Alkinyl-(heteroaryl)-carboxamide HCN1 inhibitor

Abstract

The present invention relates to a compound of formula (I) TIFF2023504177000092.tif46165 [In the formula, R 1 , R 2 or R 3 are as described herein] and pharmaceutically acceptable salts thereof. The present invention further relates to the preparation of compounds of formula (I), pharmaceutical compositions containing them, and their use as medicaments.

Description

Technical Field

[0001] The present invention relates to a compound which is an inhibitor of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channel isoform 1 (HCN1), and in particular to treating, preventing and / or delaying the progression of central nervous system disorders, more specifically cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE) and mood disorders, most specifically cognitive impairment associated with schizophrenia, a compound which is more selective than HCN2 and HCN4 isoforms, their preparation and pharmaceutical compositions containing them.

Summary of the Invention

[0002] In particular, the present invention relates to formula (I)

Chemical Formula

[0003] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention pertains. Methods and materials similar to or equivalent to those described herein may be used in carrying out or testing the present invention, but suitable methods and materials are described below.

[0004] All publications, patent applications, patents, and other references mentioned herein are invoked in their entirety by reference.

[0005] The nomenclature used in this application is based on IUPAC systematic nomenclature unless otherwise indicated.

[0006] Any open valences appearing on carbon, oxygen, sulfur, or nitrogen atoms in the structures specified herein indicate the presence of hydrogen unless otherwise indicated.

[0007] "Halo" or "halogen" means fluoro, chloro, bromo, or iodine, especially chloro or fluoro.

[0008] "Hydroxy" refers to the -OH group.

[0009] "(C1-C6) alkyl" refers to branched or straight-chain hydrocarbon chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl, pentyl, and hexyl.

[0010] "(C1-C6)alkoxy" is a formula -OR a This refers to the part, and in the formula, R a This refers to a (C1-C6) alkyl moiety as defined herein. Examples of (C1-C6) alkoxy moieties include, but are not limited to, methoxy, ethoxy, and isopropoxy.

[0011] The term "therapeutic dose" refers to the amount of the compound or molecule of the present invention, when administered to a subject, that (i) treat or prevent a particular disease, condition, or disorder; (ii) reduce, alleviate, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. The therapeutic dose will vary depending on the compound, the state of the disease being treated, the severity of the disease being treated, the age and relative health status of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0012] The term "perhalo(C1-C3)alkyl" refers to a (C1-C3) alkyl group defined above, in which all hydrogen atoms are replaced by halogen atoms. More specifically, "(C1-C3) perhaloalkyl" is a (C1-C3) perfluoroalkyl, most preferably trifluoromethyl.

[0013] "Halo-(C1-C6)alkyl" refers to the alkyl group defined above, which is substituted with one or more halogen atoms, particularly one to three halogen atoms. More specifically, halo-(C1-C6)alkyl groups are chloro- and fluoro-(C1-C6)alkyl groups. In some specific embodiments, halo-(C1-C6)alkyl groups refer to perhalo(C1-C3)alkyl groups, such as trifluoromethyl groups.

[0014] "Halo-(C1-C6)alkoxy" refers to the alkoxy defined above, which is substituted with one or more halogen atoms, particularly one to three halogen atoms. More specifically, halo-(C1-C6)alkoxy are chloro- and fluoro-(C1-C6)alkoxy.

[0015] "Heteroaryl" refers to a monovalent monocyclic or bicyclic moiety of 5 to 12 ring atoms having at least one aromatic ring containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S (preferably N or O), the remaining ring atoms being carbon, and the bonding site of the heteroaryl moiety is understood to be on the aromatic ring. More specifically, the term heteroaryl includes, but is not limited to, pyridinyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridadinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzoisoxazolyl or benzothienyl, imidazo[1,2-a]-pyridinyl, imidazo[2,1-b]thiazolyl and its derivatives. "N-heteroaryl" specifically refers to the heteroaryls defined above that contain at least one nitrogen atom. The bond site of the N-heteroaryl molecule to the rest of the molecule can be via a nitrogen or carbocyclic atom. Examples of N-heteroaryls include pyridinyl, pyrazinyl, pyridadinyl, and pyrimidinyl.

[0016] In the context of this invention, the terms “selective” or “HCN1-selective compound” refer to the potency of an inhibitor that inhibits HCN1 with greater efficiency than HCN2 and HCN4 isoforms. In preferred embodiments, the compound of formula (I) is more effective against the HCN1 isoform than the HCN2 and HCN4 isoforms. In particular embodiments, the compounds according to the present invention, more specifically the compound of formula (I), are at least 5 times, particularly at least 20 times, more specifically at least 50 times, even more specifically at least 100 times, and most specifically at least 1000 times more effective against the HCN1 isoform than the HCN2 and HCN4 isoforms.

[0017] The term "heterocyclyl" refers to a monocyclic ring system of 4 to 9 ring atoms, which contains 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring constituent atoms being carbon. Examples of heterocyclyls include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolane, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. More specifically, heterocyclyls refer to dihydrofuryl, 1,3-dioxolyl, dihydropyryl, dihydrothiophyll, dihydropyrazolyl, dihydroisoxazolyl, tetrahydropyridyl, tetrahydropyranil, tetrahydrothiopyranil, piperazinil, 3,4-dihydro-2H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-thiadyl, and 1,2,3,4-tetrahydropyradyl.

[0018] "Optional" or "optional" means that the event or situation described below may or may not occur, and the description includes both cases in which the event or situation occurs and cases in which it does not occur. For example, "aryl group which may be substituted with an alkyl group" means that an alkyl group may or may not be present, and the description includes both the case in which the aryl group is substituted with an alkyl group and the case in which the aryl group is not substituted with an alkyl group.

[0019] The terms “individual” or “subject” refer to mammals. Mammals include, but are not limited to, domestic animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human.

[0020] The terms "compound(s) of this invention" and "compound(s) of the present invention" refer to the compounds disclosed herein, as well as their stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts).

[0021] If the compounds of the present invention are solids, it will be understood by those skilled in the art that these compounds, as well as their solvates and salts, may exist in different solid forms, particularly different crystalline forms, all of which are intended to be within the scope of the present invention and within specific formulas.

[0022] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. pharmaceutically acceptable salts include both acid addition salts and base addition salts.

[0023] The term "pharmaceutically acceptable acid addition salt" refers to a pharmaceutically acceptable salt formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid, as well as organic acids selected from aliphatic, alicyclic, aromatic, aryl-containing aliphatic, heterocyclic, carboxylic acid, and sulfonic acid types, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0024] The term "pharmaceutically acceptable base addition salt" means a pharmaceutically acceptable salt formed from an organic or inorganic base. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts obtained from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperizine, piperidine, N-ethylpiperidine, and polyamine resins.

[0025] The term “active pharmaceutical ingredient” (or “API”) refers to a compound or molecule in a pharmaceutical composition that has a specific biological activity.

[0026] The terms “pharmaceutical composition” and “pharmaceutical preparation” (or “preparation”) are used interchangeably and mean a mixture or solution comprising a therapeutically effective amount of a medicinal active ingredient and pharmaceutically acceptable excipients, which is administered to a mammal in need of treatment, such as a human.

[0027] The terms “pharmaceutically acceptable excipient,” “pharmaceutically acceptable carrier,” and “therapeutically inactive excipient” are interchangeable and refer to any pharmaceutically acceptable component in a pharmaceutical composition that is non-therapeutic and non-toxic to the target of administration, such as disintegrants, binders, fillers, solvents, buffers, isotonic agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants used in the manufacture of pharmaceutical products.

[0028] The terms "to treat" or "to treat" a medical condition include inhibiting the condition, i.e., stopping the condition or the onset of the condition, or alleviating the condition, i.e., causing a temporary or permanent regression of the condition or its clinical symptoms.

[0029] Compounds with the same molecular formula but different atomic bonding properties or order, or different arrangements of atoms in space, are called "isomers." Isomers with different arrangements of atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers." If a compound has a chiral center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their chiral center, described by the R and S order sides of the Kahn-Ingold-Prelude formula, or by dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively), which rotates the plane of polarization of the molecule. Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0030] Compounds of formulas I, Ia, Ib, or Ic may have one or more chiral centers or chiral axes. Unless otherwise indicated, the descriptions or nomenclature of specific compounds in this specification and the claims are intended to include individual enantiomers, atropisomers and mixtures thereof, racemates or both, as well as individual epimers, atropisomers and mixtures thereof. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 1992).

[0031] Certain compounds can exhibit tautomerism. Tautomer compounds can exist as two or more interconvertible species. Prototype tautomers arise from the movement of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate individual tautomers usually produce a mixture whose chemical and physical properties match those of the compound mixture. The equilibrium position depends on the chemical features within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant, while in phenols, the enol form is dominant. Common protic tautomers include tautomers with keto / enol (-C(=O)-CH- and -C(-OH)=CH-), amide / imido acids (-C(=O)-NH- and -C(-OH)=N-), and amidines (-C(=NR)-NH- and -C(-NHR)=N-). The latter two are particularly common in heteroaryl and heterocyclic rings, and the present invention encompasses all tautomeristic forms of compounds.

[0032] Here, the compound of formula I, Ia, Ib, or Ic is an isoform-selective inhibitor of HCN1, and therefore, schizophrenia (e.g., cognitive impairment and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, substance abuse and drug dependence, Tourette syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, glucose It may be therapeutically useful in the treatment of CNS disorders, including mental, neurological, neurogenesis, neurodegenerative, mood, motivation, metabolic, cardiovascular, renal, ophthalmic, endocrine and / or other disorders described herein, including urinary tract disorders, sepsis, post-ischemic tubular necrosis, renal failure, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative hypotonia, sleep disorders, pain, cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain and autism (sensory sensitivity), and most specifically cognitive impairment associated with schizophrenia (CIAS), including mental, neurological, neurogenesis, neurodegenerative, mood, motivation, metabolic, cardiovascular, renal, ophthalmic, endocrine and / or other disorders described herein.

[0033] These compounds are potent inhibitors of hyperpolarization activation and cyclic nucleotide opening (HCN) channel isoform 1 (HCN1). The mammalian HCN channel family is highly conserved across species and currently includes four identified genes (HCN1-4). HCN1 expression in the brain increases during early postnatal development and remains high throughout life. The highest levels of HCN1 mRNA are found in regions supporting cognitive and executive functions, including the cortex, hippocampus, and cerebellum. h or I fThe depolarizing currents generated by the HCN channel, known as HCN1, promote cellular excitability and rhythmic activity in excitable tissues (DiFrancesco and DiFrancesco 2015). The HCN1 channel is functionally expressed in an increasing proximal-distal gradient on the dendrites of projection neurons in the hippocampus and cortex, and its activation promotes the diversion of distal synaptic currents, thereby limiting synaptic integration to these neurons (Magee, 1998). Thus, inhibiting the HCN1 channel increases synaptic integration and facilitates information transmission through projection neurons in these brain regions.

[0034] HCN ion channels are members of the voltage-gated potassium channel superfamily, but, in contrast to potassium channels, are activated by hyperpolarization. Furthermore, intracellular levels of cyclic nucleotides, most notably cAMP, promote their gating. Thus, HCN channels act as simultaneous detectors for detecting intracellular cAMP status and neuronal polarization status. Through their activity in neurons, HCN channels play a role in determining resting membrane potential, defining dendritic integration, setting action potential firing frequency and pacemaker formation, and establishing the action potential threshold (DiFrancesco and DiFrancesco, 2015).

[0035] Large-scale genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) at the HCN1 genomic locus are significantly associated with schizophrenia (SZ). This has been demonstrated in multiple experimental cohorts and confirmed by meta-analyses across these populations (Schizophrenia Research Group of the Psychiatric Genomics Consortium, 2014; Pardinas et al., 2018). Furthermore, in a recent study investigating the genetic structure of hereditary neurocognitive endophenotypes within the SZ population, HCN1 was identified as the gene of interest by being significantly associated genome-wide with performance on different cognitive tasks (Swerdlow et al., 2018). This offers hope for patient screening supporting personalized medicine approaches when addressing CIAS endophenotypes in the CIAS patient population through the regulation of HCN1. Quantitative trait locus (eQTL) analysis of SNP expression in HCN1 did not reveal significant changes in mRNA expression in postmortem tissue, but comparisons between controls and SZ showed a trend toward increased HCN1 expression in patients.

[0036] CIAS involves deficits in episodic memory and working memory (WM), which evoke hippocampal and prefrontal cortical circuits, respectively. Forebrain-restrictive deletion of HCN1 in rodents improves hippocampal-based learning and memory and enhances synaptic long-term potentiation (LTP) (Nolan et al., 2004). Inhibition of HCN1 using non-cerebral-permeable and non-selective HCN antagonists (by iontophoresis) increases relevant neuronal activity in the prefrontal cortex of non-human primates (NHPs) and rodents (PFC injection) (Wang et al., 2007). Non-selective HCN inhibitor (ZD7288) injected into the prefrontal cortex of Sprague Dawley rats improved percent correct response on a delayed alternation task in a Y-maze. Furthermore, knockdown of HCN1 in the rat prefrontal cortex improved performance on the same task 11–19 days after virus injection, which is consistent with the time course of gene expression suppression. In non-human primates, iontophoresis of ZD7288 in region 46 of the DLPFC enhanced the action potential response of delay-related neurons encoding a preferred visual orientation during the WM's delayed-ocular response task (Wang et al., 2007).

[0037] Cannabis use is a common risk factor in the development of psychotic disorders, including SZ, and is positively correlated with an earlier age of onset of first symptoms (Manseau and Goff, 2015). Cannabinoids activate endogenous cannabinoid receptors, including the cannabinoid type 1 receptor (CB1R). Activation of CB1R leads to disruption of short- and long-term synaptic plasticity and memory formation in rodents (Castillo et al., 2012; Sotesz et al., 2015). Downstream of CB1R activation in the hippocampus is HCN-mediated synaptic plasticity in rodents. h By altering electrical currents, genetic removal of HCN1 can restore deficits induced in spatial memory formation in response to endocannabinoid-induced exogenous challenges, as measured by object position memory tests in mice. Furthermore, LTP regulation by CB1R agonism is absent in brain sections of HCN1 knockout animals (Maroso et al., 2016).

[0038] EIEE represents a class of severe childhood-onset disorders similar to the range of Dravet syndrome, which was previously identified as being caused by mutations in SCN1a and dPCDH19 (Depienne et al., 2009). EIEE is typically characterized by seizures that begin within the first three months of life and resistance to standard antiepileptic treatment. The main clinical features of EIEE are 1) refractory seizures, 2) severe EEG abnormalities, and 3) developmental delay / regression or intellectual disability. Next-generation sequencing has identified numerous causative gene mutations in EIEE, including those encoding ion channels and synaptic proteins. Exome sequencing studies currently provide an estimate that approximately 3% of non-Dravet early infant epileptic encephalopathy (EIEE) cases are due to mutations in HCN1 (EIEE#24) (Nava et al., 2014; Marini et al., 2018).

[0039] The relevant HCN4 gene is highly, almost exclusively, expressed in the heart (GTEx database). These overall HCN4 KO mice suffer from a severe cardiac phenotype and embryonic lethality (Stieber et al., 2003). Furthermore, HCN2 KO mice exhibit spontaneous absence seizures and sinus arrhythmias (Ludwig et al., 2003). The lack of isoform-selective drugs significantly limits the potential use of commercially available HCN blockers such as ivabradine. Therefore, generating cerebral-permeable and HCN1-selective compounds (beyond HCN2 and HCN4) would offer strong potential for the development of precognitive drugs for the treatment of EIEE and SZ.

[0040] Several publications describe the current knowledge regarding HCN channel inhibition, including, for example, the following publications cited therein: Cerbai et al., Canadian Journal of Physiology and Pharmacology, 96(2018), 977-984 Postea&Biel,Nature Reviews Drug Discovery,10(2011),903-914 Wickenden et al., Current Pharmaceutical Design, 15(2009), 2149-2168 Romanelli et al., Current Topics in Medicinal Chemistry 16(2016), 1764-1791 Clure et al., Bioorganic&Medicinal Chemistry Letters 21(2011), 5197-5201 Romanelli et al., J.Med.Chem.53(2010), 6773-6777 He et al., Reviews in the Neuroscience (Berlin, Germany), 30 (2019), 639-649

[0041] The object of the present invention is to develop compounds of formula I, Ia, Ib, or Ic for schizophrenia (e.g., cognitive impairment and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, substance abuse and drug dependence, Tourette syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, and dyslipidemia. The use of these compounds for the preparation of pharmaceuticals for the treatment, prevention and / or delay of the progression of, mental, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine and / or other disorders described herein, including obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative hypotonia, sleep disorders, pain, and other disorders in mammals, more specifically, CIAS, early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain and autism (sensory sensitivity), as well as the manufacture of such pharmaceuticals and pharmaceuticals based on the compounds of Formula I according to the present invention.

[0042] A further object of the present invention is all forms of optically pure enantiomers, racemates, or diastereomixtures of compounds of formula I, Ia, Ib, or Ic.

[0043] In other embodiments, the present invention relates to formula Ia [ka] [In the formula, R 1 is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2, or 3 nitrogen ring atoms, and the phenyl or the N-heteroaryl is R 4 It may be substituted with 1, 2, 3, or 4 substituents selected from the following: R 2 is hydrogen or C1-C6 alkyl, R 3 is a heteroaryl or phenyl, and the heteroaryl or phenyl is R 5 It may be substituted with 1, 2, 3, or 4 substituents selected from the following: R 4 These are independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halo-C1-C6 alkyl and halo-C1-C6 alkoxy, and R 5 These are independently selected from hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl and halo-C1-C6 alkoxy, or Two adjacent R 5 The group forms a 5-membered or 6-membered heterocyclyl condensed ring, and the heterocyclyl condensed ring may be substituted with one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy. This relates to compounds of or pharmaceutically acceptable salts thereof.

[0044] In other embodiments, the present invention relates to formula Ib [ka] [In the formula, R 1 is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2, or 3 nitrogen ring atoms, and the phenyl or the N-heteroaryl is R 4 It may be substituted with 1, 2, 3, or 4 substituents selected from the following: R 2 It is a C1-C6 alkyl group, R 3 is a heteroaryl or phenyl, and the heteroaryl or phenyl is R 5 It may be substituted with 1, 2, 3, or 4 substituents selected from the following: R 4 These are independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halo-C1-C6 alkyl and halo-C1-C6 alkoxy, and R 5 These are independently selected from hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl and halo-C1-C6 alkoxy, or Two adjacent R 5 The group forms a 5-membered or 6-membered heterocyclyl condensed ring, and the heterocyclyl condensed ring may be substituted with one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy. This relates to compounds of or pharmaceutically acceptable salts thereof.

[0045] In another embodiment, the present invention relates to formula Ic [ka] [In the formula, R 1is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2, or 3 nitrogen ring atoms, and the phenyl or the N-heteroaryl is R 4 It may be substituted with 1, 2, 3, or 4 substituents selected from the following: R 2 is hydrogen or C1-C6 alkyl, R 3 is a heteroaryl or phenyl, and the heteroaryl or phenyl is R 5 It may be substituted with 1, 2, 3, or 4 substituents selected from the following: R 4 These are independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halo-C1-C6 alkyl and halo-C1-C6 alkoxy. R 5 These are independently selected from hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl and halo-C1-C6 alkoxy, or Two adjacent R 5 The group forms a 5-membered or 6-membered heterocyclyl condensed ring, and the heterocyclyl condensed ring may be substituted with one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy. This relates to compounds of or pharmaceutically acceptable salts thereof.

[0046] Furthermore, certain X disclosed herein 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 or R 5 All embodiments relating to this are other X disclosed herein. 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 or R5 It should be understood that this can be combined with any other embodiment relating to this.

[0047] A particular embodiment of the present invention is R 1 is phenyl, pyrazinyl, pyridazinyl, pyrimidinyl, or pyridinyl, and the phenyl, the pyrazinyl, the pyridazinyl, the pyrimidinyl, or the pyridinyl is R 4 It may be substituted with 1, 2, 3, or 4 substituents selected from R 4 It may be substituted with 0, 1, 2, or 3 substituents selected from R 4 This relates to compounds of formula I, Ia, Ib, or Ic, which may be substituted with 0, 1, or 2 substituents selected from the above.

[0048] A particular embodiment of the present invention is R 1 is phenyl, pyridazinyl, or pyridinyl, and the phenyl, the pyridazinyl, or the pyridinyl is R 4 It may be substituted with 1, 2, 3, or 4 substituents selected from R 4 It may be substituted with 0, 1, 2, or 3 substituents selected from R 4 This relates to compounds of formula I, Ia, Ib, or Ic, which may be substituted with 0, 1, or 2 substituents selected from the above.

[0049] Further specific embodiments of the present invention include R 1 is phenyl, pyrazinyl, pyridadinyl, pyrimidinyl, or pyridinyl, more specifically R 1 This relates to compounds of formula I, Ia, Ib, or Ic, wherein is phenyl, pyrazinyl, pyridadinyl, or pyridinyl.

[0050] A particular embodiment of the present invention is R 2 This relates to compounds of formula I, Ia, Ib, or Ic, where C1-C6 alkyl, more specifically methyl, is the most recent type.

