HK1214255B - 2-acylaminothiazole derivative and salt thereof - Google Patents

Abstract

The present inventors achieved the present invention on the basis of the knowledge that a thiazole derivative with a pyrazine-2-carbonylamine substituent at the second carbon position is an excellent positive allosteric modulator of the muscarinic M3 receptor and is useful as a prophylactic and/or therapeutic agent against bladder/urinary tract disorders associated with bladder contractions induced by the muscarinic M3 receptor. A 2-acylaminothiazole derivative or a salt thereof according to the present invention can be used as a prophylactic and/or therapeutic agent against bladder/urinary tract disorders associated with bladder contractions induced by the muscarinic M3 receptor, including, for example, urinary disorders such as underactive bladder. (In the formula, R1 is -(N(-R11)(-R12) or an optionally substituted cyclic amine; R11 is a C1-6 alkyl; R12 is an optionally substituted C1-6 alkyl or an optionally substituted C3-8 cycloalkyl; R2 is an optionally substituted aryl, an optionally substituted monocyclic aromatic heterocycle, or an optionally substituted bicyclic aromatic heterocycle; and R3 is -H,-OH, -O-( C1-6 alkyl), or a halogen.)

Description

2-acylaminothiazole derivative or salt thereof

Technical Field

The invention relates to pharmaceutical compositions useful as medicaments, in particular with muscarinic M₃2-acylaminothiazole derivatives or salts thereof as active ingredients of pharmaceutical compositions for treating bladder/urinary tract diseases associated with bladder contraction by receptors.

Background

The lower urinary tract plays an important role in storing and discharging urine, and they are regulated by the coordination of the bladder and the urethra. That is, the high resistance state of the urethra is maintained by relaxation of the bladder smooth muscle and contraction of the urethral sphincter during urine storage, thereby keeping the urine restraint. On the other hand, when urination is performed, the smooth muscle of the urinary tract relaxes while the smooth muscle of the bladder contracts, and contraction of the external urethral sphincter is also suppressed. The lower urinary tract disorder is: urine storage disorders such as overactive bladder in which urine is not retained during urine storage, and urination disorders in which urine is not sufficiently discharged during urination due to increase in urethral resistance or decrease in bladder contractility. These two obstacles sometimes occur simultaneously.

Micturition disorders are induced by a decrease in bladder contractility or an increase in urethral resistance during micturition, and cause dysuria, pain during micturition, a decrease in urinary line, an increase in micturition time, an increase in residual urine, a decrease in micturition efficiency, and the like. The decrease in the contractile force of the bladder during urination is called a decrease in the activity of the bladder or a bladder with no contractile ability. As a main cause of lowering of bladder contractility at the time of urination, there are known aging, diabetes, prostatic hypertrophy, neurological diseases such as parkinson's disease and multiple sclerosis, spinal cord injury, neurological disorders due to pelvic surgery, and the like (Reviews in Urology,15: pp.11-22 (2013)).

As a mechanism for causing bladder contraction during urination, it is known that it is associated with muscarinic receptor stimulation. That is, when urination occurs, the pelvic nerve, which is a parasympathetic nerve that innervates the bladder, is excited, and acetylcholine is released from nerve endings. The released acetylcholine binds to muscarinic receptors present in the smooth muscle of the bladder, causing contraction of the smooth muscle of the bladder (Journal of pharmaceutical sciences,112: pp.121-127 (2010)). Muscarinic receptors are currently classified as M₁、M₂、M₃、M₄、M₅5 subtypes, whereas the contraction-associated subtypes in bladder smooth muscle are known to be predominantly M₃(Pharmacological Reviews,50:pp.279-290(1998)、The Journal of Neuroscience,22:pp.10627-10632(2002))。

As therapeutic agents against a decrease in bladder contractility during urination, carbamylcholine chloride as a nonselective muscarinic receptor stimulating agent and bispyristylamine bromide as a cholinesterase inhibiting agent are known. However, these agents are known to have cholinergic side effects such as diarrhea, abdominal pain, and sweating. In addition, there are cases where a cholinergic crisis, which is a serious side effect, is found, and it is necessary to pay attention to the use (ウブレチド (registered trademark) tablet 5mg is accompanied by a manual, and birdhouse chemical co., ベサコリン (registered trademark)) powder 5% is accompanied by a manual, エーザイ co.).

In addition, as a cause causing an increase in urethral resistance, urination disorder accompanied by prostatic hypertrophy characterized by partial occlusion of the urethra due to nodular hypertrophy of the prostate tissue is common, and epinephrine α is now₁Receptor antagonists are useful as remedies for urination disorders accompanied by prostatic hypertrophy (Pharmacology,65: pp.119-128 (2002). on the other hand, epinephrine α is more effective than the one for urination disorders accompanied by prostatic hypertrophy₁The effectiveness of receptor antagonists against urination disorders that do not accompany prostatic hypertrophy is not significant (Journal of pharmaceutical Sciences,112: pp.121-127 (2010)).

In addition, in urination disorders caused by a decrease in bladder contractility or an increase in urethral resistance, residual urine after urination may be observed. Increased residual urine can cause a decrease in effective bladder capacity, sometimes resulting in overactive bladder, such as frequent urination, or severe symptoms such as hydronephrosis.

It is desired to provide a therapeutic agent more effective for these bladder/urinary tract diseases and symptoms thereof caused by a decrease in bladder contractility and an increase in urethral resistance during urination.

Patent document 1 describes: a compound represented by the following general formula (A) containing the compound of the following formula A1 disclosed in example 315 had a Ba/F3 cell-proliferating effect mediated by human c-myeloproliferative leukemia virus type P (c-Mpl) and had thrombocythemia activity.

[ chemical formula 1]

(in the formula, R³An aromatic heterocycle which may be substituted, etc. Other symbols refer to the gazette

Patent document 2 describes: a compound represented by the following general formula (B) containing a compound of the following formula B1 disclosed as compound 38 has an activation effect of the AMPK pathway.

[ chemical formula 2]

(wherein Ring B represents a heteroarylene group or the like, J represents-NR¹³C (O) -et al, D¹、D²And D³Denotes N, CH or the like, E denotes-NR¹R²And the like. Other symbols refer to the gazette

Documents of the prior art

Patent document

Patent document 1: international publication No. 2005/007651 pamphlet

Patent document 2: international publication No. 2012/016217 pamphlet

Disclosure of Invention

Problems to be solved by the invention

The invention provides pharmaceutical compositions useful as medicaments, particularly in combination with muscarinic M₃A compound as an active ingredient of a pharmaceutical composition for the prevention or treatment of bladder/urinary tract diseases associated with bladder contraction caused by a receptor.

Means for solving the problems

The present inventors have found that a thiazole derivative substituted with a pyrazine-2-carbonylamino group at the 2-position is excellent as a muscarinic M₃Receptor positive allosteric modulators useful as antagonists of muscarinic M₃A prophylactic and/or therapeutic agent for bladder/urinary tract diseases associated with bladder contraction by a receptor, and the present invention has been completed。

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 3]

(in the formula, wherein,

R¹is-N (-R)¹¹)(-R¹²) Or a cyclic amino group which may be substituted,

R¹¹is C_1-6An alkyl group, a carboxyl group,

R¹²is optionally substituted C_1-6Alkyl, or C which may be substituted_3-8A cycloalkyl group,

R²is an aryl group which may be substituted, a monocyclic aromatic heterocycle which may be substituted, or a bicyclic aromatic heterocycle which may be substituted, and

R³is-H, -OH, -O- (C)_1-6Alkyl), or halogen).

It is to be noted that, unless otherwise specified, the same symbols in a certain chemical formula are used in other chemical formulas in the present specification, and the same meanings are denoted by the same symbols.

In addition, in the above patent document 1, R in the compound of formula (A) is not disclosed³The effect on muscarinic receptors or on bladder and urinary tract diseases is not disclosed or suggested for the specific compound which is pyrazinyl.

Further, patent document 2 does not disclose any specific compound in which ring B is thiazole in the compound of formula (B), nor does it disclose or suggest its action on muscarinic receptors or its action on bladder and urinary tract diseases.

In addition, the invention relates to a composition comprisingPharmaceutical compositions containing a compound of formula (I) or a salt thereof, particularly with muscarinic M₃A pharmaceutical composition for preventing or treating bladder/urinary tract diseases associated with bladder contraction caused by receptors. In addition, the medicine composition comprises the compound and the muscarine M₃A prophylactic or therapeutic agent for bladder/urinary tract diseases associated with bladder contraction induced by a receptor, which comprises a compound represented by the formula (I) or a salt thereof.

In addition, the invention relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a medicament for treating or preventing a disease associated with muscarinic M₃Use of a compound of formula (I) or a salt thereof for preventing or treating muscarinic M₃Use of a compound for preventing or treating diseases of bladder and urinary tract related to bladder contraction induced by receptor, for preventing or treating muscarinic M₃A compound of formula (I) or a salt thereof for treating bladder/urinary tract diseases associated with bladder contraction induced by receptors, and a compound of formula (I) or a salt thereof for treating or preventing a disease associated with muscarinic M₃A method for preventing or treating bladder/urinary tract diseases associated with bladder contraction caused by receptors. In addition, "subject" refers to a human or other animal in need of such prevention or treatment, and as certain embodiments refers to a human in need of such prevention or treatment. ADVANTAGEOUS EFFECTS OF INVENTION

A compound of formula (I) or a salt thereof as a muscarinic M₃Receptor positive allosteric modulators useful as antagonists of muscarinic M₃A prophylactic and/or therapeutic agent for bladder/urinary tract diseases associated with bladder contraction by a receptor.

Brief description of the drawings

FIG. 1 shows the powder X-ray diffraction pattern of the compound of example 8.

FIG. 2 shows the powder X-ray diffraction pattern of the compound of example 206.

FIG. 3 shows the powder X-ray diffraction pattern of the compound of example 207.

The present invention is described in detail below.

Detailed Description

Positive allosteric modulators are compounds that: it binds to an allosteric site different from the ligand binding site, increases binding force of an agonist to a receptor mainly by causing a structural change of the receptor, and has an effect of changing the signal level of the agonist. In vivo, positive allosteric modulators do not exhibit agonist effects themselves, but rather enhance the effects of endogenous agonists. The advantages of positive allosteric modulators compared to agonists can be enumerated: (1) exhibit enhanced endogenous agonist stimulation-dependent effects, and thus avoid side effects; (2) binding to sites other than the ligand-binding site, and therefore high subtype selectivity is possible; (3) desensitization and the like seen in agonists are difficult to produce (pharmacological reviews,63: pp.59-126 (2011)).

In this specification, muscarinic M₃Receptor positive allosteric modulators refer to compounds that: potentiation by muscarinic M in an agonist stimulus dependent or neurostimulation dependent manner₃The receptor plays a role. Therefore, the bladder contraction-enhancing action only at the time of urination is expected, and it is considered that the compound is useful as an ameliorating agent for various symptoms accompanying urination disorders. In addition, it is expected that side effects known to be derived from choline functionality in bethanechol chloride and dipyridylamine bromide can be avoided by such a specific action at the time of urination. In addition, due to muscarinic M₃Since receptor-positive allosteric modulators increase the force of bladder contraction during urination, an effect on urination disorders caused by increased urethral resistance can also be expected. These improvements in micturition disorders lead to a reduction in residual urine, which is associated with an increase in effective bladder capacity, and improvement in urine storage function and avoidance of renal disorders can be expected. Thus, muscarinic M is expected₃Receptor positive allosteric modulators useful as antagonists of muscarinic M₃Bladder contraction related to receptorThe prophylactic and/or therapeutic agent for bladder and urinary tract diseases. The present inventors newly found a compound which functions as the regulator, and thus completed the present invention.

In the context of the present specification,

with muscarinic M₃The "bladder/urinary tract-related diseases associated with bladder contraction by a receptor" refers to, for example, urination disorders and urine storage disorders in low bladder activity, low-tension bladder, non-contractile bladder, detrusor activity deficiency, neurogenic bladder, urethral insufficiency, detrusor-external urethral sphincter insufficiency, overactive bladder, urinary frequency, nocturnal urinary frequency, urinary incontinence, prostatic hypertrophy, interstitial cystitis, chronic prostatitis, urinary calculi, and the like, and preferably bladder activity deficiency, low-tension bladder, non-contractile bladder, detrusor activity deficiency, and neurogenic bladder.

"alkyl" includes straight chain alkyl and branched chain alkyl. Thus, "C_1-6The "alkyl group" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and specifically includes, for example, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, or a n-hexyl group. In certain embodiments, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl is meant.

"cycloalkyl" refers to a saturated cyclic hydrocarbon group. Thus, "C_3-8The cycloalkyl group means a saturated cycloalkyl group having 3 to 8 ring atoms, and specifically includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In certain embodiments, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is meant, and as other embodiments, cyclopropyl.

"aryl" means C_6-14The monocyclic to tricyclic aromatic hydrocarbon ring group of (1). In particular, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl or indenyl. In certain embodiments, refers to phenyl.

The "monocyclic aromatic heterocyclic ring" is a monocyclic aromatic heterocyclic group having 5 to 7 ring atoms, which has 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom as ring-constituting atoms. Specifically, for example, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl. In certain embodiments, thienyl or thiazolyl, and as other embodiments, thienyl.

The "bicyclic aromatic heterocycle" refers to a bicyclic aromatic heterocycle obtained by condensing the above monocyclic aromatic heterocycle with a benzene ring or a monocyclic aromatic heterocycle, and includes a partially hydrogenated ring group thereof. Specifically, for example, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, thienopyridinyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, dihydrofuropyridinyl, or dihydrothienopyridinyl. In certain embodiments, refers to dihydrobenzofuranyl.

The "saturated heterocyclic ring" is a 3-to 8-membered saturated cyclic group having 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom as ring-constituting atoms, being crosslinkable with a lower alkylene group, and being oxidizable at the sulfur atom as the ring-constituting atom.

"Cyclic amino group" means a group having a bond to the nitrogen atom constituting the saturated hetero ring in the above-mentioned saturated hetero ring, and specifically includes, for example, pyrrolidin-1-yl group, piperidin-1-yl group, azetidin-1-yl group, azepan-1-yl group, morpholin-4-yl group, thiomorpholin-4-yl group, piperazin-1-yl group, 1, 4-diazepan-1-yl group, 1, 4-homomorpholin-4-yl group or 1, 4-thiazepan-4-yl group (1,4- チアゼパソ -4- イル). In certain embodiments, pyrrolidin-1-yl, piperidin-1-yl, azetidin-1-yl, or morpholin-4-yl is meant. As other embodiments, pyrrolidin-1-yl or piperidin-1-yl.

R¹The cyclic amino group in (2) may form a spiro ring together with the cyclic amino group. As the cyclic amino group in this case, specifically, for example, 2-oxa-6-azaspiro [3.5]]Nonan-6-yl, 2, 6-diazaspiro [3.5]]Nonan-6-yl, 2-thia-6-azaspiro [3.5]]Nonan-6-yl, 2-oxa-8-azaspiro [4.5 ]]Decan-8-yl, 6-oxa-9-azaspiro [4.5 ]]Decan-9-yl or 3-oxa-9-azaspiro [5.5]Undecan-9-yl, and the like.

