes, neurodegenerative disorder, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumor, hematological malignancy, renal cell carcinoma or breast cancer, the method An effective amount of a compound of the invention is administered to an individual in need thereof.

General procedure

Compounds of formula (1a), (1b) and (1c) can be prepared as outlined in Scheme 1.

plan 1

The compound of the formula (1b) can be subjected to a detergency reaction between the aldehyde (D) and the deuterium salt (E) in a solvent (for example, THF, EtOH or a mixture thereof) in the presence of a suitable base (for example, DBU) (Wittig reaction) (Step 3), then by using a copper source (such as Cu(I)I), a palladium catalyst (such as hydrazine (dibenzylideneacetone) dipalladium (0)), a base (such as cesium carbonate), and a polar solvent (for example, dioxane, DMF and water) is prepared by coupling with a transition metal catalyzed by guanamine (G) (step 4). The compound of formula (1a) is subsequently hydrogenated by the use of a catalyst (eg Pd/C, Raney nickel or Lindlar) in a solvent (eg EtOH or MeOH) under ambient pressure (balloon) (step 5 ) Obtained (Scheme 1).

Alternatively, the compound of formula (1c) can be hydrogenated by the use of a catalyst (eg, Pd/C, Raney nickel or lindra) in a solvent (eg, EtOH or MeOH) under ambient pressure (balloon) (step 8). The compound of formula (1a) is obtained (Scheme 1).

The compound of the formula (1c) may be a copper source (for example, Cu(I)I), a palladium catalyst (for example, bis(triphenylphosphine)palladium(II) chloride), a base (for example, triethylamine), and a polar solvent ( For example, DMF) is prepared by a Sonogashira reaction between a heteroaromatic halide (J) and an alkyne (H) (step 6). Especially when using chloride as a starting material, it is necessary to raise the temperature and prolong the reaction time.

Compounds of formula (H) can be prepared from compound (D) as set forth in Scheme 1 and in the experimental section below and by methods known in the literature.

Compounds of formula (A), (B), (C), (D), (E), (G) and (J) are commercially available or may be as described in the experimental section below or by familiarizing themselves with the art Prepared by methods known in the literature.

Alternatively, the compound of formula (D) can be introduced into the aldehyde functional group by introducing a protecting group (e.g., triphenylmethyl) (step 9) in a manner similar to that outlined in Scheme 1, Step 2 (step 10). Deprotection of nitrogen using a suitable reagent (such as acetic acid) (step 11) and final reaction with a reagent of formula (B) using a base (such as cesium carbonate) and a polar solvent (such as DMF) (step 12) from formula (A) Compound preparation. Protecting groups and conditions suitable for introduction and removal are known to the literature or are familiar to those skilled in the art.

Scenario 2

Another method of preparing a compound of formula (1c) involves the use of a copper source (e.g., Cu(I)I), a palladium catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride), a base (e.g., triethylamine). Sonogashira reaction between heteroaromatic halide (J) and alkyne (O) of a polar solvent (such as DMF) (step 15). The compound of the formula (O) can be obtained by using a transition metal catalyst (for example, bis(dibenzylideneacetone) dipalladium (0)), a copper source (for example, Cu(I)I), a base (for example, cesium carbonate), and a polar solvent. (for example, dioxane, DMF and water) coupled with a compound of formula (D) with decylamine of formula (G) (step 13), and then with (1-diazo-2-oxopropyl)phosphonate The base ester reaction (step 14) is prepared.

Option 3 Pharmaceutical composition and investment

Another embodiment provides a pharmaceutical composition or medicament comprising a compound of the invention and a therapeutically inert carrier, diluent or excipient, and a method of making the compositions and medicaments using the compounds of the invention.

In one example, a compound of formula (I) can be prepared by mixing a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dosages and concentrations employed) at the appropriate pH and the desired purity at ambient temperature. Formed by Galen's cast. The pH of the formulation will depend primarily on the particular use and concentration of the compound, but is preferably in the range of from about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, in the form of a solid or amorphous composition, in the form of a lyophilized formulation or in the form of an aqueous solution.

The compositions are formulated, administered, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause, the delivery site of the agent, the method of administration, the timing of administration, and the knowledge of the practitioner other factors. The "effective amount" of the compound to be administered will be governed by such considerations and is the minimum amount required to inhibit PDE10 and control the cAMP signaling pathway. For example, the amount can be less than that for normal cells or mammals as a whole. The amount of toxicity.

In one embodiment, the pharmaceutically effective amount of the compound of the invention administered parenterally in each dose is between about 0.01-100 mg/kg patient body weight/day, and the other option is about 0.1-20 mg/kg patient body weight/day, wherein A typical initial range for the compounds used is from 0.3 to 15 mg/kg/day. In another embodiment, the oral unit dosage form (e.g., tablets and capsules) preferably contains from about 25 mg to about 100 mg of the compound of the invention.

The compounds of the invention may be administered by any suitable means, including orally, topically (including buccal and sublingual), transrectal, transvaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal Intrathecal and epidural and intranasal and (if required for topical treatment) intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

The compounds of the present invention can be administered in any convenient administration form such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, lotions, patches, and the like. Such compositions may contain conventional ingredients in pharmaceutical preparations such as diluents, carriers, pH modifiers, sweeteners, bulking agents, and other active agents.

A typical formulation is prepared by mixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins , 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants , sweeteners, flavoring agents, flavoring agents, diluents, and other known additives to provide a drug (ie, the present invention The aesthetic appearance of the article or its pharmaceutical composition) or aid in the manufacture of a pharmaceutical product (ie, a pharmaceutical agent).

Examples of suitable oral dosage forms comprise about 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of a compound of the invention and about 90-300 mg of anhydrous lactose, about 5-40 mg of croscarmellose sodium, about 5-30 mg of polyvinylpyrrolidine. A ketone (PVP) K30 and a complex of about 1-10 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with the PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed into a tablet form using conventional equipment. An example of an aerosol formulation can be obtained by dissolving a compound (e.g., 5-400 mg) in a suitable buffer solution (e.g., phosphate buffer) and optionally adding a tonicifier (e.g., a salt such as sodium chloride). preparation. The solution can be filtered using, for example, a 0.2 micron filter to remove impurities and contaminants.

Accordingly, an embodiment comprises a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. In another embodiment is a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

Full length analysis of human PDE10A was performed in 96-well microtiter plates. 50 μl of the reaction mixture contained 20 mM HEPES (pH=7.5)/10 mM MgCl ₂ /0.05 mg/ml BSA (Sigma Catalog No. A-7906), 50 nM cGMP (Sigma, Cat. No. G6129) and 50 nM [3H]-cGMP (GE Healthcare, Catalog No. TRK392 SA13.2 Ci/mmol), 3.75 ng/well PDE10A enzyme with or without specific test compound (Enzo Life Science, Lausen, Switzerland Catalog No. SE-534). A range of concentrations of potential inhibitors are used to generate data for calculating the concentration of inhibitor that results in a 50% effect (eg, IC50, a competitor concentration that inhibits 50% of PDE10A activity). Non-specific activity was tested in the absence of enzyme. The reaction was initiated by the addition of a substrate solution (cGMP and [3H]-cGMP) and allowed to proceed at room temperature for 20 minutes. The reaction was terminated by the addition of 25 μl of YSi-SPA scintillation beads (GE Healthcare, Cat. No. RPNQ0150) (terminating reagent) to a 18 mM zinc sulphate solution. After shaking for 1 h, the plate was centrifuged at 170 g for 1 minute to allow the beads to settle. The radioactivity count was then measured on a Perkin Elmer TopCount scintillation plate reader.

The compound of formula (I) has an IC50 value of less than 10 [mu]M, more specifically less than 5 [mu]M, more specifically less than 1 [mu]M. The table below shows data for some examples.

Instance Example 1 1-(2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl)-1-methyl-1H -imidazol-4-yl)pyrrolidin-2-one

a) (5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-ylmethyl)-triphenylphosphonium chloride

2-(Chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (prepared as described in US 2012/178748) under an argon atmosphere (2.254 g, 11.5 mmol, eq. 1.00) and a mixture of triphenylphosphine (3.01 g, 11.5 mmol, eq. The solvent was evaporated and the solid was triturated with ether. EtOAc was filtered, washed with ether and dried under high vacuum to afford pale brown powder (5,8-dimethyl-[1,2,4]triazolo[1] , 5-c]pyrimidin-2-ylmethyl)-triphenylphosphonium chloride (3.959 g, 75.3%). MS-Cl: m/z = 423.6 (M+H+)

b) 4-bromo-1-methyl-1H-imidazole-2-formaldehyde

A 1.6 M solution of n-butyllithium in hexane (1.83 mL, 2.93 mmol, eq. 1.05) was stirred in diethyl ether (2.5 mL) and cooled to -78 ° C in dry ice bath. 4-Bromo-1-methyl-1H-imidazole (450 mg, 2.8 mmol, eq.: 1.00) dissolved in diethyl ether (0.75 ml) was added over a period of 20 min. After stirring at -78 ° C for about 60 min, DMF (215 mg, 226 μl, 2.93 mmol, eq.: 1.05) in diethyl ether (0.5 ml) was added portionwise via syringe over 15 min. The reaction mixture was stirred at -78 °C for 2.5 h. Water was added and extracted three times with ethyl acetate dried over magnesium sulfate, filtered and evaporated. The crude material was purified by column chromatography eluting EtOAc EtOAc EtOAc Formaldehyde (326 mg, 61.7%). MS: m/z = 191.3 (M+H+)

b) 2-[(E)-2-(4-Bromo-1-methyl-1H-imidazol-2-yl)-vinyl]-5,8-dimethyl-[1,2,4]3 Azolo[1,5-c]pyrimidine

To a solution of 4-bromo-1-methyl-1H-imidazol-2-carbaldehyde (50 mg, 265 μmol, equivalent: 1.00) in tetrahydrofuran (5 ml) ((5,8-dimethyl-[1,2, 4] Triazolo[1,5-c]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (121 mg, 265 μmol, equivalent: 1) and DBU (44.3 mg, 43.9 μl, 291 μmol, equivalent: 1.1 ). The reaction mixture was stirred at 25 ° C for 18 hours. The crude material was applied to a silica gel and purified by flash chromatography on a silica gel column using ethyl acetate/methanol 0-10% as a solvent to afford 2-[(E)-2-(4) as a white solid. -bromo-1-methyl-1H-imidazol-2-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (73 mg, 82.8%). MS: m/z = 333.1 (M+H+)

c) 1-{2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)-vinyl] -1-methyl-1H-imidazol-4-yl}-pyrrolidin-2-one

In a closed vessel, (E)-2-(2-(4-bromo-1-methyl-1H-imidazol-2-yl)vinyl)-5,8-dimethyl-[1,2, 4] Triazolo[1,5-c]pyrimidine (70 mg, 210 μmol, equivalent: 1.00), pyrrolidin-2-one (35.8 mg, 32.2 μl, 420 μmol, equivalent: 2), cesium carbonate (137 mg, 420 μmol, Equivalent: 2), hydrazine (dibenzylideneacetone) dipalladium (0) / Pd ₂ (dba) ₃ (3.85 mg, 4.2 μmol, equivalent: 0.02) and 4,5-bis(diphenylphosphino)- A mixture of 9,9-dimethylxanthene (xant-phos) (4.86 mg, 8.4 μmol, equivalent: 0.04) in dioxane (3.5 ml) was heated to 140 °C. Further added hydrazine (dibenzylideneacetone) dipalladium(0)/Pd ₂ (dba) ₃ (3.85 mg, 4.2 μmol, equivalent: 0.02) and 4,5-bis(diphenylphosphino)-9,9 - xant-phos (4.86 mg, 8.4 μmol, equivalent: 0.04) and stirring was continued for 4 h. The crude material was applied to a silica gel and purified by column chromatography using ethyl acetate/methanol (0-10% methanol) as a solvent to afford 1-{2-[(E)-2 -(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)-vinyl]-1-methyl-1H-imidazol-4-yl }-pyrrolidin-2-one (24 mg, 33.9%). MS: m/z = 337 (M+)

d) 1-{2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)-vinyl] -1-methyl-1H-imidazol-4-yl}-pyrrolidin-2-one

