JP2009534443A - Compounds that potentiate AMPA receptors and their use in medicine - Google Patents

Abstract

［式中：Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^１０、ＸおよびＺは、明細書に定義されるとおりである］
で示される化合物、ならびにその塩および溶媒和物が提供される。調製方法、医薬組成物、および医薬として、例えば、統合失調症または認識機能障害などの、グルタミン酸受容体機能の低下または不均衡によって媒介される疾患または病態の治療におけるその使用がまた開示される。Formula (I) for use as a medicament:

[Wherein R ¹ , R ² , R ⁴ , R ¹⁰ , X and Z are as defined in the specification]
As well as salts and solvates thereof. Also disclosed are methods of preparation, pharmaceutical compositions, and medicaments, eg, in the treatment of diseases or conditions mediated by reduced or imbalanced glutamate receptor function, such as schizophrenia or cognitive impairment.

Description

  The present invention relates to novel compounds that potentiate glutamate receptors. The present invention also relates to the use of compounds to treat diseases and conditions mediated by potentiation of glutamate receptors, compositions containing derivatives and methods for their preparation.

  The glutamate receptor, which regulates most of the fast excitatory neurotransmission of the mammalian central nervous system (CNS), is activated by the excitatory amino acid, L-glutamate (for example, Watkins JC, Krogsgaard- Larsen P, Honore T (1990) Trends Pharmacol Sci 11: 25-33).

  Glutamate receptors can be divided into two different families. The “metabolically regulated” glutamate receptor family bound to G-proteins or second messengers can be further divided into three groups based on sequence homology and intracellular transmission mechanisms (Group I, mGlu1 and mGlu5; Group II, mGlu2 and mGlu3; Group III, mGlu4, mGlu6, mGlu7, mGlu8) (For reports see Conn PJ and Pinn JP (1997) Ann Rev Pharmacol Toxicol 37: 205-237). The “ion channel type” glutamate receptor family that binds directly to ligand-gated cation channels is a selective agonist, N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole. Based on depolarization activation by -4-propionic acid (AMPA) and kainic acid (KA), it can be further classified into at least three subtypes (for example, Dingledine R, Borges K, Bowie, Trainelis S ( 1999) 51: 7-61).

  The natural AMPA receptor (AMPAR) exists as a heterotetramer consisting of a combination of four different protein subunits (GluR1-4) (for the report, Bettler B and Muller C (1995) 34: 123- 139). Diversity of receptor subunits is further increased because each subunit may undergo alternative splicing of the 38 amino acid sequence in the extracellular region immediately preceding the 4-transmembrane domain M4 To do. Such calibration results in so-called “flip” and “flop” receptor isoforms with different kinetic and pharmacological properties (Sommer B, Keinanen K, Verdon TA, Wisden W, Burnashhev N Herb A, Kohler M, Takagi T, Sakmann B, Seeburg PH (1990) Science 249: 1580-1585).

  In addition, post-transcriptional calibration of GluR2 mRNA changes neutral glutamine in M2 to positively charged arginine. In normal humans,> 99% GluR2 is calibrated in this way. AMPARs containing such calibrated GluR2 subunits exhibit low calcium permeability (Burnachev N, Monyer H, Seeburg PH, Sakmann B (1992) Neuron 8: 189-198). However, it has been suggested that the number of AMPARs with high calcium permeability is increased in symptoms associated with certain diseases (Weiss JH, and Sensi SL (2000) Trends in Neurosci 23: 365-371).

AMPAR depolarization removes the voltage-dependent Mg ²⁺ block of the NMDA receptor, which in turn leads to NMDA receptor activation, an essential step in the induction of long-term potentiation (“LTP”) (Bllis TVP, Collingridge GL (1993) Nature 361: 31-9). LTP is a physiological measure of increased synaptic strength after, for example, repetitive stimulation or activity as occurs during learning.

  Direct activation of glutamate receptors by agonists in a state of reduced glutamate receptor function has been reported to increase excitotoxicity and the risk of further neuronal damage. AMPAR positive allosteric modulators do not directly activate the receptor. However, when a ligand (L-glutamic acid or AMPA) is present, AMPAR modulators increase receptor activity. Thus, AMPA receptor modulators enhance synaptic function when glutamate is released and can bind to the postsynaptic receptor site.

Compounds that act as AMPAR positive allosteric modulators increase ligand affinity for the receptor (Arai A, Guidotti A, Costa E, Lynch G (1996) Neuroreport. 7: 2211-5.); Reduced and reduced receptor deactivation (Arai AC, Kessler M, Rogers G, Lynch G (2000) 58: 802-813); in vitro (Arai A, Guidotti A, Costa E, Lynch G (1996) 7: 2211-5.) And in vivo (Staubri U, Perez Y, Xu F, Rogers G, Ingvar M, Stone-Elander S, Lynch G (1994) Proc Natl Acad Sci 91: 1. It has been shown to facilitate the induction of LTP in 158-11162) both. Such compounds may also be used in rodents (Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBella M, Costa E, Guidotti A (1995) JPET 272: 300-309, Lebrun C, Pliere E, 2000). Eu J Pharmacol 401: 205-212), apes (Thompson DM, Guidotti A, DiBella M, Costa E (1995) Proc Natl Acad Sci 92: 76667671) and humans (Ingvar M, Ambros J, Ambros J Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997) Exp Ne. urol 146: 553-559) enhance learning and behavior of various cognitive tasks. The effectiveness of various AMPAR positive allosteric modulators in preclinical and clinical models of psychiatric disorders such as schizophrenia has been investigated (Morrow JA, McLean J KF, Jameson C (2006) Current Opinion in Drug Discovery and Development 9). (5) 571-579). In men, the ability of AMPAR positive allosteric modulators to improve preclinical and clinical cognitive work activities and potential efficacy in psychiatric disorders such as schizophrenia have been investigated (Morrow JA, McLean J KF, Jamison C (2006) Current Opinion in Drug Discovery and Development 9 (5) 571-579).
Watkins JC, Krogsgarard-Larsen P, Honore T (1990) Trends Pharmacol Sci 11: 25-33. Conn PJ and Pinn JP (1997) Ann Rev Pharmacol Toxicol 37: 205-237 Dingledine R, Borges K, Bowie, Trainelis S (1999) 51: 7-61 Bettler B and Muller C (1995) 34: 123-139 Somer B, Keinanen K, Verdonon TA, Wisden W, Burnashev N, Herb A, Kohler M, Takagi T, Sakmann B, Seeburg PH (1990) Science 249: 1580-1585. Burnachev N, Monyer H, Seeburg PH, Sakmann B (1992) Neuron 8: 189-198. Weiss JH, and Sensi SL (2000) Trends in Neurosci 23: 365-371 Bliss TVP, Collingridge GL (1993) Nature 361: 31-9 Arai A, Guidotti A, Costa E, Lynch G (1996) Neuroport. 7: 2211-5 Arai AC, Kessler M, Rogers G, Lynch G (2000) 58: 802-813 Arai A, Guidotti A, Costa E, Lynch G (1996) 7: 2211-5 Staubli U, Perez Y, Xu F, Rogers G, Ingvar M, Stone-Elander S, Lynch G (1994) Proc Natl Acad Sci 91: 11158-11162. Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBella M, Costa E, Guidotti A (1995) JPET 272: 300-309 Lebrun C, Pillier E, Lestage P (2000) Eu J Pharmacol 401: 205-212 Thompson DM, Guidotti A, DiBella M, Costa E (1995) Proc Natl Acad Sci 92: 7667-7671) Ingvar M, Ambros-Ingerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997) Exp Neurol 146: 553-559. Morrow JA, McLean J KF, Jameson C (2006) Current Opinion in Drug Discovery and Development 9 (5) 571-579

  Compounds that act as AMPAR positive allosteric modulators are known, for example, in international patent application WO 2006/015828. The present inventors have found a novel compound that also enhances the AMPA receptor.

［式中：
Ｒ^１０は、メチルまたは水素から選択され；
Ｘは、

から選択され；
Ｚは、ＳまたはＯから選択され；
Ｒ^１は、Ｈ、Ｃ_１−４アルキル、Ｃ（Ｏ）ＯＣ_１−４アルキル、Ｃ（Ｏ）Ｃ_１−４アルキル、Ｃ（Ｏ）ハロＣ_１−４アルキル、Ｃ（Ｏ）ＮＲ^６Ｒ^７、シアノから選択され、Ｒ^６およびＲ^７は、各々独立して、ＨまたはＣ_１−４アルキルから選択され；
Ｒ^２は、Ｃ_１−４アルキル、Ｃ（Ｏ）ＣＨ_３、またはＣＮから選択され；
Ｒ^３は、Ｈ、ＮＨ_２、ＣＨ_３、（ＣＨ_２）_ｎＯＨおよび（ＣＨ_２）_ｎＣ_１−４アルコキシからなる群より選択され、ここで、ｎは０または１であり；および
Ｒ^３がＣＨ_３、（ＣＨ_２）_ｎＯＨまたは（ＣＨ_２）_ｎＣ_１−４アルコキシである場合、その場合、Ｒ^４は、Ｈ、ハロ、Ｃ_１−４アルコキシ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、Ｃ_１−４アルキルチオ、ハロＣ_１−４アルキルチオ、ハロＣ_１−４アルキルおよびＮＲ^８Ｒ^９からなる群より選択され、ここで、Ｒ^８およびＲ^９は、独立して、水素またはＣ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子を所望により含有していてもよい５または６員環を形成し；
Ｒ^３がＮＨ_２である場合、その場合、Ｒ^４は、Ｈ、ハロ、Ｃ_１−４アルコキシ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、Ｃ_１−４アルキルチオ、ハロＣ_１−４アルキルチオ、ハロＣ_１−４アルキルまたはＮＲ^８Ｒ^９から選択され、ここで、Ｒ^８およびＲ^９は、独立して、Ｃ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子を所望により含有していてもよい５または６員環を形成し；
Ｒ^３がＨである場合、その場合、Ｒ^４は、Ｈ、Ｃ_１−４アルコキシ、クロロ、ブロモ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、ハロＣ_１−４アルキル、またはＮＲ^８Ｒ^９から選択され、ここで、Ｒ^８およびＲ^９は、独立して、水素またはＣ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子を所望により含有していてもよい５または６員環を形成し；
Ｘが−ＣＨ_２ＣＦ_３である場合、その場合、Ｒ^４はＣ_１−４アルコキシまたはＣ_１−４アルキルから選択され；
Ｘがメチルである場合、その場合、Ｒ^４は、Ｃ_１−４アルコキシ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、ハロＣ_１−４アルキルまたはＮＲ^８Ｒ^９から選択され、ここで、Ｒ^８およびＲ^９は、独立して、水素またはＣ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数のヘテロ原子を所望により含有していてもよい５または６員環を形成し；
Ｘが

である場合、その場合、Ｒ^４は、Ｈ、ハロ、Ｃ_１−４アルコキシ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、ハロＣ_１−４アルキルおよびＮＲ^８Ｒ^９からなる群より選択され、ここで、Ｒ^８およびＲ^９は、独立して、Ｃ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子を所望により含有していてもよい５または６員環を形成する］
で示される化合物、またはその塩もしくは溶媒和物を提供する。 According to a first aspect, the present invention provides a compound of formula (I) for use as a medicament:

[Where:
R ¹⁰ is selected from methyl or hydrogen;
X is

Selected from;
Z is selected from S or O;
R ¹ is H, C _1-4 alkyl, C (O) OC _1-4 alkyl, C (O) C _1-4 alkyl, C (O) haloC _1-4 alkyl, C (O) NR ⁶ R ^{7 is} selected from cyano, and R ⁶ and R ⁷ are each independently selected from H or C _1-4 alkyl;
R ² is selected from C _1-4 alkyl, C (O) CH ₃ , or CN;
R ³ is selected from the group consisting of H, NH ₂ , CH ₃ , (CH ₂ ) _n OH and (CH ₂ ) _n C _1-4 alkoxy, where n is 0 or 1; and R ³ Is CH ₃ , (CH ₂ ) _n OH or (CH ₂ ) _n C _1-4 alkoxy, then R ⁴ is H, halo, C _1-4 alkoxy, haloC _1-4 alkoxy, C Selected from the group consisting of _1-4 alkyl, C _1-4 alkylthio, halo C _1-4 alkylthio, halo C _1-4 alkyl and NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently Selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ , together with the nitrogen atom to which they are attached, are one or more additional heterocycles selected from O, N or S Contains atoms as desired Also forms a good 5 or 6 membered ring optionally;
When R ³ is NH ₂ , then R ⁴ is H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, C _1-4 alkylthio, halo C _1-4 Selected from alkylthio, haloC _1-4 alkyl or NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ are Together with the nitrogen atom to which is bound forms a 5 or 6 membered ring optionally containing one or more additional heteroatoms selected from O, N or S;
When R ³ is H, then R ⁴ is H, C _1-4 alkoxy, chloro, bromo, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl, or NR ⁸ Selected from R ⁹ , wherein R ⁸ and R ⁹ are independently selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ are taken together with the nitrogen atom to which they are attached. Forming a 5- or 6-membered ring optionally containing one or more additional heteroatoms selected from O, N or S;
When X is —CH ₂ CF ₃ , then R ⁴ is selected from C _1-4 alkoxy or C _1-4 alkyl;
When X is methyl, then R ⁴ is selected from C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl or NR ⁸ R ⁹ where , R ⁸ and R ⁹ are independently selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached, from O, N or S Forming a 5- or 6-membered ring optionally containing one or more selected heteroatoms;
X is

In which case R ⁴ is selected from the group consisting of H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl and NR ⁸ R ^9. Where R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached are O, N or Form a 5- or 6-membered ring optionally containing one or more additional heteroatoms selected from S]
Or a salt or solvate thereof.

  “H” refers to hydrogen. “CN” refers to cyano (C≡N). “Ph” refers to phenyl.

  Halo is selected from fluoro, chloro, bromo or iodo. For example, halo is selected from fluoro and chloro, for example fluoro.

The term “C _1-4 alkyl” refers to an alkyl group having 1 to 4 carbon atoms. Unless otherwise specified, C _1-4 alkyl may be a linear or branched alkyl group. For example, the C _1-4 alkyl group may be selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl. For example, C _1-4 alkyl is methyl. “Me” refers to methyl. “Et” refers to ethyl.

The term “C _1-4 alkoxy” refers to an O—C _1-4 alkyl group, wherein C _1-4 alkyl is as described above.

The term “C _1-4 alkylthio” refers to a S—C _1-4 alkyl group, wherein C _1-4 alkyl is as described above.

The term “haloC _1-4 alkyl” refers to a C _1-4 alkyl group as described above that is substituted with several fluorine, chlorine, bromine, and iodine atoms, including mixtures of those atoms. Halo _{C 1-4} alkyl group is, for example, may contain 1, 2 or 3 halogen atoms. For example, a halo C _1-4 alkyl group may have all hydrogen atoms replaced with halogen atoms. Examples of _{haloC1-4alkyl} groups include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl. Similarly, the terms “halo C _1-4 alkoxy” and “halo C _1-4 alkylthio” refer to C _1-4 alkoxy and C _1-4 alkylthio groups, wherein a C _1-4 alkyl group is Substituted by several fluorine, chlorine, bromine, or iodine atoms (including mixtures of those atoms). Examples of halo C _1-4 alkoxy group, trifluoromethoxy, and difluoromethoxy, and trifluoromethoxy. Examples of halo C _1-4 alkylthio group, trifluoromethylthio, include difluoromethylthio and trifluoromethylthio.

In the definition of each R ⁸ and R ⁹ in formula (I), a “5- or 6-membered ring optionally containing one or more additional heteroatoms selected from O, N or S” The term "refers to a 5- or 6-membered saturated unsubstituted ring formed by R ⁸ , R ⁹ and the nitrogen atom to which they are both attached. Examples include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isotriazolidinyl, triazolidinyl, piperidyl, piperazinyl, morpholinyl and thiomorpholinyl.

  “CO” and “C (═O)” are interchangeable and represent a carbonyl group (also known as an oxo group).

In one embodiment, R ¹⁰ is hydrogen.

  In one embodiment, Z is S. In another embodiment, Z is O.

In one embodiment, R ¹ is C _1-4 alkyl, C (O) OC _1-4 alkyl, C (O) C _1-4 alkyl, C (O) haloC _1-4 alkyl, C (O ) NR ⁶ R ⁷ or cyano, wherein R ⁶ and R ⁷ are each independently selected from H or C _1-4 alkyl.

In one embodiment, R ¹ is C (O) Me, methyl, cyano, C (O) N (Me) ₂ , C (O) NH ₂ , C (O) CF ₃ , C (O) OEt or Selected from C (O) OMe.

In one embodiment, R ² is selected from C _1-4 alkyl or C (O) CH ₃ . In one embodiment, R ² is methyl. In one embodiment, R ² is C (O) CH ₃ .

［式中：Ｒ^３は式（Ｉ）の記載と同義である］
である。 In one embodiment, X is

[Wherein R ³ has the same meaning as described in formula (I)]
It is.

In one embodiment, R ³ is H and R ⁴ is H, C _1-4 alkoxy, chloro, bromo, haloC _1-4 alkoxy, C _1-4 alkyl, haloC _1-4 alkyl, And NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ are attached to them. Together with the nitrogen atom forms a 5- or 6-membered ring optionally containing one or more additional heteroatoms selected from O, N or S.

In one embodiment, R ³ is H and R ⁴ is H, C _1-2 alkoxy, chloro, bromo, halo C _1-2 alkoxy, C _1-2 alkyl, halo C _1-2 alkyl, And NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently selected from hydrogen or C _1-2 alkyl, or R ⁸ and R ⁹ are attached to them. Together with the nitrogen atom, it forms a pyrrolidinyl, piperidinyl or morpholinyl ring.

In one embodiment, R ³ is NH ₂ and R ⁴ is H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, C _1-4 alkylthio, haloC _1-4 alkylthio, haloC _1-4 alkyl or NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R 9 ⁹ together with the nitrogen atom to which they are attached form a 5- or 6-membered ring optionally containing one or more additional heteroatoms selected from O, N or S .

In one embodiment, R ³ is NH ₂ and R ⁴ is C _1-4 alkoxy. In one embodiment, R ³ is NH ₂ and R ⁴ is methoxy or ethoxy.

In one embodiment, R ³ is CH ₃ and R ⁴ is H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, C _1-4 alkylthio, haloC Selected from the group consisting of _1-4 alkylthio, haloC _1-4 alkyl and NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently selected from hydrogen or C _1-4 alkyl; Alternatively, R ⁸ and R ⁹ together with the nitrogen atom to which they are attached may optionally contain one or more additional heteroatoms selected from O, N or S Form a member ring.

In one embodiment, R ³ is CH ₃ and R ⁴ is bromo, C _1-2 alkoxy, halo C _1-2 alkoxy, C _1-4 alkyl, C _1-2 alkylthio, halo C _1- Selected from the group consisting of ₂ alkylthio, haloC _1-2 alkyl and NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached may optionally contain one or more additional heteroatoms selected from O, N or S 5 or 6 membered rings Form.

In one embodiment, R ³ is CH ₃ and R ⁴ is bromo, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, butyl, methylthio, trifluoromethylthio, trifluoromethyl and NR ⁸ Selected from the group consisting of R ⁹ , wherein R ⁸ and R ⁹ are independently selected from hydrogen, methyl or ethyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached. To form a pyrrolidinyl, piperidinyl or morpholinyl ring.

In one embodiment, R ³ is CH ₃ and R ⁴ is trifluoromethoxy or ethoxy.

In one embodiment, R ³ is (CH ₂ ) _n OH or (CH ₂ ) _n C _1-4 alkoxy, wherein R ⁴ is H, halo, C _1-4 alkoxy, haloC _1-4 Selected from the group consisting of alkoxy, C _1-4 alkyl, C _1-4 alkylthio, halo C _1-4 alkylthio, halo C _1-4 alkyl and NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently One or more additions selected from O, N or S, or selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached To form a 5- or 6-membered ring which may optionally contain heteroatoms.

In one embodiment, R ³ is (CH ₂ ) _n OH or (CH ₂ ) _n C _1-4 alkoxy, wherein R ⁴ is bromo, C _1-2 alkoxy, haloC _1-2 alkoxy, Selected from the group consisting of C _1-4 alkyl, C _1-2 alkylthio, halo C _1-2 alkylthio, halo C _1-2 alkyl and NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently , Hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached, one or more additional selected from O, N or S A 5- or 6-membered ring optionally containing heteroatoms is formed.

In one embodiment, R ³ is (CH ₂ ) _n OH or (CH ₂ ) _n C _1-4 alkoxy, wherein R ⁴ is bromo, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methyl, Selected from the group consisting of ethyl, butyl, methylthio, trifluoromethylthio, trifluoromethyl and NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently selected from hydrogen, methyl or ethyl; Alternatively, R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl or morpholinyl ring.

In one embodiment, X is —CH ₂ CF ₃ and R ⁴ is selected from C _1-4 alkoxy or C _1-4 alkyl. In one embodiment, X is —CH ₂ CF ₃ and R ⁴ is selected from C _1-2 alkoxy or C _1-2 alkyl. In one embodiment, X is —CH ₂ CF ₃ and R ⁴ is ethyl or ethoxy.

In one embodiment, X is methyl and R ⁴ is selected from C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl or NR ⁸ R ^9. Where R ⁸ and R ⁹ are independently selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached, O, N Or form a 5- or 6-membered ring optionally containing one or more additional heteroatoms selected from S.

In one embodiment, X is methyl and R ⁴ is selected from C _1-2 alkoxy, halo C _1-2 alkoxy, C _1-2 alkyl, halo C _1-2 alkyl or NR ⁸ R ^9. Where R ⁸ and R ⁹ are independently selected from hydrogen or C _1-2 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached, O, N Or a 5- or 6-membered ring optionally containing one or more heteroatoms selected from S.

In one embodiment, X is methyl and R ⁴ is selected from methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, trifluoromethyl or NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are Independently selected from hydrogen, methyl or ethyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl or morpholinyl ring.

であって、Ｒ^４は、Ｈ、ハロ、Ｃ_１−４アルコキシ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、ハロＣ_１−４アルキルおよびＮＲ^８Ｒ^９からなる群より選択され、ここで、Ｒ^８およびＲ^９は、独立して、Ｃ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子を所望により置換されていてもよい５または６員環を形成する。 In one embodiment, X is

Wherein R ⁴ is selected from the group consisting of H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl and NR ⁸ R ⁹ , wherein Wherein R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ are selected from O, N or S together with the nitrogen atom to which they are attached. One or more additional heteroatoms are formed as optionally substituted 5- or 6-membered rings.

In a further embodiment, when X is cyclopropyl, R ⁴ is haloC _1-2 alkyl, C _1-2 alkoxy or NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently R ⁸ and R ⁹ are selected from C _1-4 alkyl, or together with the nitrogen atom to which they are attached, one or more additional heteroatoms selected from O, N or S Forms a 5- or 6-membered ring which may be optionally contained.

In a further embodiment, when X is cyclopropyl, R ⁴ is halomethyl, such as trifluoromethyl, methoxy, ethoxy, or NR ⁸ R ⁹ , where R ⁸ and R ⁹ are attached to them. Together with the nitrogen atom forms a pyrrolidinyl, piperidinyl or morpholinyl ring.

The imine bond of formula (I) (between the central nitrogen atom and the carbon atom in the triazolyl or oxazolyl group) represents E, Z or a mixture of both E and Z isomers:

  In mixtures of E and Z compounds, or compounds where the E / Z (ie, cis / trans) conformation has not been determined, the imine bond is depicted as a cross bond as shown in formula (I).

  The individual isomers (E and Z) and mixtures thereof are included within the scope of the present invention. Isomers can be separated from one another by general methods or the methods detailed below for the Example compounds. Any given isomer can also be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric form and mixtures thereof.

  In one embodiment, the compound of formula (I) is the E isomer.

  In another embodiment, the compound of formula (I) is the Z isomer.

［式中：
Ｘは、

から選択され；
Ｚは、ＳまたはＯから選択され；
Ｒ^１は、Ｈ、Ｃ_１−４アルキル、Ｃ（Ｏ）Ｃ_１−４アルキル、Ｃ（Ｏ）ＮＲ^６Ｒ^７、シアノ、およびフェニル、ＮＯ_２、ＳＯまたはＳＯ_２Ｒ^５から選択される１個または複数の基で所望により置換されていていてもよいフェニル基から選択され、ここで、Ｒ^５はＣ_１−４アルキルであり、Ｒ^６およびＲ^７は、各々独立して、ＨまたはＣ_１−４アルキルから選択され；
Ｒ^２は、Ｃ_１−４アルキル、Ｃ（Ｏ）ＣＨ_３、またはＣＮから選択され；
Ｒ^３は、Ｈ、（ＣＨ_２）_ｎＯＨおよび（ＣＨ_２）_ｎＣ_１−４アルコキシからなる群より選択され、ここで、ｎは０または１であり；および
Ｒ^３が（ＣＨ_２）_ｎＯＨまたは（ＣＨ_２）_ｎＣ_１−４アルコキシである場合、その場合、Ｒ^４は、Ｈ、ハロ、Ｃ_１−４アルコキシ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、Ｃ_１−４アルキルチオ、ハロＣ_１−４アルキルチオ、ハロＣ_１−４アルキルおよびＮＲ^８Ｒ^９からなる群より選択され、ここで、Ｒ^８およびＲ^９は、独立して、Ｃ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子を所望により含有していてもよい５または６員環を形成し；
Ｒ^３がＨである場合、その場合、Ｒ^４は、Ｈ、Ｃ_１−４アルコキシ、クロロ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、ハロＣ_１−４アルキルおよびＮＲ^８Ｒ^９からなる群より選択され、ここで、Ｒ^８およびＲ^９は、独立して、Ｃ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子を所望により含有していてもよい５または６員環を形成し；ならびに
Ｘが

である場合、その場合、Ｒ^４は、Ｈ、ハロ、Ｃ_１−４アルコキシ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、ハロＣ_１−４アルキルおよびＮＲ^８Ｒ^９からなる群より選択され、ここで、Ｒ^８およびＲ^９は、独立して、Ｃ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子を所望により含有していてもよい５または６員環を形成する］
で示される化合物、またはその塩もしくは溶媒和物を提供する。 In one embodiment, the present invention provides a compound of formula (Ia) for use as a medicament:

[Where:
X is

Selected from;
Z is selected from S or O;
R ¹ is selected from H, C _1-4 alkyl, C (O) C _1-4 alkyl, C (O) NR ⁶ R ⁷ , cyano, and phenyl, NO ₂ , SO or SO ₂ R ⁵ Selected from phenyl groups optionally substituted with one or more groups, wherein R ⁵ is C _1-4 alkyl, and R ⁶ and R ⁷ are each independently H or C Selected from _1-4 alkyl;
R ² is selected from C _1-4 alkyl, C (O) CH ₃ , or CN;
R ³ is selected from the group consisting of H, (CH ₂ ) _n OH and (CH ₂ ) _n C _1-4 alkoxy, where n is 0 or 1; and R ³ is (CH ₂ ) _n When it is OH or (CH ₂ ) _n C _1-4 alkoxy, then R ⁴ is H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, C _1-4 alkylthio, halo _{C 1-4} alkylthio, selected from the group consisting of halo _{C 1-4} alkyl and ^NR 8 ^{R 9,} wherein, ^{R 8} and ^{R 9} are _{independently} selected from _{C 1-4} alkyl Or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached may optionally contain one or more additional heteroatoms selected from O, N or S 5 Or form a 6-membered ring;
When R ³ is H, then R ⁴ is from H, C _1-4 alkoxy, chloro, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl and NR ⁸ R ⁹ Wherein R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached, Forming a 5- or 6-membered ring optionally containing one or more additional heteroatoms selected from O, N or S; and X is

In which case R ⁴ is selected from the group consisting of H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl and NR ⁸ R ^9. Where R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached are O, N or Form a 5- or 6-membered ring optionally containing one or more additional heteroatoms selected from S]
Or a salt or solvate thereof.

  It will be appreciated that the invention is intended to include compounds having any combination of the foregoing groups. It will be understood that the embodiments described above with respect to part of the invention may be combined with embodiments of other parts of the invention, if desired.

As examples of compounds of formula (I)
1- [2-{[4- (Ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone hydrochloride 1 -[2-[(4-Ethylphenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone hydrochloride 1- {2 -{[4- (Ethyloxy) phenyl] imino} -4-methyl-3- [2- (methyloxy) ethyl] -2,3-dihydro-1,3-triazol-5-yl} ethanone 1- [3 -(2-hydroxyethyl) -4-methyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] ethanone 1- (3- (2-Hydro Cyethyl) -4-methyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 1- (3-ethyl-2- { [4- (Ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone hydrochloride 2- [2-{[4- (ethyloxy) phenyl] imino} -4,5-dimethyl-1,3-triazol-3 (2H) -yl] ethanol hydrochloride 1- [2-[(4-butylphenyl) imino] -3- (2-hydroxyethyl) -4-methyl -2,3-dihydro-1,3-triazol-5-yl] ethanone hydrochloride 1- [2-{[4- (ethyloxy) phenyl] imino} -3- (3-hydroxypropyl) -4-methyl- 2, 3 Dihydro-1,3-triazol-5-yl] ethanone 1- (3- (2-hydroxyethyl) -4-methyl-2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro -1,3-triazol-5-yl) ethanone 2-{[4- (ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole -5-carbonitrile hydrochloride 3-ethyl-2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazole-5-carbonitrile hydrochloride 1- { 2-[(4-Chlorophenyl) imino] -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone 1- (3-cyclopropyl-4-methyl 2-{[4- (Trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone hydrochloride 1- (3-ethyl-4-methyl-2-{[ 4- (Trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone hydrochloride 1- [3-ethyl-4-methyl-2-({4-[( Trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] ethanone hydrochloride 1- [2-({4-[(difluoromethyl) oxy] phenyl} imino) -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone 1- [3- (2-hydroxyethyl) -4-methyl-2- ( {4-[(Tori Fluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] ethanone [(3-ethyl-4,5-dimethyl-1,3-triazole-2 (3H) -ylidene ] [4- (Trifluoromethyl) phenyl] amine 1- (3-ethyl-2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-oxazole-5 -Yl) ethanone.

In one embodiment, as examples of compounds of formula (I):
1.1- [2-{[4- (Ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone 2 1- [2-[(4-Ethylphenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone 3.1 {2-{[4- (Ethyloxy) phenyl] imino} -4-methyl-3- [2- (methyloxy) ethyl] -2,3-dihydro-1,3-triazol-5-yl} ethanone 1- [3- (2-hydroxyethyl) -4-methyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl ] Ethanone 5.1- (3- (2- Hydroxyethyl) -4-methyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 6.1- (3-ethyl- 2-{[4- (Ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone 7.2- [2-{[4- (Ethyloxy) phenyl ] Imino} -4,5-dimethyl-1,3-triazol-3 (2H) -yl] ethanol 8.1- [2-[(4-butylphenyl) imino] -3- (2-hydroxyethyl)- 4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone 9.1- [2-{[4- (ethyloxy) phenyl] imino} -3- (3-hydroxypropyl) -4 -Methyl-2, 3-Dihydro-1,3-triazol-5-yl] ethanone 10.1- (3- (2-hydroxyethyl) -4-methyl-2-{[4- (4-morpholinyl) phenyl] imino} -2 , 3-Dihydro-1,3-triazol-5-yl) ethanone 11.2-{[4- (ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro -1,3-triazole-5-carbonitrile 12.3-ethyl-2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazole-5-carb Nitrile 13.1- {2-[(4-Chlorophenyl) imino] -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone 14.1- (3-cyclo Lopyl-4-methyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 15.1- (3-ethyl-4- Methyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 16.1- [3-Ethyl-4-methyl-2- ({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] ethanone 17.1- [2-({4-[(difluoromethyl) Oxy] phenyl} imino) -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone 18.1- [3- (2-hydroxyethyl) -4-methyl -2 - ({4 - [(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] ethanone 19. [(3-Ethyl-4,5-dimethyl-1,3-triazole-2 (3H) -ylidene] [4- (trifluoromethyl) phenyl] amine 20.1- (3-ethyl-2-{[4 -(Ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-oxazol-5-yl) ethanone 21.1- {2-[(4-bromophenyl) imino] -3-ethyl -4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone 22.1- (3-ethyl-4-methyl-2-{[4- (1-pyrrolidinyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 23.1- (3-ethyl-4-methyl-2-{[4- (1-piperidinyl) phenyl] imino} -2,3 -Dihydro-1,3-triazo -5-yl) ethanone 24.3- (2-hydroxyethyl) -N, N, 4-trimethyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1 , 3-Triazole-5-carboxamide 25.1- [2-[(4-Bromophenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole- 5-yl] ethanone 26.2-{[4- (ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxamide 27 3- (2-hydroxyethyl) -N, N, 4-trimethyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazole- 5-Carboxamide 28.1- (3-Cyclopropyl-4-methyl-2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 29.3-Ethyl-N, N, 4-trimethyl-2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro-1,3-triazole-5-carboxamide 30.2,2 , 2-trifluoro-1- [3- (2-hydroxyethyl) -4-methyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3 -Triazol-5-yl] ethanone 31.3-cyclopropyl-N, N, 4-trimethyl-2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro-1,3-triazol Ru-5-carboxamide 32.1- (3- (2-hydroxyethyl) -4-methyl-2-{[4- (1-pyrrolidinyl) phenyl] imino} -2,3-dihydro-1,3-triazole -5-yl) ethanone 33.1- (3- (2-hydroxyethyl) -4-methyl-2-{[4- (methyloxy) phenyl] imino} -2,3-dihydro-1,3-triazole -5-yl) ethanone 34.1- (3- (2-hydroxyethyl) -4-methyl-2-{[4- (methylthio) phenyl] imino} -2,3-dihydro-1,3-triazole- 5-yl) ethanone 35.1- [2-[(3,4-dimethylphenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5 -Il] Ethanon 3 1- [3,4-Dimethyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] ethanone 37.1 [4-Methyl-3-propyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] ethanone 38.1- [ 4-Methyl-3- [2- (methyloxy) ethyl] -2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl ] Ethanone 39.1- (2-{[4- (Ethyloxy) phenyl] imino} -3,4-dimethyl-2,3-dihydro-1,3-triazol-5-yl) ethanone 40.1- (2 -{[4- (Ethyloxy ) Phenyl] imino} -4-methyl-3-propyl-2,3-dihydro-1,3-triazol-5-yl) ethanone 41.1- (3,4-dimethyl-2-{[4- (tri Fluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 42.1- {2-[(4-ethylphenyl) imino] -3,4-dimethyl-2, 3-dihydro-1,3-triazol-5-yl} ethanone 43.1- (2-{[4- (dimethylamino) phenyl] imino} -3,4-dimethyl-2,3-dihydro-1,3 -Triazol-5-yl) ethanone 44.1- (3-ethyl-2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazol-5-yl ) Ethanon 45.1 [2-{[4- (Diethylamino) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone 46.1- ( 2-{[4- (Diethylamino) phenyl] imino} -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone 47.1- [2-({4- [(Difluoromethyl) oxy] phenyl} imino) -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone 48.1- (3-ethyl-4-methyl- 2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 49.1- (3,4-dimethyl-2-{[4- (4-morpholinyl) fu Nyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 50.1- {2-[(4-aminophenyl) imino] -3,4-dimethyl-2,3-dihydro -1,3-triazol-5-yl} ethanone 51.1- {2-[(4-aminophenyl) imino] -3-ethyl-4-methyl-2,3-dihydro-1,3-triazole-5 -Yl} ethanone 52.1- [2-[(4-aminophenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] Ethanone 53.1- [2-{[4- (Dimethylamino) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] Ethanon 54.2-{[4- (Ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxylate 55.2-{[4- (ethyloxy) phenyl ] Imino} -3- (2-hydroxyethyl) -N, N, 4-trimethyl-2,3-dihydro-1,3-triazole-5-carboxamide 56.2-{[4- (ethyloxy) phenyl] imino } -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxylate 57.3- (2-hydroxyethyl) -N, N, 4-trimethyl -2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazole-5-carboxamide 58.3- (2-hydroxyethyl) ) -4-methyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazole-5-carboxylate 59.1- {3- (2-hydroxy) Ethyl) -4-methyl-2-[(4-methylphenyl) imino] -2,3-dihydro-1,3-triazol-5-yl} ethanone 60.1- {3-ethyl-2-[(4 -Ethylphenyl) imino] -4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone 61.1- [3-ethyl-4-methyl-2- (phenylimino) -2, 3-Dihydro-1,3-triazol-5-yl] ethanone 62.1- {3-ethyl-4-methyl-2-[(4-methylphenyl) imino] -2,3-dihydro-1,3- Triazol-5-yl} ethanone 3.1- (2-{[4- (Dimethylamino) phenyl] imino} -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone 64.1- ( 3- (2-Aminoethyl) -2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone 65.1- (3 -Cyclopropyl-2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone 66.1- [2-[(4- Ethylphenyl) imino] -4-methyl-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1,3-triazol-5-yl] ethanone 67.1- [2-{[ 4- (Ethyloxy) phenyl] imi } -4-methyl-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1,3-triazol-5-yl] ethanone as well as salts and solvates thereof.

  For the avoidance of doubt, unless otherwise stated, the term substituted means substituted with one or more given groups. In the case where a group can be selected from a number of other groups, the selected groups can be the same or different. For the avoidance of doubt, the term independent means that when one or more substituents are selected from a number of possible substituents, the substituents can be the same or different.

  In one embodiment, the salt or solvate of the compound of formula (I) is a pharmaceutically acceptable salt or solvate. In one embodiment, the present invention provides a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof.

  As used herein, the term “salt” refers to any salt, quaternary ammonium and internally formed salts of the compounds described herein that can be prepared from inorganic or organic acids or bases. Pharmaceutically acceptable salts are particularly suitable for pharmaceutical use because of their greater aqueous solubility compared to the parent compound. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitably, pharmaceutically acceptable salts of the compounds of the present invention include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and organic acids. For example, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, formic acid, propionic acid, glycolic acid, gluconic acid, maleic acid, succinic acid, (1S)-(-)- 10-camphorsulfuric acid, (1S)-(+)-10-camphorsulfuric acid, isothionic acid, mucoic acid, gentisic acid, isonicotinic acid, sugar acid, glucuronic acid, furoic acid, glutamic acid, ascorbic acid, anthranilic acid, salicylic acid, Phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, pantothenic acid, stearic acid, sulfinic acid, alginic acid, gallic acid Acid addition salts formed with kuturonic and aryl sulfonic acids such as naphthalene-1,5-disulfonic acid, naphthalene-1.3-disulfonic acid, benzene sulfonic acid, and p-toluene sulfonic acid; alkali metals and alkali Base addition salts formed with earth metals and organic bases such as N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine; As well as internally formed salts. Salts having non-pharmaceutically acceptable anions or cations are within the scope of the invention as useful intermediates for the preparation of pharmaceutically acceptable salts and / or non-therapeutic situations, eg, in vitro use. . For example, the salt can have a stoichiometry of 1: 1 or 2: 1. Non-integer stoichiometric ratios are also possible.

  Furthermore, some crystalline forms of the compounds of structure (I) may exist as polymorphs, included in the present invention. Some compounds of the invention can be crystallized or recrystallised from solvents such as aqueous or organic solvents. In such cases, solvates can be formed. Where non-stoichiometric solvates can be produced by methods such as lyophilization, the present invention includes within its scope stoichiometric solvates as well as compounds containing variable amounts of solvent. In one embodiment, the compounds of the invention are provided in the form of stoichiometric and non-stoichiometric hydrates.

  One skilled in the art will recognize that certain protected derivatives of compounds of formula (I) (which can be generated prior to the final deprotection step) themselves do not have pharmacological activity, It will be appreciated that can be metabolized in the body to form pharmacologically active compounds of the present invention after oral or parenteral administration. Such derivatives may therefore be referred to as “prodrugs”. In addition, certain compounds of the present invention can be administered as prodrugs of other compounds of the present invention. Examples of prodrug forms of certain compounds of the present invention include Drugs of Today, Volume 19, Number 9, 1983, pp 499-538 and Topics in Chemistry, Chapter 31, pp 306-316 and H.C. “Design of Prodrugs” by Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures of these documents are hereby incorporated by reference). Furthermore, those skilled in the art can, for example, As Bundgaard describes in "Design of Prodrugs" (the disclosure of this document is hereby incorporated by reference), certain parts known to those skilled in the art as "pro parts" It will be appreciated that (when such a functional group is present in a compound of the invention) can be placed on a suitable functional group. Examples of prodrugs of certain compounds of the invention include esters, carbonates, hemiesters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals and Ketal.

  Since the compounds of the invention are intended for use in pharmaceutical compositions, they are each optionally in substantially pure form, such as at least 60% pure, such as at least 75% pure or at least 85%, or at least 98%. It will be readily appreciated that it is provided in pure (% is based on weight / weight) form. The impurity preparation of the present invention can be used to prepare large quantities of the pure form used in pharmaceutical compositions.

  The compounds of the present invention can be prepared in a number of ways. These methods form a further aspect of the present invention. In the following reaction schemes and thereafter, unless otherwise stated, the groups are as defined in the first aspect.

［式中：Ｘ、Ｚ、Ｒ^４およびＲ^１０は、式（Ｉ）の記載と同義である］
で示される化合物を式（ＩＩＩ）：

［式中：Ｒ^１およびＲ^２は式（Ｉ）の記載と同義である］
で示される化合物とカップリングさせるか；または
（ｂ）式（Ｖ）：

［式中：Ｚ、Ｒ^４およびＲ^１０は式（Ｉ）の記載と同義である］
で示される化合物を第一級アミンＸ−ＮＨ_２（式中：Ｘは式（Ｉ）の記載と同義である）と反応させ、次いで、方法（ａ）に記載の式（ＩＩＩ）の化合物とカップリングさせるか；または
（ｃ）Ｒ^１がＣＯＮＨ_２である、式（Ｉ）の化合物について、式（ＩＸ）：

［式中：Ｚ、Ｘ、Ｒ^２、Ｒ^４およびＲ^１０は式（Ｉ）の記載と同義である］
で示される化合物を塩化アンモニウムおよびＨＡＴＵと反応させ、所望により方法（ａ）、（ｂ）または（ｃ）の後に、
−いずれかの保護基を除去してもよく；および／または
−塩または溶媒和物を形成してもよく；および／または
−式（Ｉ）の化合物またはその塩もしくは溶媒和物を式（Ｉ）の別の化合物またはその塩もしくは溶媒和物に変換してもよいことを含む方法を提供する。 Accordingly, the present invention is a process for producing a compound of formula (I) comprising:
(A) Formula (II):

[Wherein, X, Z, R ⁴ and R ¹⁰ have the same meanings as described in formula (I)]
A compound represented by formula (III):

[Wherein R ¹ and R ² have the same meanings as described in formula (I)]
Or (b) Formula (V):

[Wherein, Z, R ⁴ and R ¹⁰ have the same meanings as described in formula (I)]
Is reacted with a primary amine X—NH ₂ (wherein X is as defined in formula (I)) and then the compound of formula (III) as described in method (a) Or (c) for compounds of formula (I) wherein R ¹ is CONH ₂ , formula (IX):

[In the formula: Z, X, R ² , R ⁴ and R ¹⁰ are as defined in formula (I)]
Is reacted with ammonium chloride and HATU, optionally after method (a), (b) or (c)
Any protecting group may be removed; and / or a salt or solvate may be formed; and / or a compound of formula (I) or a salt or solvate thereof may be represented by formula (I ), Or a salt or solvate thereof.