"halogen" means fluorine, chlorine, bromine or iodine. In certain embodiments, fluorine, chlorine or bromine, and as other embodiments, fluorine or chlorine.

In the present specification, "may be substituted" means that the substituent is not substituted or 1 to 5 substituents are contained. When a plurality of substituents are present, the substituents may be the same or different from each other.

As "cyclic amino group which may be substituted" or "C which may be substituted_1-6Alkyl group "," optionally substituted C_3-8The substituents allowed in the cycloalkyl group "," aryl group which may be substituted "," monocyclic aromatic heterocycle which may be substituted "and" bicyclic aromatic heterocycle which may be substituted "are, for example, substituents of the following group G. In other embodiments, the substituents are those described in (a) to (G) and (m) to (o) of the following group G.

Group G

(a) Can be selected from the group consisting of-OH and-O- (C)_1-6Alkyl), -CN, -SO₂-C_1-6C substituted by more than 1 group of alkyl and halogen_1-6An alkyl group, a carboxyl group,

(b)-OH，

(c) -O- (optionally selected from-OH, -O- (C)_1-6Alkyl), -CN, -SO₂-C_1-61 of the group consisting of alkyl and halogenC substituted by more than one group_1-6An alkyl group),

(d)C_3-8a cycloalkyl group,

(e)-O-(C_3-8a cycloalkyl group),

(f) the halogen(s) are selected from the group consisting of,

(g)-CN，

(h)-SO₂-C_1-6an alkyl group, a carboxyl group,

(i)-CO₂-C_1-6an alkyl group and-COOH, and a carboxyl group,

(j)-CO-N(C_1-6alkyl radical)₂、-CO-NH(C_1-6Alkyl) and-CONH₂，

(k)-CO-C_1-6An alkyl group, a carboxyl group,

(l)-SO₂-N(C_1-6alkyl radical)₂、-SO₂-NH(C_1-6Alkyl) and-SO₂NH₂，

(m)-N(C_1-6Alkyl radical)₂、-NH(C_1-6Alkyl) and-NH₂，

(n) a saturated heterocycle, and

(O) -O-saturated heterocycles.

As a substituent in the "cyclic amino group which may be substituted", an oxo group (═ O) may be further mentioned.

As R¹Some embodiments of the substituents allowed in the "cyclic amino group which may be substituted" in (b) are the substituents shown in (a) to (d), (f) and (G) in the above-mentioned group G.

As other embodiments, the substituents shown in the following group G1.

Group G1

Can be selected from the group consisting of-OH and-O- (C)_1-6Alkyl) and halogen, and 1 to 3 same or different substituents in the group consisting of_1-6An alkyl group; -O- (C)_1-6Alkyl groups); c_3-8A cycloalkyl group; halogen; and-CN.

As a further embodiment, are optionally selected from the group consisting of-OH, -O- (C)_1-6Alkyl) and halogen, and 1 to 3 same or different substituents in the group consisting of_1-6An alkyl group.

As a further embodiment, is optionally selected from the group consisting of-O- (C)_1-6Alkyl) and halogen, and 1 to 3 same or different substituents in the group consisting of_1-6An alkyl group.

As yet another embodiment, the number of-O- (C) s which may be the same or different is 1 to 3_1-6Alkyl) substituted C_1-6An alkyl group.

As yet another embodiment, is C_1-6An alkyl group.

As yet another embodiment, methyl or ethyl.

As R¹²C in (1)_1-6Some embodiments of the permissible substituents for the alkyl group "are the substituents shown in (b) to (o) in the above-mentioned group G.

As other embodiments, is C_3-8Cycloalkyl, -O- (C)_1-6Alkyl), -O- (C)_3-8Cycloalkyl), halogen, -CN, or cyclic amino.

As other embodiments, is-O- (C)_1-6Alkyl groups).

As R¹²C in (1)_3-8Some embodiments of the substituents allowed in the cycloalkyl group "are the substituents shown in the above groups (a) to (c), (f) and (G) in group G.

As other embodiments, may be substituted by-O- (C)_1-6Alkyl) substituted C_1-6An alkyl group.

As R²Certain embodiments of the permissible substituents of "aryl which may be substituted" in (A) to (E) are in group G as described above(c) And (f), (g) and (m) to (o).

As other embodiments, the substituents shown in the following group G2.

Group G2

C which may be substituted by 1 to 5 identical or different halogens_1-6Alkyl, -O- (optionally selected from halogen and-O- (C)_1-6Alkyl) C substituted with 1 to 5 same or different substituents_1-6Alkyl), -O-saturated heterocycle, halogen, -N (C)_1-6Alkyl radical)₂、-NH(C_1-6Alkyl), -NH₂And a cyclic amino group.

As a further embodiment, are the substituents shown in group G21 below.

Group G21

C which may be substituted by 1 to 5 identical or different halogens_1-6Alkyl, -O- (optionally selected from halogen and-O- (C)_1-6Alkyl) C substituted with 1 to 5 same or different substituents_1-6Alkyl), -O-saturated heterocycle, halogen, -N (C)_1-6Alkyl radical)₂And a cyclic amino group.

As yet another embodiment, are the substituents shown in group G22 below.

Group G22

C which may be substituted by 1 to 5 identical or different halogens_1-6Alkyl, -O- (optionally selected from halogen and-O- (C)_1-6Alkyl) C substituted with 1 to 5 same or different substituents_1-6Alkyl), halogen and-N (C)_1-6Alkyl radical)₂。

As yet another embodiment, are the substituents shown in group G23 below.

Group G23

C which may be substituted by 1 to 5 identical or different halogens_1-6Alkyl, -O- (which may be substituted by 1 to 5 halogens which may be the same or different)Substituted by elements C_1-6Alkyl), halogen and-N (C)_1-6Alkyl radical)₂。

As yet another embodiment, are the substituents shown in group G24 below.

Group G24

C which may be substituted by 1 to 5 identical or different halogens_1-6Alkyl, -O- (C)_1-6Alkyl) and halogen.

As yet another embodiment, are the substituents shown in group G25 below.

Group G25

C which may be substituted by 1 to 5 identical or different halogens_1-6Alkyl and-O- (C)_1-6Alkyl groups).

As yet another embodiment, trifluoromethyl and methoxy.

As R²Some embodiments of the substituents allowed in the "monocyclic aromatic heterocycle which may be substituted" and the "bicyclic aromatic heterocycle which may be substituted" are the substituents shown in (a) to (c), (f), (G) and (m) to (o) in the above-mentioned group G.

As other embodiments, the substituents shown in the following group G3.

Group G3

C which may be substituted by 1 to 5 identical or different halogens_1-6Alkyl, -O- (C which may be substituted by 1 to 5 identical or different halogens_1-6Alkyl), halogen, -N (C)_1-6Alkyl radical)₂、-NH(C_1-6Alkyl), -NH₂And a cyclic amino group.

As a further embodiment, are the substituents shown in group G31 below.

Group G31

C which may be substituted by 1 to 5 identical or different halogens_1-6Alkyl, -O- (which may be substituted by 1 to 5 halogens which may be the same or different)Substituted by elements C_1-6Alkyl) and halogen.

As yet another embodiment, are the substituents shown in group G32 below.

Group G32

C which may be substituted by 1 to 5 identical or different halogens_1-6Alkyl and halogen.

As yet another embodiment, is halogen.

As yet another embodiment, chlorine.

Certain embodiments of the compounds of formula (I) or salts thereof are shown below.

(1)R¹Is a cyclic amino group which may be substituted with 1 to 5 substituents selected from group G and oxo, or R¹is-N (-R)¹¹)(-R¹²) Or a salt thereof.

As other embodiments, are compounds or salts thereof: r¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, azetidin-1-yl and morpholin-4-yl, or R¹is-N (-R)¹¹)(-R¹²) The cyclic amino group may be substituted with 1 to 3 same or different substituents selected from the group G1,

R¹¹is C_1-6An alkyl group, a carboxyl group,

R¹²can be replaced by-O- (C)_1-6Alkyl) substituted C_1-6Alkyl, or may be substituted by-O- (C)_1-6Alkyl) C_1-6Alkyl substituted C_3-8A cycloalkyl group.

As yet another embodiment, is a compound or salt thereof: r¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, azetidin-1-yl and morpholin-4-yl, or R¹is-N (-R)¹¹)(-R¹²) The cyclic amino group may be substituted by C_1-6Alkyl is substituted, and the C_1-6The alkyl group may be selectedfree-O- (C)_1-6Alkyl) and halogen, and 1 to 3 identical or different substituents in the group,

R¹¹is C_1-6An alkyl group, a carboxyl group,

R¹²can be replaced by-O- (C)_1-6Alkyl) substituted C_1-6An alkyl group.

As yet another embodiment, is a compound or salt thereof: r¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl and piperidin-1-yl, or R¹is-N (-R)¹¹)(-R¹²) The cyclic amino group may be substituted by C_1-6Alkyl is substituted, and the C_1-6The alkyl group may be further selected from the group consisting of-O- (C)_1-6Alkyl) and halogen, and 1 to 3 identical or different substituents in the group,

R¹¹is C_1-6An alkyl group, a carboxyl group,

R¹²can be replaced by-O- (C)_1-6Alkyl) substituted C_1-6An alkyl group.

(1-1) is a compound or a salt thereof: r¹Is a cyclic amino group which may be substituted with 1 to 5 same or different substituents selected from group G and oxo.

As other embodiments, are compounds or salts thereof: r¹Is a cyclic amino group which may be substituted with 1 to 3 same or different substituents selected from group G1.

As other embodiments, are compounds or salts thereof: r¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, azetidin-1-yl and morpholin-4-yl, which may be substituted with 1 to 3 identical or different substituents selected from group G.

As yet another embodiment, is a compound or salt thereof: r¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, azetidin-1-yl and morpholin-4-yl, which may be selected from1 to 3 same or different substituents of group G1.

As yet another embodiment, is a compound or salt thereof: r¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, azetidin-1-yl and morpholin-4-yl, which cyclic amino group may be substituted by C_1-6Alkyl is substituted, and the C_1-6The alkyl group may be further selected from the group consisting of-O- (C)_1-6Alkyl) and halogen, and 1 to 3 identical or different substituents in the group.

As yet another embodiment, is a compound or salt thereof: r¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl and piperidin-1-yl, the cyclic amino group being substituted with C_1-6Alkyl is substituted, and the C_1-6The alkyl group may be further selected from the group consisting of-O- (C)_1-6Alkyl) and halogen, and 1 to 3 identical or different substituents in the group.

As yet another embodiment, is a compound or salt thereof: r¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl and piperidin-1-yl, the cyclic amino group being substituted with C_1-6Alkyl is substituted, and the C_1-6The alkyl groups may be substituted by 1 to 3 same or different-O- (C)_1-6Alkyl) substituted.

As yet another embodiment, is a compound or salt thereof: r¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl and piperidin-1-yl, the cyclic amino group being substituted with C_1-6Alkyl substitution.

As yet another embodiment, is a compound or salt thereof: r¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl and piperidin-1-yl, which is substituted with 1 to 3 same or different substituents selected from the group consisting of methyl and ethyl.

(1-2) is a compound or a salt thereof: r¹is-N (-R)¹¹)(-R¹²)，R¹¹Is methyl, ethyl, n-propyl, or isobutyl.

(1-3) is a compound or a salt thereof: r¹is-N (-R)¹¹)(-R¹²)，R¹²Can be replaced by-O- (C)_1-6Alkyl) substituted C_1-6Alkyl or is optionally substituted by-O- (C)_1-6Alkyl) C_1-6Alkyl substituted C_3-8A cycloalkyl group.

As other embodiments, are compounds or salts thereof: r¹is-N (-R)¹¹)(-R¹²)，R¹²Is represented by-O- (C)_1-6Alkyl) substituted C_1-6An alkyl group.

As yet another embodiment, is a compound or salt thereof: r¹is-N (-R)¹¹)(-R¹²)，R¹²Is 2-methoxyethyl.

(1-4) any combination of the compounds described in (1-2) and (1-3) above or salts thereof.

(2) Is a compound or salt thereof: r²Is an aryl group which may be substituted with 1 to 5 same or different substituents selected from group G, a monocyclic aromatic heterocyclic ring which may be substituted with 1 to 5 same or different substituents selected from group G, or a bicyclic aromatic heterocyclic ring which may be substituted with 1 to 5 same or different substituents selected from group G.

As other embodiments, are compounds or salts thereof: r²Is phenyl which may be substituted with 1 to 5 same or different substituents selected from group G, thienyl which may be substituted with 1 to 3 same or different substituents selected from group G, thiazolyl which may be substituted with 1 to 2 same or different substituents selected from group G, or 2, 3-dihydro-1-benzofuranyl which may be substituted with 1 to 5 same or different substituents selected from group G.

As yet another embodiment, is a compound or salt thereof: r²Is phenyl which may be substituted by 1 to 5 same or different substituents selected from group G2, thienyl which may be substituted by 1 to 3 same or different substituents selected from group G3, 1 to 2 same or different substituents selected from group G3Thiazolyl which may be substituted with the same or different substituent, or 2, 3-dihydrobenzofuranyl which may be substituted with 1 to 5 same or different substituents selected from group G3.

In addition, as yet another embodiment, is a compound or a salt thereof: r²Is phenyl or thienyl, the phenyl group can be substituted by 1-5 same or different substituents selected from the group G21, the thienyl can be substituted by 1-3 same or different substituents selected from the group G32.

As yet another embodiment, is a compound or salt thereof: r²Is phenyl or thienyl, the phenyl group can be substituted by 1 to 5 same or different substituents selected from the group G22, the thienyl can be substituted by 1 to 3 same or different halogens.

As yet another embodiment, is a compound or salt thereof: r²Is phenyl or thienyl, the phenyl group can be substituted by 1 to 3 same or different substituents selected from the group G24, the thienyl can be substituted by 1 to 3 same or different halogens.

As yet another embodiment, is a compound or salt thereof: r²Is phenyl or thienyl, the phenyl group can be substituted by 1 to 3 same or different substituents selected from the group G25, the thienyl can be substituted by 1 to 3 same or different halogens.

As yet another embodiment, is a compound or salt thereof: r²Is phenyl or thienyl, the phenyl group can be substituted by 1-2 same or different substituents selected from the group consisting of trifluoromethyl and methoxy, and the thienyl can be substituted by 1 chlorine.

(2-1) is a compound or a salt thereof: r²Is phenyl which may be substituted by 1 to 5 identical or different substituents selected from group G.

As other embodiments, are compounds or salts thereof: r²Is a phenyl group which may be substituted by 1 to 5 same or different substituents selected from group G2.

As yet another embodiment, is a compound or salt thereof: r²Is a phenyl group which may be substituted by 1 to 5 same or different substituents selected from group G21.

As yet another embodiment, is a compound or salt thereof: r²Is a phenyl group which may be substituted by 1 to 5 same or different substituents selected from group G22.

As yet another embodiment, is a compound or salt thereof: r²Is a phenyl group which may be substituted by 1 to 5 same or different substituents selected from group G23.

As yet another embodiment, is a compound or salt thereof: r²Is a phenyl group which may be substituted with 1 to 3 same or different substituents selected from group G24.

