TW201315731A - New positive allosteric modulators of nicotinic acetylcholine receptor - Google Patents

Abstract

The present invention relates to compounds useful in therapy, to compositions comprising said compounds, and to methods of treating diseases comprising administration of said compounds. The compounds referred to are positive allosteric modulators (PAMs) of the nicotinic acetylcholine α 7 receptor.

Description

Novel positive forward ectopic modulator of nicotinic acetylcholine receptor

The present invention relates to compounds useful in therapy, compositions comprising such compounds, and methods of treating diseases in which such compounds are administered. The compound referred to is a positive ectopic modulator (PAM) of the nicotinic acetylcholine alpha 7 receptor.

The nicotinic acetylcholine receptor (nAChR) belongs to the ligand-gated ion channel superfamily and gates the flow of cations including calcium. nAChR is endogenously activated by acetylcholine (ACh) and can be classified into a neuromuscular junction nicotinic receptor and a neuronal nicotinic receptor (NNR). NNR is widely expressed throughout the central nervous system (CNS) and peripheral nervous system (PNS). It has been suggested that NNR plays an important role in CNS function by regulating a number of neurotransmitters, such as, in particular, ACh, norepinephrine, dopamine, serotonin, and GABA release. Thereby producing a wide range of physiological effects.

Seventeen subunits of nAChR have been reported so far, which are identified as α2-α10, β1-β4, γ, δ, and ε. Among these subunits, nine subunits (i.e., α2 to α7 and β2 to β4) are mainly present in the mammalian brain. There are many functionally distinct nAChR complexes, for example, five α7 subunits can form receptors in the form of homopolymeric functional pentamers, or a combination of different subunits can form heteropolymeric receptors, such as α4β2 and α3β4 receptors. (Gotti, C. et al., Prog. Neurobiol. 2004, 74: 363-396; Gotti, C. et al. Biochemical Pharmacology , 2009, 78: 703-711).

The homopolymerized α7 receptor and α4β2 receptor are one of the most abundant NNRs in the brain, and they are abundantly expressed in the hippocampus, cortex, thalamic nuclei, and ventral region in the brain. Tegmental area) and substantia nigra (Broad, LM et al., Drugs of the Future , 2007, 32(2): 161-170; Poorthuis RB, Biochem Pharmacol . 2009, 1; 78(7): 668 -76).

The role of α7 NNR in neuronal signaling has been actively studied. Alpha 7 NNR has been shown to regulate interneuron excitability and regulate excitability as well as release of inhibitory neurotransmitters. Furthermore, α7 NNR has been reported to be involved in neuroprotection in an experimental cell injury model (Shimohama, S., Biol Pharm Bull. 2009, 32(3): 332-6).

Studies have shown that α7 subunits rapidly activate and desensitize when recombined in vitro, and exhibit relatively high calcium permeability compared to other NNR combinations (Papke, RL et al, J Pharmacol Exp Ther. 2009, 329 (2) ): 791-807).

In general, NNR is involved in a variety of cognitive functions, such as learning, memory, and attention and is therefore involved in CNS disorders, namely Alzheimer's disease (AD), Parkinson's disease (Parkinson's disease, PD), attention deficit hyperactivity disorder (ADHD), Tourette's syndrome, schizophrenia, bipolar disorder, pain and tobacco dependence (Keller, JJ, Et al., Behav. Brain Res. 2005, 162: 143-52; Haydar SN et al., Curr Top Med Chem. 2010; 10(2): 144-52).

In particular, α7 NNR has also been found to be associated with cognitive disorders including, for example, ADHD, autism spectrum disorder, AD, mild cognitive impairment (MCI), age-related memory impairment ( AAMI), Alzheimer's disease, frontotemporal lobar degeneration, HIV-related dementia (HAD), HIV-related cognitive impairment (HIV-CI), Pick's disease, and Lewy body ( Lewy body) related dementia, cognitive impairment associated with multiple sclerosis, vascular dementia, cognitive impairment in epilepsy, cognitive impairment associated with X-fragile (fragile X), and Friedre Cognitive impairment associated with Friedreich's Ataxia, and dementia associated with Down's syndrome and cognitive impairment associated with schizophrenia. In addition, α7-NNR has been shown in test tubes (Jonnala, RB et al., J. Neurosci. Res. , 2001, 66: 565-572) and in vivo (Shimohama, S., Brain Res. , 1998, 779: 359-363) are both involved in the neuroprotective effects of nicotine and in pain signaling. More specifically, neurodegeneration is lurking under several progressive CNS disorders including, but not limited to, AD, PD, amyotrophic lateral sclerosis, Huntington's disease, Dementia with Lewy body and reduced CNS function caused by traumatic brain injury. For example, the α7 NNR dysfunction caused by β-amyloid peptide associated with AD has been suggested to be a key factor in the progression of cognitive deficits associated with the disease ( Liu, Q.-S., et al. PNAS, 2001, 98: 4734-4739 ). Therefore, regulation of the activity of α7 NNR suggests that it is expected to prevent or treat latent lesions involving cognitive functions (including, for example, learning, memory, and attentional features) such as AD, other dementia, other neurodegenerative diseases, and schizophrenia. Symptoms and neurodegeneration (Thomsen, MS et al., Curr Pharm Des. January 2010; 16(3): 323-43; Olincy, A. et al., Arch Gen Psychiatry. 2006, 63(6): 630-8 ; Deutsch, SI, Clin Neuropharmacol. 2010, 33(3): 114-20; Feuerbach, D., Neuropharmacology. 2009, 56(1): 254-63).

NNR ligands including alpha7 ligands have also been implicated in weight management, diabetic inflammation, angiogenesis and have been suggested as potential analgesics (Marrero, MB et al., J. Pharmacol Exp Ther. 2010, 332 ( 1): 173-80; Vincler, M., Exp . Opin . Invest. Drugs, 2005 , 14 (10): 1191-1 198; Rosas-Ballina, M., J. Intern Med. 2009, 265(6) : 663-79; Arias, HR, Int. J. Biochem Cell Biol. 2009, 41(7): 1441-51); Tizabi, Y., Biol Psychiatry. 2002, 51(2): 164-71.

Nicotine is known to enhance attention and cognitive performance, reduce anxiety, enhance sensory stimuli, and have analgesic and neuroprotective effects when administered. These effects are mediated by the non-selective action of nicotine on various nicotinic receptor subtypes. However, nicotine also produces adverse events such as cardiovascular and gastrointestinal problems (Karaconji, IB et al., Arh Hig Rada Toksikol. 2005 , 56 (4): 363-71). Therefore, there is a need to identify sub-selective compounds that retain the beneficial effects of nicotine or NNR ligands while eliminating or reducing undesirable effects.

Examples of reported NNR coordinators are α7 NNR agonists, such as DMXB-A, SSR180711, and ABT-107, which have shown some beneficial effects on cognitive processing in both rodents and humans (H312: 1213) -22; Olincy, A. et al., Arch Gen Psychiatry. 2006 63(6): 630-8; Pichat, P., et al., Neuropsychopharmacology. 2007 32(1): 17-34; Bitner, RS, J Pharmacol Exp Ther. 2010 1;334(3):875-86). In addition, regulation of α7 NNR has been reported to improve negative symptoms in patients with schizophrenia (Freedman, R. et al., Am J Psychiatry. 2008 165(8): 1040-7).

Despite the beneficial effects of NNR ligands, it is uncertain whether long-term treatment with agonists affecting NNR can provide sub-optimal benefits by sustained activation and desensitization of NNR (specifically, the a7 NNR subtype). Unlike agonists, administration of a positive ectopic modulator (PAM) enhances endogenous choline-induced transmission without directly stimulating the target receptor. Nicotine PAM selectively modulates the activity of ACh on NNR, thereby preserving the activation and deactivation kinetics of the receptor. Therefore, α7 NNR selective PAM has appeared (Faghih, R., Recent Pat CNS Drug Discov. 2007, 2(2): 99-106).

Therefore, it would be beneficial to enhance the α7 NNR function by enhancing the action of endogenous neurotransmitter acetylcholine via PAM. This enhances endogenous choline-induced neurotransmission without directly activating the α7 NNR as an agonist. In fact, PAMs used to enhance channel activity have been clinically proven successful for GABAa receptors, where benzodiazepines and barbiturates act as PAMs at different sites (Hevers, W., etc.) Man, Mol. Neurobiol. , 1998 , 18 : 35-86).

To date, only a few NNR PAMs have been known, such as 5-hydroxyindole (5-HI), ivermectin, galantamine, and SLURP-1 (one derived from acetylcholine). Peptide of acetylcholinesterase (AChE)). Genistein, a kinase inhibitor, has also been reported to increase the alpha7 response. PNU-120596 (a urea derivative) has been reported to enhance ACh potency and improve audible gland control induced by amphetamine (amphetamine) in rats. In addition, NS1738, JNJ-1930942, and Compound 6 have been reported to enhance ACh responses and play a beneficial role in rodent experimental sensory and cognitive processing models. Other NNR PAM includes Derivatives of pyridine, hydrazine, benzopyrazole, thiazole and benzisothiazole (Hurst, RS et al., J. Neurosci. 2005, 25: 4396-4405; Faghih, R., Recent Pat CNS Drug Discov. 2007 , 2(2): 99-106; Timmermann, DB, J Pharmacol Exp Ther. October 2007; 323(1): 294-307; Ng, HJ et al., Proc Natl Acad Sci US A. 2007, 104 (19): 8059-64; Dinklo, T., J Pharmacol Exp Ther. 2011, 336(2): 560-74).

In a special example, WO 01/32619 describes the following core structure of the compound as PAMs of α7 NNR

And WO 2009/100294 discloses compounds having the following core structure

This compound is reported to be PAMs of α 7 NNR.

The currently known α7 NNR PAM shows weak activity with a range of non-specific effects, or only a limited entry into the α7 NNR-expressing central nervous system when α7 NNRs are fully expressed. Thus, it would be beneficial to identify and provide novel PAM compounds and compositions for the treatment of alpha 7 NNRs of diseases and conditions involving alpha 7 NNR. It would be particularly advantageous if such compounds provide improved therapeutic efficacy while reducing the adverse effects associated with compounds that target neuronal nicotinic receptors by selectively modulating [alpha]7 NNR.

It is an object of the present invention to provide a compound which is a positive ectopic modulator (PAM) of nicotinic acetylcholine receptor subtype α7.

The compound of the present invention is defined by the following formula [I]:

Wherein A4 is C-R4 or N, A5 is C-R5 or N and A6 is C-R6 or N, provided that at least one of A4, A5 or A6 is N and no more than two of A4, A5 and A6 N; R1 is phenyl or heteroaryl; wherein the phenyl or heteroaryl is optionally substituted with one or more substituents R11, wherein each R11 is individually selected from _C1-6 alkyl, Halogen, hydroxy, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, cyano, C _1-6 alkylsulfonyl, -S(O) ₂ NH ₂ and -NR12R13, wherein R12 and R13 independently represent hydrogen or C _1-6 alkyl; R2 is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, halogen and cyano; R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -6} alkoxy, halogen, cyano and -NR9R10, wherein R9 and R10 independently represent hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halo C _1-6 alkane Or a phenyl group; R8 is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, halogen, cyano and phenyl; Pharmaceutically acceptable salts.

In a specific embodiment, the present invention relates to a compound of the formula [I] and a pharmaceutically acceptable salt thereof, which are used as a medicament.

In one embodiment, the invention relates to a compound of formula [I], and a pharmaceutically acceptable salt thereof, for use in therapy.

In a specific embodiment, the present invention relates to a compound of the formula [I] and a pharmaceutically acceptable salt thereof for use in the treatment of a disease or condition selected from the group consisting of psychosis; schizophrenia; cognitive disorders; and schizophrenia Related cognitive impairment; Attention deficit hyperactivity disorder (ADHD); Autism series disorders; Alzheimer's disease (AD); Mild cognitive impairment (MCI); Age-related memory impairment (AAMI); Dementia; AIDS dementia; Pick's disease; Dementia associated with Lewy body; Dementia associated with Down syndrome; Huntington's disease; Parkinson's disease (PD); Obsessive-compulsive and obsessive-compulsive disorder (OCD); Sexual brain injury; epilepsy; post-traumatic stress; Wernick-Korsakov syndrome (Wernicke-Korsakoff syndrome, WKS); post-traumatic amnesia; cognitive deficit associated with depression; diabetes; weight control; inflammatory conditions; reduced angiogenesis; amyotrophic lateral sclerosis and pain.

In one embodiment, the invention is directed to a pharmaceutical composition comprising a compound of formula [I], and a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

In a specific embodiment, the present invention relates to a kit comprising a compound of the formula [I], and a pharmaceutically acceptable salt thereof, and a compound selected from the list consisting of: acetylcholinesterase inhibitor; bran Amino acid receptor antagonist; dopamine transport inhibitor; norepinephrine transport inhibitor; D2 antagonist; D2 partial agonist; PDE10 antagonist; 5-HT2A antagonist; 5-HT6 antagonist; KCNQ antagonist; Lithium; sodium channel blockers and GABA signaling enhancers.

In one embodiment, the invention relates to a method of treating a disease or condition selected from the group consisting of: psychosis; schizophrenia; cognitive disorders; cognitive disorders associated with schizophrenia; attention deficit hyperactivity disorder (ADHD); Autism series disorders; Alzheimer's disease (AD); mild cognitive impairment (MCI); age-related memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; associated with Lewy bodies Dementia; Dementia associated with Down syndrome; Huntington's disease; Parkinson's disease (PD); Obsessive-compulsive and obsessive-compulsive disorder (OCD); Obsessive-compulsive and obsessive-compulsive disorder (DCD); Traumatic brain injury; Epilepsy Post-traumatic stress disorder; Wernick-Korsakov syndrome (WKS); post-traumatic amnesia; associated with depression Insufficient cognition; diabetes; weight management; inflammatory conditions; reduced angiogenesis; amyotrophic lateral sclerosis and pain, the method comprising administering a therapeutically effective amount of a compound of formula [I] and a pharmaceutically acceptable salt thereof.

In a specific embodiment, the invention relates to the use of a compound of the formula [I] and a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or condition selected from the group consisting of psychosis; schizophrenia Cognitive disorders; cognitive disorders associated with schizophrenia; attention deficit hyperactivity disorder (ADHD); autism series disorders; Alzheimer's disease (AD); mild cognitive impairment (MCI); age-related Memory impairment (AAMI); Alzheimer's disease; AIDS dementia; Pick's disease; Dementia associated with Lewy body; Dementia associated with Down syndrome; Huntington's disease; Parkinson's disease (PD); Obsessive-compulsive and compulsive behavior Condition (OCD); traumatic brain injury; epilepsy; post-traumatic stress disorder; Wernick-Korsakov syndrome (WKS); post-traumatic amnesia; cognitive deficit associated with depression; diabetes; weight control; Sexual disorders; reduced angiogenesis; amyotrophic lateral sclerosis and pain.

definition

In the context of the present invention, "optionally substituted" means that the indicated moiety may or may not be substituted, and when substituted, is monosubstituted, disubstituted or trisubstituted, such as via 1, 2, or 3 substituents. Replace. In some cases, the substituents are independently selected from the group consisting of C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, phenyl, C _1-6 alkoxy, hydroxy, and halogen. It should be understood that when a substituent is not specified for the "optionally substituted" portion, the position is occupied by a hydrogen atom.