For process (a), typical conditions include heating a mixture of compounds (II) and (III) at 90-100 ° C. in a suitable solvent such as toluene and / or ethanol until the reaction is complete. In one embodiment, R ¹ , R ² , R ⁴ , R ¹⁰ , Z and X are as defined in formula (I) and R ¹ is a C _1-4 alkoxy group. Compounds of formula (III) are commercially available. Compounds of formula (II) can be prepared as described in Scheme 2 below.

For method (b), typical conditions are that the compound of formula (V) in toluene is added to a solution of primary amine in toluene and stirred at ambient temperature for 1-2 hours, then the compound of formula (III) is added. In addition, stirring the entire mixture at 95 ° C. for the required time. In one embodiment, R ¹ , R ² , R ⁴ , R ¹⁰ , Z and X are as defined in formula (I) and R ¹ is a C _1-4 alkoxy group. Compounds of formula (III) and formula (V) are commercially available.

  For process (c), typical conditions are a mixture of a compound of formula (IX), ammonium chloride and DIPEA (diisopropylamine) in dimethylformamide at room temperature with HATU (O- (7-azabenzotriazol-1-yl). ) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate). Compounds of formula (IX) can be prepared as described in Scheme 5 below.

A compound of formula (VI) (ie, a compound of formula (I) wherein R ¹⁰ is hydrogen and R ⁴ is NR ⁸ R ⁹ ) is converted to a secondary amine according to Reaction Scheme 1 ( Prepared from the formula (VII) (ie, compound of formula (I) wherein R ¹⁰ is hydrogen and R ⁴ is bromine) by Buchwald reaction with HNR ⁸ R ⁹ ). sell. Typical reaction conditions include a suitable palladium reagent such as palladium acetate or bis (dibenzylidene) palladium, (R)-(+)-2,2′-bis (diphenyl) in a suitable solvent such as dioxane or toluene. Presence of a suitable ligand such as phosphino) -1,1′-binaphthyl (BINAP) or 2-biphenylyl [bis (1,1-dimethylethyl)] phosphane and a suitable base such as cesium carbonate or sodium tert-butoxide Under, refluxing a mixture of a compound of formula (VII) and a secondary amine.

In one embodiment, R ⁸ and R ⁹ are independently selected from C _1-4 alkyl or selected from O, N or S together with the nitrogen atom to which they are attached. A 5- or 6-membered ring is formed which may optionally contain one or more additional heteroatoms. Compounds of formula (VII) can be prepared using methods (a) and (b) above.

Intermediate compounds of formula (II) can be prepared by reaction of a compound of formula (V) with a primary amine (X—NH ₂ ) according to Reaction Scheme 2. Typical reaction conditions include adding the compound of formula (V) in ethyl acetate to a solution of the primary amine in ethyl acetate, or vice versa, typically 10 minutes until the reaction is complete at ambient temperature. Includes shaking or stirring for ~ 2 hours. Compounds of formula (V) are commercially available.

Intermediate compounds of formula (XI) can be prepared by reaction of compounds of formula (XII) via intermediates of formula (XIII) according to reaction scheme 3. Typical reaction conditions include gently refluxing the compound of formula (XII) in sulfuryl chloride to obtain intermediate (XIII), which is added to sodium hydroxide solution and stirred with cooling. Compounds of formula (XII) are commercially available.

A compound of formula (XIV) (ie a compound of formula (I) wherein R ¹ is C (O) OMe) is converted by transesterification according to reaction scheme 4 (ie It can be prepared from a compound of formula (I) wherein R ¹ is C (O) OEt. Typical reaction conditions include treating a compound of formula (XV) with sodium hydroxide and stirring in a mixture of water and methanol at room temperature. Compounds of formula (XV) can be prepared using methods (a) and (b) above.

Intermediate compounds of formula (IX) (ie compounds of formula (I) (wherein R ¹ is COOH)) are converted to compounds of formula (XIV) (ie formula (I ) (Wherein R ¹ is COOMe)). Typical reaction conditions include heating a mixture of the compound of formula (XIV) and lithium hydroxide monohydrate in a mixture of tetrahydrofuran and water at 70 ° C. overnight. Compounds of formula (XIV) can be prepared as described in Scheme 4.

Compounds of formula (XVII) can be prepared by deprotection of intermediate compounds of formula (XVI) according to reaction scheme 6. In Scheme 6 below, the R4 group of formula (XVI) is shown with a Boc protecting group. Typical reaction conditions are to stir the solution of the compound of formula (XVI) in a mixture of trifluoroacetic acid and dichloromethane, typically for 1 hour, until deprotection is complete at ambient temperature, then on an SCX cartridge. Including purification. Compounds of formula (XVI) may be prepared as described in methods (a), (b) and scheme 2.

  Further details for the preparation of compounds of formula (I) are found in the Examples section below.

  The compounds of the invention can be prepared individually or as a compound library comprising at least 2, for example 5 to 1,000 compounds, for example 10 to 100 compounds. A library of compounds of the invention can be prepared by methods known to those skilled in the art, by combined “split and mix” methods using either liquid phase or solid phase chemistry, or by multiple parallel syntheses. Thus, according to a further aspect, there is provided a compound library comprising at least two compounds of the invention.

  The compounds of the invention may be formulated in conventional dosage forms prepared by combining the compounds of the invention with standard carriers or diluents according to conventional procedures well known in the art. These processes can involve mixing, granulating and compressing or dissolving the ingredients in the desired formulation as needed.

  The pharmaceutical compositions of the present invention may be formulated for administration by any route, including those in a form suitable for oral, topical or parenteral administration to mammals, including humans.

  The composition can be formulated for administration by any route. The composition can be in the form of a tablet, capsule, powder, granule, lozenge, cream or liquid formulation, eg, an oral or sterile parenteral solution or suspension.

  The topical formulations of the present invention may exist, for example, as ointments, creams or lotions, eye ointments and eye drops or ear drops, impregnated dressings and aerosols, preservatives, solvents to aid drug permeation and ointments and creams It may contain suitable usual additives such as emollients therein.

  The formulations may also contain compatible conventional carriers such as cream or ointment bases and lotion ethanol or oleyl alcohol. Such carriers can be present as from about 1% to about 98% of the formulation. More generally, they will form up to about 80% of the formulation.

  Tablets and capsules for oral administration may be in unit dosage form or may contain conventional excipients. Binders such as syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tablet lubricants such as magnesium stearate, talc, polyethylene It may contain conventional excipients such as glycols or silicas; disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid formulations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or for reconstitution with water or other suitable vehicle prior to use. It may be present as a dry product. Such liquid formulations include conventional additives such as suspending agents such as sorbitol, methylcellulose, glucose syrup, gelatin or hydrogenated edible fat, emulsifying agents such as lecithin, sorbitan monooleate, or acacia; Non-aqueous vehicles (which may include edible fats) such as almond oil, glycerin, propylene glycol, or oily esters such as ethyl alcohol; preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid, and If necessary, it may contain a usual flavoring agent or coloring agent.

  Suppositories will contain conventional suppository bases, eg cocoa-butter or other glyceride.

  For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, such as water. Depending on the vehicle and concentration used, the compound can be suspended or dissolved in the vehicle. In preparing a liquid, the compound can be dissolved in water for injection and the filter sterilized before filling into a suitable vial or ampoule and sealing.

  Advantageously, agents such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. To enhance stability, the composition can be frozen after filling into the vial and the water removed in vacuo. The lyophilized powder may then be sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions can be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of dissolving and sterilization cannot be achieved by filtration. Prior to suspending in a sterile vehicle, the compound can be sterilized by exposure to ethylene oxide. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

  The composition may contain from 0.1% by weight of active substance, eg from 10-60% by weight, depending on the method of administration. When the composition includes a dosage unit amount, each unit amount may contain, for example, 0.1-20 mg of the active ingredient. For example, the unit amount may contain 1 to 10 mg. The dose used for adult treatment is (for example, a dose of 50 mg to 100 mg / day may be appropriate), depending on the route and frequency of administration, eg 2-50 mg / day, eg 5-20 mg / day. It may be a range. Based on a 75 kg individual, such a dose corresponds to 0.027 to 0.667 mg / kg / day. Suitably the dose is between 0.05 and 0.3 mg / kg / day.

  One of ordinary skill in the art will determine the optimal amount and interval of individual doses of the compounds of the invention depending on the characteristics and extent of the condition being treated, the mode of administration, the route and site, and the particular mammal being treated. It will be appreciated that such optimal conditions can be determined by conventional techniques. One of ordinary skill in the art will be able to ascertain the optimal course of treatment, i.e., the number of doses of the compound of the invention administered per day for a given number of days, using the usual course of treatment decision testing You will understand.

  It will be appreciated that "treatment" as used herein includes prevention as well as alleviation of established symptoms. In one embodiment, the mammal being treated is a human.

  Certain triazoline compounds falling within the scope of formula (I) above are known. For example, in GB Patent No. 1027561, 3-ethyl-4-methyl-2- (phenylimino) -4-triazoline is disclosed as an insecticide. Hunter, R F; Parken, E R and Short, Eileen, Journal of the Chemical Society (1959) 184-8; and Hunter, Robert F, Parken, Edwin R, Journal et ah. Dyson et al. Indian Chem. Soc. (1931) 8,147-80 all describe aminotriazole compounds.

［式中：
Ｒ^１０は、メチルまたは水素から選択され；
Ｘは、

から選択され；
Ｚは、ＳまたはＯから選択され；
Ｒ^１は、Ｈ、Ｃ_１−４アルキル、Ｃ（Ｏ）ＯＣ_１−４アルキル、Ｃ（Ｏ）Ｃ_１−４アルキル、Ｃ（Ｏ）ハロＣ_１−４アルキル、Ｃ（Ｏ）ＮＲ^６Ｒ^７、シアノから選択され、Ｒ^６およびＲ^７は、各独立して、ＨまたはＣ_１−４アルキルから選択され；
Ｒ^２は、Ｃ_１−４アルキル、Ｃ（Ｏ）ＣＨ_３、またはＣＮから選択され；
Ｒ^３は、Ｈ、ＮＨ_２、ＣＨ_３、（ＣＨ_２）_ｎＯＨおよび（ＣＨ_２）_ｎＣ_１−４アルコキシからなる群より選択され、ここで、ｎは０または１であり；および
Ｒ^３がＣＨ_３、（ＣＨ_２）_ｎＯＨまたは（ＣＨ_２）_ｎＣ_１−４アルコキシである場合、その場合、Ｒ^４は、Ｈ、ハロ、Ｃ_１−４アルコキシ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、Ｃ_１−４アルキルチオ、ハロＣ_１−４アルキルチオ、ハロＣ_１−４アルキルおよびＮＲ^８Ｒ^９からなる群より選択され、ここで、Ｒ^８およびＲ^９は、独立して、水素またはＣ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子を所望により含有していてもよい５または６員環を形成し；
Ｒ^３がＮＨ_２である場合、その場合、Ｒ^４は、Ｈ、ハロ、Ｃ_１−４アルコキシ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、Ｃ_１−４アルキルチオ、ハロＣ_１−４アルキルチオ、ハロＣ_１−４アルキルまたはＮＲ^８Ｒ^９から選択され、ここで、Ｒ^８およびＲ^９は、独立して、Ｃ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子を所望により含有していてもよい５または６員環を形成し；
Ｒ^３がＨである場合、その場合、Ｒ^４は、Ｈ、Ｃ_１−４アルコキシ、クロロ、ブロモ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、ハロＣ_１−４アルキル、およびＮＲ^８Ｒ^９からなる群より選択され、ここで、Ｒ^８およびＲ^９は、独立して、水素またはＣ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子を所望により含有していてもよい５または６員環を形成し；
Ｘが−ＣＨ_２ＣＦ_３である場合、その場合、Ｒ^４は、Ｃ_１−４アルコキシまたはＣ_１−４アルキルから選択され；
Ｘがメチルである場合、その場合、Ｒ^４は、Ｃ_１−４アルコキシ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、ハロＣ_１−４アルキルまたはＮＲ^８Ｒ^９から選択され、ここで、Ｒ^８およびＲ^９は、独立して、水素またはＣ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数のヘテロ原子を所望により含有していてもよい５または６員環を形成し；
Ｘが

である場合、その場合、Ｒ^４は、Ｈ、ハロ、Ｃ_１−４アルコキシ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、ハロＣ_１−４アルキルおよびＮＲ^８Ｒ^９からなる群より選択され、ここで、Ｒ^８およびＲ^９は、独立して、Ｃ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子を所望により含有していてもよい５または６員環を形成し；
ただし、化合物は、
１）同時にＲ^１＝ＣＯ（ＣＨ_３）、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝ＯＨおよびＲ^４＝エチル、クロロ、エトキシ、メチルまたはＨである化合物；
２）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝（ＣＨ_２）ＯＭｅおよびＲ^４＝メトキシ、ジフルオロメチルチオ、クロロまたはＨである化合物；
３）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝（ＣＨ_２）ＯＥｔおよびＲ^４＝ジフルオロメチルチオ、エトキシ、フルオロ、ジフルオロメトキシまたはイソプロピルである化合物；
４）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝（ＣＨ_２）ＯｎＢｕおよびＲ^４＝フルオロ、イソプロピル、エトキシ、ジフルオロメトキシまたはジフルオロメチルチオである化合物；
５）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝ＯＭｅおよびＲ^４＝エトキシ、ジフルオロメトキシ、ジフルオロメチルチオまたはＨである化合物；
６）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝シクロプロピルおよびＲ^４＝メトキシ、イソプロピル、エトキシ、水素、クロロ、ジフルオロメトキシまたはフルオロである化合物；
７）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝ＨおよびＲ^４＝Ｈまたはクロロである化合物；
８）同時にＲ^１＝Ｃ（Ｏ）ＣＨ_３、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝ＣＨ_２ＯＨおよびＲ^４＝Ｈまたはメチルである化合物；
９）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝ＣＨ_２ＯＨ、およびＲ^４＝メチル、クロロ、メトキシまたはＨである化合物；
１０）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝ＯＨおよびＲ^４＝エトキシ、メチルまたはＨである化合物；
１１）同時にＲ^１＝Ｃ（Ｏ）ＣＨ_３、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝ＨおよびＲ^４＝クロロである化合物；
１２）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝ＭｅおよびＲ^４＝メチルまたはエトキシである化合物；
１３）同時にＲ^１＝Ｈ、Ｒ^２＝Ｅｔ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝ＨおよびＲ^４＝クロロまたはブロモである化合物；
１４）同時にＲ^１＝Ｍｅ、Ｒ^２＝Ｍｅ、Ｘ＝ＭｅおよびＲ^４＝メチルである化合物；および
１５）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝ＭｅおよびＲ^４＝イソプロピル、フルオロ、エチル、ジフルオロメトキシまたはジフルオロメチルチオである化合物ではない］
で示される化合物またはその塩もしくは溶媒和物を提供する。 The invention also provides formula (A):

[Where:
R ¹⁰ is selected from methyl or hydrogen;
X is

Selected from;
Z is selected from S or O;
R ¹ is H, C _1-4 alkyl, C (O) OC _1-4 alkyl, C (O) C _1-4 alkyl, C (O) haloC _1-4 alkyl, C (O) NR ⁶ R ^{7 is} selected from cyano, and R ⁶ and R ⁷ are each independently selected from H or C _1-4 alkyl;
R ² is selected from C _1-4 alkyl, C (O) CH ₃ , or CN;
R ³ is selected from the group consisting of H, NH ₂ , CH ₃ , (CH ₂ ) _n OH and (CH ₂ ) _n C _1-4 alkoxy, where n is 0 or 1; and R ³ Is CH ₃ , (CH ₂ ) _n OH or (CH ₂ ) _n C _1-4 alkoxy, then R ⁴ is H, halo, C _1-4 alkoxy, haloC _1-4 alkoxy, C Selected from the group consisting of _1-4 alkyl, C _1-4 alkylthio, halo C _1-4 alkylthio, halo C _1-4 alkyl and NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently Selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ , together with the nitrogen atom to which they are attached, are one or more additional heterocycles selected from O, N or S Contains atoms as desired Also forms a good 5 or 6 membered ring optionally;
When R ³ is NH ₂ , then R ⁴ is H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, C _1-4 alkylthio, halo C _1-4 Selected from alkylthio, haloC _1-4 alkyl or NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ are Together with the nitrogen atom to which is bound forms a 5 or 6 membered ring optionally containing one or more additional heteroatoms selected from O, N or S;
When R ³ is H, then R ⁴ is H, C _1-4 alkoxy, chloro, bromo, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl, and NR ⁸ Selected from the group consisting of R ⁹ , wherein R ⁸ and R ⁹ are independently selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ are the nitrogen atom to which they are attached; Taken together form a 5 or 6 membered ring optionally containing one or more additional heteroatoms selected from O, N or S;
When X is —CH ₂ CF ₃ , then R ⁴ is selected from C _1-4 alkoxy or C _1-4 alkyl;
When X is methyl, then R ⁴ is selected from C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl or NR ⁸ R ⁹ where , R ⁸ and R ⁹ are independently selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached, from O, N or S Forming a 5- or 6-membered ring optionally containing one or more selected heteroatoms;
X is

In which case R ⁴ is selected from the group consisting of H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl and NR ⁸ R ^9. Where R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached are O, N or Forming a 5- or 6-membered ring optionally containing one or more additional heteroatoms selected from S;
However, the compound
1) Compounds in which R ¹ = CO (CH ₃ ), R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = OH and R ⁴ = ethyl, chloro, ethoxy, methyl or H at the same time;
2) compounds in which R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = (CH ₂ ) OMe and R ⁴ = methoxy, difluoromethylthio, chloro or H;
3) A compound wherein R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = (CH ₂ ) OEt and R ⁴ = difluoromethylthio, ethoxy, fluoro, difluoromethoxy or isopropyl;
4) A compound in which R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = (CH ₂ ) OnBu and R ⁴ = fluoro, isopropyl, ethoxy, difluoromethoxy or difluoromethylthio at the same time;
5) Compounds in which R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = OMe and R ⁴ = ethoxy, difluoromethoxy, difluoromethylthio or H at the same time;
6) Compounds in which R ¹ = H, R ² = Me, X = cyclopropyl and R ⁴ = methoxy, isopropyl, ethoxy, hydrogen, chloro, difluoromethoxy or fluoro;
7) Compounds in which R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = H and R ⁴ = H or chloro at the same time;
8) Compounds in which R ¹ = C (O) CH ₃ , R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = CH ₂ OH and R ⁴ = H or methyl simultaneously;
9) Compounds in which R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = CH ₂ OH and R ⁴ = methyl, chloro, methoxy or H at the same time;
10) Compounds wherein R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = OH and R ⁴ = ethoxy, methyl or H at the same time;
11) A compound in which R ¹ = C (O) CH ₃ , R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = H and R ⁴ = chloro simultaneously;
12) Compounds wherein R ¹ = H, R ² = Me, X = Me and R ⁴ = methyl or ethoxy at the same time;
13) Compounds wherein R ¹ = H, R ² = Et, X = CH ₂ CH ₂ R ³ , R ³ = H and R ⁴ = chloro or bromo at the same time;
14) compounds wherein R ¹ = Me, R ² = Me, X = Me and R ⁴ = methyl at the same time; and 15) simultaneously R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = Me and R ⁴ = not a compound where isopropyl, fluoro, ethyl, difluoromethoxy or difluoromethylthio]
Or a salt or solvate thereof.

［式中：
Ｘは、

から選択され；
Ｚは、ＳまたはＯから選択され；
Ｒ^１は、Ｈ、Ｃ_１−４アルキル、Ｃ（Ｏ）Ｃ_１−４アルキル、Ｃ（Ｏ）ＮＲ^６Ｒ^７、シアノ、またはフェニルから選択され、フェニル基は、ＮＯ_２、ＳＯまたはＳＯ_２Ｒ^５から選択される１個または複数の基で所望により置換されていてもよく、ここで、Ｒ^５は、Ｃ_１−４アルキルであって、Ｒ^６およびＲ^７は、各々独立して、ＨまたはＣ_１−４アルキルから選択され；
Ｒ^２は、Ｃ_１−４アルキル、Ｃ（Ｏ）ＣＨ_３、またはＣＮから選択され；
Ｒ^３は、Ｈ、（ＣＨ_２）_ｎＯＨおよび（ＣＨ_２）_ｎＣ_１−４アルコキシからなる群より選択され、ここで、ｎは０または１であり；および
Ｒ^３が（ＣＨ_２）_ｎＯＨまたは（ＣＨ_２）_ｎＣ_１−４アルコキシである場合、その場合、Ｒ^４は、Ｈ、ハロ、Ｃ_１−４アルコキシ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、Ｃ_１−４アルキルチオ、ハロＣ_１−４アルキルチオ、ハロＣ_１−４アルキルおよびＮＲ^８Ｒ^９からなる群より選択され、ここで、Ｒ^８およびＲ^９は、独立して、Ｃ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子を所望により含有していてもよい５または６員環を形成し；
Ｒ^３がＨである場合、その場合、Ｒ^４は、Ｈ、クロロ、Ｃ_１−４アルコキシ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、ハロＣ_１−４アルキルおよびＮＲ^８Ｒ^９からなる群より選択され、ここで、Ｒ^８およびＲ^９は、独立して、Ｃ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子を所望により含有していてもよい５または６員環を形成し；および
Ｘが

である場合、その場合、Ｒ^４は、Ｈ、ハロ、Ｃ_１−４アルコキシ、ハロＣ_１−４アルコキシ、Ｃ_１−４アルキル、ハロＣ_１−４アルキルおよびＮＲ^８Ｒ^９からなる群より選択され、ここで、Ｒ^８およびＲ^９は、独立して、Ｃ_１−４アルキルから選択されるか、あるいはＲ^８およびＲ^９はそれらが結合する窒素原子と一緒になって、Ｏ、ＮまたはＳから選択される１個または複数の付加的なヘテロ原子と所望により含有していてもよい５または６員環を形成し；
ただし、化合物は、
１）同時にＲ^１＝ＣＯ（ＣＨ_３）、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝ＯＨおよびＲ^４＝エチル、クロロ、エトキシまたはＨである化合物
２）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝（ＣＨ_２）ＯＭｅおよびＲ^４＝メトキシ、ジフルオロメチルチオ，クロロまたはＨである化合物
３）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝（ＣＨ_２）ＯＥｔおよびＲ^４＝ジフルオロメチルチオ、エトキシ、フルオロ、ジフルオロメトキシまたはイソプロピルである化合物
４）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝（ＣＨ_２）ＯｎＢｕおよびＲ^４＝フルオロ、イソプロピル、エトキシ、ジフルオロメトキシまたはジフルオロメチルチオである化合物
５）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝ＯＭｅおよびＲ^４＝エトキシ、ジフルオロメトキシ、ジフルオロメチルチオまたはＨである化合物
６）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝シクロプロピルおよびＲ^４＝メトキシ、イソプロピル、エトキシ、水素、クロロ、ジフルオロメトキシまたはフルオロである化合物
７）同時にＲ^１＝Ｈ、Ｒ^２＝Ｍｅ、Ｘ＝ＣＨ_２ＣＨ_２Ｒ^３、Ｒ^３＝ＨおよびＲ^４＝クロロである化合物ではない］
で示される化合物またはその塩もしくは溶媒和物を提供する。 The present invention also provides formula (J):

[Where:
X is

Selected from;
Z is selected from S or O;
R ¹ is selected from H, C _1-4 alkyl, C (O) C _1-4 alkyl, C (O) NR ⁶ R ⁷ , cyano, or phenyl, and the phenyl group is NO ₂ , SO or SO ₂ Optionally substituted with one or more groups selected from R ⁵ , wherein R ⁵ is C _1-4 alkyl and R ⁶ and R ⁷ are each independently Selected from H or C _1-4 alkyl;
R ² is selected from C _1-4 alkyl, C (O) CH ₃ , or CN;
R ³ is selected from the group consisting of H, (CH ₂ ) _n OH and (CH ₂ ) _n C _1-4 alkoxy, where n is 0 or 1; and R ³ is (CH ₂ ) _n When it is OH or (CH ₂ ) _n C _1-4 alkoxy, then R ⁴ is H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, C _1-4 alkylthio, halo _{C 1-4} alkylthio, selected from the group consisting of halo _{C 1-4} alkyl and ^NR 8 ^{R 9,} wherein, ^{R 8} and ^{R 9} are _{independently} selected from _{C 1-4} alkyl Or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached may optionally contain one or more additional heteroatoms selected from O, N or S 5 Or form a 6-membered ring;
When R ³ is H, then R ⁴ is from H, chloro, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl and NR ⁸ R ⁹ Wherein R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached, Forming a 5- or 6-membered ring optionally containing one or more additional heteroatoms selected from O, N or S; and X is

In which case R ⁴ is selected from the group consisting of H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl and NR ⁸ R ^9. Where R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached are O, N or Forming an optionally contained 5- or 6-membered ring with one or more additional heteroatoms selected from S;
However, the compound
1) Compounds where R ¹ = CO (CH ₃ ), R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = OH and R ⁴ = ethyl, chloro, ethoxy or H 2) simultaneously R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = (CH ₂ ) OMe and R ⁴ = Methoxy, Difluoromethylthio, Chloro or H 3) Simultaneously R ¹ = H, R ² = Me, compounds in which X = CH ₂ CH ₂ R ³ , R ³ = (CH ₂ ) OEt and R ⁴ = difluoromethylthio, ethoxy, fluoro, difluoromethoxy or isopropyl 4) at the same time R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = (CH ₂ ) OnBu and R ⁴ = fluoro, isopropyl, ethoxy, difluoromethoxy or difluoromethylthio 5) Compound simultaneously R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = OMe and R ⁴ = Ethoxy, difluoromethoxy, difluoromethylthio or H 6) Simultaneously R ¹ = H, R ² = Me, X = cyclopropyl and R ⁴ = methoxy, isopropyl, ethoxy, hydrogen, chloro, difluoromethoxy or fluoro 7) Simultaneously R ¹ = H, R ² = Me, X = CH Not a compound where ₂ CH ₂ R ³ , R ³ = H and R ⁴ = chloro]
Or a salt or solvate thereof.

It will be clear that the invention includes the following further aspects. The embodiments described for the first aspect apply to each of these aspects as well:
i) use of a compound of formula (I) or a salt or solvate thereof in the manufacture of a medicament for treating or preventing a disease or condition caused by reduced or imbalanced glutamate receptor function in a mammal;
ii) a compound of formula (I) or a salt or solvate thereof for use in treating or preventing a disease or condition caused by reduced or imbalanced glutamate receptor function in a mammal;
iii) a pharmaceutical composition comprising a compound of formula (I) or a salt or solvate thereof and at least one pharmaceutically acceptable carrier or diluent;
iv) a method of treating or preventing a disease or condition caused by reduced or imbalanced glutamate receptor function in a mammal, comprising administering an effective amount of a compound of formula (I) or a salt or solvate thereof. Including methods;
v) a combination product of a compound of formula (I) and an antipsychotic;
vi) a pharmaceutical composition comprising such a combination product and at least one pharmaceutically acceptable carrier or diluent;
vii) use of such combination products in the manufacture of a medicament for treating or preventing a disease or condition caused by reduced or imbalanced glutamate receptor function in a mammal;
viii) such a combination product for use in treating or preventing a disease or condition caused by reduced or imbalanced glutamate receptor function in a mammal;
ix) a method of treating or preventing a disease or condition caused by a decrease or imbalance in glutamate receptors in a mammal, comprising administering an effective amount of such a combination product;
x) Such a combination product for use as a medicament.

  The above statements regarding the embodiments of the compound of formula (I) apply equally to the compounds of formula (A) and (J).

  In the case of aspects i), ii), iv), vii), viii), ix), the related diseases or conditions are psychosis and psychotic disorders (schizophrenia, schizophrenic emotional disorder, schizophrenia-like disease, short term Reactive psychosis, early childhood-onset schizophrenia, "schizophrenia-spectrum" disorders, such as isolated pathological personality disorder or schizophrenic personality disorder, acute psychosis, alcoholic psychosis, drug-induced psychosis, autism, Accompanying neurodegenerative diseases such as delerium, gonorrhea (including acute mania), manic depression, hallucinations, intrinsic psychosis, organic psychosis, paranoid and paranoid disorders, postpartum mental disorders, and Alzheimer's disease Including cognitive dysfunction; cognitive impairment (eg, attention, adaptation, memory (ie, memory impairment, amnesia, memory loss disorder and memory impairment due to aging) and language) Treatment of cognitive impairment, including function, and other acute or subacute conditions (sham) that can cause cognitive decline such as stroke, Alzheimer's disease, AIDS dementia or other dementia states, and delirium or depression Dementia condition), trauma, aging, stroke, neurodegeneration, drug-induced condition, cognitive impairment as a result of neurotoxic substances), mild cognitive impairment, cognitive impairment due to aging, due to autism Cognitive impairment, Down's syndrome, cognitive impairment associated with psychosis, cognitive impairment after electroshock therapy; anxiety disorder (systemic anxiety disorder, social anxiety disorder, agitation, tension, social or emotional withdrawal in psychiatric patients, panic disorder Neurodegenerative diseases (eg, Alzheimer's disease, amyotrophic lateral sclerosis, motor neuron disease and other luck) Disorders such as Parkinson's disease (gait movement deficits and / or intentional movements, tremors, slow movements, hyperactivity (moderate and severe), ataxia, stiffness, balance and coordination disorders, and postural disorders Including dementia in Parkinson's disease, dementia in Huntington's disease, neuroleptic-induced parkinsonism and tardive dyskinesia, stroke, cardiac arrest, lung bypass, traumatic brain injury, spinal cord injury Later neurodegeneration and demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis); depression (the term includes bipolar (manic) depression (including type I and type II) Unipolar depression, psychotic characteristics, rigidity characteristics, depression characteristics, atypical characteristics (eg, lethargy, overeating / obesity, hypersomnia) or single or recurrent with or without postpartum onset Major depression episodes, seasonal affective disorder and mood modulation, anxiety due to depression, psychotic depression, and general health conditions including but not limited to myocardial infarction, diabetes, miscarriage or abortion Post-traumatic stress syndrome; attention deficit disorder; attention deficit hyperactivity disorder; drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine) ) Disorder; Huntington's disease; tardive dyskinesia; dystonia; myoclonus; convulsions; obesity; stroke; sexual dysfunction; sleep disorder and some types of epilepsy.

  Within the context of the present invention, the terminology used herein refers to the diagnostic and statistical manual for mental disorders and the statistical manual published by the American Psychiatric Association. Classified in 4th edition (DSM-IV) and / or the International Classification of Diseases 10th edition (ICD-10). Various subtypes of disorders listed herein are contemplated as part of the present invention. The numbers in parentheses after the diseases listed below indicate the classification code in DSM-IV.

  Within the context of the present invention, the term “psychotic disorder” includes the delusional type (295.30), the dismantled type (295.10), the tension type (295.20), the undifferentiated type (295). .90) and schizophrenia including the residual (295.60) subtype; schizophrenia-like disorder (295.40); schizophrenic emotional disorder (295.70) including bipolar and depressive subtypes Paranoia (including Erotomatic, Gradiose, Jealous, Persequential, Somatic, Mixed, and Unspecified types); 297.1); short-term psychotic disorders (298.8); common psychotic disorders (297.3) Psychiatric disorders resulting from general health conditions including subtypes with delusions and hallucinations; substance-induced psychotic disorders including subtypes with delusions (293.81) and hallucinations (293.82); and unspecified Includes psychotic disorders (298.9).

The compounds of the present invention may also be useful in the treatment of the following disorders:
Mood disorders including major depression episodes, manic episodes, mixed episodes and hypomania episodes; major depression disorders, mood modulation disorders (300.4), depression disorders including unspecified depression disorder (311); type I bipolar Bipolarity, including sexual disorders, type II bipolar disorder (recurrent major depression episode with hypomania) (296.89), mood circulatory disorder (301.13) and unspecified bipolar disorder (296.80) Sexual disorders; Depressive features, major depression-like episodes, other mood disorders, including mood disorders (293.83) due to general health, including subtypes with manic and mixed features, substance induction Sexual mood disorders (including subtypes with depressive, manic and mixed characteristics) and unspecified mood disorders (296.90):

  Panic attacks, agoraphobia, panic disorder, agoraphobia with no history of panic disorder (300.22), animal type, natural environment type, Blood-Injection-Injury type, situation type and other Specific phobia (300.29), social phobia (300.23), obsessive compulsive disorder (300.3), posttraumatic stress disorder (309.81), acute stress disorder (308.3) Anxiety disorders, including generalized anxiety disorder (300.02), anxiety disorder due to general health (293.84), substance-induced anxiety disorder, and unspecified anxiety disorder (300.00):

  Substance use disorders such as substance dependence and substance abuse; substance poisoning, substance withdrawal, substance-induced delirium, substance-induced persistent dementia, substance-induced persistent amnestic disorder, substance-induced psychotic disorder, substance-induced mood disorder Substance-induced anxiety disorders, substance-induced sexual dysfunction, substance-induced sleep disorders and hallucinogen-induced persistent sensory disturbances (flashback); alcohol dependence (303.90), alcohol abuse (305 .00), alcoholism (303.00), alcohol withdrawal (291.81), alcoholism delirium, alcohol withdrawal delirium, alcohol-induced persistent dementia, alcohol-induced persistent amnesia, alcohol-induced psychotic disorder Alcohol-induced mood disorder, alcohol-induced anxiety disorder, alcohol-induced sexual dysfunction, alcohol-induced Alcohol-related disorders such as sleep disorders and unspecified alcohol-related disorders (291.9); amphetamine dependence (304.40), amphetamine abuse (305.70), amphetamine addiction (292.89), amphetamine withdrawal (292.0) ), Amphetamine intoxication delirium, amphetamine-induced psychotic disorder, amphetamine-induced mood disorder, amphetamine-induced anxiety disorder, amphetamine-induced sexual dysfunction, amphetamine-induced sleep disorder and unspecified amphetamine-related disorder (292.9) Caffeine such as caffeine addiction (305.90), caffeine-induced anxiety disorder, caffeine-induced sleep disorder and unspecified caffeine-related disorder (292.9) Related obstacles Cannabis dependence (304.30), cannabis abuse (305.20), cannabis poisoning (292.89), cannabis poisoning delirium, cannabis-induced psychotic disorder, cannabis-induced anxiety disorder and unspecified cannabis-related disorders (292); .9) cannabis-related disorders; cocaine dependence (304.20), cocaine abuse (305.60), cocaine addiction (292.89), cocaine withdrawal (292.0), cocaine addiction delirium, cocaine-induced psychotic Cocaine-related disorders such as disorders, cocaine-induced mood disorders, cocaine-induced anxiety disorders, cocaine-induced sexual dysfunction, cocaine-induced sleep disorders and unspecified cocaine-related disorders (292.9); hallucinogen dependence (304 .50), hallucinogen abuse (305.30), hallucinogen poisoning (292.89), hallucinogen persistent sensory impairment (flashback) (292) .89), hallucinogen-related disorders such as hallucinogen poisoning delirium, hallucinogen-induced psychotic disorders, hallucinogen-induced mood disorders, hallucinogen-induced anxiety disorders and unspecified hallucinogen-related disorders (292.9); Inhalant dependence (304.60), Abuse abuse (305.90), Inhalation poisoning (292.89), Inhalation poisoning delirium, Inhalant-induced persistent dementia, Inhalant-induced psychotic disorder, Inhalation Inhalant-related disorders such as drug-induced mood disorders, inhalant-induced anxiety disorders and unspecified inhalant-related disorders (292.9); nicotine dependence (305.1), nicotine withdrawal (292.0) and unspecified Nicotine-related disorders such as nicotine-related disorders (292.9); opioid dependence (304.00), opioid abuse (305.50), opioid addiction (292.89), opioid withdrawal (292) 0), opioid-related disorders such as opioid addiction delirium, opioid-induced psychotic disorders, opioid-induced mood disorders, opioid-induced sexual dysfunction, opioid-induced sleep disorders and unspecified opioid-related disorders (292.9) Phencyclidine dependence (304.60), phencyclidine abuse (305.90), phencyclidine addiction (292.89), phencyclidine addiction delirium, phencyclidine-induced psychotic disorder, phencyclidine induction Phencyclidine (or phencyclidine-like) -related disorders such as sexual mood disorder, phencyclidine-induced anxiety disorder and unspecified phencyclidine-related disorder (292.9); sedative, hypnotic or anxiolytic (304.10), sedatives, hypnotics or anxiolytics abuse (305.4) ), Sedatives, hypnotics or anxiolytics poisoning (292.89), sedatives, hypnotics or anxiolytics withdrawal (292.0), sedatives, hypnotics or anxiolytics addiction delirium, sedatives, hypnosis Drugs or anxiolytics withdrawal delirium, sedatives, hypnotics or anxiolytics persistent dementia, sedatives, hypnotics or anxiolytics persistent amnesia, sedatives, hypnotics or anxiolytics-induced psychotic disorders Sedative, hypnotic or anxiolytic-induced mood disorder, sedative, hypnotic or anxiolytic-induced anxiety disorder, sedative, hypnotic or anxiolytic-induced sexual dysfunction, sedative, hypnotic Or anxiolytic-induced sleep disorders and unspecified sedatives, hypnotics or anxiolytic-related disorders (292.9), sedatives, hypnotics or anxiolytic-related disorders; multi-substance dependent (304.80) Many things such as Substance-related disorders; and substance-related disorders, including anabolic steroids, nitrate inhalants, and other (or unknown) substance-related disorders such as nitrous oxide:

  Primary sleep disorders such as dyssomnia such as primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), respiratory related sleep disorder (780.59), Circadian rhythm sleep disorders (307.45) and unspecified sleep disorders (307.47); primary sleep disorders such as abnormal sleep behaviors such as nightmare disorder (307.47), sleep fear disorder (307.46) ), Ambulatory gait disturbance (307.46) and unspecified sleep abnormal behavior (307.47); sleep disorder associated with another psychotic disorder, eg, insomnia associated with another psychotic disorder (307.47). 42) and hypersomnia associated with another psychotic disorder (307.44); sleep disorders due to general health conditions, particularly neuropathy, neuropathic pain, restless leg syndrome, heart Wazurao and lung disease; and insomnia type, hypersomnia type, sleep disorders including substance-induced sleep disorders including sleep abnormal behavior type and mixed type subtypes:

  Autistic disorder (299.00), Asperger's disorder (299.80), Rett disorder (299.80), childhood disintegrative disorder (299.10) and unspecified pervasive disorder (299.80, atypical self Autism spectrum disorders including autism:

  Mixed attention deficit / hyperactivity disorder (314.01), inattention attention deficit / hyperactivity disorder (314.00), hyperactivity-impulsive attention deficit / hyperactivity disorder ( 314.01) and unspecified attention deficit / hyperactivity disorder (314.9) subtypes; attention deficit / hyperactivity disorder; hyperactivity disorder; destructive behavior disorder, eg, early childhood onset ( 321.81), behavioral disorders including adolescent onset (312.82) and unspecified (312.89) subtypes, rebellious behavioral disorders (313.81) and unspecified destructive behavioral disorders; and Tic disorders such as Tourette disorder (307.23):

  Delusional personality disorder (301.0), isolated pathological personality disorder (301.20), schizophrenic personality disorder (301, 22), non-social personality disorder (301.7), borderline personality disorder (301 83), acting personality disorder (301.50), self-loving personality disorder (301, 81), avoidable personality disorder (301.82), dependent personality disorder (301.6), obsessive-compulsive personality disorder ( 301.4) and unspecified personality disorder (301.9) personality disorders including subtypes:

  Cognitive enhancement including treatment of cognitive impairment in other diseases such as Alzheimer's disease, such as schizophrenia, bipolar disorder, depression, other psychotic disorders and cognitive dysfunction:

  Sexual desire disorders such as hyposexual desire disorder (302.71) and sexual aversion disorder (302.79); Sexual stimulation disorders such as female sexual stimulation disorder (302.72) and male erectile dysfunction ( 302.72); orgasm disorders such as female orgasm disorders (302.73), male orgasm disorders (302.74) and premature ejaculation (302.75); sexual pain disorders such as sexual pain (302.76) And vaginal spasticity (306.51); unspecified sexual dysfunction (302.70); sexual perversion, eg, exposure (302.4), fetishism (302.81), tribology (302.89) , Pedophilia (302.2), sexual masochism (302.83), sexual sadism (302.84), incongruity fetishism (302.3), voyeurism (302.82) And unspecified sexual perversion (302.9); sexual self-identity disorders such as sexual self-identity disorder in children (302.6) and sexual self-identity disorder in adolescents or adults (302.85) ); And sexual dysfunction, including unspecified sexual disorders (302.9).

  All of the various forms and sub-forms of the disorders described herein are contemplated as part of the present invention.

  Within the context of the present invention, the term “cognitive impairment” includes, for example, attention, adaptation, learning impairment, memory (ie, memory impairment, amnesia, amnesia, transient global amnesia syndrome and aging Treatment of cognitive impairment, including memory impairment) and language function; stroke, Alzheimer's disease, Huntington's disease, Pick's disease, dementia due to AIDS or multiple infarct dementia, alcoholic dementia, dementia due to hypothyroidism, and Cognitive impairment as a result of other dementia conditions such as dementia associated with other degenerative disorders such as cerebellar atrophy and amyotrophic lateral sclerosis; others that can cause cognitive decline such as delirium or depression Acute or subacute state (pseudo-dementia state), trauma, head trauma, cognitive decline due to aging, stroke, neurodegeneration, drug-induced state, neurotoxic substance, mild cognitive function Cognitive impairment due to harm, aging, cognitive impairment due to autism, Down's syndrome, cognitive decline associated with psychosis, and cognitive impairment following electroshock therapy; and Parkinson's disease, neuroleptic-induced parkinsonism and Includes movement disorders such as tardive dyskinesia.