[0051] A particular embodiment of the present invention is R 3 is phenyl, pyridinyl, or thiophenyl, and the phenyl, pyridinyl, or thiophenyl is R 5 It may be substituted with 1, 2, 3, or 4 substituents selected from R 5 It may be substituted with one, two, or three substituents selected from R 5 This relates to compounds of formula I, Ia, Ib, or Ic, which may be substituted with one or two substituents selected from the following.

[0052] A more specific embodiment of the present invention is R 3 is phenyl or pyridinyl, and the phenyl, the pyridinyl is R 5 This relates to compounds of formula I, Ia, Ib, or Ic, which may be substituted with one or two substituents selected from the following.

[0053] A particular embodiment of the present invention is R 4 However, these are independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys, and more specifically R 4 is independently selected from halogen, methyl, and methoxy, most specifically R 4 This relates to compounds of formula I, Ia, Ib, or Ic, which are independently selected from fluoro, chloro, methyl, and methoxy.

[0054] A particular embodiment of the present invention is R 5 However, these may be independently selected from halogen, cyano, C1-C6 alkyl, halo-C1-C6 alkyl and C1-C6 alkoxy, or two adjacent R 5 The present invention relates to compounds of formula I, Ia, Ib, or Ic, in which a group forms a five-membered or six-membered heterocyclyl condensed ring, and the heterocyclyl condensed ring may be substituted with one or more groups independently selected from hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy.

[0055] A more specific embodiment of the present invention is R 5is independently selected from halogen, cyano, methyl, trifluoromethyl and methoxy, or two adjacent R 5 relates to a compound of formula I, Ia, Ib or Ic in which the groups form dioxolanyl.

[0056] Certain compounds of formula I according to the invention are 4-((2-Chloro-3-methylpyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide 4-((2-Chloro-3-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide 4-[2-(5-Chlorothiophen-3-yl)ethynyl]-5-methyl-1-(6-methylpyridin-3-yl)imidazole-2-carboxamide 4-[2-(3-Chlorophenyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide 4-((3-Cyanophenyl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide 4-(2-Chloro-pyridin-4-yl ethynyl)-5-methyl-1-(6-methyl-pyridin-3-yl)-1H-imidazole-2-carboxamide 4-((2-Chloro-5-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide 4-((3-Methoxyphenyl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide 4-[2-(4-Chlorophenyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide 5-Methyl-1-(6-methylpyridin-3-yl)-4-(m-tolylethynyl)-1H-imidazole-2-carboxamide 5-Methyl-1-(6-methylpyridine-3-yl)-4-((2-(trifluoromethyl)pyridine-4-yl)ethinyl)-1H-imidazole-2-carboxamide 4-[2-(2-fluoro-4-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide 4-(benzo[d][1,3]dioxol-4-ylethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((6-chloropyridine-2-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((2-chloropyrimidine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((3-fluoropyridine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-[2-(5-chloro-3-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide 4-((4-chloropyridine-2-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((6-chloropyrimidine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 5-Methyl-1-(6-methyl-3-pyridyl)-4-[2-(3-pyridyl)ethinyl]imidazole-2-carboxamide 5-Methyl-1-(6-methyl-3-pyridyl)-4-[2-(4-pyridyl)ethinyl]imidazole-2-carboxamide 5-Methyl-1-(6-methylpyridine-3-yl)-4-((2-methylpyridine-4-yl)ethinyl)-1H-imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(5-methylpyrazine-2-yl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(6-methylpyridazine-3-yl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(5-methyl-3-pyridyl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-(6-chloro-3-pyridyl)-5-methylimidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-(6-methoxy-3-pyridyl)-5-methylimidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(5-methyl-2-pyridyl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide 4-[2-(3-chloro-2-methylphenyl)ethynyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide 4-[2-(2-chloro-4-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxamide 2-[2-(2-chloro-4-pyridyl)ethinyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide 2-[2-(3-chloro-2-methylphenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide 2-[2-(3-chlorophenyl)ethinyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide 2-[2-(3-chloro-2-methylphenyl)ethynyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamide forate 2-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamide forate 5-Methyl-4-(phenylethynyl)-1-(p-tolyl)-1H-imidazole-2-carboxamide 4-[2-(2-chloro-4-pyridyl)ethinyl]-5-methyl-1-(p-tolyl)imidazole-2-carboxamide 1-(4-chlorophenyl)-4-((2-chloropyridine-4-yl)ethinyl)-5-methyl-1H-imidazole-2-carboxamide 1-(3-chlorophenyl)-4-((2-chloropyridine-4-yl)ethinyl)-5-methyl-1H-imidazole-2-carboxamide 4-(2-chloropyridine-4-ylethynyl)-1-(2,4-difluorophenyl)-5-methyl-1H-imidazole-2-carboxylic acid amide 4-(2-chloropyridine-4-ylethynyl)-1-(4-fluorophenyl)-1H-imidazole-2-carboxylic acid amide 4-((2-chloropyridine-4-yl)ethinyl)-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide, and 2-[2-(3-chloro-2-methylphenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide A compound selected from the group consisting of the following, and a pharmaceutically acceptable salt thereof. The specific compound of formula I of the present invention is 4-((2-chloro-3-methylpyridine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((2-chloro-3-fluoropyridine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-[2-(5-chlorothiophen-3-yl)ethinyl]-5-methyl-1-(6-methylpyridine-3-yl)imidazole-2-carboxamide 4-[2-(3-chlorophenyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(6-methylpyridazine-3-yl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(5-methyl-3-pyridyl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-(6-methoxy-3-pyridyl)-5-methylimidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(5-methyl-2-pyridyl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide 4-[2-(3-chloro-2-methylphenyl)ethynyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide 4-[2-(2-chloro-4-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxamide 2-[2-(3-chlorophenyl)ethinyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide 2-[2-(3-chloro-2-methylphenyl)ethynyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamide forate 2-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamidoformate, and 2-[2-(3-chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide A compound selected from the group consisting of, and a pharmaceutically acceptable salt thereof.

[0057] The compound of formula II, III or IV is suitable as an intermediate in the production of the compound of formula I.

[0058] Another embodiment of the present invention is formula II: [Chemical formula] [wherein, X 1 is either N or C, X 2 is either N or C, X 3 is either N or C, provided that at least one of X 1 X 2 and X 3 is N, and no more than two of X 1 X 2 and X 3 represent N, and when X 1 is N, X 2 cannot be N, The dotted line represents a single bond or a double bond to enable the 5-membered ring to be aromatic, R 1 is phenyl, N-heteroaryl, said N-heteroaryl contains 1, 2 or 3 nitrogen ring atoms, said phenyl or said N-heteroaryl may be substituted with 1, 2, 3 or 4 substituents selected from R 4 , R 2 is hydrogen or C1-C6 alkyl, provided that when X 2 is N, R 2 is not hydrogen, R 3is a heteroaryl or phenyl, and the heteroaryl or phenyl is R 5 It may be substituted with 1, 2, 3, or 4 substituents selected from the following: R 4 These are independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halo-C1-C6 alkyl and halo-C1-C6 alkoxy. R 5 These are independently selected from hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl and halo-C1-C6 alkoxy, or Two adjacent R 5 The group forms a 5-membered or 6-membered heterocyclyl condensed ring, and the heterocyclyl condensed ring may be substituted with one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy. R 6 [It is hydrogen or a C1-C6 alkyl group.] Regarding the compounds.

[0059] Another embodiment of the present invention is Formula III: [ka] [In the formula, X 1 is either N or C, X 2 is either N or C, X 3 is either N or C, However, X 1 , X 2 and X 3 At least one of them is N, and X 1 , X 2 and X 3 Two or fewer of these represent N, and X 1 If X is N, 2 It cannot be N, The dotted lines represent single or double bonds, allowing the five-membered ring to be aromatic. R 1 is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2, or 3 nitrogen ring atoms, and the phenyl or the N-heteroaryl is R 4 It may be substituted with 1, 2, 3, or 4 substituents selected from the following: R 2 is hydrogen or a C1-C6 alkyl group, however X 2 If R is N, 2 It is not hydrogen, R 3 is a heteroaryl or phenyl, and the heteroaryl or phenyl is R 5 It may be substituted with 1, 2, 3, or 4 substituents selected from the following: R 4 These are independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halo-C1-C6 alkyl and halo-C1-C6 alkoxy, and R 5 These are independently selected from hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl and halo-C1-C6 alkoxy, or Two adjacent R 5 The group forms a 5-membered or 6-membered heterocyclyl condensed ring, and the heterocyclyl condensed ring may be substituted with one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy. Regarding the compounds.

[0060] Another embodiment of the present invention is given by formula IV: [ka] [In the formula, X 1 is either N or C, X 2is either N or C, X 3 is either N or C, However, X 1 , X 2 and X 3 At least one of them is N, and X 1 , X 2 and X 3 Two or fewer of these represent N, and X 1 If X is N, 2 It cannot be N, The dotted lines represent single or double bonds, allowing the five-membered ring to be aromatic. R 1 is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2, or 3 nitrogen ring atoms, and the phenyl or the N-heteroaryl is R 4 It may be substituted with 1, 2, 3, or 4 substituents selected from the following: R 2 is hydrogen or a C1-C6 alkyl group, however X 2 If R is N, 2 It is not hydrogen, and R 4 [These are independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy.] Regarding the compounds.

[0061] The compound of formula I and its pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by the method described below, which is: a) Equation II [ka] [In the formula, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and R 6 [This is defined herein] The compound is reacted with ammonia (NH3) to produce formula I [ka] [In the formula, X 1 , X 2 , X 3 , R 1 , R 2 and R 3 [This is defined as specified herein] To obtain the compound, and, if desired, to convert the obtained compound into a pharmaceutically acceptable salt, or b) Formula III [ka] [In the formula, X 1 , X 2 , X 3 , R 1 , R 2 and R 3 [This is defined herein] The compound is reacted under acidic conditions such as sulfuric acid, and formula I [ka] [In the formula, X 1 , X 2 , X 3 , R 1 , R 2 and R 3 [This is defined herein] To obtain the compound, or, if desired, to convert the obtained compound into a pharmaceutically acceptable salt. or c) Formula IV [ka] [In the formula, X 1 , X 2 , X 3 , R 1 and R 2[This is defined as specified herein] The compound of formula IV a R 3 -X IV a [In the formula, X is a halo, in particular iodine or bromo, and R 3 [This is defined as specified herein] It reacts with the compound of formula I [ka] [In the formula, X 1 , X 2 , X 3 , R 1 , R 2 and R 3 [This is as defined herein] To obtain the compound, or, if desired, to convert the obtained compound into a pharmaceutical salt. Includes.

[0062] In other embodiments, the present invention provides compounds according to formulas I, Ia, Ib, or Ic described herein for use as therapeutically active substances.

[0063] In further embodiments, the present invention relates to CNS disorders, particularly schizophrenia (e.g., cognitive impairment and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, substance abuse and drug dependence, Tourette syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes mellitus, sepsis, post-ischemic tubular necrosis, The present invention provides compounds of formula I, Ia, Ib, or Ic described herein for the treatment, prevention, and / or delay of the progression of, in particular for the treatment of, mental, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine and / or other disorders described herein, including renal failure, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative hypotonia, sleep disorders, pain, cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain, and autism (sensory sensitivity), and more specifically for the treatment of, mental, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine and / or other disorders described herein.

[0064] In other embodiments, the present invention relates to CNS disorders, particularly schizophrenia (e.g., cognitive impairment and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, substance abuse and drug dependence, Tourette syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes mellitus, sepsis, post-ischemic tubular necrosis, renal failure, and resistant edema. The use of compounds of formula I, Ia, Ib or Ic described herein for the treatment, prevention and / or delay of progression of mental, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine and / or other disorders described herein, particularly for the preparation of medicaments for treatment, including schizophrenia, narcolepsy, hypertension, congestive heart failure, postoperative hypotonia, sleep disorders, pain, cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain and autism (sensory sensitivity), and more specifically for the treatment, prevention and / or delay of progression of mental, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine and / or other disorders described herein.

[0065] In one embodiment, the present application provides a method for treating an HCN1 disorder in a subject having an HCN1-related disorder, comprising administering a therapeutically effective amount of any of the above compounds to the subject in need.

[0066] In other embodiments, the present invention relates to CNS disorders, particularly schizophrenia (e.g., cognitive impairment and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, substance abuse and drug dependence, Tourette syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, and resistance. The present invention provides methods for the treatment, prevention, and / or delay of the progression of mental, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine and / or other disorders described herein, particularly methods of treatment, comprising administering an effective amount of a compound of Formula I described herein.

[0067] In certain embodiments, the present invention relates to CNS disorders, particularly schizophrenia (e.g., cognitive impairment and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, substance abuse and drug dependence, Tourette syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, resistant edema, and nal The present invention provides methods for the treatment, prevention, and / or delay of the progression of mental, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine and / or other disorders described herein, particularly methods of treatment, comprising administering an effective amount of a compound of formula I, Ia, Ib or Ic described herein.

[0068] Specifically, HCN1-related disorders or HCN1-related disorders include CNS disorders, particularly schizophrenia (e.g., cognitive impairment and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, substance abuse and drug dependence, Tourette syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, and dyslipidemia. , obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, resistance edema, narcolepsy, hypertension, congestive heart failure, postoperative hypotonia, sleep disorders, pain, cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain and autism (sensory sensitivity), more specifically, psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine and / or other disorders described herein, including cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain and autism (sensory sensitivity), most specifically, cognitive impairment associated with schizophrenia.

[0069] In one embodiment, the present application provides a pharmaceutical composition comprising any one of the above embodiments, mixed with at least one pharmaceutically acceptable carrier, such as an excipient or diluent.

[0070] In other embodiments, the present invention provides the use of compounds of formula I, Ia, Ib, or Ic in the preparation of pharmaceuticals for the treatment, prevention, and / or delay of the progression of diseases associated with HCN1, more specifically for treatment.

[0071] In further embodiments, the present invention provides pharmaceuticals comprising compounds of formula I, Ia, Ib, or Ic as described herein or pharmaceutically acceptable salts thereof, and therapeutically inert carriers, as well as methods for producing them, which include forming herbal dosage forms with one or more compounds of formula I and / or pharmaceutically acceptable salts thereof, and optionally one or more other therapeutically valuable substances together with one or more therapeutically inert carriers.

[0072] Other embodiments provide pharmaceutical compositions or pharmaceuticals containing the compounds of the present invention and therapeutic inactivating carriers, diluents, or excipients, as well as methods for using the compounds of the present invention to prepare such compositions and pharmaceuticals.

[0073] The composition is formulated, administered, and given in a manner consistent with good medical practice. Factors to be considered in this regard include the specific disorder being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to the healthcare professional. For example, such amounts may be below the amount that is toxic to normal cells or to the mammal as a whole.

[0074] The compounds of the present invention may be administered by any preferred means, including orally, topically (including buccal and sublingual), rectally, vaginally, percutaneously, parenterally, subcutaneously, intraperitoneally, intrapulmonaryly, intradermally, subarachnoidally, and epidurally and intranasally, and, if desired in topical treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

[0075] The compounds of the present invention can be administered in any convenient form, such as tablets, coated tablets, sugar-coated tablets, powders, capsules (hard gelatin capsules and soft gelatin capsules), solutions (i.e., injection solutions), dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, eye drops, ear drops, etc. Such compositions may contain components commonly used in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and further activators.

[0076] Typical formulations are prepared by mixing the compound of the present invention with a pharmaceutically acceptable carrier or excipient. Suitable pharmaceutically acceptable carriers and excipients are well known to those skilled in the art and are described in detail, 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 pharmaceutically acceptable carrier may be solid or liquid. Solid formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances that can also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrant, or encapsulating material. In powders, the carrier is generally a micronized solid, which is a mixture with the micronized active ingredient. In tablets, the active ingredient is generally mixed with a carrier having the required binding capacity in an appropriate proportion and compressed into the desired shape and size. Powders and tablets preferably contain about 1 percent to about 70 percent of the active compound. Suitable carriers, but are not limited to, include magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting-point waxes, and cocoa butter.

[0077] The dosage of the compound of the present invention can vary within a wide range and, of course, can be adapted to the specific requirements of each particular case. Generally, for oral administration, a daily dose of approximately 0.01 to 1000 mg of the compound of general formula (I) per person should be appropriate, but this upper limit may be exceeded if necessary.

[0078] A suitable oral dosage form is a tablet containing approximately 100-500 mg of the compound of the present invention, formulated with approximately 30-90 mg of anhydrous lactose, approximately 5-40 mg of croscarmellose sodium, approximately 5-30 mg of polyvinylpyrrolidone (PVP) K30, and approximately 1-10 mg of magnesium stearate. The powdered components are first mixed together, and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment.

[0079] An example of an aerosol formulation can be prepared by dissolving, for example, 10 to 100 mg of the compound of the present invention in a suitable buffer solution, such as a phosphate buffer, and optionally adding an isotonic agent, such as a salt of sodium chloride. The solution can be filtered, for example, using a 0.2 μm filter to remove impurities and contaminants.

[0080] Accordingly, one embodiment includes a pharmaceutical composition comprising the compound or stereoisomer thereof according to the present invention as described herein. Further embodiments include a pharmaceutical composition comprising the compound or stereoisomer thereof according to the present invention as described herein, together with a pharmaceutically acceptable carrier or excipient.

[0081] The compounds of the present invention, either alone or in combination with other drugs, can be used to treat HNC1-related disorders, particularly schizophrenia (e.g., cognitive impairment and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, substance abuse and drug dependence, Tourette syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, and dyslipidemia. It may be used to treat, prevent and / or delay the progression of mental, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine and / or other disorders described herein, including, more specifically, mental, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine and / or other disorders described herein, including, common, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, resistance edema, narcolepsy, hypertension, congestive heart failure, postoperative hypotonia, sleep disorders, pain, cognitive impairment associated with schizophrenia (CIAS), epileptic encephalopathy of early infants (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain and autism (sensory sensitivity).

[0082] Specific embodiments of the present invention address schizophrenia (e.g., cognitive impairment and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, substance abuse and drug dependence, Tourette syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes mellitus, sepsis, post-ischemic tubular necrosis, renal failure, resistant edema, and narcolepsy. The present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment, prevention and / or delay of the progression of cognitive impairments and / or other disorders described herein, including, more specifically, cognitive impairments related to mental, neurological, neurodevelopmental, neurodegenerative, mood, motivation, metabolic, cardiovascular, renal, ophthalmic, and endocrine disorders, including, schizophrenia-related cognitive impairment (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain and autism (sensory sensitivity).

[0083] Other embodiments include pharmaceutical compositions comprising compounds according to the present invention as described herein for use in the treatment, prevention, and / or delay of the progression of HCN1-related diseases, more specifically for treatment.

[0084] In other embodiments, the present invention provides for the production of compounds of formula I, Ia, Ib, or Ic as described herein.

[0085] The compounds of formula I, Ia, Ib, or Ic of the present invention can be prepared by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to react and purify the resulting products are known to those skilled in the art. If a mixture of enantiomers or diastereomers is produced during the reaction, these enantiomers or diastereomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography or crystallization.

[0086] Furthermore, the compounds of the present invention can be prepared from commercially available starting materials or by using common synthetic techniques and procedures known to those skilled in the art. Suitable reaction schemes for the preparation of such compounds are outlined below. Substituents and indices used in the following process description have the meanings given herein unless otherwise indicated. Further examples can be found in the specific examples detailed below.

[0087] More specifically, the compounds of formula I and their intermediates can be prepared by following the descriptions in schemes 1 to 5 and the specific examples.

[0088] X 1 N is X 2 C is X 3 A subgroup of compounds of formula I where is N can be prepared as outlined in schemes 1-3 below.

[0089] [ka]

[0090] R 1 and R 2As defined above, the intermediate of formula V, which can be synthesized as known in the art or as illustrated in specific examples, is reacted with a suitable reducing agent, e.g., lithium aluminum hydride, to the corresponding alcohol of formula VI (Scheme 1). It can then be oxidized to the aldehyde of formula VII using a suitable oxidizing agent such as manganese dioxide. The aldehyde of formula VII can be converted to the alkyne of formula VIII by reaction with a suitable diazophosphonate reagent, e.g., Bestmann-Ohira reagent, dimethyl(1-diazo-2-oxopropyl)phosphonate, in the presence of a suitable base, e.g., potassium carbonate or sodium carbonate. Prior to further functionalization of the imidazole ring, the alkyne of formula VIII needs to be protected with a suitable protecting group, e.g., trimethylsilyl (TMS), by reaction with a suitable reagent, e.g., trimethylsilyl chloride, in the presence of a strong non-nucleophilic base such as lithium hexamethyldisilazide or lithium diisopropylamide. The resulting compound of formula IX is carboxylated, followed by deprotonation with a strong base, such as n-butyllithium or lithium diisopropylamide, and then the corresponding chloroformate ester ClC(O)OR 8 Through the reaction with R, 8Compounds of formula X can be formed where [the relevant group] is methyl or ethyl. By adding an optional catalytic or stoichiometric amount of sodium cyanide and reacting with excess ammonia at a high temperature of 40 °C to 80 °C, preferably in a pressure vial, in a suitable polar or protic solvent such as methanol, composite deprotection-amide formation can be achieved. Alternatively, the deprotection-amidation sequence can be carried out stepwise. In the final step, the central component of formula IV is optionally used as a solvent adduct with a catalytic or stoichiometric amount of a suitable transition metal complex, such as bis(triphenylphosphine)palladium(II) dichloride or 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, in the presence of a stoichiometric amount of a suitable base, such as triethylamine or cesium carbonate, and optionally in the presence of a catalytic or stoichiometric amount of a suitable cocatalyst, such as copper(I) iodide, in a suitable solvent, such as dimethylformamide or acetonitrile, in a Sonogashira reaction, where R 3 is as defined above and Y is a halogen, preferably bromine or iodine, more preferably iodine, of formula R 3 -Y is coupled with a suitable reagent.