In the context of the present invention, "alkyl" is intended to mean a straight chain, a branched chain and/or a cyclic saturated hydrocarbon. Specifically, "C _1-6 alkyl (C _1-6 alkyl)" is intended to mean such a hydrocarbon having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of the C _1-6 alkyl group include methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-methyl Base-propyl and tert-butyl.

In the context of the present invention, "alkenyl" is intended to mean a non-aromatic straight chain, branched chain and/or cyclic hydrocarbon comprising at least one carbon-carbon double bond. Specifically, "C _2-6 alkenyl (C _2-6 alkenyl)" is intended to mean such a hydrocarbon having 2, 3, 4, 5 or 6 carbon atoms. Examples of the C _2-6 alkenyl group include a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, and a cyclohexenyl group.

In the context of the present invention, "alkynyl" is intended to mean a non-aromatic linear, branched and/or cyclic hydrocarbon comprising at least one carbon-carbon bond and, optionally, one or more carbon-carbon double bonds. Specifically, "C _2-6 alkynyl" is intended to mean such a hydrocarbon having 2, 3, 4, 5 or 6 carbon atoms. Examples of C _2-6 alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 5-but-1-ene- 3-alkynyl.

In the context of the present invention, "hydroxyl" is intended to mean -OH.

In the context of the present invention, "alkoxy" is intended to mean a moiety of the formula -OR', wherein R' denotes an alkyl group as defined above. Specifically, "C _1-6 alkoxy" is intended to mean that the alkyl moiety has this moiety of 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of the "C _1-6 alkoxy group" include a methoxy group, an ethoxy group, a n-butoxy group, and a third butoxy group.

In the context of the present invention, the terms "halo" (halogen) and "halogen (halogen)" are used interchangeably and mean fluoro, chloro, bromo or iodo.

In the context of the present invention, "haloalkyl" is intended to mean an alkyl group as defined above having one or more halogens. In particular, "halo C _1-6 alkyl" is intended to mean a moiety wherein the alkyl moiety has 1, 2, 3, 4, 5 or 6 carbon atoms. An example of a haloalkyl group is a trifluoromethyl group.

In the context of the present invention, "haloalkoxy" is intended to mean an alkoxy group having one or more halogens as defined above. In particular, a halogen C _1-6 alkoxy group is intended to mean a moiety wherein the alkyl moiety has 1, 2, 3, 4, 5 or 6 carbon atoms. The specific one is derived from difluoromethoxy and trifluoro. Methoxy group.

In the context of the present invention, "alkylsulfonyl" is intended to mean -S(O) ₂ alkyl. In particular, a C _1-6 alkylsulfonyl group is intended to mean this moiety wherein the alkyl moiety has 1, 2, 3, 4, 5 or 6 carbon atoms. In particular, it consists of a methylsulfonyl group.

In the context of the present invention, the term "cyano" denotes a group -C≡N which consists of a carbon atom bonded to a nitrogen atom.

In the context of the present invention, "heteroaryl" is intended to mean a 5 or 6 membered aromatic monocyclic ring containing from 1 to 5 carbon atoms and one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. Examples of heteroaryl groups of the invention include 6-membered heteroaryl groups such as pyridyl, pyridyl Base And pyrimidinyl and 5-membered heteroaryl groups, for example Thiazolyl, two Azyl, dithiazolyl, Diazolyl, thiadiazolyl, iso Azolyl, Azolyl, isothiazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furyl and thienyl. "N-containing heteroaryl" means a 5 or 6 membered aromatic system wherein at least one of the ring atoms is nitrogen.

In the context of the present invention, when a heteroaryl group is optionally substituted with one or more substituents, it means that the carbon atom of the heteroaryl group may or may not be substituted, And when substituted, substituted by, for example, 1, 2 or 3 substituents. In a preferred embodiment, the optionally substituted heteroaryl is unsubstituted or substituted with one substituent.

In the context of the present invention, when a phenyl group is optionally substituted with one or more substituents, it means that the phenyl group may or may not be substituted, and when substituted, for example, substituted by 1, 2 or 3 Substituted. In a preferred embodiment, the optionally substituted phenyl group may be unsubstituted or substituted with one substituent. In the context of the present invention, when a phenyl group is substituted with a substituent, the substituent may be in the ortho, meta or para position of the phenyl group.

In the context of the present invention, "ring atom" is intended to mean the atoms constituting the ring, and the ring atoms are selected from C, N, O and S. For example, both benzene and toluene have 6 carbons as ring atoms, while pyridine has 5 carbons and 1 nitrogen as ring atoms.

In the context of the present invention, "heteroatom" means a nitrogen, oxygen or sulfur atom.

In the context of the present invention, pharmaceutically acceptable salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. Acid addition salts include inorganic acids as well as salts of organic acids.

Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, aminesulfonic acid, nitric acid, and the like.

Examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, itaconic acid, lactic acid, methanesulfonic acid, cis. Butenedioic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, double Methylene salicylic acid, ethane disulfonic acid, gluconic acid, methyl maleic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid , benzenesulfonic acid, p-toluenesulfonic acid, theophylline acetic acid, and 8-halophylline, such as 8-bromophylline and the like. Other examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Berge, SM et al., J. Pharm. Sci. 1977, 66, 2, which The manner of reference is incorporated herein.

Examples of the metal salt include a lithium salt, a sodium salt, a potassium salt, a magnesium salt, and the like.

Examples of ammonium salts and alkylated ammonium salts include ammonium salts, methyl ammonium salts, dimethyl ammonium salts, trimethyl ammonium salts, ethyl ammonium salts, hydroxyethyl ammonium salts, diethyl ammonium salts, n-butyl A quaternary ammonium salt, a second butyl ammonium salt, a third butyl ammonium salt, a tetramethyl ammonium salt, and the like.

In the context of the present invention, pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene, and water. Similarly, the carrier can include any sustained release material known in the art, alone or mixed with a wax, such as glyceryl monostearate or glyceryl distearate.

In the context of the present invention, the term "therapeutically effective amount" of a compound means that it is sufficient to cure and reduce in the course of a therapeutic intervention involving administration of the compound. The amount of clinical manifestations that directly or partially arrest the specified disease and its complications. The amount sufficient to achieve this is defined as the "therapeutically effective amount." The effective amount for each purpose will depend on the severity of the disease or injury and the weight and general condition of the individual. It should be understood that the appropriate dosage can be determined using routine experimentation by constructing a matrix of values and testing different points in the matrix, all within the general skill of the trained physician.

In the context of the present invention, the term "treatment/treating" means managing and caring for a patient for the purpose of combating a condition, such as a disease or condition. The term is intended to cover the full range of specified conditions for treating a patient, such as administering an active compound to alleviate symptoms or complications; delaying the progression of a disease, disorder or condition; reducing or alleviating symptoms and complications; and/or Curing or eliminating a disease, disorder or condition and preventing a condition, wherein prevention is understood to govern and care for the patient for the purpose of combating the disease, condition or condition and includes administering the active compound to prevent the onset of symptoms or complications. However, prophylactic (prophylactic) and therapeutic (consistent) treatments are two separate aspects of the invention. The patient to be treated is preferably a mammal, in particular a human.

In the context of the present invention, the term "cognitive disorder" is intended to mean a feature of perception, problem solving, language, learning, working memory, memory, social recognition, attention and pre-attentional processing. Abnormal conditions such as, but not limited to, attention deficit hyperactivity disorder (ADHD), autism series, Alzheimer's disease (AD), mild cognitive impairment (MCI), age-related memory impairment ( AAMI), Alzheimer's disease, vascular dementia, frontotemporal dementia, Pick's disease, dementia associated with Lewy bodies, dementia associated with Down's syndrome, cognitive impairment associated with multiple sclerosis, cognitive impairment in epilepsy, cognitive impairment associated with X-fragile, and nerve fibers Cognitive disorders associated with neurofibromatosis, cognitive impairment associated with Friedreich's ataxia, progressive supranuclear palsy (PSP), HIV-associated dementia (HAD), HIV-related cognition Obstacle (HIV-CI), Huntington's disease, Parkinson's disease (PD), traumatic brain injury, epilepsy, post-traumatic stress disorder, Wernick-Korsakov syndrome (WKS), post-traumatic amnesia, Cognitive deficits associated with depression and cognitive impairment associated with schizophrenia.

The enhanced nature of the compound can be assessed, for example, by attentional set-shifting paradigm, which is an animal that allows learning to perform executive functions via intra-dimensional (ID) versus out-of-dimensional (ED) conversion learning. model. This study can be performed by testing whether the compound attenuates "attention dysfunction" induced by subchronic PCP administration in rats, as described by Rodefer et al. (Eur. J. Neurosci. 21: 1070-1076 (2005).

In the context of the present invention, the term "autism spectrum disorder" is intended to mean a condition characterized by social interaction and a wide range of abnormalities in speech and nonverbal communication, as well as limitations of interest, behavior and attention, such as (but not Limited to autism, Asperger syndrome, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), Rett syndrome, Angermann syndrome (Angelmann syndrome) ), X Fragile, wearing George Syndrome (DiGeorge Syndrome) and Childhood Disintegrative Disorder.

In the context of the present invention, the term "inflammatory disorder" is intended to mean a condition characterized by an abnormality of the immune system, such as, but not limited to, an allergic reaction and myopathy that causes abnormal inflammation, and an etiology during inflammation. Non-immune diseases of (etiological origin) are considered to include, but are not limited to, cancer, atherosclerosis, osteoarthritis, rheumatoid arthritis, and ischemic heart disease.

The inventors have discovered that certain novel compounds are positive ectopic modulators (PAMs) of NNR and are therefore useful in the treatment of a variety of diseases and conditions.

The PAM of NNR can be administered in combination with other drugs to achieve more effective treatment in certain patient populations. The α7 NNR PAM can act synergistically with another drug, which has been described in animals for combinations of compounds that affect nicotinic receptors (including α7 NNR) and D2 antagonism (Wiker, C., Int J Neuropsychopharmacol. 2008) September; 11 (6): 845-50).

Thus, the compounds of the invention may be selected from, for example, acetylcholinesterase inhibitors, glutamate receptor antagonists, dopamine transport inhibitors, norepinephrine transport inhibitors, D2 antagonists, D2 partial agonists, A PDE10 antagonist, a 5-HT2A antagonist, a 5-HT6 antagonist, and a KCNQ antagonist, a lithium, a sodium channel blocker, and another drug of a GABA signaling enhancer are used in combination for treatment.

In a specific embodiment, the compound of the invention is used in the treatment of a selected one selected from A patient treated with another drug listed above. In one embodiment, the compounds of the invention are suitable for administration concurrently with the other drug. In one embodiment, the compounds of the invention are suitable for sequential administration with the other agent. In one embodiment, the compounds of the invention are used as the sole agent for treating a patient. In one embodiment, the compounds of the invention are used to treat a patient not yet treated with another agent selected from the other drugs listed above

Specific examples according to the present invention

Hereinafter, specific examples of the invention are disclosed. The first specific example is denoted as E1, and the second specific example is denoted as E2 or the like.

E1. A compound of the formula [I]

Wherein A4 is C-R4 or N, A5 is C-R5 or N and A6 is C-R6 or N, provided that at least one of A4, A5 or A6 is N and no more than two of A4, A5 and A6 N; R1 is phenyl or heteroaryl; wherein the phenyl or heteroaryl is optionally substituted with one or more substituents R11, wherein each R11 is individually selected from _C1-6 alkyl, Halogen, hydroxy, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, cyano, C _1-6 alkylsulfonyl, -S(O) ₂ NH ₂ and -NR12R13, wherein R12 and R13 independently represent hydrogen or C _1-6 alkyl; R2 is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, halogen and cyano; R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -6} alkoxy, halogen, cyano and -NR9R10, wherein R9 and R10 independently represent hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halo C _1-6 alkane Or a phenyl group; R8 is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, halogen, cyano and phenyl; Pharmaceutically acceptable salts.

E2. The compound according to embodiment 1, wherein each R11 is individually selected from the group consisting of methyl, trifluoromethyl, fluoro, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, cyano, A Sulfosyl, -S(O) ₂ NH ₂ and -N(CH ₃ ) ₂ ; R ₂ is selected from H, methyl and methoxy; R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from each other H, methyl, methoxy, cyano and N(CH ₃ ) ₂ ; R 8 is selected from the group consisting of H, methyl and phenyl.

E3. The compound according to any one of embodiments 1 to 2, wherein only one of A4, A5 or A6 is N.

E4. The compound according to any one of embodiments 1 to 3, wherein A4 is N, A5 is C-R5, and A6 is C-R6.

E5. The compound according to any one of embodiments 1 to 3, wherein A5 is N and A4 is C-R4 and A6 is C-R6.

E6. The compound according to any one of embodiments 1 to 3, wherein A6 is N and A4 is C-R4 and A5 is C-R5.

E7. According to any one of the specific examples 1 to 2, wherein A4, A5 Or A6, both of which are N.

E8. The compound according to the specific example 7, wherein both A4 and A5 are N and the A6 system is C-R6.

E9. The compound according to Specific Example 7, wherein both A4 and A6 are N and A5 is C-R5.

E10. The compound according to the specific example 7, wherein both A5 and A6 are N and the A4 system is C-R4.

E11. The compound according to any one of embodiments 1 to 10, wherein R1 represents a phenyl group optionally substituted with 1 or more R11.

E12. The compound according to any one of embodiments 1 to 10, wherein R1 represents a 6-membered heteroaryl group optionally substituted with 1 or more R11.

E13. The compound according to embodiment 12, wherein R1 represents an N-containing 6-membered heteroaryl group optionally substituted with 1 or more R11.

E14. The compound according to any one of embodiments 12 to 13, wherein R1 is selected from pyridyl, pyridyl optionally substituted by 1 R11 Base A base or a pyrimidinyl group.

E15. The compound according to embodiment 14, wherein R1 represents a pyridyl group optionally substituted with 1 R11.

E16. The compound according to any one of embodiments 1 to 10, wherein R1 represents a 5-membered heteroaryl group optionally substituted with 1 or more R11.

E17. The compound according to any one of embodiments 1 to 16, wherein R1 is optionally substituted with 1 R11.

E18. The compound according to any one of embodiments 1 to 11, wherein R1 is optionally substituted by 1 R11, wherein the R11 is located in the benzene The base of the alignment.