(E)-1-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine- under a hydrogen atmosphere at room temperature 2-yl)vinyl)-1-methyl-1H-imidazol-4-yl)pyrrolidin-2-one (20 mg, 59.3 μmol, equivalent: 1.00) and 10% palladium on carbon (6.31 mg, 5.93 μmol, Equivalent: 0.1) stirred together in methanol (2 ml) overnight. The crude material was applied to a silica gel and purified by column chromatography using ethyl acetate/methanol (0-10%) methanol as a solvent to afford 1-{2-[2-(5,8 -Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)-ethyl]-1-methyl-1H-imidazol-4-yl}-pyrrolidine- 2-ketone (7.7 mg, 38.3%). MS: m/z = 340.5 (M+H+)

Example 2 1-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) -2-yl)ethyl)-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one

a) (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin -2-ylmethyl)-triphenylphosphonium chloride

It was used in a similar manner to that described in Example 1a) using 2-(chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin. Prepared (as prepared as described in US 2012/178748) (3.259 g, 16.6 mmol, eq: 1.00) to provide a light brown solid ((5,8-dimethyl-[1,2,4]triazolo[ 1,5-a]pyridyl -2-ylmethyl)-triphenyl-indole (11.5 g, 98.5%). MS-Cl: m/z = 423.4 (M+H+)

b) 4-bromo-1-phenyl-1H-imidazole

4-Bromo-1H-imidazole (3000 mg, 20.4 mmol, equivalent: 1.00), iodobenzene (3.75 g, 2.05 ml, 18.4 mmol, equivalent: 0.9), copper (I) iodide (194 mg, 1.02 mmol, equivalent: A mixture of 0.05), 8-hydroxyquinoline (148 mg, 1.02 mmol, equivalent: 0.05) and cesium carbonate (8.85 g, 27.1 mmol, eq.: 1.33) was dissolved in DMF (45.0 ml) and water (4.5 ml). The mixture was stirred at 130 ° C for 2.5 days. The residue was diluted with ethyl acetate and washed with EtOAc EtOAc. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. The crude material was applied to a silica gel and purified by flash chromatography on a 70 g silica gel column using heptane / ethyl acetate 10% to 30% as a solvent. -1H-imidazole (2.345 g, 51.5%). MS: m/z = 222.98 (M+)

c) 4-bromo-1-phenyl-1H-imidazole-2-formaldehyde

A 1.6 M solution of n-butyllithium in hexane (6.9 mL, 11.0 mmol, eq. 1.05) was stirred in THF (12.0 mL) and cooled to -78. 4-Bromo-1-phenyl-1H-imidazole/RO7016494-000-002 (2.345 g, 10.5 mmol, equivalent: 1.00) dissolved in THF (3.59 ml) was added over a period of 20 min. After stirring at -78 ° C for about 60 min, DMF (807 mg, 849 μl, 11.0 mmol, eq.: 1.05) in THF (2.39 ml) was added portionwise via syringe over 15 min. The reaction mixture was stirred at -78 °C for 2.5 h. Water was added and extracted three times with ethyl acetate dried over magnesium sulfate, filtered and evaporated. The crude material was applied to a silica gel and purified by flash chromatography using heptane / ethyl acetate 10% to 30% as elutant to afford 4-bromo-1-phenyl-1H-imidazole as a pale yellow solid. 2-formaldehyde (1.461 g, 55.4%). MS: m/z = 251.1 (M+H+)

d) 2-[(E)-2-(4-bromo-1-phenyl-1H-imidazol-2-yl)-vinyl]-5,8-dimethyl-[1,2,4]3 Oxazo[1,5-a]pyridin

It was used in a similar manner as described in Example 1c) ((5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) 2-yl)methyl)triphenylphosphonium chloride (1.16 g, 2.53 mmol, equivalent: 1.00) and 4-bromo-1-phenyl-1H-imidazol-2-carbaldehyde (635 mg, 2.53 mmol, eq.: 1.00) Prepared as starting material to give 2-[(E)-2-(4-bromo-1-phenyl-1H-imidazol-2-yl)-vinyl]-5,8- Methyl-[1,2,4]triazolo[1,5-a]pyridyl (278 mg, 27.8%). MS: m/z = 395.2 (M+H+)

e) 1-{2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrr -2-yl)-vinyl]-1-phenyl-1H-imidazol-4-yl}-pyrrolidin-2-one

Using (E)-2-(2-(4-bromo-1-phenyl-1H-imidazol-2-yl)vinyl)-5,8-di in a similar manner as described in Example 1d) Methyl-[1,2,4]triazolo[1,5-a]pyridyl (80 mg, 202 μmol, equivalent: 1.00) and pyrrolidin-2-one (34.5 mg, 31.0 μl, 405 μmol, equivalent: 2), cesium carbonate (198 mg, 607 μmol, equivalent: 3) as a starting material, provided shallow 1-{2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridine 2-yl)-vinyl]-1-phenyl-1H-imidazol-4-yl}-pyrrolidin-2-one (80.8 mg, 18.8%). MS: m/z = 400.3 (M+H+)

f) 1-{2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrr -2-yl)-ethyl]-1-phenyl-1H-imidazol-4-yl}-pyrrolidin-2-one

It was used in a similar manner to that described in Example 1e) using (E)-1-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5- a]pyridyl 2-yl)vinyl)-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one (13 mg, 32.5 μmol, equivalent: 1.00) was prepared as a starting material to afford a white solid. -{2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl)-ethyl]-1-phenyl-1H-imidazol-4-yl}-pyrrolidin-2-one (7 mg, 53.6%). MS: m/z = 402.4 (M+H+)

Example 3 1-[2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)vinyl]-1-phenylimidazol-4-yl]pyrrolidin-2-one

It was prepared as described in Example 2e). MS: m/z = 400.3 (M+H ⁺ )

Example 4 1-(1-(cyclopropylmethyl)-2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) -2-yl)ethyl)-1H-imidazol-4-yl)pyridine-2(1H)-one

a) 4-bromo-1-(cyclopropylmethyl)-1H-imidazole

4-bromo-1H-imidazole (2.38 g, 16.2 mmol, equivalent: 1.00) and (iodomethyl)cyclopropane (4.91 g, 16.2 mmol, equivalent: 1) were used in a similar manner as described in Example 2b). Prepared as starting material afforded 4-bromo-1-(cyclopropylmethyl)-1H-imidazole (980 mg, 24.1%). MS: m/z = 201 (M+H+)

b) 4-bromo-1-(cyclopropylmethyl)-1H-imidazole-2-carbaldehyde

It was prepared in a similar manner to that described in Example 2c) using 4-bromo-1-(cyclopropylmethyl)-1H-imidazole (258 mg, 1.28 mmol, eq.: 1.00) as starting material. 4-Bromo-1-(cyclopropylmethyl)-1H-imidazole-2-carbaldehyde (114 mg, 38.8%) as a yellow oil. MS: m/z = 229.0 (M+H+)

c) 2-[(E)-2-(4-Bromo-1-cyclopropylmethyl-1H-imidazol-2-yl)-vinyl]-5,8-dimethyl-[1,2, 4] Triazolo[1,5-a]pyridin

It was used in a similar manner as described in Example 1c) ((5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) 2-yl)methyl)triphenylphosphonium chloride (228 mg, 497 μmol, equivalent: 1.00) and 4-bromo-1-(cyclopropylmethyl)-1H-imidazole-2-carbaldehyde (114 mg, 498 μmol, Equivalent: 1.00) Prepared as starting material afforded 2-[(E)-2-(4-bromo-1-cyclopropylmethyl-1H-imidazol-2-yl)-vinyl]- 5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl (479 mg, 58.9%). MS: m/z = 375.2 (M+H+)

d) 1-{1-cyclopropylmethyl-2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-1H-imidazol-4-yl}-1H-pyridin-2-one

(E)-2-(2-(4-Bromo-1-(cyclopropylmethyl)-1H-imidazol-2-yl)vinyl)-5,8- in a closed vessel at 140 °C Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl (50 mg, 134 μmol, equivalent: 1.00), pyridine-2(3H)-one (25.5 mg, 268 μmol, equivalent: 2), cesium carbonate (87.3 mg, 268 μmol, equivalent: 2), copper (I) iodide (6.13) Mg, 6.7 μmol, equivalent: 0.05) and a mixture of 8-hydroxyquinoline (3.88 mg, 6.7 μmol, equivalent: 0.05) in DMF (350 μl) and water (35.0 μl). The crude material was applied to silica gel and purified by column chromatography using ethyl acetate / methanol (0-10% methanol). Still not pure. The material was purified by preparative HPLC to afford 1-{1-cyclopropylmethyl-2-[(E)-2-(5,8-dimethyl-[1,2,4] Triazolo[1,5-a]pyridyl 2-yl)-vinyl]-1H-imidazol-4-yl}-1H-pyridin-2-one (15 mg, 28.9%). MS: m/z = 388.2 (M+H+)

e) 1-{1-cyclopropylmethyl-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrr -2-yl)-ethyl]-1H-imidazol-4-yl}-1H-pyridin-2-one

It was used in a similar manner to that described in Example 1e) using (E)-1-(1-(cyclopropylmethyl)-2-(2-(5,8-dimethyl-[1,2, 4] Triazolo[1,5-a]pyridin 2-Benzyl)vinyl)-1H-imidazol-4-yl)pyridine-2(1H)-one (13 mg, 33.6 μmol, eq.: 1.00) was obtained as starting material to afford white solids 1-{1 -cyclopropylmethyl-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl)-ethyl]-1H-imidazol-4-yl}-1H-pyridin-2-one (4.06 mg, 31.1%). MS: m/z = 390.3 (M+H+)

Example 5 1-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) -2-yl)ethyl)-1-methyl-1H-imidazol-4-yl)pyridine-2(1H)-one

a) 2-[(E)-2-(4-bromo-1-methyl-1H-imidazol-2-yl)-vinyl]-5,8-dimethyl-[1,2,4] three Oxazo[1,5-a]pyridin

4-bromo-1-methyl-1H-imidazol-2-carbaldehyde (350 mg, 1.85 mmol, eq: 1.00) and ((5,8-dimethyl) was used in a similar manner as described in Example 1c). -[1,2,4]triazolo[1,5-a]pyridyl 2-Benzyl)methyl)triphenylphosphonium chloride (850 mg, 1.85 mmol, eq: 1) was obtained as starting material to afford 2-[(E)-2-(4-bromo-1) as a white solid. -methyl-1H-imidazol-2-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl (480 mg, 77.8%). MS: m/z = 333.3 (M+H+)

b) 1-{2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrr -2-yl)-vinyl]-1-methyl-1H-imidazol-4-yl}-1H-pyridin-2-one