As yet another embodiment, is a compound or salt thereof: r²Is a phenyl group which may be substituted with 1 to 3 same or different substituents selected from group G25.

As yet another embodiment, is a compound or salt thereof: r²Is a phenyl group which may be substituted by 1 to 2 identical or different substituents selected from the group consisting of a trifluoromethyl group and a methoxy group.

(2-2) is a compound or a salt thereof: r²Is thienyl which may be substituted with 1 to 3 same or different substituents selected from group G.

As other embodiments, are compounds or salts thereof: r²Is thienyl which may be substituted with 1 to 3 same or different substituents selected from group G3.

As yet another embodiment, is a compound or salt thereof: r²Is thienyl which may be substituted with 1 to 3 same or different substituents selected from group G31.

As yet another embodiment, is a compound or salt thereof: r²Is thienyl which may be substituted with 1 to 3 same or different substituents selected from group G32.

As yet another embodiment, is a compound or salt thereof: r²Is thienyl which may be substituted with 1 to 3 identical or different halogens.

In addition, as yet another embodiment, is a compound or a salt thereof: r²Thienyl which may be substituted by 1 chloro.

(3) Is a compound or salt thereof: r³is-H, -OH, methoxy or fluorine.

As other embodiments, are compounds or salts thereof: r³is-H, -OH or fluorine.

As yet another embodiment, is a compound or salt thereof: r³is-H.

(4) Is a compound or salt thereof: any one of the embodiments described in (1), (1-1) or (1-4) above, any one of the embodiments described in (2), (2-1) or (2-2), and any one of the embodiments described in (3).

(4-1) is a compound or a salt thereof: r¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, azetidin-1-yl and morpholin-4-yl, or is-N (-R)¹¹)(-R¹²) The cyclic amino group may be substituted with 1 to 3 same or different substituents selected from the group G1,

R¹¹is C_1-6An alkyl group, a carboxyl group,

R¹²can be replaced by-O- (C)_1-6Alkyl) substituted C_1-6Alkyl or is optionally substituted by-O- (C)_1-6Alkyl) C_1-6Alkyl substituted C_3-8A cycloalkyl group,

R²is phenyl which may be substituted with 1 to 5 identical or different substituents selected from group G2, may be substituted with 1 to 3 identical or different substituents selected from group G3A substituted thienyl group, a thiazolyl group which may be substituted with 1 to 2 same or different substituents selected from group G3, or a 2, 3-dihydrobenzofuranyl group which may be substituted with 1 to 5 same or different substituents selected from group G3,

R³is-H, -OH, methoxy or fluorine.

(4-2) is the compound according to the above (4-1) or a salt thereof, wherein R²Is phenyl or thienyl, the phenyl group can be substituted by 1-5 same or different substituents selected from the group G21, the thienyl can be substituted by 1-3 same or different substituents selected from the group G32.

(4-3) is the compound according to the above (4-2) or a salt thereof, wherein R¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl and piperidin-1-yl, or is-N (-R)¹¹)(-R¹²) The cyclic amino group may be substituted by C_1-6Alkyl substitution of the C_1-6Alkyl may be selected from the group consisting of-O- (C)_1-6Alkyl) and halogen, and 1 to 3 identical or different substituents in the group,

R¹²can be replaced by-O- (C)_1-6Alkyl) substituted C_1-6An alkyl group, a carboxyl group,

R²is phenyl or thienyl, said phenyl being substituted by 1 to 5 identical or different substituents selected from the group G22, said thienyl being substituted by 1 to 3 identical or different halogens,

R³is-H, -OH or fluorine.

(4-4) is the compound according to the above (4-3) or a salt thereof, wherein R¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl and piperidin-1-yl, the cyclic amino group being substituted with C_1-6Alkyl substitution of the C_1-6The alkyl groups may be substituted by 1 to 3 same or different-O- (C)_1-6Alkyl) is substituted with (a) a (b),

R²is phenyl or thienyl, the phenyl group can be substituted by 1 to 3 same or different substituents selected from the group G24, the thienyl can be substituted by 1 to 3 same or different halogensThe substitution of the element(s),

R³is-H.

(4-5) is the compound according to the above (4-4) or a salt thereof, wherein R¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl and piperidin-1-yl, the cyclic amino group being substituted with C_1-6The substitution of the alkyl group is carried out,

R²is phenyl or thienyl, the phenyl group can be substituted by 1 to 3 same or different substituents selected from the group G25, the thienyl can be substituted by 1 to 3 same or different halogens.

(4-6) is the compound according to the above (4-5) or a salt thereof, wherein R¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl and piperidin-1-yl, which cyclic amino group is substituted with 1 to 3 same or different substituents selected from the group consisting of methyl and ethyl,

R²is phenyl or thienyl, the phenyl group can be substituted by 1-2 same or different substituents selected from the group consisting of trifluoromethyl and methoxy, and the thienyl can be substituted by 1 chlorine.

(4-7) is the compound according to the above (4-6) or a salt thereof, wherein R²Is a phenyl group which may be substituted by 1 to 2 identical or different substituents selected from the group consisting of a trifluoromethyl group and a methoxy group.

(4-8) is the compound according to the above (4-6) or a salt thereof, wherein R²Thienyl which may be substituted by 1 chloro.

(4-9) is a compound or a salt thereof: r¹Is a cyclic amino group which may be substituted with 1 to 5 same or different substituents selected from group G and oxo,

R²is phenyl which may be substituted with 1 to 5 same or different substituents selected from group G, thienyl which may be substituted with 1 to 3 same or different substituents selected from group G, thiazolyl which may be substituted with 1 to 2 same or different substituents selected from group G, or 1 to 5 substituents which may be selected from group G2, 3-dihydro-1-benzofuranyl substituted by the same or different substituents,

R³is-H, -OH, methoxy or fluorine.

(4-10) the compound according to the above (4-9) or a salt thereof, wherein R²Is phenyl which may be substituted by 1 to 5 substituents selected from group G.

(4-11) is the compound according to the above (4-9) or a salt thereof, wherein R²Is thienyl which may be substituted with 1 to 3 substituents selected from group G.

(4-12) the compound according to the above (4-10) or a salt thereof, wherein R¹Is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl or piperidin-1-yl, which cyclic amino group may be substituted by C_1-6Alkyl substitution of the C_1-6Alkyl may be selected from the group consisting of-O- (C)_1-6Alkyl) and halogen, and 1 to 3 identical or different substituents in the group,

R²phenyl which may be substituted by 1 to 5 identical or different substituents selected from group G23,

R³is-H.

Examples of the specific compound included in the present invention include the following compounds and salts thereof.

1- {5- [ (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 4-propoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid,

1- {5- [ (4- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -5- { [ (2R) -2-methylpiperidin-1-yl ] methyl } -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid,

1- (5- { [4- (4-chloro-2-thienyl) -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl ] carbamoyl } pyrazin-2-yl) piperidine-4-carboxylic acid,

1- {5- [ (4- [ 4-isopropoxy-3- (trifluoromethyl) phenyl ] -5- { [ (2R) -2-propylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid,

1- (5- { [4- (3-chloro-5-fluoro-4-methoxyphenyl) -5- { [ (2S) -2- (ethoxymethyl) pyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl ] carbamoyl } pyrazin-2-yl) piperidine-4-carboxylic acid,

1- {5- [ (5- { [ (2S) -2- (ethoxymethyl) pyrrolidin-1-yl ] methyl } -4- [ 3-fluoro-4-methoxy-5- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid,

1- (5- { [4- (3, 5-dichloro-4-methoxyphenyl) -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl ] carbamoyl } pyrazin-2-yl) piperidine-4-carboxylic acid,

1- {5- [ (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 3-fluoro-5- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid,

1- {5- [ (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid,

1- {5- [ (4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -5- { [ (2R) -2-propylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid,

1- [5- ({5- [ (2-isopropylpyrrolidin-1-yl) methyl ] -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid,

1- {5- [ (4- [ 4-chloro-2-thienyl ] -5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid, and

1- {5- [ (4- [ 4-ethoxy-3- (trifluoromethyl) phenyl ] -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid.

As another embodiment, the following compounds or salts thereof may be mentioned as examples of the specific compounds contained in the present invention.

1- {5- [ (4- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -5- { [ (2R) -2-methylpiperidin-1-yl ] methyl } -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid,

1- (5- { [4- (4-chloro-2-thienyl) -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl ] carbamoyl } pyrazin-2-yl) piperidine-4-carboxylic acid,

1- {5- [ (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 3-fluoro-5- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid, and

1- {5- [ (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid.

In the compound of formula (I), tautomers or geometric isomers may exist depending on the kinds of substituents. In the present specification, only one form of the isomer of the compound of the formula (I) may be mentioned, but the present invention includes isomers other than the form, and also includes an isolated isomer or a mixture thereof.

In addition, in the compound of formula (I), there are sometimes cases where asymmetric carbon atoms or axes are asymmetric, and optical isomers based thereon may exist. The invention also includes isolated optical isomers of the compounds of formula (I), or mixtures thereof.

In addition, the present invention also includes 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 the precursor drug include those shown in Prog.Med.,5,2157-2161(1985) and "development of pharmaceuticals" (Guangchua bookshop, 1990) volume 7 molecular design 163-198.

The salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and depending on the kind of the substituent, an acid addition salt or a salt with a base may be formed. 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.; salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and the like, and organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like; salts with various amino acids and amino acid derivatives such as acetylleucine, and ammonium salts.

In addition, the present invention also encompasses various hydrates and solvates, as well as polymorphs, of the compounds of formula (I) and salts thereof. In addition, the present invention also encompasses compounds labeled with various radioactive or non-radioactive isotopes.

(production method)

The compound of formula (I) and salts thereof can be produced by various known synthetic methods utilizing characteristics based on the basic structure thereof or the kind of substituents. In this case, depending on the kind of the functional group, it may be effective in terms of production technology to convert the functional group into an appropriate protecting group (a group which can be easily converted into the functional group) in advance in a stage from the raw material to the intermediate. Examples of such a protecting group include those shown in "green's chiral Groups in Organic Synthesis (4 th edition, 2006)" by p.g.m.wuts and t.w.greene, and they can be appropriately selected and used according to the reaction conditions thereof. In such a method, the desired compound can be obtained by introducing the protecting group to carry out the reaction, and then removing the protecting group as necessary.

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

A typical production method of the compound of formula (I) is described below. Each of the production methods can also be carried out with reference to the references attached to the description. The manufacturing method of the present invention is not limited to the following examples.

[ chemical formula 4]

(wherein R represents a lower alkyl group or a benzyl group; the same applies hereinafter.)

This reaction is a process for producing a compound of the present invention, i.e., a compound of formula (I), by deprotecting a compound of formula (a).

In this reaction, the compound of formula (a) and the deprotection reagent are used in equal amounts or in an excess amount, and the reaction is carried out in a solvent inert to the reaction or without a solvent, under cooling to heating reflux, and usually stirred for 0.1 hour to 5 days. Alternatively, when R is a benzyl group, the reaction may be carried out by hydrogenating the compound of the formula (a) in a hydrogen atmosphere using a metal catalyst. Examples of the solvent used herein are not particularly limited, but include alcohols such as methanol, ethanol, and n-propanol, Dimethylformamide (DMF), tetrahydrofuran, and the like. In addition, a mixed solvent of the above solvent and water may be suitable for the reaction. Examples of the deprotection reagent include, but are not particularly limited to, bases such as aqueous sodium hydroxide solution and aqueous potassium hydroxide solution, and acids such as hydrochloric acid and trifluoroacetic acid. Examples of the metal catalyst usable under the hydrogenation conditions include palladium on carbon, palladium hydroxide and the like.

(raw Material Synthesis 1-1)

[ chemical formula 5]

(first step)

This step is a step of obtaining a compound of formula (d) by subjecting a compound of formula (b) and a compound of formula (c) to an amidation reaction.

In this reaction, the compound of formula (b) and the compound of formula (c) are used in equal amounts or in an excess amount, and in the presence of a condensing agent, in a solvent inert to the reaction, the mixture is stirred usually for 0.1 hour to 5 days under cooling to heating conditions, preferably at-20 ℃ to 150 ℃. Examples of the solvent used herein are not particularly limited, but include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as methylene chloride, 1, 2-dichloroethane and chloroform, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and cyclopentyl methyl ether, N, N-dimethylformamide, dimethyl sulfoxide (DMSO), ethyl acetate, acetonitrile and water, and mixtures thereof. Examples of the condensing agent include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, dicyclohexylcarbodiimide, 1 '-carbonyldiimidazole, diphenyl phosphate azide, phosphorus oxychloride, and O- (benzotriazol-1-yl) -N, N' -tetramethyluronium tetrafluoroborate. Sometimes, it is preferable to use an additive (e.g., 1-hydroxybenzotriazole) for the reaction. In some cases, the reaction is carried out in the presence of an organic base such as triethylamine, N-diisopropylethylamine or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide, and it is advantageous to carry out the reaction smoothly. In addition, sometimes, heating the reaction mixture by microwave irradiation is advantageous for the reaction to proceed smoothly.

Alternatively, a method of converting the carboxylic acid (c) into a reactive derivative and then reacting the reactive derivative with the amine (b) may be employed. Examples of the reactive derivative of the carboxylic acid include an acid halide obtainable by reaction with a halogenating agent such as phosphorus oxychloride or thionyl chloride, a mixed acid anhydride obtainable by reaction with isobutyl chloroformate or the like, and an active ester obtainable by condensation with 1-hydroxybenzotriazole or the like. The reaction of the reactive derivative with the compound (b) may be carried out in a solvent inert to the reaction, such as a halogenated hydrocarbon, an aromatic hydrocarbon, or an ether, under heating under cooling, preferably at-20 to 60 ℃.

[ document ]

Sandler and W.Karo, "Organic Functional Group Preparations", 2 nd edition, volume 1, Academic Press Inc., 1991

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

(second Process)

This step is a step of introducing an aminomethyl group into the 5-position of the thiazole in the compound of the formula (d) by a Mannich reaction to produce the compound of the formula (a). Albertson, N.F. Journal of American chemistry 1948,70,669, and Bhargava, P.N. may be used; sharma, s.c.; the method shown in Bulletin of the chemical society of Japan 1965,38,909, or a method based on these as a standard.

(raw Material Synthesis 1-2)

[ chemical formula 6]

(first step)

This step is a step of introducing an acetoxymethyl group into the 5-position of the thiazole in the compound of the formula (d) to produce a compound of the formula (e). The reaction of the compound of the formula (d) with an aqueous solution of formaldehyde or paraformaldehyde in an acetic acid solvent may be carried out at room temperature to under heating or at room temperature to under reflux. Instead of the acetic acid solvent, acetic acid may be added to a solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, and ethers, to allow the reaction to proceed. Further, acetic anhydride may be further added to the reaction mixture to carry out the reaction.

