Alkynyl-(heteroaryl)-carboxamide HCN1 inhibitors

Abstract

The present invention provides a compound of formula (I), wherein R 1 , R 2 or R 3 As described herein, and pharmaceutically acceptable salts thereof. In addition, the present invention relates to the preparation of said compound of formula (I), a pharmaceutical composition comprising said compound and the use of said compound as a medicament.

Description

[0001] The present invention provides compounds that are inhibitors of the hyperpolarization-activated and cyclic nucleotide-gated (HCN) channel isoform 1 (HCN1), particularly wherein these compounds have a higher selectivity than the HCN2 and HCN4 isoforms, for use in treating, preventing, and / or delaying the progression of CNS diseases, more particularly cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE) and mood disorders, most particularly cognitive impairment associated with schizophrenia, the preparation of these compounds and pharmaceutical compositions comprising these compounds.

[0002] In particular, the present invention relates to compounds of formula I

[0003]

[0004] in

[0005] X 1 N or C

[0006] X 2 N or C

[0007] X 3 N or C

[0008] The condition is X 1 , X 2 and X 3 At least one of is N, and X 1 , X 2 and X 3 No more than two of them represent N, and if X 1 is N, then X 2 Cannot be N;

[0009] Dashed lines represent single or double bonds to enable the five-membered ring to be aromatic;

[0010] R 1 is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2 or 3 nitrogen ring atoms, and wherein the phenyl or the N-heteroaryl is optionally substituted by 1, 2, 3 or 4 selected from R 4 Substituents are substituted;

[0011] R 2 is hydrogen or C1-C6 alkyl, provided that if X 2 is N, then R 2 Not hydrogen;

[0012] R 3 is heteroaryl or phenyl, wherein the heteroaryl or the phenyl is optionally substituted by 1, 2, 3 or 4 groups selected from R 5 Substituents are substituted;

[0013] R 4 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy; and

[0014] R 5 independently selected from hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy, or

[0015] Two adjacent R 5 The group forms a five-membered or six-membered heterocyclyl condensed ring, wherein the heterocyclyl condensed ring is optionally substituted by one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-substituted C1-C6 alkyl and halo-substituted C1-C6 alkoxy; or

[0016] Its pharmaceutically acceptable salts.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below.

[0018] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0019] Unless otherwise indicated, the nomenclature used in this application is based on the IUPAC systematic nomenclature.

[0020] Unless otherwise indicated, any open valence appearing on a carbon, oxygen, sulfur, or nitrogen atom in the structures herein indicates the presence of hydrogen.

[0021] "Halo" or "halogen" refers to fluorine, chlorine, bromine or iodine, particularly chlorine or fluorine.

[0022] "Hydroxy" refers to an -OH group.

[0023] "(C1-C6)alkyl" refers to a branched or straight hydrocarbon chain having one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

[0024] "(C1-C6)alkoxy" means a moiety of the formula -ORa, wherein Ra is a (C1-C6)alkyl moiety as defined herein. Examples of (C1-C6)alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0025] The term "therapeutically effective amount" refers to an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, disorder, or condition, (ii) attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, disorder, or condition, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, disorder, or condition as described herein. The therapeutically effective amount depends on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary doctor, and other factors.

[0026] The term "perhalo (C1-C3) alkyl" means a (C1-C3) alkyl group as defined above, wherein all hydrogen atoms are substituted by halogen atoms. More particularly, "(C1-C3) perhalo alkyl" is a (C1-C3) perfluoroalkyl group, most preferably trifluoromethyl.

[0027] "Halo-(C1-C6)alkyl" refers to an alkyl group as defined above, which is substituted by one or more halogen atoms, in particular by one to three halogen atoms. More particularly, halo-(C1-C6)alkyl is chloro- and fluoro-(C1-C6)alkyl. In some specific embodiments, halo-(C1-C6)alkyl refers to perhalo (C1-C3)alkyl, such as trifluoromethyl.

[0028] "Halo-(C1-C6)alkoxy" refers to an alkoxy group as defined above, which is substituted by one or more halogen atoms, in particular by one to three halogen atoms. More particularly, halo-(C1-C6)alkoxy is chloro- and fluoro-(C1-C6)alkoxy.

[0029] "Heteroaryl" means a monovalent monocyclic or bicyclic moiety having 5 to 12 ring atoms having at least one aromatic ring containing one, two or three ring heteroatoms each independently selected from N, O or S (preferably N or O), the remaining ring atoms being C, and it is understood that the point of attachment of the heteroaryl moiety will be on the aromatic ring. More specifically, the term heteroaryl includes, but is not limited to, pyridyl, furyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, imidazo [1,2-a]-pyridyl, imidazo [2,1-b] thiazolyl and derivatives thereof. "N-heteroaryl" refers in particular to heteroaryl as previously defined containing at least one nitrogen atom. The point of attachment of the N-heteroaryl to the rest of the molecule may be a nitrogen or carbon ring atom. Examples of N-heteroaryl are pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl.

[0030] The term "selective" or "HCN1 selective compound" in the context of the present invention refers to the potency of an inhibitor to inhibit HCN1 with a higher efficiency than HCN2 and HCN4 isoforms. In a preferred embodiment, the compound of formula (I) is more effective against HCN1 isoforms than against HCN2 and HCN4 isoforms. In a specific embodiment, the compound according to the invention, more particularly the compound of formula (I), is at least 5 times more effective against HCN1 isoforms than against HCN2 and HCN4 isoforms, in particular at least 20 times, more particularly at least 50 times, even more particularly at least 100 times, most particularly at least 1000 times.

[0031] The term "heterocyclyl" means a monovalent saturated or partially unsaturated monocyclic ring system having 4 to 9 ring atoms, which contains 1, 2 or 3 heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon. Examples of heterocyclyl are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, tetrahydrothiazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolane, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl. More particularly, heterocyclyl refers to dihydrofuranyl, 1,3-dioxolyl, dihydropyrrolyl, dihydrothiophenyl, dihydropyrazolyl, dihydroisoxazolyl, tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, 3,4-dihydro-2H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-thiazolyl, 1,2,3,4-tetrahydropyrazolyl.

[0032] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "an aryl group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the aryl group is substituted with an alkyl group and instances where the aryl group is not substituted with an alkyl group.

[0033] The term "individual" or "subject" refers to a mammal. Mammals include, but are not limited to, domesticated 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.

[0034] The term "compound(s) of the invention" refers to compounds as disclosed herein, and stereoisomers, tautomers, solvates, and salts (eg, pharmaceutically acceptable salts) thereof.

[0035] When the compounds of the present invention are solid, those skilled in the art will appreciate that these compounds and their solvates and salts may exist in different solid forms, particularly different crystalline forms, all of which are intended to fall within the scope of the present invention and the specified formula.

[0036] The term "pharmaceutically acceptable salts" refers to salts that are not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts.

[0037] "Pharmaceutically acceptable acid addition salts" refer to those pharmaceutically acceptable salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids, which may be selected from aliphatic, alicyclic, aromatic, aromatic aliphatic, heterocyclic, carboxylic and sulfonic acid organic acids, 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, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, and the like.

[0038] The term "pharmaceutical base addition salt" refers to those pharmaceutical salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine and polyamine resins).

[0039] The term "active pharmaceutical ingredient" (or "API") refers to a compound or molecule in a pharmaceutical composition that possesses a specific biological activity.

[0040] The terms "pharmaceutical composition" and "pharmaceutical formulation" (or "formulation") are used interchangeably and refer to a mixture or solution containing a therapeutically effective amount of an active drug ingredient together with a pharmaceutical excipient for administration to a mammal (eg, a human) in need thereof.

[0041] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inert excipient" are used interchangeably and refer to any pharmaceutical ingredient in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant used to formulate a drug product.

[0042] The term "treating" a disease state includes inhibiting the disease state, ie, arresting the development of the disease state or its clinical symptoms, or relieving the disease state, ie, temporarily or permanently regressing the disease state or its clinical symptoms.

[0043] Compounds that have the same molecular formula but differ in the bonding properties or order of their atoms or in the spatial arrangement of their atoms are called "isomers". Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and described by the R-sequencing rule and S-sequencing rule of Cahn, Ingold and Prelog, or by the mode by which the molecule rotates the plane of polarized light and is designated as right-handed or left-handed (i.e., (+)-isomer or (-)-isomer, respectively). Chiral compounds can exist as individual enantiomers or as a mixture of individual enantiomers. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0044] Compounds of Formula I, Ia, Ib or Ic may have one or more asymmetric centers or axes. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include individual enantiomers, atropisomers and mixtures thereof, racemates or other mixtures, and individual epimers, atropisomers and mixtures thereof. The determination of stereochemistry and the separation of 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).

[0045] Certain compounds may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate individual tautomers generally produce a mixture with chemical and physical properties consistent with the compound mixture. The position of equilibrium depends on the chemical features within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. Common prototropic tautomers include keto / enol Amide / Imidic Acid and The latter two are particularly common in heteroaryls and heterocycles, and the present invention encompasses all tautomeric forms of the compounds.

[0046] It has now been discovered that the compounds of formula I, Ia, Ib or Ic of the present invention are isoform selective inhibitors of HCN1 and therefore have therapeutic use for treating CNS diseases, including psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ocular, endocrine diseases, and / or other diseases described herein, including 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 dementia, Parkinson's disease, Huntington's disease, depression, anxiety, refractory depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin ... The invention relates to a group of diseases including, but not limited to, schizophrenia, encephalopathy, drug abuse and drug dependence, Tourette's syndrome, tardive dyskinesia, somnolence, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, refractory edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular 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 particularly cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain, and autism (sensory sensitivity), most particularly cognitive impairment associated with schizophrenia (CIAS).

[0047] These compounds are potent inhibitors of the hyperpolarization-activated and cyclic nucleotide-gated (HCN) channel isoform 1 (HCN1). The mammalian HCN channel family, which is highly conserved between species, currently consists of 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 that support cognitive and executive functions, including: the cortex, hippocampus, and cerebellum. The depolarizing currents (called Ih or If) generated by HCN channels promote cellular excitability and rhythmic activity in excitable tissues (DiFrancesco and DiFrancesco 2015). HCN1 channels are functionally expressed in a proximal-to-distal increasing gradient on the dendrites of projection neurons in the hippocampus and cortex, where their activation promotes shunting of distal synaptic currents, thereby limiting synaptic integration onto these neurons (Magee, 1998). Therefore, inhibition of HCN1 channels will increase synaptic integration and promote information transmission by projection neurons in these brain regions.

[0048] HCN ion channel is a member of the potassium channel superfamily of voltage gating, but unlike potassium channels, it is activated by hyperpolarization. In addition, cyclic nucleotides at intracellular levels, most notably cAMP, promote its gating. Therefore, HCN channels act as coincidence detectors to detect intracellular cAMP states and the polarization state of neurons. HCN channels, through their activity in neurons, play a role in determining resting membrane potential, defining dendrite integration, setting action potential firing frequency and pacing, and establishing action potential thresholds (DiFrancesco and DiFrancesco, 2015).

[0049] Large genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in the HCN1 genomic locus are significantly associated with schizophrenia (SZ). This has been demonstrated in multiple experimental cohorts and confirmed by meta-analyses in these cohorts (Schizophrenia working group of the Psychiatric Genomics Consortium, 2014; Pardinas et al., 2018). In addition, recent studies investigating the genetic architecture of heritable neurocognitive endophenotypes within the SZ population identified HCN1 as a target gene because of its genome-wide significant association with performance on different cognitive tasks (Swerdlow et al., 2018). This provides hope for patient screening to support a personalized healthcare approach to treat CIAS endophenotypes in CIAS patient populations by regulating HCN1. Expression quantitative trait loci (eQTL) analysis of SNPs in HCN1 showed no significant changes in mRNA expression in postmortem tissues, but controls compared to SZ showed a trend toward increased HCN1 expression in patients.

[0050] CIAS include episodic memory and working memory (WM) defects that cause hippocampal and prefrontal cortical circuits, respectively. Forebrain-restricted 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-brain permeable and non-selective HCN antagonists (by iontophoresis application) increases the relevant neuronal activity of the prefrontal cortex of non-human primates (NHP) and rodents (PFC infusion) (Wang et al., 2007). Non-selective HCN inhibitors (ZD7288) infused into the forelimb cortex of Sprague Dawley rats improve the percentage of correct responses in the delayed alternation task in the Y-maze. In addition, knocking down HCN1 in the rat forelimb cortex improves the performance in the same task 11-19 days after viral infusion, which is consistent with the time course of inhibited gene expression. In nonhuman primates, ZD7288 iontophoresis in DLPFC area 46 enhanced the action potential responses of delay-related neurons encoding preferred visual direction during an oculomotor delayed response task in WM (Wang et al., 2007).

[0051] Cannabis use is a common factor in the development of psychiatric disorders including SZ, and is also positively correlated with an earlier age of first symptom manifestation (Manseau and Goff, 2015). Cannabinoids activate endocannabinoid receptors, including cannabinoid type 1 receptors (CB1R). Activation of CB1R disrupts short-term 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 causes HCN-mediated Ih current changes, and genetic removal of HCN1 in rodents can restore the defects in spatial memory formation induced by endocannabinoids in response to exogenous challenges, as measured by the mouse object location memory test. In addition, LTP cannot be regulated by CB1R agonism in brain slices of HCN1 KO animals (Maroso et al., 2016).

[0052] EIEE represents a class of severe childhood-onset diseases similar to the Dravet syndrome spectrum, which have been previously identified as being attributed to SCN1a and dPCDH19 mutations (Depienne et al., 2009). EIEE is characterized by seizures that typically occur within the first three months of life and are resistant to standard anti-epileptic treatments. 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 many causal genetic mutations in EIEE, including genes encoding ion channels and synaptic proteins. Exome sequencing studies now estimate that approximately 3% of non-Dravet early infantile epileptic encephalopathy (EIEE) is attributed to HCN1 mutations (EIEE#24) (Nava et al., 2014; Marini et al., 2018).

[0053] The related HCN4 gene is highly and almost only expressed in the heart (GTEx database). Consistently, complete HCN4 KO mice have severe cardiac phenotypes and embryonic lethality (Stieber et al., 2003). In addition, HCN2 KO mice show spontaneous loss of consciousness type epilepsy, cardiac sinus arrhythmia (Ludwig et al., 2003). The lack of isotype selective drugs severely limits the possibility of using commercially available HCN blockers (e.g., ivabradine). Therefore, the generation of brain permeability and HCN1 selective compounds (compared to HCN2 and HCN4) will provide a strong potential for the development of pre-cognitive drugs for the treatment of EIEE and SZ.

[0054] Current knowledge on HCN channel inhibition is described in the literature, for example in the following publications, including those cited therein:

[0055] Cerbai et al., Canadian Journal of Physiology and Pharmacology, 96(2018), 977-984

[0056] Postea&Biel, Nature Reviews Drug Discovery, 10(2011), 903-914

[0057] Wickenden et al., Current Pharmaceutical Design, 15(2009), 2149-2168

[0058] Romanelli et al., Current Topics in Medicinal Chemistry 16(2016), 1764-1791

[0059] Clure et al., Bioorganic&Medicinal Chemistry Letters 21(2011), 5197-5201

[0060] Romanelli et al., J. Med. Chem. 53 (2010), 6773-6777

[0061] He et al., Reviews in the Neurosciences (Berlin, Germany), 30 (2019), 639-649

[0062] The present invention is directed to compounds of formula I, Ia, Ib or Ic, and the use of such compounds for the preparation of a medicament for treating, preventing and / or delaying the progression of psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ocular, endocrine diseases, and / or other diseases described herein in mammals, including 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 dementia, Parkinson's disease, Huntington's disease, depression, anxiety, refractory depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder The invention relates to the use of the compounds of formula I according to the invention for the treatment of cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g. depression), neuropathic pain and autism (sensory sensitivity), the preparation of the compounds and the drugs based on the compounds of formula I according to the invention.

[0063] Further objects of the invention are the compounds of the formula I, Ia, Ib or Ic in all forms of optically pure enantiomers, racemates or diastereomeric mixtures.

[0064] In another embodiment, the present invention relates to compounds of formula Ia

[0065]

[0066] in

[0067] R 1 is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2 or 3 nitrogen ring atoms, and wherein the phenyl or the N-heteroaryl is optionally substituted by 1, 2, 3 or 4 selected from R 4 Substituents are substituted;

[0068] R 2 is hydrogen or C1-C6 alkyl;

[0069] R 3 is heteroaryl or phenyl, wherein the heteroaryl or the phenyl is optionally substituted by 1, 2, 3 or 4 groups selected from R 5Substituents are substituted;

[0070] R 4 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy; and

[0071] R 5 independently selected from hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy, or

[0072] Two adjacent R 5 The group forms a five-membered or six-membered heterocyclyl condensed ring, wherein the heterocyclyl condensed ring is optionally substituted by one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy; or a pharmaceutically acceptable salt thereof.

[0073] In another embodiment, the present invention provides a compound of formula Ib,

[0074]

[0075] in

[0076] R 1 is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2 or 3 nitrogen ring atoms, and wherein the phenyl or the N-heteroaryl is optionally substituted by 1, 2, 3 or 4 selected from R 4 Substituents are substituted;

[0077] R 2 is a C1-C6 alkyl group;

[0078] R 3 is heteroaryl or phenyl, wherein the heteroaryl or the phenyl is optionally substituted by 1, 2, 3 or 4 groups selected from R 5 Substituents are substituted;

[0079] R 4 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy; and

[0080] R 5 independently selected from hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy, or

[0081] Two adjacent R 5The group forms a five-membered or six-membered heterocyclyl condensed ring, wherein the heterocyclyl condensed ring is optionally substituted by one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy; or a pharmaceutically acceptable salt thereof.

[0082] In another embodiment, the present invention relates to a compound of formula Ic

[0083]

[0084] in

[0085] R 1 is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2 or 3 nitrogen ring atoms, and wherein the phenyl or the N-heteroaryl is optionally substituted by 1, 2, 3 or 4 selected from R 4 Substituents are substituted;

[0086] R 2 is hydrogen or C1-C6 alkyl;

[0087] R 3 is heteroaryl or phenyl, wherein the heteroaryl or the phenyl is optionally substituted by 1, 2, 3 or 4 groups selected from R 5 Substituents are substituted;

[0088] R 4 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy; and

[0089] R 5 independently selected from hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy, or

[0090] Two adjacent R 5 The group forms a five-membered or six-membered heterocyclyl condensed ring, wherein the heterocyclyl condensed ring is optionally substituted by one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy; or a pharmaceutically acceptable salt thereof.

[0091] Furthermore, it should be understood that the specific X disclosed herein 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 or R 5 Each embodiment may be combined with another embodiment disclosed herein. 1 , X2 , X 3 , R 1 , R 2 , R 3 , R 4 or R 5 Any other combination of embodiments.