It was used in a similar manner to that described in Example 4d) using (E)-2-(2-(4-bromo-1-methyl-1H-imidazol-2-yl)vinyl)-5,8-di Methyl-[1,2,4]triazolo[1,5-a]pyridyl (50 mg, 150 μmol, equivalent: 1.00) and pyridine-2(3H)-one (28.5 mg, 300 μmol, equivalent: 2) were prepared as starting materials to afford 1-{2-[(E)- 2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl)-vinyl]-1-methyl-1H-imidazol-4-yl}-1H-pyridin-2-one (22.3 mg, 42.8%). MS: m/z = 348.16 (M+H+)

c) 1-{2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrr -2-yl)-ethyl]-1-methyl-1H-imidazol-4-yl}-1H-pyridin-2-one

It was used in a similar manner to that described in Example 1e) using (E)-1-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5- a]pyridyl 2-yl)vinyl)-1-methyl-1H-imidazol-4-yl)pyridine-2(1H)-one (22 mg, 63.3 μmol, eq: 1.00) was obtained as starting material to afford white solid 1-{2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl)-ethyl]-1-methyl-1H-imidazol-4-yl}-1H-pyridin-2-one (1.6 mg, 7.23%). MS: m/z = 350.3 (M+H+)

Example 6 1-[1-cyclopropyl-2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)vinyl]imidazol-4-yl]pyrrolidin-2-one

a) 4-bromo-1-cyclopropyl-1H-imidazole

4-bromo-1H-imidazole (1 g, 6.8 mmol, equivalent: 1.00), cyclopropyl at 70 ° C under argon Acid (1.17 g, 13.6 mmol, equivalent: 2), copper (II) acetate (1.24 g, 6.8 mmol, equivalent: 1.00), 2,2'-bipyridine (1.06 g, 6.8 mmol, equivalent: 1) and carbonic acid A mixture of potassium (1.88 g, 13.6 mmol, equivalent: 2) in 1,2-dichloroethane (52.3 ml) was heated for 4 h. Washed with HCl (1mol) with saturated Na ₂ CO ₃ and the reaction was diluted with 50ml of dichloromethane, washed with water,. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. The aqueous layer was made basic and extracted three times with dichloromethane, dried over magnesium sulfate, filtered and combined with the first organic phase. The solvent was evaporated under vacuum. The crude material was applied to a silica gel and purified by flash chromatography on a silica gel column using dichloromethane/methanol 0-5% as a solvent to afford 4-bromo-1-cyclopropyl-1H as a brown oil. - Imidazole (452 mg, 28.4%). MS: m/z = 186.98 (M+H+)

b) 4-bromo-1-cyclopropyl-1H-imidazole-2-formaldehyde

Prepared in a similar manner to that described in Example 1b) using 4-bromo-1-cyclopropyl-1H-imidazole (452 mg, 2.42 mmol, eq.: 1.00) as starting material to afford an off-white solid 4- Bromo-1-cyclopropyl-1H-imidazole-2-carbaldehyde (257 mg, 49.5%). MS: m/z = 215.1 (M+H+)

c) 2-[(E)-2-(4-Bromo-1-cyclopropyl-1H-imidazol-2-yl)-vinyl]-5,8-dimethyl-[1,2,4] Triazolo[1,5-a]pyridyl

It was used in a similar manner as described in Example 1c) ((5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) 2-yl)methyl)triphenylphosphonium chloride (523 mg, 1.14 mmol, eq: 1.00) and 4-bromo-1-cyclopropyl-1H-imidazol-2-carbaldehyde (245 mg, 1.14 mmol, eq. 1.00) Prepared as starting material afforded 4-bromo-1-cyclopropyl-1H-imidazole-2-carbaldehyde (340 mg, 83.1%) as a white solid. MS: m/z = 361.2 (M+H+)

d) 2-[(E)-2-(4-Bromo-1-cyclopropyl-1H-imidazol-2-yl)-vinyl]-5,8-dimethyl-[1,2,4] Triazolo[1,5-a]pyridyl

It was used in a similar manner to that described in Example 1d) using (E)-2-(2-(4-bromo-1-cyclopropyl-1H-imidazol-2-yl)vinyl)-5,8- Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl (110 mg, 306 μmol, equivalent: 1.00) and pyrrolidin-2-one (52.1 mg, 47.0 μl, 612 μmol, equivalent: 2) were prepared as starting materials to provide a yellow viscous oil 1-{2-[(E )-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin 2-yl)-vinyl]-1-phenyl-1H-imidazol-4-yl}-pyrrolidin-2-one (39 mg, 35%). MS: m/z = 364.3 (M+H+)

Example 7 1-{1-cyclopropyl-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-1H-imidazol-4-yl}-pyrrolidin-2-one

Using (E)-1-(1-cyclopropyl-2-(2-(5,8-dimethyl-[1,2,4]triazole) in a similar manner as described in Example 1e) And [1,5-a]pyridyl 2-yl)vinyl)-1H-imidazol-4-yl)pyrrolidin-2-one (35 mg, 96.3 μmol, equivalent: 1.00) was prepared as starting material to afford 1-{1-ring as a white solid Propyl-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl)-ethyl]-1H-imidazol-4-yl}-pyrrolidin-2-one (23.8 mg, 67.6%). MS: m/z = 366.3 (M+H+)

Example 8 2'-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-3,1'-dimethyl-4,5-dihydro-3H,1'H-[1,4']diimidazolyl-2-one

Using (E)-2-(2-(4-bromo-1-methyl-1H-imidazol-2-yl)vinyl)-5,8-di in a similar manner as described in Example 1d) Methyl-[1,2,4]triazolo[1,5-a]pyridyl (50 mg, 150 μmol, equivalent: 1.00) and 1-methylimidazolidin-2-one (30.0 mg, 300 μmol, equivalent: 2) were prepared as starting materials to afford 2'-[(E)-2 as a yellow solid. -(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-3,1'-dimethyl-4,5-dihydro-3H,1'H-[1,4']diimidazolyl-2-one (6 mg, 11.3%) ). MS: m/z = 353.3 (M+H+)

Example 9 1-(2-((4,8-dimethylquinazolin-2-yl)ethynyl)-1-methyl-1H-imidazol-4-yl)pyrrolidin-2-one

a) 4-bromo-2-ethynyl-1-methyl-1H-imidazole

To 4-bromo-1-methyl-1H-imidazol-2-carbaldehyde (400 mg, 2.12 mmol, eq: 1.00) and potassium carbonate (585 mg, 4.23 mmol, eq: 2) at room temperature under argon A stirred mixture of methanol (30.0 ml) was added in one portion to a full amount of 1-dimethyldiamine-2-oxopropylphosphonic acid dimethyl ester (488 mg, 381 μl, 2.54 mmol, equivalent: 1.2). Stirring was then continued overnight at room temperature. The mixture was diluted with Et ₂ O and washed with aqueous 5% KHCO _3. With Et ₂ O and the aqueous phase was back extracted dried over magnesium sulfate, filtered and concentrated to leave a pale brown oily crude product. The crude material was applied to a silica gel and purified by column chromatography using heptane/ethyl acetate (0-50% ethyl acetate) as a solvent to afford 4-bromo-2-ethynyl as a brown solid. 1-Methyl-1H-imidazole (319 mg, 81.5%). MS: m/z = 185.0 (M+H+)

b) 4,8-Dimethyl-2-(2-methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-ylethynyl)-quinazoline

To 2-chloro-4,8-dimethylquinazoline (prepared as described in WO 2013/50527) under an argon atmosphere at room temperature (100 mg, 519 μmol, equivalent: 1.00) and 4-bromo-2- Add a solution of ethynyl-1-methyl-1H-imidazole (106 mg, 571 μmol, equivalent: 1.1) in DMF (8.00 ml), triethylamine (105 mg, 144 μl, 1.04 mmol, equivalent: 2), copper iodide (I) (4.94 mg, 26.0 μmol, equivalent: 0.05) and bis(triphenylphosphine)palladium(II) chloride (18.2 mg, 26.0 μmol, equivalent: 0.05). The mixture was degassed and backfilled with argon and then heated to 80 °C. Stirring was continued throughout the weekend at this temperature (dark solution). LCMS showed the product peak. The crude material was applied to a silica gel and purified by column chromatography using heptane/ethyl acetate (0-100% ethyl acetate) as a solvent to afford 4,8-dimethyl- 2-(2-Methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-ylethynyl)-quinazoline (55 mg, 31.1%). MS: m/z = 341.1 (M+H+)

c) 1-[2-(4,8-Dimethyl-quinazolin-2-ylethynyl)-1-methyl-1H-imidazol-4-yl]-pyrrolidin-2-one

2-((4-bromo-1-methyl-1H-imidazol-2-yl)ethynyl)-4,8-dimethylquinazoline was used in a similar manner as described in Example 1d) 80 mg, 234 μmol, equivalent: 1.00) and pyrrolidin-2-one (39.9 mg, 36.0 μl, 469 μmol, equivalent: 2) were prepared as starting materials to provide 1-[2-(4,8-) as a pale yellow solid. Dimethyl-quinazolin-2-ylethynyl)-1-methyl-1H-imidazol-4-yl]-pyrrolidin-2-one (2.42 mg, 2.99%). MS: m/z = 346.2 (M + H +).

Example 10 1-{2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-methyl-1H-imidazol-4-yl}pyrrolidin-2-one

To 4-bromo-2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrene in a sealed tube at 25 °C Add pyrrrolidin-2-one (0.07 ml, 0.90 mmol) to a solution of 2-yl}vinyl]-1-methyl-1H-imidazole (200 mg, 0.60 mmol) in 1,4-dioxane (10 mL) , Brettphos cyclopalladium (71.9 mg, 0.09 mmol) and Ruphos (56 mg, 0.12 mmol), and the mixture was purged with argon for 10 min. Thereafter NaOtBu (173 mg, 1.80 mmol) was added and spurt with argon for 10 min. The reaction mixture was then heated to 110 ° C and stirred at this temperature for 6 h. The reaction mixture was warmed to EtOAc (30 mL). Washed with water (30ml) and extracted filtrate was diluted with EtOAc (2 × 50ml), and washed with water (50ml), brine (50ml) the organic layers were washed, ₂ SO ₄ and concentrated in vacuo dried over Na. The crude material was purified by column chromatography eluting with EtOAc EtOAc (EtOAc) elut -[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-methyl-1H-imidazol-4-yl}pyrrolidin-2-one (60 mg, 29%). MS: M/Z = 338.2 (M + H +).

Example 11 1-[2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1-methyl-1H-imidazol-4-yl]pyrrolidin-2-one

Then to 1-{2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl Raney nickel (30 mg) was added to a solution of 2-yl}vinyl]-1-methyl-1H-imidazol-4-yl}pyrrolidin-2-one (60 mg, 0.18 mmol) in MeOH (5 mL). The reaction mass was stirred under a hydrogen balloon pressure for 16 h. After completion of the reaction, the reaction mixture was filtered and evaporated. The crude material was purified by a ruthenium dioxide column using 4% methanol in dichloromethane to afford 1-[2-(2-{4,7-dimethyl-[1,2,4] Oxazo[1,5-a]pyridin -2-yl}ethyl)-1-methyl-1H-imidazol-4-yl]pyrrolidin-2-one (16 mg, 26%). MS: M/Z = 340.2 (M + H +).

Example 12 1-[1-(cyclopropylmethyl)-2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

a: 1-[1-(cyclopropylmethyl)-2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a] Pyridine -2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one

It was used in a similar manner to that described in Example 10 using 4-bromo-1-(cyclopropylmethyl)-2-[(E)-2-{4,7-dimethyl-[1,2, 4] Triazolo[1,5-a]pyridin 2-Benzyl}vinyl]-1H-imidazole (170 mg, 0.45 mmol) and pyrrolidin-2-one (0.07 ml, 0.91 mmol) were obtained as starting material to afford 1-[1-[ Propylmethyl)-2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one (70 mg, 40%); MS: M/Z = 378 (M+H+).

b: 1-[1-(cyclopropylmethyl)-2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin -2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

It was used in a similar manner to that described in Example 11 using 1-[1-(cyclopropylmethyl)-2-[(E)-2-{4,7-dimethyl-[1,2,4 Triazolo[1,5-a]pyridyl 2-Benzyl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one (70 mg, 0.186 mmol) was obtained as a starting material to afford 1-[1-(cyclopropylmethyl) as a white solid 2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1H-imidazol-4-ylpyrrolidin-2-one (7 mg, 11%); MS: M/Z = 380.1 (M+H+).

