HK1220192B - Sulfur-containing bicyclic compound - Google Patents

Abstract

To provide a compound useful as a pharmaceutical composition for prevention and/or treatment of diseases such as schizophrenia. [Solution] The inventors developed the present invention upon investigating a pharmaceutical composition having effects as a GABAB positive allosteric modulator (effects as a PAM), for preventing/treating diseases such as schizophrenia, and confirming that a sulfur-containing bicyclic compound has effects as a GABAB PAM. This sulfur-containing bicyclic compound has effects as a GABAB PAM and can be used as a preventive and/or therapeutic agent for diseases such as schizophrenia. (In the formula, X represents CH, R1 represents a lower alkyl, R2 represents a lower alkyl , R3 represents -H, R4 represents -H, ring A is a cyclohexane ring, RY represents a group represented by formula (III), Y represents NH, etc., and RL represents a lower alkyl.)

Description

Sulfur-containing bicyclic compound

Technical Field

The present invention relates to a pharmaceutical composition, in particular, a sulfur-containing bicyclic compound useful as an active ingredient of a pharmaceutical composition for the treatment of schizophrenia, cognitive disorders associated with schizophrenia (CIAS), cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasticity, anxiety disorder, substance dependence, pain, fibromyalgia, peroneal muscular atrophy, or the like.

Background

Gamma-aminobutyric acid (GABA) is ion channel type GABA_AAnd metabolic regulation type GABA_BThe representative inhibitory neurotransmitter, which both receptors activate. GABA_BReceptors are expressed in both the presynaptic terminal and postsynaptic portions of the mammalian brain, and have a wide range of roles in physiology and psychopathology by modulating inhibitory synaptic transmission. GABA_BThe receptor is a G protein-coupled receptor (GPCR) with seven transmembrane domains, structurally classified as Class C. The Class CGPCR has a particularly large extracellular domain and functions by forming homo-or heterodimers (Neuropharmacology,2011, Jan, vol.60(1), p.82-92). GABA_BReceptor formation of GABA_B1And GABA_B2The subunits of (a) cooperate with each other to function as a receptor. Namely, only GABA_B1GABA with positive enabling_BLigand binding function of receptor, promoting GABA_B2The coupling and activating functions of G protein. Activated GABA_BReceptor inhibition of adenylate cyclase and control of G protein-coupled K⁺Opening of channels (GIRK) or potential-dependent calcium channels.

Recent studies have reported that mental diseases such as cognitive impairment are caused by the decrease in GABA-mediated nerve function in patients (Trends in Neurosciences,2012, vol.35(1), p.57-67; molecular Psychiatry,2003, vol.8(8), p.721-737, 715; Frontiers in Psychiatry,2012, vol.3, p.51; Neuroscience & Biobehavior Reviews,2012, Oct, vol.36(9), p.2044-2055).

Baclofen is GABA_BReceptor selective agonists, for clinical use. Baclofen is reported to improve methamphetamine-induced cognitive dysfunction in mice in preclinical trials (European Journal of Pharmacology,2009, vol.602(1), p.101-104); methamphetamine and MK-801 induced prepulse inhibition disorder (Neuropsychopharmacology,2008, Dec, vol.33(13), p.3164-3175); and NMDA receptor dysfunction gene alters social behavioral disorders, spatial memory disorders and gamma band brain wave disorders in mice (translocational psychopathy, 2012, Jul 17, vol.2, p.e 142). R-baclofen is reported to be effective in patients with fragile X syndrome and Autism spectrum syndrome (Science comparative Medicine,2012, Sep 19, vol.4(152), p.152ra127; Journal of Autosm and Development disorders, 2014, Apr, vol.44(4), p.958-964). It is noted that FMR1, a causative gene of fragile X syndrome, has been reported to affect the expression of multiple related genes in autism spectrum syndrome (Nature,2012, Dec, vol.492, p.382-386; Cell,2011, Jul, vol.146(2), p.247-261).

Baclofen is clinically used for the treatment of spasms, contractures or contractures induced by spinocerebellar degeneration, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, cerebral palsy, cerebral stroke or head trauma (Neurology,2004, Oct 26, vol.63(8), p.1357-1363). In addition, baclofen anxiety disorder is reported (Journal of pharmacology and Experimental Therapeutics,2004, vol.310, p.952-963); substance Dependence such as Drug Dependence of nicotine, cocaine and morphine and Alcohol Dependence (Advances in Pharmacology,2010, vol.58, p.373-396; Drug and Alcohol Dependence,2002, Feb 1, vol.65(3), p.209-220; Synapse,2003, Oct, vol.50(1), p.1-6); pain such as neuropathic Pain (European journal of Pain,2004, Aug, vol.8(4), p.377-383); and reflux esophagitis (neurogastrology and mobility, 2012, Jun, vol.24(6), p.553-559, e 253).

Reported as GABA_BAgonist gamma-hydroxybutyrate (GHB) also improves fibridsThe fatigue of patients with the fibromyalgia is effective on the fibromyalgia (Pain,2011, vol.152, p.1007-1017). The symptoms of fatigue are similar for fibromyalgia and chronic fatigue. GABA_BAgonists are also expected to be effective in chronic fatigue.

Reported if GABA is activated_BThe signal inhibited the overexpression of the PMP22 gene, which was a cause of peroneal muscular atrophy type1A (European Journal of Neuroscience,2004, May, vol.19(10), p.2641-2649; Nature Reviews Drug Discovery,2012, vol.11, p.589).

Reported GABA_BReceptors are also present in peripheral organs such as spleen, lung, liver, intestine, stomach, esophagus or bladder (Neuroscience,2000, vol.100(1), p.155-170; The Journal of BiologicalChemistry,2000, Oct 13, vol.275(41), p.32174-32181). Therefore, GABA is expected_BReceptor ligands may also be used in the treatment of diseases of peripheral organs.

From the above, it is considered that GABA is_BThe compounds that activate the receptor are useful for the prevention or treatment of schizophrenia, CIAS, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasticity, anxiety disorders, substance dependence, pain, fibromyalgia or peroneal muscular atrophy, among others.

On the other hand, baclofen has limited its use because it narrows the therapeutic window due to adverse side effects such as sedation and muscle weakness. The decrease in motor coordination and the decrease in body temperature are also side effects of baclofen therapy.

There are several reports of Positive Allosteric Modulators (PAM) (Molecular Pharmacology,2001, vol.60(5), p.963-971; Journal of Pharmacology and Experimental Therapeutics,2004, Sep, vol.310(3), p.952-963; Psychopharmacology (Berl),2011, May, vol 215(1), p.117-128). GABA_BPAM of the receptor binds to the receptor at a site different from the binding site of the endogenous ligand, thereby enhancing the function of the receptor. GABA_BPAM of the receptor alone does not show agonist activity, but has the effect of increasing endogenous GABA to the receptorAffinity to increase GABA_BPotency and potency of the receptor. It is considered that GABA is due to this characteristic_BPAM of the receptor did not show GABA_BAgonists have side effects (such as those of baclofen described above) and have useful therapeutic effects.

Therefore, GABA is expected_BThe PAM receptor has fewer side effects, and is particularly useful for the prevention or treatment of schizophrenia, CIAS, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasticity, anxiety disorder, substance dependence, pain, fibromyalgia, peroneal muscular atrophy, and the like.

Patent document 1 discloses a compound of the following general formula, which contains a compound shown as Ex60, as a therapeutic agent for schizophrenia:

[ chemical formula 1]

(in the formula, R¹The definition of (1) includes a plurality of groups. As one of them, R¹Examples thereof include cycloalkyl groups which may be substituted. A. theⁿThe definition of (1) includes a plurality of groups. As one of them, AⁿExamples thereof include an alkyl group which may be substituted. Other symbols in the formula refer to patent document 1).

Patent document 2 discloses that mGluR1 inhibitors represented by the following general formula are useful for parkinson's disease, migraine and the like.

[ chemical formula 2]

(in the formula, R²represents-N (R)^2a)R^2b、-O-R^2a、-S-R^2a. Other symbols refer to patent document 2. )

Patent document 3 discloses that 5-HT antagonists represented by the following general formula are useful as remedies for neuropathological diseases.

[ chemical formula 3]

(the symbol in the formula is referred to in patent document 3.)

Documents of the prior art

Patent document

Patent document 1: international publication No. WO2006/030031

Patent document 2: international publication WO02/062803

Patent document 3: international publication No. WO2004/089312

Disclosure of Invention

Problems to be solved by the invention

The present invention provides a sulfur-containing bicyclic compound which is useful as an active ingredient of a pharmaceutical composition for the treatment of schizophrenia, CIAS, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasm, anxiety disorder, substance dependence, pain, fibromyalgia, peroneal muscular atrophy, or the like.

Means for solving the problems

The inventors of the present invention have investigated GABA_BPAM of receptor is intensively researched, and as a result, the sulfur-containing bicyclic compound is GABA_BPAM of a receptor, thereby completing the present invention.

That is, the present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition containing the compound of formula (I) or a salt thereof and an excipient.

[ chemical formula 4]

(in the formula, wherein,

x is a group of a CH,

R¹is a lower alkyl group, and is,

R²is a lower alkyl group, and is,

herein, R is¹And R²May form cycloalkanes together with the carbon atoms to which they are bonded,

R³is a compound of the formula-H,

R⁴is a compound of the formula-H,

the ring A is a cyclohexane ring,

R^Yis-NR^AR^B，

R^AAnd R^BForms a cyclic amino group which may be substituted in combination with the bonded nitrogen atom,

here, the cyclic amino group is a group represented by the following formula (III):

[ chemical formula 5]

Y is NH, O, S (═ O)₂Or CH₂，

R^LIs a lower alkyl group. )

It is to be noted that, unless otherwise specified, the same symbols in a certain chemical formula in this specification are used for the same meaning in the case where the symbols are used for other chemical formulas.

Further, the present invention relates to the following:

(1) a pharmaceutical composition for the treatment of schizophrenia, CIAS, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasticity, anxiety disorders, substance dependence, pain, fibromyalgia or peroneal muscular atrophy comprising a compound of formula (I) or a salt thereof;

the pharmaceutical composition contains a therapeutic agent for schizophrenia, CIAS, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasm, anxiety disorder, substance dependence, pain, fibromyalgia or peroneal muscular atrophy, which contains a compound of formula (I) or a salt thereof.

(2) Use of a compound of formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for the treatment of schizophrenia, CIAS, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasticity, anxiety disorders, substance dependence, pain, fibromyalgia or peroneal muscular atrophy;

(3) use of a compound of formula (I) or a salt thereof for the treatment of schizophrenia, CIAS, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasticity, anxiety disorders, substance dependence, pain, fibromyalgia or peroneal muscle atrophy;

(4) a compound of formula (I) or a salt thereof, for use in the treatment of schizophrenia, CIAS, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasticity, anxiety disorders, substance dependence, pain, fibromyalgia or peroneal muscular atrophy;

(5) a method of treating schizophrenia, CIAS, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasticity, anxiety disorders, substance dependence, pain, fibromyalgia, or peroneal muscular atrophy comprising administering to a subject an effective amount of a compound of formula (I) or a salt thereof.

The term "subject" refers to a human or other animal in need of prevention or treatment thereof, and in one aspect, refers to a human in need of prevention or treatment thereof.

ADVANTAGEOUS EFFECTS OF INVENTION

Compounds of formula (I) or salts thereof having GABA_BPAM action of the receptor, and can be used as a preventive and/or therapeutic agent for schizophrenia, CIAS, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasm, anxiety disorder, substance dependence, pain, fibromyalgia, or peroneal muscular atrophy.

Detailed Description

The present invention will be described in detail below.

The "lower alkyl group" is a straight-chain or branched-chain C1-6 (hereinafter also referred to as C)_1-6. The number of carbon atoms is shown in the same manner below. ) Such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. As another mode, is C_1-4In yet another embodiment, the alkyl group is methyl.

The "lower alkylene" is a straight or branched C_1-6The alkylene group of (A) is exemplified by methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene, 1, 2-dimethylethylene, 1,2, 2-tetramethylethylene, etc. As another mode, is C_1-4Still another embodiment of the alkylene group is an ethylene group.

The "halogenated lower alkyl group" refers to C substituted with 1 or more halogens_1-6An alkyl group. In another embodiment, the lower alkyl group is substituted by 1 to 5 halogens, in yet another embodiment, the lower alkyl group is substituted by 1 to 3 halogens, and in yet another embodiment, the lower alkyl group is-CF₃。

"halogen" means F, Cl, Br or I.

By "cycloalkanes" is C_3-8A saturated hydrocarbon ring of (2). For example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane. As another mode, is C_5-6The cycloalkane may be cyclohexane in another embodiment, or cyclopropane in another embodiment.

By "cycloalkyl" is C_3-8The saturated hydrocarbon ring group of (4). For example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. As another mode, is C_5-6The cycloalkyl group is a cyclohexyl group in another embodiment, and is a cyclopropyl group in another embodiment.

In the present specification, the term "optionally substituted" means that the substituent is unsubstituted or has 1 to 5 substituents. Another embodiment is unsubstituted or has 1 to 3 substituents. When a plurality of substituents are present, the substituents may be the same or different from each other.

In this specification, at "R^AAnd R^BIn the case where the cyclic amino group which may be substituted is formed integrally with the bonded nitrogen atom, "a substituent which may be substituted in the cyclic amino group may be a group selected from the group Z described below.

Group Z:

(1)＝O、

(2)-OH、

(3) -O-lower alkyl,

(4) Halogen, halogen,

(5)-CN、

(6) Lower alkyl,

(7) a halogenated lower alkyl group,

(8) Lower alkylene-OH,

(9) Lower alkylene-O-lower alkyl,

(10) -C (═ O) -lower alkyl,

(11) -C (═ O) -lower alkylene-OH,

(12) -C (═ O) -lower alkylene-CN, and

(13) cycloalkyl radicals

Examples of the "group selected from group Z" include groups selected from group Z1 described below.

Group Z1:

(1)-OH、

(2) lower alkyl,

(3) -C (═ O) -lower alkylene-OH.

An embodiment of the present invention is shown below.

[1] A compound of formula (I) or a salt thereof, wherein,

R^Yis-NR^AR^B，

R^AAnd R^BIs formed integrally with the bonded nitrogen atom to be substituted by R⁰A substituted cyclic amino group,

here, the cyclic amino group is a group represented by the following formula (III):

[ chemical formula 6]

R⁰Is a group selected from the following group Z:

group Z:

(1)＝O、

(2)-OH、

(3) -O-lower alkyl,

(4) Halogen, halogen,

(5)-CN、

(6) Lower alkyl,

(7) a halogenated lower alkyl group,

(8) Lower alkylene-OH,

(9) Lower alkylene-O-lower alkyl,

(10) -C (═ O) -lower alkyl,

(11) -C (═ O) -lower alkylene-OH,

(12) -C (═ O) -lower alkylene-CN, and

(13) a cycloalkyl group.

[2] The compound according to [1] or a salt thereof, wherein,

the group selected from group Z is a group selected from group Z1:

group Z1:

(1)-OH、

(2) lower alkyl,

(3) -C (═ O) -lower alkylene-OH.

[3] A compound of formula (I) or a salt thereof, wherein,

y is O, S or S (═ O)₂。

[4] A compound of formula (I) or a salt thereof, wherein,

R^Lis CH₃。

[5] A compound which is a combination of two or more of the groups described in the above aspects [1] to [4], or a salt thereof.

Examples of the above combinations of the present invention are shown below.

[6] A compound of formula (I) or a salt thereof, wherein,

x is CH, ring A is cyclohexane ring, R¹Is lower alkyl, R²Is lower alkyl, R³is-H, R⁴is-H, R^YIs of the following formula (III) which may be substituted:

[ chemical formula 7]

Y is O, S or S (═ O)₂，R^LIs a lower alkyl group.

Specific examples of the compound contained in the present invention include the following compounds and salts thereof.