[0092] A particular embodiment of the invention relates to compounds of formula I, Ia, Ib or Ic, wherein R 1 is phenyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridinyl, wherein the phenyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridinyl is optionally substituted by 1, 2, 3 or 4 groups selected from R 4 substituted by 0, 1, 2 or 3 substituents selected from R 4 substituted with 0, 1 or 2 substituents selected from R 4 substituted by a substituent.

[0093] A more specific embodiment of the invention relates to compounds of formula I, Ia, Ib or Ic, wherein R 1 is phenyl, pyridazinyl or pyridinyl, wherein the phenyl, pyridazinyl or pyridinyl is optionally substituted by 1, 2, 3 or 4 groups selected from R 4 substituted by 0, 1, 2 or 3 substituents selected from R 4 substituted with 0, 1 or 2 substituents selected from R 4 substituted by a substituent.

[0094] An even more particular embodiment of the invention relates to compounds of formula I, Ia, Ib or Ic, in which R 1 is phenyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridyl, more particularly R 1 is phenyl, pyrazinyl, pyridazinyl or pyridinyl.

[0095] A particular embodiment of the invention relates to compounds of formula I, Ia, Ib or Ic, wherein R 2 is C1-C6 alkyl, more particularly methyl.

[0096] A particular embodiment of the invention relates to compounds of formula I, Ia, Ib or Ic, wherein R 3 is phenyl, pyridyl or thienyl, wherein the phenyl, pyridyl or thienyl is optionally substituted by 1, 2, 3 or 4 groups selected from R 5 substituted by 1, 2 or 3 substituents selected from R 5 substituted with 1 or 2 substituents selected from R 5 substituted by a substituent.

[0097] A more specific embodiment of the invention relates to compounds of formula I, Ia, Ib or Ic, wherein R 3 is phenyl or pyridyl, wherein the phenyl, the pyridyl is optionally substituted by 1 or 2 selected from R 5 substituted by a substituent.

[0098] A particular embodiment of the invention relates to compounds of formula I, Ia, Ib or Ic, wherein R 4 independently selected from halogen, C1-C6 alkyl and C1-C6 alkoxy, more particularly R 4 are independently selected from halogen, methyl and methoxy, most particularly R 4 Independently selected from fluoro, chloro, methyl and methoxy.

[0099] A particular embodiment of the invention relates to compounds of formula I, Ia, Ib or Ic, wherein R 5 independently selected from halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy, or two ortho R 5 The group forms a five-membered or six-membered heterocyclyl condensed ring, wherein the heterocyclyl condensed ring is optionally substituted by one or more groups independently selected from the following: hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy.

[0100] A more specific embodiment of the invention relates to compounds of formula I, Ia, Ib or Ic, wherein R 5 are independently selected from halogen, cyano, methyl, trifluoromethyl and methoxy, or two ortho-position R 5 The group forms a dioxolane group.

[0101] Specific compounds of formula I according to the present invention are compounds selected from the group consisting of:

[0102] 4-((2-chloro-3-methylpyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0103] 4-((2-chloro-3-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0104] 4-[2-(5-chlorothien-3-yl)ethynyl]-5-methyl-1-(6-methylpyridin-3-yl)imidazole-2-carboxamide

[0105] 4-[2-(3-chlorophenyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide

[0106] 4-((3-cyanophenyl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0107] 4-(2-Chloro-pyridin-4-ylethynyl)-5-methyl-1-(6-methyl-pyridin-3-yl)-1H-imidazole-2-carboxylic acid amide

[0108] 4-((2-chloro-5-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0109] 4-((3-methoxyphenyl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0110] 4-[2-(4-Chlorophenyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide

[0111] 5-Methyl-1-(6-methylpyridin-3-yl)-4-(m-tolylethynyl)-1H-imidazole-2-carboxamide

[0112] 5-methyl-1-(6-methylpyridin-3-yl)-4-((2-(trifluoromethyl)pyridin-4-yl)ethynyl)-1H-imidazole-2-carboxamide

[0113] 4-[2-(2-fluoro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)imidazole-2-carboxamide

[0114] 4-(Benzo[d][1,3]dioxol-4-ylethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0115] 4-((6-chloropyridin-2-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0116] 4-((2-chloropyrimidin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0117] 4-((3-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0118] 4-[2-(5-chloro-3-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)imidazole-2-carboxamide

[0119] 4-((4-chloropyridin-2-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0120] 4-((6-chloropyrimidin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0121] 5-Methyl-1-(6-methyl-3-pyridinyl)-4-[2-(3-pyridinyl)ethynyl]imidazole-2-carboxamide

[0122] 5-Methyl-1-(6-methyl-3-pyridinyl)-4-[2-(4-pyridinyl)ethynyl]imidazole-2-carboxamide

[0123] 5-Methyl-1-(6-methylpyridin-3-yl)-4-((2-methylpyridin-4-yl)ethynyl)-1H-imidazole-2-carboxamide

[0124] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(5-methylpyrazin-2-yl)imidazole-2-carboxamide

[0125] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(6-methylpyridazin-3-yl)imidazole-2-carboxamide

[0126] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(5-methyl-3-pyridinyl)imidazole-2-carboxamide

[0127] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-(6-chloro-3-pyridinyl)-5-methyl-imidazole-2-carboxamide

[0128] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-(6-methoxy-3-pyridinyl)-5-methyl-imidazole-2-carboxamide

[0129] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(5-methyl-2-pyridinyl)imidazole-2-carboxamide

[0130] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(3-pyridinyl)imidazole-2-carboxamide

[0131] 4-[2-(3-chloro-2-methyl-phenyl)ethynyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide

[0132] 4-[2-(2-chloro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)pyrrole-2-carboxamide

[0133] 2-[2-(2-chloro-4-pyridinyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridinyl)imidazole-4-carboxamide

[0134] 2-[2-(3-chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide

[0135] 2-[2-(3-chlorophenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide

[0136] 2-[2-(3-chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamide formate

[0137] 2-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-methyl-5-(3-pyridinyl)imidazole-4-carboxamide formate

[0138] 5-Methyl-4-(phenylethynyl)-1-(p-tolyl)-1H-imidazole-2-carboxamide

[0139] 4-[2-(2-chloro-4-pyridinyl)ethynyl]-5-methyl-1-(p-tolyl)imidazole-2-carboxamide

[0140] 1-(4-Chlorophenyl)-4-((2-chloropyridin-4-yl)ethynyl)-5-methyl-1H-imidazole-2-carboxamide

[0141] 1-(3-Chlorophenyl)-4-((2-chloropyridin-4-yl)ethynyl)-5-methyl-1H-imidazole-2-carboxamide

[0142] 4-(2-Chloro-pyridin-4-ylethynyl)-1-(2,4-difluoro-phenyl)-5-methyl-1H-imidazole-2-carboxylic acid amide

[0143] 4-(2-Chloro-pyridin-4-ylethynyl)-1-(4-fluoro-phenyl)-1H-imidazole-2-carboxylic acid amide

[0144] 4-((2-chloropyridin-4-yl)ethynyl)-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0145] 2-[2-(3-chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridinyl)imidazole-4-carboxamide;

[0146] and pharmaceutically acceptable salts thereof.

[0147] Specific compounds of formula I according to the present invention are compounds selected from the group consisting of:

[0148] 4-((2-chloro-3-methylpyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0149] 4-((2-chloro-3-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0150] 4-[2-(5-chlorothien-3-yl)ethynyl]-5-methyl-1-(6-methylpyridin-3-yl)imidazole-2-carboxamide

[0151] 4-[2-(3-chlorophenyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide

[0152] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(6-methylpyridazin-3-yl)imidazole-2-carboxamide

[0153] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(5-methyl-3-pyridinyl)imidazole-2-carboxamide

[0154] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-(6-methoxy-3-pyridinyl)-5-methyl-imidazole-2-carboxamide

[0155] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(5-methyl-2-pyridinyl)imidazole-2-carboxamide

[0156] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(3-pyridinyl)imidazole-2-carboxamide

[0157] 4-[2-(3-chloro-2-methyl-phenyl)ethynyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide

[0158] 4-[2-(2-chloro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)pyrrole-2-carboxamide

[0159] 2-[2-(3-chlorophenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide

[0160] 2-[2-(3-chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamide formate

[0161] 2-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-methyl-5-(3-pyridinyl)imidazole-4-carboxamide formate

[0162] 2-[2-(3-chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridinyl)imidazole-4-carboxamide;

[0163] and pharmaceutically acceptable salts thereof.

[0164] The compounds of the formula II, III or IV are suitable as intermediates in the preparation of compounds of the formula I.

[0165] Another embodiment of the present invention relates to compounds of formula II:

[0166]

[0167] in

[0168] in

[0169] X 1 N or C

[0170] X 2 N or C

[0171] X 3 N or C

[0172] The condition is X 1 , X 2 and X 3 At least one of is N, and X 1 , X 2 and X 3 No more than two of them represent N, and if X 1 is N, then X 2 Cannot be N;

[0173] Dashed lines represent single or double bonds to enable the five-membered ring to be aromatic;

[0174] R 1 is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2 or 3 nitrogen ring atoms, and wherein the phenyl or the N-heteroaryl is optionally substituted by 1, 2, 3 or 4 selected from R 4 Substituents are substituted;

[0175] R 2 is hydrogen or C1-C6 alkyl, provided that if X 2 is N, then R2 Not hydrogen;

[0176] R 3 is heteroaryl or phenyl, wherein the heteroaryl or the phenyl is optionally substituted by 1, 2, 3 or 4 groups selected from R 5 Substituents are substituted;

[0177] R 4 Independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy;

[0178] R 5 independently selected from hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy, or

[0179] Two adjacent R 5 The group forms a five-membered or six-membered heterocyclyl condensed ring, wherein the heterocyclyl condensed ring is optionally substituted by one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-substituted C1-C6 alkyl and halo-substituted C1-C6 alkoxy; and

[0180] R 6 It is hydrogen or C1-C6 alkyl.

[0181] Another embodiment of the present invention relates to compounds of formula III:

[0182]

[0183] in

[0184] in

[0185] X 1 N or C

[0186] X 2 N or C

[0187] X 3 N or C

[0188] The condition is X 1 , X 2 and X 3 At least one of is N, and X 1 , X 2 and X 3 No more than two of them represent N, and if X 1 is N, then X 2 Cannot be N;

[0189] Dashed lines represent single or double bonds to enable the five-membered ring to be aromatic;

[0190] R 1 is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2 or 3 nitrogen ring atoms, and wherein the phenyl or the N-heteroaryl is optionally substituted by 1, 2, 3 or 4 selected from R 4 Substituents are substituted;

[0191] R 2 is hydrogen or C1-C6 alkyl, provided that if X 2 is N, then R 2 Not hydrogen;

[0192] R 3 is heteroaryl or phenyl, wherein the heteroaryl or the phenyl is optionally substituted by 1, 2, 3 or 4 groups selected from R 5 Substituents are substituted;

[0193] R 4 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy; and

[0194] R 5 independently selected from hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy, or

[0195] Two adjacent R 5 The group forms a five-membered or six-membered heterocyclyl condensed ring, wherein the heterocyclyl condensed ring is optionally substituted by one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy.

[0196] Another embodiment of the present invention relates to compounds of formula IV:

[0197]

[0198] in

[0199] X 1 N or C

[0200] X 2 N or C

[0201] X 3 N or C

[0202] The condition is X 1 , X 2 and X 3 At least one of is N, and X 1 , X 2 and X 3No more than two of them represent N, and if X 1 is N, then X 2 Cannot be N;

[0203] Dashed lines represent single or double bonds to enable the five-membered ring to be aromatic;

[0204] R 1 is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2 or 3 nitrogen ring atoms, and wherein the phenyl or the N-heteroaryl is optionally substituted by 1, 2, 3 or 4 selected from R 4 Substituents are substituted;

[0205] R 2 is hydrogen or C1-C6 alkyl, provided that if X 2 is N, then R 2 is not hydrogen; and

[0206] R 4 Independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy.

[0207] The compound of formula I and its pharmaceutically acceptable salt can be prepared by methods known in the art, for example, by the following method, which comprises

[0208] a) making a compound of formula II

[0209]

[0210] Where X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and R 6 As defined in this article

[0211] Reacts with ammonia (NH3),

[0212] To obtain a compound of formula I,

[0213]

[0214] Where X 1 , X 2 , X 3 ,,R 1 , R 2 and R 3 As defined herein, and

[0215] If necessary, converting the obtained compound into a pharmaceutically acceptable salt;

[0216] or

[0217] b) making a compound of formula III

[0218]

[0219] Where X 1 , X 2 , X 3 , R 1 , R 2 and R 3 As defined in this article

[0220] Reacting under acidic conditions (such as sulfuric acid),

[0221] To obtain a compound of formula I,

[0222]

[0223] Where X 1 , X 2 , X 3 ,,R 1 , R 2 and R 3 As defined herein, or

[0224] If necessary, converting the obtained compound into a pharmaceutically acceptable salt;

[0225] or

[0226] c) making a compound of formula IV

[0227]

[0228] Where X 1 , X 2 , X 3 , R 1 and R 2 As defined in this article

[0229] With formula IV a Compound reaction,

[0230] R 3 -X IV a

[0231] wherein X is halo, in particular iodo or bromo, and R 3 As defined in this article

[0232] To obtain a compound of formula I,

[0233]

[0234] Where X 1 , X 2 , X3 , R 1 , R 2 and R 3 The resulting compound is converted into a pharmaceutical salt as defined herein, or when necessary.

[0235] In another embodiment, the present invention provides compounds according to formula I, Ia, Ib or Ic as described herein for use as therapeutically active substances.

[0236] In yet another embodiment, the invention provides a compound according to formula I, Ia, Ib or Ic as described herein for use in treating, preventing and / or delaying progression of a disease, more particularly for treating a disease: a CNS disease, particularly a psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ocular, endocrine disease, and / or other disease as described herein, including 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 dementia, 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, drug abuse and drug dependence, Tourette syndrome, tardive dyskinesia, somnolence, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, refractory edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular 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 particularly cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain, and autism (sensory sensitivity).

[0237] In another embodiment, the invention provides the use of a compound according to formula I, Ia, Ib or Ic as described herein for the preparation of a medicament for treating, preventing and / or delaying progression of the following diseases, more particularly for treating the following diseases: CNS diseases, particularly psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivation, metabolic, cardiovascular, renal, ocular, endocrine diseases, and / or other diseases as described herein, including 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 dementia, Parkinson's disease, Huntington's disease, depression, anxiety, refractory depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder The invention relates to a group of diseases including, but not limited to, 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 particularly to a group of diseases including, but not limited to, cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain, and autism (sensory sensitivity).

[0238] In one aspect, the present application provides a method of treating HCN1 disease in a subject suffering from an HCN1-related disease, the method comprising administering a therapeutically effective amount of any of the above compounds to the subject in need thereof.

[0239] In another embodiment, the present invention provides a method for treating, preventing and / or delaying the progression of, more particularly treating, CNS diseases, particularly psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ocular, endocrine diseases, and / or other diseases described herein, including 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 dementia, 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, Drug abuse and drug dependence, Tourette's syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, refractory edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular 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 particularly cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain and autism (sensory sensitivity), the method comprising administering an effective amount of a compound of formula I as described herein.

[0240] In certain embodiments, the present invention provides methods for treating, preventing and / or delaying the progression of, more particularly treating, CNS diseases, particularly psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ocular, endocrine diseases, and / or other diseases described herein, including 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 dementia, 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's syndrome, tardive dyskinesia, somnolence, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, refractory edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular 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 particularly cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain, and autism (sensory sensitivity), the method comprising administering an effective amount of a compound according to Formula I, Ia, Ib, or Ic as described herein.

[0241] In particular, the HCN1 disease or HCN1-related disease is a CNS disease, in particular a psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ocular, endocrine disease, and / or other diseases described herein, including 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 dementia, 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, drug abuse and drug dependence, Tourette syndrome, tardive dyskinesia, somnolence, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, refractory edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular 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 particularly cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain, and autism (sensory sensitivity), most particularly cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain, and autism (sensory sensitivity), most particularly cognitive impairment associated with schizophrenia.

[0242] In one aspect, the present application provides a pharmaceutical composition comprising a mixture of a compound according to any one of the above embodiments and at least one pharmaceutically acceptable carrier, such as an excipient or a diluent.

[0243] In another embodiment, the present invention provides the use of a compound of formula I, Ia, Ib or Ic for the preparation of a medicament for treating, preventing and / or delaying the progression of HCN1-related diseases, more particularly for treating said diseases.

[0244] In yet another embodiment, the present invention provides a medicament comprising a compound of formula I, Ia, Ib or Ic as defined herein or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier and a process for the production thereof, which comprises bringing one or more compounds of formula I and / or a pharmaceutically acceptable addition salt thereof and, if necessary, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

[0245] Another embodiment provides pharmaceutical compositions or medicaments comprising a compound of the invention and a therapeutically inert carrier, diluent, or pharmaceutically acceptable excipient, and methods of using the compounds of the invention to prepare such compositions and medicaments.

[0246] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the specific disease being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disease, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to practitioners. For example, the amount may be below an amount that is toxic to normal cells or the mammal as a whole.

[0247] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and if local treatment is required, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0248] The compounds of the present invention can be administered in any convenient administration form, for example, tablets, coated tablets, dragees, powders, capsules (soft and hard gelatin capsules), solutions (i.e., injection solutions), dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, eye drops, ear drops, etc. Such compositions may contain conventional components of pharmaceutical preparations, for example, diluents, carriers, pH adjusters, sweeteners, fillers and other active agents.

[0249] Typical formulations are prepared by mixing the compounds of the invention with a pharmaceutical carrier or excipient. Suitable pharmaceutical carriers and excipients are well known to those skilled in the art and are described in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery .Systems .Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy .Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press, 2005. Pharmaceutical carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances that can also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrating agent or encapsulating material. In powders, the carrier is generally a finely powdered solid mixed with the finely powdered active ingredient. In tablets, the active ingredient is generally mixed with a carrier having the necessary binding capacity in suitable proportions and compressed into the desired shape and size. Powders and tablets preferably contain from about one (1) percent to about seventy (70) percent of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like.

[0250] The dosage that the compounds of the present invention can be used can vary within a wide range and is certainly suitable for the individual requirements in each particular case. Usually, in the case of oral administration, a daily dosage of about 0.01 mg to 1000 mg of the compound of formula (I) per person should be appropriate, but the above upper limit may also be exceeded if necessary.

[0251] An example of a suitable oral dosage form is a tablet containing about 100 mg to 500 mg of the compound of the present invention and about 30 mg to 90 mg of anhydrous lactose, about 5 mg to 40 mg of cross-linked carboxymethylcellulose sodium, about 5 mg to 30 mg of polyvinyl pyrrolidone (PVP) K30 and about 1 mg to 10 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with the PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment.