Example 13 1-[2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

a: 4-bromo-1-(triphenylmethyl)-1H-imidazole

A solution of 4-bromo-1H-imidazole (10 g, 68.04 mmol) in THF (330 mL) was cooled to 0. K ₂ CO ₃ (18.77 g, 136.08 mmol) was slowly added at 0 °C. After stirring at 0 ° C for 1 h, iodomethane (8.50 ml, 136.08 mmol) was added dropwise at 0 °C. The mixture was warmed to 25 ° C and stirred at 25 ° C for 16 h. The reaction was diluted with water (100 mL) The organic layer was washed with EtOAc (EtOAc)EtOAc. The crude material was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to afford 4-bromo-1-(triphenylmethyl)-1H-imidazole as a colorless liquid (12 g , 50%).

b: 4-bromo-1-(triphenylmethyl)-1H-imidazole-2-formaldehyde

n-Butyllithium was added dropwise to a solution of 4-bromo-1-(triphenylmethyl)-1H-imidazole (6 g, 15.42 mmol) in tetrahydrofuran (250 ml) under argon at -78 °C. 1.6M in hexane Medium, 12.44 ml, 18.55 mmol). The resulting mixture was stirred at -78 °C for 30 minutes. Then dimethylformamide (2.49 ml, 30.89 mmol) dissolved in 45 ml of THF was added dropwise at -78 °C and the mixture was slowly warmed to 25 °C. The mixture was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Filter and evaporate. The crude material was purified by a normal phase column chromatography eluting with 30% ethyl acetate in hexane to afford 4-bromo-1-(triphenylmethyl)-1H-imidazole-2-carbaldehyde as a white solid. (2g, 31%).

c: 4-bromo-1H-imidazole-2-formaldehyde

Add AcOH (1.5 ml, 26.4 mmol) to a solution of 4-bromo-1-(triphenylmethyl)-1H-imidazol-2-carbaldehyde (5.5 g, 13.18 mmol) in methanol (100 mL) The temperature was raised to 60 ° C and stirred at this temperature for 2 h. After completion of the reaction, the reaction mixture was warmed to 25 ° C and concentrated under reduced pressure. The crude residue was diluted with EtOAc (EtOAc) (EtOAc (EtOAc) Filtered and concentrated to obtain a crude material. The crude material was purified using a EtOAc EtOAc EtOAc EtOAc (EtOAc)

d: 4-bromo-1-(2,2,2-trifluoroethyl)-1H-imidazole-2-formaldehyde

A solution of 4-bromo-1H-imidazole-2-carbaldehyde (350 mg, 2 mmol) in DMF (10 mL) was cooled to 0. Cs ₂ CO ₃ (1.71 g, 2 mmol) was slowly added at 0 °C. After stirring at 0 ° C for 10 min, 2,2-difluoroethyl trifluoromethanesulfonate (928 ng, 2 mmol) was added dropwise at 0 °C. The mixture was warmed to 25 ° C and stirred at the same temperature for 2 h. The reaction was diluted with water (50 mL) The organic layer was washed with EtOAc (EtOAc)EtOAc. The crude material was purified by EtOAc EtOAc (EtOAc) eluting Imidazole-2-carbaldehyde (350 mg, 68%). MS: M/Z = 257 (M + H +).

e: 4-bromo-2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazole

4-bromo-1-(2,2,2-trifluoroethyl)-1H-imidazol-2-carbaldehyde (4d) (250 mg, 0.97 mmol) was used in a similar manner as described in Example 1c) {4,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 4-Benzyl}methyl)triphenylphosphonium chloride (5) (412 mg, 0.97 mmol) was obtained as starting material to afford 4-bromo-2-[(E)-2-{4 as a white solid. 7-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazole (180 mg, 46%); MS: M/Z = 401 (M+H+).

f: 1-{2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl}pyrrolidin-2-one

To 4-bromo-2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrene in a sealed tube at 25 °C a solution of 2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazole (6a) (160 mg, 0.4 mmol) in 1,4-dioxane (6 mL) Pyrrolidin-2-one (0.06 ml, 0.8 mmol), Brettphos cyclopalladium (47.93 mg, 0.06 mmol) and Ruphos (37.3 mg, 0.08 mmol) were added and the mixture was purged with argon for 10 min. Thereafter NaOtBu (115.3 mg, 1.2 mmol) was added and the mixture was purged with argon for 10 min. The reaction mixture was then heated to 110 ° C and stirred at this temperature for 6 h. The reaction mixture was warmed to EtOAc (30 mL). Washed with water (30ml) and extracted filtrate was diluted with EtOAc (2 × 50ml), and washed with water (50ml), brine (50ml) the organic layers were washed, ₂ SO ₄ and concentrated in vacuo dried over Na. The crude material was purified by column chromatography eluting with EtOAc EtOAc (EtOAc) elut -[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl}pyrrolidin-2-one (60 mg, 37%); MS: M/Z =406 (M+H+).

g: 1-[2-(2-{4,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

Then to 1-{2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl}pyrrolidin-2-one (8d) (70 mg, 0.17 mmol) in methanol ( Raney nickel (30 mg) was added to the solution in 5 ml). The reaction mass was stirred under a hydrogen balloon pressure for 16 h. After completion of the reaction, the reaction mixture was filtered and evaporated. The crude material was purified by a ruthenium dioxide column using 4% methanol in dichloromethane to afford 1-[2-(2-{4,7-dimethyl-[1,2,4] Oxazo[1,5-a]pyridin -2-yl}ethyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl]pyrrolidin-2-one (20 mg, 28%); MS: M/Z =408.2 (M+H+).

Example 14 1-[1-(2,2-difluoroethyl)-2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

a: 4-bromo-1-(2,2-difluoroethyl)-1H-imidazole-2-formaldehyde

A solution of 4-bromo-1H-imidazole-2-carbaldehyde (450 mg, 2.57 mmol) in DMF (12 mL) was cooled to 0. Cs ₂ CO ₃ (1.71 g, 5.14 mmol) was slowly added at 0 °C. After stirring at 0 ° C for 10 min, 2,2-difluoroethyl trifluoromethanesulfonate (825.5 mg, 3.87 mmol) was added dropwise at 0 °C. The mixture was warmed to 25 ° C and stirred at the same temperature for 2 h. The reaction was diluted with water (50 mL) The organic layer was washed with EtOAc (EtOAc)EtOAc. The crude material was purified by combiflash column chromatography eluting with 20% ethyl acetate in hexane to afford 4-bromo-1-(2,2-difluoroethyl)-1H-imidazole as colorless liquid. 2-Formaldehyde (220 mg, 36%); MS: M/Z = 239 (M+H+).

b: 4-bromo-1-(2,2-difluoroethyl)-2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1, 5-a]pyridyl -2-yl}vinyl]-1H-imidazole

4-bromo-1-(2,2-difluoroethyl)-1H-imidazol-2-carbaldehyde (200 mg, 0.84 mmol) and {4,7-di, in a similar manner as described in Example 5a. Methyl-[1,2,4]triazolo[1,5- a]pyridyl 4-Benzyl}methyl)triphenylphosphonium chloride (354 mg, 0.84 mmol) was obtained as starting material afforded 4-bromo-1-(2,2-difluoroethyl)-2- [(E)-2-{4,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl}vinyl]-1H-imidazole (120 mg, 38%); MS: M/Z = 383 (M+H+).

c: 1-[1-(2,2-Difluoroethyl)-2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5 -a]pyridyl -2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one

4-bromo-1-(2,2-difluoroethyl)-2-[(E)-2-{4,7-dimethyl-[1] was used in a similar manner as described in Example 10. , 2,4]triazolo[1,5-a]pyridyl 2-yl}vinyl]-1H-imidazole (100 mg, 0.26 mmol) and pyrrolidin-2-one (0.04 ml, 0.91 mmol) were obtained as starting material to afford 1-[1-(2) as a white solid. ,2-difluoroethyl)-2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one (13 mg, 12%); MS: M/Z = 388.2 (M+H+).

d: 1-[1-(2,2-Difluoroethyl)-2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin -2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

It was used in a similar manner to that described in Example 11 using 1-[1-(2,2-difluoroethyl)-2-[(E)-2-{4,7-dimethyl-[1, 2,4]triazolo[1,5-a]pyridyl 2-Benzyl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one (23 mg, 0.06 mmol) was obtained as a starting material to afford 1-[1-(2,2- Difluoroethyl)-2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1H-imidazol-4-ylpyrrolidin-2-one (6 mg, 25%); MS: M/Z = 390.4 (M+H+).

Example 15 1-[2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethynyl)-1-methyl-1H-imidazol-4-yl]pyrrolidin-2-one

a: 1-methyl-4-(2-oxopyrrolidin-1-yl)-1H-imidazole-2-carbaldehyde

Add Cs ₂ CO _{3 to a} solution of 4-bromo-1-methyl-1H-imidazol-2-carbaldehyde (400 mg, 5.8 mmol) and pyrrolidine-2-one (0.35 ml, 2.11 mmol) in toluene (20 ml) (3.7 g, 11.6 mmol), xantphos (335 mg, 0.58 mmol), and the mixture was purged with argon for 10 min. Pd ₂ (dba) ₃ (1.03 g, 3.17 mmol) was added and rinsed with argon for 10 min. The reaction mixture was then heated to 50 ° C and stirred at this temperature under argon for 16 h. Thereafter TLC was checked and the starting material was present, so an additional 0.5 equivalents of xantphos and 0.5 equivalents of Pd ₂ (dba) ₃ and 1 equivalent of Cs ₂ CO ₃ were added and continued at 90 ° C for an additional 3 h. The reaction mixture was warmed to 25 <0>C, filtered over a pad of celite and concentrated in vacuo. The crude material was purified by column chromatography eluting with EtOAc (EtOAc:EtOAc) Pyrrolidin-1-yl)-1H-imidazole-2-carbaldehyde (60 mg, 15%). MS: M/Z = 194 (M + H +).

b: 1-(2-ethynyl-1-methyl-1H-imidazol-4-yl)pyrrolidin-2-one

To 1-methyl-4-(2-o-oxypyrrolidin-1-yl)-1H-imidazole-2-carboxaldehyde (60 mg, 0.311 mmol) in MeOH (6 mL) A solution of Bestmann ohira reagent (72 mg, 0.373 mmol) and K ₂ CO ₃ (85 g, 0.622 mmol) was added and the mixture was stirred at 25 ° C for 2 h. Thereafter TLC was checked and filtered through a bed of diatomaceous earth and concentrated in vacuo. The crude material was purified by EtOAc EtOAc (EtOAc) elute Pyrrolidin-2-one (30 mg, 51%). MS: M/Z = 190 (M + H +).

c: 1-[2-(2-{4,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethynyl)-1-methyl-1H-imidazol-4-yl]pyrrolidin-2-one

To 1-(2-ethynyl-1-methyl-1H-imidazol-4-yl)pyrrolidin-2-one (55 mg, 0.291 mmol) and 2-bromo-4,7-dimethyl-[1, 2,4]triazolo[1,5-a]pyridyl (73 mg, 0.32 mmol) <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; Thereafter Pd(PPh ₃ ) ₂ Cl ₂ (11 mg, 0.015 mmol) was added and then purged with argon for 5 min. The reaction mixture was then heated to 75 ° C and stirred at argon for 2 h under argon. After the reaction mixture was filtered, diluted with water (30ml) via diatomaceous earth bed, and extracted with EtOAc (2 × 50ml), and washed with water (50ml), the organic layer with brine (50ml) of washed, dried over Na ₂ SO ₄ and in vacuo Concentrated in. The crude material was purified by preparative TLC to afford 1-[2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a] as a white viscous solid. Pyridine 2-yl}ethynyl)-1-methyl-1H-imidazol-4-yl]pyrrolidin-2-one (21) (4 mg, 4%). MS: M/Z = 336 (M + H +).

