Pharmacologically active heterocyclic substituted pyrazolo[1,5-a]pyrimidine derivatives

Abstract

The present invention is directed to the B The present invention relates to novel pyrazolo[1,5-a]pyrimidine derivatives of formula (I) or pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates, and hydrates thereof, which function as receptor positive allosteric modulators. The present invention also relates to methods for producing the compounds and key intermediates used in the methods. The present invention also relates to pharmaceutical compositions comprising the compounds, optionally in combination with two or more different therapeutic agents, and further relates to pharmaceutical compositions containing ... of formula (I) or pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates, and hydrates thereof, which function as receptor positive allosteric modulators. B The present invention relates to the use of the above compounds in methods for treating diseases and conditions mediated and modulated by receptor positive allosteric mechanisms. The present invention also provides methods for producing medicaments useful in the treatment of such disorders. [Formula 1] TIFF2023536197000203.tif69170

Description

[Technical Field]

[0001] This invention relates to GABA B The present invention relates to novel pyrazolo[1,5-a]pyrimidine derivatives of formula (I) or pharmaceutically acceptable salts thereof, biologically active metabolites, prodrugs, racemic compounds, enantiomers, diastereomers, solvates and hydrates that function as receptor-positive allosteric modulators. The present invention also relates to methods for producing the above compounds and key intermediates in such methods. The present invention also relates to pharmaceutical compositions comprising the above compounds in combination with two or more different therapeutic agents, and further to GABA B The present invention relates to the use of the above compounds in methods for treating diseases and conditions mediated and modulated by receptor-positive allosteric mechanisms. The present invention also provides methods for producing pharmaceuticals useful in the treatment of such disorders. [Background technology]

[0002] Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system and plays a crucial role in modulating neuronal activity. GABA is transmitted through three receptor systems, including related ion channel-type GABA receptors. A and GABA C Receptors, as well as clearly distinguishable metabotropic GABAs. B It exerts its effects via receptors (Hill and Bowery, Nature 1981, 290, 149-152). The latter is GABA. B The receptor is widely distributed throughout the mammalian central nervous system at various expression levels in different brain regions (Bovery et al, Neuroscience 1987, 20, 365-385). GABA B Receptors can be found both presynaptic and postsynaptic and may play a crucial role in the fine-tuning of neurotransmission. Most GABA receptors BThe receptor clusters around excitatory synapses at the ends of presynaptic terminals or on dendritic spines opposite to glutamatergic boutons (Ulrich and Bettler, Curr. Opin. Neurobiol. 2007, 17, 298-303).

[0003] GABA B The receptor belongs to the family 3 (C) of G-protein-coupled receptors (GPCRs), together with metabotropic glutamate receptors (mGluRs), calcium-sensing receptors, taste receptors and some orphan receptors, and shows approximately 30% highest homology to mGluRs (Bettler et al, Physiol. Rev. 2004, 84, 835-86). GABA B The receptor is a heterodimer consisting of two similar but different subunits B1 and B2. The B1 subunit has multiple splice variants, and only two (B1a and B1b) have clear physiological importance. These isoforms differ only in their extracellular domains containing two Sushi motifs that regulate the intracellular localization of the receptor (Vigot et al, Neuron 2006, 50, 589-601; Biermann et al, J. Neurosci. 2010, 30, 1385-1394). The B1 subunit binds the endogenous neurotransmitter ligand GABA as well as other orthosteric agonists (e.g., baclofen, SKF97541) and antagonists (e.g., phaclofen, saclofen). The B2 subunit is thought to be responsible for G-protein activation-mediated intracellular signaling and binds to allosteric modulators (Binet et al, J. Biol. Chem. 2004, 279, 29085-29091; Dupuis et al, Mol. Pharmacol. 2006, 70, 2027-2036). Novartis' GABA BFor the positive allosteric modulator compounds CGP7930 and GS39783, the site of action is the seven-fold heptahelical transmembrane domain of the B2 subunit; the exact binding sites for other unrelated positive allosteric modulator species are unknown.

[0004] GABA B The main synaptic effects of the receptor are presynaptic blockade and postsynaptic hyperpolarization of neurotransmitter release (GABA and glutamate) (Gassmann and Bettler, Handbook of Contemporary Neuropharmacology 2007). These effects result from inhibition of presynaptic calcium influx and stimulation of postsynaptic inward rectifying potassium (GIRK) channels, respectively. Ion channel function is G i / G o It is mediated in a membrane-separated manner through the activation of the βγ subunit of proteins. In addition to these, GABA B The receptor also signals via the α subunit of the same G protein, which inhibits adenylyl cyclase and delays synaptic vesicle recruitment (Chalifoux and Carter, Curr. Opin. Neurobiol. 2011, 21, 339~442). In addition to these rapid cellular events, GABA B The receptors also regulate cytoplasmic kinases, including mitogen-activated protein kinases, thereby influencing synaptic plasticity over longer periods.

[0005] GABA B To better understand the physiological importance of the receptor at the behavioral level, knockout mice with selective mutations in the B1, B1a, B1b, and B2 subunits have been created. Mice lacking the B1 subunit exhibited increased anxiety, increased panic, spontaneous epileptic seizures, hyperalgesia, hyperlocomotion, and memory impairment in exploratory situations (light-dark box, staircase assay) (Schuler et al, Neuron 2001, 31, 47-58). GABAB2 Mice that do not express the subunit behave similarly to B1 subunit knockouts; these animals exhibit hyperanxiety, spontaneous epileptic seizure activity, hyperalgesia, hypermotor, and memory impairment (Mombereau et al, Eur.J.Pharmacol.2004,497,119~120;Mombereau et al, Neuroreport 2005,16,307~310;Gassmann et al, J.Neurosci.2004,24,6086~6097). Based on the above, GABA B Receptor systems are thought to play a general role in regulating neuronal excitability, with consequences for various aspects of overt behavior.

[0006] The only approved and commercially available selective GABA BThe receptor ligand is the orthosteric agonist semiconducting compound baclofen. Baclofen is approved as a centrally acting muscle relaxant used to reduce spasticity associated with cerebral palsy, multiple sclerosis, and spinal cord injury. In addition to these applications, baclofen may have potential therapeutic benefits in treating conditions including asthma, pain, obesity, overeating, drug and alcohol abuse, anxiety, post-traumatic stress disorder, cough, inflammation, gastroesophageal reflux, and urinary incontinence (e.g., Breslow et al, Am.J. Psychiatry 1989, 146, 353-356; Drake et al, Ann. Pharmacother. 2003, 37, 1177-1181; Leggio et al, CNS Neurol. Disord. Drug Targets 2010, 9, 33-44). While baclofen has potential benefits in several therapeutic indications, it unfortunately also possesses a variety of undesirable characteristics, including low blood-brain barrier permeability, a narrow therapeutic range, receptor desensitization, the development of tolerance to the main effect, and withdrawal symptoms upon discontinuation of use (Vacher and Bettler, Curr. Drug Targets CNS Neurol. Disord. 2003, 2, 248~259; Ross et al, Neurocrit. Care 2011, 14, 103~108; Keegan et al, Neuropharmacology 2015, 95, 492~502).

[0007] Allosteric modulation is an alternative method for selectively stimulating GPCRs without the undesirable properties of orthosteric ligands (Conn et al, Nat Rev 2009, 8, 41-54; Wang et al, J. Pharmacol. Exp. Ther. 2009, 331, 340-348). Allosteric modulators are predominantly effective when they bind to the receptor at a site different from the binding site of endogenous (orthosteric) ligands, and when the agonist also binds to the receptor. This has consequences for the temporal and spatial patterns of potency that subsequently affect the behavioral and adaptive responses that organisms give to allosteric stimulation. In contrast to orthosteric agonism, allosteric modulation of a target is expected to show fewer side effects, desensitization, and the development of tolerance. In fact, GABA B Regarding the receptor-positive allosteric modulator GS39783, preclinical models have shown that this compound may have a favorable side effect profile (Cryan et al, J. Pharmacol. Exp. Ther. 2004, 310, 952~963), that receptor desensitization may be prevented (Gjoni and Urwyler, Neuropharmacology 2008, 55: 1293~1299), and that tolerance may not develop with chronic administration (Mombereau et al, Neuropsychopharmacology 2004, 29, 1050~1062). These results are related to GABA. B This suggests that positive allosteric modulators of receptors may be useful novel chemical substances that do not possess the undesirable properties of orthosteric ligands such as baclofen.

[0008] Several patents and patent applications describe positive allosteric GABA with different chemical structures. B The modulator is listed. GABA B Pyrimidine derivatives as positive allosteric modulators of receptors are disclosed in WO2005 / 094828 and WO2006 / 136442. GABAB Thieno[3,2-b]pyrimidine and [1,3]thiazolo[5,4-d]pyrimidine derivatives as positive allosteric modulators of receptors are disclosed in WO2015 / 056771 (US2015 / 0111876). Pyrazolo[1,5-a]pyrimidine derivatives are disclosed in US2016 / 0304527A1.

[0009] In WO2017069270, Taisho Pharmaceutical Co., Ltd. stated that GABA B Pyrazolo[1,5-a]pyrimidine and pyrazolo[1,5-a][1,3,5]triazine derivatives were described as positive allosteric modulators in receptors. In most of the examples, the R1 substituent is attached to the core via a carbon-nitrogen bond. [ka]

[0010] Two recent patent applications by Richter Gedeon Nyrt (WO2018167629 and WO2018167630) describe GABA B This document describes pyrazolopyrimidines having positive allosteric activity in receptors. These examples are carboxylic acids, and the heterocycle is connected to the pyrazolo[1,5-a]pyrimidine core via a nitrogen atom. [ka]

[0011] The objective of the present invention is GABA BThe objective is to provide further compounds with high affinity for the receptor. Unexpectedly, the inventors have found in the present invention that compounds in which the central aromatic biring at position 7 is connected via a carbon atom to an optionally substituted six-membered saturated heterocyclic ring containing one or two heteroatoms selected from N, O, or S exhibit nanomolar efficacy. Neither WO2018167629, WO2018167630, nor WO2017069270 suggest undertaking such structural modifications to obtain a compound of formula (I).

[0012] The structurally closest compounds disclosed in WO2017069270 by Taisho Pharmaceutical Co., Ltd. are Examples A148, A225, B14, B23, B30, B31, and B35. This patent suggests that a sufficiently active compound has a carbon-nitrogen bond between the core and the R1 substituent, or, in the case of a carbon-carbon bond, the core requires an additional nitrogen atom at the X position. These compounds (Examples A148, A225, B14, B23, B30, B31, and B35) are less active compounds.

[0013] Those skilled in the art did not anticipate that the substitutions present on the pyrazolo[1,5-a]pyrimidine core would maintain excellent pharmaceutically active properties.

[0014] The in vitro benefits described above are further enhanced by the unexpected finding that certain embodiments of the present invention demonstrated superior behavioral benefits in a prenatal valproate disease model that replicates the core symptoms of autism spectrum disorder. Thus, we have demonstrated that the compounds of the present invention have therapeutic potential for the core symptoms of autism spectrum disorder in humans. [Overview of the project]

[0015] This invention discloses heterocyclic derivatives having a carbocyclic-pyrazolopyrimidine skeleton. The inventors have found that these compounds generally exhibit effectiveness at nanomolar concentrations.

[0016] The inventors of this invention have identified GABA B GABA plays a unique role in the treatment of mental, neurodevelopmental, neurological, and other central nervous system disorders and peripheral conditions where receptor stimulation can provide therapeutic benefits. B We identified a class of pyrazolo[1,5-a]pyrimidine derivatives that exhibit high affinity for receptors.

[0017] The inventors have identified a novel compound that acts as a brain permeator. This invention relates to GABA B This invention relates to a compound that is a receptor-positive allosteric modulator and its synthesis. The compound of the present invention is a GABA B Receptor stimulation is useful for treating psychiatric, neurodevelopmental, neurological, and other central nervous system disorders as well as peripheral conditions, where therapeutic benefits can be provided.

[0018] The present invention relates to a pyrazolo[1,5-a]pyrimidine derivative of formula (I). [ka] or relating to pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemic compounds, enantiomers, diastereomers, solvates and hydrates thereof, in formula (I), R 1 This represents a phenyl- or cyclohexyl group substituted with a C1-C6 alkyl group or a halo-C1-C6 alkyl group; R 2 This indicates H or halogen; R 3 This represents H or C1-C6 alkyl; R 4 This indicates H;C1~C6 alkyl or halo-C1~C6 alkyl; R 5 and R 6Each of these can independently be H;C1-C6 alkyl or halogen; R 7 and R 8 Each of these can independently be H or a C1-C6 alkyl group; R 9 and R 10 Each of these can independently be H or C1-C6 alkyl, or R 9 and R 10 They can combine to form an oxo group; X is -CR x R y or -O- or -S(O) n - Indicates a group, in the formula, R x and R y Each of these can independently be H or a C1-C6 alkyl group, and n is 0, 1, or 2; Z represents a -NR-; or -O-; or -S(O)2- group. Here, R is either H or -C(O)R 11 Alternatively, -S(O)2R 12 Groups; aminocarbonyl-C1~C3 alkyl; carboxy-C1~C3 alkyl; cyano-C1~C3 alkyl; C1~C5 (cyclo)alkyl; saturated 4-6 membered heterocyclic rings with one oxygen atom, or -C(NH)(NH2) groups; Here, R 11 This can be H;C1~C3alkyl;C1~C3alkoxy;C1~C3alkoxy-C1~C3alkyl;C1~C3alkoxy-C1~C3alkoxy;methanesulfonyl-C1~C3alkyl;or R 11 This can be a saturated 3-6 membered carbocyclic ring, or a 4-6 membered saturated or unsaturated heterocyclic ring having 1-3 heteroatoms selected from N, O, or S; or an amino, monoalkylamino, or dialkylamino group; an amino-C1-C3 alkyl; or a hydroxy-C1-C3 alkyl substituted with an NH2- group; R 12 This can be a C1-C3 alkyl; amino or dialkylamino group; R 4 and CR x It can form a cycloalkyl ring.

[0019] The present invention also relates to pharmaceutical compositions containing compounds of formula (I) or pharmaceutically acceptable salts thereof, biologically active metabolites, prodrugs, racemic compounds, enantiomers, diastereomers, solvates, and hydrates.

[0020] Furthermore, the present invention relates to the synthesis of compounds of formula (I) and their optical counterparts or racemic compounds and / or salts, pharmaceutical compositions containing the same, and the chemical and pharmaceutical production of pharmaceuticals containing these compounds, as well as GABA B The present invention relates to a method of treatment using these compounds, meaning administering an effective amount of the compounds of formula (I) of the present invention, as well as their optical counterparts or racemic compounds and / or salts, either as is or as a pharmacopoeia, to a mammal to be treated—including humans—suffering from mental, neurodevelopmental, neurological, and other central nervous system disorders and peripheral conditions in which stimulation of receptors may provide therapeutic benefits. [Modes for carrying out the invention]

[0021] The present invention relates to a pyrazolo[1,5-a]pyrimidine derivative of formula (I). [ka] or relating to pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemic compounds, enantiomers, diastereomers, solvates and hydrates thereof, in formula (I), R 1 This represents a phenyl- or cyclohexyl group substituted with a C1-C6 alkyl group or a halo-C1-C6 alkyl group; R 2 This indicates H or halogen; R 3 This represents H or C1-C6 alkyl; R 4 This indicates H;C1~C6 alkyl or halo-C1~C6 alkyl; R 5 and R 6Each of these can independently be H;C1-C6 alkyl or halogen; R 7 and R 8 Each of these can independently be H or a C1-C6 alkyl group; R 9 and R 10 Each of these can independently be H or C1-C6 alkyl, or R 9 and R 10 They can combine to form an oxo group; X is -CR x R y or -O- or -S(O) n - Indicates a group, in the formula, R x and R y Each of these can independently be H or a C1-C6 alkyl group, and n is 0, 1, or 2; Z represents a -NR-; or -O-; or -S(O)2- group, in the formula, R is either H or -C(O)R 11 Alternatively, -S(O)2R 12 Groups; aminocarbonyl-C1~C3 alkyl; carboxy-C1~C3 alkyl; cyano-C1~C3 alkyl; C1~C5 (cyclo)alkyl; saturated 4-6 membered heterocyclic rings with one oxygen atom, or -C(NH)(NH2) groups; Here, R 11 This can be H;C1~C3alkyl;C1~C3alkoxy;deutero-C1~C3alkoxy;C1~C3alkoxy-C1~C3alkyl;C1~C3alkoxy-C1~C3alkoxy;methanesulfonyl-C1~C3alkyl;or R 11 This can be a saturated 3-6 membered carbocyclic ring, or a 4-6 membered saturated or unsaturated heterocyclic ring having 1-3 heteroatoms selected from N, O, or S; or an amino, monoalkylamino, or dialkylamino group; an amino-C1-C3 alkyl; or a hydroxy-C1-C3 alkyl substituted with an NH2- group; R 12 This can be a C1-C3 alkyl; amino or dialkylamino group; R 4 and CR xIt can form a cycloalkyl ring.