6- (4, 4-dimethylcyclohexyl) -4- [ (1, 1-dioxo-1. lamda.)⁶-thiomorpholin-4-yl) methyl]-2-methylthioeno [2,3-d]Pyrimidine, and their use,

Trans-1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d ] pyrimidin-4-yl ] methyl } piperidine-3, 4-diol,

1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d ] pyrimidin-4-yl ] methyl } piperidin-4-ol,

6- (4, 4-dimethylcyclohexyl) -2-methyl-4- (thiomorpholin-4-ylmethyl) thieno [2,3-d ] pyrimidine,

6- (4, 4-dimethylcyclohexyl) -4- [ (3, 3-dimethylmorpholin-4-yl) methyl ] -2-methylthio-eno [2,3-d ] pyrimidine, or

1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d ] pyrimidin-4-yl ] methyl } -2, 2-dimethylpiperidin-4-ol.

Note that "1, 1-dioxo-1. lamda.⁶The "thiomorpholin-4-yl" means the same group as "1, 1-thiomorpholin-4-yl (1,1- ジオキシドチオモルホリン -4- イル)".

In the present specification, "PAM" refers to a compound that binds to a receptor at a site different from a binding site of an endogenous ligand to improve the function of the receptor. Is a compound which does not exhibit agonist activity alone, but has an effect of increasing the potency and efficacy of a receptor.

In the present specification, the "PAM action" refers to an action possessed by the PAM. For example, in test example 1, the action of shifting the GABA dose response curve to the left and up in response to the dose on the horizontal axis and the vertical axis is referred to. If the test drug has "potency", the GABA dose response curve is shifted to the left, and if the test drug has "potency", the GABA dose response curve is shifted up.

The symptoms of the diseases in the present specification are not completely independent and may be repeated. For example, the symptoms of schizophrenia, CIAS, cognitive dysfunction may be repeated with each other.

In the present specification, the disease name is also referred to "ICD 10" which is an international disease classification of WHO (world health organization), a statistical manual of mental diagnosis of american society of psychiatry (APA), fourth edition (DSM-4) and 5 edition (DSM-5), and/or a japanese society of neurology guideline, and the like.

The compounds of formula (I) may exist as tautomers or geometric isomers depending on the kind of the substituent. In the present specification, the compound of formula (I) may be described as only one form of isomer, but the present invention also includes isomers other than the above, and includes a substance obtained by separating isomers, or a mixture thereof.

In addition, the compounds of formula (I) sometimes have asymmetric carbon atoms or axial asymmetry, and optical isomers based thereon may exist. The present invention also includes a substance obtained by separating optical isomers of the compound of formula (I) or a mixture thereof.

The present invention also encompasses pharmaceutically acceptable prodrugs of the compounds of formula (I). The pharmaceutically acceptable prodrug is a compound having a group which can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of the group forming a prodrug include those described in Progress in Medicine,1985, p.2157-2161, 1990 in "development of pharmaceuticals" (Kagaku bookshop), volume 7, and molecular design p.163-198.

The salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and may be a salt with an acid addition salt depending on the kind of the substituent. Specifically, there may be mentioned: acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, etc.

Furthermore, the present invention also encompasses various hydrates, solvates and polymorphic forms of the compound of formula (I) and a salt thereof. In addition, the present invention also encompasses compounds labeled with various radioactive or non-radioactive isotopes.

(production method)

The compounds of formula (I) and salts thereof can be produced by utilizing the characteristics based on the basic structure thereof or the kind of substituents, and applying various known synthetic methods. In this case, depending on the kind of the functional group, it may be effective in terms of production technology to replace the functional group with an appropriate protecting group (a group which can be easily converted into the functional group) at a stage from the starting material to the intermediate. Examples of such a protecting group include: ウッツ (P.G.M.Wuts) and グリーン (T.W.Greene) "Greene's protective Groups in Organic Synthesis (fourth edition), 2006", and the like, may be used as appropriate depending on the reaction conditions. In such a method, the desired compound can be obtained by introducing the protecting group and carrying out a reaction, and then removing the protecting group as necessary.

In addition, the prodrug of the compound of the formula (I) can be produced by introducing a specific group from the starting material to the intermediate in the same manner as the above-mentioned protecting group, or by further reacting the obtained compound of the formula (I). The reaction can be carried out by a method known to those skilled in the art, such as ordinary esterification, amidation, and dehydration.

Next, a typical production method of the compound of formula (I) will be described. The respective production methods can also be carried out with reference to the references attached to the description. The production method of the present invention is not limited to the following examples.

In the present specification, examples, production examples, and tables to be described later, the following abbreviations may be used.

PAM ═ positive allosteric modulators, PAM action ═ positive allosteric modulators, CIAS ═ cognitive disorders associated with schizophrenia.

AcOH ═ acetic acid, BINAP ═ 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl, bromine ═ saturated saline, CBB ═ coomassie brilliant blue, CHAPS ═ 3- [ (3-cholamidopropyl) dimethylamino group]Propanesulfonic acid salt, DABCO ═ 1, 4-diazabicyclo [2.2.2]Octane, DCE ═ 1, 2-dichloroethane, DCM ═ dichloromethane, CDI ═ 1,1' -carbonyldiimidazole, D-MEM ═ dak modified igger's medium, DIBAL ═ diisobutylaluminum hydride, DIBOC ═ di-tert-butyl dicarbonate, DIPEA ═ N, N-diisopropylethylamine, DME ═ dimethoxyethane, DMF ═ N, N-dimethylformamide, DMSO ═ dimethyl sulfoxide, DPPA ═ azidodiphenyl phosphate, DPPF ═ 1,1' -bis (diphenylphosphino) ferrocene, EGTA ═ glycolether diamine tetraacetic acid, Et ═ dichloromethane, di-tert-butyl dicarbonate, DPPA ═ di-tert-butyl dicarbonate, DIPEA ═ N, N-diisopropylethylamine, DME ═ dimethoxyethane, DMF ═ N, N₂Diethyl ether, EtOAc, EtOH, GABA, γ -aminobutyric acid, HATU, 1- [ bis (dimethylamino) methylene]-1H-1,2, 3-triazolo [4,5-b]Pyridine-1-onium 3-oxide hexafluorophosphate, HCl/EtOAc/hydrogen chloride/EtOAc solution, HCl/dioxane/hydrogen chloride/dioxane solution, HBSS balanced salt solution, Hepes 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid, HOBt 1-hydroxybenzotriazole, IPE diisopropyl ethyl ether, KOBu^tPotassium tert-butoxide, lithium LAH-alanate, MeCN-acetonitrile, MeOH-methanol, MgSO₄Anhydrous magnesium sulfate,Ms-methanesulfonyl, MsCl-methanesulfonyl chloride, NaOEt-sodium ethoxide, Na₂SO₄Sodium sulfate anhydrous, NaBH (OAc)₃Sodium triacetoxyborohydride, NaOBu^tSodium tert-butoxide, NBS ═ N-bromosuccinimide, NCS ═ N-chlorosuccinimide, N-BuLi ═ N-butyllithium, NMO ═ N-methylmorpholine, NMP ═ N-methyl-2-pyrrolidone, ORF ═ open reading frame, pd (oac)₂Palladium (II) acetate, palladium on carbon Pd/C, Pd₂dba₃Tris (dibenzylideneacetone) dipalladium (0), Pd (PPh)₃)₄Tetrakis (triphenylphosphine) palladium (0), Red-Al sodium aluminum hydride bis (2-methoxyethoxy) aluminate, TEA triethylamine, THF tetrahydrofuran, TTIP titanium Isopropoxide (IV), WSC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, silica gel column chromatography, basic silica gel column chromatography, NaHCO supercritical chromatography, saturated sodium bicarbonate water saturated₃An aqueous solution.

The following abbreviations are sometimes used in the structural formulae.

Ac ═ acetyl, Bn ═ benzyl, Boc ═ tert-butoxycarbonyl, Et ═ ethyl, Me ═ methyl, Ms ═ SO₂CH₃Ph ═ phenyl group,^tBu or Bu^tTert-butyl.

In addition, the concentration mol/L is expressed as M for convenience. For example, 1M aqueous NaOH solution means 1mol/L aqueous NaOH solution.

(first preparation method)

[ chemical formula 8]

(wherein Lv represents a leaving group; the same applies hereinafter.)

Compound (I-1) of the present invention can be produced from compound (1) and compound (1 a).

Leaving groups such as halogen, OMs groups and the like. The reaction can be carried out by using the compound (1) and the compound (1a) in the same amount or in an excess amount, in a solvent inert to the reaction or without a solvent, under cooling to heating, preferably at 0 to 80 ℃, and usually under stirring for 0.1 hour to 5 days. The solvent is not particularly limited as long as it does not inhibit the reaction, and is an aromatic hydrocarbon such as toluene or xylene, Et₂Ethers such as O, THF, DME, dioxane, halogenated hydrocarbons such as DCM, DCE, chloroform, DMF, DMSO, EtOAc, MeCN, and mixed solvents thereof. Sometimes TEA, DIPEA or NMO or K₂CO₃、Na₂CO₃Or an inorganic base such as KOH allows the reaction to proceed more smoothly.

[ document ]

Sandler and w.karo, "Organic Functional Group Preparations", 2nd edition, volume 1, Academic Press inc., 1991;

volume 14 (2005) (Wanshan) (Japan chemical society eds) "Experimental chemistry lecture (5 th edition)

(second preparation method)

[ chemical formula 9]

(wherein the double bond at the intersection represents a cis-or trans-form.)

Compound (I-2) of the present invention can be produced from compound (2) and compound (1 a).

In this reaction, the compound (2) and the compound (1a) are used in equal amounts or in an excess amount, and the mixture is stirred in a solvent inert to the reaction in the presence of a reducing agent at-30 ℃ to reflux with heating, preferably at 0 ℃ to room temperature, for usually 0.1 hour to 5 days. The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include alcohols such as MeOH, ethers, and mixed solvents thereof. As reducing agent, NaBH (OAc) can be used₃、NaBH₃CN、NaBH₄And the like. If adding dehydrating agent such as molecular sieve or AcOH, hydrochloric acid, TTIP complex, etc., the reaction may proceed more smoothly. In some cases, an imine may be formed by condensation of the compound (2) and the compound (1a), and the imine may be isolated as a stable intermediate. This imine intermediate can be reduced to produce compound (I-2). Instead of using the above-mentioned reducing agent, a reducing catalyst (e.g., Pd/C, Raney nickel, etc.) may be used in a solvent such as MeOH, EtOH, EtOAc, etc., in the presence or absence of an acid such as AcOH, hydrochloric acid, etc., under a hydrogen atmosphere of normal pressure to 50 atmospheres. The reaction can be carried out under cooling to heating.

[ document ]

Katritzky and R.J.K.Taylor, "Comprehensive Organic Functional groups formats II", Vol.2, Elsevier Pergamon, 2005;

volume 14 (2005) (Wanshan) (Japan chemical society eds) "Experimental chemistry lecture (5 th edition)

(third Process)

[ chemical formula 10]

Compound (I-3) of the present invention can be produced from compound (3) and compound (1 a).

In this reaction, the compound (3) and the compound (1a) are used in equal amounts or in an excess amount, and in the presence of a condensing agent, the mixture is cooled to heated, preferably at-20 to 60 ℃, in a solvent inert to the reaction, and usually stirred for 0.1 hour to 5 days. The solvent is not particularly limited as long as it does not inhibit the reaction, and is an aromatic hydrocarbon, a halogenated hydrocarbon such as DCM, an ether, DMF, DMSO, EtOAc or CH₃CN, water, and a mixed solvent thereof. Examples of the condensing agent include WSC, CDI, DPPA, HATU, phosphorus oxychloride and the like. Sometimes, an additive such as HOBt makes the reaction proceed smoothly. Organic bases such as pyridine, TEA, DIPEA or NMO, or K₂CO₃、Na₂CO₃Or inorganic base such as KOH for smooth reactionIs carried out.

Further, the compound (I-3) of the present invention can also be produced from a reactive derivative of the carboxylic acid (3) and the compound (1 a). Examples of the reactive derivative include acid halides obtained by reacting a carboxylic acid with a halogenating agent such as phosphorus oxychloride or thionyl chloride; mixed anhydride obtained by reacting with isobutyl chloroformate and the like; and active esters obtained by condensation with HOBt or the like. The reaction of the reactive derivative with the compound (1a) may be carried out in a solvent inert to the reaction, together with an organic base such as pyridine, TEA, DIPEA or NMO, under cooling and heating, preferably at-20 ℃ to 60 ℃ for usually 0.1 hour to 5 days with stirring. The solvent is not particularly limited as long as it does not inhibit the reaction, and halogenated hydrocarbons, aromatic hydrocarbons, ethers and the like can be used. The organic base may also be a solvent.

[ document ]

Sandler and w.karo, "Organic Functional Group Preparations", 2nd edition, volume 1, Academic Press inc., 1991;

japan chemical society compiles "Experimental chemistry lecture (5 th edition)" volume 16 (2005) (Wanshan)

(fourth Process)

[ chemical formula 11]

Compound (I-4) of the present invention can be produced by hydrogenation of compound (4).

In this reaction, the compound (4) is cooled to heated, preferably stirred at room temperature for 1 hour to 5 days in a solvent inert to the reaction together with a metal catalyst in a hydrogen atmosphere. The solvent is not particularly limited as long as it does not inhibit the reaction, and is an alcohol, an ether or the like. The metal catalyst is, for example, Pd (OH)₂And palladium catalysts, and the like. As the hydrogen source, formic acid or ammonium formate may be used in an equivalent amount to an excess amount with respect to the compound (4) in place of hydrogen.

[ document ]

Hudlicky, reduction in Organic Chemistry,2nd ed (ACS Monograph:188), ACS, 1996;

japan chemical society compiles "Experimental chemistry lecture (5 th edition)" volume 19 (2005) (Boshan)

(raw Material Synthesis 1)

[ chemical formula 12]

(wherein Prg means a protecting group; the same applies hereinafter.)

The starting compound (1) can be produced from the compound (6).

(i) The starting compound (1) having Lv as a halogen can be produced by halogenating the compound (6). In this reaction, it may be reacted with SO₂Cl₂Or phosphorus oxychloride and DMF under heating-heating reflux. The solvent is not particularly limited as long as it does not inhibit the reaction, and toluene or the like can be used. The halogenating agent may also be PBr₃NBS, etc.

(ii) The starting compound (1) having an OMs group as Lv can be produced by adding an organic base and MsCl to a compound (6) in a reaction-inert solvent under ice cooling, and then cooling the mixture at 0 ℃ to room temperature. The solvent is not particularly limited as long as it does not inhibit the reaction, and DCM or the like can be used.

The compound (6) can be produced by reducing the compound (5).

In this reaction, the compound (5) is treated with an equivalent amount or an excess amount of a reducing agent usually for 0.1 hour to 3 days in a solvent inert to the reaction at a temperature of from-20 ℃ to 80 ℃ under cooling to heating. The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include ethers, aromatic hydrocarbons, alcohols, and mixed solvents thereof. NaBH can be used as the reducing agent₄Borane (BH)₃) And the following documents. Using, for example, NaBH in a reducing agent₄In the case of (3), calcium chloride may cause the reaction to proceed more smoothly.

[ document ]

Hudlicky, reduction in Organic Chemistry,2nd ed (ACS Monograph:188), ACS,1996

Larock, Comprehensive Organic Transformations, 2nd edition, VCHPublishers, inc., 1999;

donohoe, Inc. "Oxidation and Reduction in Organic Synthesis (Oxford chemistry Primers 6)", Oxford Science Publications, 2000;

volume 14 (2005) (Wanshan) (Japan chemical society eds) "Experimental chemistry lecture (5 th edition)

The starting compound (3) can be produced by deprotecting the compound (5). This reaction can be carried out by reference to グリーン (Greene) and ウッツ (Wuts), "Protective Groups in Organic Synthesis", 3 rd edition, John Wiley & Sons Inc, 1999.

(raw Material Synthesis 2)

[ chemical formula 13]

(wherein Hal represents halogen, R^ALRepresents lower alkyl, -OR^ALRepresents a lower alkoxy group. The same applies hereinafter. )

Compound (2) can be produced by deprotecting compound (8). The reactions are described in グリーン (Greene) and ウッツ (Wuts), "Protective Groups in Organic Synthesis", 3 rd edition, John Wiley & SonsInc, 1999.