Example 16 1-[1-(cyclopropylmethyl)-2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl} Ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

a: 4-bromo-1-(cyclopropylmethyl)-2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c Pyrimidin-2-yl}vinyl]-1H-imidazole

4-bromo-1-(cyclopropylmethyl)-1H-imidazol-2-carbaldehyde (400 mg, 1.74 mmol) and {5,8-dimethyl-- was used in a similar manner as described in Example 1c. [1,2,4]Triazolo[1,5-c]pyrimidin-2-yl}methyl)triphenylphosphonium chloride (740 mg, 1.74 mmol) was prepared as a starting material to afford a white solid. -Bromo-1-(cyclopropylmethyl)-2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine- 2-yl}vinyl]-1H-imidazole (360 mg, 55%). MS: M/Z = 372.8 (M + H +).

b: 1-[1-(cyclopropylmethyl)-2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c] Pyrimidin-2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one

It was used in a similar manner to that described in Example 1d using 4-bromo-1-(cyclopropylmethyl)-2- [(E)-2-{5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}vinyl]-1H-imidazole (200 mg, 0.54 Methyl) and pyrrolidin-2-one (0.08 ml, 0.90 mmol) were obtained as starting material to afford 1-[1-(cyclopropylmethyl)-2-[(E)-2-{ 5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one ( 90mg, 45%). MS: M/Z = 378.0 (M + H +).

c: 1-[1-(cyclopropylmethyl)-2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2- }ethyl}-1H-imidazol-4-yl]pyrrolidin-2-one

It was used in a similar manner to that described in Example 11 using 1-[1-(cyclopropylmethyl)-2-[(E)-2-{5,8-dimethyl-[1,2,4 Triazolo[1,5-c]pyrimidin-2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one (90 mg, 0.239 mmol) as a starting material, white Solid 1-[1-(cyclopropylmethyl)-2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2- Base ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one (26 mg, 29%). MS: M/Z = 380.2 (M + H +).

Example 17 1-[2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl]-1-phenyl-imidazole -4-yl]pyrrolidin-2-one

a: 2-[(E)-2-(4-bromo-1-phenyl-imidazol-2-yl)vinyl]-5,8-dimethyl-[1,2,4]triazolo[ 1,5-c]pyrimidine

4-bromo-1-phenyl-1H-imidazole (200 mg, 0.80 mmol) and {5,8-dimethyl-[1,2,4]triazole were used in a similar manner as described in Example 1c. And [1,5-c]pyrimidin-2-yl}methyl)triphenylphosphonium chloride (338 mg, 0.80 mmol) was obtained as a starting material to afford 2-[(E)-2- 4-bromo-1-phenyl-imidazol-2-yl)vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (180 mg, 58% MS: M/Z = 395 (M+H+).

b: 2-[(E)-2-(4-bromo-1-phenyl-imidazol-2-yl)vinyl]-5,8-dimethyl-[1,2,4]triazolo[ 1,5-c]pyrimidine

It was used in a similar manner to that described in Example 1d using 2-[(E)-2-(4-bromo-1-phenyl-imidazol-2-yl)vinyl]-5,8-dimethyl- [1,2,4]Triazolo[1,5-c]pyrimidine (110 mg, 0.28 mmol) and pyrrolidin-2-one (0.045 ml, 0.91 mmol) were prepared as starting material to afford a white solid. -[(E)-2-(4-bromo-1-phenyl-imidazol-2-yl)vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5 -c]pyrimidine (55 mg, 50%); MS: M/Z = 399 (M+H+).

c: 1-[2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl]-1-phenyl -imidazol-4-yl]pyrrolidin-2-one

It was used in a similar manner to that described in Example 11 using 2-[(E)-2-(4-bromo-1-phenyl-imidazol-2-yl)vinyl]-5,8-dimethyl- [1,2,4]triazolo[1,5-c]pyrimidine (15 mg, 0.04 Prepared as starting material to provide 1-[2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine-2 as an off-white solid. -yl)ethyl]-1-phenyl-imidazol-4-yl]pyrrolidin-2-one (4 mg, 25%); MS: M/Z = 402 (M+H+).

Example 18 1-[2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}ethyl)-1-(2,2 ,2-trifluoroethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

a: 4-bromo-2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}vinyl] -1-(2,2,2-trifluoroethyl)-1H-imidazole

4-bromo-1-(2,2,2-trifluoroethyl)-1H-imidazol-2-carbaldehyde (250 mg, 0.97 mmol) and {5,8 were used in a similar manner as described in Example 1c. -Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}methyl)triphenylphosphonium chloride (412 mg, 0.97 mmol) as a starting material, Provided 4-bromo-2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}ethylene as a white solid 1-(2,2,2-trifluoroethyl)-1H-imidazole (170 mg, 43%); MS: M/Z = 401 (M+H+).

b: 1-{2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}vinyl]- 1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl}pyrrolidin-2-one

It was used in a similar manner to that described in Example 1d using 4-bromo-2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5- c]pyrimidin-2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazole (170 mg, 0.42 mmol) and pyrrolidine-2-one (0.065 ml, 0.85 mmol) Prepared as starting material to provide 1-{2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine as a yellow solid. -2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl}pyrrolidin-2-one (70 mg, 41%); MS: M/Z =406 (M+H+).

c: 1-[2-(2-{5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}ethyl)-1-(2) ,2,2-trifluoroethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

It was used in a similar manner to that described in Example 11 using 1-{2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c Pyrimidine-2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl}pyrrolidin-2-one (8d) (70 mg, 0.17 mmol) as The starting material was prepared to give 1-[2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl} as an off-white solid. Ethyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl]pyrrolidin-2-one (15 mg, 21%); MS: M/Z = 408.2 (M+ H+).

Example 19 1-[1-(2,2-difluoroethyl)-2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine-2 -yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

a: 4-bromo-1-(2,2-difluoroethyl)-2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1, 5-c]pyrimidin-2-yl}vinyl]-1H-imidazole

It was used in a similar manner to that described in Example 1c using 4-bromo-1-(2,2-difluoroethyl)-1H-imidazol-2-carbaldehyde (200 mg, 0.84 mmol) and {5,8- Methyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}methyl)triphenylphosphonium chloride (354 mg, 0.84 mmol) was prepared as a starting material to provide an off-white 4-Bromo-1-(2,2-difluoroethyl)-2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1, 5-c]pyrimidin-2-yl}vinyl]-1H-imidazole (125 mg, 38%); MS: M/Z = 385 (M+H+).

b: 1-[1-(2,2-Difluoroethyl)-2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5 -c]pyrimidin-2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one

4-bromo-1-(2,2-difluoroethyl)-2-[(E)-2-{5,8-dimethyl-[1] was used in a similar manner to that described in Example 10. , 2,4]triazolo[1,5-c]pyrimidin-2-yl}vinyl]-1H-imidazole (150 mg, 0.40 mmol) and pyrrolidin-2-one (0.06 ml, 0.80 mmol) beginning Material prepared to provide 1-[1-(2,2-difluoroethyl)-2-[(E)-2-{5,8-dimethyl-[1,2,4]3 as a yellow solid Zoxa[1,5-c]pyrimidin-2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one (70 mg, 41%); MS: M/Z = 406 (M+ H+).

c: 1-[1-(2,2-Difluoroethyl)-2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine -2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one

It was used in a similar manner to that described in Example 11 using 1-[1-(2,2-difluoroethyl)-2-[(E)-2-{5,8-dimethyl-[1, 2,4] Triazolo[1,5-c]pyrimidin-2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one (30 mg, 0.08 mmol) as starting material , 1-[1-(2,2-difluoroethyl)-2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5- c]pyrimidin-2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one (11 mg, 37%); MS: M/Z=390.0 (M+H+).

Example 20 1-{2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-phenyl-1H-imidazol-4-yl}pyrrolidin-2-one

It was used in a similar manner to that described in Example 1d using 4-bromo-2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5- a]pyridyl 2-yl}vinyl]-1-phenyl-1H-imidazole (110 mg, 0.28 mmol) and pyrrolidin-2-one (0.045 ml, 0.91 mmol) were prepared as starting materials to afford white solids 1- {2-[(E)-2-{4,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl}vinyl]-1-phenyl-1H-imidazol-4-yl}pyrrolidin-2-one (55 mg, 50%); MS: M/Z = 399 (M+H+).

Example 21 1-[2-(2-{5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}ethyl)-1-methyl-1H -imidazol-4-yl]pyrrolidin-2-one

a: 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester

To 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic acid (750 mg, 4.05 mmol) in methanol (100 ml) at 25 ° C under argon H ₂ SO ₄ (0.05 ml) was added to the stirred solution. The mixture was then stirred at 60 ° C for 16 h. TLC showed the starting material to react completely. The reaction mixture was then cooled and the distilled solvent was removed. Thereafter, water (50 ml) was added to the reaction mixture, and neutralized with sodium hydrogencarbonate. The aqueous phase was extracted with ethyl acetate. The combined organics were washed with brine (50 mL) dried over sodium sulfate The crude material was purified by column chromatography eluting with EtOAc EtOAc (EtOAc) Methyl 1,5-a]pyrimidine-2-carboxylate (500 mg, 60%). MS: M/Z = 207 (M + H +).

b: {5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}methanol

Methyl 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylate (300 mg, 1.45 mmol) at 25 ° C under argon for 5 min Sodium borohydride (117 mg, 2.91 mmol) was added portionwise over a stirred solution of methanol (100 mL). The mixture was then stirred at 25 ° C for 16 h. TLC showed the starting material to react completely. Water (25 ml) was then added to the reaction mixture, which was stirred at 25 ° C for 30 min and diluted with DCM (50 mL). The aqueous phase was extracted with 10% methanol (3 x 50 mL) in DCM. The combined organics were washed with brine (30 mL), dried over sodium sulfatessssssssssssssssssssssssssssss To give {5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}methanol (115 mg, 44%). MS: M/Z = 179 (M + H +).

c: 2-(Chloromethyl)-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

To {5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}methanol (200 mg, 02.52 mmol) at 0 ° C under argon Pyridine (0.4 ml, 5.06 mmol) was added dropwise to a stirred solution of dichloromethane (100 ml), and then sulphur sulphite (0.25 ml, 3.03 mmol) was added. Thereafter, the mixture was warmed to 25 ° C and stirred at 25 ° C for 16 h. The reaction mixture was diluted with water (50 ml). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with brine (30 mL) EtOAc. The crude material was purified by column chromatography chromatography eluting with 2% methanol in DCM to afford 2-(chloromethyl)-5,7-dimethyl-[1,2,4] Zoxao[1,5-a]pyrimidine (200 mg, 40%). MS: M/Z = 197 (M + H +).

d: ({5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}methyl)triphenylphosphonium chloride

2-(Chloromethyl)-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (200 mg, in a similar manner as described in Example 1a) Prepared as a starting material to provide a yellow solid ({5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}methyl) Triphenylphosphonium chloride (270 mg, crude); MS: M/Z = 423 (M+H+).

