JP2021138690A - Novel pharmaceutical comprising heteroaromatic amide derivative or salt thereof - Google Patents

Abstract

To provide a compound useful for treating or preventing disease associated with voltage-dependent sodium channel (Nav1.7) such as disease involving a pain, disease involving an itch, autonomic nerve-associated disease, or a pharmaceutical composition thereof.SOLUTION: The present disclosure provides a compound illustrated by the following formula, and a pharmaceutical composition containing the same.SELECTED DRAWING: None

Description

The present invention relates to a medicament comprising a compound or a salt thereof useful for treating or preventing a disease involving a voltage-gated sodium channel Nav1.7 (hereinafter referred to as Nav1.7).

Potential-dependent sodium channels (Nav) are present in excitatory cells, including neurons and myocardial cells of the central and peripheral nervous systems. Its role is to control the rising phase of action potentials generated by depolarization of cell membrane potentials and to be involved in the generation and propagation of electrical signals. Therefore, Nav is essential for maintaining the physiological functions of excitatory cells such as nerves and myocardium. Abnormalities in Nav are involved in diseases such as epilepsy (Non-Patent Document 1), arrhythmia (Non-Patent Document 2), muscle tone (Non-Patent Document 3), and chronic pain (Non-Patent Document 4).
Nav is composed of α subunits that form ion channel pores and β subunits that act as a supplement. At least nine types of alpha subunits are known so far (Nav1.1-Nav1.9). These subtypes are TTX-sensitive Nav (Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6, Nav1.7) that are functionally inhibited by the puffer fish venom tetrodotoxin (TTX). ) And TTX-resistant Nav (Nav1.5, Nav1.8, Nav1.9). Most of Nav1.1, Nav1.2, Nav1.3 are central nervous system, most of Nav1.4 are skeletal muscle, most of Nav1.5 are myocardium, most of Nav1.6 are nervous system, and Nav1.7, Nav1 Most of .8 and Nav1.9 are known to be expressed in the peripheral nervous system (Non-Patent Document 5).
Nav1.7 is a TTX-sensitive sodium channel distributed in the peripheral nervous system such as autonomic nerves and sensory nerves. Recently, mutations in the gene encoding Nav1.7 (SCN9A) have been shown to alter the pain threshold. That is, from a family analysis of erythromelalgia, which indicates flushing of the peripheral limbs and increased pain sensation, gain of function mutation has occurred in SCN9A (Non-Patent Document 6), and other sensations are normal. It has been reported that loss of function mutation occurs in SCN9A from the family analysis of painlessness in which only the pain sensation disappears (Non-Patent Document 7).

Examinations using anti-Nav1.7 antibodies (Non-Patent Document 8) and Nav1.7 inhibitory compounds (Non-Patent Document 9, Patent Document 1, Patent Document 2) also show that Nav1.7 is inhibited, resulting in infringement. It is known to have an analgesic effect on receptive pain and neuropathic pain.
Thus, since Nav1.7 has been suggested to be particularly associated with pain sensation, Nav1.7 inhibitors are useful as therapeutic or prophylactic agents for painful diseases, especially nociceptive pain and neuropathic pain. Is believed to be.

Furthermore, since the sensation of pruritus is transmitted by peripheral sensory nerves and Nav1.7 is distributed in the peripheral nervous system, Nav1.7 is considered to be involved in acute or chronic pruritus, and by inhibiting Nav1.7. , Antipruritic action against acute or chronic pruritus (Non-Patent Document 7) is considered to be obtained.

Nav inhibitors are effective in treating various disease states. For example, as subtype non-specific Nav inhibitors, lidocaine, a local anesthetic, mexiletine, an antiarrhythmic agent, and carbamazepine, an antiepileptic agent, are known. There is.

Subtype non-specific Nav inhibitors are known to exhibit analgesic activity clinically and are used as analgesics. However, since these subtype non-selective Nav inhibitors also have an inhibitory effect on Nav1.5 expressed in the myocardium, there is a concern that they may adversely affect cardiac function, which is particularly important for life support. To date, there are no clinically selective Nav1.7 inhibitors.

Based on the above, Nav1.7 inhibitors that are selective for Nav1.5 are extremely useful as therapeutic or prophylactic agents for various painful pathologies, with little concern about side effects resulting from Nav1.5 inhibition. Is considered to be.

So far, various heteroaromatic amide derivatives having a Nav1.7 inhibitory action have been reported (Patent Documents 3 to 10).

Further, Patent Documents 11 to 15 disclose various amide compounds having Nav1.7 inhibitory activity. For example, in Patent Document 15,

で表される化合物が記載されている。

The compounds represented by are described.

Patent Document 16 describes a compound that has an affinity for KCNQ2 / 3 potassium channels and is useful as an analgesic.

(式中、各記号は特許文献16で定義される通りである。)で表される化合物が記載されている。

(In the formula, each symbol is as defined in Patent Document 16).

Patent Document 17 describes as a compound having PDE4B inhibitory activity and effective for various diseases including pain.

(式中、各記号は特許文献17で定義される通りである。)で表される化合物が記載されている。

(In the formula, each symbol is as defined in Patent Document 17).

Non-Patent Document 10 describes a negative allosteric modulator of the metabolic glutamate receptor 5 as a compound applicable to chronic pain.

(式中、各記号は非特許文献10で定義される通りである。)で表される化合物が記載されている。

(In the formula, each symbol is as defined in Non-Patent Document 10).

International Publication No. 2014/151472 U.S. Patent Publication No. 2014-8883840 International Publication No. 2008/008020 International Publication No. 2009/145720 International Publication No. 2009/145721 International Publication No. 2013/161928 Japanese Patent Application Laid-Open No. 2014-101287 International Publication No. 2015/119998 International Publication No. 2016/117647 International Publication No. 2008/130319 International Publication No. 2008/130320 International Publication No. 2008/130321 International Publication No. 2008/130322 International Publication No. 2008/130323 International Publication No. 2012/039657 US Patent Publication No. 2009-0186902 International Publication No. 2017/145013

Yogeeswari et al., Curr. Drug Targets 2004, 5 (7), 589-602. Noble D., Proc Natl Acad Sci USA. 2002, 99 (9): 5755-5756. Cannon SC, Kidney Int. 2000, 57 (3), 772-779. Wood, JN et al., J. Neurobiol. 2004, 61 (1), 55-71. Catterall, WA et al., Pharmacol Rev. 2005, 57: 397-409. Waxman, SG Neurology. 2007, 7, 69 (6), 505-507. Cox et al., Nature 2006, 444, 894-898. Lee JH et al., Cell 2014, 157, 1393-1404. Erin McGowan BS et al., Anesth Analg 2009, 109, 951-958. G. Duvey et al., Bioorg. Med. Chem. Lett. 2013, 23 (16), 4523.

An object of the present invention is to provide a drug comprising a novel compound having a Nav1.7 inhibitory effect or a salt thereof.

As a result of diligent research to solve the above-mentioned problems, the present inventors have found that a novel heteroaromatic amide derivative represented by the following general formula (I) or a salt thereof is compatible with Nav1.5. We have found that it has a selective Nav1.7 inhibitory effect, and completed the present invention.

(0) The present invention relates to a drug comprising a heteroaromatic amide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:

［式中、X¹−X²は、N−C又はC−Nであり、
Y¹、Y²、Y³及びY⁴は、それぞれ独立して、単結合、−CH₂−、−CH₂CH₂−、−CR^4aR^4b−、−CR^4aH−、−CR^4bH−、−CH₂CR^4aR^4b−、−CH₂CR^4aH−、−NR^4c−、−NH−、−S−、−SO₂−、又は、−O−であり、
Z¹は、単結合、−CR^7aR^7b−、−O−、−S−、−NH−、−NR^7a−、−NR^7aCH₂−、−CH₂NR^7a−、−CO−、又は、−SO₂−であり、
環Aは、3〜7員の単環式芳香族環、又は、8〜12員の二環式芳香族環であり、
R^1a及びR^1bは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₄アルキル基、C₁-C₄ハロアルキル基、C₁-C₄アルコキシ基、C₁-C₄ハロアルコキシ基、C₃-C₇シクロアルキル基、C₁-C₄アルコキシ-C₁-C₄アルキル基、又は、C₁-C₄ハロアルコキシ-C₁-C₄アルキル基であり、
R²は、水素原子、ハロゲン原子、水酸基、シアノ基、置換されていてもよいC₁-C₆アルキル基、置換されていてもよいC₁-C₆ハロアルキル基、置換されていてもよいC₂-C₆アルケニル基、置換されていてもよいC₂-C₆アルキニル基、又は、置換されていてもよい飽和、部分飽和若しくは不飽和の3〜7員の単環式環であり、
R^3a、R^3b及びR^3cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、シアノメチル基、ホルミル基、ニトロ基、カルボキサミド基、水酸基、置換されていてもよいC₁-C₆アルキル基、置換されていてもよいC₁-C₆ハロアルキル基、置換されていてもよいC₁-C₆アルコキシ基、置換されていてもよいC₁-C₆ハロアルコキシ基、置換されていてもよいC₁-C₄アルコキシ-C₁-C₄アルキル基、置換されていてもよいC₁-C₄ハロアルコキシ-C₁-C₄アルキル基、置換されていてもよいC₁-C₄アルコキシ-C₁-C₄ハロアルキル基、置換されていてもよいC₁-C₄ハロアルコキシ-C₁-C₄ハロアルキル基、置換されていてもよいC₁-C₆アルキルカルボニル基、置換されていてもよいC₁-C₆アルコキシカルボニル基、置換されていてもよいC₁-C₆アルキルカルボニルオキシ基、置換されていてもよいC₁-C₆ハロアルキルカルボニル基、置換されていてもよいC₁-C₆ハロアルコキシカルボニル基、置換されていてもよいC₁-C₆ハロアルキルカルボニルオキシ基、置換されていてもよいC₃-C₇シクロアルキル基、置換されていてもよいヘテロシクロアルキル基、置換されていてもよいC₃-C₇シクロアルキルオキシ基、置換されていてもよいヘテロシクロアルキルオキシ基、置換されていてもよいC₂-C₆アルケニル基、置換されていてもよいC₂-C₆アルケニルオキシ基、置換されていてもよいC₂-C₆アルケニルオキシ-C₁-C₄アルキル基、置換されていてもよいC₂-C₆アルケニルオキシ-C₁-C₄ハロアルキル基、置換されていてもよいC₂-C₆アルキニル基、置換されていてもよいC₂-C₆アルキニルオキシ基、置換されていてもよいC₂-C₆アルキニルオキシ-C₁-C₄アルキル基、置換されていてもよいC₂-C₆アルキニルオキシ-C₁-C₄ハロアルキル基、置換されていてもよいC₁-C₄アルコキシ-C₁-C₄アルコキシ基、置換されていてもよいC₁-C₄ハロアルコキシ-C₁-C₄アルコキシ基、置換されていてもよいC₂-C₆アルケニルオキシ-C₁-C₄アルコキシ基、置換されていてもよいC₂-C₆アルキニルオキシ-C₁-C₄アルコキシ基、置換されていてもよいC₂-C₆アルケニルオキシ-C₁-C₄ハロアルコキシ基、置換されていてもよいC₂-C₆アルキニルオキシ-C₁-C₄ハロアルコキシ基、置換されていてもよいC₁-C₆アルキルチオ基、置換されていてもよいC₁-C₆ハロアルキルチオ基、置換されていてもよいC₁-C₄アルキルチオ-C₁-C₄アルキル基、置換されていてもよいC₁-C₄ハロアルキルチオ-C₁-C₄アルキル基、置換されていてもよいC₁-C₄アルキルチオ-C₁-C₄ハロアルキル基、置換されていてもよいC₁-C₄ハロアルキルチオ-C₁-C₄ハロアルキル基、置換されていてもよいC₁-C₆アルキルスルホニル基、-(CH₂)_pNR^a1R^a2（R^a1及びR^a2は、それぞれ独立して、水素原子、C₁-C₄アルキル基、又は、C₁-C₄ハロアルキル基であり、pは、0、１、又は、2である。）、又は、一般式(I-A)

[In the equation, X ¹ −X ² is N−C or C−N,
Y ¹ , Y ² , Y ³ and Y ⁴ are independently single-bonded, −CH ₂ −, _{−CH 2} CH ₂ −, −CR ^4a R ^4b −, −CR ^4a H−, −CR ^4b H, respectively. −, −CH ₂ CR ^4a R ^4b −, −CH ₂ CR ^4a H−, −NR ^4c −, _{−NH−, −S−, −SO 2−} , or −O−,
Z ¹ is a single bond, −CR ^7a R ^7b −, ^{−O−, −S−, −NH−, −NR 7a} −, −NR ^7a CH ₂ −, −CH ₂ NR ^7a −, −CO−, or , −SO ₂₋ ,
Ring A is a 3- to 7-membered monocyclic aromatic ring or an 8- to 12-membered bicyclic aromatic ring.
R ^1a and R ^1b are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, C _1- C ₄ haloalkoxy group, C _3- C ₇ cycloalkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, or C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group.
R ² is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted C _1- C ₆ alkyl group, an optionally substituted C ₁ -C ₆ haloalkyl group, an optionally substituted C. _{A 2-} C ₆ alkenyl group, an optionally substituted C _2- C ₆ alkynyl group, or an optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring.
R ^3a , R ^3b and R ^3c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, and optionally substituted C _1- C ₆ alkyl. Group, _{optionally substituted C 1-} C ₆ haloalkyl group, _{optionally substituted C 1} -C ₆ alkoxy group, optionally substituted C ₁ -C ₆ haloalkoxy group, optionally substituted good C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₆ alkylcarbonyl group, optionally substituted which may C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted C ₁ -C ₆ alkylcarbonyloxy group, an optionally substituted C ₁ -C ₆ haloalkylcarbonyl group, optionally C ₁ substituted -C ₆ haloalkoxycarbonyl group, optionally substituted C ₁ -C ₆ haloalkylcarbonyloxy _{group, optionally substituted C 3} -C ₇ cycloalkyl group, optionally substituted heterocycloalkyl group, which may be substituted C ₃ -C ₇ cycloalkyl group, an optionally substituted heterocycloalkyl group, optionally substituted C ₂ -C ₆ alkenyl group, an optionally substituted C ₂ -C ₆ Alkoxy Oxy Group, May Be Substituted C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, _{May Be Substituted C 2} -C ₆ Alkoxy Oxy-C ₁ -C ₄ Halo Alkoxy Group , May be substituted C ₂ -C ₆ alkylyl group, optionally substituted C ₂ -C ₆ alkylyloxy group, optionally substituted C ₂ -C ₆ alkylyloxy -C ₁ -C ₄ alkyl Group, _{optionally substituted C 2-} C ₆ alkynyloxy-C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₄ alkoxy-C ₁ -C ₄ alkoxy group, optionally substituted Good C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ Alkoxy groups, optionally substituted C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ haloalkoxy group, optionally substituted C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ haloalkoxy group, optionally substituted C ₁ -C ₆ alkylthio group, optionally substituted C ₁ -C ₆ haloalkylthio groups, optionally substituted C ₁ -C ₄ alkylthio-C ₁ -C ₄ alkyl groups, _{optionally substituted C 1} -C ₄ haloalkylthio-C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl group, an optionally substituted C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group, optionally substituted Good C ₁ -C ₆ Alkoxy Group,-(CH ₂ ) _p NR ^a1 R ^a2 (R a ¹ and R a ² are independent hydrogen atoms, C ₁ -C ₄ alkyl groups, or C ₁ -C, respectively. _{It is a 4-} haloalkyl group, where p is 0, 1, or 2. ) Or general formula (IA)

{式中、
環Bは、飽和、部分飽和若しくは不飽和の3〜7員の単環式環であり、
L¹は、単結合、-CR^a3R^a4-、-O-、-NR^a1-、-CR^a3R^a4O-、-OCR^a3R^a4-、-CH₂CH₂-、-CH=CH-、-C≡C-、又は、-CH₂OCH₂-であり(R^a3及びR^a4は、それぞれ独立して、水素原子、C₁-C₄アルキル基、又は、C₁-C₄ハロアルキル基である。)、
R^8a、R^8b及びR^8cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₃-C₇シクロアルキル基、C₃-C₇シクロアルキルオキシ基、ヘテロシクロアルキル基、ヘテロシクロアルキルオキシ基、C₂-C₆アルケニル基、又は、C₂-C₆アルキニル基である。｝で表される基であり、
R^4a、R^4b及びR^4cは、それぞれ独立して、ハロゲン原子、シアノ基、シアノメチル基、ホルミル基、ニトロ基、カルボキサミド基、水酸基、置換されていてもよいC₁-C₆アルキル基、置換されていてもよいC₁-C₆ハロアルキル基、置換されていてもよいC₁-C₆アルコキシ基、置換されていてもよいC₁-C₆ハロアルコキシ基、置換されていてもよいC₁-C₄アルコキシ-C₁-C₄アルキル基、置換されていてもよいC₁-C₄ハロアルコキシ-C₁-C₄アルキル基、置換されていてもよいC₁-C₄アルコキシ-C₁-C₄ハロアルキル基、置換されていてもよいC₁-C₄ハロアルコキシ-C₁-C₄ハロアルキル基、置換されていてもよいC₁-C₆アルキルカルボニル基、置換されていてもよいC₁-C₆アルコキシカルボニル基、置換されていてもよいC₁-C₆アルキルカルボニルオキシ基、置換されていてもよいC₁-C₆ハロアルキルカルボニル基、置換されていてもよいC₁-C₆ハロアルコキシカルボニル基、置換されていてもよいC₁-C₆ハロアルキルカルボニルオキシ基、置換されていてもよいC₃-C₇シクロアルキル基、置換されていてもよいヘテロシクロアルキル基、置換されていてもよいC₃-C₇シクロアルキルオキシ基、置換されていてもよいヘテロシクロアルキルオキシ基、置換されていてもよいC₂-C₆アルケニル基、置換されていてもよいC₂-C₆アルケニルオキシ基、置換されていてもよいC₂-C₆アルケニルオキシ-C₁-C₄アルキル基、置換されていてもよいC₂-C₆アルケニルオキシ-C₁-C₄ハロアルキル基、置換されていてもよいC₂-C₆アルキニル基、置換されていてもよいC₂-C₆アルキニルオキシ基、置換されていてもよいC₂-C₆アルキニルオキシ-C₁-C₄アルキル基、置換されていてもよいC₂-C₆アルキニルオキシ-C₁-C₄ハロアルキル基、置換されていてもよいC₁-C₄アルコキシ-C₁-C₄アルコキシ基、置換されていてもよいC₁-C₄ハロアルコキシ-C₁-C₄アルコキシ基、置換されていてもよいC₂-C₆アルケニルオキシ-C₁-C₄アルコキシ基、置換されていてもよいC₂-C₆アルキニルオキシ-C₁-C₄アルコキシ基、置換されていてもよいC₂-C₆アルケニルオキシ-C₁-C₄ハロアルコキシ基、置換されていてもよいC₂-C₆アルキニルオキシ-C₁-C₄ハロアルコキシ基、置換されていてもよいC₁-C₆アルキルチオ基、置換されていてもよいC₁-C₆ハロアルキルチオ基、置換されていてもよいC₁-C₄アルキルチオ-C₁-C₄アルキル基、置換されていてもよいC₁-C₄ハロアルキルチオ-C₁-C₄アルキル基、置換されていてもよいC₁-C₄アルキルチオ-C₁-C₄ハロアルキル基、置換されていてもよいC₁-C₄ハロアルキルチオ-C₁-C₄ハロアルキル基、ペンタフルオロスルファニル基、-(CH₂)_qNR^b1R^b2（R^b1及びR^b2は、それぞれ独立して、水素原子、C₁-C₄アルキル基、又はC₁-C₄ハロアルキル基であり、qは、0、１、2、又は、3である。）、又は、一般式(I-B)

{In the formula,
Ring B is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring.
L ¹ represents a single ^{bond, -CR a3 R a4 -, -} O -, - NR a1 -, - CR a3 R a4 O -, - OCR a3 R a4 -, - CH 2 CH 2 -, - CH = CH- , -C ≡ C-, or -CH ₂ OCH _2- (R ^a3 and R ^a4 are independent hydrogen atoms, C _{1 -C 4} alkyl groups, or C ₁ -C ₄ haloalkyl groups, respectively. ),
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₃ -C ₇ cycloalkyloxy group, heterocycloalkyl group, heterocycloalkyloxy group, C _2- C ₆ alkoxy group, or C _2- It is a C ₆ alkylyl group. } Is a group represented by
R ^4a , R ^4b and R ^4c are independently halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxylxamide group, hydroxyl group, optionally substituted C _1- C ₆ alkyl group, substituted. is optionally C ₁ -C ₆ haloalkyl group, an optionally substituted C ₁ -C ₆ alkoxy group, optionally substituted C ₁ -C ₆ haloalkoxy group, an optionally C ₁ substituted -C ₄ alkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₆ alkylcarbonyl group, optionally substituted C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted C ₁ -C ₆ alkylcarbonyloxy group, an optionally substituted C ₁ -C ₆ haloalkylcarbonyl group, an optionally substituted C ₁ -C _{6 Alkoxycarbonyl group optionally substituted, C 1-} C ₆ haloalkylcarbonyloxy _{group optionally substituted, C 3-} C ₇ cycloalkyl group optionally substituted, heterocycloalkyl group optionally substituted, substituted May be C _{3 -C 7} cycloalkyloxy groups, optionally substituted heterocycloalkyloxy groups, optionally substituted C ₂ -C ₆ alkoxy groups, optionally substituted C ₂ -C ₆ Alkoxyoxy groups, optionally substituted C ₂ -C ₆ alkoxyoxy-C ₁ -C ₄ alkyl groups, optionally substituted C ₂ -C ₆ alkoxyoxy -C ₁ -C ₄ haloalkyl groups, substituted May be C ₂ -C ₆ Alkoxy Group, May Be Substituted C ₂ -C ₆ Alkoxy Group, May Be Substituted C ₂ -C ₆ Alkinyl Oxy-C ₁ -C ₄ Alkoxy Group, Substituted May be C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ haloalkyl group, may be substituted C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy group, may be substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ Alkoxy groups, optionally substituted C ₂ -C _{6 Alkoxy} Niruokishi -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ haloalkoxy groups, optionally substituted C _2- C ₆ alkynyloxy-C ₁ -C ₄ haloalkoxy groups, optionally substituted C ₁ -C ₆ alkylthio groups, optionally substituted C ₁ -C ₆ haloalkylthio group, optionally substituted C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, _{optionally substituted C 1} -C ₄ haloalkylthio -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl group, an optionally substituted C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group, pentafluorosulfanyl group, - ( CH ₂ ) _q NR ^b1 R ^b2 (R ^b1 and R ^b2 are independently hydrogen atoms, C _1- C ₄ alkyl groups, or C ₁ -C ₄ haloalkyl groups, where q is 0, 1, 2 or 3. ) Or general formula (IB)

{式中、
環Cは、飽和、部分飽和、若しくは不飽和の3〜7員の単環式環、又は、飽和、部分飽和、若しくは不飽和の7〜12員の二環式環であり、
L²は、単結合、-CH=CH-、-C≡C-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2O(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2NR^c(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2CO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2CONR^c(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2NR^cCO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2S(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2SO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2SO₂(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2SO₂NR^c(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、又は、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2NR^cSO₂(CR^10eR^10f)_r3(CR^10gR^10h)_r4-であり
(R^cは、水素原子、C₁-C₄アルキル基、又は、C₁-C₄ハロアルキル基であり、
R^10a、R^10b、R^10c、R^10d、R^10e、R^10f、R^10g、R^10hは、それぞれ独立して、水素原子、ハロゲン原子、C₁-C₄アルキル基、又は、C₃-C₇シクロアルキル基であり、
R^10a及びR^10bは、これらが結合する炭素原子と一緒になって、3〜7員の単環式環を形成してもよく、
R^10c及びR^10dは、これらが結合する炭素原子と一緒になって、3〜7員の単環式環を形成してもよく、
R^10e及びR^10fは、これらが結合する炭素原子と一緒になって、3〜7員の単環式環を形成してもよく、
R^10g及びR^10hは、これらが結合する炭素原子と一緒になって、3〜7員の単環式環を形成してもよく、
r1、r2、r3及びr4は、それぞれ独立して、0、1、又は、2である。）、
R^9a、R^9b及びR^9cは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、ホルミル基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₄アルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルキル基、C₁-C₄アルコキシ-C₁-C₄ハロアルキル基、C₁-C₆アルキルカルボニル基、C₁-C₆アルコキシカルボニル基、C₁-C₆ハロアルキルカルボニル基、C₃-C₇シクロアルキル基、ヘテロシクロアルキル基、C₃-C₇シクロアルキルオキシ基、ヘテロシクロアルキルオキシ基、C₂-C₆アルケニル基、-(CH₂)_sNR^d1R^d2（R^d1及びR^d2は、それぞれ独立して、水素原子、C₁-C₄アルキル基、又は、C₁-C₄ハロアルキル基であり、sは、0、１、又は、2である。）、又は、一般式(I-C)

{In the formula,
Ring C is a saturated, partially saturated, or unsaturated 3- to 7-membered monocyclic ring, or a saturated, partially saturated, or unsaturated 7 to 12-membered bicyclic ring.
L ² is a single bond, -CH = CH-, -C ≡ C ^{-,-(CR 10a R 10b} ) _r1 (CR ^10c R ^10d ) _r2 (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- , -(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 O (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CONR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 S (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO ₂ (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO ₂ NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- or
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c SO ₂ (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4-
(R ^c is a hydrogen atom, a C _1- C ₄ alkyl group, or a C ₁ -C ₄ haloalkyl group.
R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^10f , R ^10g , R ^10h are independently hydrogen atom, halogen atom, C _1- C ₄ alkyl group, or C ₃ -C. ₇ cycloalkyl group,
R ^10a and R ^10b may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
R ^10c and R ^10d may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
R ^10e and R ^10f may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
R ^10g and R ^10h may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
r1, r2, r3 and r4 are independently 0, 1 or 2 respectively. ),
R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, formyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ Alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy- C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyl group, C _3- C ₇ cycloalkyl group, heterocycloalkyl group, C _3- C ₇ cycloalkyloxy group, heterocycloalkyloxy group, C ₂ -C ₆ alkoxy group,-(CH ₂ ) _s NR ^d1 R ^d2 (R ^d1 and R ^d2 are independent hydrogen atoms, C, respectively. _{It is a 1-} C ₄ alkyl group or a C _1- C ₄ haloalkyl group, and s is 0, 1, or 2), or the general formula (IC).

{式中、
環Dは、ハロゲン原子、水酸基、C₁-C₄アルキル基、C₁-C₄ハロアルキル基、C₁-C₄アルコキシ基、又は、C₁-C₄ハロアルコキシ基で置換されていてもよい、3〜7員の単環式環であり、
L³は、単結合、又は、酸素原子である。｝である。}で表される基であるか、あるいは、
R^4a及びR^4bは、これらが結合する炭素原子と一緒になって、3〜7員の単環式環を形成してもよく、あるいは、
R^4a及びR^4bは、一緒になって、一般式(I-D)：

{In the formula,
Ring D may be substituted with a halogen atom, a hydroxyl group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, or a C _1- C _{4 haloalkoxy group.} , A 3- to 7-membered monocyclic ring,
L ³ is a single bond or an oxygen atom. }. Is a group represented by} or
R ^4a and R ^4b may combine with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring, or
R ^4a and R ^4b together have the general formula (ID):

を形成してもよく（R^4d及びR^4eは、それぞれ独立して、水素原子、ハロゲン原子、又は、C₁-C₄アルキル基、あるいは、R^4d及びR^4eは、これらが結合する炭素原子と一緒になって、3〜7員の単環式環を形成してもよい。）、
R^5a、R^5b、R^5c、R^6a、R^6b及びnは、次の（i）から（v）で示される構成のいずれか１つを充足し
｛(i) R^5bとR^5cが一緒になって、単結合、−CH₂−、−OCH₂−、−CH₂O−、−CH₂S−、−SCH₂−、−CH₂NR^e1−、−NR^e1CH₂−、−CH₂CH₂−、−NR^e1CO−、−CR^e1R^e2O−、又は、−OCR^e1R^e2−を形成し（R^e1及びR^e2は、水素原子、又は、C₁-C₄アルキル基である。）、かつ、
R^5aが、水素原子、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₃-C₇シクロアルキル基、ヘテロシクロアルキル基、C₃-C₇シクロアルキル-C₁-C₄アルキル基、ヘテロシクロアルキル-C₁-C₄アルキル基、又は、アラルキル基であり、かつ、
R^6a及びR^6bが、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₄アルキル基、C₁-C₄ハロアルキル基、C₁-C₄アルコキシ基 、又は、C₁-C₄ハロアルコキシ基であり、かつ、
nが、1又は2である。
(ii) R^5aとR^6aが一緒になって、−CH₂−、−CH₂CH₂−、−CH₂CR^e1R^e2−、−CR^e1R^e2CH₂−、−CH₂CH₂CH₂−、−CH₂CH₂O−、−CH₂CH₂CH₂O−を形成し（R^e1とR^e2は、前記（i）において示された定義と同義である。）、かつ、
R^5bが、水素原子、C₁-C₄アルキル基、又はC₁-C₄ハロアルキル基であり、
R^5c及びR^6bが、水素原子、ハロゲン原子、水酸基、C₁-C₄アルキル基、C₁-C₄ハロアルキル基、C₁-C₄アルコキシ基、C₁-C₄ハロアルコキシ基であるか、
あるいは、R^5cとR^6bは、一緒になって、-(CH₂)_t-、-O(CH₂)_t-、-(CH₂)_tO-、-(CH₂)_tO(CH₂)_u-、-(CH₂)_tNR^e3(CH₂)_u-、-(CH₂)_tCONR^e3(CH₂)_u-、又は-(CH₂)_tNR^e3CO(CH₂)_u-を形成し（t及びuは、それぞれ独立して、０、1、2、又は、３であり、R^e3は、水素原子、又は、C₁-C₄アルキル基である。）、かつ
nが、1である。
(iii) R^5aが、水素原子、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₃-C₇シクロアルキル基、ヘテロシクロアルキル基、C₃-C₇シクロアルキル-C₁-C₄アルキル基、ヘテロシクロアルキル-C₁-C₄アルキル基、又は、アラルキル基であり、かつ、
R^5bが、水素原子、又は、C₁-C₄アルキル基であり、
R^5cが、水素原子、C₁-C₄アルキル基、又は、ハロゲン原子であり、
R^6a及びR^6bが、それぞれ独立して、水素原子、ハロゲン原子、C₁-C₆アルキル基、C₃-C₇シクロアルキル基、又は、C₁-C₆ハロアルキル基であるか、
あるいは、R^6a及びR^6bは、これらが結合する炭素原子と一緒になって、3〜7員の単環式環を形成し、かつ、
nが、1又は2である。
(iv) R^5aとR^5bが一緒になって、−CH₂CH₂−、−CH₂CH₂CH₂−、又は、−CH₂CH₂CH₂CH₂−を形成し、かつ、
R^5c、R^6a 及びR^6bが、それぞれ独立して、水素原子、又は、ハロゲン原子であり、かつ、
nが、1又は2である。
(v) R^6aとR^5cが一緒になって、−OCH₂−、−CH₂O− 、−CH₂S−、−SCH₂−、−CH₂NH−、−NHCH₂−、又は、−CH₂CH₂− を形成し、かつ、
R^5a及びR^5bが、水素原子であり、かつ、
R^6bが水素原子、又は、ハロゲン原子であり、かつ、
nが、1である。｝、
R^7a及びR^7bは、それぞれ独立して、水素原子、ハロゲン原子、又は、C₁-C₄アルキル基である。］。

(R ^4d and R ^4e are independent hydrogen atoms, halogen atoms, or C _1- C ₄ alkyl groups, or R ^4d and R ^4e are carbon atoms to which they are bonded. Together with, a 3- to 7-membered monocyclic ring may be formed.),
R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy any one of the following configurations (i) to (v) {(i) R ^5b and R ^5c are together. Single bond, −CH ₂ −, −OCH ₂ −, −CH ₂ O−, −CH ₂ S−, −SCH ₂ −, −CH ₂ NR ^e1 −, −NR ^e1 CH ₂ −, −CH ^{_{2 CH 2 -, - NR e1}} CO -, - CR e1 R e2 O-, or, -OCR ^e1 R ^e2 - to form (R ^e1 and R ^e2 is a hydrogen atom, or, C ₁ -C ₄ alkyl group ) And
R ^5a is a hydrogen atom, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, C ₃ -C ₇ cycloalkyl-C ₁ -C ₄ Alkyl group, heterocycloalkyl-C _1- C ₄ alkyl group, or aralkyl group, and
R ^6a and R ^6b are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, or C. _{It is a 1-} C ₄ haloalkoxy group and
n is 1 or 2.
(ii) R ^5a and R ^6a _{together, -CH 2 -, - CH 2} CH 2 -, - CH 2 CR e1 R e2 -, - CR e1 R e2 CH 2 -, - CH 2 CH 2 CH ₂ −, −CH ₂ CH ₂ O−, −CH ₂ CH ₂ CH ₂ O− are formed (R ^e1 and R ^e2 are synonymous with the definitions shown in (i) above), and
R ^5b is a hydrogen atom, a C _1- C ₄ alkyl group, or a C ₁ -C ₄ haloalkyl group.
^Are R 5c and R ^6b hydrogen atom, halogen atom, hydroxyl group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, C ₁ -C ₄ haloalkoxy group? ,
Alternatively, R ^5c and R ^6b together,-(CH ₂ ) _t- , -O (CH ₂ ) _t -,-(CH ₂ ) _t O-,-(CH ₂ ) _t O (CH ₂₎ ) _U -,-(CH ₂ ) _t NR ^e3 (CH ₂ ) _u -,-(CH ₂ ) _t CONR ^e3 (CH ₂ ) _u- or-(CH ₂ ) _t NR ^e3 CO (CH ₂ ) _u- (T and u are 0, 1, 2, or 3, respectively, and R ^e3 is a hydrogen atom or C _1- C ₄ alkyl group), and
n is 1.
(iii) R ^5a is a hydrogen atom, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, C ₃ -C ₇ cycloalkyl-C ₁ -C ₄ alkyl group, heterocycloalkyl -C ₁ -C ₄ alkyl group, or aralkyl group and
R ^5b is a hydrogen atom or a C _1- C ₄ alkyl group,
R ^5c is a hydrogen atom, a C _1- C ₄ alkyl group, or a halogen atom.
Whether R ^6a and R ^6b are independently hydrogen atoms, halogen atoms, C _1- C ₆ alkyl groups, C ₃ -C ₇ cycloalkyl groups, or C _1- C ₆ haloalkyl groups, respectively.
Alternatively, R ^6a and R ^6b together with the carbon atoms to which they bond form a 3- to 7-membered monocyclic ring, and
n is 1 or 2.
(iv) R ^5a and R ^5b together form −CH ₂ CH ₂ −, −CH ₂ CH ₂ CH ₂ −, or −CH ₂ CH ₂ CH ₂ CH ₂ −, and
R ^5c , R ^6a and R ^6b are independent hydrogen atoms or halogen atoms, respectively, and
n is 1 or 2.
(v) R ^6a and R ^5c _{together, -OCH 2 -, - CH 2} O-, -CH 2 S -, - SCH 2 -, - CH 2 NH -, - NHCH 2 -, or - CH ₂ CH ₂ − is formed and
R ^5a and R ^5b are hydrogen atoms and
R ^6b is a hydrogen atom or a halogen atom, and
n is 1. },
R ^7a and R ^7b are independently hydrogen atoms, halogen atoms, or C _1- C ₄ alkyl groups. ].

That is, the present invention includes the following inventions.

(1) A drug consisting of a heteroaromatic amide derivative represented by the general formula (I) or a salt thereof:

［式中、X¹−X²、Y¹、Y²、Y³、Y⁴、Z¹、環A、R^1a、R^1b、R²、R^3a、R^3b、R^3c、R^5a、R^5b、R^5c、R^6a、R^6b、nは、前記(0)において示された定義と同義である（但し、X¹−X²が、N−Cであり、Y¹、Y²、Y³及びY⁴が一緒になって、−CH₂CR^4aHCH₂CH₂−を形成し、R²が水素原子であり、R^4aが一般式(I-B)で表される基であり、かつ、L²が単結合の場合、環Cはフェニル環ではない。あるいは、環Cがフェニル環である場合、X¹−X²は、C−Nである。）］。

[In the equation, X ¹ −X ² , Y ¹ , Y ² , Y ³ , Y ⁴ , Z ¹ , ring A, R ^1a , R ^1b , R ² , R ^3a , R ^3b , R ^3c , R ^5a , R ^5b , R ^5c , R ^6a , R ^6b , n are synonymous with the definitions given in (0) above (where X ¹ −X ² is N − C, and Y ¹ , Y ² , Y ³ and Y ⁴ are combined to form −CH ₂ CR ^4a HCH ₂ CH ₂ −, R ² is a hydrogen atom, R ^4a is a group represented by the general formula (IB), and If L ² is a single bond, ring C is not a phenyl ring, or if ring C is a phenyl ring, X ¹ −X ² is C − N.)].

(2) In the general formula (I),
Y ¹ , Y ² , Y ³ and Y ⁴ together,
−OCH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ −, −OCR ^4a R ^4b CH ₂ CH ₂ −,
−OCH ₂ CH ₂ −, −OCR ^4a HCH ₂ −, −OCR ^4a R ^4b CH ₂ −,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCR ^4a R ^4b CH ₂ CH ₂ CH ₂ −,
−OCH ₂ CR ^4a HCH ₂ CH ₂ −, −OCH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −, −CH ₂ CH ₂ OCH ₂ −, −CH ₂ CR ^4a HOCH ₂ −
−CH ₂ CH ₂ CH ₂ CH ₂ −, −CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
−CH ₂ CH ₂ CR ^4a HCH ₂ −, −CH ₂ CH ₂ CR ^4a R ^4b CH ₂ −,
−CH ₂ SCH ₂ CH ₂ −, −CH ₂ SO ₂ CH ₂ CH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −,
−NHCR ^4a HCH ₂ CH ₂ −,
−CH ₂ NR ^4c CH ₂ CH ₂ −, −CH ₂ NR ^4c CR ^4a HCH ₂ −, −CH ₂ NHCR ^4a HCH ₂ −,
−CH ₂ CH ₂ NR ^4c CH ₂ −, −CH ₂ CR ^4a HNR ^4c CH ₂ −, or −CH ₂ CR ^4a HNHCH ₂ − (R ^4a , R ^4b , R ^4c are described in (0) above). It is synonymous with the definition given in),.
R ² is a hydrogen atom, halogen atom, hydroxyl group, cyano group, or a saturated, partially saturated, or unsaturated 3- to 7-membered monocyclic ring that may be substituted (where X ¹ −X ^2). There is a C-N, ^{and, Y 1, Y 2, Y} 3 and Y ⁴ is, they _{together, -OCH 2 CH 2 CH 2 -} , - OCR 4a HCH 2 CH 2 -, or, When forming −OCR ^4a R ^4b CH ₂ CH ₂ −, R ² is a hydrogen atom), the drug according to (1) above, which comprises a heteroaromatic amide derivative or a salt thereof.

(3) In the general formula (I),
X ¹ −X ² is C −N,
Y ¹ , Y ² , Y ³ and Y ⁴ together,
−OCH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ −, −OCR ^4a R ^4b CH ₂ CH ₂ −, −OCH ₂ CH ₂ −,
_{^{-OCR 4a HCH 2 -, - OCR}} 4a R 4b CH 2 -,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCH ₂ CR ^4a HCH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −,
−CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −, −CH ₂ CH ₂ CR ^4a HCH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −, −NHCR ^4a HCH ₂ CH ₂ − or −CH ₂ NR ^4c CH ₂ CH ₂ − (R ^4a , R ^4b) And R ^4c are synonymous with the definitions given in (0) above),
A ^{heteroaromatic amide derivative or a heteroaromatic amide derivative in which R 5a} , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy any one of the configurations shown in (i) to (iii) in (0) above. The pharmaceutical according to (1) or (2) above, which comprises the salt.

(4) A drug consisting of a heteroaromatic amide derivative represented by the general formula (I) or a salt thereof:

［式中、X¹−X²、Y¹、Y²、Y³、Y⁴、Z¹、環A、R^1a、R^1b、R²、R^3a、R^3b、R^3cは、前記(0)において示された定義と同義であり（但し、R²が水素原子の場合は、Y¹、Y²、Y³、又は、Y⁴の少なくとも一つが、−CR^4aR^4b−、−CR^4aH−、−CH₂CR^4aR^4b−、−CH₂CR^4aH−、又は、−NR^4c−である（R^4a、R^4b及びR^4cは、前記(0)において示された定義と同義である。）。）、
R^5a、R^5b、R^5c、R^6a、R^6b及びnは、前記(0)中の（i）又は（ii）の構成のいずれかを充足する（但し、 R^5a、R^5b、R^5c、R^6a、R^6b及びnが前記（ii）の構成を充足する場合は、Y¹、Y²、Y³及びY⁴は一緒になって、−CH₂NR^4aHCH₂CH₂−を形成しない。）。］。

[In the equation, X ¹ −X ² , Y ¹ , Y ² , Y ³ , Y ⁴ , Z ¹ , ring A, R ^1a , R ^1b , R ² , R ^3a , R ^3b , R ^3c are the above (0). ) Is synonymous with (however, if R ² is a hydrogen atom, at least one of ^{Y 1} , Y ² , Y ³ , or Y ^{4 is −CR 4a} R ^4b −, ^{−CR 4a.} H −, −CH ₂ CR ^4a R ^4b −, −CH ₂ CR ^4a H −, or −NR ^4c − (R ^4a , R ^4b, and R ^4c are synonymous with the definitions given in (0) above. ).),.
R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy any of the configurations (i) or (ii) in (0) above (provided that R ^5a , R ^5b , R ^5c). , R ^6a , R ^6b and n satisfy the configuration of (ii) above, Y ¹ , Y ² , Y ³ and Y ⁴ together form −CH ₂ NR ^4a HCH ₂ CH ₂ −. do not.). ].

(5) In the general formula (I),
Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a R 4b CH 2 CH 2 -, - OCH 2 CH 2 -, - OCR 4a HCH 2 -, - OCR 4a R 4b CH 2 -,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCR ^4a R ^4b CH ₂ CH ₂ CH ₂ −,
−OCH ₂ CR ^4a HCH ₂ CH ₂ −, −OCH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −, −CH ₂ CH ₂ OCH ₂ −, −CH ₂ CR ^4a HOCH ₂ −
−CH ₂ CH ₂ CH ₂ CH ₂ −, −CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
−CH ₂ CH ₂ CR ^4a HCH ₂ −, −CH ₂ CH ₂ CR ^4a R ^4b CH ₂ −,
−CH ₂ SCH ₂ CH ₂ −, −CH ₂ SO ₂ CH ₂ CH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −,
−NHCR ^4a HCH ₂ CH ₂ −,
−CH ₂ NR ^4c CH ₂ CH ₂ −, −CH ₂ NR ^4c CR ^4a HCH ₂ −, −CH ₂ NHCR ^4a HCH ₂ −,
−CH ₂ CH ₂ NR ^4c CH ₂ −, −CH ₂ CR ^4a HNR ^4c CH ₂ −, or −CH ₂ CR ^4a HNHCH ₂ − (R ^4a , R ^4b and R ^4c are described in (0) above). It is synonymous with the definition given in),.
R ² is a hydrogen atom, halogen atom, hydroxyl group, cyano group, or a saturated, partially saturated, or unsaturated 3- to 7-membered monocyclic ring that may be substituted (where X ¹ −X ^2). There is a C-N, ^{and, Y 1, Y 2, Y} 3 and Y ⁴ is, they _{^{together, -OCR 4a HCH 2 CH 2 -}} , - OCR 4a R 4b CH 2 CH 2 - and When formed, R ² is a hydrogen atom), a heteroaromatic amide derivative or a salt thereof as described in (4) above (where X ^1- X ² is N-C and Y ¹ , Y ² , Y ³ and Y ⁴ together form −CH ₂ CR ^4a HCH ₂ CH ₂ −, where R ² is a hydrogen atom and R ^4a is represented by the general formula (IB). If it is a group and L ² is a single bond, ring C is not a phenyl ring, or if ring C is a phenyl ring, X ¹ −X ² is C − N).