The compound (8) can be produced from the compound (7) and lower alkoxyvinylboronic acid pinacol ester (7 a). This reactionIs a so-called Suzuki coupling of the compound (7) and a boric acid compound. The reaction can be carried out at room temperature to heating reflux by adding palladium, phosphine ligand and metal alkali as reagents. The solvent is not particularly limited as long as it does not interfere with the reaction, and an inert solvent or a solvent-free solvent to the reaction, such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, aprotic solvents, and AcOH, can be used. Palladium may be used, for example, as Pd (OAc)₂Or Pd₂dba₃And the like. As phosphine ligands, for example, BINAP, DPPF, P (Bu) may be used^t)₃And the like. The metal base can be K₂CO₃、Cs₂CO₃、NaOBu^tAnd the like.

(raw Material Synthesis 3)

[ chemical formula 14]

The starting compound (6) can be produced by hydrolysis of the compound (9).

The compound (9) can be produced from the compound (7) and the compound (7 b). The reaction is radical-bank coupling, and organic zinc compound and organic halide can be condensed with palladium or nickel catalyst to produce carbon-carbon bond product. The solvent is not particularly limited as long as it does not inhibit the reaction, and THF or the like can be used. The catalyst may be, for example, Pd (PPh)₃)₄. The reaction can be carried out at room temperature.

[ document ]

Negishi, e.acc.chem.res.,1982, vol.15, p.340-348;

de Meijere and f.diederich, eds, "Metal-Catalyzed Cross-couplings," 2nd edition, VCH Publishers inc., 2004;

volume 13 (2005) (pill) of the society of chemistry, japan, eds "experimental chemistry lecture (5 th edition);

organic Letters,2004, p.3225; synlett,2008, p.543

(raw Material Synthesis 4)

[ chemical formula 15]

(Compound (10) is present as a tautomer of a ketoenol as shown above. in this specification, Compound (10) and the compound of preparation example described later, i.e., Pr23, are represented by either a keto form or an enol form for convenience.)

The compound (7) can be produced by halogenating the compound (10).

This reaction can be carried out in the same manner as in the method described in the above raw material synthesis 1.

(raw Material Synthesis 5)

[ chemical formula 16]

The starting compound (5) can be produced from the compound (11). Prg is a lower alkyl group such as Me or Et.

This reaction can be carried out by stirring the compound (11) with hydrogen chloride such as HCl/dioxane, HCl/EtOAc and the like at room temperature to under heating for several hours to one night using an alcohol (Prg-OH) as a solvent and a reagent.

The compound (11) can be produced by cyanation of the compound (7). The reaction may be with NaCN or KCN or Zn (CN)₂Equal CN sources and CH₃SO₂Na and the like are stirred together at 50 to 80 ℃ for several hours to one night. The solvent is not particularly limited as long as it does not inhibit the reaction, and DMF and the like can be used.

(raw Material Synthesis 6)

[ chemical formula 17]

The starting compound (10-1) can be produced from the compound (14).

In this reaction, the compound (14) may be heated and stirred in a solvent inert to the reaction together with an aqueous solution of an inorganic base such as an aqueous NaOH solution. The solvent is not particularly limited as long as it does not inhibit the reaction, and alcohols such as EtOH can be used.

Compound (14) can be produced from compound (13).

The reaction is carried out by reacting compound (13) with a compound of formula R^L-acid halide reaction of C (C ═ O) -Hal. The reaction can be carried out by the same method as in the third process.

The compound (13) can be produced by adding an organic base such as 2-cyanoacetamide (12a), sulfur, TEA, or the like to the compound (12) and adding the mixture to a solvent, usually by heating. The solvent is not particularly limited as long as it does not inhibit the reaction, and DMF and the like can be used.

(raw Material Synthesis 7)

[ chemical formula 18]

The starting compound (10-2) can be produced from the compound (17) and the compound (17 a).

In the present reaction, formic acid may be added to the compound (17) and the compound (17a), and the mixture may be stirred with heating in a solvent inert to the reaction. The solvent is not particularly limited as long as it does not inhibit the reaction, and an alcohol or the like can be used.

The compound (17) can be produced by amidation of the compound (15) and the compound (16).

This reaction can be carried out in the same manner as the method described in the third production method.

(raw Material Synthesis 8)

[ chemical formula 19]

The starting compound (4) can be produced from compound (18) and compound (18 a).

The process is a so-called suzuki coupling. Can be produced in the same manner as in the production method of the compound (7) from the compound (8) of the above-mentioned starting material synthesis 2.

The compound of formula (I) is isolated and purified as a free compound, a salt, a hydrate, a solvate or a polymorphic form thereof. Salts of the compounds of formula (I) can also be prepared by salt-forming reactions by conventional methods.

The separation and purification can be carried out by ordinary chemical operations such as extraction, fractional crystallization, and various kinds of fractional chromatography.

Each isomer can be produced by selecting an appropriate starting compound, or can be separated by utilizing the difference in physicochemical properties between isomers. For example, the optical isomer can be obtained by a general optical resolution method of a racemate (for example, fractional crystallization inducing the racemate to form a diastereomer salt with an optically active base or acid, chromatography using a chiral column, or the like), or can be produced from an appropriate optically active raw material compound.

The pharmacological activity of the compound of formula (I) or a salt thereof was confirmed by the following test.

(Material)

The composition of the medium and the composition of the buffer used in the following test examples are shown below (the concentration of each reagent indicates the final concentration).

KH Buffer (Krebs-Henseleit Buffer) containing 119mM NaCl, 4.8mM KCl, 1.2mM KH₂PO₄、1.2mM MgSO₄、2.5mM CaCl₂、25mM NaHCO₃10mM glucose and 20mM Tris-HCl (pH 7.4).

A, a buffering agent: containing 0.32M sucrose, 1mM MgCl₂And 1mM K₂HPO₄An aqueous solution of (a).

B, buffer agent: containing 50mM Tris-HCl (pH 7.7), 100mM NaCl, 10mM MgCl₂、2mM CaCl₂0.2mM EGTA and 30. mu.M GDP in water.

C, buffer agent: containing 20mM Tris-HCl (pH 7.7) and 5mM MgCl₂An aqueous solution of (a).

Base buffer: an aqueous solution containing 2.5mM probenecid, 20mM Hepes-NaOH (pH 7.5) and Hanks Balanced Salt Solution (HBSS) containing 0.02% CHAPS.

Fluo-4 loading solution: base buffer containing 1. mu.M Fluo-4AM (Dojindo laboratories, Inc.), 0.067% DMSO and 0.0033% Pluronic F-127(life technologies, Inc.).

Test example 1: confirmation of PAM Effect Using GTP γ S binding assay

Use of³⁵S]GTP γ S binding assay for Compounds of the invention versus GABA_BThe function of the receptor was evaluated. The method is also useful for compounds relative to GABA_BMeasurement of PAM action of receptor (Journal of Pharmacology and Experimental Therapeutics,2003, vol.307(1), p.322-330; Molecular Pharmacology,2001, vol.60(5), p.963-971).

(Membrane preparations)

Mouse brain cortical membranes were prepared by reference to the preparation method of rat meninges (European Journal of Pharmacology,1990, vol.187(1), p.27-38).

The cortex (about 30g) was excised from the brain of 90 ddY mice (SLC, Japan). The cortex was homogenized with a buffer a (cortex/buffer about 1:3(wt/vol)) on ice using a glass teflon homogenizer (teflon: registered trademark). The homogenate was centrifuged (750g, 10 min, 4 ℃) to give a supernatant. A buffer (90mL) was added to pellet (ペレット), homogenized on ice, and centrifuged (750g, 10 min, 4 ℃ C.) to obtain a supernatant. This operation was repeated and the supernatant was collected.

The supernatant was centrifuged (18000g, 15 min, 4 ℃). Ultrapure water (54mL) was added to the pellets, allowed to stand on ice for 30 minutes, and centrifuged (39000g, 20 minutes, 4 ℃). The pellets were suspended in KH buffer (54mL), freeze-thawed repeatedly, and centrifuged (18000g, 15 min, 4 ℃). The operations of adding the buffer into the pellets, freezing and thawing, and centrifuging are repeated. The protein concentration of KH buffer suspension of pellets was adjusted to 10mg/mL by the Bradford method using protein analysis (protein analysis CBB solution; Nacalai Tesque Co.).

(GTP γ S binding assay)

GABA in the cerebral cortex of mice on test drugs_BThe PAM effect of the receptor was evaluated. The test drug, which was diluted with buffer B to respective concentrations (3nM to 30. mu.M), mouse brain cortex membrane (4. mu.g), were sequentially added to each well of a 96-well microplate³⁵S]GTP γ S (final concentration of 0.34nM, Komachi, Institute of Isotips Co., Ltd.), GABA (final concentration of 0.3. mu.M; Sigma Co., Ltd.), and allowed to stand at room temperature for 1 hour. The suspension was filtered with suction through a glass filter (UniFilter 96-well GF/B filter plate, Perkin-Elmer) using a collector (Filtermate, Perkin-Elmer). The glass filter was washed with ice-cooled C buffer. After drying the glass filter, liquid scintillation fluid (50. mu.L, MicroScinti-PS; Perkinelmer) was added to each well. The membrane-bound particles were measured with a plate reader (TopCount, PerkinElmer Co.), [ solution ] of³⁵S]The amount of GTP γ S was measured.

(data analysis)

The maximum response rate of 100. mu.M GABA was set as 100%. The reaction rate in the absence of GABA and test drug was set to 0%. The concentration of the test drug in which the reaction rate of 20% was increased to 50% by 0.3. mu.M GABA without adding the test drug was set as the test drugGABA of_BPAM titer (. mu.M). GABA was administered to 30 μ M maximum of the test drug in the presence of 0.3 μ M GABA_BThe maximum response rate of the effect of the receptor was set as GABA of the test drug_BPAM potency (%).

The potency and efficacy of several representative example compounds of the invention are shown in the following table (in the table Ex indicates the example compound number, "potency" indicates GABA of the tested drug_BPAM potency of (1). "potency" means GABA of the test drug_BPAM potency (%). The same applies hereinafter).

[ Table 1]

No.	Potency (μ M)	Potency (%)	No.	Potency (μ M)	Potency (%)
						Ex2	0.11	207	Ex55	0.25	175
Ex4	0.20	161	Ex61	0.24	160
						Ex5	0.24	176	Ex72	0.089	289
Ex7	0.24	139	Ex73	0.085	272
						Ex12	0.23	377	Ex74	0.19	244
Ex31	0.11	300	Ex79	0.046	230
						Ex31-1	0.18	191	Ex101	0.38	134
Ex39	0.42	165	Ex102	0.40	127
						Ex40	0.53	203	Ex104	0.079	218
Ex43	0.26	118	Ex108	0.20	176
						Ex44	0.27	119	Ex127	0.11	338
Ex45	0.44	134	Ex132	0.15	218
						Ex46	0.18	188	Ex142	0.0071	214
Ex47	0.12	240	Ex143	1.2	182
						Ex48	0.26	238	Ex144	0.31	182
Ex50	0.54	222	Ex146	0.10	258
						Ex51	0.15	249	Ex151	0.12	168
Ex52	0.17	259	Ex153	0.059	180
						Ex54	0.32	88	Ex155	0.046	159

Test example 2: use of GABA_BConfirmation of PAM action by receptor-stably expressing cells

Natural GABA_BThe receptor is GABA_B1And GABA_B2Subunits, two subunits constituting a heterodimeric structure (Nature,1997, vol.386, p.239-246). In GABA_B1The presence of a moiety called GABA_B1aAnd_1b2 major splice variants of (a). However, the 2 variants did not differ in pharmacological effect at the downstream signal of the receptor (Nature,1998, vol.396, p.683-687).

Intracellular Ca using RFU (relative fluorescence unit) as an index²⁺The change in concentration was measured with time to express GABA_B1bAnd GABA_B2The effectiveness of PAM in the presence of GABA in HEK293 cells of heterodimers of (a) was evaluated.

(expression of GABA_BEstablishment of cell lines for receptor

Will be respectively inserted into the GABA_B1b(NM_021903.2)、GABA_B2(NM-005458.7) and G α qo chimera were all introduced by lipofection to establish stably expressed human embryonic kidney-derived strain cell HEK293 cells (ATCC).

A ga qo chimera was prepared by the following method. The gene encoding human G.alpha.q (NM-002072.3) was cloned, and the C-terminal 15 base pairs (1107-.

(use of FLIPR on GABA_BIntracellular calcium mobilisation associated with receptor activation)

The fluorescent Imaging Plate Reader (FLIPR, Molecular Devices) was used to read the fluorescent Imaging Plate Reader (FI) with GABA_BThe change in intracellular calcium concentration mobilized by activation of the receptor was measured by proliferating the stably expressing cells established above in D-MEM medium containing selection agent (0.5mg/mL G418 disulfate and 0.2mg/mL hygromycin B solution), 1% penicillin/streptomycin, 10% FCS, about 1 × 10⁴One/well of cells was diluted with D-MEM medium containing 10% FCS without selection agent and 1% penicillin/streptomycin and seeded in a black-walled 384-well poly-D-lysine-coated plate (Becton Dickinson). After 24 hours, the medium was removed from the plate, and Fluo-4 loading solution (20. mu.L) was added to each well and incubated at room temperature for 2 hours. After removing the fluorescent reagent loading solution from each well and washing the cells 3 times with Base buffer, Base buffer (20. mu.L) was added and analyzed with FLIPR TETRA (Molecular Devices). The determination of the change in fluorescence was started by adding a Base buffer (10. mu.L) solution of the test drug at the final concentration (1nM to 30. mu.M). Then, GABA (1. mu.M, 20. mu.L) was added to continue the measurement. The change in fluorescence was measured every 2 seconds or 5 seconds.

(data analysis)

The maximum response rate of 100. mu.M GABA was set as 100%. The reaction rate in the absence of GABA and test drug was set to 0%. The concentration of the test drug in which the 5% reaction rate was increased to 50% by 1. mu.M GABA without addition of the test drug was set as GABA of the test drug_BPAM titer (. mu.M). Test drug was administered up to 30 μ M in the presence of 1 μ M GABA relative to GABA_BThe maximum response rate of the effect of the receptor was set as GABA of the test drug_BPAM potency (%).

The results of the evaluation tests in FLIPR of several representative example compounds of the invention are shown in the following table.

[ Table 2]

No.	Potency (μ M)	Potency (%)
			Ex2	0.059	470
Ex31	0.22	273

Test example 3: maze test of the Y letter (Y-maze test): improving effect on cognitive dysfunction

The effect of the compounds of the present invention on the improvement of short-term memory impairment was evaluated using a spontaneous alternation-based experimental system, i.e., the Y-maze test.

(Experimental facility)

The Y-shaped labyrinth uses 3 tracks each having an arm length of 40cm, a wall height of 13cm, a floor width of 3cm and an upper width of 10cm, and is connected at 120 degrees to form a Y-shaped labyrinth.

(test method)

The test drug was orally administered once to ddY-male mice (n ═ 8) aged 5 to 6 weeks 30 minutes before the start of the Y maze test, and MK-801 (Sigma) which is an NMDA receptor antagonist causing cognitive dysfunction was administered intraperitoneally at a dose of 0.15mg/kg 20 minutes before the start of the Y maze test.

In the control group, vehicle (0.5% methylcellulose) was used instead of the test drug, and further, physiological saline was used instead of MK-801.

Vehicle (0.5% methylcellulose) was used instead of the test drug in mice of the MK-801 control group.

The mice were left to explore freely for 8 minutes after being placed at the end of either runway of the Y-maze, and the runways and the sequence of mouse invasion were recorded. The number of entries of the mice within the measurement time was counted and set as the total number of entries. A combination of 3 different runways (for example, when 3 arms are a, b, and c, respectively, and the order of the arms entered is abccbacab, the number of spontaneous alternation actions is 4, including repetition). The spontaneous alternation rate is calculated by the following calculation formula and is used as an index of spontaneous alternation.

Spontaneous alternation rate ═ spontaneous alternation count/((total entry count) -2) × 100

The higher the index value is, the more short-term memory is displayed.

(data analysis)

The measurements are expressed as mean ± standard error in each group. The significant difference test for the control group and MK-801 control group was performed with Student's (Student) t test. In addition, significant difference test between the test drug-administered group and the MK-801 control group was performed by a Dunnett (Dunnett) type multiple comparison test, and the learning disorder-improving effect of the test drug was evaluated. In each test, if p < 0.05, it was judged to have significant difference.