[0022] The terms "halogen" or "halo," as used herein, refer to chlorine, bromine, fluorine, and iodine, either alone or as part of another group.

[0023] The term "C1-C6 alkyl" as used herein refers to a branched or linear alkyl group containing 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, n-propyl, and isopropyl groups, as well as different butyl groups.

[0024] The term "C1-C6 alkoxy," as used herein, refers to a branched or linear alkyl group containing 1 to 6 carbon atoms bonded via an oxygen atom, including but not limited to methoxy, ethoxy, n-propoxy, i-propoxy, and t-butoxy.

[0025] As used herein, the term “mammal” refers to any member of the class “mammal,” which includes but is not limited to humans.

[0026] The term "salt" refers to a non-toxic base-loaded salt of the compound of the present invention, which is generally prepared by reacting an acid with a suitable organic or inorganic base.

[0027] The scope of the present invention includes all stereoisomers, geometric isomers, and tautomers of compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more of these.

[0028] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from pure precursors under appropriate optics, or decomposition of racemic compounds (or racemic compounds of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC).

[0029] The term "pharmaceutically acceptable" describes an ingredient that is useful in preparing a pharmaceutical composition, is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes those acceptable for veterinary and human medicinal use.

[0030] The term "pharmaceutical composition" refers to a mixture of the compound of the present invention with other chemical components, such as pharmaceutically acceptable auxiliary materials, such as diluents or carriers. The pharmaceutical composition facilitates the administration of the compound to a subject.

[0031] The term "excipient" refers to a chemical compound that facilitates the uptake of a compound into cells or tissues.

[0032] As used herein, the term “treatment” refers to GABA B This means using effective therapies to reduce, alleviate, or eliminate symptoms associated with diseases and conditions mediated and modulated by receptor-positive allosteric mechanisms.

[0033] In a further aspect of the present invention, the synthesis of a compound of formula (I) is provided.

[0034] The compounds according to the present invention were synthesized according to the synthetic route and scheme described below.

[0035] Therefore, the compound of formula (I) of the present invention can be synthesized by one of the following routes:

[0036] R 9 =R 10 =H;X=O and Z=NR , [ka]

[0037] R 4 If it is not H, [ka]

[0038] Route a):

Chem.

[0039] Route b):

Chem.

[0040] R 4 =R 6 =R 8 =R 10 =H; X = CR x R y ; R y =H and Z = NR,

Chem.

[0041] R 4 =H; X = CR x R y and Z = NR,

Chem.

[0042] Z = NR and X is not -S(O) n -,

Chem.

[0043] Route c)

Chem.

[0044] Route d)

Chem.

[0045] When Z = O or -S(O)2-

Chem.

[0046] When X = S(O)2 and Z = NR

Chem.

[0050] The resulting morpholine derivative of formula (IV) is then reacted with hydrogen and then with di-tert-butyl dicarbonate to provide the compound of formula (V). [ka]

[0051] The resulting morpholine derivative of formula (V) is oxidized to obtain the carboxylic acid derivative of formula (VI). [ka] I'll do that.

[0052] R 4 If it is not H , Route a): Carboxylic acid ester derivative of formula (VII) [ka] (In the formula, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 The meanings of X and Z are as described above for the compound of formula (I), and the alkyl halide of formula (IX). R 4 X (IX) (In the formula, R 4 The meaning is as described above for the compound of formula (I), which is to react with it.

[0053] The complex algebra of equation (X) obtained in this way [ka] Hydrolysis of this provides a carboxylic acid derivative of formula (VII). [ka]

[0054] Route b): Carboxylic acid ester derivative of formula (VII) [ka] (In the formula, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 The compounds X and Z (whose meanings are as described above for the compound of formula (I)) are reacted with formaldehyde.

[0055] The hydroxymethyl derivative of formula (XI) obtained in this way [ka] This is reacted with trifluoromethanesulfonic anhydride to provide the compound of formula (XII). [ka]

[0056] The triflate derivative of formula (XII) obtained in this way is reacted with tetrabutylammonium fluoride to provide the compound of formula (XIII). [ka]

[0057] The fluoromethyl derivative of formula (XIII) obtained in this manner is hydrolyzed to provide the carboxylic acid derivative of formula (VIII).

[0058] R 4 =R 6 =R 8 =R 10 =H;X=CR x R y ;R y If =H and Z=NR, a nicotinic acid derivative of formula (XIV) or a nicotinic acid ester derivative of formula (XV) [ka] (In the formula, R 5 , R 7 , R 9 The meaning of formula (I) is as described above for the compound of formula (I), which is reacted with hydrogen, and then with di-tert-butyl dicarbonate. If the product is a carboxylic acid ester, it is hydrolyzed to provide a piperidine derivative of formula (XVI). [ka]

[0059] R 4 =H;X=CR x R y And if Z=NR , lactam derivative of formula (XVII) [ka] (In the formula, R 4 , R 5 , R 6 , R 7 , R 8 The meaning of (I) is as described above for the compound of formula (I), which is reacted with a reducing agent to provide a piperidine derivative of formula (XVIII). [ka]

[0060] The resulting piperidine derivative of formula (XVIII) is reacted with hydrogen, and then with di-tert-butyl dicarbonate to provide the piperidine derivative of formula (XIX). [ka]

[0061] A piperidine derivative (XX) is provided by hydrolyzing a carboxylic acid ester. [ka]

[0062] Carboxylic acid ester derivative of formula (XXI) or carboxylic acid chloride derivative of formula (XXII) [ka] (In the formula, R 1 The meaning is as described above for the compound of formula (I), and for the acetonitrile derivative of formula (XXIII) [ka] (In the formula, R 2 The meaning is as described above for the compound of formula (I), and then the acylacetonitrile derivative of formula (XXIV) obtained therefrom. [ka] This is reacted with hydrazine hydrate to provide a compound of formula (XXV). [ka]

[0063] Z=NR, and X is S(O). n If not , an aminopyrazole derivative of formula (XXV), c) Acetylacetone derivatives of formula (XXXI) [ka] (In the formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 The meaning is as described above for the compound of formula (I), or d) Alkyne derivatives of formula (XXXIII) [ka] (In the formula, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 The meaning is as described above for the compound of formula (I) (and by reacting it with any of them, a pyrazolo[1,5-a]pyrimidine derivative of formula (XXVI) is provided). [ka]

[0064] The resulting compound is then treated with a strong acid to provide an amine derivative of formula (XXVII). [ka]

[0065] The resulting compound is then treated with an appropriate reagent to provide an example of formula (XXVIII). [ka]

[0066] Route c): Carboxylic acid derivative of formula (XXIX) [ka] (In the formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 The meaning of this is as described above for the compound of formula (I), which is reacted with acetone.

[0067] The acetylacetone derivative of formula (XXX) obtained in this way [ka] This is reacted with a suitable alkyl halide to provide an acetylacetone derivative of formula (XXXI). [ka]

[0068] Route d): Carboxylic acid derivative of formula (XXIX) [ka] (In the formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 The meaning of is as described above for the compound of formula (I), which is reacted with N,O-dimethylamine.

[0069] The winelevamide derivative obtained by formula (XXXII) [ka] This is reacted with 1-propynylmagnesium bromide to provide an alkyne derivative of formula (XXXIII). [ka]

[0070] Z = O or S(O) 2 In that case The aminopyrazole derivative of formula (XXV) is reacted with a suitable acetylacetone derivative or a suitable alkyne derivative to obtain the pyrazolo[1,5-a]pyrimidine derivative of formula (XXXIV). [ka] (In the formula, R 3 , R 4 , R 5 , R6 , R 7 , R 8 , R 9 , R 10 The meanings of X and Z are as described above for the compound of formula (I).

[0071] X=S(O) 2 And if Z=NR , an aminopyrazole derivative of formula (XXV), and an acyl acetate derivative of formula (XXXV) [ka] (In the formula, R 3 The meaning is as described above for the compound of formula (I), which is to react with it.

[0072] The compound of formula (XXXVI) obtained in this way [ka] Chlorination is performed to provide a chloro derivative of formula (XXXVII). [ka]

[0073] The compound thus obtained is a sulfone derivative of compound (XXXVII). [ka] (In the formula, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 The meaning is as described above for the compound of formula (I) (and by reacting it with a compound (XXXIX) to provide a sulfone derivative of compound (XXXIX). [ka]

[0074] The resulting compound is treated with a strong acid to provide an amine derivative of formula (XL). [ka]

[0075] The resulting compound is then treated with an appropriate reagent to provide an example of formula (XLI). [ka]

[0076] R 9 and R 10 However, when they come together to form an oxo group , the chloro derivative of formula (XXXVII) and the heterocycle of formula (XLII) [ka] (In the formula, R 4 , R 5 , R 6 , R 7 , R 8 The meaning of is as described above for the compound of formula (I), and by reacting it with, we provide an example of formula (XLIII). [ka]

[0077] The synthesis of carboxylic acid derivatives of formula (VI) can be carried out by the following method:

[0078] The reaction of the β-amino-alcohol derivative of formula (II) with 4-methoxybenzaldehyde is preferably carried out in a suitable solvent, such as methanol. The reducing agent is preferably NaBH4. The reaction is carried out at a temperature in the range of 0°C to room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is performed. The reaction is quenched by the addition of water. Product (III) is isolated by extraction using a suitable organic solvent.

[0079] Ring closure of the β-amino-alcohol derivative of formula (III) is preferably carried out in a suitable solvent, e.g., toluene, using epichlorohydrin, a suitable Lewis acid, e.g., LiClO4, and a suitable base, e.g., NaOMe in MeOH. The reaction is carried out at a temperature in the range of 0°C to room temperature. The required reaction time is 24 to 48 hours. After the reaction, thin-layer chromatography is performed. The reaction is quenched by the addition of a saturated NH4Cl solution. The crude product is isolated by extraction with a suitable organic solvent. Product (IV) is purified by column chromatography. Column chromatography is carried out in normal phase using Kieselgel 60 as an adsorbent and a different solvent system, e.g., cyclohexane / ethyl acetate.

[0080] The hydrogenation of the morpholine derivative of formula (IV) is preferably carried out in a suitable solvent, e.g., ethanol, in the presence of a suitable catalyst, e.g., palladium carbon, and di-tert-butyl dicarbonate. The reaction is preferably carried out at room temperature, preferably at 5-10 bar. The required reaction time is 24-72 hours. After the reaction, thin-layer chromatography is performed. The crude product is isolated after filtration on a Celite pad. Product (V) is purified by column chromatography. Column chromatography is carried out in normal phase using Kieselgel 60 as an adsorbent and a different solvent system, e.g., cyclohexane / ethyl acetate.

[0081] The oxidation of the morpholine derivative of formula (V) is preferably carried out in a suitable solvent system, such as dichloromethane / water, preferably in the presence of a TEMPO radical and (diacetoxyiodo)benzene. The reaction is carried out at a temperature in the range of 0°C to room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is performed. The crude product is isolated by extraction with a suitable organic solvent. Product (VI) is crystallized from a suitable solvent, preferably hexane.

[0082] The synthesis of the carboxylic acid derivative of formula (VIII) can be carried out by different routes:

[0083] Route a): The reaction of the carboxylic acid ester derivative of formula (VII) with the alkyl halide derivative of formula (IX) is preferably carried out in a suitable solvent, such as tetrahydrofuran, preferably in the presence of a strong base, such as lithium bis(trimethylsilyl)amide. The reaction is carried out at a temperature within the range of -78 °C to room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin layer chromatography is carried out. The reaction is quenched by the addition of a saturated NH4Cl solution. The product (X) is isolated by extraction with a suitable organic solvent.

[0084] The obtained carboxylic acid ester derivative of formula (X) is hydrolyzed in a suitable solvent mixture, such as ethanol / water, in the presence of an alkali, such as sodium hydroxide. The reaction is carried out at a temperature within the range of 0 °C to room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin layer chromatography is carried out. The reaction mixture is acidified to pH = 3 using a suitable acid, such as citric acid. The product (VIII) is isolated by extraction with a suitable organic solvent.

[0085] Route b): The reaction of the carboxylic acid ester derivative of formula (VII) with formaldehyde is preferably carried out in a suitable solvent, such as tetrahydrofuran, preferably in the presence of a strong base, such as lithium bis(trimethylsilyl)amide. The reaction is carried out at a temperature within the range of -78 °C to room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin layer chromatography is carried out. The reaction is quenched by the addition of a saturated NH4Cl solution. The product (XI) is isolated by extraction with a suitable organic solvent.

[0086] The triflation of the hydroxymethyl derivative of formula (XI) with, for example, trifluoromethanesulfonic anhydride is preferably carried out in a suitable solvent, such as dichloromethane, preferably in the presence of a base, such as pyridine. The reaction is carried out at a temperature within the range of -78 °C to room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is carried out. The reaction is quenched by the addition of 1M HCl solution. The product (XII) is isolated by extraction with a suitable organic solvent.

[0087] The fluorination of the triflate derivative of formula (XII) with tetrabutylammonium fluoride is preferably carried out in a suitable solvent, such as tetrahydrofuran. The reaction is preferably carried out at room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is carried out. The reaction is quenched by the addition of water. The crude product is isolated by extraction with a suitable organic solvent. The product (XIII) is purified by column chromatography. The column chromatography is carried out in the normal phase using Kieselgel 60 as the adsorbent and different solvent systems, such as cyclohexane / ethyl acetate.

[0088] The obtained carboxylic acid ester derivative of formula (XIII) is hydrolyzed in a suitable solvent mixture, such as ethanol / water, in the presence of a base, such as sodium hydroxide. The reaction is carried out at a temperature within the range of 0 °C to room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is carried out. The reaction mixture is acidified to pH = 3 using a suitable acid, such as citric acid. The product (VIII) is isolated by extraction with a suitable organic solvent.

[0089] The synthesis of the carboxylic acid derivative of formula (XVI) can be carried out by the following method:

[0090] The reaction of a nicotinic acid derivative of formula (XIV) or a nicotinic acid ester derivative of the formula with hydrogen is preferably carried out in a suitable solvent, e.g., water or alcohol, in the presence of a suitable catalyst, e.g., platinum(IV) oxide. The reaction is preferably carried out at room temperature, preferably at 5-10 bar. The required reaction time is 24-72 hours. After the reaction, thin-layer chromatography is performed. The product is isolated after filtration on a Celite pad. The reaction with di-tert-butyl dicarbonate is preferably carried out in a suitable solvent or solvent system, e.g., tetrahydrofuran with water, and optionally in the presence of a base, e.g., sodium bicarbonate. The product is isolated by extraction using a suitable organic solvent. If the product is a carboxylic acid ester, it is hydrolyzed in a suitable solvent system, e.g., ethanol / water, in the presence of an alkali, e.g., sodium hydroxide. The reaction is carried out at a temperature in the range of 0°C to room temperature. The required reaction time is 1-16 hours. After the reaction, thin-layer chromatography is performed. The reaction mixture is acidified to pH=3 using a suitable acid, such as citric acid. Product (XVI) is isolated by extraction using a suitable organic solvent.