(second Process)

This step is a step of producing a compound of formula (a) by subjecting a compound of formula (e) to nucleophilic substitution reaction under basic conditions with a compound of formula (f). The nucleophilic substitution reaction can be carried out by allowing the compound of the formula (f) to act on the compound of the formula (e) in an organic solvent inert to the reaction, such as a halogenated hydrocarbon, an aromatic hydrocarbon, an ether, an ester, acetonitrile, DMF, DMSO, and the like, in the presence of an organic base such as triethylamine, diisopropylethylamine, and the like, and/or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and the like. In addition, a catalyst such as dimethylaminopyridine may be added to accelerate the reaction. In addition, instead of the organic base and/or the inorganic base, the compound of formula (f) may be used in excess. The reaction can be carried out under cooling to room temperature, under heating at room temperature, under reflux at room temperature.

(raw Material Synthesis 2)

[ chemical formula 7]

(wherein P represents a protecting group such as acetyl.)

(first step)

This step is a step of producing a compound of formula (h) by subjecting a compound of formula (g) to a mannich reaction and then to a deprotection reaction. The Mannich reaction is the same as the second step of the starting material synthesis 1-1. Next, deprotection of P as an amino protecting group can be carried out by Greene and Wuts, supra, "Protective Groups in Organic Synthesis", 4 th edition, John Wiley & Sons Inc, 2006.

(second Process)

This step is a step of producing a compound of formula (a) by amidation reaction of a compound of formula (h) with a compound of formula (i). The reaction conditions were the same as in the first step of the starting material synthesis 1-1.

(raw Material Synthesis 3)

[ chemical formula 8]

(wherein L represents a leaving group such as chlorine.)

(first step)

This step is a method for producing a compound of formula (k) by amidation reaction of a compound of formula (h) with a compound of formula (j). The reaction conditions were the same as in the first step of the starting material synthesis 1-1.

(second Process)

This step is a step of producing a compound of formula (a) by reacting a compound of formula (k) with a compound of formula (m).

In this reaction, the compound (k) and the compound (m) are used in equal amounts or in an excess amount, and a mixture thereof is stirred in a solvent inert to the reaction or without a solvent under cooling to heating reflux conditions, preferably at 0 ℃ to 80 ℃, usually for 0.1 hour to 5 days. Examples of the solvent used herein are not particularly limited, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane and chloroform, N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile, N-methylpyrrolidone and mixtures thereof. In order to smoothly progress the reaction, it may be advantageous to carry out the reaction in the presence of an organic base such as triethylamine, N-diisopropylethylamine or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide.

[ document ]

Sandler and W.Karo, "Organic Functional Group Preparations", 2 nd edition, volume 1, Academic Press Inc., 1991, Japan chemical society eds "Experimental chemistry lecture (5 th edition)" volume 14 (2005) (pill)

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

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

The respective isomers can be produced by selecting appropriate starting compounds, or can be separated by utilizing the difference in physicochemical properties between the isomers. For example, optical isomers can be obtained by a general optical resolution method of racemic modification (for example, conversion to a diastereomer with an optically active base or acid and fractional crystallization, or 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 compounds of formula (I) was confirmed by the following assay.

Test example 1: muscarinic M₃Evaluation of receptor-Positive allosteric Modulator Activity

a) Human muscarinic M₃Construction of receptor expression vectors

Converting human muscarinic M₃The receptor gene (GenBank accession number: NM-000740.2) was introduced into expression vector pcDNA3.1^TM(Life Technologies).

b) Human muscarinic M₃Construction of cells stably expressing receptor

Converting human muscarinic M₃The receptor expression vector was introduced into CHO-K1 cells (ATCC No.: CCL-61). 2000-scale assay Using Lipofectamine (registered trademark) as a Gene transfer reagentThe drug-resistant clones were obtained by culturing cells in alpha Modified Eagle Minimum Essential Medium (α -MEM) containing 2mM glutamic acid, 10% bovine fetal serum, and 2.0mg/mL genetic in (registered trademark) (Life Technologies) for 4 weeks.

c) Intracellular Ca²⁺Determination of concentration

The cells obtained in b) above were suspended in α -MEM containing 2mM glutamic acid, 10% bovine fetal serum, and 0.2mg/mL Geneticin (registered trademark) one day before the experiment, and the suspension was adjusted to 1.2 to 1.5 × 10⁴The cells/well were injected separately into 384 well plates (model 355962, BD Biosciences) and incubated at 37 ℃ with 5% CO₂Culturing overnight. The medium was changed to a loading buffer (detection buffer (hank's balanced salt solution (HBSS), 1g/L BSA, 20mM HEPES (pH7.5), 2.5mM carboxyphenylsulfopropylamine) containing 3.1. mu.M Fluo 4-AM (Dojindo research institute of chemistry)), and left to stand at room temperature for about 2 hours. Thereafter, the plate washer ELx405 injected with detection buffer is used^TM(BIO-TEK Instrument) cells were washed and Ca was injected into cells²⁺Concentration measuring System (FLIPR)^tetra(registered trademark), Molecular Device). The test substance (final concentration 1 or 10. mu.M) and bethanechol (Sigma, final concentration 0.0024 nM-100. mu.M), each of which had been previously dissolved in the detection buffer, were injected into the FLIPR^tetra(registered trademark). Adding the substance to be detected to the cells in the device, adding bethanechol to the cells after about 5 minutes, and measuring intracellular Ca caused by bethanechol²⁺The concentration is increased (the excitation wavelength is 470-495nm, and the fluorescence wavelength is 515-575 nm).

Muscarinic M₃The activity of the receptor-positive allosteric modulator is indicated by the shift of the carbachol concentration response curve to the low concentration side caused by the test substance. That is, the minimum value of the carbachol reaction was set to 0% and the maximum value of the carbachol reaction was set to 100% on the curve of the carbachol concentration reaction, and the concentration of carbachol indicating 50% of the reaction was calculated as EC by Logistic regression method₅₀Value, and by not storingEC of carbachol in the substance to be detected₅₀Value divided by EC in the presence of the substance to be detected₅₀The value is obtained. For example, EC of carbachol in the absence of the substance to be detected₅₀EC of carbamylcholine at a value of 0.1. mu.M in the presence of the substance to be detected₅₀A value of 10 at 0.01. mu.M indicates that the test substance shifts the concentration response curve of carbachol toward the lower concentration side by 10 times. In the following table, the column of 10. mu.M (double shift) shows the value in the case where the substance to be detected was added at a final concentration of 10. mu.M; the column of 1. mu.M (double shift) shows the value when the substance to be detected is added at a final concentration of 1. mu.M.

Test example 2: evaluation of proliferation of human c-Mpl-introduced Ba/F3 cells

Proliferation of human c-Mpl-introduced Ba/F3 cells was measured by the following method.

As a positive control, 1- (5- { [4- (4-chloro-2-thienyl) -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl ] carbamoyl } -3-fluoropyridin-2-yl) piperidine-4-carboxylic acid hydrochloride disclosed as example 315 in patent document 1 shown by the above formula A1 was used. As disclosed in Table 1 of patent document 1, this compound is known to have a good proliferation activity of human c-Mpl-introduced Ba/F3 cells.

a) Construction of human c-Mpl receptor expression vector

The human c-Mpl receptor gene (GenBank accession: M90102.1) was introduced into the expression vector pEF-BOS (nucleic acids Res.18,5322, 1990).

b) Construction of human c-Mpl receptor Stable expression cells

Human c-Mpl receptor expression vector was introduced into Ba/F3 cells (Rizhao BRC: RCB0805) by electroporation, pEF-BOS-c-Mpl (10. mu.g), pSV2bsr (1. mu.g, manufactured by scientific research) and 1 × 10⁷Ba/F3 cells were placed in a cuvette having a gap width of 0.4cm, and subjected to electroporation by Gene Pulser (registered trademark) (BioRad) under the condition of 1.5kV (25. mu.F). Placing the cells inDrug-resistant clones were obtained by culturing cells in RPMI-1640 medium with 0.5% WEHI condition media (BD Biosciences) and 10% fetal bovine serum for 3 days, followed by culturing the cells in RPMI-1640 medium further supplemented with 10. mu.g/mL blasticidin for 30 days.

c) Determination of cell proliferation

The cells obtained in b) above were cultured in RPMI-1640 medium containing 0.5% WEHI conditioning medium and 10% bovine fetal serum, and then used, the test substance (final concentration: 100 nM-10. mu.M) dissolved in the test medium (RPMI-1640 medium containing 10% bovine fetal serum) was added to a 384-well plate (model 781185, Greiner bio-one) one day before the experiment, and the cells obtained after the medium was changed to the test medium were cultured at 1 × 10⁴The cells/well were injected into 384-well plates previously added with the test substance, and the mixture was incubated at 37 ℃ with 5% CO₂Culturing overnight. On the day of the experiment, a solution of Cell counting kit (Dojindo laboratories) was added to each well of 384-well plates, and 5% CO was added at 37 ℃ to₂Is cultured for about 5 hours. Thereafter, with Safire^2TM(TECAN) the absorbance (absorption wavelength 450nm) of each well was measured as an index of the number of cells. In addition, wells to which no test substance was added were prepared as negative controls.

The cell growth rate (%) was calculated from the absorbance at the time of addition of the test substance, with the absorbance of the wells to which the test substance was not added being 0% and the absorbance of the wells to which the positive control was added at a final concentration of 1. mu.M being 100%. The concentration of the substance to be detected at which 30% of proliferation was exhibited was calculated as EC from the obtained results by Logistic regression method₃₀The value is obtained.

Muscarinic M of Compounds of several embodiments of the invention₃Receptor positive allosteric modulator activity (fold shift) and proliferation of human c-Mpl-introduced Ba/F3 cells (EC)₃₀Values, nM) are shown together in table 1. Wherein Ex represents the number of examples described later (the same applies hereinafter).

[ Table 1]

In test example 1, most of the compounds of examples in which this test was carried out shifted the carbachol concentration response curve toward the low concentration side by about 100 times or more at the time of 10 μ M addition, and shifted the carbachol concentration response curve toward the low concentration side by about 10 times or more at the time of 1 μ M addition. In addition, it was confirmed for several example compounds that the compound alone did not cause intracellular Ca²⁺The concentration changes, thus confirming that these compounds are free of muscarinic M₃Receptor agonist activity.

In test example 2, it was confirmed that many of the compounds of examples subjected to this test had no or weak proliferation effect on Ba/F3 cells introduced by human c-Mpl. As some embodiments of the compounds of the present invention, human c-Mpl introduces Ba/F₃EC for cell proliferation₃₀A value of 0.3. mu.M or more, preferably 1. mu.M or more, more preferably 10. mu.M or more.

Test example 3: the electrical stimulation of the bladder wall of an extirpated rat to induce contraction

As the effect of neurostimulation-dependent bladder contraction in vitro, the effect of the example compounds of the present invention in transepithelial electrical stimulation-induced contraction of extirpated rat bladder was determined by the following method. Namely, a longitudinal bladder specimen having a width of about 2mm and a length of about 10mm was prepared from an excised bladder of female rats of Spraque-Dawley (SD) line (Japanese エスエルシー). The bladder specimens prepared were suspended in an organ bath filled with 10mL Krebs-Henseleite solution. With 95% O₂、5％CO₂Krebs-Henseleite solution was aerated and incubated at 37 ℃. After stabilization at 1g of initial tension, 2 contractions were induced with 60mM KCl. After the sample was washed with Krebs-Henseleite solution and stabilized, electrical stimulation through the wall was performed at 20V (stimulation frequency 8Hz, pulse width 0.3m sec, stimulation time 10 sec) with an electrical stimulation apparatus (Japanese photoelectric) and contraction was induced. The transmural electrical stimulation was repeated at 2 minute intervals, anThe voltage was adjusted so that the contraction height was about 50% of the contraction reaction caused by 20V. After stabilization of contraction by electrical wall stimulation, 10 μ L of the test substance pre-dissolved in 100% dimethylsulfoxide was added (final concentrations 3, 10, 30 μ M). After the low concentration of the contraction reaction was stabilized, the test substance was added cumulatively at the following concentrations. The reaction was input to a personal computer via a PowerLab (registered trademark) (AD Instruments), and analyzed by a LabChart (registered trademark) (AD Instruments). The area under reaction (AUC) of each contraction reaction was calculated, and the isolated bladder contraction enhancement rate (% of pre) after the treatment with the test substance was calculated by taking the value before the treatment with the test substance as 100%.

The enhanced rate of extirpation of bladder contraction caused by 10 μ M of several example compounds as compounds of formula (I) is shown in table 2.

In addition, it was confirmed that none of the compounds of the examples subjected to this test caused contraction in the absence of electrical stimulation, and the compound alone did not exhibit a bladder contraction effect.

[ Table 2]

Ex.	The bladder contraction enhancement rate (% of pre)
		1	132
4	180
		19	124
69	152
		84	140
92	132
		115	121
156	135
		158	125
179	120
		188	128
196	125

From the above, it was confirmed that: the compounds of the examples subjected to this test showed no contractile effect alone in extirpated rat bladders, but had the effect of enhancing the contraction induced by electrical stimulation through the wall.

Test example 4: effect in inducing intravesical pressure rise by electrical stimulation of pelvic nerve of anesthetized rat

As the effect of the neural stimulation-dependent bladder contraction in vivo, the effect of the example compounds of the present invention in inducing an increase in intravesical pressure using pelvic nerve electrical stimulation of rats was measured by the following method. That is, SD female rats (Japanese エスエルシー) were used, and the lower abdomen was cut along the midline under pentobarbital anesthesia (50mg/kg ip). After the ureters on both sides were tied off, a catheter for measuring intravesical pressure (PE-50) was inserted into the bladder through the external urethral orifice and fixed with a clip. About 200. mu.L of physiological saline was injected through a cannula inserted into the bladder, and then a pressure sensor was connected to the other end to measure the intravesical pressure. Under observation under a solid microscope, pelvic nerves near the bladder were dissected and the nerve stimulation electrode was placed (ユニークメディカル). The abdominal cavity is filled with mineral oil (MP biomedical). After the postoperative stabilization period, the pelvic nerve was electrically stimulated (stimulation frequency 8Hz, pulse width 0.3m sec, stimulation time 10 sec) using an electrical stimulation device (japanese photoelectricity) to cause an increase in intravesical pressure. The electrical stimulation was repeated at 2-minute intervals while adjusting the voltage, and the voltage was adjusted so that the increase in intravesical pressure was about 50-70% of that at the time of 10V stimulation. Thereafter, electrical stimulation was repeated at intervals of 10 minutes, and after the increase in intravesical pressure by electrical stimulation was stabilized for 3 times or more, the test substance (dose of 3 mg/kg) was administered at a volume of 1mL/kg through a catheter indwelling in a vein, and the effect of the test substance on the increase in intravesical pressure was measured for 1 hour. The substance to be detected was dissolved in water containing 10% dimethylsulfoxide, 10% polyoxyethylene castor oil (クレモフォール).

The reaction was inputted into a personal computer via PowerLab (registered trademark) and analyzed by LabChart (registered trademark). The AUC of the rise in each intravesical pressure was calculated, the rate of rise in intravesical pressure (% of pre) after the treatment with the test substance was calculated using the average of 3 times before the treatment with the test substance as 100%, and the maximum effect over a period of 1 hour after the administration of the compound was taken as the effect of the test substance.

The rate of increase in intravesical pressure (% ofpre) when 3mg/kg of the compound of several examples, which is the compound of formula (I), was administered is shown in table 3.