[0252] An example of an aerosol formulation can be prepared by dissolving a compound of the invention (e.g. 10 mg to 100 mg) in a suitable buffer solution (e.g. phosphate buffer), adding a penetration enhancer (e.g. a salt such as sodium chloride) if necessary. The solution can be filtered, for example using a 0.2 μm filter, to remove impurities and contaminants.

[0253] Thus, one embodiment includes a pharmaceutical composition comprising a compound of the invention as described herein, or a stereoisomer thereof. In another embodiment includes a pharmaceutical composition comprising a compound of the invention as described herein, or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0254] The compounds of the present invention can be used alone or in combination with other drugs to treat, prevent and / or delay the progression of the following diseases: HCN1-related diseases, particularly psychiatric, neurological, neurodevelopmental, neurodegenerative, emotional, motivational, metabolic, cardiovascular, renal, ocular, endocrine diseases, and / or other diseases described herein, including 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 dementia, Parkinson's disease, Huntington's disease, depression, anxiety, refractory depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome , drug abuse and drug dependence, Tourette's syndrome, tardive dyskinesia, somnolence, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, refractory 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 particularly cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain, and autism (sensory sensitivity), most particularly cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain, and autism (sensory sensitivity), most particularly cognitive impairment associated with schizophrenia.

[0255] A particular embodiment of the invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, for use in the treatment, prevention and / or delay of progression of: cognitive disorders associated with: psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ocular, endocrine diseases, and / or other diseases described herein, including 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 dementia, Parkinson's disease, Huntington's disease, depression, anxiety, refractory depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social Anxiety disorders, postpartum depression, serotonin syndrome, drug abuse and drug dependence, Tourette's syndrome, tardive dyskinesia, somnolence, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, refractory 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 particularly cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain, and autism (sensory sensitivity), most particularly cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain, and autism (sensory sensitivity), most particularly cognitive impairment associated with schizophrenia.

[0256] Another embodiment includes a pharmaceutical composition comprising a compound of the present invention as described herein for use in treating, preventing and / or delaying the progression of HCN1-related diseases, more particularly for treating HCN1-related diseases. Another embodiment includes a pharmaceutical composition comprising a compound of the present invention as described herein for use in treating, preventing and / or delaying the progression of HCN1-related diseases, more particularly for treating HCN1-related diseases.

[0257] In another embodiment, the present invention provides the preparation of a compound of Formula I, Ia, Ib or Ic as described herein.

[0258] The preparation of the compounds of formula I, Ia, Ib or Ic of the present invention can be carried out according to sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required for performing the reaction and purifying the resulting product 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 methods described herein or known to those skilled in the art such as chiral chromatography or crystallization.

[0259] In addition, the compounds of the present invention can be prepared from commercially available substances or by using general synthesis techniques and procedures known to those skilled in the art. The following summarizes the reaction schemes suitable for preparing such compounds. The substituents and indices used in the following method descriptions have the meanings provided herein. Further examples can be found in the specific examples detailed below.

[0260] In more detail, compounds of formula I and intermediates thereof can be prepared by Schemes 1-5 and as described by specific examples.

[0261] A subgroup of compounds of formula I (wherein X 1 N, X 2 is C, and X 3 is N) can be prepared as described in Schemes 1-3 below.

[0262] Solution 1

[0263]

[0264] The intermediate of formula V (wherein R 1 and R 2 As defined above, and which can be synthesized as known in the art or as exemplified in the specific examples) is reacted with a suitable reducing agent (e.g., lithium aluminum hydride) to obtain the corresponding alcohol of formula VI (Scheme 1). Subsequently, it can be oxidized to the aldehyde of formula VII using a suitable oxidizing agent (e.g., manganese dioxide). The aldehyde of formula VII can be converted to the alkyne of formula VIII by reacting with a suitable diazo-phosphonate 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 functionalizing the imidazole ring, the alkyne of formula VIII needs to be protected with a suitable protecting group (e.g., trimethylsilyl (TMS)) by reacting with a suitable reagent (e.g., trimethylsilyl chloride) in the presence of a strong non-nucleophilic base (e.g., lithium hexamethyldisilazane or lithium diisopropylamide). The chloroformate can be prepared by reacting with the corresponding chloroformate ClC(O)OR after deprotonation with a strong base such as n-butyllithium or lithium diisopropylamide. 8The obtained compound of formula IX is carboxylated to form a compound of formula X (wherein R 8 The combined deprotection-amide formation can be achieved by reacting the compound of formula X with excess ammonia, preferably in a pressure vial, at elevated temperatures of 40° C. to 80° C., in a suitable polar or protic solvent (e.g. methanol), optionally with the addition of catalytic or stoichiometric amounts of sodium cyanide. Alternatively, the deprotection-amidation procedure can be performed in a stepwise manner. In the last step, in the Sonogashira reaction, the central building block of formula IV is reacted with a compound of formula R using a catalytic or stoichiometric amount of a suitable transition metal complex (e.g. bis(triphenylphosphine)palladium(II) dichloride or 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride), optionally as a solvent adduct, in the presence of a stoichiometric amount of a suitable base (e.g. triethylamine or cesium carbonate), optionally in the presence of a catalytic or stoichiometric amount of a suitable co-catalyst (e.g. copper(I) iodide), in a suitable solvent (such as dimethylformamide or acetonitrile). 3 -Y suitable reagent (where R 3 As defined above, and wherein Y is halogen, preferably bromine or iodine, more preferably iodine).

[0265] A particular embodiment of the present invention relates to a process for preparing a compound of formula (Ia) as defined above and a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (IV) as defined above with a compound of formula R in the presence of 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 co-catalyst such as copper(I) iodide. 3 -Y compounds, where R 3 and Y are as defined above.

[0266] Solution 2

[0267]

[0268] Alternatively, compounds of formula Ia can be obtained as described in Scheme 2, wherein R 1 , R 2 and R 3 As defined above. The intermediate of formula V (wherein R 1 and R 2As defined above) is converted to the corresponding Weinreb anmide of formula XI. Alternatively, this conversion can be achieved by a two-step process consisting of ester hydrolysis followed by amide formation using standard conditions known in the art. Next, the Weinreb anmide of formula XI can be reacted with a suitable methyl-substituted heteroaromatic compound of formula XII after deprotonation using a strong non-nucleophilic lithium base (e.g., lithium diisopropylamide) to obtain a ketone of formula XIII. The intermediate of formula XIII is then further converted to an alkyne of formula XV via an intermediate of formula XIV by reacting with N-(chloromethylene)-N-methylmethylammonium chloride, followed by reaction with a non-nucleophilic base (e.g., potassium tert-butoxide). It can be reacted with the corresponding chloroformate ClC(O)OR after deprotonation using a strong base (e.g., n-butyllithium or lithium diisopropylamide). 7 The obtained compound of formula XV is carboxylated to form a compound of formula IIa (wherein R 7 Finally, compounds of formula I can be synthesized by reacting intermediates of formula IIa with excess ammonia, preferably in a sealed pressure vial at elevated temperatures of 70°C to 100°C in a suitable solvent such as methanol.

[0269] Alternatively, the compound of formula XV can be carboxylated by reaction with carbon dioxide after deprotonation using a strong base (e.g., n-butyllithium or lithium diisopropylamide) to form a compound of formula IIa (wherein R 7 =H). In the final step, amide formation can be achieved using methods known in the scientific literature, for example using stoichiometric amounts of N,N′-carbonyldiimidazole and ammonia to obtain compounds of formula Ia.

[0270] Alternatively, the procedure described in Scheme 3 can be used to synthesize compounds of Formula IX, wherein R 1 and R 2 As defined above.

[0271] Solution 3

[0272]

[0273] The compound of formula XVI (wherein R 2 As defined above, and X is halogen, preferably iodine, and can be obtained using methods known in the art) can be combined with a compound of formula XVII (wherein R 1 As defined above, and Y is halogen or B (OR 9 )2, where R 9 is hydrogen, methyl, or B(OR 9)2 is pinacol boronyl) optionally in the presence of a suitable transition metal catalyst (such as a palladium- or copper-containing complex), optionally in the presence of a suitable base (e.g. cesium carbonate or potassium phosphate). In ChamLam coupling (Y is B(OR 9 )2) In the case of oxidizing agent (e.g. oxygen) is also required. The compound of formula XVIII can be converted to the compound of formula IX by reacting with trimethylsilyl acetylene under standard Sonogashira coupling conditions using a catalytic or stoichiometric amount of a suitable transition metal complex (e.g. bis(triphenylphosphine)palladium(II) dichloride or 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride), optionally as a solvent adduct, in the presence of a stoichiometric amount of a suitable base (e.g. triethylamine or cesium carbonate), optionally in the presence of a catalytic or stoichiometric amount of a suitable co-catalyst (e.g. copper(I) iodide), in a suitable solvent (such as dimethylformamide or acetonitrile).

[0274] Another subgroup of compounds of formula I (wherein X 1 C, X 2 is N, and X 3 is N) can be prepared as described in Scheme 4.

[0275] Solution 4

[0276]

[0277] Commercially available compounds of formula XX can be selectively methylated under standard conditions, for example, using sodium hydride as a base and using 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 (wherein X is a halogen, preferably bromine or iodine) by reaction with an appropriate halogenating agent (e.g., N-bromosuccinimide, N-iodosuccinimide, or bromine). Subsequently, the compound can be selectively converted to a compound of formula XXII (wherein X is a halogen, preferably bromine or iodine) by, for example, reacting with a reagent of formula XXV (wherein R 1 As defined above, and Y is B (OR 9 )2, where R 9 is hydrogen, methyl, or B(OR 9 )2 is a pinacol boronyl) reaction to introduce a substituent R 1The intermediate of formula XXIII can be selectively halogenated again to the intermediate of formula XXIV (wherein Z is bromine or iodine, preferably iodine) by reaction with a suitable halogenating agent (e.g. N-iodosuccinimide (provided that Z=I)). In the next step, the intermediate of formula XXIII can be selectively halogenated ... R) by reaction with a suitable halogenating agent (e.g. N-iodosuccinimide (provided that Z=I)). In the next step, the intermediate of formula XXIII can be selectively halogenated to the intermediate of formula XXIV (wherein R) by reaction with a suitable halogenating agent (e.g. N-iodosuccinimide (provided that Z=I)). In the next step, the intermediate of formula XXIII can be selectively halogenated to the intermediate of formula XXIV (wherein R) by reaction with a suitable halogenating agent (e.g. N-iodos 3 As defined above, and which are commercially available or can be synthesized by methods known in the art) reaction to introduce the substituent R 3 In a final step, the cyano group is hydrolyzed to the carboxamide using methods known in the art, for example by reaction with sulfuric acid.

[0278] Another subgroup of compounds of formula I (wherein X 1 N, X 2 is C, and X 3 C) can be prepared by the procedure shown in Scheme 5.

[0279] Solution 5

[0280]

[0281] Commercially available compounds of the formula XXVII can be reacted with an appropriate reagent of the formula XXVIII (wherein R 1As defined above, and Y is a halogen, preferably bromine or iodine). The intermediate of the obtained formula XXIX can then be halogenated using an appropriate halogenating agent (such as N-iodosuccinimide or N-bromosuccinimide) to produce a compound of formula XXX (wherein X is bromine or iodine, preferably iodine). In the next step, the corresponding alkyne of formula XXVI (wherein R) can be reacted by using standard Sonogashira reaction conditions, for example, using a catalytic or stoichiometric amount of a suitable transition metal complex (such as dichlorobis(triphenylphosphine)palladium(II) or dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)), optionally as a solvent adduct, in the presence of a 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 iodide(I)), in a suitable solvent (such as dimethylformamide or acetonitrile). 3 As defined above, and which are commercially available or can be synthesized by methods known in the art) reaction to introduce the substituent R 3 The resulting intermediate of formula XXXI can be converted to the desired compound of formula I by direct reaction with ammonia, optionally in a sealed vial at elevated temperature, or via intermediate II″ as described in Scheme 5. Hydrolysis can be achieved by standard methods known in the art, for example by reaction with an alkali metal hydroxide, for example lithium hydroxide, in a suitable solvent, such as tetrahydrofuran or water or a mixture thereof. As a final step, amide formation can be achieved using methods known in the scientific literature, for example using stoichiometric amounts of N,N′-carbonyldiimidazole and ammonia to obtain the compound of formula I.

[0282] A particular embodiment of the present invention relates to a process for preparing a compound of formula (I) as defined according to the present invention and a pharmaceutically acceptable salt thereof, which comprises, as shown in Scheme 6, reacting a compound of formula (IVa) (wherein R 1 , R 2 , R 3 , X 1 , X 2 and X 3 as defined above) and formula R 3 -Y compounds (wherein Y is as defined above).

[0283] Solution 6

[0284]

[0285] This compound was studied according to the test given hereinafter.

[0286] Description of HCN1, HCN2, HCN3, and HCN4 assays

[0287] In vitro, libraries were assayed using high-throughput cellular electrophysiology in 384-well plates and medicinal chemistry assays were used for single concentration screening of compounds as well as voltage and dose dependence of compounds in IC50 determinations.

[0288] HEK-293 cell lines stably expressing the coding DNA of HCN1, 2, 3 or 4 were verified on the automated patch clamp (APC) platform Ionworks Barracuda. ​​Cell cultures were maintained for up to 20 generations in DMEM / F12 cell growth medium containing FBS and appropriate antibiotics at 37°C, 5% CO2. The expression of HCN protein in cells was induced by adding tetracycline at a time point of 40-72 hours before the assay. Cells can be incubated at 27°C for 2-24 hours for induction. Intracellular (containing glucose) and extracellular HEPES buffers containing various divalent cations were adjusted to pH 7.2 and 7.4, respectively. Cells were harvested at 80% confluence and resuspended in extracellular buffer and added to the wells. Freshly prepared escin solution was added to the intracellular buffer and used to establish whole-cell recordings via perforated patch clamps by APC.

[0289] Directly measure the current through the activated channel by APC by adopting hyperpolarization voltage step.Increase and stabilize the activation window by adding Br-cAMP that can permeate cells.Use -30mV holding potential and -100mV or from -120mV with 20mV step length to increase to multiple test pulses under 0mV to establish the baseline of use and voltage-dependent protocol respectively.Add test compound after baseline recording, then carry out 10min incubation, voltage-dependent protocol recording and use-dependent recording.Data are corrected for baseline and current decay (based on hole), and normalized for inhibition % (based on plate).HCN inhibitors and zatebradine with different effects and selectivity reported five kinds of previously are used for run to run and plate to plate quality control.Use non-selective and potent inhibitor as positive control.Analyze inhibition percentage under -80, -100, -120mV of voltage-dependent protocol and pulse 0 and 50 of use-dependent protocol. A similar approach was used to assess selectivity for HCN2, HCN3, and HCN4 overexpressing cell lines. Since HCN4 activates more slowly than other HCN channels, activation was prolonged to achieve steady-state activation.

[0290] The table below shows the current inhibition data for selected compounds during a hyperpolarizing pulse at -100 mV:

[0291]

[0292]

[0293] Experimental Section

[0294] The following examples are provided to illustrate the present invention. They should not be considered as limiting the scope of the present invention, but merely as representative thereof.

[0295] conventional

[0296] Analytical methods

[0297] HPLC (method LCMS_fastgradient)

[0298] Column: Agilent Zorbax Eclipse Plus C18 Rapid Separation High Throughput Column, 2.1 × 30 mm, 1.8 μm, Part No. 959731-902

[0299] Solvent A: 0.01% formic acid in water; Solvent B: acetonitrile (MeCN)

[0300] gradient:

[0301] Time [min] Flow rate [ml / min] ％A ％B initial 0.8 97 3 0.2 1.0 97 3 1.7 1.0 3 97 2.0 1.0 3 97 2.1 1.0 97 3

[0302] abbreviation

[0303] The following abbreviations are used in the experimental section:

[0304] THF = tetrahydrofuran;

[0305] MTBE = methyl tert-butyl ether;

[0306] DMF = dimethylformamide;

[0307] TLC = thin layer chromatography;

[0308] rt = room temperature, 20°C-25°C.

[0309] Starting material

[0310] Basic chemicals and solvents were purchased and used as received without further purification. Intermediates Int-1, Int-2, Int-13-Int-15, Int-35-Int-43, Int-50, Int-51, Int-57, Int-58, Int-67-Int-71, Int-78, Int-81, Int-84, Int-91-Int-96 are commercially available or can be synthesized using methods known in the art.

[0311] Intermediates

[0312] Intermediate 9

[0313] 4-Ethynyl-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide (General Procedure A)

[0314]

[0315] Step 1: 5-Methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-4-carboxylic acid ethyl ester (Int-3)

[0316] At 0 ° C, ethyl 3-oxobutanoate (Int-1) (5.17g, 5.03mL, 39.7mmol) was dissolved in acetic acid (9mL), and a solution of sodium nitrite (3.01g, 43.7mmol) in water (13mL) was added dropwise. The mixture was stirred for 2 hours at 5-10 ° C. Then, it was diluted with tert-butyl methyl ether (100mL), the organic layer was washed with saturated sodium dihydrogen phosphate aqueous solution (50mL) and water (2×50mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude (Z)-2-(hydroxyimino)-3-oxobutanoic acid ethyl ester (6.2g, 39mmol, 98% yield) in the form of a colorless oil. No further purification is required.

[0317] Crude (Z)-2-(hydroxyimino)-3-oxobutanoic acid ethyl ester (6.2 g, 39 mmol) was dissolved in toluene (80 mL), and 6-methylpyridin-3-amine (Int-2) (4.42 g, 40.9 mmol) was added in sequence, followed by pyridinium p-toluenesulfonate (196 mg, 779 μmol). The dark reaction mixture was stirred at reflux in a Dean-Stark apparatus for 12 hours. 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 black reaction mixture was stirred under a hydrogen atmosphere for 24 h. Because the reaction does not show complete conversion, fresh Pd / C 10% (829mg, 779μmol) and scandium (III) trifluoromethanesulfonate (192mg, 390μmol) are added, and stirring for another 24h is continued under hydrogen atmosphere. Then, the black reaction mixture is filtered, and the filtrate is concentrated in a vacuum. The crude product is adsorbed on isolute HM-N and purified by column chromatography (80g, silica gel, methanol / dichloromethane, gradient 0: 100 to 10: 90 (v / v)), the title compound (5.3g, 21.6mmol, 55% yield) is obtained in the form of a light brown solid. HPLC (LCMS_ fast gradient method) t R =0.79min.MS(ES+)m / z 246.0[M+H].