(6) In the general formula (I),
X ¹ −X ² is C −N,
Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a R 4b CH 2 CH 2 -, - OCH 2 CH 2 -,
_{^{-OCR 4a HCH 2 -, - OCR}} 4a R 4b CH 2 -,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCH ₂ CR ^4a HCH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −,
−CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −, −CH ₂ CH ₂ CR ^4a HCH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −, −NHCR ^4a HCH ₂ CH ₂ − or −CH ₂ NR ^4c CH ₂ CH ₂ − (R ^4a , R ^4b) And R ^4c are synonymous with the definitions given in (0) above),
The above (4) or (5) consisting of a heteroaromatic amide derivative or a salt thereof, wherein ^{R 5a} , R ^5b , R ^5c , R ^6a , R ^{6b and n satisfy the composition of (i) in (0) above.} ).

(7) General formula (I-E2):

［式中、X¹、X²、Y¹、Y²、Y³、Y⁴、R^1a、R^1b、R²は、前記(0)において示された定義と同義であり、
Z²-Z³は、-CH₂-、-OCH₂-、-CH₂O-、-SCH₂-、-CH₂S-、-CH₂NR^f1-、-NR^f1CH₂-、-CH₂CH₂-、-CONR^f1-、-NR^f1CO-、-OCR^f1R^f2-、又は、-CR^f1R^f2O-であり(R^f1及びR^f2は、水素原子、C₁-C₄アルキル基、又は、C₁-C₄ハロアルキル基である。)、
R^5aは、水素原子、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₃-C₇シクロアルキル基、ヘテロシクロアルキル基、C₃-C₇シクロアルキル-C₁-C₄アルキル基、ヘテロシクロアルキル-C₁-C₄アルキル基、又は、アラルキル基であり、
R^6a、R^6bは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₄アルキル基、C₁-C₄ハロアルキル基、C₁-C₄アルコキシ基 、又は、C₁-C₄ハロアルコキシ基であり、
Z⁴は、C-R^11a又は窒素原子であり、
R^11aは、水素原子、ハロゲン原子、シアノ基、シアノメチル基、ホルミル基、ニトロ基、カルボキサミド基、水酸基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₄アルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルキル基、C₃-C₇シクロアルキル基、C₂-C₆アルケニル基、C₂-C₆アルケニルオキシ基、C₂-C₆アルキニル基、又は、C₂-C₆アルキニルオキシ基であり、
R^11bは、前記(0)におけるR^3bと同義であり、
R^11cは、前記(0)におけるR^3cと同義である
（但し、R²が水素原子の場合は、Y¹、Y²、Y³、又は、Y⁴の少なくとも一つが、-CR^4aR^4b-、-CR^4aH-、-CH₂CR^4aR^4b-、-CH₂CR^4aH-、又は、-NR^4c-である(R^4a、R^4b及びR^4cは、前記(0)において示された定義と同義である。)。）。］
で表されるヘテロ芳香族アミド誘導体又はその塩からなる医薬。

[In the equation, X ¹ , X ² , Y ¹ , Y ² , Y ³ , Y ⁴ , R ^1a , R ^1b , R ² are synonymous with the definitions given in (0) above.
Z ² -Z ³ is -CH _2- , -OCH _2- , -CH ₂ O-, -SCH _2- , -CH ₂ S-, -CH ₂ NR ^f1- , -NR ^f1 CH _2- , -CH ^{_{2 CH 2 -, - CONR f1}} -, - NR f1 CO -, - OCR f1 R f2 -, or, -CR ^f1 R ^f2 O-a and (R ^f1 and R ^f2 is hydrogen atom, C ₁ -C ₄ Alkyl group or C _1- C ₄ haloalkyl group),
R ^5a is a hydrogen atom, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, C ₃ -C ₇ cycloalkyl-C ₁ -C ₄ Alkyl group, heterocycloalkyl-C _1- C ₄ alkyl group, or aralkyl group,
R ^6a and R ^6b are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, or C. ₁ -C ₄ haloalkoxy group,
Z ⁴ is a CR ^11a or nitrogen atom
R ^11a is a hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group. , C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group, C ₃ -C ₇ cycloalkyl group, C _2- C ₆ Alkoxy Group, C _2- C ₆ Alkoxy Oxy Group, C _2- C ₆ Alkinyl Group, or C _2- C ₆ Alkoxy Oxy Group.
R ^11b is synonymous with ^{R 3b} in (0) above.
R ^{11c is synonymous with R 3c} in (0) above (however, if R ² is a hydrogen atom, at least one of ^{Y 1} , Y ² , Y ³ , or Y ^{4 is -CR 4a} R ^4b. -, -CR ^4a H-, -CH ₂ CR ^4a R ^4b- , -CH ₂ CR ^4a H-, or -NR ^4c- (R ^4a , R ^4b and R ^4c are shown in (0) above. It is synonymous with the defined definition.).). ]
A drug comprising a heteroaromatic amide derivative represented by or a salt thereof.

(8) In the general formula (I-E2),
X ¹ -X ² is CN,
Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a R 4b CH 2 CH 2 -, - OCH 2 CH 2 -,
_{^{-OCR 4a HCH 2 -, - OCR}} 4a R 4b CH 2 -,
-OCH ₂ CH ₂ CH ₂ CH _2- , -OCR ^4a HCH ₂ CH ₂ CH _2- , -OCH ₂ CR ^4a HCH ₂ CH _2- ,
-CH ₂ OCH ₂ CH _2- , -CH ₂ OCH ₂ CH ₂ CH _2- ,
-CH ₂ CR ^4a HCH ₂ CH _2- , -CH ₂ CR ^4a R ^4b CH ₂ CH _2- , -CH ₂ CH ₂ CR ^4a HCH _2- ,
-NHCH ₂ CH ₂ CH _2- , -NR ^4c CR ^4a HCH ₂ CH _2- , -NHCR ^4a HCH ₂ CH _2- , or -CH ₂ NR ^4c CH ₂ CH _2-
(R ^4a , R ^4b and R ^4c are synonymous with the definitions given in (0) above.),
The pharmaceutical according to (7) above, which comprises a heteroaromatic amide derivative or a salt thereof (where X ¹ -X ² is CN, and Y ¹ , Y ² , Y ³ and Y ⁴ are together. And -OCR ^4a HCH ₂ CH ₂ -or
When forming -OCR ^4a R ^4b CH ₂ CH _2- , R ² is a hydrogen atom. ).

(9) In the general formula (I-E2),
Z ² -Z ³ is -CH ₂ O-,
R ^6a and R ^6b are independently hydrogen atoms, fluorine atoms, hydroxyl groups, or methoxy groups.
The pharmaceutical according to (7) or (8) above, wherein R ^11a and R ^11c each consist of a heteroaromatic amide derivative or a salt thereof, which are hydrogen atoms.

(10) In the general formula (I-E2),
X ¹ -X ² is CN,
Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a HCH 2 -,
-OCR ^4a HCH ₂ CH ₂ CH _2- , -CH ₂ CR ^4a HCH ₂ CH _2- ,
Forming -NR ^4c CR ^4a HCH ₂ CH _2- , -NHCR ^4a HCH ₂ CH _2- , or -CH ₂ NR ^4c CH ₂ CH _2- ,
R ^4a is substituted with halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, optionally substituted with hydroxyl group C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, substituted with hydroxyl group. May be _{substituted with C 1} -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ haloalkoxy group C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyl group, C ₃ -C ₇ cycloalkyl group, halogen atom or C ₁ -C ₄ haloalkyl group in optionally substituted C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ Alkoxy group, optionally substituted with halogen atom C _2- C ₆ Alkoxyoxy-C _1- C ₄ Alkoxy group, C _2- C ₆ Alkoxy group, optionally substituted with halogen atom or methoxy group C _2- C ₆ alkoxy group, C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₆ alkylthio group, C _1- C ₆ haloalkylthio group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ alkyl group,-(CH ₂ ) _q NR ^b1 R ^b2 (q, R ^b1 and R ^b2 are synonymous with the definitions given in (0) above) or the general formula (IB).

{式中、
環Cは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L²は、単結合、-CH=CH-、-C≡C-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2O(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2NR^c(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2CO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2S(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、又は、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2SO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-であり(R^10a、R^10b、R^10c、R^10d、R^10e、R^10f、R^10g、R^10h、r1、r2、r3、r4及びR^cは、前記(0)において示された定義と同義である。)、
R^9a、R^9b及びR^9cは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₆アルコキシカルボニル基、ヘテロシクロアルキルオキシ基、又は、-(CH₂)_sNR^d1R^d2(s、R^d1及びR^d2は、前記(0)において示された定義と同義である。)である。}である、
ヘテロ芳香族アミド誘導体又はその塩からなる前記(7)から(9)のいずれか1つに記載の医薬。

{In the formula,
Ring C is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ² is a single bond, -CH = CH-, -C ≡ C ^{-,-(CR 10a R 10b} ) _r1 (CR ^10c R ^10d ) _r2 (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- , -(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 O (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 S (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- or
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- and (R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^10f , R ^10g , R ^10h , r1, r2, r3, r4 and R ^c are synonymous with the definitions given in (0) above),
R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, respectively. C ₁ -C ₆ haloalkoxy group, C ₁ -C ₆ alkoxycarbonyl group, heterocycloalkyloxy group, or-(CH ₂ ) _s NR ^d1 R ^d2 (s, R ^d1 and R ^d2 are the above (0). It is synonymous with the definition shown in.). },
The medicament according to any one of (7) to (9) above, which comprises a heteroaromatic amide derivative or a salt thereof.

(11) In the general formula (I-E2),
X ¹ -X ² is NC,
Y ¹ , Y ² , Y ³ and Y ⁴ together,
-CH ₂ CR ^4a HOCH _2- , -CH ₂ CR ^4a HCH ₂ CH _2- , -CH ₂ CR ^4a R ^4b CH ₂ CH _2- ,
-CH ₂ CH ₂ NR ^4c CH _2- , -CH ₂ CR ^4a HNR ^4c CH _2- , or -CH ₂ CR ^4a HNHCH _2- (R ^4a , R ^4b and R ^4c are described in (0) above. It is synonymous with the definition given in),
The pharmaceutical according to (7) consisting of heteroaromatic amide derivative or a salt thereof ^{(wherein, Y 1, Y 2, Y} 3 and Y ^{4 _{together, -CH 2 CR 4a HCH 2 CH}} 2 - to form If R ² is a hydrogen atom, R ^4a is a group represented by the general formula (IB), and L ² is a single bond, then ring C is not a phenyl ring, or ring C is. If it is a phenyl ring, X ¹ -X ² is CN.).

(12) In the general formula (I-E2),
Z ² -Z ³ is -CH ₂ O-,
The above (7) or (11), which comprises a heteroaromatic amide derivative or a salt thereof, wherein ^{R 6a} , R ^6b and R ^11c are hydrogen atoms, respectively, and R ^{11a is a hydrogen atom or a halogen atom.} Medicine.

(13) In the general formula (I-E2),
X ¹ -X ² is NC,
Y ¹ , Y ² , Y ³ and Y ⁴ together,
-CH ₂ CR ^4a HOCH _2- , -CH ₂ CR ^4a HCH ₂ CH _2- , -CH ₂ CH ₂ NR ^4c CH _2- ,
Forming -CH ₂ CR ^4a HNR ^4c CH _2- or-or -CH ₂ CR ^4a _{HNHCH 2-}
R ^4a and R ^4c may be independently substituted with halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, hydroxyl group, C _1- C ₆ alkyl group, C _1- C ₆ haloalkyl, respectively. It may be substituted with a group or a hydroxyl group. It may be substituted with a C _1- C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or a C _1- C ₄ haloalkoxy group. C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl groups, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl groups, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ Alkoxy-C ₁ -C ₄ Haloalkyl groups, C ₁ -C ₆ alkylcarbonyl groups, C ₁ -C ₆ alkoxycarbonyl groups, C ₁ -C ₆ haloalkylcarbonyl groups, C ₃ -C ₇ cycloalkyl groups, halogen atoms or C ₁ -C ₄ optionally substituted with a haloalkyl group C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ Alkoxyoxy-C _1- C ₄ Alkoxy group, optionally substituted with halogen atom C ₂ -C ₆ Alkoxyoxy-C ₁ -C ₄ Alkoxy group, C _2- C ₆ Alkinyl group, halogen atom or methoxy group in optionally substituted C ₂ -C ₆ alkynyl group, C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkoxy groups, C ₁ - C ₆ Alkoxy Group, C ₁ -C ₆ Halo Alkoxy Group, C ₁ -C ₄ Alkoxy-C ₁ -C ₄ Alkoxy Group, C ₁ -C ₄ Halo Alkoxy-C ₁ -C ₄ Alkoxy Group,-(CH ₂ ) _q NR ^b1 R ^b2 (q, R ^b1 and R ^b2 are synonymous with the definitions given in (0) above) or the general formula (IB).

{式中、
環Cは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L²は、単結合、-CH=CH-、-C≡C-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2O(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2NR^c(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2CO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2S(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、又は、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2SO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-であり(R^10a、R^10b、R^10c、R^10d、R^10e、R^10f、R^10g、R^10h、r1、r2、r3、r4及びR^cは、前記(0)において示された定義と同義である。)、
R^9a、R^9b及びR^9cは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₆アルコキシカルボニル基、ヘテロシクロアルキルオキシ基、又は、-(CH₂)_sNR^d1R^d2(s、R^d1及びR^d2は、前記(0)において示された定義と同義である。)である。}である、
ヘテロ芳香族アミド誘導体又はその塩からなる前記(7)、(11)、(12)のいずれか1つに記載の医薬。

{In the formula,
Ring C is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ² is a single bond, -CH = CH-, -C ≡ C ^{-,-(CR 10a R 10b} ) _r1 (CR ^10c R ^10d ) _r2 (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- , -(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 O (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 S (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- or
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- and (R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^10f , R ^10g , R ^10h , r1, r2, r3, r4 and R ^c are synonymous with the definitions given in (0) above),
R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, respectively. C ₁ -C ₆ haloalkoxy group, C ₁ -C ₆ alkoxycarbonyl group, heterocycloalkyloxy group, or-(CH ₂ ) _s NR ^d1 R ^d2 (s, R ^d1 and R ^d2 are the above (0). It is synonymous with the definition shown in.). },
The medicament according to any one of (7), (11), and (12) above, which comprises a heteroaromatic amide derivative or a salt thereof.

(14) In the general formula (I-E2),
R ^11b is a hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group. , C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, optionally substituted with dimethylaminocarbonyl group or dimethylamino group C ₁ -C ₄ alkoxy -C ₁ - C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl Group, C _1- C ₆ Alkoxy carbonyl group, C ₂ -C ₆ Alkoxy group, C ₂ -C ₆ Alkoxy group, C ₂ -C ₆ Alkoxy group optionally _{substituted with halogen atom, C 1} -C _{6 Alkoxy group} Group, C ₁ -C ₆ haloalkylthio group,-(CH ₂ ) _p NR ^a1 R ^a2 (p, R ^a1 and R a ² are synonymous with the definitions given in (0) above), or general. Equation (IA)

{式中、
環Bは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、卜リアゾリル、テトラゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L¹は、単結合、-CH₂-、-CH₂O-、-OCH₂-、-CH₂CH₂-、又は、-CH₂OCH₂-であり、
R^8a、R^8b及びR^8cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₃-C₇シクロアルキル基、C₃-C₇シクロアルキルオキシ基、ヘテロシクロアルキル基、ヘテロシクロアルキルオキシ基、C₂-C₆アルケニル基、又は、C₂-C₆アルキニル基である。｝で表される基である、ヘテロ芳香族アミド誘導体又はその塩からなる前記(7)から(13)のいずれか1つに記載の医薬。

{In the formula,
Ring B is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, pyrazil, tetrazolyl, pyridyl, pyrazil. , Pyridadinyl, or pyrimidinyl,
L ¹ represents a single _{bond, -CH 2 -, - CH 2} O -, - OCH 2 -, - CH 2 CH 2 -, or, -CH ₂ OCH ₂ - and is,
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₃ -C ₇ cycloalkyloxy group, heterocycloalkyl group, heterocycloalkyloxy group, C _2- C ₆ alkoxy group, or C _2- It is a C ₆ alkylyl group. } The pharmaceutical according to any one of (7) to (13) above, which comprises a heteroaromatic amide derivative or a salt thereof, which is a group represented by.

(15) The compound represented by the general formula (I-E2) (the asterisk (*) shown in the structural formula means that the corresponding asymmetric carbon has a single solid. Numerical values are examples. With respect to the notation of "isomer A", "isomer B", "isomer C" and "isomer D", among a plurality of compounds indicated by the same example numbers, the high-speed liquid chromatograph in the examples. (Identified by the notation of "isomer A", "isomer B", "isomer C" and "isomer D", in order from the isomers previously sorted by imaging).

のいずれかであるヘテロ芳香族アミド誘導体又はその塩からなる前記(7)に記載の医薬。

The medicament according to (7) above, which comprises a heteroaromatic amide derivative or a salt thereof.

(16) The medicament according to any one of (1) to (15) above, which is a prophylactic or therapeutic agent for a disease related to voltage-gated sodium channel Nav1.7.

(17) The drug according to any one of (1) to (15) above, which is a prophylactic or therapeutic agent for painful diseases, pruritus-related diseases, and autonomic nerve-related diseases.
(18) The drug according to any one of (1) to (15) above, which is a preventive or therapeutic agent for a painful disease.
(19) The drug according to any one of (1) to (15) above, which is an analgesic.
(20) The medicament according to any one of (1) to (15) above, which is a prophylactic or therapeutic agent for nociceptive pain or neuropathic pain.
(21) Use of a heteroaromatic amide derivative or a salt thereof contained in any one of the above-mentioned (1) to (15) drugs for producing a drug for use in the prevention or treatment of pain.
(22) Use of a heteroaromatic amide derivative or a salt thereof contained in any one of the above-mentioned (1) to (15) pharmaceuticals for producing an analgesic.

The medicament comprising the heteroaromatic amide derivative of the present invention or a salt thereof has a strong Nav1.7 inhibitory activity and is therefore useful as a therapeutic agent and / or a preventive agent for various diseases associated with Nav1.7. For example, it is useful as an analgesic for various painful diseases.
The medicament consisting of the heteroaromatic amide derivative of the present invention or a salt thereof has little concern about side effects derived from Nav1.5, and is useful as a therapeutic agent and / or a preventive agent for a wide range of pathological conditions in which Nav1.7 is involved.
The compounds described in Patent Documents 3 to 15 are significantly different in structure from the heteroaromatic amide derivative contained in the medicament of the present invention or a salt thereof.
Further, Patent Document 16, Patent Document 17, and Non-Patent Document 10 do not describe sodium channels, let alone compounds having selectivity for Nav1.5 and selective Nav1.7 inhibitory action. There is no description or suggestion about.

The present invention will be described in more detail below.
First, a substituent that the heteroaromatic amide derivative or a salt thereof contained in the medicament of the present invention may have will be described.

Specific examples of the "halogen atom" are a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
"C _1- C ₆ alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, tert-pentyl group, 3-methylbutyl group (isopentyl group), neopentyl group, n-hexyl group, 3,3-dimethyl Butyl groups and the like can be mentioned.
The "C _1- C ₄ alkyl group" means a linear or branched alkyl group having 1 to 4 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, and an n-butyl group. Group etc. can be mentioned.
The "C _1- C ₆ haloalkyl group" means an _{alkyl group in which one or more of the hydrogen atoms of the "C 1-} C ₆ alkyl group" is substituted with a halogen atom, and as a specific example, mono. Fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 1-fluoroethyl group, 1,1-difluoroethyl group Group, 3,3,3-trifluoropropyl group, 3,3-difluoropropyl group, 2-fluoroisopropyl group, 2,3,3,3-tetrafluoropropyl group, 2,2,3,3-tetrafluoro Propyl group, 2,2,3,3,3-pentafluoropropyl group, 1,1,2,2,3,3,3-heptafluoropropyl group, 1,1,1,3,3,3-hexa Fluoroisopropyl group, 4,4,4-trifluorobutyl group, 2,2,3,4,4-pentafluorobutyl group, 2,2,3,4,4,4-hexafluorobutyl group, 2,2 , 3,3,4,4,4-Heptafluorobutyl group, 3,3-difluorobutyl group, 3,3,3-trifluoro-2- (trifluoromethyl) -propyl group, 3-fluoro-3- Methylbutyl group and the like can be mentioned.
The "C _1- C ₄ haloalkyl group" means an alkyl group in which one or more of the hydrogen atoms of the _{"C 1-} C _{4 alkyl group" is substituted with a halogen atom.}

The "C _1- C ₆ alkoxy group" means an alkoxy group in which the alkyl moiety is _{synonymous with the "C 1-} C ₆ alkyl group", and specific examples thereof include a methoxy group, an ethoxy group, and an n-propoxy. Group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, n-pentyloxy group, tert-amyloxy group, 3-methylbutoxy group, neopentyloxy group, n-hexyloxy The group etc. can be mentioned.
The "C _1- C ₄ alkoxy group" means an alkoxy group in which the alkyl moiety is synonymous with the _{"C 1-} C _{4 alkyl group".}
The "C _1- C ₆ haloalkoxy group" means a haloalkoxy group in which the haloalkyl moiety is _{synonymous with the "C 1-} C ₆ haloalkyl group", and specific examples thereof include a trifluoromethoxy group and a difluoromethoxy group. Group, 2-fluoroethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 3,3,3-trifluoropropoxy group, 2,2,3,3-tetrafluoropropoxy group , 2,2,3,3,3-pentafluoropropoxy group, 1,1,1,3,3,3-hexafluoroisopropoxy group, 2,2,3,4,4,4-hexafluorobutoxy group And so on.
The "C _1- C ₄ haloalkoxy group" means a haloalkoxy group in which the haloalkyl moiety is synonymous with the _{"C 1-} C _{4 haloalkyl group".}

The "C _1- C ₄ alkoxy-C _1- C ₄ alkyl group" is the "C ₁ -C ₄ alkyl group" _{substituted with the "C 1} -C ₄ alkoxy group", and these can be substituted. Can be combined at all positions. Specific examples include methoxymethyl group, ethoxymethyl group, isopropoxymethyl group, n-propoxymethyl group, tert-butoxymethyl group, isobutoxymethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 1-ethoxy. Ethyl group, isobutoxyethyl group, tert-butoxyethyl group and the like can be mentioned.
The "C _1- C ₄ haloalkoxy-C _1- C ₄ alkyl group" is the "C ₁ -C ₄ alkyl group" _{substituted with the "C 1} -C ₄ haloalkoxy group", and these are Can be combined at all replaceable positions. Specific examples include trifluoromethoxymethyl group, difluoromethoxymethyl group, monofluoromethoxymethyl group, 2,2,2-trifluoroethoxymethyl group, 2,2-difluoroethoxymethyl group, and 3,3,3-tri. Fluoropropoxymethyl group, 4,4,4-trifluorobutoxymethyl group, 1,1,1,3,3,3-pentafluoroisopropoxymethyl group, 3,3,3-trifluoro-2- (trifluoro) Methyl) -propoxymethyl group, 2- (trifluoromethoxy) ethyl group, 2- (difluoromethoxy) ethyl group, 2- (2', 2', 2'-trifluoroethoxy) ethyl group, 2- (2' , 2'-difluoroethoxy) ethyl group, 2- (1', 1', 1', 3', 3', 3'-pentafluoroisopropoxy) ethyl group, 3- (trifluoromethoxy) propyl group, 3 -(Difluoromethoxy) propyl group, 3- (2', 2', 2'-trifluoroethoxy) propyl group, 3- (2', 2'-difluoroethoxy) propyl group, 3- (1', 1' , 1', 3', 3', 3'-pentafluoroisopropoxy) propyl group and the like.
The "C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group" is the "C ₁ -C ₄ haloalkyl group" _{substituted with the "C 1} -C ₄ alkoxy group", and these can be substituted. Can be combined at all positions. Specific examples include an ethoxymonofluoromethyl group and the like.
The "C _1- C ₄ haloalkoxy-C _1- C ₄ haloalkyl group" is the "C ₁ -C ₄ haloalkyl group" _{substituted with the "C 1} -C ₄ haloalkoxy group". Can be combined at all replaceable positions.

The "C _1- C ₆ alkylcarbonyl group" means an alkylcarbonyl group whose alkyl moiety is the "C _1- C ₆ alkyl group", and specific examples thereof include a methylcarbonyl group, an ethylcarbonyl group, and n. -A propylcarbonyl group and the like can be mentioned.
The "C _1- C ₆ alkoxycarbonyl group" means an alkoxycarbonyl group whose alkoxy moiety is the "C ₁ -C ₆ alkoxy group", and specific examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and n. -Propoxycarbonyl group, tert-butoxycarbonyl and the like can be mentioned.
The "C _1- C ₆ alkylcarbonyloxy group" means an alkylcarbonyloxy group whose alkylcarbonyl moiety is the above-mentioned "C _1- C ₆ alkylcarbonyl group", and specific examples thereof include a methylcarbonyloxy group. Ethylcarbonyloxy group, n-propylcarbonyloxy group and the like can be mentioned.
The "C _1- C ₆ haloalkylcarbonyl group" means a haloalkylcarbonyl group whose haloalkyl moiety is the "C _1- C ₆ haloalkyl group", and specific examples thereof include a trifluoromethylcarbonyl group. ..
The "C _1- C ₆ haloalkoxycarbonyl group" means a haloalkoxycarbonyl group whose haloalkoxy moiety is the "C _1- C ₆ haloalkoxy group".
The "C _1- C ₆ haloalkylcarbonyloxy group" means a haloalkylcarbonyloxy group whose haloalkylcarbonyl moiety is the "C _1- C ₆ haloalkylcarbonyl group".

The "C _3- C ₇ cycloalkyl group" represents a monocyclic saturated carbocyclic group having 3 to 7 carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like.

The "monocyclic saturated heterocycle" is a 3- to 7-membered saturated monocyclic ring containing at least one oxygen atom, nitrogen atom or sulfur atom, and specific examples thereof include aziridine, azetidine, pyrrolidine, and the like. Examples thereof include piperidine, piperazine, azepane, oxetane, tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine and the like.
The "heterocycloalkyl group" represents a monocyclic saturated heterocyclic group, and is a group in which _{at least one carbon atom of the "C 3-} C ₇ cycloalkyl group" is replaced with an oxygen atom, a nitrogen atom or a sulfur atom. be. Specific examples of the "heterocycloalkyl group" include an azetidinyl group, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholino group and the like.

The "C _3- C ₇ cycloalkyloxy group" means a cycloalkyloxy group in which the cycloalkyl moiety is the "C _3- C ₇ cycloalkyl group".
The "heterocycloalkyloxy group" means a heterocycloalkyloxy group in which the heterocycloalkyl moiety is the "heterocycloalkyl group".

"C _2- C ₆ alkenyl group" means a linear or branched alkenyl group having 2 to 6 carbon atoms having one or more double bonds. The position of the double bond is not particularly limited. Specific examples include a vinyl group, an allyl group, a 1-propenyl group, a 2-propenyl group, an isopropenyl group, an isobutenyl group, a 3-methyl-3-butenyl group and the like.
The "C _2- C ₆ alkenyloxy group" means an alkenyloxy group in which the alkenyl moiety is the above-mentioned "C _2- C ₆ alkenyl group", and specific examples thereof include a vinyloxy group, an aryloxy group, and 1-butenyloxy. Groups, 2-butenyloxy groups, 3-butenyloxy groups and the like can be mentioned.
The "C _2- C ₆ alkenyloxy-C _1- C ₄ alkyl group" is the "C _1- C ₄ alkyl group" _{substituted with the "C 2-} C ₆ alkenyloxy group", and these are Can be combined at all replaceable positions. For example, a vinyloxymethyl group, an aryloxymethyl group and the like can be mentioned.
The "C _2- C ₆ alkenyloxy-C _1- C ₄ haloalkyl group" is the above-mentioned "C _1- C ₄ haloalkyl group" _{substituted with the above "C 2-} C ₆ alkenyloxy group", and these are Can be combined at all replaceable positions.

"C _2- C ₆ alkynyl group" means a linear or branched alkynyl group having 2 to 6 carbon atoms having one or more triple bonds. The position of the triple bond is not particularly limited. Specific examples include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 3-methyl-1-butynyl group and the like.
The "C _2- C ₆ alkynyloxy group" means an alkynyloxy group in which the alkynyl moiety is the "C _2- C ₆ alkynyl group".
The "C _2- C ₆ alkynyloxy-C _1- C ₄ alkyl group" is the "C _1- C ₄ alkyl group" _{substituted with the "C 2-} C ₆ alkynyl oxy group". Can be combined at all replaceable positions.
The "C _2- C ₆ alkynyloxy-C _1- C ₄ haloalkyl group" is the above-mentioned "C ₁ -C ₄ haloalkyl group" _{substituted with the above "C 2-} C ₆ alkynyloxy group", and these are Can be combined at all replaceable positions.

The "C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkoxy group", those wherein the "C ₁ -C ₄ alkoxy group", "C ₁ -C ₄ alkoxy group" is substituted, it can be substituted Can be combined at all positions.
The "C _1- C ₄ haloalkoxy-C _1- C ₄ alkoxy group" is the "C ₁ -C ₄ alkoxy group" _{substituted with the "C 1} -C ₄ haloalkoxy group", and these are Can be combined at all replaceable positions. Specific examples include 2- (trifluoromethoxy) ethoxy group and the like.
The "C _2- C ₆ alkenyloxy-C _1- C ₄ alkoxy group" is the "C ₁ -C ₄ alkoxy group" _{substituted with the "C 2-} C ₆ alkoxy oxy group", and these are Can be combined at all replaceable positions.
The "C _2- C ₆ alkynyloxy -C ₁ -C ₄ alkoxy group" is the "C ₁ -C ₄ alkoxy group" _{replaced with the "C 2-} C ₆ alkynyl oxy group". Can be combined at all replaceable positions. For example, an aryloxymethoxy group and the like can be mentioned.
The "C _2- C ₆ alkenyloxy-C _1- C ₄ haloalkoxy group" is the "C _1- C ₄ haloalkoxy group" replaced with the "C _2- C _{6 alkenyloxy group".} These can be combined at all substitutable positions.
The "C _2- C ₆ alkynyloxy-C _1- C ₄ haloalkoxy group" is the "C _1- C ₄ haloalkoxy group" replaced with the "C _2- C _{6 alkynyloxy group".} These can be combined at all substitutable positions.

The "C _1- C ₆ alkyl thio group" means an alkyl thio group whose alkyl moiety is _{synonymous with the above "C 1} -C ₆ alkyl group", and specific examples thereof include a methyl thio group, an ethyl thio group and an n-propyl thio. Examples include a group, an isopropylthio group, an n-butylthio group and the like.
The "C _1- C ₄ alkyl thio group" means an alkyl thio group whose alkyl moiety is _{synonymous with the "C 1} -C ₄ alkyl group".
The "C _1- C ₆ haloalkylthio group" means an alkylthio group in which one or more of the hydrogen atoms of the _{"C 1-} C _{6 alkylthio group" is substituted with a halogen atom.} Examples thereof include a trifluoromethylthio group and a 2,2,2-trifluoroethylthio group.
The "C _1- C ₄ haloalkylthio group" means an alkylthio group in which one or more of the hydrogen atoms of the _{"C 1-} C _{4 alkylthio group" is substituted with a halogen atom.}
The "C _1- C ₄ alkylthio-C _1- C ₄ alkyl group" is the "C ₁ -C ₄ alkyl group" _{substituted with the "C 1} -C ₄ alkyl thio group", and these are substitutable. Can be combined at all positions.
The "C _1- C ₄ haloalkylthio-C _1- C ₄ alkyl group" is the "C ₁ -C ₄ alkyl group" _{substituted with the "C 1} -C ₄ haloalkyl thio group". Can be combined at all replaceable positions. Specific examples include a trifluoromethylthiomethyl group, a ((2', 2', 2'-trifluoroethyl) thio) methyl group, a 2-((trifluoromethyl) thio) ethyl group, and a 2-((2'). , 2', 2'-trifluoroethyl) thio) ethyl group and the like.
The "C _1- C ₄ alkylthio-C _1- C ₄ haloalkyl group" is the "C ₁ -C ₄ haloalkyl group" _{substituted with the "C 1} -C ₄ alkyl thio group", and these are substitutable. Can be combined at all positions.
The "C _1- C ₄ haloalkylthio-C _1- C ₄ haloalkyl group" is the "C ₁ -C ₄ haloalkyl group" _{substituted with the "C 1} -C ₄ haloalkyl thio group". Can be combined at all replaceable positions.
The "C _1- C ₆ alkyl sulfonyl group" is the above-mentioned "C _1- C ₆ alkyl group" substituted with a sulfonyl group, and these can be bonded at all substitutable positions.

The "C _3- C ₇ cycloalkyl-C _1- C ₄ alkyl group" is the "C ₁ -C ₄ alkyl group" _{substituted with the "C 3} -C ₇ cycloalkyl group", and these are Can be combined at all replaceable positions. Specific examples include a cyclopropylmethyl group and the like.
The "heterocycloalkyl-C _1- C ₄ alkyl group" is the "C _1- C ₄ alkyl group" substituted with the "heterocycloalkyl group", and these are bonded at all substitutable positions. Can be done. Specific examples include an oxetanylmethyl group, a pyrrolidinylmethyl group, a morpholinomethyl group and the like.
The "aralkyl group" is the above-mentioned "C _1- C ₆ alkyl group" substituted with a phenyl group, a 5-membered heteroaryl group, or a 6-membered heteroaryl group. These can be combined at all substitutable positions. Specific examples include a benzyl group and a phenethyl group.

A "5-membered ring heteroaryl" is a 5-membered monocyclic aromatic heterocycle containing one or more (for example, 1 to 4) heteroatoms selected from nitrogen, sulfur, and oxygen atoms in addition to carbon atoms. Represents. Specific examples include pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, oxadiazole, triazole, tetrazole and the like.
The "5-membered ring heteroaryl group" is a group of the "5-membered ring heteroaryl", and specific examples thereof include a pyrrolyl group (for example, 2-pyrrolill group) and a frill group (for example, 3-furyl group). , Thienyl group (eg, 2-thienyl group), imidazolyl group (eg, 4-imidazolyl group), pyrazolyl group (eg, 3-pyrazolyl group) and the like.
The "6-membered ring heteroaryl" represents a 6-membered monocyclic aromatic heterocyclic ring containing one or more nitrogen atoms (for example, 1 to 3) in addition to the carbon atom. Specific examples include pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like.
The "6-membered ring heteroaryl group" is a group of the "6-membered ring heteroaryl", and specific examples thereof include a pyridyl group (for example, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group). Examples thereof include a pyridazinyl group (for example, 3-pyridazinyl group), a pyrimidinyl group (for example, 5-pyrimidinyl group), a pyrazinyl group (for example, 2-pyrazinyl group) and the like.

In the present specification, unless otherwise specified, the term "monocyclic ring" includes a monocyclic saturated carbocycle, a monocyclic partially saturated carbocycle, a monocyclic unsaturated carbocycle, and a monocyclic saturated heterocycle. Includes all monocyclic partially saturated heterocycles, monocyclic unsaturated heterocycles, and monocyclic aromatic rings.
Unless otherwise specified, the "bicyclic ring" in the present specification includes a bicyclic saturated carbocycle, a bicyclic partially saturated carbocycle, a bicyclic unsaturated carbocycle, a bicyclic saturated heterocycle, and two. Includes all cyclic partially saturated heterocycles, bicyclic unsaturated heterocycles, and bicyclic aromatic rings.

Next, the meaning of the substituent with the word "may be substituted" in the present specification will be described. In addition, "substitution" means that one or more hydrogen atoms at arbitrary positions are substituted with atoms or functional groups other than hydrogen atoms, unless otherwise specified.
The medicine of the present invention is a medicine comprising a heteroaromatic amide derivative represented by the general formula (I) or a salt thereof. That is, the medicament of the present invention comprises a heteroaromatic amide derivative represented by the general formula (I) or a salt thereof alone, or these components and a pharmacologically acceptable solid or liquid pharmaceutical carrier. It is a pharmaceutical composition comprising.
Further, the medicament of the present invention may be a pharmaceutical composition containing a component having medicinal activity other than the heteroaromatic amide derivative represented by the general formula (I) or a salt thereof.

In the general formula (I) or the general formula (I-E2), "optionally substituted C _1- C ₆ alkyl group" and "optionally substituted C _1- C ₆ haloalkyl group ^{" in R 2} , "C _2- C ₆ Alkenyl Group May Be Substituted", "C ₂ -C ₆ Alkinyl Group May Be Substitutable", "Saturated, Partially Saturated or Unsaturated Group May Be Substitutable 3" The substituents of "~ 7-membered monocyclic ring" are halogen atom, cyano group, carboxyl group, carboxamide group, hydroxyl group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ Alkoxy group, C _1- C ₄ haloalkoxy group, C _3- C ₇ cycloalkyl group, heterocycloalkyl group, C _3- C ₇ cycloalkyloxy group, heterocycloalkyloxy group, C _1- C ₄ alkylthio group, C ₁ -C ₄ haloalkylthio group and -NR ^d1 R ^d2 (R ^d1 and R ^d2 are independently hydrogen atoms, C ₁ -C ₄ alkyl groups, or C ₁ -C ₄ haloalkyl groups, respectively. ) Represents a substituent selected from the group. These can be replaced one or more at all replaceable positions.

In the general formula (I) or the general formula (I-E2), in R ^3a , R ^3b , R ^3c , R ^11b and R ^11c , " _{optionally substituted C 1-} C ₆ alkyl group", "substituted" which may be C ₁ -C ₆ haloalkyl group "," optionally substituted C ₁ -C ₆ alkoxy group "," optionally substituted C ₁ -C ₆ haloalkoxy group "," optionally substituted which may be C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group "," optionally substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group "," optionally substituted C ₁ -C ₄ Alkoxy-C ₁ -C ₄ Haloalkyl groups "," May be substituted C ₁ -C ₄ Alkoxy -C ₁ -C ₄ Haloalkyl groups "," May be substituted C _1- C ₆ alkylcarbonyl group "," optionally substituted C ₁ -C ₆ alkoxycarbonyl group "," optionally substituted C ₁ -C ₆ alkylcarbonyloxy group "," optionally substituted C ₁ -C ₆ haloalkylcarbonyl group "," _{optionally substituted C 1} -C ₆ haloalkoxycarbonyl group "," optionally substituted C ₁ -C ₆ haloalkylcarbonyloxy group "," substituted May be C _{3 -C 7} cycloalkyl group, "may be substituted heterocycloalkyl group", "may be substituted C ₃ -C ₇ cycloalkyloxy group", "may be substituted" heterocycloalkyl group "," optionally substituted C ₂ -C ₆ alkenyl group "," optionally substituted C ₂ -C ₆ alkenyloxy group "," optionally substituted C ₂ - C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group "," May Substituted C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Halo Alkoxy Group "," May Substituted C ₂ -C _{6 "} Alkoxy group "," optionally substituted C _2- C ₆ alkylyloxy group "," optionally substituted C _2- C ₆ alkylyloxy -C ₁ -C ₄ alkyl group "," substituted May be C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ haloalkyl groups "," _{optionally substituted C 1} -C ₄ alkoxy -C ₁ -C ₄ alkoxy groups "," optionally substituted C ₁ -C ₄ Halo Alkoxy Shi -C ₁ -C ₄ alkoxy group "," optionally substituted C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ alkoxy group "," optionally substituted C ₂ -C ₆ alkynyloxy - "C ₁ -C ₄ alkoxy group", "optionally C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ haloalkoxy group", "optionally C ₂ -C ₆ alkynyloxy-C" _1- C ₄ haloalkoxy groups "," optionally substituted C _1- C ₆ alkylthio groups "," optionally substituted C ₁ -C ₆ haloalkylthio groups "," optionally substituted C _1- C ₄ Alkylthio-C ₁ -C ₄ Alkyl Group "," May Substituted C ₁ -C ₄ Haloalkylthio -C ₁ -C ₄ Alkyl Group "," May Substituted C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl group "," optionally substituted C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group "," optionally substituted C ₁ -C ₆ alkylsulfonyl The "group" substituents are halogen atom, cyano group, carboxyl group, carboxamide group, hydroxyl group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, C ₁ -C. ₄ Haloalkoxy groups, C _3- C ₇ cycloalkyl groups, heterocycloalkyl groups, C _3- C ₇ cycloalkyloxy groups, heterocycloalkyloxy groups, C _1- C ₄ alkylthio groups, C _1- C ₄ haloalkylthio groups Group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, ethylmethylamino group, (2,2,2-trifluoroethyl) amino group, methyl (2,2,2-trifluoroethyl) amino group , Ethyl (2,2,2-trifluoroethyl) amino group, bis (2,2,2-trifluoroethyl) amino group, methylaminocarbonyl group, dimethylaminocarbonyl group, ethylaminocarbonyl group, diethylaminocarbonyl group and Represents a substituent selected from the group consisting of ethylmethylaminocarbonyl groups. These can be replaced one or more at all replaceable positions.

In the general formula (I) or the general formula (I-E2), in R ^4a , R ^4b or R ^4c , " _{optionally substituted C 1-} C ₆ alkyl group", "optionally substituted C _1". -C ₆ haloalkyl group "," _{optionally substituted C 1} -C ₆ alkoxy group "," optionally substituted C ₁ -C ₆ haloalkoxy group "," optionally substituted C _1- C ₄ alkoxy -C ₁ -C ₄ alkyl group "," optionally substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group "," optionally substituted C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl group "," _{optionally substituted C 1} -C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl group "," _{optionally substituted C 1} -C ₆ alkylcarbonyl group " , "May be substituted C ₁ -C ₆ alkoxycarbonyl group", "May be substituted C ₁ -C ₆ alkylcarbonyloxy group", "May be substituted C ₁ -C ₆ alkoxycarbonyl""Oxygroup","C _1- C ₆ haloalkylcarbonyl group which may be substituted", "C ₁ -C ₆ haloalkoxycarbonyl group which may be substituted", "C _1- C which may be substituted" ₆ Haloalkylcarbonyloxy groups, optionally substituted C _3- C ₇ cycloalkyl groups, optionally substituted heterocycloalkyl groups, optionally substituted C _3- C ₇ cyclo alkyl group "," optionally substituted heterocycloalkyl group "," optionally substituted C ₂ -C ₆ alkenyl group "," optionally substituted C ₂ -C ₆ alkenyloxy group , "May be substituted C _2- C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group", "May be Substituted C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Halo Alkoxy Group", "optionally substituted C ₂ -C ₆ alkynyl group", "optionally substituted C ₂ -C ₆ alkynyloxy group", "optionally substituted C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ alkyl group "," _{optionally substituted C 2} -C ₆ alkynyloxy -C ₁ -C ₄ haloalkyl group "," _{optionally substituted C 1} -C ₄ alkoxy-C ₁ -C ₄ Alkoxy group "," substituted May be C _{1 -C 4} haloalkoxy -C ₁ -C ₄ alkoxy group "," may be substituted C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ alkoxy group "," substituted May be C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ alkoxy group "," may be substituted C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ haloalkoxy group "," substituted May be C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ haloalkoxy groups "," optionally substituted C ₁ -C ₆ alkylthio groups "," optionally substituted C ₁ -C ₆ haloalkylthios ""Groups"," _{optionally C 1-} C ₄ alkylthio-C ₁ -C ₄ alkyl groups", " _{optionally C 1-} C ₄ haloalkylthio-C ₁ -C ₄ alkyl groups", "optionally substituted C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl group", the substituent of the "optionally substituted C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group" Halogen atom, cyano group, carboxyl group, carboxamide group, hydroxyl group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, C ₁ -C ₄ haloalkoxy group, C Select from the group consisting of _3- C ₇ cycloalkyl group, heterocycloalkyl group, C _3- C ₇ cycloalkyloxy group, heterocycloalkyloxy group, C _1- C ₄ alkylthio group and C _1- C _{4 haloalkylthio group.} Represents a substituent to be used. These can be replaced one or more at all replaceable positions.

Next, in the heteroaromatic amide derivative of the general formula (I) or the general formula (I-E2) or a salt thereof contained in the medicament of the present invention, preferable atoms, substituents, and rings will be described below. As the heteroaromatic amide derivative, a compound having at least one preferable atom, substituent, or ring is preferable, and a compound having a plurality of preferable atoms, substituents, or rings is more preferable.