The MED (mg/kg) of several representative example compounds of the invention are shown in the following table.

[ Table 3]

No.	MED(mg/kg)
		Ex2	0.1
Ex31	1.0

Test example 4: effect of tenderness threshold on reserpine induced myalgia model

The model is a model for simulating the symptoms of fibromyalgia. The test was carried out based on the description of Pain,2009, vol.146, p.26-33. Male SD rats (Japan SLC) were subcutaneously administered reserpine (1mg/kg) 1 time 1 day for 3 days. The solvent or test drug was administered orally after 5 days. After 30 minutes, the tenderness threshold was measured in gastrocnemius muscle using a Randall-Selitto apparatus (tonkin mechanical co). Significant difference tests between the solvent group and the test drug administration group were performed as a group comparison using Student's t-test or Dunnett multiple comparison test. Here, the value obtained by administering the solvent to normal rats to which reserpine was not administered was set to 100%, and the value obtained by administering the solvent to reserpine group was set to 0%. In each test, a significant difference was judged when p < 0.05.

[ Table 4]

No.	MED(mg/kg)
		Ex2	0.03

From the results of the above test, it was confirmed that the compound of the present invention has GABA_BPAM action of the receptor. Therefore, to GABA_BThe prevention or treatment of a receptor-associated disease or disorder, for example, schizophrenia, CIAS, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasticity, anxiety disorder, substance dependence, pain, fibromyalgia, or peroneal muscular atrophy, is useful.

Pharmaceutical compositions containing 1 or 2 or more compounds represented by formula (I) or salts thereof as active ingredients can be prepared by a conventional method using a conventional excipient (i.e., a pharmaceutical excipient, a pharmaceutical carrier, or the like) used in the art.

Administration may be oral administration using tablets, pills, capsules, granules, powders, liquid preparations, or the like, or non-oral administration using injections, suppositories, eye drops, eye ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalants, or the like, for intra-articular, intravenous, intramuscular, or the like.

As the solid composition for oral administration, tablets, powders, granules and the like can be used. In such solid compositions, 1 or more than 2 active ingredients may be mixed with at least 1 inert excipient. The compositions may contain inert additives such as lubricants or disintegrants, stabilisers, dissolution aids, according to conventional methods. The tablets or pills may be coated with sugar coatings or films of gastro-or enteric substances as desired.

The liquid composition for oral administration contains pharmaceutically acceptable opacifier, solution, suspension, syrup, elixir and the like, and contains a generally used inert diluent such as pure water or ethanol. The liquid composition may contain, in addition to the inert diluent, adjuvants such as solubilizers, wetting agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, preservatives.

Injections for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions or emulsions. The aqueous solvent includes, for example, distilled water for injection or physiological saline. Examples of the nonaqueous solvent include alcohols such as ethanol. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, or dissolution aids. They are, for example, filtered through a bacteria retaining filter, sterilized by the incorporation of a bactericide or irradiation. In addition, they can also be prepared into sterile solid compositions, and before using dissolved or suspended in sterile water or sterile solvent for injection and use.

The external preparations include ointments, plasters, creams, jellies, pastes, sprays, lotions, eye drops, eye ointments and the like. Comprises a generally used ointment base, lotion base, aqueous or non-aqueous liquid preparation, suspension, emulsion, etc.

The transmucosal agent such as an inhalant or nasal agent can be produced by a conventionally known method using a solid, liquid or semisolid. For example, a known excipient may be appropriately added, or a pH adjuster, a preservative, a surfactant, a lubricant, a stabilizer, a thickener, or the like may be further appropriately added. Administration may use means for appropriate inhalation or insufflation. For example, the compounds may be administered alone or as a powder of a formulated mixture, or may be combined with a pharmaceutically acceptable carrier and administered as a solution or suspension using a known device such as a metered dose inhaler or a nebulizer. The dry powder inhaler and the like may be used for single or multiple administration, and may use dry powder or powder-containing capsules. Or may be in the form of a pressurized aerosol spray or the like using a suitable propellant, e.g., a suitable gas such as chlorofluoroalkane or carbon dioxide.

In general, when the drug is orally administered, the dose of 1 day is about 0.001 to 100mg/kg, preferably 0.1 to 30mg/kg, and more preferably 0.1 to 10mg/kg per body weight, and the dose is administered 1 time or 2 to 4 times. When the administration is carried out intravenously, the dosage for 1 day is suitably about 0.0001 to 10mg/kg of body weight, and the administration is carried out once or in several times per day. Moreover, when the transmucosal is used, the transmucosal is administered once or in several portions per day at a weight of about 0.001 to 100 mg/kg. The dose is appropriately determined for each patient in consideration of symptoms, age, sex, and the like.

The pharmaceutical composition of the present invention contains 0.01 to 100% by weight of 1 or more compounds of formula (I) or salts thereof as an active ingredient, which is 0.01 to 50% by weight of one of the formulae, although the amount varies depending on the route of administration, dosage form, site of administration, excipient or additive.

The compound of the formula (I) may be used in combination with various therapeutic or prophylactic agents for diseases for which the compound of the formula (I) is considered to be effective. When used in combination, the administration may be simultaneous, or may be continuous or may be performed at desired time intervals. The preparation for simultaneous administration may be a compounding agent or may be prepared separately.

Examples

The following will explain the production method of the compound of formula (I) in further detail based on examples. The present invention is not limited to the compounds described in the following examples. The production examples are shown for the production of the starting compounds. The method for producing the compound of formula (I) is not limited to the production methods of the specific examples shown below, and the compound of formula (I) can be produced by a combination of these production methods or a method obvious to those skilled in the art.

The compounds shown in the tables described below were produced by the production methods described above and methods obvious to those skilled in the art or by modifications of these methods. In the table, the structure and physicochemical data of the compounds of these examples and the methods of their manufacture are shown. The symbols in the table indicate the following meanings.

No. example number or manufacturing example number.

No./Inf ═ (example No. or manufacturing example No. of the compound)/(salt information of the compound). for/Inf, for example/HCl means that the compound of this example is the monohydrochloride salt. In addition, the compound is a dihydrochloride when it is described as/2 HCl. further,/FUM means that the compound is a fumarate salt. In the absence of any description, the compound is an episome. In the table, Chiral indicates that the compound is an optically active substance.

Pr is a manufacturing example number, Ex is an example number, ref is a production method (the number indicates that the example compound is produced by the same production method as the example compound of the number, and it is to be noted that, in the table, when, for example, Ex86 is Pr8+ Ex85, it indicates that a substance is produced by the same method as that for producing example compound 8(Pr8), and then the resultant substance is used as a starting material, and further, a target is produced by the same method as that for producing example compound 85(Ex 85). in the table, when, for example, Pr26 is Pr8+ Ex1, it indicates that a target is produced by the same method as that for producing example compound 8(Pr8), and then, the resultant substance is used as a starting material, and further, a target is produced by the same method as that for producing example compound 1(Ex 1)).

Str is a structural formula and Data is physicochemical Data.

NMR(CDCl₃) In CDCl₃Measured for solvent¹Chemical shift value of H-NMR, NMR (DMSO-d)₆) In DMSO-d₆Measured for solvent¹Chemical shift values in H-NMR, EI-m/z values measured by EI-MS, ESI-m/z values measured by ESI-MS, APCI-m/z values measured by APCI-MS, APCI/ESI-m/z values measured simultaneously with APCI and ESI. CI is the m/z value measured in CI-MS. In the case where + or-is described as a suffix such as ESI, the + means an MS value measured in a positive ion mode, and the-means a negative ion modeThe measured MS value.

Production example 3

To a mixture of 2-acetamido-5- (4, 4-dimethylcyclohexyl) thiophene-3-carboxamide (37.3g) and EtOH (200mL) was added 2M aqueous NaOH solution (200mL), and the mixture was stirred at 80 ℃ for 2 hours. After the reaction mixture was allowed to cool to room temperature, 1M hydrochloric acid (500mL) was added and the mixture was stirred at room temperature. The precipitate was filtered to give 6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ] pyrimidin-4 (3H) -one (26.3 g).

Production example 4

In 6-cyclohexyl-2-methylthiophene [2,3-d ]]To a mixture of pyrimidin-4 (3H) -one (25.0g) and toluene (300mL) was added phosphorus oxychloride (14mL) and DMF (200. mu.L), and the mixture was heated at reflux for 14 hours at 150 ℃. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. Chloroform, water and saturated sodium bicarbonate water were added to the residue, and the mixture was stirred. The reaction mixture was extracted with chloroform. The organic layer was washed with water and brine in this order. Adding MgSO to the organic layer₄Stirring, activated carbon (2g), silica gel (100mL), filtering with Celite, and concentrating under reduced pressure to obtain 4-chloro-6-cyclohexyl-2-methylthioeno [2,3-d ]]Pyrimidine (27.4 g).

Production example 4-1

In 6- (4, 4-dimethylcyclohexyl) -2-methylthio-thieno [2,3-d]To a mixture of pyrimidin-4 (3H) -one (30.0g) and toluene (240mL) was added phosphorus oxychloride (40mL) and DMF (1.0mL) and the mixture was heated at reflux for 2H at 130 ℃. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. Chloroform and saturated sodium bicarbonate water were added to the residue, and the mixture was stirred. The organic layer was washed with water and brine in this order. Adding MgSO to the organic layer₄Stirring the mixture with activated carbon (10g) and silica gel (100mL), filtering the mixture with Celite, and concentrating the filtrate under reduced pressure to obtain 4-chloro-6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ]]Pyrimidine (31.3 g).

Production examples 4 to 6

In 2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3]]Thiazolo [5,4-d]Of pyrimidin-7-ol (16.2g) and toluene (160mL)DMF (10mL) and phosphorus oxychloride (11mL) were added to the mixture, and the mixture was stirred at 95 ℃ for 30 minutes. The reaction mixture was concentrated under reduced pressure. Chloroform was added to the residue, which was neutralized with a 1M aqueous NaOH solution under ice bath, and extracted with chloroform. The organic layer was washed with MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to give 7-chloro-2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3]]Thiazolo [5,4-d]Pyrimidine (13.2 g).

Production example 5

In the presence of 4-chloro-6- (4, 4-dimethylcyclohexyl) -2-methylthio-eno [2,3-d]To a mixture of pyrimidine (31.1g) and DMF (220mL) was added CH₃SO₂Na (11g) and KCN (10g) were stirred at 70 ℃ for 15 hours. The reaction mixture was concentrated under reduced pressure to about half amount, diluted with water (300mL), and stirred. The precipitate was collected by filtration. Adding chloroform to dissolve precipitate, adding MgSO₄Activated charcoal (10g) and silica gel (100mL) were stirred, filtered through Celite, and concentrated under reduced pressure to give 6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ]]Pyrimidine-4-carbonitrile (27.4 g).

Production example 6

To a mixture of 6-cyclohexyl-2-methylthioeno [2,3-d ] pyrimidine-4-carbonitrile (23.5g) and EtOH (100mL) was added 4M HCl/dioxane (100mL) and stirred at 80 ℃ for 2 days. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. Chloroform was added to the residue to dissolve it, and further activated carbon (2g) and basic silica gel (100mL) were added thereto, followed by stirring, filtration through Celite and concentration under reduced pressure to obtain ethyl 6-cyclohexyl-2-methylthioeno [2,3-d ] pyrimidine-4-carboxylate (30.8 g).

Production example 6-1

In 6- (4, 4-dimethylcyclohexyl) -2-methylthio-thieno [2,3-d]To a mixture of pyrimidine-4-carbonitrile (27.4g) and EtOH (200mL) was added 4M HCl/dioxane (200mL) and stirred overnight at 80 ℃. After the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, EtOH (200mL) and water (200mL) were added to the residue and stirred. The precipitate was collected by filtration. The resulting precipitate was dissolved in chloroform, and MgSO was added₄Activated charcoal (10g) and basic silica gel (100mL) were stirred, filtered through Celite, and concentrated under reduced pressure to give 6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ]]Pyrimidine-4-carboxylic acid ethyl ester (23.3 g).

Production example 7

In 6-cyclohexyl-2-methylthiophene [2,3-d ]]To a mixture of ethyl pyrimidine-4-carboxylate (29.3g), calcium chloride (18g) and THF (200mL) was added NaBH in small portions at room temperature₄(5.5g), EtOH (200mL) was added slowly over 5 minutes and stirred at room temperature for 4 hours. Ice water was added to the reaction mixture, followed by stirring, addition of 1M hydrochloric acid to make the suspension into a solution, and extraction with EtOAc. The organic layer was washed with water, saturated sodium bicarbonate and brine in this order. Adding MgSO to the organic layer₄Activated carbon, basic silica gel and stirring, filtering through Celite, and concentrating under reduced pressure. The residue was purified by silica gel column (chloroform/EtOAc) to give (6-cyclohexyl-2-methylthioeno [2, 3-d)]Pyrimidin-4-yl) methanol (12.7 g).

Production example 7-1

In 6- (4, 4-dimethylcyclohexyl) -2-methylthio-thieno [2,3-d]To a mixture of ethyl pyrimidine-4-carboxylate (13.0g), THF (150mL) and EtOH (150mL) was added calcium chloride (6.6g), and after stirring at room temperature for 30 minutes, under ice-cooling, NaBH was added in small portions over 15 minutes₄(1.8 g). After stirring at room temperature for 4.5 hours, water (100mL) and EtOAc (100mL) were added to the reaction mixture under ice cooling, and further, 1M hydrochloric acid (100mL) was added to make a suspension into a solution, which was then concentrated under reduced pressure and extracted with EtOAc. The organic layer was washed with water, saturated sodium bicarbonate and brine in this order, and MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform/EtOAc) to give [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ]]Pyrimidin-4-yl]Methanol (9.35 g).

Production example 8

In [6- (4, 4-dimethylcyclohexyl) -2-methylthio-thieno [2,3-d ]]Pyrimidin-4-yl]To a mixture of methanol (16.0g), TEA (10mL) and DCM (200mL) was added MsCl (5.0mL) dropwise over 15 minutes at 0 deg.C, at the same temperatureStirred for 1 hour. Saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with saturated sodium bicarbonate and brine in this order. Adding MgSO to the organic layer₄Activated charcoal (5g) and basic silica gel (20mL) were stirred, filtered through Celite, and concentrated under reduced pressure to give methanesulfonic acid [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ]]Pyrimidin-4-yl]Methyl ester (18.9 g).

Production examples 8 to 7

Under ice cooling in [2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3]]Thiazolo [5,4-d]Pyrimidin-7-yl]TEA (4.5mL) and MsCl (2.1mL) were added dropwise to a mixture of methanol (6.42g) and EtOAc (65mL) and stirred at 0 ℃ for 1 hour. After the reaction mixture was filtered, saturated sodium bicarbonate was added to the filtrate, and extraction was performed with EtOAc. The organic layer was washed with MgSO₄Drying, and concentrating under reduced pressure to obtain methanesulfonic acid [2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3]]Thiazolo [5,4-d]Pyrimidin-7-yl]Methyl ester (9.3 g).

Production example 9

To a mixture of N- (4, 6-dichloro-2-methylpyrimidin-5-yl) -4, 4-dimethylcyclohexanecarboxamide (23.8g) and EtOH (200mL) were added thiourea (6g) and formic acid (900. mu.L), and the mixture was stirred at 85 ℃ for 15 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/MeOH) to give 2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3]]Thiazolo [5,4-d]Pyrimidin-7-ol (16.2 g).

Production example 10

Under argon atmosphere, dibromoethane (200. mu.L) and trimethylsilyl chloride (200. mu.L) were added to a suspension of zinc powder (7.5g) in THF (50mL), a solution of iodomethyl benzoate (15g) in THF (50mL) was added, and after stirring at room temperature for 1 hour, 7-chloro-2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3] -was added]Thiazolo [5,4-d]Solutions of pyrimidine (10.9g) in THF (50mL) and Pd (PPh)₃)₄(4.25g) and stirred at room temperature for 15 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. Adding into the residueInto 1M NH₄Aqueous Cl, extracted with EtOAc. Adding MgSO to the organic layer₄And alkaline silica gel, stirring, filtering, and concentrating under reduced pressure. The residue was purified with a silica gel column (hexane/EtOAc) to give [2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3] benzoic acid]Thiazolo [5,4-d]Pyrimidin-7-yl]Methyl ester (13.8 g).