[0091] The synthesis of carboxylic acid derivatives of formula (XX) can be carried out by the following method:

[0092] The reaction of the lactam derivative of formula (XVII) with NaBH4 accompanied by a suitable reducing agent, such as diethyl boron trifluoride, is preferably carried out in a suitable solvent, such as tetrahydrofuran. The reaction is carried out at a temperature in the range of -15°C to room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is performed. The reaction is quenched by the addition of water. The product (XVIII) is isolated by extraction using a suitable organic solvent.

[0093] The hydrogenation of the piperidine derivative of formula (XVIII) is preferably carried out in a suitable solvent, e.g., methanol, in the presence of a suitable catalyst, e.g., palladium carbon, and di-tert-butyl dicarbonate. The reaction is preferably carried out at room temperature, preferably at 5-10 bar. The required reaction time is 24-72 hours. After the reaction, thin-layer chromatography is performed. The crude product is isolated after filtration on a Celite pad. Product (XIX) is purified by column chromatography. Column chromatography is carried out in normal phase using Kieselgel 60 as an adsorbent and a different solvent system, e.g., cyclohexane / ethyl acetate.

[0094] The resulting carboxylic acid ester derivative of formula (XIX) is preferably hydrolyzed in a suitable solvent, such as tetrahydrofuran, in the presence of potassium trimethylsilanolate. The reaction is carried out at reflux temperature. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is performed. The reaction mixture is acidified to pH=4 with a suitable acid, such as citric acid. The product (XX) is isolated by extraction using a suitable organic solvent.

[0095] The synthesis of aminopyrazole derivatives of formula (XXV) can be carried out by the following method:

[0096] The reaction of a carboxylic acid ester derivative of formula (XXI) or a carboxylic acid chloride derivative of formula (XXII) with an acetonitrile derivative of formula (XXIII) is preferably carried out in a suitable solvent, such as tetrahydrofuran, and preferably in the presence of a strong base, such as n-butyllithium or lithium bis(trimethylsilyl)amide. The reaction is carried out at a temperature in the range of -78°C to room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is performed. The reaction mixture is quenched by adding water and hydrochloric acid (pH about 2 to 3) or a saturated ammonium chloride solution. The product acylacetonitrile derivative of formula (XXIV) is isolated by extraction using a suitable organic solvent.

[0097] The cyclocondensation reaction of the aminopyrazole derivative of formula (XXV) with the acylacetonitrile derivative of formula (XXIV) and hydrazine hydrate is preferably carried out in a suitable solvent, such as ethanol. The reaction is preferably carried out at the boiling point of the solvent. The required reaction time is 1 to 6 hours. After the reaction, thin-layer chromatography is performed. The reaction is quenched by the addition of water. The product (XXV) is isolated by extraction using a suitable organic solvent.

[0098] The synthesis of the pyrazolo[1,5-a]pyrimidine derivative of formula (XXVI) can be carried out by the following method:

[0099] Route c): The cyclization condensation reaction of the aminopyrazole derivative of formula (XXV) with the acetylacetone derivative of formula (XXXI) is preferably carried out in a suitable solvent, e.g., toluene, in the presence of a suitable catalyst, e.g., p-toluenesulfonic acid monohydrate. The reaction is preferably carried out at the boiling point of the solvent. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is performed. The product (XXVI) is purified by column chromatography. Column chromatography is carried out in normal phase using Kieselgel 60 as an adsorbent and a different solvent system, e.g., cyclohexane / ethyl acetate.

[0100] Route d): The cyclization condensation reaction of the aminopyrazole derivative of formula (XXV) with the alkyne derivative of formula (XXXIII) is preferably carried out in a suitable solvent, e.g., ethanol, in the presence of a suitable base, e.g., pyrrolidine, and a suitable acid, e.g., acetic acid. The reaction is preferably carried out at 60°C. The required reaction time is 4 to 16 hours. After the reaction, thin-layer chromatography is performed. The product (XXVI) is purified by column chromatography. Column chromatography is carried out in normal phase using Kieselgel 60 as an adsorbent and a different solvent system, e.g., cyclohexane / ethyl acetate.

[0101] The synthesis of the pyrazolo[1,5-a]pyrimidine derivative of formula (XXVIII) can be carried out by the following method:

[0102] The reaction of the pyrazolo[1,5-a]pyrimidine derivative of formula (XXVI) with a strong acid, such as trifluoroacetic acid, is preferably carried out in a suitable solvent, such as dichloromethane. The reaction is carried out at a temperature in the range of 0°C to room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is performed. The reaction mixture is quenched by adding a 2M sodium hydroxide solution (pH approximately 12 to 14). The product pyrazolo[1,5-a]pyrimidine derivative of formula (XXVII) is isolated by extraction using a suitable organic solvent.

[0103] The pyrazolo[1,5-a]pyrimidine derivative of formula (XXVII) can be converted to the pyrazolo[1,5-a]pyrimidine derivative of formula (XXVIII) by the following method:

[0104] In certain embodiments, the reaction of the pyrazolo[1,5-a]pyrimidine derivative of formula (XXVII) with methyl bromoacetate in the presence of a base, such as N,N-diisopropylethylamine, is preferably carried out in a suitable solvent, such as toluene. The reaction is preferably carried out at room temperature. The required reaction time is 4 to 16 hours. After the reaction, thin-layer chromatography is performed. The reaction is quenched by the addition of water. The crude product is isolated by extraction with a suitable organic solvent. The crude product is purified by column chromatography. Column chromatography is carried out in normal phase using Kieselgel 60 as an adsorbent and a different solvent system, such as acetone / dichloromethane. The product is hydrolyzed in a suitable solvent, such as water, in the presence of hydrochloric acid to provide the pyrazolo[1,5-a]pyrimidine derivative of formula (XXVIII).

[0105] In certain embodiments, the reaction of a pyrazolo[1,5-a]pyrimidine derivative of formula (XXVII) with an N-Boc protected amino acid in the presence of a base, such as N,N-diisopropylethylamine, is carried out using a suitable coupling agent, such as HBTU, in a suitable solvent, such as dimethylformamide. The reaction is preferably carried out at room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin layer chromatography is carried out. The reaction is quenched by the addition of water. The crude product is isolated by extraction with a suitable organic solvent. The product is purified by column chromatography. Column chromatography is carried out in normal phase using Kieselgel 60 as the adsorbent and different solvent systems, such as methanol / dichloromethane. The product is reacted with a strong acid, such as trifluoroacetic acid, in a suitable solvent, such as dichloromethane. The reaction is preferably carried out at 0 °C to room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin layer chromatography is carried out. The product (XXVIII) is purified by column chromatography. Column chromatography is carried out in normal phase using Kieselgel 60 as the adsorbent and different solvent systems, such as methanol / dichloromethane.

[0106] In certain embodiments, the reaction of a pyrazolo[1,5-a]pyrimidine derivative of formula (XXVII) with an acyl chloride in the presence of a base, such as triethylamine, is preferably carried out in a suitable solvent, such as dichloromethane. The reaction is preferably carried out at 0 °C to room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin layer chromatography is carried out. The reaction is quenched by the addition of water. The crude product is isolated by extraction with a suitable organic solvent. The product (XXVIII) is purified by column chromatography. Column chromatography is carried out in normal phase using Kieselgel 60 as the adsorbent and different solvent systems, such as methanol / dichloromethane.

[0107] In certain embodiments, the reaction of the pyrazolo[1,5-a]pyrimidine derivative of formula (XXVII) with formic acid is preferably carried out in a suitable solvent, such as toluene. The reaction is preferably carried out at the boiling point of the solvent. The required reaction time is 4 to 16 hours. After the reaction, thin-layer chromatography is performed. The reaction is quenched by the addition of water. The crude product is isolated by extraction with a suitable organic solvent. Product (XXVIII) is purified by column chromatography. Column chromatography is carried out in normal phase using Kieselgel 60 as an adsorbent and a different solvent system, such as methanol / dichloromethane.

[0108] In certain embodiments, the reaction of a pyrazolo[1,5-a]pyrimidine derivative of formula (XXVII) with a carboxylic acid in the presence of a base, e.g., N,N-diisopropylethylamine, is carried out in a suitable solvent, e.g., dimethylformamide, using a suitable coupling agent, e.g., HBTU. The reaction is preferably carried out at room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is performed. The reaction is quenched by the addition of water. The crude product is isolated by extraction with a suitable organic solvent. Product (XXVIII) is purified by column chromatography. Column chromatography is carried out in normal phase using Kieselgel 60 as an adsorbent and a different solvent system, e.g., methanol / dichloromethane.

[0109] In certain embodiments, the reaction of a pyrazolo[1,5-a]pyrimidine derivative of formula (XXVII) with 1-amidinopyrazole hydrochloride in the presence of a base, such as N,N-diisopropylethylamine, is preferably carried out in a suitable solvent, such as dimethylformamide. The reaction is preferably carried out at room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is performed. The product (XXVIII) is isolated by filtration.

[0110] In certain embodiments, the reaction of a pyrazolo[1,5-a]pyrimidine derivative of formula (XXVII) with a suitable aldehyde or ketone in the presence of a reducing agent, e.g., sodium triacetoxyborohydride, or acetic acid, is preferably carried out in a suitable solvent, e.g., 1,2-dichloroethane. The reaction is preferably carried out at room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is performed. The reaction is quenched by the addition of water. The crude product is isolated by extraction with a suitable organic solvent. Product (XXVIII) is purified by column chromatography. Column chromatography is carried out in normal phase using Kieselgel 60 as an adsorbent and a different solvent system, e.g., methanol / dichloromethane.

[0111] In certain embodiments, the reaction of the pyrazolo[1,5-a]pyrimidine derivative of formula (XXVII) with trimethylsilyl isocyanate is preferably carried out in a suitable solvent, such as dichloromethane. The reaction is preferably carried out at room temperature. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is performed. The reaction is quenched by the addition of water. The crude product is isolated by extraction with a suitable organic solvent. Product (XXVIII) is purified by column chromatography. Column chromatography is carried out in normal phase using Kieselgel 60 as an adsorbent and a different solvent system, such as methanol / dichloromethane.

[0112] In certain embodiments, the reaction of the pyrazolo[1,5-a]pyrimidine derivative of formula (XXVII) with a sulfamide is preferably carried out in a suitable solvent, such as dioxane. The reaction is preferably carried out at the boiling point of the solvent. The required reaction time is 1 to 16 hours. After the reaction, thin-layer chromatography is performed. The reaction is quenched by the addition of water. The crude product is isolated by extraction with a suitable organic solvent. Product (XXVIII) is purified by column chromatography. Column chromatography is carried out in normal phase using Kieselgel 60 as an adsorbent and a different solvent system, such as methanol / dichloromethane.

[0113] The compounds of the present invention, as well as their optical counterparts or racemic compounds and / or salts, can be used as is or appropriately in the form of pharmaceutical compositions.

[0114] This invention relates to GABA B The present invention also relates to a pharmaceutical composition containing a compound of formula (I) or its optical counterpart or racemic compound and / or salt as an active ingredient for the treatment of certain disorders related to receptor positive allosteric modulator activity.

[0115] The compounds of the present invention can be co-administered to a subject in combination with two or more different therapeutic agents (for example, most preferably antipsychotics and psychostimulants; and also preferably antidepressants, anxiolytics, antihypertensives, anticonvulsants, sedatives, and narcotics).

[0116] Appropriate routes of administration may include, for example, oral, rectal, transmucosal, transdermal, or intra-intestinal administration; intramuscular, subcutaneous, intravenous, intrathecal injection; and parenteral delivery including intra-articular, intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injection and eye drops.

[0117] Alternatively, the compound can be administered locally rather than systemically, for example, by direct injection of the compound into the renal or cardiac region, often in depot or sustained-release formulations. Furthermore, the drug can be administered via a targeted drug delivery system, for example, by liposomes coated with tissue-specific antibodies. The liposomes are selectively targeted to organs and taken up by those organs.

[0118] Pharmaceutical compositions can be administered via various routes and forms of dosing. The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers, either as a single dose or in multiple doses. The dosage required to exert a therapeutic effect can vary within a broad range and be adapted to the individual requirements in each particular case, depending on the stage, condition, and weight of the patient being treated, as well as the patient's sensitivity to the active ingredient, the route of administration, and the number of daily treatments.

[0119] For simple administration, the pharmaceutical composition may contain a dosing unit containing the amount of the active ingredient to be administered in a single dose, or several times that amount, or half, a third, or a quarter of that amount. Such dosing units are, for example, tablets that can be powdered with grooves to facilitate the division of the tablet in half or into quarters in order to administer the required amount of the active ingredient.

[0120] Pharmaceutical compositions containing the active ingredient according to the present invention typically contain 0.01 to 500 mg of the active ingredient in a single dosing unit. Of course, in some compositions, the amount of the active ingredient may exceed the upper or lower limits specified above.

[0121] A further aspect of the present invention provides a method for the pharmaceutically manufacturing of a pharmaceutical product containing a compound of formula (I), or an optical counterpart thereof, or a racemic compound and / or a salt thereof.

[0122] The pharmaceutical compositions of the present invention can be formulated as various pharmaceutical forms of administration, such as solid oral forms, e.g., tablets (e.g., buccal, sublingual, effervescent, chewable, orally disintegrating, lyophilized), capsules, lozenges, troches, pills, orally disintegrating films, granules, powders; liquid oral forms, e.g., solutions, emulsions, suspensions, syrups, elixirs, oral drops; parenteral forms, e.g., intravenous injection, intramuscular injection, subcutaneous injection; and other forms of administration, such as eye drops, semi-solid eye preparations, transdermal forms, suppositories, rectal capsules, rectal solutions, emulsions, and suspensions, but are not limited to these.

[0123] In one embodiment, the present invention relates to pharmaceutical dosage forms specifically intended for pediatric use, such as solutions, syrups, elixirs, suspensions, powders for reconstitution as suspensions, dispersible or effervescent tablets, chewable tablets, orally disintegrating tablets, tablets or coated tablets, granular oral powders or granules, and capsules.

[0124] The pharmaceutical compositions of the present invention can be manufactured in a manner known to the present, for example, by conventional processes such as mixing, dissolving, emulsifying, suspending, encapsulating, freeze-drying, extruding, laminating, film forming, granulation, grinding, encapsulating, sugar coating, or tableting.

[0125] Accordingly, pharmaceutical compositions for use according to the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. Any of the well-known techniques, carriers, and excipients can be used as understood and required in the art.

[0126] Suitable excipients for preparing drug formulations may be selected from categories including, but are not limited to, tablet and capsule fillers, tablet and capsule binders, modified release agents, disintegrants, flow enhancers, lubricants, sweeteners, taste maskers, flavoring agents, coating agents, surfactants, antioxidants, buffers, complexing agents, emulsifiers, lyophilization aids, microencapsulating agents, ointment bases, permeability enhancers, solubilizers, solvents, suppository bases, and suspending agents.

[0127] In one embodiment, the present invention relates to the use of specific excipients that can improve the solubility, dissolution, permeation, adsorption, or bioavailability of active ingredients(s), including but not limited to hydrophilic polymers, hot-melt extrusion excipients, surfactants, buffers, complexing agents, emulsifiers, freeze-drying aids, superdisintegrants, microencapsulating agents, permeation enhancers, solubilizers, cosolvents, and suspending agents.

[0128] The above-mentioned ingredients and different manufacturing routes are merely representative. Other materials and processing techniques well known in the field may also be used.

[0129] These compounds are GABA B Receptor stimulation is effective in treating mental, neurodevelopmental, neurological, and other central nervous system disorders as well as peripheral conditions where therapeutic benefits can be provided.