  The compounds of the present invention may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics (eg, olanzapine, risperidone, clozapine, zipradidone and talnetant); ii) extrapyramidal side effects Therapeutic agents such as anticholinergics (eg benztropine, biperidene, procyclidine and trihexyphenidyl), antihistamines (eg diphenhydramine) and dopamine agonists (eg amantadine); iii) antidepressants; iv A) anxiolytics; and v) nootropics such as cholinesterase inhibitors (eg tacrine, donepezil, rivastigmine and galantamine).

  The compounds of the present invention can be used in combination with antidepressants to treat or prevent depression and mood disorders.

  The compounds of the present invention may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilizers; ii) antipsychotics; and iii) antidepressants.

  The compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.

  The compounds of the present invention may be used in combination with the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy, such as nicotinic β-cyclodextrin sublingual and nicotine patches; And ii) Bupropion.

  The compounds of the invention may be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists such as acamprosate; ii) GABA receptor agonists such as Tetrabamate; and iii) opioid receptor antagonists such as naltrexone.

  The compounds of the present invention may be used in combination with the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid μ receptor agonist / opioid κ receptor antagonist, eg, buprenorphine: ii) vasodilatation Antihypertensive agents such as lofexidine.

  The compounds of the present invention may be used in combination with the following agents to treat or prevent sleep disorders: i) benzodiazepines such as temazepam, lormetazepam, estazolam and triazolam: ii) non-benzodiazepine hypnotics such as zolpidem, Zopiclone, zaleplon and indiplon; iii) barbitur systems such as aprobarbital, butabarbital, pentobarbital, secobarbital and phenobarbital; iv) antidepressants; v) other hypnotic analgesics such as chloral hydrate and Chlormethiazole.

  The compounds of the present invention may be used in combination with the following agents to treat anorexia: i) appetite enhancers such as cyproheptidine, ii) antidepressants; iii) antipsychotics; iv) zinc And v) premenstrual drugs such as pyridoxine and progesterone.

  The compounds of the present invention may be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics such as ondansetron; iv) Testosterone receptor antagonists such as flutamide; v) mood stabilizers; vi) zinc; and vii) premenstrual drugs.

  The compounds of the present invention may be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulants, such as , Methylphenidate, amphetamine prescription and pemoline.

  The compounds of the present invention may be used in combination with the following agents to treat or prevent attention deficit / hyperactivity disorder: i) stimulants such as methylphenidate, amphetamine prescription and pemoline; and ii) non-excitability Drugs, such as norepinephrine reuptake inhibitors (eg, atomoxetine), α2 adrenergic receptor agonists (eg, clonidine), antidepressants, modafinil, and cholinesterase inhibitors (eg, galantamine and donepezil).

  The compounds of the present invention may be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilizers; and iv) anxiolytics.

  The compounds of the present invention may be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors such as vardenafil and sildenafil; ii) dopamine agonist / dopamine transporter inhibition Drugs such as apomorphine and buproprion; iii) alpha adrenergic receptor antagonists such as phentolamine; iv) prostaglandin agonists such as alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transporter inhibitors, For example, serotonin reuptake inhibitors; v) noradrenaline transporter inhibitors such as reboxetine and vii) 5-HT1A agonists such as flibanserin.

  The compounds of the present invention can be used in combination with the same drugs prescribed for male sexual dysfunction, and estrogen agonists such as estradiol, to treat or prevent female sexual dysfunction

  Antipsychotics include typical antipsychotics (eg, chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, morindon and loxapine); and atypical antipsychotics ( For example, clozapine, olanzapine, risperidone, quetiapine, aripyrazole, ziprasidone, amisulpiride, ziprazidone and talnetant).

  Antidepressants include serotonin reuptake inhibitors (eg citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin / noradrenaline reuptake inhibitors (eg venlafaxine, duloxetine and milnacipran); noradrenaline reuptake Inhibitors (eg, reboxetine); tricyclic antidepressants (eg, amitriptine, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (eg, isocarboxazide, moclobemide, phenelzine and tranylcypromine) And others (eg, bupropion, mianserin, mirtazapine, nefazodone and trazodone).

  Mood stabilizers include lithium, sodium valproate / valproic acid / divalprox, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.

  Anti-anxiety drugs include benzodiazepines such as alprazolam and lorazepam.

  The invention is illustrated by the following examples.

  Starting materials were obtained from commercial sources and used without further purification unless otherwise stated. Flash chromatography was performed using a prepacked Isolute Flash ™ or Biotage ™ silica gel column as the stationary phase and an analytical grade solvent as the eluent.

NMR spectra were obtained at 298 K at the indicated frequency using either a Bruker ™ DPX400 or Oxford Instruments ™ 250 MHz instrument, unless otherwise stated, and were performed as a diluted solution of CDCl ₃ . All NMR spectra were based on tetramethylsilane (TMS δ _H 0, δ _C 0). All coupling constants are recorded in hertz (Hz) and the multiplicity is s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet. Of doublet), dt (doublet of triplet) and m (multiplet).

  Total ion current traces were obtained for electrospray positive and negative ionization (ES + / ES−) and / or atmospheric pressure chemical positive and negative ionization (AP + / AP−).

  The starting material need not necessarily be prepared from the group mentioned. All quoted retention times are measured using LC / MS (liquid chromatography / mass spectrometry). If necessary, these retention times are used as a guide for preparation using mass directed autopreparation (MDAP), which represents purification by HPLC, where fraction collection is the programmed mass ion of the target compound. Achieved by detection.

Analytical chromatography conditions One of the following methods was used:

Method A
Column: Gemini C18, 50x4.6mm, 5um
Mobile phase: A: NH ₄ HCO ₃ solution 10 mM, pH 10; B: CH ₃ CN
Gradient: 35% (B) 0.5 minutes, 35% (B) → 95% (B) 4.5 minutes,
95% (B) 1.5 minutes Flow rate: 2 ml / min UV wavelength range: 210-350 nm
Ionization: ES + / ES-
Mass range: 100-900 amu

流速： ３ｍｌ／分
注入量： ５ｕｌ
カラム温度： ３０℃
ＵＶ波長域： ２２０−３３０ｎｍ Method B
Column : Waters Atlantis, 4.6 mm x 50 mm, 3 um.
Solvent: A: Aqueous solvent = water + 0.05% formic acid;
B: Organic solvent = acetonitrile + 0.05% formic acid
Method: The general method used has a runtime of 5 minutes.

Flow rate: 3ml / min
Injection volume: 5ul
Column temperature : 30 ° C
UV wavelength range : 220-330 nm

Method C
Column: 3.3cmx 4.6mm ID, 3um ABZ + PLUS
Flow rate: 3 ml / min Injection volume: 5 μl
Temperature: Room temperature UV detection range: 215-330nm
Solvent: A: 0.1% formic acid + 10 mmol ammonium acetate.
B: 95% acetonitrile + 0.05% formic acid

Method D
Column: Acquity UPLC BEH C18 1.7 μm 2.1 m
mx50mm
Temperature: Column oven set at 40 ° C. Solvent A: Aqueous solvent = water 0.1% formic acid + 10 mM ammonium acetate.
B: Organic solvent = MeCN: water 95: 5 + 0.05% formic acid. Weak cleaning solution
Medium = MeOH: water 50:50. Powerful washing solvent = MeOH
Injection volume 0.5 μl
Injection method: Partial loop overfill Weak cleaning: 500 μl
Powerful washing: 500 μl
UV detection: 220-330nm
UV extraction speed: 40 points per second MS scanning range: 100-000 amu
MS scan rate: 0.2 second scan with 0.1 second interscan delay MS scan function Electrospray with positive / negative switching Cycle time 2 minutes 30 seconds Gradient

SCX Column Chromatography SCX column chromatography is performed using a solid support sulfonic acid column such as a Varian Bond Elut SCX column or a 2 g Flash SCX-2 cartridge (Isolute ™ ion exchange SPE column) for capture release purification. It was. Typically, the mixture to be purified is packed on a column with a non-basic solvent such as methanol, and then the column is washed out with an appropriate volume of the solvent or a similar solvent. The column is then rinsed with a basic solvent system such as methanolic ammonia to release the desired material and collect the eluate. The solvent is removed using a rotary evaporator to obtain the purified product.

Mass directed preparative chromatography conditions One of the following methods was used:

Method A
Waters Atlantis, 19 mmx with column particle size 5 mm
100mm
Solvent A: Aqueous solvent = water + 0.1% trifluoroacetic acid
B: Organic solvent = acetonitrile + 0.1% trifluoroacetic acid
Post-treatment solvent = methanol: water 80: 20 + 0.1% formic acid
Needle washing solvent = methanol Method Five methods used depending on the analysis retention time of the target compound. 15.5 minutes
Elution followed by a 3.5 minute column wash and re-equilibration step,
20 minutes execution time.
Method 1.8-2.1 = 0-30% B
Method 2.1-2.6 = 10-45% B
Method 2.6-3.1 = 15-65% B
Method 3.1-4.1 = 30-75% B
Method> 4.1 = 50-100% B (14 minutes then 5 minutes wash
And re-equilibration)
Flow rate 20 ml / min.
Injection volume 500ul partial partial loop injection.
Column temperature

Method B
Column: Waters Atlantis, 19 mm x 100 mm (small scale
And 30 mm × 100 mm (large scale).
Stationary phase particle size = 5 um.
Solvent: A: Aqueous solvent = water + 0.1% formic acid;
B: Organic solvent = acetonitrile + 0.1% formic acid.
Post-treatment solvent = methanol: water 80:20
Needle cleaning solvent = methanol
Methods: Five methods used depending on the analytical retention time of the target compound. 10 minutes
13.5 including a 3.5 minute column wash and re-equilibration step
Running time in minutes.
Large / Small scale 1.0-1.5 = 5-30% B
Large / Small scale 1.5-2.2 = 15-55% B
Large / Small scale 2.2-2.9 = 30-85% B
Large / Small Scale 2.9-3.6 = 50-99% B
Large / Small scale 3.6-5.0 = 80-99% B (6 minutes, then
7.5 minutes wash and re-equilibration)
Flow rate: 20 ml / min (small scale) or 40 ml / min (large scale).

Method C
Column: Small scale preparative column: Supelcosil ABZ + Plus
Ram 21.2mm x 100mm. The stationary phase particle size is 5 μm. Large scale
Preparative column: Supelcosil ABZ + Plus column 3
0.0mm x 150mm. The stationary phase particle size is 12 μm.
Solvent: A: Aqueous solvent = Water + 0.1% formic acid; B: Organic solvent = MeCN: Water 9
5: 5 + 0.05% formic acid. Post-treatment solvent-ZQ = MeOH: water 80:
20 + 50 mMol ammonium acetate. 2767 needle wash solvent =
MeOH: water: DMSO 80:10:10
Methods: Five methods, 10 minute gradient, then 5 minute column wash and re-equilibration
15 minutes execution time including process. The other five have 25 minutes of execution time
The The method has the same start and end of the organic content of B,
The gradient extends over 20 minutes.
Small scale Large scale MDP 1.5-2.2 = 00-30% B MDP 1.5-2.2 = 00-30% B
MDP 2.0-2.8 = 10-40% B MDP 2.0-2.8 = 10-40% B
MDP 2.5-3.0 = 15-55% B MDP 2.5-3.0 = 25-55% B
MDP 2.8-4.0 = 30-80% B MDP 2.8-4.0 = 40-75% B
MDP 3.8-5.5 = 60-90% B MDP 3.8-5.5 = 60-90% B
Flow rate: 20 ml / min (small scale) or 40 ml / min (large scale).

The fractionation and analysis conditions of Example 31 are as follows:
About sorting conditions:
Column Waters X-bridge 30 mm x 100 mm;
The stationary phase particle size is 5um.
Solvent: A: Aqueous solvent = 10 mM adjusted to pH 10 with ammonia solution
Ammonium bicarbonate solution. B: Organic solvent = acetonitrile. Post-processing
Solvent = methanol: water 80:20. Needle washing solvent = methanol Analysis conditions:
Column Waters X-Bridge 4.6 mm x 50 mm;
The stationary phase particle size is 3.5 m.
Solvent: A: Aqueous solvent = 10 mM adjusted to pH 10 with ammonia solution
Ammonium bicarbonate solution. B: Organic solvent = acetonitrile.
The above conditions were the same except for.

Abbreviation TEA Triethylamine TMS-Cl Trimethyl-silyl DME Dimethyl ether ss Saturated solution TFA Trifluoroacetic acid DAD Diode array detector CD Circular dichroism a / a% Area ratio under concentration curve LC / MS Liquid chromatography / mass spectrometry NMR Nuclei Chromatography column (TM) supplied by magnetic resonance SCX Varian
THF tetrahydrofuran DMSO dimethyl sulfoxide DMF dimethylformamide DCM / MDC dichloromethane / methylene dichloride CDI 1,1′-carbonyldiimidazole LDA lithium diisopropylamide EDC 1-ethyl-3- (dimethylaminopropyl) carbodiimide MsCl methanesulfonyl chloride AcOH acetic acid HOAt 1 -Hydroxy-7-azabenzotriazole HOBt 1-Hydroxybenzotriazole Pd on C Carbon support palladium MeCN Acetonitrile MDAP Mass directed auto-purification LCMS Rt LC / MS Retention time

イソチオシアン酸４−エチルフェニル（２．０ｇ；１２．３ｍｍｏｌ）の酢酸エチル（１０ｍｌ）中溶液を、２５℃で１０分かけて２−アミノエタノール（０．７４ｍｌ；１２．３ｍｍｏｌ）の酢酸エチル（１０ｍｌ）中攪拌溶液に滴下した。次いで、反応混合物を、２５℃で一晩攪拌した。固体を濾去し、酢酸エチルで洗浄し、減圧下で乾燥し、白色固体として標記化合物を得た（１．４４９ｇ，５２％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：９．５１（１Ｈ，ｂｒ ｓ），７．５８（１Ｈ，ｂｒ ｓ），７．２８（２Ｈ，ｍ），７．１４（２Ｈ，ｍ），４．７９（１Ｈ，ｂｒ ｓ），３．５２（４Ｈ，ａｐｐ ｓ），２．５８（２Ｈ，ｍ），１．１７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．１７／（ＥＳ^＋） ２２５ （Ｍ＋Ｈ，Ｃ_１１Ｈ_１７Ｎ_２ＯＳ 理論値２２５）。 Intermediate Description Example 1: N- (4-ethylphenyl) -N ′-(2-hydroxyethyl) thiourea

A solution of 4-ethylphenyl isothiocyanate (2.0 g; 12.3 mmol) in ethyl acetate (10 ml) was added to ethyl acetate (10 ml) of 2-aminoethanol (0.74 ml; 12.3 mmol) at 25 ° C. over 10 minutes. ) In a stirred solution. The reaction mixture was then stirred at 25 ° C. overnight. The solid was filtered off, washed with ethyl acetate and dried under reduced pressure to give the title compound as a white solid (1.449 g, 52%).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 9.51 (1H, brs), 7.58 (1H, brs), 7.28 (2H, m), 7.14 (2H, m), 4.79 (1H, br s), 3.52 (4H, app s), 2.58 (2H, m), 1.17 (3H, t, J = 7 Hz); LC / MS retention time 2.17 / (ES ⁺ ) 225 (M + H, C ₁₁ H ₁₇ N ₂ OS theoretical 225).

標記化合物（１．２５ｇ）を、記載例１に記載の製法によって、酢酸エチル（１０ｍｌ）中で１−（エチルオキシ）−４−イソチオシアナトベンゼン（１．０ｇ；５．５ｍｍｏｌ）および２−アミノエタノール（０．３３５ｇ；５．５ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：９．３９（１Ｈ，ｂｒ ｓ），７．４３（１Ｈ，ｂｒ ｓ），７．２２（２Ｈ，ｍ），６．８６（２Ｈ，ｍ），４．７８（１Ｈ，ｂｒ ｓ），４．００（２Ｈ，ｍ），３．５２（４Ｈ，ａｐｐ ｓ），１．０３（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 １．８９／（ＥＳ^＋） ２４１ （Ｍ＋Ｈ，Ｃ_１１Ｈ_１７Ｎ_２Ｏ_２Ｓ 理論値２４１）。 Description Example 2: N- [4- (ethyloxy) phenyl] -N ′-(2-hydroxyethyl) thiourea

The title compound (1.25 g) was prepared according to the procedure described in Description 1 in 1- (ethyloxy) -4-isothiocyanatobenzene (1.0 g; 5.5 mmol) and 2-amino acid in ethyl acetate (10 ml). Prepared from ethanol (0.335 g; 5.5 mmol).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 9.39 (1H, br s), 7.43 (1H, br s), 7.22 (2H, m), 6.86 (2H, m), 4.78 (1H, br s), 4.00 (2H, m), 3.52 (4H, app s), 1.03 (3H, t, J = 7 Hz); LC / MS retention time 1.89 / (ES ⁺ ) 241 (M + H, C ₁₁ H ₁₇ N ₂ O ₂ S theoretical 241).

１−（エチルオキシ）−４−イソチオシアナトベンゼン（１．０ｇ；５．５７ｍｍｏｌ）の酢酸エチル（５ｍｌ）中溶液を、２５℃で１０分かけて２−メトキシエチルアミン（０．４１９ｇ；５．５７ｍｍｏｌ）の酢酸エチル（５ｍｌ）中攪拌溶液に滴下した。次いで、反応混合物を、２５℃で一晩攪拌した。固体を濾去し、酢酸エチルで洗浄し、減圧下で乾燥し、白色固体として標記化合物を得た（１．２８８ｇ，９１％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：９．３７（１Ｈ，ｂｒ ｓ），７．５０（１Ｈ，ｂｒ ｓ），７．２１（２Ｈ，ｍ），６．８７（２Ｈ，ｍ），４．００（２Ｈ，ｍ），３．６１（２Ｈ，ｍ），３．４５（２Ｈ，ｍ），３．２６（３Ｈ，ｓ），１．３０（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．４０／（ＥＳ^＋） ２５５ （Ｍ＋Ｈ，Ｃ_１２Ｈ_１９Ｎ_２Ｏ_２Ｓ 理論値２５５）． Description Example 3: N- [4- (ethyloxy) phenyl] -N ′-[2- (methyloxy) ethyl] thiourea

A solution of 1- (ethyloxy) -4-isothiocyanatobenzene (1.0 g; 5.57 mmol) in ethyl acetate (5 ml) was added to 2-methoxyethylamine (0.419 g; 5.57 mmol) at 25 ° C. over 10 minutes. ) In ethyl acetate (5 ml) dropwise. The reaction mixture was then stirred at 25 ° C. overnight. The solid was filtered off, washed with ethyl acetate and dried under reduced pressure to give the title compound as a white solid (1.288 g, 91%).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 9.37 (1H, br s), 7.50 (1H, br s), 7.21 (2H, m), 6.87 (2H, m), 4.00 (2H, m), 3.61 (2H, m), 3.45 (2H, m), 3.26 (3H, s), 1.30 (3H, t, J = 7 Hz); LC / MS retention time 2.40 / (ES ⁺ ) 255 (M + H, C ₁₂ H ₁₉ N ₂ O ₂ S theoretical 255).

１−イソチオシアナト−４−［（トリフルオロメチル）オキシ］ベンゼン（１．０ｇ；４．５６ｍｍｏｌ）の酢酸エチル（５ｍｌ）中溶液を、２５℃で１０分かけて２−アミノエタノール（０．２７４ｍｌ；４．５６ｍｍｏｌ）の酢酸エチル（５ｍｌ）中攪拌溶液に滴下した。次いで、反応混合物を、２５℃で一晩攪拌した。次いで、溶媒を真空中で除去し、灰白色固体として標記化合物を得た（１．０８５ｇ，８５％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：９．７２（１Ｈ，ｂｒ ｓ），７．８８（１Ｈ，ｂｒ ｓ），７．５８（２Ｈ，ｍ），７．２９（２Ｈ，ｍ），４．８２（１Ｈ，ｂｒ ｓ），３．５５（４Ｈ，ａｐｐ ｓ）；ＬＣ／ＭＳ 保持時間 ２．４３／（ＥＳ^＋） ２８１ （Ｍ＋Ｈ，Ｃ_１０Ｈ_１２Ｎ_２Ｆ_３Ｏ_２Ｓ 理論値２８１）。 Description Example 4: N- (2-hydroxyethyl) -N ′-{4-[(trifluoromethyl) oxy] phenyl} thiourea

A solution of 1-isothiocyanato-4-[(trifluoromethyl) oxy] benzene (1.0 g; 4.56 mmol) in ethyl acetate (5 ml) was added to 2-aminoethanol (0.274 ml; 4.56 mmol) in ethyl acetate (5 ml) was added dropwise. The reaction mixture was then stirred at 25 ° C. overnight. The solvent was then removed in vacuo to give the title compound as an off-white solid (1.085 g, 85%).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 9.72 (1H, br s), 7.88 (1H, br s), 7.58 (2H, m), 7.29 (2H, m), 4.82 (1H, br s), 3.55 (4H, app s); LC / MS retention time 2.43 / (ES ⁺ ) 281 (M + H, C ₁₀ H ₁₂ N ₂ F ₃ O ₂ S Theoretical value 281).

１−イソチオシアナト−４−（トリフルオロメチル）ベンゼン（２．０ｇ；９．８４ｍｍｏｌ）の酢酸エチル（１０ｍｌ）中溶液を、２５℃で１０分かけて２−アミノエタノール（０．６０ｍｌ；９．８４ｍｍｏｌ）の酢酸エチル（１０ｍｌ）中攪拌溶液に滴下した。次いで、反応混合物を、２５℃で一晩攪拌した。次いで、溶媒を真空中で除去し、灰白色固体として標記化合物を得た（２．５５ｇ，９８％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：９．９４（１Ｈ，ｂｒ ｓ），８．０２（１Ｈ，ｂｒ ｓ），７．７５（２Ｈ，ｍ），７．１２（２Ｈ，ｍ），４．８４（１Ｈ，ｂｒ ｓ），３．５４（４Ｈ，ａｐｐ ｓ）；ＬＣ／ＭＳ 保持時間 ２．３６／（ＥＳ^＋） ２６５ （Ｍ＋Ｈ，Ｃ_１０Ｈ_１２Ｎ_２Ｆ_３ＯＳ 理論値２６５）。 Description Example 5: N- (2-hydroxyethyl) -N ′-[4- (trifluoromethyl) phenyl] thiourea

A solution of 1-isothiocyanato-4- (trifluoromethyl) benzene (2.0 g; 9.84 mmol) in ethyl acetate (10 ml) was added to 2-aminoethanol (0.60 ml; 9.84 mmol) at 25 ° C. over 10 minutes. ) In ethyl acetate (10 ml) dropwise. The reaction mixture was then stirred at 25 ° C. overnight. The solvent was then removed in vacuo to give the title compound as an off-white solid (2.55 g, 98%).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 9.94 (1H, br s), 8.02 (1H, br s), 7.75 (2H, m), 7.12 (2H, m), 4.84 (1H, br s), 3.54 (4H, app s); LC / MS retention time 2.36 / (ES ⁺ ) 265 (M + H, C ₁₀ H ₁₂ N ₂ F ₃ OS theoretical 265) .

標記化合物（１．１４７ｇ）を、記載例１に記載の製法によって、酢酸エチル（１０ｍｌ）中で１−（エチルオキシ）−４−イソチオシアナトベンゼン（１．０ｇ；５．５ｍｍｏｌ）およびエチルアミン（２．７９ｍｌのＴＨＦ中２Ｍ溶液；５．５ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：９．２０（１Ｈ，ｂｒ ｓ），７．４７（１Ｈ，ｂｒ ｓ），７．１８（２Ｈ，ｍ），６．８６（２Ｈ，ｍ），４．０（２Ｈ，ｍ），３．４２（２Ｈ，ｍ），１．３０（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．１０（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．４０／（ＥＳ^＋） ２２５ （Ｍ＋Ｈ，Ｃ_１１Ｈ_１７Ｎ_２ＯＳ 理論値２２５）。 Description Example 6: N-ethyl-N ′-[4- (ethyloxy) phenyl] thiourea

The title compound (1.147 g) was prepared according to the procedure described in Description 1 in 1- (ethyloxy) -4-isothiocyanatobenzene (1.0 g; 5.5 mmol) and ethylamine (2 in ethyl acetate (10 ml). .79 ml of a 2M solution in THF; 5.5 mmol).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 9.20 (1H, br s), 7.47 (1H, br s), 7.18 (2H, m), 6.86 (2H, m), 4.0 (2H, m), 3.42 (2H, m), 1.30 (3H, t, J = 7 Hz), 1.10 (3H, t, J = 7 Hz); LC / MS retention time 2 .40 / (ES ⁺ ) 225 (M + H, C ₁₁ H ₁₇ N ₂ OS theoretical 225).

標記化合物（０．５１１ｇ）を、記載例１に記載の製法によって、酢酸エチル（１０ｍｌ）中で１−ブチル−４−イソチオシアナトベンゼン（０．４００ｇ；２．１ｍｍｏｌ）および２−アミノエタノール（０．１３ｍｌ；２．１ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：９．５０（１Ｈ，ｂｒ ｓ），７．５８（１Ｈ，ｂｒ ｓ），７．２８（２Ｈ，ｍ），７．１２（２Ｈ，ｍ），４．７９（１Ｈ，ｂｒ ｓ），３．５２（４Ｈ，ａｐｐ ｓ），２．５２（２Ｈ，ｍ），１．５２（２Ｈ，ｍ），１．３０（２Ｈ，ｍ），０．９０（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．６１／（ＥＳ^＋） ２５３ （Ｍ＋Ｈ，Ｃ_１３Ｈ_２１Ｎ_２ＯＳ 理論値２５３）。 Description Example 7: N- (4-butylphenyl) -N ′-(2-hydroxyethyl) thiourea

The title compound (0.511 g) was prepared according to the procedure described in Description 1 in 1-butyl-4-isothiocyanatobenzene (0.400 g; 2.1 mmol) and 2-aminoethanol (10 ml) in ethyl acetate (10 ml). 0.13 ml; 2.1 mmol).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 9.50 (1H, br s), 7.58 (1H, br s), 7.28 (2H, m), 7.12 (2H, m), 4.79 (1H, br s), 3.52 (4H, app s), 2.52 (2H, m), 1.52 (2H, m), 1.30 (2H, m), 0.90 (3H, t, J = 7 Hz); LC / MS retention time 2.61 / (ES ⁺ ) 253 (M + H, C ₁₃ H ₂₁ N ₂ OS theoretical 253).

標記化合物（０．７２９ｇ）を、記載例１に記載の製法によって、酢酸エチル（１０ｍｌ）中で１−（エチルオキシ）−４−イソチオシアナトベンゼン（０．５ｇ；２．７９ｍｍｏｌ）および３−アミノ−１−プロパノール（０．２０９ｇ；２．７９ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：９．２８（１Ｈ，ｂｒ ｓ），７．５０（１Ｈ，ｂｒ ｓ），７．２０（２Ｈ，ｍ），６．８６（２Ｈ，ｍ），４．５０（１Ｈ，ｂｒ ｓ），４．２０（２Ｈ，ｍ），３．４６（４Ｈ，ｍ），１．６３（２Ｈ，ｍ），１．３０（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 １．９３／（ＥＳ^＋） ２５５ （Ｍ＋Ｈ，Ｃ_１２Ｈ_１９Ｎ_２Ｏ_２Ｓ 理論値２５５）。 Description Example 8: N- [4- (ethyloxy) phenyl] -N ′-(3-hydroxypropyl) thiourea

The title compound (0.729 g) was prepared according to the procedure described in Description 1 in 1- (ethyloxy) -4-isothiocyanatobenzene (0.5 g; 2.79 mmol) and 3-amino acid in ethyl acetate (10 ml). Prepared from -1-propanol (0.209 g; 2.79 mmol).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 9.28 (1H, br s), 7.50 (1H, br s), 7.20 (2H, m), 6.86 (2H, m), 4.50 (1H, br s), 4.20 (2H, m), 3.46 (4H, m), 1.63 (2H, m), 1.30 (3H, t, J = 7 Hz); LC / MS retention time _{^{1.93 / (ES +) 255 (}} M + H, C 12 H 19 N 2 O 2 S theory 255).

４−（４−イソチオシアナトフェニル）モルホリン（０．２５０ｇ；１．１４ｍｍｏｌ）の酢酸エチル（５ｍｌ）中溶液を、２５℃で１０分かけて２−アミノエタノール（０．０７ｍｌ；１．１４ｍｍｏｌ）の酢酸エチル（５ｍｌ）中攪拌溶液に滴下した。次いで、反応混合物を、２５℃で一晩攪拌した。次いで、溶媒を真空中で除去し、白色固体として標記化合物を得た（０．２３７ｇ，７４％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：９．３５（１Ｈ，ｂｒ ｓ），７．３８（１Ｈ，ｂｒ ｓ），７．１８（２Ｈ，ｍ），６．９０（２Ｈ，ｍ），４．７５（１Ｈ，ｂｒ ｓ），３．７２（４Ｈ，ｍ），３．５１（４Ｈ，ａｐｐ ｓ），３．０７（４Ｈ，ｍ）；ＬＣ／ＭＳ 保持時間 １．４５／（ＥＳ^＋） ２８２ （Ｍ＋Ｈ，Ｃ_１３Ｈ_２０Ｎ_３Ｏ_２Ｓ 理論値２８２）。 Description Example 9: N- (2-hydroxyethyl) -N ′-[4- (4-morpholinyl) phenyl] thiourea

A solution of 4- (4-isothiocyanatophenyl) morpholine (0.250 g; 1.14 mmol) in ethyl acetate (5 ml) was added 2-aminoethanol (0.07 ml; 1.14 mmol) over 10 minutes at 25 ° C. Of ethyl acetate (5 ml) in a stirred solution. The reaction mixture was then stirred at 25 ° C. overnight. The solvent was then removed in vacuo to give the title compound as a white solid (0.237 g, 74%).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 9.35 (1H, br s), 7.38 (1H, br s), 7.18 (2H, m), 6.90 (2H, m), 4.75 (1H, br s), 3.72 (4H, m), 3.51 (4H, app s), 3.07 (4H, m); LC / MS retention time 1.45 / (ES ⁺ _{) 282 (M + H, C} 13 H 20 N 3 O 2 S theory 282).

標記化合物（０．３１３ｇ）を、記載例１に記載の製法によって、酢酸エチル（１０ｍｌ）中で１−クロロ−４−イソチオシアナトベンゼン（０．５ｇ；２．９４ｍｍｏｌ）およびエチルアミン（１．４７ｍｌのＴＨＦ中２Ｍ溶液；２．９４ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：９．５０（１Ｈ，ｂｒ ｓ），７．８２（１Ｈ，ｂｒ ｓ），７．４３（２Ｈ，ｍ），７．３４（２Ｈ，ｍ），３．４６（２Ｈ，ｍ），１．１１（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．５２／（ＥＳ^＋） ２１５ （Ｍ＋Ｈ，Ｃ_９Ｈ_１２Ｎ_２ＳＣｌ 理論値２１５）。 Description Example 10: N- (4-chlorophenyl) -N′-ethylthiourea

The title compound (0.313 g) was prepared according to the procedure described in Description 1 in 1-chloro-4-isothiocyanatobenzene (0.5 g; 2.94 mmol) and ethylamine (1.47 ml) in ethyl acetate (10 ml). Of 2M in THF; 2.94 mmol).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 9.50 (1H, br s), 7.82 (1H, br s), 7.43 (2H, m), 7.34 (2H, m), 3.46 (2H, m), 1.11 (3H, t, J = 7 Hz); LC / MS retention time 2.52 / (ES ⁺ ) 215 (M + H, C ₉ H ₁₂ N ₂ SCl Theoretical 215) .

標記化合物（０．３１８ｇ）を、記載例１に記載の製法によって、酢酸エチル（５ｍｌ）中で１−イソチオシアナト−４−（トリフルオロメチル）ベンゼン（０．３００ｇ；１．４８ｍｍｏｌ）およびシクロプロピルアミン（０．０８４ｇ；１．４８ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：９．６２（１Ｈ，ｂｒ ｓ），８．２３（１Ｈ，ｂｒ ｓ），７．７２（２Ｈ，ｍ），７．６２（２Ｈ，ｍ），２．９２（１Ｈ，ｂｒ ｓ），０．７８（２Ｈ，ｍ），０．６０（２Ｈ，ａｐｐ ｓ）；ＬＣ／ＭＳ 保持時間 ２．７７／（ＥＳ^＋） ２６１ （Ｍ＋Ｈ，Ｃ_１１Ｈ_１２Ｎ_２Ｆ_３Ｓ 理論値２６１）。 Description Example 11 N-cyclopropyl-N ′-[4- (trifluoromethyl) phenyl] thiourea

The title compound (0.318 g) was prepared according to the procedure described in Description 1 in 1-isothiocyanato-4- (trifluoromethyl) benzene (0.300 g; 1.48 mmol) and cyclopropylamine in ethyl acetate (5 ml). (0.084 g; 1.48 mmol).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 9.62 (1H, br s), 8.23 (1H, br s), 7.72 (2H, m), 7.62 (2H, m), 2.92 (1H, br s), 0.78 (2H, m), 0.60 (2H, app s); LC / MS retention time 2.77 / (ES ⁺ ) 261 (M + H, C ₁₁ H ₁₂ N ₂ F ₃ S theory 261).

４−（トリフルオロメチル）フェニルイソチオシアネート（２．１５ｇ）の酢酸エチル（１４ｍｌ）中溶液を、エチルアミン（ＴＨＦ中２Ｍ溶液；１０ｍｌ）の酢酸エチル（３７ｍｌ）中攪拌溶液に加えた。６日間静置した後、溶媒を真空中で除去し、灰白色固体として標記分子を得た（２．５７ｇ）。
^１Ｈ ＮＭＲ（４００ＭＨｚ；ＣＤＣｌ_３） δ：７．７６（１Ｈ，ｂｒ ｓ），７．６９（２Ｈ，ｄ，Ｊ＝８Ｈｚ），７．３４（２Ｈ，ｄ，Ｊ＝８Ｈｚ），６．０７（１Ｈ，ｂｒ ｓ），３．７０（２Ｈ，ｍ），１．２４（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．７５／（ＥＳ^＋） ２４９ （Ｍ＋Ｈ，Ｃ_１０Ｈ_１２Ｆ_３Ｎ_２Ｓ 理論値２４９）。 Description Example 12: N-ethyl-N ′-[4- (trifluoromethyl) phenyl] thiourea

A solution of 4- (trifluoromethyl) phenyl isothiocyanate (2.15 g) in ethyl acetate (14 ml) was added to a stirred solution of ethylamine (2M solution in THF; 10 ml) in ethyl acetate (37 ml). After standing for 6 days, the solvent was removed in vacuo to give the title molecule as an off-white solid (2.57 g).
¹ H NMR (400 MHz; CDCl ₃ ) δ: 7.76 (1H, br s), 7.69 (2H, d, J = 8 Hz), 7.34 (2H, d, J = 8 Hz), 6.07 (1H, br s), 3.70 (2H, m), 1.24 (3H, t, J = 7 Hz); LC / MS retention time 2.75 / (ES ⁺ ) 249 (M + H, C ₁₀ H ₁₂ F ₃ N ₂ S theory 249).

標記化合物（１．２０ｇ）を、記載例１に記載の製法によって、酢酸エチル（２０ｍｌ）中で１−イソチオシアナト−４−［（トリフルオロメチル）オキシ］ベンゼン（１．０ｇ；４．５６ｍｍｏｌ）およびエチルアミン（２．７３ｍｌのＴＨＦ中２Ｍ溶液；４．５６ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：９．５８（１Ｈ，ｂｒ ｓ），７．８９（１Ｈ，ｂｒ ｓ），７．５２（２Ｈ，ｍ），７．３０（２Ｈ，ｍ），３．４８（２Ｈ，ｂｒ ｍ），１．１３（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．７６／（ＥＳ^＋） ２６５ （Ｍ＋Ｈ，Ｃ_１０Ｈ_１２Ｎ_２Ｆ_３ＳＯ 理論値２６５）。 Description Example 13: N-ethyl-N ′-{4-[(trifluoromethyl) oxy] phenyl} thiourea

The title compound (1.20 g) was prepared according to the procedure described in Description 1 in 1-isothiocyanato-4-[(trifluoromethyl) oxy] benzene (1.0 g; 4.56 mmol) in ethyl acetate (20 ml) and Prepared from ethylamine (2.73 ml of 2M solution in THF; 4.56 mmol).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 9.58 (1H, br s), 7.89 (1H, br s), 7.52 (2H, m), 7.30 (2H, m), 3.48 (2H, br m), 1.13 (3H, t, J = 7 Hz); LC / MS retention time 2.76 / (ES ⁺ ) 265 (M + H, C ₁₀ H ₁₂ N ₂ F ₃ SO theory Value 265).

標記化合物（０．６４ｇ）を、記載例１に記載の製法によって、酢酸エチル（１０ｍｌ）中で１−［（ジフルオロメチル）オキシ］−４−イソチオシアナトベンゼン（０．５ｇ；２．４８ｍｍｏｌ）および２−アミノエタノール（０．１５ｍｌ；２．４８ｍｍｏｌ）から調製した。
ＬＣ／ＭＳ 保持時間 ２．０３／（ＥＳ^＋） ２６３ （Ｍ＋Ｈ，Ｃ_１０Ｈ_１３Ｎ_２Ｆ_２ＳＯ_２ 理論値２６３）。 Description Example 14: N- {4-[(difluoromethyl) oxy] phenyl} -N ′-(2-hydroxyethyl) thiourea

The title compound (0.64 g) was prepared according to the procedure described in Description 1 in 1-[(difluoromethyl) oxy] -4-isothiocyanatobenzene (0.5 g; 2.48 mmol) in ethyl acetate (10 ml). And 2-aminoethanol (0.15 ml; 2.48 mmol).
LC / MS retention time _{^{2.03 / (ES +) 263 (}} M + H, C 10 H 13 N 2 F 2 SO 2 theory 263).

１−イソチオシアナト−４−［（トリフルオロメチル）チオ］ベンゼン（０．５００ｇ；２．１３ｍｍｏｌ）の酢酸エチル（５ｍｌ）中溶液を、２５℃で１０分かけて２−アミノエタノール（０．１２８ｍｌ；２．１３ｍｍｏｌ）の酢酸エチル（５ｍｌ）中攪拌溶液に滴下した。次いで、反応混合物を、２５℃で一晩攪拌した。次いで、溶媒を真空中で除去し、白色固体として標記化合物を得た（０．７３０ｇ，９１％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：９．９３（１Ｈ，ｂｒ ｓ），８．０３（１Ｈ，ｂｒ ｓ），７．７２（２Ｈ，ｍ），７．６２（２Ｈ，ｍ），４．８６（１Ｈ，ｂｒ ｓ），３．５６（４Ｈ，ａｐｐ ｓ）；ＬＣ／ＭＳ 保持時間 ２．６１／（ＥＳ^＋） ２９７ （Ｍ＋Ｈ，Ｃ_１０Ｈ_１２Ｎ_２Ｆ_３ＯＳ_２ 理論値２９７）。 Description Example 15: N- (2-hydroxyethyl) -N ′-{4-[(trifluoromethyl) thio] phenyl} thiourea

A solution of 1-isothiocyanato-4-[(trifluoromethyl) thio] benzene (0.500 g; 2.13 mmol) in ethyl acetate (5 ml) was added to 2-aminoethanol (0.128 ml; 2.13 mmol) in ethyl acetate (5 ml) was added dropwise. The reaction mixture was then stirred at 25 ° C. overnight. The solvent was then removed in vacuo to give the title compound as a white solid (0.730 g, 91%).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 9.93 (1H, br s), 8.03 (1H, br s), 7.72 (2H, m), 7.62 (2H, m), 4.86 (1H, br s), 3.56 (4H, app s); LC / MS retention time 2.61 / (ES ⁺ ) 297 (M + H, C ₁₀ H ₁₂ N ₂ F ₃ OS ₂ Theoretical value 297 ).

５−メチルイソオキサゾール（５．０ｇ；６０ｍｍｏｌ）を、穏やかな還流を保持するような速度でコンデンサーに通して塩化スルフリル（５．５４ｍｌ；６９ｍｍｏｌ）で滴下処理した。（フラスコを水流吸引器に接続し、ＨＣｌおよびＳＯ_２を除去した）。添加を終了すると、１時間加熱還流し続けた。粗４−クロロ−５−メチルイソオキサゾールを、水酸化ナトリウム（３．６ｇ、１．５当量）の水（３０ｍｌ）中溶液に加え、多量の水（１０ｍｌ）で洗い流した。加熱することなく反応が進行するような方法で、該混合物を断続的に冷却しながら攪拌した。透明な溶液を形成すると、氷で冷却し、１２ｍｌの濃塩酸（約２当量）で処理した。得られた黄色溶液を、塩化ナトリウムで飽和し、エーテルで抽出した（ｘ３）。合した抽出液をＮａ_２ＳＯ_４で乾燥し、エーテルを減圧下で除去した。淡黄色液体を得た（５．１７ｇ、５８％）。所望の生成物をさらに精製することなく用いた（純度＞８０％）。
４−クロロ−５−メチルイソオキサゾール
^１ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３） δ：８．１８（１Ｈ，ｓ），２．４３（３Ｈ，ｓ）；ＬＣ／ＭＳ 保持時間 ２．０３
２−クロロ−３−オキソブタンニトリル
ＬＣ／ＭＳ 保持時間 １．７０／（ＥＳ⁻） １１６，１１８ （Ｍ−Ｈ，Ｃ_４Ｈ_４ ^３５ＣｌＮＯ 理論値１１７）。 Description Example 16: 2-chloro-3-oxobutanenitrile

5-Methylisoxazole (5.0 g; 60 mmol) was treated dropwise with sulfuryl chloride (5.54 ml; 69 mmol) through a condenser at a rate to maintain a gentle reflux. (The flask was connected to a water aspirator to remove HCl and SO ₂ ). When the addition was complete, the mixture was heated to reflux for 1 hour. Crude 4-chloro-5-methylisoxazole was added to a solution of sodium hydroxide (3.6 g, 1.5 eq) in water (30 ml) and rinsed with copious amounts of water (10 ml). The mixture was stirred with intermittent cooling in such a way that the reaction proceeded without heating. When a clear solution formed, it was cooled with ice and treated with 12 ml of concentrated hydrochloric acid (about 2 equivalents). The resulting yellow solution was saturated with sodium chloride and extracted with ether (x3). The combined extracts were dried over Na ₂ SO ₄ and the ether was removed under reduced pressure. A pale yellow liquid was obtained (5.17 g, 58%). The desired product was used without further purification (purity> 80%).
4-chloro-5-methylisoxazole
¹ NMR (400 MHz, CDCl ₃ ) δ: 8.18 (1H, s), 2.43 (3H, s); LC / MS retention time 2.03
2-Chloro-3-oxobutanenitrile LC / MS Retention time 1.70 / (ES ⁻ ) 116,118 (M−H, C ₄ H ₄ ³⁵ ClNO Theoretical 117).