E19. The compound according to any one of embodiments 1 to 11, wherein R1 is optionally substituted by 1 R11, wherein the R11 is in the meta position of the phenyl group.

E20. The compound according to any one of embodiments 1 to 11, wherein R1 is optionally substituted by 1 R11, wherein the R11 is ortho to the phenyl.

E21. The compound according to any one of embodiments 17 to 20, wherein the R11 is selected from the group consisting of methyl, trifluoromethyl, fluoro, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, cyano, Methylsulfonyl, -S(O) ₂ NH ₂ and -N(CH ₃ ) ₂ .

E22. The compound according to any one of embodiments 17 to 20, wherein the R11 is selected from the group consisting of _C1-6 alkyl, halogen, hydroxy, halo _C1-6 alkyl, _C1-6 alkoxy, and cyano.

E23. The compound according to embodiment 22, wherein R11 represents _C1-6 alkoxy.

E24. The compound according to embodiment 23, wherein R11 represents methoxy.

E25. The compound according to embodiment 22, wherein R11 represents _C1-6 alkyl.

E26. The compound according to embodiment 25, wherein the R11 represents a methyl group.

E27. The specific examples 1 to 26 of the compounds, wherein R2, R3, R4, R5, R6 and R7 are independently selected H, C _1-6 alkyl each other, C _2-6 alkenyl, C _{2- 6} alkynyl and C _1-6 alkoxy.

E28. A compound according to the specific example 27, wherein R2, R3, R4, R5, R6 and R7 are independently selected from the group consisting of H, methyl and methoxy.

E29. A compound according to any one of embodiments 1 to 28 wherein R2 is methyl.

The compound according to any one of the embodiments 1 to 29, wherein the compound according to any one of the examples 17 to 20, wherein at least one of R3 and R7 is independently selected from the group consisting of a methyl group and a methoxy group.

E31. The compound according to embodiment 30, wherein both R3 and R7 are independently selected from the group consisting of methyl and methoxy.

E32. The compound according to any one of embodiments 1 to 31, wherein R4, R5 and R6 are hydrogen.

E33. The compound according to any one of embodiments 1 to 32, wherein R8 is selected from the group consisting of H, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, and phenyl.

E34. The compound according to embodiment 33, wherein R8 is selected from the group consisting of H, methyl and phenyl.

E35. The compound according to embodiment 33, wherein R8 is _C1-6 alkyl.

E36. The compound according to embodiment 35, wherein R8 is methyl.

E37. A compound according to the specific example 1, which is selected from the group consisting of : 1-(4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]-4 -carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 2: 3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine 4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 3: 3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-b Pyridine-4-carboxylic acid (3,5-dimethyl-pyridin-4-yl)-decylamine; 4: 1-(2-methoxy-phenyl)-3,6-dimethyl-1H -pyrazolo[3,4-b] pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 5: 1-(4-methoxy-phenyl) -3,6-Dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-methyl-pyridin-3-yl)-decylamine; 6: 3.6-dimethyl -1-p-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 7: 1-( 4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-methoxy-4-methyl-pyridine- 3-yl)-guanamine; 8: 1-(4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ( 4-methyl-pyridin-3-yl)-decylamine; 9: 1-(3-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b] Pyridine-4-carboxylate (2,4-dimethyl - pyridin-3-yl) - Amides; 10: 3,6-dimethyl-1- (6-methyl - pyridin-3-yl) lH-pyrazolo [ 3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 11: 1-(4-methoxy-phenyl)-6-methyl -1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 12: 1-(4-methoxy-benzene -3,6-Dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4,6-dimethyl-pyrimidin-5-yl)-decylamine; 13: 1-(4-Fluoro-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridine-3- Base)-decylamine; 14: 1-(4-cyano-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4 - dimethyl-pyridin-3-yl)-decylamine; 15: 1-(4-methoxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4 -carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 16: 1-(6-methoxy-pyridin-3-yl)-3,6-dimethyl-1H- Pyrazolo [3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 17: 3,6-dimethyl-1-(4- Trifluoromethoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 18: 1 -(4-methoxy-phenyl)-3,6- Dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4,6-trimethyl-pyridin-3-yl)-decylamine; 19: 1-(4- Difluoromethoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl) )-decylamine; 20: 1-(4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4-A) -pyrimidin-5-yl)-guanamine; 21: 3,6-dimethyl-1-(4-aminesulfonyl-phenyl)-1H-pyrazolo[3,4-b]pyridine- 4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 22: 3,6-dimethyl-1-(4-trifluoromethyl-phenyl)-1H-pyridyl Zoxao[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-guanamine; 23: 1-(4-dimethylamino-phenyl) -3,6-Dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 24: 3- Methoxy-1-(4-methoxy-phenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridine -3-yl)-guanamine; 25: 3,6-dimethyl-1-thiophen-3-yl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4- Dimethyl-pyridin-3-yl)-decylamine; 26: 3,6-dimethyl-1pyrimidin-5-yl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ( 2,4-dimethyl-pyridine-3 -yl)-guanamine; 27: 3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-methoxy-4-methyl) -pyridin-3-yl)-decylamine; 28: 3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4-A Oxy-2-methyl-pyridin-3-yl)-decylamine; 29: 3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate Acid (4-methoxy-6-methyl-pyridin-3-yl)-decylamine; 30: 1-(4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazole And [3,4-b]pyridine-4-carboxylic acid (4-dimethylamino-pyridin-3-yl)-decylamine; 31: 3,6-dimethyl-1-phenyl-1H- Pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-methyl-pyridin-3-yl)-decylamine; 32: 3,6-dimethyl-1-phenyl-1H-pyridyl Zoxao[3,4-b]pyridine-4-carboxylic acid (4-methyl-pyridin-3-yl)-decylamine; 33: 1-(4-methoxy-phenyl)-3,6- Dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4,6-dimethyl-pyridin-3-yl)-decylamine; 34: 1-(4-methanesulfonate) Mercapto-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-indole Amine; 35: 1-(4-methoxy-phenyl)-3-methyl-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4- Dimethyl-pyridine-3- ))-decylamine; 36: 1-(4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4- Cyano-pyridin-3-yl)-decylamine; 37: 1-(4-hydroxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4- Carboxylic acid (2,4-dimethyl-pyridin-3-yl)-guanamine; and pharmaceutically acceptable salts of any of these compounds.

E38. A compound according to any one of embodiments 1-37, for use as a medicament.

E39. A compound according to any one of embodiments 1-37 for use in therapy.

E40. The compound according to any one of embodiments 1 to 37 for use in the treatment of a disease or condition selected from the group consisting of: psychosis; schizophrenia; cognitive disorders; cognitive disorders associated with schizophrenia; Alzheimer's disease (ADHD); autism series; Alzheimer's disease (AD); mild cognitive impairment (MCI); age-related memory impairment (AAMI); senile dementia; AIDS dementia; Dementia associated with Lewy body; dementia associated with Down syndrome; Huntington's disease; Parkinson's disease (PD); obsessive-compulsive and obsessive-compulsive disorder (OCD); traumatic brain injury; epilepsy; post-traumatic stress Disease; Wernick-Korsakov syndrome (WKS); post-traumatic amnesia; cognitive deficit associated with depression; diabetes; weight control; inflammatory conditions; reduced angiogenesis; amyotrophic lateral sclerosis and pain.

E41. The compound according to embodiment 40, wherein the disease or condition is selected from the group consisting of schizophrenia; AD; ADHD; autism series disorders; PD; amyotrophic lateral sclerosis; Huntington's disease; dementia associated with Lewy bodies And pain.

E42. The compound according to embodiment 41, wherein the disease or condition is selected from the group consisting of schizophrenia; AD; ADHD and autism series disorders.

E43. The compound according to embodiment 42, wherein the disease or condition is selected from the group consisting of negative and/or cognitive symptoms of schizophrenia.

E44. A compound according to any one of embodiments 1 to 37 for use in a therapeutically effective amount of a compound selected from the list consisting of: acetylcholinesterase inhibitor; glutamic acid Body antagonist; dopamine transport inhibitor; norepinephrine transport inhibitor; D2 antagonist; D2 partial agonist; PDE10 antagonist; 5-HT2A antagonist; 5-HT6 antagonist A KCNQ antagonist; a lithium; a sodium channel blocker and a GABA signaling enhancer for treating a disease or condition according to any one of the specific examples 40 to 43.

E45. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 37 and one or more pharmaceutically acceptable carriers or excipients.

E46. The composition of embodiment 45, further comprising a second compound selected from the group consisting of: an acetylcholinesterase inhibitor; a glutamate receptor antagonist; a dopamine transport inhibitor; Adrenergic transport inhibitor; D2 antagonist; D2 partial agonist; PDE10 antagonist; 5-HT2A antagonist; 5-HT6 antagonist; KCNQ antagonist; lithium; sodium channel blocker and GABA signaling enhancer.

E47. The composition of embodiment 46, wherein the second compound is an acetylcholinesterase inhibitor.

E48. A kit comprising the compound according to any one of embodiments 1 to 37 and a second compound selected from the list consisting of: an acetylcholinesterase inhibitor; a glutamate receptor antagonist; dopamine Transport inhibitors; norepinephrine transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancer.

E49. The kit of embodiment 48, wherein the second compound is an acetylcholinesterase inhibitor.

E50. A method of treating a disease or condition selected from the group consisting of a psychotic disorder; schizophrenia; a cognitive disorder; and a recognition associated with schizophrenia Attention deficit disorder; attention deficit hyperactivity disorder (ADHD); autism series disorders; Alzheimer's disease (AD); mild cognitive impairment (MCI); age-related memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; Dementia associated with Lewy body; Dementia associated with Down syndrome; Huntington's disease; Parkinson's disease (PD); Obsessive-compulsive and obsessive-compulsive disorder (OCD); Traumatic brain injury Epilepsy; post-traumatic stress disorder; Wernick-Korsakov syndrome (WKS); post-traumatic amnesia; cognitive deficit associated with depression; diabetes; weight control; inflammatory disease; reduced angiogenesis; Side sclerosis and pain, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1 to 32.

E51. The method of embodiment 50, wherein the disease or condition is selected from the group consisting of schizophrenia; AD; ADHD; autism series disorders; PD; amyotrophic lateral sclerosis; Huntington's disease; dementia associated with Lewy bodies And pain.

E52. The method of embodiment 51, wherein the disease or condition is selected from the group consisting of schizophrenia; AD; ADHD and autism series disorders.

E53. The method of embodiment 52, wherein the treatment comprises treating a negative and/or cognitive symptom of schizophrenia.

The method of any one of embodiments 50 to 58, wherein the treatment further comprises administering a therapeutically effective amount of a second compound selected from the group consisting of: an acetylcholinesterase inhibitor; glutamine receptor antagonism Dopamine transport inhibitor; norepinephrine transport inhibitor; D2 antagonist; D2 partial agonist; PDE10 antagonist; 5-HT2A antagonist; 5-HT6 antagonist; KCNQ antagonist; lithium; sodium channel block Broken agent and GABA signal Conductivity enhancer.

E55. The method of embodiment 54, wherein the second compound is an acetylcholinesterase inhibitor.

E56. Use of a compound according to any one of embodiments 1 to 37 for the manufacture of a medicament for the treatment of a disease or condition selected from the group consisting of psychosis; schizophrenia; cognitive disorders; associated with schizophrenia Cognitive impairment; attention deficit hyperactivity disorder (ADHD); autism series disorders; Alzheimer's disease (AD); mild cognitive impairment (MCI); age-related memory impairment (AAMI); senile dementia AIDS dementia; Pick's disease; Dementia associated with Lewy body; Dementia associated with Down syndrome; Huntington's disease; Parkinson's disease (PD); Obsessive-compulsive and obsessive-compulsive disorder (OCD); Traumatic brain Injury; epilepsy; post-traumatic stress disorder; Wernick-Korsakov syndrome (WKS); post-traumatic amnesia; cognitive deficit associated with depression; diabetes; weight control; inflammatory disease; reduced angiogenesis; Lateral lateral sclerosis and pain.

E57. The use according to the specific example 56, wherein the disease or condition is selected from the group consisting of schizophrenia; AD; ADHD; autism series disorders; PD; amyotrophic lateral sclerosis; Huntington's disease; dementia associated with Lewy bodies And pain.

E58. The use according to the specific example 57, wherein the disease or condition is selected from the group consisting of schizophrenia; AD; ADHD and autism series disorders.

E59. The use according to the specific example 58, wherein the disease or condition is selected from the group consisting of positive, negative, and/or cognitive symptoms of schizophrenia.

The use according to any one of the examples 56 to 59, wherein the manufacturing additionally comprises using a second compound selected from the list consisting of: Acetylcholinesterase inhibitor; glutamate receptor antagonist; dopamine transport inhibitor; norepinephrine transport inhibitor; D2 antagonist; D2 partial agonist; PDE10 antagonist; 5-HT2A antagonist; 5-HT6 antagonist; KCNQ antagonist; lithium; sodium channel blocker and GABA signaling enhancer.

E61. The use according to embodiment 60, wherein the second compound is an acetylcholinesterase inhibitor.

The compounds of the invention may exist in unsolvated as well as solvated forms of solvent molecules selected from pharmaceutically acceptable solvents such as water, ethanol and the like. In general, such solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention.

The racemic form can be resolved into the optical antipode by known methods, for example by isolating its diastereomeric salt with an optically active acid, and by treatment with a base to release the optically active amine compound. Another method of resolving a racemate into an optical enantiomer is based on chromatography of an optically active substrate. The compounds of the invention may also be resolved by the formation of diastereomeric derivatives. Other methods known to those skilled in the art for the resolution of optical isomers can be used. Such methods include those discussed by J. Jaques, A. Collet, and S. Wilen in "Mirror Isomers, Racemates, and Re Solutions", John Wiley, and Sons, New York (1981). Optically active compounds can also be prepared from optically active starting materials.

Furthermore, geometric isomers can be formed when a double bond or a fully or partially saturated ring system is present in the molecule. Any geometric isomers, or mixtures thereof, intended to be isolated, pure or partially purified geometric isomers are included within the scope of the invention. Similarly, molecules with rotationally restricted bonds form geometry isomer. Such isomers are also intended to be included within the scope of the invention.

In addition, some of the tautomeric forms of the compounds of the invention which may exist in different tautomeric forms and which the claimed compounds are capable of forming are encompassed within the scope of the invention.

The compounds of the invention may be administered as a pure compound in a single dose or in multiple doses or in combination with a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition of the present invention can be pharmaceutically acceptable according to conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th edition, Gennaro ed., Mack Publishing Co., Easton, PA, 1995. The carrier or diluent and any other known adjuvants and excipients are formulated together.