e: 4-bromo-2-[(E)-2-{5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}vinyl] -1-methyl-1H-imidazole

4-bromo-1-methyl-1H-imidazol-2-carbaldehyde (150 mg, 0.80 mmol) and ({5,7-dimethyl-[1,2) were used in a similar manner as described in Example 1c. , 4] Triazolo[1,5-a]pyrimidin-2-yl}methyl)triphenylphosphonium (336 mg, 0.80 mmol) was obtained as a starting material to afford 4-bromo-2-[ (E)-2-{5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}vinyl]-1-methyl-1H-imidazole (75 mg, 28%); MS: M/Z = 335 (M+H+).

f: 1-{2-[(E)-2-{5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}vinyl]- 1-methyl-1H-imidazol-4-yl}pyrrolidin-2-one

It was used in a similar manner to that described in Example 10 using 4-bromo-2-[(E)-2-{5,7-dimethyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}vinyl]-1-methyl-1H-imidazole (60 mg, Prepared by using 0.18 mmol) and pyrrolidin-2-one (0.016 ml, 0.216 mmol) as starting material to provide 1-{2-[(E)-2-{5,7-dimethyl-[1,2 , 4] Triazolo[1,5-a]pyrimidin-2-yl}vinyl]-1-methyl-1H-imidazol-4-yl}pyrrolidin-2-one (60 mg, crude); MS :M/Z = 338.1 (M+H+).

g: 1-[2-(2-{5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}ethyl)-1-methyl -1H-imidazol-4-yl]pyrrolidin-2-one

It was used in a similar manner to that described in Example 11 using 41-{2-[(E)-2-{5,7-dimethyl-[1,2,4]triazolo[1,5-a Pyrimidin-2-yl}ethenyl]-1-methyl-1H-imidazol-4-yl}pyrrolidin-2-one (60 mg, 0.18 mmol) was obtained as a starting material to afford a yellow solid. 2-(2-{5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}ethyl)-1-methyl-1H-imidazole- 4-yl]pyrrolidin-2-one (6 mg, 10%); MS: M/Z = 340 (M+H+).

Example 22 1-[2-(2-{5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}ethyl)-1-methyl-1H -imidazol-4-yl]pyrrolidin-2-one

a: 6-chloropurine 3-amine

3,6-Dichloropurine at 120 ° C (10.0 g, 67.5 mmol) was heated in a solution of 28% aqueous ammonium hydroxide (100 mL). The mixture was cooled to 0 ° C and precipitated. Thereafter, the resulting precipitate was filtered, and the residue was washed with hexane and dried to give 6-chloroindole as a white solid. 3-Amine (5.0 g, 57%). MS: M/Z = 129.9 (M + H +).

b: 6-chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole

6-Chloropurine at 60 ° C under argon A solution of 3-amine (1.0 g, 7.75 mmol) and 3-bromo-1,1,1-trifluorobutan-2-one (1.75 g, 37.02 mmol) in dimethoxymethane (10 mL) . After completion of the reaction, it was cooled to 25 ° C, and then the volatiles were evaporated under reduced pressure. The crude residue obtained was purified by column chromatography eluting EtOAc EtOAc EtOAc EtOAc Fluoromethyl)imidazo[1,2-b]indole (400 mg, 22%). MS: M/Z = 236 (M + H +).

c: 6-vinyl-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole

6-Chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole with argon A solution of (1.6 g, 6.8 mmol) in DMF (50 mL) was evaporated. To the mixture was then added tributyl(vinyl)stannane (2.3 g, 7.48 mmol) and tetrakis(triphenylphosphine)palladium(0) (394 mg, 0.34 mmol) at 25 °C. The mixture was again degassed with argon for 10 min and then heated to 80 ° C for 5 h. The mixture was cooled to 25 &lt;0&gt;C, diluted with EtOAc (EtOAc &lt With ice cold water (3 × 50ml) and brine (100ml) The organics were washed, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The resulting crude mass was purified by column chromatography eluting EtOAc EtOAc (EtOAc) Imidazo[1,2-b]嗒 (1.1g, 71%). MS: M/Z = 228 (M + H +).

d: 3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-formaldehyde

6-vinyl-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole at 120 °C (1.1 g, 4.86 mmol), osmium tetroxide (4% aqueous solution, 37 mg, 0.95 ml, 0.14 mmol), sodium periodate (4.14 g, 19.38 mmol) and benzyltriethylammonium chloride (441 mg, 1.93 mmol) The solution in dioxane (20 ml) and water (4 ml) was heated for 90 minutes. After cooling, the solvent was evaporated. EtOAc m. The organic layer was separated, dried over sodium sulfate, filtered and evaporated The resulting crude mass was purified by column chromatography eluting with EtOAc EtOAc (EtOAc) ,2-b]嗒 -6-formaldehyde (700 mg, 63%). MS: M/Z = 230 (M+H+).

e: [3-methyl-2-(trifluoromethyl)imidazo[1,2-b]fluorene -6-yl]methanol

To 3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole at 25 ° C under argon A solution of -6-formaldehyde (700 mg, 3.05 mmol) in MeOH (5 mL) The mixture was stirred at 25 ° C for 2 h. After completion of the reaction, the mixture was quenched with EtOAc (EtOAc)EtOAc. The aqueous phase was extracted with DCM (2 x 100 mL). Dried over anhydrous Na ₂ SO ₄ the combined organics were dried, filtered and concentrated in vacuo. The resulting crude material was triturated with hexanes and filtered to give crystals of [3-methyl-2-(trifluoromethyl)imidazo[1,2-b] -6-yl]methanol (500 mg, 70%). MS: M/Z = 232 (M+H+).

f: 6-(Chloromethyl)-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole

To (3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole at 0 ° C under nitrogen A solution of -6-yl]methanol (500 mg, 2.16 mmol) in DCM (10 mL). The mixture was stirred at 25 ° C for 15 min and then heated to 40 ° C for 2 h. After the reaction was completed, the volatiles were removed in vacuo. The obtained crude mass was purified by combiflash column chromatography using 20% ethyl acetate in hexane to afford 6-(chloromethyl)-3-methyl-2-(trifluoromethyl)imidazole as a yellow solid. And [1,2-b]嗒 (450 mg, 83%). MS: M/Z = 250 (M+H+).

g:{[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]methyl}triphenylphosphonium chloride

It was used in a similar manner to that described in Example 1a using 6-(chloromethyl)-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]fluorene. (45 mg, 1.80 mmol) and triphenylphosphine (521 mg, 1.98 mmol) were prepared as starting material to afford {[3-methyl-2-(trifluoromethyl)imidazo[1,2- b]嗒 -6-yl]methyl}triphenylphosphonium chloride (800 mg, crude).

h: 4-bromo-1-methyl-2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]vinyl]-1H-imidazole

4-bromo-1-methyl-1H-imidazol-2-carbaldehyde (200 mg, 1.05 mmol) and {[3-methyl-2-(trifluoromethyl) were used in a similar manner as described in Example 1c. Imidazo[1,2-b]嗒 -6-yl]methyl}triphenylphosphonium chloride (504 mg, 1.05 mmol) was obtained as starting material to afford 4-bromo-1-methyl-2-[(E)-2-[ 3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]vinyl]-1H-imidazole (210 mg, 52%). MS: M/Z = 386.0 (M + H +).

i:{[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]methyl}triphenylphosphonium chloride

It was used in a similar manner to that described in Example 10 using 4-bromo-1-methyl-2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1, 2-b]嗒 -6-yl]vinyl]-1H-imidazole (150 mg, 0.39 mmol) and pyrrolidin-2-one (0.06 ml, 0.78 mmol) were obtained as starting material to afford 1-{1-methyl as a yellow solid. -2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]vinyl]-1H-imidazol-4-yl}pyrrolidin-2-one (80 mg, 52%). MS: M/Z = 391.0 (M + H +).

j: 1-(1-methyl-2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethyl}-1H-imidazol-4-yl)pyrrolidin-2-one

It was used in a similar manner to that described in Example 11 using 1-{1-methyl-2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1,2 -b]嗒 -6-yl]vinyl]-1H-imidazol-4-yl}pyrrolidin-2-one (80 mg, 0.21 mmol) was obtained as a starting material to afford 1-(1-methyl-2- {2-[3-Methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethyl}- 1H-imidazol-4-yl)pyrrolidin-2-one (14 mg, 18%). MS: M/Z = 393.0 (M + H +).

Example 23 1-(2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethyl}-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one

a: 4-bromo-2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]vinyl]-1-phenyl-1H-imidazole

4-bromo-1-phenyl-1H-imidazole-2-carboxaldehyde (200 mg, 0.79 mmol) and {[3-methyl-2-(trifluoromethyl) were used in a similar manner as described in Example 1c. Imidazo[1,2-b]嗒 -6-yl]methyl}triphenylphosphonium chloride (380 mg, 0.79 mmol) was obtained as starting material afforded 4-bromo-2-[(E)-2-[3-methyl- as a white solid. 2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]vinyl]-1-phenyl-1H-imidazole (180 mg, 50%); MS: M/Z = 450 (M+H+).

b: 1-{2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]fluorene -6-yl]vinyl]-1-phenyl-1H-imidazol-4-yl}pyrrolidin-2-one

It was used in a similar manner to that described in Example 10 using 4-bromo-2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]vinyl]-1-phenyl-1H-imidazole (150 mg, 0.335 mmol) and pyrrolidin-2-one (0.05 ml, 0.67 mmol) were prepared as starting materials to afford yellow solids 1- {2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole 6-yl]vinyl]-1-phenyl-1H-imidazol-4-yl}pyrrolidin-2-one (70 mg, 46%); MS: M/Z = 452 (M+H+).

c: 1-(2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethyl}-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one

Using 1-{2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]fluorene in a similar manner as described in Example 11. -6-yl]vinyl]-1-phenyl-1H-imidazol-4-yl}pyrrolidin-2-one (70 mg, 0.155 mmol) was obtained as a starting material to afford 1-(2- {2-[3-Methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethyl}-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one (12 mg, 17%); MS: M/Z = 455 (M+H+).

Example 24 1-(1-methyl-2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethynyl}-1H-imidazol-4-yl)pyrrolidin-2-one

a:6-iodine 3-amine

6-chloropurine A solution of 3-amine (2.5 g, 19.38 mmol) in 57% EtOAc (1. The reaction was cooled to room temperature and ethyl acetate (5 mL) was evaporated. The suspension was stirred vigorously for 5 minutes at 25 °C. The solid was collected by filtration, washed with ethyl acetate and dried under vacuum to afford crystals of yellow solid. The solid was dissolved in methanol (60 mL) and sodium hydroxide (0.93 g, 23.. The suspension was heated at 100 °C for 5 min and cooled to 25 °C. The reaction mass was concentrated under reduced pressure and washed with water to give pure 6-iodonium as a white solid. 3-Amine (2 g, 43%). LC-MS (ESI): 422 (21.

b: 6-iodo-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole

It uses 6-iodoquinone in a similar manner to that described in Example 22b. 3-Amine (500mg, 2.26mmol) and 3-bromo-1,1,1-trifluorobutan-2-one (555mg, 2.7mmol) were prepared as starting materials to provide 6-iodine as a brown viscous solid. -3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole (200 mg, 27%). MS: M/Z = 328 (M + H +).

c: 1-(1-methyl-2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethynyl}-1H-imidazol-4-yl)pyrrolidin-2-one

1-(2-ethynyl-1-methyl-1H-imidazol-4-yl)pyrrolidin-2-one (30 mg, 0.16 mmol) and 6-iodine were used in a similar manner as described in Example 15c. -3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole (57 mg, 0.17 mmol) was obtained as starting material afforded 1-(1-methyl-2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2 -b]嗒 -6-yl]ethynyl}-1H-imidazol-4-yl)pyrrolidin-2-one (4 mg, 6%). MS: M/Z = 389 (M + H +).