標記化合物（６．３２ｇ；１００％）を、記載例１に記載の製法によって、酢酸エチル（５０ｍｌ）中で１−ブロモ−４−イソチオシアナトベンゼン（５．０ｇ；２３ｍｍｏｌ）および３−アミノエタノール（２．１１ｍｌ；３４．５ｍｍｏｌ）から調製した。
ＬＣ／ＭＳ 保持時間 ２．１４／（ＥＳ^＋） ２７５＆２７７ （Ｍ＋Ｈ，Ｃ_９Ｈ_１２ＢｒＮ_２ＯＳ 理論値２７５＆２７７）。 Description Example 17: N- (4-bromophenyl) -N ′-(2-hydroxyethyl) thiourea

The title compound (6.32 g; 100%) was prepared according to the procedure described in Description 1 in 1-bromo-4-isothiocyanatobenzene (5.0 g; 23 mmol) and 3-aminoethanol in ethyl acetate (50 ml). (2.11 ml; 34.5 mmol).
LC / MS retention time ^{2.14 / (ES +) 275 &} 277 (M + H, C 9 H 12 BrN 2 OS theory 275 & 277).

Ｎ−［４−（エチルオキシ）フェニル］−Ｎ’−（２−ヒドロキシエチル）チオ尿素（１．５０ｇ；６．２５ｍｍｏｌ）および２−クロロ−３−オキソブタン酸エチル（２．０５７ｇ；１２．５ｍｍｏｌ）のトルエン（４０ｍｌ）中混合物を、９０℃で１時間攪拌しながら加熱した。混合物を一晩冷却し、溶媒を回転蒸発により除去し、標記化合物を得た（１．６８ｇ；７０％）。
ＬＣ／ＭＳ 保持時間 ２．５８／（ＥＳ^＋） ３５１ （Ｍ＋Ｈ，Ｃ_１７Ｈ_２３Ｎ_２Ｏ_４Ｓ 理論値３５１）。 Description Example 18: 2-{[4- (Ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxylate hydrochloride

N- [4- (ethyloxy) phenyl] -N ′-(2-hydroxyethyl) thiourea (1.50 g; 6.25 mmol) and ethyl 2-chloro-3-oxobutanoate (2.057 g; 12.5 mmol) Of toluene in toluene (40 ml) was heated at 90 ° C. with stirring for 1 hour. The mixture was cooled overnight and the solvent was removed by rotary evaporation to give the title compound (1.68 g; 70%).
LC / MS retention time _{^{2.58 / (ES +) 351 (}} M + H, C 17 H 23 N 2 O 4 S theory 351).

２−｛［４−（エチルオキシ）フェニル］イミノ｝−３−（２−ヒドロキシエチル）−４−メチル−２，３−ジヒドロ−１，３−トリアゾール−５−カルボン酸エチル 塩酸塩（１．３７ｇ；３．９３ｍｍｏｌ）、水酸化ナトリウム（０．６３ｇ；１５．７ｍｍｏｌ）のメタノール（２０ｍｌ）および水（５ｍｌ）中混合物を、一晩室温で攪拌した。メタノールを減圧下で除去し、ｐＨ＝７になるまで５Ｎ ＨＣｌを加えた。標記化合物を濾過により回収し、乾燥した（０．７５１ｇ、５９％）。
ＬＣ／ＭＳ 保持時間 ２．４１／（ＥＳ^＋） ３３７ （Ｍ＋Ｈ，Ｃ_１６Ｈ_２１Ｎ_２Ｏ_４Ｓ 理論値３３７）。 Description Example 19: Methyl 2-{[4- (ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxylate

2-{[4- (Ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxylate hydrochloride (1.37 g 3.93 mmol), sodium hydroxide (0.63 g; 15.7 mmol) in methanol (20 ml) and water (5 ml) was stirred overnight at room temperature. Methanol was removed under reduced pressure and 5N HCl was added until pH = 7. The title compound was collected by filtration and dried (0.751 g, 59%).
LC / MS retention time _{^{2.41 / (ES +) 337 (}} M + H, C 16 H 21 N 2 O 4 S theory 337).

２−｛［４−（エチルオキシ）フェニル］イミノ｝−３−（２−ヒドロキシエチル）−４−メチル−２，３−ジヒドロ−１，３−トリアゾール−５−カルボン酸メチル（０．６９ｇ；２．０５ｍｍｏｌ）および水酸化リチウム一水和物（０．１７７ｇ；４．１ｍｍｏｌ）のテトラヒドロフラン（１０ｍｌ）および水（１０ｍｌ）中混合物を、７０℃で一晩加熱した。溶媒を減圧下で除去し、溶液をｐＨが５−６になるまで５Ｎ ＨＣｌ溶液で酸性化し、水を減圧下で除去し、真空下で乾燥し、塩化リチウムと混合される粗生成物として標記化合物を得た（１．０８ｇ）。
ＬＣ／ＭＳ 保持時間 １．７２／（ＥＳ^＋） ３２３ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１９Ｎ_２Ｏ_４Ｓ 理論値３２３）。 Description Example 20: 2-{[4- (ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxylic acid

2-{[4- (Ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxylate (0.69 g; 2 .05 mmol) and lithium hydroxide monohydrate (0.177 g; 4.1 mmol) in tetrahydrofuran (10 ml) and water (10 ml) were heated at 70 ° C. overnight. The solvent is removed under reduced pressure, the solution is acidified with 5N HCl solution until the pH is 5-6, the water is removed under reduced pressure, dried under vacuum and titled as a crude product mixed with lithium chloride. Compound was obtained (1.08 g).
LC / MS retention time _{^{1.72 / (ES +) 323 (}} M + H, C 15 H 19 N 2 O 4 S theory 323).

シクロプロピルアミン（０．４ｍｌ；５．５ｍｍｏｌ）を酢酸エチル（１０ｍｌ）で溶解し、４−（４−イソチオシアナトフェニル）モルホリン（６００ｍｇ；２．７２ｍｍｏｌ）を、室温で１０分かけて攪拌しながら滴下した。反応混合物を室温で５時間攪拌した。次いで、溶媒を回転蒸発により除去し、黄色固体として標記化合物を得た（０．７６０ｇ；１００％）。
ＬＣ／ＭＳ 保持時間 １．８９／（ＥＳ^＋） ２７８ （Ｍ＋Ｈ，Ｃ_１４Ｈ_２０Ｎ_３ＯＳ 理論値２７８）。 Description Example 21: N-cyclopropyl-N ′-[4- (4-morpholinyl) phenyl] thiourea

Cyclopropylamine (0.4 ml; 5.5 mmol) was dissolved in ethyl acetate (10 ml) and 4- (4-isothiocyanatophenyl) morpholine (600 mg; 2.72 mmol) was stirred at room temperature for 10 minutes. While dripping. The reaction mixture was stirred at room temperature for 5 hours. The solvent was then removed by rotary evaporation to give the title compound as a yellow solid (0.760 g; 100%).
LC / MS retention time _{^{1.89 / (ES +) 278 (}} M + H, C 14 H 20 N 3 OS theory 278).

エチルアミンのテトラヒドロフラン（２Ｍ溶液、３．７８ｍｌ；７．５７ｍｍｏｌ）および酢酸エチル（１０ｍｌ）中混合物を、アルゴン下で氷浴にて冷却した。次いで、４−（４−イソチオシアナトフェニル）モルホリン（４１７ｍｇ；１．８９ｍｍｏｌ）を、１０分かけて攪拌しながら滴下した。反応混合物を１時間氷浴で攪拌した。次いで、溶媒を回転蒸発により除去し、黄色固体として標記化合物を得た（０．４９８ｇ；９９％）。
ＬＣ／ＭＳ 保持時間 １．９４／（ＥＳ^＋） ２６６ （Ｍ＋Ｈ，Ｃ_１３Ｈ_２０Ｎ_３ＯＳ 理論値２６６）． Description Example 22: N-ethyl-N ′-[4- (4-morpholinyl) phenyl] thiourea

A mixture of ethylamine in tetrahydrofuran (2M solution, 3.78 ml; 7.57 mmol) and ethyl acetate (10 ml) was cooled in an ice bath under argon. Then, 4- (4-isothiocyanatophenyl) morpholine (417 mg; 1.89 mmol) was added dropwise with stirring over 10 minutes. The reaction mixture was stirred in an ice bath for 1 hour. The solvent was then removed by rotary evaporation to give the title compound as a yellow solid (0.498 g; 99%).
LC / MS retention time _{^{1.94 / (ES +) 266 (}} M + H, C 13 H 20 N 3 OS theory 266).

Ｎ，Ｎ−ジエチル−４−イソチオシアナトアニリン（０．３７ｍｍｏｌ、８３ｍｇ）および２−アミノエタノール（０．３７ｍｍｏｌ、２３μＬ）を酢酸エチルで溶解し、室温で１時間攪拌した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ １．５０分、ｍ／ｚ（ＥＳ^＋） ２６８ （Ｍ＋Ｈ，Ｃ_１３Ｈ_２１Ｎ_３ＯＳ＋Ｈ 理論値２６８）。 Description Example 23: N- [4- (diethylamino) phenyl] -N ′-(2-hydroxyethyl) thiourea

N, N-diethyl-4-isothiocyanatoaniline (0.37 mmol, 83 mg) and 2-aminoethanol (0.37 mmol, 23 μL) were dissolved in ethyl acetate and stirred at room temperature for 1 hour. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 1.50 ^{min, m / z (ES +)} 268 (M + H, C 13 H 21 N 3 OS + H theory 268).

Ｎ，Ｎ−ジエチル−４−イソチオシアナトアニリン（０．３７ｍｍｏｌ、８３ｍｇ）およびエチルアミン（ＴＨＦ中２Ｍ溶液、１．００ｍｍｏｌ、５００μＬ）を酢酸エチルで溶解し、室温で１時間攪拌した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ １．７３分、ｍ／ｚ（ＥＳ^＋） ２５２ （Ｍ＋Ｈ，Ｃ_１３Ｈ_２１Ｎ_３Ｓ＋Ｈ 理論値２５２）。 Description Example 24: N- [4- (diethylamino) phenyl] -N′-ethylthiourea

N, N-diethyl-4-isothiocyanatoaniline (0.37 mmol, 83 mg) and ethylamine (2M solution in THF, 1.00 mmol, 500 μL) were dissolved in ethyl acetate and stirred at room temperature for 1 hour. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 1.73 ^{min, m / z (ES +)} 252 (M + H, C 13 H 21 N 3 S + H theory 252).

１−［（ジフルオロメチル）オキシ］−４−イソチオシアナトベンゼン（０．３７ｍｍｏｌ、７５ｍｇ）およびエチルアミン（ＴＨＦ中２Ｍ溶液、１．００ｍｍｏｌ、５００μＬ）を酢酸エチルで溶解し、室温で１時間攪拌した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ ２．７６分、ｍ／ｚ（ＥＳ^＋） ２４７ （Ｍ＋Ｈ，Ｃ_１０Ｈ_１２Ｆ_２Ｎ_２ＯＳ＋Ｈ 理論値２４７）。 Description Example 25: N- {4-[(difluoromethyl) oxy] phenyl} -N′-ethylthiourea

1-[(Difluoromethyl) oxy] -4-isothiocyanatobenzene (0.37 mmol, 75 mg) and ethylamine (2M solution in THF, 1.00 mmol, 500 μL) were dissolved in ethyl acetate and stirred at room temperature for 1 hour. . The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 2.76 ^{min, m / z (ES +)} 247 (M + H, C 10 H 12 F 2 N 2 OS + H theory 247).

エチルアミン（ＴＨＦ中２Ｍ溶液、２．００ｍｍｏｌ、１ｍＬ）の酢酸エチル（３ｍＬ）中溶液を、４−（４−イソチオシアナトフェニル）モルホリンに加えた。溶液を室温で１時間攪拌した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ ２．２９分、ｍ／ｚ（ＥＳ^＋） ２６６ （Ｍ＋Ｈ，Ｃ_１３Ｈ_１９Ｎ_３ＯＳ＋Ｈ 理論値２６６）。 Description Example 26: N-ethyl-N ′-[4- (4-morpholinyl) phenyl] thiourea

A solution of ethylamine (2M solution in THF, 2.00 mmol, 1 mL) in ethyl acetate (3 mL) was added to 4- (4-isothiocyanatophenyl) morpholine. The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 2.29 ^{min, m / z (ES +)} 266 (M + H, C 13 H 19 N 3 OS + H theory 266).

メチルアミン（エタノール中３３％溶液、１ｍＬ）の酢酸エチル（３ｍＬ）中溶液を、４−（４−イソチオシアナトフェニル）モルホリンに加えた。溶液を室温で１時間攪拌した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ ２．０７分、ｍ／ｚ（ＥＳ^＋） ２５２ （Ｍ＋Ｈ，Ｃ_１２Ｈ_１７Ｎ_３ＯＳ＋Ｈ 理論値２５２）。 Description Example 27: N-methyl-N ′-[4- (4-morpholinyl) phenyl] thiourea

A solution of methylamine (33% solution in ethanol, 1 mL) in ethyl acetate (3 mL) was added to 4- (4-isothiocyanatophenyl) morpholine. The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 2.07 ^{min, m / z (ES +)} 252 (M + H, C 12 H 17 N 3 OS + H theory 252).

Ｂｏｃ−保護−Ｎ−（４−アミノフェニル）−Ｎ’−メチルチオ尿素（０．６７ｍｍｏｌ、１８８ｍｇ）および３−クロロ−２，４−ペンタンジオン（１．０１ｍｍｏｌ、１０２μＬ）をエタノール（２．５ｍＬ）中で合し、マイクロ波にて２０分間１００℃で加熱した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ ３．０８分、ｍ／ｚ（ＥＳ^＋） ３６２ （Ｍ＋Ｈ，Ｃ_１８Ｈ_２３Ｎ_３Ｏ_３Ｓ＋Ｈ 理論値３６２）。 Description Example 28: Boc-protected-1- {2-[(4-aminophenyl) imino] -3,4-dimethyl-2,3-dihydro-1,3-triazol-5-yl} ethanone

Boc-protected-N- (4-aminophenyl) -N′-methylthiourea (0.67 mmol, 188 mg) and 3-chloro-2,4-pentanedione (1.01 mmol, 102 μL) in ethanol (2.5 mL) Combined and heated in microwave at 100 ° C. for 20 minutes. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 3.08 ^{min, m / z (ES +)} 362 (M + H, C 18 H 23 N 3 O 3 S + H theory 362).

Ｂｏｃ−保護−Ｎ−（４−アミノフェニル）−Ｎ’−エチルチオ尿素（０．６７ｍｍｏｌ、１９８ｍｇ）および３−クロロ−２，４−ペンタンジオン（１．０１ｍｍｏｌ、１０２μＬ）をエタノール（２．５ｍＬ）中で合し、マイクロ波にて２０分間１００℃で加熱した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ ３．２７分、ｍ／ｚ（ＥＳ^＋） ３７６ （Ｍ＋Ｈ，Ｃ_１９Ｈ_２５Ｎ_３Ｏ_３Ｓ＋Ｈ 理論値３７６）。 Description Example 29: Boc-protected-1- {2-[(4-aminophenyl) imino] -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone

Boc-protected-N- (4-aminophenyl) -N′-ethylthiourea (0.67 mmol, 198 mg) and 3-chloro-2,4-pentanedione (1.01 mmol, 102 μL) in ethanol (2.5 mL) Combined and heated in microwave at 100 ° C. for 20 minutes. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 3.27 ^{min, m / z (ES +)} 376 (M + H, C 19 H 25 N 3 O 3 S + H theory 376).

Ｂｏｃ−保護−Ｎ−（４−アミノフェニル）−Ｎ’−（２−ヒドロキシエチル）チオ尿素（０．６７ｍｍｏｌ、２０８ｍｇ）および３−クロロ−２，４−ペンタンジオン（１．０１ｍｍｏｌ、１０２μＬ）をエタノール（２．５ｍＬ）中で合し、マイクロ波にて１００℃で２０分間加熱した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ ２．９５分、ｍ／ｚ（ＥＳ^＋） ３９２ （Ｍ＋Ｈ，Ｃ_１９Ｈ_２５Ｎ_３Ｏ_４Ｓ＋Ｈ 理論値３９２）。 Description 30: Boc-protected-1- [2-[(4-aminophenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5 Il] Ethanon

Boc-protected-N- (4-aminophenyl) -N ′-(2-hydroxyethyl) thiourea (0.67 mmol, 208 mg) and 3-chloro-2,4-pentanedione (1.01 mmol, 102 μL) Combined in ethanol (2.5 mL) and heated in microwave at 100 ° C. for 20 minutes. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 2.95 ^{min, m / z (ES +)} 392 (M + H, C 19 H 25 N 3 O 4 S + H theory 392).

メチルアミン（エタノール中３３％、３ｍＬ）を、Ｂｏｃ−保護−４−イソチオシアナトアニリン（０．６７ｍｍｏｌ、１６７ｍｇ）に加え、溶液を室温で１時間攪拌した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ ２．７３分、ｍ／ｚ（ＥＳ^＋） ２８２ （Ｍ＋Ｈ，Ｃ_１３Ｈ_１９Ｎ_３Ｏ_２Ｓ＋Ｈ 理論値２８２）。 Description Example 31: Boc-protected-N- (4-aminophenyl) -N′-methylthiourea

Methylamine (33% in ethanol, 3 mL) was added to Boc-protected-4-isothiocyanatoaniline (0.67 mmol, 167 mg) and the solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 2.73 ^{min, m / z (ES +)} 282 (M + H, C 13 H 19 N 3 O 2 S + H theory 282).

エチルアミン（ＴＨＦ中２Ｍ、３ｍＬ）を、Ｂｏｃ−保護−４−イソチオシアナトアニリン（０．６７ｍｍｏｌ、１６７ｍｇ）に加え、溶液を室温で１時間攪拌した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ ２．９１分、ｍ／ｚ（ＥＳ^＋） ２９６ （Ｍ＋Ｈ，Ｃ_１４Ｈ_２１Ｎ_３Ｏ_２Ｓ＋Ｈ 理論値２９６）。 Description Example 32: Boc-protected-N- (4-aminophenyl) -N'-ethylthiourea

Ethylamine (2M in THF, 3 mL) was added to Boc-protected-4-isothiocyanatoaniline (0.67 mmol, 167 mg) and the solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 2.91 ^{min, m / z (ES +)} 296 (M + H, C 14 H 21 N 3 O 2 S + H theory 296).

２−アミノエタノール（０．６７ｍｍｏｌ、４０μＬ）の酢酸エチル（３ｍＬ）中溶液を、Ｂｏｃ−保護−４−イソチオシアナトアニリン（０．６７ｍｍｏｌ、１６７ｍｇ）に加え、溶液を室温で１時間攪拌した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ ２．５６分、ｍ／ｚ（ＥＳ^＋） ３１２ （Ｍ＋Ｈ，Ｃ_１４Ｈ_２１Ｎ_３Ｏ_３Ｓ＋Ｈ 理論値３１２）。 Description Example 33: Boc-protected-N- (4-aminophenyl) -N ′-(2-hydroxyethyl) thiourea

A solution of 2-aminoethanol (0.67 mmol, 40 μL) in ethyl acetate (3 mL) was added to Boc-protected-4-isothiocyanatoaniline (0.67 mmol, 167 mg) and the solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 2.56 ^{min, m / z (ES +)} 312 (M + H, C 14 H 21 N 3 O 3 S + H theory 312).

２−アミノエタノールを酢酸エチル（３ｍＬ）で溶解した。４−イソチオシアナト−Ｎ，Ｎ−ジメチルアニリンを酢酸エチル（１ｍＬ）で溶解し、２−アミノエタノール溶液に滴下した。得られた溶液を室温で４時間攪拌した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく用いた。
ＬＣＭＳ Ｒｔ １．５４分、ｍ／ｚ（ＥＳ^＋） ２４０ （Ｍ＋Ｈ，Ｃ_１１Ｈ_１７Ｎ_３ＯＳ＋Ｈ 理論値２４０）。 Description Example 34: N- [4- (dimethylamino) phenyl] -N ′-(2-hydroxyethyl) thiourea

2-Aminoethanol was dissolved in ethyl acetate (3 mL). 4-Isothiocyanato-N, N-dimethylaniline was dissolved in ethyl acetate (1 mL) and added dropwise to the 2-aminoethanol solution. The resulting solution was stirred at room temperature for 4 hours. The solvent was removed in vacuo to give the title compound that was used without further purification.
LCMS Rt 1.54 ^{min, m / z (ES +)} 240 (M + H, C 11 H 17 N 3 OS + H theory 240).

１−イソチオシアナト−４−メチルベンゼン（０．３７ｍｍｏｌ、５６ｍｇ）および２−アミノエタノール（０．３７ｍｍｏｌ、２３μＬ）を酢酸エチル（３ｍＬ）で溶解し、室温で１時間振盪した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ ２．１８分、ｍ／ｚ（ＥＳ^＋） ２１１ （Ｍ＋Ｈ，Ｃ_１０Ｈ_１４Ｎ_２ＯＳ＋Ｈ 理論値２１１）。 Description Example 35: N- (2-hydroxyethyl) -N ′-(4-methylphenyl) thiourea

1-isothiocyanato-4-methylbenzene (0.37 mmol, 56 mg) and 2-aminoethanol (0.37 mmol, 23 μL) were dissolved in ethyl acetate (3 mL) and shaken at room temperature for 1 hour. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 2.18 ^{min, m / z (ES +)} 211 (M + H, C 10 H 14 N 2 OS + H theory 211).

１−エチル−４−イソチオシアナトベンゼン（０．３７ｍｍｏｌ、６１ｍｇ）およびエチルアミン（ＴＨＦ中２Ｍ、１００μＬ）を酢酸エチル（３ｍＬ）で溶解し、室温で１時間振盪した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ ２．８５分、ｍ／ｚ（ＥＳ^＋） ２０９ （Ｍ＋Ｈ，Ｃ_１１Ｈ_１６Ｎ_２Ｓ＋Ｈ 理論値２０９）。 Description Example 36: N-ethyl-N ′-(4-ethylphenyl) thiourea

1-ethyl-4-isothiocyanatobenzene (0.37 mmol, 61 mg) and ethylamine (2M in THF, 100 μL) were dissolved in ethyl acetate (3 mL) and shaken at room temperature for 1 hour. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 2.85 ^{min, m / z (ES +)} 209 (M + H, C 11 H 16 N 2 S + H theory 209).

イソチオシアナトベンゼン（０．３７ｍｍｏｌ、５０ｍｇ）およびエチルアミン（ＴＨＦ中２Ｍ、１００μＬ）を酢酸エチル（３ｍＬ）で溶解し、室温で１時間振盪した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ ２．２５分。ｍ／ｚ（ＥＳ^＋） １８１ （Ｍ＋Ｈ，Ｃ_９Ｈ_１２Ｎ_２Ｓ＋Ｈ 理論値１８１）。 Description Example 37: N-ethyl-N′-phenylthiourea

Isothiocyanatobenzene (0.37 mmol, 50 mg) and ethylamine (2M in THF, 100 μL) were dissolved in ethyl acetate (3 mL) and shaken at room temperature for 1 hour. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 2.25 min. ^{m / z (ES +) 181} (M + H, C 9 H 12 N 2 S + H theory 181).

１−イソチオシアナト−４−メチルベンゼン（０．３７ｍｍｏｌ、５６ｍｇ）およびエチルアミン（ＴＨＦ中２Ｍ、１００μＬ）を酢酸エチル（３ｍＬ）で溶解し、室温で１時間振盪した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ ２．５９分、ｍ／ｚ（ＥＳ^＋） １９５ （Ｍ＋Ｈ，Ｃ_１０Ｈ_１４Ｎ_２Ｓ＋Ｈ 理論値１９５）。 Description Example 38: N-ethyl-N ′-(4-methylphenyl) thiourea

1-isothiocyanato-4-methylbenzene (0.37 mmol, 56 mg) and ethylamine (2M in THF, 100 μL) were dissolved in ethyl acetate (3 mL) and shaken at room temperature for 1 hour. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 2.59 ^{min, m / z (ES +)} 195 (M + H, C 10 H 14 N 2 S + H theory 195).

４−イソチオシアナト−Ｎ，Ｎ−ジメチルアニリン（０．３７ｍｍｏｌ、６６ｍｇ）およびエチルアミン（ＴＨＦ中２Ｍ、１００μＬ）を酢酸エチル（３ｍＬ）で溶解し、室温で１時間振盪した。溶媒を真空中で除去し、標記化合物を得、さらに精製することなく直接用いた。
ＬＣＭＳ Ｒｔ １．９０分、ｍ／ｚ（ＥＳ^＋） ２２４ （Ｍ＋Ｈ，Ｃ_１１Ｈ_１７Ｎ_３Ｓ＋Ｈ 理論値２２４）。 Description Example 39 N- [4- (dimethylamino) phenyl] -N′-ethylthiourea

4-Isothiocyanato-N, N-dimethylaniline (0.37 mmol, 66 mg) and ethylamine (2M in THF, 100 μL) were dissolved in ethyl acetate (3 mL) and shaken at room temperature for 1 hour. The solvent was removed in vacuo to give the title compound that was used directly without further purification.
LCMS Rt 1.90 ^{min, m / z (ES +)} 224 (M + H, C 11 H 17 N 3 S + H theory 224).

攪拌しながら、エチレンジアミン（２２μＬ、０．３３ｍｍｏｌ）の酢酸エチル（２ｍＬ）中溶液に、４−エトキシフェニルイソチオシアン酸（０．０５９ｇ、０．３３ｍｍｏｌ）を滴下した。反応物を室温で一晩攪拌した。次いで、窒素流下で溶媒を除去し、白色固体として粗標記化合物を得、（ＬＣＭＳで７５％）、さらに精製することなく次の工程で直接用いた。
ＬＣＭＳ Ｒｔ １．７３分、ｍ／ｚ（ＥＳ^＋） ２４０ （Ｍ＋Ｈ，Ｃ_１１Ｈ_１７Ｎ_３ＯＳ＋Ｈ 理論値２４０）。 Description Example 40: N- (2-aminoethyl) -N ′-[4- (ethyloxy) phenyl] thiourea

While stirring, 4-ethoxyphenylisothiocyanic acid (0.059 g, 0.33 mmol) was added dropwise to a solution of ethylenediamine (22 μL, 0.33 mmol) in ethyl acetate (2 mL). The reaction was stirred at room temperature overnight. The solvent was then removed under a stream of nitrogen to give the crude title compound as a white solid (75% by LCMS), which was used directly in the next step without further purification.
LCMS Rt 1.73 ^{min, m / z (ES +)} 240 (M + H, C 11 H 17 N 3 OS + H theory 240).

攪拌しながら、シクロプロピルアミン（２３μＬ、０．３３ｍｍｏｌ）の酢酸エチル（２ｍＬ）中溶液に、４−エトキシフェニルイソチオシアン酸（０．０５９ｇ、０．３３ｍｍｏｌ）を滴下した。反応物を室温で一晩攪拌した。その後、さらに一部の酢酸エチル（０．５ｍＬ）中シクロプロピルアミン（０．１６ｍｍｏｌ）を加え、反応物を３時間攪拌し続けた。次いで、窒素流下で溶媒を除去し、白色固体として粗標記化合物を得、（ＬＣＭＳで完全に変換し）、さらに精製することなく次の工程で用いた。
ＬＣＭＳ Ｒｔ ２．６０分。ｍ／ｚ（ＥＳ^＋） ２３７ （Ｍ＋Ｈ，Ｃ_１２Ｈ_１６Ｎ_２ＯＳ＋Ｈ 理論値２３７） Description 41: N-cyclopropyl-N ′-[4- (ethyloxy) phenyl] thiourea

With stirring, 4-ethoxyphenylisothiocyanic acid (0.059 g, 0.33 mmol) was added dropwise to a solution of cyclopropylamine (23 μL, 0.33 mmol) in ethyl acetate (2 mL). The reaction was stirred at room temperature overnight. Thereafter, a further portion of cyclopropylamine (0.16 mmol) in ethyl acetate (0.5 mL) was added and the reaction continued to stir for 3 hours. The solvent was then removed under a stream of nitrogen to give the crude title compound as a white solid (completely converted by LCMS) and used in the next step without further purification.
LCMS Rt 2.60 min. m / z (ES ⁺ ) 237 (M + H, C ₁₂ H ₁₆ N ₂ OS + H Theoretical value 237)

記載例４０に記載の製法にしたがって、粗標記化合物（ＬＣＭＳで８１％）を、酢酸エチル（３ｍＬ）中で２，２，２−トリフルオロメチルエチルアミン（０．０３ｍＬ、０．３３ｍｍｏｌ）および４−エチルフェニルイソチオシアン酸（０．０５４ｇ、０．３３ｍｍｏｌ）から調製し、さらに精製することなく次の工程で直接用いた。
ＬＣＭＳ Ｒｔ ３．１６分。ｍ／ｚ（ＥＳ^＋） ２６３ （Ｍ＋Ｈ，Ｃ_１１Ｈ_１３Ｆ_３Ｎ_２Ｓ＋Ｈ 理論値２６３） Description Example 42: N- (4-ethylphenyl) -N ′-(2,2,2-trifluoroethyl) thiourea

The crude title compound (81% by LCMS) was prepared according to the procedure described in Description 40, and 2,2,2-trifluoromethylethylamine (0.03 mL, 0.33 mmol) and 4- Prepared from ethylphenylisothiocyanate (0.054 g, 0.33 mmol) and used directly in the next step without further purification.
LCMS Rt 3.16min. m / z (ES ⁺ ) 263 (M + H, C ₁₁ H ₁₃ F ₃ N ₂ S + H Theoretical value 263)

記載例４０に記載の製法にしたがって、粗標記化合物（ＬＣＭＳで７３％）を、酢酸エチル（３ｍＬ）中で２，２，２−トリフルオロメチルエチルアミン（０．０３ｍＬ、０．３３ｍｍｏｌ）および４−（エチルオキシ）フェニルイソチオシアン酸（０．０５９ｇ、０．３３ｍｍｏｌ）から調製し、さらに精製することなく次の工程で直接用いた。
ＬＣＭＳ Ｒｔ ２．９６分。ｍ／ｚ（ＥＳ^＋） ２７９ （Ｍ＋Ｈ，Ｃ_１１Ｈ_１３Ｆ_３Ｎ_２ＯＳ＋Ｈ 理論値２７９） Description Example 43: N- [4- (ethyloxy) phenyl] -N ′-(2,2,2-trifluoroethyl) thiourea

The crude title compound (73% by LCMS) was prepared according to the procedure described in Description 40, and 2,2,2-trifluoromethylethylamine (0.03 mL, 0.33 mmol) and 4- Prepared from (ethyloxy) phenylisothiocyanic acid (0.059 g, 0.33 mmol) and used directly in the next step without further purification.
LCMS Rt 2.96 min. m / z (ES ⁺ ) 279 (M + H, C ₁₁ H ₁₃ F ₃ N ₂ OS + H Theoretical value 279)

Ｎ−［４−（エチルオキシ）フェニル］−Ｎ’−（２−ヒドロキシエチル）チオ尿素（０．３００ｇ、１．２５ｍｍｏｌ）および３−クロロ−２，４−ペンタンジオン（０．１７６ｇ；１．３１ｍｍｏｌ）のトルエン（５ｍｌ）中混合物を、９０℃で１５分間加熱した。溶媒を減圧下で蒸発させた。残存物質をメタノール／酢酸エチルから再結晶し、白色固体として標記化合物を得た（０．２９６ｇ）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．１７−７．０８（２Ｈ，ｍ），７．０２−６．９６（２Ｈ，ｍ），４．２１（２Ｈ，ｍ），４．０３（２Ｈ，ｍ），３．７７（２Ｈ，ｍ），２．６６（３Ｈ，ｓ），２．４０（３Ｈ，ｓ），１．３３（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．２１／（ＥＳ^＋） ３２１ （Ｍ＋Ｈ，Ｃ_１６Ｈ_２１Ｎ_２Ｏ_３Ｓ 理論値３２１）。 Example 1: 1- [2-{[4- (Ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] Ethanone hydrochloride

N- [4- (ethyloxy) phenyl] -N ′-(2-hydroxyethyl) thiourea (0.300 g, 1.25 mmol) and 3-chloro-2,4-pentanedione (0.176 g; 1.31 mmol) ) In toluene (5 ml) was heated at 90 ° C. for 15 minutes. The solvent was evaporated under reduced pressure. The remaining material was recrystallized from methanol / ethyl acetate to give the title compound as a white solid (0.296 g).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.17-7.08 (2H, m), 7.02-6.96 (2H, m), 4.21 (2H, m), 4.03 (2H, m), 3.77 (2H, m), 2.66 (3H, s), 2.40 (3H, s), 1.33 (3H, t, J = 7 Hz); LC / MS retention time _{^{2.21 / (ES +) 321 (}} M + H, C 16 H 21 N 2 O 3 S theory 321).

標記化合物（０．１９８ｇ）を、実施例１に記載の製法によって、トルエン（４ｍｌ）中でＮ−（４−エチルフェニル）−Ｎ’−（２−ヒドロキシエチル）チオ尿素［ヨーロッパ特許ＥＰ００２１８０６］（０．２００ｇ；０．８９ｍｍｏｌ）、および３−クロロ−２，４−ペンタンジオン（１．０５ｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．２５（２Ｈ，ｍ），７．０３（２Ｈ，ｍ），４．１２（２Ｈ，ｍ），３．７３（２Ｈ，ｍ），２．６６（３Ｈ，ｓ），２．６３−２．５７（２Ｈ，ｍ），２．３８（３Ｈ，ｓ），１．１７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．５７／（ＥＳ^＋） ３０５ （Ｍ＋Ｈ，Ｃ_１６Ｈ_２１Ｎ_２Ｏ_２Ｓ 理論値３０５）。 Example 2: 1- [2-[(4-Ethylphenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone Hydrochloric acid salt

The title compound (0.198 g) is prepared according to the procedure described in Example 1 in N- (4-ethylphenyl) -N ′-(2-hydroxyethyl) thiourea [European Patent EP0021806] in toluene (4 ml) ( 0.200 g; 0.89 mmol), and 3-chloro-2,4-pentanedione (1.05 mol).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.25 (2H, m), 7.03 (2H, m), 4.12 (2H, m), 3.73 (2H, m), 2. 66 (3H, s), 2.63-2.57 (2H, m), 2.38 (3H, s), 1.17 (3H, t, J = 7 Hz); LC / MS retention time 2.57 / (ES ⁺ ) 305 (M + H, C ₁₆ H ₂₁ N ₂ O ₂ S theoretical value 305).

Ｎ−［４−（エチルオキシ）フェニル］−Ｎ’−［２−（メチルオキシ）エチル］チオ尿素（０．２００ｇ；０．７８ｍｍｏｌ）、および３−クロロ−２，４−ペンタンジオン（１．０５ｍｍｏｌ）のエタノール（５ｍｌ）中混合物を、９０℃で１５分間加熱した。エタノールを真空中で蒸発させることにより、所望の生成物を単離した。残存物質を、酢酸エチルと重炭酸ナトリウム溶液の間に分配し、硫酸ナトリウムで乾燥し、濾過し、真空中で蒸発させた。酢酸エチル／ｎ−ペンタンから再結晶し、黄色固体として標記化合物を得た（１２３ｍｇ）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３） δ：６．９７（２Ｈ，ｍ），６．９０（２Ｈ，ｍ），４．１２（２Ｈ，ｍ），４．０４（２Ｈ，ｍ），３．７０（２Ｈ，ｍ），３．３６（３Ｈ，ｓ），２．６６（３Ｈ，ｓ），２．２７（３Ｈ，ｓ），１．４１（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．８７／（ＥＳ^＋） ３３５ （Ｍ＋Ｈ，Ｃ_１７Ｈ_２３Ｎ_２Ｏ_３Ｓ 理論値３３５）。 Example 3: 1- {2-{[4- (Ethyloxy) phenyl] imino} -4-methyl-3- [2- (methyloxy) ethyl] -2,3-dihydro-1,3-triazole-5 -Il} ethanone

N- [4- (ethyloxy) phenyl] -N ′-[2- (methyloxy) ethyl] thiourea (0.200 g; 0.78 mmol), and 3-chloro-2,4-pentanedione (1.05 mmol) ) In ethanol (5 ml) was heated at 90 ° C. for 15 minutes. The desired product was isolated by evaporating the ethanol in vacuo. The remaining material was partitioned between ethyl acetate and sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated in vacuo. Recrystallization from ethyl acetate / n-pentane gave the title compound as a yellow solid (123 mg).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.97 (2H, m), 6.90 (2H, m), 4.12 (2H, m), 4.04 (2H, m), 3.70 (2H, m), 3.36 (3H, s), 2.66 (3H, s), 2.27 (3H, s), 1.41 (3H, t, J = 7 Hz); LC / MS retention time _{^{2.87 / (ES +) 335 (}} M + H, C 17 H 23 N 2 O 3 S theory 335).

Ｎ−（２−ヒドロキシエチル）−Ｎ’−｛４−［（トリフルオロメチル）オキシ］フェニル｝チオ尿素（０．２００ｇ；０．７１ｍｍｏｌ）、および３−クロロ−２，４−ペンタンジオン（０．１ｍｌ；０．７５ｍｍｏｌ）のトルエン（１０ｍｌ）中混合物を、９５℃で１時間加熱した。トルエンを真空中で蒸発させることにより、所望の生成物を単離した。残存物質を、酢酸エチルと重炭酸ナトリウム溶液の間に分配し、硫酸ナトリウムで乾燥し、濾過し、真空中で蒸発させ、油を得、１００％ジエチルエーテルを用いてシリカゲル上のフラッシュカラムクロマトグラフィーに付して、黄色固体として標記化合物を得た（９２ｍｇ、３６％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３） δ：７．２０（２Ｈ，ｄ，Ｊ＝９Ｈｚ），７．０５（２Ｈ，ｄ，Ｊ＝８Ｈｚ），４．１７（２Ｈ，ｍ），３．９８（２Ｈ，ｍ），３．３５（１Ｈ，ｂｒ ｓ），２．６２（３Ｈ，ｓ），２．３０（３Ｈ，ｓ）；ＬＣ／ＭＳ 保持時間 ２．９４／（ＥＳ^＋） ３６１ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１６Ｆ_３Ｎ_２Ｏ_３Ｓ 理論値３６１）。 Example 4: 1- [3- (2-hydroxyethyl) -4-methyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazole -5-yl] ethanone

N- (2-hydroxyethyl) -N ′-{4-[(trifluoromethyl) oxy] phenyl} thiourea (0.200 g; 0.71 mmol) and 3-chloro-2,4-pentanedione (0 .1 ml; 0.75 mmol) in toluene (10 ml) was heated at 95 ° C. for 1 hour. The desired product was isolated by evaporating the toluene in vacuo. The residual material was partitioned between ethyl acetate and sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated in vacuo to give an oil that was flash column chromatographed on silica gel using 100% diethyl ether. To give the title compound as a yellow solid (92 mg, 36%).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.20 (2H, d, J = 9 Hz), 7.05 (2H, d, J = 8 Hz), 4.17 (2H, m), 3.98 ( 2H, m), 3.35 (1H, br s), 2.62 (3H, s), 2.30 (3H, s); LC / MS retention time 2.94 / (ES ⁺ ) 361 (M + H, _{C 15 H 16 F 3 N 2} O 3 S theory 361).

Ｎ−（２−ヒドロキシエチル）−Ｎ’−［４−（トリフルオロメチル）フェニル］チオ尿素（０．９００ｇ；３．４０ｍｍｏｌ）、および３−クロロ−２，４−ペンタンジオン（０．０１ｍｏｌ）のトルエン（３０ｍｌ）中混合物を、９５℃で３０分間加熱した。トルエンを真空中で蒸発させることにより、所望の生成物を単離した。残存物質を、ジクロロメタンと重炭酸ナトリウム溶液の間に分配し、硫酸ナトリウムで乾燥し、濾過し、真空中で蒸発させ、油を得、ｎ−ペンタン中２０〜７０％酢酸エチルを用いてシリカゲル上のフラッシュカラムクロマトグラフィーに付して、淡黄色固体として標記化合物を得た（１６７ｍｇ、１４％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３） δ：７．６１（２Ｈ，ｄ，Ｊ＝８Ｈｚ），７．１４（２Ｈ，ｄ，Ｊ＝８Ｈｚ），４．１８（２Ｈ，ｍ），４．０１（２Ｈ，ｍ），３．１３（１Ｈ，ｍ），２．６６（３Ｈ，ｓ），２．２８（３Ｈ，ｓ）；ＬＣ／ＭＳ 保持時間 ２．８７／（ＥＳ^＋） ３４５ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１６Ｆ_３Ｎ_２Ｏ_２Ｓ 理論値３４５）。 Example 5: 1- (3- (2-hydroxyethyl) -4-methyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazole-5 Il) Ethanon

N- (2-hydroxyethyl) -N ′-[4- (trifluoromethyl) phenyl] thiourea (0.900 g; 3.40 mmol), and 3-chloro-2,4-pentanedione (0.01 mol) Of toluene in toluene (30 ml) was heated at 95 ° C. for 30 minutes. The desired product was isolated by evaporating the toluene in vacuo. The remaining material was partitioned between dichloromethane and sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated in vacuo to give an oil on silica gel using 20-70% ethyl acetate in n-pentane. Of the title compound as a pale yellow solid (167 mg, 14%).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.61 (2H, d, J = 8 Hz), 7.14 (2H, d, J = 8 Hz), 4.18 (2H, m), 4.01 ( 2H, m), 3.13 (1H, m), 2.66 (3H, s), 2.28 (3H, s); LC / MS retention time 2.87 / (ES ⁺ ) 345 (M + H, C _{15 H 16 F 3 N 2 O} 2 S theory 345).