Production example 11

In benzoic acid [2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3]]Thiazolo [5,4-d]Pyrimidin-7-yl]To a mixture of methyl ester (13.8g) and MeOH (250mL) was added 28% NaOCH₃MeOH (670. mu.L) and stirred at room temperature for 3 hours. The reaction mixture was neutralized by adding 4M HCl/EtOAc (870. mu.L) and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with EtOAc. Adding MgSO to the organic layer₄And basic silica gel with stirring, filtered through Celite, and concentrated under reduced pressure. The residue was purified with a silica gel column (hexane/EtOAc) to give [2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3]]Thiazolo [5,4-d]Pyrimidin-7-yl]Methanol (7.9 g).

Production example 12

Acetyl chloride (18mL) and TEA (36mL) were added dropwise to a mixture of 2-amino-5-cyclohexylthiophene-3-carboxamide (53.5g) and THF (500mL) under ice-cooling, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. EtOH (500mL) and 1M aqueous NaOH (500mL) were added to the residue, and the mixture was stirred at 80 ℃ for 24 hours. After the reaction mixture was allowed to cool to room temperature, 1M hydrochloric acid (500mL) was added and stirred, and the precipitate was filtered, washed with water and then air-dried to give 6-cyclohexyl-2-methylthioeno [2,3-d ] pyrimidin-4 (3H) -one (57.0 g).

Production example 13

In (6-cyclohexyl-2-methylthiophene [2, 3-d)]Pyrimidin-4-yl) methanol (1.28g) and DCM (20mL) were added thionyl chloride (1mL) and DMF (50. mu.L) and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried. To the residue was added EtOAc. The organic layer was washed with saturated sodium bicarbonate and brine in this order. The organic layer was washed with MgSO₄After drying, reduceConcentrating under reduced pressure. The residue was purified by silica gel column (chloroform/EtOAc) to give 4- (chloromethyl) -6-cyclohexyl-2-methylthioeno [2,3-d]Pyrimidine (663 mg).

Production example 14

In the presence of 4-chloro-6-cyclohexyl-2-methylthiophene [2,3-d]To a mixture of pyrimidine (1.0g) and DMF (40mL) were added (E) -1-ethoxyvinyl-2-boronic acid pinacol ester (900mg) and K₃PO₄(4.3g) after that, Pd (PPh) was added under an argon atmosphere₃)₄(500mg) and stirred with heating at 85 ℃ for 2 hours. Water was added to the reaction mixture, which was extracted with EtOAc. Washing the organic layer with brine, and washing with Na₂SO₄After drying, concentration under reduced pressure and purification with silica gel column (hexane/EtOAc) gave 6-cyclohexyl-4- [ (E) -2-ethoxyvinyl group]-2-methylthioeno [2,3-d]Pyrimidine (885 mg).

Production example 15

To tert-butyl 4- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d ] pyrimidin-4-yl ] methyl } -3, 3-dimethylpiperazine-1-carboxylate (645mg) and dioxane (6.45mL) was added 4M HCl/EtOAc (1.66mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue was added EtOAc, and the mixture was stirred. After the precipitate was filtered, it was dried under reduced pressure to give 6- (4, 4-dimethylcyclohexyl) -4- [ (2, 2-dimethylpiperazin-1-yl) methyl ] -2-methylthioeno [2,3-d ] pyrimidine (422 mg).

Production example 15-1

In (1S,4S) -5- { [2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3 [ ]]Thiazolo [5,4-d]Pyrimidin-7-yl]Methyl } -2, 5-diazabicyclo [2.2.1]To tert-butyl heptane-2-carboxylate (476mg) and DCM (10mL) was added trifluoroacetic acid (2.0mL), and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate was added to the reaction mixture and extracted with EtOAc. Washing the organic layer with brine, and washing with Na₂SO₄After drying, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column to obtain 7- [ (1S,4S) -2, 5-diazabicyclo [2.2.1]Hept-2-ylmethyl]-2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3]]Thiazolo [5,4-d]Pyrimidine (332 mg).

Production example 16

In 6-cyclohexyl-4- [ (E) -2-ethoxyvinyl]-2-methylthioeno [2,3-d]To a mixture of pyrimidine (300mg) and THF (3mL) was added 1M hydrochloric acid (3mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added with saturated sodium bicarbonate, and the mixture was extracted with EtOAc after pH 8 to 9. Washing the organic layer with brine, and washing with Na₂SO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/MeOH) to give (Z) -2- (6-cyclohexyl-2-methylthioeno [2, 3-d)]Pyrimidin-4-yl) vinyl alcohol (248 mg).

Production example 17

In (Z) -2- (6-cyclohexyl-2-methylthio-eno [2, 3-d)]Pyrimidin-4-yl) vinyl alcohol (430mg) in a mixture with MeOH (10mL) NaBH was added in small portions₄(65mg) and stirred for 15 minutes. After water was added to the reaction mixture, it was extracted with EtOAc. The organic layer was treated with saturated NH₄Sequentially washing with Cl aqueous solution and brine, and adding Na₂SO₄Drying and purifying the residue with silica gel column (hexane/EtOAc) to obtain 2- (6-cyclohexyl-2-methylthioeno [2, 3-d)]Pyrimidin-4-yl) ethanol (315 mg).

Production example 18

To a mixture of ethyl 6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ] pyrimidine-4-carboxylate (1.0g) and EtOH (10mL) was added 1M aqueous NaOH solution (3.9mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid was added, and stirred for 30 minutes. The precipitate was collected by filtration, washed with water, washed with hexane, air-dried, and dried under reduced pressure to give 6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ] pyrimidine-4-carboxylic acid (900 mg).

Production example 19

Under ice-cooling in [2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3]]Thiazolo [5,4-d]Pyrimidin-7-yl]To a mixture of methanol (500mg) and DCM (10mL) was added dessimutane oxidant (1.46g), and the mixture was stirred at 0 ℃ for 3 hours. Adding Na to the reaction mixture₂S₂O₃After the aqueous solution, it was extracted with DCM. The organic layer was washed with saturated sodium bicarbonate and brine in sequence, and then with Na₂SO₄Drying, and concentrating under reduced pressure to obtain 2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3]Thiazolo [5,4-d]Pyrimidine-7-carbaldehyde (492 mg). In the resulting aldehyde and NaH₂PO₄To a mixture of (245mg), 2-methyl-2-butene (542. mu.L), water (5mL) and acetone (10mL) was added NaClO under ice-cooling₂(231mg) and stirred at room temperature for 1 hour. Adding Na to the reaction mixture₂S₂O₃Aqueous solution and Na₂SO₄Then, the mixture was extracted with a mixture (1:9) of 2-propanol and chloroform. The organic layer was washed with Na₂SO₄Drying, and concentrating under reduced pressure to obtain 2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3]Thiazolo [5,4-d]Pyrimidine-7-carboxylic acid (870 mg).

Production example 20

In the presence of 4-chloro-6- (4, 4-dimethylcyclohexyl) -2-methylthio-eno [2,3-d]Pd (PPh) was added to a mixture of pyrimidine (1.0g), tributyl (1-ethoxyvinyl) tin (1.16mL) and toluene (10.8mL)₃)₄(392mg), heated to reflux for 5 hours. After the reaction mixture was allowed to cool to room temperature, saturated NH was added to the reaction mixture₄Aqueous Cl, extracted with EtOAc. Washing the organic layer with water and brine in sequence, and then with MgSO₄Drying, and concentrating under reduced pressure to obtain a mixture containing 6- (4, 4-dimethylcyclohexyl) -4- (1-ethoxyvinyl) -2-methylthiophene [2,3-d]Crude product of pyrimidine (1.12 g). To the crude product were added EtOH (9.0mL) and 1M hydrochloric acid (10.2mL) at room temperature, and the mixture was stirred overnight at 50 ℃. The reaction mixture was allowed to cool and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with EtOAc. The organic layer was washed with brine, MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ]]Pyrimidin-4-yl]Ethanone (820 mg).

Production example 22

A mixed solution of MeOH (2mL) and THF (15mL) was cooled in an ice bath, NaH (60% oil, 600mg) was added and stirred for 15 minThen, 6-bromo-4-chloro-2-methylthiophene [2,3-d ] is added]A solution of pyrimidine (2.0g) in THF (5mL) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was extracted with EtOAc. Washing the organic layer with brine, and washing with Na₂SO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with a silica gel column (hexane/EtOAc) to give 6-bromo-4-methoxy-2-methylthioeno [2,3-d]Pyrimidine (1.8 g).

Production example 23

NCS (4.8g) was added to a mixture of 2-methylthioeno [2,3-d ] pyrimidin-4 (3H) -one (5.0g) and AcOH (50mL), and the mixture was stirred at 40 ℃ for 2 days. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, followed by stirring, and the precipitate was collected by filtration and dried to give 6-chloro-2-methylthioeno [2,3-d ] pyrimidin-4 (3H) -one (5.5 g).

Production example 24

In the presence of 4-chloro-6-cyclohexyl-2-methylthiophene [2,3-d]To a mixture of pyrimidine (27.3g), DABCO (1.2g) and DMSO (150mL) was slowly added an aqueous solution of KCN (8g) (14mL) and stirred at room temperature for 15 hours. Water (150mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred. The precipitate was collected by filtration and dissolved in chloroform. Adding MgSO to the organic layer₄Activated carbon (2g) and basic silica gel (100mL) with stirring, filtered through Celite, and concentrated under reduced pressure to give 6-cyclohexyl-2-methylthioeno [2,3-d ]]Pyrimidine-4-carbonitrile (23.7 g).

Production example 25

NaH (60% oil, 203mg) was added to ice-cooled DME (12.5mL) under an argon atmosphere and stirred for 10 minutes. To the mixture was added dropwise a DME solution (10mL) of ethyl 3- (1, 1-thiomorpholin-4-yl) -3-oxopropionate (1.40g), and after stirring at the same temperature for 30 minutes, 4-chloro-6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ] was added]Pyrimidine (750mg), stirred overnight at 60 ℃. After the reaction mixture was allowed to cool, saturated NH was added₄Aqueous Cl, extracted with EtOAc. Washing the organic layer with water and brine in sequence, and then with MgSO₄After drying, the mixture was concentrated under reduced pressure. Purifying the residue with silica gel column to obtain 2-, [2], [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d]Pyrimidin-4-yl]-ethyl 3- (1, 1-thiomorpholin-4-yl) -3-oxopropanoate (559 mg).

Production example 28

In the 6-bromo-4- [ (1, 1-thiomorpholin-4-yl) methyl group]-2-methylthioeno [2,3-d]Pyrimidine (200mg), 4,5, 5-tetramethyl-2- (spiro [2.5 ]]To a mixture of oct-5-en-6-yl) -1,3, 2-dioxaborolan (185mg) and dioxane (4mL) was added Pd₂dba₃(25mg), dicyclohexyl (2',4',6' -triisopropylbiphenyl-2-yl) phosphine (50mg), K₃PO₄(340mg) and water (200. mu.L) were stirred with heating at 100 ℃ overnight. The reaction mixture was cooled to room temperature, water was added and extracted with EtOAc. The organic layer was washed with MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with a basic silica gel column (hexane/EtOAc) to give 4- [ (1, 1-thiomorpholin-4-yl) methyl group]-2-methyl-6- (spiro [2.5 ]]Oct-5-en-6-yl) thieno [2,3-d]Pyrimidine (167 mg).

Production example 31

In the presence of N- [ (6-cyclohexyl-2-methylthio-2-eno [2, 3-d)]Pyrimidin-4-yl) methyl]Cycloheptaneamine (132mg) and CH₃CN (3mL) mixture was added CH₃I (100. mu.L) and DIPEA (200. mu.L) were stirred at room temperature for 15 hours. Water was added to the reaction mixture, which was extracted with EtOAc. The organic layer was washed with MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with a silica gel column (hexane/EtOAc) to give N- [ (6-cyclohexyl-2-methylthioeno [2, 3-d)]Pyrimidin-4-yl) methyl]-N-methylcycloheptaneamine (77 mg).

Production example 32

In N- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d]Pyrimidin-4-yl]Methyl } Cyclopentanamine (128mg) and DMF (3mL) was added 3-bromopropan-1-ol (100. mu.L), Na₂CO₃(110mg) was stirred at 100 ℃ for 15 hours. After cooling the reaction mixture to room temperature, water was added and extracted with EtOAc. The organic layer was washed with MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with basic silica gel column (hexane/EtOAc) to give3- (cyclopentyl { [6- (4, 4-dimethylcyclohexyl) -2-methylthiothieno [2,3-d { [2, 4-dimethylcyclohexyl group ]]Pyrimidin-4-yl]Methyl } amino) propan-1-ol (88 mg).

Production example 33

In methanesulfonic acid (6-cyclohexyl-2-methylthio [2,3-d ]]Pyrimidin-4-yl) methyl ester (500mg) and CH₃CN (10mL) was added to the mixture, and the mixture was stirred at room temperature for 3 hours with cyclopentylamine (1.0 mL). After water was added to the reaction mixture, it was extracted with EtOAc. The organic layer was washed with MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with an alkaline silica gel column (hexane/EtOAc) and a silica gel column (hexane/EtOAc), whereby N- [ (6-cyclohexyl-2-methylthioeno [2,3-d ] was obtained]Pyrimidin-4-yl) methyl]Cyclopentanamine (326 mg).

Production example 34

In methanesulfonic acid (6-cyclohexyl-2-methylthio [2,3-d ]]Pyrimidin-4-yl]Methyl ester (150mg), cyclopentylmethyl amine (100mg), and CH₃CN (3mL) was added DIPEA (200. mu.L) to the mixture and stirred overnight at room temperature. Saturated sodium bicarbonate was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with brine, MgSO₄After drying, concentration was performed under reduced pressure, and the residue was purified by a silica gel column (hexane/EtOAc) to give N- [ (6-cyclohexyl-2-methylthioeno [2, 3-d)]Pyrimidin-4-yl) methyl]-N-methylcyclopentanamine (131 mg).

Production example 37

To a mixture of (4, 4-dimethylcyclohexyl) acetaldehyde (27.3g) and DMF (100mL) was added 2-cyanoacetamide (12g), sulfur (5g) and TEA (24mL), and the mixture was stirred at 60 ℃ for 12 hours. Water was added to the reaction mixture, which was extracted with EtOAc. Washing the organic layer with water and brine in sequence, adding Na₂SO₄And activated carbon (2g) were stirred, filtered through Celite, and concentrated under reduced pressure to give 2-amino-5- (4, 4-dimethylcyclohexyl) thiophene-3-carboxamide (33.0 g).

Production example 38

In the presence of 2-amino-5- (4, 4-dimethylcyclohexyl) thiophene-3-carboxamide (33g), pyridine (40mL) and DCM (200mL) was added dropwise to the mixture at 0 ℃ to stir at room temperature for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, water and 1M hydrochloric acid were added, and extraction was performed with chloroform. The organic layer was washed with water, saturated sodium bicarbonate and brine in this order. Adding MgSO to the organic layer₄Activated charcoal (2g) and basic silica gel (100mL) were stirred, filtered through Celite, and concentrated under reduced pressure to give 2-acetamido-5- (4, 4-dimethylcyclohexyl) thiophene-3-carboxamide (37.3 g).

Production example 39

To a mixture of WSC hydrochloride (4.5g), HOBt (3.2g) and DMF (50mL) were added difluoroacetic acid (2mL) and 2-amino-5-cyclohexylthiophene-3-carboxamide (5.0g), and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added 50% brine and extracted with EtOAc. The organic layer was washed with saturated sodium bicarbonate water and brine in this order. Adding MgSO to the organic layer₄Stirring the mixture with basic silica gel, filtering the mixture with Celite, and concentrating the filtered product under reduced pressure to obtain 5-cyclohexyl-2- [ (difluoroacetyl) amino]Thiophene-3-carboxamide (7.0 g).