Example 25 1-(2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethynyl}-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one

a: 4-(2-Sideoxypyrrolidin-1-yl)-1-phenyl-1H-imidazole-2-formaldehyde

4-bromo-1-phenyl-1H-imidazol-2-carbaldehyde (800 mg, 3.18 mmol) and pyrrolidin-2-one (0.54 ml, 6.35 mmol) were used in a similar manner as described in Example 15a. Prepared from the starting material to provide 4-(2-oxopyrrolidin-1-yl)-1-phenyl as a white viscous solid -1H-imidazole-2-carbaldehyde (50 mg, 7%); MS: M/Z = 256 (M+H+).

b: 1-(2-ethynyl-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one

Starting with 4-(2-oxopyrrolidin-1-yl)-1-phenyl-1H-imidazol-2-carbaldehyde (90 mg, 0.35 mmol) in a similar manner as described in Example 15b Prepared to give 1-(2-ethynyl-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one as a brown viscous solid (18 mg, 20%); MS: M/Z = 252.2 (M+H+).

c: 1-(2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethynyl}-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one

1-(2-ethynyl-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one (18 mg, 0.07 mmol) and (6-) were used in a similar manner as described in Example 15c. Iodo-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole (26 mg, 0.08 mmol) was prepared as starting material to afford 1-(2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b] as a brown solid. despair -6-yl]ethynyl}-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one (5 mg, 15%); MS: M/Z = 451 (M+H+).

Example 26 N,3-Dimethyl-6-{2-[1-methyl-4-(2-o-oxypyrrolidin-1-yl)-1H-imidazol-2-yl]ethyl}-2-tri Fluoromethyl)imidazo[1,2-b]indole -8-carbamamine

a: 3,6-dichloropurine -4-carbonyl hydrazine

3,6-Dichloropurine at 0 ° C under argon A solution of 4-carboxylic acid (5 g, 26.04 mmol) in EtOAc (EtOAc) The reaction mass was stirred at 25 ° C for 5 h. After completion of the reaction, the solvent was removed under reduced pressure under nitrogen to remove the volatiles and evaporated to give 3,6-dichloroindole as a white liquid. 4-carbonylcarbonyl chloride (5.5 g, crude). This crude material was used in the next step.

b: 3,6-dichloro-N-methylindole -4-carboxamide

3,6-Dichloropurine at 0 ° C under argon To a solution of -4-carbonylindole chloride (5.5 g, 26.6 mmol) in EtOAc (EtOAc) The reaction mass was stirred at 25 ° C for 1 h. After completion of the reaction, the reaction mixture was diluted with H~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The crude material was purified by combi flash chromatography using 20% ethyl acetate in hexane to afford 3,6-dichloro-N-methylindole as a white solid. 4-Metformamide (3.2 g, 60%).

c: 3-amino-6-chloro-N-methylindole -4-carboxamide

3,6-Dichloro-N-methylindole at 120 ° C 4-Methylguanamine (6.6 g, 32.19 mmol) was heated in a solution of 28% aqueous ammonium hydroxide (100 mL). The mixture was cooled to 0 ° C and precipitated. Thereafter, the obtained precipitate was filtered, and the residue was washed with hexane and dried to afford 3-amino-6-chloro-N-methylindole as a white solid. 4-Metformamide (2.2 g, 50%). MS: M/Z = 187 (M + H +).

d: 6-Chloro-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine

3-Amino-6-chloro-N-methylindole at 60 ° C under argon a solution of 4-carbamoylamine (6.7 g, 36.02 mmol) and 3-bromo-1,1,1-trifluorobutan-2-one (4.3 ml, 36.02 mmol) in dimethoxymethane (100 ml) Heat for 18h. After completion of the reaction, it was cooled to 25 ° C, and then the volatiles were evaporated under reduced pressure. The crude residue was purified by EtOAc EtOAc EtOAc elut elut elut elut (trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine (3 g, 28%). MS: M/Z = 293 (M + H +).

e:6-vinyl-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine

6-Chloro-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]indole with argon A solution of -8-mercaptoamine (3 g, 10.27 mmol) in DMF (10 mL) was degassed for 10 min. To the mixture was then added tributyl(vinyl)stannane (3.9 g, 12.32 mmol) and tetrakis(triphenylphosphine)palladium(0) (594 mg, 0.514 mmol) at 25 °C. The mixture was again degassed with argon for 10 min and then heated to 80 ° C for 5 h. The mixture was cooled to 25 &lt;0&gt;C, diluted with EtOAc (EtOAc &lt With ice cold water (3 × 50ml) and brine (100ml) The organics were washed, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The resulting crude mass was purified by column chromatography eluting EtOAc EtOAc (EtOAc) elute Fluoromethyl)imidazo[1,2-b]indole -8-carbamamine (1.1 g, 38%). MS: M/Z = 285 (M + H +).

f:6-Mercapto-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine

6-vinyl-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]fluorene at 120 °C -8-carbamamine (1.1 g, 3.87 mmol), osmium tetroxide (4% aqueous solution, 30 mg, 0.90 ml, 0.12 mmol), sodium periodate (3.3 g, 15.4 mmol) and benzyltriethyl chloride A solution of ammonium (370 mg, 1.63 mmol) in dioxane (44 ml) After cooling, the solvent was evaporated. EtOAc m. The organic layer was separated, dried over sodium sulfate, filtered and evaporated The resulting crude mass was purified by column chromatography eluting EtOAc EtOAc (EtOAc) (trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine (800 mg, crude). MS: M/Z = 286 (M + H +).

g: 6-(hydroxymethyl)-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine

It was used in a similar manner to that described in Example 22e using 6-mercapto-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]fluorene. -8-Protonamine (800 mg, 2.79 mmol) was prepared as starting material to provide 6-(hydroxymethyl)-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2 -b]嗒 -8-carbamamine (240 mg, 30%). MS: M/Z = 289 (M + H +).

h:6-(Chloromethyl)-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine

It was used in a similar manner to that described in Example 22f using 6-(hydroxymethyl)-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]fluorene. -8-Protonamine (240 mg, 0.84 mmol) was obtained as a starting material to afford 6-(chloromethyl)-N,3-dimethyl-2-(trifluoromethyl)imidazole as a white solid. 1,2-b]嗒 -8-carbamamine (150 mg, 59%). MS: M/Z = 307 (M + H +).

i:{[3-methyl-8-(methylamine-mercapto)-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]methyl}triphenylphosphonium chloride

It was used in a similar manner to that described in Example 1a using 6-(chloromethyl)-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]fluorene. -8-Mergamine (150 mg, 0.50 mmol) and triphenylphosphine (192 mg, 0.58 mmol) were obtained as starting material to afford as a white solid. )-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]methyl}triphenylphosphonium chloride (320 mg, crude). MS: M/Z = 533 (M + H +).

j:6-[(E)-2-(4-Bromo-1-methyl-1H-imidazol-2-yl)vinyl]-N,3-dimethyl-2-(trifluoromethyl)imidazole And [1,2-b]嗒 -8-carbamamine

4-bromo-1-methyl-1H-imidazol-2-carbaldehyde (85 mg, 0.45 mmol) and {[3-methyl-8-(methylamine A) were used in a similar manner as described in Example 5a. Mercapto)-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]methyl}triphenylphosphonium chloride (240 mg, 0.45 mmol) was obtained as a starting material to afford 6-[(E)-2-(4-bromo-1-methyl- 1H-imidazol-2-yl)vinyl]-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine) (90 mg, 45%). MS: M/Z = 445.0 (M + H +).

k: N,3-Dimethyl-6-[(E)-2-[1-methyl-4-(2-o-oxypyrrolidin-1-yl)-1H-imidazol-2-yl]ethene 2-(trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine

6-[(E)-2-(4-bromo-1-methyl-1H-imidazol-2-yl)vinyl]-N,3-dimethyl was used in a similar manner to that described in Example 10. 2-(trifluoromethyl)imidazo[1,2-b]indole -8-Mergamine (60 mg, 0.14 mmol) was obtained as starting material to afford N,3-dimethyl-6-[(E)-2-[1-methyl-4-(2) -Sideoxypyrrolidin-1-yl)-1H-imidazol-2-yl]vinyl]-2-(trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine (20 mg, 33%). MS: M/Z = 448.0 (M + H +).

l: N,3-Dimethyl-6-{2-[1-methyl-4-(2-o-oxypyrrolidin-1-yl)-1H-imidazol-2-yl]ethyl}-2 -trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine

Using N,3-dimethyl-6-[(E)-2-[1-methyl-4-(2-o-oxypyrrolidin-1-yl) in a similar manner to that described in Example 11 -1H-imidazol-2-yl]vinyl]-2-(trifluoromethyl)imidazo[1,2-b]indole -8-Protonamine (20 mg, 0.05 mmol) was prepared as a starting material to afford N,3-dimethyl-6-{2-[1-methyl-4-(2- </RTI> Pyrrrolidin-1-yl)-1H-imidazol-2-yl]ethyl}-2-trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine (14 mg, 69%). MS: M/Z = 450.0 (M + H +).

Example 27 N,3-Dimethyl-6-{2-[4-(2-o-oxypyrrolidin-1-yl)-1-phenyl-1H-imidazol-2-yl]ethyl}-2-( Trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine

a: 6-[(E)-2-(4-bromo-1-phenyl-1H-imidazol-2-yl)vinyl]-N,3-dimethyl-2-(trifluoromethyl)imidazole And [1,2-b]嗒 -8-carbamamine

4-bromo-1-phenyl-1H-imidazol-2-carbaldehyde (150 mg, 0.6 mmol) and {[3-methyl-8-(methylamine A) were used in a similar manner as described in Example 5a. Mercapto)-2-(trifluoromethyl)imidazo[1,2-b]indole 6-yl]methyl}triphenylphosphonium chloride (318 mg, 0.6 mmol) was obtained as a starting material to afford 6-[(E)-2-(4-bromo-1-phenyl- 1H-imidazol-2-yl)vinyl]-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]indole -8-Mergamine (150 mg, crude); MS: M/Z = 506 (M+H+).

b: N,3-Dimethyl-6-[(E)-2-[4-(2-o-oxypyrrolidin-1-yl)-1-phenyl-1H-imidazol-2-yl]ethene 2-(trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine

6-[(E)-2-(4-bromo-1-phenyl-1H-imidazol-2-yl)vinyl]-N,3-dimethyl was used in a similar manner to that described in Example 10. 2-(trifluoromethyl)imidazo[1,2-b]indole -8-Protonamine (110 mg, 0.22 mmol) and pyrrolidin-2-one (0.04 mL, 0.44 mmol) were obtained as starting material to afford N,3-dimethyl-6-[(E) -2-[4-(2-Sideoxypyrrolidin-1-yl)-1-phenyl-1H-imidazol-2-yl]vinyl]-2-(trifluoromethyl)imidazo[1] ,2-b]嗒 -8-Mergamine (70 mg, crude); MS: M/Z = 510 (M+H+).

c: N,3-dimethyl-6-{2-[4-(2-o-oxypyrrolidin-1-yl)-1-phenyl-1H-imidazol-2-yl]ethyl}-2 -(trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine

N,3-dimethyl-6-[(E)-2-[4-(2-o-oxypyrrolidin-1-yl)-1-benzene was used in a similar manner to that described in Example 11. -1H-imidazol-2-yl]vinyl]-2-(trifluoromethyl)imidazo[1,2-b]indole -8-Mergamine (70 mg, 0.14 mmol) was obtained as a starting material to afford N,3-dimethyl-6-{2-[4-(2- s. 1-phenyl-1H-imidazol-2-yl]ethyl}-2-(trifluoromethyl)imidazo[1,2-b]indole -8-Mergamine (12 mg, 17%); MS: M/Z = 512 (M+H+).