[0091] Certain embodiments of the present invention relate to a method for preparing a compound of formula (Ia) as defined above and a pharmaceutically acceptable salt thereof, which comprises a reaction between a compound of formula (IV) as defined above and a compound of formula R 3 and Y is as defined above, using a catalytic or stoichiometric amount of any suitable transition metal complex, such as bis(triphenylphosphine)palladium(II) dichloride or 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, in the presence of a stoichiometric amount of a suitable base, such as triethylamine or cesium carbonate, and optionally in the presence of a catalytic or stoichiometric amount of a suitable cocatalyst, such as copper(I) iodide.

[0092]

Chemical formula

[0093] Alternatively, R 1 , R 2 and R 3 The compound of formula Ia, wherein are as defined above, can be accessed as outlined in Scheme 2. R 1 and R 2 The intermediate of formula V, wherein are as defined above, is converted to the corresponding Weinreb amide of formula XI by reaction with N,O-dimethylhydroxylamine in the presence of a suitable Lewis acid, such as trimethylaluminum. Alternatively, this conversion can be achieved by a two-step process consisting of ester hydrolysis followed by amide formation under standard conditions known in the art. Next, the Weinreb amide of formula XI can be deprotonated to the ketone of formula XIII using a strong non-nucleophilic lithium base, such as lithium diisopropylamide, and then reacted with a suitable methyl-substituted heteroaromatic compound of formula XII. Then, the intermediate of formula XIII is further converted to the alkyne of formula XV via the intermediate of formula XIV by reaction with N-(chloromethylene)-N-methylmethanaminium chloride, followed by reaction with a non-nucleophilic base such as potassium tert-butoxide. The resulting compound of formula XV is carboxylated and, after deprotonation using a strong base, such as n-butyllithium or lithium diisopropylamide, reacted with the corresponding chloroformate ClC(O)OR 7 to form a compound of formula IIa, wherein R 7 is methyl or ethyl. Finally, the compound of formula I can be synthesized by reaction of the intermediate of formula IIa with excess ammonia in a suitable solvent such as methanol at a high temperature of 70 °C to 100 °C, preferably in a sealed pressure vial.

[0094] Alternatively, the compound of formula XV is carboxylated and, after deprotonation using a strong base, such as n-butyllithium or lithium diisopropylamide, reacted with carbon dioxide to give R s 7A compound of formula IIa can be formed, where is hydrogen. The final step, amide formation to access the compound of formula Ia, can be achieved using methods known in the scientific literature, for example, using stoichiometric amounts of N,N'-carbonyldiimidazole and ammonia.

[0095] Alternatively, R 1 and R 2 Compounds of formula IX, as defined above, can be synthesized using the sequence shown in scheme 3.

[0096] [ka]

[0097] R 2 The compound of formula XVI, which is as defined above, where X is a halogen, preferably iodine, and which can be accessed using methods known in the art, optionally in the presence of a suitable base, e.g., cesium carbonate or potassium phosphate, optionally in the presence of a suitable transition metal catalyst, e.g., palladium or copper-containing complex, R 1 As defined above, Y is halogen or B(OR 9 )2, R 9 is hydrogen, methyl, or B(OR 9 )2 can react with the compound of formula XVII where pinacolboronyl. Chanmuram coupling (Y is B(OR 9In the case of (2), the presence of an oxidizing agent such as oxygen is also required. The compound of formula XVIII can be converted to the compound of formula IX by reaction with trimethylsilylacetylene under standard Sonogashira coupling conditions, in a suitable solvent such as dimethylformamide or acetonitrile, in the presence of a catalytic or stoichiometric amount of a suitable base, such as triethylamine or cesium carbonate, optionally in the presence of a catalytic or stoichiometric amount of a suitable co-catalyst, such as copper(I) iodide, and optionally as a solvent adduct, a catalytic or stoichiometric amount of a suitable transition metal complex, such as bis(triphenylphosphine)palladium(II) dichloride or 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride.

[0098] X 1 C is X 2 N is X 3 Other subgroups of compounds of formula I where is N can be prepared as outlined in scheme 4.

[0099] [ka]

[0100] Commercial starting materials of formula XX can be selectively methylated under standard conditions, for example, using sodium hydride as a base and methyl iodide or dimethyl sulfate as a methylating agent. The resulting compound of formula XXI can be selectively converted to a compound of formula XXII, where X is a halogen, preferably bromine or iodine, by reaction with a suitable halogenating agent, such as N-bromosuccinimide, N-iodosuccinimide, or bromine. Next, substituent R 1 R 1 As defined above, Y is B(OR 9 )2, R 9 Is it hydrogen, methyl, or B(OR) 9)2 is pinacol boronyl, and can be introduced, for example, under standard Suzuki-Miyaura reaction conditions, by reaction with the reagent of formula XXV. The intermediate of formula XXIII can be selectively halogenated to the intermediate of formula XXIV, where Z is bromine or iodine, preferably iodine, by reaction with a suitable halogenating agent such as N-iodosuccinimide (when Z=I). In the following steps, substituent R 3 The reaction is carried out using standard Sonogashira reaction conditions, for example, using a catalytic or stoichiometric amount of a suitable transition metal complex, for example, bis(triphenylphosphine)palladium(II) dichloride or 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloride as an optional solvent adduct, in the presence of a stoichiometric amount of a suitable base, for example, triethylamine or cesium carbonate, and optionally in the presence of a catalytic or stoichiometric amount of a suitable cocatalyst, for example, copper(I) iodide, in a suitable solvent such as dimethylformamide or acetonitrile, R 3 As defined above, the cyano group can be introduced by reaction with the corresponding alkyne of formula XXVI, which is commercially available or can be synthesized by methods known in the art. In the final step, the cyano group is hydrolyzed to carboxamide, for example, by reaction with sulfuric acid, using methods known in the art.

[0101] X 1 N is X 2 C is X 3 A subgroup of compounds of formula I where C can be prepared in the order shown in scheme 5.

[0102] [ka]

[0103] A commercially available compound of formula XXVII is subjected to catalytic or stoichiometric amounts of a suitable transition metal complex, e.g., copper(I) iodide, and suitable ligands, e.g., N,N'-dimethylcyclohexane-1,2-diamine, respectively, and further subjected to a suitable base, e.g., potassium phosphate, R 1 As defined above, Y is a halogen, preferably bromine or iodine, and can be reacted with a suitable reagent of formula XXVIII. The resulting intermediate of formula XXIX can then be halogenated with a suitable halogenating agent, such as N-iodosuccinimide or N-bromosuccinimide, to produce a compound of formula XXX, where X is bromine or iodine, preferably iodine. In the following steps, substituent R 3 The reaction is carried out using standard Sonogashira reaction conditions, for example, using a catalytic or stoichiometric amount of a suitable transition metal complex, for example, bis(triphenylphosphine)palladium(II) dichloride or 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloride as an optional solvent adduct, in the presence of a stoichiometric amount of a suitable base, for example, triethylamine or cesium carbonate, and optionally in the presence of a catalytic or stoichiometric amount of a suitable cocatalyst, for example, copper(I) iodide, in a suitable solvent such as dimethylformamide or acetonitrile, R 3 As defined above, the compound can be introduced by reaction with the corresponding alkyne of formula XXVI, which is commercially available or can be synthesized by methods known in the art. The resulting intermediate of formula XXXI can be converted to the desired compound of formula I either by direct reaction with ammonia at high temperature in a sealed vial, as shown in Scheme 5, or via intermediate II''. Hydrolysis can be achieved by standard methods known in the art, for example, by reaction with an alkali hydroxide such as lithium hydroxide in a suitable solvent such as tetrahydrofuran or water, or a mixture thereof. The final step, amide formation to access the compound of formula I, can also be achieved by using methods known in the scientific literature, for example, by using stoichiometric amounts of N,N'-carbonyldiimidazole and ammonia.

[0104] A particular embodiment of the present invention, as shown in Scheme 6, uses either a catalytic or stoichiometric amount of a suitable transition metal complex, for example, bis(triphenylphosphine)palladium(II) dichloride or 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloride, in the presence of a stoichiometric amount of a suitable base, for example, triethylamine or cesium carbonate, and optionally in the presence of a catalytic or stoichiometric amount of a suitable cocatalyst, for example, copper(I) iodide, R 1 , R 2 , R 3、 X 1 , X 2 and X 3 A compound of formula (IVa) as defined herein, where Y is defined above, and R is defined above. 3 The present invention relates to a method for preparing a compound of formula (I) as defined herein and a pharmaceutically acceptable salt thereof, including a reaction with a compound of -Y.

[0105] [ka]

[0106] These compounds were examined according to the tests described below.

[0107] Description of HCN1, HCN2, HCN3, and HCN4 assays Using in vitro high-throughput cell electrophysiology, we detected the voltage and use-dependent properties of compounds in single-concentration screening and IC50 determination for compound libraries and medicinal chemistry profiling in 384-well plates.

[0108] HEK-293 cell lines stably expressing the coding DNA of HCN1, 2, 3, or 4 were verified using an automated patch clamp (APC) platform, Ionworks Barracuda. Cell cultures were maintained for up to 20 passages at 37 °C and 5% CO2 in DMEM / F12 cell growth medium containing FBS and appropriate antibiotics. At a point 40 - 72 hours prior to the assay, the expression of HCN protein in the cells was induced by the addition of tetracycline. The cells can be induced and incubated at 27 °C for 2 - 24 hours. Intracellular (glucose-containing) and extracellular HEPES buffers containing various divalent cations were adjusted to pH 7.2 and 7.4, respectively. Cells were harvested at 80% confluency, resuspended in extracellular buffer, and added to the wells. Freshly prepared Escin solution was added to the intracellular buffer and applied to establish whole-cell recordings via perforated patch clamping with APC.

[0109] The current through the activation channel was directly measured by APC using a hyperpolarization voltage step. The activation window was increased and stabilized by the addition of cell-permeable Br-cAMP. Baselines were established for both use-dependent and voltage-dependent protocols using holding potentials of -30mV and multiple test pulses in 20mV steps from -100mV or -120mV to 0mV, respectively. After baseline recording, the test compound was added, followed by a 10-minute incubation, voltage-dependent protocol recording, and use-dependent recording. Data were corrected for baseline and rundown (well-based) and normalized for inhibition % (plate-based). Five previously reported HCN inhibitors and zetabradine of varying potency and selectivity were used for running and inter-plate quality control. Non-selective and potent inhibitors were used as positive controls. Inhibition % was analyzed at -80, -100, and -120mV for the voltage-dependent protocol, and at pulses 0 and 50 for the use-dependent protocol. Using a similar method, we evaluated the selectivity for HCN2, HCN3, and HCN4 overexpressing cell lines. Because HCN4 has slower activation than other HCN channels, activation was prolonged to achieve steady-state activation. The following table shows data for selected compounds regarding current inhibition during a -100mV hyperpolarization pulse: [Table 1] TIFF0007862306000021.tif222165

[0110] Experimental section The following examples are provided for illustrative purposes of the present invention. They should not be considered limiting to the scope of the invention, but rather should be understood as representative examples.

[0111] General Analysis method HPLC (Method: LC-MS_fastgradient) Column:Agilent Zorbax Eclipse Plus C18,Rapid Resolution HT,2.1x30mm,1.8μm,Part.no.959731-902 Solvent A: Water 0.01% formic acid; Solvent B: Acetonitrile (MeCN) gradient: [Table 2]

[0112] abbreviation The following abbreviations were used in the experimental section: THF = tetrahydrofuran; MTBE = methyl tert-butyl ether; DMF = Dimethylformamide; TLC = Thin-layer chromatography; rt=room temperature, 20~25℃

[0113] Starting material Basic chemicals and solvents were purchased and used as is without further purification. Intermediates Int-1, Int-2, Int-13 to Int-15, Int-35 to Int-43, Int-50, Int-51, Int-57, Int-58, Int-67 to Int-71, Int-78, Int-81, Int-84, and Int-91 to Int-96 are commercially available or can be synthesized using methods known in the art.

[0114] intermediate Intermediate 9 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (General Procedure A) [ka]

[0115] Step 1: Ethyl 5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-4-carboxylate (Int-3)

[0116] Ethyl 3-oxobutanoate (Int-1) (5.17 g, 5.03 mL, 39.7 mmol) was dissolved in acetic acid (9 mL) at 0°C, and a solution of sodium nitrite (3.01 g, 43.7 mmol) in water (13 mL) was added dropwise. The mixture was stirred at 5-10°C for 2 hours. This was then diluted with tert-butyl methyl ether (100 mL), the organic layer was washed with saturated sodium hydrogen phosphate aqueous solution (50 mL) and water (2 × 50 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain crude ethyl(Z)-2-(hydroxyimino)-3-oxobutanoate (6.2 g, 39 mmol, yield 98%) as a colorless oil. No further purification was performed.

[0117] Crude ethyl(Z)-2-(hydroxyimino)-3-oxobutanoate (6.2 g, 39 mmol) was dissolved in toluene (80 mL), and 6-methylpyridine-3-amine (Int-2) (4.42 g, 40.9 mmol), followed by pyridinium p-toluenesulfonate (196 mg, 779 μmol), were added sequentially. The reaction mixture was stirred under reflux for 12 hours in a Dean-Stark apparatus. After cooling, triethoxymethane (21.2 g, 23.5 mL, 143 mmol), p-toluenesulfonic acid monohydrate (148 mg, 779 μmol), and Pd / C 10% (829 mg, 779 μmol) were added under argon. The resulting reaction mixture was stirred at room temperature for 24 hours. Since the reaction did not show complete conversion, fresh Pd / C 10% (829 mg, 779 μmol) and scandium(III) trifluoromethanesulfonate (192 mg, 390 μmol) were added, and stirring was continued for a further 24 hours under a hydrogen atmosphere. The reaction mixture was then filtered and the filtrate was concentrated under vacuum. The crude product was adsorbed onto HM-N for separation and purified by column chromatography (80 g, silica gel, methanol / dichloromethane, gradient 0:100~10:90 (v / v)) to obtain the title compound as a light brown solid (5.3 g, 21.6 mmol, yield 55%). HPLC (Method LCMS_fastgradient) R=0.79 minutes. MS(ES+)m / z246.0[M+H].

[0118] Step 2: (5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-4-yl)methanol(Int-4)

[0119] In a 100 ml four-necked flask, ethyl 5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-4-carboxylate (Int-3) (2.1 g, 8.58 mmol) was dissolved in THF (50 mL). The resulting solution was cooled to 0°C. Then, lithium aluminum hydride (1 M in THF) (11.3 mL, 11.3 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour. Subsequently, water (0.44 mL), 1 M sodium hydroxide aqueous solution (0.44 mL), and water (1.32 mL) were added, and the mixture was stirred at room temperature for 1 hour. Sodium sulfate (30 g) was added, the slurry was filtered, washed with THF (50 mL), and the filtrate was concentrated under vacuum to obtain the title compound as a yellow solid (1.35 g, 6.64 mmol, yield 77%). HPLC (Method LC-MS_fastgradient) R =0.23 minutes. MS(ES+)m / z204.1[M+H].

[0120] Step 3: 5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-4-carbaldehyde(Int-5)

[0121] (5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-4-yl)methanol (Int-4) (1.35 g, 6.64 mmol) was suspended in dichloromethane (70 mL), and manganese dioxide (11.5 g, 133 mmol) was added. The dark mixture was stirred at room temperature for 1 hour. This was then filtered, washed with dichloromethane (20 mL), and the filtrate was concentrated under vacuum to obtain the title compound as a yellow solid (0.97 g, 4.82 mmol, yield 73%). HPLC (Method LC-MS_fastgradient) R =0.62 minutes. MS(ES+)m / z202.1[M+H].

[0122] Step 4: 5-(4-ethynyl-5-methyl-1H-imidazole-1-yl)-2-methylpyridine(Int-6)

[0123] 5-Methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-4-carbaldehyde (Int-5) (0.97 g, 4.82 mmol) was dissolved in methanol (40 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.3 g, 1.01 mL, 6.75 mmol) and potassium carbonate (1.33 g, 9.64 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. Then, it was poured into saturated sodium bicarbonate aqueous solution (100 mL) and extracted with dichloromethane (2 × 80 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was adsorbed onto HM-N for separation and purified by column chromatography (40 g, silica gel, methanol / dichloromethane, gradient 0:100~5:95 (v / v)) to obtain the title compound as a yellow oily substance (570 mg, 2.89 mmol, yield 60%). HPLC (Method LCMS_fastgradient) R =0.71 minutes. MS(ES+)m / z198.1[M+H].

[0124] Step 5: 2-methyl-5-(5-methyl-4-((trimethylsilyl)ethinyl)-1H-imidazole-1-yl)pyridine(Int-7)

[0125] 5-(4-ethynyl-5-methyl-1H-imidazole-1-yl)-2-methylpyridine (Int-6) (1.27 g, 6.45 mmol) was dissolved in THF (70 mL), the solution was cooled to -60°C, and LHMDS (1 M in THF / ethylbenzene, 6.45 mL, 6.45 mmol) was added dropwise. The reaction mixture was stirred at -60°C for 1 hour. Then, trimethylchlorosilane (701 mg, 825 μL, 6.45 mmol) was added at -60°C, and the reaction mixture was stirred at -60°C for a further 2 hours. Then, saturated aqueous ammonium chloride (30 mL) was added, followed by ethyl acetate (50 mL). After phase separation, the aqueous layer was extracted with ethyl acetate (50 mL), the combined organic layers were washed with water (50 mL) and brine (50 mL), dried on sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the title compound as a brown solid (1.74 g), which was used in the next step without further purification. HPLC (Method LCMS_fastgradient) R =1.18 minutes. MS(ES+)m / z270.3[M+H].

[0126] Step 6: Methyl 5-methyl-1-(6-methylpyridine-3-yl)-4-((trimethylsilyl)ethynyl)-1H-imidazole-2-carboxylate (Int-8)

[0127] 2-Methyl-5-(5-methyl-4-((trimethylsilyl)ethynyl)-1H-imidazole-1-yl)pyridine (Int-7, crude product from the previous step) (1.74 g, 6.46 mmol) was dissolved in THF (50 mL), and the solution was cooled to -60°C. n-butyllithium (1.6 M in hexane, 4.4 mL, 7.1 mmol) was added all at once at -60°C. The resulting brown solution was stirred at -60°C for 10 minutes. Methyl chloroformate (1.04 g, 850 μl, 11 mmol) was then added all at once at -60°C. The reaction mixture was stirred at -60°C for 1 hour. Then saturated ammonium chloride aqueous solution (20 mL), followed by ethyl acetate (20 mL), was added. After phase separation, the aqueous layer was extracted with ethyl acetate (2 × 20 mL), and the combined organic layers were washed with water (30 mL) and brine (30 mL). The mixture was dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was adsorbed onto separation HM-N and purified by column chromatography (40 g, silica gel, ethyl acetate / n-heptane, gradient 0:100~80:20 (v / v)) to obtain the title compound as a white solid (940 mg, 2.87 mmol, 44% yield in 2 steps). HPLC (Method LC-MS_fastgradient) R =1.28 minutes. MS(ES+)m / z328.2[M+H].

[0128] Step 7: 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9)

[0129] A solution of methyl 5-methyl-1-(6-methylpyridine-3-yl)-4-((trimethylsilyl)ethynyl)-1H-imidazole-2-carboxylate (Int-8) (426 mg, 1.3 mmol) and sodium cyanide (8.93 mg, 182 μmol) in ammonia (7N in methanol) (11.2 mL, 78.1 mmol) was stirred in a pressure tube at 50°C for 1.5 hours. After cooling, the reaction mixture was concentrated under vacuum. The residue was adsorbed onto separation HM-N and purified by column chromatography (40 g, silica gel, methanol / dichloromethane, gradient 0:100~10:90 (v / v)) to obtain the title compound as a grayish-white solid (273 mg, 1.14 mmol, yield 87%). HPLC (Method LCMS_fastgradient) R =0.72 minutes. MS(ES+)m / z241.2[M+H].