Production example 40

To a mixture of 4, 4-dimethylcyclohexanecarboxylic acid (20.4g) and toluene (150mL) was added thionyl chloride (19mL), and the mixture was stirred at 80 ℃ for 15 hours. The reaction mixture was concentrated under reduced pressure. 4, 6-dichloro-2-methylpyrimidin-5-amine (23.3g) was added to the residue, and the mixture was stirred at 90 ℃ for 10 minutes. DCE (207mL) was added and stirred at 100 ℃ for 15 hours. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed with chloroform. The organic layer was washed with MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by a silica gel column (hexane/EtOAc) to give N- (4, 6-dichloro-2-methylpyrimidin-5-yl) -4, 4-dimethylcyclohexanecarboxamide (23.8 g).

Production example 41

To a mixture of adamantane-1-carboxylic acid (2.43g) and DCM (40mL) was added 1-chloro-N, N, 2-trimethylpropenylamine (2.23mL) at room temperature and stirred for 1 hour. To the mixture were added 4, 6-dichloro-2-methylpyrimidin-5-amine (2.0g) and pyridine (2.71mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, which was extracted with EtOAc. The organic layer was washed with brine, MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N- (4, 6-dichloro-2-methylpyrimidin-5-yl) adamantane-1-carboxamide (3.51 g).

Production example 42

To a mixture of thiomorpholine 1, 1-dioxide (3.22g) and DCM (48mL) was added ethyl 3-chloro-3-oxopropionate (2.0mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with brine, MgSO₄After drying, the reaction mixture was concentrated under reduced pressure to give a crude product (3.11g) of ethyl 3- (1, 1-thiomorpholin-4-yl) -3-oxopropanoate. The crude product was thus not purified and was used directly in the following reaction.

Production example 43

DMSO (50mL) and TEA (100mL) were added to a mixture of 2- (4, 4-dimethylcyclohexyl) ethanol (25.3g) and DCM (200mL) under an argon atmosphere, and then the internal temperature was kept below 10 ℃ under ice cooling, and sulfur trioxide pyridine complex (77.7g) was added in small portions. After stirring at room temperature for 2 hours, ice water was added to the reaction mixture, the mixture was concentrated under reduced pressure, and the mixture was extracted with chloroform. The organic layer was washed with 1M hydrochloric acid and brine in this order. Adding MgSO to the organic layer₄After stirring, the mixture was filtered and concentrated under reduced pressure to give (4, 4-dimethylcyclohexyl) acetaldehyde (27.3 g).

Production example 44

To a mixture of malonic acid ethyl 1- (3-ethoxy-3-oxopropanoyl) piperidin-4-yl ester (1.02g) and EtOH (5.1mL) was added NaOEt (20% EtOH solution, 105mg), and the mixture was stirred at room temperature for 30 minutes. Adding saturated NH to the reaction mixture₄Aqueous Cl, extracted with EtOAc. Washing the organic layer with brine, and washing with Na₂SO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 3- (4-hydroxypiperidin-1-yl) -3-oxopropanoate (368 mg).

Production example 45

Trifluoroacetic anhydride (4.4mL) was added dropwise to a mixture of 30% hydrogen peroxide solution (2.7mL) and DCM (100mL) under ice-cooling, and a solution of 1-benzyl-5-methyl-1, 2,3, 6-tetrahydropyridine (2.1g) in DCM (5mL) was added thereto and stirred for 1.5 hours. Adding saturated Na into the reaction mixture₂SO₃After the aqueous solution, it was extracted with DCM. The organic layer was washed with saturated sodium bicarbonate solution and MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by a silica gel column (chloroform/MeOH) to give trans-1-benzyl-3-methylpiperidine-3, 4-diol (2.0 g).

Production example 46

In 5-benzyl-2, 5-diazabicyclo [2.2.2]To a solution of oct-3-one (400mg) in EtOH (5mL) was added 20% Pd (OH)₂C (65mg), stirred at room temperature under an atmosphere of atmospheric hydrogen, evening-out. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give 2, 5-diazabicyclo [2.2.2]Oct-3-one (219 mg).

Production example 47

A mixture of trans-1-benzyl-4-methylpiperidine-3, 4-diol acetate (256mg), 10% Pd/C (193mg), acetic acid (5mL) and EtOH (5mL) was stirred under a hydrogen atmosphere of 3 atm at room temperature for 12 hours. The reaction mixture was filtered through Celite, and concentrated under reduced pressure to give trans-4-methylpiperidine-3, 4-diol acetate (212 mg). The impurities were used for the following reaction.

Production example 48

Trans-1-benzyl-3-methylpiperidine-3, 4-diol (460mg), DIBOC (907mg), 20% Pd (OH) under a hydrogen atmosphere of 3 atmospheres₂A mixture of/C (291mg) and EtOAc (28mL) was stirred at room temperature for 12 h. The reaction mixture was filtered through Celite, and concentrated under reduced pressure to give tert-butyl trans-3, 4-dihydroxy-3-methylpiperidine-1-carboxylate (80 mg).

Production example 49

To a mixture of 10% Pd/C (409mg) and MeOH (7mL) was added a mixture of ammonium formate (2.92g) and 1- (diphenylmethyl) -2, 2-dimethylazetidin-3-ol (1.03g) in MeOH (7mL) and THF (14mL), and stirred at 50 ℃ for 2 h. The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified with a basic silica gel column (chloroform/MeOH) to give 2, 2-dimethylazetidin-3-ol (378 mg).

Production example 50

Trifluoroacetic anhydride (6.0mL) was added to a mixture of 30% hydrogen peroxide solution (3.6mL) and DCM (120mL) at 0 ℃ followed by a solution of 1-benzyl-4-methyl-1, 2,3, 6-tetrahydropyridine (2.9g) in DCM (10mL) and stirring at room temperature for 12 hours and then at 50 ℃ for another 3 hours. Adding Na to the reaction mixture₂SO₃The aqueous solution was stirred until the peroxide disappeared and extracted with DCM. The organic layer was washed with saturated sodium bicarbonate solution and MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/MeOH) to give 3-benzyl-6-methyl-7-oxa-3-azabicyclo [4.1.0]]Heptane (1.8 g).

Production example 51

AcOH (10mL) was added to a mixture of 3-benzyl-6-methyl-7-oxa-3-azabicyclo [4.1.0] heptane (700mg) in THF (10mL), and the mixture was stirred at 80 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/MeOH) to give trans-1-benzyl-4-methylpiperidine-3, 4-diol acetate (256 mg).

Production example 52

To a mixture of trans-3, 4-dihydroxy-3-methylpiperidine-1-carboxylic acid tert-butyl ester (80mg) and EtOAc (5mL) at room temperature was added 4M HCl/EtOAc (0.4mL) and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give trans-3-methylpiperidine-3, 4-diol hydrochloride (50 mg).

Example 1

To a mixture of thiomorpholine-1, 1-dioxide (65mg) and DMF (4mL) was added methanesulfonic acid (6-cyclohexyl-2-methylthiothieno [2,3-d ]]Pyrimidin-4-yl) methylThe ester (110mg) and TEA (150. mu.L) were stirred at room temperature for 24 hours. Water was added to the reaction mixture, which was extracted with EtOAc. Washing the organic layer with brine, and washing with Na₂SO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with a basic silica gel column (hexane/EtOAc) to give 6-cyclohexyl-4- [ (1, 1-thiomorpholin-4-yl) methyl group]-2-methylthioeno [2,3-d]Pyrimidine (94 mg).

Example 2

To a mixture of thiomorpholine-1, 1-dioxide (70mg) and DMF (4mL) was added methanesulfonic acid [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ]]Pyrimidin-4-yl]Methyl ester (120mg) and TEA (150. mu.L) were stirred overnight at room temperature. Water was added to the reaction mixture, which was extracted with EtOAc. The organic layer was washed with brine, MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with a basic silica gel column (hexane/EtOAc) to give 6- (4, 4-dimethylcyclohexyl) -4- [ (1, 1-dioxo-1. lambda⁶-thiomorpholin-4-yl) methyl]-2-methylthioeno [2,3-d]Pyrimidine (102 mg).

Example 31 and example 31-1

Trans-1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ] pyrimidin-4-yl ] methyl } piperidine-3, 4-diol (321mg) as a racemic modification was purified by supercritical fluid chromatography (column: Chiralpak IC 10X250mm manufactured by Daicel, mobile phase: liquefied carbon dioxide gas/MeOH containing 0.1% diethylamine ═ 75/25, flow rate: 10mL/min, column temperature: 40 ℃ C.). After adding IPE to the residue and stirring, precipitates were collected by filtration to give optically active trans-1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d ] pyrimidin-4-yl ] methyl } piperidine-3, 4-diol (110mg) having a retention time of 8.48 minutes and optically active trans-1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d ] pyrimidin-4-yl ] methyl } piperidine-3, 4-diol (112mg) having a retention time of 9.44 minutes, respectively.

Example 33

To a mixture of 6-cyclohexyl-4- [ (2, 2-dimethylmorpholin-4-yl) methyl ] -2-methylthioeno [2,3-d ] pyrimidine (130mg) and EtOAc (2mL) was added 4M HCl/EtOAc (100. mu.L) and stirred at room temperature. The precipitated solid was collected by filtration to give 6-cyclohexyl-4- [ (2, 2-dimethylmorpholin-4-yl) methyl ] -2-methylthioeno [2,3-d ] pyrimidine hydrochloride (90 mg).

Example 52

In methanesulfonic acid [6- (4, 4-dimethylcyclohexyl) -2-methylthiophene [2,3-d ]]Pyrimidin-4-yl]To a mixture of methyl ester (120mg) and DMF (4mL) was added piperidin-4-ol (70mg) and TEA (100. mu.L), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, which was extracted with EtOAc. The organic layer was washed with saturated sodium bicarbonate and brine, and Na₂SO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with a basic silica gel column (hexane/EtOAc). After addition of EtOAc to the resulting purified product, 4M HCl/EtOAc (100. mu.L) was added and stirred at room temperature. The precipitate was filtered to give 1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d]Pyrimidin-4-yl]Methyl } piperidin-4-ol hydrochloride (115 mg).

Example 85

Methanesulfonic acid [6- (4, 4-dimethyl cyclohexyl) -2-methyl thieno [2,3-d ]]Pyrimidin-4-yl]Methyl ester (100mg), cis-pyrrolidine-3, 4-diol hydrochloride (57mg) and K₂CO₃A suspension of (75mg) in DMF (3mL) was stirred at 50 ℃ for 12 h. The reaction mixture was cooled to room temperature, water was added and extracted with EtOAc. The organic layer was washed with MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/MeOH). The resulting purified product was suspended in IPE, and the precipitate was filtered to give cis-1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ]]Pyrimidin-4-yl]Methyl } pyrrolidine-3, 4-diol (9 mg).

Example 96

Methanesulfonic acid [6- (4, 4-dimethyl cyclohexyl) -2-methyl thieno [2,3-d ]]Pyrimidin-4-yl]Methyl ester (100mg), 2- (azetidin-3-yl) propan-2-ol hydrochloride (62mg) and K₂CO₃A suspension of (94mg) in DMF (1.0mL) was stirred at 70 ℃ for 12 h. The reaction mixture was cooled to room temperature, water was added and extracted with EtOAc. The organic layer was washed with MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/MeOH), salified with 4M HCl/EtOAc and washed with EtOAc to give 2- (1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ]]Pyrimidin-4-yl]Methyl } azetidin-3-yl) propan-2-ol hydrochloride (32 mg).

Example 105

In the presence of 5- [ (6-cyclohexyl-2-methylthio-2-eno [2,3-d ]]Pyrimidin-4-yl) methyl]-2, 5-diazabicyclo [2.2.2]To a mixture of octane-3-one (113mg) and DMF was added NaH (60% oily, 12mg) under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes, followed by addition of CH₃I (38. mu.L), stirred at the same temperature for 20 minutes. Water was added to the reaction mixture, which was extracted with EtOAc. Washing the organic layer with water and brine in sequence, and then with MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with a basic silica gel column (hexane/EtOAc). The residue was dissolved in EtOAc, and after addition of an excess of 4M HCl/EtOAc, was concentrated under reduced pressure. Et was added to the resulting purified product₂O and stirring, and filtering to obtain a precipitate to obtain 5- [ (6-cyclohexyl-2-methylthiophene [2,3-d ]]Pyrimidin-4-yl) methyl]-2-methyl-2, 5-diazabicyclo [2.2.2]Octane-3-one hydrochloride (83 mg).

Example 106

In (Z) -2- (6-cyclohexyl-2-methylthio-eno [2, 3-d)]Pyrimidin-4-yl) vinyl alcohol (120mg) and AcOH (12mL) in a mixture was added morpholine (400. mu.L) and NaBH (OAc)₃(200mg) and stirred at room temperature for 15 hours. After saturated sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with chloroform. Washing the organic layer with brine, and washing with Na₂SO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with a basic silica gel column (hexane/EtOAc) to give 6-cyclohexyl-2-methyl-4- [2- (morpholin-4-yl) ethyl]Thieno [2,3-d ]]Pyrimidine (53 mg).

Example 107

In 2- [ (6-cyclohexyl-2-methylthio-2-eno [2,3-d ]]Pyrimidin-4-yl) methyl]-2, 5-diazabicyclo [2.2.2]To a mixture of octane-3-one (67mg), 1H-benzotriazole-1-methanol (54mg) and DCE was added NaBH (OAc) at room temperature₃(115mg) was stirred at the same temperature for 5 hours. Water was added to the reaction mixture, which was extracted with EtOAc. Washing the organic layer with brine, and washing with Na₂SO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with a basic silica gel column (hexane/EtOAc). The resulting purified material was dissolved in EtOAc, and an excess of 4M HCl/EtOAc was added and concentrated under reduced pressure. Et was added to the residue₂O, stirring, and filtering to obtain a precipitate to obtain 2- [ (6-cyclohexyl-2-methylthiophene [2,3-d ]]Pyrimidin-4-yl) methyl]-5-methyl-2, 5-diazabicyclo [2.2.2]Octane-3-one hydrochloride (57 mg).

Example 108

4- [ (1, 1-Thiomolin-4-yl) methyl group was reacted with H-Cube (registered trademark, 10% Pd/C cartridge, Thalesnano Co., Ltd.)]-2-methyl-6- (spiro [2.5 ]]Oct-5-en-6-yl) thieno [2,3-d]A mixture of pyrimidine (165mg), THF (5mL) and EtOH (5mL) in H₂Reacting at 50bar and 50 ℃ under the atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/MeOH) to give 4- [ (1, 1-thiomorpholin-4-yl) methyl group]-2-methyl-6- (spiro [2.5 ]]Oct-6-yl) thieno [2,3-d]Pyrimidine (59 mg).

Example 109

In the process of { (3S) -4- [ (6-cyclohexyl-2-methylthieno [2,3-d ]]Pyrimidin-4-yl) methyl]Morpholin-3-yl } methanol (132mg) and DMF to a mixture was added NaH (60% oily, 15mg) under ice-cooling and stirred at the same temperature for 5 minutes, followed by addition of CH₃I (17. mu.L), and stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, which was extracted with EtOAc. The organic layer was washed with brine and then Na₂SO₄Drying, and concentrating under reduced pressure. The residue was purified with a basic silica gel column (hexane/EtOAc) to give 6-cyclohexyl-4- { [ (3S) -3- (methoxymethyl) morpholin-4-yl]Methyl } -2-methylthio-eno [2, 3-d)]Pyrimidine (102 mg).

Example 112

To a mixture of piperidin-2-one (100mg), THF (4mL) and DMF (1mL) was added NaH (60% oily, 40mg), and after stirring at room temperature for 30 minutes, methanesulfonic acid (6-cyclohexyl-2-methylthioeno [2, 3-d) was added]Pyrimidin-4-yl) methyl ester (150mg) was further stirred at room temperature for 1 hour. To the reaction mixture was added water and 1M hydrochloric acid, and extracted with EtOAc. The organic layer was washed with brine, MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to give 1- [ (6-cyclohexyl-2-methylthioeno [2, 3-d)]Pyrimidin-4-yl) methyl]Piperidin-2-one (13 mg).

Example 116

In methanesulfonic acid (6-cyclohexyl-2-methylthio [2,3-d ]]Pyrimidin-4-yl) methyl ester (130mg) and CH₃CN (5mL) was added 3-fluoropiperidine hydrochloride (107mg) and TEA (200. mu.L), and the mixture was stirred at room temperature for 15 hours. After water was added to the reaction mixture, it was extracted with EtOAc. Washing the organic layer with brine, and washing with Na₂SO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with a basic silica gel column (hexane/EtOAc). To the resulting purified product were added EtOH and fumaric acid (35mg) to dissolve the product, and the solution was concentrated under reduced pressure. EtOH and acetone (1:5) were added to the residue, and after heating and dissolving, the mixture was allowed to cool with stirring. Filtering to obtain precipitateTo obtain 6-cyclohexyl-4- [ (3-fluoropiperidin-1-yl) methyl]-2-methylthioeno [2,3-d]Pyrimidine fumarate (105 mg).