Claims (15)

a compound of formula (I) Wherein A is selected from the group consisting of: B is a C ₁ -C ₄ -alkylene group, a C ₂ -C ₄ -alkenyl group, a C ₂ -C ₄ -exetylene group, and the R ¹ group is selected from the group consisting of hydrogen, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxyalkyl, C ₁ -C ₇ -haloalkyl, -(CH ₂ ) _0,1,2- C ₃ -C ₅ -cycloalkyl, optionally halogen, C ₁ -C ₇ -alkyl or C ₁ -C ₇ alkoxy substituted -(CH ₂ ) _0,1,2- (hetero-)aryl, R ² is selected from 1 to 3, optionally selected from the following Heteroaryl substituted by a substituent: halogen, hydroxy, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -hydroxyalkyl, C ₁ -C ₇ -haloalkoxy, C ₁ -C ₇ -halide Alkyl, C ₃ -C ₅ -cycloalkyl, cyano, amine, nitro, -OR ⁶ -C(O)-R ⁷ , heteroaryl, heterocycloalkyl, -SO ₂ R ¹² -C (O) NR'R ", NR'R" , wherein R 'and R "are independently selected hydrogen, C ₁ -C ₇ - alkyl or R' and R" appended thereto together form a hetero nitrogen atom of contact a cycloalkyl group, or R ² is selected from C ₁ -C ₂ -alkoxy optionally substituted by halogen, R ⁶ and R ¹² are independently selected from C ₁ -C ₇ -alkyl, and R ⁷ is selected from Heterocycloalkyl, X-based NR ³ or CR ³ , Y-based (CH ₂ ) _n , n-system 1, 2, ³ , 4, and R ³ is selected from hydrogen and C ₁ -C ₇ -alkyl. The compound of claim 1, wherein the A system The compound of claim 1 or 2, wherein R ² is selected from the group consisting of: One or more of R ⁵ are selected from the group consisting of hydrogen, halogen, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -hydroxyalkyl, C ₁ -C ₇ -haloalkoxy, C ₁ -C ₇ - haloalkyl, C ₃ -C ₅ - cycloalkyl, cyano, amino, ^{nitro, -OR 6 -C (O) -R} 7, -SO 2 R 12, optionally substituted by halogen of C ₁ - C ₂ -alkoxy, C ₁ -C ₂ -alkoxy or heterocycloalkyl, R ⁶ and R ¹² are independently selected from C ₁ -C ₇ -alkyl, and R ⁷ is selected from heterocycloalkyl , R ⁸ and R ⁹ are independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -haloalkyl, C ₁ -C ₇ -hydroxyalkyl, cyano, or R ⁸ Forming a C ₃ -C ₈ cycloalkyl group together with R ⁹ ; R ¹⁰ is selected from the group consisting of hydrogen, C ₁ -C ₇ -haloalkoxy, C ₃ -C ₈ cycloalkyl, C ₁ -C ₇ alkoxy, Hydroxy, halogen, S(O) ₂ -C ₁ -C ₇ -alkyl, -C(O)NR'R", NR'R", wherein R' and R" are independently selected from hydrogen, C ₁ - C ₇ -alkyl or R' and R" together with the nitrogen atom to which they are attached form a heterocycloalkyl group, or R ¹⁰ together with R ⁴ form a C ₃ -C ₈ cycloalkyl group, and R ¹¹ is selected from heteroaryl Or a heterocycloalkyl group, preferably a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl group, X ₁ is N or CR ⁴ , wherein R ⁴ is selected from hydrogen, C ₁ -C ₇ -alkyl, C ₁ -C ₇ alkoxy, C ₁ -C ₇ -haloalkyl, C ₃ -C ₈ cycloalkyl, -C(O)NR'R", wherein R' and R "Department independently selected from hydrogen and C ₁ -C ₇ - alkyl. The compound of claim 1 or 2, wherein R ² is selected from the group consisting of: Wherein R ⁵ is independently selected from the group consisting of hydrogen, halogen, C _1-7 alkyl, C ₁ -C ₇ -haloalkyl, and R ⁸ and R ⁹ are independently selected from C _1-7 alkyl, C ₁ -C _7-- haloalkyl, and R ¹⁰ is selected from hydrogen and -C (O) NR'R ", wherein R 'and R" are independently selected hydrogen and C ₁ -C ₇ - alkyl. A compound according to claim 1 or 2, wherein the B is selected from the group consisting of an exoethyl group, a vinyl group and an ethynyl group. The compound of claim 1 or 2, wherein X is CR ³ and Y is CH ₂ , wherein R ³ is hydrogen. The compound of claim 1 or 2, wherein X is NR ³ and Y is CH ₂ , wherein R ³ is C _1-7 alkyl. The compound of claim 1 or 2, wherein R ¹ is selected from the group consisting of C ₁ -C ₇ -alkyl, C ₁ -C ₇ -haloalkyl, -(CH ₂ ) _0,1,2- C ₃ -C ₅ - cycloalkyl, phenyl. A compound according to claim 1 or 2 which is selected from the group consisting of 1-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5- c]pyrimidin-2-yl)ethyl)-1-methyl-1H-imidazol-4-yl)pyrrolidin-2-one 1-(2-(2-(5,8-dimethyl-[1] , 2,4]triazolo[1,5-a]pyridyl -2-yl)ethyl)-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one 1-[2-[(E)-2-(5,8-dimethyl-[ 1,2,4]triazolo[1,5-a]pyridyl -2-yl)vinyl]-1-phenylimidazol-4-yl]pyrrolidin-2-one 1-(1-(cyclopropylmethyl)-2-(2-(5,8-dimethyl) -[1,2,4]triazolo[1,5-a]pyridyl -2-yl)ethyl)-1H-imidazol-4-yl)pyridine-2(1H)-one 1-(2-(2-(5,8-dimethyl-[1,2,4]3 Oxazo[1,5-a]pyridin -2-yl)ethyl)-1-methyl-1H-imidazol-4-yl)pyridine-2(1H)-one 1-[1-cyclopropyl-2-[(E)-2-(5 , 8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)vinyl]imidazol-4-yl]pyrrolidin-2-one 1-(1-cyclopropyl-2-(2-(5,8-dimethyl-[1,2,4]] Triazolo[1,5-a]pyridyl -2-yl)ethyl)-1H-imidazol-4-yl)pyrrolidin-2-one 1-[2-[(E)-2-(5,8-dimethyl-[1,2,4 Triazolo[1,5-a]pyridyl -2-yl)vinyl]-1-methyl-imidazol-4-yl]-3-methyl-imidazolidin-2-one 1-(2-((4,8-dimethylquinazoline)- 2-yl)ethynyl)-1-methyl-1H-imidazol-4-yl)pyrrolidin-2-one 1-{2-[(E)-2-{4,7-dimethyl-[1 , 2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-methyl-1H-imidazol-4-yl}pyrrolidin-2-one 1-[2-(2-{4,7-dimethyl-[1,2, 4] Triazolo[1,5-a]pyridin -2-yl}ethyl)-1-methyl-1H-imidazol-4-yl]pyrrolidin-2-one 1-[1-(cyclopropylmethyl)-2-(2-{4,7 -dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one 1-[2-(2-{4,7-dimethyl-[1,2,4]triazolo [1,5-a]pyridyl -2-yl}ethyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl]pyrrolidin-2-one 1-[1-(2,2-difluoro Ethyl)-2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one 1-[2-(2-{4,7-dimethyl-[1,2,4]triazolo [1,5-a]pyridyl -2-yl}ethynyl)-1-methyl-1H-imidazol-4-yl]pyrrolidin-2-one 1-[1-(cyclopropylmethyl)-2-(2-{5,8 -Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one 1-[2 -[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl]-1-phenyl-imidazol-4-yl Pyrrolidin-2-one 1-[2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}ethyl) 1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl]pyrrolidin-2-one 1-[1-(2,2-difluoroethyl)-2-(2 -{5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidine-2- Ketone 1-{2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-phenyl-1H-imidazol-4-yl}pyrrolidin-2-one 1-[2-(2-{5,7-dimethyl-[1,2, 4] Triazolo[1,5-a]pyrimidin-2-yl}ethyl)-1-methyl-1H-imidazol-4-yl]pyrrolidin-2-one 1-(2-{2-[ 3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethyl}-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one 1-(1-methyl-2-{2-[3-methyl-2-(three Fluoromethyl)imidazo[1,2-b]indole -6-yl]ethynyl}-1H-imidazol-4-yl)pyrrolidin-2-one 1-(2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1, 2-b]嗒 -6-yl]ethynyl}-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one N,3-dimethyl-6-{2-[1-methyl-4-( 2-sided oxypyrrolidin-1-yl)-1H-imidazol-2-yl]ethyl}-2-trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine N,3-dimethyl-6-{2-[4-(2-o-oxypyrrolidin-1-yl)-1-phenyl-1H-imidazol-2-yl]B }}-2-(trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine. A process for the manufacture of a compound of formula (I) according to any one of claims 1 to 9, wherein B is an ethyl or vinyl group, and the process comprises: c) compound of formula II d) reacting with a compound of formula III or IV (III) or (IV) producing a compound of formula (I), and optionally hydrogenating, wherein R ¹ , R ² , R ³ , X and Y are as defined above. A method of producing a compound of formula (I) according to any one of claims 1 to 9, wherein B is an ethynyl group, the method comprising: c) compound of formula V d) reacting with a compound of formula III or IV (III) or (IV) producing a compound of formula (I) wherein R ¹ , R ² , X and Y are as defined above. Use of a compound according to claims 1 to 9 for the preparation of a medicament for the treatment or prevention of a psychiatric disorder, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, Paranoia, substance-induced psychosis, anxiety, panic disorder, obsessive-compulsive disorder, acute stress disorder, generalized anxiety disorder, drug addiction, motor disorder, Parkinson's disease, restless leg syndrome, cognitive deficit Disease, Alzheimer's disease, multiple infarct dementia, mood disorders, depression, two-way affective disorder, neuropsychiatric condition, psychosis, attention deficit/hyperactivity disorder, attention disorder, diabetes and related disorders, 2 Type 2 diabetes, neurodegenerative disorders, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumors, hematological malignancies, renal cell carcinoma or breast cancer. A compound according to claim 1 or 2 for use in the treatment or prevention of a psychiatric disorder, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusions, substance-induced psychotic disorders, anxiety disorders , panic disorder, obsessive-compulsive disorder, acute stress disorder, generalized anxiety disorder, drug addiction, motor disorder, Parkinson's disease, restless leg syndrome, cognitive deficit disorder, Alzheimer's disease, multiple infarct dementia, Emotional disorders, depression, two-way affective disorders, neuropsychiatric conditions, psychosis, attention deficit/hyperactivity disorder, attention disorders, diabetes and related disorders, type 2 diabetes, neurodegenerative disorders, Huntington's disease, multiple sclerosis, stroke, spinal cord injury , solid tumors, hematological malignancies, renal cell carcinoma or breast cancer. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a therapeutically inert carrier. A compound of claim 1 or 2 for use as a therapeutically active substance.