[0318] Step 2: (5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazol-4-yl)methanol (Int-4)

[0319] In a 100ml four-necked flask, 5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-4-carboxylic acid ethyl ester (Int-3) (2.1g, 8.58mmol) was dissolved in THF (50mL). The brown solution was cooled to 0°C. Then, lithium aluminum hydride (1M in THF) (11.3mL, 11.3mmol) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour. After that, water (0.44mL), 1M aqueous sodium hydroxide solution (0.44mL) and water (1.32mL) were subsequently added, and the mixture was stirred at room temperature for 1h. Sodium sulfate (30g) was added, the slurry was filtered, washed with THF (50mL), and the filtrate was concentrated in vacuo to give the title compound (1.35g, 6.64mmol, 77% yield) as a yellow solid. HPLC (LCMS fast gradient method) t R =0.23min.MS(ES+)m / z 204.1[M+H].

[0320] Step 3: 5-Methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-4-carbaldehyde (Int-5)

[0321] (5-methyl-1-(6-methylpyridin-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 black mixture was stirred at room temperature for 1 h. Then, it was filtered, washed with dichloromethane (20 mL), and the filtrate was concentrated in vacuo to give the title compound (0.97 g, 4.82 mmol, 73% yield) as a yellow solid. HPLC (LCMS-fast gradient method) t R =0.62min.MS(ES+)m / z 202.1[M+H].

[0322] Step 4: 5-(4-ethynyl-5-methyl-1H-imidazol-1-yl)-2-methylpyridine (Int-6)

[0323] 5-Methyl-1-(6-methylpyridin-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 was stirred at room temperature for 18 h. Afterwards, it was poured into saturated aqueous sodium bicarbonate solution (100 mL) and extracted with dichloromethane (2×80 mL). The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was adsorbed on isolute HM-N and purified by column chromatography (40 g, silica gel, methanol / dichloromethane, gradient 0:100 to 5:95 (v / v)) to give the title compound (570 mg, 2.89 mmol, 60% yield) as a yellow oil. HPLC (LCMS_fast gradient method) t R =0.71min.MS(ES+)m / z 198.1[M+H].

[0324] Step 5: 2-Methyl-5-(5-methyl-4-((trimethylsilyl)ethynyl)-1H-imidazol-1-yl)pyridine (Int-7)

[0325] 5-(4-ethynyl-5-methyl-1H-imidazol-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 (1M in THF / ethylbenzene, 6.45 mL, 6.45 mmol) was added dropwise. The reactants were stirred at -60 ° C for 1 h. Then, trimethylsilyl chloride (701 mg, 825 μL, 6.45 mmol) was added at -60 ° C, and the reaction mixture was stirred at -60 ° C for another 2 h. Next, saturated aqueous ammonium chloride solution (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 over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the title compound (1.74 g) as a brown solid, which was used in the next step without further purification. HPLC (LCMS-fast gradient method) t R =1.18min.MS(ES+)m / z 270.3[M+H].

[0326] Step 6: 5-methyl-1-(6-methylpyridin-3-yl)-4-((trimethylsilyl)ethynyl)-1H-imidazole-2-yl Methyl formate (Int-8)

[0327] 2-Methyl-5-(5-methyl-4-((trimethylsilyl)ethynyl)-1H-imidazol-1-yl)pyridine (Int-7, crude material 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-Butyl lithium (1.6 M in hexane, 4.4 mL, 7.1 mmol) was added in one portion at -60°C. The resulting brown solution was stirred at -60°C for 10 min. Then, methyl chloroformate (1.04 g, 850 μl, 11 mmol) was added in one portion at -60°C. The reaction mixture was stirred at -60°C for one hour. Then, saturated aqueous ammonium chloride solution (20 mL) was added, followed by ethyl acetate (20 mL). After phase separation, the aqueous layer was extracted with ethyl acetate (2×20 mL), the combined organic layer was washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was adsorbed on isolute HM-N and purified by column chromatography (40 g, silica gel, ethyl acetate / n-hexane, gradient 0: 100 to 80: 20 (v / v)) to give the title compound (940 mg, 2.87 mmol, 44% yield over 2 steps) as a white solid. HPLC (LCMS_fast gradient method) t R =1.28min.MS(ES+)m / z 328.2[M+H].

[0328] Step 7: 4-ethynyl-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide (Int-9)

[0329] At 50 ° C, in a pressure tube, a solution of 5-methyl-1-(6-methylpyridin-3-yl)-4-((trimethylsilyl)ethynyl)-1H-imidazole-2-carboxylic acid methyl ester (Int-8) (426 mg, 1.3 mmol) and sodium cyanide (8.93 mg, 182 μmol) in ammonia (7N methanol solution) (11.2 mL, 78.1 mmol) was stirred for 1.5 h. After cooling, the reaction mixture was concentrated in vacuo. The residue was adsorbed on isolute HM-N and purified by column chromatography (40 g, silica gel, methanol / dichloromethane, gradient 0: 100 to 10: 90 (v / v)) to give the title compound (273 mg, 1.14 mmol, 87% yield) as an off-white solid. HPLC (LCMS_fast gradient method) t R =0.72min.MS(ES+)m / z 241.2[M+H].

[0330] The following intermediates can be synthesized similarly to the synthesis of Int-9 using the procedure described in General Procedure A and replacing reagent Int-2 with the reagents listed in the table below:

[0331]

[0332] Intermediate 22

[0333] 4-Ethynyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide

[0334]

[0335] Step 1: Ethyl 1-(6-methyl-3-pyridyl)imidazole-4-carboxylate (Int-16)

[0336] 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 ethyl 2-nitroacetate (Int-15) (7.38 g, 6.15 ml, 55.5 mmol) and acetic acid (1 mL) were added. The dark brown solution was stirred at 140 ° C for 2 h. Then, it was cooled to 75 ° C and more 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 h. A second portion of iron (6.45 g, 115 mmol) was added and stirring was continued at 130 ° C for 1 h. After cooling, the mixture was diluted with ethyl acetate (175 mL) and the resulting suspension was stirred at 23 ° C for 1 h. It was filtered through a Celite pad, washed (ethyl acetate), and the filtrate was concentrated in vacuo. The crude product was adsorbed on isolute HM-N and purified by column chromatography (200 g, silica gel, methanol / dichloromethane, isocratic, 10:90 (v / v)), followed by crystallization from dichloromethane / tert-butyl methyl ether to give the title compound (3.2 g, 13.8 mmol, 30% yield) as a light brown solid. HPLC (LCMS-fast gradient method) t R =0.76min.MS(ES+)m / z 232.2[M+H].

[0337] The following steps 2-7 were performed similarly to the protocols described in General Procedure A, steps 2-7, respectively.

[0338] Step 7: Ethyl 1-(6-methyl-3-pyridyl)imidazole-4-carboxylate (Int-22)

[0339] HPLC (LCMS_fast gradient method)t R =0.64min.MS(ES+)m / z 227.2[M+H].

[0340] Intermediate 28

[0341] Methyl 4-[2-(2-chloro-3-fluoro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)imidazole-2-carboxylate (General Procedure B)

[0342]

[0343] Step 1: Ethyl 5-methyl-1-(6-methyl-3-pyridyl)imidazole-4-carboxylate (Int-3)

[0344] At 0 ° C, 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). The reaction mixture was stirred at 5 ° C-10 ° C for 2 h. The resulting reaction mixture was diluted with tert-butyl methyl ether (100 mL), and the organic layer was washed with saturated disodium hydrogen phosphate solution (2 × 50 mL), dried (sodium sulfate), filtered, and concentrated in vacuo to give (Z)-2-(hydroxyimino)-3-oxobutanoic acid ethyl ester (6.204 g, 39 mmol, 98% yield) as a colorless oil, which can be used without further purification. HPLC (LCMS_fast gradient method) t R =0.72min.MS(ES+)m / z 160.1[M+H].

[0345] To a solution of ethyl (Z)-2-(hydroxyimino)-3-oxobutanoate (6.2 g, 39 mmol) in toluene (78 ml) were added 6-methylpyridin-3-amine (Int-2) (4.42 g, 40.9 mmol) and pyridinium p-toluenesulfonate (196 mg, 779 μmol) in sequence. The dark reaction mixture was stirred at reflux using a Dean-Stark apparatus for 12 h (the desired intermediate ethyl (2Z,3E)-2-hydroxyimino-3-[(6-methyl-3-pyridinyl)imino]butanoate, HPLC (LCMS-fast gradient method) t R =0.61 min.MS (ES+) m / z 250.2 [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 added to the solution in sequence under argon at room temperature. The resulting black reaction mixture was stirred for 24 h under a hydrogen atmosphere. Fresh Pd / C 10% (829 mg, 779 μmol) and scandium trifluoromethanesulfonate (192 mg, 390 μmol) were added and stirring was continued for 24 h under hydrogen. The black reaction mixture was filtered and evaporated to dryness in vacuo. The residue was adsorbed on isolute HM-N and purified by column chromatography (80 g, silica gel, methanol / dichloromethane, gradient 0:100 to 10:90) to give the title compound (5.3 g, 21.6 mmol, 56% yield) as a light brown solid. HPLC (LCMS_fast gradient method) t R =0.79min.MS(ES+)m / z 246.0[M+H].

[0346] Step 2: N-methoxy-N,5-dimethyl-1-(6-methyl-3-pyridyl)imidazole-4-carboxamide (Int-23)

[0347] In a 100mL three-necked flask, N, O-dimethylhydroxylamine hydrochloride (2.68g, 27.5mmol) is combined with dioxane (15mL) to obtain a white suspension. Trimethylaluminum (2M toluene solution) (13.7mL, 27.5mmol) is added dropwise at 5°C. The reaction mixture is stirred at room temperature for 45min, and then a solution of 5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-4-carboxylic acid ethyl ester (Int-3) (2.246g, 9.16mmol) in 15mL dioxane is added at 10°C. The reaction mixture is allowed to reach room temperature and stirred for 20h. Then, the reaction mixture is cooled to 0°C and water (10mL) is slowly added (exothermic!!). The orange slurry obtained is filtered through a Celite pad and washed several times with water (3×20mL) and EtOAc (3×20mL). The filtrate layer was separated and the organic phase was washed with brine (20 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was adsorbed on isolute HM-N and purified by column chromatography (70 g, silica gel, methanol / dichloromethane, gradient 0: 100 to 10: 90) to give the title compound (1.27 g, 4.85 mmol, 53% yield) as a light brown solid. HPLC (LCMS_fast gradient method) t R =0.66min.MS(ES+)m / z 261.3[M+H].

[0348] Step 3: 2-(2-chloro-3-fluoro-4-pyridinyl)-1-[5-methyl-1-(6-methyl-3-pyridinyl)imidazol-4-yl] Ethyl Ketone (Int-25)

[0349] Under Ar, in a dry Schlenk tube, diisopropylamine (816 mg, 1.14 ml, 8.07 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 ° C. n-Butyl lithium solution (1.6 M in hexane) (4.92 mL, 7.88 mmol) was added dropwise, and the mixture was stirred at 0 ° C for 15 min. The reaction mixture was cooled to -78 ° C, and then 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 min (the mixture became an orange suspension). A solution of N-methoxy-N, 5-dimethyl-1-(6-methylpyridin-3-yl)-1H-imidazole-4-carboxamide (Int-23) (500mg, 1.92mmol) in THF (3mL) was added dropwise, and the mixture was stirred at -78 °C for 1h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (10mL) and allowed to reach room temperature. The reaction mixture was diluted with ethyl acetate (50mL) and water (20mL). The organic layer was washed with saturated aqueous ammonium chloride solution (20mL) and brine (20mL), dried (sodium sulfate), filtered and concentrated. The crude product was adsorbed on isolute HM-N and purified by column chromatography (20g, silica gel, methanol / dichloromethane, gradient 0: 100 to 10: 90) to give the title compound (612mg, 1.78mmol, 92% yield) as a white powder. HPLC (LCMS_ fast gradient method) t R =1.01 min.MS (ES+) m / z 345.3, 347.3 [M+H, Cl isotope].

[0350] Step 4: (E)-3-chloro-2-(2-chloro-3-fluoro-4-pyridinyl)-3-[5-methyl-1-(6-methyl-3-pyridinyl)]-amidine [4-oxazol-4-yl]prop-2-enal (Int-26)

[0351] Under Ar, chlorination N-(chloromethylene)-N-methylmethylammonium (500mg, 3.91mmol) is suspended in dichloromethane (5mL), and the suspension is cooled to 0°C.Add 2-(2-chloro-3-fluoropyridin-4-yl)-1-(5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazoles-4-yl) second-1-ketone (Int-25) (612mg, 1.78mmol) in dichloromethane (5mL) dropwise at 0°C, and the reaction mixture is brought to room temperature.The reaction mixture is stirred at room temperature for 2h.Then, it is diluted with dichloromethane (50mL), and quenched by adding saturated sodium bicarbonate aqueous solution (30mL). The aqueous layer was extracted with dichloromethane (2 x 20 mL) and the combined organic layers were washed with water (2 x 20 mL) and brine (20 mL), dried (sodium sulfate) and concentrated in vacuo to give the title compound (543 mg, 1.39 mmol, 78% yield) as a yellow solid. HPLC (LCMS-fast gradient method) t R =1.10 min.MS (ES+) m / z 391.2, 393.2 [M+H, C1 isotope].

[0352] Step 5: 2-Chloro-3-fluoro-4-[2-[5-methyl-1-(6-methyl-3-pyridinyl)imidazol-4-yl]ethynyl]pyridine (Int-27)

[0353] A solution of (E)-3-chloro-2-(2-chloro-3-fluoro-4-pyridinyl)-3-[5-methyl-1-(6-methyl-3-pyridinyl)imidazol-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 5 portions (once every 2 minutes). The mixture was stirred at -25 ° C for 1 h. Saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (40 mL) 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 phases were dried (sodium sulfate), filtered, and concentrated in vacuo. The crude product was adsorbed on isolute HM-N and purified by column chromatography (20 g, silica gel, methanol / dichloromethane, gradient 0:100 to 5:95) to give the title compound (340 mg, 1.04 mmol, 63% yield) as an off-white solid. HPLC (LCMS_fast gradient method) t R =1.10 min.MS (ES+) m / z 327.3, 329.2 [M+H, Cl isotope].

[0354] Step 6: 4-[2-(2-chloro-3-fluoro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)imidazole Methyl oxadiazole-2-carboxylate (Int-28)

[0355] A solution of 2-chloro-3-fluoro-4-((5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazol-4-yl)ethynyl)pyridine (Int-27) (160 mg, 490 μmol) in THF (5 mL) was cooled to -78 °C under Ar. n-Butyl lithium solution (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 min. Methyl chloroformate (46.3 mg, 490 μmol) was added in one portion, and the mixture was stirred at -78 °C for 1 h, then allowed to reach room temperature and stirred for 1 h. The mixture was cooled to -78 °C again and saturated aqueous ammonium chloride solution (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 combined organic layers were washed with brine (20 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was adsorbed on isolute HM-N and purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100 to 5:95) to give the title compound (102 mg, 265 μmol, 54% yield) as a light brown solid. HPLC (LCMS_fast gradient method) t R =1.17min.MS(ES+)m / z385.2,387.1[M+H,Cl isotope].

[0356] The following intermediates can be synthesized similarly to the synthesis of Int-28, using the procedure described in General Procedure B and replacing reagents Int-2 and Int-24 with the reagents listed in the table below:

[0357]

[0358]

[0359]

[0360] Intermediate 49

[0361] 4-[2-(2-chloro-4-pyridinyl)ethynyl]-1-(4-fluorophenyl)imidazole-2-carboxylic acid methyl ester

[0362]

[0363] Step 1 was performed similarly to step 1 of the preparation of intermediate Int-22, but using 4-fluoroaniline (Int-43) in place of Int-2.

[0364] Steps 2-6 below were performed similarly to the protocols described in General Procedure B, Steps 2-6, respectively, but with Int-40 replacing Int-24.

[0365] Step 6: Methyl 4-[2-(2-chloro-4-pyridinyl)ethynyl]-1-(4-fluorophenyl)imidazole-2-carboxylate (Int-49)

[0366] MS (ES+) m / z 356.2, 358.2 [M+H, Cl isotope].

[0367] Intermediate 55

[0368] 4-Ethynyl-5-methyl-1-(5-methylpyrazin-2-yl)-1H-imidazole-2-carboxamide (General Procedure C)

[0369]

[0370] Step 1: 2-(4-iodo-5-methyl-1H-imidazol-1-yl)-5-methylpyrazine (Int-52)

[0371] To a solution of 2-chloro-5-methylpyrazine (Int-51) (980 mg, 7.62 mmol, 1 eq) in DMF (15 mL) was added 4-iodo-5-methyl-1H-imidazole (Int-50) (1.90 g, 9.15 mmol, 1.2 eq) and cesium carbonate (4.97 g, 15.25 mmol, 2 eq). The mixture was stirred at 100 ° C for 14 h. The reaction was then terminated by adding water (50 mL) and extracted with dichloromethane / methanol (10: 1 (v / v), 3×50 mL). The combined organic layers were concentrated in vacuo, 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 substrate between 70:30 and 10:90 v / v), followed by lyophilization to afford the title compound (830 mg, 2.77 mmol, 36% yield) as a white solid. MS (ES+) m / z 301.0 [M+H].

[0372] Step 2: 2-Methyl-5-(5-methyl-4-((trimethylsilyl)ethynyl)-1H-imidazol-1-yl)pyrazine (Int-53)

[0373] To a solution of 2-(4-iodo-5-methyl-imidazol-1-yl)-5-methyl-pyrazine (Int-52) (780 mg, 2.6 mmol) in DMF (4 mL) was added triethylamine (1.09 mL, 7.8 mmol), dichloro 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (106 mg, 0.13 mmol) and copper(I) iodide (14.8 mg, 78 μmol). The mixture was stirred at 70° C. for 1 h. Then, trimethylsilylacetylene (766 mg, 7.8 mmol) was added. The mixture was stirred at 70° C. for another 2 h. Then, it was concentrated in vacuo and purified by column chromatography (80 g, silica gel, n-heptane / (ethyl acetate+30% ethanol), gradient 95:5 to 50:50 (v / v)) to give the title compound (700 mg, 2.59 mmol, 99% yield) as a yellow solid. MS (ES+) m / z 271.1 [M+H].

[0374] Step 3: 5-methyl-1-(5-methylpyrazin-2-yl)-4-((trimethylsilyl)ethynyl)-1H-imidazole-2-yl Ethyl formate (Int-54)

[0375] 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. Diisopropylamide lithium solution (2M in THF, 1.1 mL, 2.2 mmol) was added, and the resulting brown solution was stirred at -78 ° C for 30 min. Then, ethyl chloroformate (0.79 mL, 8.9 mmol) was added, and the mixture was stirred at -78 ° C for 1 h. The mixture was concentrated in vacuo and purified by column chromatography (40 g, silica gel, n-heptane / ethyl acetate, gradient 90: 10 to 75: 25 (v / v)) to give the title compound (290 mg, 0.850 mmol, 57% yield) as a yellow oil. MS (ES+) m / z 343.1 [M+H].