Preferred Y ¹ , Y ² , Y ³ and Y ⁴ together,
-OCH ₂ CH ₂ CH _2- , -OCR ^4a HCH ₂ CH _2- , -OCR ^4a R ^4b CH ₂ CH _2-
-OCH ₂ CH _2- , -OCR ^4a HCH _2- , -OCR ^4a R ^4b CH _2- ,
-OCH ₂ CH ₂ CH ₂ CH _2- , -OCR ^4a HCH ₂ CH ₂ CH _2- , -OCR ^4a R ^4b CH ₂ CH ₂ CH _2- ,
-OCH ₂ CR ^4a HCH ₂ CH _2- , -OCH ₂ CR ^4a R ^4b CH ₂ CH _2- ,
-CH ₂ OCH ₂ CH _2- , -CH ₂ OCH ₂ CH ₂ CH _2- , -CH ₂ CH ₂ OCH _2- , -CH ₂ CR ^4a HOCH _2-
-CH ₂ CH ₂ CH ₂ CH _2- , -CH ₂ CR ^4a HCH ₂ CH _2- , -CH ₂ CR ^4a R ^4b CH ₂ CH _2- ,
-CH ₂ CH ₂ CR ^4a HCH _2- , -CH ₂ CH ₂ CR ^4a R ^4b CH _2- ,
-CH ₂ SCH ₂ CH _2- , -CH ₂ SO ₂ CH ₂ CH _2- ,
-NHCH ₂ CH ₂ CH _2- , -NR ^4c CH ₂ CH ₂ CH _2- , -NR ^4c CR ^4a HCH ₂ CH _2- ,
-NHCR ^4a HCH ₂ CH _2- ,
-CH ₂ NR ^4c CH ₂ CH _2- , -CH ₂ NR ^4c CR ^4a HCH _2- , -CH ₂ NHCR ^4a HCH _2- ,
-CH ₂ CH ₂ NR ^4c CH _2- , -CH ₂ CR ^4a HNR ^4c CH _2- , or -CH ₂ CR ^4a HNHCH _2-
Is the case to form
The more preferred Y ¹ , Y ² , Y ³ and Y ⁴ are these together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a R 4b CH 2 CH 2 -
-OCH ₂ CH _2- , -OCR ^4a HCH _2- , -OCR ^4a R ^4b CH _2- ,
-OCH ₂ CH ₂ CH ₂ CH _2- , -OCR ^4a HCH ₂ CH ₂ CH _2- , -OCR ^4a R ^4b CH ₂ CH ₂ CH _2- ,
-OCH ₂ CR ^4a HCH ₂ CH _2- , -OCH ₂ CR ^4a R ^4b CH ₂ CH _2- ,
-CH ₂ OCH ₂ CH _2- , -CH ₂ OCH ₂ CH ₂ CH _2- , -CH ₂ CH ₂ OCH _2- , -CH ₂ CR ^4a HOCH _2-
-CH ₂ CH ₂ CH ₂ CH _2- , -CH ₂ CR ^4a HCH ₂ CH _2- , -CH ₂ CR ^4a R ^4b CH ₂ CH _2- ,
-CH ₂ CH ₂ CR ^4a HCH _2- , -CH ₂ CH ₂ CR ^4a R ^4b CH _2- ,
-CH ₂ SCH ₂ CH _2- , -CH ₂ SO ₂ CH ₂ CH _2- ,
-NHCH ₂ CH ₂ CH _2- , -NR ^4c CH ₂ CH ₂ CH _2- , -NR ^4c CR ^4a HCH ₂ CH _2- ,
-NHCR ^4a HCH ₂ CH _2- ,
-CH ₂ NR ^4c CH ₂ CH _2- , -CH ₂ NR ^4c CR ^4a HCH _2- , -CH ₂ NHCR ^4a HCH _2- ,
-CH ₂ CH ₂ NR ^4c CH _2- , -CH ₂ CR ^4a HNR ^4c CH _2- , or -CH ₂ CR ^4a HNHCH _2-
Is the case of forming.
For example, "Y ¹ , Y ² , Y ³ and Y ⁴ together ^{form -OCR 4a} HCH ₂ CH _2- " means that Y ¹ is -O-. It means that Y ² is -CR ^4a H-, Y ³ is -CH _2- , and Y ⁴ is -CH _2- .

If X ¹ -X ² is CN (ie, X ¹ is a carbon atom and X ² is a nitrogen atom), then the preferred Y ¹ , Y ² , Y ³ and Y ⁴ are together. become,
-OCH ₂ CH ₂ CH _2- , -OCR ^4a HCH ₂ CH _2- , -OCR ^4a R ^4b CH ₂ CH _2- , -OCH ₂ CH _2- ,
_{^{-OCR 4a HCH 2 -, - OCR}} 4a R 4b CH 2 -,
-OCH ₂ CH ₂ CH ₂ CH _2- , -OCR ^4a HCH ₂ CH ₂ CH _2- , -OCH ₂ CR ^4a HCH ₂ CH _2- ,
-CH ₂ OCH ₂ CH _2- , -CH ₂ OCH ₂ CH ₂ CH _2- ,
-CH ₂ CR ^4a HCH ₂ CH _2- , -CH ₂ CR ^4a R ^4b CH ₂ CH _2- , -CH ₂ CH ₂ CR ^4a HCH _2- ,
-NHCH ₂ CH ₂ CH _2- , -NR ^4c CR ^4a HCH ₂ CH _2- , -NHCR ^4a HCH ₂ CH _2- , or -CH ₂ NR ^4c CH ₂ CH _2-
In this case, the more preferred Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a R 4b CH 2 CH 2 -, - OCH 2 CH 2 -,
_{^{-OCR 4a HCH 2 -, - OCR}} 4a R 4b CH 2 -,
-OCH ₂ CH ₂ CH ₂ CH _2- , -OCR ^4a HCH ₂ CH ₂ CH _2- , -OCH ₂ CR ^4a HCH ₂ CH _2- ,
-CH ₂ OCH ₂ CH _2- , -CH ₂ OCH ₂ CH ₂ CH _2- ,
-CH ₂ CR ^4a HCH ₂ CH _2- , -CH ₂ CR ^4a R ^4b CH ₂ CH _2- , -CH ₂ CH ₂ CR ^4a HCH _2- ,
-NHCH ₂ CH ₂ CH _2- , -NR ^4c CR ^4a HCH ₂ CH _2- , -NHCR ^4a HCH ₂ CH _2- , or -CH ₂ NR ^4c CH ₂ CH _2-
In this case, the more preferred Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a R 4b CH 2 CH 2 -, - OCH 2 CH 2 -, - OCR 4a HCH 2 -, - OCR 4a R 4b CH 2 -,
-OCH ₂ CH ₂ CH ₂ CH _2- , -OCR ^4a HCH ₂ CH ₂ CH _2- , -OCH ₂ CR ^4a HCH ₂ CH _2- , -CH ₂ CR ^4a HCH ₂ CH _2- ,
-NR ^4c CR ^4a HCH ₂ CH _2- , -NHCR ^4a HCH ₂ CH _2- , or -CH ₂ NR ^4c CH ₂ CH _2-
Is the case to form
In this case, the even more preferred Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a HCH 2 -,
-OCR ^4a HCH ₂ CH ₂ CH _2- , -CH ₂ CR ^4a HCH ₂ CH _2- ,
-NR ^4c CR ^4a HCH ₂ CH _2- , -NHCR ^4a HCH ₂ CH _2- , or -CH ₂ NR ^4c CH ₂ CH _2-
In this case, the particularly preferred Y ¹ , Y ² , Y ³ and Y ⁴ together,
This is the case when ^{-OCR 4a} HCH ₂ CH _{2-is formed.}
Also, in another aspect of the invention in this case, particularly preferred Y ¹ , Y ² , Y ³ and Y ⁴ are when they together form -CH ₂ NR ^4c CH ₂ CH _2-. be.

If X ¹ -X ² is NC (ie, X ¹ is a nitrogen atom and X ² is a carbon atom), then the preferred Y ¹ , Y ² , Y ³ and Y ⁴ are together. become,
-CH ₂ CH ₂ OCH _2- , -CH ₂ CR ^4a HOCH _2-
-CH ₂ CH ₂ CH ₂ CH _2- , -CH ₂ CR ^4a HCH ₂ CH _2- , -CH ₂ CR ^4a R ^4b CH ₂ CH _2- ,
-CH ₂ CH ₂ NR ^4c CH _2- , -CH ₂ CR ^4a HNR ^4c CH _2- , or -CH ₂ CR ^4a HNHCH _2-
Is the case to form
In this case, the more preferred Y ¹ , Y ² , Y ³ and Y ⁴ together,
-CH ₂ CH ₂ OCH _2- , -CH ₂ CR ^4a HOCH _2- , -CH ₂ CR ^4a HCH ₂ CH _2- ,
-CH ₂ CH ₂ NR ^4c CH _2- , -CH ₂ CR ^4a HNR ^4c CH _2- , or -CH ₂ CR ^4a HNHCH _2-
In this case, the more preferred Y ¹ , Y ² , Y ³ and Y ⁴ together,
-CH ₂ CR ^4a HOCH _2- , -CH ₂ CR ^4a HCH ₂ CH _2- , -CH ₂ CH ₂ NR ^4c CH _2- ,
-CH ₂ CR ^4a HNR ^4c CH _2- or -CH ₂ CR ^4a HNHCH ₂ -is formed.

Z ¹ is preferably a single bond, −CR ^7a R ^7b −, −O−, or −S−, and more preferably a single bond.

Ring A is a 3- to 7-membered monocyclic aromatic ring or an 8- to 12-membered bicyclic aromatic ring.
In one embodiment of the invention, the preferred ring A is a 3- to 7-membered monocyclic aromatic ring, eg, ring A in this case is phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, Thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, pyrimidinyl, tetrazolyl, isothiazolyl, oxadialyl, isoxazolyl, or thiadiazolyl.
In this case, preferably ring A is phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl.
In this case, more preferably, ring A is phenyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl.
In this case, more preferably, ring A is phenyl.

In one embodiment of the invention, the preferred ring A is an 8- to 12-membered bicyclic aromatic ring.
For example, ring A in this case is quinolinyl, isoquinolyl phthalazinyl, naphthyldinyl, quinoxalinyl, quinazolinyl, synnolinyl, benzoimidazolyl, indolyl, isoindrill, benzoxazolinyl, benzofuranyl, isobenzofuranyl, or indazolyl.
In this case, preferably ring A is quinolyl, benzoimidazolyl, indolyl, or benzoxazolinyl.
In this case, more preferably, ring A is 8-quinolyl, 1-benzoimidazolyl, 3-indrill, or 2-benzoxazolinyl.

R ^1a and R ^1b are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, C _1- C ₄ haloalkoxy group, C _3- C ₇ cycloalkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, or C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group.
Preferably, R ^1a and R ^1b are independently hydrogen atoms, halogen atoms, C _1- C ₄ alkyl groups, or C _1- C ₄ haloalkyl groups, respectively.
More preferably, R ^1a and R ^1b are independently hydrogen atoms or halogen atoms, respectively.

R ² is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted C _1- C ₆ alkyl group, an optionally substituted C ₁ -C ₆ haloalkyl group, an optionally substituted C. _{A 2-} C ₆ alkenyl group, an optionally substituted C _2- C ₆ alkynyl group, or an optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring.
Preferably, R ² is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring that may be substituted.
More preferably, R ² is a hydrogen atom or a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring that may be substituted.

In one embodiment of the invention, the preferred R ² is a hydrogen atom, a halogen atom, a hydroxyl group, or a cyano group, with a particularly preferred R ² being a hydrogen atom.

Also, in another aspect of the invention, if R ² is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring that may be ^{substituted, then R 2} may be substituted. A good 3- to 7-membered monocyclic aromatic ring is preferred.

Also, in another aspect of the invention, if R ² is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring that may be substituted.
R ² is preferably a halogen atom, a cyano group, a carboxyl group, a carboxamide group, a hydroxyl group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, a C _1- C ₄ halo. Alkoxy group, C _3- C ₇ cycloalkyl group, heterocycloalkyl group, C _3- C ₇ cycloalkyloxy group, heterocycloalkyloxy group, C _1- C ₄ alkylthio group, C _1- C ₄ haloalkylthio group, Alternatively, even if it is substituted with ^{-NR d1} R ^d2 (R ^d1 and R ^d2 are independently substituted with a hydrogen atom, a C _1- C ₄ alkyl group, or a C ₁ -C _{4 haloalkyl group, respectively).} A good, saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring,
In this case, more preferably, R ² is a halogen atom, a cyano group, a C _1- C ₄ alkyl group, a C _1- C ₄ haloalkyl group, a C _1- C ₄ alkoxy group, a C _1- C ₄ haloalkoxy group. , Or -NR ^d1 R ^d2 (R ^d1 and R ^d2 are independently substituted with a hydrogen atom, a C _1- C ₄ alkyl group, or a C ₁ -C ₄ haloalkyl group, respectively). It is also an unsaturated 3- to 7-membered monocyclic ring.

Also, in another aspect of the invention, if R ² is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring that may be substituted.
R ² is preferably a halogen atom, a cyano group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkoxy group or -NR ^{d1 respectively.} R ^d2 (R ^d1 and R ^d2 are independently substituted with a hydrogen atom, a C _1- C ₄ alkyl group, or a C _1- C ₄ haloalkyl group), phenyl, pyrrolyl, respectively. , Frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, pyrimidinyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, or thiadiazolyl.
In this case, R ² is more preferably a halogen atom, a cyano group, a C _1- C ₄ alkyl group, a C _1- C ₄ haloalkyl group, a C _1- C ₄ alkoxy group, and a C _1- C ₄ haloalkoxy, respectively. Even if it is substituted with a group or -NR ^d1 R ^d2 (R ^d1 and R ^d2 are independent hydrogen atoms, C _1- C ₄ alkyl groups, or C ₁ -C ₄ haloalkyl groups, respectively). Good, phenyl, pyrrolyl, frills, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, pyrimidinyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, or thiadiazolyl.
In this case, R ² is more preferably a halogen atom, a cyano group, a C _1- C ₄ alkyl group, a C _1- C ₄ haloalkyl group, a C _1- C ₄ alkoxy group, and a C _1- C ₄ haloalkoxy, respectively. Even if it is substituted with a group or -NR ^d1 R ^d2 (R ^d1 and R ^d2 are independent hydrogen atoms, C _1- C ₄ alkyl groups, or C ₁ -C ₄ haloalkyl groups, respectively). Good, phenyl, pyrazolyl, lyazolyl, pyridyl, or pyrazinyl,
In this case, R ² is even more preferably a halogen atom, a methyl group, an ethyl group, a trifluoromethyl group, a trifluoromethoxy group, a trifluoroethyl group, a trifluoroethoxy group or -NHR ^d2 (R ^d2 is , Methyl group, ethyl group, trifluoromethyl group, or trifluoroethyl group), phenyl, pyrazolyl, or pyridyl.

Further, in another aspect of the present invention, the preferred R ² _{is a C 1-} C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, which may be substituted with a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a hydroxyl group. C _2- C ₆ alkenyl group or C _2- C ₆ alkynyl group or
Preferred R ² is halogen atom, cyano group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, C ₁ -C ₄ haloalkoxy group or -NR ^d1 R ^d2 ( R ^d1 and R ^d2 may be independently substituted with a hydrogen atom, a C _1- C ₄ alkyl group, or a C _1- C ₄ haloalkyl group), saturated, partially saturated or unsaturated. It is a saturated 3- to 7-membered monocyclic ring.
More preferred R ² is a hydrogen atom, a halogen atom, a hydroxyl group, or a cyano group, or
More preferred R ² are halogen atom, cyano group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, C ₁ -C ₄ haloalkoxy group or -NR ^{d1 respectively.} R ^d2 (R ^d1 and R ^d2 are independently substituted with a hydrogen atom, a C _1- C ₄ alkyl group, or a C _1- C ₄ haloalkyl group), phenyl, pyrrolyl, respectively. , Frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, or thiadiazolyl.

R ^3a , R ^3b and R ^3c are preferably independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, C _1- C ₆ alkyl group, hetero C ₁ -C ₆ alkyl group substituted with Shikurookishi group, C ₁ -C ₆ alkyl substituted with cyano, C ₁ -C ₆ alkyl substituted by a morpholino group, C ₁ -C ₆ haloalkyl group , C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ haloalkoxy groups, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl groups, C substituted by dimethylamino group ₁ -C ₄ alkoxy -C ₁ - C _4- alkyl group, C _1- C ₄ alkoxy-C _1- C ₄ alkyl group substituted with dimethylaminocarbonyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ alkylcarbonyl Oxy group, C ₁ -C ₆ haloalkylcarbonyl group, C ₁ -C ₆ haloalkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyloxy group, C _3- C ₇ cycloalkyl group, heterocycloalkyl group, C _3- C ₇ Cycloalkyloxy Group, Heterocycloalkyloxy Group, C _2- C ₆ Alkoxy Group, C _2- C ₆ Alkoxy Oxy Group, C _2- C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C _2- C ₆ alkenyloxy -C ₁ -C ₄ haloalkyl groups, C ₂ -C ₆ alkynyl group, optionally substituted by a halogen atom C ₂ -C ₆ alkynyl group, C ₂ -C ₆ alkynyloxy group, C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkoxy groups, C ₁ -C ₄ haloalkoxy - C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkinyl Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Haloalkoxy group, C _2- C ₆ alkynyloxy-C ₁ -C ₄ haloalkoxy group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ Alkoxysulfonyl group,-(CH ₂ ) _p NR ^a1 R ^a2 (R ^a1 and R ^a2 are independent hydrogen atoms, C ₁ -C ₄ alkyl groups, or C ₁ -C ₄ It is a haloalkyl group, where p is 0, 1, or 2. ) Or general formula (IA)

{式中、環B、L¹、R^8a、R^8b、R^8cは、前記(0)と同義である。｝で表される基である。

{In the equation, rings B, L ¹ , R ^8a , R ^8b , and R ^8c are synonymous with (0) above. } Is a group represented by.

R ^3a , R ^3b and R ^3c are more preferably independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, C _1- C ₆ alkyl group, respectively. Substituted with C _1- C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, dimethylaminocarbonyl group or dimethylamino group which may be C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl group , C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₂ -C ₆ alkoxy group, C ₂ -C ₆ alkynyl group, even if substituted with halogen atom Good C ₂ -C ₆ Alkoxyyl Group, C ₁ -C ₆ Alkoxy Group, C ₁ -C ₆ Halo Alkoxy Group,-(CH ₂ ) _p NR ^a1 R ^a2 (p, R ^a1 and R a ² are (0) above. It is synonymous with the definition given in) or the general formula (IA).

{式中、
環Bは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L¹は、単結合、-CH₂-、-CH₂O-、-OCH₂-、-CH₂CH₂-、又は、-CH₂OCH₂-であり、
R^8a、R^8b及びR^8cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₃-C₇シクロアルキル基、C₃-C₇シクロアルキルオキシ基、ヘテロシクロアルキル基、ヘテロシクロアルキルオキシ基、C₂-C₆アルケニル基、又は、C₂-C₆アルキニル基である。｝で表される基である。

{In the formula,
Ring B is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ¹ represents a single _{bond, -CH 2 -, - CH 2} O -, - OCH 2 -, - CH 2 CH 2 -, or, -CH ₂ OCH ₂ - and is,
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₃ -C ₇ cycloalkyloxy group, heterocycloalkyl group, heterocycloalkyloxy group, C _2- C ₆ alkoxy group, or C _2- It is a C ₆ alkylyl group. } Is a group represented by.

More preferably, R ^3a , R ^3b and R ^3c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C _1- C ₆ Alkoxy Group, C ₁ -C ₆ Halo Alkoxy Group, C ₁ -C ₄ Alkoxy-C ₁ -C ₄ Alkyl Group, C ₁ -C ₄ Halo Alkoxy -C ₁ -C ₄ Alkyl Group, C ₂ -C ₆ Alkoxy group, C ₂ -C ₆ alkynyl group,-(CH ₂ ) _p NR ^a1 R ^a2 (p is 1, and R ^a1 and R ^a2 are independently hydrogen atom, methyl group, ethyl group, or , 2,2,2-trifluoroethyl group), or general formula (IA)

{式中、
環Bは、C₃-C₇シクロアルキル、モルホリノ、フェニル、ピラゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L¹は、単結合であり、
R^8a、R^8b及びR^8cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、又は、C₁-C₆ハロアルコキシ基である。｝で表される基である。

{In the formula,
Ring B is C _3- C ₇ cycloalkyl, morpholino, phenyl, pyrazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl,
L ¹ is a single bond,
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, or C ₁ -C ₆ Haloalkoxy group. } Is a group represented by.

Even more preferably, R ^3a , R ^3b and R ^3c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group and C ₁ -C _{6 respectively.} It is an alkoxy group or a C _1- C ₆ haloalkoxy group.

R ^4a , R ^4b and R ^4c are preferably independently substituted with halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxyl group, hydroxyl group, C _1- C ₆ alkyl group and hydroxyl group, respectively. May be C _{1 -C 6} alkyl group, C ₁ -C ₆ haloalkyl group, may be substituted with hydroxyl group C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ halo Alkoxy group, may be substituted with _{C 1} -C _{4 haloalkoxy group C 1} -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ Alkoxy-C ₁ -C ₄ Haloalkyl Group, C ₁ -C ₄ Haloalkoxy-C ₁ -C ₄ Haloalkyl Group, C ₁ -C ₆ Alkoxycarbonyl Group, C ₁ -C ₆ Alkoxycarbonyl Group, C ₁ Substituted with -C ₆ alkylcarbonyloxy group, C ₁ -C ₆ haloalkylcarbonyl group, C ₁ -C ₆ haloalkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyloxy group, C ₃ -C ₇ cycloalkyl group, halogen atom which may be C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group, C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, May be substituted with halogen atom C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy -C ₁ -C ₄ haloalkyl groups, C ₂ -C ₆ alkynyl group, optionally substituted with a halogen atom or a methoxy group C ₂ -C ₆ alkynyl group, C ₂ -C ₆ alkynyloxy group, C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkinyloxy -C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Haloalkoxy groups, C _2- C ₆ alkynyloxy-C ₁ -C ₄ haloalkoxy groups, C ₁ -C ₆ alkylthio groups, C ₁ -C ₆ haloalkylthio groups, C ₁ -C ₄ alkylthio-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group , Pentafluorosulfanyl group,-(CH ₂ ) _q NR ^b1 R ^b2 (R ^b1 and R ^b2 are independently hydrogen atoms, C ₁ -C ₄ alkyl groups, or C ₁ -C ₄ haloalkyl groups, respectively. , Q is 0, 1, 2, or 3. ) Or general formula (IB)

{式中、環C、L²、R^9a、R^9b、R^9cは、前記(0)と同義である。}で表される基である。

{In the equation, rings C, L ² , R ^9a , R ^9b , and R ^9c are synonymous with (0) above. } Is a group represented by.

R ^4a, R ^4b and R ^4c are, more preferably, each independently, a halogen atom, a hydroxyl group, a cyano group, C ₁ -C ₆ alkyl group, optionally substituted by hydroxyl C ₁ -C ₆ alkyl group , C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ haloalkyl group optionally substituted with hydroxyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ haloalkoxy group in optionally substituted C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ Haloalkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyl group, C ₃ -C ₇ cycloalkyl group, a halogen atom or a C ₁ -C ₄ optionally C ₃ -C be substituted by haloalkyl group ₇ cycloalkyl group, a heterocycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyl Oxy group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy group, optionally substituted with halogen atom C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy group, C ₂ -C ₆ Alkinyl _{C 2-} C ₆ alkynyl group optionally substituted with group, halogen atom or methoxy group _{, C 2-} C ₆ alkynyloxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ Alkoxy groups, C ₁ -C ₆ alkyl thio groups, C ₁ -C ₆ haloalkyl thio groups, C ₁ -C ₄ alkyl thio-C ₁ -C ₄ alkyl groups, C ₁ -C ₄ halo alkyl thio-C ₁ -C ₄ alkyl Group,-(CH ₂ ) _q NR ^b1 R ^b2 (q, R ^b1 and R ^b2 are synonymous with the definitions given in (0) above), or the general formula (IB).

{式中、
環Cは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L²は、単結合、-CH=CH-、-C≡C-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2O(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2NR^c(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2CO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2S(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、又は、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2SO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-であり(R^10a、R^10b、R^10c、R^10d、R^10e、R^10f、R^10g、R^10h、r1、r2、r3、r4及びR^cは、前記(0)において示された定義と同義である。)、
R^9a、R^9b及びR^9cは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₆アルコキシカルボニル基、ヘテロシクロアルキルオキシ基、又は、-(CH₂)_sNR^d1R^d2(s、R^d1及びR^d2は、前記(0)において示された定義と同義である。)である。}である。

{In the formula,
Ring C is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ² is a single bond, -CH = CH-, -C ≡ C ^{-,-(CR 10a R 10b} ) _r1 (CR ^10c R ^10d ) _r2 (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- , -(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 O (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 S (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- or
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- and (R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^10f , R ^10g , R ^10h , r1, r2, r3, r4 and R ^c are synonymous with the definitions given in (0) above),
R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, respectively. C ₁ -C ₆ haloalkoxy group, C ₁ -C ₆ alkoxycarbonyl group, heterocycloalkyloxy group, or-(CH ₂ ) _s NR ^d1 R ^d2 (s, R ^d1 and R ^d2 are the above (0). It is synonymous with the definition shown in.). }.

In one embodiment of the invention, the preferred R ^4a , R ^4b and R ^4c are independently halogen atoms, hydroxyl groups, cyano groups, C _1- C ₆ alkyl groups, C ₁ -C ₆ haloalkyl groups, C ₁ May be substituted with _{-C 6} alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C _{4 haloalkoxy group C 1} -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkoxy groups, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio - C ₁ -C ₄ alkyl group, or- _{(CH 2} ) _q ^{NR b1} R ^b2 (q, R ^b1 and R ^b2 are synonymous with the definitions given in (0) above).
More preferably, a halogen atom, a cyano group, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl group, C ₁ -C ₄ optionally substituted with a haloalkoxy group C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group, or C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkoxy group.

Further, in another aspect of the present invention, when R ^4a , R ^4b and R ^4c are the groups represented by the general formula (IB), R ^4a , R ^4b and R ^4c are expressed by the following formulas.

(式中、R^9a、R^9b及びR^9cは、前記(0)において示された定義と同義である。)からなる群から選択される置換基が好ましく、
この場合において、R^4a、R^4b及びR^4cは、下記式

(In the formula, R ^9a , R ^9b and R ^9c are synonymous with the definition shown in (0) above.) A substituent selected from the group consisting is preferable.
In this case, R ^4a , R ^4b and R ^4c are given by the following equations.

(式中、R^9a、R^9b及びR^9cは、前記(0)において示された定義と同義である。)からなる群から選択される置換基がより好ましく、
この場合において、R^4a、R^4b及びR^4cは、

(In the formula, R ^9a , R ^9b and R ^9c are synonymous with the definition shown in (0) above.) A substituent selected from the group consisting is more preferable.
In this case, R ^4a , R ^4b and R ^4c are

(式中、R^9a、R^9b及びR^9cは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、又は、C₁-C₆ハロアルコキシ基である。)からなる群から選択される置換基が更に好ましい。

(In the formula, R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C. Substituents selected from the group consisting of ₆ alkoxy groups or C _1- C _{6 haloalkoxy groups) are more preferred.}

Further, in another aspect of the present invention, the preferred R ^4a , R ^4b and R ^4c are independently halogen atoms, hydroxyl groups, cyano groups, C _1- C ₆ alkyl groups, C _1- C ₆ haloalkyl groups, respectively. C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ optionally C ₁ -C be substituted with a haloalkoxy group ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ - C ₄ haloalkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ halo Alkoxythio -C ₁ -C ₄ Alkoxy group,-(CH ₂ ) _q NR ^b1 R ^b2 (q, R ^b1 and R ^b2 are synonymous with the definition given in (0) above), or the following formula.

(式中、R^9a、R^9b及びR^9cは、前記(0)において示された定義と同義である。)からなる群から選択される置換基であり、
より好ましいR^4a、R^4b及びR^4cは、それぞれ独立して、ハロゲン原子、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₄ハロアルコキシ基で置換されていてもよいC₁-C₄アルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルコキシ基、又は、下記式

(In the formula, R ^9a , R ^9b and R ^9c are synonymous with the definition shown in (0) above.)
The more preferred R ^4a , R ^4b and R ^4c are independently substituted with halogen atoms, cyano groups, C _1- C ₆ alkyl groups, C ₁ -C ₆ haloalkyl groups and C ₁ -C ₄ haloalkoxy groups, respectively. May be C _{1 -C 4} alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkoxy group Or, the following formula

(式中、R^9a、R^9b及びR^9cは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、又は、C₁-C₆ハロアルコキシ基である。)からなる群から選択される置換基である。

(In the formula, R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C. It is a substituent selected from the group consisting of ₆ alkoxy groups or C ₁ -C _{6 haloalkoxy groups).}

^{R 5a} , R ^5b , R ^5c , R ^6a , R ^6b and n in each case where the configurations (i) to (v) in (0) above are satisfied will be further described.

When R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy the configuration of (i) in (0) above.
R ^5b and R ^5c together form a single _{bond, -CH 2 O -, - CH} 2 S -, - CH 2 NR e1 -, - CH 2 CH 2 -, or, -CONR ^e1 - to form ( R ^e1 and R ^e2 are synonymous with the definitions given in (0) above) and
R ^5a is a hydrogen atom or a C _1- C ₆ alkyl group, and
R ^6a and R ^6b are independently hydrogen atoms, fluorine atoms, hydroxyl groups, or methoxy groups, respectively.
Compounds in which n is 1 or 2 are preferred.
More preferably, R ^5a , R ^5b , R ^5c , R ^6a and R ^{6b combine} R ^5b and R ^5c to form −CH ₂ O− and R ^5a , R ^6a and R ^6b. However, a compound which is a hydrogen atom and n is 1 is preferable.

When R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy the configuration of (ii) in (0) above.
R ^5a and R ^6a _{together, -CH 2 -, - CH 2} CH 2 -, - CH 2 CR e1 R e2 -, - CH 2 CH 2 CH 2 -, - CH 2 CH 2 O -, - CH ₂ CH ₂ CH ₂ O− is formed (R ^e1 and R ^e2 are synonymous with the definition shown in (0) above), and
R ^5b is a hydrogen atom or a C _1- C ₄ alkyl group,
R ^5c and R ^6b are hydrogen atoms, halogen atoms, hydroxyl groups, C _1- C ₄ alkyl groups, or C _1- C ₄ alkoxy groups.
Compounds with n of 1 are preferred.
More preferably, R ^5a , R ^5b , R ^5c , R ^6a and R ^{6b combine} R ^5a and R ^6a to form −CH ₂ CH ₂ − or −CH ₂ CH ₂ O−, and R ^5b , R ^5c and R ^6b are hydrogen atoms,
Compounds with n of 1 are preferred.

When R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy the configuration of (iii) in (0) above.
R ^5a is a hydrogen atom, C _1- C ₆ alkyl group, C ₃ -C ₇ cycloalkyl group, or heterocycloalkyl group, C ₃ -C ₇ cycloalkyl-C ₁ -C ₄ alkyl group, and ,
R ^5b and R ^5c are hydrogen atoms,
Whether R ^6a and R ^6b are independent hydrogen atoms or halogen atoms, respectively.
Alternatively, R ^6a and R ^6b together with the carbon atoms to which they bond form a 3- to 7-membered monocyclic ring, and
Compounds in which n is 1 or 2 are preferred.

When R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy the configuration of (iv) in (0) above.
R ^5a and R ^5b together form −CH ₂ CH ₂ − or −CH ₂ CH ₂ CH ₂ −, and
R ^5c , R ^6a and R ^6b are hydrogen atoms,
Compounds with n of 1 or 2 are preferred.

When R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy the configuration of (v) in (0) above.
R ^6a and R ^5c together form −OCH ₂ −, −CH ₂ O−, or −CH ₂ CH ₂ −, and
R ^5a is a hydrogen atom and
R ^5b is a hydrogen atom or a halogen atom, and
R ^6b is a hydrogen atom and
Compounds with n of 1 are preferred.

To further explain each case where the configurations (i) to (v) in (0) above are satisfied,
If R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy the configuration of (i) in (0) above ^{, a compound in which Z 1} is a single bond is preferred;
When R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy the configuration of (ii) in (0) above ^{, the compound in which Z 1} is a single bond or −O− preferable;
If R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy the configuration of (iii) in (0) above, then Z ¹ is a single bond, −CR ^7a R ^7b − or −O. Compounds that are-are preferred;
When R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy the configuration of (iv) in (0) above, Z ¹ is a single bond or −CR ^7a R ^7b −. Certain compounds are preferred;
When R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy the configuration of (v) in (0) above, Z ¹ is a single bond or −CR ^7a R ^7b −. Certain compounds are preferred.

In one embodiment of the present invention, the ring A of the compound represented by the general formula (I) is phenyl, Z ¹ is a single bond, and R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n. However, when the configuration of (i) in (0) above is satisfied, the following equation (IE):

［式中、
X¹−X²、Y¹、Y²、Y³、Y⁴、R^1a、R^1b、R²、R^6a、R^6bは、前記(0)において示された定義と同義であり（但し、R²が水素原子の場合は、Y¹、Y²、Y³、又は、Y⁴の少なくとも一つが、−CR^4aR^4b−、−CR^4aH−、−CH₂CR^4aR^4b−、又は、−CH₂CR^4aH−であり（R^4a、R^4bは、前記(0)において示された定義と同義である。）、
Z²−Z³、R^5a、R^11a 、R^11b、R^11cは、前記(7)において示された定義と同義である。］
で表されるヘテロ芳香族アミド誘導体又はその塩からなる医薬は好ましい。

[During the ceremony,
X ¹ −X ² , Y ¹ , Y ² , Y ³ , Y ⁴ , R ^1a , R ^1b , R ² , R ^6a , R ^6b are synonymous with the definitions given in (0) above (however, If R ² is a hydrogen atom, then at least one of ^{Y 1} , Y ² , Y ³ , or Y ^{4 is −CR 4a} R ^4b −, ^{−CR 4a} H−, −CH ₂ CR ^4a R ^4b −, or , -CH ₂ CR ^4a H- (R ^4a and R ^4b are synonymous with the definitions given in (0) above).
Z ² −Z ³ , R ^5a , R ^11a , R ^11b , and R ^11c are synonymous with the definitions given in (7) above. ]
A pharmaceutical consisting of a heteroaromatic amide derivative represented by (1) or a salt thereof is preferable.

In the general formula (IE), ^{the preferred substituents of X 1} −X ² , Y ¹ , Y ² , Y ³ , Y ⁴ , R ^1a , R ^1b , R ² are as described above.

In the general formula (IE) or general formula (I-E2), Z ² -Z ³ is preferably -CH ₂ O- _{, -CH 2} S-, -CH ₂ NR ^f1- , -CH ₂ CH _2- or -CONR ^f1 - a is, (R ^f1 and R ^f2 is hydrogen, or a C ₁ -C ₄ alkyl group.)
More preferably, Z ² -Z ³ forms -CH ₂ O-.

In the general formula (I), the general formula (IE) or the general formula (I-E2), R ^5a is more preferably a hydrogen atom, a C _1- C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, and a C ₃ -C ₇ cycloalkyl group or heterocycloalkyl group,
More preferably, R ^5a is a hydrogen atom.

In the general formula (I-E2), when Z ⁴ is CR ^11a , R ^11a is preferably a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a C _1- C ₆ alkyl group, or a C _1- C ₆ haloalkyl. Group, C ₁ -C ₆ alkoxy group, or C ₁ -C ₆ haloalkoxy group,
More preferably, R ^11a is a hydrogen atom, a halogen atom, a cyano group, a C _1- C ₆ alkyl group, or a C ₁ -C ₆ haloalkyl group.
More preferably, R ^11a is a hydrogen atom.

In the general formula (I-E2), R ^{11b is R 3b} in (0) above, and the preferred substituent thereof is the above-mentioned preferred R ^3b .
In the general formula (I-E2), R ^{11c is R 3c} in the above (0), and the preferred substituent thereof is the above-mentioned preferred R ^3c .

Next, in the heteroaromatic amide derivative represented by the general formula (I), the general formula (IE) or the general formula (I-E2) or a salt thereof contained in the medicament of the present invention, the preferred atom, substituent or ring The combination will be described below.

In one embodiment of the present invention, ^{in a compound having at least one of R 3a} , R ^3b and R ^{3c represented} by the general formula (I) and R ^4a , R ^4b and R ^4c , a preferable combination of these substituents is used. teeth,
R ^3a , R ^3b and R ^3c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxyl group, hydroxyl group, C _1- C ₆ alkyl group, C ₁ -C. _{Even if substituted with 6} haloalkyl groups, C _1- C ₆ alkoxy groups, C ₁ -C ₆ haloalkoxy groups, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl groups, dimethylaminocarbonyl groups or dimethylamino groups good C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ - C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₆ alkylcarbonyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, an optionally C ₂ be substituted by a halogen atom - C ₆ Alkoxyyl Group, C ₁ -C ₆ Alkoxy Group, C ₁ -C ₆ Halo Alkoxy Group,-(CH ₂ ) _p NR ^a1 R ^a2 (p, R ^a1 and R a ² are shown in (0) above. Synonymous with definition) or general formula (IA)

{式中、
環Bは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L¹は、単結合、-CH₂-、-CH₂O-、-OCH₂-、-CH₂CH₂-、又は、-CH₂OCH₂-であり、
R^8a、R^8b及びR^8cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₃-C₇シクロアルキル基、C₃-C₇シクロアルキルオキシ基、ヘテロシクロアルキル基、ヘテロシクロアルキルオキシ基、C₂-C₆アルケニル基、又は、C₂-C₆アルキニル基である。｝で表される基であり、かつ、
R^4a、R^4b及びR^4cが、それぞれ独立して、ハロゲン原子、水酸基、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₄ハロアルコキシ基で置換されていてもよいC₁-C₄アルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルコキシ基、C₁-C₄アルキルチオ-C₁-C₄アルキル基、C₁-C₄ハロアルキルチオ-C₁-C₄アルキル基、-(CH₂)_qNR^b1R^b2（q、R^b1及びR^b2は、前記(0)において示された定義と同義である。）、又は、下記式

{In the formula,
Ring B is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ¹ represents a single _{bond, -CH 2 -, - CH 2} O -, - OCH 2 -, - CH 2 CH 2 -, or, -CH ₂ OCH ₂ - and is,
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₃ -C ₇ cycloalkyloxy group, heterocycloalkyl group, heterocycloalkyloxy group, C _2- C ₆ alkoxy group, or C _2- It is a C ₆ alkylyl group. } And is a group represented by
R ^4a , R ^4b and R ^4c are independent halogen atoms, hydroxyl groups, cyano groups, C _1- C ₆ alkyl groups, C ₁ -C ₆ haloalkyl groups, C ₁ -C ₆ alkoxy groups, C _1- C ₆ haloalkoxy group, C ₁ -C ₄ optionally C ₁ -C be substituted with a haloalkoxy group ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl Group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₄ alkylthio-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ alkyl group,- (CH ₂ ) _q NR ^b1 R ^b2 (q, R ^b1 and R ^b2 are synonymous with the definitions shown in (0) above) or the following formula.

（式中、R^9a、R^9b及びR^9cは、前記(0)において示された定義と同義である。）からなる群から選択される置換基である、組み合わせである。

(In the formula, R ^9a , R ^9b and R ^9c are synonymous with the definition shown in (0) above.) It is a combination that is a substituent selected from the group consisting of.

In one embodiment of the present invention, a compound having at least one of ^{R 4a} , R ^4b and R ^{4c represented by} the general formula (IE) or the general formula (I-E 2), ^{and R 11a} and R ^11b and R ^11c. In, the preferred combination of these substituents is
R ^11a is a hydrogen atom, halogen atom, cyano group, cyanomethyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, or C ₁ -C ₆ haloalkoxy group. And
R ^11b and R ^11c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, C _1- C ₆ alkyl group, C _1- C ₆ haloalkyl group. , C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, optionally substituted with dimethylaminocarbonyl group or dimethylamino group C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ halo alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₆ alkylcarbonyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, an optionally C ₂ -C ₆ alkynyl optionally substituted with halogen atoms Group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group,-(CH ₂ ) _p NR ^a1 R ^a2 (p, R ^a1 and R a ² are synonymous with the definitions given in (0) above. ) Or the general formula (IA)

{式中、
環Bは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L¹は、単結合、-CH₂-、-CH₂O-、-OCH₂-、-CH₂CH₂-、又は、-CH₂OCH₂-であり、
R^8a、R^8b及びR^8cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₃-C₇シクロアルキル基、C₃-C₇シクロアルキルオキシ基、ヘテロシクロアルキル基、ヘテロシクロアルキルオキシ基、C₂-C₆アルケニル基、又は、C₂-C₆アルキニル基である。｝で表される基であり、かつ、
R^4a、R^4b及びR^4cが、それぞれ独立して、ハロゲン原子、水酸基、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₄ハロアルコキシ基で置換されていてもよいC₁-C₄アルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルコキシ基、C₁-C₄アルキルチオ-C₁-C₄アルキル基、C₁-C₄ハロアルキルチオ-C₁-C₄アルキル基、-(CH₂)_qNR^b1R^b2(q、R^b1及びR^b2は、前記(0)において示された定義と同義である。)、又は、下記式

{In the formula,
Ring B is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ¹ represents a single _{bond, -CH 2 -, - CH 2} O -, - OCH 2 -, - CH 2 CH 2 -, or, -CH ₂ OCH ₂ - and is,
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₃ -C ₇ cycloalkyloxy group, heterocycloalkyl group, heterocycloalkyloxy group, C _2- C ₆ alkoxy group, or C _2- It is a C ₆ alkylyl group. } And is a group represented by
R ^4a , R ^4b and R ^4c are independent halogen atoms, hydroxyl groups, cyano groups, C _1- C ₆ alkyl groups, C ₁ -C ₆ haloalkyl groups, C ₁ -C ₆ alkoxy groups, C _1- C ₆ haloalkoxy group, C ₁ -C ₄ optionally C ₁ -C be substituted with a haloalkoxy group ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl Group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₄ alkylthio-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ alkyl group,- (CH ₂ ) _q NR ^b1 R ^b2 (q, R ^b1 and R ^b2 are synonymous with the definitions given in (0) above) or the following formula.

(式中、R^9a、R^9b及びR^9cは、前記(0)において示された定義と同義である。)からなる群から選択される置換基である、組み合わせである。

(In the formula, R ^9a , R ^9b and R ^9c are synonymous with the definition shown in (0) above.) It is a combination that is a substituent selected from the group consisting of.

In one embodiment of the present invention, in a compound having at least one of ^{R 4a} , R ^4b and R ^{4c represented by} the general formula (I) or the general formula (I-E2) ^{and R 2} , the substituents of these substituents are used. The preferred combination is
R ² is a hydrogen atom, a halogen atom, a hydroxyl group, or a cyano group, and
R ^4a , R ^4b and R ^4c may be independently substituted with halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, hydroxyl group C ₁ -C ₆ alkyl group, C _1- C ₆ haloalkyl group, optionally substituted with hydroxyl group C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ haloalkoxy group substituted which may be C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C _1- C ₄ Alkoxy-C ₁ -C ₄ Haloalkyl Group, C ₁ -C ₆ Alkoxycarbonyl Group, C ₁ -C ₆ Alkoxycarbonyl Group, C ₁ -C ₆ Haloalkylcarbonyl Group, C ₃ -C ₇ Cycloalkyl Group , halogen atom or C ₁ -C ₄ optionally C ₃ -C be substituted by haloalkyl group ₇ cycloalkyl, heterocycloalkyl groups, C ₂ -C ₆ alkenyl groups, C ₂ -C ₆ alkenyloxy groups, C _2- C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, May Be Substituted with Halogen Ax C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Group, Halogen Atomic or a methoxy group in an optionally substituted C ₂ -C ₆ alkynyl group, C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkoxy group, C ₁ -C ₆ Alkoxy Group, C ₁ -C ₆ Halo Alkoxy Group, C ₁ -C ₄ Alkoxy-C ₁ -C ₄ Alkoxy Group, C ₁ -C ₄ Halo Alkoxy-C ₁ -C ₄ Alkoxy Group,-( CH ₂ ) _q NR ^b1 R ^b2 (q, R ^b1 and R ^b2 are synonymous with the definitions given in (0) above) or the general formula (IB).