Ｎ−エチル−Ｎ’−［４−（エチルオキシ）フェニル］チオ尿素（０．２００ｇ；０．８９ｍｍｏｌ）、および３−クロロ−２，４−ペンタンジオン（２．６８ｍｍｏｌ）のトルエン（５ｍｌ）中混合物を、９５℃で２時間加熱した。トルエンを真空中で蒸発させることにより、所望の生成物を単離した。残存物質を、酢酸エチルと重炭酸ナトリウム溶液の間に分配し、硫酸ナトリウムで乾燥し、濾過し、真空中で蒸発させ、油を得、５０：５０ ジクロロメタン／ｎ−ペンタン〜ジクロロメタン中５％メタノールを用いてシリカゲル上のフラッシュカラムクロマトグラフィーに付して、エーテル性塩酸で処理し、淡黄色固体として標記化合物を得た（９６ｍｇ、３５％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．１０（２Ｈ，ｄ，Ｊ＝９Ｈｚ），６．９７（２Ｈ，ｄ，Ｊ＝９Ｈｚ），４．１３（２Ｈ，ｍ），４．０３（２Ｈ，ｍ），２．６３（３Ｈ，ｓ），２．４０（３Ｈ，ｓ），１．３０（６Ｈ，ｍ）；ＬＣ／ＭＳ 保持時間 ２．５６／（ＥＳ^＋） ３０５ （Ｍ＋Ｈ，Ｃ_１６Ｈ_２１Ｎ_２Ｏ_２Ｓ 理論値３０５）。 Example 6: 1- (3-Ethyl-2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone hydrochloride

A mixture of N-ethyl-N ′-[4- (ethyloxy) phenyl] thiourea (0.200 g; 0.89 mmol) and 3-chloro-2,4-pentanedione (2.68 mmol) in toluene (5 ml). Was heated at 95 ° C. for 2 hours. The desired product was isolated by evaporating the toluene in vacuo. The residual material was partitioned between ethyl acetate and sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated in vacuo to give an oil, 50:50 dichloromethane / n-pentane to 5% methanol in dichloromethane. Was subjected to flash column chromatography on silica gel and treated with ethereal hydrochloric acid to give the title compound as a pale yellow solid (96 mg, 35%).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.10 (2H, d, J = 9 Hz), 6.97 (2H, d, J = 9 Hz), 4.13 (2H, m), 4.03 (2H, m), 2.63 (3H, s), 2.40 (3H, s), 1.30 (6H, m); LC / MS retention time 2.56 / (ES ⁺ ) 305 (M + H, _{C 16 H 21 N 2 O 2} S theory 305).

Ｎ−［４−（エチルオキシ）フェニル］−Ｎ’−（２−ヒドロキシエチル）チオ尿素（０．２００ｇ；０．８３ｍｍｏｌ）および３−クロロ−２−ブタノン（０．５５ｍｌ；５．４２ｍｍｏｌ）のトルエン（５ｍｌ）中混合物を、９０℃で１６時間加熱した。溶媒を減圧下で蒸発させた。残存物質を、メタノール／酢酸エチルから再結晶し、白色固体として標記化合物を得た（９０ｍｇ、３７％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：１１．４０（１Ｈ ｂｒ ｓ），７．３５（２Ｈ，ｄ，Ｊ＝９Ｈｚ），７．０６（２Ｈ，ｍ），４．３０（２Ｈ，ｍ），４．０７（２Ｈ，ｍ），３．７８（２Ｈ，ｍ），３．４０（１Ｈ ｂｒ ｓ），２．２５（３Ｈ，ｓ），２．１７（３Ｈ，ｓ），１．３２（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 １．６７／（ＥＳ^＋） ２９３ （Ｍ＋Ｈ，Ｃ_１５Ｈ_２１Ｎ_２Ｏ_２Ｓ 理論値２９３）。 Example 7: 2- [2-{[4- (Ethyloxy) phenyl] imino} -4,5-dimethyl-1,3-triazol-3 (2H) -yl] ethanol hydrochloride

N- [4- (ethyloxy) phenyl] -N '-(2-hydroxyethyl) thiourea (0.200 g; 0.83 mmol) and 3-chloro-2-butanone (0.55 ml; 5.42 mmol) in toluene The mixture in (5 ml) was heated at 90 ° C. for 16 hours. The solvent was evaporated under reduced pressure. The remaining material was recrystallized from methanol / ethyl acetate to give the title compound as a white solid (90 mg, 37%).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 11.40 (1H br s), 7.35 (2H, d, J = 9 Hz), 7.06 (2H, m), 4.30 (2H, m ), 4.07 (2H, m), 3.78 (2H, m), 3.40 (1H br s), 2.25 (3H, s), 2.17 (3H, s), 1.32 (3H, t, J = 7 Hz); LC / MS retention time 1.67 / (ES ⁺ ) 293 (M + H, C ₁₅ H ₂₁ N ₂ O ₂ S theoretical 293).

標記化合物（０．１４６ｇ）を、実施例６に記載の製法によって、トルエン（５ｍｌ）中でＮ−（４−ブチルフェニル）−Ｎ’−（２−ヒドロキシエチル）チオ尿素（０．２００ｇ；０．８０ｍｍｏｌ）、および３−クロロ−２，４−ペンタンジオン（１．２ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．２２（２Ｈ，ｄ，Ｊ＝８Ｈｚ），７．０３（２Ｈ，ｍ），４．１４（２Ｈ，ｍ），３．７１（２Ｈ，ｍ），２．６５（３Ｈ，ｓ），２．５７（２Ｈ，ｔ，Ｊ＝７Ｈｚ），２．３５（３Ｈ，ｓ），１．５６（２Ｈ，ｍ），１．３０（２Ｈ，ｍ），０．９０（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ３．０７／（ＥＳ^＋） ３３３ （Ｍ＋Ｈ，Ｃ_１８Ｈ_２５Ｎ_２Ｏ_２Ｓ 理論値３３３）。 Example 8: 1- [2-[(4-Butylphenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone Hydrochloric acid salt

The title compound (0.146 g) was prepared according to the procedure described in Example 6 in toluene (5 ml) with N- (4-butylphenyl) -N ′-(2-hydroxyethyl) thiourea (0.200 g; 0 .80 mmol), and 3-chloro-2,4-pentanedione (1.2 mmol).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.22 (2H, d, J = 8 Hz), 7.03 (2H, m), 4.14 (2H, m), 3.71 (2H, m ), 2.65 (3H, s), 2.57 (2H, t, J = 7 Hz), 2.35 (3H, s), 1.56 (2H, m), 1.30 (2H, m) , 0.90 (3H, t, J = 7 Hz); LC / MS retention time 3.07 / (ES ⁺ ) 333 (M + H, C ₁₈ H ₂₅ N ₂ O ₂ S theoretical 333).

標記化合物（０．１０５ｇ）を、実施例６に記載の製法によって、トルエン（５ｍｌ）中でＮ−［４−（エチルオキシ）フェニル］−Ｎ’−（３−ヒドロキシプロピル）チオ尿素（０．２００ｇ；０．８６ｍｍｏｌ）、および３−クロロ−２，４−ペンタンジオン（１．２９ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．１３（２Ｈ，ｄ，Ｊ＝９Ｈｚ），６．９７（２Ｈ，ｄ，Ｊ＝９Ｈｚ），６．８４−５．６８（２Ｈ，ｂｒ ｓ），４．１８（２Ｈ，ｍ），４．０３（２Ｈ，ｍ），３．５２（２Ｈ，ｍ），２．６３（３Ｈ，ｓ），２．３９（３Ｈ，ｓ），１．９０（２Ｈ，ｍ），１．３２（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．３１／（ＥＳ^＋） ３３５ （Ｍ＋Ｈ，Ｃ_１７Ｈ_２３Ｎ_２Ｏ_３Ｓ 理論値３３５）。 Example 9: 1- [2-{[4- (Ethyloxy) phenyl] imino} -3- (3-hydroxypropyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] Ethanone hydrochloride

The title compound (0.105 g) was prepared according to the procedure described in Example 6 in N- [4- (ethyloxy) phenyl] -N ′-(3-hydroxypropyl) thiourea (0.200 g) in toluene (5 ml). 0.86 mmol), and 3-chloro-2,4-pentanedione (1.29 mmol).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.13 (2H, d, J = 9 Hz), 6.97 (2H, d, J = 9 Hz), 6.84-5.68 (2H, br s ), 4.18 (2H, m), 4.03 (2H, m), 3.52 (2H, m), 2.63 (3H, s), 2.39 (3H, s), 1.90. (2H, m), 1.32 (3H, t, J = 7 Hz); LC / MS retention time 2.31 / (ES ⁺ ) 335 (M + H, C ₁₇ H ₂₃ N ₂ O ₃ S theoretical 335).

Ｎ−（２−ヒドロキシエチル）−Ｎ’−［４−（４−モルホリニル）フェニル］チオ尿素（０．２００ｇ；０．７１ｍｍｏｌ）、および３−クロロ−２，４−ペンタンジオン（０．１３ｍｌ；１．０７ｍｍｏｌ）トルエン（１０ｍｌ）中混合物を９５℃で２時間加熱し、過剰の３−クロロ−２，４−ペンタンジオン（０．２６ｍｌ；２．１４ｍｍｏｌ）を少量ずつ加えた。得られた混合物を、９５℃でさらに１０時間加熱した。トルエンを真空中で蒸発させることにより、所望の生成物を単離した。残存物質を、酢酸エチルと重炭酸ナトリウム溶液の間に分配し、硫酸ナトリウムで乾燥し、濾過し、真空中で蒸発させ、油を得、メタノール／酢酸エチルから再結晶し、淡黄色固体として標記化合物を得た（４２ｍｇ、１６％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３） δ：７．０１（２Ｈ，ｍ），６．９１（２Ｈ，ｍ），４．１８（２Ｈ，ｍ），３．９５（２Ｈ，ｍ），３．８４（４Ｈ，ｍ），３．１２（４Ｈ，ｍ），２．６０（３Ｈ，ｓ），２．２７（３Ｈ，ｓ）；ＬＣ／ＭＳ 保持時間 １．７４／（ＥＳ^＋） ３６２ （Ｍ＋Ｈ，Ｃ_１８Ｈ_２４Ｎ_３Ｏ_３Ｓ 理論値３６２）。 Example 10: 1- (3- (2-hydroxyethyl) -4-methyl-2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro-1,3-triazole-5 Il) Ethanon

N- (2-hydroxyethyl) -N ′-[4- (4-morpholinyl) phenyl] thiourea (0.200 g; 0.71 mmol) and 3-chloro-2,4-pentanedione (0.13 ml; 1.07 mmol) A mixture in toluene (10 ml) was heated at 95 ° C. for 2 h and excess 3-chloro-2,4-pentanedione (0.26 ml; 2.14 mmol) was added in small portions. The resulting mixture was heated at 95 ° C. for an additional 10 hours. The desired product was isolated by evaporating the toluene in vacuo. The remaining material was partitioned between ethyl acetate and sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated in vacuo to give an oil that was recrystallized from methanol / ethyl acetate and titled as a pale yellow solid The compound was obtained (42 mg, 16%).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.01 (2H, m), 6.91 (2H, m), 4.18 (2H, m), 3.95 (2H, m), 3.84 (4H, m), 3.12 (4H, m), 2.60 (3H, s), 2.27 (3H, s); LC / MS retention time 1.74 / (ES ⁺ ) 362 (M + H, _{C 18 H 24 N 3 O 3} S theory 362).

Ｎ−［４−（エチルオキシ）フェニル］−Ｎ’−（２−ヒドロキシエチル）チオ尿素（０．３００ｇ；１．２４ｍｍｏｌ）および２−クロロ−３−オキソブタンニトリル（０．２９４ｇ；２．４８ｍｍｏｌ）のトルエン（１０ｍｌ）中混合物を、９０℃で１５分間加熱した。溶媒を減圧下で蒸発させた。残存物質を、酢酸エチルから再結晶し、白色固体として標記化合物を得た（０．３２６ｇ、７７％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：６．９３（４Ｈ，ｓ），６．５７（１Ｈ，ｂｒ ｓ），４．００（４Ｈ，ｍ），３．７２（２Ｈ，ｍ），２．４１（３Ｈ，ｓ），１．３０（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．７５／（ＥＳ^＋） ３０４ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１８Ｎ_３Ｏ_２Ｓ 理論値３０４）。 Example 11: 2-{[4- (Ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carbonitrile hydrochloride

N- [4- (ethyloxy) phenyl] -N ′-(2-hydroxyethyl) thiourea (0.300 g; 1.24 mmol) and 2-chloro-3-oxobutanenitrile (0.294 g; 2.48 mmol) Of toluene in toluene (10 ml) was heated at 90 ° C. for 15 minutes. The solvent was evaporated under reduced pressure. The remaining material was recrystallized from ethyl acetate to give the title compound as a white solid (0.326 g, 77%).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 6.93 (4H, s), 6.57 (1H, br s), 4.00 (4H, m), 3.72 (2H, m), 2 .41 (3H, s), 1.30 (3H, t, J = 7 Hz); LC / MS retention time 2.75 / (ES ⁺ ) 304 (M + H, C ₁₅ H ₁₈ N ₃ O ₂ S Theoretical 304 ).

Ｎ−エチル−Ｎ’−［４−（エチルオキシ）フェニル］チオ尿素（０．２００ｇ；０．８９ｍｍｏｌ）および２−クロロ−３−オキソブタンニトリル（０．２１０ｇ；１．７８ｍｍｏｌ）のトルエン（１０ｍｌ）中混合物を、９０℃で１５分間加熱した。溶媒を減圧下で蒸発させた。残存物質を、酢酸エチルから再結晶し、白色固体として標記化合物を得た（０．１８５ｇ；６４％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：６．９２（４Ｈ，ｓ），６．７１（１Ｈ，ｂｒ ｓ），３．９８（４Ｈ，ｍ），２．３９（３Ｈ，ｓ），１．３３（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．２７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ３．２８／（ＥＳ^＋） ２８８ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１８Ｎ_３ＯＳ 理論値２８８）。 Example 12: 3-ethyl-2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazole-5-carbonitrile hydrochloride

N-ethyl-N ′-[4- (ethyloxy) phenyl] thiourea (0.200 g; 0.89 mmol) and 2-chloro-3-oxobutanenitrile (0.210 g; 1.78 mmol) in toluene (10 ml) The medium mixture was heated at 90 ° C. for 15 minutes. The solvent was evaporated under reduced pressure. The remaining material was recrystallized from ethyl acetate to give the title compound as a white solid (0.185 g; 64%).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 6.92 (4H, s), 6.71 (1H, br s), 3.98 (4H, m), 2.39 (3H, s), 1 .33 (3H, t, J = 7 Hz), 1.27 (3H, t, J = 7 Hz); LC / MS retention time 3.28 / (ES ⁺ ) 288 (M + H, C ₁₅ H ₁₈ N ₃ OS theory Value 288).

標記化合物（０．０８３ｇ）を、実施例１に記載の製法によって、トルエン（１０ｍｌ）中でＮ−（４−クロロフェニル）−Ｎ’−エチルチオ尿素（０．１５０ｇ；０．７０ｍｍｏｌ）および３−クロロ−２，４−ペンタンジオン（０．３９ｍｌ；３．１４ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．１７（２Ｈ，ｍ），６．９８（２Ｈ，ｍ），４．０４（２Ｈ，ｍ），２．５８（３Ｈ，ｓ），２．３２（３Ｈ，ｓ），１．２６（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．８７／（ＥＳ^＋） ２９５ （Ｍ＋Ｈ，Ｃ_１４Ｈ_１６ ^３５ＣｌＮ_２ＯＳ 理論値２９５）。 Example 13: 1- {2-[(4-Chlorophenyl) imino] -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone hydrochloride

The title compound (0.083 g) was prepared according to the procedure described in Example 1 in toluene (10 ml) with N- (4-chlorophenyl) -N′-ethylthiourea (0.150 g; 0.70 mmol) and 3-chloro Prepared from -2,4-pentanedione (0.39 ml; 3.14 mmol).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.17 (2H, m), 6.98 (2H, m), 4.04 (2H, m), 2.58 (3H, s), 2. 32 (3H, s), 1.26 (3H, t, J = 7 Hz); LC / MS retention time 2.87 / (ES ⁺ ) 295 (M + H, C ₁₄ H ₁₆ ³⁵ ClN ₂ OS theoretical 295).

標記化合物（０．１０２ｇ）を、実施例１に記載の製法によって、トルエン（１０ｍｌ）中でＮ−シクロプロピル−Ｎ’−［４−（トリフルオロメチル）フェニル］チオ尿素（０．１５０ｇ；０．５７ｍｍｏｌ）および３−クロロ−２，４−ペンタンジオン（０．８５ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．７９（２Ｈ，ｍ），７．１９（２Ｈ，ｍ），６．６８（１Ｈ，ｂｒ ｓ），３．０３（１Ｈ，ｍ），２．６４（３Ｈ，ｓ），２．３３（３Ｈ，ｓ），１．１７（２Ｈ，ｍ），１．０３（２Ｈ，ｍ）；ＬＣ／ＭＳ 保持時間 ３．２３／（ＥＳ^＋） ３４１ （Ｍ＋Ｈ，Ｃ_１６Ｈ_１６Ｆ_３Ｎ_２ＯＳ 理論値３４１）。 Example 14: 1- (3-Cyclopropyl-4-methyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone Hydrochloric acid salt

The title compound (0.102 g) was prepared according to the procedure described in Example 1 in toluene (10 ml) with N-cyclopropyl-N ′-[4- (trifluoromethyl) phenyl] thiourea (0.150 g; 0 .57 mmol) and 3-chloro-2,4-pentanedione (0.85 mmol).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.79 (2H, m), 7.19 (2H, m), 6.68 (1H, brs), 3.03 (1H, m), 2 .64 (3H, s), 2.33 (3H, s), 1.17 (2H, m), 1.03 (2H, m); LC / MS retention time 3.23 / (ES ⁺ ) 341 ( _{M + H, C 16 H 16} F 3 N 2 OS theory 341).

標記化合物（０．０４０ｇ）を、実施例１０に記載の製法によって、トルエン（１０ｍｌ）中でＮ−エチル−Ｎ’−［４−（トリフルオロメチル）フェニル］チオ尿素（０．１５０ｇ；０．６０ｍｍｏｌ）および３−クロロ−２，４−ペンタンジオン（０．３８ｍｌ）から調製した。反応混合物を減圧下で蒸発させ、次いで、メタノールから再結晶することにより、標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．７０（２Ｈ，ｄ，Ｊ＝８Ｈｚ），７．１８（２Ｈ，ｄ，Ｊ＝８Ｈｚ），４．０６（２Ｈ，ｍ），２．６１（３Ｈ，ｓ），２．３３（３Ｈ，ｓ），１．２９（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ３．４１／（ＥＳ^＋） ３２９ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１６Ｆ_３Ｎ_２ＯＳ 理論値３２９）。 Example 15: 1- (3-Ethyl-4-methyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone hydrochloride

The title compound (0.040 g) was prepared according to the procedure described in Example 10 in N-ethyl-N ′-[4- (trifluoromethyl) phenyl] thiourea (0.150 g; 0.15 g) in toluene (10 ml). 60 mmol) and 3-chloro-2,4-pentanedione (0.38 ml). The title compound was isolated by evaporating the reaction mixture under reduced pressure and then recrystallizing from methanol.
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.70 (2H, d, J = 8 Hz), 7.18 (2H, d, J = 8 Hz), 4.06 (2H, m), 2.61 (3H, s), 2.33 (3H, s), 1.29 (3H, t, J = 7 Hz); LC / MS retention time 3.41 / (ES ⁺ ) 329 (M + H, C ₁₅ H ₁₆ F ₃ N ₂ OS theoretical 329).

標記化合物（０．０６９ｇ）を、実施例１０に記載の製法によって、トルエン（１０ｍｌ）中でＮ−エチル−Ｎ’−｛４−［（トリフルオロメチル）オキシ］フェニル｝チオ尿素（０．３００ｇ；１．１３ｍｍｏｌ）および３−クロロ−２，４−ペンタンジオン（０．４０ｍｌ；３当量）から調製した。反応混合物を減圧下で蒸発させ、メタノールから再結晶することにより、標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．５０（２Ｈ，ｍ），７．２５（２Ｈ，ｍ），４．１８（２Ｈ，ｍ），２．５６（３Ｈ，ｓ），２．５０（３Ｈ，ｓ），１．４０（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ３．４５／（ＥＳ^＋） ３４５ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１６Ｆ_３Ｎ_２Ｏ_２Ｓ 理論値３４５）。 Example 16a: 1- [3-ethyl-4-methyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] Ethanone hydrochloride

The title compound (0.069 g) was prepared according to the procedure described in Example 10 in N-ethyl-N ′-{4-[(trifluoromethyl) oxy] phenyl} thiourea (0.300 g) in toluene (10 ml). 1.13 mmol) and 3-chloro-2,4-pentanedione (0.40 ml; 3 eq). The title compound was isolated by evaporating the reaction mixture under reduced pressure and recrystallizing from methanol.
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.50 (2H, m), 7.25 (2H, m), 4.18 (2H, m), 2.56 (3H, s), 2. 50 (3H, s), 1.40 (3H, t, J = 7 Hz); LC / MS retention time 3.45 / (ES ⁺ ) 345 (M + H, C ₁₅ H ₁₆ F ₃ N ₂ O ₂ S Theoretical value 345).

１−イソチオシアナト−４−［（トリフルオロメチル）オキシ］ベンゼン（０．２５ｍｍｏｌ、４０．５９ｍｇ）を、酢酸エチル（２ｍＬ）中でテトラヒドロフラン中２−メチルアミン（０．２５ｍｍｏｌ、０．１２５ｍｌ）と合した。該反応物を２０分間攪拌した後、溶媒を真空中で除去した。次いで、残渣をエタノール（２ｍＬ）で溶解した。これに３１．３μＬ（０．２６３ｍｍｏｌ）量の３−クロロ−２，４−ペンタンジオンを加え、混合物をマイクロ波にて１５分間１００℃で加熱した。次いで、溶媒を真空中で除去し、該反応物からの残渣をマスディレクティッド自動精製に付して精製し、１０．５ｍｇの標記化合物を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ）： δ ７．２２−７．２７（２Ｈ，ｍ，ＡｒＨ），７．０６−７．１１（２Ｈ，ｍ，ＡｒＨ），４．０５−４．１２（２Ｈ，ｍ），２．６１（３Ｈ，ｓ），２．３２（３Ｈ，ｓ），１．３４（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ３．５２分、ｍ／ｚ（ＥＳ^＋） ３４５ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１５Ｆ_３Ｎ_２Ｏ_２Ｓ＋Ｈ 理論値３４５）。 Example 16b: 1- [3-ethyl-4-methyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] Ethanon

1-isothiocyanato-4-[(trifluoromethyl) oxy] benzene (0.25 mmol, 40.59 mg) was combined with 2-methylamine (0.25 mmol, 0.125 ml) in tetrahydrofuran in ethyl acetate (2 mL). did. After the reaction was stirred for 20 minutes, the solvent was removed in vacuo. The residue was then dissolved with ethanol (2 mL). To this was added 31.3 μL (0.263 mmol) of 3-chloro-2,4-pentanedione and the mixture was heated in the microwave at 100 ° C. for 15 minutes. The solvent was then removed in vacuo and the residue from the reaction was purified by mass directed auto-purification to give 10.5 mg of the title compound.
¹ H NMR (400 MHz, MeOD): δ 7.22-7.27 (2H, m, ArH), 7.06-7.11 (2H, m, ArH), 4.05-4.12 (2H, m), 2.61 (3H, s), 2.32 (3H, s), 1.34 (3H, t)
LCMS Rt 3.52 _{^{min, m / z (ES +)}} 345 (M + H, C 15 H 15 F 3 N 2 O 2 S + H theory 345).

標記化合物（０．０７６ｇ）を、実施例６に記載の製法であるが、エーテル性塩酸で処理することなく、トルエン（１０ｍｌ）中でＮ−｛４−［（ジフルオロメチル）オキシ］フェニル｝−Ｎ’−（２−ヒドロキシエチル）チオ尿素（０．２００ｇ；０．７６ｍｍｏｌ）および３−クロロ−２，４−ペンタンジオン（０．４０ｍｌ；３当量）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．１６（２Ｈ，ｍ），７．０１（２Ｈ，ｍ），５．０４（１Ｈ，ｍ），４．０３（２Ｈ，ｍ），３．７１（２Ｈ，ｍ），２．６１（３Ｈ，ｓ），２．３２（３Ｈ，ｓ）；ＬＣ／ＭＳ 保持時間 ２．５７／（ＥＳ^＋） ３４３ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１７Ｆ_２Ｎ_２Ｏ_３Ｓ 理論値３４３）。 Example 17: 1- [2-({4-[(Difluoromethyl) oxy] phenyl} imino) -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole- 5-Il] ethanone

The title compound (0.076 g) was prepared according to Example 6, but treated with N- {4-[(difluoromethyl) oxy] phenyl}-in toluene (10 ml) without treatment with ethereal hydrochloric acid. Prepared from N ′-(2-hydroxyethyl) thiourea (0.200 g; 0.76 mmol) and 3-chloro-2,4-pentanedione (0.40 ml; 3 eq).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.16 (2H, m), 7.01 (2H, m), 5.04 (1H, m), 4.03 (2H, m), 3. 71 (2H, m), 2.61 (3H, s), 2.32 (3H, s); LC / MS retention time 2.57 / (ES ⁺ ) 343 (M + H, C ₁₅ H ₁₇ F ₂ N ₂ O ₃ S theory 343).

標記化合物（０．０９３ｇ）を、実施例６に記載の製法であるが、エーテル性塩酸で処理することなく、トルエン（１０ｍｌ）中でＮ−（２−ヒドロキシエチル）−Ｎ’−｛４−［（トリフルオロメチル）チオ］フェニル｝チオ尿素（０．２５０ｇ；０．８４ｍｍｏｌ）および３−クロロ−２，４−ペンタンジオン（０．３０ｍｌ；３当量）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．６１（２Ｈ，ｍ），７．０９（２Ｈ，ｍ），４．１８（２Ｈ，ｍ），４．０１（２Ｈ，ｍ），３．１５（１Ｈ，ｂｒ ｓ），２．６７（３Ｈ，ｓ），２．３２（３Ｈ，ｓ）；ＬＣ／ＭＳ 保持時間 ３．１３／（ＥＳ^＋） ３７７ （Ｍ＋Ｈ Ｃ_１５Ｈ_１６Ｆ_３Ｎ_２Ｏ_２Ｓ_２ 理論値３７７）。 Example 18: 1- [3- (2-hydroxyethyl) -4-methyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazole -5-yl] ethanone

The title compound (0.093 g) was prepared according to Example 6, but treated with N- (2-hydroxyethyl) -N ′-{4- in toluene (10 ml) without treatment with ethereal hydrochloric acid. Prepared from [(trifluoromethyl) thio] phenyl} thiourea (0.250 g; 0.84 mmol) and 3-chloro-2,4-pentanedione (0.30 ml; 3 eq).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.61 (2H, m), 7.09 (2H, m), 4.18 (2H, m), 4.01 (2H, m), 3. 15 (1H, br s), 2.67 (3H, s), 2.32 (3H, s); LC / MS retention time 3.13 / (ES ⁺ ) 377 (M + HC ₁₅ H ₁₆ F ₃ N ₂ O ₂ S ₂ theoretical value 377).

３−クロロ−２−ブタノン（９０ｕｌ）を、Ｎ−エチル−Ｎ’−［４−（トリフルオロメチル）フェニル］チオ尿素（１０２ｍｇ）のトルエン（２ｍｌ）中攪拌溶液に少量ずつ加えた。混合物を２０分間９５℃に加熱し、多量の３−クロロ−２−ブタノン（６０ｕｌ）を少量ずつ加えた。反応物を、該温度で２７時間攪拌し、室温に冷却し、ＳＣＸカラムクロマトグラフィーに付して精製し、黄色油として標的分子を得た（６７ｍｇ）。
^１Ｈ ＮＭＲ（４００ＭＨｚ；ＣＤＣｌ_３） δ：７．５３（２Ｈ，ｄ，Ｊ＝８Ｈｚ），７．１３（２Ｈ，ｄ，Ｊ＝８Ｈｚ），３．９２（２Ｈ，ｑ，Ｊ＝７Ｈｚ），２．０７（３Ｈ，ｓ），２．０４（３Ｈ，ｓ），１．３０（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．３７／（ＥＳ^＋） ３０１ （Ｍ＋Ｈ，Ｃ_１４Ｈ_１６Ｆ_３Ｎ_２Ｓ 理論値３０１）。 Example 19: N- [3-Ethyl-4,5-dimethyl-1,3-triazole-2 (3H) -ylidene] -4- (trifluoromethyl) aniline

3-Chloro-2-butanone (90 ul) was added in small portions to a stirred solution of N-ethyl-N ′-[4- (trifluoromethyl) phenyl] thiourea (102 mg) in toluene (2 ml). The mixture was heated to 95 ° C. for 20 minutes and a large amount of 3-chloro-2-butanone (60 ul) was added in small portions. The reaction was stirred at that temperature for 27 hours, cooled to room temperature and purified by SCX column chromatography to give the target molecule as a yellow oil (67 mg).
¹ H NMR (400 MHz; CDCl ₃ ) δ: 7.53 (2H, d, J = 8 Hz), 7.13 (2H, d, J = 8 Hz), 3.92 (2H, q, J = 7 Hz), 2.07 (3H, s), 2.04 (3H, s), 1.30 (3H, t, J = 7 Hz); LC / MS retention time 2.37 / (ES ⁺ ) 301 (M + H, C ₁₄ H ₁₆ F ₃ N ₂ S theory 301).

エチルアミン（ＴＨＦ中２Ｍ溶液；９４０ｕｌ）を、４−エトキシフェニルイソシアネート（２７０ｕｌ）のトルエン（９ｍｌ）中攪拌溶液に１０秒かけて滴下した。室温で２時間攪拌した後、反応物を９５℃の油浴中で加熱し、３−クロロ−２，４−ペンタンジオン（１ｍｌ）を約５時間かけてシリンジポンプで滴下した。該温度で１７時間攪拌した後、反応物を加熱還流し、多量の３−クロロ−２，４−ペンタンジオン（５００ｕｌ）を１０時間かけて滴下した。合計３日間還流した後、所望の生成物を、ＳＣＸカラムクロマトグラフィーを用いて単離した。得られた褐色油（５７ｍｇ）を、さらにマスディレクティッド自動精製に付して精製し、褐色油状固体として標記化合物を得た（７．５１ｍｇ）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３） δ：７．２４−７．１７（２Ｈ，ｍ），６．７９（２Ｈ，ｍ），４．０３（２Ｈ，ｑ，Ｊ＝７Ｈｚ），３．７９（２Ｈ，ｑ，Ｊ＝７Ｈｚ），２．４５（３Ｈ，ｓ），２．３２（３Ｈ，ｓ），１．３７（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．３３（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．０６／（ＥＳ^＋） ２８９ （Ｍ＋Ｈ，Ｃ_１６Ｈ_２１Ｎ_２Ｏ_３ 理論値２８９）。 Example 20 1- (3-ethyl-2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-oxazol-5-yl) ethanone

Ethylamine (2M solution in THF; 940 ul) was added dropwise over 10 seconds to a stirred solution of 4-ethoxyphenyl isocyanate (270 ul) in toluene (9 ml). After stirring at room temperature for 2 hours, the reaction was heated in a 95 ° C. oil bath and 3-chloro-2,4-pentanedione (1 ml) was added dropwise with a syringe pump over about 5 hours. After stirring at this temperature for 17 hours, the reaction was heated to reflux and a large amount of 3-chloro-2,4-pentanedione (500 ul) was added dropwise over 10 hours. After refluxing for a total of 3 days, the desired product was isolated using SCX column chromatography. The resulting brown oil (57 mg) was further purified by mass directed automatic purification to give the title compound as a brown oily solid (7.51 mg).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.24-7.17 (2H, m), 6.79 (2H, m), 4.03 (2H, q, J = 7 Hz), 3.79 ( 2H, q, J = 7 Hz), 2.45 (3H, s), 2.32 (3H, s), 1.37 (3H, t, J = 7 Hz), 1.33 (3H, t, J = LC / MS retention time 2.06 / (ES ⁺ ) 289 (M + H, C ₁₆ H ₂₁ N ₂ O ₃ theoretical 289).

イソチオシアン酸４−ブロモフェニル（６．４２ｇ；３０ｍｍｏｌ）のトルエン（２５ｍｌ）中溶液を、室温で１５分かけてエチルアミン（テトラヒドロフラン中２Ｍ溶液として入手可能；１５ｍｌ；３０ｍｍｏｌ）のトルエン（２５ｍｌ）中攪拌溶液に加えた。反応混合物を、室温で１．５時間攪拌した。反応混合物を、さらにトルエン（４０ｍｌ）で希釈し、３−クロロ−２，４−ペンタンジオン（４．２４ｇ；３１．５ｍｍｏｌ；３．８ｍｌ）を少量ずつ加え、得られた混合物を９０℃（油浴温度）で２時間攪拌した。反応混合物を冷却し、大部分のトルエンを回転蒸発により除去し、残渣を、酢酸エチル（１００ｍｌ）と飽和水性重炭酸ナトリウム溶液（１００ｍｌ）の間に分配した。有機層を分離し、硫酸ナトリウムで乾燥し、溶媒を回転蒸発により除去し、金色油を得、石油エーテル中０−５０％酢酸エチルから溶出しながら、５０ｇのｉｓｏｌｕｔｅシリカカラムを用いてカラムクロマトグラフィーに付して精製した。得られたフラクションを合し、溶媒を回転蒸発により除去し、黄色油を得（８．１ｇ）、次いで、酢酸エチルで２ｘ１０ｇのＳＣＸカラムに通して、溶媒を減圧下で除去し、黄色固体として標記化合物を得た（３．４０ｇ、３４％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３） δ：７．４５（２Ｈ，ｍ），６．９４（２Ｈ，ｍ），４．０３（２Ｈ，カルテット，Ｊ＝７Ｈｚ），２．６２（３Ｈ，ｓ），２．２６（３Ｈ，ｓ），１．３５（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ３．３４／（ＥＳ^＋） ３３９＆３４１ （Ｍ＋Ｈ，Ｃ_１４Ｈ_１６ＢｒＮ_２ＯＳ 理論値３３９＆３４１）。 Example 21: 1- {2-[(4-Bromophenyl) imino] -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone

A solution of 4-bromophenyl isothiocyanate (6.42 g; 30 mmol) in toluene (25 ml) over 15 minutes at room temperature in ethylamine (available as a 2M solution in tetrahydrofuran; 15 ml; 30 mmol) in toluene (25 ml) Added to. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture is further diluted with toluene (40 ml), 3-chloro-2,4-pentanedione (4.24 g; 31.5 mmol; 3.8 ml) is added in small portions and the resulting mixture is heated to 90 ° C. (oil (Bath temperature) for 2 hours. The reaction mixture was cooled, most of the toluene was removed by rotary evaporation, and the residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The organic layer is separated, dried over sodium sulfate, and the solvent is removed by rotary evaporation to give a golden oil, column chromatography using a 50 g isolute silica column eluting from 0-50% ethyl acetate in petroleum ether. And purified. The resulting fractions were combined and the solvent was removed by rotary evaporation to give a yellow oil (8.1 g), then passed through a 2 × 10 g SCX column with ethyl acetate, and the solvent was removed under reduced pressure as a yellow solid. The title compound was obtained (3.40 g, 34%).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.45 (2H, m), 6.94 (2H, m), 4.03 (2H, quartet, J = 7 Hz), 2.62 (3H, s) , 2.26 (3H, s), 1.35 (3H, t, J = 7 Hz); LC / MS retention time 3.34 / (ES ⁺ ) 339 & 341 (M + H, C ₁₄ H ₁₆ BrN ₂ OS Theoretical 339 & 341 ).

酢酸パラジウム（１０ｍｏｌ％、２２．５ｍｍｏｌ；０．１ｍｍｏｌ）、（Ｒ）−（＋）−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル（１５ｍｏｌ％、９３ｍｇ；０．１５ｍｍｏｌ）および炭酸セシウム（４８９ｍｇ；１．５ｍｍｏｌ）の無水ジオキシン（２５ｍｌ）中混合物を、一面のアルゴン下で０．５時間超音波分解した。次いで、１−｛２−［（４−ブロモフェニル）イミノ］−３−エチル−４−メチル−２，３−ジヒドロ−１，３−トリアゾール−５−イル｝エタノン（３３８ｍｇ；１ｍｍｏｌ）およびピロリジン（７１ｍｇ；１ｍｍｏｌ；０．０８ｍｌ）を加え、全混合物を２２時間還流下で攪拌した。多量の酢酸パラジウム（１０ｍｏｌ％、２２．５ｍｍｏｌ；０．１ｍｍｏｌ）および（Ｒ）−（＋）−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル（１５ｍｏｌ％、９３ｍｇ；０．１５ｍｍｏｌ）を、無水ジオキシン（１０ｍｌ）中で２０分間超音波分解し、次いで、該混合物を、還流している反応混合物に加え、さらに２４時間還流し続け、反応物を室温に冷却した。反応混合物を、珪藻土層に通して濾過し、濾液を回転蒸発により残渣に蒸発させ、暗色油を得（７３０ｍｇ）、５ｇのプレパックｉｓｏｌｕｔｅシリカゲルカラムに加え、石油エーテル中２０−１００％酢酸エチル、次いで、酢酸エチル中５％アンモニア（メタノール中２Ｍ）から溶出した。関連フラクションを合し、溶媒を回転蒸発により除去し、褐色油を得（２０５ｍｇ）、マスディレクティッド自動精製（ＭＤＡＰ）に付してさらに精製し、橙色固体を得た（６９ｍｇ）。遊離塩基を、ジクロロメタン（１ｍｌ）で溶解し、エーテル中１Ｍ塩化水素（１ｍｌ）で処理し、溶媒を空気乾燥しながら除去した。生成物をエーテルでトリチュレートし、真空オーブンで乾燥し、黄色固体として標記化合物を得た（６３ｍｇ；１７％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ−ｄ_４） δ：７．４９（２Ｈ，ｄ，Ｊ＝９Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝８Ｈｚ），４．３０（２Ｈ，カルテット．Ｊ＝７Ｈｚ），３．５６（４Ｈ，ｍ），２．７５（３Ｈ，ｓ），２．５１（３Ｈ，ｓ），２．１８（４Ｈ，ｍ），１．４８（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 ２．４４／（ＥＳ^＋） ３３０ （Ｍ＋Ｈ，Ｃ_１８Ｈ_２４Ｎ_３ＯＳ 理論値３３０）。 Example 22: 1- (3-Ethyl-4-methyl-2-{[4- (1-pyrrolidinyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone hydrochloride

Palladium acetate (10 mol%, 22.5 mmol; 0.1 mmol), (R)-(+)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (15 mol%, 93 mg; 0.15 mmol) ) And cesium carbonate (489 mg; 1.5 mmol) in anhydrous dioxin (25 ml) was sonicated for 0.5 h under a single side of argon. 1- {2-[(4-Bromophenyl) imino] -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone (338 mg; 1 mmol) and pyrrolidine ( 71 mg; 1 mmol; 0.08 ml) was added and the whole mixture was stirred at reflux for 22 hours. Large amounts of palladium acetate (10 mol%, 22.5 mmol; 0.1 mmol) and (R)-(+)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (15 mol%, 93 mg; 0 .15 mmol) was sonicated in anhydrous dioxin (10 ml) for 20 minutes, then the mixture was added to the refluxing reaction mixture and continued to reflux for a further 24 hours and the reaction was cooled to room temperature. The reaction mixture is filtered through a diatomaceous earth layer and the filtrate is evaporated to the residue by rotary evaporation to give a dark oil (730 mg) added to a 5 g pre-packed isolute silica gel column, 20-100% ethyl acetate in petroleum ether, then Elute from 5% ammonia in ethyl acetate (2M in methanol). The relevant fractions were combined and the solvent was removed by rotary evaporation to give a brown oil (205 mg) and further purified by mass directed autopurification (MDAP) to give an orange solid (69 mg). The free base was dissolved in dichloromethane (1 ml), treated with 1M hydrogen chloride in ether (1 ml) and the solvent removed with air drying. The product was triturated with ether and dried in a vacuum oven to give the title compound as a yellow solid (63 mg; 17%).
¹ H NMR (400 MHz, MeOD-d ₄ ) δ: 7.49 (2H, d, J = 9 Hz), 7.22 (2H, d, J = 8 Hz), 4.30 (2H, quartet. J = 7 Hz) ), 3.56 (4H, m), 2.75 (3H, s), 2.51 (3H, s), 2.18 (4H, m), 1.48 (3H, t, J = 7 Hz) LC / MS retention time 2.44 / (ES ⁺ ) 330 (M + H, C ₁₈ H ₂₄ N ₃ OS theoretical 330).