[0130] Similar to the synthesis of Int-9, the following intermediates can be synthesized using the procedure outlined in General Procedure A, by replacing reagent Int-2 with the reagents listed in the table below. [Table 3]

[0131] Intermediate 22 4-Ethinyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide [ka]

[0132] Step 1: Ethyl 1-(6-methyl-3-pyridyl)imidazole-4-carboxylate (Int-16)

[0133] 6-Methylpyridine-3-amine (Int-2) (5.00 g, 46.2 mmol) was dissolved in triethoxymethane (9.18 g, 10.3 ml, 62 mmol), and 2-ethyl nitro(Int-15) (7.38 g, 6.15 ml, 55.5 mmol) and acetic acid (1 mL) were added. The solution was stirred at 140°C for 2 hours. It was then cooled to 75°C, and further triethoxymethane (44.5 g, 50 mL, 300 mmol), acetic acid (50 mL), and iron (12.9 g, 231 mmol) were added. Stirring was continued at 130°C for 1 hour. The second portion of iron (6.45 g, 115 mmol) was added, and stirring was continued at 130°C for 1 hour. After cooling, the mixture was diluted with ethyl acetate (175 mL), and the resulting suspension was stirred at 23°C for 1 hour. The reaction mixture was passed through Celite and filtered, washed with ethyl acetate, and the filtrate was concentrated under vacuum. The crude product was adsorbed onto HM-N for separation and purified by column chromatography (200 g, silica gel, methanol / dichloromethane, fixed composition, 10:90 (v / v)). Subsequently, crystallization was performed from dichloromethane / tert-butyl methyl ether to obtain the title compound as a light brown solid (3.2 g, 13.8 mmol, yield 30%). HPLC (method LC-MS_fastgradient) R =0.76 minutes. MS(ES+)m / z232.2[M+H].

[0134] Steps 2-7 below were performed in the same manner as the protocols described in General Procedure A and Steps 2-7, respectively.

[0135] Step 7: Ethyl 1-(6-methyl-3-pyridyl)imidazole-4-carboxylate (Int-22) HPLC (Method LCMS_fastgradient) R =0.64 minutes. MS(ES+)m / z227.2[M+H].

[0136] Intermediate 28 Methyl 4-[2-(2-chloro-3-fluoro-4-pyridyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxylate (General Procedure B) [ka]

[0137] Step 1: Ethyl 5-methyl-1-(6-methyl-3-pyridyl)imidazole-4-carboxylate (Int-3)

[0138] A solution of sodium nitrite (3.01 g, 43.7 mmol) in water (13 ml) was added dropwise to a solution of ethyl 3-oxobutanoate (Int-1) (5.17 g, 5.03 ml, 39.7 mmol) in acetic acid (8 mL) at 0°C. The reaction mixture was stirred at 5-10°C for 2 hours. The resulting reaction mixture was diluted with butyl methyl ether (100 mL), the organic layer was washed with a saturated solution of disodium phosphate (2 × 50 mL), dried, filtered, and concentrated under vacuum to obtain ethyl (Z)-2-(hydroxyimino)-3-oxobutanoate (6.204 g, 39 mmol, 98% yield) as a colorless oil, which was used without further purification. HPLC (Method LCMS_fastgradient) R =0.72 minutes. MS(ES+)m / z160.1[M+H].

[0139] To a solution of ethyl(Z)-2-(hydroxyimino)-3-oxobutanoate (6.2 g, 39 mmol) in toluene (78 ml), 6-methylpyridine-3-amine (Int-2) (4.42 g, 40.9 mmol) and pyridinium p-toluenesulfonate (196 mg, 779 μmol) were sequentially added. The reaction mixture was stirred under reflux for 12 hours using a Dean-Stark apparatus (desired intermediate ethyl(2Z,3E)-2-hydroxyimino-3-[(6-methyl-3-pyridyl)imino]butanoate, HPLC (method LCMS_fastgradient) R=0.61 min. MS(ES+)m / z250.2[M+H]). After cooling, triethoxymethane (21.2 g, 23.5 ml, 143 mmol), p-toluenesulfonic acid monohydrate (148 mg, 779 μmol), and Pd / C 10% (829 mg, 779 μmol) were sequentially added to the solution under argon at room temperature. The resulting reaction mixture was stirred at room temperature for 24 hours. Fresh Pd / C 10% (829 mg, 779 μmol) and scandium trifluoromethanesulfonate (192 mg, 390 μmol) were added, and stirring was continued under hydrogen for 24 hours. The black reaction mixture was filtered off and evaporated to dryness under vacuum. The residue was adsorbed onto HM-N for separation and purified by column chromatography (80g, silica gel, methanol / dichloromethane, gradient 0:100~10:90) to obtain the title compound as a light brown solid (5.3g, 21.6 mmol, yield 56%). HPLC (Method LCMS_fastgradient) R =0.79 minutes. MS(ES+)m / z246.0[M+H].

[0140] Step 2: N-methoxy-N,5-dimethyl-1-(6-methyl-3-pyridyl)imidazole-4-carboxamide (Int-23)

[0141] In a 100 mL three-necked flask, N,O-dimethylhydroxylamine hydrochloride (2.68 g, 27.5 mmol) was combined with dioxane (15 mL) to obtain a white suspension. Trimethylaluminum (2 M in toluene) (13.7 mL, 27.5 mmol) was added dropwise at 5 °C. The reaction mixture was stirred at room temperature for 45 minutes, and then ethyl 5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-4-carboxylate (Int-3) (2.246 g, 9.16 mmol) in 15 mL of dioxane was added at 10 °C. The reaction mixture was allowed to reach room temperature and stirred for 20 hours. The reaction mixture was cooled to 0 °C and water (10 mL) was slowly added (exothermic!). The resulting orange slurry was filtered through a Celite pad and washed several times with water (3 × 20 mL) and ethyl phosphate (3 × 20 mL). The filtrate layers were separated, the organic phase was washed with brine (20 mL), dried (sodium sulfate), filtered, and concentrated under vacuum. The crude product was adsorbed onto HM-N for separation and purified by column chromatography (70 g, silica gel, methanol / dichloromethane, gradient 0:100~10:90) to obtain the title compound as a light brown solid (1.27 g, 4.85 mmol, yield 53%). HPLC (method LCMS_fastgradient) R =0.66 minutes. MS(ES+)m / z261.3[M+H].

[0142] Step 3: 2-(2-chloro-3-fluoro-4-pyridyl)-1-[5-methyl-1-(6-methyl-3-pyridyl)imidazole-4-yl]ethanone (Int-25)

[0143] Diisopropylamine (816 mg, 1.14 ml, 8.07 mmol) was dissolved in THF (5 mL) in a dry Schlenk tube. The solution was cooled to 0°C. A solution of n-butyllithium (1.6 M in hexane) (4.92 mL, 7.88 mmol) was added dropwise, and the mixture was stirred at 0°C for 15 minutes. The reaction mixture was cooled to -78°C, and subsequently, a solution of 2-chloro-3-fluoro-4-methylpyridine (Int-24) (1.2 g, 8.26 mmol) in THF (2 mL) was added dropwise. The mixture was stirred at -78°C for 15 minutes (the mixture became an orange suspension). A solution of N-methoxy-N,5-dimethyl-1-(6-methylpyridine-3-yl)-1H-imidazole-4-carboxamide (Int-23) (500 mg, 1.92 mmol) in THF (3 mL) was added dropwise, and the mixture was stirred at -78°C for 1 hour. The reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL) and allowed to reach room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and water (20 mL). The organic layer was washed with saturated ammonium chloride aqueous solution (20 mL) and brine (20 mL), dried, filtered, and concentrated. The crude product was adsorbed onto HM-N for separation and purified by column chromatography (20 g, silica gel, methanol / dichloromethane, gradient 0:100~10:90) to obtain the title compound as a white powder (612 mg, 1.78 mmol, yield 92%). HPLC (Method LCMS_fastgradient) R =1.01 minutes. MS(ES+)m / z345.3,347.3[M+H,Cl isotope].

[0144] Step 4: (E)-3-chloro-2-(2-chloro-3-fluoro-4-pyridyl)-3-[5-methyl-1-(6-methyl-3-pyridyl)imidazole-4-yl]propa-2-enal(Int-26)

[0145] N-(chloromethylene)-N-methylmethaneaminium chloride (500 mg, 3.91 mmol) was suspended in dichloromethane (5 mL) under Ar, and the suspension was cooled to 0°C. A solution of 2-(2-chloro-3-fluoropyridine-4-yl)-1-(5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-4-yl)ethane-1-one (Int-25) (612 mg, 1.78 mmol) in dichloromethane (5 mL) was added dropwise at 0°C, and the reaction mixture was brought to room temperature. The reaction mixture was stirred at room temperature for 2 hours. Then, it was diluted with dichloromethane (50 mL) and quenched by adding saturated aqueous solution of sodium bicarbonate (30 mL). The aqueous layer was extracted with dichloromethane (2 × 20 mL), and the combined organic layers were washed with water (2 × 20 mL) and brine (20 mL), dried, and concentrated under vacuum to obtain the title compound as a yellow solid (543 mg, 1.39 mmol, yield 78%). HPLC (Method LC-MS_fastgradient) R =1.10 minutes. MS(ES+)m / z391.2,393.2[M+H,Cl isotope].

[0146] Step 5: 2-Chloro-3-fluoro-4-[2-[5-methyl-1-(6-methyl-3-pyridyl)imidazole-4-yl]ethinyl]pyridine (Int-27)

[0147] A solution of (E)-3-chloro-2-(2-chloro-3-fluoro-4-pyridyl)-3-[5-methyl-1-(6-methyl-3-pyridyl)imidazole-4-yl]prop-2-enal (Int-26) (650 mg, 1.66 mmol) in THF (25 mL) and water (0.04 mL) was cooled to -25°C (acetone / dry ice), and potassium tert-butoxide (410 mg, 3.66 mmol) was added in five portions (once every 2 minutes). The mixture was stirred at -25°C for 1 hour. A saturated ammonium chloride aqueous solution (25 mL) and a dichloromethane (40 mL) solution were added at -25°C, and the mixture was allowed to reach room temperature. The aqueous layer was extracted with dichloromethane (2 × 20 mL). The combined organic phase was dried (sodium sulfate), filtered, and concentrated under vacuum. The crude product was adsorbed onto HM-N for separation and purified by column chromatography (20 g, silica gel, methanol / dichloromethane, gradient 0:100~5:95) to obtain the title compound as a grayish-white solid (340 mg, 1.04 mmol, yield 63%). HPLC (Method LCMS_fastgradient) R =1.10 minutes. MS(ES+)m / z 327.3,329.2[M+H,Cl isotope].

[0148] Step 6: Methyl 4-[2-(2-chloro-3-fluoro-4-pyridyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxylate (Int-28)

[0149] A solution of 2-chloro-3-fluoro-4-((5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-4-yl)ethynyl)pyridine (Int-27) (160 mg, 490 μmol) in THF (5 mL) under Ar was cooled to -78°C. A solution of n-butyllithium (1.6 M in hexane) (367 μl, 588 μmol) was added dropwise over 5 minutes, and the mixture was stirred at -78°C for 30 minutes. Methyl chloroformate (46.3 mg, 490 μmol) was added all at once, and the mixture was stirred at -78°C for 1 hour, then allowed to reach room temperature and stirred for 1 hour. The mixture was cooled again to -78°C, and a saturated aqueous solution of ammonium chloride (10 mL) was added. The mixture was allowed to reach room temperature and extracted with ethyl acetate (50 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The mixed organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto HM-N for separation and purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100~5:95) to obtain the title compound as a light brown solid (102 mg, 265 μmol, yield 54%). HPLC (method LCMS_fastgradient) R =1.17 minutes. MS(ES+)m / z385.2,387.1[M+H,Cl isotope]. Similar to the synthesis of Int-28, the following intermediates can be synthesized using the procedure outlined in General Procedure B, by replacing reagents Int-2 and Int-24 with the reagents listed in the table below: [Table 4] TIFF0007862306000028.tif196170

[0150] Intermediate 49 Methyl 4-[2-(2-chloro-4-pyridyl)ethynyl]-1-(4-fluorophenyl)imidazole-2-carboxylate [ka]

[0151] Step 1 was carried out in the same manner as Step 1 for the preparation of intermediate Int-22, but Int-2 was replaced with 4-fluoroaniline (Int-43).

[0152] Steps 2-6 below were performed, respectively, in the same manner as the general procedure B and the protocols described in steps 2-6, but with Int-24 replaced by Int-40.

[0153] Step 6: Methyl 4-[2-(2-chloro-4-pyridyl)ethynyl]-1-(4-fluorophenyl)imidazole-2-carboxylate (Int-49) MS(ES+)m / z 356.2,358.2[M+H,Cl isotope].

[0154] Intermediate 55 4-Ethinyl-5-methyl-1-(5-methylpyrazine-2-yl)-1H-imidazole-2-carboxamide (General procedure C) [ka]

[0155] Step 1: 2-(4-iodo-5-methyl-1H-imidazole-1-yl)-5-methylpyrazine(Int-52)

[0156] To a solution of 2-chloro-5-methylpyrazine (Int-51) (980 mg, 7.62 mmol, 1 equivalent) in DMF (15 mL), 4-iodo-5-methyl-1H-imidazole (Int-50) (1.90 g, 9.15 mmol, 1.2 equivalents) and cesium carbonate (4.97 g, 15.25 mmol, 2 equivalents) were added. The mixture was stirred at 100°C for 14 hours. The reaction was then stopped by adding water (50 mL), and the mixture was extracted with dichloromethane / methanol (10:1 (v / v), 3 × 50 mL). The combined organic layers were concentrated under vacuum, and the crude product was purified by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates of 70:30 to 10:90 v / v). Subsequent lyophilization yielded the title compound as a white solid (830 mg, 2.77 mmol, 36% yield). MS(ES+) m / z 301.0[M+H].

[0157] Step 2: 2-methyl-5-(5-methyl-4-((trimethylsilyl)ethinyl)-1H-imidazole-1-yl)pyrazine (Int-53)

[0158] To a solution of 2-(4-iodo-5-methylimidazole-1-yl)-5-methylpyrazine (Int-52) (780 mg, 2.6 mmol) in DMF (4 mL), triethylamine (1.09 mL, 7.8 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex (106 mg, 0.13 mmol), and copper(I) iodide (14.8 mg, 78 μmol) were added. The mixture was stirred at 70°C for 1 hour. Then, trimethylsilylacetylene (766 mg, 7.8 mmol) was added. The mixture was stirred at 70°C for a further 2 hours. Next, this was concentrated in vacuum and purified by column chromatography (80 g, silica gel, n-heptane / (ethyl acetate + 30% ethanol), gradient 95:5~50:50 (v / v)) to obtain the title compound as a yellow solid (700 mg, 2.59 mmol, yield 99%). MS(ES+)m / z 271.1[M+H].

[0159] Step 3: Ethyl 5-methyl-1-(5-methylpyrazine-2-yl)-4-((trimethylsilyl)ethynyl)-1H-imidazole-2-carboxylate (Int-54)

[0160] 2-Methyl-5-(5-methyl-4-((trimethylsilyl)ethynyl)-1H-imidazole-1-yl)pyrazine (Int-53) (400 mg, 1.48 mmol) was dissolved in THF (10 mL), and the solution was cooled to -78°C. A solution of lithium diisopropylamide (2 M in THF, 1.1 mL, 2.2 mmol) was added, and the resulting brown solution was stirred at -78°C for 30 minutes. Then, ethyl chloroformate (0.79 mL, 8.9 mmol) was added, and the mixture was stirred at -78°C for 1 hour. The mixture was concentrated under vacuum and purified by column chromatography (40 g, silica gel, n-heptane / ethyl acetate, gradient 90:10~75:25 (v / v)) to obtain the title compound as a yellow oil (290 mg, 0.850 mmol, yield 57%). MS(ES+)m / z343.1[M+H].

[0161] Step 4: 4-Ethinyl-5-methyl-1-(5-methylpyrazine-2-yl)-1H-imidazole-2-carboxamide (Int-55)

[0162] Methyl 5-methyl-1-(5-methylpyrazine-2-yl)-4-(2-trimethylsilylethynyl)imidazole-2-carboxylate (Int-54) (280 mg, 0.850 mmol) was dissolved in methanol (2 mL) using a pressure tube, and concentrated ammonium hydroxide solution (5.0 mL, 25-28% in water) was added. The resulting mixture was stirred at 50°C for 14 hours. After cooling, the mixture was concentrated under vacuum to obtain the title compound as a yellow solid (165 mg, 0.68 mmol, yield 80%). MS(ES+)m / z 242.1[M+H]. Similar to the synthesis of Int-55, the following intermediates can be synthesized using the procedure outlined in general procedure C, by replacing reagent Int-51 with the reagents listed in the table below: [Table 5]

[0163] Intermediate 62 4-Ethinyl-5-methyl-1-(5-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (General Procedure D) [ka]

[0164] Step 1: 3-(4-iodo-5-methyl-1H-imidazole-1-yl)-5-methylpyridine (Int-59)

[0165] 5-methylpyridine-3-boronic acid (Int-58) (1.50 g, 11.0 mmol) was dissolved in DMF (30 mL), and 4-iodo-5-methyl-1H-imidazole (Int-50) (2.73 g, 13.1 mmol) and di-μ-hydroxo-bis(N,N,N',N'-tetramethylethylenediamine)copper(II) chloride (1.017 g, 2.19 mmol) were added. The mixture was stirred at 50°C for 16 hours under an oxygen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Shim-pack C18, 150x25mmx10μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates with a 70:30 to 10:90 v / v ratio), followed by lyophilization to obtain the title compound as a white solid (800 mg, 2.67 mmol, yield 24%). 1 H NMR (CDCl3,400MHz): δ2.19(s,3H),2.47(s,3H),7.44(s,1H),7.58(s,1H),8.47(br s,1H),8.61(br s,1H).MS(ES+)m / z300.1[M+H].

[0166] Steps 2 through 4 were carried out in the same manner as general procedure C and steps 2 through 4, respectively. Similar to the synthesis of Int-62, the following intermediates can be synthesized using the procedure outlined in general procedure D, by replacing reagent Int-58 with the reagents listed in the table below: [Table 6]

[0167] Intermediate 77 4-Ethinyl-5-methyl-1-(5-methylpyridine-2-yl)-1H-imidazole-2-carboxamide [ka]

[0168] Step 1: Ethyl 5-methyl-1-(5-methylpyridine-2-yl)-1H-imidazole-4-carboxylate (Int-72)

[0169] 2-Fluoro-5-methylpyridine (Int-71) (1.9 g, 17.1 mmol) was dissolved in DMA (38 mL), and ethyl 4-methyl-1H-imidazole-5-carboxylate (Int-70) (2.64 g, 17.1 mmol), followed by cesium carbonate (11.14 g, 34.2 mmol), was added. The mixture was stirred at 120°C for 12 hours. After cooling, the mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography (40 g, silica gel, petroleum ether / ethyl acetate, constant composition 50:50 (v / v)) to obtain the title compound as a yellow solid (1.3 g, 5.3 mmol, yield 31%). MS(ES+)m / z 246.1[M+H].

[0170] Step 2: 5-methyl-1-(5-methylpyridine-2-yl)-1H-imidazole-4-carbaldehyde (Int-73)

[0171] Ethyl 5-methyl-1-(5-methyl-2-pyridyl)imidazole-4-carboxylate (Int-72) (500 mg, 2.0 mmol) was dissolved in THF (12.5 mL), and diisobutylaluminum hydride (1 M in toluene, 6.12 mL, 6.12 mmol) was added at 25°C. The mixture was stirred at 25°C for 4 hours. Then, sodium sulfate decahydrate (3 g) was added, and the resulting slurry was stirred for 0.5 hours. This was filtered, washed with THF (10 mL), and the filtrate was concentrated under vacuum to obtain crude [5-methyl-1-(5-methyl-2-pyridyl)imidazole-4-yl]methanol (350 mg, 1.72 mmol, yield 84%) as a yellow oil. This substance was dissolved in THF (15 mL), manganese(IV) oxide (449 mg, 5.17 mmol) was added, and the mixture was stirred at 30°C for 10 hours. Next, the mixture was filtered and concentrated under vacuum to obtain the crude title compound as a yellow oil (240 mg, 1.19 mmol, 69% yield). The crude product was used directly in the next step without further purification. MS(ES+)m / z 202.1[M+H].

[0172] Step 3: 2-(4-ethynyl-5-methyl-1H-imidazole-1-yl)-5-methylpyridine(Int-74)

[0173] 5-Methyl-1-(5-methyl-2-pyridyl)imidazole-4-carbaldehyde (Int-73) (240 mg, 1.19 mmol) was dissolved in methanol (8 mL), and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (275 mg, 1.43 mmol) and potassium carbonate (198 mg, 1.43 mmol) were added. The mixture was stirred at 25°C for 24 hours. The mixture was then poured into water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic phase was dried (sodium sulfate), concentrated under vacuum, and the crude title compound was obtained as a yellow oil (170 mg, 0.860 mmol, yield 72%), which was used in the next step without further purification. MS(ES+)m / z 198.1[M+H].