{式中、
環Cは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L²は、単結合、-CH=CH-、-C≡C-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2NR^c(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2CO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2S(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、又は、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2SO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-であり(R^10a、R^10b、R^10c、R^10d、R^10e、R^10f、R^10g、R^10h、r1、r2、r3、r4及びR^cは、前記(0)において示された定義と同義である。)、
R^9a、R^9b及びR^9cは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₆アルコキシカルボニル基、ヘテロシクロアルキルオキシ基、又は、-(CH₂)_sNR^d1R^d2(s、R^d1及びR^d2は、前記(0)において示された定義と同義である。)である。}である、組み合わせである。

{In the formula,
Ring C is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ² is a single bond, -CH = CH-, -C ≡ C ^{-,-(CR 10a R 10b} ) _r1 (CR ^10c R ^10d ) _r2 (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 S (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- or
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- and (R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^10f , R ^10g , R ^10h , r1, r2, r3, r4 and R ^c are synonymous with the definitions given in (0) above),
R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, respectively. C ₁ -C ₆ haloalkoxy group, C ₁ -C ₆ alkoxycarbonyl group, heterocycloalkyloxy group, or-(CH ₂ ) _s NR ^d1 R ^d2 (s, R ^d1 and R ^d2 are the above (0). It is synonymous with the definition shown in.). }, A combination.

^{In one embodiment of the present invention, in a compound having Z 2-} Z ^{3 represented} by the general formula (I-E 2), R ^6a and R ^6b , and R ^11a , R ^11b and R ^11c , the substituents of these substituents are used. The preferred combination is
Is _{^{Z 2 -Z 3, -CH 2 O}} -, - CH 2 S -, - CH 2 NR f1 -, - CH 2 CH 2 -, or, -CONR ^f1 - a and (R ^f1 and R ^f2 is hydrogen Atom or C _1- C ₄ alkyl group),
R ^6a and R ^6b are independently hydrogen atoms, fluorine atoms, hydroxyl groups, or methoxy groups, respectively.
R ^11a is a hydrogen atom, halogen atom, cyano group, cyanomethyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, or C ₁ -C ₆ haloalkoxy group. And
R ^11b and R ^11c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, C _1- C ₆ alkyl group, C _1- C ₆ haloalkyl group. , C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, optionally substituted with dimethylaminocarbonyl group or dimethylamino group C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ halo alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₆ alkylcarbonyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, an optionally C ₂ -C ₆ alkynyl optionally substituted with halogen atoms Group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group,-(CH ₂ ) _p NR ^a1 R ^a2 (p, R ^a1 and R a ² are synonymous with the definitions given in (0) above. ) Or the general formula (IA)

{式中、
環Bは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L¹は、単結合、-CH₂-、-CH₂O-、-OCH₂-、-CH₂CH₂-、又は、-CH₂OCH₂-であり、
R^8a、R^8b及びR^8cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₃-C₇シクロアルキル基、C₃-C₇シクロアルキルオキシ基、ヘテロシクロアルキル基、ヘテロシクロアルキルオキシ基、C₂-C₆アルケニル基、又は、C₂-C₆アルキニル基である。｝で表される基である、組み合わせである。

{In the formula,
Ring B is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ¹ represents a single _{bond, -CH 2 -, - CH 2} O -, - OCH 2 -, - CH 2 CH 2 -, or, -CH ₂ OCH ₂ - and is,
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₃ -C ₇ cycloalkyloxy group, heterocycloalkyl group, heterocycloalkyloxy group, C _2- C ₆ alkoxy group, or C _2- It is a C ₆ alkylyl group. } Is a combination, which is a group represented by.

Next, a preferable compound of the heteroaromatic amide derivative represented by the general formula (I) or the general formula (I-E2) contained in the medicament of the present invention will be described.

In one embodiment of the present invention, the preferred compound of the heteroaromatic amide derivative represented by the general formula (I) or the general formula (I-E2) is contained in the medicines described in (1) to (15) above. A heteroaromatic amide derivative or a salt thereof.

In another embodiment of the present invention, the preferred compound of the heteroaromatic amide derivative represented by the general formula (I) or the general formula (I-E2) is, for example, the following "derivative". Each "derivative" also includes its pharmaceutically acceptable salt, and one compound may belong to more than one "derivative".

Type (a) derivative:
^{X 1} -X ² in the general formula (I) or the general formula (I-E 2) is a group of compounds in which CN is CN and Y ^{1 is -O-. Specifically, 2,3-} Dihydropyrazolo [5,1-b] oxazole derivative, 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine derivative, 5,6,7,8-tetrahydropyrazolo [5] , 1-b] [1,3] Oxepine derivatives and the like.
Type (b) derivative:
^{X 1} -X ² in the general formula (I) or the general formula (I-E 2) is a group of compounds in which CN is CN and Y ¹ is -CH _2-. , 6,7-Tetrahydropyrazolo [1,5-a] pyrazine derivative, 4,5,6,7-Tetrahydropyrazolo [1,5-a] pyridine derivative, 6,7-dihydro-4H-pyrazolo [5 , 1-c] [1,4] Oxazine derivatives and the like.
Type (c) derivative:
^{X 1} -X ² in the general formula (I) or the general formula (I-E 2) is a group of compounds in which NC is NC and Y ¹ is -CH _2-. , 7,8-Tetrahydroimidazole [1,2-a] pyridine derivative, 5,6,7,8-Tetrahydroimidazole [1,2-a] pyrazine derivative, 5,6-dihydro-8H-imidazole [2,1 -c] [1,4] Oxazine derivatives, etc.
Type (d) derivative:
^{R 2} in the general formula (I) or general formula (I-E2) is a heteroaromatic amide derivative which is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring which may be substituted. be.

Next, the compounds of preferred embodiments are shown by breaking down into each "derivative". It should be noted that any of the compounds included in these is a concept including the optically active substance thereof, and also includes a pharmaceutically acceptable salt thereof.

Preferred type (a) derivatives included in the general formula (I) or the general formula (I-E2) contained in the medicament of the present invention are the following compounds.

a1) The following general formula (I-F):

［式中、Y²、Y³、Y⁴、Z¹、環A、R^1a、R^1b、R^3a、R^3b、R^3c、R^5a、R^5b、R^5c、R^6a、R^6b、nは、前記(0)において示された定義と同義であり、
R²は、水素原子、ハロゲン原子、水酸基、又は、シアノ基であり、
但し、Y²、Y³、又は、Y⁴の少なくとも一つが、−CR^4aR^4b−、−CR^4aH−、−CH₂CR^4aR^4b−、−CH₂CR^4aH−、又は、−NR^4c−である（R^4a、R^4b及びR^4cは、前記(0)において示された定義と同義である。）。］で表されるヘテロ芳香族アミド誘導体又はその塩。

[In the equation, Y ² , Y ³ , Y ⁴ , Z ¹ , ring A, R ^1a , R ^1b , R ^3a , R ^3b , R ^3c , R ^5a , R ^5b , R ^5c , R ^6a , R ^6b , n Is synonymous with the definition given in (0) above.
R ² is a hydrogen atom, a halogen atom, a hydroxyl group, or a cyano group.
However, Y ^2, Y ^3, or at least one of Y ^{4 is, -CR 4a R 4b -, -} CR 4a H -, - CH 2 CR 4a R 4b -, - CH 2 CR 4a H-, or, - NR ^4c − (R ^4a , R ^4b and R ^4c are synonymous with the definitions given in (0) above). ] Is a heteroaromatic amide derivative or a salt thereof.

a2) The following general formula (I-G)

［式中、Y²、Y³、Y⁴、R^1a、R^1b、R^6a、R^6bは、前記(0)において示された定義と同義であり、
Z²−Z³、Z⁴、R^5a、R^11b、R^11cは、前記(7)において示された定義と同義であり、 R²は、水素原子、ハロゲン原子、水酸基、又は、シアノ基であり、
但し、Y²、Y³、又は、Y⁴の少なくとも一つが、-CR^4aR^4b-、-CR^4aH-、-CH₂CR^4aR^4b-、-CH₂CR^4aH-、又は、-NR^4c-である(R^4a、R^4b及びR^4cは、前記(0)において示された定義と同義である。)。］
で表されるヘテロ芳香族アミド誘導体又はその塩。

[In the equation, Y ² , Y ³ , Y ⁴ , R ^1a , R ^1b , R ^6a , R ^6b are synonymous with the definitions given in (0) above.
Z ² −Z ³ , Z ⁴ , R ^5a , R ^11b , R ^11c are synonymous with the definition given in (7) above, and R ² is a hydrogen atom, a halogen atom, a hydroxyl group, or a cyano group. can be,
However, Y ^2, Y ^3, or at least one of Y ^{4 is, -CR 4a R 4b -, -} CR 4a H -, - CH 2 CR 4a R 4b -, - CH 2 CR 4a H-, or, - NR ^4c- (R ^4a , R ^4b and R ^4c are synonymous with the definitions given in (0) above). ]
A heteroaromatic amide derivative represented by or a salt thereof.

a3) In the general formula (IG),
Y ² , Y ³ and Y ⁴ together,
_{^{-CR 4a HCH 2 CH 2 -,}} - CR 4a R 4b CH 2 CH 2 -, - CH 2 CH 2 -, - CR 4a HCH 2 -,
Form -CR ^4a R ^4b CH _2- , -CH ₂ CH ₂ CH ₂ CH _2- , -CR ^4a HCH ₂ CH ₂ CH _2- , or -CH ₂ CR ^4a HCH ₂ CH _2- (R ^4a , R ^4b is synonymous with the definition given in (0) above), the heteroaromatic amide derivative or salt thereof according to a1) above.

a4) In the general formula (IG),
Z ² -Z ³ _{is, -CH 2 O -, - CH} 2 S -, - CH 2 NR f1 -, - CH 2 CH 2 -, or, -CONR ^f1 - a and (R ^f1 and R ^f2 are the It is synonymous with the definition given in (7)),
The heteroaromatic amide derivative or a salt thereof according to the above a2) or a3), wherein R ^5a , R ^6a and R ^{6b are hydrogen atoms.}

a5) A heteroaromatic amide derivative according to any one of a2) to a4) or a salt thereof, which is used in the general formula (IG).
Z ² -Z ³ is -CH ₂ O-,
R ^11a is a hydrogen atom, a halogen atom, a cyano group, a C _1- C ₆ alkyl group, or a C _1- C ₆ haloalkyl group.
R ^11b and R ^11c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, C _1- C ₆ alkyl group, C _1- C ₆ haloalkyl group. , C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, optionally substituted with dimethylaminocarbonyl group or dimethylamino group C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ halo alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₆ alkylcarbonyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, an optionally C ₂ -C ₆ alkynyl optionally substituted with halogen atoms Group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group,-(CH ₂ ) _p NR ^a1 R ^a2 (p, R ^a1 and R a ² are synonymous with the definitions given in (0) above. ) Or the general formula (IA)

{式中、
環Bは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L¹は、単結合、-CH₂-、-CH₂O-、-OCH₂-、-CH₂CH₂-、又は、-CH₂OCH₂-であり(R^a1及びR^a2は、前記(0)において示された定義と同義である。)、
R^8a、R^8b及びR^8cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₃-C₇シクロアルキル基、C₃-C₇シクロアルキルオキシ基、ヘテロシクロアルキル基、ヘテロシクロアルキルオキシ基、C₂-C₆アルケニル基、又は、C₂-C₆アルキニル基である。｝で表される基である、ヘテロ芳香族アミド誘導体又はその塩。

{In the formula,
Ring B is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ¹ represents a single _{bond, -CH 2 -, - CH 2} O -, - OCH 2 -, - CH 2 CH 2 -, or, -CH ₂ OCH ₂ - a and (R ^a1 and R ^a2 are the ( It is synonymous with the definition given in 0).),
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₃ -C ₇ cycloalkyloxy group, heterocycloalkyl group, heterocycloalkyloxy group, C _2- C ₆ alkoxy group, or C _2- It is a C ₆ alkylyl group. }, A heteroaromatic amide derivative or a salt thereof.

a6) A heteroaromatic amide derivative according to any one of a2) to a5) or a salt thereof, which is used in the general formula (IG).
R ^4a is substituted with halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, optionally substituted with hydroxyl group C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, substituted with hydroxyl group. May be _{substituted with C 1} -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ haloalkoxy group C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyl group, C ₃ -C ₇ cycloalkyl group, halogen atom or C ₁ -C ₄ haloalkyl group in optionally substituted C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ Alkoxy group, optionally substituted with halogen atom C _2- C ₆ Alkoxyoxy-C _1- C ₄ Alkoxy group, C _2- C ₆ Alkoxy group, optionally substituted with halogen atom or methoxy group C _2- C ₆ alkoxy group, C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₆ alkylthio group, C _1- C ₆ haloalkylthio group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ alkyl group,-(CH ₂ ) _q NR ^b1 R ^b2 (q, R ^b1 and R ^b2 are synonymous with the definitions given in (0) above) or the general formula (IB).

{式中、
環Cは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L²は、単結合、-CH=CH-、-C≡C-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2O(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2NR^c(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2CO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2S(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、又は、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2SO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-であり(R^10a、R^10b、R^10c、R^10d、R^10e、R^10f、R^10g、R^10h、r1、r2、r3、r4及びR^cは、前記(0)において示された定義と同義である。)、
R^9a、R^9b及びR^9cは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₆アルコキシカルボニル基、ヘテロシクロアルキルオキシ基、又は、-(CH₂)_sNR^d1R^d2(s、R^d1及びR^d2は、前記(0)において示された定義と同義である。)である。}である、
ヘテロ芳香族アミド誘導体又はその塩。

{In the formula,
Ring C is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ² is a single bond, -CH = CH-, -C ≡ C ^{-,-(CR 10a R 10b} ) _r1 (CR ^10c R ^10d ) _r2 (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- , -(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 O (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 S (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- or
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- and (R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^10f , R ^10g , R ^10h , r1, r2, r3, r4 and R ^c are synonymous with the definitions given in (0) above),
R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, respectively. C ₁ -C ₆ haloalkoxy group, C ₁ -C ₆ alkoxycarbonyl group, heterocycloalkyloxy group, or-(CH ₂ ) _s NR ^d1 R ^d2 (s, R ^d1 and R ^d2 are the above (0). It is synonymous with the definition shown in.). },
Heteroaromatic amide derivative or salt thereof.

a7) A heteroaromatic amide derivative according to any one of a2) to a6) or a salt thereof, which is used in the general formula (IG).
Y ² , Y ³ and Y ⁴ together form ^{-CR 4a} HCH ₂ CH _2-
R ^4a is halogen atom, hydroxyl group, cyano group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C _{4 C 1-} C ₄ alkoxy-C ₁ -C ₄ alkyl groups optionally substituted with haloalkoxy groups, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl groups, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkoxy groups, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ alkyl _{group, - (CH 2) q NR} b1 R b2 (q , R ^b1 and R ^b2 are synonymous with the definitions given in (0) above), or the following formula.

(式中、R^9a、R^9b及びR^9cは、前記(0)において示された定義と同義である。)からなる群から選択される置換基であり、
R^11aが、水素原子であり、
R^11b及びR^11cが、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、シアノメチル基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₄アルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルキル基、C₂-C₆アルケニル基、C₂-C₆アルキニル基、-(CH₂)_pNR^a1R^a2(pは1であり、R^a1及びR^a2は、それぞれ独立して、水素原子、メチル基、エチル基、又は、2,2,2-トリフルオロエチル基である。)、又は、一般式(I-A)

(In the formula, R ^9a , R ^9b and R ^9c are synonymous with the definition shown in (0) above.)
R ^11a is a hydrogen atom
R ^11b and R ^11c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkoxy group, C ₂ -C ₆ Alkoxy group,-(CH ₂ ) _p NR ^a1 R ^a2 (p is 1, and R ^a1 and R ^a2 are independently hydrogen atom, methyl group, ethyl group, or 2,2,2- It is a trifluoroethyl group.) Or general formula (IA).

{式中、
環Bは、C₃-C₇シクロアルキル、モルホリノ、フェニル、ピラゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L¹は、単結合であり、
R^8a、R^8b及びR^8cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、又は、C₁-C₆ハロアルコキシ基である。｝で表される基である、
ヘテロ芳香族アミド誘導体又はその塩。

{In the formula,
Ring B is C _3- C ₇ cycloalkyl, morpholino, phenyl, pyrazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl,
L ¹ is a single bond,
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, or C ₁ -C ₆ Haloalkoxy group. }, Which is the group represented by
Heteroaromatic amide derivative or salt thereof.

a8) The compound represented by the general formula (I-F) or the general formula (I-G) (the meaning of numbers and asterisks (*) conforms to (15) above).

である前記a1)又はa2)に記載のヘテロ芳香族アミド誘導体又はその塩。

The heteroaromatic amide derivative according to the above a1) or a2) or a salt thereof.

Preferred type (b) derivatives included in the general formula (I) or general formula (I-E2) contained in the medicament of the present invention are the following compounds.

b1) General formula (I-H):

［式中、Y²、Y³、Y⁴、Z¹、環A、R^1a、R^1b、R²、R^3a、R^3b、R^3c、R^5a、R^5b、R^5c、R^6a、R^6b、nは、前記(0)において示された定義と同義である
（但し、Y²、Y³、又は、Y⁴の少なくとも一つが、−CR^4aR^4b−、−CR^4aH−、−CH₂CR^4aR^4b−、−NR^4c−、−CH₂CR^4aH−、又は、−NR^4c−であり（R^4a、R^4b及びR^4cは、前記(0)において示された定義と同義である。）、
R^5a、R^5b、R^5c、R^6a、R^6b及びnが、前記(0)中の（ii）の構成を充足する場合は、Y¹、Y²、Y³及びY⁴が一緒になって、−CH₂NR^4aHCH₂CH₂−を形成しない。］
で表されるヘテロ芳香族アミド誘導体又はその塩。

[In the formula, Y ² , Y ³ , Y ⁴ , Z ¹ , ring A, R ^1a , R ^1b , R ² , R ^3a , R ^3b , R ^3c , R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n are synonymous with the definitions given in (0) above (provided that at least one of ^{Y 2} , Y ³ or Y ^{4 is −CR 4a} R ^4b −, ^{−CR 4a} H−, − CH ₂ CR ^4a R ^4b −, −NR ^4c −, −CH ₂ CR ^4a H −, or −NR ^4c − (R ^4a , R ^4b, and R ^4c are the definitions shown in (0) above. It is synonymous.),
If R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy the configuration of (ii) in (0) above, then Y ¹ , Y ² , Y ³ and Y ⁴ are combined. And does not form _{−CH 2} NR ^4a HCH ₂ CH _{2 −.} ]
A heteroaromatic amide derivative represented by or a salt thereof.

b2) General formula (I-I)

［式中、Y²、Y³、Y⁴、R^1a、R^1b、R²、R^6a、R^6bは、前記(0)において示された定義と同義であり、
Z²−Z³、Z⁴、R^5a、R^11b、R^11cは、前記(7)において示された定義と同義である(但し、Y²、Y³、又は、Y⁴の少なくとも一つが、-CR^4aR^4b-、-CR^4aH-、-CH₂CR^4aR^4b-、-CH₂CR^4aH-、又は、-NR^4c-である(R^4a、R^4b及びR^4cは、前記(0)において示された定義と同義である。)。］
で表されるヘテロ芳香族アミド誘導体又はその塩。

[In the equation, Y ² , Y ³ , Y ⁴ , R ^1a , R ^1b , R ² , R ^6a , R ^6b are synonymous with the definitions given in (0) above.
Z ² −Z ³ , Z ⁴ , R ^5a , R ^11b , R ^11c are synonymous with the definitions given in (7) above (provided that at least one of ^{Y 2} , Y ³ , or Y ^{4 is -CR 4a R 4b -, - CR} 4a H -, - CH 2 CR 4a R 4b -, - CH 2 CR 4a H-, or, -NR ^4c - a is (R ^4a, R ^4b and R ^4c, the It is synonymous with the definition given in (0).).]
A heteroaromatic amide derivative represented by or a salt thereof.

b3) In the general formula (II),
Y ² , Y ³ and Y ⁴ together,
-OCH ₂ CH _2- , -OCH ₂ CH ₂ CH _2- ,
_{^{-CR 4a HCH 2 CH 2 -,}} - CR 4a R 4b CH 2 CH 2 -, - CH 2 CR 4a HCH 2 -, or, -NR ^4c CH ₂ CH ₂ - to form (R ^4a, R ^4b and R ^4c is synonymous with the definition given in (0) above), the heteroaromatic amide derivative or salt thereof according to b2) above.

b4) The heteroaromatic amide derivative of b2) or b3) or a salt thereof, which is used in the general formula (II).
Z ² -Z ³ _{is, -CH 2 O -, - CH} 2 S -, - CH 2 NR f1 -, - CH 2 CH 2 -, or, -CONR ^f1 - a and (R ^f1 and R ^f2 are the It is synonymous with the definition given in (7)),
A heteroaromatic amide derivative or a salt thereof, wherein ^{R 5a} , R ^6a and R ^{6b are hydrogen atoms.}

b5) The compound represented by the general formula (I-H) or the general formula (I-I) (the meaning of the numbers conforms to (15) above)

である前記b1)又はb2)に記載のヘテロ芳香族アミド誘導体又はその塩。

The heteroaromatic amide derivative or salt thereof according to the above b1) or b2).

Preferred type (c) derivatives included in the general formula (I) or the general formula (I-E2) contained in the medicament of the present invention are the following compounds.

c1) General formula (I-J):

［式中、Y²、Y³、Y⁴、Z¹、環A、R^1a、R^1b、R²、R^3a、R^3b、R^3c、R^5a、R^5b、R^5c、R^6a、R^6b、nは、前記(0)において示された定義と同義であり、
但し、Y²、Y³及びY⁴が一緒になって、−CR^4aHCH₂CH₂−を形成し、R²が水素原子であり、R^4aが一般式(I-B)で表される基であり、かつ、L²が単結合の場合は、環Cはフェニル環ではなく、
但し、Y²、Y³、又は、Y⁴の少なくとも一つが、−CR^4aR^4b−、−CR^4aH−、−CH₂CR^4aR^4b−、−CH₂CR^4aH−、又は、−NR^4c−である（R^4a、R^4b及びR^4cは、前記(0)において示された定義と同義である。）。］で表されるヘテロ芳香族アミド誘導体又はその塩。

[In the equation, Y ² , Y ³ , Y ⁴ , Z ¹ , ring A, R ^1a , R ^1b , R ² , R ^3a , R ^3b , R ^3c , R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n are synonymous with the definitions given in (0) above.
However, Y ² , Y ³ and Y ⁴ are combined to form −CR ^4a HCH ₂ CH ₂ −, where R ² is a hydrogen atom and R ^4a is a group represented by the general formula (IB). If there is and L ² is a single bond, then ring C is not a phenyl ring,
However, Y ^2, Y ^3, or at least one of Y ^{4 is, -CR 4a R 4b -, -} CR 4a H -, - CH 2 CR 4a R 4b -, - CH 2 CR 4a H-, or, - NR ^4c − (R ^4a , R ^4b and R ^4c are synonymous with the definitions given in (0) above). ] Is a heteroaromatic amide derivative or a salt thereof.

c2) General formula (I-K)

［式中、Y²、Y³、Y⁴、R^1a、R^1b、R²、R^6a、R^6bは、前記(0)において示された定義と同義であり、
Z²−Z³、Z⁴、R^5a、R^11b、R^11cは、前記(7)において示された定義と同義である(但し、Y²、Y³及びY⁴が一緒になって、-CR^4aHCH₂CH₂-を形成し、R²が水素原子であり、R^4aが一般式(I-B)で表される基であり、かつ、L²が単結合の場合は、環Cはフェニル環ではなく、
但し、Y²、Y³、又は、Y⁴の少なくとも一つが、-CR^4aR^4b-、-CR^4aH-、-CH₂CR^4aR^4b-、-CH₂CR^4aH-、又は、-NR^4c-である(R^4a、R^4b及びR^4cは、前記(0)において示された定義と同義である。)。］
で表されるヘテロ芳香族アミド誘導体又はその塩。

[In the equation, Y ² , Y ³ , Y ⁴ , R ^1a , R ^1b , R ² , R ^6a , R ^6b are synonymous with the definitions given in (0) above.
Z ² −Z ³ , Z ⁴ , R ^5a , R ^11b , R ^11c are synonymous with the definition given in (7) above (provided that Y ² , Y ³ and Y ⁴ are combined,- If CR ^4a HCH ₂ CH _2- forms, R ² is a hydrogen atom, R ^4a is a group represented by the general formula (IB), and L ² is a single bond, then ring C is phenyl. Not a ring,
However, Y ^2, Y ^3, or at least one of Y ^{4 is, -CR 4a R 4b -, -} CR 4a H -, - CH 2 CR 4a R 4b -, - CH 2 CR 4a H-, or, - NR ^4c- (R ^4a , R ^4b and R ^4c are synonymous with the definitions given in (0) above). ]
A heteroaromatic amide derivative represented by or a salt thereof.

c3) The heteroaromatic amide derivative of c2) or a salt thereof, which is used in the general formula (IK).
Y ² , Y ³ and Y ⁴ together,
_{^{-CR 4a HOCH 2 -, - CR}} 4a HCH 2 CH 2 -,
Form -CH ₂ NR ^4c CH _2- ^{, -CR 4a} HNR ^4c CH _2- , or -CR ^4a _{HNHCH 2-} (R ^4a and R ^4c are synonymous with the definitions given in (0) above. ), Heteroaromatic amide derivative or salt thereof.

c4) The heteroaromatic amide derivative of c2) or c3) or a salt thereof, which is used in the general formula (IK).
Z ² -Z ³ _{is, -CH 2 O -, - CH} 2 S -, - CH 2 NR f1 -, - CH 2 CH 2 -, or, -CONR ^f1 - a and (R ^f1 and R ^f2 are the It is synonymous with the definition given in (7)),
A heteroaromatic amide derivative or a salt thereof, wherein ^{R 5a} , R ^6a and R ^{6b are hydrogen atoms.}

c5) The compound represented by the general formula (I-J) or the general formula (I-K) (the meaning of the numbers conforms to (15) above)

である前記c1)に記載のヘテロ芳香族アミド誘導体又はその塩。

The heteroaromatic amide derivative according to c1) or a salt thereof.

Preferred type (d) derivatives included in the general formula (I) or the general formula (I-E2) contained in the medicament of the present invention are the following compounds.

d1) General formula (I):

［式中、環A、Z¹、R^1a、R^1b、R^3a、R^3b、R^3c、R^5a、R^5b、R^5c、R^6a、R^6b、nは、前記(0)において示された定義と同義であり、
R²が、置換されていてもよい飽和、部分飽和若しくは不飽和の3〜7員の単環式環であり、
Y¹、Y²、Y³及びY⁴は、これらが一緒になって、
−OCH₂CH₂CH₂−、−OCR^4aHCH₂CH₂−、−OCR^4aR^4bCH₂CH₂−
−OCH₂CH₂−、−OCR^4aHCH₂−、−OCR^4aR^4bCH₂−、
−OCH₂CH₂CH₂CH₂−、−OCR^4aHCH₂CH₂CH₂−、−OCR^4aR^4bCH₂CH₂CH₂−、
−OCH₂CR^4aHCH₂CH₂−、−OCH₂CR^4aR^4bCH₂CH₂−、
−CH₂OCH₂CH₂−、−CH₂OCH₂CH₂CH₂−、−CH₂CH₂OCH₂−、−CH₂CR^4aHOCH₂−
−CH₂CH₂CH₂CH₂−、−CH₂CR^4aHCH₂CH₂−、−CH₂CR^4aR^4bCH₂CH₂−、
−CH₂CH₂CR^4aHCH₂−、−CH₂CH₂CR^4aR^4bCH₂−、
−CH₂SCH₂CH₂−、−CH₂SO₂CH₂CH₂−、
−NHCH₂CH₂CH₂−、−NR^4cCH₂CH₂CH₂−、−NR^4cCR^4aHCH₂CH₂−、−NHCR^4aHCH₂CH₂−、
−CH₂NR^4cCH₂CH₂−、−CH₂NR^4cCR^4aHCH₂−、−CH₂NHCR^4aHCH₂−、
−CH₂CH₂NR^4cCH₂−、−CH₂CR^4aHNR^4cCH₂−、又は、−CH₂CR^4aHNHCH₂−
を形成し（R^4a、R^4b及びR^4cは、前記(0)において示された定義と同義である。）、
X¹−X²は、C-N、又は、N-Cである（但し、C-Nの場合は、Y¹、Y²、Y³及びY⁴は、これらが一緒になって、−OCH₂CH₂CH₂−、−OCR^4aHCH₂CH₂−、又は、−OCR^4aR^4bCH₂CH₂−を形成しない。）。］で表されるヘテロ芳香族アミド誘導体又はその塩。

[In the equation, rings A, Z ¹ , R ^1a , R ^1b , R ^3a , R ^3b , R ^3c , R ^5a , R ^5b , R ^5c , R ^6a , R ^6b , n are shown in (0) above. Is synonymous with the definition
R ² is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring that may be substituted.
Y ¹ , Y ² , Y ³ and Y ⁴ together,
−OCH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ −, −OCR ^4a R ^4b CH ₂ CH ₂ −
−OCH ₂ CH ₂ −, −OCR ^4a HCH ₂ −, −OCR ^4a R ^4b CH ₂ −,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCR ^4a R ^4b CH ₂ CH ₂ CH ₂ −,
−OCH ₂ CR ^4a HCH ₂ CH ₂ −, −OCH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −, −CH ₂ CH ₂ OCH ₂ −, −CH ₂ CR ^4a HOCH ₂ −
−CH ₂ CH ₂ CH ₂ CH ₂ −, −CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
−CH ₂ CH ₂ CR ^4a HCH ₂ −, −CH ₂ CH ₂ CR ^4a R ^4b CH ₂ −,
−CH ₂ SCH ₂ CH ₂ −, −CH ₂ SO ₂ CH ₂ CH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −, −NHCR ^4a HCH ₂ CH ₂ −,
−CH ₂ NR ^4c CH ₂ CH ₂ −, −CH ₂ NR ^4c CR ^4a HCH ₂ −, −CH ₂ NHCR ^4a HCH ₂ −,
−CH ₂ CH ₂ NR ^4c CH ₂ −, −CH ₂ CR ^4a HNR ^4c CH ₂ −, or −CH ₂ CR ^4a HNHCH ₂ −
(R ^4a , R ^4b and R ^4c are synonymous with the definitions given in (0) above).
X ¹ −X ² is CN or NC (however, in the case of CN, Y ¹ , Y ² , Y ³ and Y ⁴ are together, −OCH ₂ CH ₂ CH ₂ − , -OCR ^4a HCH ₂ CH _2- , or -OCR ^4a R ^4b CH ₂ CH _2- does not form). ] Is a heteroaromatic amide derivative or a salt thereof.

d2) General formula (I-E2):

[式中、R^1a、R^1b、R^6a、R^6bは、前記(0)において示された定義と同義であり、
Z²-Z³、Z⁴、R^5a、R^11b、R^11cは、前記(7)において示された定義と同義であり、
R²が、置換されていてもよい飽和、部分飽和若しくは不飽和の3〜7員の単環式環であり、
Y¹、Y²、Y³及びY⁴は、これらが一緒になって、
-OCH₂CH₂CH₂-、-OCR^4aHCH₂CH₂-、-OCR^4aR^4bCH₂CH₂-
-OCH₂CH₂-、-OCR^4aHCH₂-、-OCR^4aR^4bCH₂-、
-OCH₂CH₂CH₂CH₂-、-OCR^4aHCH₂CH₂CH₂-、-OCR^4aR^4bCH₂CH₂CH₂-、
-OCH₂CR^4aHCH₂CH₂-、-OCH₂CR^4aR^4bCH₂CH₂-、
-CH₂OCH₂CH₂-、-CH₂OCH₂CH₂CH₂-、-CH₂CH₂OCH₂-、-CH₂CR^4aHOCH₂-
-CH₂CH₂CH₂CH₂-、-CH₂CR^4aHCH₂CH₂-、-CH₂CR^4aR^4bCH₂CH₂-、
-CH₂CH₂CR^4aHCH₂-、-CH₂CH₂CR^4aR^4bCH₂-、
-CH₂SCH₂CH₂-、-CH₂SO₂CH₂CH₂-、
-NHCH₂CH₂CH₂-、-NR^4cCH₂CH₂CH₂-、-NR^4cCR^4aHCH₂CH₂-、-NHCR^4aHCH₂CH₂-、
-CH₂NR^4cCH₂CH₂-、-CH₂NR^4cCR^4aHCH₂-、-CH₂NHCR^4aHCH₂-、
-CH₂CH₂NR^4cCH₂-、-CH₂CR^4aHNR^4cCH₂-、又は、-CH₂CR^4aHNHCH₂-
を形成し(R^4a、R^4b及びR^4cは、前記(0)において示された定義と同義である。)、
X¹-X²は、N-C又はC-Nである(但し、C-Nの場合は、Y¹、Y²、Y³及びY⁴は、これらが一緒になって、-OCH₂CH₂CH₂-、-OCR^4aHCH₂CH₂-、又は、-OCR^4aR^4bCH₂CH₂-を形成しない。)。]で表されるヘテロ芳香族アミド誘導体又はその塩。

[In the equation, R ^1a , R ^1b , R ^6a , R ^6b are synonymous with the definitions given in (0) above.
Z ² -Z ³ , Z ⁴ , R ^5a , R ^11b , R ^11c are synonymous with the definitions given in (7) above.
R ² is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring that may be substituted.
Y ¹ , Y ² , Y ³ and Y ⁴ together,
-OCH ₂ CH ₂ CH _2- , -OCR ^4a HCH ₂ CH _2- , -OCR ^4a R ^4b CH ₂ CH _2-
-OCH ₂ CH _2- , -OCR ^4a HCH _2- , -OCR ^4a R ^4b CH _2- ,
-OCH ₂ CH ₂ CH ₂ CH _2- , -OCR ^4a HCH ₂ CH ₂ CH _2- , -OCR ^4a R ^4b CH ₂ CH ₂ CH _2- ,
-OCH ₂ CR ^4a HCH ₂ CH _2- , -OCH ₂ CR ^4a R ^4b CH ₂ CH _2- ,
-CH ₂ OCH ₂ CH _2- , -CH ₂ OCH ₂ CH ₂ CH _2- , -CH ₂ CH ₂ OCH _2- , -CH ₂ CR ^4a HOCH _2-
-CH ₂ CH ₂ CH ₂ CH _2- , -CH ₂ CR ^4a HCH ₂ CH _2- , -CH ₂ CR ^4a R ^4b CH ₂ CH _2- ,
-CH ₂ CH ₂ CR ^4a HCH _2- , -CH ₂ CH ₂ CR ^4a R ^4b CH _2- ,
-CH ₂ SCH ₂ CH _2- , -CH ₂ SO ₂ CH ₂ CH _2- ,
-NHCH ₂ CH ₂ CH _2- , -NR ^4c CH ₂ CH ₂ CH _2- , -NR ^4c CR ^4a HCH ₂ CH _2- , -NHCR ^4a HCH ₂ CH _2- ,
-CH ₂ NR ^4c CH ₂ CH _2- , -CH ₂ NR ^4c CR ^4a HCH _2- , -CH ₂ NHCR ^4a HCH _2- ,
-CH ₂ CH ₂ NR ^4c CH _2- , -CH ₂ CR ^4a HNR ^4c CH _2- , or -CH ₂ CR ^4a HNHCH _2-
(R ^4a , R ^4b and R ^4c are synonymous with the definitions given in (0) above).
X ¹ -X ² is NC or CN (however, in the case of CN, Y ¹ , Y ² , Y ³ and Y ⁴ together, -OCH ₂ CH ₂ CH ₂ -,- Does not form OCR ^4a HCH ₂ CH _2- or-or -OCR ^4a R ^4b CH ₂ CH _2-). ] Is a heteroaromatic amide derivative or a salt thereof.

d3) The heteroaromatic amide derivative of d2) or a salt thereof, which is used in the general formula (I-E2).
Z ² -Z ³ _{is, -CH 2 O -, - CH} 2 S -, - CH 2 NR f1 -, - CH 2 CH 2 -, or, -CONR ^f1 - a and (R ^f1 and R ^f2 are the It is synonymous with the definition given in (7)),
A heteroaromatic amide derivative or a salt thereof, wherein ^{R 5a} , R ^6a and R ^{6b are hydrogen atoms.}

d4) The heteroaromatic amide derivative according to any one of d2) to d3) or a salt thereof In the general formula (I-E2),
R ² is a halogen atom, a cyano group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkoxy group or -NR ^d1 R ^{d2, respectively.} (R ^d1 and R ^d2 are independently substituted with a hydrogen atom, a C _1- C ₄ alkyl group, or a C _1- C ₄ haloalkyl group, respectively), phenyl, pyrrolyl, frill. , Thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, pyrimidinyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, or a heteroaromatic amide derivative or a salt thereof.

d5) A heteroaromatic amide derivative according to any one of d3) to d4) or a salt thereof, which is used in the general formula (I-E2).
R ² is a halogen atom, a cyano group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkoxy group or -NR ^d1 R ^{d2, respectively.} (R ^d1 and R ^d2 are independently substituted with a hydrogen atom, a C _1- C ₄ alkyl group, or a C _1- C ₄ haloalkyl group, respectively), phenyl, pyrazolyl, 卜A heteroaromatic amide derivative or a salt thereof, which is riazolyl, pyridyl, or pyrazinyl.

d6) A heteroaromatic amide derivative according to any one of d3) to d5) or a salt thereof, which is used in the general formula (I-E2).
R ² is a halogen atom, a methyl group, an ethyl group, a trifluoromethyl group, a trifluoromethoxy group, a trifluoroethyl group, a trifluoroethoxy group or -NHR ^d2 (R ^d2 is a methyl group, an ethyl group, a tri). A heteroaromatic amide derivative or salt thereof, which is phenyl, pyrazolyl, or pyridyl, which may be substituted with a fluoromethyl group or a trifluoroethyl group).

d7) The compound represented by the general formula (I) or the general formula (I-E2) (the meaning of the numbers conforms to (15) above)

である前記d1)又はd2)に記載のヘテロ芳香族アミド誘導体又はその塩。

The heteroaromatic amide derivative according to the above d1) or d2) or a salt thereof.

Next, another embodiment of the present invention will be described. The present invention also includes, for example, the following inventions.

A1) In the general formula (I), X ¹ −X ² , Z ¹ , ring A, R ^1a , R ^1b , R ^5a , R ^5b , R ^5c , R ^6a , R ^{6 b} and n are the above (0). Synonymous with the definition given in
Y ¹ , Y ² , Y ³ and Y ⁴ are independently single-bonded, −CH ₂ −, _{−CH 2} CH ₂ −, −CR ^4a R ^4b −, −CR ^4a H−, −CR ^4b H, respectively. −, −CH ₂ CR ^4a R ^4b −, −CH ₂ CR ^4a H−, −NR ^4c −, _{−NH−, −S−, −SO 2−} , or −O−,
R ² _{is a C 1-} C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C _2- C ₆ alkenyl group, or a C which may be substituted with a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a hydroxyl group. _2- C ₆ alkynyl group or
R ² is a halogen atom, a cyano group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkoxy group or -NR ^d1 R ^d2 (R). ^d1 and R ^d2 may be independently substituted with a hydrogen atom, a C _1- C ₄ alkyl group, or a C _1- C ₄ haloalkyl group), saturated, partially saturated or unsaturated, respectively. It is a 3- to 7-membered monocyclic ring,
R ^3a , R ^3b and R ^3c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxyl group, hydroxyl group, C _1- C ₆ alkyl group and heterocyclooxy substitution. C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkyl substituted with cyano, C ₁ -C ₆ alkyl substituted by a morpholino group, C ₁ -C ₆ haloalkyl groups, C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ haloalkoxy groups, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl groups, C ₁ -C substituted by dimethylamino group ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C substituted with dimethylaminocarbonyl group ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ haloalkyl groups, C ₁ -C ₆ alkylcarbonyl groups, C ₁ -C ₆ alkoxycarbonyl groups, C ₁ -C ₆ alkylcarbonyloxy groups, C ₁ -C ₆ haloalkylcarbonyl group, C ₁ -C ₆ haloalkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyloxy group, C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, C ₃ -C ₇ cycloalkyloxy group , Heterocycloalkyloxy Group, C ₂ -C ₆ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ haloalkyl group, C ₂ -C ₆ alkylyl group, optionally substituted with halogen atom C ₂ -C ₆ alkylyl group, C ₂ -C ₆ alkylyloxy group, C ₂ -C ₆ alkylyloxy -C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkinyl Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C _{4 Alkoxy} Basic , C _2- C ₆ alkynyloxy-C ₁ -C ₄ haloalkoxy group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group, C ₁ -C ₄ alkylthio-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group, C _1- C ₆ alkylsulfonyl group,-(CH ₂ ) _p NR ^a1 R ^a2 (R ^a1 and R ^a2 are independent hydrogen atoms, C _1- C ₄ alkyl groups, or C ₁ -C ₄ haloalkyl groups, respectively. Yes, p is 0, 1, or 2. ) Or general formula (IA)

{式中、環B、L¹、R^8a、R^8b、R^8cは、前記(0)において示された定義と同義である。｝で表される基であり、
R^4a、R^4b及びR^4cは、それぞれ独立して、ハロゲン原子、シアノ基、シアノメチル基、ホルミル基、ニトロ基、カルボキサミド基、水酸基、C₁-C₆アルキル基、水酸基で置換されていてもよいC₁-C₆アルキル基、C₁-C₆ハロアルキル基、水酸基で置換されていてもよいC₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₄アルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルキル基、C₁-C₄アルコキシ-C₁-C₄ハロアルキル基、C₁-C₄ハロアルコキシ-C₁-C₄ハロアルキル基、C₁-C₆アルキルカルボニル基、C₁-C₆アルコキシカルボニル基、C₁-C₆アルキルカルボニルオキシ基、C₁-C₆ハロアルキルカルボニル基、C₁-C₆ハロアルコキシカルボニル基、C₁-C₆ハロアルキルカルボニルオキシ基、C₃-C₇シクロアルキル基、ハロゲン原子で置換されていてもよいC₃-C₇シクロアルキル基、ヘテロシクロアルキル基、C₃-C₇シクロアルキルオキシ基、ヘテロシクロアルキルオキシ基、C₂-C₆アルケニル基、C₂-C₆アルケニルオキシ基、C₂-C₆アルケニルオキシ-C₁-C₄アルキル基、ハロゲン原子で置換されていてもよいC₂-C₆アルケニルオキシ-C₁-C₄アルキル基、C₂-C₆アルケニルオキシ-C₁-C₄ハロアルキル基、C₂-C₆アルキニル基、ハロゲン原子若しくはメトキシ基で置換されていてもよいC₂-C₆アルキニル基、C₂-C₆アルキニルオキシ基、C₂-C₆アルキニルオキシ-C₁-C₄アルキル基、C₂-C₆アルキニルオキシ-C₁-C₄ハロアルキル基、C₁-C₄アルコキシ-C₁-C₄アルコキシ基、C₁-C₄ハロアルコキシ-C₁-C₄アルコキシ基、C₂-C₆アルケニルオキシ-C₁-C₄アルコキシ基、C₂-C₆アルキニルオキシ-C₁-C₄アルコキシ基、C₂-C₆アルケニルオキシ-C₁-C₄ハロアルコキシ基、C₂-C₆アルキニルオキシ-C₁-C₄ハロアルコキシ基、C₁-C₆アルキルチオ基、C₁-C₆ハロアルキルチオ基、C₁-C₄アルキルチオ-C₁-C₄アルキル基、C₁-C₄ハロアルキルチオ-C₁-C₄アルキル基、C₁-C₄アルキルチオ-C₁-C₄ハロアルキル基、C₁-C₄ハロアルキルチオ-C₁-C₄ハロアルキル基、ペンタフルオロスルファニル基、-(CH₂)_qNR^b1R^b2（R^b1及びR^b2は、それぞれ独立して、水素原子、C₁-C₄アルキル基、又はC₁-C₄ハロアルキル基であり、qは、0、１、2、又は、3である。）、又は、一般式(I-B)

{In the equation, rings B, L ¹ , R ^8a , R ^8b , and R ^8c are synonymous with the definitions given in (0) above. } Is a group represented by
Even if R ^4a , R ^4b and R ^4c are independently substituted with halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxylxamide group, hydroxyl group, C _1- C ₆ alkyl group and hydroxyl group, respectively. good C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, hydroxyl group optionally substituted C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl groups, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl groups, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ Alkoxy-C ₁ -C ₄ Haloalkyl groups, C ₁ -C ₆ alkylcarbonyl groups, C ₁ -C ₆ alkoxycarbonyl groups, C ₁ -C ₆ alkylcarbonyloxy groups, C ₁ -C ₆ haloalkylcarbonyl groups, C ₁ -C ₆ haloalkoxycarbonyl groups, C ₁ -C ₆ haloalkylcarbonyl group, C ₃ -C ₇ cycloalkyl group, optionally substituted with a halogen atom a C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group , C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ alkyl group, _{C 2} -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Halo Alkoxy Group, C ₂ -C ₆ Alkinyl Group, Halogen, May Be Substituted with Halogen Atom _{C 2-} C ₆ Alkoxyyl Group, C _2- C ₆ Alkoxyloxy Group, C _2- C ₆ Alkoxyloxy-C ₁ -C ₄ Alkoxy Group, C _2- C ₆ Alkoxyl Group May Be Substituted with Atomic Or methoxy Group Oxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkoxy group, C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkinyloxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkinyl Oxy-C ₁ --- C ₄ haloalkoxy group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group, pentafluorosulfanyl _{group, - (CH 2) q NR} b1 R b2 (R ^b1 and R ^b2 are independently hydrogen atoms, C _1- C ₄ alkyl groups, or C _1- C ₄ haloalkyl groups, where q is 0, 1, 2, or 3. ) Or general formula (IB)

{式中、環C、L²、R^9a、R^9b、R^9cは、前記(0)において示された定義と同義である。}で表される基であるか、あるいは、
R^4a及びR^4bは、これらが結合する炭素原子と一緒になって、3〜7員の単環式環を形成してもよく、あるいは、
R^4a及びR^4bは、一緒になって、一般式(I-D)：

{In the equation, rings C, L ² , R ^9a , R ^9b , and R ^9c are synonymous with the definitions given in (0) above. Is a group represented by} or
R ^4a and R ^4b may combine with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring, or
R ^4a and R ^4b together have the general formula (ID):

を形成してもよい（R^4d及びR^4eは、それぞれ独立して、水素原子、ハロゲン原子、又は、C₁-C₄アルキル基、あるいは、R^4d及びR^4eは、これらが結合する炭素原子と一緒になって、3〜7員の単環式環を形成してもよい。）、ヘテロ芳香族アミド誘導体又はその塩からなる医薬（但し、X¹−X²が、N−Cであり、Y¹、Y²、Y³及びY⁴が一緒になって、−CH₂CR^4aHCH₂CH₂−を形成し、R²が水素原子であり、R^4aが一般式(I-B)で表される基であり、かつ、L²が単結合の場合、環Cはフェニル環ではない。あるいは、環Cがフェニル環である場合、X¹−X²は、C−Nである。）。

(R ^4d and R ^4e are independent hydrogen atoms, halogen atoms, or C _1- C ₄ alkyl groups, or R ^4d and R ^4e are carbon atoms to which they are bonded. Together with, a 3- to 7-membered monocyclic ring may be formed), a drug consisting of a heteroaromatic amide derivative or a salt thereof (where X ^1- X ² is NC. , Y ¹ , Y ² , Y ³ and Y ⁴ together form −CH ₂ CR ^4a HCH ₂ CH ₂ −, where R ² is a hydrogen atom and R ^4a is represented by the general formula (IB). If the group ^{is a single bond and L 2} is a single bond, then ring C is not a phenyl ring, or if ring C is a phenyl ring, then X ¹ −X ² is C − N).