[0130] Biological evaluation in vitro in rat cortical membrane [ 35 S]GTPγS binding assay Freshly recovered rat brain cortices were dissected on an ice-cold surface and immediately homogenized in ice-cold buffer (pH=7.6) containing 50 mM Tris, 5 mM MgCl2, and 1 mM EDTA using a glass Dounce homogenizer. The tissue homogenates were centrifuged at 40,000 g for 15 minutes at 4°C. The membrane pellets were resuspended in the same buffer, and the membranes were incubated in a shaking water bath at 30°C for 10 minutes to eliminate endogenous GABA. The homogenates were centrifuged again under the same conditions. The final pellets were resuspended in ice-cold buffer (pH=7.6) containing 50 mM Tris, 100 mM NaCl, 7 mM MgCl2, 1 mM EDTA, and 1 mM dithiotreithol (DTT) to a concentration of 20 mg tissue weight / ml, and frozen at -70°C until use. The assay was performed in a buffer containing 50 mM Tris (pH=7.4), 100 mM NaCl, 7 mM MgCl2, 1 mM EDTA, and 1 mM DTT. Each assay tube contained 150 μL GDP (final concentration 50 μM), 100 μL ligand, and 125 μL membrane suspension (250 μg tissue / tube). Assay tubes were incubated at 30°C for 10 minutes to ensure equilibrium. Nonspecific binding was determined in the presence of 10 μM GTPγS; basal binding was determined in the presence of buffer alone. 50 pM [25 μL volume] was added to the tubes. 35 After adding [S]GTPγS, the membrane was incubated at 30°C for a further 60 minutes. The assay was terminated by rapid filtration through a Packard UniFilter GF / B using a Packard harvester and washed four times with 1 ml ice-cold buffer. After drying the filter at 40°C for 1 hour, 40 μL of Microscint (Packard) was added to the filter, and the radioactivity of the filter was determined by TopCount NXT (PerkinElmer, Waltham, MA; Alper and Nelson, Eur.J.Pharmacol. 1998, 343, 303~312; Rinken et al, Biochem.Pharmacol. 1999, 57, 155~162). Using the data thus collected, PAM EC for each compound was determined. 50The value was determined to be the primary in vitro activity endpoint.

[0131] Table 1 contains, 35 The compounds of the present invention, as measured by the [S]GTPγS binding assay, are listed below.

[0132] [Table 1-1]

[0133] [Table 1-2]

[0134] Foot shock-induced ultrasonic vocalization (USV) in adult rats Under stressful conditions, adult rats emit 22 kHz ultrasound, which can be reduced by various pharmacological treatments (De Vry et al, Eur.J.Pharmacol. 1993, 249, 331~339; Sanchez, Eur.J.Pharmacol. 2003, 463, 133~143). Previous unpublished experiments have shown that GABA B It has been shown that receptor ligands can also inhibit vocalizations induced by electrical foot shock as a stressor. Therefore, using the foot shock-induced vocalization paradigm in adult rats, centrally acting GABA BThe in vivo efficacy of receptor ligands was evaluated. Behavioral measurements were performed on male Wistar rats (200–250 g, Toxicoop, Hungary, or Janvier, France). The rats were housed in groups of four in plastic cages with wire mesh toppings in a temperature and light controlled laboratory animal care unit (22±2°C, 12-hour light / dark cycle, lights turned on at 6:00 AM) with free access to commercially available pellet rat food and tap water. The study was approved by the Local Ethical Committee of Gedeon Richter Plc. and conducted in strict compliance with European Directive 2010 / 63 / EU on the care and use of laboratory animals for experimental procedures, with all efforts made to minimize the number of animals and their suffering. To induce ultrasound generation, animals were subjected to foot shocks (6 shocks, 1 second each, 0.8 mA, 10-second intervals between shocks) after a 30-second acclimatization period in a soundproof shocking chamber (Experimetria, 40 × 40 × 80 cm). The compounds under investigation were orally administered at a dose of 10 mg / kg in a solid dispersion or Tween 80 suspension in distilled water one hour prior to administering the shocks. Vocalizations were measured for 10 minutes immediately after the last foot shock using a Metris Sonotrack system, and the total number of vocalizations was recorded. Vocalizations in animals treated with parallel vehicles were considered as a control, and the inhibition percentage was calculated for each compound.

[0135] Table 2 lists the compounds of the present invention as measured by the USV assay.

[0136] [Table 2]

[0137] Prenatal Valproate Model of Autism Spectrum Disorder (ASD) The prenatal valproate model has excellent composition and face validity and is therefore a widely accepted disease model for ASD (Christensen et al, JAMA 2013, 309, 1696-1703; Roullet et al, Neurotox.Teratol. 2013, 36, 45-56). In this method, time-mating female Wistar rats (Harlan UK) were administered a single dose of valproic acid (VPA, 600 mg / kg, ip) on day 12.5 of gestation. Male offspring were housed under standard laboratory conditions until the time of testing, 59 days after birth. The animals were housed in groups of four in conventional cages, with free access to food and water, and maintained at 22-24°C with a standard 12-hour light / dark cycle (07:30-19:30). After investigational drug treatment, offspring were behaviorally tested in a social preference assay 59 days after birth. The social preference assay is a well-established assay for evaluating autistic behaviors in rodents (Nadler et al, Genes Brain Behav. 2007, 3, 303-314; Bambini-Junior et al, Brain Res. 2011, 1408, 8-16). Briefly, this assay involves test animals investigating regions of the same species, or similar regions without target same species, separated by perforated septa. Autistic animals (e.g., rats exposed to valproate prenatally) spend very little time on social investigations during the study period.

[0138] The inventors unexpectedly found that embodiments of the present invention yielded significant behavioral benefits in a preclinical disease model of the present invention that reproduced the core symptoms of ASD. Therefore, the inventors demonstrated that these compounds may have therapeutic potential for the core symptoms of ASD in humans. [Examples]

[0139] The present invention is further defined in the following embodiments. It should be understood that the embodiments are provided for illustrative purposes only. From the above discussion and embodiments, those skilled in the art can determine the essential features of the invention and make various changes and modifications to adapt the invention to various uses and conditions without departing from its spirit and scope. As a result, the invention is not limited by the exemplary embodiments shown herein below, but is defined by the claims appended herein.

[0140] Generally, compounds of formula (I) can be prepared according to the general knowledge of those skilled in the art and / or by the methods shown in the following Examples and / or Intermediates sections. Solvents, temperatures, pressures, and other reaction conditions can be readily selected by those skilled in the art. Starting materials are commercially available and / or readily prepared by those skilled in the art.

[0141] The present invention is illustrated herein by the following non-limiting embodiments.

[0142] Intermediate 1 [ka] (2S,5R)-4-[(tert-butoxy)carbonyl]-5-methylmorpholine-2-carboxylic acid a) (2R)-2-{[(4-methoxyphenyl)methyl]amino}propan-1-ol Under nitrogen, 10.3 g (75.9 mmol) 4-methoxybenzaldehyde was added to a solution of 6.00 g (80 mmol) (R)-2-amino-1-propanol in 60 ml of methanol. After the addition, the mixture was stirred at RT for 3 hours, and then 3.02 g (80 mmol) NaBH4 was added in installments at 0°C. The resulting mixture was warmed to RT and stirred at this temperature for 18 hours.

[0143] The reaction mixture was quenched at 0°C by the slow addition of 70 ml of distilled water. Methanol was evaporated, and the resulting mixture was extracted with dichloromethane. The combined organic layers were washed with distilled water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 13.77 g (88%) of the title compound. GC-MS(EI) m / z 196.2[MH] + ]

[0144] b) [(2S,5R)-4-[(4-methoxyphenyl)methyl]-5-methylmorpholine-2-yl]methanol The (2R)-2-{[(4-methoxyphenyl)methyl]amino}propan-1-ol obtained above was suspended in 100 ml of toluene, and 3.98 g (43 mmol)(R)-epichlorohydrin was added, followed by 4.58 g (43 mmol)LiClO4. The reaction mixture was stirred in RT for 18 hours, and then 30 ml of sodium methoxide solution (25 wt% in CH3OH) was added. The reaction mixture was stirred in RT for 18 hours. 100 ml of saturated aqueous solution NH4Cl was added, followed by 30 ml of distilled water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with 0-100% ethyl acetate in cyclohexane to obtain 4.01 g (52%) of the title compound. GC-MS(EI) m / z 252.2[MH] + ]

[0145] c) (2S,5R)-2-(hydroxymethyl)-5-methylmorpholine-4-carboxylate tert-butyl The [(2S,5R)-4-[(4-methoxyphenyl)methyl]-5-methylmorpholine-2-yl]methanol obtained above was dissolved in 100 ml of ethanol and hydrogenated at 10 bar for 2 days at RT in the presence of 500 mg 10% Pd / C and 5.22 g (23.9 mmol) BOC2O. The reaction mixture was filtered through Celite, concentrated under vacuum, and purified by silica gel chromatography by elution with 0-100% ethyl acetate in cyclohexane to obtain 1.55 g (42%) of the title compound. GC-MS(EI) m / z 232.2 [MH] + ]

[0146] d) (2S,5R)-4-[(tert-butoxy)carbonyl]-5-methylmorpholine-2-carboxylic acid The (2S,5R)-2-(hydroxymethyl)-5-methylmorpholine-4-carboxylate tert-butyl obtained above was dissolved in 50 ml of dichloromethane and 25 ml of distilled water. 210 mg (1.34 mmol) TEMPO and 4.97 g (15.4 mmol) (diacetoxyiodo)benzene were added to the reaction mixture at 0°C. The resulting mixture was heated to RT and stirred at this temperature for 18 hours. The reaction was quenched by the addition of 10 ml of methanol. The mixture was extracted with dichloromethane. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was pulverized with hexane and filtered to obtain 1.02 g (62%) of the title compound. GC-MS(EI) m / z 246.1[MH] + ]

[0147] Intermediate 2 [ka] (2R,5R)-4-[(tert-butoxy)carbonyl]-5-methylmorpholine-2-carboxylic acid a) [(2R,5R)-4-[(4-methoxyphenyl)methyl]-5-methylmorpholine-2-yl]methanol The title compound is prepared from (2R)-2-{[(4-methoxyphenyl)methyl]amino}propan-1-ol and (S)-epichlorohydrin according to the method described in intermediate 1b.

[0148] b) (2R,5R)-2-(hydroxymethyl)-5-methylmorpholine-4-carboxylate tert-butyl The title compound is prepared from [(2R,5R)-4-[(4-methoxyphenyl)methyl]-5-methylmorpholine-2-yl]methanol according to the method described in intermediate 1c.

[0149] c) (2R,5R)-4-[(tert-butoxy)carbonyl]-5-methylmorpholine-2-carboxylic acid The title compound is prepared from (2R,5R)-2-(hydroxymethyl)-5-methylmorpholine-4-carboxylate tert-butyl according to the method described in intermediate 1d.

[0150] Intermediate 3 [ka] (2R,5S)-4-[(tert-butoxy)carbonyl]-5-methylmorpholine-2-carboxylic acid a) (2S)-2-{[(4-methoxyphenyl)methyl]amino}propan-1-ol The title compound is prepared from (S)-2-amino-1-propanol according to the method described in intermediate 1a.

[0151] b) [(2R,5S)-4-[(4-methoxyphenyl)methyl]-5-methylmorpholine-2-yl]methanol The title compound is prepared from (2S)-2-{[(4-methoxyphenyl)methyl]amino}propan-1-ol and (S)-epichlorohydrin according to the method described in intermediate 1b.

[0152] c) (2R,5S)-2-(hydroxymethyl)-5-methylmorpholine-4-carboxylate tert-butyl The title compound is prepared from tert-butyl[(2R,5S)-4-[(4-methoxyphenyl)methyl]-5-methylmorpholine-2-yl]methanol according to the method described in intermediate 1c.

[0153] d) (2R,5S)-4-[(tert-butoxy)carbonyl]-5-methylmorpholine-2-carboxylic acid The title compound is prepared from (2R,5S)-2-(hydroxymethyl)-5-methylmorpholine-4-carboxylate tert-butyl according to the method described in intermediate 1d.

[0154] Intermediate 4 [ka] (2S,5S)-4-[(tert-butoxy)carbonyl]-5-methylmorpholine-2-carboxylic acid a) [(2S,5S)-4-[(4-methoxyphenyl)methyl]-5-methylmorpholine-2-yl]methanol The title compound is prepared from (2S)-2-{[(4-methoxyphenyl)methyl]amino}propan-1-ol and (R)-epichlorohydrin according to the method described in intermediate 1b.

[0155] b) (2S,5S)-2-(hydroxymethyl)-5-methylmorpholine-4-carboxylate tert-butyl The title compound is prepared from [(2S,5S)-4-[(4-methoxyphenyl)methyl]-5-methylmorpholine-2-yl]methanol according to the method described in intermediate 1c.

[0156] c) (2R,5R)-4-[(tert-butoxy)carbonyl]-5-methylmorpholine-2-carboxylic acid The title compound is prepared from (2S,5S)-2-(hydroxymethyl)-5-methylmorpholine-4-carboxylate tert-butyl according to the method described in intermediate 1d.

[0157] Intermediate 5 [ka] (2S)-4-[(tert-butoxy)carbonyl]-5,5-dimethylmorpholine-2-carboxylic acid a) 2-(benzylamino)-2-methylpropane-1-ol The title compound is prepared from 2-amino-2-methylpropan-1-ol according to the method described in intermediate 1a.

[0158] b) [(2S)-4-benzyl-5,5-dimethylmorpholine-2-yl]methanol The title compound is prepared from 2-(benzylamino)-2-methylpropan-1-ol and (R)-epichlorohydrin according to the method described in intermediate 1b.

[0159] c) (2S)-2-(hydroxymethyl)-5,5-dimethylmorpholine-4-carboxylate tert-butyl The title compound is prepared from tert-butyl[(2S)-4-benzyl-5,5-dimethylmorpholine-2-yl]methanol according to the method described in intermediate 1c.

[0160] e) (2S)-4-[(tert-butoxy)carbonyl]-5,5-dimethylmorpholine-2-carboxylic acid The title compound is prepared from (2S)-2-(hydroxymethyl)-5,5-dimethylmorpholine-4-carboxylate tert-butyl according to the method described in intermediate 1d.

[0161] Intermediate 6 [ka] (2R)-4-[(tert-butoxy)carbonyl]-5,5-dimethylmorpholine-2-carboxylic acid a) [(2R)-4-benzyl-5,5-dimethylmorpholine-2-yl]methanol The title compound is prepared from 2-(benzylamino)-2-methylpropan-1-ol and (S)-epichlorohydrin according to the method described in intermediate 1b.

[0162] b) (2R)-2-(hydroxymethyl)-5,5-dimethylmorpholine-4-carboxylate tert-butyl The title compound is prepared from tert-butyl[(2R)-4-benzyl-5,5-dimethylmorpholine-2-yl]methanol according to the method described in intermediate 1c.

[0163] c) (2R)-4-[(tert-butoxy)carbonyl]-5,5-dimethylmorpholine-2-carboxylic acid The title compound is prepared from (2R)-2-(hydroxymethyl)-5,5-dimethylmorpholine-4-carboxylate tert-butyl according to the method described in intermediate 1d.

[0164] Intermediate 7 [ka] (2R,6R)-4-[(tert-butoxy)carbonyl]-6-methylmorpholine-2-carboxylic acid a) (2R)-1-{[(4-methoxyphenyl)methyl]amino}propan-2-ol The title compound is prepared from (R)-1-amino-2-propanol according to the method described in intermediate 1a.

[0165] b) [(2R,6R)-4-[(4-methoxyphenyl)methyl]-6-methylmorpholine-2-yl]methanol The title compound is prepared from (2R)-1-{[(4-methoxyphenyl)methyl]amino}propan-2-ol and (S)-epichlorohydrin according to the method described in intermediate 1b.