[0376] Step 4: 4-ethynyl-5-methyl-1-(5-methylpyrazin-2-yl)-1H-imidazole-2-carboxamide (Int-55)

[0377] 5-Methyl-1-(5-methylpyrazine-2-yl)-4-(2-trimethylsilylethynyl)imidazole-2-carboxylic acid methyl ester (Int-54) (280 mg, 0.850 mmol) was dissolved in methanol (2 mL) in 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 h. After cooling, the mixture was concentrated in vacuo to give the title compound (165 mg, 0.68 mmol, 80% yield) as a yellow solid. MS (ES +) m / z 242.1 [M + H].

[0378] The following intermediates can be synthesized similarly to the synthesis of Int-55 using the procedure described in General Procedure C and replacing reagent Int-51 with the reagents listed in the table below:

[0379]

[0380] Intermediate 62

[0381] 4-Ethynyl-5-methyl-1-(5-methylpyridin-3-yl)-1H-imidazole-2-carboxamide (General Procedure D)

[0382]

[0383] Step 1: 3-(4-iodo-5-methyl-1H-imidazol-1-yl)-5-methylpyridine (Int-59)

[0384] 5-Methylpyridine-3-boronic acid (Int-58) (1.50 g, 11.0 mmol) was dissolved in DMF (30 mL), 4-iodo-5-methyl-1H-imidazole (Int-50) (2.73 g, 13.1 mmol) and di-μ-hydroxy-bis(N,N,N′,N′-tetramethylethylenediamine) copper (II) chloride [1.017 g, 2.19 mmol) were added, and the mixture was stirred at 50° C. under an oxygen atmosphere for 16 h. Then, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Shim-pack C18, 150×25 mm×10 μm, eluted with acetonitrile / (water+0.225% formic acid), linear, substrate optimized between 70:30 and 10:90 v / v) and then lyophilized to give the title compound (800 mg, 2.67 mmol, 24% yield) as a white solid. 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 / z 300.1[M+H].

[0385] Step 2 to Step 4 are performed similarly to General Procedure C Step 2 to Step 4, respectively.

[0386] The following intermediates can be synthesized similarly to the synthesis of Int-62 using the procedure described in General Procedure D and replacing reagent Int-58 with the reagents listed in the table below:

[0387]

[0388]

[0389] Intermediate 77

[0390] 4-Ethynyl-5-methyl-1-(5-methylpyridin-2-yl)-1H-imidazole-2-carboxamide

[0391]

[0392] Step 1: 5-Methyl-1-(5-methylpyridin-2-yl)-1H-imidazole-4-carboxylic acid ethyl ester (Int-72)

[0393] 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) was added, followed by cesium carbonate (11.14 g, 34.2 mmol). The mixture was stirred at 120 ° C for 12 h. After cooling, the mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g, silica gel, petroleum ether / ethyl acetate, isocratic 50: 50 (v / v)) to give the title compound (1.3 g, 5.3 mmol, 31% yield) as a yellow solid. MS (ES+) m / z 246.1 [M+H].

[0394] Step 2: 5-Methyl-1-(5-methylpyridin-2-yl)-1H-imidazole-4-carbaldehyde (Int-73)

[0395] 5-Methyl-1-(5-methyl-2-pyridyl)imidazole-4-carboxylic acid ethyl ester (Int-72) (500mg, 2.0mmol) was dissolved in THF (12.5mL), diisobutylaluminum hydride (1M in toluene, 6.12mL, 6.12mmol) was added at 25°C, and the mixture was stirred at 25°C for 4h. Afterwards, sodium sulfate decahydrate (3g) was added, and the resulting slurry was stirred for 0.5h. It was filtered, washed with THF (10mL), and the filtrate was concentrated in vacuo to give crude [5-methyl-1-(5-methyl-2-pyridyl)imidazol-4-yl]methanol (350mg, 1.72mmol, 84% yield) as a yellow oil. The substance was dissolved in THF (15mL), manganese (IV) oxide (449mg, 5.17mmol) was added, and the mixture was stirred at 30°C for 10h. The mixture was then filtered and concentrated in vacuo to give the crude title compound (240 mg, 1.19 mmol, 69% yield) as a yellow oil. The crude product was used in the next step without further purification. MS (ES+) m / z 202.1 [M+H].

[0396] Step 3: 2-(4-ethynyl-5-methyl-1H-imidazol-1-yl)-5-methylpyridine (Int-74)

[0397] 5-Methyl-1-(5-methyl-2-pyridyl)imidazole-4-carboxaldehyde (Int-73) (240 mg, 1.19 mmol) was dissolved in methanol (8 mL), 1-diazo-1-dimethoxyphosphoryl-propan-2-one (275 mg, 1.43 mmol) and potassium carbonate (198 mg, 1.43 mmol) were added, and the mixture was stirred at 25 ° C for 24 h. Then, the mixture was poured into water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic phases were dried (sodium sulfate) and concentrated in vacuo to give the crude title compound (170 mg, 0.860 mmol, 72% yield) as a yellow oil, which was used in the next step without further purification. MS (ES +) m / z 198.1 [M + H].

[0398] Step 4: 5-methyl-2-(5-methyl-4-((trimethylsilyl)ethynyl)-1H-imidazol-1-yl)pyridine (Int-75)

[0399] 2-(4-ethynyl-5-methyl-imidazol-1-yl)-5-methyl-pyridine (Int-74) (150 mg, 0.76 mmol) was dissolved in THF (3 mL), the solution was cooled to -78 ° C, and lithium hexamethyldisilazane (LiHDMS) (1M in THF, 1.14 mL, 1.14 mmol) was added at -78 ° C. The mixture was stirred at this temperature for 1 h. Then, trimethylsilyl chloride (91 mg, 0.84 mmol) was added. The mixture was warmed to 25 ° C and stirred for 3 h. The reactant was cooled to -78 ° C and terminated by adding water (20 mL). After warming to room temperature, it was extracted with ethyl acetate (2×20 mL), the combined organic layers were washed with brine (20 mL), and concentrated in vacuo to give the crude title compound (150 mg, 0.56 mmol, 68% yield) as a yellow oil, which was used in the next step without further purification. MS (ES+) m / z 270.1 [M+H].

[0400] Step 5: 5-methyl-1-(5-methylpyridin-2-yl)-4-((trimethylsilyl)ethynyl)-1H-imidazole-2-yl Methyl formate (Int-76)

[0401] 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 (2M in THF, 0.42 mL, 0.84 mmol) was added at -78 ° C. The resulting brown solution was stirred for 30 min. Then, ethyl chloroformate (0.15 mL, 1.67 mmol) was added and the mixture was stirred at -78 ° C for 1.5 h. After warming to room temperature, the reaction was terminated by adding sodium sulfate decahydrate (10 g), the resulting slurry was stirred for 30 min, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (12 g, silica gel, petroleum ether / ethyl acetate, gradient, 91:9 to 75:25 (v / v)) to give the title compound (70 mg, 0.200 mmol, 37% yield) as a yellow solid. MS (ES+) m / z 342.1 [M+H].

[0402] Step 6: 4-ethynyl-5-methyl-1-(5-methylpyridin-2-yl)-1H-imidazole-2-carboxamide (Int-77)

[0403] 5-Methyl-1-(5-methylpyridin-2-yl)-4-((trimethylsilyl)ethynyl)-1H-imidazole-2-carboxylic acid methyl ester (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 at 50 ° C for 4 h in a sealed pressure tube. After cooling, the mixture was concentrated in vacuo to give the title compound (50 mg, 0.21 mmol, 89% yield) as a brown solid, which was used in the next step without further purification. MS (ES+) m / z 241.1 [M+H].

[0404] Intermediate 85

[0405] 2-((2-Chloropyridin-4-yl)ethynyl)-1-methyl-5-(6-methylpyridin-3-yl)-1H-imidazole-4-carbonitrile (General Procedure E)

[0406]

[0407] Step 1: 1-Methylimidazole-4-carbonitrile (Int-79)

[0408] 1H-imidazole-4-carbonitrile (Int-78) (4.000g, 43mmol) is dissolved in DMF (80mL), the solution is cooled to 0°C, and sodium hydride (60% dispersion in mineral oil, 1.89g, 47.3mmol) is added at 0°C. The mixture is stirred at 25°C for 1h. Then, iodomethane (9.30g, 65.5mmol) is added. The mixture is stirred at 25°C for 2h. Afterwards, water (100mL) is added, the mixture is extracted with dichloromethane / methanol (10: 1 (v / v), 3×100mL), and the combined organic layers are concentrated in vacuo. The crude product is purified by column chromatography (240g, silica gel, petroleum ether / ethyl acetate, gradient, 91: 9 to 33: 66 (v / v)) to give the title compound (3.95g, 36.9mmol, 86% yield) as a white solid.

[0409] Step 2: 5-Bromo-1-methyl-imidazole-4-carbonitrile (Int-80)

[0410] A solution of 1-methylimidazole-4-carbonitrile (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 h. Then, water (80 mL) was added and the mixture was stirred at 25 ° C for 1 h. A precipitate was formed, which was filtered off and dried in vacuo to give the title compound (6.00 g, 32.3 mmol, 86% yield) as a white solid. MS (ES+) m / z 186.0, 188.0 [M+H, Br isotopes].

[0411] Step 3: 1-Methyl-5-(6-methyl-3-pyridyl)imidazole-4-carbonitrile (Int-82)

[0412] 5-Bromo-1-methyl-imidazole-4-carbonitrile (Int-80) (3.000g, 16.1mmol) is dissolved in 1,4-dioxane (45mL), 6-methylpyridine-3-boric acid (Int-81) (2.21g, 16.1mmol), dichloro 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (1.316g, 1.61mmol) and cesium carbonate (10.51g, 32.3mmol) are added under argon, and the mixture is stirred at 110°C for 14h. After cooling, the mixture is filtered and the filtrate is concentrated in vacuo. The crude product is purified by column chromatography (240g, silica gel, petroleum ether / ethyl acetate, gradient, 85: 15 to 0: 100 (v / v)) to give the title compound (3.00g, 15.1mmol, 70% yield) as a gray solid. MS (ES+) m / z 199.1 [M+H].

[0413] Step 4: 2-iodo-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carbonitrile (Int-83)

[0414] 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 (2M in THF, 11.35 mL, 22.7 mmol) was added. The mixture was stirred at -78 ° C for 0.5 h. Then, 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 h. Afterwards, the reaction was terminated by adding an aqueous sodium sulfite solution (2 M, 100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were concentrated in vacuo and the crude product was purified by column chromatography (40 g, silica gel, petroleum ether / (ethyl acetate+30% ethanol), gradient, 91:9 to 33:66 (v / v)) to give the title compound (350 mg, 1.08 mmol, 7% yield) as a light yellow solid. MS (ES+) m / z 325.0 [M+H].

[0415] Step 5: 2-[2-(2-chloro-4-pyridinyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridinyl)imidazole-4-carboxylate Nitrile (Int-85)

[0416] 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 dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) 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 h. Then, 2-chloro-4-ethynyl-pyridine (Int-84) (297 mg, 2.2 mmol) was added. The mixture was stirred at 70° C. for another 2 h. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (24 g, silica gel, petroleum ether / (ethyl acetate+30% ethanol), gradient, 91:9 to 50:50 (v / v)) to give the title compound (210 mg, 0.63 mmol, 58% yield) as a pale yellow solid. MS (ES+) m / z 334.0, 336.1 [M+H, Cl isotope].

[0417] The following intermediates can be synthesized analogously to the synthesis of Int-85 using the procedure described in General Procedure E and replacing reagents Int-81 and Int-84 with the reagents listed in the table below:

[0418]

[0419]

[0420] Intermediate 100

[0421] 4-[2-(2-chloro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)pyrrole-2-carboxylic acid

[0422]

[0423] Step 1: Ethyl 5-methyl-1-(6-methyl-3-pyridinyl)pyrrole-2-carboxylate (Int-97)

[0424] 5-Methyl-1H-pyrrole-2-carboxylic acid ethyl ester (Int-95) (1.460g, 9.53mmol) was dissolved in toluene (40mL), and 5-bromo-2-methylpyridine (Int-96) (1.803g, 10.5mmol), copper (I) iodide (726g, 3.8mmol), (1s, 2s)-(+)-N, N'-dimethylcyclohexane-1,2-diamine (1.085g, 7.6mmol) and potassium phosphate (6.06g, 28.6mmol) were added. The mixture was degassed with nitrogen for 5min and stirred at 120°C for 16h. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (100 g, silica gel, petroleum ether / ethyl acetate, gradient, 99:1 to 75:25 (v / v)) to give the title compound (460 mg, 1.88 mmol, 19% yield) as a light yellow oil. MS (ES+) m / z 245.2 [M+H].

[0425] Step 2: 4-iodo-5-methyl-1-(6-methyl-3-pyridinyl)pyrrole-2-carboxylic acid ethyl ester (Int-98)

[0426] 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 in portions. The mixture was stirred at -10 ° C for 2 h and then at 25 ° C for 2 h. After that, water (15 mL) was added, and after phase separation, the aqueous phase was extracted with dichloromethane (3×15 mL), and the combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo to give the crude title compound (520 mg) as a dark brown oil, which was used in the next step without further purification. MS (ES+) m / z 371.0 [M+H].

[0427] Step 3: 4-[2-(2-chloro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)pyrrole-2-carboxylate Ethyl Ester (Int-99)

[0428] 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 dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) 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 h. Then, 2-chloro-4-ethynyl-pyridine (Int-84) (167 mg, 1.22 mmol) was added, and the mixture was stirred at 80° C. for another 2 h. After cooling, the mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (50 g, silica gel, petroleum ether / ethyl acetate, gradient, 91:9 to 50:50 (v / v)) to give the title compound (157 mg, 0.41 mmol, 51% yield) as a light yellow oil. MS (ES+) m / z 380.2 [M+H].

[0429] Step 4: 4-[2-(2-chloro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)pyrrole-2-carboxylate Acid (Int-100)

[0430] Ethyl 4-[2-(2-chloro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)pyrrole-2-carboxylate (Int-99) (157 mg, 0.41 mmol) was dissolved in THF (2 mL) and lithium hydroxide (2M in water, 2.0 mL, 4 mmol) was added. The mixture was stirred at 25 °C for 16 h. 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 aqueous hydrochloric acid solution, extracted with ethyl acetate (5×20 mL), and the combined organic layers were dried (sodium sulfate), filtered, and concentrated in vacuo. The crude product (a yellow solid) (85 mg, 0.24 mmol, 59% yield) was used in the next step without further purification. MS (ES+) m / z 352.0 [M+H].

[0431] Examples

[0432] Example 1

[0433] 4-((2-chloro-3-methylpyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0434]

[0435] 4-ethynyl-5-methyl-1-(6-methylpyridin-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 at 0 ° C, triethylamine (178 mg, 245 μL, 1.76 mmol) and dichlorobis(triphenylphosphine)palladium (II) (33 mg, 46.9 μmol) were added under argon. The flask was evacuated and purged with argon. Then, copper iodide (I) (4.5 mg, 23.5 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0 ° C for 3 h and then allowed to warm to room temperature within 1 h. The reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was stripped with dichloromethane (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 in vacuo. The crude product was adsorbed on isolute HM-N and purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0: 100 to 5: 95 (v / v)), then crystallized from dichloromethane / tert-butyl methyl ether to obtain the title compound (89 mg, 243 μmol, 69% yield) in an off-white solid state. HPLC (LCMS-fast gradient method) t R =1.04min. 1 H NMR (CDCl3, 300 MHz): 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, 8.1 Hz, 1H), 8.21 (d, J = 5.0 Hz, 1H), 8.40 (s, 1H). MS (ES+) m / z 366.2, 368.2 [M+H, Cl isotope].

[0436] Example 2

[0437] 4-((2-chloro-3-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0438]

[0439] A solution of 4-((2-chloro-3-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxylic acid methyl ester (Int-28) (310 mg, 806 μmol) in ammonia (7N in MeOH) (11.5 ml, 80.6 mmol) was stirred in a pressure tube at 70 ° C for 6 h. Afterwards, the reaction mixture was concentrated in vacuo, the residue was adsorbed on isolute HM-N, and purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0: 100 to 5: 95 (v / v)), followed by trituration in dichloromethane / tert-butyl methyl ether to give the title compound (126 mg, 341 μmol, 42% yield) as a white solid. HPLC (LCMS_fast gradient method) t R =1.06min. 1 H NMR (d6-DMSO, 300MHz): δ2.14 (s, 3H), 2.56 (s, 3H), 7.42 (d, J=8.1Hz, 1H), 7.48 (br s, 1H), 7.71 (dd, J=5.0, 5.0Hz, 1H), 7.76 (dd, J=2.5, 8.2Hz, 1H), 8.43 (br s, 1H), 8.32 (d, J=5.0Hz, 1H), 8.44 (d, J=2.2Hz, 1H). MS (ES+) m / z 370.2, 372.1 [M+H, Cl isotope].

[0440] Example 3

[0441] 4-[2-(5-chlorothien-3-yl)ethynyl]-5-methyl-1-(6-methylpyridin-3-yl)imidazole-2-carboxamide

[0442]

[0443] 4-Ethynyl-5-methyl-1-(6-methylpyridin-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 dichlorobis(triphenylphosphine)palladium (II) (24 mg, 33 μmol) were added under argon at 23 ° C. The flask was evacuated and purged with argon. Then, copper iodide (I) (3.2 mg, 16.6 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 23 ° C for 16 h. The reaction mixture was extracted with water (15 mL) and dichloromethane (15 mL), and the water layer was stripped with dichloromethane (15 mL). The combined organic layer was dried (sodium sulfate), filtered and the filtrate was concentrated in vacuo. The crude product was adsorbed on isolute HM-N and purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100 to 10:90 (v / v)) to give the title compound (80 mg, 224 μmol, 67% yield) as an off-white solid. HPLC (LCMS_fast gradient method) t R =1.17min. 1 H NMR (CDCl3, 300MHz): δ2.15 (s, 3H), 2.66 (s, 3H), 5.25 (br s, 1H), 7.02 (d, J=1.6Hz, 1H), 7.12 (br s, lH), 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].

[0444] Example 4

[0445] 4-[2-(3-chlorophenyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide

[0446]

[0447] 4-ethynyl-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide (Int-9) (600mg, 2.5mmol) and 1-chloro-3-iodobenzene (774mg, 3.25mmol) were dissolved in DMF (15mL), and triethylamine (758mg, 1.94mL, 7.5mmol) and dichlorobis(triphenylphosphine)palladium (II) (140mg, 200μmol) were added under argon at 0-5°C. The flask was evacuated and purged with argon. Then, copper iodide (I) (19mg, 100μmol) was added to obtain a light brown solution. The resulting mixture was stirred for 4h at 0-5°C. The reaction mixture was extracted with water (110mL) and dichloromethane (110mL), and the aqueous layer was stripped with dichloromethane (2×110mL). The combined organic layers were washed with brine (100 mL), dried (sodium sulfate), filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (40 g, silica gel, isopropanol / dichloromethane, gradient 0: 100 to 20: 80 (v / v)) to give the title compound (449 mg, 1.28 mmol, 51% yield) as an off-white solid. HPLC (LCMS-fast gradient method) t R =1.18min. 1 H NMR (CDCl3, 300 MHz): 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, 7.0 Hz, 1H), 7.49-7.55 (m, 2H), 8.38 (d, J = 2.2 Hz, 1H). MS (ES+) m / z 351.2, 353.2 [M+H, Cl isotope].