The pharmaceutical composition can be specifically formulated to be administered by any suitable route, such as oral, rectal, nasal, transpulmonary, topical (including buccal and sublingual), transdermal, intracranial, intraperitoneal, transvaginal And parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes, wherein the oral route is preferred. It will be appreciated that the preferred route will depend on the general condition and age of the patient to be treated, the nature of the condition to be treated, and the active ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, lozenges, dragees, pills, buccal tablets, powders, and granules. It can be prepared to have a coating, as appropriate.

Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions, and sterile prior to use A sterile powder that is reconstituted in an injection solution or dispersion.

Other suitable forms of administration include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants and the like.

In one embodiment, the compound of the invention is administered in an amount of from about 0.001 mg per kilogram of body weight per day to about 100 mg per kilogram of body weight per day. In particular, the daily dose may range from 0.01 milligrams per kilogram of body weight per day to about 50 milligrams per kilogram of body weight per day. The exact dose will depend on the frequency and mode of administration; the sex, age, weight and general condition of the patient to be treated; the nature and severity of the condition to be treated; any concurrent disease to be treated; the therapeutic effect and familiarity with the subject It depends on other factors.

A typical oral dose for an adult will range from 0.1 to 1000 mg/day of a compound of the invention, such as 1-500 mg/day, such as 1-100 mg/day or 1-50 mg/day.

The compounds of the invention are preferably administered in unit dosage forms containing such compounds in amounts of from about 0.1 to 500 mg, such as 10 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg of the compound of the invention.

For parenteral administration, solutions of the compounds of the invention in sterile aqueous solutions, aqueous propylene glycol, aqueous solutions of vitamin E or sesame or peanut oil may be employed. These aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient physiological saline or glucose. Aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium employed can be readily obtained by standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions, and various organic solvents. Examples of solid carriers are lactose, white clay, and sugar cane. Sugar, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. The pharmaceutical compositions formed by combining the compounds of the invention with a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.

Formulations of the invention suitable for oral administration may each be provided in the form of a predetermined amount of the active ingredient and may comprise a separate unit, such as a capsule or lozenge, in a suitable vehicle. In addition, the orally acceptable formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil type liquid emulsion.

If a solid vehicle is used for oral administration, the preparation may be in the form of a lozenge, for example, in the form of a powder or pellets or in the form of a sugar-coated lozenge or an ingot. The amount of solid carrier can vary but will generally range from about 25 mg to about 1 gram.

If a liquid vehicle is employed, the preparation may be in the form of a syrup, an emulsion, a soft gelatin capsule or a sterile injectable liquid such as an aqueous or nonaqueous liquid suspension or solution.

The lozenge can be prepared by mixing the active ingredient with conventional adjuvants and/or diluents, followed by compression of the mixture in a conventional tablet machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvant or additive commonly used for such purposes may be used, such as coloring agents, flavoring agents, preservatives, and the like, with the proviso that they are compatible with the active ingredient.

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety herein in their entirety in the the the the the the The manner in which the present invention is incorporated by reference in its entirety is hereby incorporated by reference in its entirety in its entirety in its entirety in the the the the the

The use of the terms "a", "an" and "the", and the like, are used in the context of the description of the invention. By. For example, unless otherwise indicated, the phrase "the compound" is understood to mean a "compound" of the invention or a particular description.

Terms such as "comprising", "having", "including" or "containing" are used herein with respect to one or more elements, unless otherwise stated or clearly contradicted by the context. Any aspect or aspect of the present invention is intended to be "consisting of one or more elements," "substantially consisting of one or more elements," or "substantially containing one or more elements." A similar aspect or aspect of the invention provides support (e.g., unless otherwise stated or clearly contradicted by context, a composition described herein as comprising a particular element is to be understood as a composition that also comprises the element.

It should be understood that the various aspects, specific examples, embodiments and features of the invention described herein may be claimed individually or in any combination.

General synthetic process

The compound of the formula [I] can be used as an organic chemical technique by the method described below The synthetic methods of the prior art are prepared together, or by modifications known to those skilled in the art. The starting materials used herein are either commercially available or can be routinely practiced for this purpose, for example as described in standard reference books such as "Compendium of Organic Synthetic Methods, Vol. I-XII" (Wiley-Interscience). The method was prepared. Preferred methods include, but are not limited to, those described below.

These processes are representative methods that can be used to synthesize the compounds of the invention. It is not intended to limit the scope of the invention in any way.

Experimental procedure and examples

The synthesis of various compounds of the invention is as follows. Additional compounds within the scope of the invention may be prepared using the individual methods exemplified in the examples or in combination with techniques well known in the art.

The synthesis of various compounds of the invention is as follows. Additional compounds within the scope of the invention may be prepared using the individual methods exemplified in the examples or in combination with techniques well known in the art. Scheme 1 is illustrative of the preparation of compounds of formula 1.6. This method involves the formation of a substituted pyrazole of formula 1.3. The synthesis of pyrazoles of formula 1.3 can be exemplified by heating the enamines of formula 1.2 with, for example, ethanol, isopropanol, aqueous HCl, aqueous acetic acid, and with or without an alkali additive such as triethylamine. Telluride of formula 1.1. Some other methods have also been disclosed in the following literature to prepare compounds of formula 1.3 (e.g., Beilstein J. Org. Chem., 2011 , 7 , 179-197). The substituted pyrazole of the formula 1.3 can be reacted with a compound of the formula 1.4 in a solvent such as acetic acid to prepare a compound of the formula 1.5. The ester functional group of the compound of formula 1.5 can be hydrolyzed to provide the corresponding acid derivative of formula 1.6, for example by treatment with aqueous base KOH or LiOH in a solvent such as MeOH or THF.

Scheme 2 illustrates a method of preparing a compound of formula 2.3. The preparation of the nitro compound of formula 2.2 is carried out under nitrification conditions, for example in HNO ₃ in H ₂ SO ₄ , KNO ₃ in H ₂ SO ₄ or on a N ₂ O ₅ basis ( Synthesis, 1997 , 281 The compound of formula 2.1 is nitrated by treatment with -283). The compound of formula 2.2 can be reduced to the formula 2.3 by a reduction method such as a Pd/C catalyst used in a solvent such as EtOH or THF, or a Fe in a solvent such as EtOH and a proton source such as NH ₄ Cl. Show compound.

Scheme 3 illustrates a method for the preparation of a compound of formula I. The carboxylic acid of formula 1.6 can be coupled to the formula using EDC and HOBt or another suitable coupling agent in the presence of a base such as diisopropylethylamine or N-methylmorpholine in a solvent such as DMF or DMAC. 2.3 amines. Other methods for the preparation of compounds of Formula I include a mixture of a carboxylic acid with an amine of formula 1.6 2.3 The formula used in the treatment of warm pyridine POCl _3, or the use of pre-carboxylic acids of formula T3P process of forming a salt with 1.6 and 2.3 of the formula amine.

The process also exemplifies a process for the preparation of a compound of formula I wherein the carboxylic acid ester of formula 1.5 or its corresponding methyl ester is combined with an amine of formula 2.3 and an aluminum hydride agent such as AlMe ₃ in a solvent such as toluene or CH ₂ Cl ₂ . Preform the complex reaction.

Example

The invention will be exemplified by the following non-limiting examples.

abbreviation

Br=wide. Brine = saturated aqueous sodium chloride solution. Conc.=Concent. d = double peak. DIPEA = N,N-diisopropylethylamine. DMAC = N, N-dimethylacetamide. DMAP = 4-(dimethylamino)pyridine. DMF = dimethylformamide. DMSO = dimethyl hydrazine. EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. EtOAc = ethyl acetate. h = hour. HATU = O - (benzotriazol-1-yl) -N, N, N', N' -tetramethylurea cation hexafluorophosphate. HOBt = 1-hydroxybenzotriazole. HPLC = high performance liquid chromatography. LC = liquid chromatography. m = multiple peaks. Min=minutes. mL = ml. s = single peak. t = three peaks. T3P = 1 - propanephosphonic acid cyclic anhydride. TFA = trifluoroacetic acid. THF = tetrahydrofuran.

Spectral method

Analytical LC-MS was performed on a Waters Aquity UPLC-MS consisting of Waters Aquity, including a column manager, binary solvent manager, sample processor, PDA detector (operating at 254 nm), ELS The detector and SQ-MS (ESI-source, APCI-source positive ion mode, negative ion mode) equipped with APPI source operating in positive ion mode.

LC conditions: column was Acquity UPLC BEH C18 1.7 μm; 2.1 × 50 mm, at 120 ° C at 1.2 ° / min from water + 0.05% trifluoroacetic acid (A) and acetonitrile + 5% water + 0.035% trifluoro Binary gradient operation of acetic acid (B) composition.

Preparative HPLC was performed using a Waters delta prep HPLC equipped with Waters 2545 binary gradient mercury and a Waters 2998 PDA detector. Column Sunfire (30 x 250 mm) 10 μm particle size. Solvent system A = 0.01 M ammonium acetate: water and B = acetonitrile. Isocratic A: B = 35:65, flow rate is 30 ml / min.

¹ H NMR spectra were obtained on a Bruker Avance DRX-500 instrument (T=303.3 K) at 500.13 MHz or on a Bruker Avance AV-III-600 instrument at 600 MHz or on a Varian 400MR instrument (T=298.15 K) at 400 Recorded at 400 MHz on MHz or on a Varian vnmrs instrument.

Preparation of intermediates Synthesis of anilines

IM01: 2-methoxy-4-methyl-pyridin-3-ylamine

The title compound is commercially available. 4-methyl-2-methoxy-3-nitropyridine (4.5 g, 26.8 mmol), NH ₄ Cl (7.16 g, 133.9 mmol) and Fe powder (7.5 g, 133.9 mmol) The mixture was stirred at 25 ° C in ethanol (50 mL). The mixture was slowly heated to 90 ° C and stirred at this temperature for 2 hours. The reaction mixture was filtered through a filter aid plug and the filter plug was washed with ethanol (50 mL). The combined filtrate was evaporated to dryness. The residue was diluted with water (50 mL) The organic layer was dried over Na ₂ SO ₄ . The title compound (3.5 g, 81%) 1H NMR (CDCl ₃ , 400 MHz) δ 7.50-7.49 (1H, d, J = 5.2 Hz), 6.62-6.61 (1H, d, J = 5.2 Hz), 3.97 (3H, s), 3.79-3.69 (2H , br s), 2.15 (3H, s).

IM02 + IM03: 4- methoxy-2-methyl-3-nitro - pyridine and 4-methoxy-2-methyl-5-nitro - pyridine mixture, IM02 + IM03

A mixture of (3.2 ml of concentrated H ₂ SO ₄ + 3.2 mL of HNO ₃ ) was slowly added dropwise to 4-methoxy-2-methylpyridine (4.8 g, 39.0 mmol) in H ₂ SO ₄ (22.2 mL, Concentrated) was kept in a solution at 0 °C. After the completion of the addition, the reaction temperature was slowly increased to 65 ° C and the mixture was stirred at this temperature for 16 hours. The reaction mixture was poured into ice-water (50 mL) and filtered. The residue was washed with EtOAc EtOAcqqqqqq The mixture was used without further purification.

IM04 + IM05: a mixture of 4-methoxy-2-methyl-pyridin-3-ylamine and 4-methoxy-6-methyl-pyridin-3-ylamine

IM02 and IM03 compound mixture of (3.0 g, 17.9 mmol) in ethanol (50 mL) was added 10% Pd / C (300 mg). The mixture was then hydrogenated at 60 psi for 24 hours at room temperature. The mixture was then filtered through a filter aid plug. The filter aid was washed with ethanol (20 ml). The combined filtrate was evaporated to dryness crystals crystals crystals The mixture was used without further purification.

IM06: 4,6-dimethyl step pyrimidin-5-ylamine

step 1:

A solution of urea (20.0 g, 333.3 mmol) and acetalacetone (33.3 g, 333.3 mmol) in EtOH (166 mL). The mixture was stirred at 80 ° C for 24 hours. The mixture was then cooled to room temperature, filtered and washed with EtOAc EtOAc EtOAc EtOAc 1H NMR (DMSO-d6, 400 MHz) δ 7.35 (1H, s), 2.43 (6H, s).

Step 2:

To a solution of concentrated H ₂ SO ₄ at 0 ° C was added 4,6-dimethylpyrimidin-2-ol (10 g, 80.6 mmol) with stirring. Then fuming HNO ₃ (7.8 ml) was slowly added. The cooling was removed and the mixture was allowed to stir at room temperature for 5 hours. The reaction mixture was poured into crushed ice and the pH was adjusted to about 4 by the addition of aqueous NaOH. The mixture was extracted with EtOAc and EtOAc (EtOAc m.

Step 3:

The 4,6-dimethyl-5-nitropyrimidine -2-8 (1 g, 5.9 mmol) was dissolved in POCl ₃ (10 ml), and the reaction mixture was heated to reflux for 5 hours. The reaction mixture was cooled to room temperature and then poured into ice-water. The mixture was extracted with EtOAc. The combined organic layers were washed with water and evaporated to dryness to give crude 2-chloro-4,6-dimethyl-5-nitropyrimidine (0.20 g, 18%). .

Step 4:

To a solution of 2-chloro-4,6-dimethyl-5-nitropyrimidine (50 mg, 0.26 mmol) in ethanol was added 10% Pd/C. The mixture was stirred at room temperature under H ₂ atmosphere for 5 hours. The reaction mixture was filtered with EtOAc EtOAc m . 1H NMR (DMSO-d6, 400 MHz) δ 7.17 (1H, s), 4.99 (2H, s), 2.26 (6H, s).

Synthesis of pyrazol-3-ylamine

IM07: 2-(2-methoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamine

Add 3-amino-but-2-ene to a solution of (2-methoxy-phenyl)-hydrazine HCl salt (10.0 g, 57.3 mmol) in concentrated aqueous HCl (50 mL). Nitrile (5.0 g, 60.9 mmol). The reaction temperature was raised to 100 ° C, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to room temperature and poured into ice-cold 2N NaOH solution (200 mL). The resulting mixture was filtered. The residue was taken with EtOAc EtOAc m. 1H NMR (DMSO-d6, 400 MHz) δ 7.39-7.35 (1H, m), 7.24-7.22 (1H, m), 7.17-7.15 (1H, m), 7.03-6.99 (1H, m), 5.21. , s), 4.76 (2H, s), 3.78 (3H, s), 2.02 (3H, s).

The following compounds were prepared in a similar manner:

IM08: 2-(3-methoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamine

The title compound (1.5 g, 65%) was obtained as a white solid, which was used for the next step.

IM09: 5-methyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylamine

The title compound (1.6 g, 36%) was obtained as a yellow solid, which was used for the next step.

IM10: 2-(4-fluoro-phenyl)-5-methyl-2H-pyrazol-3-ylamine

The title compound (4.0 g, 72%) was obtained as a white solid.

IM11: 4-(5-amino-3-methyl-pyrazol-1-yl)-benzotriazole

The title compound (4.5 g, 77%) was obtained as a white solid, which was used for the next step.