[0166] c) (2R,6R)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate tert-butyl The title compound is prepared from tert-butyl[(2R,6R)-4-[(4-methoxyphenyl)methyl]-6-methylmorpholine-2-yl]methanol according to the method described in intermediate 1c.

[0167] d) (2R,6R)-4-[(tert-butoxy)carbonyl]-6-methylmorpholine-2-carboxylic acid The title compound is prepared from (2R,6R)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate tert-butyl according to the method described in intermediate 1d.

[0168] Intermediate 8 [ka] (2S,6S)-4-[(tert-butoxy)carbonyl]-6-methylmorpholine-2-carboxylic acid a) (2S)-1-{[(4-methoxyphenyl)methyl]amino}propan-2-ol The title compound is prepared from (S)-1-amino-2-propanol according to the method described in intermediate 1a.

[0169] b) [(2S,6S)-4-[(4-methoxyphenyl)methyl]-6-methylmorpholine-2-yl]methanol The title compound is prepared from (2S)-1-{[(4-methoxyphenyl)methyl]amino}propan-2-ol and (R)-epichlorohydrin according to the method described in intermediate 1b.

[0170] c) (2S,6S)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate tert-butyl The title compound is prepared from tert-butyl[(2S,6S)-4-[(4-methoxyphenyl)methyl]-6-methylmorpholine-2-yl]methanol according to the method described in intermediate 1c.

[0171] d) (2S,6S)-4-[(tert-butoxy)carbonyl]-6-methylmorpholine-2-carboxylic acid The title compound is prepared from (2S,6S)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate tert-butyl according to the method described in intermediate 1d.

[0172] Intermediate 9 [ka] (2R,6S)-4-[(tert-butoxy)carbonyl]-6-methylmorpholine-2-carboxylic acid a) [(2R,6S)-4-[(4-methoxyphenyl)methyl]-6-methylmorpholine-2-yl]methanol The title compound is prepared from (2S)-1-{[(4-methoxyphenyl)methyl]amino}propan-2-ol and (S)-epichlorohydrin according to the method described in intermediate 1b.

[0173] b) (2R,6S)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate tert-butyl The title compound is prepared from [(2R,5S)-4-[(4-methoxyphenyl)methyl]-6-methylmorpholine-2-yl]methanol according to the method described in intermediate 1c.

[0174] c) (2R,6S)-4-[(tert-butoxy)carbonyl]-6-methylmorpholine-2-carboxylic acid The title compound is prepared from (2R,6S)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate tert-butyl according to the method described in intermediate 1d.

[0175] Intermediate 10 [ka] (2R,5S)-4-[(tert-butoxy)carbonyl]-5-(propan-2-yl)morpholine-2-carboxylic acid a) (2S)-2-{[(4-methoxyphenyl)methyl]amino}-3-methylbutan-1-ol The title compound is prepared from (S)-2-amino-3-methyl-1-butanol according to the method described in intermediate 1a.

[0176] b) [(2R,5S)-4-[(4-methoxyphenyl)methyl]-5-(propan-2-yl)morpholin-2-yl]methanol The title compound is prepared from (2S)-2-{[(4-methoxyphenyl)methyl]amino}-3-methylbutan-1-ol and (S)-epichlorohydrin according to the method described in intermediate 1b.

[0177] c) (2R,5S)-2-(hydroxymethyl)-5-(propan-2-yl)morpholine-4-carboxylate tert-butyl The title compound is prepared from [(2R,5S)-4-[(4-methoxyphenyl)methyl]-5-(propan-2-yl)morpholin-2-yl]methanol according to the method described in intermediate 1c.

[0178] d) (2R,5S)-4-[(tert-butoxy)carbonyl]-5-(propan-2-yl)morpholine-2-carboxylic acid The title compound is prepared from (2R,5S)-2-(hydroxymethyl)-5-(propan-2-yl)morpholine-4-carboxylate tert-butyl according to the method described in intermediate 1d.

[0179] Intermediate 11 [ka] (2S,5S)-4-[(tert-butoxy)carbonyl]-5-(propan-2-yl)morpholine-2-carboxylic acid a) [(2S,5S)-4-[(4-methoxyphenyl)methyl]-5-(propan-2-yl)morpholin-2-yl]methanol The title compound is prepared from (2S)-2-{[(4-methoxyphenyl)methyl]amino}propan-1-ol and (R)-epichlorohydrin according to the method described in intermediate 1b.

[0180] b) (2S,5S)-2-(hydroxymethyl)-5-(propan-2-yl)morpholine-4-carboxylate tert-butyl The title compound is prepared from [(2S,5S)-4-[(4-methoxyphenyl)methyl]-5-methylmorpholine-2-yl]methanol according to the method described in intermediate 1c.

[0181] c) (2S,5S)-4-[(tert-butoxy)carbonyl]-5-(propan-2-yl)morpholine-2-carboxylic acid The title compound is prepared from (2S,5S)-2-(hydroxymethyl)-5-(propan-2-yl)morpholine-4-carboxylate tert-butyl according to the method described in intermediate 1d.

[0182] Intermediate 12 [ka] 3-[(tert-butoxy)carbonyl]-3-azabicyclo[4.1.0]heptane-1-carboxylic acid The title compound is prepared as described in Tetrahedron, 2010, 66, 5492-5497.

[0183] Intermediate 13 [ka] 1-[(tert-butoxy)carbonyl]-5,5-difluoropiperidine-3-carboxylic acid The title compound is prepared as described in WO2015 / 164508.

[0184] Intermediate 14 [ka] 1-[(tert-butoxy)carbonyl]-5,5-difluoro-3-methylpiperidine-3-carboxylic acid a) 5,5-difluoro-3-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-methyl Under nitrogen, 2.18 g (7.8 mmol) of 1-tert-butyl 3-methyl 5,5-difluoropiperidine-1,3-dicarboxylic acid (prepared as described in WO2015 / 164508) in 50 ml of dry tetrahydrofuran was mixed with 8.6 mL (8.6 mmol) of 1 M lithium bis(trimethylsilyl)amide solution in tetrahydrofuran, added dropwise at (-78) °C to (-65) °C. After addition, the mixture was stirred at -78 °C for 1 hour, and 0.73 mL (11.7 mmol) of iodomethane was added dropwise. The resulting mixture was then heated to RT and stirred at this temperature for 18 hours. The reaction mixture was quenched by adding 25 ml of saturated ammonium chloride solution and 10 ml of distilled water. The reaction mixture was extracted with ethyl acetate, the combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 2.22 g (97%) of the title compound. GC-MS(EI) m / z 294.1[MH] + ]

[0185] b) 1-[(tert-butoxy)carbonyl]-5,5-difluoro-3-methylpiperidine-3-carboxylic acid The 5,5-difluoro-3-methylpiperidine-1,3-dicarboxylic acid tert-butyl 1-tert-butyl 3-methyl obtained above was dissolved in 30 ml of methanol. 30.3 ml (15.1 mmol) of 2 M aqueous sodium hydroxide was added dropwise at 0°C. The resulting mixture was heated to RT and stirred at this temperature for 18 hours. The reaction mixture was acidified to pH=3 with citric acid, and the methanol was evaporated. The mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 2.20 g (100%) of the title compound. GC-MS(EI) m / z 280.1[MH]+ ]

[0186] Intermediate 15 [ka] 4-[(tert-butoxy)carbonyl]-2-methylmorpholine-2-carboxylic acid The title compound is prepared as described in WO2011 / 26917.

[0187] Intermediate 16 [ka] cis-1-[(tert-butoxy)carbonyl]-4-methylpiperidine-3-carboxylic acid a) cis-4-methylpiperidine-3-carboxylate hydrochloride A solution of 15 g (86.6 mmol) of 4-methylpyridine-3-carboxylate hydrochloride in 100 ml of distilled water was hydrogenated at 10 bar for 12 hours at RT in the presence of 1.5 g PtO2 × H2O. The mixture was filtered through Celite and concentrated under vacuum to obtain 16.6 g (100%) of the title compound.

[0188] b) cis-1-[(tert-butoxy)carbonyl]-4-methylpiperidine-3-carboxylic acid 33.29 g (185.3 mmol) of cis-4-methylpiperidine-3-carboxylic acid was dissolved in 300 ml of distilled water and 200 ml of tetrahydrofuran. At 0°C, 39.3 g (371 mmol) Na2CO3 was added, followed by 40.4 g (185 mmol) BOC2O dissolved in 100 ml of tetrahydrofuran. The resulting mixture was heated to RT and stirred at this temperature for 18 hours. The reaction mixture was acidified to pH=3 with citric acid. The mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 29.40 g (65%) of the title compound. GC-MS(EI) m / z 243.2[MH] + ]

[0189] Intermediate 17 [ka] trans-1-[(tert-butoxy)carbonyl]-4-methylpiperidine-3-carboxylic acid a) cis-4-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-methyl To a solution of 1.22 g (5 mmol) cis-1-[(tert-butoxy)carbonyl]-4-methylpiperidine-3-carboxylic acid (intermediate 15) in 6 ml of dimethylformamide, 6.52 g (20 mmol) Cs2CO3 and 2.5 ml (40 mmol) iodomethane were added. The resulting mixture was stirred at RT for 18 hours. 50 ml of distilled water was added. The mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 1.29 g (100%) of the title compound. GC-MS(EI) m / z 258.2 [MH] + ]

[0190] b) trans-1-[(tert-butoxy)carbonyl]-4-methylpiperidine-3-carboxylic acid Under nitrogen, 0.76 g (3 mmol) of 1-tert-butyl 3-methyl cis-4-methylpiperidine-1,3-dicarboxylic acid was dissolved in 25 ml of dry tetrahydrofuran. To this solution, 10 mL (10 mmol) of 1 M tert-butoxy potassium solution in tetrahydrofuran was added dropwise at (-78) °C to (-65) °C. After addition, the mixture was stirred at -78 °C for 2 hours, and 8 mL of distilled water, 8 ml of methanol, and 5 ml (50 mmol) of 10 M aqueous sodium hydroxide were added dropwise. The reaction mixture was heated to RT and stirred for 2 hours. The reaction mixture was acidified to pH=3 with citric acid, and the methanol was evaporated. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was dissolved in ethyl acetate, and ethanolic ammonia was added. The precipitated crystals were filtered and partitioned between 10% citric acid solution and ethyl acetate. The mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 0.59 g (82%) of the title compound. GC-MS(EI) m / z 244.1[MH] + ]

[0191] Intermediate 18 [ka] 1-[(tert-butoxy)carbonyl]-4-ethylpiperidine-3-carboxylic acid a) 4-Ethylpiperidine-3-carboxylate hydrochloride The title compound is prepared from 4-ethylpyridine-3-carboxylic acid according to the method described in intermediate 16a.

[0192] b) 1-[(tert-butoxy)carbonyl]-4-ethylpiperidine-3-carboxylic acid The title compound is prepared from 4-ethylpiperidine-3-carboxylate hydrochloride according to the method described in intermediate 16b.

[0193] Intermediate 19 [ka] (3S)-1-[(tert-butoxy)carbonyl]-3-methylpiperidine-3-carboxylic acid a) (3S)-3-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl To a suspension of 7.1 g (34.2 mmol) (3S)-3-methylpiperidine-3-carboxylate ethyl hydrochloride (prepared as described in WO2018 / 167631) in 100 ml of dichloromethane, 10.5 ml (75.2 mmol) triethylamine and 8.21 g (37.6 mmol) BOC2O were added at 0°C. The resulting mixture was heated to RT and stirred for 3 hours. The reaction mixture was washed with distilled water, 10% citric acid solution, and brine, and concentrated under vacuum to obtain 9.68 g (104%) of the title compound. GC-MS (EI) m / z 272.2 [MH] + ]

[0194] b) (3S)-1-[(tert-butoxy)carbonyl]-3-methylpiperidine-3-carboxylic acid The (3S)-3-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl obtained above was dissolved in 200 ml of ethanol, and 65 ml (300 mmol) of 4 M aqueous sodium hydroxide was added dropwise at 0°C. The reaction mixture was heated to RT and stirred for 18 hours. The reaction mixture was acidified to pH=3 with citric acid, and the ethanol was evaporated. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 8.0 g (96%) of the title compound. GC-MS(EI) m / z 244.1[MH] + ]

[0195] Intermediate 20 [ka] (3R)-1-[(tert-butoxy)carbonyl]-3-methylpiperidine-3-carboxylic acid a) (3R)-3-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl The title compound is prepared from (3R)-3-methylpiperidine-3-carboxylate hydrochloride (prepared as described in WO2018 / 167631) according to the method described in intermediate 19a.

[0196] b) (3R)-1-[(tert-butoxy)carbonyl]-3-methylpiperidine-3-carboxylic acid The title compound is prepared from (3R)-3-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl according to the method described in intermediate 19a.

[0197] Intermediate 21 [ka] 1-[(tert-butoxy)carbonyl]-4,4-dimethylpiperidine-3-carboxylic acid a) 1-Benzyl-4,4-dimethylpiperidine-3-carboxylate methyl Under nitrogen, 2.20 g (8 mmol) methyl 1-benzyl-4,4-dimethyl-6-oxopiperidine-3-carboxylate (prepared as described in J. Org. Chem. 2005, 70, 3957~3962) was dissolved in 22 ml of dry tetrahydrofuran. 0.92 g (24.4 mmol) NaBH4 and 3.96 ml of diethyl boron trifluoride were added dropwise at -15°C. The reaction mixture was heated to RT and stirred for 3 hours. 15 ml of distilled water was added, and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 1.87 g (89%) of the title compound. GC-MS (EI) m / z 262.2 [MH] + ]

[0198] b) 4,4-dimethylpiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-methyl The methyl 1-benzyl-4,4-dimethylpiperidine-3-carboxylate obtained above was dissolved in 20 ml methanol and hydrogenated at 10 bar for 18 hours at RT in the presence of 0.4 g 10% Pd / C and 1.60 g (7.1 mmol) BOC2O. The reaction mixture was filtered through Celite, concentrated under vacuum, and purified by silica gel chromatography by elution with 20% ethyl acetate in cyclohexane to obtain 0.89 g (47%) of the title compound. GC-MS(EI) m / z 271.2 [MH] + ]

[0199] c) 1-[(tert-butoxy)carbonyl]-4,4-dimethylpiperidine-3-carboxylic acid To a solution of 0.48 g (1.9 mmol) of 1-tert-butyl 3-methyl 4,4-dimethylpiperidine-1,3-dicarboxylic acid in 15 ml of dry tetrahydrofuran, 0.49 g (3.7 mmol) of potassium trimethylsilanolate was added, and the reaction mixture was refluxed for 1 hour. Distilled water was added, and the reaction mixture was acidified to pH=4 with acetic acid. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 0.39 g (85%) of the title compound. GC-MS(EI) m / z 258.2[MH] + ]

[0200] Intermediate 22 [ka] cis-1-[(tert-butoxy)carbonyl]-2-methylpiperidine-3-carboxylic acid a) cis-2-methylpiperidine-3-carboxylate ethyl A solution of 4.27 g (25.8 mmol) of ethyl 2-methylpyridine-3-carboxylate in 40 ml of distilled water was hydrogenated at 10 bar for 12 hours at RT in the presence of 0.3 g PtO2 × H2O. The mixture was filtered through Celite and concentrated under vacuum to obtain 3.94 g (89%) of the title compound. GC-MS (EI) m / z 172.1 [MH] + ]

[0201] b) cis-2-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl The cis-2-methylpiperidine-3-carboxylate ethyl obtained above was dissolved in 20 ml of distilled water and 40 ml of tetrahydrofuran. 2.00 g (23.8 mmol) NaHCO3 and 5.00 g (22.9 mmol) BOC2O were added at 0°C. The reaction mixture was heated to RT and stirred for 3 hours. 30 ml of distilled water was added. The mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 3.57 g (57%) of the title compound. GC-MS(EI) m / z 272.2[MH] + ]

[0202] c) cis-1-[(tert-butoxy)carbonyl]-2-methylpiperidine-3-carboxylic acid The cis-2-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl obtained above was dissolved in 50 ml of ethanol. 10 ml (60 mmol) of 6 M aqueous sodium hydroxide was added dropwise at 0°C. The resulting mixture was heated to RT and stirred at this temperature for 18 hours. The reaction mixture was acidified to pH=3 with 1 M HCl solution, and the ethanol was evaporated. The mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 2.81 g (88%) of the title compound. GC-MS(EI) m / z 244.1[MH] + ]

[0203] Intermediate 23 [ka] 1-[(tert-butoxy)carbonyl]-2-methylpiperidine-3-carboxylic acid a) 2-methylpiperidine-3-carboxylate ethyl Under nitrogen, 23.00 g (160.63 mmol) of cis-2-methylpiperidine-3-carboxylate ethyl (intermediate 22a) was dissolved in 50 ml of ethanol, to which 2.00 g (87 mmol) of sodium dissolved in 50 ml of ethanol was added. The reaction mixture was refluxed for 16 hours. The mixture was concentrated under vacuum to obtain the title compound as an oil. The crude product was used in the next step.