[ Table 3]

Ex.	Rate of increase of intravesical pressure (% of pre)
		4	184
115	131
		156	130

In addition, it was confirmed that the compounds of the above examples evaluated in this test did not cause an increase in intravesical pressure in a state where no electrical stimulation was applied, and the compounds alone did not exhibit an effect of increasing intravesical pressure.

From the above, it was confirmed that: the compounds of the examples shown in table 3 did not exhibit an increase in intravesical pressure in anesthetized rats alone, but had an effect of enhancing the increase in intravesical pressure induced by electrical stimulation of pelvic nerves.

As a result of the above-mentioned experiments, it was confirmed that the compound of formula (I) has muscarinic M₃Receptor positive allosteric modulator activity, and in addition, neural stimulation-dependent enhancement of bladder contraction in vitro, and neural stimulation-dependent enhancement of intravesical pressure elevation in vivo as well, were confirmed. Thus, the compounds of formula (I) are useful in combination with muscarinic M₃The prevention or treatment of bladder and urinary tract diseases associated with bladder contraction by receptors, particularly, urination disorders and urine storage disorders in the bladder and urinary tract diseases. For example, it can be used for low bladder activity, low tension bladder, non-contractile bladder, low detrusor activity, neurogenic bladder, urethral insufficiency, detrusor-external urethral sphincter dyssynergia, overactive bladderPrevention or treatment of urination disorders and urine storage disorders in motility, pollakiuria, nocturnal pollakiuria, urinary incontinence, prostatic hypertrophy, interstitial cystitis, chronic prostatitis, urinary calculus, and the like. In particular, it can be used for the prevention or treatment of urination disorders and urine storage disorders in low bladder activity, low-tension bladder, non-contractile bladder, low detrusor activity and neurogenic bladder.

Furthermore, since the compounds alone do not exhibit muscarinic M₃The compound of formula (I) has a receptor agonistic action and a neurostimulation-dependent bladder contraction-enhancing action, and therefore can be a therapeutic agent with higher safety from the viewpoint that side effects from choline functionality reported in conventional drugs can be avoided.

Pharmaceutical compositions containing 1 or 2 or more compounds of 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) commonly used in the art.

When administered, the administration can be oral administration using tablets, pills, capsules, granules, powders, liquid preparations, and the like; or by parenteral administration such as injection, suppository, transdermal liquid preparation, ointment, transdermal patch, transmucosal liquid preparation, transmucosal patch, or inhalant for intra-articular, intravenous, or intramuscular administration.

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 are mixed with at least 1 inert excipient. According to the usual methods, the compositions may contain inert additives, such as lubricants or disintegrants, stabilizers, dissolution aids. Tablets or pills may also be coated with a sugar coating or a film of a gastrosoluble or enteric substance, as desired.

The liquid composition for oral administration contains a pharmaceutically acceptable opacifier, solution, suspension, syrup, elixir or the like, and contains a generally used inert diluent such as purified 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 compounding with a bactericide or irradiation. In addition, they can also be prepared into sterile solid compositions, before use dissolved or suspended in sterile water or sterile solvent for injection and use.

The external preparations include ointments, plasters, creams, jellies, pastes, sprays, lotions 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. Alternatively, a pressurized aerosol spray or the like may be used, 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. In addition, the transmucosal preparation is administered once or in several portions per day at a weight of about 0.001-100 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, and in one embodiment, 0.01 to 50% by weight, of 1 or more compounds of formula (I) or salts thereof as an active ingredient, depending on the route of administration, dosage form, site of administration, excipient or additive.

The compound of formula (I) may be used in combination with various therapeutic or prophylactic agents for those diseases for which the above-mentioned compound of formula (I) is considered to exhibit effectiveness. 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 can be a compounding agent or can be prepared into preparations respectively.

Examples

The following examples further illustrate the production method of the compound of formula (I). The present invention is not limited to the compounds described in the following examples. The production methods of the starting compounds are shown in the production examples. 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) may be produced by a combination of these production methods or a method obvious to one skilled in the art.

Note that in this specification, naming software such as ACD/Name (registered trademark, Advanced Chemistry Development, Inc.) is sometimes used in naming of compounds.

In the examples, production examples, and tables described below, the following abbreviations may be used.

PEx: production example No. Ex: example number, PSyn: production example No. and Syn manufactured by the same method: example No. and No.: compound number, Str: chemical structural formula (Me: methyl, Et: ethyl, nPr: n-propyl, iPr: isopropyl, cPr: cyclopropyl, nBu: n-butyl, iBu: isobutyl, Boc: t-butyloxycarbonyl, Ac: acetyl, Z: benzyloxycarbonyl, Ts: 4-methylbenzenesulfonyl), DATA: physicochemical data, ESI +: m/z value in Mass analysis (ionization ESI, [ M + H ] without particular indication]⁺) ESI-: the M/z value in the mass analysis (ionization ESI, [ M-H ] without special indication]^-) APCI/ESI +: APCI/ESI-MS (atmospheric pressure chemical ionization method APCI, APCI/ESI means APCI and ESI are measured simultaneously, and [ M + H ] is used when no special indication is given]⁺) EI: m/z value in mass analysis (ionization method EI, [ M ] unless otherwise specified]⁺) And CI +: m/z value in mass analysis (ionization method CI, [ M + H ] when not specified]⁺) M.p.: melting point, NMR (DMSO-d 6): DMSO-d₆In (1)¹Peak of H-NMR (ppm), s: singlet (spectrum), d: doublet (spectrum), t: triplet (spectrum), q: quartet (spectrum), br: broad peak (spectrum) (e.g.: brs), m: multiplet (spectrum). Further, HCl in the structural formula indicates that the compound is monohydrochloride, 2HCl indicates that the compound is dihydrochloride, and 3HCl indicates that the compound is trihydrochloride.

In addition, for convenience, the concentration mol/L is represented by M. For example, a 1M aqueous sodium hydroxide solution refers to a 1mol/L aqueous sodium hydroxide solution.

The melting points of the DSC curves measured under the following conditions are shown in the following table.

DSC measurements were performed using TA Instruments DSC Q20 and at measurement temperature ranges: room temperature-300 ℃, heating rate: 10 ℃/min, nitrogen flow: 50 mL/min, using an aluminum sample dish.

Powder X-ray diffraction using RINT-TTRII, at bulb: cu, tube current: 300mA, tube voltage: 50kV, sampling width: 0.020 °, scanning speed: 4 °/min, wavelength:diffraction angle range (2 θ): the measurement is carried out under the condition of 2.5-40 degrees.

In the powder X-ray diffraction spectrum, the cell pitch and the overall pattern are important in the identification of the nature of data and the identity of crystals, and the diffraction angle and the diffraction intensity are somewhat variable depending on the direction of crystal growth, the size of particles, and the measurement conditions, and therefore, the solution should not be strictly made.

Production example 1

To a solution of 1- [ 4-hydroxy-3- (trifluoromethyl) phenyl ] ethanone (1g) in acetonitrile (10mL) were added 1-bromopropane (0.90mL), potassium carbonate (1.7g), and tetrabutylammonium iodide (180mg), and the mixture was stirred at room temperature overnight. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1- [ 4-propoxy-3- (trifluoromethyl) phenyl ] ethanone (1.16g) as an oil.

Production example 2

A mixture of 1- [ 4-hydroxy-3- (trifluoromethyl) phenyl ] ethanone (1g), iodoethane (1.19mL), cerium carbonate (1.92g), and N, N-dimethylformamide (15mL) was stirred at 60 ℃ for 3 hours. The reaction mixture was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1- [ 4-ethoxy-3- (trifluoromethyl) phenyl ] ethanone (1.1g) as a solid.

Production example 3

To a solution of 1- [ 4-hydroxy-3- (trifluoromethyl) phenyl ] ethanone (1g) in tetrahydrofuran (10mL) were added 2-propanol (0.46mL), a diethyl azodicarboxylate 40% toluene solution (2.3mL), and triphenylphosphine (1.55g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1- [ 4-isopropoxy-3- (trifluoromethyl) phenyl ] ethanone (1.05g) as an oil.

Production example 4

Zinc powder (1.86g), cobalt (II) bromide (520mg) and acetonitrile (20mL) were mixed under argon, and trifluoroacetic acid (0.14mL) was added thereto and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture were added a solution of 1-bromo-3-methoxy-5- (trifluoromethoxy) benzene (4.61g) in acetonitrile (10mL) and acetic anhydride (1.93mL), and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1- [ 3-methoxy-5- (trifluoromethoxy) phenyl ] ethanone (2.29g) as an oil.

Production example 5

1- [ 4-methoxy-3- (trifluoromethyl) phenyl ] ethanone (15g) was mixed with tetrahydrofuran (270mL), phenyltrimethylammonium tribromide (28.42g) was added, and the mixture was stirred at room temperature for 30 minutes. Insoluble matter precipitated was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was mixed with ethanol (260mL), and thiourea (6.81g) was added thereto and stirred at 80 ℃ for 3 hours. The reaction mixture was cooled to room temperature, and water, 1M aqueous sodium hydroxide solution and ethyl acetate were added. The organic layer was washed with a 1M aqueous solution of sodium hydroxide, water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-amine (16.18g) as a solid.

Production example 6

5-chloropyrazine-2-carboxylic acid (3.00g), N-dimethylformamide (30mL), piperidine-4-carboxylic acid ethyl ester (5.83mL), and diisopropylethylamine (6.50mL) were mixed and stirred at 80 ℃ overnight. The reaction mixture was cooled to room temperature, and ethyl acetate was added. The mixture was washed with an aqueous citric acid solution, water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with diisopropyl ether and dried to give 5- [4- (ethoxycarbonyl) piperidin-1-yl ] pyrazine-2-carboxylic acid (3.96g) as a solid.

Production example 7

To a mixture of 4- [ 4-propoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-amine (1.27g), 5- [4- (ethoxycarbonyl) piperidin-1-yl ] pyrazine-2-carboxylic acid (1.29g) and pyridine (20mL), phosphorus oxychloride (0.44mL) was added dropwise at-10 ℃ and stirred at the same temperature for 1 hour. After ethyl acetate and an aqueous citric acid solution were added to the reaction mixture to dissolve insoluble substances, silica gel was added and stirred. Insoluble matter was filtered off, and the aqueous layer of the filtrate was separated and extracted with ethyl acetate. The organic layers were combined, basic silica gel was added and stirred, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added diisopropyl ether and stirred, and filtered to obtain a solid, which was dried to obtain ethyl 1- [5- ({4- [ 4-propoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (1.38g) as a solid.

Production example 8

A3M lithium borohydride/tetrahydrofuran solution (19.87mL) was added to a tetrahydrofuran (28mL) solution of 1-tert-butyl 3-ethyl 3-methylpiperidine-1, 3, 3-tricarboxylate (2.35g) under an argon atmosphere at an internal temperature of-5 ℃ or lower, and the mixture was stirred for 30 minutes and then at 60 ℃ for 20 hours. The reaction mixture was cooled with ice, and a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give tert-butyl 3, 3-bis (hydroxymethyl) piperidine-1-carboxylate (1.22 g).

Production example 9

4- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-amine (500mg), tetrahydrofuran (10mL), 5- [4- (ethoxycarbonyl) piperidin-1-yl ] pyrazine-2-carboxylic acid (560mg), O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (645mg), and diisopropylethylamine (0.69mL) were mixed and stirred under microwave irradiation at 145 ℃ for 30 minutes. The reaction mixture was cooled to room temperature, and ethyl acetate was added. The mixture was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, then insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and the resulting solid was washed with diisopropyl ether and dried to give ethyl 1- [5- ({4- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (704mg) as a solid.

Production example 9

4- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-amine (500mg), tetrahydrofuran (10mL), 5- [4- (ethoxycarbonyl) piperidin-1-yl ] pyrazine-2-carboxylic acid (560mg), O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (645mg), and diisopropylethylamine (0.69mL) were mixed and stirred under microwave irradiation at 145 ℃ for 30 minutes. The reaction mixture was cooled to room temperature, and ethyl acetate was added. The mixture was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, then insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and the resulting solid was washed with diisopropyl ether and dried to give ethyl 1- [5- ({4- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (704mg) as a solid.

Production example 10

5- { [ (2R) -2-Methylpyrrolidin-1-yl ] methyl } -4- [ 3-methyl-5- (trifluoromethoxy) phenyl ] -1, 3-thiazol-2-amine (1.75g), 5-chloropyrazine-2-carboxylic acid (1.13g), N- [ ({ [ (1Z) -1-cyano-2-ethoxy-2-oxoethylidene ] amino } oxo) (morpholin-4-yl) methylene ] -N-methylmethanamine hexafluorophosphate (3.1g), dioxane (20mL) and diisopropylethylamine (2.43mL) were mixed, stirred at room temperature for 1 hour, and ethyl acetate was added to the reaction mixture. The mixture was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, then insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 5-chloro-N- (5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -4- [ 3-methyl-5- (trifluoromethoxy) phenyl ] -1, 3-thiazol-2-yl) pyrazine-2-carboxamide (1.71 g).

Production example 11

5-chloropyrazine-2-carboxylic acid (15.0g) was mixed with ethyl acetate (200mL), thionyl chloride (30mL) and N, N-dimethylformamide (0.28mL) were added, and the mixture was stirred at 55 to 60 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure, and 2 times of addition of toluene and concentration were performed.

4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-amine (19.96g) was mixed with cyclopentyl methyl ether (200mL), and a solution of the previously obtained residue in cyclopentyl methyl ether (40mL) was added dropwise to the mixture at 10 ℃ or lower, after which the reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction mixture was ice-cooled, water (600mL) was added dropwise at 15 ℃ or lower, and the mixture was stirred at room temperature overnight. The precipitated solid was filtered, washed with methyl ethyl ketone and dried to obtain 5-chloro-N- {4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } pyrazine-2-carboxamide (29g) as a solid.

Production example 12

5- [4- (ethoxycarbonyl) piperidin-1-yl ] pyrazine-2-carboxylic acid (895mg), N, N-dimethylformamide (10mL), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (1.34g), and diisopropylethylamine (1.10mL) were mixed and stirred for 10 minutes. 4- [3, 5-bis (trifluoromethyl) phenyl ] -1, 3-thiazol-2-amine (1.0g) and N, N-dimethylformamide (10mL) were mixed under a nitrogen atmosphere, and after sodium hydride (154mg) was added under ice cooling and stirred for 10 minutes, the reaction mixture prepared before was added, and stirred for 30 minutes under heating at 80 ℃. After the reaction mixture was heated at 120 ℃ and further stirred for 1 hour, 4- [3, 5-bis (trifluoromethyl) phenyl ] -1, 3-thiazol-2-amine (0.72g) was added and further stirred at the same temperature for 2 hours. The reaction mixture was cooled to room temperature, and ethyl acetate was added. The mixture was washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, then insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-ethyl acetate). To the resulting residue was added diisopropyl ether, and the resulting solid was filtered and dried to give ethyl 1- [5- ({4- [3, 5-bis (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (167mg) as a solid.