１−｛２−［（４−ブロモフェニル）イミノ］−３−エチル−４−メチル−２，３−ジヒドロ−１，３−トリアゾール−５−イル｝エタノン（３３８ｍｇ；１ｍｍｏｌ）、ピペリジン（８５ｍｇ；１ｍｍｏｌ）、ナトリウムｔｅｒｔ−ブトキシド（１３４ｍｇ；１．４ｍｍｏｌ）、ビス（ジベンジリデンアセトン）パラジウム（３ｍｏｌ％、０．０３ｍｍｏｌ；１７．３ｍｇ）および２−（ジ−ｔ−ブチルホスフィノ）ビフェニル（１０ｍｏｌ％、０．１ｍｍｏｌ；３０ｍｇ）のトルエン（１０ｍｌ）中混合物を、１１０℃（油浴温度）で５時間攪拌した。新しいピペリジン（８５ｍｇ；１ｍｍｏｌ）、ビス（ジベンジリデンアセトン）パラジウム（３ｍｏｌ％、０．０３ｍｍｏｌ；１７．３ｍｇ）および２−（ジ−ｔ−ブチルホスフィノ）ビフェニル（１０ｍｏｌ％、０．１ｍｍｏｌ；３０ｍｇ）を加え、さらに２時間攪拌し続けた。反応混合物を室温に冷却し、ジエチルエーテル（２０ｍｌ）で希釈し、珪藻土層に通して濾過した。濾液を回転蒸発により濃縮し、残渣を、石油エーテル中０−１００％酢酸エチルから溶出しながら１０ｇのシリカプレパックｉｓｏｌｕｔｅカラム上でクロマトグラフィーに付した。関連フラクションを合し、減圧下で蒸発させ、橙色固体を得（１９４ｍｇ）、マスディレクティッド自動精製（ＭＤＡＰ）に付してさらに精製した。関連フラクションを合し、溶媒を回転蒸発により除去し、黄色固体を得た（９１ｍｇ）。遊離塩基をジクロロメタン（１ｍｌ）で溶解し、エーテル中１Ｍ塩化水素（１ｍｌ）で処理し、溶媒を空気乾燥しながら除去した。生成物をエーテルでトリチュレートし、真空オーブンで乾燥し、淡黄色固体として標記化合物を得た（１０２ｍｇ；２７％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ−ｄ_４） δ：７．９５（２Ｈ，ｄ，Ｊ＝９Ｈｚ），７．７５（２Ｈ，ｄ，Ｊ＝９Ｈｚ），４．３３（２Ｈ，カルテット，Ｊ＝７Ｈｚ），３．７１（４Ｈ，ｔ，Ｊ＝６Ｈｚ），２．７６（３Ｈ，ｓ），２．５２（３Ｈ，ｓ），２．１０（４Ｈ，ｍ），１．８４（２Ｈ，ｍ），１．４９（３Ｈ，ｔ，Ｊ＝７Ｈｚ）；ＬＣ／ＭＳ 保持時間 １．９８／（ＥＳ^＋） ３４４ （Ｍ＋Ｈ，Ｃ_１９Ｈ_２６Ｎ_３ＯＳ 理論値３４４）。 Example 23: 1- (3-Ethyl-4-methyl-2-{[4- (1-piperidinyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone hydrochloride

1- {2-[(4-Bromophenyl) imino] -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone (338 mg; 1 mmol), piperidine (85 mg; 1 mmol), sodium tert-butoxide (134 mg; 1.4 mmol), bis (dibenzylideneacetone) palladium (3 mol%, 0.03 mmol; 17.3 mg) and 2- (di-t-butylphosphino) biphenyl (10 mol%) , 0.1 mmol; 30 mg) in toluene (10 ml) was stirred at 110 ° C. (oil bath temperature) for 5 hours. Fresh piperidine (85 mg; 1 mmol), bis (dibenzylideneacetone) palladium (3 mol%, 0.03 mmol; 17.3 mg) and 2- (di-t-butylphosphino) biphenyl (10 mol%, 0.1 mmol; 30 mg) And continued to stir for another 2 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether (20 ml) and filtered through a diatomaceous earth layer. The filtrate was concentrated by rotary evaporation and the residue was chromatographed on a 10 g silica pre-packed isolute column eluting from 0-100% ethyl acetate in petroleum ether. The relevant fractions were combined and evaporated under reduced pressure to give an orange solid (194 mg), which was further purified by mass directed automatic purification (MDAP). The relevant fractions were combined and the solvent was removed by rotary evaporation to give a yellow solid (91 mg). The free base was dissolved in dichloromethane (1 ml), treated with 1M hydrogen chloride in ether (1 ml) and the solvent was removed with air drying. The product was triturated with ether and dried in a vacuum oven to give the title compound as a pale yellow solid (102 mg; 27%).
¹ H NMR (400 MHz, MeOD-d ₄ ) δ: 7.95 (2H, d, J = 9 Hz), 7.75 (2H, d, J = 9 Hz), 4.33 (2H, quartet, J = 7 Hz) ), 3.71 (4H, t, J = 6 Hz), 2.76 (3H, s), 2.52 (3H, s), 2.10 (4H, m), 1.84 (2H, m) , 1.49 (3H, t, J = 7 Hz); LC / MS retention time 1.98 / (ES ⁺ ) 344 (M + H, C ₁₉ H ₂₆ N ₃ OS theoretical 344).

Ｎ−（２−ヒドロキシエチル）−Ｎ’−［４−（トリフルオロメチル）フェニル］チオ尿素（５００ｍｇ；１．８９ｍｍｏｌ）および２−クロロ−Ｎ，Ｎ−ジメチル−３−オキソブタンアミド（６８０ｍｇ；４．１６ｍｍｏｌ）のトルエン（１５ｍｌ）中混合物を、９０℃で２時間加熱した。溶媒を減圧下で蒸発させた。残存物質をメタノール／酢酸エチルから再結晶し、固体として標記化合物を得た（４６０ｍｇ；６５％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．８７（１Ｈ，ｂｒ，ｓ），７．６９（２Ｈ，ｄ，Ｊ＝８Ｈｚ），７．２６（２Ｈ，ｄ，Ｊ＝８Ｈｚ），４．０２（２Ｈ，ｍ），３．７３（２Ｈ，ｍ），２．９４（６Ｈ，ｓ），２．２６（３Ｈ，ｓ）；ＬＣ／ＭＳ 保持時間 ２．５３／（ＥＳ^＋） ３７４ （Ｍ＋Ｈ，Ｃ_１６Ｈ_１９Ｆ_３Ｎ_３Ｏ_２Ｓ 理論値３７４）。 Example 24: 3- (2-hydroxyethyl) -N, N, 4-trimethyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazole-5 -Carboxamide hydrochloride

N- (2-hydroxyethyl) -N ′-[4- (trifluoromethyl) phenyl] thiourea (500 mg; 1.89 mmol) and 2-chloro-N, N-dimethyl-3-oxobutanamide (680 mg; 4.16 mmol) in toluene (15 ml) was heated at 90 ° C. for 2 hours. The solvent was evaporated under reduced pressure. The residual material was recrystallized from methanol / ethyl acetate to give the title compound as a solid (460 mg; 65%).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.87 (1H, br, s), 7.69 (2H, d, J = 8 Hz), 7.26 (2H, d, J = 8 Hz), 4 .02 (2H, m), 3.73 (2H, m), 2.94 (6H, s), 2.26 (3H, s); LC / MS retention time 2.53 / (ES ⁺ ) 374 ( _{M + H, C 16 H 19} F 3 N 3 O 2 S theory 374).

Ｎ−（４−ブロモフェニル）−Ｎ’−（２−ヒドロキシエチル）チオ尿素（６．３２ｇ；２３ｍｍｏｌ）を、エタノール（２０ｍｌ）およびトルエン（１００ｍｌ）で溶解した。次いで、３−クロロ−２，４−ペンタンジオン（５．４５ｍｌ；４６ｍｍｏｌ）を加えた。得られた混合物を、アルゴン下、９０℃で３０分間加熱した。溶媒を減圧下で蒸発させることにより、所望の生成物を単離した。残存物質を、酢酸エチルと重炭酸ナトリウム溶液の間に分配し、硫酸ナトリウムで乾燥し、濾過し、真空中で濃縮し、次いで、回収した物質を酢酸エチル／ｎ−ペンタンから再結晶し、黄色固体として標記化合物を得た（５．５９ｇ；６８％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３） δ：７．４５（２Ｈ，ｍ），６．９４（２Ｈ，ｍ），４．１７（２Ｈ，ｍ），３．９９（２Ｈ，ａｐｐｒ ｓ），３．３５（１Ｈ，ｓ），２．６３（３Ｈ，ｓ），２．２９（３Ｈ，ｓ）；ＬＣ／ＭＳ 保持時間 ２．７９／（ＥＳ^＋） ３５５＆３５７ （Ｍ＋Ｈ，Ｃ_１４Ｈ_１６ＢｒＮ_２Ｏ_２Ｓ 理論値３５５＆３５７）。 Example 25: 1- [2-[(4-Bromophenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone

N- (4-Bromophenyl) -N ′-(2-hydroxyethyl) thiourea (6.32 g; 23 mmol) was dissolved in ethanol (20 ml) and toluene (100 ml). Then 3-chloro-2,4-pentanedione (5.45 ml; 46 mmol) was added. The resulting mixture was heated at 90 ° C. for 30 minutes under argon. The desired product was isolated by evaporating the solvent under reduced pressure. The remaining material was partitioned between ethyl acetate and sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo, then the recovered material was recrystallized from ethyl acetate / n-pentane, yellow The title compound was obtained as a solid (5.59 g; 68%).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.45 (2H, m), 6.94 (2H, m), 4.17 (2H, m), 3.99 (2H, apprs), 3. 35 (1H, s), 2.63 (3H, s), 2.29 (3H, s); LC / MS retention time 2.79 / (ES ⁺ ) 355 & 357 (M + H, C ₁₄ H ₁₆ BrN ₂ O ₂ S Theoretical values 355 & 357).

２−｛［４−（エチルオキシ）フェニル］イミノ｝−３−（２−ヒドロキシエチル）−４−メチル−２，３−ジヒドロ−１，３−トリアゾール−５−カルボン酸（２６４ｍｇ；０．８２ｍｍｏｌ）、ＤＩＰＥＡ（ジイソプロピルエチルアミン）（１．３８ｍｌ；９ｍｍｏｌ）および塩化アンモニウム（０．４４ｇ；８．２ｍｍｏｌ）のジメチルホルムアミド（２０ｍｌ）中混合物を、室温で共栓フラスコ中にて攪拌した。ＨＡＴＵ（Ｏ−（７−アザベンゾトリアゾール−１−イル）−Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチルウロニウム ヘキサフルオロホスフェート）（０．３１２ｇ；０．８２ｍｍｏｌ）を攪拌溶液に加えた。混合物を室温で４時間攪拌した。ジメチルホルムアミドを回転蒸発により除去し、残存物質を、酢酸エチルと水の間に分配した。水相を酢酸エチル（４ｘ１０ｍｌ）で抽出し、合した有機層をブライン（１００ｍｌ）で洗浄し、硫酸ナトリウムで乾燥し、濾過し、蒸発させた。所望の生成物を、酢酸エチル中０〜１０％メタノールを用いてシリカ上のカラムクロマトグラフィーに付して単離し、標記化合物を得た（６８ｍｇ；２６％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．０５（２Ｈ，ｓ），６．８９（４Ｈ，ａｐｐｒ ｓ），５．００（１Ｈ ｂｒ ｓ） ３．９７（２Ｈ，ｍ），３．９２（２Ｈ，ｍ），３．６８（２Ｈ，ｍ），２．５１（３Ｈ，ｓ），１．２９（３Ｈ，ｍ）；ＬＣ／ＭＳ 保持時間 １．６７／（ＥＳ^＋） ３２２ （Ｍ＋Ｈ，Ｃ_１５Ｈ_２０Ｎ_３Ｏ_３Ｓ 理論値３２２）。 Example 26: 2-{[4- (Ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxamide

2-{[4- (Ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxylic acid (264 mg; 0.82 mmol) A mixture of DIPEA (diisopropylethylamine) (1.38 ml; 9 mmol) and ammonium chloride (0.44 g; 8.2 mmol) in dimethylformamide (20 ml) was stirred in a stoppered flask at room temperature. HATU (O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate) (0.312 g; 0.82 mmol) was added to the stirred solution. The mixture was stirred at room temperature for 4 hours. Dimethylformamide was removed by rotary evaporation and the remaining material was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (4 × 10 ml) and the combined organic layers were washed with brine (100 ml), dried over sodium sulfate, filtered and evaporated. The desired product was isolated by column chromatography on silica using 0-10% methanol in ethyl acetate to give the title compound (68 mg; 26%).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.05 (2H, s), 6.89 (4H, apprs), 5.00 (1H br s) 3.97 (2H, m), 3. 92 (2H, m), 3.68 (2H, m), 2.51 (3H, s), 1.29 (3H, m); LC / MS retention time 1.67 / (ES ⁺ ) 322 (M + H , C ₁₅ H ₂₀ N ₃ O ₃ S theoretical 322).

Ｎ−（２−ヒドロキシエチル）−Ｎ’−｛４−［（トリフルオロメチル）オキシ］フェニル｝チオ尿素（０．５ｇ；１．７８ｍｍｏｌ）をエタノール（３０ｍｌ）で溶解した。次いで、２−クロロ−Ｎ，Ｎ−ジメチル−３−オキソブタンアミド（０．５ｍｌ；３．５６ｍｍｏｌ）を加えた。反応混合物を９５℃で２時間加熱した。エタノールを回転蒸発により除去し、残存物質を酢酸エチルから再結晶し、白色固体を得、ＭＤＡＰ（マスディレクティッド自動精製）に付してさらに精製し、エーテル性塩酸で処理し、ジエチルエーテルでトリチュレートし、白色固体として標記化合物を得た（２５１ｍｇ；３３％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．３９（２Ｈ，ｍ），７．２５（２Ｈ，ｍ），４．７０（１Ｈ ｂｒ ｓ），４．０６（２Ｈ，ａｐｐｒ ｓ），３．７４（２Ｈ，ｍ），２．９４（６Ｈ，ｓ），２．２６（３Ｈ，ｓ）；ＬＣ／ＭＳ 保持時間 ２．３８／（ＥＳ^＋） ３９０ （Ｍ＋Ｈ，Ｃ_１６Ｈ_１９Ｆ_３Ｎ_３Ｏ_３Ｓ 理論値３９０）。 Example 27: 3- (2-hydroxyethyl) -N, N, 4-trimethyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3- Triazole-5-carboxamide hydrochloride

N- (2-hydroxyethyl) -N ′-{4-[(trifluoromethyl) oxy] phenyl} thiourea (0.5 g; 1.78 mmol) was dissolved in ethanol (30 ml). Then 2-chloro-N, N-dimethyl-3-oxobutanamide (0.5 ml; 3.56 mmol) was added. The reaction mixture was heated at 95 ° C. for 2 hours. Ethanol is removed by rotary evaporation and the remaining material is recrystallized from ethyl acetate to give a white solid that is further purified by MDAP (mass directed autopurification), treated with ethereal hydrochloric acid and triturated with diethyl ether. To give the title compound as a white solid (251 mg; 33%).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.39 (2H, m), 7.25 (2H, m), 4.70 (1H br s), 4.06 (2H, appr s), 3 .74 (2H, m), 2.94 (6H, s), 2.26 (3H, s); LC / MS retention time 2.38 / (ES ⁺ ) 390 (M + H, C ₁₆ H ₁₉ F ₃ N ₃ O ₃ S theoretical 390).

Ｎ−シクロプロピル−Ｎ’−［４−（４−モルホリニル）フェニル］チオ尿素（２００ｍｇ；０．７２ｍｍｏｌ）、３−クロロ−２，４−ペンタンジオン（０．３ｍｌ；２．２ｍｍｏｌ）のエタノール（２０ｍｌ）中混合物を、９０℃で２０分間加熱した。溶媒を回転蒸発により除去し、試料をＭＤＡＰ（マスディレクティッド自動精製）に付して精製した。溶媒を回転蒸発により除去し、所望の生成物を得、エーテル性塩酸で処理し、黄色固体として標記化合物を得た（１０８ｍｇ；３８％）。
^１Ｈ ＮＭＲ（５００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．３０（２Ｈ，ｍ），７．２０（２Ｈ，ｍ），５．２１（１Ｈ ｂｒ ｓ），３．８０（４Ｈ，ａｐｐｒ ｓ），３．３０−３．１９（５Ｈ，ｍ），２．７２（３Ｈ，ｓ），２．４７（３Ｈ，ｓ），１．３４（２Ｈ，ｍ），１．２０（２Ｈ，ｍ）；ＬＣ／ＭＳ 保持時間 １．７２／（ＥＳ^＋） ３５８ （Ｍ＋Ｈ，Ｃ_１９Ｈ_２４Ｎ_３Ｏ_２Ｓ 理論値３５８）。 Example 28: 1- (3-Cyclopropyl-4-methyl-2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone Hydrochloric acid salt

N-cyclopropyl-N ′-[4- (4-morpholinyl) phenyl] thiourea (200 mg; 0.72 mmol), 3-chloro-2,4-pentanedione (0.3 ml; 2.2 mmol) in ethanol ( In 20 ml) was heated at 90 ° C. for 20 minutes. The solvent was removed by rotary evaporation and the sample was purified by MDAP (mass directed automatic purification). The solvent was removed by rotary evaporation to give the desired product which was treated with ethereal hydrochloric acid to give the title compound as a yellow solid (108 mg; 38%).
¹ H NMR (500 MHz, DMSO D ₆ ) δ: 7.30 (2H, m), 7.20 (2H, m), 5.21 (1H br s), 3.80 (4H, apprs), 3 .30-3.19 (5H, m), 2.72 (3H, s), 2.47 (3H, s), 1.34 (2H, m), 1.20 (2H, m); LC / MS retention time _{^{1.72 / (ES +) 358 (}} M + H, C 19 H 24 N 3 O 2 S theory 358).

標記化合物（１９３ｍｇ；８３％）を、実施例２８に記載の製法によって、エタノール（１０ｍｌ）中でＮ−エチル−Ｎ’−［４−（４−モルホリニル）フェニル］チオ尿素（１５０ｍｇ；０．５７ｍｍｏｌ）および２−クロロ−Ｎ，Ｎ−ジメチル−３−オキソブタンアミド（０．２３ｍｌ；１．７ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：７．４６（２Ｈ，ｍ），７．１４（２Ｈ，ｍ），５．２１（１Ｈ，ｂｒ ｓ），４．２６（２Ｈ，ｍ），３．７７（４Ｈ，ｍ），３．７２（４Ｈ，ｍ），２．９４（６Ｈ，ｓ），２．３１（３Ｈ，ｓ），１．３５（３Ｈ，ｍ）；ＬＣ／ＭＳ 保持時間 １．５３／（ＥＳ^＋） ３７５ （Ｍ＋Ｈ，Ｃ_１９Ｈ_２７Ｎ_４Ｏ_２Ｓ 理論値３７５）。 Example 29: 3-ethyl-N, N, 4-trimethyl-2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro-1,3-triazole-5-carboxamide hydrochloride

The title compound (193 mg; 83%) was prepared according to the procedure described in Example 28 in N-ethyl-N ′-[4- (4-morpholinyl) phenyl] thiourea (150 mg; 0.57 mmol) in ethanol (10 ml). ) And 2-chloro-N, N-dimethyl-3-oxobutanamide (0.23 ml; 1.7 mmol).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.46 (2H, m), 7.14 (2H, m), 5.21 (1H, brs), 4.26 (2H, m), 3 .77 (4H, m), 3.72 (4H, m), 2.94 (6H, s), 2.31 (3H, s), 1.35 (3H, m); LC / MS retention time 1 .53 / (ES ⁺ ) 375 (M + H, C ₁₉ H ₂₇ N ₄ O ₂ S theoretical 375).

標記化合物（４９ｍｇ；１５％）を、実施例２８に記載の製法によって、エタノール（１０ｍｌ）中でＮ−（２−ヒドロキシエチル）−Ｎ’−｛４−［（トリフルオロメチル）オキシ］フェニル｝チオ尿素（２００ｍｇ；０．７１ｍｍｏｌ）および３−クロロ−１，１，１−トリフルオロ−２，４−ペンタンジオン（５４０ｍｇ；２．８６ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ） δ：７．６１（２Ｈ，ｍ），７．５０（２Ｈ，ｍ），４．３８（２Ｈ，ｍ），３．９７（２Ｈ，ｍ），３．３８（１Ｈ，ｓ），２．５０（３Ｈ，ｓ）；ＬＣ／ＭＳ 保持時間 ３．４５／（ＥＳ^＋） ４１５ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１３Ｆ_６Ｎ_２Ｏ_３Ｓ 理論値４１５）。 Example 30: 2,2,2-trifluoro-1- [3- (2-hydroxyethyl) -4-methyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2, 3-Dihydro-1,3-triazol-5-yl] ethanone hydrochloride

The title compound (49 mg; 15%) was prepared according to the procedure described in Example 28 in N- (2-hydroxyethyl) -N ′-{4-[(trifluoromethyl) oxy] phenyl} in ethanol (10 ml). Prepared from thiourea (200 mg; 0.71 mmol) and 3-chloro-1,1,1-trifluoro-2,4-pentanedione (540 mg; 2.86 mmol).
¹ H NMR (400 MHz, MeOD) δ: 7.61 (2H, m), 7.50 (2H, m), 4.38 (2H, m), 3.97 (2H, m), 3.38 ( 1H, s), 2.50 (3H , s); LC / MS retention time _{^{3.45 / (ES +) 415 (}} M + H, C 15 H 13 F 6 N 2 O 3 S theory 415).

Ｎ−シクロプロピル−Ｎ’−［４−（４−モルホリニル）フェニル］チオ尿素（２００ｍｇ；０．７２ｍｍｏｌ）、２−クロロ−Ｎ，Ｎ−ジメチル−３−オキソブタンアミド（０．３ｍｌ；２．２ｍｍｏｌ）のエタノール（２０ｍｌ）中混合物を、９０℃で１時間加熱した。溶媒を回転蒸発により除去し、試料を高ｐＨ ＭＤＡＰに付して精製した。溶媒を回転蒸発により除去し、所望の生成物を得、エーテル性塩酸で処理し、黄色固体として標記化合物を得た（５２ｍｇ；１７％）。
^１Ｈ ＮＭＲ（５００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：１１．４０（１Ｈ，ｂｒ ｓ），７．３５（２Ｈ，ｍ），７．１１（２Ｈ，ｍ），４．７８（１Ｈ，ｂｒ ｓ），３．７５（４Ｈ，ｍ），３．２５−３．１３（４Ｈ，ｍ），２．９５（６Ｈ，ｓ），２．３３（３Ｈ，ｓ） １．３２（２Ｈ，ｍ），１．２２（２Ｈ，ｍ）；ＬＣ／ＭＳ 高ｐＨ 保持時間 ２．１４／（ＥＳ^＋） ３８７ （Ｍ＋Ｈ，Ｃ_２０Ｈ_２７Ｎ_４Ｏ_２Ｓ 理論値３８７）。 Example 31: 3-Cyclopropyl-N, N, 4-trimethyl-2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro-1,3-triazole-5-carboxamide hydrochloride

N-cyclopropyl-N ′-[4- (4-morpholinyl) phenyl] thiourea (200 mg; 0.72 mmol), 2-chloro-N, N-dimethyl-3-oxobutanamide (0.3 ml; 2. 2 mmol) in ethanol (20 ml) was heated at 90 ° C. for 1 h. The solvent was removed by rotary evaporation and the sample was purified by high pH MDAP. The solvent was removed by rotary evaporation to give the desired product and treated with ethereal hydrochloric acid to give the title compound as a yellow solid (52 mg; 17%).
¹ H NMR (500 MHz, DMSO D ₆ ) δ: 11.40 (1H, br s), 7.35 (2H, m), 7.11 (2H, m), 4.78 (1H, br s), 3.75 (4H, m), 3.25-3.13 (4H, m), 2.95 (6H, s), 2.33 (3H, s) 1.32 (2H, m), 1. 22 (2H, m); LC / MS high pH retention time 2.14 / (ES ⁺ ) 387 (M + H, C ₂₀ H ₂₇ N ₄ O ₂ S theoretical 387).

１−［２−［（４−ブロモフェニル）イミノ］−３−（２−ヒドロキシエチル）−４−メチル−２，３−ジヒドロ−１，３−トリアゾール−５−イル］エタノン（２００ｍｇ；０．５６ｍｍｏｌ）、ピロリジン（総量２９４ｍｇ；４．１ｍｍｏｌ）、ビス（ジベンジリデンアセトン）パラジウム（１０ｍｇ；３ｍｏｌ％）、２−ビフェニルイル［ビス（１，１−ジメチルエチル）］ホスファン（１７ｍｇ；１０ｍｏｌ％）およびナトリウムｔｅｒｔ−ブトキシド（７５ｍｇ；０．７８ｍｍｏｌ）のトルエン（５ｍｌ）中混合物を、１１０℃で８時間加熱した。反応混合物を室温に冷却し、ジエチルエーテルで希釈した。混合物を、珪藻土層に通して濾過し、触媒を除去し、濾液を真空中で濃縮し、黄色油を得た。所望の生成物を、ＭＤＡＰ（マスディレクティッド自動精製）に付して単離し、黄色固体として標記化合物を得た（３３ｍｇ；１７％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６） δ：６．８４（２Ｈ，ｍ），６．５４（２Ｈ，ｍ），５．０２（１Ｈ，ｂｒ ｓ），４．００（２Ｈ，ｍ），３．７０（２Ｈ，ｍ），３．２０（４Ｈ，ｍ），２．６０（３Ｈ，ｓ） ２．２９（３Ｈ，ｓ），１．９４（４Ｈ，ｍ）；ＬＣ／ＭＳ 保持時間 ２．００／（ＥＳ^＋） ３４６ （Ｍ＋Ｈ，Ｃ_１８Ｈ_２４Ｎ_３Ｏ_２Ｓ 理論値３４６）。 Example 32: 1- (3- (2-hydroxyethyl) -4-methyl-2-{[4- (1-pyrrolidinyl) phenyl] imino} -2,3-dihydro-1,3-triazole-5 Il) Ethanon

1- [2-[(4-Bromophenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone (200 mg; 56 mmol), pyrrolidine (total 294 mg; 4.1 mmol), bis (dibenzylideneacetone) palladium (10 mg; 3 mol%), 2-biphenylyl [bis (1,1-dimethylethyl)] phosphane (17 mg; 10 mol%) and A mixture of sodium tert-butoxide (75 mg; 0.78 mmol) in toluene (5 ml) was heated at 110 ° C. for 8 hours. The reaction mixture was cooled to room temperature and diluted with diethyl ether. The mixture was filtered through a diatomaceous earth layer to remove the catalyst and the filtrate was concentrated in vacuo to give a yellow oil. The desired product was isolated by MDAP (mass directed autopurification) to give the title compound as a yellow solid (33 mg; 17%).
¹ H NMR (400 MHz, DMSO D ₆ ) δ: 6.84 (2H, m), 6.54 (2H, m), 5.02 (1 H, br s), 4.00 (2H, m), 3 .70 (2H, m), 3.20 (4H, m), 2.60 (3H, s) 2.29 (3H, s), 1.94 (4H, m); LC / MS retention time 00 / (ES ⁺ ) 346 (M + H, C ₁₈ H ₂₄ N ₃ O ₂ S theoretical 346).

１−イソチオシアナト−４−（メチルオキシ）ベンゼン（０．２５ｍｍｏｌ、４１．３ｍｇ）を酢酸エチル（１ｍＬ）で溶解した。該溶液に、エタノールアミン（１５．１μＬ、０．２５ｍｍｏｌ）含有酢酸エチルの１ｍＬ溶液を加えた。該反応物を２０−３０分間振盪した後、溶媒を真空中で除去した。次いで、残渣をエタノール（１ｍＬ）で溶解した。これに３１．３μＬ（０．２６３ｍｍｏｌ）量のエタノール（１ｍＬ）中３−クロロ−２，４−ペンタンジオンを加え、混合物をマイクロ波にて１００℃で１５分間加熱した。次いで、溶媒を真空中で除去し、該反応物からの残渣を、マスディレクティッド自動精製に付して精製し、１１．１ｍｇの標記化合物を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ）： δ ７．９（４Ｈ，ｓ，ＡｒＨ），５．０１（１Ｈ，ｍ，ＯＨ），４．０１（２Ｈ，ｍ），３．６８−３．７５（５Ｈ，ｍ），２．６０（３Ｈ，ｓ），２．４０（３Ｈ，ｓ）
ＬＣＭＳ Ｒｔ ２．５７分、ｍ／ｚ（ＥＳ^＋） ３０７ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１８Ｎ_２Ｏ_３Ｓ＋Ｈ 理論値３０７）。 Example 33: 1- (3- (2-hydroxyethyl) -4-methyl-2-{[4- (methyloxy) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl ) Ethanon

1-isothiocyanato-4- (methyloxy) benzene (0.25 mmol, 41.3 mg) was dissolved in ethyl acetate (1 mL). To this solution was added a 1 mL solution of ethyl acetate containing ethanolamine (15.1 μL, 0.25 mmol). After the reaction was shaken for 20-30 minutes, the solvent was removed in vacuo. The residue was then dissolved with ethanol (1 mL). To this was added 31.3 μL (0.263 mmol) of 3-chloro-2,4-pentanedione in ethanol (1 mL) and the mixture was heated in the microwave at 100 ° C. for 15 minutes. The solvent was then removed in vacuo and the residue from the reaction was purified by mass directed auto-purification to give 11.1 mg of the title compound.
¹ H NMR (400 MHz, MeOD): δ 7.9 (4H, s, ArH), 5.01 (1H, m, OH), 4.01 (2H, m), 3.68-3.75 (5H M), 2.60 (3H, s), 2.40 (3H, s)
LCMS Rt 2.57 ^{min, m / z (ES +)} 307 (M + H, C 15 H 18 N 2 O 3 S + H theory 307).

１−イソチオシアナト−４−（メチルチオ）ベンゼン（０．２５ｍｍｏｌ、４５．３ｍｇ）を酢酸エチル（１ｍＬ）で溶解した。該溶液に、エタノールアミン（１５．１μＬ、０．２５ｍｍｏｌ）含有酢酸エチルの１ｍＬ溶液を加えた。該反応物を２０−３０分間振盪した後、溶媒を真空中で除去した。次いで、残渣をエタノール（１ｍＬ）で溶解した。これに３１．３μＬ（０．２６３ｍｍｏｌ）量のエタノール（１ｍＬ）中３−クロロ−２，４−ペンタンジオンを加え、混合物をマイクロ波にて１００℃で１５分間加熱した。次いで、溶媒を真空中で除去し、該反応物からの残渣をマスディレクティッド自動精製に付して精製し、４０．５ｍｇの標記化合物を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ）： δ ７．２５−７．２９（２Ｈ，ｍ，ＡｒＨ），６．９５−６．９９（２Ｈ，ｍ，ＡｒＨ），４．１２（２Ｈ，ｍ），３．８８（２Ｈ，ｍ），２．６６（３Ｈ，ｓ），２．４６（３Ｈ，ｓ），２．３２（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ２．９６分、ｍ／ｚ（ＥＳ^＋） ３２３ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１８Ｎ_２Ｏ_２Ｓ_２＋Ｈ 理論値３２３）。 Example 34: 1- (3- (2-hydroxyethyl) -4-methyl-2-{[4- (methylthio) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) Ethanon

1-isothiocyanato-4- (methylthio) benzene (0.25 mmol, 45.3 mg) was dissolved in ethyl acetate (1 mL). To this solution was added a 1 mL solution of ethyl acetate containing ethanolamine (15.1 μL, 0.25 mmol). After the reaction was shaken for 20-30 minutes, the solvent was removed in vacuo. The residue was then dissolved with ethanol (1 mL). To this was added 31.3 μL (0.263 mmol) of 3-chloro-2,4-pentanedione in ethanol (1 mL) and the mixture was heated in the microwave at 100 ° C. for 15 minutes. The solvent was then removed in vacuo and the residue from the reaction was purified by mass directed auto-purification to give 40.5 mg of the title compound.
¹ H NMR (400 MHz, MeOD): δ 7.25-7.29 (2H, m, ArH), 6.95-6.99 (2H, m, ArH), 4.12 (2H, m), 3 .88 (2H, m), 2.66 (3H, s), 2.46 (3H, s), 2.32 (3H, t)
LCMS Rt 2.96 ^{min, m / z (ES +)} 323 (M + H, C 15 H 18 N 2 O 2 S 2 + H theory 323).

４−イソチオシアナト−１，２−ジメチルベンゼン（０．２５ｍｍｏｌ、４０．８ｍｇ）を酢酸エチル（１ｍＬ）で溶解した。該溶液に、エタノールアミン（１５．１μＬ、０．２５ｍｍｏｌ）含有酢酸エチルの１ｍＬ溶液を加えた。該反応物を２０−３０分間振盪した後、溶媒を真空中で除去した。次いで、残渣をエタノール（１ｍＬ）で溶解した。これに３１．３μＬ（０．２６３ｍｍｏｌ）量のエタノール（１ｍＬ）中３−クロロ−２，４−ペンタンジオンを加え、混合物をマイクロ波にて１００℃で１５分間加熱した。次いで、溶媒を真空中で除去し、該反応物からの残渣をマスディレクティッド自動精製に付して精製し、８．１ｍｇの標記化合物を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ）： δ ７．０６−７．１（１Ｈ，ｍ，ＡｒＨ），６．７７−６．８０（１Ｈ，ｍ，ＡｒＨ），６．７０−６．７５（１Ｈ，ｍ，ＡｒＨ），４．１１（２Ｈ，ｍ），３．８８（２Ｈ，ｍ），２．６６（３Ｈ，ｓ），２．３０（３Ｈ，ｓ），２．２２−２．２６（６Ｈ，ｍ）
ＬＣＭＳ Ｒｔ ２．９３分、ｍ／ｚ（ＥＳ^＋） ３０５ （Ｍ＋Ｈ，Ｃ_１６Ｈ_２０Ｎ_２Ｏ_２Ｓ＋Ｈ 理論値３０５）。 Example 35: 1- [2-[(3,4-Dimethylphenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] Ethanon

4-Isothiocyanato-1,2-dimethylbenzene (0.25 mmol, 40.8 mg) was dissolved in ethyl acetate (1 mL). To this solution was added a 1 mL solution of ethyl acetate containing ethanolamine (15.1 μL, 0.25 mmol). After the reaction was shaken for 20-30 minutes, the solvent was removed in vacuo. The residue was then dissolved with ethanol (1 mL). To this was added 31.3 μL (0.263 mmol) of 3-chloro-2,4-pentanedione in ethanol (1 mL) and the mixture was heated in the microwave at 100 ° C. for 15 minutes. The solvent was then removed in vacuo and the residue from the reaction was purified by mass directed auto-purification to give 8.1 mg of the title compound.
¹ H NMR (400 MHz, MeOD): δ 7.06-7.1 (1H, m, ArH), 6.77-6.80 (1H, m, ArH), 6.70-6.75 (1H, m, ArH), 4.11 (2H, m), 3.88 (2H, m), 2.66 (3H, s), 2.30 (3H, s), 2.22-2.26 (6H) , M)
LCMS Rt 2.93 ^{min, m / z (ES +)} 305 (M + H, C 16 H 20 N 2 O 2 S + H theory 305).

１−イソチオシアナト−４−［（トリフルオロメチル）オキシ］ベンゼン（０．２５ｍｍｏｌ、４０．５９ｍｇ）を、酢酸エチル（２ｍＬ）中で３３重量％メチルアミンのエタノール溶液（０．２５ｍｍｏｌ、７．７７ｍｇメチルアミン≡２３．３ｍｇの溶液）と合した。該反応物を２０分間攪拌した後、溶媒を真空中で除去した。次いで、残渣をエタノール（２ｍＬ）で溶解した。これに３１．３μＬ（０．２６３ｍｍｏｌ）量の３−クロロ−２，４−ペンタンジオンを加え、混合物をマイクロ波にて１００℃で１５分間加熱した。次いで、溶媒を真空中で除去し、該反応物からの残渣をマスディレクティッド自動精製に付して精製し、８．２ｍｇの標記化合物を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ）： δ ７．２１−７．２７（２Ｈ，ｍ，ＡｒＨ），７．０６−７．１１（２Ｈ，ｍ，ＡｒＨ），３．５０（３Ｈ，ｓ），２．６１（３Ｈ，ｓ），２．３２（３Ｈ，ｓ）
ＬＣＭＳ Ｒｔ ３．３５分、ｍ／ｚ（ＥＳ^＋） ３３１ （Ｍ＋Ｈ，Ｃ_１４Ｈ_１３Ｆ_３Ｎ_２Ｏ_２Ｓ＋Ｈ 理論値３３１）。 Example 36: 1- [3,4-dimethyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] ethanone

1-isothiocyanato-4-[(trifluoromethyl) oxy] benzene (0.25 mmol, 40.59 mg) was added in 33% by weight methylamine in ethanol (0.25 mmol, 7.77 mg methyl in ethyl acetate (2 mL). Amine ≡ 23.3 mg solution). After the reaction was stirred for 20 minutes, the solvent was removed in vacuo. The residue was then dissolved with ethanol (2 mL). To this was added 31.3 μL (0.263 mmol) of 3-chloro-2,4-pentanedione and the mixture was heated in the microwave at 100 ° C. for 15 minutes. The solvent was then removed in vacuo and the residue from the reaction was purified by mass directed auto-purification to give 8.2 mg of the title compound.
¹ H NMR (400 MHz, MeOD): δ 7.21-7.27 (2H, m, ArH), 7.06-7.11 (2H, m, ArH), 3.50 (3H, s), 2 .61 (3H, s), 2.32 (3H, s)
LCMS Rt 3.35 _{^{min, m / z (ES +)}} 331 (M + H, C 14 H 13 F 3 N 2 O 2 S + H theory 331).

１−イソチオシアナト−４−［（トリフルオロメチル）オキシ］ベンゼン（０．２５ｍｍｏｌ、４０．５９ｍｇ）を、酢酸エチル（２ｍＬ）中でｎ−プロピルアミン（０．２５ｍｍｏｌ、１４．８ｍｇ）と合した。該反応物を２０分間攪拌した後、溶媒を真空中で除去した。次いで、残渣をエタノール（２ｍＬ）で溶解した。これに３１．３μＬ（０．２６３ｍｍｏｌ）量の３−クロロ−２，４−ペンタンジオンを加え、混合物をマイクロ波にて１００℃で１５分間加熱した。次いで、溶媒を真空中で除去し、該反応物からの残渣をマスディレクティッド自動精製に付して精製し、３．１ｍｇの標記化合物を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ）： δ ７．２６−７．３０（２Ｈ，ｍ，ＡｒＨ），７．１１−７．１７（２Ｈ，ｍ，ＡｒＨ），４．００（２Ｈ，ｍ），２．６３（３Ｈ，ｓ），２．３３（３Ｈ，ｓ），１．８１（２Ｈ，ｍ），１．３２（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ３．６７分、ｍ／ｚ（ＥＳ^＋） ３５９ （Ｍ＋Ｈ，Ｃ_１６Ｈ_１７Ｆ_３Ｎ_２Ｏ_２Ｓ＋Ｈ 理論値３５９）。 Example 37: 1- [4-Methyl-3-propyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] Ethanon

1-isothiocyanato-4-[(trifluoromethyl) oxy] benzene (0.25 mmol, 40.59 mg) was combined with n-propylamine (0.25 mmol, 14.8 mg) in ethyl acetate (2 mL). After the reaction was stirred for 20 minutes, the solvent was removed in vacuo. The residue was then dissolved with ethanol (2 mL). To this was added 31.3 μL (0.263 mmol) of 3-chloro-2,4-pentanedione and the mixture was heated in the microwave at 100 ° C. for 15 minutes. The solvent was then removed in vacuo and the residue from the reaction was purified by mass directed auto-purification to give 3.1 mg of the title compound.
¹ H NMR (400 MHz, MeOD): δ 7.26-7.30 (2H, m, ArH), 7.11-7.17 (2H, m, ArH), 4.00 (2H, m), 2 .63 (3H, s), 2.33 (3H, s), 1.81 (2H, m), 1.32 (3H, t)
LCMS Rt 3.67 _{^{min, m / z (ES +)}} 359 (M + H, C 16 H 17 F 3 N 2 O 2 S + H theory 359).

１−イソチオシアナト−４−［（トリフルオロメチル）オキシ］ベンゼン（０．２５ｍｍｏｌ、４０．５９ｍｇ）を、酢酸エチル（２ｍＬ）中で［２−（メチルオキシ）エチル］アミン（０．２５ｍｍｏｌ、１８．８ｍｇ）と合した。該反応物を２０分間攪拌した後、溶媒を真空中で除去した。次いで、残渣をエタノール（２ｍＬ）で溶解した。これに３１．３μＬ（０．２６３ｍｍｏｌ）量の３−クロロ−２，４−ペンタンジオンを加え、混合物をマイクロ波にて１００℃で１５分間加熱した。次いで、溶媒を真空中で除去し、該反応物からの残渣をマスディレクティッド自動精製に付して精製し、２．１ｍｇの標記化合物を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ）： δ ７．２２−７．２７（２Ｈ，ｍ，ＡｒＨ），７．０６−７．１１（２Ｈ，ｍ，ＡｒＨ），４．２０（２Ｈ，ｍ），３．７２（２Ｈ，ｍ），３．３５（３Ｈ，ｓ），２．６４（３Ｈ，ｓ），２．３２（３Ｈ，ｓ）
ＬＣＭＳ Ｒｔ ３．４７分、ｍ／ｚ（ＥＳ^＋） ３７５ （Ｍ＋Ｈ，Ｃ_１６Ｈ_１７Ｆ_３Ｎ_２Ｏ_３Ｓ＋Ｈ 理論値３７５）。 Example 38: 1- [4-Methyl-3- [2- (methyloxy) ethyl] -2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1, 3-Triazol-5-yl] ethanone

1-isothiocyanato-4-[(trifluoromethyl) oxy] benzene (0.25 mmol, 40.59 mg) was added to [2- (methyloxy) ethyl] amine (0.25 mmol, 18.59 mg) in ethyl acetate (2 mL). 8 mg). After the reaction was stirred for 20 minutes, the solvent was removed in vacuo. The residue was then dissolved with ethanol (2 mL). To this was added 31.3 μL (0.263 mmol) of 3-chloro-2,4-pentanedione and the mixture was heated in the microwave at 100 ° C. for 15 minutes. The solvent was then removed in vacuo and the residue from the reaction was purified by mass directed auto-purification to give 2.1 mg of the title compound.
¹ H NMR (400 MHz, MeOD): δ 7.22-7.27 (2H, m, ArH), 7.06-7.11 (2H, m, ArH), 4.20 (2H, m), 3 .72 (2H, m), 3.35 (3H, s), 2.64 (3H, s), 2.32 (3H, s)
LCMS Rt 3.47 _{^{min, m / z (ES +)}} 375 (M + H, C 16 H 17 F 3 N 2 O 3 S + H theory 375).