[0174] Step 4: 5-methyl-2-(5-methyl-4-((trimethylsilyl)ethynyl)-1H-imidazole-1-yl)pyridine(Int-75)

[0175] 2-(4-ethinyl-5-methylimidazole-1-yl)-5-methylpyridine (Int-74) (150 mg, 0.76 mmol) was dissolved in THF (3 mL), the solution was cooled to -78°C, and lithium hexamethyldisilazide (LiHDMS) (1 M in THF, 1.14 mL, 1.14 mmol) was added at -78°C. The mixture was stirred at room temperature for 1 hour. Then, trimethylchlorosilane (91 mg, 0.84 mmol) was added. The mixture was heated to 25°C and stirred for 3 hours. The reaction was cooled to -78°C, and water (20 mL) was added to stop the reaction. After heating to room temperature, the mixture was extracted with ethyl acetate (2 × 20 mL), the combined organic layer was washed with brine (20 mL), and concentrated under vacuum to obtain the crude title compound as a yellow oil (150 mg, 0.56 mmol, yield 68%). This was used in the next step without further purification. MS(ES+)m / z 270.1[M+H].

[0176] Step 5: Methyl 5-methyl-1-(5-methylpyridine-2-yl)-4-((trimethylsilyl)ethynyl)-1H-imidazole-2-carboxylate (Int-76)

[0177] 5-Methyl-2-(5-methyl-4-((trimethylsilyl)ethynyl)-1H-imidazole-1-yl)pyridine (Int-75) (150 mg, 0.56 mmol) was dissolved in THF (3 mL), the solution was cooled to -78°C, and lithium diisopropylamide (2 M in THF, 0.42 mL, 0.84 mmol) was added at -78°C. The resulting brown solution was stirred for 30 minutes. Then, ethyl chloroformate (0.15 mL, 1.67 mmol) was added, and the mixture was stirred at -78°C for 1.5 hours. After warming to room temperature, sodium sulfate decahydrate (10 g) was added to stop the reaction, the resulting slurry was stirred for 30 minutes, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (12 g, silica gel, petroleum ether / ethyl acetate, gradient, 91:9~75:25 (v / v)) to obtain the title compound as a yellow solid (70 mg, 0.200 mmol, yield 37%). MS(ES+)m / z 342.1[M+H].

[0178] Step 6: 4-Ethinyl-5-methyl-1-(5-methylpyridine-2-yl)-1H-imidazole-2-carboxamide (Int-77)

[0179] Methyl 5-methyl-1-(5-methylpyridine-2-yl)-4-(trimethylsilylethynyl)-1H-imidazole-2-carboxylate (Int-76) (60 mg, 0.18 mmol) was dissolved in methanol (1 mL) in a pressure tube, and concentrated aqueous ammonia (1.0 mL) was added. The mixture was stirred in a sealed pressure tube at 50°C for 4 hours. After cooling, the mixture was concentrated under vacuum to obtain the title compound as a brown solid (50 mg, 0.21 mmol, yield 89%), which was used in the next step without further purification. MS(ES+)m / z 241.1[M+H].

[0180] Intermediate 85 2-((2-chloropyridine-4-yl)ethynyl)-1-methyl-5-(6-methylpyridine-3-yl)-1H-imidazole-4-carbonilicate (General Procedure E) [ka]

[0181] Step 1: 1-Methylimidazole-4-Carbonitrile (Int-79)

[0182] 1H-imidazole-4-carbonitrile (Int-78) (4.000 g, 43 mmol) was dissolved in DMF (80 mL), the solution was cooled to 0°C, and sodium hydride (60% dispersion in mineral oil, 1.89 g, 47.3 mmol) was added at 0°C. The mixture was stirred at 25°C for 1 hour. Then, iodomethane (9.30 g, 65.5 mmol) was added. The mixture was stirred at 25°C for 2 hours. After that, water (100 mL) was added, and the mixture was extracted with dichloromethane / methanol (10:1 (v / v), 3 × 100 mL), and the combined organic layer was concentrated under vacuum. The crude product was purified by column chromatography (240 g, silica gel, petroleum ether / ethyl acetate, gradient, 91:9~33:66 (v / v)) to obtain the title compound as a white solid (3.95 g, 36.9 mmol, yield 86%).

[0183] Step 2: 5-bromo-1-methylimidazole-4-carbonitrile (Int-80)

[0184] A solution of 1-methylimidazole-4-carbonitride (Int-79) (4.000 g, 37.3 mmol) and N-bromosuccinimide (7.976 g, 44.8 mmol) in DMF (15 mL) was stirred at 25°C for 14 hours. Then, water (80 mL) was added, and the mixture was stirred at 25°C for 1 hour. A precipitate formed, which was filtered off and dried in a backup to obtain the title compound as a white solid (6.00 g, 32.3 mmol, yield 86%). MS(ES+)m / z 186.0,188.0 [M+H,Br isotope].

[0185] Step 3: 1-Methyl-5-(6-methyl-3-pyridyl)imidazole-4-carbonitrile (Int-82)

[0186] 5-bromo-1-methylimidazole-4-carbonitride (Int-80) (3,000 g, 16.1 mmol) was dissolved in 1,4-dioxane (45 mL), 6-methylpyridine-3-boronic acid (Int-81) (2.21 g, 16.1 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1,316 g, 1.61 mmol). Cesium carbonate (10.51 g, 32.3 mmol) was added under argon, and the mixture was stirred at 110°C for 14 hours. The mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (240 g, silica gel, petroleum ether / ethyl acetate, gradient, 85:15~0:100 (v / v)) to obtain the title compound as a gray solid (3.00 g, 15.1 mmol, 70% yield). MS(ES+)m / z 199.1[M+H].

[0187] Step 4: 2-iodo-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carbonitrile (Int-83)

[0188] 1-Methyl-5-(6-methyl-3-pyridyl)imidazole-4-carbonitrile (Int-82) (3.00 g, 15.1 mmol) was dissolved in THF (35 mL), the solution was cooled to -78°C, and lithium diisopropylamide (2 M in THF, 11.35 mL, 22.7 mmol) was added. The mixture was stirred at -78°C for 0.5 hours. Next, a solution of iodine (7.68 g, 30.3 mmol) in THF (15 mL) was added. The resulting mixture was stirred at -78°C for 1.5 hours. Then, the reaction was stopped by adding aqueous sodium sulfite solution (2 M, 100 mL), and the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were concentrated under vacuum, and the crude product was purified by column chromatography (40 g, silica gel, petroleum ether / (ethyl acetate + 30% ethanol), gradient, 91:9~33:66 (v / v)) to obtain the title compound as a pale yellow solid (350 mg, 1.08 mmol, yield 7%). MS(ES+)m / z 325.0[M+H].

[0189] Step 5: 2-[2-(2-chloro-4-pyridyl)ethinyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carbonitrile (Int-85)

[0190] 2-iodo-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carbonitrile (Int-83) (350 mg, 1.08 mmol) was dissolved in DMF (5 mL), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (44 mg, 0.05 mmol), copper(I) iodide (6.2 mg, 0.03 mmol), and triethylamine (0.45 mL, 3.24 mmol) were added under argon. The mixture was stirred at 70°C for 1 hour. Then, 2-chloro-4-ethynylpyridine (Int-84) (297 mg, 2.2 mmol) was added. The mixture was stirred at 70°C for a further 2 hours. After cooling, the mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (24 g, silica gel, petroleum ether / (ethyl acetate + 30% ethanol), gradient, 91:9~50:50 (v / v)) to obtain the title compound as a pale yellow solid (210 mg, 0.63 mmol, yield 58%). MS(ES+)m / z 334.0,336.1 [M+H,Cl isotope]. Similar to the synthesis of Int-85, the following intermediates can be synthesized using the procedure outlined in general procedure E, by replacing reagents Int-81 and Int-84 with the reagents listed in the table below: [Table 7] TIFF0007862306000037.tif126170

[0191] Intermediate 100 4-[2-(2-chloro-4-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxylic acid [ka]

[0192] Step 1: Ethyl 5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxylate (Int-97)

[0193] Ethyl 5-methyl-1H-pyrrole-2-carboxylate (Int-95) (1.460 g, 9.53 mmol) was dissolved in toluene (40 mL), and 5-bromo-2-methylpyridine (Int-96) (1.803 g, 10.5 mmol), copper(I) iodide (726 g, 3.8 mmol), (1s,2s)-(+)-N,N'-dimethylcyclohexane-1,2-diamine (1.085 g, 7.6 mmol), and potassium phosphate (6.06 g, 28.6 mmol) were added. The mixture was degassed with nitrogen for 5 minutes and stirred at 120°C for 16 hours. After cooling, the mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (100 g, silica gel, petroleum ether / ethyl acetate, gradient, 99:1~75:25 (v / v)) to obtain the title compound as a pale yellow oily substance (460 mg, 1.88 mmol, yield 19%). MS(ES+)m / z 245.2[M+H].

[0194] Step 2: Ethyl 4-iodo-5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxylate (Int-98)

[0195] Ethyl 5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxylate (Int-97) (300 mg, 1.23 mmol) was dissolved in dichloromethane (5 mL), the solution was cooled to -10°C, and N-iodosuccinimide (553 mg, 2.46 mmol) was added gradually. The mixture was stirred at -10°C for 2 hours, then at 25°C for 2 hours. Water (15 mL) was then added, and after phase separation, the aqueous phase was extracted with dichloromethane (3 × 15 mL). The combined organic layers were dried (with sodium sulfate), filtered, and concentrated under vacuum to obtain the crude title compound (520 mg) as a dark brown oily substance, which was used in the next step without further purification. MS(ES+)m / z 371.0[M+H].

[0196] Step 3: Ethyl 4-[2-(2-chloro-4-pyridyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxylate (Int-99)

[0197] Ethyl 4-iodo-5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxylate (Int-98) (300 mg, 0.81 mmol) was dissolved in DMF (5 mL), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (33 mg, 0.04 mmol), copper(I) iodide (4.6 mg, 24 μmol), and triethylamine (0.34 mL, 2.43 mmol) were added. The mixture was degassed and stirred at 80°C for 1 hour. Then, 2-chloro-4-ethynylpyridine (Int-84) (167 mg, 1.22 mmol) was added, and the mixture was stirred for a further 2 hours at 80°C. After cooling, the mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (50 g, silica gel, petroleum ether / ethyl acetate, gradient, 91:9~50:50 (v / v)) to obtain the title compound as a pale yellow oily substance (157 mg, 0.41 mmol, yield 51%). MS(ES+)m / z 380.2[M+H].

[0198] Step 4: 4-[2-(2-chloro-4-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxylic acid (Int-100)

[0199] Ethyl 4-[2-(2-chloro-4-pyridyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxylate (Int-99) (157 mg, 0.41 mmol) was dissolved in THF (2 mL), and lithium hydroxide (2 M in water, 2.0 mL, 4 mmol) was added. The mixture was stirred at 25°C for 16 hours. Then, water (5 mL) was added, and the organic solvent was removed under vacuum. The resulting mixture was acidified to pH 5 by adding 2N hydrochloric acid aqueous solution, extracted with ethyl acetate (5 × 20 mL), and the combined organic layers were dried (sodium sulfate), filtered, and concentrated under vacuum. The crude product, a yellow solid (85 mg, 0.24 mmol, yield 59%), was used in the next step without further purification. MS(ES+)m / z 352.0[M+H]. [Examples]

[0200] Example 1 4-((2-chloro-3-methylpyridine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide [ka]

[0201] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (141 mg, 587 μmol) and 2-chloro-4-iodo-3-methylpyridine (164 mg, 646 μmol) were dissolved in DMF (6 mL), and triethylamine (178 mg, 245 μL, 1.76 mmol) and bis(triphenylphosphine)palladium(II) dichloride (33 mg, 46.9 μmol) were added under argon at 0°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (4.5 mg, 23.5 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0°C for 3 hours and then warmed to room temperature within 1 hour. The reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was back-extracted with dichloromethane (30 mL). The combined organic layers were washed with water (80 mL) and brine (80 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under vacuum. The crude product was adsorbed onto isolate HM-N and purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100~5:95 (v / v)), followed by crystallization from dichloromethane / tert-butyl methyl ether to obtain the title compound as a grayish-white solid (89 mg, 243 μmol, yield 69%). HPLC (method LC-MS_fastgradient) R =1.04 minutes. 1 H NMR(CDCl3,300MHz):δ 2.20(s,3H),2.60(s,3H),2.67(s,3H),5.31(br s,1H),7.11(br s,1H),7.30-7.37(m,2H),7.52(dd,J=2.6,8.1Hz,1H),8.21(d,J=5.0Hz,1H),8.40(s,1H).MS(ES+)m / z 366.2,368.2[M+H,Cl isotope].

[0202] Example 2 4-((2-chloro-3-fluoropyridine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide [ka]

[0203] A solution of methyl 4-((2-chloro-3-fluoropyridine-4-yl)ethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxylate (Int-28) (310 mg, 806 μmol) in ammonia (7N in MeOH) (11.5 ml, 80.6 mmol) was stirred at 70°C in a pressure tube for 6 hours. The reaction mixture was then concentrated under vacuum, and the residue was adsorbed onto isolation HM-N. Purification was performed by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100~5:95 (v / v)), followed by grinding in dichloromethane / tert-butyl methyl ether to obtain the title compound as a white solid (126 mg, 341 μmol, yield 42%). HPLC (Method LC-MS_fastgradient) R =1.06 minutes. 1 H NMR(d6-DMSO,300MHz):δ 2.14(s,3H),2.56(s,3H),7.42(d,J=8.1Hz,1H),7.48(br m / z 370.2,372.1[M+H,Cl isotope].

[0204] Example 3 4-[2-(5-chlorothiophen-3-yl)ethinyl]-5-methyl-1-(6-methylpyridine-3-yl)imidazole-2-carboxamide [ka]

[0205] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (80 mg, 333 μmol) and 2-chloro-4-iodothiophene (98 mg, 400 μmol) were dissolved in DMF (3 mL), and triethylamine (101 mg, 139 μL, 0.99 mmol) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 33 μmol) were added under argon at 23 °C. The flask was evacuated and purged with argon. Then, copper(I) iodide (3.2 mg, 16.6 μmol) was added to obtain a pale brown solution. The resulting mixture was stirred at 23 °C for 16 hours. The reaction mixture was extracted with water (15 mL) and dichloromethane (15 mL), and the aqueous layer was back-extracted with dichloromethane (15 mL). The combined organic layers were dried (with sodium sulfate), filtered, and the filtrate was concentrated under vacuum. The crude product was adsorbed onto HM-N for separation and purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100~10:90 (v / v)) to obtain the title compound as a grayish-white solid (80 mg, 224 μmol, yield 67%). HPLC (method LCMS_fastgradient) R =1.17 minutes. 1 H NMR(CDCl3,300MHz):δ 2.15(s,3H),2.66(s,3H),5.25(br s,1H),7.02(d,J=1.6Hz,1H),7.12(br s,1H),7.28-7.33(m,2H),7.50(dd,J=2.6,8.3Hz,1H),8.38(d,J=2.2Hz,1H).MS(ES+)m / z 357.2,359.1[M+H,Cl isotope].

[0206] Example 4 4-[2-(3-chlorophenyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide [ka]

[0207] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (600 mg, 2.5 mmol) and 1-chloro-3-iodobenzene (774 mg, 3.25 mmol) were dissolved in DMF (15 mL), and triethylamine (758 mg, 1.94 mL, 7.5 mmol) and bis(triphenylphosphine)palladium(II) dichloride (140 mg, 200 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (19 mg, 100 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 4 hours. The reaction mixture was extracted with water (110 mL) and dichloromethane (110 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 110 mL). The combined organic layer was washed with brine (100 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (40 g, silica gel, isopropanol / dichloromethane, gradient 0:100~20:80 (v / v)) to obtain the title compound as a grayish-white solid (449 mg, 1.28 mmol, yield 51%). HPLC (Method LCMS_fastgradient) R =1.18 minutes. 1 H NMR(CDCl3,300MHz):δ 2.18(s,3H),2.67(s,3H),5.27(br s,1H),7.13(br s,1H),7.27-7.35(m,3H),7.44(ddd,J=1.6,1.6,7.0Hz,1H),7.49-7.55(m,2H),8.38(d,J=2.2Hz,1H).MS(ES+)m / z 351.2,353.2[M+H,Cl isotope].

[0208] Example 5 4-((3-cyanophenyl)ethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide [ka]

[0209] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (69 mg, 287 μmol) and 3-iodobenzonitrile (78.9 mg, 345 μmol) were dissolved in DMF (2 mL), and triethylamine (87.2 mg, 120 μl, 862 μmol) and bis(triphenylphosphine)palladium(II) dichloride (16.1 mg, 23 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (2.2 mg, 11.5 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 2 hours. The reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was back-extracted with dichloromethane (30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100~5:95 (v / v)) to obtain the title compound as a pale yellow solid (47 mg, 138 μmol, yield 48%). HPLC (Method LCMS_fastgradient) R =1.03 minutes. 1 H NMR(CDCl3,300MHz):δ 2.19(s,3H),2.67(s,3H),5.29(br s,1H),7.12(br s,1H),7.32(d,J=8.3Hz,1H),7.44-7.55(m,2H),7.62(ddd,J=1.4,1.4,7.9Hz,1H),7. 76(ddd,J=1.4,1.4,7.9Hz,1H),7.80-7.84(m,1H),8.40(d,J=2.4Hz,1H).MS(ES+)m / z 342.2[M+H].

[0210] Example 6 4-(2-chloropyridine-4-ylethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxylic acid amide [ka]

[0211] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (217 mg, 903 μmol) and 2-chloro-4-iodopyridine (273 mg, 1.08 mmol) were dissolved in DMF (5 mL), and triethylamine (274 mg, 378 μl, 2.71 mmol) and bis(triphenylphosphine)palladium(II) dichloride (32.3 mg, 45.2 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (5.2 mg, 27.1 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 3 hours. After warming to room temperature, the reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 30 mL). The combined organic layer was washed with water (80 mL) and brine (80 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100~5:95 (v / v)) to obtain the title compound as a pale yellow solid (257 mg, 731 μmol, yield 81%). HPLC (Method LCMS_fastgradient) R =1.00 minutes. 1 H NMR(CDCl3,300MHz):δ 2.20(s,3H),2.67(s,3H),5.32(br s,1H),7.10(br s,1H),7.29-7.36(m,2H),7.44(s,1H),7.51(dd,J=2.6,8.3Hz,1H),8.35-8.42(m,2H).MS(ES+)m / z 352.2,354.1[M+H,Cl isotope].

[0212] Example 7 4-((2-chloro-5-fluoropyridine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide [ka]

[0213] A solution of methyl 4-((2-chloro-5-fluoropyridine-4-yl)ethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxylate (Int-29) (41 mg, 107 μmol) in ammonia (7N in MeOH) (3 ml, 21 mmol) was stirred at 85°C in a pressure tube for 20 hours. The reaction mixture was then concentrated under vacuum, and the residue was purified by preparative HPLC (YMC-Actus Triart C18, 100 × 30 mm × 5 μm, eluted with acetonitrile / (water + 0.1% triethylamine), gradient 20:80~98:2 v / v), followed by lyophilization to obtain the title compound as a white solid (4 mg, 11 μmol, yield 10%). HPLC (Method LCMS_fastgradient) R =1.05 minutes. 1 H NMR(CDCl3,300MHz):δ 2.20(s,3H),2.67(s,3H),5.33(br s,1H),7.12(br s,1H),7.33(d,J=8.3Hz,1H),7.45(d,J=4.8Hz,1H),7.51(dd,J=2.6,8.3Hz,1H),8.29(s,1H),8.40(d,J=2.4Hz,1H).MS(ES+)m / z 370.2,372.2[M+H,Cl isotope].

[0214] Example 8 4-((3-methoxyphenyl)ethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide [ka]

[0215] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (73 mg, 304 μmol) and 1-iodo-3-methoxybenzene (85 mg, 43 μl, 365 μmol) were dissolved in DMF (4 mL), and triethylamine (92 mg, 127 μl, 911 μmol) and bis(triphenylphosphine)palladium(II) dichloride (17.1 mg, 24.3 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (2.3 mg, 12 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 1 hour. After stirring at room temperature for a further 1 hour, the reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 30 mL). The combined organic layer was washed with water (80 mL) and brine (80 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100~10:90 (v / v)) to obtain the title compound as a grayish-white solid (58 mg, 167 μmol, yield 55%). HPLC (Method LCMS_fastgradient) R =1.10 minutes. 1 H NMR(CDCl3,300MHz):δ 2.18(s,3H),2.66(s,3H),3.82(s,3H),5.26(br s,1H),6.91(ddd,J=1.0,2.6,8.3Hz,1H),7.07-7.11(m,1H),7.12-7.19(m,2H),7 .22-7.35(m,2H),7.51(dd,J=2.6,8.3Hz,1H),8.39(d,J=2.2Hz,1H).MS(ES+)m / z 347.2[M+H].

[0216] Example 9 4-[2-(4-chlorophenyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide [ka]

[0217] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (100 mg, 420 μmol) and 1-chloro-4-iodobenzene (109 mg, 460 μmol) were dissolved in DMF (5 mL), and triethylamine (170 μl, 1.25 mmol) and bis(triphenylphosphine)palladium(II) dichloride (14.6 mg, 20 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (2.3 mg, 10 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 3 hours. The crude reaction mixture was directly purified by preparative HPLC (YMC-Actus Triart C18, 100 × 30 mm × 5 μm, eluted with acetonitrile / (water + 0.1% triethylamine), gradient 20:80~98:2 v / v), followed by lyophilization to obtain the title compound as a white solid (66 mg, 190 μmol, yield 45%). 1 H NMR(DMSO-d6,400MHz):δ 2.11(s,3H),2.57(s,3H),7.42(br s,1H),7.42(d,J=8.2Hz,1H),7.47-7.53(m,2H),7.54-7.60(m,2H),7.74(dd,J=2.6,8.2Hz,1H),7.94(br s,1H),8.42(d,J=2.4Hz,1H).MS(ES+)m / z 351.0,353.1[M+H,Cl isotope].