[0448] Example 5

[0449] 4-((3-cyanophenyl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0450]

[0451] 4-ethynyl-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide (Int-9) (69 mg, 287 μmol) and 3-iodobenzonitrile (78.9 mg, 345 μmol) are dissolved in DMF (2 mL), and at 0-5 ° C, triethylamine (87.2 mg, 120 μl, 862 μmol) and dichlorobis(triphenylphosphine)palladium (II) (16.1 mg, 23 μmol) are added under argon. The flask is evacuated and purged with argon. Then, copper iodide (I) (2.2 mg, 11.5 μmol) is added to obtain a light brown solution. The resulting mixture is stirred for 2 h at 0-5 ° C. The reaction mixture is extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer is stripped with dichloromethane (30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0: 100 to 5: 95 (v / v)) to give the title compound (47 mg, 138 μmol, 48% yield) as a pale yellow solid. HPLC (LCMS_fast gradient method) t R =1.03min. 1 H NMR (CDCl3, 300MHz): δ2.19 (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, 1 H), 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].

[0452] Example 6

[0453] 4-(2-Chloro-pyridin-4-ylethynyl)-5-methyl-1-(6-methyl-pyridin-3-yl)-1H-imidazole-2-carboxylic acid amide

[0454]

[0455] 4-Ethynyl-5-methyl-1-(6-methylpyridin-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 dichlorobis(triphenylphosphine)palladium (II) (32.3 mg, 45.2 μmol) were added under argon at 0-5 ° C. The flask was evacuated and purged with argon. Then, copper iodide (I) (5.2 mg, 27.1 μmol) was added to give a light brown solution. The resulting mixture was stirred at 0-5 ° C for 3 h. After warming to room temperature, the reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was stripped 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 in vacuo. The crude product was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0: 100 to 5: 95 (v / v)) to give the title compound (257 mg, 731 μmol, 81% yield) as a pale yellow solid. HPLC (LCMS_fast gradient method) t R =1.00min. 1 H NMR (CDCl3, 300 MHz): 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, 8.3 Hz, 1H), 8.35-8.42 (m, 2H). MS (ES+) m / z 352.2, 354.1 [M+H, Cl isotope].

[0456] Example 7

[0457] 4-((2-chloro-5-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0458]

[0459] A solution of 4-((2-chloro-5-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxylic acid methyl ester (Int-29) (41 mg, 107 μmol) in ammonia (7N in MeOH) (3 ml, 21 mmol) was stirred in a pressure tube at 85 ° C for 20 h. Afterwards, the reaction mixture was concentrated in vacuo 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 to 98:2 v / v) and then lyophilized to give the title compound (4 mg, 11 μmol, 10% yield) as a white solid. HPLC (LCMS_fast gradient method) t R =1.05min. 1 H NMR (CDCl3, 300MHz): δ2.20 (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].

[0460] Example 8

[0461] 4-((3-methoxyphenyl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0462]

[0463] 4-Ethynyl-5-methyl-1-(6-methylpyridin-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 dichlorobis(triphenylphosphine)palladium (II) (17.1 mg, 24.3 μmol) were added under argon at 0-5 ° C. The flask was evacuated and purged with argon. Then, copper iodide (I) (2.3 mg, 12 μmol) was added to give a light brown solution. The resulting mixture was stirred at 0-5 ° C for 1 h. After stirring for another 1 h at 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 layers were washed with water (80 mL) and brine (80 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0: 100 to 10: 90 (v / v)) to give the title compound (58 mg, 167 μmol, 55% yield) as an off-white solid. HPLC (LCMS_fast gradient method) t R =1.10min. 1 H NMR (CDCl3, 300MHz): δ2.18 (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].

[0464] Example 9

[0465] 4-[2-(4-Chlorophenyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide

[0466]

[0467] 4-ethynyl-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide (Int-9) (100mg, 420μmol) and 1-chloro-4-iodobenzene (109mg, 460μmol) are dissolved in DMF (5mL), and at 0-5°C, triethylamine (170μl, 1.25mmol) and dichlorobis(triphenylphosphine)palladium (II) (14.6mg, 20μmol) are added under argon. The flask is evacuated and purged with argon. Then, copper iodide (I) (2.3mg, 10μmol) is added to obtain a light brown solution. The resulting mixture is stirred for 3h at 0-5°C. 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 to 98:2 v / v) and then lyophilized to give the title compound (66 mg, 190 μmol, 45% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz): δ 2.11 (s, 3H), 2.57 (s, 3H), 7.42 (br s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.47-7.53 (m, 2H), 7.54-7.60 (m, 2H), 7.74 (dd, J = 2.6, 8.2 Hz, 1H), 7.94 (br s, 1H), 8.42 (d, J = 2.4 Hz, 1H). MS (ES+) m / z 351.0, 353.1 [M+H, Cl isotope].

[0468] Example 10

[0469] 5-Methyl-1-(6-methylpyridin-3-yl)-4-(m-tolylethynyl)-1H-imidazole-2-carboxamide

[0470]

[0471] 4-Ethynyl-5-methyl-1-(6-methylpyridin-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 dichlorobis(triphenylphosphine)palladium (II) (19 mg, 27 μmol) were added under argon at 0-5 ° C. The flask was evacuated and purged with argon. Then, copper iodide (I) (2.3 mg, 10 μmol) was added to give a light brown solution. The resulting mixture was stirred at 0-5 ° C for 3 h. After stirring for another 1 h at 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 layers were washed with water (80 mL) and brine (80 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0: 100 to 5: 95 (v / v)) to give the title compound (39 mg, 118 μmol, 35% yield) as a pale yellow solid. HPLC (LCMS_fast gradient method) t R =1.17min. 1 H NMR (CDCl3, 300MHz): δ2.18 (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, 1 H), 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].

[0472] Example 11

[0473] 5-methyl-1-(6-methylpyridin-3-yl)-4-((2-(trifluoromethyl)pyridin-4-yl)ethynyl)-1H-imidazole-2-carboxamide

[0474]

[0475] A solution of 5-methyl-1-(6-methylpyridin-3-yl)-4-((2-(trifluoromethyl)pyridin-4-yl)ethynyl)-1H-imidazole-2-carboxylic acid methyl ester (Int-31) (15 mg, 37 μmol) in ammonia (7N in MeOH) (1.1 ml, 7.7 mmol) was stirred in a pressure tube at 80 °C for 16 h. Afterwards, the reaction mixture was concentrated in vacuo 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 to 98:2 v / v) and then lyophilized to give the title compound (6 mg, 16 μmol, 41% yield) as a white solid. HPLC (LCMS_fast gradient method) t R =1.06min. 1 H NMR (CDCl3, 300MHz): δ2.22 (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, 5.0Hz, 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].

[0476] Example 12

[0477] 4-[2-(2-fluoro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)imidazole-2-carboxamide

[0478]

[0479] A solution of 4-[2-(2-fluoro-4-pyridyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxylic acid methyl ester (Int-34) (28 mg, 80 μmol) in ammonia (7N in MeOH) (2.3 ml, 16 mmol) was stirred at 85 ° C in a pressure tube for 20 h. Afterwards, the reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (YMC-ActusTriart C18, 100×30 mm×5 μm, eluted with acetonitrile / (water+0.1% triethylamine), gradient 20:80 to 98:2 v / v), followed by lyophilization to give the title compound (14 mg, 40 μmol, 50% yield) as a white solid. HPLC (LCMS_fast gradient method) t R =0.94min.1 H NMR (CDCl3, 300MHz): δ2.20 (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].

[0480] Example 13

[0481] 4-(Benzo[d][1,3]dioxol-4-ylethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0482]

[0483] 4-Ethynyl-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide (Int-9) (92 mg, 383 μmol) and 4-iodobenzo[d][1,3]dioxole (114 mg, 459 μmol) were dissolved in DMF (2 mL), and triethylamine (116 mg, 160 μl, 1.15 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21.5 mg, 30.6 μmol) were added under argon at 0-5 ° C. The flask was evacuated and purged with argon. Then, copper iodide (I) (2.9 mg, 15 μmol) was added to give a light brown solution. The resulting mixture was stirred for 2 h at 0-5 ° C. The reaction mixture was extracted with water (30 mL) and dichloromethane (30 mL), and the aqueous layer was stripped 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 in vacuo. The crude product was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0: 100 to 5: 95 (v / v)) to give the title compound (78 mg, 216 μmol, 56% yield) as a pale yellow solid. HPLC (LCMS_fast gradient method) t R =1.08min. 1H NMR (CDCl3, 300MHz): δ2.18 (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 / z361.2[M+H].

[0484] Example 14

[0485] 4-((6-chloropyridin-2-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0486]

[0487] 4-Ethynyl-5-methyl-1-(6-methylpyridin-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 mmol) and dichlorobis(triphenylphosphine)palladium (II) (14 mg, 20 μmol) were added under argon at 0-5 ° C. The flask was evacuated and purged with argon. Then, copper iodide (I) (1.9 mg, 10 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5 ° C for 3 h. After stirring for another 1 h at 23 ° C, 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 in vacuo. The crude product was purified by preparative HPLC (YMC-Actus TriartC18, 100 × 30 mm × 5 μm, eluted with acetonitrile / (water+0.1% triethylamine), gradient 20: 80 to 98: 2 v / v), then freeze-dried and crystallized from dichloromethane / tert-butyl methyl ether / n-heptane to give the title compound (29 mg, 82 μmol, 33% yield) as a white solid. HPLC (LCMS_fast gradient method) t R =0.99min. 1H NMR (DMSO-d6, 300MHz): δ2.12 (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].

[0488] Example 15

[0489] 4-((2-chloropyrimidin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0490]

[0491] 4-Ethynyl-5-methyl-1-(6-methylpyridin-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 dichlorobis(triphenylphosphine)palladium (II) (7.2 mg, 10.2 μmol) were added under argon at 0-5 ° C. The flask was evacuated and purged with argon. Then, copper iodide (I) (1.2 mg, 6.1 μmol) was added to give a light brown solution. The resulting mixture was stirred at 0-5 ° C for 3 h. After stirring for another 1 h at 23 ° C, 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 in vacuo. The crude product was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0: 100 to 5: 95 (v / v)) to give the title compound (27 mg, 76 μmol, 37% yield) as a pale yellow solid. HPLC (LCMS_fast gradient method) t R =0.90min. 1H NMR (CDCl3, 300MHz): δ2.23 (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 / z 353.2, 355.1 [M+H, Cl isotope].

[0492] Example 16

[0493] 4-((3-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0494]

[0495] A solution of 4-((3-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxylic acid methyl ester (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 h. Afterwards, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0:100 to 5:95 (v / v)) to give the title compound (35 mg, 104 μmol, 36% yield) as a light yellow solid. HPLC (LCMS fast gradient method) t R =0.89min. 1 H NMR (DMSO-d6, 300MHz): δ2.13 (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].

[0496] Example 17

[0497] 4-[2-(5-chloro-3-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)imidazole-2-carboxamide

[0498]

[0499] 4-ethynyl-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide (Int-9) (100mg, 420μmol) and 3-chloro-5-iodopyridine (110mg, 461μmol) are dissolved in DMF (5mL), and at 0-5°C, triethylamine (170μL, 1.25mmol) and dichlorobis(triphenylphosphine)palladium (II) (14.6mg, 20μmol) are added under argon. The flask is evacuated and purged with argon. Then, copper iodide (I) (2.4mg, 12μmol) is added to obtain a light brown solution. The resulting mixture is stirred for 3h at 0-5°C. 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, substrate optimized between 70:30 and 10:90 v / v) and then lyophilized to give the title compound (55 mg, 160 μmol, 38% yield) as a light yellow solid. 1 H NMR (DMSO-d6, 400MHz): δ2.13 (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].

[0500] Example 18

[0501] 4-((4-chloropyridin-2-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0502]

[0503] 4-Ethynyl-5-methyl-1-(6-methylpyridin-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 dichlorobis(triphenylphosphine)palladium (II) (17 mg, 24 μmol) were added under argon at 0-5 ° C. The flask was evacuated and purged with argon. Then, copper iodide (I) (2.3 mg, 12 μmol) was added to give a light brown solution. The resulting mixture was stirred at 0-5 ° C for 1 h. After stirring for another 1 h at 23 ° C, 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 in vacuo. The crude product was purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0: 100 to 10: 90 (v / v)) to give the title compound (50 mg, 142 μmol, 47% yield) as an off-white solid. HPLC (LCMS_fast gradient method) t R =0.98min. 1 H NMR (CDCl3, 300 MHz): 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, 8.1 Hz, 1H), 7.55-7.61 (m, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 5.2 Hz, 1H). MS (ES+) m / z 352.2, 354.1 [M+H, Cl isotope].

[0504] Example 19

[0505] 4-((6-chloropyrimidin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0506]

[0507] 4-Ethynyl-5-methyl-1-(6-methylpyridin-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 dichlorobis(triphenylphosphine)palladium (II) (7.9 mg, 11 μmol) were added under argon at 0-5 ° C. The flask was evacuated and purged with argon. Then, copper iodide (I) (1.3 mg, 6.7 μmol) was added to give a light brown solution. The resulting mixture was stirred at 0-5 ° C for 3 h. After stirring for another 1 h at 23 ° C, 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 in vacuo. The crude product was adsorbed on isolute HM-N and purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0: 100 to 5: 95 (v / v)) to give the title compound (31 mg, 88 μmol, 39% yield) in a light yellow solid. HPLC (LCMS_fast gradient method) t R =0.92min. 1 HNMR (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 = 8.3 Hz, 1H), 7.48-7.56 (m, 2H), 8.39 (d, J = 2.2 Hz, 1H), 8.97 (d, J = 1.2 Hz, 1H). MS (ES+) m / z 353.1, 355.1 [M+H, Cl isotope].

[0508] Example 20

[0509] 5-Methyl-1-(6-methyl-3-pyridinyl)-4-[2-(3-pyridinyl)ethynyl]imidazole-2-carboxamide

[0510]

[0511] 4-ethynyl-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide (Int-9) (30 mg, 120 μmol) and 3-iodopyridine (26.9 mg, 130 μmol) are dissolved in DMF (5 mL), and at 0-5 ° C, triethylamine (50 μL, 370 μmol) and dichlorobis(triphenylphosphine)palladium (II) (4.4 mg, 6 μmol) are added under argon. The flask is evacuated and purged with argon. Then, copper iodide (I) (0.7 mg, 3.7 μmol) is added to obtain a light brown solution. The resulting mixture is stirred for 3 h at 0-5 ° C. 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 the substrate between 70:30 and 10:90 v / v), and lyophilized, followed by preparative TLC (silica gel, eluted with ethyl acetate) to give the title compound (7 mg, 20 μmol, 17% yield) as a white solid. 1 H NMR (DMSO-d6, 400MHz): δ2.12 (s, 3H), 2.56 (s, 3H), 7.38-7.50 (m, 3H), 7.74 (dd, J=2.4, 8.2 Hz, 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].

[0512] Example 21

[0513] 5-Methyl-1-(6-methyl-3-pyridinyl)-4-[2-(4-pyridinyl)ethynyl]imidazole-2-carboxamide

[0514]

[0515] 4-Ethynyl-5-methyl-1-(6-methylpyridin-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 dichlorobis(triphenylphosphine)palladium (II) (11 mg, 16 μmol) were added under argon at 0-5 ° C. The flask was evacuated and purged with argon. Then, copper iodide (I) (1.7 mg, 9 μmol) was added to obtain a light brown solution. The resulting mixture was stirred at 0-5 ° C for 3 h. After stirring for another 1 h at 23 ° C, 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 in vacuo. The crude product was purified by preparative HPLC (YMC-ActusTriart C18, 100×30 mm×5 μm, eluted with acetonitrile / (water+0.1% triethylamine), gradient 20:80 to 98:2 v / v) to give the title compound (36 mg, 113 μmol, 37% yield) as a white solid. HPLC (LCMS_fast gradient method) t R =0.69min. 1 H NMR (CDCl3, 300MHz): δ2.20 (s, 3H), 2.66 (s, 3H), 5.36 (br s, 1H), 7.13 (brs, 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].

[0516] Example 22

[0517] 5-Methyl-1-(6-methylpyridin-3-yl)-4-((2-methylpyridin-4-yl)ethynyl)-1H-imidazole-2-carboxamide

[0518]

[0519] 4-Ethynyl-5-methyl-1-(6-methylpyridin-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 dichlorobis(triphenylphosphine)palladium (II) (14 mg, 20 μmol) were added under argon at 0-5 ° C. The flask was evacuated and purged with argon. Then, copper iodide (I) (3.9 mg, 20 μmol) was added to give a light brown solution. The resulting mixture was stirred at 0-5 ° C for 3 h. After stirring for another 1 h at 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 layers were washed with water (80 mL) and brine (80 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated in vacuo. The crude product was adsorbed on isolute HM-N and purified by column chromatography (12 g, silica gel, methanol / dichloromethane, gradient 0: 100 to 5: 95 (v / v)) to give the title compound (23 mg, 69 μmol, 34% yield) in the form of a light yellow solid. HPLC (LCMS_fast gradient method) t R =0.65min. 1 H NMR (CDCl3, 300MHz): δ2.19 (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].

[0520] Example 23

[0521] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(5-methylpyrazin-2-yl)imidazole-2-carboxamide

[0522]

[0523] 4-Ethynyl-5-methyl-1-(5-methylpyrazine-2-yl)imidazole-2-carboxamide (Int-55) (140 mg, 580 μmol) was dissolved in DMF (4 mL), and dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) 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 resulting mixture was stirred at 80° C. for 1 h. Then, 2-chloro-4-iodo-3-methyl-pyridine (147 mg, 580 μmol) was added, and the reaction mixture was stirred at 80° C. for another 2 h. 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 the substrate between 70:30 and 10:90 v / v) to give the title compound (50 mg, 140 μl, 23% yield) as a white solid after lyophilization. 1 H NMR (400MHz, DMSO-d6) δppm2.21 (s, 3H), 2.53-2.55 (m, 3H), 2.62 (s, 3H), 7.46-7. 65 (m, 2H), 8.13 (s, 1H), 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].