Production example 13

4- [ 4-chloro-3- (trifluoromethyl) phenyl ] -5- [ (3-methoxy-3-methylpiperidin-1-yl) methyl ] -1, 3-thiazol-2-amine (80mg), 5- [4- (ethoxycarbonyl) piperidin-1-yl ] pyrazine-2-carboxylic acid (64mg), n- [ ({ [ (1Z) -1-cyano-2-ethoxy-2-oxoethylidene ] amino } oxo) (morpholin-4-yl) methylene ] -N-methylmethanaminium hexafluorophosphate (101mg), diisopropylethylamine (0.082mL) and dioxane (1.2mL) were mixed and stirred under microwave irradiation at 80 ℃ for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (chloroform-hexane) and basic silica gel column chromatography (ethyl acetate-hexane). The resulting solid was washed with ethyl acetate-hexane and dried to give ethyl 1- [5- ({4- [ 4-chloro-3- (trifluoromethyl) phenyl ] -5- [ (3-methoxy-3-methylpiperidin-1-yl) methyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (71mg) as a solid.

Production example 14

4- [ 3-methyl-5- (trifluoromethoxy) phenyl ] -1, 3-thiazol-2-amine (500mg), N-dimethylformamide (10mL), 5- [4- (ethoxycarbonyl) piperidin-1-yl ] pyrazine-2-carboxylic acid (764mg), N- [ ({ [ (1Z) -1-cyano-2-ethoxy-2-oxoethylidene ] amino } oxo) (morpholin-4-yl) methylene ] -N-methylmethaninium hexafluorophosphate (1.17g), diisopropylethylamine (0.94mL) were mixed and stirred at 150 ℃ for 30 minutes under microwave irradiation. The reaction mixture was cooled to room temperature, and ethyl acetate was added. The mixture was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, then insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and the obtained residue was washed with diisopropyl ether and dried to give ethyl 1- [5- ({4- [ 3-methyl-5- (trifluoromethoxy) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (476mg) as a solid.

Production example 15

4- [ 4-chloro-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-amine (748mg), 5- [4- (ethoxycarbonyl) piperidin-1-yl ] pyrazine-2-carboxylic acid (500mg), N, N-dimethylformamide (10mL), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (1.02 g), and diisopropylethylamine (0.93mL) were mixed and stirred at 100 ℃ overnight. The reaction mixture was cooled to room temperature, and ethyl acetate was added. The mixture was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, then insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-ethyl acetate), and the obtained residue was washed with diisopropyl ether and dried to give ethyl 1- [5- ({4- [ 4-chloro-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (294mg) as a solid.

Production example 16

4- [ 3-methyl-5- (trifluoromethoxy) phenyl ] -1, 3-thiazol-2-amine (5.68g), pyridine (17mL) and acetic anhydride (7.8mL) were mixed and stirred at 60 ℃ for 1 hour. The reaction mixture was cooled to room temperature, and ethyl acetate was added. The mixture was washed with water, 1M hydrochloric acid and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, then insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with diisopropyl ether and dried to give N- {4- [ 3-methyl-5- (trifluoromethoxy) phenyl ] -1, 3-thiazol-2-yl } acetamide (6.21g) as a solid.

Production example 17

To ethyl 1- [5- ({4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (2.0g) were added acetic acid (50mL) and 36% aqueous formaldehyde solution (1.5mL), and the mixture was stirred at 100 ℃ for 1.5 hours. Acetic anhydride (0.71mL) was added to the reaction mixture, and after further stirring at the same temperature for 1.5 hours, acetic anhydride (0.71mL) was added again and stirred for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and ethanol was added to the residue and stirred. The resulting solid was filtered and dried to give ethyl 1- [5- ({5- (acetoxymethyl) -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (1.77g) as a solid.

Production example 18

Ethyl 1- [5- ({4- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (1.87g), acetic acid (8mL), 36% aqueous formaldehyde (2.69mL) and acetic anhydride (3.30mL) were mixed and stirred under microwave irradiation at 150 ℃ for 30 minutes. The reaction mixture was concentrated under reduced pressure, and water and a saturated aqueous sodium hydrogencarbonate solution were added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-ethyl acetate), and the obtained solid was washed with diisopropyl ether and dried to give ethyl 1- [5- ({5- (acetoxymethyl) -4- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (705mg) as a solid.

Production example 19

To ethyl 1- [5- ({4- [ 4-propoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (1.38g) were added acetic acid (35mL), acetic anhydride (1.2mL) and 36% aqueous formaldehyde (0.98mL), and the mixture was stirred at 100 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-ethyl acetate). The resulting residue was dissolved in pyridine (14mL), acetic anhydride (1.4mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-ethyl acetate), and the resulting solid was stirred in an ethyl acetate-diisopropyl ether mixed solvent, filtered, and dried to give ethyl 1- [5- ({5- (acetoxymethyl) -4- [ 4-propoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (771mg) as a solid.

Production example 20

Ethyl 1- [5- ({4- [ 4-chloro-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (1.15g), acetic acid (12.0mL), 36% aqueous formaldehyde (2.0mL) and acetic anhydride (2.5mL) were mixed and stirred at 150 ℃ for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and pyridine (8mL) and acetic anhydride (2.5mL) were added to the residue and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and water was added to the residue to conduct extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with a chloroform-ethyl acetate mixed solvent and dried to give ethyl 1- [5- ({5- (acetoxymethyl) -4- [ 4-chloro-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (564mg) as a solid.

Production example 21

5-chloro-N- {4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } pyrazine-2-carboxamide (4.27g), acetic acid (50mL), 36% aqueous formaldehyde (4.0mL), and (2R) -2-ethylpyrrolidine hydrochloride (7.0g) were mixed, stirred at 90 ℃ for 1 hour, dichloroethane (50mL) was added and stirred overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and ethyl acetate was added to the resulting residue. The mixture was washed with a 1M aqueous sodium hydroxide solution, water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane-ethyl acetate). The resulting solid was washed with hexane and dried to give 5-chloro-N- (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) pyrazine-2-carboxamide (954mg) as a solid.

Production example 22

Ethyl 1- [5- ({4- [4- (dimethylamino) -3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (200mg), acetic acid (3mL), 36% aqueous formaldehyde (0.14mL), and (2R) -2-methylpyrrolidine L- (+) -tartrate (425mg) were mixed and stirred at 110 ℃ for 30 minutes under microwave irradiation. Saturated aqueous sodium bicarbonate was added to the reaction mixture to neutralize, and extracted with ethyl acetate. The organic layer was washed with a 1M aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give ethyl 1- {5- [ (4- [4- (dimethylamino) -3- (trifluoromethyl) phenyl ] -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylate (110mg) as a solid.

Production example 23

Ethyl 1- [5- ({5- (acetoxymethyl) -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (2.5g), (2R) -2-ethylpyrrolidine hydrochloride (690mg), diisopropylethylamine (1.42mL) and N, N-dimethylformamide (25mL) were mixed and stirred at 90 ℃ for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and then insoluble matter was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with an alkaline silica gel column chromatography (chloroform-ethyl acetate) to give ethyl 1- {5- [ (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylate (2.28 g).

Production example 24

To a solution of ethyl 1- [5- ({5- (acetoxymethyl) -4- [ 4-chloro-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (160mg) in tetrahydrofuran (1.6mL) were added (2R) -2-methylpyrrolidine hydrochloride (64mg) and diisopropylethylamine (0.18mL), and the mixture was stirred at 150 ℃ for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give ethyl 1- {5- [ (4- [ 4-chloro-3- (trifluoromethyl) phenyl ] -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylate (117mg) as an oil.

Production example 25

To a solution of benzyl (2S) -2- (2-methoxypropan-2-yl) pyrrolidine-1-carboxylate (650mg) in ethanol (6.5mL) was added 10% palladium on carbon (aqueous 50%, 150mg), and the mixture was stirred at room temperature under a hydrogen atmosphere of 1 atmosphere for 1 hour. Insoluble matter was filtered off, and 4M hydrogen chloride/dioxane solution (2mL) was added to the filtrate, and concentrated under reduced pressure. The residue was dried overnight to give (2S) -2- (2-methoxypropan-2-yl) pyrrolidine hydrochloride (438mg) as a solid.

Production example 26

To a solution of tert-butyl (2R) -2-ethylpyrrolidine-1-carboxylate (3.41g) in dioxane (25mL) was added a 4M hydrogen chloride/dioxane solution (25mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue and stirred. The precipitated solid was filtered and dried to obtain (2R) -2-ethylpyrrolidine hydrochloride (2.1g) as a solid.

Production example 27

N- (5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -4- [ 3-methyl-5- (trifluoromethoxy) phenyl ] -1, 3-thiazol-2-yl) acetamide (3.05g), ethanol (20mL), and 6M aqueous sodium hydroxide (12mL) were mixed, and stirred under microwave irradiation at 120 ℃ for 15 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with basic silica gel column chromatography (hexane-ethyl acetate) to give 5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -4- [ 3-methyl-5- (trifluoromethoxy) phenyl ] -1, 3-thiazol-2-amine (1.75g) as an oil.

Production example 28

To a mixture of 2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4- [ 3-methoxy-4- (trifluoromethyl) phenyl ] -1, 3-thiazole (280mg) in ethanol (2.5mL) and water (0.84mL) was added hydroxylamine hydrochloride (828mg) and triethylamine (0.55mL), and the mixture was stirred under microwave irradiation at 130 ℃ for 30 minutes. Ethanol was removed by distillation under the reduced pressure, and water was added to the residue to conduct extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) and silica gel column chromatography (chloroform-methanol) to give 4- [ 3-methoxy-4- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-amine (113mg) as a solid.

Production example 29

To a solution of tert-butyl 3, 3-bis (hydroxymethyl) piperidine-1-carboxylate (0.9g) in tetrahydrofuran (18mL) at-5 ℃ or below was added a 2.69M n-butyllithium/tetrahydrofuran solution (1.39mL) under argon and stirred for 20 minutes. To the reaction mixture was added dropwise a solution of tosyl chloride (0.7g) in tetrahydrofuran (4.5mL) below-5 ℃ and stirred for 40 minutes. To the resulting mixture was added a 2.69M n-butyllithium/tetrahydrofuran solution (1.43mL), and after stirring for 30 minutes, it was heated to 60 ℃ and further stirred for 1 hour. The reaction mixture was cooled with ice, and saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give tert-butyl 2-oxa-6-azaspiro [3.5] nonane-6-carboxylate (436 mg).

Production example 30

To a solution of (3R) -tetrahydrofuran-3-ol (1.0g) in N-methylpyrrolidone (20mL) was added 60% oily sodium hydride (430mg) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added dropwise a solution of 1- [ 4-fluoro-3- (trifluoromethyl) phenyl ] ethane (2.0g) in N-methylpyrrolidone (10mL), and the mixture was stirred under ice-cooling for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1- {4- [ (3R) -tetrahydrofuran-3-yloxy ] -3- (trifluoromethyl) phenyl } ethanone (1.84g) as an oil.

Production example 31

A mixture of 1- [ 4-fluoro-3- (trifluoromethyl) phenyl ] ethanone (2.0g), pyrrolidine (10mL), potassium carbonate (2.0g) and acetonitrile (3.0mL) was stirred at 80 ℃ for 2 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1- [4- (pyrrolidin-1-yl) -3- (trifluoromethyl) phenyl ] ethanone (2.5g) as an oil.

Production example 32

To a solution of 2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -1, 3-thiazole (300mg) in tetrahydrofuran (2.4mL) was added sodium methoxide (60mg), and the mixture was stirred under microwave irradiation at 100 ℃ for 30 minutes. Sodium methoxide (90mg) was added to the reaction mixture and stirred at 130 ℃ for 1 hour under microwave irradiation, and sodium methoxide (150mg) was further added and stirred at 150 ℃ for 30 minutes under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4- [ 3-methoxy-4- (trifluoromethyl) phenyl ] -1, 3-thiazole (289mg) as an oil.

Production example 33

4- (5-chloro-3-thienyl) -1, 3-thiazol-2-amine (4.30g), dichloromethane (80mL) and diisopropylethylamine (4.2mL) were mixed, and trifluoroacetic anhydride (4.2mL) was added under ice cooling, warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with chloroform, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, then insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and the resulting solid was washed with hexane and dried to give N- [4- (5-chloro-3-thienyl) -1, 3-thiazol-2-yl ] -2,2, 2-trifluoroacetamide (5.56g) as a solid.

Production example 34

To a solution of 4- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-amine (600mg) in toluene (3.6mL) were added hexane-2, 5-dione (0.32mL) and p-toluenesulfonic acid (44mg), and the mixture was stirred at 170 ℃ for 30 minutes under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the residue to conduct extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -1, 3-thiazole (634mg) as a solid.

Production example 35

To a solution of (2-methylpyrrolidin-2-yl) methanol (300mg) in tetrahydrofuran (3mL) was added a solution of di-tert-butyl dicarbonate (0.85g) in tetrahydrofuran (1.5mL) at room temperature, and after stirring at room temperature for 3 days, a 1M aqueous sodium hydroxide solution (1.8mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give tert-butyl 2- (hydroxymethyl) -2-methylpyrrolidine-1-carboxylate (396mg) as an oil.

Production example 36

To a solution of 2- [ (2S) -pyrrolidin-2-yl ] propane-2-ol hydrochloride (1.0g) in dichloroethane (15mL) was added triethylamine (2.52mL) and the mixture was cooled with water, and after adding benzyl chloroformate (1.29mL), the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue to conduct extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give benzyl (2S) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate (1.01g) as an oil.

Production example 37

N- [4- (5-chloro-3-thienyl) -1, 3-thiazol-2-yl ] -2,2, 2-trifluoroacetamide (5.56g), (2R) -2-methylpyrrolidine (3.36g), acetic acid (60mL) and 36% aqueous formaldehyde solution (2.75mL) were mixed and stirred at 60 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and after drying over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was mixed with ethanol (60mL) and a 6M aqueous solution of sodium hydroxide (15mL), and the mixture was stirred at 90 ℃ for 2 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with basic silica gel column chromatography (hexane-ethyl acetate) to give 4- (5-chloro-3-thienyl) -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-amine (2.28 g).

Production example 38

1- [ 4-hydroxy-3- (trifluoromethyl) phenyl ] ethanone (3.0g), N-dimethylformamide (36mL) and water (3.6mL) were mixed, sodium chloro (difluoro) acetate (5.76g) and cerium carbonate (7.2g) were added, and stirring was carried out at 100 ℃ for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1- [4- (difluoromethoxy) -3- (trifluoromethyl) phenyl ] ethanone (3.80g) as an oil. 1- [4- (difluoromethoxy) -3- (trifluoromethyl) phenyl ] ethanone (3.80g) was mixed with tetrahydrofuran (50mL), phenyltrimethylammonium tribromide (5.66g) was added, and the mixture was stirred at room temperature for 45 minutes. Insoluble matters precipitated were filtered off, and the filtrate was concentrated under reduced pressure. The residue was mixed with ethanol (50mL), thiourea (1.47g) was added, and the mixture was stirred at 80 ℃ for 2 hours. The reaction mixture was cooled to room temperature, and water (30mL) and a 1M aqueous solution of sodium hydroxide (30mL) were added to conduct extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added diisopropyl ether, and the mixture was concentrated under reduced pressure, diisopropyl ether and hexane were again added, and the resulting solid was filtered and dried to give 4- [4- (difluoromethoxy) -3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-amine (3.48g) as a solid.