A2) In the general formula (I),
Y ¹ , Y ² , Y ³ and Y ⁴ together,
−OCH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ −, −OCR ^4a R ^4b CH ₂ CH ₂ −,
−OCH ₂ CH ₂ −, −OCR ^4a HCH ₂ −, −OCR ^4a R ^4b CH ₂ −,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCR ^4a R ^4b CH ₂ CH ₂ CH ₂ −,
−OCH ₂ CR ^4a HCH ₂ CH ₂ −, −OCH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −, −CH ₂ CH ₂ OCH ₂ −, −CH ₂ CR ^4a HOCH ₂ −
−CH ₂ CH ₂ CH ₂ CH ₂ −, −CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
−CH ₂ CH ₂ CR ^4a HCH ₂ −, −CH ₂ CH ₂ CR ^4a R ^4b CH ₂ −,
−CH ₂ SCH ₂ CH ₂ −, −CH ₂ SO ₂ CH ₂ CH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −,
−NHCR ^4a HCH ₂ CH ₂ −,
−CH ₂ NR ^4c CH ₂ CH ₂ −, −CH ₂ NR ^4c CR ^4a HCH ₂ −, −CH ₂ NHCR ^4a HCH ₂ −,
−CH ₂ CH ₂ NR ^4c CH ₂ −, −CH ₂ CR ^4a HNR ^4c CH ₂ −, or −CH ₂ CR ^4a HNHCH ₂ − is formed (R ^4a , R ^4b and R ^4c are A1). Synonymous with the definition given. ),
R ² is a hydrogen atom, a halogen atom, a hydroxyl group, or a cyano group, or
R ² is a halogen atom, a cyano group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkoxy group or -NR ^d1 R ^{d2, respectively.} (R ^d1 and R ^d2 are independently substituted with a hydrogen atom, a C _1- C ₄ alkyl group, or a C _1- C ₄ haloalkyl group, respectively), phenyl, pyrrolyl, frill. , thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, Bok Riazoriru, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, or thiadiazolyl (provided that the X ¹ -X ^2, be a C-N ^{and, Y 1, Y 2, Y} 3 and Y ⁴ is, they _{together, -OCH 2 CH 2 CH 2 -} , - OCR 4a HCH 2 CH 2 -, or, -OCR ^4a R ^4b CH ₂ When _{forming CH 2} −, R ² is a hydrogen atom), the pharmaceutical according to A1) above, which comprises a heteroaromatic amide derivative or a salt thereof.

A3) In the general formula (I),
X ¹ −X ² is C −N,
Y ¹ , Y ² , Y ³ and Y ⁴ together,
−OCH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ −, −OCR ^4a R ^4b CH ₂ CH ₂ −, −OCH ₂ CH ₂ −,
_{^{-OCR 4a HCH 2 -, - OCR}} 4a R 4b CH 2 -,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCH ₂ CR ^4a HCH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −,
−CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −, −CH ₂ CH ₂ CR ^4a HCH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −, −NHCR ^4a HCH ₂ CH ₂ − or −CH ₂ NR ^4c CH ₂ CH ₂ − (R ^4a , R ^4b) And R ^4c are synonymous with the definitions given in A1) above. ),
A ^{heteroaromatic amide derivative or a heteroaromatic amide derivative in which R 5a} , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy any one of the configurations shown in (i) to (iii) in (0) above. The drug according to the above A1) or A2), which comprises the salt.

A4) In the general formula (I),
X ¹ −X ² , Z ¹ , rings A, R ^1a , and R ^1b are synonymous with the definitions given in (0) above.
Y ¹ , Y ² , Y ³ and Y ⁴ are independently single-bonded, −CH ₂ −, _{−CH 2} CH ₂ −, −CR ^4a R ^4b −, −CR ^4a H−, −CR ^4b H, respectively. −, −CH ₂ CR ^4a R ^4b −, −CH ₂ CR ^4a H−, −NR ^4c −, _{−NH−, −S−, −SO 2−} , or −O−,
R ² _{is a C 1-} C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C _2- C ₆ alkenyl group, or a C which may be substituted with a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a hydroxyl group. _2- C ₆ alkynyl group or
R ² is a halogen atom, a cyano group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkoxy group or -NR ^d1 R ^d2 (R). ^d1 and R ^d2 may be independently substituted with a hydrogen atom, a C _1- C ₄ alkyl group, or a C _1- C ₄ haloalkyl group), saturated, partially saturated or unsaturated, respectively. It is a 3- to 7-membered monocyclic ring,
R ^3a , R ^3b and R ^3c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxyl group, hydroxyl group, C _1- C ₆ alkyl group and heterocyclooxy substitution. C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkyl substituted with cyano, C ₁ -C ₆ alkyl substituted by a morpholino group, C ₁ -C ₆ haloalkyl groups, C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ haloalkoxy groups, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl groups, C ₁ -C substituted by dimethylamino group ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C substituted with dimethylaminocarbonyl group ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ haloalkyl groups, C ₁ -C ₆ alkylcarbonyl groups, C ₁ -C ₆ alkoxycarbonyl groups, C ₁ -C ₆ alkylcarbonyloxy groups, C ₁ -C ₆ haloalkylcarbonyl group, C ₁ -C ₆ haloalkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyloxy group, C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, C ₃ -C ₇ cycloalkyloxy group , Heterocycloalkyloxy Group, C ₂ -C ₆ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ haloalkyl group, C ₂ -C ₆ alkylyl group, optionally substituted with halogen atom C ₂ -C ₆ alkylyl group, C ₂ -C ₆ alkylyloxy group, C ₂ -C ₆ alkylyloxy -C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkinyl Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C _{4 Alkoxy} Basic , C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ haloalkoxy group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group, C _1- C ₆ alkylsulfonyl group,-(CH ₂ ) _p NR ^a1 R ^a2 (R ^a1 and R ^a2 are independently hydrogen atoms, C _1- C ₄ alkyl groups, or C ₁ -C ₄ haloalkyl groups, respectively. Yes, p is 0, 1, or 2. ) Or general formula (IA)

{式中、環B、L¹、R^8a、R^8b、R^8cは、前記(0)において示された定義と同義である。｝で表される基であり、
R^4a、R^4b及びR^4cは、それぞれ独立して、ハロゲン原子、シアノ基、シアノメチル基、ホルミル基、ニトロ基、カルボキサミド基、水酸基、C₁-C₆アルキル基、水酸基で置換されていてもよいC₁-C₆アルキル基、C₁-C₆ハロアルキル基、水酸基で置換されていてもよいC₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₄アルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルキル基、C₁-C₄アルコキシ-C₁-C₄ハロアルキル基、C₁-C₄ハロアルコキシ-C₁-C₄ハロアルキル基、C₁-C₆アルキルカルボニル基、C₁-C₆アルコキシカルボニル基、C₁-C₆アルキルカルボニルオキシ基、C₁-C₆ハロアルキルカルボニル基、C₁-C₆ハロアルコキシカルボニル基、C₁-C₆ハロアルキルカルボニルオキシ基、C₃-C₇シクロアルキル基、ハロゲン原子で置換されていてもよいC₃-C₇シクロアルキル基、ヘテロシクロアルキル基、C₃-C₇シクロアルキルオキシ基、ヘテロシクロアルキルオキシ基、C₂-C₆アルケニル基、C₂-C₆アルケニルオキシ基、C₂-C₆アルケニルオキシ-C₁-C₄アルキル基、ハロゲン原子で置換されていてもよいC₂-C₆アルケニルオキシ-C₁-C₄アルキル基、C₂-C₆アルケニルオキシ-C₁-C₄ハロアルキル基、C₂-C₆アルキニル基、ハロゲン原子若しくはメトキシ基で置換されていてもよいC₂-C₆アルキニル基、C₂-C₆アルキニルオキシ基、C₂-C₆アルキニルオキシ-C₁-C₄アルキル基、C₂-C₆アルキニルオキシ-C₁-C₄ハロアルキル基、C₁-C₄アルコキシ-C₁-C₄アルコキシ基、C₁-C₄ハロアルコキシ-C₁-C₄アルコキシ基、C₂-C₆アルケニルオキシ-C₁-C₄アルコキシ基、C₂-C₆アルキニルオキシ-C₁-C₄アルコキシ基、C₂-C₆アルケニルオキシ-C₁-C₄ハロアルコキシ基、C₂-C₆アルキニルオキシ-C₁-C₄ハロアルコキシ基、C₁-C₆アルキルチオ基、C₁-C₆ハロアルキルチオ基、C₁-C₄アルキルチオ-C₁-C₄アルキル基、C₁-C₄ハロアルキルチオ-C₁-C₄アルキル基、C₁-C₄アルキルチオ-C₁-C₄ハロアルキル基、C₁-C₄ハロアルキルチオ-C₁-C₄ハロアルキル基、ペンタフルオロスルファニル基、-(CH₂)_qNR^b1R^b2（R^b1及びR^b2は、それぞれ独立して、水素原子、C₁-C₄アルキル基、又はC₁-C₄ハロアルキル基であり、qは、0、1、2、又は、3である。）、又は、一般式(I-B)

{In the equation, rings B, L ¹ , R ^8a , R ^8b , and R ^8c are synonymous with the definitions given in (0) above. } Is a group represented by
Even if R ^4a , R ^4b and R ^4c are independently substituted with halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxylxamide group, hydroxyl group, C _1- C ₆ alkyl group and hydroxyl group, respectively. good C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, hydroxyl group optionally substituted C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl groups, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl groups, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ Alkoxy-C ₁ -C ₄ Haloalkyl groups, C ₁ -C ₆ alkylcarbonyl groups, C ₁ -C ₆ alkoxycarbonyl groups, C ₁ -C ₆ alkylcarbonyloxy groups, C ₁ -C ₆ haloalkylcarbonyl groups, C ₁ -C ₆ haloalkoxycarbonyl groups, C ₁ -C ₆ haloalkylcarbonyl group, C ₃ -C ₇ cycloalkyl group, optionally substituted with a halogen atom a C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group , C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ alkyl group, _{C 2} -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Halo Alkoxy Group, C ₂ -C ₆ Alkinyl Group, Halogen, May Be Substituted with Halogen Atom _{C 2-} C ₆ Alkoxyyl Group, C _2- C ₆ Alkoxyloxy Group, C _2- C ₆ Alkoxyloxy-C ₁ -C ₄ Alkoxy Group, C _2- C ₆ Alkoxyl Group May Be Substituted with Atomic Or methoxy Group Oxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkoxy group, C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkinyloxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkinyl Oxy-C ₁ --- C ₄ haloalkoxy group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group, pentafluorosulfanyl _{group, - (CH 2) q NR} b1 R b2 (R ^b1 and R ^b2 are independently hydrogen atoms, C _1- C ₄ alkyl groups, or C _1- C ₄ haloalkyl groups, where q is 0, 1, 2, or 3. ) Or general formula (IB)

{式中、環C、L²、R^9a、R^9b、R^9cは、前記(0)において示された定義と同義である。}で表される基であるか、あるいは、
R^4a及びR^4bは、これらが結合する炭素原子と一緒になって、3〜7員の単環式環を形成してもよく、あるいは、
R^4a及びR^4bは、一緒になって、一般式(I-D)：

{In the equation, rings C, L ² , R ^9a , R ^9b , and R ^9c are synonymous with the definitions given in (0) above. Is a group represented by} or
R ^4a and R ^4b may combine with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring, or
R ^4a and R ^4b together have the general formula (ID):

を形成してもよく（R^4d及びR^4eは、それぞれ独立して、水素原子、ハロゲン原子、又は、C₁-C₄アルキル基、あるいは、R^4d及びR^4eは、これらが結合する炭素原子と一緒になって、3〜7員の単環式環を形成してもよい。）、
R^5a、R^5b、R^5c、R^6a、R^6b及びnは、前記(0)の（i）又は（ii）の構成のいずれかを充足する（但し、 R^5a、R^5b、R^5c、R^6a、R^6b及びnが前記（ii）の構成を充足する場合は、Y¹、Y²、Y³及びY⁴は一緒になって、−CH₂NR^4aHCH₂CH₂−を形成しない。）。］
で表されるヘテロ芳香族アミド誘導体又はその塩からなる医薬（但し、R²が水素原子の場合は、Y¹、Y²、Y³、又は、Y⁴の少なくとも一つが、−CR^4aR^4b−、−CR^4aH−、−CH₂CR^4aR^4b−、−CH₂CR^4aH−、又は、−NR^4c−である。）

(R ^4d and R ^4e are independent hydrogen atoms, halogen atoms, or C _1- C ₄ alkyl groups, or R ^4d and R ^4e are carbon atoms to which they are bonded. Together with, a 3- to 7-membered monocyclic ring may be formed.),
R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy any of the configurations (i) or (ii) of (0) above (provided that R ^5a , R ^5b , R ^5c , If R ^6a , R ^6b and n satisfy the configuration of (ii) above, Y ¹ , Y ² , Y ³ and Y ⁴ together do not form _{−CH 2} NR ^4a HCH ₂ CH _{2 −.} .). ]
A drug consisting of a heteroaromatic amide derivative represented by or a salt thereof (however, when R ² is a hydrogen atom, at least one of ^{Y 1} , Y ² , Y ³ or Y ^{4 is −CR 4a} R ^4b. −, −CR ^4a H−, −CH ₂ CR ^4a R ^4b −, −CH ₂ CR ^4a H−, or −NR ^4c −)

A5) In the general formula (I),
Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a R 4b CH 2 CH 2 -,
−OCH ₂ CH ₂ −, −OCR ^4a HCH ₂ −, −OCR ^4a R ^4b CH ₂ −,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCR ^4a R ^4b CH ₂ CH ₂ CH ₂ −,
−OCH ₂ CR ^4a HCH ₂ CH ₂ −, −OCH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −, −CH ₂ CH ₂ OCH ₂ −, −CH ₂ CR ^4a HOCH ₂ −
−CH ₂ CH ₂ CH ₂ CH ₂ −, −CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
−CH ₂ CH ₂ CR ^4a HCH ₂ −, −CH ₂ CH ₂ CR ^4a R ^4b CH ₂ −,
−CH ₂ SCH ₂ CH ₂ −, −CH ₂ SO ₂ CH ₂ CH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −,
−NHCR ^4a HCH ₂ CH ₂ −,
−CH ₂ NR ^4c CH ₂ CH ₂ −, −CH ₂ NR ^4c CR ^4a HCH ₂ −, −CH ₂ NHCR ^4a HCH ₂ −,
−CH ₂ CH ₂ NR ^4c CH ₂ −, −CH ₂ CR ^4a HNR ^4c CH ₂ −, or −CH ₂ CR ^4a HNHCH ₂ − is formed (R ^4a , R ^4b and R ^4c are A4). Synonymous with the definition given. ),
R ² is a hydrogen atom, a halogen atom, a hydroxyl group, or a cyano group, or
R ² is a halogen atom, a cyano group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkoxy group or -NR ^d1 R ^{d2, respectively.} (R ^d1 and R ^d2 are independently substituted with a hydrogen atom, a C _1- C ₄ alkyl group, or a C _1- C ₄ haloalkyl group, respectively), phenyl, pyrrolyl, frill. , Thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, pyrimidinyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, or thiadiazolyl (where X ^1- X ² is C-N). , And if Y ¹ , Y ² , Y ³ and Y ⁴ together form −OCR ^4a HCH ₂ CH ₂ −, ^{−OCR 4a} R ^4b CH ₂ CH ₂ −, then R ² Is a hydrogen atom), the pharmaceutical according to A4) consisting of a heteroaromatic amide derivative or a salt thereof (where X ^1- X ² is N-C, and Y ¹ , Y ² , Y ³ and Y ⁴ together form −CH ₂ CR ^4a HCH ₂ CH ₂ −, R ² is a hydrogen atom, R ^4a is a group represented by the general formula (IB), and L ² If is a single bond, ring C is not a phenyl ring, or if ring C is a phenyl ring, X ¹ −X ² is C − N).

A6) In the general formula (I),
X ¹ −X ² is C −N,
Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a R 4b CH 2 CH 2 -, - OCH 2 CH 2 -,
_{^{-OCR 4a HCH 2 -, - OCR}} 4a R 4b CH 2 -,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCH ₂ CR ^4a HCH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −,
−CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −, −CH ₂ CH ₂ CR ^4a HCH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −, −NHCR ^4a HCH ₂ CH ₂ − or −CH ₂ NR ^4c CH ₂ CH ₂ − (R ^4a , R ^4b) , R ^4c are synonymous with the definitions given in A4) above. ),
R ^5a , R ^5b , R ^5c , R ^6a , R ^6b , and n are the above A4) or A5) consisting of a heteroaromatic amide derivative or a salt thereof, which satisfies the constitution of (i) of (0) above. The listed drug.

A7) In the general formula (IE),
X ¹ , X ² , R ^1a , and R ^1b are synonymous with the definitions given in (0) above.
Y ¹ , Y ² , Y ³ and Y ⁴ are independently single-bonded, −CH ₂ −, _{−CH 2} CH ₂ −, −CR ^4a R ^4b −, −CR ^4a H−, −CR ^4b H, respectively. −, −CH ₂ CR ^4a R ^4b −, −CH ₂ CR ^4a H−, −NR ^4c −, _{−NH−, −S−, −SO 2−} , or −O−,
Z ² −Z ³ is −CH ₂ −, −OCH ₂ −, −CH ₂ O−, −SCH ₂ −, −CH ₂ S−, −CH ₂ NR ^f1 −, −NR ^f1 CH ₂ −, −CH ₂ CH ₂ −, −CONR ^f1 −, −NR ^f1 CO −, −OCR ^f1 R ^f2 −, or −CR ^f1 R ^f2 O − (R ^f1 and R ^f2 are hydrogen atoms, C ₁ -C ₄ Alkyl group or C _1- C ₄ haloalkyl group),
R ² _{is a C 1-} C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C _2- C ₆ alkenyl group, or a C which may be substituted with a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a hydroxyl group. _2- C ₆ alkynyl group or
R ² is a halogen atom, a cyano group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkoxy group or -NR ^d1 R ^d2 (R). ^d1 and R ^d2 may be independently substituted with a hydrogen atom, a C _1- C ₄ alkyl group, or a C _1- C ₄ haloalkyl group), saturated, partially saturated or unsaturated, respectively. It is a 3- to 7-membered monocyclic ring,
Even if R ^4a , R ^4b and R ^4c are independently substituted with halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxylxamide group, hydroxyl group, C _1- C ₆ alkyl group and hydroxyl group, respectively. good C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, hydroxyl group optionally substituted C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl groups, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl groups, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ Alkoxy-C ₁ -C ₄ Haloalkyl groups, C ₁ -C ₆ alkylcarbonyl groups, C ₁ -C ₆ alkoxycarbonyl groups, C ₁ -C ₆ alkylcarbonyloxy groups, C ₁ -C ₆ haloalkylcarbonyl groups, C ₁ -C ₆ haloalkoxycarbonyl groups, C ₁ -C ₆ haloalkylcarbonyl group, C ₃ -C ₇ cycloalkyl group, optionally substituted with a halogen atom a C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group , C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ alkyl group, _{C 2} -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Halo Alkoxy Group, C ₂ -C ₆ Alkinyl Group, Halogen, May Be Substituted with Halogen Atom _{C 2-} C ₆ Alkoxyyl Group, C _2- C ₆ Alkoxyloxy Group, C _2- C ₆ Alkoxyloxy-C ₁ -C ₄ Alkoxy Group, C _2- C ₆ Alkoxyl Group May Be Substituted with Atomic Or methoxy Group Oxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkoxy group, C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkinyloxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkinyl Oxy-C ₁ --- C ₄ haloalkoxy group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group, pentafluorosulfanyl _{group, - (CH 2) q NR} b1 R b2 (R ^b1 and R ^b2 are independently hydrogen atoms, C _1- C ₄ alkyl groups, or C _1- C ₄ haloalkyl groups, where q is 0, 1, 2, or 3. ) Or general formula (IB)

{式中、環C、L²、R^9a、R^9b、R^9cは、前記(0)において示された定義と同義である。}で表される基であるか、あるいは、
R^4a及びR^4bは、これらが結合する炭素原子と一緒になって、3〜7員の単環式環を形成してもよく、あるいは、
R^4a及びR^4bは、一緒になって、一般式(I-D)：

{In the equation, rings C, L ² , R ^9a , R ^9b , and R ^9c are synonymous with the definitions given in (0) above. Is a group represented by} or
R ^4a and R ^4b may combine with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring, or
R ^4a and R ^4b together have the general formula (ID):

を形成してもよく（R^4d及びR^4eは、それぞれ独立して、水素原子、ハロゲン原子、又は、C₁-C₄アルキル基、あるいは、R^4d及びR^4eは、これらが結合する炭素原子と一緒になって、3〜7員の単環式環を形成してもよい。）、
R^5aは、水素原子、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₃-C₇シクロアルキル基、ヘテロシクロアルキル基、C₃-C₇シクロアルキル-C₁-C₄アルキル基、ヘテロシクロアルキル-C₁-C₄アルキル基、又は、アラルキル基であり、
R^6a、R^6bは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₄アルキル基、C₁-C₄ハロアルキル基、C₁-C₄アルコキシ基 、又は、C₁-C₄ハロアルコキシ基であり、
R^11aは、水素原子、ハロゲン原子、シアノ基、シアノメチル基、ホルミル基、ニトロ基、カルボキサミド基、水酸基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₄アルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルキル基、C₃-C₇シクロアルキル基、C₂-C₆アルケニル基、C₂-C₆アルケニルオキシ基、C₂-C₆アルキニル基、又は、C₂-C₆アルキニルオキシ基であり、
R^11b及びR^11cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、シアノメチル基、ホルミル基、ニトロ基、カルボキサミド基、水酸基、C₁-C₆アルキル基、ヘテロシクロオキシ置換されたC₁-C₆アルキル基、シアノ基で置換されたC₁-C₆アルキル基、モルホリノ基で置換されたC₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₄アルコキシ-C₁-C₄アルキル基、ジメチルアミノ基で置換されたC₁-C₄アルコキシ-C₁-C₄アルキル基、ジメチルアミノカルボニル基で置換されたC₁-C₄アルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルキル基、C₁-C₄アルコキシ-C₁-C₄ハロアルキル基、C₁-C₄ハロアルコキシ-C₁-C₄ハロアルキル基、C₁-C₆アルキルカルボニル基、C₁-C₆アルコキシカルボニル基、C₁-C₆アルキルカルボニルオキシ基、C₁-C₆ハロアルキルカルボニル基、C₁-C₆ハロアルコキシカルボニル基、C₁-C₆ハロアルキルカルボニルオキシ基、C₃-C₇シクロアルキル基、ヘテロシクロアルキル基、C₃-C₇シクロアルキルオキシ基、ヘテロシクロアルキルオキシ基、C₂-C₆アルケニル基、C₂-C₆アルケニルオキシ基、C₂-C₆アルケニルオキシ-C₁-C₄アルキル基、C₂-C₆アルケニルオキシ-C₁-C₄ハロアルキル基、C₂-C₆アルキニル基、ハロゲン原子で置換されていてもよいC₂-C₆アルキニル基、C₂-C₆アルキニルオキシ基、C₂-C₆アルキニルオキシ-C₁-C₄アルキル基、C₂-C₆アルキニルオキシ-C₁-C₄ハロアルキル基、C₁-C₄アルコキシ-C₁-C₄アルコキシ基、C₁-C₄ハロアルコキシ-C₁-C₄アルコキシ基、C₂-C₆アルケニルオキシ-C₁-C₄アルコキシ基、C₂-C₆アルキニルオキシ-C₁-C₄アルコキシ基、C₂-C₆アルケニルオキシ-C₁-C₄ハロアルコキシ基、C₂-C₆アルキニルオキシ-C₁-C₄ハロアルコキシ基、C₁-C₆アルキルチオ基、C₁-C₆ハロアルキルチオ基、C₁-C₄アルキルチオ-C₁-C₄アルキル基、C₁-C₄ハロアルキルチオ-C₁-C₄アルキル基、C₁-C₄アルキルチオ-C₁-C₄ハロアルキル基、C₁-C₄ハロアルキルチオ-C₁-C₄ハロアルキル基、C₁-C₆アルキルスルホニル基、-(CH₂)_pNR^a1R^a2（R^a1及びR^a2は、それぞれ独立して、水素原子、C₁-C₄アルキル基、又は、C₁-C₄ハロアルキル基であり、pは、0、１、又は、２である。）、又は、一般式(I-A)

(R ^4d and R ^4e are independent hydrogen atoms, halogen atoms, or C _1- C ₄ alkyl groups, or R ^4d and R ^4e are carbon atoms to which they are bonded. Together with, a 3- to 7-membered monocyclic ring may be formed.),
R ^5a is a hydrogen atom, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, C ₃ -C ₇ cycloalkyl-C ₁ -C ₄ Alkyl group, heterocycloalkyl-C _1- C ₄ alkyl group, or aralkyl group,
R ^6a and R ^6b are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, or C. ₁ -C ₄ haloalkoxy group,
R ^11a is a hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group. , C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group, C ₃ -C ₇ cycloalkyl group, C _2- C ₆ Alkoxy Group, C _2- C ₆ Alkoxy Oxy Group, C _2- C ₆ Alkinyl Group, or C _2- C ₆ Alkoxy Oxy Group.
R ^11b and R ^11c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxylxamide group, hydroxyl group, C _1- C ₆ alkyl group, heterocyclooxy-substituted C. ₁ -C ₆ alkyl group, C ₁ -C ₆ alkyl substituted with cyano, C ₁ -C ₆ alkyl substituted by a morpholino group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group , C ₁ -C ₆ haloalkoxy groups, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl groups, C ₁ -C substituted by dimethylamino group ₄ alkoxy -C ₁ -C ₄ alkyl group, dimethylaminocarbonyl C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group substituted with a group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl group , C ₁ -C ₄ Alkoxy-C ₁ -C ₄ Haloalkyl Group, C ₁ -C ₆ Alkoxycarbonyl Group, C ₁ -C ₆ Alkoxycarbonyl Group, C ₁ -C ₆ Alkoxycarbonyloxy Group, C ₁ -C ₆ haloalkylcarbonyl group, C ₁ -C ₆ haloalkoxycarbonyl groups, C ₁ -C ₆ haloalkylcarbonyl group, C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group, C ₃ -C ₇ cycloalkyl group, heterocyclo Alkoxy Oxy Group, C ₂ -C ₆ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Haloalkyl group, C ₂ -C ₆ alkylyl group, optionally substituted with halogen atom C ₂ -C ₆ alkylyl group, C ₂ -C ₆ alkylyloxy group, C ₂ -C ₆ alkylyloxy -C ₁ -C ₄ Alkoxy group, C _2- C ₆ alkynyloxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkoxy group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkinyl Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Halo Alkoxy Group, C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ haloalkoxy group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C _1- C ₄ haloalkylthio-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkylthio-C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ haloalkyl thio-C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkyl Sulfonyl group,-(CH ₂ ) _p NR ^a1 R ^a2 (R ^a1 and R ^a2 are independently hydrogen atoms, C _1- C ₄ alkyl groups, or C ₁ -C ₄ haloalkyl groups, p. Is 0, 1, or 2. ) Or general formula (IA)

{式中、環B、L¹、R^8a、R^8b、R^8cは、前記(0)において示された定義と同義である。｝で表される基である
（但し、R²が水素原子の場合は、Y¹、Y²、Y³、又は、Y⁴の少なくとも一つが、−CR^4aR^4b−、−CR^4aH−、−CH₂CR^4aR^4b−、−CH₂CR^4aH−、又は、−NR^4c−である。）、ヘテロ芳香族アミド誘導体又はその塩からなる医薬。

{In the equation, rings B, L ¹ , R ^8a , R ^8b , and R ^8c are synonymous with the definitions given in (0) above. } (However, if R ² is a hydrogen atom, at least one of ^{Y 1} , Y ² , Y ³ , or Y ^{4 is −CR 4a} R ^4b −, ^{−CR 4a} H−. _{^{, -CH 2 CR 4a R 4b -}} , - CH 2 CR 4a H-, or, -NR ^4c -. a a) a pharmaceutical comprising a heteroaromatic amide derivative or a salt thereof.

A8) In the general formula (IE),
X ¹ −X ² is C −N,
Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a R 4b CH 2 CH 2 -, - OCH 2 CH 2 -,
_{^{-OCR 4a HCH 2 -, - OCR}} 4a R 4b CH 2 -,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCH ₂ CR ^4a HCH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −,
−CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −, −CH ₂ CH ₂ CR ^4a HCH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −, −NHCR ^4a HCH ₂ CH ₂ − or −CH ₂ NR ^4c CH ₂ CH ₂ − (R ^4a , R ^4b) , R ^4c is synonymous with the definition given in A7). ),
The pharmaceuticals according to the above A7) consisting of a heteroaromatic amide derivative or a salt thereof (where X ¹ − X ² is C − N, and Y ¹ , Y ² , Y ³ and Y ⁴ are these. When combined to form −OCR ^4a HCH ₂ CH ₂ − or −OCR ^4a R ^4b CH ₂ CH ₂ −, R ² is a hydrogen atom).

A9) In the general formula (IE),
Z ² −Z ³ is −CH ₂ O−,
The medicament according to the above A7) or A8), which comprises a heteroaromatic amide derivative or a salt thereof, wherein R ^6a , R ^6b , R ^11a and R ^{11c are hydrogen atoms, respectively.}

A10) In the general formula (IE),
X ¹ −X ² is C −N,
Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a HCH 2 -,
−OCR ^4a HCH ₂ CH ₂ CH ₂ −, −CH ₂ CR ^4a HCH ₂ CH ₂ −,
Forming −NR ^4c CR ^4a HCH ₂ CH ₂ −, −NHCR ^4a HCH ₂ CH ₂ −, or −CH ₂ NR ^4c CH ₂ CH ₂ −
R ^4a is a halogen atom, a hydroxyl group, a cyano group, C ₁ -C ₆ alkyl group, hydroxyl group optionally substituted C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, substituted by hydroxyl group May be C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy- C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyl group, C ₃ -C ₇ cycloalkyl group, a halogen atom or a C ₁ -C ₄ haloalkyl optionally substituted with a group C ₃ -C ₇ cycloalkyl group , a heterocycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ alkyl group, optionally C ₂ be substituted by a halogen atom -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, C ₂ -C _{6 Alkinyl Group, C 2} -C ₆ Alkinyl Group, C ₂ -C ₆ Alkinyl Oxy- May Be Substituted with Halogen Atomic Or methoxy Group C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkoxy groups, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ alkyl group,-(CH ₂ ) _q NR ^b1 R ^b2 (q, R ^b1 and R ^b2 are shown in (0) above. Synonymous with definition) or general formula (IB)

{式中、
環Cは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L²は、単結合、-CH=CH-、-C≡C-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2O(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2NR^c(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2CO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2S(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、又は、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2SO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-であり（R^10a、R^10b、R^10c、R^10d、R^10e、R^10f、R^10g、R^10h、r1、r2、r3、r4及びR^cは、前記(0)において示された定義と同義である。）、
R^9a、R^9b及びR^9cは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₆アルコキシカルボニル基、ヘテロシクロアルキルオキシ基、又は、-(CH₂)_sNR^d1R^d2（s、R^d1及びR^d2は、前記(0)において示された定義と同義である。）である。}である、
ヘテロ芳香族アミド誘導体又はその塩からなる前記A7)からA9)のいずれか１つに記載の医薬。

{In the formula,
Ring C is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ² is a single bond, -CH = CH-, -C ≡ C ^{-,-(CR 10a R 10b} ) _r1 (CR ^10c R ^10d ) _r2 (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- , -(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 O (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 S (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- or
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- and (R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^10f , R ^10g , R ^10h , r1, r2, r3, r4 and R ^c are synonymous with the definitions given in (0) above),
R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, respectively. C ₁ -C ₆ haloalkoxy group, C ₁ -C ₆ alkoxycarbonyl group, heterocycloalkyloxy group, or-(CH ₂ ) _s NR ^d1 R ^d2 (s, R ^d1 and R ^d2 are the above (0). It is synonymous with the definition shown in.). },
The medicament according to any one of A7) to A9), which comprises a heteroaromatic amide derivative or a salt thereof.

Next, another embodiment of the present invention will be described. The present invention also includes, for example, the following inventions.

B1) In the general formula (I),
X ¹ −X ² , Z ¹ , rings A, R ^1a , and R ^1b are synonymous with the definitions given in (0) above.
Y ¹ , Y ² , Y ³ and Y ⁴ are independently single-bonded, −CH ₂ −, _{−CH 2} CH ₂ −, −CR ^4a R ^4b −, −CR ^4a H−, −CR ^4b H, respectively. −, −CH ₂ CR ^4a R ^4b −, −CH ₂ CR ^4a H−, −NR ^4c −, _{−NH−, −S−, −SO 2−} , or −O−,
R ² _{is a C 1-} C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C _2- C ₆ alkenyl group, or a C which may be substituted with a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a hydroxyl group. _2- C ₆ alkynyl group or
R ² is a halogen atom, a cyano group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkoxy group or -NR ^d1 R ^d2 (R). ^d1 and R ^d2 may be independently substituted with a hydrogen atom, a C _1- C ₄ alkyl group, or a C _1- C ₄ haloalkyl group), saturated, partially saturated or unsaturated, respectively. It is a 3- to 7-membered monocyclic ring,
R ^3a , R ^3b and R ^3c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxyl group, hydroxyl group, C _1- C ₆ alkyl group, C ₁ -C. _{Even if substituted with 6} haloalkyl groups, C _1- C ₆ alkoxy groups, C ₁ -C ₆ haloalkoxy groups, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl groups, dimethylaminocarbonyl groups or dimethylamino groups good C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ - C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₆ alkylcarbonyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, an optionally C ₂ be substituted by a halogen atom - C ₆ Alkoxyyl Group, C ₁ -C ₆ Alkoxy Group, C ₁ -C ₆ Halo Alkoxy Group,-(CH ₂ ) _p NR ^a1 R ^a2 (p, R ^a1 and R a ² are shown in (0) above. Synonymous with definition) or general formula (IA)

{式中、
環Bは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L¹は、単結合、-CH₂-、-CH₂O-、-OCH₂-、-CH₂CH₂-、又は、-CH₂OCH₂-であり、
R^8a、R^8b及びR^8cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₃-C₇シクロアルキル基、C₃-C₇シクロアルキルオキシ基、ヘテロシクロアルキル基、ヘテロシクロアルキルオキシ基、C₂-C₆アルケニル基、又は、C₂-C₆アルキニル基である。｝で表される基であり、
R^4a、R^4b及びR^4cは、それぞれ独立して、ハロゲン原子、水酸基、シアノ基、C₁-C₆アルキル基、水酸基で置換されていてもよいC₁-C₆アルキル基、C₁-C₆ハロアルキル基、水酸基で置換されていてもよいC₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₄アルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルキル基、C₁-C₄アルコキシ-C₁-C₄ハロアルキル基、C₁-C₄ハロアルコキシ-C₁-C₄ハロアルキル基、C₁-C₆アルキルカルボニル基、C₁-C₆アルコキシカルボニル基、C₁-C₆ハロアルキルカルボニル基、C₃-C₇シクロアルキル基、ハロゲン原子若しくはC₁-C₄ハロアルキル基で置換されていてもよいC₃-C₇シクロアルキル基、ヘテロシクロアルキル基、C₂-C₆アルケニル基、C₂-C₆アルケニルオキシ基、C₂-C₆アルケニルオキシ-C₁-C₄アルキル基、ハロゲン原子で置換されていてもよいC₂-C₆アルケニルオキシ-C₁-C₄アルキル基、C₂-C₆アルキニル基、ハロゲン原子若しくはメトキシ基で置換されていてもよいC₂-C₆アルキニル基、C₂-C₆アルキニルオキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルコキシ基、C₁-C₆アルキルチオ基、C₁-C₆ハロアルキルチオ基、C₁-C₄アルキルチオ-C₁-C₄アルキル基、C₁-C₄ハロアルキルチオ-C₁-C₄アルキル基、-(CH₂)_qNR^b1R^b2（q、R^b1及びR^b2は、前記(0)において示された定義と同義である。）、又は、一般式(I-B)

{In the formula,
Ring B is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ¹ represents a single _{bond, -CH 2 -, - CH 2} O -, - OCH 2 -, - CH 2 CH 2 -, or, -CH ₂ OCH ₂ - and is,
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₃ -C ₇ cycloalkyloxy group, heterocycloalkyl group, heterocycloalkyloxy group, C _2- C ₆ alkoxy group, or C _2- It is a C ₆ alkylyl group. } Is a group represented by
R ^4a , R ^4b and R ^4c are independently substituted with halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, hydroxyl group and C ₁ -C ₆ alkyl group, C _1-. C ₆ haloalkyl group, optionally substituted with hydroxyl group C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ Alkoxy group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ haloalkyl group, Substituted with C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyl group, C ₃ -C ₇ cycloalkyl group, halogen atom or C ₁ -C _{4 haloalkyl group} good C ₃ -C ₇ cycloalkyl group also, a heterocycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ alkyl group, May be substituted with halogen atom C ₂ -C ₆ Alkoxyoxy-C ₁ -C ₄ Alkoxy group, C ₂ -C ₆ Alkinyl group May be substituted with halogen atom or methoxy group C ₂ -C ₆ Alkinyl group, C _2- C ₆ alkynyloxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ alkyl _{group, - (CH 2) q NR} b1 R b2 (q, R b1 and R ^b2 is synonymous with the definition given in (0) above) or the general formula (IB).

{式中、
環Cは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L²は、単結合、-CH=CH-、-C≡C-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2O(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2NR^c(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2CO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2S(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、又は、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2SO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-であり（R^10a、R^10b、R^10c、R^10d、R^10e、R^10f、R^10g、R^10h、r1、r2、r3、r4及びR^cは、前記(0)において示された定義と同義である。）、
R^9a、R^9b及びR^9cは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₆アルコキシカルボニル基、ヘテロシクロアルキルオキシ基、又は、-(CH₂)_sNR^d1R^d2（s、R^d1及びR^d2は、前記(0)において示された定義と同義である。）である。}であり、
R^5a、R^5b、R^5c、R^6a、R^6b及びnは、前記(0)の（i）又は（ii）の構成のいずれかを充足する（但し、 R^5a、R^5b、R^5c、R^6a、R^6b及びnが前記（ii）の構成を充足する場合は、Y¹、Y²、Y³及びY⁴は一緒になって、−CH₂NR^4aHCH₂CH₂−を形成しない。）、ヘテロ芳香族アミド誘導体又はその塩からなる医薬（但し、R²が水素原子の場合は、Y¹、Y²、Y³、又は、Y⁴の少なくとも一つが、−CR^4aR^4b−、−CR^4aH−、−CH₂CR^4aR^4b−、−CH₂CR^4aH−、又は、−NR^4c−である。）。

{In the formula,
Ring C is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ² is a single bond, -CH = CH-, -C ≡ C ^{-,-(CR 10a R 10b} ) _r1 (CR ^10c R ^10d ) _r2 (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- , -(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 O (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 S (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- or
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- and (R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^10f , R ^10g , R ^10h , r1, r2, r3, r4 and R ^c are synonymous with the definitions given in (0) above),
R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, respectively. C ₁ -C ₆ haloalkoxy group, C ₁ -C ₆ alkoxycarbonyl group, heterocycloalkyloxy group, or-(CH ₂ ) _s NR ^d1 R ^d2 (s, R ^d1 and R ^d2 are the above (0). It is synonymous with the definition shown in.). } And
R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and n satisfy any of the configurations (i) or (ii) of (0) above (provided that R ^5a , R ^5b , R ^5c , If R ^6a , R ^6b and n satisfy the configuration of (ii) above, Y ¹ , Y ² , Y ³ and Y ⁴ together do not form _{−CH 2} NR ^4a HCH ₂ CH _{2 −.} ), A drug consisting of a heteroaromatic amide derivative or a salt thereof (however, if R ² is a hydrogen atom, at least one of ^{Y 1} , Y ² , Y ³ or Y ^{4 is −CR 4a} R ^4b − , -CR ^4a H-, -CH ₂ CR ^4a R ^4b- , -CH ₂ CR ^4a H-, or -NR ^4c- ).