[0524] Example 24

[0525] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(6-methylpyridazin-3-yl)imidazole-2-carboxamide

[0526]

[0527] 2-Chloro-4-iodo-3-methyl-pyridine (63 mg, 250 μmol) was dissolved in DMF (2 mL), and dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) 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 h. Then, 4-ethynyl-5-methyl-1-(6-methylpyridazine-3-yl)imidazole-2-carboxamide (Int-56) (60 mg, 250 μmol) was added, and the reaction mixture was stirred at 70° C. for another 2 h. 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 the substrate between 70:30 and 10:90 v / v) to give the title compound (18 mg, 49 μmol, 20% yield) as a light yellow solid after lyophilization. 1 H NMR (400MHz, DMSO-d6) δppm 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].

[0528] Example 25

[0529] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(5-methyl-3-pyridinyl)imidazole-2-carboxamide

[0530]

[0531] 4-Ethynyl-5-methyl-1-(5-methyl-3-pyridyl)imidazole-2-carboxamide (Int-62) (70 mg, 290 μmol) was dissolved in DMF (0.5 mL), and dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) 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-methyl-pyridine (89 mg, 0.35 mmol) were added. The resulting mixture was stirred at 70° C. for 1 h. After cooling, the mixture was filtered and the filtrate 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 the substrate between 70:30 and 10:90 v / v) to give the title compound (7 mg, 20 μmol, 6% yield) as a yellow solid after lyophilization. 1 H NMR (400MHz, CDCl3) δppm 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].

[0532] Example 26

[0533] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-(6-chloro-3-pyridinyl)-5-methyl-imidazole-2-carboxamide

[0534]

[0535] 2-Chloro-4-iodo-3-methyl-pyridine (77.8 mg, 0.310 mmol) was dissolved in DMF (2 mL), and dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) 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 h. Then, 1-(6-chloro-3-pyridyl)-4-ethynyl-5-methyl-imidazole-2-carboxamide (Int-64) (80 mg, 310 μmol) was added, and the reaction mixture was stirred at 70° C. for another 3 h. 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 the substrate between 70:30 and 10:90 v / v) to give the title compound (23 mg, 60 μmol, 19% yield) as a yellow solid after lyophilization. 1 H NMR (400MHz, DMSO-d6) δppm 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].

[0536] Example 27

[0537] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-(6-methoxy-3-pyridinyl)-5-methyl-imidazole-2-carboxamide

[0538]

[0539] 4-Ethynyl-1-(6-methoxy-3-pyridyl)-5-methyl-imidazole-2-carboxamide (Int-65) (60 mg, 230 μmol) was dissolved in DMF (1 mL), and dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) 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-methyl-pyridine (71 mg, 0.28 mmol) were added. The resulting mixture was stirred at 70° C. for 4 h. After cooling, the mixture was filtered and the filtrate 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 the substrate between 70:30 and 10:90 v / v) to give the title compound (10 mg, 26 μmol, 11% yield) as a yellow solid after lyophilization. 1 H NMR (400MHz, CDCl3) δppm 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].

[0540] Example 28

[0541] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(5-methyl-2-pyridinyl)imidazole-2-carboxamide

[0542]

[0543] 2-Chloro-4-iodo-3-methyl-pyridine (63.3 mg, 0.250 mmol) was dissolved in DMF (1 mL), and dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) 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 h. 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 another 3 h. After cooling, the mixture was filtered and the filtrate 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 the substrate between 70:30 and 10:90 v / v) to give the title compound (4 mg, 11 μmol, 4% yield) as a yellow solid after lyophilization. 1H NMR (400MHz, DMSO-d6) δppm 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].

[0544] Example 29

[0545] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(3-pyridinyl)imidazole-2-carboxamide

[0546]

[0547] 2-Chloro-4-iodo-3-methyl-pyridine (687 mg, 2.71 mmol) was dissolved in DMF (10 mL), and dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) 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 h. 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 another 1 h. After cooling, the mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (200 g, silica gel, n-heptane / (ethyl acetate + 30% ethanol), gradient 90:10 to 66:33 (v / v)) followed by trituration with tert-butyl methyl ether to give the title compound (311 mg, 0.88 mmol, 38% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δppm 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].

[0548] Example 30

[0549] 4-[2-(3-chloro-2-methyl-phenyl)ethynyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide

[0550]

[0551] 1-Chloro-3-iodo-2-methyl-benzene (179 mg, 0.71 mmol) was dissolved in DMF (2 mL), and dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) 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 h. 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 another 1 h. After cooling, the mixture was filtered, the filtrate was concentrated in vacuo and purified by preparative HPLC (Shim-pack C18, 150×25 mm×10 μm, eluted with acetonitrile / (water+0.225% formic acid), linear, optimized for the substrate between 70:30 and 10:90 v / v) to give the title compound (29 mg, 83 μmol, 23% yield) as a light yellow solid after lyophilization. 1 H NMR (400MHz, DMSO-d6) δppm 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].

[0552] Example 31

[0553] 4-[2-(2-chloro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)pyrrole-2-carboxamide

[0554]

[0555] 4-[2-(2-chloro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)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 h. Then, the mixture was 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 h and then at 25° C. for 2 h. Afterwards, the solvent was removed in vacuo 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 the substrate between 70:30 and 10:90 v / v) to give the title compound (20 mg, 57 μmol, 23% yield) as a white solid after lyophilization. 1 H NMR (400MHz, DMSO-d6) δppm2.55 (s, 3H), 3.65 (s, 3H), 7.19 (brs, 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].

[0556] Example 32

[0557] 2-[2-(2-chloro-4-pyridinyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridinyl)imidazole-4-carboxamide

[0558]

[0559] 2-[2-(2-chloro-4-pyridinyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridinyl)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 h. Afterwards, the pH was adjusted to about 8 by adding 2N aqueous sodium hydroxide solution. A precipitate was formed, which was filtered off, washed (tert-butyl methyl ether), and dried in vacuo to give the title compound (200 mg, 0.57 mmol, 53% yield) as an off-white solid. 1HNMR (400MHz, DMSO-d6) δppm 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].

[0560] Example 33

[0561] 2-[2-(3-chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide

[0562]

[0563] 2-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridinyl)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 h. Afterwards, the pH was adjusted to about 8 by adding 2N aqueous sodium hydroxide solution. A precipitate was 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 substrate between 70:30 and 10:90 v / v) to give the title compound (29 mg, 70 μmol, 30% yield) as a formate salt as an off-white solid after lyophilization. 1 H NMR (400MHz, DMSO-d6) δppm 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].

[0564] Example 34

[0565] 2-[2-(3-chlorophenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide

[0566]

[0567] 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 h. Afterwards, the pH was adjusted to about 8 by adding 2N aqueous sodium hydroxide solution. A precipitate was 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 substrate between 70:30 and 10:90 v / v) to give the title compound (41 mg, 120 μmol, 35% yield) as an off-white solid after lyophilization. 1 H NMR (400MHz, DMSO-d6) δppm 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, 2 H), 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].

[0568] Example 35

[0569] 2-[2-(3-Chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamide formate

[0570]

[0571] 2-[2-(3-Chloro-2-methyl-phenyl)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 h. Afterwards, the pH was adjusted to about 8 by adding 2N aqueous sodium hydroxide solution. A precipitate was 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 substrate between 70:30 and 10:90 v / v) to give the title compound (36 mg, 90 μmol, 19% yield) as a formate salt as a white solid after lyophilization. 1 H NMR (400MHz, DMSO-d6) δppm 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, 4H), 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].

[0572] Example 36

[0573] 2-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-methyl-5-(3-pyridinyl)imidazole-4-carboxamide formate

[0574]

[0575] 2-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-methyl-5-(3-pyridinyl)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 h. Afterwards, the pH was adjusted to about 8 by adding 2N aqueous sodium hydroxide solution. A precipitate was 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 substrate between 70:30 and 10:90 v / v) to give the title compound (25 mg, 71 μmol, 47% yield) as a formate salt as a white solid after lyophilization. 1H NMR (400MHz, DMSO-d6) δppm 2.57 (s, 3H), 3.65 (s, 3H), 7.20 (br s, 1H), 7.50-7.55 (m, 1H), 7.61 (br s, 1H), 7.67 (d, J=5.0Hz, 1H), 7.95 (dt, J=8.0, 2.0Hz, 1H), 8.35 (d, J=4.9Hz, 1H), 8.65 (dd, J=4.9, 1.6Hz, 1H), 8.67-8.69 (m, 1H). MS(ES+)m / z 351.8[M+H].

[0576] Example 37

[0577] 5-Methyl-4-(phenylethynyl)-1-(p-tolyl)-1H-imidazole-2-carboxamide

[0578]

[0579] 4-ethynyl-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 at 0-5 ° C, triethylamine (81 mg, 112 μL, 802 μmol) and dichlorobis(triphenylphosphine)palladium (II) (9.4 mg, 13 μmol) were added under argon. The flask was evacuated and purged with argon. Then, copper iodide (I) (1.5 mg, 8.0 μmol) was added to obtain a light brown solution. The resulting mixture was stirred for 2 h at 0-5 ° C. Then, the reaction mixture was extracted with water (20 mL) and dichloromethane (20 mL), and the aqueous layer was stripped with dichloromethane (2 × 20 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (sodium sulfate), filtered, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (24 g, silica gel, ethyl acetate / n-heptane, gradient 0: 100 to 40: 60 (v / v)) to give the title compound (26 mg, 82 μmol, 31% yield) as a white solid. HPLC (LCMS_fast gradient method) t R =1.34min. 1 H NMR (300MHz, CDCl3) δppm 2.16 (s, 3H), 2.43 (s, 3H), 5.31 (br s, 1H), 7.11 (d, J=8.3Hz, 2H), 7.17 (br s, 1H), 7.29 (d, J=7.9Hz, 2H), 7.32-7.37 (m, 3H), 7.53-7.58 (m, 2H). MS(ES+)m / z 316.2[M+H].

[0580] Example 38

[0581] 4-[2-(2-chloro-4-pyridinyl)ethynyl]-5-methyl-1-(p-tolyl)imidazole-2-carboxamide

[0582]

[0583] 4-Ethynyl-5-methyl-1-(p-tolyl)-1H-imidazole-2-carboxamide (Int-10) (75 mg, 314 μmol) was dissolved in DMF (5 mL), and dichlorobis(triphenylphosphine)palladium(II) (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 h. After cooling, the mixture was filtered and the filtrate 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 the substrate between 70:30 and 10:90 v / v) to give the title compound (29 mg, 80 μmol, 25% yield) as a white solid after lyophilization. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.11 (s, 3H), 2.39 (s, 3H), 7.21 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.39 (br s, 1H), 7.53 (dd, J = 1.3, 5.1 Hz, 1H), 7.69 (s, 1H), 7.89 (br s, 1H), 8.44 (d, J = 5.1 Hz, 1H). MS (ES+) m / z 351.3, 353.2 [M+H, Cl isotope].

[0584] Example 39

[0585] 1-(4-Chlorophenyl)-4-((2-chloropyridin-4-yl)ethynyl)-5-methyl-1H-imidazole-2-carboxamide

[0586]

[0587] 1-(4-chlorophenyl)-4-ethynyl-5-methyl-1H-imidazole-2-carboxamide (Int-11) (55mg, 212μmol) and 2-chloro-4-iodopyridine (55.8mg, 233μmol) were dissolved in DMF (2mL), and at 0-5°C, triethylamine (64mg, 89μL, 635μmol) and dichlorobis(triphenylphosphine)palladium (II) (12mg, 17μmol) were added under argon. The flask was evacuated and purged with argon. Then, copper iodide (I) (1.6mg, 8.5μmol) was added to obtain a light brown solution. The resulting mixture was stirred for 2h at 0-5°C. Then, the reaction mixture was extracted with water (40mL) and dichloromethane (50mL), and the aqueous layer was stripped with dichloromethane (2×40mL). The combined organic layers were washed with brine (30 mL), dried (sodium sulfate), filtered and the filtrate was concentrated in vacuo. The crude product was triturated with hot ethyl acetate (5 mL), the precipitate was filtered off after cooling, washed (ethyl acetate), and dried in vacuo to give the title compound (23 mg, 62 μmol, 29% yield) as an off-white solid. 1 H NMR (600 MHz, 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, 2Cl isotope].

[0588] Example 40

[0589] 1-(3-Chlorophenyl)-4-((2-chloropyridin-4-yl)ethynyl)-5-methyl-1H-imidazole-2-carboxamide

[0590]

[0591] A solution of 1-(3-chloro-phenyl)-4-(2-chloro-pyridin-4-ylethynyl)-5-methyl-1H-imidazole-2-carboxylic acid 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 h. Afterwards, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (20 g, silica gel functionalized with NH2, ethyl acetate / n-heptane, isocratic 50:50 (v / v)) to give the title compound (44 mg, 118 μmol, 42% yield) as an off-white solid. MS (ES+) m / z 370 [M+H].

[0592] Example 41

[0593] 4-(2-Chloro-pyridin-4-ylethynyl)-1-(2,4-difluoro-phenyl)-5-methyl-1H-imidazole-2-carboxylic acid amide

[0594]

[0595] A solution of 4-(2-chloro-pyridin-4-ylethynyl)-1-(2,4-difluoro-phenyl)-5-methyl-1H-imidazole-2-carboxylic acid methyl ester (Int-33) (70 mg, 180 μmol) in ammonia (7N in MeOH) (2.6 mL, 18 mmol) was stirred at 90 ° C in a pressure tube for 16 h. Afterwards, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (20 g, silica gel, ethyl acetate / n-heptane, gradient 0: 100 to 33: 67 (v / v)) to give the title compound (15 mg, 40 μmol, 22% yield) as an off-white solid. MS (ES+) m / z 373 [M+H].

[0596] Example 42

[0597] 4-(2-Chloro-pyridin-4-ylethynyl)-1-(4-fluoro-phenyl)-1H-imidazole-2-carboxylic acid amide

[0598]

[0599] A solution of methyl 4-((2-chloropyridin-4-yl)ethynyl)-1-(4-fluorophenyl)-1H-imidazole-2-carboxylate (Int-49) (100 mg, 197 μmol), sodium cyanide (1.4 mg, 28 μmol) in ammonia (7N in MeOH) (2 mL, 14 mmol) was stirred in a pressure tube at 50 °C for 15 h. 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 (sodium sulfate), filtered and the filtrate was concentrated in vacuo. The crude product was purified by trituration with dichloromethane (1.5 mL) at room temperature, filtration, then trituration with dichloromethane (1 mL) at reflux, stirring at room temperature for 1 h before filtration and drying in vacuo to afford the title compound (29 mg, 85 μmol, 43% yield) as an off-white solid. HPLC (LCMS_fast gradient method) t R =1.12min. 1HNMR (300 MHz, 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, 5.2 Hz, 1H). MS (ES+) m / z 341.2, 343.2 [M+H, Cl isotope].

[0600] Example 43

[0601] 4-((2-chloropyridin-4-yl)ethynyl)-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0602]

[0603] 4-ethynyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide (Int-22) (95mg, 420μmol) and 2-chloro-4-iodopyridine (111mg, 462μmol) are dissolved in DMF (3.5mL), and at 0-5°C, triethylamine (127mg, 176μL, 1.26mmol) and dichlorobis(triphenylphosphine)palladium (II) (24mg, 34μmol) are added under argon. The flask is evacuated and purged with argon. Then, copper iodide (I) (3.2mg, 17μmol) is added to obtain a light brown solution. The resulting mixture is stirred for 1h at 0-5°C. Then, the reaction mixture is extracted with water (40mL) and dichloromethane (50mL), and the water layer is stripped with dichloromethane (2x40mL). The combined organic layers were washed with brine (30 mL), dried (sodium sulfate), filtered and the filtrate was concentrated in vacuo. The crude product was ground with dichloromethane (5 mL) under reflux, filtered after cooling, then ground with ethanol (5 mL) at 50 ° C, filtered after cooling, and dried under high vacuum to purify to give the title compound (80 mg, 237 μ mol, 56% yield) as an off-white solid. HPLC (LCMS fast gradient method) t R =0.93min. 1H NMR (300MHz, DMSO-d6) δppm 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 / z 338.2, 340.2 [M+H, Cl isotope].

[0604] Example 44

[0605] 2-[2-(3-chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide

[0606]

[0607] 2-[2-(3-Chloro-2-methyl-phenyl)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 h. Afterwards, the pH was adjusted to about 8 by adding 2N aqueous sodium hydroxide solution. A precipitate was 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 substrate between 70:30 and 10:90 v / v) to give the title compound (20 mg, 50 μmol, 19% yield) as a white solid after lyophilization. 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 (brs, 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 / z364.9, 366.9 [M+H, Cl isotope].

[0608] Aspects of the invention:

[0609] 1. A compound of formula I

[0610]

[0611] in

[0612] X 1 N or C

[0613] X 2 N or C

[0614] X 3 N or C

[0615] The condition is X 1 , X 2 and X 3 At least one of is N, and X 1 , X 2 and X 3 No more than two of them represent N, and if X 1 is N, then X 2 Cannot be N;

[0616] Dashed lines represent single or double bonds to enable the five-membered ring to be aromatic;

[0617] R 1 is phenyl, N-heteroaryl, wherein the N-heteroaryl contains 1, 2 or 3 nitrogen ring atoms, and wherein the phenyl or the N-heteroaryl is optionally substituted by 1, 2, 3 or 4 selected from R 4 Substituents are substituted;

[0618] R 2 is hydrogen or C1-C6 alkyl, provided that if X 2 is N, then R 2 Not hydrogen;

[0619] R 3 is heteroaryl or phenyl, wherein the heteroaryl or the phenyl is optionally substituted by 1, 2, 3 or 4 groups selected from R 5 Substituents are substituted;

[0620] R 4 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy; and

[0621] R 5 independently selected from hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy, or

[0622] Two adjacent R 5The group forms a five-membered or six-membered heterocyclyl condensed ring, wherein the heterocyclyl condensed ring is optionally substituted by one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-substituted C1-C6 alkyl and halo-substituted C1-C6 alkoxy; or

[0623] Its pharmaceutically acceptable salts.

[0624] 2. The compound according to aspect 1, wherein the compound has formula Ia

[0625]

[0626] Where R 1 , R 2 or R 3 According to the definition in aspect 1, or a pharmaceutically acceptable salt thereof.

[0627] 3. The compound according to aspect 1, wherein the compound has formula Ib

[0628]

[0629] Where R 1 , R 2 or R 3 According to the definition in aspect 1, or a pharmaceutically acceptable salt thereof.

[0630] 4. The compound according to aspect 1, wherein the compound has formula Ic

[0631]

[0632] Where R 1 , R 2 or R 3 According to the definition in aspect 1, or a pharmaceutically acceptable salt thereof.

[0633] 5. A compound according to any one of aspects 1 to 4, wherein R 1 is phenyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridinyl, wherein the phenyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridinyl is optionally substituted by 1, 2, 3 or 4 groups selected from R 4 Substituents, where R 4 Defined according to aspect 1.