Example 126

Methanesulfonic acid [6- (4, 4-dimethyl cyclohexyl) -2-methyl thieno [2,3-d ]]Pyrimidin-4-yl]Methyl ester (100mg), 2-oxa-6-azaspiro [3.3]Heptane oxalate (67mg), K₂CO₃A mixture of (94mg) and DMF (1.0mL) was stirred at 80 ℃ for 12 h. The reaction mixture was cooled to room temperature, water was added and extracted with EtOAc. The organic layer was washed with MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by a silica gel column (chloroform/MeOH), salified by addition of fumaric acid (10mg), and washed with EtOAc to give 6- (4, 4-dimethylcyclohexyl) -2-methyl-4- (2-oxa-6-azaspiro [3.3 ]]Hept-6-ylmethyl) thieno [2,3-d]Pyrimidine fumarate (23 mg).

Example 130

In methanesulfonic acid 2- (6-cyclohexyl-2-methylthio-2-o [2,3-d]Pyrimidin-4-yl) ethyl ester (64mg) and CH₃CN (2mL) was added slowly to piperidine (800. mu.L) and stirred at room temperature for 3 days. After water was added to the reaction mixture, it was extracted with EtOAc. Washing the organic layer with brine, and washing with Na₂SO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with a basic silica gel column (hexane/EtOAc). To a chloroform (3mL) solution of the obtained purified product was added 4M HCl/EtOAc (150. mu.L), and the mixture was concentrated under reduced pressure. Adding EtOAc into the residue, heating and washing, and filtering to obtain precipitate to obtain 6-cyclohexyl-2-methyl-4- [2- (piperidin-1-yl) ethyl]Thieno [2,3-d ]]Pyrimidine dihydrochloride (61 mg).

Example 134

In methanesulfonic acid (6-cyclohexyl-2-methylthio [2,3-d ]]Pyrimidin-4-yl) methyl ester (150mg) and CH₃CN (2mL) to a mixture of (2S) -pyrrolidin-2-ylmethanol (100mg) was added slowlyCH₃CN (1mL) solution was stirred at room temperature for 15 hours. Water was added to the reaction mixture, which was extracted with EtOAc. Washing the organic layer with brine, and washing with Na₂SO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with a basic silica gel column (hexane/EtOAc). To the resulting purified product were added EtOH and fumaric acid (39mg) to dissolve the product, and the solution was concentrated under reduced pressure. EtOH/acetone (1:10) was added to the residue to dissolve it under heating, and after cooling under stirring, the precipitate was collected by filtration to give { (2S) -1- [ (6-cyclohexyl-2-methylthiophene [2,3-d ]]Pyrimidin-4-yl) methyl]Pyrrolidin-2-yl } methanol fumarate (76 mg).

Example 150

In methanesulfonic acid [6- (4, 4-dimethylcyclohexyl) -2-methylthiophene [2,3-d ]]Pyrimidin-4-yl]To a mixture of methyl ester (150mg), DIPEA (209. mu.L) and DMF (2.25mL) was added 2, 2-dimethylazetidin-3-ol (54mg), and the mixture was stirred at room temperature for 18 hours. Water and EtOAc were added to the reaction mixture and extracted with EtOAc. Washing the organic layer with brine, and washing with Na₂SO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc). The resulting purified product was dissolved in EtOAc (1.5mL), a mixture of fumaric acid (38mg) and MeOH (300. mu.L) was added, and the precipitate was filtered to give 1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ]]Pyrimidin-4-yl]Methyl } -2, 2-dimethylazetidin-3-ol fumarate (106 mg).

Example 152

To a mixture of 2- { [ (6-cyclohexyl-2-methylthioeno [2,3-d ] pyrimidin-4-yl) methyl ] amino } -2-methylpropan-1-ol (55mg) and DCM was added CDI (40mg), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by a silica gel column (hexane/EtOAc) to give 3- [ (6-cyclohexyl-2-methylthioeno [2,3-d ] pyrimidin-4-yl) methyl ] -4, 4-dimethyl-1, 3-oxazolidin-2-one (54 mg).

Example 153

In the 6- (4, 4-dimethylcyclohexyl) -4- [ (2, 2-dimethylpiperazin-1-yl) methyl group]-2-methylthioeno [2,3-d]Acetic anhydride (49. mu.L) was added to a mixture of pyrimidine (40mg), pyridine (83. mu.L) and DCM (1.2mL), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was extracted with EtOAc. The organic layer was washed with brine, MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column. 4M HCl/dioxane was added dropwise to the EtOAc solution of the purified product obtained, and the precipitate was collected by filtration and dried to obtain 1- (4- { [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ]]Pyrimidin-4-yl]Methyl } -3, 3-dimethylpiperazin-1-yl) ethanone hydrochloride (35 mg).

Example 155

In the 6- (4, 4-dimethylcyclohexyl) -4- [ (2, 2-dimethylpiperazin-1-yl) methyl group]-2-methylthioeno [2,3-d]HATU (306mg) and DIPEA (492. mu.L) were added to a mixture of pyrimidine (222mg), glycolic acid (52mg) and NMP (3.2mL), and the mixture was stirred at room temperature overnight. Adding saturated NH to the reaction mixture₄Aqueous Cl, extracted with EtOAc. Washing the organic layer with water and brine in sequence, and then with MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- (4- { [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ]]Pyrimidin-4-yl]Methyl } -3, 3-dimethylpiperazin-1-yl) -2-hydroxyacetophenone (102 mg).

Example 161

(3S) -1- { [2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3] thiazolo [5,4-d ] pyrimidin-7-yl ] methyl } pyrrolidin-3-ol (73mg) was dissolved in EtOH (3mL), fumaric acid (24mg) was added, and the mixture was concentrated under reduced pressure. IPE was added to the residue, and the mixture was stirred at room temperature. The precipitate was collected by filtration to give (3S) -1- { [2- (4, 4-dimethylcyclohexyl) -5-methyl [1,3] thiazolo [5,4-d ] pyrimidin-7-yl ] methyl } pyrrolidin-3-ol fumarate (81 mg).

Example 163

In the presence of 5-benzyl-2- [ (6-cyclohexyl-2-methylthio ] thieno [2,3-d]Pyrimidin-4-yl) methyl]-2, 5-diazabicyclo [2.2.2]To a mixture of octane-3-one (140mg) and DCE (5mL) was added 1-chloroethyl chloroformate (50. mu.L) and stirred at room temperature for evening-out. The reaction solution was subjected to silica gel column without concentration (chloroform/MeOH/saturated NH)₃Water) purification. The residue was dissolved in MeOH and heated at reflux for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column (chloroform/MeOH/saturated NH)₃Water) to obtain 2- [ (6-cyclohexyl-2-methylthiophene [2, 3-d)]Pyrimidin-4-yl) methyl]-2, 5-diazabicyclo [2.2.2]Octane-3-one (87 mg).

Example 187

In the presence of N- [ (6-cyclohexyl-2-methylthio-2-eno [2, 3-d)]Pyrimidin-4-yl) methyl]To a mixture of cyclohexane amine (47mg) and DCM (4mL) was added acetyl chloride (20. mu.L) and TEA (40. mu.L) dropwise at 0 ℃ and stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, which was extracted with EtOAc. The organic layer was washed with 1M hydrochloric acid, saturated sodium bicarbonate and brine in this order, and MgSO₄Drying, and concentrating under reduced pressure to obtain N-cyclohexyl-N- [ (6-cyclohexyl-2-methylthiophene [2,3-d ]]Pyrimidin-4-yl) methyl]Acetamide (50 mg).

Example 188

In N- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d]Pyrimidin-4-yl]To a mixture of methyl } tetrahydro-2H-pyran-4-amine (60mg), pyridine (129. mu.L) and DCM (1.8mL) was added acetic anhydride (76. mu.L), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was extracted with EtOAc. Washing the organic layer with brine, and washing with Na₂SO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by a silica gel column to give N- { [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d]Pyrimidin-4-yl]Methyl } -N- (tetrahydro-2H-pyran-4-yl) methyl ester-yl) acetamide (23 mg).

Example 190

In N- { [6- (4, 4-difluorocyclohexyl) -2-methylthieno [2,3-d]Pyrimidin-4-yl]To a mixture of methyl } -1-methoxy-2-methylpropan-2-amine (110mg), 1H-benzotriazole-1-methanol (86mg) and DCE was added NaBH (OAc)₃(182mg) was stirred at room temperature for 4 hours. Water was added to the reaction mixture, which was extracted with EtOAc. Washing the organic layer with brine, and washing with Na₂SO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified with a basic silica gel column (hexane/EtOAc) to give N- { [6- (4, 4-difluorocyclohexyl) -2-methylthieno [2,3-d]Pyrimidin-4-yl]Methyl } -1-methoxy-N, 2-dimethylpropan-2-amine (93 mg). This was dissolved in MeOH, fumaric acid (27mg) was added, and the mixture was concentrated under reduced pressure to give N- { [6- (4, 4-difluorocyclohexyl) -2-methylthioeno [2,3-d]Pyrimidin-4-yl]Methyl } -1-methoxy-N, 2-dimethylpropan-2-amine fumarate (117 mg).

Example 191

In N- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d]Pyrimidin-4-yl]Methyl } tetrahydro-2H-thiopyran-4-amine 1, 1-dioxide hydrochloride (100mg), CH₃K was added to a mixture of I (16. mu.L) and DMF (2.0mL)₂CO₃(60mg) was stirred overnight at 50 ℃. After the reaction mixture was allowed to cool, saturated NH was added₄Aqueous Cl, extracted with EtOAc. Washing the organic layer with water and brine in sequence, and then with MgSO₄And (5) drying. The residue was purified by silica gel column. The resulting purified material was dissolved in EtOAc and 4M HCl/EtOAc (55 μ L) was added dropwise. The precipitate was collected by filtration and dried to give N- { [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d]Pyrimidin-4-yl]Methyl } -N-methyltetrahydro-2H-thiopyran-4-amine 1, 1-dioxide hydrochloride (69 mg).

Example 196

In N- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d]Pyrimidin-4-yl]To a mixture of methyl } tetrahydro-2H-pyran-4-amine (100mg), 1, 4-dioxane-2, 5-diol (64mg), DCE (2mL) and MeOH (1mL) was added NaBH (OAc) under ice-cooling₃(170mg) was stirred at 0 ℃ for 1 hour. To the reaction mixture was added water and EtOAc, and extracted with EtOAc. The organic layer was washed with brine, dried, and concentrated under reduced pressure. Purifying the residue with silica gel column to obtain 2- [ { [6- (4, 4-dimethylcyclohexyl) -2-methylthiophene [2,3-d { [6- (4, 4-dimethylcyclohexyl) -2-methyl-thieno [2]Pyrimidin-4-yl]Methyl } (tetrahydro-2H-pyran-4-yl) amino]Ethanol (51 mg).

Example 198

In methanesulfonic acid [6- (4, 4-dimethylcyclohexyl) -2-methylthiophene [2,3-d ]]Pyrimidin-4-yl]To a mixture of methyl ester (200mg), DIPEA (139. mu.L) and DMF (3.0mL) was added tetrahydro-2H-thiopyran-4-amine 1, 1-dioxide (97mg), and the mixture was stirred at room temperature for 4 hours. Adding saturated NH to the reaction mixture₄Aqueous Cl, extracted with EtOAc. Washing the organic layer with water and brine in sequence, and then with MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified on a silica gel column, dissolved in EtOAc and 4M HCl/EtOAc (137. mu.L) was added dropwise. The precipitate was collected by filtration and dried to give N- { [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d]Pyrimidin-4-yl]Methyl } tetrahydro-2H-thiopyran-4-amine 1, 1-dioxide hydrochloride (165 mg).

Example 205

In N- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d]Pyrimidin-4-yl]To a suspension of methyl } -4-methyltetrahydro-2H-thiopyran-4-amine (55mg) and sodium tungstate (IV) dihydrate (9.0mg) in MeOH (1.1mL) was added dropwise 1M hydrochloric acid (313. mu.L) and a 35% hydrogen peroxide solution (56. mu.L) in this order under ice-cooling, followed by stirring at the same temperature for 10 minutes and at room temperature for 6 hours. Adding Na to the ice-cooled reaction mixture₂S₂O₃Stirring the aqueous solution at room temperature for 30 minutes, addingSaturated sodium bicarbonate was added and extracted with chloroform. The organic layer was washed with brine, MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column. The resulting purified product was dissolved in EtOAc and 4M HCl/dioxane was added dropwise. The precipitate was collected by filtration and dried under reduced pressure to give N- { [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d]Pyrimidin-4-yl]Methyl } -4-methyltetrahydro-2H-thiopyran-4-amine 1, 1-dioxide hydrochloride (22 mg).

Example 206

In 6- (4, 4-dimethylcyclohexyl) -2-methylthio-thieno [2,3-d]DIPEA (244. mu.L) was added to a mixture of pyrimidine-4-carboxylic acid (150mg), 4-methylpiperidin-4-ol (68mg), HATU (262mg) and NMP (2.1mL), and the mixture was stirred at room temperature overnight. Adding saturated NH to the reaction mixture₄Aqueous Cl, extracted with EtOAc. Washing the organic layer with water and brine in sequence, and then with MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column. Suspending the obtained purified product with IPE, filtering, and drying under reduced pressure to obtain [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ]]Pyrimidin-4-yl](4-hydroxy-4-methylpiperidin-1-yl) methanone (120 mg).

Example 229

In the presence of 2- [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d]Pyrimidin-4-yl]Ethyl (3- (1, 1-thiomorpholin-4-yl) -3-oxopropanoate (520mg) and THF (16mL) were added MeOH (2.7mL) and 1M aqueous NaOH (3.9mL) at room temperature and stirred at 60 ℃ for 8 h. After the reaction mixture was allowed to cool, 1M hydrochloric acid was added, and the mixture was concentrated under reduced pressure. EtOAc was added to the residue, followed by extraction. The organic layer was washed with brine, MgSO₄After drying, the mixture was concentrated under reduced pressure. The residue was purified by a silica gel column to give 2- [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ]]Pyrimidin-4-yl]-1- (1, 1-thiomorpholin-4-yl) ethanone (322 mg).

The compounds of the production examples and examples shown in the following table were produced in the same manner as in the production examples or examples.