IM12: 2-(6-methoxy-pyridin-3-yl)-5-methyl-2H-pyrazol-3-ylamine

(6-Methoxy-pyridin-3-yl)-indole was prepared from 6-methoxy-pyridin-3-ylamine as described in Org. Lett., 2009, 11, 22, 5142-5145. The title compound (4.0 g, 48%) was obtained as a white solid.

IM13: 5-methyl-2-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylamine

The title compound (3.0 g, 72%) was obtained as a white solid, which was used for the next step.

IM14: 2-(4-Difluoromethoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamine

The intermediate (4-difluoromethoxy-phenyl)-indole was prepared from 4-difluoromethoxy-phenylamine as described in Org. Lett., 2009, 11, 22 , 5142-5145. The title compound (4.0 g, 58%) was obtained as a white solid.

IM15: 5-methyl-2-thiophen-3-yl-2H-pyrazol-3-ylamine

The intermediate thiophen-3-yl-indole was prepared as described in Organic Letters 2003, 4129-4131, followed by HCl (two Boc deprotection in the alkane). The title compound (1.5 g, 40%) was obtained.

IM16: 2-(4-Methanesulfonyl-phenyl)-5-methyl-2H-pyrazol-3-ylamine

(4-Methanesulfonyl-phenyl)-indole (1.5 g, 6.76 mmol) in EtOH (20 mL) was added 3-amino-but-2-enenitrile (0.55 g, 6.76 mmol) ear). The resulting mixture was refluxed for 8 hours. The mixture was concentrated in vacuo and EtOAc (2 <RTI ID=0.0> (100 mL) The organic layers were washed with saturated aqueous NaHCO _3, dried over Na ₂ SO ₄ and evaporated to dryness. Flash chromatography ( cerium dioxide , methylene chloride: MeOH = 10:1) gave compound mp .

IM17: 4-(5-Amino-3-methyl-pyrazol-1-yl)-benzenesulfonamide

The title compound (2.31 g, 86%) was obtained as a white solid.

IM18: 5-methyl-2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylamine

The title compound (4.1 g, 71%) was obtained as a solid, which was used for the next step.

IM19: 5-methyl-2-(4-nitro-phenyl)-2H-pyrazol-3-ylamine

The title compound (7.1 g, 99%) was obtained as a solid.

IM20: 5-methyl-2-pyrimidin-5-yl-2H-pyrazol-3-ylamine

The intermediate pyrimidine-5-yl-indole was prepared as described in Tetrahedron Lett., 51 (2010), 5005-5008, followed by HCl (two Boc deprotection in the alkane). The title compound (3.85 g, 99%) was obtained as a solid.

IM21: 2-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine

step 1:

Add 2-cyano-3-ethoxyethyl acrylate 2 (600 mg) to a solution of 4-methoxyphenylindole 1 (500 mg, 3.59 mmol) in ethanol (3 mL). , 3.53 millimoles). The reaction temperature was allowed to warm to 85 ° C, and the mixture was stirred at this temperature for 10 hours. The reaction mixture was cooled to room temperature then poured into ice-cold 2N NaOH solution (10 mL). The mixture was filtered and dried <RTI ID=0.0> 1H NMR (DMSO-d6, 400 MHz) δ 7.65 (1H, s), 7.43-7.40 (2H, d), 7.08-7.06 (2H, d), 6.17 (2H, s), 4.23-4.18 (2H, m ), 3.81 (3H, s), 1.28-1.24 (3H, t).

Step 2:

Ethyl 5-amino-1-(4-methoxy-phenyl)-1H-pyrazole-4-carboxylate (8.9 g, 34.1 mmol) in concentrated aqueous HCl (100 mL). The solution in the mixture was stirred for 10 hours. The reaction mixture was cooled to room temperature then poured into ice-cooled 1N NaOH solution (100 mL). The mixture was extracted with dichloromethane (2 x 150 mL). The organic layer was washed with water mixed, Na ₂ SO ₄ dried and concentrated in vacuo to give an off-white solid was the title compound of IM21 (3.0 g, 16%). 1H NMR (DMSO-d6, 400 MHz) δ 7.46-7.42 (2H, m), 7.23-7.22 (1H, d), 7.04-7.0 (2H, m), 5.44-5.43 (1H, d), 5.16 (2H , s), 3.78 (3H, s).

IM22: 5-methoxy-2-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine

Add 3,3-dimethoxy-acrylonitrile (1.1 g, 10 mmol) to a solution of (4-methoxy-phenyl)-indole (1.7, 0.01 mol) in MeOH (20 mL) . The resulting mixture was heated to reflux overnight. The mixture was concentrated in vacuo and EtOAc (EtOAc) The organic layer (100 mL) and washed with saturated aqueous NaHCO _3, dried over Na ₂ SO ₄ and evaporated to dryness. The title compound IM22 (1.2 g, 57%) was obtained. 1H NMR (DMSO-d6 400 MHz) δ 7.41 (d, 2 H), 6.99 (d, 2 H), 5.25 (s, 2 H), 4.94 (s, 1 H), 3.78 (s, 3 H), 3.72 (s, 3 H).

Synthesis of pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester

IM23: Ethyl 1-(4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

A round bottom flask was charged with 2-(4-methoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamine (2.0 g, 9.85 mmol) in acetic acid (10 mL). To the mixture was added 2,4-dioxyacetic acid ethyl ester (1.55 g, 9.85 mmol) and the mixture was then stirred at 125 ° C for 16 hours. The mixture was cooled to room temperature and poured into ice-cold 2N NaOH solution (50 mL). The mixture was filtered and the residue was washed with water (50 mL) and dried. The crude material was purified by flash chromatography eluting elut elut elut elut elut 1H NMR (400 MHz, CDCl ₃ ) δ 8.09-8.02 (m, 2H), 7.47 (1H, s), 7.04-7.02 (m, 2H), 4.52-4.47 (m, 2H), 3.86 (3H, s) , 2.75 (3H, s), 2.72 (3H, s), 1.49-1.45 (3H, t, J = 7.2 Hz).

The following compounds were prepared in a similar manner:

IM24: 3,6-Dimethyl-1-p-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate Ethyl acetate

The title compound (1.4 g, 85%) was obtained eluted elute

IM25: Ethyl 1-(2-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Preparation was carried out using IM07 . The title compound (1.2 g, 38%) eluted elute 1H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.41 (3H, m), 7.11-7.07 (2H, m), 4.53-4.47 (2H, m), 3.76 (3H, s), 2.75 (3H, s) 2.64 (3H, s), 1.49-1.45 (3H, t, J = 7.6 Hz).

IM26: Ethyl 1-(3-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Preparation was carried out using IM08 . The title compound (1.6 g, 66%). 1H NMR (CDCl ₃ , 400 MHz) δ 7.91-7.87 (2H, m), 7.48 (1H, s), 7.41-7.37 (1H, m), 6.85-6.82 (1H, m) 4.52-4.47 (2H, m ), 3.90 (3H, s), 2.75 (3H, s), 2.73 (3H, s), 1.49-1.45 (3H, t).

IM27: Ethyl 3,6-dimethyl-1-(6-methyl-pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Preparation was carried out using IM09 . The title compound (1.5 g, 58%) eluted elute 1H NMR (CDCl3, 400 MHz) δ 9.46-9.45 (1H, d), 8.44-8.42 (1H, m), 7.51 (1H, s), 7.30-7.27 (1H, m), 4.52-4.47 (2H, m ), 2.76 (3H, s), 2.72 (3H, s), 2.61 (3H, s), 1.49-1.45 (3H, t).

IM28: Ethyl 1-(4-methoxy-phenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Preparation was carried out using IM21 . The title compound (3.4 g, 69%) eluted elute 1H NMR (CDCl3, 400 MHz) δ 8.50 (1H, s), 8.13-8.09 (2H, m), 7.67 (1H, s), 7.08-7.04 (2H, m), 4.55-4.49 (2H, m), 3.87 (3H, s), 2.76 (3H, s), 1.55-1.48 (3H, m).

IM29: Ethyl 1-(4-fluoro-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Preparation was carried out using IM10 . The title compound (1.6 g, 66%). 1H NMR (DMSO-d6, 300 MHz) δ 8.23-8.19 (2H, m), 7.57 (1H, s), 7.43-7.37 (2H, m), 4.49-4.42 (2H, m), 2.69 (3H, s ), 2.65 (3H, s), 1.42-1.37 (3H, t).

IM30: Ethyl 1-(4-cyano-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Preparation was carried out using IM11 . The title compound (4.0 g, 83%). 1H NMR (CDCl ₃ , 400 MHz) δ 8.63-8.61 (2H, d), 7.79-7.77 (2H, d), 7.54 (1H, s), 4.53-4.47 (2H, m), 2.77 (3H, s) , 2.75 (3H, s), 1.55-1.48 (3H, t).

IM31: Ethyl 1-(6-methoxy-pyridin-3-yl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Preparation was carried out using IM12 . The title compound (4.0 g, 62%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.89-8.90 (1H, m), 8.37-8.34 (1H, m), 7.56 (1H, s), 7.04 (1H, s), 7.01 (1H, s) 4.48-4.42 (2H, m), 3.92 (3H, s), 2.68 (3H, s), 2.64 (3H, s), 1.41-1.38 (3H, m).

IM32: 3,6-Dimethyl-1-(4-trifluoromethoxy-phenyl)-1H-pyrazolo[3,4-b] Ethyl pyridin-4-carboxylate

Preparation was carried out using IM13 . The title compound (4.0 g, 66%). 1H NMR (DMSO-d6, 300 MHz) δ 8.36-8.34 (2H, m), 7.57-7.55 (2H, m), 7.56 (1H, s) 4.47-4.42 (2H, m), 2.69 (3H, s) , 2.64 (3H, s), 1.41-1.38 (3H, m).

IM33: Ethyl 1-(4-difluoromethoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Preparation was carried out using IM14 . The title compound (1.6 g, 26%). 1H NMR (DMSO-d6, 300 MHz) δ 8.25-8.23 (2H, m), 7.58 (1H, s), 7.47-7.10 (3H, m) 4.48-4.43 (2H, m), 2.70 (3H, s) , 2.66 (3H, s), 1.42-1.37 (3H, m).

IM34: Ethyl 1-(4-methoxy-phenyl)-3-methyl-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Prepared by using 2-(4-methoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamine and 2,4-di-oxy-4-phenyl-butyric acid ethyl ester The title compound (2.5 g, 87%) was obtained as a solid, which was used for the next step.

IM35: Ethyl 1-(4-methylsulfonyl-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

To give the title compound as a solid (2.0 g, 79%), pure enough for the next step using a using preparative IM16.

IM36: Ethyl 3,6-dimethyl-1-(4-aminesulfonyl-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

To give the title compound as a solid (1.97 g, 76%), pure enough for the next step using a using preparative IM17.

IM37: Ethyl 3,6-dimethyl-1-(4-trifluoromethyl-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

To give a solid of the title compound (2.66 g, 58%), pure enough for the next step using a using preparative IM18.

IM38: Ethyl 3,6-dimethyl-1-(4-nitro-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

To give the title compound as a solid (3.39 g, 31%), pure enough for the next step using a using preparative IM19.

IM39: 3-methoxy-1-(4-methoxy-phenyl)-6-methyl-1H-pyrazole Ethyl [3,4-b]pyridine-4-carboxylate

To give the title compound as a solid (0.9 g, 48%) was prepared using IM22. 1H NMR (CDCl ₃ 400) δ 8.08 (d, 2 H), 7.36 (s, 1 H), 7.00 (d, 2 H), 4.47 (q, 2 H), 4.14 (s, 3 H), 3.85 ( s, 3 H), 2.69 (s, 3 H), 1.44 (t, 3 H).

IM40: Ethyl 3,6-dimethyl-1-thiophen-3-yl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

To give the title compound as a yellow solid (1.62 g, 64%) was prepared using IM15. 1H NMR (CDCl3 400) δ 8.03-8.04 (m, 1 H), 7.93-7.95 (m, 1 H), 7.37-7.39 (m, 1 H), 4.49 (m, 2 H), 2.74 (s, 3) H), 2.73 (s, 3 H), 1.46 (t, J = 7.2 Hz, 3 H).

IM41: Ethyl 3,6-dimethyl-1-pyrimidin-5-yl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

It was prepared using IM20 to give the title compound as a colorless solid (0.25 g, 4%). 1H NMR (DMSO-d6) δ 9.62 (s, 2 H), 9.12 (s, 1 H), 7.63 (s, 1 H), 4.44 (m, 2 H), 2.71 (s, 3 H), 2.66 ( s, 3 H), 1.37 (t, 3 H).

IM42: Ethyl 1-(4-dimethylamino-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

To a solution of compound IM38 (1.63 g, 4.79 mmol) in THF (30 mL) and 5 mL EtOAc, 5% Pd / C (2 g). The mixture was kept at room temperature under H ₂ (50 psi) Release of 12 hours. The mixture was filtered and the filtrate was evaporated to dryness. The title compound (0.62 g, 61%) was obtained. 1H NMR (CDCl ₃ , 400 MHz) δ 7.91 (d2 H), 7.45 (s, 1 H), 6.86 (d, 2 H), 4.50 (m, 2 H), 2.99 (s, 6 H), 2.78 ( s, 3 H), 2.74 (s, 3 H), 1.47 (m, 3 H).

Synthesis of pyrazolo[3,4-b]pyridine-4-carboxylic acid

IM43: 3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

To a round bottom flask was added 3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxyl in a mixture of THF (18 mL) and MeOH (18 mL) Ethyl acetate (3.00 g, 10.2 mmol). To this solution was added 2 M sodium hydroxide (in water (10.2 mL)). The mixture was stirred at 80 ° C for 1.5 hours and then evaporated to dryness. The resulting mixture was dissolved in a small amount of water and 2N HCl (aqueous) was added until pH > The mixture was extracted with EtOAc. The mixed organic layers were dried with brine, Na ₂ SO ₄ dried, and evaporated to dryness to give the title compound as colorless crystals (2.51 g, 92%). 1H NMR (500 MHz, DMSO) δ 8.26-8.20 (m, 1H), 7.59-7.53 (m, 1H), 7.36-7.31 (m, 1H), 2.70 (s, 1H), 2.67 (s, 1H).

IM44: 1-(4-methoxy-phenyl)-3-methyl-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

To give the title compound as a yellow solid (2.26 g, 97%) was prepared using IM34, a sufficiently pure for the next steps.

IM45: 1-(4-Methanesulfonyl-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

To give the title compound as a yellow solid (1.61 g, 87%) was prepared using IM35, a sufficiently pure for the next steps.

IM46: 3,6-Dimethyl-1-(4-aminesulfonyl-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

To give the title compound as a solid (2.4 g, 99%), pure enough for the next step using a using preparative IM36. The hydrolysis is carried out at room temperature.