B2) In the general formula (I),
R ^3a , R ^3b and R ^3c are independent hydrogen atom, halogen atom, cyano group, cyanomethyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group. , C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkynyl group, C _2- C ₆ Alkinyl group,-(CH ₂ ) _p NR ^a1 R ^a2 (p is 1, and R ^a1 and R ^a2 are independently hydrogen atom, methyl group, ethyl group, or 2,2. , 2-Trifluoroethyl group), or general formula (IA)

{式中、
環Bは、C₃-C₇シクロアルキル、モルホリノ、フェニル、ピラゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L¹は、単結合であり、
R^8a、R^8b及びR^8cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、又は、C₁-C₆ハロアルコキシ基である。｝で表される基である、ヘテロ芳香族アミド誘導体又はその塩からなる前記B1)に記載の医薬。

{In the formula,
Ring B is C _3- C ₇ cycloalkyl, morpholino, phenyl, pyrazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl,
L ¹ is a single bond,
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, or C ₁ -C ₆ Haloalkoxy group. } The pharmaceutical according to B1), which comprises a heteroaromatic amide derivative or a salt thereof, which is a group represented by.

B3) In the general formula (I), R ^4a , R ^4b and R ^4c are independently halogen atoms, hydroxyl groups, cyano groups, C _1- C ₆ alkyl groups, C ₁ -C ₆ haloalkyl groups and C. ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ - C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ alkyl _{group, - (CH 2) q NR} b1 R b2 (q, R b1 and R ^b2 are the ( It is synonymous with the definition shown in 0)) or the following formula.

（式中、R^9a、R^9b及びR^9cは、前記(0)において示された定義と同義である。）からなる群から選択される置換基である、ヘテロ芳香族アミド誘導体又はその塩からなる前記B1)又はB2)に記載の医薬。

(In the formula, R ^9a , R ^9b and R ^9c are synonymous with the definition shown in (0) above.) From a heteroaromatic amide derivative or a salt thereof, which is a substituent selected from the group consisting of. The pharmaceutical according to the above B1) or B2).

B4) In the general formula (IE),
X ¹ , X ² , R ^1a , and R ^1b are synonymous with the definitions given in (0) above.
Y ¹ , Y ² , Y ³ and Y ⁴ are independently single-bonded, −CH ₂ −, _{−CH 2} CH ₂ −, −CR ^4a R ^4b −, −CR ^4a H−, −CR ^4b H, respectively. −, −CH ₂ CR ^4a R ^4b −, −CH ₂ CR ^4a H−, −NR ^4c −, _{−NH−, −S−, −SO 2−} , or −O−,
Z ² −Z ³ is −CH ₂ −, −OCH ₂ −, −CH ₂ O−, −SCH ₂ −, −CH ₂ S−, −CH ₂ NR ^f1 −, −NR ^f1 CH ₂ −, −CH ₂ CH ₂ −, −CONR ^f1 −, −NR ^f1 CO −, −OCR ^f1 R ^f2 −, or −CR ^f1 R ^f2 O − (R ^f1 and R ^f2 are hydrogen atoms, C ₁ -C ₄ Alkyl group or C _1- C ₄ haloalkyl group),
R ² _{is a C 1-} C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C _2- C ₆ alkenyl group, or a C which may be substituted with a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a hydroxyl group. _2- C ₆ alkynyl group or
R ² is a halogen atom, a cyano group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkoxy group or -NR ^d1 R ^d2 (R). ^d1 and R ^d2 may be independently substituted with a hydrogen atom, a C _1- C ₄ alkyl group, or a C _1- C ₄ haloalkyl group), saturated, partially saturated or unsaturated, respectively. It is a 3- to 7-membered monocyclic ring,
R ^4a , R ^4b and R ^4c are independently substituted with halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, hydroxyl group and C ₁ -C ₆ alkyl group, C _1-. C ₆ haloalkyl group, optionally substituted with hydroxyl group C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ Alkoxy group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ haloalkyl group, Substituted with C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyl group, C ₃ -C ₇ cycloalkyl group, halogen atom or C ₁ -C _{4 haloalkyl group} good C ₃ -C ₇ cycloalkyl group also, a heterocycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ alkyl group, May be substituted with halogen atom C ₂ -C ₆ Alkoxyoxy-C ₁ -C ₄ Alkoxy group, C ₂ -C ₆ Alkinyl group May be substituted with halogen atom or methoxy group C ₂ -C ₆ Alkinyl group, C _2- C ₆ alkynyloxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ alkyl _{group, - (CH 2) q NR} b1 R b2 (q, R b1 and R ^b2 is synonymous with the definition given in (0) above) or the general formula (IB).

{式中、
環Cは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L²は、単結合、-CH=CH-、-C≡C-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、-(CR^10aR^10b)_r1(CR^10cR^10d)_r2O(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2NR^c(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2CO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2S(CR^10eR^10f)_r3(CR^10gR^10h)_r4-、又は、
-(CR^10aR^10b)_r1(CR^10cR^10d)_r2SO(CR^10eR^10f)_r3(CR^10gR^10h)_r4-であり（R^10a、R^10b、R^10c、R^10d、R^10e、R^10f、R^10g、R^10h、r1、r2、r3、r4及びR^cは、前記(0)において示された定義と同義である。）、
R^9a、R^9b及びR^9cは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₆アルコキシカルボニル基、ヘテロシクロアルキルオキシ基、又は、-(CH₂)_sNR^d1R^d2（s、R^d1及びR^d2は、前記(0)において示された定義と同義である。）である。}であり、
R^5aは、水素原子、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₃-C₇シクロアルキル基、ヘテロシクロアルキル基、C₃-C₇シクロアルキル-C₁-C₄アルキル基、ヘテロシクロアルキル-C₁-C₄アルキル基、又は、アラルキル基であり、
R^6a、R^6bは、それぞれ独立して、水素原子、ハロゲン原子、水酸基、シアノ基、C₁-C₄アルキル基、C₁-C₄ハロアルキル基、C₁-C₄アルコキシ基 、又は、C₁-C₄ハロアルコキシ基であり、
R^11aは、水素原子、ハロゲン原子、シアノ基、シアノメチル基、ホルミル基、ニトロ基、カルボキサミド基、水酸基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₄アルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルキル基、C₃-C₇シクロアルキル基、C₂-C₆アルケニル基、C₂-C₆アルケニルオキシ基、C₂-C₆アルキニル基、又は、C₂-C₆アルキニルオキシ基であり、
R^11b及びR^11cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、シアノメチル基、ホルミル基、ニトロ基、カルボキサミド基、水酸基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₁-C₄アルコキシ-C₁-C₄アルキル基、ジメチルアミノカルボニル基若しくはジメチルアミノ基で置換されていてもよいC₁-C₄アルコキシ-C₁-C₄アルキル基、C₁-C₄ハロアルコキシ-C₁-C₄アルキル基、C₁-C₄アルコキシ-C₁-C₄ハロアルキル基、C₁-C₄ハロアルコキシ-C₁-C₄ハロアルキル基、C₁-C₆アルキルカルボニル基、C₂-C₆アルケニル基、C₂-C₆アルキニル基、ハロゲン原子で置換されていてもよいC₂-C₆アルキニル基、C₁-C₆アルキルチオ基、C₁-C₆ハロアルキルチオ基、-(CH₂)_pNR^a1R^a2（p、R^a1及びR^a2は、前記(0)において示された定義と同義である。）、又は、一般式(I-A)

{In the formula,
Ring C is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ² is a single bond, -CH = CH-, -C ≡ C ^{-,-(CR 10a R 10b} ) _r1 (CR ^10c R ^10d ) _r2 (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- , -(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 O (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 S (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- or
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- and (R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^10f , R ^10g , R ^10h , r1, r2, r3, r4 and R ^c are synonymous with the definitions given in (0) above),
R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, respectively. C ₁ -C ₆ haloalkoxy group, C ₁ -C ₆ alkoxycarbonyl group, heterocycloalkyloxy group, or-(CH ₂ ) _s NR ^d1 R ^d2 (s, R ^d1 and R ^d2 are the above (0). It is synonymous with the definition shown in.). } And
R ^5a is a hydrogen atom, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, C ₃ -C ₇ cycloalkyl-C ₁ -C ₄ Alkyl group, heterocycloalkyl-C _1- C ₄ alkyl group, or aralkyl group,
R ^6a and R ^6b are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, or C. ₁ -C ₄ haloalkoxy group,
R ^11a is a hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group. , C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group, C ₃ -C ₇ cycloalkyl group, C _2- C ₆ Alkoxy Group, C _2- C ₆ Alkoxy Oxy Group, C _2- C ₆ Alkinyl Group, or C _2- C ₆ Alkoxy Oxy Group.
R ^11b and R ^11c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, C _1- C ₆ alkyl group, C _1- C ₆ haloalkyl group. , C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, optionally substituted with dimethylaminocarbonyl group or dimethylamino group C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ halo alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₆ alkylcarbonyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, an optionally C ₂ -C ₆ alkynyl optionally substituted with halogen atoms Group, C ₁ -C ₆ Alkoxy Group, C ₁ -C ₆ Halo Alkoxy Group,-(CH ₂ ) _p NR ^a1 R ^a2 (p, R ^a1 and R a ² are synonymous with the definitions given in (0) above. ) Or the general formula (IA)

{式中、
環Bは、C₃-C₇シクロアルキル、アゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリノ、フェニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、卜リアゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L¹は、単結合、-CH₂-、-CH₂O-、-OCH₂-、-CH₂CH₂-、又は、-CH₂OCH₂-であり、
R^8a、R^8b及びR^8cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、C₁-C₆ハロアルコキシ基、C₃-C₇シクロアルキル基、C₃-C₇シクロアルキルオキシ基、ヘテロシクロアルキル基、ヘテロシクロアルキルオキシ基、C₂-C₆アルケニル基、又は、C₂-C₆アルキニル基である。｝で表される基である（但し、R²が水素原子の場合は、Y¹、Y²、Y³、又は、Y⁴の少なくとも一つが、−CR^4aR^4b−、−CR^4aH−、−CH₂CR^4aR^4b−、−CH₂CR^4aH−、又は、−NR^4c−である。）、ヘテロ芳香族アミド誘導体又はその塩からなる医薬。

{In the formula,
Ring B is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ¹ represents a single _{bond, -CH 2 -, - CH 2} O -, - OCH 2 -, - CH 2 CH 2 -, or, -CH ₂ OCH ₂ - and is,
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₃ -C ₇ cycloalkyloxy group, heterocycloalkyl group, heterocycloalkyloxy group, C _2- C ₆ alkoxy group, or C _2- It is a C ₆ alkylyl group. } (However, if R ² is a hydrogen atom, at least one of ^{Y 1} , Y ² , Y ³ , or Y ^{4 is −CR 4a} R ^4b −, ^{−CR 4a} H−. ^{_{, -CH 2 CR 4a R 4b -}} , - CH 2 CR 4a H-, or, -NR ^4c -. a a) a pharmaceutical comprising a heteroaromatic amide derivative or a salt thereof.

B5) In the general formula (IE),
R ^11b and R ^11c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkoxy group, C ₂ -C ₆ Alkoxy group,-(CH ₂ ) _p NR ^a1 R ^a2 (p is 1, and R ^a1 and R ^a2 are independently hydrogen atom, methyl group, ethyl group, or 2,2,2- It is a trifluoroethyl group) or the general formula (IA).

{式中、
環Bは、C₃-C₇シクロアルキル、モルホリノ、フェニル、ピラゾリル、ピリジル、ピラジニル、ピリダジニル、又は、ピリミジニルであり、
L¹は、単結合であり、
R^8a、R^8b及びR^8cは、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C₁-C₆アルキル基、C₁-C₆ハロアルキル基、C₁-C₆アルコキシ基、又は、C₁-C₆ハロアルコキシ基である。｝で表される基である、ヘテロ芳香族アミド誘導体又はその塩からなる前記B4)に記載の医薬。

{In the formula,
Ring B is C _3- C ₇ cycloalkyl, morpholino, phenyl, pyrazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl,
L ¹ is a single bond,
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, or C ₁ -C ₆ Haloalkoxy group. } The pharmaceutical according to B4), which comprises a heteroaromatic amide derivative or a salt thereof, which is a group represented by.

B6) In the general formula (IE),
R ^4a , R ^4b and R ^4c are independent halogen atoms, hydroxyl groups, cyano groups, C _1- C ₆ alkyl groups, C ₁ -C ₆ haloalkyl groups, C ₁ -C ₆ alkoxy groups, C _1- C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkyl thio-C ₁ -C ₄ alkyl Group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ Alkoxy group,-(CH ₂ ) _q NR ^b1 R ^b2 (q, R ^b1 and R ^b2 are synonymous with the definitions given in (0) above. There is), or the following formula

（式中、R^9a、R^9b及びR^9cは、前記(0)において示された定義と同義である。）からなる群から選択される置換基である、ヘテロ芳香族アミド誘導体又はその塩からなる前記B4)又はB5)に記載の医薬。

(In the formula, R ^9a , R ^9b and R ^9c are synonymous with the definition shown in (0) above.) From a heteroaromatic amide derivative or a salt thereof, which is a substituent selected from the group consisting of. The pharmaceutical according to the above B4) or B5).

The salt of the compound represented by the general formula (I) is preferably a pharmacologically acceptable salt. The "pharmaceutically acceptable salt" is not particularly limited as long as it is a pharmacologically acceptable salt, but is an inorganic acid such as hydrochloride, hydrobromide, nitrate, sulfate, or phosphate. Organic carboxylates such as salts, acetates, oxalates, fumarates, maleates, malonates, citrates, succinates, lactates, tartrates, malates, salicylates, benzoic acids Aromatic carboxylates such as salts, organic sulfonates such as methanesulfonates, tosylates and benzenesulfonates, alkali metal salts such as lithium salts, sodium salts and potassium salts, alkaline earths such as calcium salts Examples include metal salts and magnesium salts.

In the compound represented by the general formula (I), when an asymmetric carbon is present, any of its racemate, diastereoisomer and individual optically active substance is included in the medicament of the present invention. Also, if a geometric isomer is present, any of the (E) form, the (Z) form and a mixture thereof are included in the medicament of the present invention.

In the compound represented by the general formula (I), if a solvate such as a hydrate is present, they are also included in the medicament of the present invention.

Next, the compound represented by the general formula (I) can be produced by various methods, and for example, a method shown below, a method similar to the following production method, or a synthetic method well known to those skilled in the art can be appropriately combined. Can be manufactured. All of the starting materials and reaction reagents used in these synthesis can be produced using commercially available or commercially available compounds according to methods well known to those of skill in the art. In addition, extraction, purification, and the like may be carried out in ordinary organic chemistry experiments. In addition, the order of the steps to be carried out can be appropriately changed for all the following steps.

The compound represented by the general formula (I) can be produced, for example, by the method represented by the following reaction formula-1.
<Reaction formula-1>

［式中、環A、R^1a、R^1b、R²、R^3a、R^3b、R^3c、R^5a、R^5b、R^5c、R^6a、R^6b、n、X¹、X²、Y¹、Y²、Y³、Y⁴及びZ¹については、前記(0)における一般式(I)について定義したとおりである。］

[In the equation, rings A, R ^1a , R ^1b , R ² , R ^3a , R ^3b , R ^3c , R ^5a , R ^5b , R ^5c , R ^6a , R ^6b , n, X ¹ , X ² , Y ¹ , Y ² , Y ³ , Y ⁴ and Z ¹ are as defined in the general formula (I) in (0) above. ]

(Step 1)
In step 1, the compound represented by the general formula (2) and the compound represented by the general formula (3) are generally subjected to a condensation reaction using a condensing agent in the presence or absence of a base. The compound represented by the formula (I) can be produced. Condensing agents include N, N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), 1,1'-carbonyldiimidazole (CDI), 2- Chloro-1-methylpyridinium iodine, propylphosphonic anhydride (cyclic trimmer), O- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) and the like.
Bases include trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nano-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,1,3,3-tetramethylguanidine, or 1 , 8-Diazabicyclo [5.4.0] -7-Organic bases such as undecene (DBU).
Examples of the reaction solvent include halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate; ethers such as tetrahydrofuran; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; acetone, methyl ethyl ketone and the like. Examples thereof include ketones; aromatic hydrocarbons such as toluene; and mixed solvents thereof. If necessary, a reaction reagent such as 1-hydroxybenzotriazole (HOBt) may be added.
The reaction temperature is not particularly limited, and is usually carried out at 0 ° C to 100 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

In addition, the compound represented by the general formula (2) can be induced into a reaction intermediate using an activator for a carboxyl group, and then reacted with the compound represented by the general formula (3). The compound represented by (I) can be produced.
Examples of the activator for the carboxyl group include thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosgene, triphosgene, 1,1'-carbonyldiimidazole, ethyl chlorocarbonate and the like.
Examples of the reaction solvent include aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, nitrobenzene and xylene; halogenated hydrocarbon solvents such as chloroform and dichloromethane; ethers such as tetrahydrofuran; ketones such as acetone and methyl ethyl ketone; acetonitrile and pro Examples thereof include nitriles such as pionitrile; and mixed solvents thereof.
The reaction temperature is not particularly limited, and is usually carried out at 0 ° C to 100 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

Among the compounds represented by the general formula (2) in the reaction formula-1, the compounds represented by the general formulas (2-a) and (2-b) are represented by, for example, the following reaction formula-2. It can be manufactured by the method.
<Reaction equation-2>

［式中、R^1a、R^1b、R^4a及びR^4cについては、前記(0)における一般式(I)について定義したとおりである。
LGは脱離基（例えば、塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基、又はp−トルエンスルホニルオキシ基等）であり、
R^alkは炭素数1〜8のアルキル基であり、YはCH、又はNであり、Y^3aはCH₂、又はNHである。］

[In the formula, R ^1a , R ^1b , R ^4a and R ^4c are as defined in the general formula (I) in (0) above.
LG is a leaving group (eg, chlorine atom, bromine atom, iodine atom, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, or p-toluenesulfonyloxy group, etc.).
R ^alk is an alkyl group with 1 to 8 carbon atoms, Y is CH or N, and Y ^3a is CH ₂ or NH. ]

(Step 2)
In step 2, the compound represented by the general formula (4) and the compound represented by the general formula (5) are subjected to a cyclization reaction in the presence or absence of a base, thereby subjecting the compound to the general formula (4). The compound represented by can be produced.
Bases include: potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium hydroxide, sodium hydroxide, water. Inorganic bases such as lithium oxide, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine , N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-dizabicyclo, 1,5-diazabicyclo [4.3.0] nano-5- Organic bases such as amine, 1,4-diazabicyclo [2.2.2] octane (DABCO), or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
Additives may coexist in order to carry out the reaction smoothly, and examples of the additives include potassium iodide, sodium iodide, tetrabutylammonium iodide, potassium bromide, sodium bromide, tetrabutylammonium bromide and the like. Be done.
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but is not particularly limited, but aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile and propionitrile; diethyl ether, tetrahydrofuran, 1, 4 Ethers such as −dioxane, 1,2-dimethoxyethane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetoamide, N-methylpyrrolidone, dimethylsulfoxide; and mixed solvents thereof. Be done.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 120 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

Further, the compound represented by the general formula (6) obtained in this step 2 is a palladium catalyst of various organic typical metal compounds (for example, a boronic acid derivative), which is a method well known to those skilled in the art. And by reacting in the presence of a base, the halogen atom (chlorine atom, bromine atom or iodine atom) of ^{R 4a} _{may be substituted C 1-} C ₆ alkyl group or optionally substituted saturated or unsaturated. It can be converted to a saturated 3, 4, 5, 6 or 7-membered monocyclic ring. This reaction may be carried out after the completion of step 2, and may be carried out after the subsequent step as appropriate as long as it does not affect the subsequent step. For example, a compound represented by the general formula (6) is mixed with a boronic acid derivative such as phenylboronic acid and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine in a mixed solvent of 1,4-dioxane and water. ) Converting a halogen atom (chlorine atom, bromine atom, or iodine atom) of ^{R 4a} into a substituent such as a phenyl group by reacting with a palladium catalyst such as dichloropalladium (II) and a base such as cesium carbonate. Can be done. Examples of the palladium catalyst include: palladium-carbon and metal palladium such as palladium black; tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium acetate, palladium chloride-1,1'-bis. Organopalladium salts such as (diphenylphosphino) ferrocene, or bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II); and polymer-supported bis (acetate) triphenylphosphine palladium (II) and Polymer-supported di (acetate) dicyclohexylphenylphosphine Palladium (II) and other polymer-immobilized organic palladium complexes and the like. These palladium catalysts may be used in combination.
The amount of the palladium catalyst added is usually 1 to 50 mol%, preferably 5 to 20 mol%, based on the compound represented by the general formula (6). Bases include: potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium hydroxide, sodium hydroxide, water. Inorganic bases such as lithium oxide, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride, or trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tri Butylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diazabicyclo, 1,5-diazabicyclo [4.3.0] nano-5 Organic bases such as −ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
Additives may coexist to facilitate the reaction, and the additives include: trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricyclos such as tricyclohexylphosphine. Alkylphosphins; triarylphosphines such as triphenylphosphine and tritrilphosphine; trialkylphosphites such as trimethylphosphite, triethylphosphite and tributylphosphite; tricycloalkylphosphite such as tricyclohexylphosphite; Triarylphosphite such as triphenylphosphite; imidazolium salts such as 1,3-bis (2,4,6-trimethylphenyl) imidazolium chloride; diketones such as acetylacetone and octafluoroacetylacetone; trimethylamine, triethylamine, Amines such as tripropylamine, triisopropylamine and tributylamine; 1,1'-bis (diphenylphosphino) ferrocene; 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl; 2-dicyclohexyl Phosphino-2', 6'-dimethoxybiphenyl;2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; 2- (di-tert-butylphosphino) -2', 4', 6 '-Triisopropylbiphenyl;2-dicyclohexylphosphino-2'-(N, N-dimethylamino) biphenyl; 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene; and 2- (di-tert -Butylphosphino) Biphenyl. These additives may be used in combination.
As the reaction solvent, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; diethyl ether, tetrahydrofuran, Ethers such as 1,4-dioxane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetoamide, dimethylsulfoxide; water; and mixed solvents thereof are included, but are not limited to these. ..
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 140 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

Further, the compound represented by the general formula (6) obtained in this step 2 can be converted into an alkynyl group by a method well known to those skilled in the art. Specifically, various alkyne compounds can be converted into alkynyl groups in which the halogen atom of ^{R 4a} may be substituted by allowing a palladium catalyst and a copper catalyst to act in the presence of a base. This reaction may be carried out after the completion of step 2, and may be carried out after the subsequent step as appropriate as long as it does not affect the subsequent step. For example, the compound represented by the general formula (6) is reacted with an alkyne derivative such as phenylacetylene and a palladium catalyst such as dichlorobis (triphenylphosphine) palladium, a copper catalyst such as copper iodide, and a base such as triethylamine in acetonitrile. By doing so, the halogen atom (chlorine atom, bromine atom or iodine atom) of ^{R 4a can be converted into a substituent such as a phenylalkynyl group.}
Bases include: potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium tert-butoxide , Inorganic bases such as potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholin, pyridine, 4- (N , N-dimethylamino) Pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] Nano-5-ene, 1,4-diazabicyclo [2.2. 2] Organic bases such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium acetate, palladium chloride-1,1'-bis (diphenylphosphino) ferrocene and the like.
The amount of the palladium catalyst added is usually 1 to 50 mol%, preferably 5 to 20 mol%, based on the compound represented by the general formula (6).
Examples of the copper catalyst include copper iodide and the like. The amount of the copper catalyst added is usually 1 to 50 mol%, preferably 5 to 20 mol%, based on the compound represented by the general formula (6).
As the reaction solvent, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; diethyl ether, tetrahydrofuran, Ethers such as 1,4-dioxane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, and dimethylsulfoxide can be mentioned, but are not limited thereto.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 140 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

Further, the compound represented by the general formula (6) obtained in this step 2 is obtained by allowing various alkyl halides, which are well known to those skilled in the art, to act in the presence of a base, thereby causing R ^4a. It is possible to convert the hydroxyl group of the above into an alkoxy group which may be substituted. This reaction may be carried out after the completion of step 2, and may be carried out after the subsequent step as appropriate as long as it does not affect the subsequent step. For example, by reacting a compound represented by the general formula (6) with an alkyl halide such as iodoethane and a base such as cesium carbonate in N, N-dimethylformamide, ^{the hydroxyl group of R 4a} is made into an alkoxy such as an ethoxy group. Can be converted to a group.
Bases include: potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium tert-butoxide , Inorganic bases such as potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholin, pyridine, 4- (N , N-dimethylamino) Pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] Nano-5-ene, 1,4-diazabicyclo [2.2. 2] Organic bases such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
As the reaction solvent, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ketones such as acetone Ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, etc. Not limited to these.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 100 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 3)
In step 3, the compound represented by the general formula (7) can be produced by subjecting the compound represented by the general formula (6) to a catalytic reduction reaction in the presence of a transition metal catalyst and hydrogen.
Examples of the transition metal catalyst include palladium carbon, palladium hydroxide, Raney nickel, platinum oxide and the like. The amount of the transition metal catalyst added is usually 5 times or less, preferably 0.01 to 0.5 times the weight of the compound represented by the general formula (6).
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but alcohols such as methanol and ethanol; esters such as methyl acetate and ethyl acetate; diethyl ether, tetrahydrofuran, 1,4-dioxane, 1, Ethers such as 2-dimethoxyethane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide; protic polar solvents such as acetic acid; water; and them. Examples of the mixed solvent of.
The reaction temperature is not particularly limited, and is usually 0 ° C. to 80 ° C., and is carried out under normal pressure or pressure. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 4)
In step 4, the compound represented by the general formula (7) can be produced by hydrolyzing the compound represented by the general formula (7) in the presence of a base or an acid.
Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, and the base may be used as an aqueous solution. Examples of the acid include hydrogen chloride, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid and the like.
The reaction solvent is appropriately selected depending on the type of base or acid used, but ethers such as tetrahydrofuran and 1,4-dioxane; nitriles such as acetonitrile and propionitrile; benzene, toluene, xylene and the like. Aromatic hydrocarbons; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide; alcohols such as methanol, ethanol, 2-propanol; water; and their mixed solvents Can be mentioned.
The reaction temperature is not particularly limited, and is usually carried out at 0 ° C to 100 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 48 hours.

(Step 5)
In step 5, the compound represented by the general formula (7) in which Y ^3a is NH is reacted with the compound represented by the general formula (8) or the compound represented by the general formula (9). , Is a step of producing a compound represented by the general formula (10).

By reacting the compound represented by the general formula (7) in which Y ^3a is NH with the compound represented by the general formula (8) in the presence or absence of a base, the general formula ( The compound represented by 10) can be produced.
Bases include: potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium tert-butoxide , Inorganic bases such as potassium fluoride, potassium hexamethyldisilazane, or sodium hydride: trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholin, pyridine, 4- (N , N-dimethylamino) Pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] Nano-5-ene, 1,4-diazabicyclo [2.2. 2] Organic bases such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
Additives may coexist in order to carry out the reaction smoothly, and examples of the additives include potassium iodide, sodium iodide, tetrabutylammonium iodide, potassium bromide, sodium bromide, tetrabutylammonium bromide and the like. Be done.
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but is not particularly limited, but aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile and propionitrile; diethyl ether, tetrahydrofuran, 1, 4 Ethers such as −dioxane, 1,2-dimethoxyethane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetoamide, N-methylpyrrolidone, dimethylsulfoxide; and mixed solvents thereof. Be done.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 120 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

Further, among the compounds represented by the general formula (7), the compound in which Y ^3a is NH and the compound represented by the general formula (9) are used with a reducing agent in the presence or absence of an acid or a base. By subjecting the compound to a reducing alkylation reaction, a compound represented by the general formula (10) can be produced.
Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, DBU and the like.
Examples of the acid used include formic acid, acetic acid, propionic acid, isobutyric acid, hexanic acid, p-toluenesulfonic acid, benzoic acid and the like.
The reducing agents used include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, dimethylamineborane, triethylamineborane, trimethylamineborane, tert-butylamineborane, N, N-diethylanilineborane, 2-picolinborane. And so on.
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but is not limited to aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol and 2-propanol; dichloromethane, chloroform, 1, Halogenized hydrocarbons such as 2-dichloroethane; nitriles such as acetonitrile and propionitrile; ketones such as acetone; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane; N, N-dimethylformamide, N , N-Dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and other aprotic polar solvents; and mixed solvents thereof.
The reaction temperature is not particularly limited, and is usually carried out at 0 ° C to 100 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 6)
In step 6, the compound represented by the general formula (10) is hydrolyzed in the presence of a base or an acid by the same method as that described in step 4 of the reaction formula -1, and thus the general formula ( The compound represented by 2-b) can be produced.

Among the compounds represented by the general formula (2) in the reaction formula-1, the compound represented by the general formula (2-c) can be produced, for example, by the method represented by the following reaction formula-3. can.
<Reaction equation-3>

［式中、R^4aについては前記(0)における一般式(I)について定義したとおりである。
R^alkは炭素数1〜8のアルキル基であり、Pは保護基であり、LGは脱離基(例えば、塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基、又はp-トルエンスルホニルオキシ基等)であり、Y^1aはO、又はNHであり、Y^3aは単結合、メチレン、又はエチレンである。］

[In the formula, R ^4a is as defined in the general formula (I) in (0) above.
R ^alk is an alkyl group with 1 to 8 carbon atoms, P is a protective group, LG is a leaving group (eg, chlorine atom, bromine atom, iodine atom, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, or p-toluenesulfonyloxy group, etc.), Y ^1a is O or NH, and Y ^3a is single bond, methylene, or ethylene. ]

The protective group represented by P is not particularly limited as long as it is generally used as a protective group for a hydroxyl group, and examples thereof include the following: lower alkyl groups such as methyl groups; methoxymethyl groups, Lower alkoxyalkyl group such as ethoxyethyl group; optionally substituted benzyl group (substituents include nitro group, lower alkoxy group, etc.); lower alkoxycarbonyl group; halogeno lower alkoxycarbonyl group; substituted Also good benzyloxycarbonyl group (substituents include nitro group, lower alkoxy group, etc.); acyl group such as acetyl group, benzoyl group; triphenylmethyl group; tetrahydropyranyl group; trimethylsilyl group, triethylsilyl group, Tri-substituted silyl groups such as t-butyldimethylsilyl group, triisopropylsilyl group, dimethylhexylsilyl group, t-butyldiphenylsilyl group and the like.

(Step 7)
In step 7, the compound represented by the general formula (11) and the compound represented by the general formula (12) are subjected to the action of the azodicarboxylic acid derivative and the phosphine derivative to obtain the general formula (13). The compound represented can be produced.
Examples of the azodicarboxylic acid derivative include ethyl azodicarboxylate, isopropyl azodicarboxylate, and 1,1'-(azodicarbonyl) dipiperidin.
Examples of the phosphine derivative include triphenylphosphine and tri-n-butylphosphine. Further, the same reaction can be carried out by using a phosphorane reagent such as cyanomethylenetributylphosphorane or cyanomethylenetrimethylphosphorane instead of the azodicarboxylic acid derivative and the phosphine derivative.
The reaction solvent is not particularly limited as long as it is a neutral solvent, and examples thereof include tetrahydrofuran, toluene, and a mixed solvent thereof.
The reaction temperature is not particularly limited, and is usually carried out at 0 ° C to 80 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

Further, after converting the hydroxyl group of the compound represented by the general formula (12) into a leaving group by a method well known to those skilled in the art, it reacts with the compound represented by the general formula (11) in the presence of a base. The compound represented by the general formula (13) can also be produced by allowing the compound to be produced.
Reagents for conversion to leaving groups include: thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, carbon tetrabromide, dimethylbromo. Sulfonium bromide, thionyl bromide, phosphorus triiodide, p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic acid anhydride, etc.
Bases include: potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium tert-butoxide , Inorganic bases such as potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholin, pyridine, 4- (N , N-dimethylaminopyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nano-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) ), Or organic bases such as 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
As the reaction solvent, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; diethyl ether, tetrahydrofuran, Ethers such as 1,4-dioxane, 1,2-dimethoxyethane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide; and mixtures thereof. Examples include, but are not limited to, solvents and the like.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 140 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 8)
In step 8, the compound represented by the general formula (13) can be produced by subjecting the compound represented by the general formula (13) to a deprotection reaction. Such deprotection reactions are described in methods well known to those of skill in the art (eg, "Protective Groups in Organic Synthesis (3rd Edition, 1999)" by Green and Wuts. You can do it according to the method etc.).

(Step 9)
In step 9, the compound represented by the general formula (16) is produced by allowing a halogenating agent and a phosphine derivative to act on the compound represented by the general formula (14) in the presence or absence of a base. be able to.
Bases include: potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium tert-butoxide , Inorganic bases such as potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholin, pyridine, 4- (N , N-dimethylaminopyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nano-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) ), Or organic bases such as 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
Examples of the halogenating agent include carbon tetrachloride, carbon tetrabromide, hexachloroacetone, hexabromoacetone, triphosgene, lithium bromide, methane iodide, bromine and iodine.
Examples of the phosphine derivative include triphenylphosphine and tri-n-butylphosphine.
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but is not limited to aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile and propionitrile; dichloromethane, chloroform, 1,2-. Halogenated hydrocarbons such as dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, Aprotic polar solvents such as dimethyl sulfoxide; and mixed solvents thereof can be mentioned.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 120 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 10)
In step 10, the compound represented by the general formula (11) and the compound represented by the general formula (15) are subjected to a cyclization reaction in the presence or absence of a base, thereby subjecting the compound to the general formula (16). The compound represented by can be produced.
Bases include: potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium tert-butoxide , Inorganic bases such as potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholin, pyridine, 4-N, N-dimethylaminopyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nano-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) , Or organic bases such as 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
Additives may coexist in order to carry out the reaction smoothly, and examples of the additives include potassium iodide, sodium iodide, tetrabutylammonium iodide, potassium bromide, sodium bromide, tetrabutylammonium bromide and the like. Be done.
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; acetonitrile. , Solvents such as propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, An aprotic polar solvent such as dimethyl sulfoxide; and a mixed solvent thereof can be mentioned.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 120 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 11)
In step 11, the compound represented by the general formula (16) is hydrolyzed in the presence of a base or an acid by the same method as that described in step 4 of the reaction formula-1 to obtain a general formula ( The compound represented by 2-c) can be produced.

Among the compounds represented by the general formulas (12) and (15) in the reaction formula-3, the compounds represented by the general formulas (12-a) and (15-a) are, for example, the following reaction formula-. It can be manufactured by the method shown in 4.
<Reaction equation-4>

［式中、R^4aについては前記(O)における一般式(I)について定義したとおりである。
各R^alkは、それぞれ独立して、炭素数1〜8のアルキル基であり、Pは保護基であり、LGは脱離基（例えば、塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基、又はp−トルエンスルホニルオキシ基等）であり、Halはハロゲン原子であり、Y^3aは単結合、メチレン、又はエチレンである。］

[In the formula, R ^4a is as defined in the general formula (I) in (O) above.
Each R ^alk is independently an alkyl group with 1 to 8 carbon atoms, P is a protective group, and LG is a desorbing group (eg, chlorine atom, bromine atom, iodine atom, methanesulfonyloxy group, (Trifluoromethanesulfonyloxy group, p-toluenesulfonyloxy group, etc.), H is a halogen atom, and Y ^3a is a single bond, methylene, or ethylene. ]

Examples of the protective group represented by P include the following: a lower alkyl group such as a methyl group; a lower alkoxyalkyl group such as a methoxymethyl group and an ethoxyethyl group; a benzyl group which may be substituted (as a substituent). Is a nitro group, a lower alkoxy group, etc.); a lower alkoxycarbonyl group; a halogeno lower alkoxycarbonyl group; a optionally substituted benzyloxycarbonyl group (substituents include a nitro group, a lower alkoxy group, etc.) Acrylic groups such as acetyl group and benzoyl group; triphenylmethyl group; tetrahydropyranyl group; trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, triisopropylsilyl group, dimethylhexylsilyl group, t-butyldiphenylsilyl Tri-substituted silyl groups such as groups.

(Step 12)
In step 12, the compound represented by the general formula (17) and the compound represented by the general formula (18) are reacted in the presence of zinc to produce the compound represented by the general formula (19). be able to. As the reaction solvent, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, and dimethylsulfoxide; and mixed solvents thereof include, but are not limited to. Additives may coexist in order to carry out the reaction smoothly, and examples of the additives include chlorotrimethylsilane and 1,2-dibromoethane. The reaction temperature is not particularly limited, and is usually carried out at room temperature to 120 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours. Further, the zinc powder and the compound represented by the general formula (18) can be treated in advance and used as a Reformatsky reagent in the reaction.

(Step 13)
In step 13, the compound represented by the general formula (20-a) can be produced by reducing the ester of the compound represented by the general formula (19) to an alcohol using a reducing agent. .. Examples of the reducing agent include lithium aluminum hydride, sodium borohydride, lithium borohydride, borane and the like. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but is not limited to aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol and 2-propanol; diethyl ether, tetrahydrofuran, 1 , 4-Dioxane and other ethers; N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and other aprotic polar solvents; and mixed solvents thereof. The reaction temperature is not particularly limited, and is usually carried out at 0 ° C to 100 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 14)
In step 14, the compound represented by the general formula (20-a) or the general formula (20-b) is subjected to the protection reaction of the primary hydroxyl group, and is represented by the general formula (12-a). Compounds can be produced and such protecting reactions are performed by methods well known to those skilled in the art (eg, by Green and Wuts, Protective Groups in Organic Synthesis (3rd Edition, 1999). ) ”)”.

(Step 15)
In step 15, leaving groups such as halogen atoms and substituted sulfonyloxy groups from the primary and secondary hydroxyl groups of the compound represented by the general formula (20-a) in the presence of a sulfonylating agent and a base. By converting to, the compound represented by the general formula (15-a) can be produced. Examples of the sulfonylating agent include methanesulfonyl chloride, ethanesulfonyl chloride, p-toluenesulfonyl chloride, phenylsulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride and the like. Bases include: potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium tert-butoxide , Inorganic bases such as potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholin, pyridine, 4- (N , N-dimethylamino) Pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] Nano-5-ene, 1,4-diazabicyclo [2.2. 2] Organic bases such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; acetonitrile; , Nitriles such as propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, An aprotic polar solvent such as dimethyl sulfoxide; and a mixed solvent thereof can be mentioned. The reaction temperature is not particularly limited, and the reaction is carried out at 0 ° C to 120 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

Further, by subjecting the primary and secondary hydroxyl groups of the compound represented by the general formula (20-a) to the Appel reaction using a halogenating agent and a phosphine derivative, the general formula (15-a) can also be used. The compound represented can be produced.
Examples of the halogenating agent include carbon tetrachloride, carbon tetrabromide, hexachloroacetone, hexabromoacetone, triphosgene, lithium bromide, methane iodide, bromine and iodine.
Examples of the phosphine derivative include triphenylphosphine and tri-n-butylphosphine.
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; acetonitrile; , Nitriles such as propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, An aprotic polar solvent such as dimethyl sulfoxide; and a mixed solvent thereof can be mentioned.
The reaction temperature is not particularly limited, and is usually carried out at 0 ° C to 120 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 16)
In step 16, the compound represented by the general formula (22) is produced by allowing the compound represented by the general formula (21) to act on the compound represented by the general formula (17) in the presence of a base. be able to.
Bases include: potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium tert-butoxide. , Inorganic bases such as potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholine, pyridine, 4- (N) , N-Dimethylamino) Pyridine, N, N-Dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] Nano-5-ene, 1,4-diazabicyclo [2.2. 2] Organic bases such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), 1,1,3,3-tetramethylguanidine.
As the reaction solvent, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate. Classes; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide; and mixed solvents thereof. , Not limited to these.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 120 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 17)
In step 17, the compound represented by the general formula (22) can be produced by subjecting the compound represented by the general formula (22) to a catalytic reduction reaction in the presence of a transition metal catalyst and hydrogen.
Examples of the transition metal catalyst include palladium carbon, palladium hydroxide, Raney nickel, platinum oxide and the like. The amount of the transition metal catalyst added is usually 5 times or less, preferably 0.01 to 0.5 times the weight of the compound represented by the general formula (22).
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include the following: alcohols such as methanol and ethanol; esters such as methyl acetate and ethyl acetate; diethyl ether, tetrahydrofuran, 1 , 4-Dioxane, 1,2-Dimethoxyethane and other ethers; N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and other aprotic polar solvents; Polar solvents; water; and mixed solvents thereof.
The reaction temperature is not particularly limited, and is usually 0 ° C. to 80 ° C., and is carried out under normal pressure or pressure. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 18)
In step 18, the ester of the compound represented by the general formula (23) is generally reduced to an alcohol using a reducing agent by the same method as that described in step 13 of the reaction formula-4. The compound represented by the formula (24) can be produced.

(Step 19)
In step 19, the hydroxyl group of the compound represented by the general formula (24) is replaced with a halogen atom or a halogen atom in the presence of a sulfonylating agent and a base by the same method as that described in step 15 of the reaction formula-4. A compound represented by the general formula (25) can be produced by converting it into a leaving group such as a sulfonyloxy group.
Further, among the compounds represented by the general formula (25), the compound in which LG is a chlorine atom acts on the compound represented by the general formula (24) with or without a formamide derivative. It can also be manufactured by allowing it to be produced.
Examples of the formamide derivative used include N, N-dimethylformamide and the like. Examples of the chlorinating agent used include thionyl chloride, phosphorus oxychloride, phosgene, oxalyl chloride, cyanuric chloride and the like.
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include the following: halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; aromatics such as benzene, toluene and xylene. Group hydrocarbons; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; N, N-dimethylformamide, N, N-dimethylacetamide , N-Methylpyrrolidone, dimethylsulfoxide and other aprotic polar solvents; and mixed solvents thereof.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 120 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 20)
In step 20, among the compounds represented by the general formula (25), R ^4a is a partially saturated or unsaturated 3- to 7-membered monocyclic ring, or a partially saturated or unsaturated 7 to 12-membered two-membered ring. A compound represented by the general formula (15-a) can be produced by allowing a halogenating agent to act on a compound having a cyclic ring in the presence of a radical initiator.
Radical initiators include azobis compounds such as 2,2'-azobis (isobutyronitrile) (AIBN), 2,2'-azobis (4-methoxy-2,4-dimethylvaleronitrile); and peroxides. Peroxides such as benzoyl and ditert-butyl peroxide can be mentioned. Examples of the halogenating agent used include chlorine, N-chlorosuccinimide, bromine, N-bromosuccinimide, sodium bromoisocyanurate, dibromoisocyanuric acid, 1,3-dibromo-5,5-dimethylhydantoin, iodine, and N-iodosuccinimide. And so on.
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include the following: halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride; monochlorobenzene, Aromatic hydrocarbons having electron-attracting groups on aromatic rings such as monobromobenzene and nitrobenzene; nitriles such as acetonitrile and propionitrile; diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxy Ethers such as ethane; hydrocarbons such as hexane, heptane and cyclohexane, esters such as methyl acetate, ethyl acetate and methyl propionate; water; and mixed solvents thereof.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 140 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 21)
In step 21, of the compounds represented by the general formula (26), R ^4a is a partially saturated or unsaturated 3- to 7-membered monocyclic ring, or a partially saturated or unsaturated 7 to 12-membered two-membered ring. A compound represented by the general formula (28) can be produced by allowing a palladium catalyst and a copper catalyst to act on a compound having a cyclic ring and a compound represented by the general formula (27) in the presence of a base. can.
Examples of the base include organic bases such as triethylamine and diisopropylethylamine.
Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium acetate, palladium chloride-1,1'-bis (diphenylphosphino) ferrocene and the like. The amount of the palladium catalyst added is usually 1 to 50 mol%, preferably 5 to 20 mol%, based on the compound represented by the general formula (26).
Examples of the copper catalyst include copper iodide and the like.
The amount of the copper catalyst added is usually 1 to 50 mol%, preferably 5 to 20 mol%, based on the compound represented by the general formula (26).
As the reaction solvent, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; diethyl ether, tetrahydrofuran, Ethers such as 1,4-dioxane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, and dimethylsulfoxide can be mentioned, but are not limited thereto.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 140 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 22)
In step 22, the compound represented by the general formula (28) is subjected to a catalytic reduction reaction in the presence of a transition metal catalyst and hydrogen by the same method as that described in step 17 of reaction formula-4. A compound represented by the general formula (23) can be produced.