[0204] b) 2-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl The ethyl 2-methylpiperidine-3-carboxylate obtained above was dissolved in 200 ml of tetrahydrofuran and 200 ml of distilled water, and 13.00 g (60 mmol) BOC2O was added. The reaction mixture was stirred at RT for 16 hours. The reaction mixture was acidified to pH=3 with 1 M HCl solution and extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to chromatography on silica gel eluted with 33% ethyl acetate in cyclohexane, and then reeluted with dichloromethane to obtain 2.3 g (16%) of the title compound.

[0205] c) 1-[(tert-butoxy)carbonyl]-2-methylpiperidine-3-carboxylic acid The title compound is prepared from 1-tert-butyl 3-ethyl 2-methylpiperidine-1,3-dicarboxylic acid according to the method described in intermediate 22c.

[0206] Intermediate 24 [ka] (3S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpiperidine-3-carboxylic acid a) (3S,4R)-4-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-methyl The title compound is prepared from (3S,4R)-4-methylpiperidine-3-carboxylate methyl (prepared as described in US2010 / 0093706) according to the method described in intermediate 22b.

[0207] b) (3S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpiperidine-3-carboxylic acid The title compound is prepared from (3S,4R)-4-methylpiperidine-1,3-dicarboxylate methyl 1-tert-butyl 3-methyl according to the method described in intermediate 22c.

[0208] Intermediate 25 [ka] (3R,4S)-1-[(tert-butoxy)carbonyl]-4-methylpiperidine-3-carboxylic acid a) (3R,4S)-4-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-methyl The title compound is prepared from (3R,4S)-4-methylpiperidine-3-carboxylate methyl (prepared as described in US2010 / 0093706) according to the method described in intermediate 22b.

[0209] b) (3R,4S)-1-[(tert-butoxy)carbonyl]-4-methylpiperidine-3-carboxylic acid The title compound is prepared from (3R,4S)-4-methylpiperidine-1,3-dicarboxylate methyl 1-tert-butyl 3-methyl according to the method described in intermediate 22c.

[0210] Intermediate 26 [ka] cis-1-[(tert-butoxy)carbonyl]-5-methylpiperidine-3-carboxylic acid a) cis-5-methylpiperidine-3-carboxylic acid A solution of 1.00 g (7.3 mmol) of 5-methylpyridine-3-carboxylic acid in 20 ml of acetic acid was hydrogenated at 10 bar for 12 hours at RT in the presence of 0.2 g PtO2 × H2O. The mixture was filtered through Celite and concentrated under vacuum to obtain 1.00 g (96%) of the title compound. GC-MS (EI) m / z 144.1 [MH] + ]

[0211] b) cis-1-[(tert-butoxy)carbonyl]-5-methylpiperidine-3-carboxylic acid The cis-5-methylpiperidine-3-carboxylic acid obtained above was dissolved in 10 ml of distilled water and 10 ml of tetrahydrofuran. 1.52 g (7 mmol) BOC2O was added at 0°C. The reaction mixture was heated to RT and stirred for 3 hours. 30 ml of distilled water was added. The mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 0.45 g (25%) of the title compound. GC-MS (EI) m / z 244.1 [MH] + ]

[0212] Intermediate 27 [ka] 1-[(tert-butoxy)carbonyl]-3-(fluoromethyl)piperidine-3-carboxylic acid a) 3-(hydroxymethyl)piperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl The title compound is prepared from piperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl and paraformaldehyde according to the method described in intermediate 14a.

[0213] b) 3-{[(1,1,2-trifluoroethanesulfonyl)oxy]methyl}piperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl Under nitrogen, 0.230 ml of 1.48 mmol of trifluoromethanesulfonic acid anhydride was added dropwise at (-78)°C to (-65)°C to a stirred solution of 0.296 g (1.03 mmol) ethyl 3-(hydroxymethyl)piperidine-3-carboxylate and 0.120 ml (1.48 mmol) pyridine in 5 ml of dichloromethane. After the addition, the mixture was stirred at -78°C for 5 minutes, warmed to room temperature, and stirred at this temperature for 18 hours. The reaction mixture was quenched by the addition of 1 M hydrochloric acid solution. The reaction mixture was extracted with dichloromethane, and the combined organic layers were washed with distilled water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound as oil. The crude product was used in the next step.

[0214] c) 3-(fluoromethyl)piperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl The 3-{[(1,1,2-trifluoroethanesulfonyl)oxy]methyl}piperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl obtained above was dissolved in 4 ml of tetrahydrofuran, and 1.25 ml (1.25 mmol) of 1 M tetrabutylammonium fluoride in tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 1 hour, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with distilled water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to chromatography on silica gel eluted with 33% ethyl acetate in cyclohexane to obtain 0.121 g (40%) of the title compound.

[0215] d) 1-[(tert-butoxy)carbonyl]-3-(fluoromethyl)piperidine-3-carboxylic acid The title compound is prepared from 1-tert-butyl 3-ethyl 3-(fluoromethyl)piperidine-1,3-dicarboxylic acid according to the method described in intermediate 22c.

[0216] Intermediate 28 [ka] 3-(3-oxobutanoyl)piperidine-1-carboxylate tert-butyl To a solution of 5.00 g (21.8 mmol) of 1-[(tert-butoxy)carbonyl]piperidine-3-carboxylic acid in 30 ml of dry tetrahydrofuran, 3.89 g (24 mmol) of CDI was added at 0°C, and the reaction mixture was heated to RT and stirred for 2 hours. In a separate flask, under nitrogen, 3.2 ml (43.6 mmol) of acetone was added dropwise to 24 ml (48 mmol) of a solution of 2 M lithium diisopropylamide in tetrahydrofuran / heptane / ethylbenzene in 30 ml of dry tetrahydrofuran at (-78)°C to (-65)°C. After the addition, the mixture was stirred at -78°C for 1 hour, and the activated acid solution was added dropwise at (-78)°C to (-65)°C. After the addition, the mixture was stirred at -78°C for 10 minutes and quenched by the addition of 10% citric acid. The mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography with dichloromethane elution to obtain 2.28 g (39%) of the title compound. GC-MS(EI) m / z 270.2[MH] + ]

[0217] The compounds in Table 3 were prepared from appropriate carboxylic acids and acetone according to the method described in Intermediate 28.

[0218] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0219] Intermediate 47 [ka] (3R)-3-(2-methyl-3-oxobutanoyl)piperidine-1-carboxylate tert-butyl To a solution of 0.80 g (2.97 mmol) (3R)-3-(3-oxobutanoyl)piperidine-1-carboxylate tert-butyl (intermediate 29) in 20 ml of acetone, 0.56 ml (8.91 mmol) iodomethane and 1.23 g (8.91 mmol) K2CO3 were added. The reaction mixture was refluxed for 3 hours. The reaction mixture was cooled to RT, the acetone was evaporated, and the residue was partitioned between distilled water and ethyl acetate. The mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 0.70 g (83%) of the title compound. GC-MS (EI) m / z 284.2 [MH] + ]

[0220] The compounds in Table 4 were prepared from appropriate diketones and iodoalkanes according to the method described in Intermediate 47.

[0221] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0222] Intermediate 63 [ka] (2R)-2-(buta-2-inoyl)morpholine-4-carboxylate tert-butyl a) (2R)-2-[Methoxy(methyl)carbamoyl]morpholine-4-carboxylate tert-butyl Under nitrogen, in a solution of 1.00 g (4.32 mmol) (2R)-4-[(tert-butoxy)carbonyl]morpholine-2-carboxylic acid in 10 ml of dimethylformamide, add 1.27 g (13 mmol) N,O-dimethylhydroxylamine hydrochloride, 3.77 ml (21.6 mmol) N,N-diisopropylethylamine, 1.8 g (4.76 mmol) HBTU, and 0.73 g (4.76 mmol) HOBt * H2O was added at 0°C. The reaction mixture was heated to RT and stirred for 16 hours. Distilled water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with 1 M HCl solution, 1 M NaOH solution, distilled water, and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 1.00 g (84%) of the title compound. GC-MS (EI) m / z 275.2 [MH] + ]

[0223] b) (2R)-2-(buta-2-inoyl)morpholine-4-carboxylate tert-butyl Under nitrogen, the (2R)-2-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate tert-butyl obtained above was dissolved in 20 ml of dry tetrahydrofuran, and 11 ml (5.5 mmol) of 0.5 M 1-propynyl magnesium bromide in tetrahydrofuran was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 20 minutes and quenched by adding 10 ml of saturated NH4Cl solution and 5 ml of distilled water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 0.83 g (90%) of the title compound. GC-MS(EI) m / z 254.1[MH] + ]

[0224] The compounds in Table 5 were prepared from suitable winerebamide and 1-propynylmagnesium bromide according to the method described in intermediate 63.

[0225] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0226] Intermediate 82 [ka] 3-[trans-4-(trifluoromethyl)cyclohexyl]-1H-pyrazole-5-amine a) trans-4-(trifluoromethyl)cyclohexane-1-carboxylate methyl carboxylate To a solution of 10 g (51 mmol) trans-4-(trifluoromethyl)cyclohexane-1-carboxylic acid in 150 ml methanol, 10 ml (137 mmol) thionyl chloride was added dropwise at -10°C. After addition, the mixture was warmed to room temperature and stirred at this temperature for 16 hours, then concentrated under vacuum. The residue was partitioned between ethyl acetate and water. The combined organic layers were washed with NaHCO3 solution and water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 8.96 g (84%) of the title compound. GC-MS(EI) m / z 211.2[MH] + ]

[0227] b) 3-Oxo-3-[trans-4-(trifluoromethyl)cyclohexyl]propannitrile Under nitrogen, 51 ml (127 mmol) of 2.5 M n-butyllithium solution in n-hexane was added dropwise to a mixture of 9.1 ml (174 mmol) of acetonitrile in 260 ml of dry tetrahydrofuran at (-78)°C to (-65)°C. After the addition, the mixture was stirred at -78°C for 1 hour, and 8.96 g (42.6 mmol) of trans-4-(trifluoromethyl)cyclohexane-1-carboxylate methyl was added dropwise. The resulting mixture was warmed to room temperature and stirred at this temperature for 1 hour. The reaction mixture was quenched by the addition of 150 mL of saturated ammonium chloride solution. The tetrahydrofuran was evaporated, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was used in the next step.

[0228] c) 3-[trans-4-(trifluoromethyl)cyclohexyl]-1H-pyrazole-5-amine The 3-oxo-3-[trans-4-(trifluoromethyl)cyclohexyl]propanenitrile obtained above was dissolved in 187 ml of ethanol, and 4.4 ml (167 mmol) of hydrazine monohydrate was added. The reaction mixture was refluxed under an inert gas atmosphere for 16 hours. The solvent was removed under vacuum, and dry toluene was evaporated from the residue several times to obtain 11.15 g of the title compound. LC-MS(ESI) m / z 234.2[MH] + ]

[0229] Intermediate 83 [ka] 4-Fluoro-3-[trans-4-(trifluoromethyl)cyclohexyl]-1H-pyrazole-5-amine a) trans-4-(trifluoromethyl)cyclohexane-1-carbonyl chloride A mixture of 5 g (25.5 mmol) trans-4-(trifluoromethyl)cyclohexane-1-carboxylic acid, 100 ml dichloromethane, 5 ml (68.5 mmol) thionyl chloride, and 0.1 ml dimethyformamide was refluxed for 6 hours. The reaction mixture was concentrated under vacuum, and dry tetrahydrofuran was evaporated from the residue several times. The crude product was used in the next step.

[0230] b) 2-Fluoro-3-oxo-3-[trans-4-(trifluoromethyl)cyclohexyl]propannitrile Under an inert gas atmosphere, a solution of trans-4-(trifluoromethyl)cyclohexane-1-carbonyl chloride and 1.5 ml (26.96 mmol) fluoroacetonitrile, obtained on 50 ml of dry tetrahydrofuran, was to be dropwise added to 50 ml (50 mmol) 1 M lithium bis(trimethylsilyl)amide at -78°C. After addition, the mixture was stirred at -78°C for 1 hour, then warmed to room temperature and poured into 200 ml of water. The pH of the mixture was adjusted to 2 by adding 1 M hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was used in the next step.

[0231] c) 4-Fluoro-3-[trans-4-(trifluoromethyl)cyclohexyl]-1H-pyrazole-5-amine The 2-fluoro-3-oxo-3-[trans-4-(trifluoromethyl)cyclohexyl]propanenitrile obtained above was dissolved in 65 ml of ethanol, and 4.4 ml (77 mmol) of hydrazine monohydrate was added. The reaction mixture was refluxed under an inert gas atmosphere for 16 hours. The solvent was removed under vacuum, and the title compound was obtained as an oil. LC-MS(ESI) m / z 252.2[MH] + ]

[0232] Intermediate 84 [ka] 3-(trans-4-methylcyclohexyl)-1H-pyrazole-5-amine a) trans-4-methylcyclohexane-1-carboxylate methyl The title compound is prepared from trans-4-methylcyclohexane-1-carboxylic acid according to the method described in intermediate 82a.

[0233] b) 3-Oxo-3-(trans-4-methylcyclohexyl)propanenitrile The title compound is prepared from trans-4-methylcyclohexane-1-carboxylate methyl according to the method described in intermediate 82b.

[0234] c) 3-(trans-4-methylcyclohexyl)-1H-pyrazole-5-amine The title compound is prepared from 3-oxo-3-(trans-4-methylcyclohexyl)propanenitrile according to the method described in intermediate 82c.

[0235] Intermediate 85 [ka] 3-[(trans-4-tert-butylcyclohexyl]-1H-pyrazole-5-amine a) trans-4-tert-butylcyclohexane-1-carboxylate methyl carboxylate The title compound is prepared from trans-4-tert-butylcyclohexane-1-carboxylic acid according to the method described in intermediate 82a.

[0236] b) 3-Oxo-3-(trans-4-tert-butylcyclohexyl)propanenitrile The title compound is prepared from trans-4-tert-butylcyclohexane-1-carboxylate methyl according to the method described in intermediate 82b.

[0237] c) 3-(trans-4-tert-butylcyclohexyl)-1H-pyrazole-5-amine The title compound is prepared from 3-oxo-3-(trans-4-tert-butylcyclohexyl)propanenitrile according to the method described in intermediate 82c.

[0238] Intermediate 86 [ka] 3-[4-(trifluoromethyl)phenyl]-1H-pyrazole-5-amine The title compound is prepared as described in WO2018 / 167629.