[0634] 6. A compound according to any one of aspects 1 to 5, wherein R 1 is phenyl, pyrazinyl, pyridazinyl or pyridinyl, wherein the phenyl, pyrazinyl, pyridazinyl or pyridinyl is optionally substituted by 1, 2 or 3 selected from R 4 Substituents, where R 4 Defined according to aspect 1.

[0635] 7. A compound according to any one of aspects 1 to 4, wherein R 1 is phenyl, pyrazinyl, pyridazinyl or pyridinyl, wherein the phenyl, pyrazinyl, pyridazinyl or pyridinyl is optionally substituted by 1 or 2 selected from R 4 Substituents, where R 4 Defined according to aspect 1.

[0636] 8. A compound according to any one of aspects 1 to 7, wherein R 2 It is a C1-C6 alkyl group.

[0637] 9. A compound according to any one of aspects 1 to 8, wherein R 2 It is methyl.

[0638] 10. A compound according to any one of aspects 1 to 9, wherein R 3 is phenyl, pyrazolyl, pyridyl, pyrimidinyl or thienyl, wherein the phenyl, pyrazolyl, pyridyl, pyrimidinyl or thienyl is optionally substituted by 1, 2, 3 or 4 groups selected from R 5 Substituents, where R 5 Defined according to aspect 1.

[0639] 11. A compound according to any one of aspects 1 to 10, wherein R 3 is phenyl, pyrazolyl, pyridyl, pyrimidinyl or thienyl, wherein the phenyl, pyrazolyl, pyridyl, pyrimidinyl or thienyl is optionally substituted by 1, 2 or 3 selected from R 5 Substituents, where R 5 As defined in aspect 11.

[0640] 12. A compound according to any one of aspects 1 to 11, wherein R 3 is phenyl, pyrazolyl, pyridyl, pyrimidinyl or thienyl, wherein the phenyl, pyrazolyl, pyridyl, pyrimidinyl or thienyl is optionally substituted by 1 or 2 selected from R 5 Substituents, where R 5 Defined according to aspect 1.

[0641] 13. A compound according to any one of aspects 1 to 12, wherein R 3 is phenyl, pyridyl or thienyl, wherein the phenyl, pyridyl or thienyl is optionally substituted by 1 or 2 selected from R 5 Substituents, where R 5 Defined according to aspect 1.

[0642] 14. A compound according to any one of aspects 1 to 13, wherein R4 Independently selected from halogen, C1-C6 alkyl and C1-C6 alkoxy.

[0643] 15. A compound according to any one of aspects 1 to 14, wherein R 4 Independently selected from halogen, methyl and methoxy.

[0644] 16. A compound according to any one of aspects 1 to 15, wherein R 4 Independently selected from fluoro, chloro, methyl and methoxy.

[0645] 17. A compound according to any one of aspects 1 to 13, wherein R 1 is phenyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridyl.

[0646] 18. A compound according to any one of aspects 1 to 13, wherein R 1 is phenyl, pyrazinyl, pyridazinyl or pyridinyl.

[0647] 19. A compound according to any one of aspects 1 to 18, wherein R 5 independently selected from halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy, or two ortho R 5 The group forms a five-membered or six-membered heterocyclyl condensed ring, wherein the heterocyclyl condensed ring is optionally substituted by one or more groups independently selected from the following: hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy.

[0648] 20. A compound according to any one of aspects 1 to 19, wherein R 5 are independently selected from halogen, cyano, methyl, trifluoromethyl and methoxy, or two ortho-position R 5 The group forms a dioxolane group.

[0649] 21. A compound according to any one of aspects 1 to 13, selected from:

[0650] 4-((2-chloro-3-methylpyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0651] 4-((2-chloro-3-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0652] 4-[2-(5-chlorothien-3-yl)ethynyl]-5-methyl-1-(6-methylpyridin-3-yl)imidazole-2-carboxamide

[0653] 4-[2-(3-chlorophenyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide

[0654] 4-((3-cyanophenyl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0655] 4-(2-Chloro-pyridin-4-ylethynyl)-5-methyl-1-(6-methyl-pyridin-3-yl)-1H-imidazole-2-carboxylic acid amide

[0656] 4-((2-chloro-5-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0657] 4-((3-methoxyphenyl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0658] 4-[2-(4-Chlorophenyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide

[0659] 5-Methyl-1-(6-methylpyridin-3-yl)-4-(m-tolylethynyl)-1H-imidazole-2-carboxamide

[0660] 5-methyl-1-(6-methylpyridin-3-yl)-4-((2-(trifluoromethyl)pyridin-4-yl)ethynyl)-1H-imidazole-2-carboxamide

[0661] 4-[2-(2-fluoro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)imidazole-2-carboxamide

[0662] 4-(Benzo[d][1,3]dioxol-4-ylethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0663] 4-((6-chloropyridin-2-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0664] 4-((2-chloropyrimidin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0665] 4-((3-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0666] 4-[2-(5-chloro-3-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)imidazole-2-carboxamide

[0667] 4-((4-chloropyridin-2-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0668] 4-((6-chloropyrimidin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide

[0669] 5-Methyl-1-(6-methyl-3-pyridinyl)-4-[2-(3-pyridinyl)ethynyl]imidazole-2-carboxamide

[0670] 5-Methyl-1-(6-methyl-3-pyridinyl)-4-[2-(4-pyridinyl)ethynyl]imidazole-2-carboxamide

[0671] 5-Methyl-1-(6-methylpyridin-3-yl)-4-((2-methylpyridin-4-yl)ethynyl)-1H-imidazole-2-carboxamide

[0672] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(5-methylpyrazin-2-yl)imidazole-2-carboxamide

[0673] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(6-methylpyridazin-3-yl)imidazole-2-carboxamide

[0674] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(5-methyl-3-pyridinyl)imidazole-2-carboxamide

[0675] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-(6-chloro-3-pyridinyl)-5-methyl-imidazole-2-carboxamide

[0676] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-(6-methoxy-3-pyridinyl)-5-methyl-imidazole-2-carboxamide

[0677] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(5-methyl-2-pyridinyl)imidazole-2-carboxamide

[0678] 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(3-pyridinyl)imidazole-2-carboxamide

[0679] 4-[2-(3-chloro-2-methyl-phenyl)ethynyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide

[0680] 4-[2-(2-chloro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)pyrrole-2-carboxamide

[0681] 2-[2-(2-chloro-4-pyridinyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridinyl)imidazole-4-carboxamide

[0682] 2-[2-(3-chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide

[0683] 2-[2-(3-chlorophenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide

[0684] 2-[2-(3-Chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamide formate

[0685] 2-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-methyl-5-(3-pyridinyl)imidazole-4-carboxamide formate

[0686] 5-Methyl-4-(phenylethynyl)-1-(p-tolyl)-1H-imidazole-2-carboxamide

[0687] 4-[2-(2-chloro-4-pyridinyl)ethynyl]-5-methyl-1-(p-tolyl)imidazole-2-carboxamide

[0688] 1-(4-Chlorophenyl)-4-((2-chloropyridin-4-yl)ethynyl)-5-methyl-1H-imidazole-2-carboxamide

[0689] 1-(3-Chlorophenyl)-4-((2-chloropyridin-4-yl)ethynyl)-5-methyl-1H-imidazole-2-carboxamide

[0690] 4-(2-Chloro-pyridin-4-ylethynyl)-1-(2,4-difluoro-phenyl)-5-methyl-1H-imidazole-2-carboxylic acid amide

[0691] 4-(2-Chloro-pyridin-4-ylethynyl)-1-(4-fluoro-phenyl)-1H-imidazole-2-carboxylic acid amide

[0692] 4-((2-chloropyridin-4-yl)ethynyl)-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide; and

[0693] 2-[2-(3-Chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridinyl)imidazole-4-carboxamide.

[0694] 22. A compound according to any one of aspects 1 to 21 for use as therapeutically active substance.

[0695] 23. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 21, and one or more pharmaceutically acceptable excipients.

[0696] 24. A compound of formula I according to any one of aspects 1 to 21, or a pharmaceutically acceptable salt thereof as described above, for use as a therapeutically active substance.

[0697] 25. A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 21 for use in treating, preventing and / or delaying progression of a CNS disease.

[0698] 26. A method for treating or preventing a CNS disease, the method comprising administering to a subject a compound of formula I according to any one of aspects 1 to 21 as defined above, or a pharmaceutically acceptable salt thereof.

[0699] 27. Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 21 for treating, preventing and / or delaying progression of a CNS disease.

[0700] 28. An HCN1 selective compound for use in treating, preventing and / or delaying the progression of a CNS disease.

[0701] 29. The HCN1 selective compound according to aspect 28, wherein the HCN1 selective compound has higher selectivity than HCN2 and HCN4.

[0702] 30. The HCN1 selective compound of aspect 28 or 29, wherein the CNS disease is selected from the group consisting of psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ocular, endocrine diseases, and / or other diseases described herein, including 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 dementia, 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, drug abuse and drug dependence, Tourette's syndrome, tardive dyskinesia, somnolence, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, refractory 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 particularly cognitive impairment associated with schizophrenia (CIAS), early infantile epileptic encephalopathy (EIEE), epilepsy, mood disorders (e.g., depression), neuropathic pain, and autism (sensory sensitivity).

[0703] 31. The HCN1 selective compound according to aspects 28 to 30, wherein the CNS disease is schizophrenia-related cognitive impairment.

[0704] 32. An HCN1 selective compound according to aspects 28 to 31 for use in treating schizophrenia-related cognitive impairment.

Claims

1. A compound of formula I I in X 1 N or C X 2 N or C X 3 N or C The condition is X 1 , X 2 and X 3 At least one of is N, and X 1 , X 2 and X 3 No more than two of them represent N, and if X 1 is N, then X 2 Cannot be N; Dashed lines represent single or double bonds to enable the five-membered ring to be aromatic; R 1 is phenyl, N-heteroaryl, wherein the phenyl or N-heteroaryl is optionally substituted by 1, 2, 3 or 4 selected from R 4 wherein the N-heteroaryl group refers to a monovalent monocyclic or bicyclic moiety having 5 to 12 ring atoms and having at least one aromatic ring, the aromatic ring containing 1, 2 or 3 nitrogen ring atoms, and the remaining ring atoms are C; R 2 is hydrogen or C1-C6 alkyl, provided that if X 2 is N, then R 2 Not hydrogen; R 3 is heteroaryl or phenyl, wherein the heteroaryl or the phenyl is optionally substituted by 1, 2, 3 or 4 selected from R 5 wherein the heteroaryl group refers to a monovalent monocyclic or bicyclic moiety having 5 to 12 ring atoms and having at least one aromatic ring, wherein the aromatic ring contains one, two or three ring heteroatoms independently selected from N, O or S, and the remaining ring atoms are C; R 4 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy; and R 5 independently selected from hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy, or Two adjacent R 5 The group forms a five-membered or six-membered heterocyclyl condensed ring, wherein the heterocyclyl condensed ring is optionally substituted by one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy; or Its pharmaceutically acceptable salts.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula Ia It Where R 1 , R 2 or R 3 As defined in claim 1.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula Ib One Where R 1 , R 2 or R 3 As defined in claim 1.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula Ic Ic Where R 1 , R 2 or R 3 As defined in claim 1.

5. The compound according to any one of claims 1 to 4, wherein R 1 is phenyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridinyl, wherein the phenyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridinyl is optionally substituted by 1, 2, 3 or 4 selected from R 4 Substituents, where R 4 As defined in claim 1.

6. A compound according to any one of claims 1 to 4, wherein R 1 is phenyl, pyrazinyl, pyridazinyl or pyridinyl, wherein the phenyl, pyrazinyl, pyridazinyl or pyridinyl is optionally substituted by 1, 2 or 3 selected from R 4 Substituents, where R 4 As defined in claim 1.

7. A compound according to any one of claims 1 to 4, wherein R 1 is phenyl, pyrazinyl, pyridazinyl or pyridinyl, wherein the phenyl, pyrazinyl, pyridazinyl or pyridinyl is optionally substituted by 1 or 2 selected from R 4 Substituents, where R 4 As defined in claim 1.

8. A compound according to any one of claims 1 to 4, wherein R 2 It is a C1-C6 alkyl group.

9. The compound according to any one of claims 1 to 4, wherein R 2 It is methyl.

10. The compound according to any one of claims 1 to 4, wherein R 3 is phenyl, pyrazolyl, pyridyl, pyrimidinyl or thienyl, wherein the phenyl, pyrazolyl, pyridyl, pyrimidinyl or thienyl is optionally substituted by 1, 2, 3 or 4 selected from R 5 Substituents, where R 5 As defined in claim 1.

11. A compound according to any one of claims 1 to 4, wherein R 3 is phenyl, pyrazolyl, pyridyl, pyrimidinyl or thienyl, wherein the phenyl, pyrazolyl, pyridyl, pyrimidinyl or thienyl is optionally substituted by 1, 2 or 3 selected from R 5 Substituents, where R 5 As defined in claim 1.

12. A compound according to any one of claims 1 to 4, wherein R 3 is phenyl, pyrazolyl, pyridyl, pyrimidinyl or thienyl, wherein the phenyl, pyrazolyl, pyridyl, pyrimidinyl or thienyl is optionally substituted by 1 or 2 selected from R 5 Substituents, where R 5 As defined in claim 1.

13. A compound according to any one of claims 1 to 4, wherein R 3 is phenyl, pyridyl or thienyl, wherein the phenyl, pyridyl or thienyl is optionally substituted by 1 or 2 selected from R 5 Substituents, where R 5 As defined in claim 1.

14. A compound according to any one of claims 1 to 4, wherein R 4 Independently selected from halogen, C1-C6 alkyl and C1-C6 alkoxy.

15. A compound according to any one of claims 1 to 4, wherein R 4 Independently selected from halogen, methyl and methoxy.

16. A compound according to any one of claims 1 to 4, wherein R 4 Independently selected from fluoro, chloro, methyl and methoxy.

17. A compound according to any one of claims 1 to 4, wherein R 1 is phenyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridyl.

18. A compound according to any one of claims 1 to 4, wherein R 1 is phenyl, pyrazinyl, pyridazinyl or pyridinyl.

19. A compound according to any one of claims 1 to 4, wherein R 5 independently selected from halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy, or two ortho-position R 5 The group forms a five-membered or six-membered heterocyclyl condensed ring, wherein the heterocyclyl condensed ring is optionally substituted by one or more groups independently selected from -hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy.

20. A compound according to any one of claims 1 to 4, wherein R 5 are independently selected from halogen, cyano, methyl, trifluoromethyl and methoxy, or two ortho R 5 The group forms a dioxolane group.

21. The compound according to claim 1, selected from: 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-chlorothien-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-ylethynyl)-5-methyl-1-(6-methyl-pyridin-3-yl)-1H-imidazole-2-carboxylic acid amide 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-methylpyridin-3-yl)-4-((2-(trifluoromethyl)pyridin-4-yl)ethynyl)-1H-imidazole-2-carboxamide 4-[2-(2-fluoro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)imidazole-2-carboxamide 4-(Benzo[d][1,3]dioxol-4-ylethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide 4-((6-chloropyridin-2-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide 4-((2-chloropyrimidin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide 4-((3-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide 4-[2-(5-chloro-3-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)imidazole-2-carboxamide 4-((4-chloropyridin-2-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide 4-((6-chloropyrimidin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide 5-Methyl-1-(6-methyl-3-pyridinyl)-4-[2-(3-pyridinyl)ethynyl]imidazole-2-carboxamide 5-Methyl-1-(6-methyl-3-pyridinyl)-4-[2-(4-pyridinyl)ethynyl]imidazole-2-carboxamide 5-Methyl-1-(6-methylpyridin-3-yl)-4-((2-methylpyridin-4-yl)ethynyl)-1H-imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(5-methylpyrazin-2-yl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(6-methylpyridazin-3-yl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(5-methyl-3-pyridinyl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-(6-chloro-3-pyridinyl)-5-methyl-imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-(6-methoxy-3-pyridinyl)-5-methyl-imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(5-methyl-2-pyridinyl)imidazole-2-carboxamide 4-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-5-methyl-1-(3-pyridinyl)imidazole-2-carboxamide 4-[2-(3-chloro-2-methyl-phenyl)ethynyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide 4-[2-(2-chloro-4-pyridinyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridinyl)pyrrole-2-carboxamide 2-[2-(2-chloro-4-pyridinyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridinyl)imidazole-4-carboxamide 2-[2-(3-chloro-2-methyl-phenyl)ethynyl]-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-methyl-phenyl)ethynyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamide formate 2-[2-(2-chloro-3-methyl-4-pyridinyl)ethynyl]-1-methyl-5-(3-pyridinyl)imidazole-4-carboxamide formate 5-Methyl-4-(phenylethynyl)-1-(p-tolyl)-1H-imidazole-2-carboxamide 4-[2-(2-chloro-4-pyridinyl)ethynyl]-5-methyl-1-(p-tolyl)imidazole-2-carboxamide 1-(4-Chlorophenyl)-4-((2-chloropyridin-4-yl)ethynyl)-5-methyl-1H-imidazole-2-carboxamide 1-(3-Chlorophenyl)-4-((2-chloropyridin-4-yl)ethynyl)-5-methyl-1H-imidazole-2-carboxamide 4-(2-Chloro-pyridin-4-ylethynyl)-1-(2,4-difluoro-phenyl)-5-methyl-1H-imidazole-2-carboxylic acid amide 4-(2-Chloro-pyridin-4-ylethynyl)-1-(4-fluoro-phenyl)-1H-imidazole-2-carboxylic acid amide 4-((2-chloropyridin-4-yl)ethynyl)-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide; and 2-[2-(3-Chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridinyl)imidazole-4-carboxamide.

22. Compounds according to any one of claims 1 to 21 for use as therapeutically active substances.

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

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

25. A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21 for use in treating, preventing and / or delaying the progression of a CNS disease.

26. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 25, wherein the CNS disease is selected from the group consisting of schizophrenia, cognitive impairment associated with D2 antagonist therapy, ADHD, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's dementia, Parkinson's disease, Huntington's disease, anxiety disorders, chronic apathy, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, Tourette's syndrome, tardive dyskinesia, sexual dysfunction, systemic lupus erythematosus (SLE), sleep disorders, pain, cognitive impairment associated with schizophrenia (CIAS), epilepsy and mood disorders.

27. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 25, wherein the CNS disease is selected from the group consisting of neurodevelopmental diseases, neurodegenerative diseases, postpartum depression, treatment-resistant depression (TRD) and neuropathic pain.

28. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 25, wherein the CNS disease is selected from the group consisting of depression, bipolar disorder, hypersomnia, narcolepsy, migraine and early infantile epileptic encephalopathy (EIEE).

29. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 25, wherein the CNS disease is selected from the group consisting of autism and psychosis.

30. Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21 for the preparation of a medicament as an HCN1 inhibitor.

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