１−（エチルオキシ）−４−イソチオシアナトベンゼン（０．２５ｍｍｏｌ、４４．８ｍｇ）を、酢酸エチル（２ｍＬ）中で３３重量％メチルアミンのエタノール溶液（０．２５ｍｍｏｌ、７．７７ｍｇメチルアミン≡２３．３ｍｇの溶液）と合した。該反応物を２０分間攪拌した後、溶媒を真空中で除去した。次いで、残渣をエタノール（２ｍＬ）で溶解した。これに３１．３μＬ（０．２６３ｍｍｏｌ）量の３−クロロ−２，４−ペンタンジオンを加え、混合物をマイクロ波にて１００℃で１５分間加熱した。次いで、溶媒を真空中で除去し、該反応物からの残渣をマスディレクティッド自動精製に付して精製し、３．０ｍｇの標記化合物を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ）： δ ６．８７−６．９５（４Ｈ，ｍ，ＡｒＨ），４．０１（２Ｈ，ｍ，），３．４７（３Ｈ，ｓ），２．６０（３Ｈ，ｓ），２．３０（３Ｈ，ｓ），１．３７（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ３．８４分、ｍ／ｚ（ＥＳ^＋） ２９１ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１８Ｎ_２Ｏ_２Ｓ＋Ｈ 理論値２９１）。 Example 39: 1- (2-{[4- (Ethyloxy) phenyl] imino} -3,4-dimethyl-2,3-dihydro-1,3-triazol-5-yl) ethanone

1- (Ethyloxy) -4-isothiocyanatobenzene (0.25 mmol, 44.8 mg) was added to an ethanol solution of 33 wt% methylamine (0.25 mmol, 7.77 mg methylamine≡23 in ethyl acetate (2 mL). 3 mg solution). After the reaction was stirred for 20 minutes, the solvent was removed in vacuo. The residue was then dissolved with ethanol (2 mL). To this was added 31.3 μL (0.263 mmol) of 3-chloro-2,4-pentanedione and the mixture was heated in the microwave at 100 ° C. for 15 minutes. The solvent was then removed in vacuo and the residue from the reaction was purified by mass directed auto-purification to give 3.0 mg of the title compound.
¹ H NMR (400 MHz, MeOD): δ 6.87-6.95 (4H, m, ArH), 4.01 (2H, m,), 3.47 (3H, s), 2.60 (3H, s), 2.30 (3H, s), 1.37 (3H, t)
LCMS Rt 3.84 ^{min, m / z (ES +)} 291 (M + H, C 15 H 18 N 2 O 2 S + H theory 291).

１−（エチルオキシ）−４−イソチオシアナトベンゼン（０．２５ｍｍｏｌ、４４．８ｍｇ）を、酢酸エチル（２ｍＬ）中でプロピルアミン（０．２５ｍｍｏｌ、１４．８ｍｇ）と合した。該反応物を２０分間攪拌した後、溶媒を真空中で除去した。次いで、残渣をエタノール（２ｍＬ）で溶解した。これに３１．３μＬ（０．２６３ｍｍｏｌ）量の３−クロロ−２，４−ペンタンジオンを加え、混合物をマイクロ波にて１００℃で１５分間加熱した。次いで、溶媒を真空中で除去し、該反応物からの残渣をマスディレクティッド自動精製に付して精製し、１．９ｍｇの標記化合物を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ）： δ ６．８７−６．９４（４Ｈ，ｍ，ＡｒＨ），３．９２−４．０４（４Ｈ，ｍ），２．６１（３Ｈ，ｓ），２．２９（３Ｈ，ｓ），１．７８（２Ｈ，ｍ），１．３７（３Ｈ，ｔ），１．０１（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ３．３５分、ｍ／ｚ（ＥＳ^＋） ３１９ （Ｍ＋Ｈ，Ｃ_１７Ｈ_２２Ｎ_２Ｏ_２Ｓ＋Ｈ 理論値３１９）。 Example 40: 1- (2-{[4- (Ethyloxy) phenyl] imino} -4-methyl-3-propyl-2,3-dihydro-1,3-triazol-5-yl) ethanone

1- (Ethyloxy) -4-isothiocyanatobenzene (0.25 mmol, 44.8 mg) was combined with propylamine (0.25 mmol, 14.8 mg) in ethyl acetate (2 mL). After the reaction was stirred for 20 minutes, the solvent was removed in vacuo. The residue was then dissolved with ethanol (2 mL). To this was added 31.3 μL (0.263 mmol) of 3-chloro-2,4-pentanedione and the mixture was heated in the microwave at 100 ° C. for 15 minutes. The solvent was then removed in vacuo and the residue from the reaction was purified by mass directed auto-purification to give 1.9 mg of the title compound.
¹ H NMR (400 MHz, MeOD): δ 6.87-6.94 (4H, m, ArH), 3.92-4.04 (4H, m), 2.61 (3H, s), 2.29 (3H, s), 1.78 (2H, m), 1.37 (3H, t), 1.01 (3H, t)
LCMS Rt 3.35 ^{min, m / z (ES +)} 319 (M + H, C 17 H 22 N 2 O 2 S + H theory 319).

１−イソチオシアナト−４−（トリフルオロメチル）ベンゼン（０．２５ｍｍｏｌ、５０．７５ｍｇ）を、酢酸エチル（２ｍｌ）中で３３重量％メチルアミンのエタノール溶液（０．２５ｍｍｏｌ、７．７７ｍｇメチルアミン≡２３．３ｍｇの溶液）と合した。該反応物を１０分間攪拌した後、溶媒を真空中で除去した。次いで、残渣をエタノール（２ｍＬ）で溶解した。これに３１．３μＬ（０．２６３ｍｍｏｌ）量の３−クロロ−２，４−ペンタンジオンを加え、混合物をマイクロ波にて１００℃で２０分間加熱した。次いで、溶媒を真空中で除去し、該反応物からの残渣をマスディレクティッド自動精製に付して精製し、１４．８ｍｇの標記化合物を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ_６）： δ ７．７２−７．６７（２Ｈ，ｍ，ＡｒＨ），７．１７−７．２１（２Ｈ，ｍ，ＡｒＨ），３．４８（３Ｈ，ｓ），２．５８（３Ｈ，ｓ），２．３４（３Ｈ，ｓ）
ＬＣＭＳ Ｒｔ ３．３７分、ｍ／ｚ（ＥＳ^＋） ３１５ （Ｍ＋Ｈ，Ｃ_１４Ｈ_１３Ｆ_３Ｎ_２ＯＳ＋Ｈ 理論値３１５）。 Example 41: 1- (3,4-dimethyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone

1-isothiocyanato-4- (trifluoromethyl) benzene (0.25 mmol, 50.75 mg) was added to a solution of 33 wt% methylamine in ethanol (0.25 mmol, 7.77 mg methylamine≡23 in ethyl acetate (2 ml). 3 mg solution). After the reaction was stirred for 10 minutes, the solvent was removed in vacuo. The residue was then dissolved with ethanol (2 mL). To this was added 31.3 μL (0.263 mmol) of 3-chloro-2,4-pentanedione and the mixture was heated in the microwave at 100 ° C. for 20 minutes. The solvent was then removed in vacuo and the residue from the reaction was purified by mass directed auto-purification to give 14.8 mg of the title compound.
¹ H NMR (400 MHz, DMSO D ₆ ): δ 7.72-7.67 (2H, m, ArH), 7.17-7.21 (2H, m, ArH), 3.48 (3H, s) , 2.58 (3H, s), 2.34 (3H, s)
LCMS Rt 3.37 ^{min, m / z (ES +)} 315 (M + H, C 14 H 13 F 3 N 2 OS + H theory 315).

１−エチル−４−イソチオシアナトベンゼン（０．２５ｍｍｏｌ、４０．７５ｍｇ）を、酢酸エチル（２ｍｌ）中で３３重量％メチルアミンのエタノール溶液（０．２５ｍｍｏｌ、７．７７ｍｇメチルアミン≡２３．３ｍｇの溶液）と合した。該反応物を１０分間攪拌した後、溶媒を真空中で除去した。次いで、残渣をエタノール（２ｍＬ）で溶解した。これに３１．３μＬ（０．２６３ｍｍｏｌ）量の３−クロロ−２，４−ペンタンジオンを加え、混合物をマイクロ波にて１００℃で２０分間加熱した。次いで、溶媒を真空中で除去し、該反応物からの残渣をマスディレクティッド自動精製に付して精製し、３．３ｍｇの標記化合物を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ）： δ ７．１５−７．２０（２Ｈ，ｍ，ＡｒＨ），６．８９−６．９４（２Ｈ，ｍ，ＡｒＨ），３．４８（３Ｈ，ｓ），２．５９（５Ｈ，ｓ），２．２９（３Ｈ，ｓ），１．２２（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ３．４２分、ｍ／ｚ（ＥＳ^＋） ２７５ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１８Ｎ_２ＯＳ＋Ｈ 理論値２７５）。 Example 42: 1- {2-[(4-Ethylphenyl) imino] -3,4-dimethyl-2,3-dihydro-1,3-triazol-5-yl} ethanone

1-ethyl-4-isothiocyanatobenzene (0.25 mmol, 40.75 mg) was added to a solution of 33 wt% methylamine in ethanol (0.25 mmol, 7.77 mg methylamine≡23.3 mg) in ethyl acetate (2 ml). Solution). After the reaction was stirred for 10 minutes, the solvent was removed in vacuo. The residue was then dissolved with ethanol (2 mL). To this was added 31.3 μL (0.263 mmol) of 3-chloro-2,4-pentanedione and the mixture was heated in the microwave at 100 ° C. for 20 minutes. The solvent was then removed in vacuo and the residue from the reaction was purified by mass directed auto-purification to give 3.3 mg of the title compound.
¹ H NMR (400 MHz, MeOD): δ 7.15-7.20 (2H, m, ArH), 6.89-6.94 (2H, m, ArH), 3.48 (3H, s), 2 .59 (5H, s), 2.29 (3H, s), 1.22 (3H, t)
LCMS Rt 3.42 ^{min, m / z (ES +)} 275 (M + H, C 15 H 18 N 2 OS + H theory 275).

４−（イソチオシアナトフェニル）ジメチルアミン（０．２５ｍｍｏｌ、４４．５ｍｇ）を、酢酸エチル（２ｍｌ）中で３３重量％メチルアミンのエタノール溶液（０．２５ｍｍｏｌ、７．７７ｍｇメチルアミン≡２３．３ｍｇの溶液）と合した。該反応物を１０分間攪拌した後、溶媒を真空中で除去した。次いで、残渣をエタノール（２ｍＬ）で溶解した。これに３１．３μＬ（０．２６３ｍｍｏｌ）量の３−クロロ−２，４−ペンタンジオンを加え、混合物をマイクロ波にて１００℃で２０分間加熱した。次いで、溶媒を真空中で除去し、該反応物からの残渣をマスディレクティッド自動精製に付して精製し、２１．２ｍｇの標記化合物を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ）： δ ６．９８−７．０６（４Ｈ，ｍ，ＡｒＨ），３．４８（３Ｈ，ｓ），２．９８（６Ｈ，ｔ） ２．５７（３Ｈ，ｓ），２．３４（３Ｈ，ｓ）
ＬＣＭＳ Ｒｔ ２．１５分、ｍ／ｚ（ＥＳ^＋） ２９０ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１９Ｎ_３ＯＳ＋Ｈ 理論値２９０）。 Example 43: 1- (2-{[4- (dimethylamino) phenyl] imino} -3,4-dimethyl-2,3-dihydro-1,3-triazol-5-yl) ethanone

4- (isothiocyanatophenyl) dimethylamine (0.25 mmol, 44.5 mg) was added to a solution of 33% by weight methylamine in ethyl acetate (2 ml) (0.25 mmol, 7.77 mg methylamine≡23.3 mg). Solution). After the reaction was stirred for 10 minutes, the solvent was removed in vacuo. The residue was then dissolved with ethanol (2 mL). To this was added 31.3 μL (0.263 mmol) of 3-chloro-2,4-pentanedione and the mixture was heated in the microwave at 100 ° C. for 20 minutes. The solvent was then removed in vacuo and the residue from the reaction was purified by mass directed auto-purification to give 21.2 mg of the title compound.
¹ H NMR (400 MHz, MeOD): δ 6.98-7.06 (4H, m, ArH), 3.48 (3H, s), 2.98 (6H, t) 2.57 (3H, s) , 2.34 (3H, s)
LCMS Rt 2.15 ^{min, m / z (ES +)} 290 (M + H, C 15 H 19 N 3 OS + H theory 290).

１−（エチルオキシ）−４−イソチオシアナトベンゼン（１．５ｍｍｏｌ、３０４．８ｍｇ）を５ｍｌの酢酸エチルで溶解した。該溶液にテトラヒドロフラン中２−メチルアミン（１．５ｍｍｏｌ、０．７５ｍｌ）を加えた。該反応物を２０分間攪拌した後、溶媒を真空中で除去した。次いで、残渣を５ｍｌのエタノールで溶解した。これに２６８μＬ（２．２５ｍｍｏｌ）量の３−クロロ−２，４−ペンタンジオンを加え、混合物をマイクロ波にて１００℃で２０分間加熱した。次いで、溶媒を真空中で除去し、該反応物からの約２０％の残渣をマスディレクティッド自動精製に付して精製し、１０．２ｍｇの標記化合物を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ）： δ ６．９０（４Ｈ，ｓ，ＡｒＨ），４．００（４Ｈ，ｍ），２．５８（３Ｈ，ｓ），２．３０（３Ｈ，ｓ），１．３１（３Ｈ，ｔ） １．２４（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ３．１０分、ｍ／ｚ（ＥＳ^＋） ３０５ （Ｍ＋Ｈ，Ｃ_１６Ｈ_２０Ｎ_２Ｏ_２Ｓ＋Ｈ 理論値３０５）。 Example 44: 1- (3-ethyl-2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone

1- (Ethyloxy) -4-isothiocyanatobenzene (1.5 mmol, 304.8 mg) was dissolved in 5 ml of ethyl acetate. To the solution was added 2-methylamine (1.5 mmol, 0.75 ml) in tetrahydrofuran. After the reaction was stirred for 20 minutes, the solvent was removed in vacuo. The residue was then dissolved with 5 ml of ethanol. To this was added 268 μL (2.25 mmol) of 3-chloro-2,4-pentanedione and the mixture was heated in the microwave at 100 ° C. for 20 minutes. The solvent was then removed in vacuo and approximately 20% of the residue from the reaction was purified by mass directed auto-purification to give 10.2 mg of the title compound.
¹ H NMR (400 MHz, MeOD): δ 6.90 (4H, s, ArH), 4.00 (4H, m), 2.58 (3H, s), 2.30 (3H, s), 1. 31 (3H, t) 1.24 (3H, t)
LCMS Rt 3.10 ^{min, m / z (ES +)} 305 (M + H, C 16 H 20 N 2 O 2 S + H theory 305).

Ｎ−［４−（ジエチルアミノ）フェニル］−Ｎ’−（２−ヒドロキシエチル）チオ尿素（０．３７ｍｍｏｌ、９９ｍｇ）および３−クロロ−２，４−ペンタンジオン（０．５６ｍｍｏｌ，６７μＬ）をエタノール（２．５ｍＬ）中で合し、マイクロ波にて１００℃で２０分間加熱した。ＭＤＡＰに付して精製し、０．０７９ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）： δ ６．９７−７．０１（２Ｈ，ｍ，ＡｒＨ），６．６８−６．７４（２Ｈ，ｍ，ＡｒＨ），４．１８（２Ｈ，ｍ），３．９８（２Ｈ，ｍ），３．３５（２ｘ２Ｈ，ｑ），２．６１（３Ｈ，ｓ），２．２９（３Ｈ，ｓ），１．１６（２ｘ３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ １．９６分。ｍ／ｚ（ＥＳ^＋） ３４８ （Ｍ＋Ｈ，Ｃ_１８Ｈ_２５Ｎ_３Ｏ_２Ｓ＋Ｈ 理論値３４８）。 Example 45: 1- [2-{[4- (Diethylamino) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] Ethanon

N- [4- (diethylamino) phenyl] -N ′-(2-hydroxyethyl) thiourea (0.37 mmol, 99 mg) and 3-chloro-2,4-pentanedione (0.56 mmol, 67 μL) were added to ethanol ( 2.5 mL) and heated in a microwave at 100 ° C. for 20 minutes. Purified by MDAP and isolated 0.079 g of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ 6.97-7.01 (2H, m, ArH), 6.68-6.74 (2H, m, ArH), 4.18 (2H, m), 3.98 (2H, m), 3.35 (2 × 2H, q), 2.61 (3H, s), 2.29 (3H, s), 1.16 (2 × 3H, t)
LCMS Rt 1.96 min. _{^{m / z (ES +) 348}} (M + H, C 18 H 25 N 3 O 2 S + H theory 348).

Ｎ−［４−（ジエチルアミノ）フェニル］−Ｎ’−エチルチオ尿素（０．３７ｍｍｏｌ、９３ｍｇ）および３−クロロ−２，４−ペンタンジオン（０．５６ｍｍｏｌ、６７μＬ）をエタノール（２．５ｍＬ）中で合し、マイクロ波にて１００℃で２０分間加熱した。ＭＤＡＰに付して精製し、０．００５ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）： δ ６．９５−７．００（２Ｈ，ｍ，ＡｒＨ），６．７０−６．７３（２Ｈ，ｍ，ＡｒＨ），４．０４（２Ｈ，ｑ），３．３５（２ｘ２Ｈ，ｑ），２．６１（３Ｈ，ｓ），２．２６（３Ｈ，ｓ），１．３５（３Ｈ，ｔ），１．１７（２ｘ３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ２．１９分、ｍ／ｚ（ＥＳ^＋） ３３２ （Ｍ＋Ｈ，Ｃ_１８Ｈ_２５Ｎ_３ＯＳ＋Ｈ 理論値３３２）。 Example 46: 1- (2-{[4- (diethylamino) phenyl] imino} -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone

N- [4- (diethylamino) phenyl] -N′-ethylthiourea (0.37 mmol, 93 mg) and 3-chloro-2,4-pentanedione (0.56 mmol, 67 μL) in ethanol (2.5 mL) And heated in a microwave at 100 ° C. for 20 minutes. Purification by MDAP isolated 0.005 g of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ 6.95-7.00 (2H, m, ArH), 6.70-6.73 (2H, m, ArH), 4.04 (2H, q), 3.35 (2 × 2H, q), 2.61 (3H, s), 2.26 (3H, s), 1.35 (3H, t), 1.17 (2 × 3H, t)
LCMS Rt 2.19 ^{min, m / z (ES +)} 332 (M + H, C 18 H 25 N 3 OS + H theory 332).

Ｎ−｛４−［（ジフルオロメチル）オキシ］フェニル｝−Ｎ’−エチルチオ尿素（０．３７ｍｍｏｌ、９１ｍｇ）および３−クロロ−２，４−ペンタンジオン（０．５６ｍｍｏｌ、６７μＬ）をエタノール（２．５ｍＬ）中で合し、マイクロ波にて１００℃で２０分間加熱した。ＭＤＡＰに付して精製し、０．０６０５ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）： δ ７．１０−７．１５（２Ｈ，ｍ，ＡｒＨ），７．０１−７．０７（２Ｈ，ｍ，ＡｒＨ），６．５０（１Ｈ，ｔ，ＣＨＦ_２），４．０５（２Ｈ，ｑ），２．６３（３Ｈ，ｓ），２．２７（３Ｈ，ｓ），１．３６（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ３．２２分、ｍ／ｚ（ＥＳ^＋） ３２７ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１６Ｆ_２Ｎ_２Ｏ_２Ｓ＋Ｈ 理論値３２７）。 Example 47: 1- [2-({4-[(Difluoromethyl) oxy] phenyl} imino) -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone

N- {4-[(difluoromethyl) oxy] phenyl} -N′-ethylthiourea (0.37 mmol, 91 mg) and 3-chloro-2,4-pentanedione (0.56 mmol, 67 μL) were added to ethanol (2. 5 mL) and heated in a microwave at 100 ° C. for 20 minutes. Purification by MDAP isolated 0.0605 g of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.10-7.15 (2H, m, ArH), 7.01-7.07 (2H, m, ArH), 6.50 (1H, t, CHF) ₂ ), 4.05 (2H, q), 2.63 (3H, s), 2.27 (3H, s), 1.36 (3H, t)
LCMS Rt 3.22 _{^{min, m / z (ES +)}} 327 (M + H, C 15 H 16 F 2 N 2 O 2 S + H theory 327).

Ｎ−エチル−Ｎ’−［４−（４−モルホリニル）フェニル］チオ尿素（０．２３ｍｍｏｌ、６１ｍｇ）および３−クロロ−２，４−ペンタンジオン（０．３５ｍｍｏｌ、３５μＬ）をエタノール（２．５ｍＬ）中で合し、マイクロ波にて１００℃で２０分間加熱した。ＭＤＡＰに付して精製し、０．０１６ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ６）： δ ６．８７−６．９７（４Ｈ，ｍ，ＡｒＨ），４．０１（２Ｈ，ｑ），３．７３（２ｘ２Ｈ，ｍ），３．０６（２ｘ２Ｈ，ｍ），２．５８（３Ｈ，ｓ），２．３０（３Ｈ，ｓ），１．２４（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ２．６４分、ｍ／ｚ（ＥＳ^＋） ３４６ （Ｍ＋Ｈ，Ｃ_１８Ｈ_２３Ｎ_３Ｏ_２Ｓ＋Ｈ 理論値３４６）。 Example 48: 1- (3-Ethyl-4-methyl-2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone

N-ethyl-N ′-[4- (4-morpholinyl) phenyl] thiourea (0.23 mmol, 61 mg) and 3-chloro-2,4-pentanedione (0.35 mmol, 35 μL) in ethanol (2.5 mL) ) And heated in a microwave at 100 ° C. for 20 minutes. Purified by MDAP and isolated 0.016 g of the title compound.
¹ H NMR (400 MHz, DMSO D6): δ 6.87-6.97 (4H, m, ArH), 4.01 (2H, q), 3.73 (2 × 2H, m), 3.06 (2 × 2H, m), 2.58 (3H, s), 2.30 (3H, s), 1.24 (3H, t)
LCMS Rt 2.64 ^{min, m / z (ES +)} 346 (M + H, C 18 H 23 N 3 O 2 S + H theory 346).

Ｎ−メチル−Ｎ’−［４−（４−モルホリニル）フェニル］チオ尿素（０．２３ｍｍｏｌ、５８ｍｇ）および３−クロロ−２，４−ペンタンジオン（０．３５ｍｍｏｌ、３５μＬ）をエタノール（２．５ｍＬ）中で合し、マイクロ波にて１００℃で２０分間加熱した。ＭＤＡＰに付して精製し、０．００６７ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ６）： δ ６．８７−６．９７（４Ｈ，ｍ，ＡｒＨ），３．７３（２ｘ２Ｈ，ｍ），３．４３（３Ｈ，ｓ），３．０６（２ｘ２Ｈ，ｍ），２．５６（３Ｈ，ｓ），２．３０（３Ｈ，ｓ）
ＬＣＭＳ Ｒｔ ２．４２分、ｍ／ｚ（ＥＳ^＋） ３３２ （Ｍ＋Ｈ，Ｃ_１７Ｈ_２１Ｎ_３Ｏ_２Ｓ＋Ｈ 理論値３３２）。 Example 49: 1- (3,4-dimethyl-2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone

N-methyl-N ′-[4- (4-morpholinyl) phenyl] thiourea (0.23 mmol, 58 mg) and 3-chloro-2,4-pentanedione (0.35 mmol, 35 μL) in ethanol (2.5 mL) ) And heated in a microwave at 100 ° C. for 20 minutes. Purification by MDAP isolated 0.0067 g of the title compound.
¹ H NMR (400 MHz, DMSO D6): δ 6.87-6.97 (4H, m, ArH), 3.73 (2 × 2H, m), 3.43 (3H, s), 3.06 (2 × 2H, m), 2.56 (3H, s), 2.30 (3H, s)
LCMS Rt 2.42 ^{min, m / z (ES +)} 332 (M + H, C 17 H 21 N 3 O 2 S + H theory 332).

Ｂｏｃ−保護−１−｛２−［（４−アミノフェニル）イミノ］−３，４−ジメチル−２，３−ジヒドロ−１，３−トリアゾール−５−イル｝エタノン（０．６７ｍｍｏｌ、２４２ｍｇ）を、トリフルオロ酢酸（２ｍＬ）およびＤＣＭ（２ｍＬ）で溶解し、混合物を室温で１時間攪拌した。２ｇのＳＣＸカートリッジに付して精製し、０．０６４６ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）： δ ６．８５−６．９０（２Ｈ，ｍ，ＡｒＨ），６．６７−６．７２（２Ｈ，ｍ，ＡｒＨ），３．４６（３Ｈ，ｓ），２．５９（３Ｈ，ｓ），２．２５（３Ｈ，ｓ）
ＬＣＭＳ Ｒｔ １．９５分、ｍ／ｚ（ＥＳ^＋） ２６２ （Ｍ＋Ｈ，Ｃ_１３Ｈ_１５Ｎ_３ＯＳ＋Ｈ 理論値２６２）。 Example 50: 1- {2-[(4-aminophenyl) imino] -3,4-dimethyl-2,3-dihydro-1,3-triazol-5-yl} ethanone

Boc-protected-1- {2-[(4-aminophenyl) imino] -3,4-dimethyl-2,3-dihydro-1,3-triazol-5-yl} ethanone (0.67 mmol, 242 mg) , Dissolved in trifluoroacetic acid (2 mL) and DCM (2 mL) and the mixture was stirred at room temperature for 1 h. Purification by 2g SCX cartridge isolated 0.0646g of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ 6.85-6.90 (2H, m, ArH), 6.67-6.72 (2H, m, ArH), 3.46 (3H, s), 2.59 (3H, s), 2.25 (3H, s)
LCMS Rt 1.95 ^{min, m / z (ES +)} 262 (M + H, C 13 H 15 N 3 OS + H theory 262).

Ｂｏｃ−保護−１−｛２−［（４−アミノフェニル）イミノ］−３−エチル−４−メチル−２，３−ジヒドロ−１，３−トリアゾール−５−イル｝エタノン（０．６７ｍｍｏｌ、２５１ｍｇ）を、トリフルオロ酢酸（２ｍＬ）およびＤＣＭ（２ｍＬ）で溶解し、混合物を室温で１時間攪拌した。２ｇのＳＣＸカートリッジに付して精製し、０．０７０５ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）： δ ６．８５−６．９０（２Ｈ，ｍ，ＡｒＨ），６．６７−６．７２（２Ｈ，ｍ，ＡｒＨ），４．００（２Ｈ，ｑ），２．５９（３Ｈ，ｓ），２．２３（３Ｈ，ｓ），１．３２（３Ｈ，ｓ）
ＬＣＭＳ Ｒｔ ２．１３分。ｍ／ｚ（ＥＳ^＋） ２７６ （Ｍ＋Ｈ，Ｃ_１４Ｈ_１７Ｎ_３ＯＳ＋Ｈ 理論値２７６）。 Example 51: 1- {2-[(4-aminophenyl) imino] -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone

Boc-protected-1- {2-[(4-aminophenyl) imino] -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone (0.67 mmol, 251 mg ) Was dissolved in trifluoroacetic acid (2 mL) and DCM (2 mL) and the mixture was stirred at room temperature for 1 h. Purification on a 2 g SCX cartridge isolated 0.0705 g of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ 6.85-6.90 (2H, m, ArH), 6.67-6.72 (2H, m, ArH), 4.00 (2H, q), 2.59 (3H, s), 2.23 (3H, s), 1.32 (3H, s)
LCMS Rt 2.13min. ^{m / z (ES +) 276} (M + H, C 14 H 17 N 3 OS + H theory 276).

Ｂｏｃ−保護−１−［２−［（４−アミノフェニル）イミノ］−３−（２−ヒドロキシエチル）−４−メチル−２，３−ジヒドロ−１，３−トリアゾール−５−イル］エタノン（０．６７ｍｍｏｌ、２６２ｍｇ）をトリフルオロ酢酸（２ｍＬ）およびＤＣＭ（２ｍＬ）で溶解し、混合物を室温で１時間攪拌した。２ｇのＳＣＸカートリッジに付して精製し、０．０８２４ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）： δ ６．８６−６．９１（２Ｈ，ｍ，ＡｒＨ），６．６７−６．７２（２Ｈ，ｍ，ＡｒＨ），４．１４（２Ｈ，ｍ），３．９６（２Ｈ，ｍ），２．６０（３Ｈ，ｓ），２．２７（３Ｈ，ｓ）
ＬＣＭＳ Ｒｔ １．９０分。ｍ／ｚ（ＥＳ^＋） ２９２ （Ｍ＋Ｈ，Ｃ_１４Ｈ_１７Ｎ_３Ｏ_２Ｓ＋Ｈ 理論値２９２）。 Example 52: 1- [2-[(4-Aminophenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone

Boc-protected-1- [2-[(4-aminophenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone ( 0.67 mmol, 262 mg) was dissolved in trifluoroacetic acid (2 mL) and DCM (2 mL) and the mixture was stirred at room temperature for 1 h. Purification by 2 g SCX cartridge isolated 0.0824 g of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ 6.86-6.91 (2H, m, ArH), 6.67-6.72 (2H, m, ArH), 4.14 (2H, m), 3.96 (2H, m), 2.60 (3H, s), 2.27 (3H, s)
LCMS Rt 1.90 min. _{^{m / z (ES +) 292}} (M + H, C 14 H 17 N 3 O 2 S + H theory 292).

Ｎ−［４−（ジメチルアミノ）フェニル］−Ｎ’−（２−ヒドロキシエチル）チオ尿素（０．１７ｍｍｏｌ、４１ｍｇ）をエタノール（２ｍＬ）で溶解し、３−クロロ−２，４−ペンタンジオン（０．５１ｍｍｏｌ、６１μＬ）を加えた。バイアルをマイクロ波にて１００℃で１０分間加熱した。ＭＤＡＰに付して精製し、０．００６６ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ６）： δ ６．８４−６．８９（２Ｈ，ｍ，ＡｒＨ），６．７１−６．７６（２Ｈ，ｍ，ＡｒＨ），５．０１（１Ｈ，ｔ，ＯＨ），４．００（２Ｈ，ｔ），３．７０（２Ｈ，ｑ），２．８６（２ｘ３Ｈ，ｓ），２．６０（３Ｈ，ｓ），２．２９（３Ｈ，ｓ）
ＬＣＭＳ Ｒｔ ２．０３分、ｍ／ｚ（ＥＳ^＋） ３２０ （Ｍ＋Ｈ，Ｃ_１６Ｈ_２１Ｎ_３Ｏ_２Ｓ＋Ｈ 理論値３２０）。 Example 53: 1- [2-{[4- (dimethylamino) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl ] Ethanon

N- [4- (dimethylamino) phenyl] -N ′-(2-hydroxyethyl) thiourea (0.17 mmol, 41 mg) was dissolved in ethanol (2 mL) and 3-chloro-2,4-pentanedione ( 0.51 mmol, 61 μL) was added. The vial was heated in the microwave at 100 ° C. for 10 minutes. Purification by MDAP isolated 0.0066 g of the title compound.
¹ H NMR (400 MHz, DMSO D6): δ 6.84-6.89 (2H, m, ArH), 6.71-6.76 (2H, m, ArH), 5.01 (1H, t, OH) ), 4.00 (2H, t), 3.70 (2H, q), 2.86 (2 × 3H, s), 2.60 (3H, s), 2.29 (3H, s)
LCMS Rt 2.03 ^{min, m / z (ES +)} 320 (M + H, C 16 H 21 N 3 O 2 S + H theory 320).

Ｎ−［４−（エチルオキシ）フェニル］−Ｎ’−（２−ヒドロキシエチル）チオ尿素（０．４５ｍｍｏｌ、１０７ｍｇ）をエタノール（２ｍＬ）で溶解した。２−クロロ−３−オキソブタン酸エチル（０．４５ｍｍｏｌ、７４ｍｇ）を加え、反応物をマイクロ波にて１００℃で１０分間加熱した。さらに０．５当量の２−クロロ−３−オキソブタン酸エチルを加え、混合物を５分間加熱した。ＭＤＡＰに付して精製し、０．０３７３ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ６）： δ ６．８６−６．９２（４Ｈ，ｍ，ＡｒＨ），５．０１（１Ｈ，ｍ，ＯＨ），４．１３（２Ｈ，ｑ），３．９４−４．０２（２ｘ２Ｈ，ｍ），３．７０（２Ｈ，ｍ），２．６０（３Ｈ，ｓ），１．３１（３Ｈ，ｔ），１．１９（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ３．１１分。ｍ／ｚ（ＥＳ^＋） ３５１ （Ｍ＋Ｈ，Ｃ_１７Ｈ_２２Ｎ_２Ｏ_４Ｓ＋Ｈ 理論値３５１）。 Example 54: ethyl 2-{[4- (ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxylate

N- [4- (ethyloxy) phenyl] -N ′-(2-hydroxyethyl) thiourea (0.45 mmol, 107 mg) was dissolved in ethanol (2 mL). Ethyl 2-chloro-3-oxobutanoate (0.45 mmol, 74 mg) was added and the reaction was heated in the microwave at 100 ° C. for 10 minutes. An additional 0.5 equivalents of ethyl 2-chloro-3-oxobutanoate was added and the mixture was heated for 5 minutes. Purified by MDAP and isolated 0.0373 g of the title compound.
¹ H NMR (400 MHz, DMSO D6): δ 6.86-6.92 (4H, m, ArH), 5.01 (1H, m, OH), 4.13 (2H, q), 3.94- 4.02 (2 × 2H, m), 3.70 (2H, m), 2.60 (3H, s), 1.31 (3H, t), 1.19 (3H, t)
LCMS Rt 3.11 min. _{^{m / z (ES +) 351}} (M + H, C 17 H 22 N 2 O 4 S + H theory 351).

Ｎ−［４−（エチルオキシ）フェニル］−Ｎ’−（２−ヒドロキシエチル）チオ尿素（０．４５ｍｍｏｌ、１０７ｍｇ）をエタノール（２ｍＬ）で溶解した。２−クロロ−Ｎ，Ｎ−ジメチル−３−オキソブタンアミド（０．４５ｍｍｏｌ、７３ｍｇ）を加え、反応物をマイクロ波にて１００℃で１０分間加熱した。さらに０．５当量の２−クロロ−Ｎ，Ｎ−ジメチル−３−オキソブタンアミドを加え、混合物を５分間加熱した。ＭＤＡＰに付して精製し、０．００７２ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ６）： δ ６．８５−６．９０（４Ｈ，ｍ，ＡｒＨ），４．９９（１Ｈ，ｍ，ＯＨ），３．９７（２Ｈ，ｑ），３．８９（２Ｈ，ｍ），３．６９（２Ｈ，ｍ），２．９２（２ｘ３Ｈ，ｓ），２．２１（３Ｈ，ｓ），１．３０（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ２．１６分。ｍ／ｚ（ＥＳ^＋） ３５０ （Ｍ＋Ｈ，Ｃ_１７Ｈ_２３Ｎ_３Ｏ_３Ｓ＋Ｈ 理論値３５０）。 Example 55: 2-{[4- (ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -N, N, 4-trimethyl-2,3-dihydro-1,3-triazole-5-carboxamide

N- [4- (ethyloxy) phenyl] -N ′-(2-hydroxyethyl) thiourea (0.45 mmol, 107 mg) was dissolved in ethanol (2 mL). 2-Chloro-N, N-dimethyl-3-oxobutanamide (0.45 mmol, 73 mg) was added and the reaction was heated in the microwave at 100 ° C. for 10 minutes. An additional 0.5 equivalents of 2-chloro-N, N-dimethyl-3-oxobutanamide was added and the mixture was heated for 5 minutes. Purification by MDAP isolated 0.0072 g of the title compound.
¹ H NMR (400 MHz, DMSO D6): δ 6.85-6.90 (4H, m, ArH), 4.99 (1H, m, OH), 3.97 (2H, q), 3.89 ( 2H, m), 3.69 (2H, m), 2.92 (2 × 3H, s), 2.21 (3H, s), 1.30 (3H, t)
LCMS Rt 2.16min. _{^{m / z (ES +) 350}} (M + H, C 17 H 23 N 3 O 3 S + H theory 350).

Ｎ−［４−（エチルオキシ）フェニル］−Ｎ’−（２−ヒドロキシエチル）チオ尿素（０．４５ｍｍｏｌ、１０７ｍｇ）をエタノール（２ｍＬ）で溶解した。２−クロロ−３−オキソブタン酸メチル（０．４５ｍｍｏｌ、６８ｍｇ）を加え、反応物をマイクロ波にて１００℃で１０分間加熱した。ＭＤＡＰに付して精製し、０．０２６６ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ６）： δ ６．８９−６．９１（４Ｈ，ｍ，ＡｒＨ），５．０２（１Ｈ，ｔ，ＯＨ），３．９５−４．０２（２ｘ２Ｈ，ｍ），３．７０（２Ｈ，ｍ），３．６７（３Ｈ，ｓ），２．６２（３Ｈ，ｓ），１．３１（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ２．９６分。ｍ／ｚ（ＥＳ^＋） ３３７ （Ｍ＋Ｈ，Ｃ_１６Ｈ_２０Ｎ_２Ｏ_４Ｓ＋Ｈ 理論値３３７）。 Example 56: Methyl 2-{[4- (ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxylate

N- [4- (ethyloxy) phenyl] -N ′-(2-hydroxyethyl) thiourea (0.45 mmol, 107 mg) was dissolved in ethanol (2 mL). Methyl 2-chloro-3-oxobutanoate (0.45 mmol, 68 mg) was added and the reaction was heated in the microwave at 100 ° C. for 10 minutes. Purified by MDAP and isolated 0.0266 g of the title compound.
¹ H NMR (400 MHz, DMSO D6): δ 6.89-6.91 (4H, m, ArH), 5.02 (1H, t, OH), 3.95-4.02 (2 × 2H, m), 3.70 (2H, m), 3.67 (3H, s), 2.62 (3H, s), 1.31 (3H, t)
LCMS Rt 2.96 min. _{^{m / z (ES +) 337}} (M + H, C 16 H 20 N 2 O 4 S + H theory 337).

Ｎ−（２−ヒドロキシエチル）−Ｎ’−［４−（トリフルオロメチル）フェニル］チオ尿素（０．３９ｍｍｏｌ、１０４ｍｇ）をエタノール（２ｍＬ）で溶解した。２−クロロ−Ｎ，Ｎ−ジメチル−３−オキソブタンアミド（０．５９ｍｍｏｌ、９８ｍｇ）を加え、反応物をマイクロ波にて１００℃で２０分間加熱した。ＭＤＡＰに付して精製し、０．０２９６ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ６）： δ ７．６３−７．６８（２Ｈ，ｍ，ＡｒＨ），７．１４−７．１９（２Ｈ，ｍ，ＡｒＨ），５．０２（１Ｈ，ｔ，ＯＨ），３．９５（２Ｈ，ｔ），３．７２（２Ｈ，ｍ），２．９３（２ｘ３Ｈ，ｓ），２．２４（３Ｈ，ｓ）
ＬＣＭＳ Ｒｔ ２．９０分。ｍ／ｚ（ＥＳ^＋） ３７４ （Ｍ＋Ｈ，Ｃ_１６Ｈ_１８Ｆ_３Ｎ_３Ｏ_２Ｓ＋Ｈ 理論値３７４）。 Example 57: 3- (2-hydroxyethyl) -N, N, 4-trimethyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazole-5 -Carboxamide

N- (2-hydroxyethyl) -N ′-[4- (trifluoromethyl) phenyl] thiourea (0.39 mmol, 104 mg) was dissolved in ethanol (2 mL). 2-Chloro-N, N-dimethyl-3-oxobutanamide (0.59 mmol, 98 mg) was added and the reaction was heated in the microwave at 100 ° C. for 20 minutes. Purified by MDAP and isolated 0.0296 g of the title compound.
¹ H NMR (400 MHz, DMSO D6): δ 7.63-7.68 (2H, m, ArH), 7.14-7.19 (2H, m, ArH), 5.02 (1H, t, OH) ), 3.95 (2H, t), 3.72 (2H, m), 2.93 (2 × 3H, s), 2.24 (3H, s)
LCMS Rt 2.90 min. _{^{m / z (ES +) 374}} (M + H, C 16 H 18 F 3 N 3 O 2 S + H theory 374).

Ｎ−（２−ヒドロキシエチル）−Ｎ’−［４−（トリフルオロメチル）フェニル］チオ尿素（０．３９ｍｍｏｌ、１０４ｍｇ）をエタノール（２ｍＬ）で溶解した。２−クロロ−３−オキソブタン酸メチル（０．５９ｍｍｏｌ、９０ｍｇ）を加え、反応物をマイクロ波にて１００℃で２０分間加熱した。ＭＤＡＰに付して精製し、０．０２６１ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ６）： δ ７．６７−７．７２（２Ｈ，ｍ，ＡｒＨ），７．１７−７．２１（２Ｈ，ｍ，ＡｒＨ），５．０５（１Ｈ，ｔ，ＯＨ），４．０２（２Ｈ，ｔ），３．７３（２Ｈ，ｍ），３．６９（３Ｈ，ｓ），２．６４（３Ｈ，ｓ）
ＬＣＭＳ Ｒｔ ３．３８分。ｍ／ｚ（ＥＳ^＋） ３６１ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１５Ｆ_３Ｎ_２Ｏ_３Ｓ＋Ｈ 理論値３６１）。 Example 58: methyl 3- (2-hydroxyethyl) -4-methyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazole-5-carboxylate

N- (2-hydroxyethyl) -N ′-[4- (trifluoromethyl) phenyl] thiourea (0.39 mmol, 104 mg) was dissolved in ethanol (2 mL). Methyl 2-chloro-3-oxobutanoate (0.59 mmol, 90 mg) was added and the reaction was heated in the microwave at 100 ° C. for 20 minutes. Purification by MDAP isolated 0.0261 g of the title compound.
¹ H NMR (400 MHz, DMSO D6): δ 7.67-7.72 (2H, m, ArH), 7.17-7.21 (2H, m, ArH), 5.05 (1H, t, OH) ), 4.02 (2H, t), 3.73 (2H, m), 3.69 (3H, s), 2.64 (3H, s)
LCMS Rt 3.38min. _{^{m / z (ES +) 361}} (M + H, C 15 H 15 F 3 N 2 O 3 S + H theory 361).