Among the compounds represented by the general formula (2) in the reaction formula-1, the compound represented by the general formula (2-d) can be produced, for example, by the method represented by the following reaction formula-5. can.
<Reaction equation-5>

［式中、R^4cについては前記(0)における一般式(I)について定義したとおりである。また、R^alkは炭素数1〜8のアルキル基であり、Pは保護基であり、LGは脱離基（例えば、塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基、又はp−トルエンスルホニルオキシ基等）であり、Y^3aはメチレン、又はエチレンである。］

[In the equation, R ^4c is as defined in the general equation (I) in (0) above. R ^alk is an alkyl group having 1 to 8 carbon atoms, P is a protective group, and LG is a leaving group (for example, chlorine atom, bromine atom, iodine atom, methanesulfonyloxy group, trifluoromethanesulfonyloxy group). , Or p-toluenesulfonyloxy group, etc.), and Y ^3a is methylene or ethylene. ]

The protecting group represented by P is not particularly limited as long as it is generally used as a protecting group for an amino group, but for example, a tert-butoxycarbonyl (Boc) group, a benzyloxycarbonyl (Cbz), 9- Examples thereof include fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac) group, trifluoroacetyl group, benzyl (Bn) group, 4-methoxybenzyl (PMB) group and the like.

(Step 23)
In step 23, the compound represented by the general formula (29) and the compound represented by the general formula (30) are subjected to a reductive alkylation reaction using a reducing agent in the presence or absence of an acid or a base. The compound represented by the general formula (31) can be produced by subjecting to.
Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, potassium hexamethyldisilazane, triethylamine, diisopropylethylamine, and DBU.
Examples of the acid used include formic acid, acetic acid, propionic acid, isobutyric acid, hexanic acid, p-toluenesulfonic acid, benzoic acid and the like.
Examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, dimethylamineborane, triethylamineborane, trimethylamineborane, tert-butylamineborane, N, N-diethylanilineborane, 2-picolinborane and the like. Can be mentioned.
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but is not limited to aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol and 2-propanol; dichloromethane, chloroform, 1, Halogenized hydrocarbons such as 2-dichloroethane; nitriles such as acetonitrile and propionitrile; ketones such as acetone; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane; N, N-dimethylformamide, N , N-Dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and other aprotic polar solvents; and mixed solvents thereof.
The reaction temperature is not particularly limited, and is usually carried out at 0 ° C to 100 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 24)
In step 24, the compound represented by the general formula (31) and the compound represented by the general formula (32) are subjected to the presence of a base or by the same method as that described in step 10 of Reaction Scheme-3. By subjecting to the cyclization reaction in the absence, the compound represented by the general formula (33) can be produced.

(Step 25)
In step 25, the compound represented by the general formula (29) and the compound represented by the general formula (34) are reacted in the presence or absence of a base to be represented by the general formula (35). Can be produced.
Bases include: potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium tert-butoxide , Inorganic bases such as potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholin, pyridine, 4- (N , N-dimethylamino) Pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] Nano-5-ene, 1,4-diazabicyclo [2.2. 2] Organic bases such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
Additives may coexist in order to carry out the reaction smoothly, and examples of the additives include potassium iodide, sodium iodide, tetrabutylammonium iodide, potassium bromide, sodium bromide, tetrabutylammonium bromide and the like. Be done.
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; halogens such as dichloromethane, chloroform and 1,2-dichloroethane. Hydrocarbons; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; N, N-dimethylformamide, N, N-dimethylacetamide , N-Methylpyrrolidone, aprotic polar solvents such as dimethylsulfoxide; and mixed solvents thereof.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 120 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 26)
In step 26, the compound represented by the general formula (35) and the compound represented by the general formula (30) are subjected to acid or base by the same method as that described in step 23 of the reaction formula-5. The compound represented by the general formula (36) can be produced by subjecting the compound to a reductive alkylation reaction in the presence or absence of a reducing agent.

(Step 27)
In step 27, the halogenating agent and the phosphine derivative are acted on the compound represented by the general formula (36) in the presence or absence of a base by the same method as that described in step 9 of the reaction formula-3. By allowing the compound to be produced, the compound represented by the general formula (33) can be produced.

(Step 28)
In step 28, the compound represented by the general formula (37) can be produced by subjecting the compound represented by the general formula (37) to a deprotection reaction. Such deprotection reactions are described in methods well known to those of skill in the art (eg, "Protective Groups in Organic Synthesis (3rd Edition, 1999)" by Green and Wuts. The method may be followed.

(Step 29)
In step 29, the compound represented by the general formula (38) and the compound represented by the general formula (8) or the general formula (9) are subjected to the same method as that described in step 5 of the reaction formula-2. The compound represented by the general formula (33) can be produced by reacting with the compound represented by.

(Step 30)
In step 30, the compound represented by the general formula (33) is hydrolyzed in the presence of a base or an acid by the same method as that described in step 4 of the reaction formula-2. The compound represented by 2-d) can be produced.

Among the compounds represented by the general formula (2) in the reaction formula-1, the compound represented by the general formula (2-e) can be produced, for example, by the method represented by the following reaction formula-6. can.
<Reaction equation-6>

［式中、R^1a、R^1b、X¹、X²、Y¹、Y²、Y³及びY⁴については前記(0)における一般式(I)について定義したとおりである。
R^alkは炭素数1〜8のアルキル基であり、
R^g及びR^hは、それぞれ独立して、水素原子、又は置換されていてもよいアルキル基であるか、あるいは、
R^g及びR^hは、それらが結合する酸素原子と、その酸素原子が結合するホウ素原子と一緒になって、置換されていてもよい非芳香族複素環を形成し、
R^2aは置換されていてもよい部分飽和若しくは不飽和の3〜7員の単環式環であり、
Halはハロゲン原子(例えば、塩素原子、臭素原子、ヨウ素原子)である。］

[In the formula, R ^1a , R ^1b , X ¹ , X ² , Y ¹ , Y ² , Y ³ and Y ⁴ are as defined in the general formula (I) in (0) above.
R ^alk is an alkyl group with 1 to 8 carbon atoms.
R ^g and R ^h are each independently a hydrogen atom, or an optionally substituted alkyl group, or
R ^g and R ^h together with the oxygen atom to which they are bonded and the boron atom to which the oxygen atom is bonded form a non-aromatic heterocycle that may be substituted.
R ^2a is a partially saturated or unsaturated 3- to 7-membered monocyclic ring that may be substituted.
Hal is a halogen atom (eg, chlorine atom, bromine atom, iodine atom). ]

(Step 31)
In step 31, the compound represented by the general formula (40) can be produced by allowing a halogenating agent to act on the compound represented by the general formula (39).
Halogenating agents include chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5- Examples include dimethyl hydantin.
Appropriate acids such as acetic acid, trifluoroacetic acid and hydrochloric acid may be added to this reaction.
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; halogens such as dichloromethane, chloroform and 1,2-dichloroethane. Hydrocarbons; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; N, N-dimethylformamide, N, N-dimethylacetamide , N-Methylpyrrolidone, aprotic polar solvents such as dimethylsulfoxide; and mixed solvents thereof.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 140 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 32)
In step 32, the compound represented by the general formula (40) is represented by the general formula (42) by allowing the compound represented by the general formula (41) to act in the coexistence of a palladium catalyst and a base. Compounds can be produced.
Palladium catalysts include: palladium-carbon and metal palladium such as palladium black; tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium acetate, palladium-1,1'-bis chloride. Organopalladium salts such as (diphenylphosphino) ferrocene, or bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II); and polymer-supported bis (acetate) triphenylphosphine palladium (II) and Polymer-supported di (acetate) dicyclohexylphenylphosphine Palladium (II) and other polymer-immobilized organic palladium complexes and the like. These may be used in combination.
The amount of the palladium catalyst added is usually 1 to 50 mol%, preferably 5 to 20 mol%, based on the compound represented by the general formula (40).
Bases include: potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, potassium hexamethyldisilazane, triethylamine, diisopropylethylamine, or 1,8-diazabicyclo [ 5.4.0] -7-Undesen (DBU) etc.
Additives may coexist to facilitate the reaction, and the additives include: trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricyclos such as tricyclohexylphosphine. Alkylphosphins; triarylphosphines such as triphenylphosphine and tritrilphosphine; trialkylphosphites such as trimethylphosphite, triethylphosphite and tributylphosphite; tricycloalkylphosphite such as tricyclohexylphosphite; Triarylphosphite such as triphenylphosphite; imidazolium salts such as 1,3-bis (2,4,6-trimethylphenyl) imidazolium chloride; diketones such as acetylacetone and octafluoroacetylacetone; trimethylamine, triethylamine, Amines such as tripropylamine, triisopropylamine and tributylamine; 1,1'-bis (diphenylphosphino) ferrocene; 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl; 2-dicyclohexyl Phosphino-2', 6'-dimethoxybiphenyl;2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; 2- (di-tert-butylphosphino) -2', 4', 6 '-Triisopropylbiphenyl;2-dicyclohexylphosphino-2'-(N, N-dimethylamino) biphenyl; 4,5-bis (diphenylphosphino)-9,9-dimethylxanthene; and 2- (di-tert -Butylphosphino) Biphenyl. These additives may be used in combination.
As the reaction solvent, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, and dimethylsulfoxide; and mixed solvents thereof include, but are not limited to.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 140 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 33)
In step 33, the compound represented by the general formula (42) is hydrolyzed in the presence of a base or an acid by the same method as that described in step 4 of the reaction formula-2. The compound represented by 2-e) can be produced.

Among the compounds represented by the general formula (3) in the reaction formula-1, the compound represented by the general formula (3-a) can be produced, for example, by the method represented by the following reaction formula-7. can.
<Reaction equation-7>

［式中、R^3a、R^3b、R^3cについては前記(0)における一般式(I)について定義したとおりである。環A¹は3〜7員の単環式芳香族環であり、R^alkは炭素数1〜8のアルキル基であり、Pは保護基である。］

[In the equation, R ^3a , R ^3b , and R ^3c are as defined in the general equation (I) in (0) above. Ring A ¹ is a 3- to 7-membered monocyclic aromatic ring, R ^alk is an alkyl group with 1 to 8 carbon atoms, and P is a protecting group. ]

The protecting group represented by P is not particularly limited as long as it is generally used as a protecting group for an amino group, but for example, a tert-butoxycarbonyl (Boc) group, a benzyloxycarbonyl (Cbz), 9- Examples thereof include fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac) group, trifluoroacetyl group, benzyl (Bn) group, 4-methoxybenzyl (PMB) group and the like.

(Step 34)
In step 34, the compound represented by the general formula (45) is produced by allowing the compound represented by the general formula (44) to act on the compound represented by the general formula (43) in the presence of a base. be able to.
Bases include: potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium tert-butoxide. , Inorganic bases such as potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholin, pyridine, 4- (N , N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nano-5-ene, 1,4-diazabicyclo [2.2.2] octane ( DABCO), or organic bases such as 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), 1,1,3,3-tetramethylguanidine.
Examples of the reaction solvent include the following: aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile Esters such as ethyl acetate; Ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide; and these Mixed solvent. The reaction solvent is not limited to these.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 120 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Process 35)
In step 35, the compound represented by the general formula (46) can be produced by subjecting the compound represented by the general formula (45) to a catalytic reduction reaction in the presence of a transition metal catalyst and hydrogen.
Examples of the transition metal catalyst include palladium carbon, palladium hydroxide, Raney nickel, platinum oxide and the like.
The amount of the transition metal catalyst added is usually 5 times or less, preferably 0.01 to 0.5 times the weight of the compound represented by the general formula (45).
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include the following: alcohols such as methanol and ethanol; esters such as methyl acetate and ethyl acetate; diethyl ether, tetrahydrofuran, 1, Ethers such as 4-dioxane and 1,2-dimethoxyethane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide; protic polarities such as acetic acid Solvents; water; and mixed solvents thereof.
The reaction temperature is not particularly limited, and is usually 0 ° C. to 80 ° C., and is carried out under normal pressure or pressure. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 36)
In step 36, the compound represented by the general formula (47) can be produced by reducing the ester of the compound represented by the general formula (46) to an alcohol using a reducing agent.
Examples of the reducing agent include lithium aluminum hydride, sodium borohydride, lithium borohydride, borane and the like.
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol and 2-propanol; Ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide; and mixed solvents thereof.
The reaction temperature is not particularly limited, and is usually carried out at 0 ° C to 100 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 37)
In step 37, the compound represented by the general formula (48) can be produced by reacting the compound represented by the general formula (47) with the azodicarboxylic acid derivative and the phosphine derivative.
Examples of the azodicarboxylic acid derivative include ethyl azodicarboxylate, isopropyl azodicarboxylate, and 1,1'-(azodicarbonyl) dipiperidin.
Examples of the phosphine derivative include triphenylphosphine and tri-n-butylphosphine.
Further, the same reaction can be carried out by using a phosphorane reagent such as cyanomethylenetributylphosphorane or cyanomethylenetrimethylphosphorane instead of the azodicarboxylic acid derivative and the phosphine derivative.
The reaction solvent is not particularly limited as long as it is a neutral solvent, and examples thereof include tetrahydrofuran, toluene, and a mixed solvent thereof.
The reaction temperature is not particularly limited, and is usually carried out at 0 ° C to 80 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 38)
In step 38, the compound represented by the general formula (48) can be subjected to a deprotection reaction to produce the compound represented by the general formula (3-a). Such deprotection reactions are described in methods well known to those of skill in the art (eg, "Protective Groups in Organic Synthesis (3rd Edition, 1999)" by Green and Wuts. You can do it according to the method etc.).

Among the compounds represented by the general formula (3) in the reaction formula-1, the compound represented by the general formula (3-b) can be produced, for example, by the method represented by the following reaction formula-8. can.
<Reaction equation-8>

［式中、環A、R^3a、R^3b、R^3cについては前記(0)における一般式(I)について定義したとおりである。Halはハロゲン原子（例えば、塩素原子、臭素原子、ヨウ素原子）であり、MはMgBr、MgCl、Li、ZnBr、又はZnClであり、Pは保護基であり、Qは単結合、メチレン、エチレン、又は酸素原子である。］

[In the equation, rings A, R ^3a , R ^3b , and R ^3c are as defined in the general equation (I) in (0) above. Hal is a halogen atom (eg, chlorine atom, bromine atom, iodine atom), M is MgBr, MgCl, Li, ZnBr, or ZnCl, P is a protecting group, Q is a single bond, methylene, ethylene, Or it is an oxygen atom. ]

The protecting group represented by P is not particularly limited as long as it is generally used as a protecting group for an amino group, but for example, a tert-butoxycarbonyl (Boc) group, a benzyloxycarbonyl (Cbz), 9- Examples thereof include fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac) group, trifluoroacetyl group, benzyl (Bn) group, 4-methoxybenzyl (PMB) group and the like.

(Step 39)
In step 39, the compound represented by the general formula (52) can be produced by allowing the compound represented by the general formula (51) to act on the compound represented by the general formula (49).
As the compound represented by the general formula (51), a lithium reagent prepared by halometal exchange using a compound represented by the general formula (50) with a base such as normal butyllithium, sec-butyllithium, or tert-butyllithium. ; Grignard reagent prepared with magnesium, isopropylmagnesium bromide, isopropylmagnesium chloride, etc .; zinc reagent prepared with activated zinc, zinc bromide, zinc chloride, etc. can be mentioned.
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but tetrahydrofuran, diethyl ether, 1,4-dioxane, dimethoxyethane and the like are preferable.
The reaction temperature is not particularly limited, and is usually carried out at −100 ° C. to room temperature. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 40)
In step 40, the compound represented by the general formula (53) can be produced by allowing trialkylsilane to act on the compound represented by the general formula (52) in the presence of an acid.
Examples of the acid include trifluoroacetic acid.
Examples of the trialkylsilane include triethylsilane.
The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane are preferable.
The reaction temperature is not limited to the side and is usually carried out at 0 ° C to 50 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 41)
In step 41, the compound represented by the general formula (53) can be subjected to a deprotection reaction to produce the compound represented by the general formula (3-b). Such deprotection reactions are described in methods well known to those of skill in the art (eg, "Protective Groups in Organic Synthesis (3rd Edition, 1999)" by Green and Wuts. The method may be followed.

Among the compounds represented by the general formula (3) in the reaction formula-1, the compound represented by the general formula (3-c) can be produced, for example, by the method represented by the following reaction formula-9. can.
<Reaction equation-9>

［式中、環A、R^3a、R^3b、R^3cについては前記(0)における一般式(I)について定義したとおりである。mは0、1、又は2であり、Halはハロゲン原子（例えば、フッ素原子、塩素原子、又は臭素原子）であり、Pは保護基であり、Z^1aは、O、S、又はNHである。］

[In the equation, rings A, R ^3a , R ^3b , and R ^3c are as defined in the general equation (I) in (0) above. m is 0, 1, or 2, H is a halogen atom (eg, fluorine atom, chlorine atom, or bromine atom), P is a protecting group, Z ^1a is O, S, or NH. .. ]

The protecting group represented by P is not particularly limited as long as it is generally used as a protecting group for an amino group, but for example, a tert-butoxycarbonyl (Boc) group, a benzyloxycarbonyl (Cbz), 9- Examples thereof include fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac) group, trifluoroacetyl group, benzyl (Bn) group, 4-methoxybenzyl (PMB) group and the like.

(Step 42)
In step 42, the compound represented by the general formula (54) is reacted with the compound represented by the general formula (55) in the presence or absence of a base, thereby being represented by the general formula (56). Compounds can be produced.
Bases include: potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium tert-butoxide , Inorganic bases such as potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholin, pyridine, 4- (N , N-dimethylamino) Pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] Nano-5-ene, 1,4-diazabicyclo [2.2. 2] Organic bases such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
The reaction solvent is not particularly limited as long as it is a solvent that does not significantly inhibit the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile and propionitrile; diethyl ether. , Ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide; A mixed solvent of them.
The reaction temperature is not particularly limited, and is usually carried out at room temperature to 120 ° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

(Step 43)
In step 43, the compound represented by the general formula (56) can be subjected to a deprotection reaction to produce the compound represented by the general formula (3-c). Such deprotection reactions are described in methods well known to those of skill in the art (eg, "Protective Groups in Organic Synthesis (3rd Edition, 1999)" by Green and Wuts. The method may be followed.

The starting material, intermediate, or final product in the above production method can also be derived to another compound contained in the present invention by appropriately converting its functional group. Conversion of functional groups can be performed by methods well known to those skilled in the art (eg, methods described in "Comprehensive Organic Transformations (1989)" by R.C. Larock).

The compound represented by the general formula (I) produced by the above-mentioned method is isolated and purified as a free compound, a salt thereof, a hydrate thereof, a solvate thereof, or a polymorphic substance. good. The pharmaceutically acceptable salt of the compound of the present invention can be produced by a conventional salt-forming reaction. Isolation and purification may be carried out by applying chemical operations such as extraction fractionation, crystallization, and various fractional chromatography.

In addition, the optically active substance can be obtained as a stereochemically pure isomer by selecting an appropriate raw material compound or by optical resolution of the racemic mixture by a conventional method. For example, when a racemate is optically resolved using a chiral column, a method known to those skilled in the art (for example, "Separation of optical isomers" (Quarterly Chemistry Review No. 6, 1989, Journal of the Chemical Society of Japan)) Etc.). In addition, various chiral columns to be used are commercially available, and an appropriate one may be appropriately selected, and preferred examples thereof include CHIRALPAK IA, CHIRALPK IB, and CHIRALPAK IC manufactured by Daicel Corporation.

The heteroaromatic amide derivative or salt thereof contained in the medicament of the present invention may have optical isomers, stereoisomers, tautomers, and / or geometrical isomers. Includes all possible isomers and mixtures thereof, including. Similarly, the raw materials and intermediates for synthesizing the compounds contained in the medicament of the present invention may also have optical isomers, stereoisomers, tautomers, and / or geometrical isomers. Raw materials and intermediates used to make pharmaceuticals include all of these.

Prodrugs of the compounds contained in the medicament of the present invention can be prepared by, for example, a method known to those skilled in the art (for example, "Design of Prodrugs" H. Bundgaard (for example, "Design of Prodrugs"). It can be produced by substituting with a protecting group according to the method described in Elsevuer, 1985).

Since the compound contained in the medicament of the present invention or a salt thereof selectively inhibits Nav1.7 with respect to Nav1.5, there is little concern about side effects derived from Nav1.5, and a wide range of pathological conditions in which Nav1.7 is involved. It works very effectively against. Although there are various pathological conditions in which Nav1.7 is involved, the compound of the present invention or a salt thereof is effective for, for example, treating or preventing pain. More specifically, the compounds of the invention or salts thereof are particularly useful in the treatment or prevention of acute pain, chronic pain, nociceptive pain, neuropathic pain, and headache.
In addition, the compounds or salts thereof contained in the medicament of the present invention are particularly useful in the treatment or prevention of acute or chronic pruritus, autonomic nervous system-related diseases.

Nociceptive pain is pain caused by tissue damage, or strong stimuli that can cause damage, and includes the following pains:
Perioperative pain; Prolonged postoperative pain; Post-traumatic pain; Inflammatory pain; Cancer-related pain; Pain associated with osteoarthritis; Herpes zoster pain; Renosacral pain; Bladder pain; Visceral pain; Pain; Pain associated with heart disease; Pain associated with pancreatitis; Pain associated with contusion / contusion; Back pain; Pain associated with musculoskeletal disorders, and Pain associated with chronic arthritis.
Inflammatory pain includes pain associated with pathological conditions involving the following inflammatory factors:
Rheumatoid arthritis; interstitial cystitis; skin disorders (eg, sunburn, burns, eczema, dermatitis, or psoriasis); eye disorders (eg, glaucoma, retinitis, retinopathy, vasculitis, or acute eye tissue) Disorders); Pulmonary disease (eg, asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, respiratory urgency syndrome, or farmer's lung); Sexual ulcer, irritable bowel syndrome, inflammatory bowel syndrome, atopic gastrointestinal disorder, functional gastrointestinal disorders, gastroesophageal reflux syndrome, Crohn's disease, ileitis, or ulcerative colitis); Nodular periarteritis; thyroiditis; malregenerative anemia; Hodgkin's disease; strong skin disease; severe myasthenia; systemic erythematosus; Bechet's disease; Schoenglen syndrome; nephrosis syndrome; polymyositis; gingitis; and fever ..
Cancer-related pain includes pain associated with tumors and pain associated with cancer therapy.
Pain associated with musculoskeletal disorders includes myalgia, fibromyalgia, polymyositis, pyomyositis, and temporal mandibular fascial pain. Back pain includes pain due to abnormalities in the herniated disc, lumbar spine joint, sacroiliac joint, paraspinal muscles, or posterior longitudinal ligament.
Chronic arthropathy includes rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, and juvenile arthritis.

Neuropathic pain is pain caused by injury to the nervous system due to trauma or illness, and neuropathic pain includes many disorders derived from various causes. Neuropathic pain includes, but is not limited to, the following pains:
Peripheral neuropathy pain; Central neuropathy pain; Post-herpes zoster neuropathy; Diabetic neuropathy; Trifurcation neuropathy; Nonspecific low back pain; Cancer neuropathy pain; Pain associated with Parkinson's disease; Multiple neurosclerosis Pain associated with HIV-related neuropathy pain; sciatic nerve pain; complex local pain syndrome; spinal canal stenosis; carpal canal syndrome; phantom limb pain; post-stroke pain; pain associated with spinal cord injury; pain associated with epilepsy; spasm Pain associated with; pain associated with vitamin deficiency; familial limb erythema; primary limb erythema; paroxysmal severe pain; oral and facial pain; and results from oral burning syndrome, toxins or chronic inflammatory conditions Pain that occurs.
These allodynic pains include spontaneous pain, sensory disturbances and dysesthesia, hyperesthesia, high sensitivity to noxious stimuli (heat, cold, mechanical hyperalgesia), and painful sensations to non-noxious stimuli (dynamic, Static, fever, or cold allodynia), or hyperalgesia is included.

Headaches include migraine, cluster headaches, tension-type headaches, mixed-type headaches, vascular disorder-related headaches, secondary headaches, and autonomic headaches.

Pruritus includes pruritus associated with skin diseases, drug rash, renal dialysis-related pruritus, pruritus of the eyes, pruritus of the ears, pruritus bitten by insects, pruritus induced by opioids, pruritus associated with infection with viruses, etc. , Cutaneous lymphoma, and neuropathy pruritus.

Autonomic nerve-related diseases include autonomic imbalance, neurogenic gastric inflammation, irritable bowel syndrome, Meniere's disease, hyperventilation syndrome, and autonomic neuropathy.
However, the above-mentioned diseases as diseases mediated by the action of Nav1.7 are examples, and the above-mentioned diseases are not limited to the above-mentioned ones.

The medicament of the present invention comprises a novel heteroaromatic amide derivative or a salt thereof alone, or a mixture thereof with a pharmacologically acceptable solid or liquid pharmaceutical carrier, and is used in the art. It can be prepared by a conventional method. Examples of pharmacologically acceptable solid or liquid pharmaceutical carriers include:
For example, excipients, binders, disintegrants, disintegrants, fluidizers, lubricants, stabilizers, coatings, plasticizers, brighteners, bases, emulsifiers, thickeners, suspending agents, dispersions. Agents, solvents, solubilizers, solubilizers, surfactants, antioxidants, buffers, isotonic agents, pH regulators, preservatives, preservatives, fragrances, colorants, sweeteners, flavoring agents, and Other additives.

The medicament of the present invention can be orally or parenterally administered to mammals (for example, humans, monkeys, cows, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice, etc.). Dosage forms for administering the medicament of the present invention are exemplified as follows:
For example, tablets (including sugar-coated tablets and film-coated tablets), capsules, granules, powders, oral solutions, syrups, oral jelly agents, oral tablets, oral solutions, oral sprays, oral semi-solids, Injections, dialysis agents, inhalants, eye drops, eye ointments, ear drops, nasal drops, suppositories, rectal semi-solids, enema, vaginal tablets, vaginal suppositories, topical solids, External liquids (including liniments and lotions), sprays, ointments, creams, gels, patches, etc.
Further, the medicament of the present invention may be prepared with other drugs as needed.

When the medicament of the present invention is orally administered, the dosage form is not particularly limited as long as it is a dosage form used as a pharmaceutical composition for oral administration, and for example, an agent such as a tablet, a capsule, a granule, or a syrup. Can be prepared into shapes. In preparing the pharmaceutical product of the present invention consisting of these dosage forms, each dosage form can be prepared by a conventional method in the art.
Further, the dose and frequency of administration of the medicament of the present invention are not limited, and can be determined and / or adjusted in consideration of the age and body weight of the subject to be administered. For example, when orally administered to an adult patient, the amount of the compound of the present invention as an active ingredient or a salt thereof administered at one time is usually about 0.001 mg to about 1000 mg per kg body weight. , Can be administered at normal frequency.

The features of the present invention will be described in more detail with reference to Examples and Test Examples.
The materials, amounts used, ratios, treatment contents, treatment procedures, etc. shown in the following examples can be appropriately changed as long as they do not deviate from the gist of the present invention.
Therefore, the scope of the present invention should not be construed in a limited manner by the specific examples shown below.

^{The 1} H-NMR spectrum shown below is _{JNM with deuterated chloroform (CDCl 3} ), deuterated dimethylsulfoxide (DMSO-d ₆ ), and _{deuterated methanol (CD 3} OD) as solvents and tetramethylsilane (TMS) as the internal standard. -Measured with an ECA400 type spectrum meter (400 MHz, manufactured by JEOL Ltd.) or AVANCE III HD400 type (400 MHz, manufactured by Bruker Biospin Co., Ltd.). The chemical shift measurement results showed the δ value in ppm and the J value of the coupling constant in Hz. The abbreviation s means singlet, d means doublet, t means triplet, q means quartet, m means multiplet, and br means broad. The mass spectrum (ESI-MS) was measured by Exactive (manufactured by Thermo Fisher Scientific Co., Ltd.) by an electrospray ionization method. The chemical structural formulas and physical property values of the compounds in each example are shown in the table below.

In each embodiment, each abbreviation has the following meaning.
Ac: Acetyl
ADDP: 1,1'-(azodicarbonyl) dipiperidin
(A ^ta Phos) ₂ PdCl ₂ : Bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II)
Bn: benzyl
Boc: tert-butoxycarbonyl
BPO: Benzoyl peroxide
Bu: Butyl
CAN: Ammonium Cerium Nitrate (IV)
DAST: N, N-diethylaminosulfur trifluoride
DBU: Diazabicycloundesen
DCE: 1,2-dichloroethane
DCM: Dichloromethane
DDQ: 2,3-dichloro-5,6-dicyano-p-benzoquinone
DIAD: Diisopropyl azodicarboxylate
DIEA: N, N-diisopropylethylamine
DMAP: N, N-dimethyl-4-aminopyridine
DME: 1,2-dimethoxyethane
DMF: N, N-dimethylformamide
DMSO: Dimethyl sulfoxide
Et: Ethyl
EDCI: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
HATU: O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate
HOBt: 1-hydroxybenzotriazole
HPLC: high performance liquid chromatography
i: iso
IPA: Isopropyl alcohol
Me: Methyl
Ms: Methanesulfonyl
n: normal
NBS: N-Bromosuccinimide
NCS: N-Chlorosuccinimide
NIS: N-iodosuccinimide
NMM: N-methylmorpholine
nor-AZADO: 9-Azanor Adamantane N-Oxil
p: para
Ph: Phenyl
PTSA: p-toluenesulfonic acid
TBAB: Tetrabutylammonium bromide
TBA-HS: Tetrabutylammonium Hydrogen Sulfate
TBAI: Tetrabutylammonium iodide
TBAF: Tetrabutylammonium fluoride
Ruphos: 2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl
Ruphos Pd G3: (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl) [2- (2'-amino-1,1'-biphenyl)] palladium (II) methane Sulfonate
TBDPS: tert-butyldiphenylsilyl
tert: tertiary (tertiary)
tBuXphos: 2-di-tert-butylphosphino-2', 4', 6'-triisopropylbiphenyl
Tf: Trifluoromethylsulfonyl
TEA: Triethylamine
TFA: Trifluoroacetic acid
TFAA: Trifluoroacetic anhydride
THF: tetrahydrofuran
TMEDA: Tetramethylethylenediamine
TMS: Trimethylsilyl
TMG: 1,1,3,3-tetramethylguanidine
Ts: p-toluenesulfonyl
Xantphos: 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene
Xantphos Pd G3: [(4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene) -2- (2'-amino-1,1'-biphenyl)] palladium (II) methanesulfo Nate The asterisk (*) shown in the structural formula in the examples means that the corresponding asymmetric carbon has a single solid. Regarding the notation of "isomer A", "isomer B", "isomer C" and "isomer D", among the plurality of compounds indicated by the numbers of the same example, the high-speed liquid chromatography in the example is used first. It is identified by the notation of "isomer A", "isomer B", "isomer C" and "isomer D" in order from the isomers taken.

Example 1
Production of N- (6-fluorochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

Process 1
Ethyl bromopyruvic acid (776 μL, 6.18) in a mixed solution of 5- (trifluoromethyl) pyridine-2-amine (835 mg, 5.15 mmol) with 1,2-dimethoxyethane (12.9 mL) and methanol (12.9 mL). Ethyl) was added, and the mixture was stirred at 80 ° C. for 14 hours. After concentrating the reaction under reduced pressure, the residue was purified by silica gel column chromatography and ethyl 6- (trifluoromethyl) imidazole [1,2-a] pyridine-2-carboxylate (yield 557 mg, yield). 42%) was obtained.

Process 2
A mixed solution of ethyl 6- (trifluoromethyl) imidazole [1,2-a] pyridine-2-carboxylate (5.96 g, 23.1 mmol) in tetrahydrofuran (100 mL), ethanol (100 mL) and acetic acid (11.9 mL). 20% Palladium on carbon (2.43 g) was added thereto, and the mixture was stirred under pressure (about 3 atm) under a hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered through Celite, and then the solvent was distilled off under reduced pressure. Toluene was added to the residue, the solvent was distilled off under reduced pressure, and ethyl 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylate (yield). 6.42 g) was obtained as a crude product.

Process 3
Ethyl 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] Pyridine-2-carboxylate (6.42 g, 24.5 mmol) in ethanol (49 mL) solution at 4 mol / L Sodium hydroxide aqueous solution (24.5 mL, 98.0 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After adding 1 mol / L hydrochloric acid (98.0 mL, 98.0 mmol) to the reaction mixture, the solvent was distilled off under reduced pressure. The operation of adding toluene to the residue and distilling off the solvent under reduced pressure was repeated 3 times, and 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2- Carboxylic acid (yield 11.2 g, yield 98%) was obtained as a mixture with 4 equivalents of sodium chloride.

Process 4
N, N-dimethyl of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid (mixed sodium tetrachloride) (30.0 mg, 0.0641 mmol) HATU (29.2 mg, 0.0769 mmol), N, N-diisopropylethylamine (55 μL, 0.32 mmol) and 6-fluorochroman-3-amine hydrochloride (14.4 mg, 0.0705 mmol) were added to a formamide (641 μL) suspension. In addition, it was stirred at 40 ° C. for 6 hours. Water and ethyl acetate were added to the reaction solution to separate the layers, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography and N- (6-fluorochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8- Tetrahydroimidazo [1,2-a] pyridine-2-carboxamide (yield 17.9 mg, yield 73%) was obtained.

Reference example 1
Production of (R) -6-chlorochroman-3-amine hydrochloride

Process 1
N, N-diisopropylethylamine (555 μL, 3.23 mmol) and trifluoroacetic anhydride (180 μL) in a dichloromethane (11 mL) suspension of (R) -chroman-3-amine hydrochloride (200 mg, 1.08 mmol). , 1.29 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction under reduced pressure, the residue was purified by silica gel column chromatography to purify (R) -N- (chroman-3-yl) -2,2,2-trifluoroacetamide (yield 245 mg, yield). Rate 93%) was obtained.

Process 2
N-Chlorosuccinimide (2.60 g, 19.5 mmol) in a solution of (R) -N- (chroman-3-yl) -2,2,2-trifluoroacetamide (4.00 g, 16.3 mmol) in acetonitrile (100 mL). Was added, and the mixture was stirred at 70 ° C. for 6 hours. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution to separate the layers, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain (R) -N- (6-chlorochroman-3-yl) -2,2,2, -trifluoroacetamide (yield 4.60 g, yield 100%).

Process 3
(R) -N- (6-chlorochroman-3-yl) -2,2,2, -trifluoroacetamide (297 mg, 1.06 mmol) in chloroform (2.7 mL) solution in 4 mol / L sodium hydroxide aqueous solution (2.7 mL, 10.8 mmol) was added, and the mixture was stirred at room temperature for 17 hours. Water and chloroform were added to the reaction solution to separate the layers, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. After adding a 4 mol / L hydrogen chloride-ethyl acetate solution to the ethyl acetate solution of the purified compound, the precipitated solid was collected by filtration and (R) -6-chlorochroman-3-amine hydrochloride (yield 60.9). mg, yield 67%) was obtained.

Example 2
Production of N-((R) -6-chlorochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide Isomeric separation

Process 1
6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid (mixture of sodium tetrachloride) synthesized by the method described in step 3 of Example 1 In a suspension of (128 mg, 0.273 mmol) N, N-dimethylformamide (2.27 mL), HATU (95.0 mg, 0.250 mmol), N, N-diisopropylethylamine (195 μL, 1.14 mmol) and Reference Example 1. (R) -6-chlorochroman-3-amine hydrochloride (50.0 mg, 0.227 mmol) synthesized by the method described was added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration. The obtained solid was purified by silica gel column chromatography, and N-((R) -6-chlorochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1]. , 2-a] Pyridine-2-carboxamide (yield 60.9 mg, yield 67%) was obtained.

Process 2
N-((R) -6-chlorochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] Pyridine-2-carboxamide (50.0 mg) , 0.125 mmol) is dissolved in ethanol (20 mL) and subjected to HPLC preparative (column: CHIRALPAK IB, developing solvent: ethanol / n-hexane = 50/50, flow velocity: 5.0 mL / min, room temperature) and isomerized. A (yield 16.8 mg, yield 34%) and isomer B (yield 14.3 mg, yield 29%) were obtained.

Example 3
N-((R) -6-chlorochroman-3-yl) -N-methyl-6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] Pyridine-2- Carboxamide (isomer A)

N-((R) -6-chlorochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-] synthesized by the method described in Example 2. a] Sodium hydride (60% in oil) (12.5 mg, 0.313 mmol) and iodomethane in a solution of pyridine-2-carboxamide (isomer A) (50.0 mg, 0.125 mmol) in N, N-dimethylformamide (1.3 mL). (11.7 μL, 0.188 mmol) was added, and the mixture was stirred at 80 ° C. for 15 hours. Water, ethyl acetate and n-hexane were added to the reaction mixture to separate them. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -6-chlorochroman-3-yl) -N-methyl-6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole. [1,2-a] Pyridine-2-carboxamide (isomer A) (yield 24.4 mg, yield 47%) was obtained.

Example 4
N-((R) -6-chlorochroman-3-yl) -N-methyl-6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] Pyridine-2- Carboxamide (isomer B)

N-((R) -6-chlorochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] in the same manner as in Example 3. ] N-((R) -6-chlorochroman-3-yl) -6- (trifluoromethyl) -5 synthesized by the method described in Example 2 instead of pyridine-2-carboxamide (isomer A). , 6,7,8-Tetrahydroimidazo [1,2-a] Pyridine-2-carboxamide (isomer B) with N-((R) -6-chlorochroman-3-yl) -N-methyl- 6- (Trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxamide (isomer B) was obtained.

Reference example 2
Production of (R) -6-bromochroman-3-amine hydrochloride

Process 1
N-Bromosuccinimide (5.16 g, 29.0 mmol) in a solution of (R) -N- (chroman-3-yl) -2,2,2-trifluoroacetamide (6.46 g, 26.3 mmol) in acetonitrile (132 mL). Was added, and the mixture was stirred at room temperature for 22 hours. After concentrating the reaction under reduced pressure, the residue was purified by silica gel column chromatography and (R) -N- (6-bromochroman-3-yl) -2,2,2, -trifluoroacetamide (yield 8.47). g, yield 99%) was obtained.

Process 2
In the same manner as in step 3 of Reference Example 1, instead of (R) -N- (6-chlorochroman-3-yl) -2,2,2, -trifluoroacetamide, (R) -N-( (R) -6-bromochroman-3-amine hydrochloride was obtained using 6-bromochroman-3-yl) -2,2,2, -trifluoroacetamide.

Example 5
Production of N-((R) -6-bromochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

実施例1と同様の方法で、工程4の6-フルオロクロマン-3-アミン塩酸塩の代わりに、参考例2に記載の方法で合成した(R)-6-ブロモクロマン-3-アミン塩酸塩を用いて、N-((R)-6-ブロモクロマン-3-イル)-6-(トリフルオロメチル)-5,6,7,8-テトラヒドロイミダゾ［1,2-a］ピリジン-2-カルボキサミドを得た。

In the same manner as in Example 1, instead of 6-fluorochroman-3-amine hydrochloride in step 4, (R) -6-bromochroman-3-amine hydrochloride synthesized by the method described in Reference Example 2 was used. Using N-((R) -6-bromochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide. Obtained.

Reference example 3
Production of (R) -6- (difluoromethyl) chroman-3-amine hydrochloride

Process 1
(R) -N- (6-Bromochroman-3-yl) -2,2,2, -trifluoroacetamide (6.47 g, 20.0 mmol), potassium vinyl trifluoroborate (4.01 g, 29.9 mmol), cesium carbonate ( 13.0 g, 39.9 mmol) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (707 mg, 0.998 mmol) 1,4-dioxane (167 mL) and water (33 mL) ) Was stirred at 100 ° C. for 15 hours. Water and ethyl acetate were added to the reaction solution to separate the layers, and then the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography and (R) -2,2,2-trifluoro-N- (6-vinylchroman-3-yl) acetamide (yield 3.03). g, yield 56%) was obtained.

Process 2
Water (37 mL), 2, in a 1,4-dioxane solution of (R) -2,2,2-trifluoro-N- (6-vinylchroman-3-yl) acetamide (3.03 g, 11.2 mmol). Add 6-lutidine (2.6 mL, 22.3 mmol), sodium periodate (9.56 g, 44.7 mmol) and 2.5 w / v% osmium tetroxide t-butanol solution (5.7 mL, 0.56 mmol) and stir at room temperature for 3 hours. bottom. Water and ethyl acetate were added to the reaction mixture, and the mixture was filtered. After separating the filtrate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography and (R) -2,2,2-trifluoro-N- (6-formylroman-3-yl) acetamide (yield). 2.56 g, yield 84%) was obtained.

Process 3
(R) -2,2,2-trifluoro-N- (6-formylroman-3-yl) acetamide (1.45 g, 5.31 mmol) and N, N-diethylaminosulfur trifluoride (2.8 mL, 21.2 mmol) ) Was added, and the mixture was stirred at room temperature for 5 days. The reaction mixture was diluted with dichloromethane, added dropwise to a mixed solution of chloroform and water, and then separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and (R) -N- (6- (difluoromethyl) chroman-3-yl) -2,2,2-trifluoroacetamide (yield 1.11 g, yield 71%). Got

Process 4
In the same manner as in step 3 of Reference Example 1, instead of (R) -N- (6-chlorochroman-3-yl) -2,2,2, -trifluoroacetamide, (R) -N-( 6- (Difluoromethyl) chroman-3-yl) -2,2,2-trifluoroacetamide was used to obtain (R) -6- (difluoromethyl) chroman-3-amine hydrochloride.

Example 6
N-((R) -6- (difluoromethyl) chroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxamide Manufacturing of

In the same manner as in Example 1, instead of 6-fluorochroman-3-amine hydrochloride in step 4, the (R) -6- (difluoromethyl) chroman-3- was synthesized by the method described in Reference Example 3. Using amine hydrochloride, N-((R) -6- (difluoromethyl) chroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2- a] Pyridine-2-carboxamide was obtained.

Example 7
N-((R) -6- (difluoromethyl) chroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxamide Isomer separation

N-((R) -6- (difluoromethyl) chroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole synthesized by the method described in Example 6 [1] , 2-a] Pyridine-2-carboxamide (50.0 mg, 0.120 mmol) was dissolved in ethanol (20 mL) and preparative by HPLC (column: CHIRALPAK IB, developing solvent: ethanol / n-hexane = 50/50, flow velocity. : 10.0 mL / min, room temperature) to obtain isomer A (yield 24.4 mg, yield 49%) and isomer B (yield 21.4 mg, yield 43%).

Reference example 4
Production of 5-chlorochroman-3-amine hydrochloride

Process 1
2-Chloro-6-hydroxy-benzaldehyde (1.10 g, 7.03 mmol) in a solution of ice-cooled N- (tert-butoxycarbonyl) -2-phosphonoglycinetrimethyl (2.30 g, 7.73 mmol) in tetrahydrofuran (30 mL). And 1,1,3,3-tetramethylguanidine (970 μL, 7.73 mmol) in tetrahydrofuran (30 mL) were added, and the mixture was stirred at room temperature for 18 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography and methyl 2-((tert-butoxycarbonyl) amino) -3- (2-chloro-6-hydroxyphenyl) acrylate (yield 2.05). g, yield 89%) was obtained.

Process 2
3 mol / L in a solution of ice-cold methyl 2-((tert-butoxycarbonyl) amino) -3- (2-chloro-6-hydroxyphenyl) acrylate (2.05 g, 6.25 mmol) in tetrahydrofuran (60 mL). A lithium borohydride-tetrahydrofuran solution (14.6 mL, 43.8 mmol) was added, and the mixture was stirred at 30 ° C. for 18 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography and tert-butyl (1- (2-chloro-6-hydroxyphenyl) -3-hydroxypropan-yl) carbamate (yield 220 mg). , Yield 12%) was obtained.