[0218] Example 10 5-Methyl-1-(6-methylpyridine-3-yl)-4-(m-tolylethinyl)-1H-imidazole-2-carboxamide [ka]

[0219] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (81 mg, 337 μmol) and 1-iodo-3-methylbenzene (81 mg, 371 μmol) were dissolved in DMF (2 mL), and triethylamine (102 mg, 141 μl, 1.01 mmol) and bis(triphenylphosphine)palladium(II) dichloride (19 mg, 27 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (2.3 mg, 10 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 3 hours. After stirring at room temperature for a further 1 hour, the reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 30 mL). The combined organic layer was washed with water (80 mL) and brine (80 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100~5:95 (v / v)) to obtain the title compound as a pale yellow solid (39 mg, 118 μmol, yield 35%). HPLC (Method LCMS_fastgradient) R =1.17 minutes. 1 H NMR(CDCl3,300MHz):δ 2.18(s,3H),2.35(s,3H),2.66(s,3H),5.30(br s,1H),7.13-7.19(m,2H),7.24(dd,J=7.2,7.2Hz,1H),7.31(d,J=8.3Hz,1H),7. 34-7.40(m,2H),7.51(dd,J=2.4,8.2Hz,1H),8.39(d,J=2.4Hz,1H).MS(ES+)m / z 331.3[M+H].

[0220] Example 11 5-Methyl-1-(6-methylpyridine-3-yl)-4-((2-(trifluoromethyl)pyridine-4-yl)ethinyl)-1H-imidazole-2-carboxamide [ka]

[0221] A solution of methyl 5-methyl-1-(6-methylpyridine-3-yl)-4-((2-(trifluoromethyl)pyridine-4-yl)ethynyl)-1H-imidazole-2-carboxylate (Int-31) (15 mg, 37 μmol) in ammonia (7N in MeOH) (1.1 ml, 7.7 mmol) was stirred at 80°C in a pressure tube for 16 hours. The reaction mixture was then concentrated under vacuum, and the residue was purified by preparative HPLC (YMC-Actus Triart C18, 100 × 30 mm × 5 μm, eluted with acetonitrile / (water + 0.1% triethylamine), gradient 20:80~98:2 v / v), followed by lyophilization to obtain the title compound as a white solid (6 mg, 16 μmol, yield 41%). HPLC (Method LCMS_fastgradient) R =1.06 minutes. 1 H NMR(CDCl3,300MHz):δ 2.22(s,3H),2.67(s,3H),5.30(br s,1H),7.10(br s,1H),7.33(d,J=8.3Hz,1H),7.52(dd,J=2.5,8.2Hz,1H),7.58(dd,J=1.0,5.0 Hz,1H),7.78(s,1H),8.40(d,J=2.4Hz,1H),8.73(d,J=5.0Hz,1H).MS(ES+)m / z 386.2[M+H].

[0222] Example 12 4-[2-(2-fluoro-4-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide [ka]

[0223] A solution of methyl 4-[2-(2-fluoro-4-pyridyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxylate (Int-34) (28 mg, 80 μmol) in ammonia (7N in MeOH) (2.3 ml, 16 mmol) was stirred in a pressure tube at 85°C for 20 hours. The reaction mixture was then concentrated under vacuum, and the residue was purified by preparative HPLC (YMC-Actus Triart C18, 100 × 30 mm × 5 μm, eluted with acetonitrile / (water + 0.1% triethylamine), gradient 20:80~98:2 v / v), followed by lyophilization to obtain the title compound as a white solid (14 mg, 40 μmol, yield 50%). HPLC (Method LCMS_fastgradient) R =0.94 minutes. 1 H NMR(CDCl3,300MHz):δ 2.20(s,3H),2.67(s,3H),5.30(br s,1H),7.03-7.06(m,1H),7.11(br s,1H),7.27-7.36(m,2H),7.52(dd,J=2.5,8.2Hz,1H),8.22(d,J=5.2Hz,1H),8.40(d,J=2.4Hz,1H).MS(ES+)m / z 336.2[M+H].

[0224] Example 13 4-(benzo[d][1,3]dioxol-4-ylethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide [ka]

[0225] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (92 mg, 383 μmol) and 4-iodobenzo[d][1,3]dioxol (114 mg, 459 μmol) were dissolved in DMF (2 mL), and triethylamine (116 mg, 160 μl, 1.15 mmol) and bis(triphenylphosphine)palladium(II) dichloride (21.5 mg, 30.6 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (2.9 mg, 15 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 2 hours. The reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed with water (80 mL) and brine (80 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100~5:95 (v / v)) to obtain the title compound as a pale yellow solid (78 mg, 216 μmol, yield 56%). HPLC (Method LCMS_fastgradient) R =1.08 minutes. 1 H NMR(CDCl3,300MHz):δ 2.18(s,3H),2.66(s,3H),5.43(br s,1H),6.06(s,2H),6.76-6.84(m,2H),6.95-7.02(m,1H),7.27-7.34(m,2H),7.50(dd,J=2.5,8.2Hz,1H),8.38(d,J=2.4Hz,1H).MS(ES+)m / z 361.2[M+H].

[0226] Example 14 4-((6-chloropyridine-2-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide [ka]

[0227] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (60 mg, 250 μmol) and 2-chloro-6-iodopyridine (65.8 mg, 275 μmol) were dissolved in DMF (2 mL), and triethylamine (75.8 mg, 104 μl, 749 μmol) and bis(triphenylphosphine)palladium(II) dichloride (14 mg, 20 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (1.9 mg, 10 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 3 hours. After stirring at 23°C for a further 1 hour, the reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 30 mL). The combined organic layer was washed with water (80 mL) and brine (80 mL), dried, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by preparative HPLC (YMC-Actus Triart C18, 100 × 30 mm × 5 μm, eluted with acetonitrile / (water + 0.1% triethylamine), gradient 20:80~98:2 v / v), subsequently lyophilized, and crystallized from dichloromethane / tert-butyl methyl ether / n-heptane to obtain the title compound as a white solid (29 mg, 82 μmol, yield 33%). HPLC (Method LCMS_fastgradient) R =0.99 minutes. 1 H NMR(DMSO-d6,300MHz):δ 2.12(s,3H),2.56(s,3H),7.41(d,J=8.3Hz,1H),7.46(br s,1H),7.54(dd,J=0.7,8.1Hz,1H),7.65(dd,J=0.8,7.6Hz,1H),7.76(dd,J=2.5,8.2Hz,1H),7.92(dd,J=7.7,8.1Hz,1H),7.98(br s,1H),8.44(d,J=2.4Hz,1H).MS(ES+)m / z 352.1,354.1[M+H,Cl isotope].

[0228] Example 15 4-((2-chloropyrimidine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide [ka]

[0229] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (49 mg, 204 μmol) and 2-chloro-4-iodopyrimidine (54 mg, 224 μmol) were dissolved in DMF (2 mL), and triethylamine (62 mg, 85 μl, 612 μmol) and bis(triphenylphosphine)palladium(II) dichloride (7.2 mg, 10.2 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (1.2 mg, 6.1 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 3 hours. After stirring at 23°C for a further 1 hour, the reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed with water (80 mL) and brine (80 mL), dried with sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100~5:95 (v / v)) to obtain the title compound as a pale yellow solid (27 mg, 76 μmol, yield 37%). HPLC (Method LCMS_fastgradient) R =0.90 minutes. 1 H NMR(CDCl3,300MHz):δ 2.23(s,3H),2.67(s,3H),5.30(br s,1H),7.09(br s,1H),7.33(d,J=8.3Hz,1H),7.42(d,J=5.0Hz,1H),7.51(dd,J=2.5,8.2Hz,1H),8 .39(d,J=2.4Hz,1H),8.61(d,J=5.0Hz,1H).MS(ES+)m / z353.2,355.1[M+H,Cl isotope].

[0230] Example 16 4-((3-fluoropyridine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide [ka]

[0231] A solution of methyl 4-((3-fluoropyridine-4-yl)ethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxylate (Int-30) (101 mg, 288 μmol) in ammonia (7N in MeOH) (4.1 ml, 28.7 mmol) was stirred in a pressure tube at 85°C for 20 hours. The reaction mixture was then concentrated under vacuum, and the residue was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100~5:95 (v / v)) to obtain the title compound as a pale yellow solid (35 mg, 104 μmol, yield 36%). HPLC (Method LCMS_fastgradient) R =0.89 minutes. 1 H NMR(DMSO-d6,300MHz):δ 2.13(s,3H),2.56(s,3H),7.42(d,J=8.3Hz,1H),7.47(br s,1H),7.66(dd,J=4.9,6.1Hz,1H),7.76(dd,J=2.6,8.3Hz,1H),8.02(br s,1H),8.44(d,J=2.4Hz,1H),8.49(dd,J=1.1,4.9Hz,1H),8.70(d,J=1.2Hz,1H).MS(ES+)m / z 336.1[M+H].

[0232] Example 17 4-[2-(5-chloro-3-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide [ka]

[0233] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (100 mg, 420 μmol) and 3-chloro-5-iodopyridine (110 mg, 461 μmol) were dissolved in DMF (5 mL), and triethylamine (170 μL, 1.25 mmol) and bis(triphenylphosphine)palladium(II) dichloride (14.6 mg, 20 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (2.4 mg, 12 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 3 hours. The crude reaction mixture was directly purified by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates with a ratio of 70:30 to 10:90 v / v), followed by lyophilization to obtain the title compound as a pale yellow solid (55 mg, 160 μmol, yield 38%). 1 H NMR (DMSO-d6,400MHz):δ 2.13(s,3H),2.56(s,3H),7.41(d,J=8.3Hz,1H),7.44(br s,1H),7.74(dd,J=2.6,8.2Hz,1H),7.95(br s,1H),8.19(dd,J=2.0,2.0Hz,1H),8.42(d,J=2.6Hz,1H),8.65(d,J=2.4Hz,1H),8.71(d,J=1.7Hz,1H).MS(ES+)m / z 352.0,354.0[M+H,Cl isotope].

[0234] Example 18 4-((4-chloropyridine-2-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide [ka]

[0235] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (73 mg, 304 μmol) and 4-chloro-2-iodopyridine (87 mg, 365 μmol) were dissolved in DMF (4.5 mL), and triethylamine (92 mg, 127 μL, 911 μmol) and bis(triphenylphosphine)palladium(II) dichloride (17 mg, 24 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (2.3 mg, 12 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 1 hour. After stirring at 23°C for a further 1 hour, the reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 30 mL). The combined organic layer was washed with water (80 mL) and brine (80 mL), dried with sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100~10:90 (v / v)) to obtain the title compound as a grayish-white solid (50 mg, 142 μmol, yield 47%). HPLC (Method LCMS_fastgradient) R =0.98 minutes. 1 H NMR(CDCl3,300MHz):δ 2.21(s,3H),2.66(s,3H),5.32(br s,1H),7.14(br s,1H),7.25-7.34(m,2H),7.51(dd,J=2.6,8.1Hz,1H),7.55-7.61(m,1H),8.39(d,J=2.2Hz,1H),8.51(d,J=5.2Hz,1H).MS(ES+)m / z 352.2,354.1[M+H,Cl isotope].

[0236] Example 19 4-((6-chloropyrimidine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide [ka]

[0237] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (54 mg, 225 μmol) and 4-chloro-6-iodopyrimidine (59.4 mg, 247 μmol) were dissolved in DMF (2 mL), and triethylamine (68 mg, 94 μL, 674 μmol) and bis(triphenylphosphine)palladium(II) dichloride (7.9 mg, 11 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (1.3 mg, 6.7 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 3 hours. After stirring at 23°C for a further 1 hour, the reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed with water (80 mL) and brine (80 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under vacuum. The crude product was adsorbed onto HM-N for separation and purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100~5:95 (v / v)) to obtain the title compound as a pale yellow solid (31 mg, 88 μmol, yield 39%). HPLC (Method LCMS_fastgradient) R =0.92 minutes. 1 H NMR(CDCl3,300MHz):δ 2.23(s,3H),2.67(s,3H),5.32(br s,1H),7.11(br s,1H),7.32(d,J=8.3Hz,1H),7.48-7.56(m,2H),8.39(d,J=2.2Hz,1H),8.97(d,J=1.2Hz,1H).MS(ES+)m / z 353.1,355.1[M+H,Cl isotope].

[0238] Example 20 5-Methyl-1-(6-methyl-3-pyridyl)-4-[2-(3-pyridyl)ethinyl]imidazole-2-carboxamide [ka]

[0239] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (30 mg, 120 μmol) and 3-iodopyridine (26.9 mg, 130 μmol) were dissolved in DMF (5 mL), and triethylamine (50 μL, 370 μmol) and bis(triphenylphosphine)palladium(II) dichloride (4.4 mg, 6 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (0.7 mg, 3.7 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 3 hours. The crude reaction mixture was purified directly by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates with a ratio of 70:30 to 10:90 v / v) and lyophilization, followed by preparative TLC (silica gel, eluted with ethyl acetate) to obtain the title compound as a white solid (7 mg, 20 μmol, yield 17%). 1 H NMR(DMSO-d6,400MHz):δ 2.12(s,3H),2.56(s,3H),7.38-7.50(m,3H),7.74(dd,J=2.4,8.2Hz,1H),7.94-8.02 (m,2H),8.42(d,J=2.3Hz,1H),8.59(dd,J=1.3,4.8Hz,1H),8.75(s,1H).MS(ES+)m / z 318.2[M+H].

[0240] Example 21 5-Methyl-1-(6-methyl-3-pyridyl)-4-[2-(4-pyridyl)ethinyl]imidazole-2-carboxamide [ka]

[0241] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (73 mg, 304 μmol) and 4-iodopyridine (71.4 mg, 334 μmol) were dissolved in DMF (2 mL), and triethylamine (92.2 mg, 127 μl, 991 μmol) and bis(triphenylphosphine)palladium(II) dichloride (11 mg, 16 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (1.7 mg, 9 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 3 hours. After stirring at 23°C for a further 1 hour, the reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 30 mL). The combined organic layer was washed with water (80 mL) and brine (80 mL), dried, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by preparative HPLC (YMC-Actus Triart C18, 100 × 30 mm × 5 μm, eluted with acetonitrile / (water + 0.1% triethylamine), gradient 20:80~98:2 v / v) to obtain the title compound as a white solid (36 mg, 113 μmol, yield 37%). HPLC (Method LCMS_fastgradient) R =0.69 minutes. 1 H NMR(CDCl3,300MHz):δ 2.20(s,3H),2.66(s,3H),5.36(br s,1H),7.13(br s,1H),7.32(d,J=8.1Hz,1H),7.37-7.43(m,2H),7.51(dd,J=2.6,8.3Hz,1H),8.39(d,J=2.2Hz,1H),8.61(d,J=5.8Hz,1H).MS(ES+)m / z 318.2[M+H].

[0242] Example 22 5-Methyl-1-(6-methylpyridine-3-yl)-4-((2-methylpyridine-4-yl)ethinyl)-1H-imidazole-2-carboxamide [ka]

[0243] 4-Ethinyl-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-9) (49 mg, 204 μmol) and 4-iodo-2-methylpyridine (67 mg, 306 μmol) were dissolved in DMF (2 mL), and triethylamine (62 mg, 85 μL, 612 μmol) and bis(triphenylphosphine)palladium(II) dichloride (14 mg, 20 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (3.9 mg, 20 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 3 hours. After stirring at room temperature for a further 1 hour, the reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 30 mL). The combined organic layer was washed with water (80 mL) and brine (80 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under vacuum. The crude product was adsorbed onto separation HM-N and purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100~5:95 (v / v)) to obtain the title compound as a pale yellow solid (23 mg, 69 μmol, yield 34%). HPLC (Method LCMS_fastgradient) R =0.65 minutes. 1 H NMR(CDCl3,300MHz):δ 2.19(s,3H),2.57(s,3H),2.66(s,3H),5.30(br s,1H),7.12(br s,1H),7.18-7.35(m,3H),7.51(dd,J=2.5,8.2Hz,1H),8.39(d,J=2.0Hz,1H),8.50(br s,1H).MS(ES+)m / z 332.1[M+H].

[0244] Example 23 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(5-methylpyrazine-2-yl)imidazole-2-carboxamide [ka]

[0245] 4-Ethinyl-5-methyl-1-(5-methylpyrazine-2-yl)imidazole-2-carboxamide (Int-55) (140 mg, 580 μmol) was dissolved in DMF (4 mL), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (23.7 mg, 30 μmol), copper(I) iodide (3.3 mg, 20 μmol), and triethylamine (0.24 mL, 1.74 mmol) were added. The reaction mixture was stirred at 80°C for 1 hour. Then, 2-chloro-4-iodo-3-methylpyridine (147 mg, 580 μmol) was added, and the reaction mixture was stirred at 80°C for a further 2 hours. After cooling, the mixture was directly purified by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates with a ratio of 70:30 to 10:90 v / v), and after lyophilization, the title compound was obtained as a white solid (50 mg, 140 μmol, yield 23%). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.21(s,3H),2.53-2.55(m,3H),2.62(s,3H),7.46-7.65(m,2H),8.13(s,1 H),8.29(d,J=4.9Hz,1H),8.59(s,1H),8.75(d,J=1.1Hz,1H).MS(ES+)m / z 367[M+H].

[0246] Example 24 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(6-methylpyridazine-3-yl)imidazole-2-carboxamide [ka]

[0247] 2-Chloro-4-iodo-3-methylpyridine (63 mg, 250 μmol) was dissolved in DMF (2 mL), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (10.1 mg, 12 μmol), copper(I) iodide (1.4 mg, 7 μmol), and triethylamine (100 μL, 0.72 mmol) were added. The resulting mixture was stirred at 70°C for 1 hour. Then, 4-ethynyl-5-methyl-1-(6-methylpyridazin-3-yl)imidazole-2-carboxamide (Int-56) (60 mg, 250 μmol) was added, and the reaction mixture was stirred at 70°C for a further 2 hours. After cooling, the mixture was directly purified by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates with a ratio of 70:30 to 10:90 v / v), and after lyophilization, the title compound was obtained as a pale yellow solid (18 mg, 49 μmol, 20% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.19(s,3H),2.54(s,3H),2.74(s,3H),7.51-7.59(m,2H),7.81-7.89(m,2H),8.11-8.17(m,1H),8.27-8.30(m,1H).MS(ES+)m / z 367[M+H].

[0248] Example 25 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(5-methyl-3-pyridyl)imidazole-2-carboxamide [ka]

[0249] 4-Ethinyl-5-methyl-1-(5-methyl-3-pyridyl)imidazole-2-carboxamide (Int-62) (70 mg, 290 μmol) was dissolved in DMF (0.5 mL), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (11.9 mg, 14 μmol), copper(I) iodide (2.8 mg, 15 μmol), triethylamine (88 mg, 0.87 mmol), and 2-chloro-4-iodo-3-methylpyridine (89 mg, 0.35 mmol) were added. The resulting mixture was stirred at 70°C for 1 hour. After cooling, the mixture was filtered, and the filtrate was separated and purified directly by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates with a ratio of 70:30 to 10:90 v / v). After lyophilization, the title compound was obtained as a yellow solid (7 mg, 20 μmol, yield 6%). 1 H NMR(400MHz,CDCl3)δ ppm 2.21(s,3H),2.46(s,3H),2.61(s,3H),5.32(brs,1H),7.13(brs,1H),7.35(d,J=4.8Hz, 1H),7.45(s,1H),8.23(d,J=4.8Hz,1H),8.35(d,J=2.0Hz,1H),8.60(s,1H).MS(ES+)m / z 366[M+H].

[0250] Example 26 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-(6-chloro-3-pyridyl)-5-methylimidazole-2-carboxamide [ka]

[0251] 2-Chloro-4-iodo-3-methylpyridine (77.8 mg, 0.310 mmol) was dissolved in DMF (2 mL), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (12.5 mg, 15 μmol), copper(I) iodide (1.7 mg, 9 μmol), and triethylamine (130 μL, 0.92 mmol) were added. The resulting mixture was stirred at 70°C for 1 hour. Then, 1-(6-chloro-3-pyridyl)-4-ethynyl-5-methylimidazole-2-carboxamide (Int-64) (80 mg, 310 μmol) was added, and the reaction mixture was stirred at 70°C for a further 3 hours. After cooling, the mixture was directly purified by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates with a ratio of 70:30 to 10:90 v / v), and after lyophilization, the title compound was obtained as a yellow solid (23 mg, 60 μmol, yield 19%). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.17(s,3H),2.53(br s,3H),7.50-7.54(m,2H),7.73(d,J=8.6Hz,1H),8.01(dd,J=8.4,2.7Hz,1H),8.07(s,1H),8.28(d,J=5.1Hz,1H),8.51(d,J=2.7Hz,1H).MS(ES+)m / z 386[M+H].