Production example 39

3-bromo-5- (trifluoromethoxy) phenol (4.84g), N-dimethylformamide (50mL), potassium carbonate (3.12g) and iodomethane (2.35mL) were mixed, and stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1-bromo-3-methoxy-5- (trifluoromethoxy) benzene (4.61g) as an oil.

Production example 40

To a mixture of benzyl (2S) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate (1.0g), プロトンスポンジ (registered trademark) (2.44g) and methylene chloride (15mL) was added trimethyloxonium tetrafluoroborate (1.77g) under ice-cooling, and the mixture was warmed to room temperature and stirred overnight. Insoluble matter was filtered off, and water and a 10% aqueous solution of citric acid were added to the filtrate to conduct extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give benzyl (2S) -2- (2-methoxypropan-2-yl) pyrrolidine-1-carboxylate (664mg) as an oil.

Production example 41

To a solution of diisopropylamine (5.05mL) in tetrahydrofuran (30mL) was added a 2.66M n-butyllithium/hexane solution (12.86mL) under argon at-78 ℃ and stirred for 15 minutes. To the reaction mixture was added dropwise a solution of 1-tert-butyl 3-ethylpiperidine-1, 3-dicarboxylate (4.0g) in tetrahydrofuran (20mL) over 10 minutes, and stirred for 30 minutes. A solution of methyl iodide (1.455mL) in tetrahydrofuran (10mL) was added dropwise to the reaction mixture over 10 minutes, and the resulting mixture was warmed to 0 ℃ over 1 hour and stirred at the same temperature for 30 minutes, then further warmed to room temperature and stirred for 3 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1-tert-butyl 3-ethyl 3-methylpiperidine-1, 3-dicarboxylate (3.29g) as an oil.

Production example 42

A suspension of 55% oily sodium hydride (126mg) in tetrahydrofuran (3mL) was cooled with water under argon, and a solution of tert-butyl 3- (hydroxymethyl) -3-methylpiperidine-1-carboxylate (442mg) in tetrahydrofuran (2mL) was added thereto, followed by stirring at room temperature for 5 minutes and then at 60 ℃ for 30 minutes. The reaction mixture was cooled with ice, and after methyl iodide (0.3mL) was added, it was warmed to room temperature and stirred for 1.5 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give tert-butyl 3- (methoxymethyl) -3-methylpiperidine-1-carboxylate (414mg) as an oil.

Production example 43

N- {4- [ 3-fluoro-5- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } acetamide (2.84g), acetic acid (20mL), 36% aqueous formaldehyde (3.6mL), and acetic anhydride (4.40mL) were mixed and stirred at 170 ℃ for 30 minutes under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the resulting solid was washed with methanol and dried to give a white solid.

The resulting solid was mixed with N-methylpyrrolidone (20mL), (2R) -2-methylpyrrolidine (608mg), and diisopropylethylamine (2.45mL), and stirred at 100 ℃ for 30 minutes. The reaction mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give N- (4- [ 3-fluoro-5- (trifluoromethyl) phenyl ] -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl) acetamide (1.38g) as a solid.

Production example 44

3-bromo-1, 1, 1-trifluoroacetone (3.0g), ethyl amino (thio) acetate (2.10g) and ethanol (45mL) were combined and heated at reflux for 15 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue were added saturated aqueous sodium hydrogencarbonate (50mL) and water (50mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give ethyl 4- (trifluoromethyl) -1, 3-thiazole-2-carboxylate (2.19g) as an oil. To a solution of ethyl 4- (trifluoromethyl) -1, 3-thiazole-2-carboxylate (2.07g) in ethanol (50mL) was added 1M aqueous sodium hydroxide solution (30mL) and stirred at 50 ℃ for 30 minutes. The reaction mixture was cooled to room temperature, 1M hydrochloric acid (30mL) and water (100mL) were added, and extraction was performed with a chloroform-isopropanol mixed solvent. The organic layer was dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain a solid. Hexane was added to the resulting solid, and after removing the solvent by decantation, the solid was dried to obtain 4- (trifluoromethyl) -1, 3-thiazole-2-carboxylic acid (832mg) as a solid.

Production example 45

To 4- (trifluoromethyl) -1, 3-thiazole-2-carboxylic acid (790mg) were added thionyl chloride (4.0mL), dichloromethane (6mL) and N, N-dimethylformamide (1 drop), and stirred at 40 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure, subjected to twice toluene azeotropy, and then dried under reduced pressure. To a mixture of magnesium chloride (382mg) and toluene (12mL) were added dimethyl malonate (0.55mL) and triethylamine (1.3mL), and the mixture was stirred at room temperature for 1.5 hours. A toluene (3mL) solution of the residue obtained before was added dropwise to the reaction mixture, and stirred at room temperature for 16 hours. After 6M hydrochloric acid (5mL) was slowly added to the reaction mixture, water (30mL) was added and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (4mL) and water (0.4mL), and stirred at 160 ℃ for 2 hours. After the reaction mixture was cooled to room temperature, water (30mL) was added and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1- [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] ethanone (498mg) as an oil.

Production example 46

To a solution of tert-butyl (2S) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (17g), triethylamine (17.66mL) and 1-methyl-1H-imidazole (10.05mL) in dichloromethane (255mL) was added p-toluenesulfonyl chloride (17.71g) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give tert-butyl (2S) -2- ({ [ (4-methylphenyl) sulfonyl ] oxy } methyl) pyrrolidine-1-carboxylate (29.51g) as an oil.

Production example 47

To a mixture of copper (I) iodide (9.4g) and diethyl ether (180mL) was added dropwise an about 1M methyllithium/diethyl ether solution (100mL) at an internal temperature of 0 to 5 ℃ over 30 minutes, followed by stirring for 15 minutes. After keeping the internal temperature below 5 ℃ and adding a solution of tert-butyl (2S) -2- ({ [ (4-methylphenyl) sulfonyl ] oxy } methyl) pyrrolidine-1-carboxylate (7.0g) in methylene chloride (30mL) dropwise over 20 minutes to the reaction mixture, it was stirred at room temperature for 2.5 hours. To the reaction mixture was added dropwise a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give tert-butyl (2R) -2-ethylpyrrolidine-1-carboxylate (3.52g) as an oil.

Production example 48

A2.69M n-butyllithium/hexane solution (25.43mL) was added to a tetrahydrofuran (60mL) solution of diisopropylamine (10.09mL) at-78 ℃ under an argon atmosphere, and the mixture was stirred at the same temperature for 15 minutes, then heated to-20 ℃ and stirred for 30 minutes. The reaction mixture was again cooled to-78 ℃ and a solution of 1-tert-butyl-3-ethylpiperidine-1, 3-dicarboxylate (8.0g) in tetrahydrofuran (20mL) was added dropwise over 20 minutes, warmed to-20 ℃ and stirred for 30 minutes. The resulting mixture was cooled to-78 deg.C, and after a solution of methyl chloroformate (5.98mL) in tetrahydrofuran (16mL) was added dropwise over 15 minutes, the mixture was warmed to room temperature and stirred for 2 hours. To the reaction mixture was added dropwise a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1-tert-butyl 3-ethyl 3-methylpiperidine-1, 3, 3-tricarboxylate (5.63g) as an oil.

Production example 92

To a mixture of 5-chloro-N- {4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } pyrazine-2-carboxamide (29g) and N-methylpyrrolidinone (150mL) were added diisopropylethylamine (18mL) and piperidine-4-carboxylic acid ethyl ester (14mL), and stirred at room temperature for 2 hours. The reaction mixture was cooled with ice, water was added, and the mixture was stirred at room temperature for 1 hour. The solid was obtained by filtration and dried to give ethyl 1- [5- ({4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (36.85g) as a solid.

Production example 209

A mixture of 1- [ 4-fluoro-3- (trifluoromethyl) phenyl ] ethanone (3.75g) and dimethylamine (2M in tetrahydrofuran, 22.3mL) was stirred under microwave irradiation at 110 ℃ for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate). To the resulting compound, dimethylamine (2M tetrahydrofuran solution, 15mL) was added and stirred under microwave irradiation at 130 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1- [4- (dimethylamino) -3- (trifluoromethyl) phenyl ] ethanone (2.89 g).

The compounds of production examples 49 to 91, 93 to 208 and 210 to 212 shown in the following tables were produced by the same methods as production examples 1 to 48, 92 and 209. The structures, physicochemical data, and production methods of the compounds of the production examples are shown in tables 4 to 36.

Example 1

To a solution of ethyl 1- {5- [ (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 4-propoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylate (159mg) in dioxane (2mL) was added 1M aqueous sodium hydroxide solution (2mL) and stirred at 60 ℃ for 30 minutes. The reaction mixture was cooled to room temperature, neutralized by adding 1M hydrochloric acid, extracted with chloroform, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give a pale yellow solid. The resulting solid was dissolved in dioxane (2mL) and 4M hydrogen chloride/dioxane solution (0.25mL) was added, and the precipitated solid was stirred in acetonitrile, filtered and dried to give 1- {5- [ (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 4-propoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid dihydrochloride (132mg) as a solid.

Example 2

Ethyl 1- [5- ({5- (acetoxymethyl) -4- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (100mg), N-dimethylformamide (2mL), (2R) -2-methylpiperidine hydrochloride (45mg), and diisopropylethylamine (0.115mL) were mixed and stirred at 100 ℃ for 1 hour. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water, a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, then insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane-ethyl acetate). The resulting residue was mixed with ethanol (2mL) and tetrahydrofuran (1mL), and a 1M aqueous solution of sodium hydroxide (0.83mL) was added and stirred at 50 ℃ for 20 minutes. The reaction mixture was cooled to room temperature, 1M hydrochloric acid (0.83mL) and water were added, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was mixed with ethyl acetate, and a 4M hydrogen chloride/ethyl acetate solution (0.3mL) was added to the mixture, followed by concentration under reduced pressure. The resulting solid was washed with ethyl acetate and dried to give 1- {5- [ (4- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -5- { [ (2R) -2-methylpiperidin-1-yl ] methyl } -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid dihydrochloride (56mg) as a solid.

Example 3

5-chloro-N- (5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -4- [ 3-methyl-5- (trifluoromethoxy) phenyl ] -1, 3-thiazol-2-yl) pyrazine-2-carboxamide (170mg), N-methylpyrrolidone (3mL), ethyl 4-fluoropiperidine-4-carboxylate (120mg), diisopropylethylamine (0.23mL) were mixed, and stirred at 70 ℃ for 1 hour. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, then insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate).

The resulting residue was mixed with ethanol (4mL) and tetrahydrofuran (2mL), and a 1M aqueous solution of sodium hydroxide (1.7mL) was added thereto, followed by stirring at 50 ℃ for 20 minutes. The reaction mixture was cooled to room temperature, 1M hydrochloric acid (1.7mL) and water were added, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was mixed with ethyl acetate, and a 4M hydrogen chloride/ethyl acetate solution (0.5mL) was added to the mixture, followed by concentration under reduced pressure. The resulting solid was washed with ethyl acetate and dried to give 4-fluoro-1- {5- [ (5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -4- [ 3-methyl-5- (trifluoromethoxy) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid dihydrochloride (116mg) as a solid.

Example 4

Ethyl 1- (5- { [4- (4-chloro-2-thienyl) -1, 3-thiazol-2-yl ] carbamoyl } pyrazin-2-yl) piperidine-4-carboxylate (26.27g), acetic acid (545mL), 36% aqueous formaldehyde (16.98mL) and (2R) -2-methylpyrrolidine L- (+) -tartrate (51.71g) were mixed and stirred at 110 ℃ for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane-ethyl acetate).

The resulting residue was mixed with ethanol (450mL), and 1M aqueous sodium hydroxide solution (150mL) was added thereto, followed by stirring at 70 ℃ for 1 hour. The reaction mixture was cooled to room temperature, water and 1M hydrochloric acid (150mL) were added, and the precipitated solid was filtered, washed with water, and dried under reduced pressure. The resulting solid was mixed with ethyl acetate, and an excess of 4M hydrogen chloride/ethyl acetate solution was added and stirred at room temperature for 1 hour. The solid was obtained by filtration and dried to give 1- (5- { [4- (4-chloro-2-thienyl) -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl ] carbamoyl } pyrazin-2-yl) piperidine-4-carboxylic acid dihydrochloride (23g) as a solid.

Example 5

4- (5-chloro-3-thienyl) -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-amine (300mg) was mixed with methylene chloride (6mL), and 5- [4- (ethoxycarbonyl) piperidin-1-yl ] pyrazine-2-carboxylic acid (347mg), N- [3- (dimethylamino) propyl ] -N' -ethylcarbodiimide hydrochloride (240mg), 4- (dimethylamino) pyridine (35mg) were added to stir at 40 ℃ for 1 hour. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. After being washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, the filtrate was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) and basic silica gel column chromatography (hexane-ethyl acetate). The resulting residue was mixed with ethanol (4mL) and tetrahydrofuran (2mL), and a 1M aqueous solution of sodium hydroxide (3mL) was added thereto, followed by stirring at 50 ℃ for 30 minutes. The reaction mixture was cooled to room temperature, water and 1M hydrochloric acid (3mL) were added, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with diisopropyl ether. The resulting solid was mixed with ethyl acetate, and a 4M hydrogen chloride/ethyl acetate solution (1mL) was added and concentrated under reduced pressure. The resulting solid was washed with ethyl acetate and dried to give 1- [5- { [4- { 5-chloro-3-thienyl } -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl ] carbamoyl } pyrazin-2-yl) piperidine-4-carboxylic acid dihydrochloride (143mg) as a solid.

Example 6

Ethyl 1- [5- ({4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (1.45g), acetic acid (10mL), 36% aqueous formaldehyde (1.50mL) and acetic anhydride (1.8mL) were mixed and stirred at 170 ℃ for 30 minutes under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and water and a saturated aqueous sodium hydrogencarbonate solution were added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-ethyl acetate). The resulting residue was mixed with N, N-dimethylformamide (15mL), N- (2-methoxyethyl) -2-methylpropane-1-amine hydrochloride (685mg) and diisopropylethylamine (1.4mL), and the mixture was stirred at 100 ℃ for 1 hour. The reaction mixture was cooled to room temperature, and ethyl acetate was added. The mixture was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, then insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and the resulting solid was washed with diisopropyl ether. The resulting solid was mixed with ethanol (5mL), 1M aqueous sodium hydroxide solution (2.8mL) was added, and stirred at 60 ℃ for 15 minutes. The reaction mixture was cooled to room temperature, water and 1M hydrochloric acid (2.8mL) were added, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with diisopropyl ether and dried to give 1- {5- [ (5- { [ isobutyl (2-methoxyethyl) amino ] methyl } -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid (224 mg) as a solid.

Example 7

Trifluoroacetic acid (0.30mL) was added to a solution of tert-butyl 2-oxa-6-azaspiro [3,5] nonane-6-carboxylate (110mg) in dichloromethane (1.1mL) under ice-cooling, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give 2-oxa-6-azaspiro [3,5] nonane trifluoroacetate salt. The resulting 2-oxa-6-azaspiro [3,5] nonane trifluoroacetate was used in the following procedure without further purification.