IM47: 3,6-Dimethyl-1-(4-trifluoromethyl-phenyl)-1H-pyrazolo[3,4-b] Pyridine-4-carboxylic acid

To give the title compound as a solid (1.6 g, 85%), pure enough for the next step using a using preparative IM37. The hydrolysis is carried out at room temperature.

IM48: 1-(4-Dimethylamino-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

To give the title compound as a solid (0.223 g, 97%) was prepared using Im42, a sufficiently pure for the next steps.

IM49: 3,6-Dimethyl-1-thiophen-3-yl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

To give the title compound as a solid (0.41 g, 91%) was prepared using IM40, a sufficiently pure for the next steps.

IM50: 3,6-Dimethyl-1pyrimidin-5-yl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

To give the title compound as a solid (0.113 g, 62%) was prepared using Im41, a sufficiently pure for the next steps.

IM51: 1-(4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

Adding a round bottom flask to 1-(4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4- in methanol/water (1:1, 600 mL) b] Ethyl pyridin-4-carboxylate IM23 (16.0 g, 49.2 mmol). LiOH hydrate (6.2 g, 147.6 mmol) was added to this mixture at room temperature. The resulting reaction mixture was stirred for 16 hours. Methanol was removed under reduced pressure, and the resulting mixture was diluted with water (500 mL). Acetic acid was added to adjust the pH >4. After stirring for 30 minutes, the mixture was filtered and the residue was washed with water and dried under vacuum. The crude material was purified by EtOAcjjjjjjj 1H NMR (400 MHz, DMSO-d6) δ 13.89 (1H, br), 8.03-8.01 (m, 2H), 7.35 (1H, s), 7.12-7.10 (m, 2H, d), 3.82 (3H, s ), 2.66 (3H, s), 2.65 (3H, s).

The following compounds were prepared in a similar manner:

IM52: 3,6-Dimethyl-1-p-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

The crude compound was prepared from IM24, and then the title compound was washed with diethyl ether, to give of a pale yellow powder (1.0 g, 79%). 1H NMR (DMSO-d6, 400 MHz) δ 13.89 (1H, br), 8.07-8.05 (2H, d), 7.52 (1H, s), 7.36-7.34 (2H, d), 2.68 (3H, s), 2.65 (3H, s), 2.37 (3H, s).

IM53: 1-(2-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

The crude compound was prepared from IM25, and then the title compound was washed with diethyl ether, to give of a pale yellow powder (0.9 g, 83%). 1H NMR (DMSO-d6, 400 MHz) δ 13.80 (1H, br), 7.54-7.5 (1H, m), 7.45 (1H, s), 7.39-7.37 (1H, m), 7.27-7.25 (1H, d ), 7.12-7.09 (1H, t) 3.69 (3H, s), 2.62 (3H, s), 2.55 (3H, s).

IM54: 1-(3-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

The crude compound was prepared from IM26, and subsequently washed with diethyl ether, to give the title compound as a pale yellow powder (0.90 g, 62%). 1H NMR (DMSO-d6, 400 MHz) δ 13.92 (1H, br s), 7.89-7.84 (2H, m), 7.54 (1H, s), 7.47-7.43 (1H, m), 6.91-6.89 (1H, m), 3.84 (3H, s), 2.69 (3H, s), 2.66 (3H, s).

IM55: 3,6-Dimethyl-1-(6-methyl-pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

The crude compounds, followed by washing with diethyl ether and was prepared from IM27, to give the title compound as a pale yellow solid of (1.0 g, 74%). 1H NMR (DMSO-d6, 400 MHz) δ 13.96 (1H, br s), 9.27-9.28 (1H, d), 8.48-8.46 (1H, m), 7.57 (1H, s), 7.48-7.46 (1H, m), 2.72 (3H, s), 2.68 (3H, s), 2.56 (3H, s).

IM56: 1-(4-methoxy-phenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

The crude compound, followed by washing with diethyl ether and was prepared from IM28, to give the title compound as a pale yellow solid of (2.2 g, 71%). 1H NMR (DMSO-d6, 400 MHz) δ 13.95 (1H, broad), 8.51 (1H, s), 8.07-8.04 (2H, m), 7.68 (1H, s), 7.15-7.13 (2H, m), 3.83 (3H, s), 2.71 (3H, s).

IM57: 1-(4-Fluoro-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

The crude compound was prepared from IM29, and subsequently washed with diethyl ether, to give the title compound as a pale yellow solid of the title compound (3.0 g, 65%).

1H NMR (DMSO-d6, 300 MHz) δ 13.94 (1H, br s), 8.24-8.20 (2H, m), 7.54 (1H, s), 7.43-7.37 (2H, m), 2.68 (3H, s) , 2.66 (3H, s).

IM58: 1-(4-cyano-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

The crude compound was prepared from IM30, and then the title compound was washed with diethyl ether, to give of a pale yellow solid (1.5 g, 55%).

1H NMR (DMSO-d6, 400 MHz) δ 8.59-8.56 (1H, m), 8.39-8.37 (1H, m), 8.05-7.98 (2H, m), 7.44-7.43 (1H, m), 2.68 (3H) , s), 2.64 (3H, s).

IM59: 1-(6-methoxy-pyridin-3-yl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

The crude compound was prepared from IM31, and then the title compound was washed with diethyl ether, to give of a pale yellow solid (3.0 g, 83%). 1H NMR (DMSO-d6, 300 MHz) δ 12.0 (1H, br s), 8.96-8.95 (1H, d), 8.43-8.40 (1H, m), 7.21 (1H, s), 7.01-6.99 (1H, m), 3.91 (3H, s), 2.61 (3H, s), 2.60 (3H, s).

IM60: 3,6-Dimethyl-1-(4-trifluoromethoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

The crude compound was prepared from IM32, and subsequently washed with diethyl ether, to give the title compound as a pale yellow solid (3.0 g, 65%). 1H NMR (DMSO-d6, 300 MHz) δ 13.97 (1H, br s), 8.39-8.35 (2H, m), 7.58-7.56 (3H, m), 2.70 (3H, s), 2.67 (3H, s) .

IM61: 1-(4-Difluoromethoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

The crude compound was prepared from IM33, and then the title compound was washed with diethyl ether, to give of a pale yellow solid (1.0 g, 72%). 1H NMR (DMSO-d6, 400 MHz) δ 13.09 (1H, br s), 8.26-8.24 (2H, m), 7.51 (1H, s), 7.46-7.09 (3H, m), 2.68 (3H, s) , 2.65 (3H, s).

IM62: 3-methoxy-1-(4-methoxy-phenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid,

To give the title compound as a solid (0.16 g, 89%), pure enough for the next step using a using preparative IM39. The hydrolysis is carried out at room temperature.

IM63: 1-(4-methoxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

The Pharmaceutica Acta Helvetiae 71 (1996) 213-219 and the derivatives described therein are prepared in a similar manner.

step 1:

a solution of 2-(4-methoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamine (1.0 g, 4.9 mmol) in EtOH (10 mL) Diethyl 2-(ethoxymethylene)malonate (1.17 g, 5.4 mmol) was added. The mixture was then stirred at 80 ° C for 12 hours. The reaction mixture was cooled to room temperature and excess ethanol was removed under reduced pressure. The resulting mixture was poured into ice-cold 1N NaOH solution (20 mL). The mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water and evaporated to dryness. Flash chromatography (cerium oxide, 10% EtOAc in hexanes) gave 2-{[2-(4-methoxy-phenyl)-5-methyl-2H-pyrazole as a solid. Diethyl 3-aminoamino]-methylene}-malonate (0.80 g, 43).

Step 2:

POCl ₃ and diethyl 2-{[2-(4-methoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamino]-methylene}-malonate (0.80 A mixture of grams, 2.13 millimoles) was refluxed for 6 hours. The reaction mixture was cooled to room temperature and then poured into ice water. The mixture was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with water and evaporated to dryness. The crude product was washed with diethyl ether to give 4-chloro-1-(4-methoxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5 as a crude brown solid. Ethyl carboxylate (0.40 g, 54%), the purity is sufficient for the next step.

Step 3:

Ethyl 4-chloro-1-(4-methoxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (9.0 g, 26.0 mmol) To the solution of EtOH (100 mL) was added KOH (7.3 g, 130.0 mmol). The mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature and then poured into ice water. The mixture was acidified by the addition of 10% HCl. The mixture was filtered and washed with EtOAcqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 3,4-b]pyridine-5-carboxylic acid (4.2 g, 53%), the purity is sufficient for the next step.

Step 4:

4-hydroxy-1-(4-methoxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (4.2 g, 14.0 mmol) The solution in diphenyl ether was heated to 180 ° C for 3 hours. The reaction mixture was cooled to room temperature, diluted with petroleum ether and filtered. The residue is washed with petroleum ether to give 1-(4-methoxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol as a brown solid. It is for the next step. (2.40 g, 61%). 1H NMR (DMSO-d6, 400 MHz) δ 11.57 (1H, s), 8.24-8.22 (1H, m), 8.10-8.08 (2H, m), 7.08-7.08 (2H, m), 6.59-6.58 (1H , m), 3.80 (3H, s), 2.61 (3H, s).

Step 5:

1-(4-Methoxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (2.2 g, 8.6 mmol) at room temperature The solution in acetonitrile was added in portions to POBr ₃ (4.90 g, 17.1 mmol). The reaction mixture was refluxed for 10 hours. The reaction mixture was cooled to room temperature and then poured into ice water. The mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water and evaporated to dryness to give crude 4-bromo-1-(4-methoxy-phenyl)-3-methyl-1H-pyrazole [3, 4-b]pyridine (2.0 g, 74%), the purity is sufficient for the next step. 1H NMR (DMSO-d6, 300 MHz) δ 8.42-8.40 (1H, m), 8.03-7.98 (2H, m), 7.59-7.57 (1H, m), 7.14-7.05 (2H, m), 3.82 (3H) , s), 2.74 (3H, s).

Step 6:

A solution of 4-bromo-1-(4-methoxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (2.0 g, 6.3 mmol) in DMF CuCN (1.12 g, 12.6 mmol) was added. The reaction mixture was stirred at 145 ° C for 18 hours. The reaction mixture was diluted with water and filtered with a pad of EtOAc. The combined organic layers are washed with water and evaporated to dryness to give crude 1-(4-methoxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4- The carbonitrile (1.5 g, 90%) is pure enough for the next step. 1H NMR (DMSO-d6, 400 MHz) δ : 8.83-8.82 (1H, m), 8.07-7.97 (2H, m), 7.85-7.84 (1H, m), 7.15-7.11 (2H, m), 3.82 ( 3H, s), 2.75 (3H, s).

Step 7:

1-(4-Methoxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carbonitrile (1.2 g, 4.54 mmol) in EtOH (15 The solution in ML) was added with NaOH (1.82 g, 45.5 mmol) and the reaction mixture was stirred at 80 °C for 24 hours. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The mixture was diluted with water and acidified by the addition of 10% HCl. The mixture was then extracted with dichloromethane (2 x 75 mL). The combined organic layers were washed with EtOAc EtOAc m . 1H NMR (DMSO-d6, 400 MHz) δ 13.95 (1H, s) 8.73-8.71 (1H, m), 8.04-8.01 (2H, m), 7.62-7.61 (1H, m), 7.13-7.10 (2H, m), 3.82 (3H, s), 2.69 (3H, s).

Preparation example

1: 1-(4-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridine- 3-yl)-guanamine

To a round bottom flask was added 1-(4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4- in pyridine (10 mL) Carboxylic acid IM51 (800 mg, 2.69 mmol). To the mixture was added 3-amino-2,4-dimethyl-pyridine (427 mg, 3.50 mmol) and POCl ₃ (618 mg, 4.04 mmol), and the resulting mixture was slowly heated to 100 deg.] C, And stirring at this temperature for 2 hours. The reaction mixture was cooled to room temperature then poured into ice- cold water (30 mL). The mixture was extracted with EtOAc (2×40 mL). The organic layer was washed with brine mixture, dried over anhydrous Na ₂ SO ₄ and was evaporated to dryness. The title compound (260 mg, 24%) was obtained as a crystal. Mp = 224-227 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.40 (1H, s), 8.30-8.29 (1H, d), 8.07-8.04 (m, 2H), 7.48 (1H, br), 7.23-7.22 (1H, d ), 7.14 - 7.12 (m, 2H), 3.83 (3H, s), 2.73 (3H, s), 2.56 (3H, s), 2.50 (3H, s), 2.32 (3H, s).

LC-MS (m / z) 402.2 (MH +); t R = 0.51.

The following compounds were prepared in a similar manner:

2: 3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine

3,6-Dimethyl-1-phenyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM43 (1.09 g, 4.08 mmol), 3-amino-2, 4-Dimethylpyridine (0.498 g, 4.08 mmol), pyridine (20 mL) and phosphonium chloride (0.688 g, 4.48 mmol). The title compound (0.35 g, 23%) was obtained.

LC-MS (m / z) 372.2 (MH +); t R = 0.54.

3: 3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3,5-dimethyl-pyridin-4-yl)-decylamine

3,6-Dimethyl-1-phenyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM43 (1.75 g, 6.55 mmol), 3,5-dimethyl Pyridin-4-amine (0.800 g, 6.55 mmol), pyridine (30 mL) and phosphonium chloride (0.671 mL, 7.20 mmol). The title compound (0.24 g, 10%) was obtained.

LC-MS (m / z) 372.2 (MH +); t R = 0.56.

4: 1-(2-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridine- 3-yl)-guanamine

1-(2-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM53 (0.90 g, 3.03 mmol) 2,4-Dimethyl-pyridin-3-ylamine (0.37 g, 3.03 mmol), pyridine (15 mL) and phosphonium chloride (0.55 g, 4.57 mmol). The title compound (0.48 g, 39%) was obtained.

LC-MS (m / z) 402.2 (MH +); t R = 0.43.

5: 1-(4-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-methyl-pyridin-3-yl) )-guanamine

1-(4-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM51 (0.50 g, 1.68 mmol) 2-Methyl-pyridin-3-ylamine (0.181 g, 1.68 mmol), pyridine (8) and phosphonium chloride (0.387 g, 2.46 mmol). The title compound (0.20 g, 30%) was obtained.

LC-MS (m / z) 388.2 (MH +); t R = 0.51.

6: 3,6-Dimethyl-1-p-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-indole amine

3,6-Dimethyl-1-p-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM52 (1.00 g, 3.55 mmol), 2,4-di Methyl-pyridin-3-ylamine (0.43 g, 3.52 mmol), pyridine (15 mL) and phosphonium chloride (0.60 g, 3.95 mmol). The crude product was purified using EtOAcqqqqqq

LC-MS (m / z) 386.2 (MH +); t R = 0.58.

7: 1-(4-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-methoxy-4-methyl) -pyridin-3-yl)-guanamine

1-(4-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM51 (0.50 g, 1.68 mmol) 2-methoxy-4-methyl-pyridin-3-ylamine IM01 (0.240 g, 1.74 mmol), pyridine (8) and phosphonium chloride (0.387 g, 2.52 mmol). The title compound (0.13 g, 19%) was obtained.