[0252] Example 27 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-(6-methoxy-3-pyridyl)-5-methylimidazole-2-carboxamide [ka]

[0253] 4-Ethinyl-1-(6-methoxy-3-pyridyl)-5-methylimidazole-2-carboxamide (Int-65) (60 mg, 230 μmol) was dissolved in DMF (1 mL), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (9.5 mg, 12 μmol), copper(I) iodide (2.2 mg, 11 μmol), triethylamine (71 mg, 0.70 mmol), and 2-chloro-4-iodo-3-methylpyridine (71 mg, 0.28 mmol) were added. The resulting mixture was stirred at 70°C for 4 hours. After cooling, the mixture was filtered, and the filtrate was separated and purified directly by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates with a ratio of 70:30 to 10:90 v / v). After lyophilization, the title compound was obtained as a yellow solid (10 mg, 26 μmol, yield 11%). 1 H NMR(400MHz,CDCl3)δ ppm 2.22(s,3H),2.61(s,3H),4.01(s,3H),5.32(br s,1H),6.90(d,J=8.8Hz,1H),7.14(br s,1H),7.34(d,J=4.8Hz,1H),7.49(dd,J=4.8,2.8Hz,1H),8.06(d,J=2.8Hz,1H),8.22(d,J=4.8Hz,1H).MS(ES+)m / z 382[M+H].

[0254] Example 28 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(5-methyl-2-pyridyl)imidazole-2-carboxamide [ka]

[0255] 2-chloro-4-iodo-3-methylpyridine (63.3 mg, 0.250 mmol) was dissolved in DMF (1 mL), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (10.2 mg, 12 μmol), copper(I) iodide (1.4 mg, 7 μmol), and triethylamine (100 μL, 0.75 mmol) were added. The resulting mixture was stirred at 70°C for 1 hour. Then, 4-ethynyl-5-methyl-1-(5-methyl-2-pyridyl)imidazole-2-carboxamide (Int-77) (60 mg, 250 μmol) was added, and the reaction mixture was stirred at 70°C for a further 3 hours. After cooling, the mixture was filtered, and the filtrate was separated and purified directly by HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates with a ratio of 70:30 to 10:90 v / v). After lyophilization, the marked compound was obtained as a yellow solid (4 mg, 11 μmol, yield 4%). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.16(s,3H),2.41(s,3H),2.53(br s,3H),7.42-7.49(m,2H),7.53(d,J=5.0Hz,1H),7.85(dd,J=8.1,1.7Hz,1H),8.03(br s,1H),8.28(d,J=4.9Hz,1H),8.41(s,1H).MS(ES+)m / z 366[M+H].

[0256] Example 29 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide [ka]

[0257] 2-Chloro-4-iodo-3-methylpyridine (687 mg, 2.71 mmol) was dissolved in DMF (10 mL), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (92 mg, 110 μmol), copper(I) iodide (13 mg, 70 μmol), and triethylamine (0.94 mL, 6.77 mmol) were added. The resulting mixture was stirred at 70°C for 0.5 hours. Then, 4-ethynyl-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide (Int-66) (700 mg, 2.26 mmol) was added, and the reaction mixture was stirred at 70°C for a further 1 hour. After cooling, the mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (200 g, silica gel, n-heptane / (ethyl acetate + 30% ethanol), gradient 90:10~66:33 (v / v)), followed by grinding with tert-butyl methyl ether to obtain the title compound as a yellow solid (311 mg, 0.88 mmol, yield 38%). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.15(s,3H),2.53(br s,3H),7.50(br s,1H),7.54(d,J=5.0Hz,1H),7.59(dd,J=8.0,4.8Hz,1H),7.91(br d,J=8.1Hz,1H),8.05(br s,1H),8.28(d,J=4.9Hz,1H),8.61(d,J=2.0Hz,1H),8.69(br d,J=4.0Hz,1H).MS(ES+)m / z 352[M+H].

[0258] Example 30 4-[2-(3-chloro-2-methylphenyl)ethynyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide [ka]

[0259] 1-Chloro-3-iodo-2-methylbenzene (179 mg, 0.71 mmol) was dissolved in DMF (2 mL), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (14.4 mg, 18 μmol), copper(I) iodide (2.0 mg, 10 μmol), and triethylamine (150 μL, 1.06 mmol) were added. The resulting mixture was stirred at 70°C for 0.5 hours. Then, 4-ethynyl-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide (Int-66) (80 mg, 350 μmol) was added, and the reaction mixture was stirred at 70°C for a further 1 hour. After cooling, the mixture was filtered, the filtrate was concentrated under vacuum, and purified by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates with a ratio of 70:30 to 10:90 v / v). After lyophilization, the title compound was obtained as a pale yellow solid (29 mg, 83 μmol, yield 23%). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.13(s,3H),2.54(s,3H),7.25-7.32(m,1H),7.43-7.47(m,1H),7.51(t,J=7.5Hz,2H),7.57-7.62( m,1H),7.86-7.95(m,1H),7.98-8.07(m,1H),8.61(d,J=2.3Hz,1H),8.65-8.74(m,1H).MS(ES+)m / z 351[M+H].

[0260] Example 31 4-[2-(2-chloro-4-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxamide [ka]

[0261] 4-[2-(2-chloro-4-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxylic acid (Int-100) (85 mg, 0.24 mmol) was dissolved in THF (4 mL), and N,N'-carbonyldiimidazole (47 mg, 0.29 mmol) was added at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was then cooled to 0°C, and concentrated ammonium hydroxide solution (3.0 mL, 25-28% in water) was added. The resulting mixture was stirred at 0°C for 1 hour, and then at 25°C for 2 hours. Subsequently, the solvent was removed under vacuum, and the residue was purified by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates with a ratio of 70:30 to 10:90 v / v). After lyophilization, the title compound was obtained as a white solid (20 mg, 57 μmol, yield 23%). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.55(s,3H),3.65(s,3H),7.19(br s,1H),7.38(d,J=7.9Hz,1H),7.49-7.59(m,1H),7.68(dd,J=5.0,1.2Hz,1H ),7.82(dd,J=7.9,2.2Hz,1H),7.89(s,1H),8.47-8.59(m,2H).MS(ES+)m / z 351[M+H].

[0262] Example 32 2-[2-(2-chloro-4-pyridyl)ethinyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide [ka]

[0263] 2-[2-(2-chloro-4-pyridyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carbonitrile (Int-85) (350 mg, 1.05 mmol) was dissolved in concentrated sulfuric acid (3.0 mL, 98%, 55 mmol) and stirred at 25°C for 16 hours. Then, 2 N sodium hydroxide aqueous solution was added to adjust the pH to around 8. A precipitate formed, which was filtered off, washed (with tert-butyl methyl ether), and dried under vacuum to obtain the title compound as a grayish-white solid (200 mg, 0.57 mmol, yield 53%). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.55(s,3H),3.65(s,3H),7.19(br s,1H),7.38(d,J=7.9Hz,1H),7.49-7.59(m,1H),7.68(dd,J=5.0,1.2Hz,1H ),7.82(dd,J=7.9,2.2Hz,1H),7.89(s,1H),8.47-8.59(m,2H).MS(ES+)m / z 352[M+H].

[0264] Example 33 2-[2-(3-chloro-2-methylphenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide [ka]

[0265] 2-[2-(2-chloro-3-methyl-4-pyridyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carbonitrile (Int-86) (80 mg, 0.23 mmol) was dissolved in concentrated sulfuric acid (1.0 mL, 98%, 18 mmol) and stirred at 25°C for 1 hour. Then, 2 N sodium hydroxide aqueous solution was added to adjust the pH to around 8. A precipitate formed, which was filtered off, washed (tert-butyl methyl ether), and purified by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates of 70:30 to 10:90 v / v). After lyophilization, the title compound was obtained as formate as a grayish-white solid (29 mg, 70 μmol, yield 30%). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.55(s,3H),2.56(s,3H),3.63(s,3H),7.08-7.20(m,1H),7.34-7.44(m,1H),7.37-7.38(m,1H),7.51-7.62(m,1H),7.52 -7.59(m,1H),7.62-7.68(m,1H),7.75-7.87(m,1H),8.29-8.37(m,1H),8.38-8.44(m,1H),8.47-8.58(m,1H).MS(ES+)m / z 365.9[M+H].

[0266] Example 34 2-[2-(3-chlorophenyl)ethinyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide [ka]

[0267] 2-[2-(3-chlorophenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carbonitrile (Int-87) (110 mg, 0.33 mmol) was dissolved in concentrated sulfuric acid (2.0 mL, 98%, 37 mmol) and stirred at 25°C for 1 hour. Then, 2 N sodium hydroxide aqueous solution was added to adjust the pH to around 8. A precipitate formed, which was filtered off, washed (tert-butyl methyl ether), and purified by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates of 70:30 to 10:90 v / v). After lyophilization, the title compound was obtained as a grayish-white solid (41 mg, 120 μmol, yield 35%). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.55(s,3H),3.62(s,3H),7.09-7.18(m,1H),7.38(d,J=8.1Hz,1H),7.48-7.56(m,2H),7. 56-7.61(m,1H),7.65(d,J=7.6Hz,1H),7.78-7.84(m,2H),8.51-8.55(m,1H).MS(ES+)m / z 350.8[M+H].

[0268] Example 35 2-[2-(3-chloro-2-methylphenyl)ethynyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamide forate [ka]

[0269] 2-[2-(3-chloro-2-methylphenyl)ethynyl]-1-methyl-5-(3-pyridyl)imidazole-4-carbonitrile (Int-88) (180 mg, 0.54 mmol) was dissolved in concentrated sulfuric acid (1.0 mL, 98%, 18 mmol) and stirred at 0°C for 1.5 hours. Then, 2 N sodium hydroxide aqueous solution was added to adjust the pH to around 8. A precipitate formed, which was filtered off, washed (tert-butyl methyl ether), and purified by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates of 70:30 to 10:90 v / v). After lyophilization, the title compound was obtained as formate as a white solid (36 mg, 90 μmol, yield 19%). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.57(s,3H),3.63(s,3H),7.16(br s,1H),7.34(t,J=7.8Hz,1H),7.50-7.67(m,4 H),7.94(dt,J=7.9,1.9Hz,1H),8.64(dd,J=1.6,4.9Hz,1H),8.68(d,J=1.5Hz,1H).MS(ES+)m / z 351.0[M+H].

[0270] Example 36 2-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamide forate [ka]

[0271] 2-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-methyl-5-(3-pyridyl)imidazole-4-carbonitrile (Int-89) (50 mg, 0.15 mmol) was dissolved in concentrated sulfuric acid (1.0 mL, 98%, 18 mmol) and stirred at 0°C for 1 hour. Then, 2 N sodium hydroxide aqueous solution was added to adjust the pH to around 8. A precipitate formed, which was filtered off, washed (tert-butyl methyl ether), and purified by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates of 70:30 to 10:90 v / v). After lyophilization, the title compound was obtained as formate as a white solid (25 mg, 71 μmol, yield 47%). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.57(s,3H),3.65(s,3H),7.20(br s,1H),7.50-7.55(m,1H),7.61(br m / z 351.8[M+H].

[0272] Example 37 5-Methyl-4-(phenylethynyl)-1-(p-tolyl)-1H-imidazole-2-carboxamide [ka]

[0273] 4-Ethinyl-5-methyl-1-(p-tolyl)-1H-imidazole-2-carboxamide (Int-10) (64 mg, 267 μmol) and iodobenzene (76.4 mg, 374 μmol) were dissolved in DMF (2 mL), and triethylamine (81 mg, 112 μL, 802 μmol) and bis(triphenylphosphine)palladium(II) dichloride (9.4 mg, 13 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (1.5 mg, 8.0 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 2 hours. The reaction mixture was then extracted with water (20 mL) and dichloromethane (20 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 20 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (24 g, silica gel, ethyl acetate / n-heptane, gradient 0:100~40:60 (v / v)) to obtain the title compound as a white solid (26 mg, 82 μmol, yield 31%). HPLC (Method LCMS_fastgradient) R =1.34 minutes. 1 H NMR(300MHz,CDCl3)δ ppm 2.16(s,3H),2.43(s,3H),5.31(br s,1H),7.11(d,J=8.3 Hz,2H),7.17(br s,1H),7.29(d,J=7.9 Hz,2H),7.32-7.37(m,3H),7.53-7.58(m,2H).MS(ES+)m / z 316.2[M+H].

[0274] Example 38 4-[2-(2-chloro-4-pyridyl)ethinyl]-5-methyl-1-(p-tolyl)imidazole-2-carboxamide [ka]

[0275] 4-Ethinyl-5-methyl-1-(p-tolyl)-1H-imidazole-2-carboxamide (Int-10) (75 mg, 314 μmol) was dissolved in DMF (5 mL), and bis(triphenylphosphine)palladium(II) dichloride (11 mg, 15 μmol), copper(I) iodide (1.8 mg, 9 μmol), triethylamine (130 μL, 0.94 mmol), and 2-chloro-4-iodopyridine (83 mg, 0.34 mmol) were added. The resulting mixture was degassed with nitrogen and stirred at 0°C for 3 hours. After cooling, the mixture was filtered, and the filtrate was separated and purified directly by HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates with a ratio of 70:30 to 10:90 v / v). After lyophilization, the title compound was obtained as a white solid (29 mg, 80 μmol, yield 25%). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.11(s,3H),2.39(s,3H),7.21(d,J=8.2 Hz,2H),7.30(d,J=8.1Hz,2H),7.39(br s,1H),7.53(dd,J=1.3,5.1Hz,1H),7.69(s,1H),7.89(br s,1H),8.44(d,J=5.1Hz,1H).MS(ES+)m / z 351.3,353.2[M+H,Cl isotope].

[0276] Example 39 1-(4-chlorophenyl)-4-((2-chloropyridine-4-yl)ethinyl)-5-methyl-1H-imidazole-2-carboxamide [ka]

[0277] 1-(4-chlorophenyl)-4-ethynyl-5-methyl-1H-imidazole-2-carboxamide (Int-11) (55 mg, 212 μmol) and 2-chloro-4-iodopyridine (55.8 mg, 233 μmol) were dissolved in DMF (2 mL), and triethylamine (64 mg, 89 μL, 635 μmol) and bis(triphenylphosphine)palladium(II) dichloride (12 mg, 17 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (1.6 mg, 8.5 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 2 hours. The reaction mixture was then extracted with water (40 mL) and dichloromethane (50 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 40 mL). The combined organic layers were washed with brine (30 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under vacuum. The crude product was pulverized with hot ethyl acetate (5 mL), cooled, filtered off the precipitate, washed (ethyl acetate), and dried under vacuum to obtain the title compound as a grayish-white solid (23 mg, 62 μmol, yield 29%). 1 H NMR(600MHz,trifluoroacetic acid)δ ppm 2.45(s,3H),7.53(d,J=6.6 Hz,2H),7.75(d,J=7.7 Hz,2H),8.13(br s,1H),8.18(s,1H),8.84(br s,1H).MS(EI+)m / z 369.9,371.9[M+H,2 Cl isotope].

[0278] Example 40 1-(3-chlorophenyl)-4-((2-chloropyridine-4-yl)ethinyl)-5-methyl-1H-imidazole-2-carboxamide [ka]

[0279] A solution of 1-(3-chlorophenyl)-4-(2-chloropyridine-4-ylethynyl)-5-methyl-1H-imidazole-2-carboxylate methyl ester (Int-32) (110 mg, 285 μmol) in ammonia (7N in MeOH) (3 mL, 21 mmol) was stirred in a pressure tube at 90°C for 16 hours. The reaction mixture was then concentrated under vacuum, and the residue was purified by column chromatography (20 g, NH2-functionalized silica gel, ethyl acetate / n-heptane, constant composition 50:50 (v / v)) to obtain the title compound as a grayish-white solid (44 mg, 118 μmol, yield 42%). MS(ES+)m / z 370[M+H].

[0280] Example 41 4-(2-chloropyridine-4-ylethynyl)-1-(2,4-difluorophenyl)-5-methyl-1H-imidazole-2-carboxylic acid amide [ka]

[0281] A solution of 4-(2-chloropyridine-4-ylethynyl)-1-(2,4-difluorophenyl)-5-methyl-1H-imidazole-2-carboxylate methyl ester (Int-33) (70 mg, 180 μmol) in ammonia (7N in MeOH) (2.6 mL, 18 mmol) was stirred in a pressure tube at 90°C for 16 hours. The reaction mixture was then concentrated under vacuum, and the residue was purified by column chromatography (20 g, silica gel, ethyl acetate / n-heptane, gradient 0:100~33:67 (v / v)) to obtain the title compound as a grayish-white solid (15 mg, 40 μmol, yield 22%). MS(ES+)m / z 373[M+H].

[0282] Example 42 4-(2-chloropyridine-4-ylethynyl)-1-(4-fluorophenyl)-1H-imidazole-2-carboxylic acid amide [ka]

[0283] A suspension of methyl 4-((2-chloropyridine-4-yl)ethynyl)-1-(4-fluorophenyl)-1H-imidazole-2-carboxylate (Int-49) (100 mg, 197 μmol) and sodium cyanide (1.4 mg, 28 μmol) in ammonia (7N in MeOH) (2 mL, 14 mmol) was stirred at 50°C in a pressure tube for 15 hours. After cooling, the reaction mixture was extracted with water (15 mL) and dichloromethane (30 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed with brine (15 mL), dried, filtered, and the filtrate was concentrated under vacuum. The crude product was pulverized at room temperature with dichloromethane (1.5 mL), filtered, and subsequently pulverized under reflux with dichloromethane (1 mL), stirred at room temperature for 1 hour, filtered, and dried under vacuum to purify it and obtain the title compound as a grayish-white solid (29 mg, 85 μmol, yield 43%). HPLC (Method LC-MS_fastgradient) R =1.12 minutes. 1 H NMR(300MHz,CDCl3)δ ppm 7.29-7.36(m,2H),7.46-7.54(m,3H),7.58(br s,1H),7.64-7.66(m,1H),8.06(s,2H),8.47(dd,J=0.6,5.2Hz,1H).MS(ES+)m / z 341.2,343.2[M+H,Cl isotope].

[0284] Example 43 4-((2-chloropyridine-4-yl)ethinyl)-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide [ka]

[0285] 4-Ethinyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide (Int-22) (95 mg, 420 μmol) and 2-chloro-4-iodopyridine (111 mg, 462 μmol) were dissolved in DMF (3.5 mL), and triethylamine (127 mg, 176 μL, 1.26 mmol) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 34 μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper(I) iodide (3.2 mg, 17 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5°C for 1 hour. Next, the reaction mixture was extracted with water (40 mL) and dichloromethane (50 mL), and the aqueous layer was back-extracted with dichloromethane (2 × 40 mL). The combined organic layers were washed with brine (30 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated under vacuum. The crude product was pulverized with dichloromethane (5 mL) under reflux, filtered after cooling, and subsequently pulverized with ethanol (5 mL) at 50°C, filtered after cooling, and purified by drying under high vacuum to obtain the title compound as a grayish-white solid (80 mg, 237 μmol, yield 56%). HPLC (Method LC MS_fastgradient) R =0.93 minutes. 1 H NMR(300MHz,DMSO-d6)δ ppm 2.54(s,3H),7.38(d,J=8.5Hz,1H),7.52(dd,J=1.3,5.1Hz,1H),7.61(br s,1H),7.65(s,1H),7.80(dd,J=2.6,8.3Hz,1H),8.10(s,2H),8.47(d,J=4.8Hz,1H),8.50(d,J=2.4Hz,1H).MS(ES+)m / z338.2,340.2[M+H,Cl isotope].

[0286] Example 44 2-[2-(3-chloro-2-methylphenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide [ka]

[0287] 2-[2-(3-chloro-2-methylphenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carbonitrile (Int-90) (100 mg, 0.29 mmol) was dissolved in concentrated sulfuric acid (2.0 mL, 98%, 36 mmol) and stirred at 0°C for 2 hours. Then, 2N sodium hydroxide aqueous solution was added to adjust the pH to around 8. A precipitate formed, which was filtered off, washed (tert-butyl methyl ether), and purified by preparative HPLC (Shim-pack C18, 150 × 25 mm × 10 μm, eluted with acetonitrile / (water + 0.225% formic acid), linear, optimized for substrates of 70:30 to 10:90 v / v). After lyophilization, the title compound was obtained as a white solid (20 mg, 50 μmol, yield 19%). 1 H NMR(400MHz,DMSO-d6)δppm 2.54(s,3H),2.57(s,3H),3.61(s,3H),7.12(br s,1H),7.33(dd,J=8.1,8.1Hz,1H),7.37(d,J=8.1Hz,1H),7.55(br s,1H),7.56-7.59(m,1H),7.61-7.65(m,1H),7.81(dd,J=2.2,8.0Hz,1H).MS(ES+)m / z 364.9,366.9[M+H,Cl isotope].