To a solution of ethyl 1- [5- ({5- (acetoxymethyl) -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (118mg) in N, N-dimethylformamide (2.4mL) were added diisopropylethylamine (0.33mL) and the previously synthesized 2-oxa-6-azaspiro [3,5] nonane trifluoroacetate, and stirred at 100 ℃ for 1.5 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting solid was obtained by filtration, dried and purified by basic silica gel column chromatography (hexane-ethyl acetate). To a solution of the obtained residue (66mg) in ethanol (2mL) was added a 1M aqueous solution of sodium hydroxide (0.29mL), and the mixture was stirred at 60 ℃ for 1 hour. To the reaction mixture was added 1M hydrochloric acid for neutralization, and water, a saturated aqueous sodium chloride solution and chloroform were added, and an organic layer was separated using a phase separator (International sorbent technology corporation) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol), and the resulting solid was washed with ethanol and dried to give 1- [5- ({4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -5- (2-oxa-6-azaspiro [3,5] nonan-6-ylmethyl) -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylic acid (52mg) as a solid.

Example 8

To a mixture of ethyl 1- {5- [ (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylate (21.6g) and ethanol (216mL) was added 1M aqueous sodium hydroxide solution (74mL), and the mixture was stirred at 50-55 ℃ for 1.5 hours. A1M aqueous solution of sodium hydroxide (36mL) was further added to the reaction mixture, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added acetic acid (6.5mL) at the same temperature to adjust the pH of the mixture to 5-6, water (106mL) was added, and the mixture was stirred at 55 ℃ overnight. The mixture was cooled to room temperature and filtered to obtain a solid.

The resulting solid was mixed with ethanol (80mL) and dissolved under heated reflux. After cooling to room temperature, the precipitated solid was filtered, and ethanol (80mL) was added again to the filtrate, and the mixture was refluxed for 1 hour and then cooled to room temperature. The precipitated solid was filtered and dried to give crystalline 1- {5- [ (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid (12.78 g).

The crystal obtained in example 8 had peaks in the vicinity of 2 θ (°) of 5.0, 7.1, 10.0, 11.0, 11.8, 12.0, 15.6, 17.1, 20.4, 23.1, 24.9 and 26.8 in the powder X-ray diffraction.

Example 103

To a mixture of ethyl 1- [5- ({5- (acetoxymethyl) -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (110mg) and N, N-dimethylformamide (2.2mL), was added (3-methylpiperidin-3-yl) methanol hydrochloride (65mg) and diisopropylethylamine (0.16mL), and the mixture was stirred at 100 ℃ for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate). The resulting compound was mixed with ethanol (1.8mL), and 1M aqueous sodium hydroxide solution (0.35mL) was added thereto, followed by stirring at 60 ℃ for 1 hour. The reaction mixture was neutralized by adding 1M hydrochloric acid, and then concentrated under reduced pressure. To the residue were added water and chloroform, and the organic layer was separated by a phase separator (International Sorbent Technology Co.), and concentrated under reduced pressure. The resulting solid was washed with ethanol/diisopropyl ether, filtered and dried to give 1- {5- [ (5- { [3- (hydroxymethyl) -3-methylpiperidin-1-yl ] methyl } -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid (36 mg).

Example 107

A mixture of ethyl 1- [5- ({5- (acetoxymethyl) -4- [4- (morpholin-4-yl) -3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylate (300mg), (2R) -2 propyl pyrrolidine hydrochloride (150mg), diisopropylethylamine (0.40mL) and N, N-dimethylformamide (5.0mL) was stirred at 100 ℃ for 2 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give a solid (200 mg). The resulting compound was mixed with tetrahydrofuran (5mL) and ethanol (5mL), and 1M aqueous sodium hydroxide solution was added and stirred at 60 ℃ for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by ODS silica gel column chromatography (acetonitrile-water). Hexane (20mL) was mixed with the resulting solid, which was filtered to obtain a solid, which was dried to give sodium 1- {5- [ (4- [4- (morpholin-4-yl) -3- (trifluoromethyl) phenyl ] -5- { [ (2R) -2-propylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylate (190 mg).

Example 141

Ethyl 1- (5- { [4- (4-chloro-2-thienyl) -1, 3-thiazol-2-yl ] carbamoyl } pyrazin-2-yl) piperidine-4-carboxylate (200mg), acetic acid (4mL), 36% aqueous formaldehyde (0.113mL) and 2-ethylpyrrolidine (208mg) were mixed and stirred at 90 ℃ for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with a 1M aqueous solution of sodium hydroxide, water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate). The resulting compound was mixed with ethanol (4mL), tetrahydrofuran (2mL) and a 1M aqueous solution of sodium hydroxide (2.10mL) were added, and the mixture was stirred at 50 ℃ for 20 minutes. The reaction mixture was cooled to room temperature, water and 1M hydrochloric acid (2.10mL) were added, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with diisopropyl ether, filtered and dried to give 1- [5- ({4- (4-chloro-2-thienyl) -5- [ (2-ethylpyrrolidin-1-yl) methyl ] -1, 3-thiazol-2-yl } carbamoyl) pyrazin-2-yl ] piperidine-4-carboxylic acid (129 mg).

Example 206

To a mixture of ethyl 1- (5- { [4- (4-chloro-2-thienyl) -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl ] carbamoyl } pyrazin-2-yl) piperidine-4-carboxylate (695mg) with ethanol (5mL) and tetrahydrofuran (5mL) was added 1M aqueous sodium hydroxide solution (5mL), and the mixture was stirred at 50 ℃ for 30 minutes. Acetic acid (0.29mL) was added to the reaction mixture, which was concentrated under reduced pressure, followed by addition of water (5 mL). The mixture was stirred at 50 ℃ for 3 hours, then cooled to room temperature, stirred overnight, and the precipitated solid was filtered. The resulting solid was mixed with ethanol (4mL) and stirred at 80 ℃ for 30 minutes. The mixture was cooled to room temperature and stirred for 18 hours. The solid was collected by filtration and dried to give crystals of 1- (5- { [4- (4-chloro-2-thienyl) -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl ] carbamoyl } pyrazin-2-yl) piperidine-4-carboxylic acid (567 mg).

The crystal obtained in example 206 had peaks at powder X-ray diffraction in the vicinity of 2 θ (°) of 4.8, 6.6, 9.1, 10.3, 13.3, 14.5, 15.7, 17.2, 18.3, 19.0, 24.7 and 26.0.

Example 207

To a mixture of ethyl 1- {5- [ (4- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -5- { [ (2R) -2-methylpiperidin-1-yl ] methyl } -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylate (987mg) and ethanol (5mL), 1M aqueous sodium hydroxide solution (5mL) was added, and the mixture was stirred at 50 ℃ for 30 minutes. To the reaction mixture was added acetic acid (0.29mL) and water. The mixture was stirred at 50 ℃ for 3 hours, then cooled to room temperature, stirred overnight, and the precipitated solid was filtered. The resulting solid was mixed with ethanol (4mL) and stirred at 80 ℃ for 3 hours. The mixture was cooled to room temperature and stirred for 3 days. The precipitated solid was filtered to give crystals of 1- {5- [ (4- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -5- { [ (2R) -2-methylpiperidin-1-yl ] methyl } -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid (275 mg).

The crystal obtained in example 207 had peaks at powder X-ray diffraction in the vicinity of 2 θ (°) of 4.7, 7.5, 9.6, 10.4, 13.7, 16.9, 17.1, 18.0, 18.3, 19.2, 20.1 and 25.9.

The compounds of examples 9 to 205 shown in the following tables were produced in the same manner as in examples 1 to 8. The structures, physicochemical data, and manufacturing methods of the compounds of examples are shown in tables 37 to 81 and tables 82 to 97, respectively.

In tables 98 to 113, structures of other compounds of the compound of formula (I) are shown. They can be easily produced by the methods described in the above production examples or examples, and the methods obvious to those skilled in the art or modifications thereof.

[ Table 4]

[ 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]

[ Table 44]

[ Table 45]

[ Table 46]

[ Table 47]

[ Table 48]

[ Table 49]

[ Table 50]

[ Table 51]

[ Table 52]

[ Table 53]

[ Table 54]

[ Table 55]

[ Table 56]

[ Table 57]

[ Table 58]

[ Table 59]

[ Table 60]

[ Table 61]

[ Table 62]

[ Table 63]

[ Table 64]

[ Table 65]

[ Table 66]

[ Table 67]

[ Table 68]

[ Table 69]

[ Table 70]

[ Table 71]

[ Table 72]

[ Table 73]

[ Table 74]

[ Table 75]

[ Table 76]

[ Table 77]

[ Table 78]

[ Table 79]

[ Table 80]

[ Table 81]

[ Table 82]

[ Table 83]

[ Table 84]

[ Table 85]

Ex	Syn	DATA
			48	2	ESI+:659
49	2	ESI+:651
			50	2	ESI+:633
51	2	ESI+:625
			52	2	ESI+:585
53	2	ESI+:619
			54	2	ESI+:619
55	2	ESI+:585
			56	2	ESI+:599
57	2	APCI/ESI+:603
			58	2	APCI/ESI+:603
59	2	APCI/ESI+:617
			60	2	APCI/ESI+:643
61	2	ESI+:621
			62	2	ESI+:635
63	2	ESI+:635
			64	2	ESI+:649
65	2	ESI+:649
			66	2	ESI+:635
67	2	ESI+:579
			68	2	ESI+:579

[ Table 86]

[ Table 87]

[ Table 88]

[ Table 89]

[ Table 90]

[ Table 91]

[ Table 92]

[ Table 93]

[ Table 94]

[ Table 95]

[ Table 96]

[ Table 97]

[ Table 98]

[ Table 99]

[ Table 100]

[ watch 101]

[ Table 102]

[ Table 103]

[ Table 104]

[ Table 105]

[ Table 106]

[ Table 107]

[ Table 108]

[ Table 109]

[ Table 110]

[ Table 111]

[ Table 112]

[ Table 113]

Industrial applicability

A compound of formula (I) or a salt thereof as a muscarinic M₃Receptor positive allosteric modulators useful as antagonists of muscarinic M₃A prophylactic and/or therapeutic agent for bladder/urinary tract diseases associated with bladder contraction by a receptor.

Claims (15)

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

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

R¹is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl and piperidin-1-yl, or is-N (-R)¹¹)(-R¹²) Said cyclic amino group may be substituted by C_1-6Alkyl substitution of the C_1-6Alkyl may be selected from the group consisting of-O- (C)_1-6Alkyl) and halogen, and 1 to 3 identical or different substituents in the group,

R¹¹is C_1-6An alkyl group, a carboxyl group,

R¹²is optionally substituted by-O- (C)_1-6Alkyl) substituted C_1-6An alkyl group, a carboxyl group,

R²is phenyl which may be substituted with 1 to 5 identical or different substituents selected from the group G22, or thienyl which may be substituted with 1 to 3 identical or different halogens,

here, group G22 is C which may be substituted by 1 to 5 identical or different halogens_1-6Alkyl, -O- (optionally selected from halogen and-O- (C)_1-6Alkyl) C substituted with 1 to 5 same or different substituents_1-6Alkyl), halogen and-N (C)_1-6Alkyl radical)₂The group of the components is composed of,

R³is-H, -OH or fluorine.

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

R¹is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl and piperidin-1-yl, said cyclic amino group being substituted by C_1-6Alkyl substitution of the C_1-6The alkyl groups may be substituted by 1 to 3 same or different-O- (C)_1-6Alkyl) is substituted with (a) a (b),

R²is phenyl which may be substituted with 1 to 3 identical or different substituents selected from the group G24, or thienyl which may be substituted with 1 to 3 identical or different halogens,

here, group G24 is C which may be substituted by 1 to 5 identical or different halogens_1-6Alkyl, -O- (C)_1-6Alkyl) and halogen,

R³is-H.

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

R¹is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl and piperidin-1-yl, said cyclic amino group being substituted by C_1-6The substitution of the alkyl group is carried out,

R²is phenyl which may be substituted with 1 to 3 identical or different substituents selected from the group G25, or thienyl which may be substituted with 1 to 3 identical or different halogens,

here, group G25 is C which may be substituted by 1 to 5 identical or different halogens_1-6Alkyl and-O- (C)_1-6Alkyl) groups.

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

R¹is a cyclic amino group selected from the group consisting of pyrrolidin-1-yl and piperidin-1-yl, said cyclic amino group being substituted with 1 to 3 same or different substituents selected from the group consisting of methyl and ethyl,

R²is phenyl or thienyl, said phenyl being optionally substituted with 1-2 identical or different substituents selected from the group consisting of trifluoromethyl and methoxy, said thienyl being optionally substituted with 1 chloro.

5. The compound or salt thereof according to claim 4,

R²is a phenyl group which may be substituted by 1 to 2 identical or different substituents selected from the group consisting of a trifluoromethyl group and a methoxy group.

6. The compound or salt thereof according to claim 4,

R²thienyl which may be substituted by 1 chloro.

7. The compound or salt thereof according to claim 1, wherein the compound is a compound selected from the group consisting of:

1- {5- [ (4- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -5- { [ (2R) -2-methylpiperidin-1-yl ] methyl } -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid,

1- (5- { [4- (4-chloro-2-thienyl) -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl ] carbamoyl } pyrazin-2-yl) piperidine-4-carboxylic acid,

1- {5- [ (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 3-fluoro-5- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid, and

1- {5- [ (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid.

8. The compound according to claim 7, wherein the compound is a compound of:

1- {5- [ (4- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -5- { [ (2R) -2-methylpiperidin-1-yl ] methyl } -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid.

9. The compound according to claim 7, wherein the compound is a compound of:

1- (5- { [4- (4-chloro-2-thienyl) -5- { [ (2R) -2-methylpyrrolidin-1-yl ] methyl } -1, 3-thiazol-2-yl ] carbamoyl } pyrazin-2-yl) piperidine-4-carboxylic acid.

10. The compound according to claim 7, wherein the compound is a compound of:

1- {5- [ (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 3-fluoro-5- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid.

11. The compound according to claim 7, wherein the compound is a compound of:

1- {5- [ (5- { [ (2R) -2-ethylpyrrolidin-1-yl ] methyl } -4- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -1, 3-thiazol-2-yl) carbamoyl ] pyrazin-2-yl } piperidine-4-carboxylic acid.

12. A pharmaceutical composition comprising the compound or salt according to claim 7 and a pharmaceutically acceptable excipient.

13. The pharmaceutical composition according to claim 12 for use with muscarinic M₃Prevention or treatment of bladder/urinary tract diseases associated with bladder contraction by receptors.

14. The pharmaceutical composition according to claim 12, for the prevention or treatment of dysuria and polyuria in low bladder activity, low-tension bladder, non-contractile bladder, low detrusor activity or neurogenic bladder.

15. Use of a compound according to claim 7 or a salt thereof in the manufacture of a medicament for use with muscarinic M₃To a pharmaceutical composition for preventing or treating bladder/urinary tract diseases associated with bladder contraction by a receptor.