LC-MS (m / z) 418.2 (MH +); t R = 0.73.

8: 1-(4-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4-methyl-pyridin-3-yl) )-guanamine

1-(4-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM51 (0.50 g, 1.68 mmol) 4-methyl-pyridin-3-ylamine (0.181 g, 1.68 mmol), pyridine (8) and phosphonium chloride (0.387 g, 2.46 mmol). The title compound (0.20 g, 30%) was obtained.

LC-MS (m / z) 388.2 (MH +); t R = 0.52.

9: 1-(3-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridine- 3-yl)-guanamine

1-(3-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM54 , 2,4-dimethyl- Pyridin-3-ylamine (0.37 g, 3.03 mmol), pyridine (15 mL) and phosphonium chloride (0.55 g, 3.63 mmol). The title compound (0.697 g, 58%) was obtained.

LC-MS (m / z) 402.2 (MH +); t R = 0.54.

10: 3,6-Dimethyl-1-(6-methyl-pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-) Pyridin-3-yl)-guanamine

Using 3,6-dimethyl-1-(6-methyl-pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM55 (1.00 g, 3.54 mmol) Ear), 2,4-dimethyl-pyridin-3-ylamine (0.43 g, 3.54 mmol), pyridine (15 mL) and phosphonium chloride (0.39 mL, 4.25 mmol). The title compound (0.400 g, 29%) was obtained.

LC-MS (m / z) 387.2 (MH +); t R = 0.32.

11: 1-(4-Methoxy-phenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl) )-guanamine

Prepared using IM56 and 3-amino-2,4-dimethylpyridine.

LC-MS (m / z) 388.2 (MH +); t R = 0.51.

12: 1-(4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4,6-dimethylpyrimidine-5 -yl)-guanamine

Prepared using IM56 and IM06.

LC-MS (m / z) 403.2 (MH +); t R = 0.62.

13: 1-(4-Fluoro-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridine-3- Amine

Prepared using IM57 and 3-amino-2,4-dimethylpyridine.

LC-MS (m / z) 390.2 (MH +); t R = 0.56.

14: 1-(4-cyano-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridine-3 -yl)-guanamine

Prepared using IM58 and 3-amino-2,4-dimethylpyridine.

LC-MS (m / z) 397.2 (MH +); t R = 0.52.

15: 1-(4-Methoxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl) )-guanamine

Prepared using IM63 and 3-amino-2,4-dimethylpyridine.

LC-MS (m / z) 388.2 (MH +); t R = 0.48.

16: 1-(6-Methoxy-pyridin-3-yl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl -pyridin-3-yl)-guanamine

Prepared using IM59 and 3-amino-2,4-dimethylpyridine.

LC-MS (m / z) 403.2 (MH +); t R = 0.48.

17: 3,6-Dimethyl-1-(4-trifluoromethoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-) Pyridin-3-yl)-guanamine

Prepared using IM60 and 3-amino-2,4-dimethylpyridine.

LC-MS (m / z) 456.2 (MH +); t R = 0.68.

18: 1-(4-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4,6-trimethyl- Pyridin-3-yl)-guanamine

Prepared using IM51 and 2,4,6-trimethyl-pyridin-3-ylamine.

LC-MS (m / z) 416.2 (MH +); t R = 0.52.

19: 1-(4-Difluoromethoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-) Pyridin-3-yl)-guanamine

Prepared using IM61 and 2,6-dimethyl-pyridin-3-ylamine.

LC-MS (m / z) 438.2 (MH +); t R = 0.58.

20: 1-(4-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4-methylpyrimidin-5-yl) - guanamine

Prepared using IM51 and 4-methylpyrimidin-5-ylamine.

LC-MS (m / z) 389.2 (MH +); t R = 0.62.

twenty one: 3,6-Dimethyl-1-(4-aminesulfonyl-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridine -3-yl)-nonylamine

Prepared using IM46 and 3-amino-2,4-dimethylpyridine.

LC-MS (m / z) 451.2 (MH +); t R = 0.37.

twenty two: 3,6-Dimethyl-1-(4-trifluoromethyl-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridine -3-yl)-nonylamine

IM47 and 3-amino-2,4-dimethylpyridine were used.

LC-MS (m / z) 440.2 (MH +); t R = 0.67.

twenty three: 1-(4-Dimethylamino-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-) Pyridin-3-yl)-guanamine

Prepared using IM48 and 3-amino-2,4-dimethylpyridine, containing a catalytic amount of DMAP in the reaction mixture.

LC-MS (m / z) 415.2 (MH +); t R = 0.37.

twenty four: 3-methoxy-1-(4-methoxy-phenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl -pyridin-3-yl)-guanamine

Prepared using IM62 and 3-amino-2,4-dimethylpyridine.

LC-MS (m / z) 418.2 (MH +); t R = 0.56.

25: 3,6-Dimethyl-1-thiophen-3-yl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)- Guanamine

Prepared using IM49 and 3-amino-2,4-dimethylpyridine.

LC-MS (m / z) 378.1 (MH +); t R = 0.53.

26: 3,6-Dimethyl-1 pyrimidin-5-yl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-indole amine

Prepared using IM50 and 3-amino-2,4-dimethylpyridine.

LC-MS (m / z) 374.4 (MH +); t R = 0.38.

27: 3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-methoxy-4-methyl-pyridin-3-yl)- Guanamine

The round bottom flask was charged with 3,6-dimethyl-1-phenyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM43 (1.2 g, 4.49 mmol) at room temperature. 3-Amino-4-methyl-2-methoxypyridine (620 mg, 4.49 mmol) and DIPEA (2.94 mL, 8.09 mmol) (in DMF (50 mL)). To this mixture was added HATU (2.04 g, 5.39 mmol) and the resulting mixture was stirred 16 hr. The mixture was then poured into water (100 mL). The mixture was extracted with ethyl acetate (2×200 mL). The organic layer was washed with brine mixture, dried over anhydrous Na ₂ SO ₄ and was evaporated to dryness. The title compound (600 mg, 34%) was obtained as a crystal. Mp = 172-174 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (1H, s), 8.27-8.25 (2H, d), 8.03-8.02 (1H, d), 7.58-7.54 (2H, m), 7.41 (1H, s ), 7.35-7.31 (1H, m), 6.99-6.98 (1H, m), 3.90 (3H, s), 2.73, (3H, s), 2.60 (3H, s), 2.31 (3H, s).

LC-MS (m / z) 388.2 (MH +); t R = 0.77.

The following compounds were prepared in a similar manner:

28: 3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4-methoxy-2-methyl-pyridin-3-yl)- Indoleamine and 29: 3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4-methoxy-6-methyl-pyridine- 3-yl)-guanamine

3,6-Dimethyl-1-phenyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM43 (1.2 g, 4.49 mmol), 4-methoxy-2 a mixture of -methyl-pyridin-3-ylamine and 4-methoxy-6-methyl-pyridin-3-ylamine regioisomer, IM04 + IM05 , (620 mg as a mixture, 4.49 mmol) , DIPEA (2.94 mL, 8.99 mmol) and HATU (2.05 g, 5.39 mmol) (in DMF (50 mL)). Purification by preparative HPLC gave the title compound as a solid.

28: (237 mg, 14%), mp = 206-207 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (1H, s), 8.33-8.32 (1H, d), 8.27-8.25 (2H, d), 7.58-7.54 (2H, m), 7.40 (1H, s ), 7.35-7.31 (1H, m), 7.07-7.05 (1H, d), 3.89 (3H, s), 2.73 (3H, s), 2.60 (3H, s), 2.45 (3H, s).

LC-MS (m / z) 388.2 (MH +); t R = 0.52.

29: (87 mg, 5%), mp = 230-232 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (1H, s), 8.57 (1H, s), 8.27-8.25 (2H, d), 7.58-7.50 (2H, m), 7.38-7.30 (m, 2H) ), 7.07 (1H, s), 3.00 (3H, s), 2.71 (3H, s), 2.56 (3H, s), 2.47 (3H, s).

LC-MS (m / z) 388.2 (MH +); t R = 0.54.

30: 1-(4-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4-dimethylamino-pyridine- 3-yl)-guanamine

Use IM51 and N ^4, N ⁴ - Preparation of dimethyl pyridine-3,4-diamine.

LC-MS (m / z) 417.2 (MH +); t R = 0.50.

31: 3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-methyl-pyridin-3-yl)-decylamine

The round bottom flask was charged with 3,6-dimethyl-1-phenyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM43 (1.2, 4.49 mmol) at room temperature. 3-Amino-2-methylpyridine (485 mg, 4.49 mmol) and N-methylmorpholine (907 mg, 8.99 mmol) (in DMF (50 mL)). To this mixture was added EDC.HCl (947 mg, 4.94 mmol) and HOBt (606 mg, 4.49 mmol). The mixture was stirred for 16 hours. The reaction mixture was then poured into water (100 mL). The mixture was extracted with ethyl acetate (2×200 mL). The organic layer was washed with brine mixture, dried over anhydrous Na ₂ SO ₄ dried, and evaporated to dryness. The title compound (277 mg, 17%) was obtained as a crystal. Mp = 208-209 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (1H, s), 8.39-8.38 (1H, m), 8.27-8.25 (2H, d), 7.93-7.91 (1H, m), 7.59-7.55 (2H m), 7.49 (1H, s), 7.35-7.32 (2H, m), 2.74 (3H, s), 2.58 (3H, s), 2.52 (3H, s).

LC-MS (m / z) 358.2 (MH +); t R = 0.53.

The following compounds were prepared in a similar manner:

32: 3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4-A Base-pyridin-3-yl)-guanamine

3,6-Dimethyl-1-phenyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM43 (500 mg, 1.87 mmol), 3-amino-4- Methylpyridine (202 mg, 1.87 mmol), N-methylmorpholine (378 mg, 3.74 mmol), EDC.HCl (394 mg, 2.06 mmol), and HOBt (252 mg, 1.87 mmol) Ear) (in DMF (20 ml)). Flash chromatography (20% EtOAc (EtOAc:EtOAc) Mp = 227-228 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.52 (1H, s), 8.64 (1H, s), 8.37-8.36 (1H, d), 8.27-8.25 (2H, m), 7.59-7.55 (2H, m ), 7.51 (1H, s), 7.38-7.32 (2H, m), 2.74 (3H, s), 2.59 (3H, s), 2.34 (3H, s).

LC-MS ( m/z ) 358.0 (MH ⁺ ).

33: 1-(4-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4,6-dimethyl-pyridine- 3-yl)-guanamine

1-(4-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM51 (1.60 g, 5.38) over 10 min. a suspension of mM, 5-amino-2,4-dimethylpyridine (786 mg, 6.43 mmol) and triethylamine (3.00 mL, 21.5 mmol) in THF (20 mL) A 50% (w/w) solution of 1-propanephosphonic acid cyclic anhydride in THF (6.84 g, 10.7 mmol) was added. The mixture was stirred overnight at room temperature. The mixture was poured into water (20 mL). The THF was removed under vacuum. An aqueous NH ₃ solution was added to adjust the pH to about 10. EtOH (25 mL) was added, and the mixture was briefly heated to reflux and then stood at room temperature overnight. The mixture was then cooled to an ice-water bath for 45 minutes. The residue was washed with water and dried title crystals 1H NMR (600 MHz, DMSO) δ 10.43 (s, 1H), 8.47 (s, 1H), 8.09-8.04 (m, 2H), 7.46 (s, 1H), 7.23 (s, 1H), 7.16-7.11 ( m, 2H), 3.83 (s, 3H), 2.71 (s, 3H), 2.57 (s, 3H), 2.46 (s, 3H), 2.29 (s, 3H).

LC-MS (m / z) 402.2 (MH +); t R = 0.52.

The following compounds were prepared in a similar manner:

34: 1-(4-Methanesulfonyl-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridine) -3-yl)-nonylamine

Prepared using IM45 and 2,6-dimethyl-pyridin-3-ylamine.

LC-MS (m / z) 450.2 (MH +); t R = 0.43.

35: 1-(4-Methoxy-phenyl)-3-methyl-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-) Pyridin-3-yl)-guanamine

To a solution of IM44 (200 mg, 0.56 mmol) in 1 mL of DMF was added SOCI ₂ (5 mL). The resulting mixture was heated at 100 ° C for 1 hour. The mixture was then evaporated to dryness to give crude acid chloride (0.23 g).

A small amount of NaH (23 mg, 0.58 mmol) was added to a separated solution of 3-amino-2,4-dimethylpyridine (68 mg, 0.56 mmol) in THF (5 mL). The mixture was stirred at 25 ° C for 30 minutes. Crude acid chloride (0.23 g) was added to this solution. The resulting mixture was maintained at 25 ° C for 2 hours. The mixture was poured into ice water and extracted with EtOAc (100 mL). The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and evaporated to dryness. The title compound (172 mg, 67%) was obtained as crystals. 1H NMR (CDCl3 400 MHz) δ 8.39 (m, 1H), 8.13-8.18 (m, 4 H), 7.82 (s, 1 H), 7.51-7.56 (m, 4 H), 7.14 (d, 1 H) , 7.06-7.08 (m, 2 H), 3.88 (s, 3 H), 2.70 (s, 3 H), 2.64 (s, 3 H), 2.43 (s, 3 H).

LC-MS (m / z) 464.2 (MH +); t R = 0.66.

The following compounds were prepared in a similar manner:

36: 1-(4-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4-cyano-pyridin-3-yl) )-guanamine

IM51 and 3-amino-iso-nicobutyl nitrile were used.

LC-MS (m / z) 399.2 (MH +); t R = 0.68.

37: 1-(4-Hydroxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridine-3- Amine

At -78 deg.] C for 1 (6.0 g, 15.0 mmol) in dichloromethane (70 mL) was added BBr ₃ (18 mL, 18.0 mmol). The resulting mixture was slowly warmed to room temperature and maintained at this temperature for 18 hours. The reaction mixture was quenched with MeOH (15 mL) and diluted. The mixture was basified by the addition of Na ₂ CO ₃ and then filtered. The residue was washed with water and dried then evaporated 1H NMR (DMSO-d6, 400 MHz, TMS) δ 10.39 (1H, s), 9.62 (1H, s), 8.30-8.28 (1H, m), 7.89-7.87 (2H, m), 7.46 (1H, s ), 7.23 - 7.22 (1H, m), 6.94 - 6.92 (2H, m), 2.71 (3H, s), 2.55 (3H, s), 2.50 (3H, s), 2.32 (3H, s).

LC-MS (m / z) 388.2 (MH +); t R = 0.37.

In vitro assay

The nicotinic acetylcholine receptor alpha 7 is a calcium permeable ion channel whose activity can be measured by overexpression in mammalian cells or oocytes. These two individual analyses are described in Examples 2 and 3, respectively.