Ｎ−（２−ヒドロキシエチル）−Ｎ’−（４−メチルフェニル）チオ尿素（０．３７ｍｍｏｌ、７８ｍｇ）、３−クロロ−２，４−ペンタンジオン（０．４１ｍｍｏｌ、４９μＬ）およびエタノール（２ｍＬ）を合し、マイクロ波にて１００℃で１０分間加熱した。さらに０．５当量の３−クロロ−２，４−ペンタンジオンを加え、反応物をマイクロ波にて１００℃でさらに１０分間加熱した。ＭＤＡＰに付して精製し、０．０１８４ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）： δ ７．１８−７．２５（２Ｈ，ｍ，ＡｒＨ），７．００−７．０５（２Ｈ，ｍ，ＡｒＨ），４．２５（２Ｈ，ｍ），４．０２（２Ｈ，ｍ），２．６７（３Ｈ，ｓ），２．３６（３Ｈ，ｓ），２．２９（３Ｈ，ｓ）
ＬＣＭＳ Ｒｔ ２．８２分。ｍ／ｚ（ＥＳ^＋） ２９１ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１８Ｎ_２Ｏ_２Ｓ＋Ｈ 理論値２９１）。 Example 59: 1- {3- (2-hydroxyethyl) -4-methyl-2-[(4-methylphenyl) imino] -2,3-dihydro-1,3-triazol-5-yl} ethanone

N- (2-hydroxyethyl) -N ′-(4-methylphenyl) thiourea (0.37 mmol, 78 mg), 3-chloro-2,4-pentanedione (0.41 mmol, 49 μL) and ethanol (2 mL) And heated in a microwave at 100 ° C. for 10 minutes. An additional 0.5 equivalents of 3-chloro-2,4-pentanedione was added and the reaction was heated in the microwave at 100 ° C. for an additional 10 minutes. Purification by MDAP isolated 0.0184 g of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.18-7.25 (2H, m, ArH), 7.00-7.05 (2H, m, ArH), 4.25 (2H, m), 4.02 (2H, m), 2.67 (3H, s), 2.36 (3H, s), 2.29 (3H, s)
LCMS Rt 2.82 min. _{^{m / z (ES +) 291}} (M + H, C 15 H 18 N 2 O 2 S + H theory 291).

Ｎ−エチル−Ｎ’−（４−エチルフェニル）チオ尿素（０．３７ｍｍｏｌ、７７ｍｇ）、３−クロロ−２，４−ペンタンジオン（０．５６ｍｍｏｌ、６７μＬ）およびエタノール（２．５ｍＬ）を合し、マイクロ波にて１００℃で２０分間加熱した。ＭＤＡＰに付して精製し、０．００６ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）： δ ７．１７−７．２１（２Ｈ，ｍ，ＡｒＨ），６．９６−７．００（２Ｈ，ｍ，ＡｒＨ），４．０５（２Ｈ，ｑ），２．６５（２Ｈ，ｑ），２．６３（３Ｈ，ｓ），２．２５（３Ｈ，ｓ），１．３６（３Ｈ，ｔ），１．２５（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ３．３６分。ｍ／ｚ（ＥＳ^＋） ２８９ （Ｍ＋Ｈ，Ｃ_１６Ｈ_２０Ｎ_２ＯＳ＋Ｈ 理論値２８９）。 Example 60: 1- {3-Ethyl-2-[(4-ethylphenyl) imino] -4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone

N-ethyl-N ′-(4-ethylphenyl) thiourea (0.37 mmol, 77 mg), 3-chloro-2,4-pentanedione (0.56 mmol, 67 μL) and ethanol (2.5 mL) were combined. And heated in a microwave at 100 ° C. for 20 minutes. Purification by MDAP isolated 0.006 g of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.17-7.21 (2H, m, ArH), 6.96-7.00 (2H, m, ArH), 4.05 (2H, q), 2.65 (2H, q), 2.63 (3H, s), 2.25 (3H, s), 1.36 (3H, t), 1.25 (3H, t)
LCMS Rt 3.36 min. ^{m / z (ES +) 289} (M + H, C 16 H 20 N 2 OS + H theory 289).

Ｎ−エチル−Ｎ’−フェニルチオ尿素（０．３７ｍｍｏｌ、６７ｍｇ）、３−クロロ−２，４−ペンタンジオン（０．５６ｍｍｏｌ、６７μＬ）およびエタノール（２．５ｍＬ）を合し、マイクロ波にて１００℃で２０分間加熱した。ＭＤＡＰに付して精製し、０．００７１ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）： δ ７．３４−７．４０（２Ｈ，ｍ，ＡｒＨ），７．０５−７．１３（３Ｈ，ｍ，ＡｒＨ），４．０８（２Ｈ，ｑ），２．６３（３Ｈ，ｓ），２．２６（３Ｈ，ｓ），１．３７（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ３．０５分。ｍ／ｚ（ＥＳ^＋） ２６１ （Ｍ＋Ｈ，Ｃ_１４Ｈ_１６Ｎ_２ＯＳ＋Ｈ 理論値２６１）。 Example 61: 1- [3-Ethyl-4-methyl-2- (phenylimino) -2,3-dihydro-1,3-triazol-5-yl] ethanone

N-ethyl-N′-phenylthiourea (0.37 mmol, 67 mg), 3-chloro-2,4-pentanedione (0.56 mmol, 67 μL) and ethanol (2.5 mL) were combined and 100 μm in the microwave. Heat at 20 ° C. for 20 minutes. Purification by MDAP isolated 0.0071 g of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.34-7.40 (2H, m, ArH), 7.05-7.13 (3H, m, ArH), 4.08 (2H, q), 2.63 (3H, s), 2.26 (3H, s), 1.37 (3H, t)
LCMS Rt 3.05min. ^{m / z (ES +) 261} (M + H, C 14 H 16 N 2 OS + H theory 261).

Ｎ−エチル−Ｎ’−（４−メチルフェニル）チオ尿素（０．３７ｍｍｏｌ、７２ｍｇ）、３−クロロ−２，４−ペンタンジオン（０．５６ｍｍｏｌ、６７μＬ）およびエタノール（２．５ｍＬ）を合し、マイクロ波にて１００℃で２０分間加熱した。ＭＤＡＰに付して精製し、０．０１３３ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）： δ ７．１６−７．２０（２Ｈ，ｍ，ＡｒＨ），６．９６−７．０１（２Ｈ，ｍ，ＡｒＨ），４．０８（２Ｈ，ｑ），２．６３（３Ｈ，ｓ），２．３５（３Ｈ，ｓ），２．２６（３Ｈ，ｓ），１．３７（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ３．１６分。ｍ／ｚ（ＥＳ^＋） ２７５ （Ｍ＋Ｈ，Ｃ_１５Ｈ_１８Ｎ_２ＯＳ＋Ｈ 理論値２７５）。 Example 62: 1- {3-Ethyl-4-methyl-2-[(4-methylphenyl) imino] -2,3-dihydro-1,3-triazol-5-yl} ethanone

N-ethyl-N ′-(4-methylphenyl) thiourea (0.37 mmol, 72 mg), 3-chloro-2,4-pentanedione (0.56 mmol, 67 μL) and ethanol (2.5 mL) were combined. And heated in a microwave at 100 ° C. for 20 minutes. Purification by MDAP isolated 0.0133 g of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.16-7.20 (2H, m, ArH), 6.96-7. 01 (2H, m, ArH), 4.08 (2H, q), 2.63 (3H, s), 2.35 (3H, s), 2.26 (3H, s), 1.37 (3H, t)
LCMS Rt 3.16min. ^{m / z (ES +) 275} (M + H, C 15 H 18 N 2 OS + H theory 275).

Ｎ−［４−（ジメチルアミノ）フェニル］−Ｎ’−エチルチオ尿素（０．３７ｍｍｏｌ、８３ｍｇ）、３−クロロ−２，４−ペンタンジオン（０．５６ｍｍｏｌ、６７μＬ）およびエタノール（２．５ｍＬ）を合し、マイクロ波にて１００℃で２０分間加熱した。ＭＤＡＰに付して精製し、０．００５７ｇの標記化合物を単離した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）： δ ６．９６−７．０１（２Ｈ，ｍ，ＡｒＨ），６．７５−６．８０（２Ｈ，ｍ，ＡｒＨ），４．０５（２Ｈ，ｑ），２．９４（２ｘ３Ｈ，ｓ），２．６３（３Ｈ，ｓ），２．２６（３Ｈ，ｓ），１．３５（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ２．３１分。ｍ／ｚ（ＥＳ^＋） ３０４ （Ｍ＋Ｈ，Ｃ_１６Ｈ_２１Ｎ_３ＯＳ＋Ｈ 理論値３０４）． Example 63: 1- (2-{[4- (dimethylamino) phenyl] imino} -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone

N- [4- (dimethylamino) phenyl] -N′-ethylthiourea (0.37 mmol, 83 mg), 3-chloro-2,4-pentanedione (0.56 mmol, 67 μL) and ethanol (2.5 mL). And heated in a microwave at 100 ° C. for 20 minutes. Purification by MDAP isolated 0.0057 g of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ 6.96-7.01 (2H, m, ArH), 6.75-6.80 (2H, m, ArH), 4.05 (2H, q), 2.94 (2 × 3H, s), 2.63 (3H, s), 2.26 (3H, s), 1.35 (3H, t)
LCMS Rt 2.31 min. ^{m / z (ES +) 304} (M + H, C 16 H 21 N 3 OS + H theory 304).

Ｎ−（２−アミノエチル）−Ｎ’−［４−（エチルオキシ）フェニル］チオ尿素（０．０７９ｇ、０．３３ｍｍｏｌ）のエタノール（２．５ｍＬ）中懸濁液に、３−クロロ−２，４−ペンタンジオン（３９．３μＬ、０．３３ｍｍｏｌ）のエタノール（２．５ｍＬ）中溶液を加えた。次いで、混合物を、１０分間マイクロ波にて１００℃で加熱した。得られた溶液を真空中で濃縮し、ＭＤＡＰに付して精製し、標記化合物を得た（０．０２２ｇ）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ６）： δ ６．８９−６．９６（４Ｈ，ｍ，ＡｒＨ），４．１５（２Ｈ，ｔ），３．９９（２Ｈ，ｑ），３．１２（２Ｈ，ｔ），２．５９（３Ｈ，ｓ），２．３２（３Ｈ，ｓ），１．３２（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ２．２７分。ｍ／ｚ（ＥＳ^＋） ３２０ （Ｍ＋Ｈ，Ｃ_１６Ｈ_２１Ｎ_３Ｏ_２Ｓ＋Ｈ 理論値３２０） Example 64: 1- (3- (2-aminoethyl) -2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazol-5-yl) Ethanon

To a suspension of N- (2-aminoethyl) -N ′-[4- (ethyloxy) phenyl] thiourea (0.079 g, 0.33 mmol) in ethanol (2.5 mL) was added 3-chloro-2, A solution of 4-pentanedione (39.3 μL, 0.33 mmol) in ethanol (2.5 mL) was added. The mixture was then heated in a microwave at 100 ° C. for 10 minutes. The resulting solution was concentrated in vacuo and purified by MDAP to give the title compound (0.022 g).
¹ H NMR (400 MHz, DMSO D6): δ 6.89-6.96 (4H, m, ArH), 4.15 (2H, t), 3.99 (2H, q), 3.12 (2H, t), 2.59 (3H, s), 2.32 (3H, s), 1.32 (3H, t)
LCMS Rt 2.27 min. m / z (ES ⁺ ) 320 (M + H, C ₁₆ H ₂₁ N ₃ O ₂ S + H Theoretical value 320)

標記化合物（０．０２ｇ）を、実施例６４に記載の製法にしたがって、エタノール（５．０ｍＬ）中でＮ−シクロプロピル−Ｎ’−［４−（エチルオキシ）フェニル］チオ尿素（０．０７８ｇ、０．３３ｍｍｏｌ）および３−クロロ−２，４−ペンタンジオン（３９．３μＬ、０．３３ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ６）： δ ７．１９（２Ｈ，ｄ，ＡｒＨ），７．０１（２Ｈ，ｄ，ＡｒＨ），４．０６（２Ｈ，ｑ），２．３８（３Ｈ，ｓ），２．３２（１Ｈ，クインテット），２．１５（３Ｈ，ｓ），１．３４（３Ｈ，ｔ），０．６７（２Ｈ，ｄｔ），０．３０（２Ｈ，ｄｔ）
ＬＣＭＳ Ｒｔ ２．０９分。ｍ／ｚ（ＥＳ^＋） ３１７ （Ｍ＋Ｈ，Ｃ_１７Ｈ_２０Ｎ_２Ｏ_２Ｓ＋Ｈ 理論値３１７） Example 65: 1- (3-cyclopropyl-2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone

The title compound (0.02 g) was prepared according to the procedure described in Example 64 in N-cyclopropyl-N ′-[4- (ethyloxy) phenyl] thiourea (0.078 g, 0.33 mmol) and 3-chloro-2,4-pentanedione (39.3 μL, 0.33 mmol).
¹ H NMR (400 MHz, DMSO D6): δ 7.19 (2H, d, ArH), 7.01 (2H, d, ArH), 4.06 (2H, q), 2.38 (3H, s) , 2.32 (1H, quintet), 2.15 (3H, s), 1.34 (3H, t), 0.67 (2H, dt), 0.30 (2H, dt)
LCMS Rt 2.09min. m / z (ES ⁺ ) 317 (M + H, C ₁₇ H ₂₀ N ₂ O ₂ S + H Theoretical value 317)

標記化合物（０．０１５ｇ）を、２０分に拡大し、加熱しながら、実施例６４に記載の製法にしたがって、エタノール（５．０ｍＬ）中でＮ−（４−エチルフェニル）−Ｎ’−（２，２，２−トリフルオロエチル）チオ尿素（０．３３ｍｍｏｌ）および３−クロロ−２，４−ペンタンジオン（３９．３μＬ、０．３３ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ６）： δ ７．１８（２Ｈ，ｄ，ＡｒＨ），６．９０（２Ｈ，ｄ，ＡｒＨ），４．８７（２Ｈ，ｑ），２．６２（２Ｈ，ｑ），２．６１（３Ｈ，ｓ），２．３３（３Ｈ，ｓ），１．２２（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ３．５４分。ｍ／ｚ（ＥＳ^＋） ３４３ （Ｍ＋Ｈ，Ｃ_１６Ｈ_１７Ｆ_３Ｎ_２ＯＳ＋Ｈ 理論値３４３） Example 66: 1- [2-[(4-Ethylphenyl) imino] -4-methyl-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1,3-triazole-5 -Il] Ethanon

The title compound (0.015 g) is expanded to 20 minutes and heated with N- (4-ethylphenyl) -N ′-(in ethanol (5.0 mL) according to the procedure described in example 64 Prepared from 2,2,2-trifluoroethyl) thiourea (0.33 mmol) and 3-chloro-2,4-pentanedione (39.3 μL, 0.33 mmol).
¹ H NMR (400 MHz, DMSO D6): δ 7.18 (2H, d, ArH), 6.90 (2H, d, ArH), 4.87 (2H, q), 2.62 (2H, q) 2.61 (3H, s), 2.33 (3H, s), 1.22 (3H, t)
LCMS Rt 3.54 min. m / z (ES ⁺ ) 343 (M + H, C ₁₆ H ₁₇ F ₃ N ₂ OS + H Theoretical value 343)

標記化合物（０．００９ｇ）を、２０分に拡大し、加熱しながら、実施例６４に記載の製法にしたがって、エタノール（５．０ｍＬ）中でＮ−［４−（エチルオキシ）フェニル］−Ｎ’−（２，２，２−トリフルオロエチル）チオ尿素（０．３３ｍｍｏｌ）および３−クロロ−２，４−ペンタンジオン（３９．３μＬ、０．３３ｍｍｏｌ）から調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ Ｄ６）： δ ６．８８−６．９７（４Ｈ，ｍ，ＡｒＨ），４．８９（２Ｈ，ｑ），４．０２（２Ｈ，ｑ），２．６２（３Ｈ，ｓ），２．３４（３Ｈ，ｓ），１．３８（３Ｈ，ｔ）
ＬＣＭＳ Ｒｔ ３．３８分。ｍ／ｚ（ＥＳ^＋） ３５９ （Ｍ＋Ｈ，Ｃ_１６Ｈ_１７Ｆ_３Ｎ_２Ｏ_２Ｓ＋Ｈ 理論値３５９） Example 67: 1- [2-{[4- (Ethyloxy) phenyl] imino} -4-methyl-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1,3-triazole -5-yl] ethanone

The title compound (0.009 g) was expanded to 20 minutes and heated with N- [4- (ethyloxy) phenyl] -N ′ in ethanol (5.0 mL) according to the procedure described in Example 64. Prepared from-(2,2,2-trifluoroethyl) thiourea (0.33 mmol) and 3-chloro-2,4-pentanedione (39.3 μL, 0.33 mmol).
¹ H NMR (400 MHz, DMSO D6): δ 6.88-6.97 (4H, m, ArH), 4.89 (2H, q), 4.02 (2H, q), 2.62 (3H, s), 2.34 (3H, s), 1.38 (3H, t)
LCMS Rt 3.38min. m / z (ES ⁺ ) 359 (M + H, C ₁₆ H ₁₇ F ₃ N ₂ O ₂ S + H Theoretical value 359)

Biological Assays The ability of the compounds of the invention to enhance glutamate receptor mediated responses is further demonstrated by: a) using fluorescent calcium indicator dyes such as FLUO4; and b) glutamic acid recorded from human GluR2 flip uncalibrated HEK293 cells. It can be determined by measuring the evoked current.

a) Calcium Influx Fluorescence Assay Prepare 384-well plates containing inducible monolayers of HEK293 cells that are stably expressed or transiently transfected with human GluR2 flip (uncalibrated) AMPA receptor subunits. These cells form functional homotetrameric AMPA receptors. Tissue culture medium in the wells is discarded and each well is filled with standard buffer (80 μL) (145 mM NaCl, 5 mM KCl, 1 mM MgCl ₂ , 2 mM CaCl ₂ , 20 mM N- [2-hydroxyethyl] for each stable cell line. Piperazine-N- [2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3) or transiently transfected cells with Na release buffer (145 mM N-methyl-instead of NaCl) Glucamine) was washed 3 times. Plates are then incubated with 2 μM FLUO4-AM dye (20 μL) (molecular probe, Netherlands) in the dark for 60 minutes to allow cellular uptake of FLUO-4AM and then released from the cells. It is converted to FLUO-4 by an intracellular esterase that cannot. After incubation, each well is washed 3 times with buffer (80 μL) (30 μL of buffer remained in each well after washing).

  A compound of the invention (or a target compound such as cyclothiazide) is dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 10 mM. These solutions are further diluted with DMSO using a Biomek FX (Beckman Coulter) in 384 compound plates. Each dilution (1 μL) is transfected into another compound plate and buffer (50 μL) is added. Agonist stimulation (glutamate) plates are prepared by dissolving sodium glutamate with water to obtain a concentration of 100 mM. The solution is diluted with buffer to obtain a final concentration of 500 μM and dispensed into another 384 well plate (50 μL / well) using Multidrop (Thermolabsystems).

  The cell plate is then transferred into a fluorescence imaging plate based reader [eg, FLIPR384 (Molecular Devices)]. Baseline fluorescence readings were taken over 10-240 seconds, then 10 μL from each plate (concentration range 100 μM to 10 pM) containing compounds of the invention made in standard buffer solution was added and (30 μM to 3 pM Get final concentration range). Read fluorescence over 5 minutes. Add 500 μM glutamic acid solution (10 μL) (to obtain a final concentration of 100 μM). The fluorescence is then read over 4 minutes. The activity of the compound of the present invention and the target compound is determined by measuring the peak fluorescence after the final addition. Activity is also expressed relative to the increase in fluorescence induced by cyclothiazide for its maximal response (ie, 30 μM or greater).

The assay is believed to detect a pEC ₅₀ near the effective limit of 3.5-4.0 due to compound solubility limits. pEC ₅₀ results are generally considered to be +/− 0.3 to be precise. Thus, a compound exhibiting a pEC ₅₀ value within that range from such an assay may indeed have a suitable affinity for the receptor, but may also have a low affinity, including a much lower affinity.

Example compounds were screened using the above assay. All examples yielded an average pEC _{50 of} 3.7 or greater, demonstrating an activity of at least 20% of the activity of cyclothiazide (of its maximal response).

b) Whole-cell voltage-clamped electrophysiological assay The ability of the compounds of the invention to enhance AMPA-subtype glutamate receptor-mediated responses is determined by measuring AMPA-induced currents recorded from rat cultured hippocampal neurons. .

The assay involves the electrophysiological characterization of AMPA receptor positive modulators using rat cultured hippocampal neurons. Extracellular stock _{solution, 145mM NaCl, 2.5mM KCl, 1.2mM} MgCl 2, 1.5mM CaCl 2, 10mM N- [2- hydroxyethyl] - piperazine -N- [2- ethanesulfonic acid (HEPES), Contains pH 7.3 with 10 mM D-glucose, NaOH. The intracellular solution was 80 mM CsCl, 80 mM CsF, 10 mM N- [2-hydroxyethyl] -piperazine-N- [2-ethanesulfonic acid (HEPES), 10 mM ethylene glycol-bis (g-aminoethyl ether) -N, Contains pH 7.3 with N, N ', N, -tetra-acetic acid (EGTA), 14 mM MgATP, 14 mM ditris creatine phosphokinase, 50 U / ml creatine phosphokinase, CsOH. The recording electrode is prepared from two equal length glass capillaries (Clark Electrochemical GC120-F10) using the Zeitz Instruments DMZ Universal Puller, program 09, and about 3-6 MΩ when measured in extracellular solution. Resulting in an electrode having a resistance of The electrode is filled with the internal recording solution and backed. Positive pressure is applied to the electrode that suppresses the mixture of internal and external solutions and assists in forming a high resistance seal when the electrode contacts the cell membrane. A glass coverslip fragment with rat cultured hippocampal neurons is placed in a recording chamber located on the stage of an inverted microscope. The tube at the end of the chamber is used to apply extracellular solution to the bath. Rapid solution exchange uses a fast step perfusion system (Biologic RSC160). Two drain tubes that join together along their length are located near the selected cells so that the outflow from only one tube can pass directly through the cell surface. The motorized stepper can be relocated to the tube so that the outflow from the second drain tube can pass cells that cause a solution exchange at the cell membrane surface within 10-20 ms. Excess bath solution is removed through a tube located at the end of the chamber that connects to the vacuum line.

Expected cells are located in the center of the microscope viewing area. The cell recording electrode is placed directly on the membrane surface. A superior manipulator control (Luigs and Neumann, SM-6) is used to lower the electrode while monitoring changes in electrode resistance during delivery of a 5 mV depolarizing pulse until a high resistance seal (Gigaseal) is achieved. Whole cell structure is achieved by removal of small pieces of cell membranes by aspiration just below the recording electrode tip. The cell membrane potential is maintained at -70 mV (voltage fixed) via an electrode (Axopatch 200B integrating patch clamp amplifier, pClamp software, Axon instrument). The test solution is applied using a rapid application system using the following protocol, and changes in inward current are recorded and stored for off-line analysis.
1) Control current-The exchange of extracellular solution + 30 μM AMPA (application time 2 seconds, application interval 30 seconds) was repeated until the measurement was stable.
2) Test current-The exchange of extracellular solution + 10 nM compound of the invention from extracellular solution + 10 nM compound of the invention + 30 μM AMPA (application time 2 seconds, application interval 30 seconds) was repeated until the measurement was stable.

  The concentration of the compound of the invention is increased to 100 nM in both solutions and step 2 is repeated. The concentration is then increased 10-fold and tested up to 100 uM.

  All experiments are performed at room temperature (20-22 ° C).

  The activity of the compounds of the invention is determined by measuring the area under the curve (during application time of 2 seconds) for a 30 μM AMPA reaction in the presence of the compounds of the invention, and the reaction of 30 μM AMPA alone (this Expressed as% of synergism of 30 μM AMPA in the absence of inventive compounds.

  Examples 4, 5 and 24 above were examined using the assay. When applied at 10 nM, they increased the 30 μM AMPA-mediated current to 15-42%.

Claims (23)

Formula (I) for use as a medicament:

[Where:
R ¹⁰ is selected from methyl or hydrogen;
X is

Selected from;
Z is selected from S or O;
R ¹ is H, C _1-4 alkyl, C (O) OC _1-4 alkyl, C (O) C _1-4 alkyl, C (O) haloC _1-4 alkyl, C (O) NR ⁶ R ^{7 is} selected from cyano, and R ⁶ and R ⁷ are each independently selected from H or C _1-4 alkyl;
R ² is selected from C _1-4 alkyl, C (O) CH ₃ , or CN;
R ³ is selected from the group consisting of H, NH ₂ , CH ₃ , (CH ₂ ) _n OH and (CH ₂ ) _n C _1-4 alkoxy, where n is 0 or 1; and R ³ Is CH ₃ , (CH ₂ ) _n OH or (CH ₂ ) _n C _1-4 alkoxy, then R ⁴ is H, halo, C _1-4 alkoxy, haloC _1-4 alkoxy, C Selected from the group consisting of _1-4 alkyl, C _1-4 alkylthio, halo C _1-4 alkylthio, halo C _1-4 alkyl and NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently Selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ , together with the nitrogen atom to which they are attached, are one or more additional heterocycles selected from O, N or S Even if it contains atoms There 5 or 6-membered ring to form;
When R ³ is NH ₂ , then R ⁴ is H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, C _1-4 alkylthio, halo C _1-4 Selected from alkylthio, haloC _1-4 alkyl or NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ are Together with the nitrogen atom to which is bound forms a 5- or 6-membered ring which may contain one or more additional heteroatoms selected from O, N or S;
When R ³ is H, then R ⁴ is H, C _1-4 alkoxy, chloro, bromo, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl, and NR ⁸ Selected from the group consisting of R ⁹ , wherein R ⁸ and R ⁹ are independently selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ are the nitrogen atom to which they are attached; Taken together form a 5 or 6 membered ring which may contain additional heteroatoms selected from O, N or S;
When X is —CH ₂ CF ₃ , then R ⁴ is selected from C _1-4 alkoxy or C _1-4 alkyl;
When X is methyl, then R ⁴ is selected from C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl or NR ⁸ R ⁹ where , R ⁸ and R ⁹ are independently selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached, from O, N or S Forming a 5- or 6-membered ring optionally containing one or more selected heteroatoms;
X is

In which case R ⁴ is selected from the group consisting of H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl and NR ⁸ R ^9. Where R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached are O, N or Forms a 5- or 6-membered ring optionally containing one or more additional heteroatoms selected from S]
Or a salt or solvate thereof. R ¹ is C _1-4 alkyl, C (O) OC _1-4 alkyl, C (O) C _1-4 alkyl, C (O) haloC _1-4 alkyl, C (O) NR ⁶ R ⁷ or It is selected from cyano, wherein, ^{R 6} and ^{R 7} are each independently selected from H or _{C 1-4} alkyl the compound of claim 1, wherein. R ² _is selected from _{C 1-4} alkyl or C (O) CH _3, The compound according to claim 1 or claim 2. X is

[Wherein R ³ is H]
Wherein R ⁴ is selected from the group consisting of H, C _1-4 alkoxy, chloro, bromo, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl, and NR ⁸ R ^9. Wherein R ⁸ and R ⁹ are independently selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached, O, 4. A compound according to claim 1, 2 or 3 which forms a 5 or 6 membered ring which may contain one or more additional heteroatoms selected from N or S. X is

[Wherein R ³ is NH ₂ ]
R ⁴ is H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, C _1-4 alkylthio, halo C _1-4 alkylthio, halo C _1-4 alkyl Or selected from NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ are taken together with the nitrogen atom to which they are attached. 4. A compound according to claim 1, 2 or 3 which forms a 5- or 6-membered ring which may contain one or more additional heteroatoms selected from O, N or S. X is

[Wherein R ³ is CH ₃ , (CH ₂ ) _n OH or (CH ₂ ) _n C _1-4 alkoxy]
R ⁴ is H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, C _1-4 alkylthio, halo C _1-4 alkylthio, halo C _1-4 alkyl And NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ are attached to them. Together with the nitrogen atom, it forms a 5- or 6-membered ring which may contain one or more additional heteroatoms selected from O, N or S. Compound described in 1. X is a _-CH 2 CF _3, ^{R 4} is selected from _{C 1-4} alkoxy or _{C 1-4} alkyl, A compound according to claim 1, 2 or 3. X is methyl and R ⁴ is selected from C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl or NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ is independently selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ are selected from O, N or S together with the nitrogen atom to which they are attached. 4. A compound according to claim 1, 2 or 3, forming a 5- or 6-membered ring which may contain one or more heteroatoms. X is

Wherein R ⁴ is selected from the group consisting of H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl and NR ⁸ R ⁹ , wherein Wherein R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached are selected from O, N or S 4. A compound according to claim 1, 2 or 3, forming a 5- or 6-membered ring which may contain one or more additional heteroatoms. 1.1- [2-{[4- (Ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone 2 1- [2-[(4-Ethylphenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone 3.1 {2-{[4- (Ethyloxy) phenyl] imino} -4-methyl-3- [2- (methyloxy) ethyl] -2,3-dihydro-1,3-triazol-5-yl} ethanone 1- [3- (2-hydroxyethyl) -4-methyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl ] Ethanone 5.1- (3- (2- Hydroxyethyl) -4-methyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 6.1- (3-ethyl- 2-{[4- (Ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone 7.2- [2-{[4- (Ethyloxy) phenyl ] Imino} -4,5-dimethyl-1,3-triazol-3 (2H) -yl] ethanol 8.1- [2-[(4-butylphenyl) imino] -3- (2-hydroxyethyl)- 4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone 9.1- [2-{[4- (ethyloxy) phenyl] imino} -3- (3-hydroxypropyl) -4 -Methyl-2, 3-Dihydro-1,3-triazol-5-yl] ethanone 10.1- (3- (2-hydroxyethyl) -4-methyl-2-{[4- (4-morpholinyl) phenyl] imino} -2 , 3-Dihydro-1,3-triazol-5-yl) ethanone 11.2-{[4- (ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro -1,3-triazole-5-carbonitrile 12.3-ethyl-2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazole-5-carb Nitrile 13.1- {2-[(4-Chlorophenyl) imino] -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone 14.1- (3-cyclo Lopyl-4-methyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 15.1- (3-ethyl-4- Methyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 16.1- [3-Ethyl-4-methyl-2- ({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] ethanone 17.1- [2-({4-[(difluoromethyl) Oxy] phenyl} imino) -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone 18.1- [3- (2-hydroxyethyl) -4-methyl -2 - ({4 - [(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] ethanone 19. [(3-Ethyl-4,5-dimethyl-1,3-triazole-2 (3H) -ylidene] [4- (trifluoromethyl) phenyl] amine 20.1- (3-ethyl-2-{[4 -(Ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-oxazol-5-yl) ethanone 21.1- {2-[(4-bromophenyl) imino] -3-ethyl -4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone 22.1- (3-ethyl-4-methyl-2-{[4- (1-pyrrolidinyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 23.1- (3-ethyl-4-methyl-2-{[4- (1-piperidinyl) phenyl] imino} -2,3 -Dihydro-1,3-triazo -5-yl) ethanone 24.3- (2-hydroxyethyl) -N, N, 4-trimethyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1 , 3-Triazole-5-carboxamide 25.1- [2-[(4-Bromophenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole- 5-yl] ethanone 26.2-{[4- (ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxamide 27 3- (2-hydroxyethyl) -N, N, 4-trimethyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazole- 5-Carboxamide 28.1- (3-Cyclopropyl-4-methyl-2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 29.3-Ethyl-N, N, 4-trimethyl-2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro-1,3-triazole-5-carboxamide 30.2,2 , 2-trifluoro-1- [3- (2-hydroxyethyl) -4-methyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3 -Triazol-5-yl] ethanone 31.3-cyclopropyl-N, N, 4-trimethyl-2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro-1,3-triazol Ru-5-carboxamide 32.1- (3- (2-hydroxyethyl) -4-methyl-2-{[4- (1-pyrrolidinyl) phenyl] imino} -2,3-dihydro-1,3-triazole -5-yl) ethanone 33.1- (3- (2-hydroxyethyl) -4-methyl-2-{[4- (methyloxy) phenyl] imino} -2,3-dihydro-1,3-triazole -5-yl) ethanone 34.1- (3- (2-hydroxyethyl) -4-methyl-2-{[4- (methylthio) phenyl] imino} -2,3-dihydro-1,3-triazole- 5-yl) ethanone 35.1- [2-[(3,4-dimethylphenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5 -Il] Ethanon 3 1- [3,4-Dimethyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] ethanone 37.1 [4-Methyl-3-propyl-2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl] ethanone 38.1- [ 4-Methyl-3- [2- (methyloxy) ethyl] -2-({4-[(trifluoromethyl) oxy] phenyl} imino) -2,3-dihydro-1,3-triazol-5-yl ] Ethanone 39.1- (2-{[4- (Ethyloxy) phenyl] imino} -3,4-dimethyl-2,3-dihydro-1,3-triazol-5-yl) ethanone 40.1- (2 -{[4- (Ethyloxy ) Phenyl] imino} -4-methyl-3-propyl-2,3-dihydro-1,3-triazol-5-yl) ethanone 41.1- (3,4-dimethyl-2-{[4- (tri Fluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 42.1- {2-[(4-ethylphenyl) imino] -3,4-dimethyl-2, 3-dihydro-1,3-triazol-5-yl} ethanone 43.1- (2-{[4- (dimethylamino) phenyl] imino} -3,4-dimethyl-2,3-dihydro-1,3 -Triazol-5-yl) ethanone 44.1- (3-ethyl-2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazol-5-yl ) Ethanon 45.1 [2-{[4- (Diethylamino) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone 46.1- ( 2-{[4- (Diethylamino) phenyl] imino} -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone 47.1- [2-({4- [(Difluoromethyl) oxy] phenyl} imino) -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl] ethanone 48.1- (3-ethyl-4-methyl- 2-{[4- (4-morpholinyl) phenyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 49.1- (3,4-dimethyl-2-{[4- (4-morpholinyl) fu Nyl] imino} -2,3-dihydro-1,3-triazol-5-yl) ethanone 50.1- {2-[(4-aminophenyl) imino] -3,4-dimethyl-2,3-dihydro -1,3-triazol-5-yl} ethanone 51.1- {2-[(4-aminophenyl) imino] -3-ethyl-4-methyl-2,3-dihydro-1,3-triazole-5 -Yl} ethanone 52.1- [2-[(4-aminophenyl) imino] -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] Ethanone 53.1- [2-{[4- (Dimethylamino) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazol-5-yl] Ethanon 54.2-{[4- (Ethyloxy) phenyl] imino} -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxylate 55.2-{[4- (ethyloxy) phenyl ] Imino} -3- (2-hydroxyethyl) -N, N, 4-trimethyl-2,3-dihydro-1,3-triazole-5-carboxamide 56.2-{[4- (ethyloxy) phenyl] imino } -3- (2-hydroxyethyl) -4-methyl-2,3-dihydro-1,3-triazole-5-carboxylate 57.3- (2-hydroxyethyl) -N, N, 4-trimethyl -2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazole-5-carboxamide 58.3- (2-hydroxyethyl) ) -4-methyl-2-{[4- (trifluoromethyl) phenyl] imino} -2,3-dihydro-1,3-triazole-5-carboxylate 59.1- {3- (2-hydroxy) Ethyl) -4-methyl-2-[(4-methylphenyl) imino] -2,3-dihydro-1,3-triazol-5-yl} ethanone 60.1- {3-ethyl-2-[(4 -Ethylphenyl) imino] -4-methyl-2,3-dihydro-1,3-triazol-5-yl} ethanone 61.1- [3-ethyl-4-methyl-2- (phenylimino) -2, 3-Dihydro-1,3-triazol-5-yl] ethanone 62.1- {3-ethyl-4-methyl-2-[(4-methylphenyl) imino] -2,3-dihydro-1,3- Triazol-5-yl} ethanone 3.1- (2-{[4- (Dimethylamino) phenyl] imino} -3-ethyl-4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone 64.1- ( 3- (2-Aminoethyl) -2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone 65.1- (3 -Cyclopropyl-2-{[4- (ethyloxy) phenyl] imino} -4-methyl-2,3-dihydro-1,3-triazol-5-yl) ethanone 66.1- [2-[(4- Ethylphenyl) imino] -4-methyl-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1,3-triazol-5-yl] ethanone 67.1- [2-{[ 4- (Ethyloxy) phenyl] imi } -4-methyl-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1,3-triazol-5-yl] ethanone or a salt or solvate thereof. The described compound.   A pharmaceutical composition comprising a compound according to any of claims 1-9 and at least one pharmaceutically acceptable carrier or diluent.   10. A compound according to any one of claims 1-9 for use in treating or preventing a disease or condition caused by reduced or imbalanced glutamate receptor function in a mammal.   12. A compound according to claim 11 wherein the disease is schizophrenia.   12. A compound according to claim 11 wherein the disease is cognitive impairment.   Use of a compound according to any of claims 1-9 in the manufacture of a medicament for treating or preventing a disease or condition caused by reduced or imbalanced glutamate receptor function.   15. Use according to claim 14, wherein the disease is schizophrenia.   15. Use according to claim 14, wherein the disease is cognitive impairment.   A method for the treatment or prevention of a disease or condition caused by reduced or imbalanced glutamate receptor function in a mammal, comprising administering an effective amount of a compound according to any of claims 1-9.   18. A method according to claim 17, wherein the disease is schizophrenia.   19. The method of claim 18, wherein the disease is cognitive impairment.   A combined product comprising an antipsychotic drug and the compound of any one of claims 1-9. Formula (A):

[Where:
R ¹⁰ is selected from methyl or hydrogen;
X is

Selected from;
Z is selected from S or O;
R ¹ is H, C _1-4 alkyl, C (O) OC _1-4 alkyl, C (O) C _1-4 alkyl, C (O) haloC _1-4 alkyl, C (O) NR ⁶ R ^{7 is} selected from cyano, and R ⁶ and R ⁷ are each independently selected from H or C _1-4 alkyl;
R ² is selected from C _1-4 alkyl, C (O) CH ₃ , or CN;
R ³ is selected from the group consisting of H, NH ₂ , CH ₃ , (CH ₂ ) _n OH and (CH ₂ ) _n C _1-4 alkoxy, where n is 0 or 1; and R ³ Is CH ₃ , (CH ₂ ) _n OH or (CH ₂ ) _n C _1-4 alkoxy, then R ⁴ is H, halo, C _1-4 alkoxy, haloC _1-4 alkoxy, C Selected from the group consisting of _1-4 alkyl, C _1-4 alkylthio, halo C _1-4 alkylthio, halo C _1-4 alkyl and NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently Selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ , together with the nitrogen atom to which they are attached, are one or more additional heterocycles selected from O, N or S Even if it contains atoms There 5 or 6-membered ring to form;
When R ³ is NH ₂ , then R ⁴ is H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, C _1-4 alkylthio, halo C _1-4 Selected from alkylthio, haloC _1-4 alkyl or NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ are Together with the nitrogen atom to which is bound forms a 5- or 6-membered ring which may contain one or more additional heteroatoms selected from O, N or S;
When R ³ is H, then R ⁴ is H, C _1-4 alkoxy, chloro, bromo, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl, and NR ⁸ Selected from the group consisting of R ⁹ , wherein R ⁸ and R ⁹ are independently selected from hydrogen and C _1-4 alkyl, or R ⁸ and R ⁹ are the nitrogen atom to which they are attached; Taken together form a 5- or 6-membered ring which may contain one or more additional heteroatoms selected from O, N or S;
When X is —CH ₂ CF ₃ , then R ⁴ is selected from C _1-4 alkoxy or C _1-4 alkyl;
When X is methyl, then R ⁴ is selected from C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl or NR ⁸ R ⁹ where , R ⁸ and R ⁹ are independently selected from hydrogen or C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached, from O, N or S Forming a 5- or 6-membered ring optionally containing one or more selected heteroatoms;
X is

In which case R ⁴ is selected from the group consisting of H, halo, C _1-4 alkoxy, halo C _1-4 alkoxy, C _1-4 alkyl, halo C _1-4 alkyl and NR ⁸ R ^9. Wherein R ⁸ and R ⁹ are independently selected from C _1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached are O, N or Forming a 5- or 6-membered ring optionally containing one or more additional heteroatoms selected from S;
However, the compound
1) Compounds in which R ¹ = CO (CH ₃ ), R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = OH and R ⁴ = ethyl, chloro, ethoxy, methyl or H at the same time;
2) compounds in which R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = (CH ₂ ) OMe and R ⁴ = methoxy, difluoromethylthio, chloro or H;
3) Compounds wherein R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = (CH ₂ ) OEt and R ⁴ = difluoromethylthio, ethoxy, fluoro, difluoromethoxy, or isopropyl;
4) A compound in which R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = (CH ₂ ) OnBu and R ⁴ = fluoro, isopropyl, ethoxy, difluoromethoxy or difluoromethylthio at the same time;
5) Compounds in which R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = OMe and R ⁴ = ethoxy, difluoromethoxy, difluoromethylthio or H at the same time;
6) Compounds in which R ¹ = H, R ² = Me, X = cyclopropyl and R ⁴ = methoxy, isopropyl, ethoxy, hydrogen, chloro, difluoromethoxy or fluoro;
7) Compounds in which R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = H and R ⁴ = H or chloro at the same time;
8) Compounds in which R ¹ = C (O) CH ₃ , R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = CH ₂ OH and R ⁴ = H or methyl simultaneously;
9) Compounds in which R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = CH ₂ OH and R ⁴ = methyl, chloro, methoxy or H at the same time;
10) Compounds wherein R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = OH and R ⁴ = ethoxy, methyl or H at the same time;
11) A compound in which R ¹ = C (O) CH ₃ , R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = H and R ⁴ = chloro simultaneously;
12) Compounds wherein R ¹ = H, R ² = Me, X = Me and R ⁴ = methyl or ethoxy at the same time;
13) Compounds wherein R ¹ = H, R ² = Et, X = CH ₂ CH ₂ R ³ , R ³ = H and R ⁴ = chloro or bromo at the same time;
14) compounds wherein R ¹ = Me, R ² = Me, X = Me and R ⁴ = methyl at the same time; and 15) simultaneously R ¹ = H, R ² = Me, X = CH ₂ CH ₂ R ³ , R ³ = Me and R ⁴ = not a compound where isopropyl, fluoro, ethyl, difluoromethoxy or difluoromethylthio]
Or a salt or solvate thereof. A method for producing the compound according to claim 1, comprising:
(A) Formula (II):

[Wherein, X, Z, R ⁴ and R ¹⁰ are as defined in claim 1]
A compound of formula (III):

[Wherein, R ¹ and R ² are as defined in claim 1]
Or (b) Formula (V):

[Wherein, Z, R ⁴ and R ¹⁰ are as defined in claim 1]
Is reacted with a primary amine X—NH ₂ (wherein X is as defined in claim 1) and then of formula (III) as described in step (a) Or (c) for compounds of formula (I) of claim 1, wherein R ¹ is CONH ₂ ;

[In the formula: Z, X, R ² , R ⁴ and R ¹⁰ are as defined in claim 1.]
Is reacted with ammonium chloride and HATU, and after step (a), (b) or (c),
Any protecting group may be removed; and / or a salt or solvate may be formed; and / or a compound of formula (I) or a salt or solvent thereof according to claim 1 A process comprising converting a hydrate to another compound of formula (I) according to claim 1 or a salt or solvate thereof.