[0239] Intermediate 87 [ka] 7-Chloro-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine a) 5-Methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-ol To a solution of 0.50 g (2.14 mmol) 3-[trans-4-(trifluoromethyl)cyclohexyl]-1H-pyrazole-5-amine (intermediate 82) in 30 ml of toluene, 0.30 ml (2.37 mmol) of ethyl acetoacetate and a catalytic amount of p-toluenesulfonic acid monohydrate were added. The reaction mixture was refluxed for 16 hours and heated to RT. The precipitated crystals were filtered to obtain 0.51 g (79%) of the title compound. LC-MS (ESI) m / z 300.1 [MH] + ]

[0240] b) 7-Chloro-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine The 5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-ol obtained above was suspended in 10 ml of toluene, and 0.59 ml (3.40 mmol) N,N-diisopropylethylamine and 0.80 ml (8.50 mmol) phosphoryl chloride were added. The reaction mixture was refluxed for 2 hours and then quenched by adding ice. The reaction mixture was neutralized by adding saturated NaHCO3 solution. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 0.53 g (99%) of the title compound. LC-MS(ESI) m / z 318.1[MH] + ]

[0241] Route c) Intermediate 88 [ka] 3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-carboxylate tert-butyl To a solution of 0.81 g (3 mmol) 3-(3-oxobutanoyl)piperidine-1-carboxylate tert-butyl (intermediate 28) in 25 ml of toluene, 0.50 g (2.14 mmol) 3-[trans-4-(trifluoromethyl)cyclohexyl]-1H-pyrazole-5-amine (intermediate 82) and 0.02 g (0.1 mmol) p-toluenesulfonic acid monohydrate were added. The reaction mixture was refluxed for 16 hours, and the solvent was evaporated. The residue was purified by silica gel chromatography using elution with 0-30% ethyl acetate in cyclohexane to obtain 0.26 g (26%) of the title compound. LC-MS (ESI) m / z 467.2 [MH] + ]

[0242] Route d) Intermediate 89 [ka] (2R)-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine-4-carboxylate tert-butyl To a solution of 0.83 g (3.28 mmol) (2R)-2-(buta-2-inoyl)morpholine-4-carboxylate tert-butyl (intermediate 63) in 10 ml of ethanol, 0.27 ml (3.28 mmol) pyrrolidine was added. The reaction mixture was stirred at RT for 30 minutes, and 0.77 g (3.28 mmol) 3-[trans-4-(trifluoromethyl)cyclohexyl]-1H-pyrazole-5-amine (intermediate 82) and 1.5 ml of acetic acid were added. The reaction mixture was stirred at 60°C for 4 hours, and the solvent was evaporated. The residue was purified by silica gel chromatography by elution with 0-50% ethyl acetate in cyclohexane to obtain 1.45 g (95%) of the title compound. LC-MS (ESI) m / z 469.2 [MH] + ]

[0243] Intermediate 90 [ka] 2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-1,1-dioxo-1λ 6 -Tert-butyl thiomorpholine-4-carboxylate 1.12 g (4.75 mmol) 1,1-dioxo-1λ in 30 ml of dry tetrahydrofuran 6To a solution of tert-butyl thiomorpholine-4-carboxylate (prepared as described in EP1140904), 4.8 mL (4.8 mmol) of 1 M lithium bis(trimethylsilyl)amide solution in tetrahydrofuran was added dropwise at (-78)°C to (-65)°C. After the addition, the mixture was stirred at -78°C for 1 hour, and 1.26 g (3.96 mmol) 7-chloro-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine (intermiediate 87) was added. The resulting mixture was heated to RT and stirred at this temperature for 18 hours. The reaction mixture was quenched by adding 20 ml of saturated ammonium chloride solution and 10 ml of distilled water. The reaction mixture was extracted with ethyl acetate, and the combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using elution with 0-35% ethyl acetate in cyclohexane to obtain 0.63 g (31%) of the title compound. LC-MS(ESI) m / z 517.2[MH] + ]

[0244] Intermediates 91-155 are prepared using a method similar to that of the intermediates described above, and are illustrated in Table 6 below.

[0245] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12] [Table 6-13] [Table 6-14] [Table 6-15]

[0246] Intermediate 156 [ka] 3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine To a solution of 1.00 g (2.14 mmol) of 3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-carboxylate tert-butyl (intermediate 88) in 20 ml of dichloromethane, 3.3 ml (42.8 mmol) of trifluoroacetic acid was added dropwise at 0°C. The reaction mixture was heated to RT and stirred for 16 hours. 10 ml of distilled water was added, and the pH was adjusted to 10 by adding 2 M aqueous sodium hydroxide. The mixture was extracted with dichloromethane. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 0.70 g (89%) of the title compound. LC-MS (ESI) m / z 367.2 [MH] + ]

[0247] Intermediates 157-221 are prepared using a method similar to that of the intermediates described above, and are illustrated in Table 7 below.

[0248] [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11] [Table 7-12] [Table 7-13]

[0249] Intermediate 224 [ka] 2-[(3R)-3-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-yl]methyl acetate To a solution of 0.07 g (0.18 mmol) (3R)-3-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine (intermediate 167) in 2 ml of toluene, 0.03 ml (0.28 mmol) methyl bromoacetate and 0.1 ml (0.57 mmol) N,N-diisopropylethylamine were added. The reaction mixture was stirred at RT for 16 hours and diluted with toluene. The mixture was washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography with elution in 5% acetone in dichloromethane to obtain 0.06 g (80%) of the title compound. LC-MS (ESI) m / z 453.2 [MH] + ]

[0250] Intermediate 225 [ka] N-[(2S)-1-[(3R)-3-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-yl]-3-hydroxy-1-oxopropan-2-yl]tert-butyl carbamate Under nitrogen, 0.17 g (0.45 mmol) (3R)-3-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine (intermediate 158) was added at 0°C to a solution of 0.17 g (0.45 mmol) (3R)-3-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine (intermediate 158) in 10 ml of dimethylformamide. 0.09 g (0.46 mmol) Boc-Ser-OH, 0.08 g (0.54 mmol) 1-hydroxybenzotriazole hydrate, 0.2 ml (1.12 mmol) N,N-diisopropylethylamine, and 0.1 g (0.54 mmol) EDC were added at 0°C. The reaction mixture was heated to RT and stirred for 16 hours. The reaction mixture was diluted with distilled water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using elution with 4% methanol in dichloromethane to obtain 0.12 g (46%) of the title compound. LC-MS(ESI) m / z 568.3[MH] + ]

[0251] Intermediates 225-226 are prepared using a method similar to that of the intermediates described above and are illustrated in Table 8 below.

[0252] [Table 8]

[0253] Example 1 [ka] 1-(3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-yl)ethane-1-one To a solution of 0.18 g (0.47 mmol) of 3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine (intermediate 156) in 15 ml of dichloromethane, 0.1 ml (0.7 mmol) of triethylamine and 0.04 ml (0.56 mmol) of acetyl chloride were added. The reaction mixture was stirred at RT for 2 hours, washed with distilled water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to obtain 0.17 g (85%) of the title compound. LC-MS (ESI) m / z 409.2 [MH] + ]

[0254] Example 2 and Example 3 [ka] 1-[(3S,4S)-3-{3-fluoro-5-methyl-2-[(trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-4-methylpiperidine-1-yl]ethane-1-one and 1-[(3R,4R)-3-{3-fluoro-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-4-methylpiperidine-1-yl]ethane-1-one The racemic form of the title compound (Example 158) was prepared from cis-3-{3-fluoro-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-4-methylpiperidine (intermediate 159) according to the method described in Example 1. LC-MS(ESI) m / z 441.2[MH]+ Enantiomers A and B were separated using chiral preparative HPLC (Lux i-Amylose-1 5μm 250×21.2mm; F=21.34ml / min; eluent: A:n-heptane B:2-propanol; isocratic 5% B t=25℃) to obtain enantiomer A(T r 13.625, Example 2), and Enantiomer B(T r 20.089, Example 3) was obtained. Their absolute configurations were not determined.

[0255] Example 4 and Example 5 [ka] (3R,4S)-4-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-carboxylate methyl and (3S,4R)-4-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-carboxylate methyl The racemic form of the title compound (Example 159) was prepared from trans-4-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine (intermediate 171) and methyl chloroformate according to the method described in Example 1. LC-MS(ESI) m / z 439.2[MH] + Enantiomers A and B were separated using chiral preparative HPLC (Lux i-Amylose-1 5μm 150×21.1mm; F=10ml / min; eluent: A: water B: 2-propanol; isocratic 55% B t=40℃) to obtain enantiomer A(T r 18.886, Example 4), and Enantiomer B(T r Examples 24.444 and 5) were obtained. Their absolute configurations were determined using VCD spectroscopy. Example 4 was (3R,4S) and Example 5 was (3S,4R).

[0256] Example 6 and Example 7 [ka] (3S,4S)-4-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-carboxylate methyl and (3R,4R)-4-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-carboxylate methyl The racemic form of the title compound (Example 76) was prepared from cis-4-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine (intermediate 180) and methyl chloroformate according to the method described in Example 1. LC-MS(ESI) m / z 439.2[MH] + Enantiomers A and B were separated using chiral preparative HPLC (Lux i-Amylose-1 5μm 150×21.1mm; F=10ml / min; eluent: A: water B: 2-propanol; isocratic 55% B t=40℃) to obtain enantiomer A(T r 18.886, Example 6), and Enantiomer B(T r 29.748, Example 7) was obtained. Their absolute configurations are not determined.

[0257] Example 8 and Example 9 [ka] (3S,4S)-4-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-carbaldehyde and (3R,4R)-4-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-carbaldehyde The racemic form of the title compound (Example 160) was prepared from cis-4-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine (intermediate 180) and formic acid according to the method described in Example 22. LC-MS(ESI) m / z 409.2[MH] + Enantiomers A and B were separated using chiral preparative HPLC (Chiral Pak IG 20 μm 200 × 50 mm; F ​​= 50 ml / min; Eluent: A: n-heptane B: dichloromethane; Isocratic 50% B t = 25 °C) to obtain enantiomer A (T r 27. Example 8), and enantiomer B(T r51, Example 9) was obtained. Their absolute configurations are not determined.

[0258] Example 10 and Example 11 [ka] (2S)-5,5-dimethyl-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine-4-carbaldehyde and (2R)-5,5-dimethyl-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine-4-carbaldehyde The enantiomerized form of the title compound was prepared from (2S)-5,5-dimethyl-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine or (2R)-5,5-dimethyl-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine (intermediate 200 or intermediate 201) and formic acid according to the method described in Example 22. LC-MS(ESI) m / z 425.2[MH] + Enantiomers A and B were separated using chiral preparative HPLC (Reprosil Chiral MIX 5μm 150×20mm; F=20ml / min; Eluent: A: Water B: Acetonitrile; Isocratic 50% B t=40℃) to obtain enantiomer A(T r 12.783, Example 10), and Enantiomer B(T r 15.088, Example 11) was obtained.

[0259] Example 12 [ka] (2S)-5,5-dimethyl-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine-4-carboxylate methyl The enantiomerized form of the title compound was prepared from (2S)-5,5-dimethyl-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine (intermediate 200) and methyl chloroformate according to the method described in Example 1. LC-MS(ESI) m / z 455.2[MH] + Enantiomers A and B were separated using chiral preparative HPLC (Lux Cellulose-3 5μm 250×21.1mm; F=20ml / min; eluent: A:n-heptane B:2-propanol; isocratic 10% B t=40℃) to obtain enantiomer A(T r 4.788, Example 12) was obtained.

[0260] Example 13 and Example 14 [ka] (1S,6R)-1-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-azabicyclo[4.1.0]heptan-3-carboxylate methyl and (1R,6S)-1-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-azabicyclo[4.1.0]heptan-3-carboxylate methyl The racemic form of the title compound was prepared from 1-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-azabicyclo[4.1.0]heptane (intermediate 206) and methyl chloroformate according to the method described in Example 1. LC-MS(ESI) m / z 437.2[MH] + Enantiomers A and B were separated using chiral preparative HPLC (Lux Cellulose-3 5μm 250×21.2mm; F=25ml / min; Eluent: A: Water B: Acetonitrile; Isocratic 50% B t=40℃) to obtain enantiomer A(T r 6.811, Example 13), and Enantiomer B(T r 7.479, Example 14) was obtained. Their absolute configurations are not determined.

[0261] Example 15 and Example 16 [ka] (1S,6R)-1-{3-fluoro-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-azabicyclo[4.1.0]heptan-3-carboxylate methyl and (1R,6S)-1-{3-fluoro-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-azabicyclo[4.1.0]heptan-3-carboxylate methyl The racemic form of the title compound was prepared from 1-{3-fluoro-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-azabicyclo[4.1.0]heptane (intermediate 207) and methyl chloroformate according to the method described in Example 1. LC-MS(ESI) m / z 455.2[MH] + Enantiomers A and B were separated using chiral preparative HPLC (Lux Cellulose-3 5μm 250×21.2mm; F=25ml / min; Eluent: A: Water B: Acetonitrile; Isocratic 50% B t=40℃) to obtain enantiomer A(T r 8.811, Example 15), and Enantiomer B(T r 10.414, Example 16) was obtained. Their absolute configurations are not determined.

[0262] Example 17 [ka] 2-{5-methyl-2-[(trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-1-oxo-1λ 4 -thiomorpholine-4-carboxylate methyl To a solution of 0.16 g (0.73 mmol) of sodium periodate in 10 ml of distilled water, 0.1 g (0.23 mmol) of 2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}thiomorpholine-4-carboxylate methyl (Example 126), 10 ml of methanol, and 10 ml of dioxane were added at 0°C. The reaction mixture was heated to RT and stirred for 16 hours. The organic solvent was evaporated, and the mixture was filtered to obtain 0.07 g (66%) of the title compound. LC-MS (ESI) m / z 459.2 [MH] + ].

[0263] Example 18 [ka] 2-[(3R)-3-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-methylpiperidine-1-yl]acetonitrile hydrochloride a) 2-[(3R)-3-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-methylpiperidine-1-yl]acetonitrile The title compound is prepared from (3R)-3-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-methylpiperidine (intermediate 170) and bromoacetonitrile according to the method described in intermediate 224.

[0264] b) 2-[(3R)-3-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-methylpiperidine-1-yl]acetonitrile hydrochloride To a solution of 0.05 g (0.12 mmol) 2-[(3R)-3-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-methylpiperidine-1-yl]acetonitrile in 5 ml of diethyl ether, 1 ml of hydrochloric acid in ethyl acetate was added. The precipitate was filtered to obtain 0.04 g (67%) of the title compound. LC-MS (ESI) m / z 434.3 [MH] + ].

[0265] Example 19 [ka] 2-[(3R)-3-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-methylpiperidine-1-yl]acetate hydrochloride 0.06 g of 2-[(3R)-3-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-yl]methyl acetate (intermediate 224) was suspended in 0.5 ml of distilled water, to which 0.5 ml of 37% hydrochloric acid was added. The mixture was refluxed for 16 hours. The reaction mixture was concentrated under vacuum and ground with diethyl ether. The mixture was filtered to obtain 0.04 g (73%) of the title compound. LC-MS(ESI) m / z 439.2[MH] + ].