Example 2: α7 NNR flux analysis

The nicotinic acetylcholine receptor alpha 7 is a calcium permeable ion channel whose activity can be measured by overexpression in mammalian cells or oocytes. In this assay version, the human α7 receptor was stably expressed in the rat GH4C1 cell line. This assay was used to identify the forward ectopic modulator (PAM) of the alpha 7 receptor. Channel activation was measured by loading cells with calcium sensitive fluorescent dye calcium-4 (Calcium-4) (analytical kit from Molecular Devices) and then measuring the immediate fluorescence change as it was treated with the test compound.

The cell line from Genionics, ChanClone GH4C1-nAChRalpha7, was seeded in a medium in a 384-well dish from the frozen stock 2-3 days prior to the experiment to form an approximately 80% confluent layer on the day of the experiment.

Cell coating and dye loading

The cell culture was dispensed into a "22.5 cm x 22.5 cm" dish at approximately 100 x 10 ³ cells/cm 2 . After incubation for 4 days at 37 ° C and 5% CO ₂ in a moisture containing incubator, it had grown to a 80-90% confluent layer and cells were harvested.

Medium: 500 ml DMEM/F12 (Gibco 31331)

50 ml FBS (Gibco 10091-155, lot number 453269FD)

5 ml of sodium pyruvate (Gibco 11360)

5 ml penicillin (Pen) / streptomycin (Strep) (Gibco 15140)

0.1 mg/ml G-418 (Gibco 11811-064)

Two or three days prior to the experiment, cells were seeded in 384 well plates (781946, CELLCOAT, poly D-lysine, black, μClear) from Greiner bio-one.

The medium was decanted and the plate was washed with PBS and drained. Add ml of trypsin, wash the cells and incubate (at room temperature) for about 10 seconds. Trypsin was quickly poured out and the cells were incubated for 2 minutes at 37 ° C (if the cells had not been isolated). The cells were resuspended in 10 mL of medium and transferred to a 50 ml tube.

The cell suspension from the first plate was counted (NucleoCounter, total cell count) to estimate the total number of cells throughout the batch.

Cells were seeded in 384 well plates at 30 μL per well (30,000 cells/well) while stirring the cell suspension or otherwise preventing cell pelleting.

Each plate was incubated for 30-45 minutes at room temperature.

Each plate was placed in an incubator for 2 days (37 ° C and 5% CO ₂ ).

Load cell

Load buffer is 5% v/v calcium-4 kit and 2.5 mM probenecid (Probenecid) assay buffer.

190 ml of assay buffer

10 ml kit solution

2 ml 250 mM probenecid

This volume is sufficient for 3 x 8 cell dishes.

The medium was removed from the cell disk and 20 μL of loading buffer was added to each well. The cell plates were placed in a tray and incubated for 90 minutes in an incubator (37 ° C). Thereafter, each plate was still incubated at room temperature for 30 minutes in the dark.

The cell plate is now ready for operation in a Functional Drug Screening System (FDSS). The assay buffer was HBSS containing 20 mM HEPES (pH 7.4) and 3 mM CaCl ₂ .

FDSS Ca analysis

200 nL of 10 mM compound in DMSO was diluted in 50 μL of assay buffer. The final test concentration in the cell disk was 20-10-5-2.5-1.25-0.625-0.312-0.156-0.078-0.039 μM. Analytical buffer and 3 μM PNU-120596 were used for the control.

The agonist acetylcholine was added to obtain a final concentration of 20 μM (about EC100).

In the FDSS7000, the Ex480-Em540 was measured at 1 second intervals. The baseline consisted of 5 frames prior to the addition of the test compound and an additional 95 frames were generated prior to the addition of acetylcholine. After the second addition, the measurement terminates 30 frames.

The raw data of each hole is collected as the "maximum fluorescence count" in the interval of 100-131 seconds and the interval is 96-100 seconds. The "average fluorescence count" inside. The positive ectopic regulation in the second addition is an enhanced agonist response in the presence of the test compound compared to the agonist alone.

The results were calculated as the % adjustment of the test compound compared to the reference PNU-120596 set to 100%. Since other information to generate EC ₅₀ curve to obtain EC _50, slope (hill) and the maximum stimulation.

EC compound in the assay of the flux characteristics of the present invention is generally less than 20.000 nM ₅₀ value 20.000 nM or less, such as less than 10.000 nM. Many compounds of the EC ₅₀ value is actually lower than 5.000 nM. Table 1 shows the EC ₅₀ value of the exemplary compounds of the present invention.

* Selected compounds of the invention were tested in a more comprehensive oocyte assay (Examples). Compound Nos. 21, 22, 24, 34, 35 and 36 were subsequently tested in oocyte assays and the results in the assay were positive NNR PAM activity.

Example 3: Analysis of α7 NNR oocytes

The expression of the α7 nACh receptor in Xenopus oocytes.

Oocytes were removed surgically using 0.4% MS-222 anesthetized for 10-15 minutes in mature female Xenopus laevis . The oocytes were then subjected to OR2 buffer (82.5 mM NaCl, 2.0 mM KCl, 1.0 mM MgCl ₂ and 5.0 mM HEPES) containing 0.5 mg/ml collagenase (type IA, Sigma-Aldrich) at room temperature. pH 7.6) Digestion for 2-3 hours. Modified oat cells that eliminated the follicular layer and modified Bart's Saline buffer supplemented with 2 mM sodium pyruvate, 0.1 U/l penicillin, and 0.1 μg/l streptomycin (Modified Barth's Saline) Buffered (88 mM NaCl, 1 mM KCl, 15 mM HEPES, 2.4 mM NaHCO ₃ , 0.41 mM CaCl ₂ , 0.82 mM MgSO ₄ , 0.3 mM Ca(NO ₃ ) ₂ ) for 24 hours. Identify stage IV oocytes and inject 4.2-48 nl of nuclease-free water containing 0.1-1.2 ng of cRNA encoding human α7 nACh receptor or 3.0-32 ng of cRNA encoding rat α7 nACh receptor and at 18 ° C Incubate for 1-10 days at which time it is used for electrophysiological recording.

Electrophysiological recording of the α7 nACh receptor expressed in oocytes.

Electron physiological recordings were performed using oocytes 1 to 10 days after the injection.

The oocytes were placed in a 1 ml bath and perfused with Ringer buffer (115 mM NaCl, 2.5 mM KCl, 10 mM HEPES, 1.8 mM CaCl ₂ , 0.1 mM MgCl ₂ , pH 7.5). Cells were pierced with a 0.2-1 MΩ electrode containing 3 M KCl in agar and clamped at -90 mV by the GeneClamp 500B amplifier voltage. The experiment was carried out at room temperature. The oocytes were continuously perfused with Ringer's buffer and the drug was applied in the perfusate. ACh (30 μM) applied for 30 seconds was used as a standard agonist to activate the α7 nACh receptor. In a standard screening protocol, a novel test compound (10 μM or 30 μM) was applied for 1 minute pre-application to allow evaluation of the agonistic activity, followed by a total of 30 seconds with ACh (30 μM) allowing for assessment of PAM activity. The co-applied reaction was compared to the agonistic reaction obtained with ACh alone. The effect of both drug-induced peak response and total charge (AUC) response was calculated, thereby giving the effect of drug-induced PAM activity in a regulated fold of the control reaction. Table 2 shows the adjustment folds of compound numbers 21, 22, 24, 34, 35 and 36 in the 10 μM assay.

For a more detailed study, to the dose - response curves to assess the maximum peak value of ₅₀ is reacted with the reaction of both the AUC and adjust multiple EC.

Claims (15)

a compound of formula [I] Wherein A4 is C-R4 or N, A5 is C-R5 or N and A6 is C-R6 or N, provided that at least one of A4, A5 or A6 is N and no more than two of A4, A5 and A6 N; R1 is phenyl or heteroaryl; wherein the phenyl or heteroaryl is optionally substituted with one or more substituents R11, wherein each R11 is individually selected from _C1-6 alkyl, Halogen, hydroxy, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, cyano, C _1-6 alkylsulfonyl, -S(O) ₂ NH ₂ and -NR12R13, wherein R12 and R13 independently represent hydrogen or C _1-6 alkyl; R2 is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, halogen and cyano; R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -6} alkoxy, halogen, cyano and -NR9R10, wherein R9 and R10 independently represent hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halo C _1-6 alkane Or a phenyl group; R8 is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, halogen, cyano and phenyl; Pharmaceutically acceptable salts. A compound according to claim 1, wherein each R11 is individually selected from the group consisting of methyl, trifluoromethyl, fluoro, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, cyano, Methylsulfonyl, -S(O) ₂ NH ₂ and -N(CH ₃ ) ₂ ; R ₂ is selected from H, methyl and methoxy; R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from each other From H, methyl, methoxy, cyano and N(CH ₃ ) ₂ ; R 8 is selected from the group consisting of H, methyl and phenyl. The compound of any one of claims 1 to 2, wherein only one of A4, A5 or A6 is N. The compound of any one of claims 1 to 2, wherein A4, A5 or A6 are both N. The compound of any one of claims 1 to 4, wherein R1 represents a phenyl group optionally substituted with 1 or more R11. The compound of any one of claims 1 to 4, wherein R1 represents a 6-membered heteroaryl group optionally substituted with 1 or more R11. The compound of any one of claims 1 to 4, wherein R1 represents a 5-membered heteroaryl group optionally substituted with 1 or more R11. The compound of any one of claims 1 to 7 wherein R1 is optionally substituted with 1 R11. The compound of claim 8 wherein the R11 is selected from the group consisting of methyl, trifluoromethyl, fluoro, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, cyano, methyl sulfonate Mercapto, -S(O) ₂ NH ₂ and -N(CH ₃ ) ₂ . The compound of any one of claims 1 to 9, wherein R2, R3, R4, R5, R6 and R7 are independently of each other selected from the group consisting of H, methyl and methoxy. The compound of any one of claims 1 to 10 wherein R8 is selected from the group consisting of H, methyl and phenyl. A compound according to claim 1 which is selected from the group consisting of 1: 1-(4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]- 4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 2: 3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-b] Pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 3: 3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4- b] pyridine-4-carboxylic acid (3,5-dimethyl-pyridin-4-yl)-decylamine; 4: 1-(2-methoxy-phenyl)-3,6-dimethyl- 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 5: 1-(4-methoxy-phenyl -3,6-Dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-methyl-pyridin-3-yl)-decylamine; 6: 3.6-dimethyl Base-1-p-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 7: 1- (4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-methoxy-4-methyl-pyridine 3-yl)-decylamine; 8: 1-(4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4-methyl-pyridin-3-yl)-decylamine; 9: 1-(3-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b Pyridine-4 -carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 10: 3,6-dimethyl-1-(6-methyl-pyridin-3-yl)-1H-pyridyl Zoxao[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 11: 1-(4-methoxy-phenyl)-6 -methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 12: 1-(4-methoxy -phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4,6-dimethyl-pyrimidin-5-yl)-decylamine ; 13: 1- (4-fluoro - phenyl) -3,6-dimethyl -1H- pyrazolo [3,4-b] pyridine-4-carboxylic acid (2,4-dimethyl - pyridine 3-yl)-decylamine; 14: 1-(4-cyano-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ( 2,4-dimethyl-pyridin-3-yl)-decylamine; 15: 1-(4-methoxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b] Pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 16: 1-(6-methoxy-pyridin-3-yl)-3,6-dimethyl -1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 17: 3,6-dimethyl-1- (4-trifluoromethoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 18: 1-(4-methoxy-phenyl)-3 ,6-Dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4,6-trimethyl-pyridin-3-yl)-decylamine; 19: 1- (4-Difluoromethoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridine- 3-yl)-guanamine; 20: 1-(4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ( 4-methyl-pyrimidin-5-yl)-decylamine; 21: 3,6-dimethyl-1-(4-aminesulfonyl-phenyl)-1H-pyrazolo[3,4-b Pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 22: 3,6-dimethyl-1-(4-trifluoromethyl-phenyl)- 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 23: 1-(4-dimethylamino- Phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-decylamine; 24 : 3-methoxy-1-(4-methoxy-phenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl -pyridin-3-yl)-guanamine; 25: 3,6-dimethyl-1-thiophen-3-yl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2 , 4-dimethyl-pyridin-3-yl)-decylamine; 26: 3,6-dimethyl-1pyrimidin-5-yl-1H-pyrazolo[3,4-b]pyridine-4- Carboxylic acid (2,4-dimethyl- 3-yl) - Amides; 27: 3,6-dimethyl-1-phenyl -1H- pyrazolo [3,4-b] pyridine-4-carboxylic acid (2-methoxy - 4-methyl-pyridin-3-yl)-decylamine; 28: 3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ( 4-methoxy-2-methyl-pyridin-3-yl)-decylamine; 29: 3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine- 4-carboxylic acid (4-methoxy-6-methyl-pyridin-3-yl)-guanamine; 30: 1-(4-methoxy-phenyl)-3,6-dimethyl-1H -pyrazolo[3,4-b]pyridine-4-carboxylic acid (4-dimethylamino-pyridin-3-yl)-decylamine; 31: 3,6-dimethyl-1-phenyl -1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-methyl-pyridin-3-yl)-decylamine; 32: 3,6-dimethyl-1-phenyl- 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4-methyl-pyridin-3-yl)-decylamine; 33: 1-(4-methoxy-phenyl)-3 ,6-Dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4,6-dimethyl-pyridin-3-yl)-decylamine; 34: 1-(4 -Methanesulfonyl-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl) - decylamine; 35: 1-(4-methoxy-phenyl)-3-methyl-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2 ,4-dimethyl-pyridyl Pyridin-3-yl)-guanamine; 36: 1-(4-methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate Acid (4-cyano-pyridin-3-yl)-guanamine; 37: 1-(4-hydroxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b] Pyridine-4-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-guanamine; and pharmaceutically acceptable salts of any of these compounds. A compound for use as a medicament according to any one of claims 1 to 12. A compound for use in the treatment of a disease or condition, according to any one of claims 1 to 12, which is selected from the group consisting of: psychosis; schizophrenia; cognitive disorders; cognitive disorders associated with schizophrenia; Attention deficit hyperactivity disorder (ADHD); autism series disorders; Alzheimer's disease (AD); mild cognitive impairment (MCI); age-related memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy body; dementia associated with Down's syndrome; Huntington's disease; Parkinson's disease (PD); obsessive-compulsive and obsessive-compulsive disorder (OCD); traumatic brain injury; Post-traumatic stress disorder; Wernick-Korsakov syndrome (WKS); post-traumatic amnesia; cognitive deficit associated with depression; diabetes; weight control; inflammatory disease; reduced angiogenesis; amyotrophic lateral sclerosis And pain. A pharmaceutical composition comprising, as claimed in claims 1 to 12 A compound according to any one of the preceding claims, and one or more pharmaceutically acceptable carriers or excipients.