[0288] [Means for solving the problem] 1. Equation I [ka] [In the formula, X 1 is either N or C, X 2 is either N or C, X 3 is either N or C, However, X 1 , X 2 and X 3 At least one of them is N, and X 1 , X 2and X 3 Two or fewer of these represent N, and X 1 If X is N, 2 It cannot be N, The dotted lines represent single or double bonds, allowing the five-membered ring to be aromatic. R 1 is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2, or 3 nitrogen ring atoms, and the phenyl or the N-heteroaryl is R 4 It may be substituted with 1, 2, 3, or 4 substituents selected from the following: R 2 is hydrogen or a C1-C6 alkyl group, however X 2 If R is N, 2 It is not hydrogen, R 3 is a heteroaryl or phenyl, and the heteroaryl or phenyl is R 5 It may be substituted with 1, 2, 3, or 4 substituents selected from the following: R 4 These are independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halo-C1-C6 alkyl and halo-C1-C6 alkoxy. R 5 These are independently selected from hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl and halo-C1-C6 alkoxy, or Two adjacent R 5 The group forms a 5-membered or 6-membered heterocyclyl condensed ring, and the heterocyclyl condensed ring may be substituted with one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy. Compounds thereof, or pharmaceutically acceptable salts thereof.

[0289] 2. The compound is of formula Ia [ka] [In the formula, R 1 , R 2 or R 3 This is defined in Embodiment 1. A compound of the compound described in Embodiment 1 or a pharmaceutically acceptable salt thereof.

[0290] 3. The compound is of formula Ib [ka] [In the formula, R 1 , R 2 or R 3 This is defined in Embodiment 1. A compound of the compound described in Embodiment 1 or a pharmaceutically acceptable salt thereof.

[0291] 4. The compound has the formula Ic [ka] [In the formula, R 1 , R 2 or R 3 This is defined in Embodiment 1. A compound of the compound described in Embodiment 1 or a pharmaceutically acceptable salt thereof.

[0292] 5. R 1 is phenyl, pyrazinyl, pyridazinyl, pyrimidinyl, or pyridinyl, and the phenyl, the pyrazinyl, the pyridazinyl, the pyrimidinyl, or the pyridinyl is R 4 R may be substituted with 1, 2, 3, or 4 substituents selected from 4 A compound according to any one of embodiments 1 to 4, wherein the compound is defined in embodiment 1.

[0293] 6. R 1 is phenyl, pyrazinyl, pyridazinyl, or pyridinyl, and the phenyl, the pyrazinyl, the pyridazinyl, or the pyridinyl is R 4R may be substituted with one, two, or three substituents selected from 4 A compound according to any one of embodiments 1 to 5, wherein the compound is defined in embodiment 1.

[0294] 7. R 1 is phenyl, pyrazinyl, pyridazinyl, or pyridinyl, and the phenyl, the pyrazinyl, the pyridazinyl, or the pyridinyl is R 4 It may be substituted with one or two substituents selected from R 4 A compound according to any one of embodiments 1 to 4, wherein the compound is defined in embodiment 1.

[0295] 8. R 2 The compound according to any one of embodiments 1 to 7, wherein the compound is a C1-C6 alkyl group.

[0296] 9. R 2 A compound according to any one of embodiments 1 to 8, wherein the compound is methyl.

[0297] 10. R 3 is phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiophenyl, and the phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiophenyl is R 5 R may be substituted with 1, 2, 3, or 4 substituents selected from 5 A compound according to any one of embodiments 1 to 9, wherein the compound is defined in embodiment 1.

[0298] 11. R 3 is phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiophenyl, and the phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiophenyl is R 5 R may be substituted with one, two, or three substituents selected from 5 A compound according to any one of embodiments 1 to 10, wherein is defined in embodiment 11.

[0299] 12. R 3is phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiophenyl, and the phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiophenyl is R 5 It may be substituted with one or two substituents selected from R 5 A compound according to any one of embodiments 1 to 11, wherein the compound is defined in embodiment 1.

[0300] 13. R 3 is phenyl, pyridinyl, or thiophenyl, and the phenyl, the pyridinyl, or the thiophenyl is R 5 It may be substituted with one or two substituents selected from R 5 A compound according to any one of embodiments 1 to 12, wherein is defined in embodiment 1.

[0301] 14. R 4 The compound according to any one of embodiments 1 to 13, wherein the compound is independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys.

[0302] 15. R 4 The compound according to any one of embodiments 1 to 14, which is independently selected from halogen, methyl, and methoxy.

[0303] 16. R 4 The compound according to any one of embodiments 1 to 15, which is independently selected from fluoro, chloro, methyl, and methoxy.

[0304] 17. R 1 The compound according to any one of embodiments 1 to 13, wherein is phenyl, pyrazinyl, pyridadinyl, pyrimidinyl, or pyridinyl.

[0305] 18. R 1 The compound according to any one of embodiments 1 to 13, wherein is phenyl, pyrazinyl, pyridadinyl, or pyridinyl.

[0306] 19. R 5However, these may be independently selected from halogen, cyano, C1-C6 alkyl, halo-C1-C6 alkyl and C1-C6 alkoxy, or two adjacent R 5 The compound according to any one of embodiments 1 to 18, wherein the group forms a 5-membered or 6-membered heterocyclyl condensed ring, and the heterocyclyl condensed ring may be substituted with one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy.

[0307] 20. R 5 However, these are independently selected from halogen, cyano, methyl, trifluoromethyl and methoxy, or two adjacent R 5 A compound according to any one of embodiments 1 to 19, wherein the group is dioxolanil.

[0308] 21. 4-((2-chloro-3-methylpyridine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((2-chloro-3-fluoropyridine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-[2-(5-chlorothiophen-3-yl)ethinyl]-5-methyl-1-(6-methylpyridine-3-yl)imidazole-2-carboxamide 4-[2-(3-chlorophenyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide 4-((3-cyanophenyl)ethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-(2-chloropyridine-4-ylethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxylic acid amide 4-((2-chloro-5-fluoropyridine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((3-methoxyphenyl)ethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-[2-(4-chlorophenyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide 5-Methyl-1-(6-methylpyridine-3-yl)-4-(m-tolylethinyl)-1H-imidazole-2-carboxamide 5-Methyl-1-(6-methylpyridine-3-yl)-4-((2-(trifluoromethyl)pyridine-4-yl)ethinyl)-1H-imidazole-2-carboxamide 4-[2-(2-fluoro-4-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide 4-(benzo[d][1,3]dioxol-4-ylethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((6-chloropyridine-2-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((2-chloropyrimidine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((3-fluoropyridine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-[2-(5-chloro-3-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide 4-((4-chloropyridine-2-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((6-chloropyrimidine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 5-Methyl-1-(6-methyl-3-pyridyl)-4-[2-(3-pyridyl)ethinyl]imidazole-2-carboxamide 5-Methyl-1-(6-methyl-3-pyridyl)-4-[2-(4-pyridyl)ethinyl]imidazole-2-carboxamide 5-Methyl-1-(6-methylpyridine-3-yl)-4-((2-methylpyridine-4-yl)ethinyl)-1H-imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(5-methylpyrazine-2-yl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(6-methylpyridazine-3-yl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(5-methyl-3-pyridyl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-(6-chloro-3-pyridyl)-5-methylimidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-(6-methoxy-3-pyridyl)-5-methylimidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(5-methyl-2-pyridyl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide 4-[2-(3-chloro-2-methylphenyl)ethynyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide 4-[2-(2-chloro-4-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxamide 2-[2-(2-chloro-4-pyridyl)ethinyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide 2-[2-(3-chloro-2-methylphenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide 2-[2-(3-chlorophenyl)ethinyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide 2-[2-(3-chloro-2-methylphenyl)ethynyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamide forate 2-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamide forate 5-Methyl-4-(phenylethynyl)-1-(p-tolyl)-1H-imidazole-2-carboxamide 4-[2-(2-chloro-4-pyridyl)ethinyl]-5-methyl-1-(p-tolyl)imidazole-2-carboxamide 1-(4-chlorophenyl)-4-((2-chloropyridine-4-yl)ethinyl)-5-methyl-1H-imidazole-2-carboxamide 1-(3-chlorophenyl)-4-((2-chloropyridine-4-yl)ethinyl)-5-methyl-1H-imidazole-2-carboxamide 4-(2-chloropyridine-4-ylethynyl)-1-(2,4-difluorophenyl)-5-methyl-1H-imidazole-2-carboxylic acid amide 4-(2-chloropyridine-4-ylethynyl)-1-(4-fluorophenyl)-1H-imidazole-2-carboxylic acid amide 4-((2-chloropyridine-4-yl)ethinyl)-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide, and 2-[2-(3-chloro-2-methylphenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide A compound according to any one of embodiments 1 to 13, selected from the above.

[0309] 22. A compound according to any one of embodiments 1 to 21, for use as a therapeutically active substance.

[0310] 23. A pharmaceutical composition comprising a compound of formula I described in any one of embodiments 1 to 21 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0311] 24. A compound of formula I as described in any one of embodiments 1 to 21, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0312] 25. A compound of formula I as described in any one of embodiments 1 to 21 or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of progression of CNS disorders.

[0313] 26. A method for treating or preventing CNS disorders, comprising administering a compound of formula I as described in any one of embodiments 1 to 21 or a pharmaceutically acceptable salt thereof as defined above.

[0314] 27. Use of a compound of formula I or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 21 for use in the treatment, prevention and / or delay of progression of CNS disorders.

[0315] 28. HCN1-selective compounds for use in the treatment, prevention, and / or delay of progression of CNS disorders.

[0316] 29. The HCN1-selective compound according to embodiment 28, wherein the HCN1-selective compound is selective for HCN2 and HCN4.

[0317] 30. The CNS disorder is associated with schizophrenia (e.g., cognitive impairment and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, substance abuse and drug dependence, Tourette syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes mellitus, sepsis, and post-ischemic tubular necrosis. HCN1-selective compounds according to embodiment 28 or 29, selected from the group consisting of mental, neurological, neurogenesis, neurodegenerative, mood, motivation, metabolic, cardiovascular, renal, ophthalmic, endocrine and / or other disorders described herein, including renal failure, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative hypotonia, sleep disorders, pain, cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain and autism (sensory sensitivity), and more specifically, mental, neurological, neurogenesis, neurodegenerative, mood, motivation, metabolic, cardiovascular, renal, ophthalmic, endocrine and / or other disorders described herein.

[0318] 31. An HCN1-selective compound according to any one of embodiments 28 to 30, wherein the CNS disorder is a cognitive disorder associated with schizophrenia.

[0319] 32. An HCN1-selective compound according to any one of embodiments 28 to 31, for use in the treatment of cognitive impairment associated with schizophrenia.

Claims

1. Equation I 【Chemistry 1】 [In the formula, X １ is either N or C, X ２ is either N or C, X ３ is either N or C, However, X １ , X ２ and X ３ at least one of which is N, and X １ , X ２ and X ３ no more than two of which represent N, and if X １ is N, then X ２ cannot be N The dotted lines represent single or double bonds, allowing the five-membered ring to be aromatic. R １ is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2, or 3 nitrogen ring atoms, and the phenyl or the N-heteroaryl is R ４ It may be substituted with one, two, three, or four substituents selected from the following: R ２ is hydrogen or C １ -C ６ It is alkyl, however X ２ If R is N, ２ It is not hydrogen, R ３ is a heteroaryl or phenyl, and the heteroaryl or phenyl is R ５ It may be substituted with one, two, three, or four substituents selected from the following: R ４ These are, independently, halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, cyano, halo C １ -C ６ Alkyl and Halo C １ -C ６ Selected from alkoxy, R ５ These are independently hydroxy, halogen, cyano, and C １ -C ６ Alkyl, C １ -C ６ Alkoxy, Halo C １ -C ６ Alkyl and Halo C １ -C ６ Selected from alkoxy, or Two adjacent R ５ The group forms a 5-membered or 6-membered heterocyclyl condensed ring, and the heterocyclyl condensed ring is composed of -hydroxy, halogen, and C １ -C ６ Alkyl, C １ -C ６ Alkoxy, Halo C １ -C ６ Alkyl and Halo C １ -C ６ [May be substituted with one or more groups independently selected from the alkoxy.] Compounds thereof, or pharmaceutically acceptable salts thereof.

2. The aforementioned compound is, Formula Ia 【Chemistry 2】 [In the formula, R １ , R ２ or R ３ [as defined in claim 1] A compound of the compound described in claim 1 or a pharmaceutically acceptable salt thereof.

3. The aforementioned compound is, Formula Ib 【Transformation 3】 [In the formula, R １ , R ２ or R ３ [as defined in claim 1] A compound of the compound described in claim 1 or a pharmaceutically acceptable salt thereof.

4. The compound has the formula Ic 【Chemistry 4】 [In the formula, R １ , R ２ or R ３ [as defined in claim 1] A compound of the compound described in claim 1 or a pharmaceutically acceptable salt thereof.

5. R １ is phenyl, pyrazinyl, pyridazinyl, pyrimidinyl, or pyridinyl, and the phenyl, the pyrazinyl, the pyridazinyl, the pyrimidinyl, or the pyridinyl is R ４ R may be substituted with one, two, three, or four substituents selected from the above, ４ A compound according to any one of claims 1 to 4, wherein is defined in claim 1.

6. R １ is phenyl, pyrazinyl, pyridazinyl, or pyridinyl, and the phenyl, the pyrazinyl, the pyridazinyl, or the pyridinyl is R ４ R may be substituted with one, two, or three substituents selected from the following: ４ A compound according to any one of claims 1 to 5, wherein is defined in claim 1.

7. R １ is phenyl, pyrazinyl, pyridazinyl, or pyridinyl, and the phenyl, the pyrazinyl, the pyridazinyl, or the pyridinyl is R ４ R may be substituted with one or two substituents selected from ４ A compound according to any one of claims 1 to 6, wherein is defined in claim 1.

8. R ２ However, C １ -C ６ A compound according to any one of claims 1 to 7, wherein it is alkyl.

9. R ２ The compound according to any one of claims 1 to 8, wherein the compound is methyl.

10. R ３ is phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiophenyl, and the phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiophenyl is R ５ R may be substituted with one, two, three, or four substituents selected from the above, ５ A compound according to any one of claims 1 to 9, wherein is defined in claim 1.

11. R ３ is phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiophenyl, and the phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiophenyl is R ５ R may be substituted with one, two, or three substituents selected from the following: ５ A compound according to any one of claims 1 to 10, wherein is defined in claim 1.

12. R ３ is phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiophenyl, and the phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiophenyl is R ５ R may be substituted with one or two substituents selected from ５ A compound according to any one of claims 1 to 11, wherein is defined in claim 1.

13. R ３ is phenyl, pyridinyl, or thiophenyl, and the phenyl, the pyridinyl, or the thiophenyl is R ５ R may be substituted with one or two substituents selected from ５ A compound according to any one of claims 1 to 12, wherein is defined in claim 1.

14. R ４ However, halogen, C １ -C ６ Alkyl and C １ -C ６ A compound according to any one of claims 1 to 13, independently selected from alkoxys.

15. R ４ The compound according to any one of claims 1 to 14, which is independently selected from halogen, methyl, and methoxy.

16. R ４ The compound according to any one of claims 1 to 15, wherein the compound is independently selected from fluoro, chloro, methyl, and methoxy.

17. R １ The compound according to any one of claims 1 to 16, wherein is phenyl, pyrazinyl, pyridadinyl, pyrimidinyl, or pyridinyl.

18. R １ The compound according to any one of claims 1 to 17, wherein R is phenyl, pyrazinyl, pyridazinyl, or pyridinyl.

19. R ５ is independently selected from halogen, cyano, C １ -C ６ alkyl, haloC １ -C ６ alkyl and C １ -C ６ alkoxy, or two adjacent R ５ groups form a 5- or 6-membered heterocyclic fused ring, and the heterocyclic fused ring is substituted with one or more groups independently selected from -hydroxy, halogen, C １ -C ６ alkyl, C １ -C ６ alkoxy, haloC １ -C ６ alkyl and haloC １ -C ６ alkoxy, and may be a compound according to any one of claims 1 to 18.

20. R ５ However, these are independently selected from halogen, cyano, methyl, trifluoromethyl and methoxy, or two adjacent R ５ The compound according to any one of claims 1 to 19, wherein the group is dioxolanil.

21. 4-((2-chloro-3-methylpyridine-4-yl)ethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((2-chloro-3-fluoropyridine-4-yl)ethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-[2-(5-chlorothiophen-3-yl)ethinyl]-5-methyl-1-(6-methylpyridine-3-yl)imidazole-2-carboxamide 4-[2-(3-chlorophenyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide 4-((3-cyanophenyl)ethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-(2-chloropyridine-4-ylethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxylic acid amide 4-((2-chloro-5-fluoropyridine-4-yl)ethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((3-methoxyphenyl)ethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-[2-(4-chlorophenyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide 5-methyl-1-(6-methylpyridine-3-yl)-4-(m-tolylethinyl)-1H-imidazole-2-carboxamide 5-Methyl-1-(6-methylpyridine-3-yl)-4-((2-(trifluoromethyl)pyridine-4-yl)ethinyl)-1H-imidazole-2-carboxamide 4-[2-(2-fluoro-4-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide 4-(benzo[d][1,3]dioxol-4-ylethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((6-chloropyridine-2-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((2-chloropyrimidine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((3-fluoropyridine-4-yl)ethynyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-[2-(5-chloro-3-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide 4-((4-chloropyridine-2-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 4-((6-chloropyrimidine-4-yl)ethinyl)-5-methyl-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide 5-methyl-1-(6-methyl-3-pyridyl)-4-[2-(3-pyridyl)ethinyl]imidazole-2-carboxamide 5-methyl-1-(6-methyl-3-pyridyl)-4-[2-(4-pyridyl)ethinyl]imidazole-2-carboxamide 5-methyl-1-(6-methylpyridine-3-yl)-4-((2-methylpyridine-4-yl)ethinyl)-1H-imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(5-methylpyrazine-2-yl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(6-methylpyridazine-3-yl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(5-methyl-3-pyridyl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-(6-chloro-3-pyridyl)-5-methylimidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-(6-methoxy-3-pyridyl)-5-methylimidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(5-methyl-2-pyridyl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide 4-[2-(3-chloro-2-methylphenyl)ethynyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide 4-[2-(2-chloro-4-pyridyl)ethinyl]-5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxamide 2-[2-(2-chloro-4-pyridyl)ethinyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide 2-[2-(3-chlorophenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide 2-[2-(3-chloro-2-methylphenyl)ethynyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamidoformate 2-[2-(2-chloro-3-methyl-4-pyridyl)ethinyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamidoformate 5-methyl-4-(phenylethynyl)-1-(p-tolyl)-1H-imidazole-2-carboxamide 4-[2-(2-chloro-4-pyridyl)ethinyl]-5-methyl-1-(p-tolyl)imidazole-2-carboxamide 1-(4-chlorophenyl)-4-((2-chloropyridine-4-yl)ethinyl)-5-methyl-1H-imidazole-2-carboxamide 1-(3-chlorophenyl)-4-((2-chloropyridine-4-yl)ethynyl)-5-methyl-1H-imidazole-2-carboxamide 4-(2-chloropyridine-4-ylethynyl)-1-(2,4-difluorophenyl)-5-methyl-1H-imidazole-2-carboxylic acid amide 4-(2-chloropyridine-4-ylethynyl)-1-(4-fluorophenyl)-1H-imidazole-2-carboxylic acid amide 4-((2-chloropyridine-4-yl)ethinyl)-1-(6-methylpyridine-3-yl)-1H-imidazole-2-carboxamide, and 2-[2-(3-chloro-2-methylphenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide A compound according to any one of claims 1 to 20, selected from the above.

22. A compound according to any one of claims 1 to 21, for use as a therapeutically active substance.

23. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

24. A compound of formula I according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

25. A compound of formula I according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of progression of CNS disorders.

26. The aforementioned CNS disorder is associated with schizophrenia, cognitive impairment related to D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, substance abuse and drug dependence, Tourette syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, and systemic lupus erythematosus (S). Compounds of formula I for use in treatment, prevention and / or delay, as described in claim 25, selected from the group consisting of mental, neurological, neurodevelopmental, neurodegenerative, mood, motivation, metabolic, cardiovascular, renal, ophthalmic and endocrine disorders, including LE), hyperglycemia, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, resistance edema, narcolepsy, hypertension, congestive heart failure, postoperative hypotonia, sleep disorders, pain, cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders, neuropathic pain and autism (sensory sensitivity).

27. A pharmaceutical composition according to claim 23 for the treatment, prevention, and / or delay of the progression of CNS disorders.

28. The pharmaceutical composition according to claim 23 or 27, wherein the compound of formula I is HCN1 selective with respect to HCN2 and HCN4.

29. The aforementioned CNS disorder is associated with schizophrenia, cognitive impairment related to D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, substance abuse and drug dependence, Tourette syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraines, and systemic dyskinesia. A pharmaceutical composition according to claim 27 or 28, selected from the group consisting of mental, neurological, neurogenesis, neurodegenerative, mood, motivation, metabolic, cardiovascular, renal, ophthalmic, and endocrine disorders, including erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative hypotonia, sleep disorders, pain, cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders, neuropathic pain, and autism (sensory sensitivity).

30. The pharmaceutical composition according to any one of claims 27 to 29, wherein the CNS disorder is a cognitive disorder related to schizophrenia.

Images