[0266] Example 20 [ka] 5-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}3,3-difluoro-1-(3-methyloxetane-3-carbonyl)piperidine Under nitrogen, 0.08 g (0.19 mmol) 5-{5,6-dimethyl-2-[-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3,3-difluoropiperidine (intermediate 179) was dissolved in 1 ml of dimethylformamide. 0.03 g (0.23 mmol) 3-methyloxetane-3-carboxylic acid, 0.07 g (0.19 mmol) HBTU, and 0.11 ml (0.634 mmol) N,N-diisopropylethylamine were added. The reaction mixture was stirred for 16 hours. The reaction mixture was diluted with distilled water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with distilled water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution in 5% methanol in dichloromethane to obtain 0.05 g (50%) of the title compound. LC-MS(ESI)m / z 515.2[MH + ]

[0267] Example 21 [ka] (2S)-2-amino-1-[(3R)-3-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-yl]-3-hydroxypropan-1-one To a solution of 0.12 g (0.21 mmol) of N-[(2S)-1-[(3R)-3-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-yl]-3-hydroxy-1-oxopropan-2-yl]tert-butyl carbamate (intermediate 225) in 5 ml of dichloromethane, 1 ml (10 mmol) of trifluoroacetic acid was added. The reaction mixture was stirred at RT for 16 hours, and the pH was adjusted to 8 by adding saturated NaHCO3 solution. The mixture was extracted with dichloromethane. The combined organic layers were washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography eluted with 10% methanol in dichloromethane to obtain 0.04 g (43%) of the title compound. LC-MS(ESI)m / z 468.2[MH + ]

[0268] Example 22 [ka] (3R)-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-carbaldehyde To a solution of 0.16 g (0.45 mmol) (3R)-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine (intermediate 157) in 10 ml of toluene, 0.2 ml (53.4 mmol) of formic acid was added. The reaction mixture was refluxed for 3 hours and evaporated. The crude product was purified by silica gel chromatography by elution with 0-100% ethyl acetate in cyclohexane to obtain 0.14 g (78%) of the title compound. LC-MS (ESI) m / z 395.2 [MH] + ]

[0269] Example 23 [ka] (3R)-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-carboxymidohydrochloride To a solution of 0.08 g (0.2 mmol) (3R)-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine (intermediate 157) in 1 ml of dimethylformamide, 0.06 g (0.4 mmol) 1-amidinopyrazole hydrochloride and 0.07 ml (0.4 mmol) N,N-diisopropylethylamine were added. The reaction mixture was stirred at RT for 16 hours and filtered to obtain 0.09 g (97%) of the title compound. LC-MS (ESI) m / z 409.3 [MH] + ]

[0270] Example 24 [ka] (3R)-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-1-(propan-2-yl)piperidine To a solution of 0.13 g (0.34 mmol) (3R)-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine (intermediate 157) in 5 ml of 1,2-dichloroethane, 0.03 ml (0.34 mmol) acetone, 0.1 g (0.48 mmol) sodium triacetoxyborohydride, and 0.02 ml (0.34 mmol) acetic acid were added. The reaction mixture was stirred at RT for 16 hours and washed with 1 M NaOH solution. The organic layer was washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to obtain 0.05 g (38%) of the title compound. LC-MS (ESI) m / z 409.3 [MH] + ]

[0271] Example 25 [ka] (2R)-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine-4-sulfonamide To a solution of 0.12 g (0.33 mmol) (2R)-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine (intermediate 222) in 15 ml of dioxane, 0.31 g (3.23 mmol) of sulfamide was added. The reaction mixture was refluxed for 1 hour and evaporated. The crude product was purified by silica gel chromatography by elution with 0-100% ethyl acetate in cyclohexane to obtain 0.03 g (21%) of the title compound. LC-MS (ESI) m / z 448.2 [MH] + ]

[0272] Example 26 [ka] (2R)-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine-4-carboxamide To a solution of 0.12 g (0.33 mmol) (2R)-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine (intermediate 222) in 10 ml of dichloromethane, 0.1 ml (0.72 mmol) of trimethylsilyl isocyanate was added. The reaction mixture was stirred at RT for 3 hours. The reaction mixture was washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to obtain 0.06 g (48%) of the title compound. LC-MS (ESI) m / z 412.2 [MH] + ]

[0273] Example 27 [ka] 3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-1λ 6 -Chian-1,1-Zion The title compound was obtained according to the method described in intermediate 89 as 3-[trans-4-(trifluoromethyl)cyclohexyl]-1H-pyrazole-5-amine (intermediate 82) and 3-(buta-2-inoyl)-1λ 6 Prepared from -thian-1,1-zion (intermediate 73). LC-MS(ESI)m / z 416.2[MH] + ]

[0274] Example 28 and Example 29 [ka] 5-Methyl-7-[(3R)-oxan-3-yl]-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine and 5-methyl-7-[(3S)-oxan-3-yl]-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine The racemic form of the title compound (Example 161) was prepared from 3-[trans-4-(trifluoromethyl)cyclohexyl]-1H-pyrazole-5-amine (intermediate 82) and 1-(oxan-3-yl)butan-1,3-dione (intermediate 45) according to the method described in intermediate 88. LC-MS(ESI) m / z 368.2[MH] + Enantiomers A and B were separated using chiral preparative HPLC (Lux i-Amylose-1 5μm 150×21.1mm; F=20ml / min; Eluent: A: Water B: Acetonitrile; Isocratic 50% B t=40℃) to obtain enantiomer A(T r 26.148, Example 28), and Enantiomer B(T r 30.798, Example 29) was obtained.

[0275] Example 30 [ka] 4-methyl-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholin-3-one The title compound is prepared from 7-chloro-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine (intermediate 87) and 4-methylmorpholine-3-one according to the method described in intermediate 90. LC-MS(ESI) m / z 397.2[MH] + ]

[0276] Example 31 [ka] (2S)-2-{5-methyl-2-[(trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine-4-carboxylic acid 2 H 3 ) Methyl To a solution of 0.39 g (2.42 mmol) carbonyldiimidazole in 20 ml of dichloromethane, 0.1 ml (2.42 mmol) CD3OD was added at 0°C. The reaction mixture was stirred at RT for 1 hour. To this mixture, 0.89 g (2.42 mmol) (2S)-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine (intermediate 187), dissolved in 10 ml of dichloromethane, was added. The reaction mixture was stirred at RT for 16 hours. The reaction mixture was washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography with elution in 0-10% methanol in dichloromethane to obtain 0.09 g (8%) of the title compound. LC-MS(ESI)m / z 430.4[MH + ]

[0277] Examples 32 to 161 were prepared using methods similar to those described above and are illustrated in Table 9 below.

[0278] [Table 9-1] [Table 9-2] [Table 9-3] Table 9-4 Table 9-5 Table 9-6 Table 9-7 Table 9-8 Table 9-9 Table 9-10 Table 9-11 Table 9-12 Table 9-13 Table 9-14 Table 9-15 Table 9-16 Table 9-17 Table 9-18 Table 9-19 Table 9-20 [Table 9-21] [Table 9-22] [Table 9-23] [Table 9-24] [Table 9-25] [Table 9-26] [Table 9-27] [Table 9-28] [Table 9-29] [Table 9-30] [Table 9-31]

[0279] Preparation of pharmaceutical compositions The following examples illustrate typical pharmaceutical compositions of the present invention. However, the present invention is not limited to these pharmaceutical compositions.

[0280] A) Solid oral medication form I. Tablets Active ingredients (multiple ingredients allowed): 0.01-90% Filler 1-99.9% Binder 0-20% Disintegrant 0-20% Lubricant 0-10% Other specific excipients (multiple) 0-50%

[0281] II. Intraoral Disintegrating Films Active ingredients (multiple ingredients allowed): 0.01-90% Film-forming agent 1-99.9% Plasticizer 0-40% Other specific excipients (multiple) 0-50%

[0282] B) Liquid oral medication form III. Oral Suspensions Active ingredients (multiple ingredients allowed): 0.01-50% Liquid vehicle 10-99.9% Humectant 0-50% Thickener 0-50% Appropriate amount of cushioning material Osmotic agent 0-50% Preservative (appropriate amount)

[0283] IV. Syrup Active ingredients (multiple ingredients allowed): 0.01-50% Solvent 10-99.9% Sugar content 1~20% Flavoring agents 0-10%

[0284] C) Parenteral medication forms V. Intravenous injection Active ingredients (multiple ingredients allowed): 0.01-50% Solvent 10-99.9% Cosolvent 0-99.9% Osmotic agent 0-50% Appropriate amount of cushioning material

[0285] D) Other forms of medication VI. Suppositories Active ingredients (multiple ingredients allowed): 0.01-50% Suppository base 1-99.9% Surfactants 0-20% Lubricant 0-20% Preservative (appropriate amount)

[0286] VII. Eye drops Active ingredients (multiple ingredients allowed): 0.01-50% Water 0~99.9% Solvent 0-99.9% Osmotic agent 0-20% Viscosity enhancer 0-20% Appropriate amount of cushioning material Preservative (appropriate amount)

Claims

1. Compound of formula (I): 【Chemistry 1】 (In formula (I), R １ C １ ~C ６ Alkyl or Halo-C １ ~C ６ Represents a phenyl or cyclohexyl group substituted with an alkyl group; R ２ indicates H or halogen; R ３ is H or C １ -C ６ alkyl; R ４ H;C １ ~C ６ Alkyl or Halo-C １ ~C ６ It indicates alkyl; R ５ and R ６ H;C are each independent of each other. １ ~C ６ It can be alkyl or halogen; R ７ and R ８ Each is independently H or C １ ~C ６ It can be alkyl; R ９ and R １０ Each is independently H or C １ ~C ６ It may be alkyl, or R ９ and R １０ They can combine to form an oxo group; X is -CR ｘ R ｙ or -O- or -S(O) ｎ - Indicates a group, in the formula, R ｘ and R ｙ Each is independently H or C １ ~C ６ It can be an alkyl group, where n is 0, 1, or 2; Z is -NR-; or -O-; or -S(O) ２ - Indicates the base, Here, R is either H or -C(O)R １１ Or -S(O) ２ R １２ Group: aminocarbonyl-C １ ~C ３ Alkyl; Carboxy-C １ ~C ３ Alkyl; cyano-C １ ~C ３ Alkyl; C １ ~C ５ (Cyclo)alkyl; saturated 4- to 6-membered heterocyclic ring having one oxygen atom, or -C(NH)(NH ２ ) It can be a base; Here, R １１ H;C １ ~C ３ Alkyl; C １ ~C ３ Alkoxy; Deutero-C １ ~C ３ Alkoxy; C １ ~C ３ Alkoxy-C １ ~C ３ Alkyl; C １ ~C ３ Alkoxy-C １ ~C ３ Alkoxy; Methanesulfonyl-C １ ~C ３ It could be alkyl; or R １１ This refers to a saturated 3-6 membered carbon ring, or a 4-6 membered saturated or unsaturated heterocyclic ring having 1-3 heteroatoms selected from N, O, or S; or an amino, monoalkylamino, or dialkylamino group; amino-C １ ~C ３ Alkyl; NH ２ - Hydroxy-C substituted with a group １ ~C ３ It can be alkyl; R １２ C １ ~C ３ Alkyl; may be an amino or dialkylamino group; R ４ and CR ｘ (It can form a cycloalkyl ring.) or its pharmaceutically acceptable salts, enantiomers, or diastereomers.

2. X is -CR ｘ R ｙ When indicating this, Z indicates a -NR- group; an -O- group; or an -S(O)²- group; or If X represents a -O- or -S(O)n- group, then Z represents a -NR- group. The compound according to claim 1.

3. X is -CR ｘ R ｙ This shows that Z represents a -NR- group, where R is -C(O)R １１ The compound according to claim 2.

4. X is -O- or -S(O) ２ - indicates a group, Z indicates a -NR- group, and here R is -C(O)R １１ or -S(O) ２ R １２ The compound according to claim 2, which is a base.

5. The following groups: 1-[(3R)-3-{6-ethyl-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-methylpiperidine-1-yl]ethane-1-one, 1-[(3S)-3-{6-ethyl-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-methylpiperidine-1-yl]ethane-1-one, 1-{3-[5-methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl]piperidine-1-yl}ethane-1-one, 1-[(3R)-3-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-yl]ethane-1-one, 1-[(3S)-3-{6-ethyl-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-yl]ethane-1-one, (3R)-3-{6-ethyl-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-1-methanesulfonyl-3-methylpiperidine, (3R,4S)-4-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-carboxylate methyl, (3S,4R)-4-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-carboxylate methyl, trans-3-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-4-methylpiperidine-1-carbaldehyde, 1-[trans-3-{6-ethyl-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-4-methylpiperidine-1-yl]ethane-1-one, trans-4-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-carbaldehyde, trans-3-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-4-methylpiperidine-1-carboxylate methyl, 5-{5,6-dimethyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3,3-difluoropiperidine-1-carbaldehyde, 2-{6-ethyl-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine-4-carbaldehyde, (2R)-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine-4-carboxylate methyl, trans-2-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine-1-carboxylate methyl, (2R)-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine-4-sulfonamide, (2R,5S)-5-methyl-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine-4-carboxylate methyl, (2R)-2-{3-fluoro-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine-4-carboxylate methyl, 5-methyl-7-[(3R)-oxan-3-yl]-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine, and 5-methyl-7-[(3S)-oxan-3-yl]-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine A compound according to claim 1, selected from the following.

6. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) described in claim 1 or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, as an active ingredient, and a pharmaceutically acceptable carrier.

7. A combination comprising a therapeutically effective amount of the compound of formula (I) described in claim 1 or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, and one or more therapeutically active co-agents.

8. GABA Ｂ A method for producing a pharmaceutical composition having a positive allosteric modulator effect on a receptor, comprising mixing a therapeutically effective amount of the compound of formula (I) described in claim 1, or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer thereof, or an optical counterpart of the compound of formula (I), or a combination thereof, with a pharmaceutically acceptable excipient.

9. GABA Ｂ A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, for use as a receptor-positive allosteric modulator.

10. GABA Ｂ A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, for use in the treatment or prevention of disorders associated with receptor positive allosteric modulator activity.

11. GABA Ｂ The compound for use according to claim 10, wherein the impairment associated with receptor positive allosteric modulator activity is selected from the group consisting of mental disorders (anxiety, panic disorder, post-traumatic disorder, depression, schizophrenia), neurodevelopmental disorders (autism spectrum disorder, obsessive-compulsive disorder, fragile X syndrome), cognitive impairment, epilepsy, spasticity, skeletal muscle rigidity, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, cerebral palsy, essential tremor, pain (neuropathic, visceral, osteoarthritis), drug abuse (cocaine, nicotine, alcohol), obesity, bulimia, asthma, cough, urinary incontinence, gastroesophageal reflux disease, transient lower esophageal sphincter relaxation, and irritable bowel syndrome.

12. GABA Ｂ A pharmaceutical composition for the treatment and / or prevention of disorders requiring positive allosteric modulation of a receptor, comprising an effective amount of the compound of formula (I) according to claim 1 or an optical isomer or salt thereof or a combination thereof, or an effective amount of the compound of formula (I) according to claim 1 or an optical isomer or salt thereof or a combination thereof, in combination with pharmaceutically acceptable auxiliary materials customarily applied in pharmaceuticals.

13. The aforementioned GABA Ｂ The pharmaceutical composition according to claim 12, wherein the disorder requiring positive allosteric modulation to the receptor is selected from the group consisting of mental disorders (anxiety, panic disorder, post-traumatic disorder, depression, schizophrenia), neurodevelopmental disorders (autism spectrum disorder, obsessive-compulsive disorder, fragile X syndrome), cognitive impairment, epilepsy, spasticity, skeletal muscle rigidity, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, cerebral palsy, essential tremor, pain (neuropathic, visceral, osteoarthritis), drug abuse (cocaine, nicotine, alcohol), obesity, bulimia, asthma, cough, urinary incontinence, gastroesophageal reflux disease, transient lower esophageal sphincter relaxation, and irritable bowel syndrome.

14. A pharmaceutical composition for treating and / or preventing a disorder requiring positive allosteric modulation of a GABA B receptor, comprising an effective amount of the compound of formula (I) described in Claim 1 or its optical counterpart or salt or a combination thereof, characterized in that the pharmaceutical composition is used together with a pharmaceutical composition comprising pharmaceutically acceptable auxiliary materials commonly used in pharmaceuticals.

15. The following compounds serve as intermediates in the synthesis of the compound of formula (I): (3S,4R)-4-methyl-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine (intermediate 213), (3S)-3-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine (intermediate 222), (3R)-3-{6-ethyl-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}-3-methylpiperidine (intermediate 160), (3S)-3-{6-ethyl-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}piperidine (intermediate 168), (2R,5S)-5-methyl-2-{5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine-7-yl}morpholine (intermediate 189).

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