[ Table 5]

[ Table 6]

[ Table 7]

[ Table 8]

[ Table 9]

[ Table 10]

[ Table 11]

[ Table 12]

[ Table 13]

[ Table 14]

[ Table 15]

[ Table 16]

[ Table 17]

[ Table 18]

[ Table 19]

[ Table 20]

[ Table 21]

[ Table 22]

[ Table 23]

[ Table 24]

[ Table 25]

[ Table 26]

[ Table 27]

[ Table 28]

[ Table 29]

[ Table 30]

[ Table 31]

[ Table 32]

[ Table 33]

[ Table 34]

[ Table 35]

[ Table 36]

[ Table 37]

[ Table 38]

[ Table 39]

[ Table 40]

[ Table 41]

[ Table 42]

[ Table 43]

No.	Ref	Data
			Pr1	Ex1	ESI+：418
Pr1-1	Ex1	ESI+：360
			Pr1-2	Ex1	ESI+：360
Pr1-3	Ex1
			Pr1-4	Ex1	ESI+：358
Pr1-5	Ex1	ESI+：388
			Pr1-6	Ex1	ESI+：388
Pr1-7	Ex1	ESI+：372
			Pr1-8	Ex1	ESI+：344
Pr1-9	Ex1	ESI+：384
			Pr1-10	Ex1	ESI+：386
Pr1-11	Ex1	ESI+：386
			Pr1-12	Ex1	ESI+：418
Pr1-13	Ex1	ESI+：388
			Pr1-14	Ex1	ESI+：402
Pr1-15	Ex1	ESI+：360
			Pr1-16	Ex1	ESI+：361

[ Table 44]

No.	Ref	Data
			Pr1-17	Ex1	ESI+：361
Pr1-18	Ex1	ESI+：346
			Pr2	Pr34
Pr2-1	Pr34	ESI+：487
			Pr2-2	Pr34	ESI+：392
Pr2-3	Pr34	ESI+：488
			Pr2-4	Pr34	ESI+：472
Pr3	Pr3	ESI+：277
			Pr3-1	Pr3	ESI+：285
Pr4	Pr4	ESI+：267
			Pr4-1	Pr4-1	ESI+：295
Pr4-2	Pr4	ESI+：263，265
			Pr4-3	Pr4	EI：218，220
Pr4-4	Pr4	ESI+：303，305
			Pr4-5	Pr4	ESI+：303
Pr4-6	Pr4-6	ESI+：296，298
			Pr4-7	Pr4	ESI+：268，270
Pr4-8	Pr4	ESI+：320
			Pr4-9	Pr4-6	ESI+：336，338
Pr4-10	Pr4-6	ESI+：282，284
			Pr5	Pr5	ESI+：286
Pr5-1	Pr5	ESI+：294
			Pr6	Pr6	ESI+：305
Pr6-1	Pr6-1	ESI+：333
			Pr6-2	Pr6	ESI+：301，303
Pr6-3	Pr6	ESI+：341
			Pr6-4	Pr6	ESI+：341
Pr7	Pr7	ESI+：263
			Pr7-1	Pr7-1	ESI+：291
Pr7-2	Pr7	ESI+：259，261
			Pr7-3	Pr7	ESI+：299
Pr7-4	Pr7	APCI/ESI+：299
			Pr8	Pr8	ESI+：369

[ Table 45]

No.	Ref	Data
			Pr8-1	Pr8	ESI+：341
Pr8-2	Pr8
			Pr8-3	Pr8
Pr8-4	Pr8
			Pr8-5	Pr8	ESI+：377
Pr8-6	Pr8-7	ESI+：356
			Pr8-7	Pr8-7	ESI+：370
Pr8-8	Pr8
			Pr8-9	Pr8-7	ESI+：342
Pr8-10	Pr8-7	ESI+：410
			Pr9	Pr9	ESI+：278
Pr9-1	Pr9	ESI+：250
			Pr9-2	Pr9	ESI+：302
Pr9-3	Pr9	ESI+：318
			Pr9-4	Pr9	ESI+：264
Pr10	Pr10	ESI+：396
			Pr10-1	Pr10	ESI+：368
Pr10-2	Pr10	ESI+：420
			Pr10-3	Pr10	ESI+：436
Pr10-4	Pr10	ESI+：382
			Pr11	Pr11	ESI+：292
Pr11-1	Pr11	ESI+：264
			Pr11-2	Pr11	ESI+：278
Pr11-3	Pr11	ESI+：332
			Pr12	Pr12	ESI+：249
Pr12-1	Pr12	ESI+：285
			Pr13	Pr13	ESI+：281，283
Pr14	Pr14	ESI+：303
			Pr14-1	Pr14	ESI+：331
Pr15	Pr15	ESI+：387
			Pr15-1	Pr15-1	ESI+：372
Pr15-2	Pr15-1	ESI+：388
			Pr16	Pr16	ESI+：275

[ Table 46]

No.	Ref	Data
			Pr16-1	Pr16	ESI+：303
Pr17	Pr17	ESI+：277
			Pr17-1	Pr17	ESI+：305
Pr17-2	Pr17	ESI+：305
			Pr18	Pr18	ESI+：305
Pr18-1	Pr18	ESI+：316
			Pr19	Pr19	ESI+：306
Pr20	Pr20
			Pr21	Ex112	ESI+：461
Pr22	Pr22	ESI+：259，261
			Pr23	Pr23	ESI+：201，203
Pr24	Pr24	ESI+：258
			Pr24-1	Pr24	ESI+：294
Pr24-2	Pr24	ESI+：254，256
			Pr25	Pr25	ESI+：508
Pr25-1	Pr25	APCI/ESI+：460
			Pr25-2	Pr25	ESI+：474
Pr26	Pr8+Ex1	ESI+：376，378
			Pr26-1	Pr8+Ex1	ESI+：362
Pr27	Pr15	ESI+：371
			Pr28	Pr28	ESI+：404
Pr29	Ex1	APCI/ESI+：344
			Pr30	Ex85	ESI+：384
Pr30-1	Ex85	ESI+：388
			Pr30-2	Ex85	ESI+：388
Pr31	Pr31	ESI+：372
			Pr31-1	Pr31	ESI+：374
Pr31-2	Pr31	ESI+：388
			Pr31-3	Pr31	ESI+：394
Pr31-4	Pr31	ESI+：388
			Pr32	Pr32	ESI+：416
Pr32-1	Pr32	ESI+：402
			Pr32-2	Pr32	ESI+：432

[ Table 47]

No.	Ref	Data
			Pr32-3	Pr32	ESI+：432
Pr33	Pr33	ESI+：330
			Pr33-1	Pr33	ESI+：358
Pr33-2	Pr33	ESI+：358
			Pr34	Pr34	ESI+：344
Pr34-1	Pr34	ESI+：360
			Pr34-2	Pr34	ESI+：374
Pr34-3	Pr34	ESI+：380
			Pr34-4	Pr34	APCI/ESI+：404
Pr34-5	Pr34	ESI+：358
			Pr34-6	Pr34	ESI+：374
Pr34-7	Pr34	ESI+：346
			Pr35	Ex130	ESI+：326
Pr36	Ex198	ESI+：394
			Pr37	Pr37	ESI+：253
Pr37-1	Pr37	ESI+：261
			Pr37-2	Pr37	ESI+：225
Pr38	Pr38	ESI+：295
			Pr39	Pr39	ESI+：303
Pr40	Pr40	ESI+：316，318
			Pr40-1	Pr40	ESI+：288，290
Pr40-2	Pr40	ESI+：356，358
			Pr40-3	Pr40	ESI-：300，302
Pr41	Pr41	ESI+：340
			Pr42	Pr42
Pr42-1	Pr42	ESI+：330
			Pr43	Pr43	CI+：155
Pr44	Pr44	ESI+：216
			Pr45	Pr45	ESI+：222
Pr46	Pr46	ESI+：127
			Pr47	Pr47	ESI+：132

[ Table 48]

[ Table 49]

[ Table 50]

[ Table 51]

[ Table 52]

[ Table 53]

No.	Ref	Data
			Ex94	Ex85	ESI+：431
Ex95	Ex85	ESI+：395
			Ex96	Ex96	ESI+：388
Ex97	Pr8+Ex96	ESI+：396
			Ex98	Ex96	ESI+：366
Ex99	Pr8+Ex96	ESI+：396
			Ex100	Ex96	ESI+：422
Ex101	Ex96	ESI+：390
			Ex102	Ex96	ESI+：390
Ex103	Ex96	ESI+：372
			Ex104	Ex96	ESI+：404
Ex105	Ex105	ESI+：385
			Ex106	Ex106	ESI+：346
Ex107	Ex107	ESI+：385
			Ex108	Ex108	ESI+：406
Ex109	Ex109	ESI+：376
			Ex110	Ex109	ESI+：376
Ex111	Ex109	ESI+：360
			Ex112	Ex112	APCI/ESI+：344
Ex113	Ex112	ESI+：346
			Ex114	Ex112	APCI/ESI+：330
Ex115	Ex112	ESI+：370
			Ex116	Ex116	ESI+：348
Ex117	Ex116	ESI+：346
			Ex118	Ex116	ESI+：374
Ex119	Ex116	ESI+：374
			Ex120	Ex116	ESI+：388
Ex121	Ex116	ESI+：372
			Ex122	Ex116	ESI+：373
Ex123	Ex116	ESI+：389
			Ex124	Ex116	ESI+：415
Ex125	Ex116	ESI+：376
			Ex126	Ex126	ESI+：372
Ex127	Ex126	ESI+：404
			Ex128	Ex126	ESI+：391

[ Table 54]

No.	Ref	Data
			Ex129	Pr33	ESI+：358
Ex130	Ex130	ESI+：344
			Ex131	Ex130	ESI+：376
Ex132	Ex130	ESI+：360
			Ex133	Ex130	ESI+：360
Ex134	Ex134	ESI+：346
			Ex135	Ex134	ESI+：346
Ex136	Ex134	ESI+：360
			Ex137	Ex134	ESI+：360
Ex138	Ex134	ESI+：332
			Ex139	Ex134	ESI+：332
Ex140	Pr8+Pr34	ESI+：362
			Ex141	Pr8+Pr34	ESI+：362
Ex142	Pr34	ESI+：402
			Ex143	Pr34	ESI+：392
Ex144	Pr34	ESI+：392
			Ex145	Pr34	ESI+：393
Ex146	Ex198	ESI+：402
			Ex147	Ex198	ESI+：400
Ex148	Ex198	ESI+：348
			Ex149	Ex198	ESI+：355
Ex150	Ex150	ESI+：374
			Ex151	Ex150	ESI+：401
Ex152	Ex152	ESI+：360
			Ex153	Ex153	ESI+：429
Ex154	Ex153	ESI+：413
			Ex155	Ex155	ESI+：445
Ex156	Ex155	ESI+：429
			Ex157	Ex155	ESI+：438
Ex158	Ex155	ESI+：446
			Ex159	Ex155	ESI+：430
Ex160	Ex155	ESI+：455
			Ex161	Ex161	ESI+：361
Ex162	Ex161	ESI+：361
			Ex163	Ex163	ESI+：371
Ex164	Pr13+Ex52	ESI+：384

[ Table 55]

No.	Ref	Data
			Ex165	Pr13+Ex52	ESI+：402
Ex166	Pr13+Ex52	ESI+：368
			Ex167	Pr13+Ex52	ESI+：402
Ex168	Ex1	ESI+：388
			Ex169	Ex1	ESI+：414
Ex170	Ex1	ESI+：332
			Ex171	Ex33	ESI+：358
Ex172	Ex33	ESI+：372
			Ex173	Ex33	ESI+：394
Ex174	Ex33	ESI+：388
			Ex175	Ex33	ESI+：374
Ex176	Ex33	ESI+：416
			Ex177	Ex33	ESI+：402
Ex178	Ex33	ESI+：432
			Ex179	Ex33	ESI+：360
Ex180	Ex33	ESI+：388
			Ex181	Ex33	ESI+：432
Ex182	Ex33	ESI+：344
			Ex183	Ex52	ESI+：318
Ex184	Ex130	ESI+：378
			Ex185	Ex52	ESI+：346
Ex186	Pr8+Ex85	ESI+：334
			Ex187	Ex187	APCI/ESI+：386
Ex188	Ex188	ESI+：416
			Ex189	Ex190	ESI+：348
Ex190	Ex190	ESI+：398
			Ex191	Ex191	ESI+：436
Ex192	Ex191	ESI+：408
			Ex193	Ex191	ESI+：450
Ex194	Ex191	ESI+：466
			Ex195	Ex191	ESI+：360
Ex196	Ex196	ESI+：418
			Ex197	Ex130	ESI+：290
Ex198	Ex198	ESI+：422
			Ex199	Ex198	ESI+：422
Ex200	Ex198	ESI+：422

[ Table 56]

Industrial applicability

The compound of the present invention is GABA_BPAM of a receptor is useful as a preventive and/or therapeutic agent for schizophrenia, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasm, anxiety disorder, substance dependence, pain, fibromyalgia, and peroneal muscular atrophy.

Further, according to the findings obtained in the present invention, GABA_BPAM of the receptor is useful as a preventive and/or therapeutic agent for schizophrenia, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasm, anxiety disorder, substance dependence, pain, fibromyalgia, and peroneal muscular atrophy.

Claims (14)

1. A compound of formula (I) or a salt thereof:

in the formula (I), the compound is shown in the specification,

x is a group of a CH,

R¹is C_1-6An alkyl group, a carboxyl group,

R²is C_1-6An alkyl group, a carboxyl group,

herein, R is¹And R²Can be bonded with themThe carbon atoms of the ring together form a cyclopropane,

R³is a compound of the formula-H,

R⁴is a compound of the formula-H,

the ring A is a cyclohexane ring,

R^Yis-NR^AR^B，

R^AAnd R^BIs formed integrally with the bonded nitrogen atom to be substituted by R⁰A substituted cyclic amino group,

here, the cyclic amino group is a group represented by the following formula (III):

R⁰is a group selected from the following group Z:

group Z:

(1)-OH、

(2)-O-C_1-6alkyl, aryl, heteroaryl, and heteroaryl,

(3) Halogen, halogen,

(4)C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,

(5) Halogen substituted C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,

(6)C_1-6alkylene-OH,

(7)-C(＝O)-C_1-6An alkylene group-OH group, which is a substituent,

y is NH, O, S (═ O)₂Or CH₂And are and

R^Lis C_1-6An alkyl group.

2. The compound or salt thereof according to claim 1,

the group selected from group Z is a group selected from group Z1:

group Z1:

(1)-OH、

(2)C_1-6alkyl, aryl, heteroaryl, and heteroaryl,

(3)-C(＝O)-C_1-6alkylene-OH.

3. The compound or salt thereof according to claim 2,

y is O, S or S (═ O)₂。

4. The compound or salt thereof according to claim 3, wherein,

R^Lis CH₃。

5. The compound or salt thereof according to claim 1, selected from the group of compounds consisting of:

6- (4, 4-dimethylcyclohexyl) -4- [ (1, 1-dioxo-1. lamda.)⁶-thiomorpholin-4-yl) methyl]-2-methylthioeno [2,3-d]Pyrimidine, and their use,

Trans-1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d ] pyrimidin-4-yl ] methyl } piperidine-3, 4-diol,

1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d ] pyrimidin-4-yl ] methyl } piperidin-4-ol,

6- (4, 4-dimethylcyclohexyl) -2-methyl-4- (thiomorpholin-4-ylmethyl) thieno [2,3-d ] pyrimidine,

6- (4, 4-dimethylcyclohexyl) -4- [ (3, 3-dimethylmorpholin-4-yl) methyl ] -2-methylthio-eno [2,3-d ] pyrimidine, and

1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d ] pyrimidin-4-yl ] methyl } -2, 2-dimethylpiperidin-4-ol.

6. The compound according to claim 5, which is 6- (4, 4-dimethylcyclohexyl) -4- [ (1, 1-dioxo-1. lamda.) -or a salt thereof⁶-thiomorpholin-4-yl) methyl]-2-methylthioeno [2,3-d]A pyrimidine.

7. A compound according to claim 5, which is trans-1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d ] pyrimidin-4-yl ] methyl } piperidine-3, 4-diol, or a salt thereof.

8. A compound according to claim 5, which is 1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthieno [2,3-d ] pyrimidin-4-yl ] methyl } piperidin-4-ol, or a salt thereof.

9. The compound according to claim 5, or a salt thereof, which is 6- (4, 4-dimethylcyclohexyl) -2-methyl-4- (thiomorpholin-4-ylmethyl) thieno [2,3-d ] pyrimidine.

10. The compound according to claim 5, which is 6- (4, 4-dimethylcyclohexyl) -4- [ (3, 3-dimethylmorpholin-4-yl) methyl ] -2-methylthioeno [2,3-d ] pyrimidine, or a salt thereof.

11. A compound according to claim 5, which is 1- { [6- (4, 4-dimethylcyclohexyl) -2-methylthioeno [2,3-d ] pyrimidin-4-yl ] methyl } -2, 2-dimethylpiperidin-4-ol, or a salt thereof.

12. A pharmaceutical composition comprising the compound or salt thereof according to claim 1 and a pharmaceutically acceptable excipient.

13. The pharmaceutical composition according to claim 12, which is a pharmaceutical composition for preventing or treating a disease selected from the group consisting of schizophrenia, CIAS, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasticity, anxiety disorder, substance dependence, pain, fibromyalgia, and peroneal muscular atrophy.

14. Use of the compound or a salt thereof according to claim 1 for the manufacture of a pharmaceutical composition for the prevention or treatment of a disease selected from the group consisting of schizophrenia, CIAS, cognitive dysfunction, fragile X syndrome, autism spectrum syndrome, spasticity, anxiety disorder, substance dependence, pain, fibromyalgia, and peroneal muscle atrophy.