Process 3
Triphenylphosphine (246 mg, 0.939 mmol) in tetrahydrofuran (2 mL) solution of tert-butyl (1- (2-chloro-6-hydroxyphenyl) -3-hydroxypropan-yl) carbamate (218 mg, 0.722 mmol). ), Diisopropyl azodicarboxylate (186 μL, 0.939 mmol) was added, and the mixture was stirred at room temperature for 18 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography to obtain tert-butyl (5-chlorochroman-3-yl) carbamate (yield 177 mg, yield 86%).

Process 4
To a solution of tert-butyl (5-chlorochroman-3-yl) carbamate (172 mg, 0.606 mmol) in ethyl acetate (4 mL) was added 4 mol / L hydrogen chloride-ethyl acetate solution (4.55 mL, 18.2 mL). , Stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain 5-chlorochroman-3-amine hydrochloride (yield 129 mg, yield 97%).

Example 8
Production of N- (5-chlorochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

In the same manner as in Example 1, instead of 6-fluorochroman-3-amine hydrochloride in step 4, 5-chlorochroman-3-amine hydrochloride synthesized by the method described in Reference Example 4 was used. N- (5-chlorochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide was obtained.

Example 9
N- (5-Bromochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-carboxamide (isomer A, enantiomer mixture) and Manufacture of (isomer B, enantiomer mixture)

In the same manner as in Example 1, 5-bromochroman-3-amine hydrochloride was used instead of 6-fluorochroman-3-amine hydrochloride in step 4, and N- (5-bromochroman-3-yl) was used. -6- (Trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide was obtained. Furthermore, the diastereomers were partitioned by silica gel column chromatography and N- (5-bromochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a]. ] Pyridine-2-carboxamide (isomer A, mixture of enantiomers) and N- (5-bromochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] ] Pyridine-2-carboxamide (isomer B, a mixture of enantiomers) was obtained.

Example 10
Production of N- (5-Cyclopropyl Chroman-3-yl) -6- (Trifluoromethyl) -5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-carboxamide

N- (5-Bromochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2 synthesized by the method described in Example 9. -Cesium carbonate (73.3 mg, 0.225 mmol) in a mixed solution of 1,4-dioxane (833 μL) and water (133 μL) of carboxamide (50.0 mg, 0.113 mmol) and cyclopropylboronic acid (14.5 mg, 0.169 mmol). ), Bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (7.9 mg, 0.011 mmol) was added, and the mixture was stirred at 140 ° C. for 1 hr under microwave irradiation. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and N- (5-cyclopropylchroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a]. Pyridine-2-carboxamide (yield 20.9 mg, yield 46%) was obtained.

Reference example 5
Production of (R) -6-ethylchroman-3-amine hydrochloride

Process 1
Ethanol (10.9) of (R) -2,2,2-trifluoro-N- (6-vinylchroman-3-yl) acetamide (148 mg, 0.546 mmol) synthesized by the method described in step 1 of Reference Example 3 20% Palladium hydroxide carbon (38.3 mg) was added to the mL) solution, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 12 hours. After filtering the reaction solution through Celite, the solvent was distilled off under reduced pressure to obtain (R) -N- (6-ethylchroman-3-yl) -2,2,2-trifluoroacetamide (yield 133 mg, yield). 89%) was obtained.

Process 2
In the same manner as in step 3 of Reference Example 1, instead of (R) -N- (6-chlorochroman-3-yl) -2,2,2, -trifluoroacetamide, (R) -N-( (R) -6-ethylchroman-3-amine hydrochloride was obtained using 6-ethylchroman-3-yl) -2,2,2-trifluoroacetamide.

Example 11
Production of N-((R) -6-ethylchroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

(R) -6-ethylchroman-3-amine hydrochloride synthesized by the method described in Reference Example 5 instead of 6-fluorochroman-3-amine hydrochloride in Step 4 in the same manner as in Example 1. N-((R) -6-ethylchroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2- Carboxamide was obtained.

Reference example 6
Production of 6-bromochroman-3-amine hydrochloride

6-Bromochroman-3-amine hydrochloride was obtained by using 5-bromo-2-hydroxy-benzaldehyde instead of 2-chloro-6-hydroxy-benzaldehyde in step 1 in the same manner as in Reference Example 4. ..

Example 12
Production of N- (6-Bromochroman-3-yl) -6- (Trifluoromethyl) -5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-carboxamide

In the same manner as in Example 1, 6-bromochroman-3-amine hydrochloride synthesized by the method described in Reference Example 6 was used instead of 6-fluorochroman-3-amine hydrochloride in step 4, and N -(6-Bromochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide was obtained.

Example 13
Production of N-((R) -6-methoxychroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

Process 1
N- (6-Bromochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2 synthesized by the method described in Example 12. -In a solution of carboxamide (50.0 mg, 0.113 mmol) in 1,4-dioxane (1.0 mL), water (500 μL), 85 w / w% potassium hydroxide (12.6 mg, 0.191 mmol), 2-di-tert-butyl Add phosphino-2', 4', 6'-triisopropylphenyl (4.8 mg, 0.011 mmol), tris (dibenzylideneacetone) palladium (0) (5.2 mg, 0.0056 mmol), and irradiate with a microwave at 120 ° C. Stirred for 1 hour. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and N- (6-hydroxychroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine. -2-Carboxamide (yield 34.5 mg, yield 80%) was obtained.

Process 2
N- (6-Hydroxychroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] Pyridine-2-carboxamide (15.0 mg, 0.0393 mmol) Cesium carbonate (25.6 mg, 0.0787 mmol) and methyl iodide (3.7 μL, 0.0590 mmol) were added to a solution of N, N-dimethylformamide (787 μL), and the mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -6-methoxychroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2]. -a] Pyridine-2-carboxamide (yield 12.0 mg, yield 77%) was obtained.

Reference example 7
Production of N-((R) -Chroman-3-yl) -6- (Trifluoromethyl) -5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-carboxamide

実施例1と同様の方法で、工程4の6-フルオロクロマン-3-アミン塩酸塩の代わりに、(R)-クロマン-3-アミン塩酸塩を用いて、N-((R)-クロマン-3-イル)-6-(トリフルオロメチル)-5,6,7,8-テトラヒドロイミダゾ［1,2-a］ピリジン-2-カルボキサミドを得た。

Using (R) -chroman-3-amine hydrochloride instead of 6-fluorochroman-3-amine hydrochloride in step 4, N-((R) -chroman- 3-Il) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide was obtained.

Example 14
Production of N-((R) -Chroman-3-yl) -3-iodo-6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

N-((R) -chroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine synthesized by the method described in Reference Example 7. To a solution of -2-carboxamide (79.7 mg, 0.218 mmol) in N, N-dimethylformamide (2.2 mL) was added N-iodosuccinimide (73.6 mg, 0.327 mmol), and the mixture was stirred at 80 ° C. for 14 hours. Further, N-iodosuccinimide (73.6 mg, 0.327 mmol) was added, and the mixture was stirred at 100 ° C. for 8 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -chroman-3-yl) -3-iodo-6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1, 2-a] Pyridine-2-carboxamide (yield 97.5 mg, yield 91%) was obtained.

Example 15
N-((R) -Chroman-3-yl) -3- (6-Methoxypyridin-2-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-Imidazo] a] Production of pyridine-2-carboxamide

N-((R) -Chroman-3-yl) -3-iodo-6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxamide (30.0) Cesium carbonate (39.8 mg, 0.122) in a mixed solution of 1,4-dioxane (500 μL) and water (100 μL) of mg, 0.0611 mmol) and 6-methoxypyridin-2-boronic acid (18.7 mg, 0.122 mmol). mmol) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (4.3 mg, 0.0061 mmol) were added, and the mixture was stirred at 140 ° C. for 1 hr under microwave irradiation. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -chroman-3-yl) -3- (6-methoxypyridin-2-yl) -6- (trifluoromethyl) -5,6, 7,8-Tetrahydroimidazole [1,2-a] pyridine-2-carboxamide (yield 9.4 mg, yield 33%) was obtained.

Example 16
Production of (R) -N- (Chroman-3-yl) -3-Phenyl-5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-carboxamide

Process 1
It was synthesized by the method described in Reference Example 9 instead of ethyl 6- (trifluoromethyl) imidazole [1,2-a] pyridine-2-carboxylate in the same manner as in Step 2 of Example 1 (R). )-6-Bromo-N- (chroman-3-yl) imidazole [1,2-a] using pyridine-2-carboxamide, (R) -N- (chroman-3-yl) -5,6, 7,8-Tetrahydroimidazole [1,2-a] pyridine-2-carboxamide was obtained.

Process 2
N-((R) -chroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-in the same manner as in Example 14. Using (R) -N- (chroman-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxamide instead of 2-carboxamide, (R)- N- (chroman-3-yl) -3-iodo-5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxamide was obtained.

Process 3
In the same manner as in Example 15, N-((R) -chroman-3-yl) -3-iodo-6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2- a] Instead of pyridine-2-carboxamide (R) -N- (chroman-3-yl) -3-iodo-5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide With phenylboronic acid instead of 6-methoxypyridin-2-boronic acid, (R) -N- (chroman-3-yl) -3-phenyl-5,6,7,8-tetrahydroimidazole [1,2-a] Pyridine-2-carboxamide was obtained.

Example 17
(R) -N- (6-chlorochroman-3-yl) -3- (6-methoxypyridin-2-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2 -Manufacture of carboxamide

Process 1
N-((R) -chroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-in the same manner as in Example 14. Ethyl 3-iodo-5,6,7,8-tetrahydroimidazole using ethyl 5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxylate instead of 2-carboxamide [1,2-a] 1,2-a] Pyridine-2-carboxylate was obtained.

Process 2
In the same manner as in Example 15, N-((R) -chroman-3-yl) -3-iodo-6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2- a] Ethyl 3- (6-methoxy) using ethyl 3-iodo-5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylate instead of pyridine-2-carboxamide. Pyridine-2-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylate was obtained.

Process 3
In the same manner as in Step 3 of Example 1, instead of ethyl 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylate, ethyl 3 -(6-Methylpyridin-2-yl) -5,6,7,8-Tetrahydroimidazole [1,2-a] Using pyridine-2-carboxylate, 3- (6-methoxypyridin-2-yl) )-5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-carboxylic acid was obtained as a mixture of 4 equivalents of sodium chloride.

Process 4
In the same manner as in Step 4 of Example 1, instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid, 3-( 6-methoxypyridin-2-yl) -5,6,7,8-tetrahydroimidazo [1,2-a] Pyridine-2-carboxylic acid was used instead of 6-fluorochroman-3-amine hydrochloride. Using the (R) -6-chlorochroman-3-amine hydrochloride synthesized by the method described in Reference Example 1, (R) -N- (6-chlorochroman-3-yl) -3- (6- (6- Methoxypyridin-2-yl) -5,6,7,8-tetrahydroimidazo [1,2-a] Pyridine-2-carboxamide was obtained.

Example 18
(R) -N- (6-Chlorochroman-3-yl) -3- (Pyridine-2-yl) -5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-carboxamide Manufacturing

Process 1
Ethyl 3- (6-chloropyridin-2) using 6- (chloropyridin-2-yl) boronic acid instead of 6-methoxypyridin-2-boronic acid in the same manner as in step 2 of Example 17. -Il) -5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-carboxylate was obtained.

Process 2
Ethyl 3- (6-chloropyridin-2-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylate (1.05 g, 3.43 mmol) in tetrahydrofuran (10 mL) Ethanol (10 mL), acetic acid (1.8 mL) and 20% palladium hydroxide carbon (0.72 g) were added to the solution, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at 50 ° C. for 2 hours. The reaction mixture was filtered through Celite, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and ethyl 3- (pyridin-2-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylate (yield 900 g, Yield 97%) was obtained.

Process 3
In the same manner as in Step 3 of Example 1, instead of ethyl 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylate, ethyl 3 -(Pyridine-2-yl) -5,6,7,8-Tetrahydroimidazole [1,2-a] Using pyridine-2-carboxylate, 3- (Pyridine-2-yl) -5,6, 7,8-Tetrahydroimidazole [1,2-a] pyridine-2-carboxylic acid was obtained as a mixture of 4 equivalents of sodium chloride.

Process 4
3- (Pyridine-2-yl) -5,6,7,8-tetrahydroimidazo [1,2-a] Pyridine-2-carboxylic acid (mixed with sodium tetrachloride) (15 mg, 0.031 mmol), Reference Example 1 (R) -6-chlorochroman-3-amine hydrochloride (6.9 mg, 0.031 mmol), 1-hydroxybenzotriazole (7.2 mg, 0.047 mmol) and 1-ethyl-3- (3) synthesized by the method described in 1. To a suspension of -dimethylaminopropyl) carbodiimide hydrochloride (9.0 mg, 0.047 mmol) in dichloromethane (1 mL) was added 4-methylmorpholine (21 μL, 0.19 mmol), and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and (R) -N- (6-chlorochroman-3-yl) -3- (pyridin-2-yl) -5,6,7,8-tetrahydroimidazole [1]. , 2-a] Pyridine-2-carboxamide (yield 8.0 mg, yield 62%) was obtained.

Reference example 8
Production of 3- (1H-Pyrazole-5-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylic acid

Using 1H-pyrazole-5-ylboronic acid instead of 6-methoxypyridin-2-boronic acid in step 2 in the same manner as in steps 2 and 3 of Example 17, 3- (1H-pyrazole-). 5-Il) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylic acid was obtained.

Example 19
(R) -3- (1H-pyrazole-5-yl) -N- (6- (trifluoromethyl) chroman-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] Production of pyridine-2-carboxamide

In the same manner as in Step 4 of Example 18, instead of 3- (pyridin-2-yl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid, reference Using 3- (1H-pyrazole-5-yl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-carboxylic acid synthesized by the method described in Example 8, (R) Using (R) -6- (trifluoromethyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 43 instead of -6-chlorochroman-3-amine hydrochloride, (R)- 3- (1H-Pyrazole-5-yl) -N- (6- (trifluoromethyl) chroman-3-yl) -5,6,7,8-tetrahydroimidazo [1,2-a] Pyridine-2- Carboxamide was obtained.

Example 20
(R) -3- (1H-pyrazole-5-yl) -N-(6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -5,6,7,8- Production of tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

In the same manner as in Step 4 of Example 18, instead of 3- (pyridin-2-yl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid, reference Using 3- (1H-pyrazole-5-yl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid synthesized by the method described in Example 8, (R) (R) -6-((2,2,2-trifluoroethoxy) methyl) chromane-3-amine hydrochloride synthesized by the method described in Reference Example 44 instead of -6-chlorochroman-3-amine hydrochloride Using salt, (R) -3- (1H-pyrazole-5-yl) -N- (6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -5,6 , 7,8-Tetrahydroimidazo [1,2-a] Pyridine-2-carboxamide was obtained.

Example 21
(R) -N- (6-chlorochroman-3-yl) -3- (1H-pyrazole-5-yl) -5,6,7,8-tetrahydroimidazo [1,2-a] Pyridine-2- Manufacture of carboxamide

In the same manner as in Example 17, 1H-pyrazole-5-boronic acid was used instead of 6-methoxypyridin-2-boronic acid in step 2, and (R) -N- (6-chlorochroman-3) was used. -Il) -3- (1H-Pyrazole-5-Il) -5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-carboxamide was obtained.

Example 22
Production of 3-Phenyl-N- (3- (Trifluoromethyl) Phenethyl) -5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-carboxamide

In the same manner as in Example 17, phenylboronic acid was used instead of 6-methoxypyridin-2-boronic acid in step 2, and instead of (R) -6-chlorochroman-3-amine hydrochloride in step 4. 3-Phenyl-N-(3- (trifluoromethyl) phenethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] with 2- (3-trifluoromethyl) phenyl) ethaneamine Pyridine-2-carboxamide was obtained.

Reference example 9
Production of (R) -6-bromo-N- (chroman-3-yl) imidazole [1,2-a] pyridine-2-carboxamide

6-Bromoimidazole instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylic acid in the same manner as in Step 4 of Example 1. [1,2-a] Pyridine-2-carboxylic acid was used, and (R) -chroman-3-amine hydrochloride was used instead of 6-fluorochroman-3-amine hydrochloride to (R)-. 6-Bromo-N- (chroman-3-yl) imidazole [1,2-a] pyridine-2-carboxamide was obtained.

Example 23
Production of N-((R) -Chroman-3-yl) -6-ethyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

Process 1
(R) -6-bromo-N- (chroman-3-yl) imidazo [1,2-a] pyridin-2-carboxamide (40.0 mg, 0.107 mmol) synthesized by the method described in Reference Example 9, potassium vinyl Of trifluoroborate (28.8 mg, 0.215 mmol), cesium carbonate (70.0 mg, 0.215 mmol) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (7.6 mg, 0.011 mmol) A mixed suspension of 1,4-dioxane (833 μL) and water (167 μL) was stirred at 90 ° C. for 16 hours. Water and ethyl acetate were added to the reaction solution to separate the layers, and then the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to purify (R) -N- (chroman-3-yl) -6-vinylimidazole [1,2-a] pyridine-2-. Carboxamide (yield 31.0 mg, yield 90%) was obtained.

Process 2
In the same manner as in Step 2 of Example 1, instead of ethyl 6- (trifluoromethyl) imidazole [1,2-a] pyridin-2-carboxylate, (R) -N- (chroman-3-yl) -6-Vinyl imidazole [1,2-a] Using pyridine-2-carboxamide, N-((R) -chroman-3-yl) -6-ethyl-5,6,7,8-tetrahydroimidazole [ 1,2-a] Pyridine-2-carboxamide was obtained.

Example 24
Production of N-((R) -Chroman-3-yl) -6-cyclopentyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

In the same manner as in Example 23, 2- (cyclopenten-1-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of the potassium vinyltrifluoroborate in step 1. N-((R) -Chroman-3-yl) -6-cyclopentyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide was obtained.

Reference example 10
Production of N-((R) -Chroman-3-yl) -6-Phenyl-5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-carboxamide

N-((R) -chroman-3-yl) -6-phenyl-5,6, using phenylboronic acid instead of potassium vinyltrifluoroborate in step 1 in the same manner as in Example 23, 7,8-Tetrahydroimidazo [1,2-a] pyridine-2-carboxamide was obtained.

Example 25
Production of 3-Chloro-N-((R) -Chroman-3-yl) -6-Phenyl-5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-carboxamide

N-((R) -chroman-3-yl) -6-phenyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxamide synthesized by the method described in Reference Example 10. N-Chlorosuccinimide (5.7 mg, 0.042 mmol) was added to a solution of (13.2 mg, 0.0354 mmol) in chloroform (2.4 mL), and the mixture was stirred at 70 ° C. for 20 hours. The reaction mixture was directly purified by silica gel column chromatography and 3-chloro-N-((R) -chroman-3-yl) -6-phenyl-5,6,7,8-tetrahydroimidazole [1,2-a]. ] Pyridine-2-carboxamide (yield 12.4 mg, yield 86%) was obtained.

Reference example 11
Production of (6-Bromoimidazo [1,2-a] Pyridine-2-yl) (3-Phenylpyrrolidine-1-yl) Metanone

Using 3-phenylpyrrolidine instead of (R) -chroman-3-amine hydrochloride in the same manner as in Reference Example 9, (6-bromoimidazole [1,2-a] pyridin-2-yl) ( 3-Phenylpyrrolidine-1-yl) metanone was obtained.

Example 26
Production of (6- (2-Methoxypyridin-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-yl) (3-phenylpyrrolidine-1-yl) methanone

In the same manner as in Example 23, instead of (R) -6-bromo-N- (chroman-3-yl) imidazole [1,2-a] pyridin-2-carboxamide in step 1, in Reference Example 11. Using the (6-bromoimidazole [1,2-a] pyridin-2-yl) (3-phenylpyrrolidin-1-yl) methanone synthesized by the method described, instead of the potassium vinyltrifluoroborate of step 1, Using (2-methoxypyridin-3-yl) boronic acid, (6- (2-methoxypyridin-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2 -Il) (3-phenylpyrrolidin-1-yl) metanone was obtained.

Reference example 12
Production of (R) -N- (Chroman-3-yl) -6-iodoimidazo [1,2-a] Pyridine-2-carboxamide

6- (Trifluoromethyl) -5,6,7,8-Tetrahydroimidazo [1,2-a] 6-iodoimidazo instead of pyridine-2-carboxylic acid in the same manner as in Step 4 of Example 1. [1,2-a] Pyridine-2-carboxylic acid was used, and (R) -chroman-3-amine hydrochloride was used instead of 6-fluorochroman-3-amine hydrochloride to (R)-. N- (chroman-3-yl) -6-iodoimidazo [1,2-a] pyridine-2-carboxamide was obtained.

Example 27
N-((R) -Chroman-3-yl) -6- (6-methoxypyridin-2-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] Pyridine-2-carboxamide Manufacturing

Described in Reference Example 12 in place of (R) -6-bromo-N- (chroman-3-yl) imidazole [1,2-a] pyridin-2-carboxamide in step 1 in the same manner as in Example 23. (R) -N- (chroman-3-yl) -6-iodoimidazole [1,2-a] pyridin-2-carboxamide synthesized by the method of (3) was used instead of potassium vinyltrifluoroborate. N-((R) -Chroman-3-yl) -6- (6-methoxypyridin-2-yl) -5,6,7,8-tetrahydroimidazole with -methoxy-2-pyridyl) boronic acid [1,2-a] Pyridine-2-carboxamide was obtained.

Reference example 13
Production of (6-iodoimidazo [1,2-a] pyridin-2-yl) (3-((6-methoxypyridin-2-yl) oxy) pyrrolidine-1-yl) metanone

In the same manner as in Reference Example 12, 2-methoxy-6- (pyrrolidin-3-yloxy) pyridine was used instead of (R) -chroman-3-amine hydrochloride, and ((6-iodoimidazo [1] , 2-a] Pyridine-2-yl) (3-((6-Methoxypyridin-2-yl) oxy) pyrrolidine-1-yl) metanone was obtained.

Example 28
(6-Cyclopentyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-yl) (3-((6-methoxypyridin-2-yl) oxy) pyrrolidine-1-yl) Manufacture of methanone

In the same manner as in Example 23, instead of (R) -6-bromo-N- (chroman-3-yl) imidazole [1,2-a] pyridin-2-carboxamide in step 1, in Reference Example 13. Using ((6-iodoimidazole [1,2-a] pyridin-2-yl) (3-((6-methoxypyridin-2-yl) oxy) pyrrolidine-1-yl) methanone produced by the method described. , (6-Cyclopentyl- using 2- (cyclopenten-1-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of potassium vinyltrifluoroborate in step 1 5,6,7,8-Tetrahydroimidazole [1,2-a] pyridin-2-yl) (3-((6-methoxypyridin-2-yl) oxy) pyrrolidine-1-yl) metanone was obtained.

Reference example 14
Production of (6-iodoimidazo [1,2-a] pyridin-2-yl) (3- (pyridin-2-yloxy) pyrrolidine-1-yl) metanone

Using 2- (pyrrolidin-3-yloxy) pyridine instead of (R) -chroman-3-amine hydrochloride in the same manner as in Reference Example 12, (6-iodoimidazo [1,2-a] Pyridine-2-yl) (3- (pyridin-2-yloxy) pyrrolidine-1-yl) metanone was obtained.

Example 29
Production of (6-phenethyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2yl) (3- (pyridin-2-yloxy) pyrrolidine-1-yl) metanone

Process 1
(6-Iodoimidazo [1,2-a] pyridin-2-yl) (3- (pyridin-2-yloxy) pyrrolidine-1-yl) methanone (30.0 mg, 0.0691) synthesized by the method described in Reference Example 14. In an acetonitrile (691 μL) solution of mmol), phenylacetylene (15.2 μL, 0.138 mmol), triethylamine (38.4 μL, 0.276 mmol), copper (I) iodide (2.6 mg, 0.014 mmol), cesium carbonate (45.0 mg,) 0.138 mmol) and (1,1'-bis (diphenylphosphino) ferrocene) dichloropalladium (II) (10.1 mg, 0.0138 mmol) were added, and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was filtered through Celite, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and (6- (phenylethynyl) imidazole [1,2-a] pyridin-2yl) (3- (pyridine-2-yloxy) pyrrolidine-1-yl) metanone (yield). 24.3 mg, yield 86%) was obtained.

Process 2
In the same manner as in Step 2 of Example 1, instead of ethyl 6- (trifluoromethyl) imidazole [1,2-a] pyridin-2-carboxylate, (6- (phenylethynyl) imidazole [1,2] -a] Pyridine-2yl) (3- (pyridin-2-yloxy) pyrrolidine-1-yl) using methanone, (6-phenethyl-5,6,7,8-tetrahydroimidazole [1,2-a] ] Pyridine-2 yl) (3- (pyridin-2-yloxy) pyrrolidine-1-yl) metanone was obtained.

Example 30
(2-Benzylazetidine-1-yl) (6- (2- (trifluoromethyl) pyridin-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-yl Il) Manufacture of methanone

Process 1
In the same manner as in Step 1 of Step 23, instead of (R) -6-bromo-N- (chroman-3-yl) imidazole [1,2-a] pyridine-2-carboxamide, ethyl 6-iodoimidazole [1,2-a] Pyridine-2-carboxylate is used instead of potassium vinyltrifluoroborate, 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl). ) -2- (Trifluoromethyl) pyridine was used to obtain ethyl 6- (2- (trifluoromethyl) pyridin-3-yl) imidazole [1,2-a] pyridine-2-carboxylate.

Process 2
Ethyl 6- (2- (trifluoromethyl) pyridine" instead of ethyl 6- (trifluoromethyl) imidazole [1,2-a] pyridine-2-carboxylate in the same manner as in Step 2 of Example 1. -3-yl) Imidazo [1,2-a] Pyridine-2-carboxylate with ethyl 6- (2- (trifluoromethyl) pyridin-3-yl) -5,6,7,8-tetrahydro Imidazo [1,2-a] pyridine-2-carboxylate was obtained.

Process 3
In the same manner as in Step 3 of Example 1, instead of ethyl 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylate, ethyl 6 -(2- (Trifluoromethyl) Pyridine-3-yl) -5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-carboxylate, 6- (2- (Trifluoromethyl) Fluoromethyl) Pyridine-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxylic acid was obtained as a mixture with 24 equivalents of sodium chloride.

Process 4
6- (2) instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid in the same manner as in step 4 of Example 1. -(Trifluoromethyl) Pyridine-3-yl) -5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-carboxylic acid, 6-fluorochroman-3-amine hydrochloride Using 2-benzylazetidine hydrochloride instead, (2-benzylazetidine-1-yl) (6- (2- (trifluoromethyl) pyridin-3-yl) -5,6,7,8- Tetrahydroimidazo [1,2-a] pyridin-2-yl) metanone was obtained.

Example 31
Production of (2-benzylazetidine-1-yl) (6-cyclohexyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-yl) methanone

Process 1
In the same manner as in Example 30, phenylboronic acid was used instead of 3- (4,4,5,5-tetramethyl-1,3-dioxolan-2-yl) -2- (trifluoromethyl) pyridine. To obtain ethyl 6-phenylimidazole [1,2-a] pyridine-2-carboxylate.

Process 2
A 4 mol / L sodium hydroxide aqueous solution (5.8 mL, 23.2 mmol) in an ethanol (25.8 mL) solution of ethyl 6-phenylimidazole [1,2-a] pyridine-2-carboxylate (2.06 g, 7.74 mmol). In addition, it was stirred at room temperature for 40 minutes. After neutralizing by adding 2 mol / L hydrochloric acid to the reaction solution, the precipitated solid was collected by filtration and 6-phenylimidazo [1,2-a] pyridine-2-carboxylic acid (yield 712 mg, yield 39%). Got

Process 3
6-Phenylimidazole [1,2-a] Pyridine-2-carboxylic acid (1.50 g, 6.30 mmol) in methanol (63 mL) solution with acetic acid (360 μL, 6.30 mmol) and platinum oxide (IV) (200.0 mg). ) Was added, and the mixture was stirred under pressure (about 4 atm), in a hydrogen atmosphere, and at room temperature for 4 hours. After filtering the reaction solution through Celite, the solvent was distilled off under reduced pressure to add 6-cyclohexyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid (yield 207 mg). It was obtained as a mixture with 6-phenyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylic acid (yield 1.49 g).

Process 4
6- (2- (Trifluoromethyl) Pyridine-3-yl) -5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-in in the same manner as in Step 4 of Example 30. Instead of carboxylic acid, 6-cyclohexyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxylic acid and 6-phenyl-5,6,7,8-tetrahydroimidazole [1] , 2-a] Using a mixture of pyridine-2-carboxylic acid, (2-benzylazetidine-1-yl) (6-cyclohexyl-5,6,7,8-tetrahydroimidazole [1,2-a] Pyridine-2-yl) methanone was obtained.

Reference example 15
Production of 2- (2,4-difluorophenyl) morpholine

Process 1
A 1.6 mol / L n-butyllithium-n-hexane solution (1.67 mL,) in a solution of 1-bromo-2,4-difluorobenzene (575 mg, 2.98 mmol) in tetrahydrofuran (3 mL) cooled to -78 ° C. 2.73 mmol) was added, and the mixture was stirred for 20 minutes, then a solution of tert-butyl 2-oxomorpholin-4-carboxylate (500 mg, 2.48 mmol) in tetrahydrofuran (3 mL) was added, and the mixture was stirred at −78 ° C. for 1 hour. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain tert-butyl 2- (2,4-difluorophenyl) -2-hydroxymorpholine-4-carboxylate (yield 540 mg, yield). The rate was 69%).

Process 2
Trifluoroacetic acid (8.56 mL, 112) in a solution of ice-cooled tert-butyl 2- (2,4-difluorophenyl) -2-hydroxymorpholine-4-carboxylate (540 mg, 1.71 mmol) in dichloromethane (8.6 mL). mmol) and triethylsilane (547 μL, 3.43 mmol) were added, and the mixture was stirred at room temperature for 12 hours. Toluene was added to the reaction solution, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution and chloroform were added, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2- (2,4-difluorophenyl) morpholine (yield 408 mg) as a crude product. ..

Example 32
(2- (2,4-difluorophenyl) morpholino) (6- (2-methoxy-5- (trifluoromethyl) pyridin-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-] a] Manufacture of pyridin-2-yl) methanone

Process 1
In the same manner as in Step 1 of Example 30, instead of ethyl 6-iodoimidazole [1,2-a] pyridine-2-carboxylate, ethyl 6-bromoimidazole [1,2-a] pyridine-2- Using carboxylate, instead of 3- (4,4,5,5-tetramethyl-1,3-dioxolan-2-yl) -2- (trifluoromethyl) pyridine, (2-methoxy-5- (2-methoxy-5- ( With trifluoromethyl) pyridin-3-yl) boronic acid, ethyl 6- (2-methoxy-5- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-a] pyridin-2-carboxy Got a rate.

Process 2
Ethyl 6- (2- (trifluoromethyl) pyridin-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2 in the same manner as in step 3 of Example 30. Instead of -carboxylate, use ethyl 6- (2-methoxy-5- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-a] pyridin-2-carboxylate, 6- (2) -Methoxy-5- (trifluoromethyl) pyridin-3-yl) imidazole [1,2-a] pyridin-2-carboxylic acid was obtained.

Process 3
In the same manner as in Step 2 of Example 30, instead of ethyl 6- (2- (trifluoromethyl) pyridin-3-yl) imidazole [1,2-a] pyridin-2-carboxylate, 6-( 2-methoxy-5- (trifluoromethyl) Pyridine-3-yl) Imidazo [1,2-a] Pyridine-2-carboxylic acid, 6- (2-methoxy-5- (trifluoromethyl) pyridine -3-yl) -5,6,7,8-Tetrahydroimidazo [1,2-a] Pyridine-2-carboxylic acid was obtained.

Process 4
6- (2- (Trifluoromethyl) Pyridine-3-yl) -5,6,7,8-Tetrahydroimidazole [1,2-a] Pyridine-2-in in the same manner as in Step 4 of Example 30. Instead of carboxylic acid, 6- (2-methoxy-5- (trifluoromethyl) pyridin-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxylic acid , And instead of 2-benzyl azetidine hydrochloride, 2- (2,4-difluorophenyl) morpholin produced by the method described in Reference Example 15 was used to (2- (2,4-difluorophenyl). Morphorino) (6- (2-methoxy-5- (trifluoromethyl) pyridin-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-yl) metanone rice field.

Example 33
Production of N-((R) -Chroman-3-yl) -6- (phenoxymethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

Process 1
Bromopyruvic acid (615 mg, 3.68 mmol) was added to a solution of ice-cooled ethyl 6-aminonicotinate (510 mg, 3.07 mmol) in acetonitrile (15.3 mL), and the mixture was stirred under heating under reflux for 14 hours. The reaction solution was ice-cooled, and the precipitated solid was collected by filtration. The obtained solid was washed with acetonitrile to obtain 6- (ethoxycarbonyl) imidazole [1,2-a] pyridine-2-carboxylic acid (yield 295 mg, yield 41%).

Process 2
6- (ethoxy) instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid in the same manner as in step 4 of Example 1. Using (carbonyl) imidazo [1,2-a] pyridin-2-carboxylic acid and using (R) -chroman-3-amine hydrochloride instead of 6-fluorochroman-3-amine hydrochloride, ( R) -Ethyl 2- (chroman-3-ylcarbamoyl) imidazole [1,2-a] pyridine-2-carboxylate was obtained.

Process 3
In the same manner as in Step 2 of Example 1, instead of ethyl 6- (trifluoromethyl) imidazole [1,2-a] pyridine-2-carboxylate, (R) -ethyl 2- (chroman-3-a) Ethyl 2-((R) -chroman-3-ylcarbamoyl) -5,6,7,8-tetrahydroimidazole [1,2 -a] Pyridine-6-carboxylate was obtained.

Process 4
Ice-cooled ethyl 2-((R) -chroman-3-ylcarbamoyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-6-carboxylate (578 mg, 1.56 mmol) To a solution of tetrahydrofuran (7.8 mL) was added 3 mol / L lithium borohydride-tetrahydrofuran solution (2.61 mL, 7.82 mmol), and the mixture was stirred at 50 ° C. for 4 hours. A saturated aqueous solution of ammonium chloride, water, chloroform and methanol were added to the ice-cooled reaction solution, and the layers were separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography and N-((R) -chroman-3-yl) 6- (hydroxymethyl) -5,6,7,8-tetrahydro. Imidazo [1,2-a] pyridine-2-carboxamide (yield 520 mg, yield 101%) was obtained.

Process 5
Ice-cooled N-((R) -chroman-3-yl) 6- (hydroxymethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-carboxamide (165 mg, 0.504) Triethylamine (210 μL, 1.51 mmol) and methanesulfonyl chloride (78.2 μL, 1.01 mmol) were added to a solution of (mmol) in dichloromethane (1.7 mL), and the mixture was stirred at room temperature for 1 hour. Water and chloroform were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (2-((R) -chroman-3-ylcarbamoyl) -5,6. , 7,8-Tetrahydroimidazo [1,2-a] Pyridine-6-yl) methylmethanesulfonate (yield 155 mg, yield 76%) was obtained.

Process 6
Sodium hydride (60% in oil) (11.8 mg, 0.296 mmol) was added to a solution of phenol (27.9 mg, 0.296 mmol) in N, N-dimethylformamide (493 μL), and the mixture was stirred at room temperature for 30 minutes. 2-((R) -Chroman-3-ylcarbamoyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-6-yl) methylmethanesulfonate (40.0 mg, 0.0986 mmol) in the reaction solution ) N, N-Dimethylformamide (493 μL) solution was added, and the mixture was stirred at 60 ° C. for 2 hours. Water and chloroform were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to purify N-((R) -chroman-3-yl) -6- (phenoxymethyl). )-5,6,7,8-Tetrahydroimidazole [1,2-a] pyridine-2-carboxamide (yield 25.4 mg, yield 64%) was obtained.

Example 34
Production of 6- (tert-butoxymethyl) -N-((R) -chroman-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

Ice-cooled N-((R) -chroman-3-yl) 6- (hydroxymethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxamide (51.0 mg, 0.156) To a solution of mmol) in dichloromethane (779 μL) was added tert-butyl 2,2,2-trichloroacetoimidate (83.6 μL, 0.467 mmol) and boron trifluoride diethyl ether complex (23.5 μL, 0.187 mmol) at room temperature. Was stirred for 14 hours. A saturated aqueous sodium hydrogen carbonate solution, water, chloroform and methanol were added to the ice-cooled reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to purify 6- (tert-butoxymethyl) -N-((R) -chroman-3. -Il) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide (yield 2.7 mg, yield 4.5%) was obtained.

Example 35
Production of N-((R) -Chroman-3-yl) -6- (1-fluorocyclobutyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

Process 1
(R) -6-bromo-N- (chroman-3-yl) imidazo [1,2-a] pyridine-2-carboxamide (100 mg,) synthesized by the method described in Reference Example 9 cooled to -78 ° C. To a solution of 0.269 mmol) in tetrahydrofuran (5 mL) was added a solution of 1.64 mol / L n-butyllithium-n-hexane (344 μL, 0.564 mmol), and the mixture was stirred at −78 ° C. for 20 minutes. Cyclobutanone (41.4 mg, 0.591 mmol) in tetrahydrofuran (3 mL) was added to the reaction mixture, and the mixture was stirred at −78 ° C. for 1 hr and then at room temperature for 6 hr. A saturated aqueous sodium chloride solution and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography to purify (R) -N- (chroman-3-yl) -6- (1-). Hydroxycyclobutyl) imidazo [1,2-a] pyridine-2-carboxamide (yield 26.0 mg, yield 27%) was obtained.

Process 2
Ethanol (3 mL) solution of (R) -N- (chroman-3-yl) -6- (1-hydroxycyclobutyl) imidazole [1,2-a] pyridin-2-carboxamide (21.0 mg, 0.0578 mmol) Platinum oxide (IV) (4.0 mg) was added to the mixture, and the mixture was stirred under pressure (about 4 atm) and in a hydrogen atmosphere at room temperature for 20 hours. The reaction mixture was filtered through Celite, and then the solvent was distilled off under reduced pressure. Residue Purified by silica gel column chromatography, N-((R) -chroman-3-yl) -6- (1-hydroxycyclobutyl) -5,6,7,8-tetrahydroimidazo [1,2-a ] Pyridine-2-carboxamide (yield 18.5 mg, yield 87%) was obtained as a crude product.

Process 3
Ice-cooled N-((R) -chroman-3-yl) -6- (1-hydroxycyclobutyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxamide ( To a solution of 15.0 mg, 0.0408 mmol) in dichloromethane (1.36 mL) was added N, N-diethylaminosulfur trifluoride (11 μL, 0.082 mmol), and the mixture was stirred at room temperature for 1 hr. A saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added to the reaction solution, and the layers were separated. The organic layer is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography to purify N-((R) -chroman-3-yl) -6- (1-. Fluorocyclobutyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxamide (yield 9.0 mg, yield 60%) was obtained.

Example 36
Production of 6- (tert-butyl) -N-((R) -chroman-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

Process 1
Ethyl 6- (tert-) using 5- (tert-butyl) pyridine-2-amine instead of 5- (trifluoromethyl) pyridine-2-amine in the same manner as in Step 1 of Example 1. Butyl) imidazo [1,2-a] pyridine-2-carboxylate was obtained.

Process 2
In the same manner as in Step 3 of Example 1, instead of ethyl 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylate, ethyl 6 -(tert-Butyl) imidazole [1,2-a] pyridine-2-carboxylate was used to give 6- (tert-butyl) imidazole [1,2-a] pyridine-2-carboxylic acid.

Process 3
In the same manner as in Step 4 of Example 1, instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid, 6-( Use tert-butyl) imidazo [1,2-a] pyridine-2-carboxylic acid and use (R) -chroman-3-amine hydrochloride instead of 6-fluorochroman-3-amine hydrochloride. As a result, (R) -6- (tert-butyl) -N- (chroman-3-yl) imidazo [1,2-a] pyridine-2-carboxamide was obtained.

Process 4
In the same manner as in Step 2 of Example 1, instead of ethyl 6- (trifluoromethyl) imidazole [1,2-a] pyridine-2-carboxylate, (R) -6- (tert-butyl)- Using N- (chroman-3-yl) imidazole [1,2-a] pyridin-2-carboxamide, 6- (tert-butyl) -N-((R) -chroman-3-yl) -5, 6,7,8-Tetrahydroimidazole [1,2-a] pyridine-2-carboxamide was obtained.

Example 37
N-((R) -Chroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxamide Manufacturing of

Process 1
Ethyl 6-hydroxyimidazole [1,2-] using 6-aminopyridine-3-ol instead of 5- (trifluoromethyl) pyridine-2-amine in the same manner as in Step 1 of Example 1. a] Pyridine-2-carboxylate was obtained.

Process 2
Sodium hydride (60% in oil) in an N, N-dimethylformamide (34 mL) solution of ice-cooled ethyl 6-hydroxyimidazole [1,2-a] pyridine-2-carboxylate (1.38 g, 6.69 mmol). (535 mg, 13.4 mmol) was added, and the mixture was stirred for 5 minutes, 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.93 mL, 13.4 mmol) was added, and the mixture was stirred at 80 ° C. for 1 hour. Water and ethyl acetate were added to the reaction solution to separate the layers, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography and ethyl 6- (2,2,2-trifluoroethoxy) imidazole [1,2-a] pyridine-2-carboxylate ( Yield 1.55 g, yield 80%) was obtained.

Process 3
In the same manner as in Step 2 of Example 1, instead of ethyl 6- (trifluoromethyl) imidazole [1,2-a] pyridine-2-carboxylate, ethyl 6- (2,2,2-trifluoro) Ethyl 6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylate with ethoxy) imidazole [1,2-a] pyridine-2-carboxylate. a] Pyridine-2-carboxylate was obtained.

Process 4
In the same manner as in Step 3 of Example 1, instead of ethyl 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylate, ethyl 6 -(2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydroimidazole [1,2-a] with pyridine-2-carboxylate, 6- (2,2,2-tri Fluoroethoxy) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylic acid was obtained.

Process 5
In the same manner as in Step 4 of Example 1, instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid, 6-( 2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-carboxylic acid is used and also of 6-fluorochroman-3-amine hydrochloride. Instead, use (R) -chroman-3-amine hydrochloride, N-((R) -chroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5,6,7 , 8-Tetrahydroimidazo [1,2-a] Pyridine-2-carboxamide was obtained.

Example 38
N-((R) -6-chlorochroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine- 2-Manufacture of carboxamide

(R) -6-chlorochroman-3-amine hydrochloride synthesized by the method described in Reference Example 1 instead of (R) -chroman-3-amine hydrochloride in step 5 in the same manner as in Example 37. N-((R) -6-chlorochroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydroimidazo [1,2- a] Pyridine-2-carboxamide was obtained.

Example 39
N-((R) -6-chlorochroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine- Isolation of 2-carboxamide

N-((R) -6-chlorochroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydro synthesized by the method described in Example 38 Imidazo [1,2-a] pyridine-2-carboxamide (50.0 mg, 0.125 mmol) was dissolved in ethanol (20 mL) and preparative by HPLC (column: CHIRALPAK IB, developing solvent: ethanol / n-hexane = 50 / The mixture was subjected to 50, flow rate: 10.0 mL / min, room temperature) to obtain isomer A (yield 11.9 mg, yield 24%) and isomer B (yield 13.3 mg, yield 27%).

Example 40
N-((R) -6- (difluoromethyl) chroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydroimidazole [1,2-a ] Production of pyridine-2-carboxamide

In the same manner as in Example 37, (R) -6- (difluoromethyl) chroman-3- was synthesized by the method described in Reference Example 3 instead of (R) -chroman-3-amine hydrochloride in step 5. N-((R) -6- (difluoromethyl) chroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydro using amine hydrochloride Imidazo [1,2-a] pyridine-2-carboxamide was obtained.

Example 41
Production of N-((R) -Chroman-3-yl) -6-isobutoxy-5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

Process 1
In the same manner as in Step 3 of Example 1, instead of ethyl 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylate, ethyl 6 -Hydroxyimidazo [1,2-a] pyridine-2-carboxylate was used to give 6-hydroxyimidazo [1,2-a] pyridine-2-carboxylic acid as a mixture with 10 equivalents of sodium chloride.

Process 2
6-Hydroxymidazo [1,2-a] pyridine-2-carboxylic acid (10 sodium chloride mixture) (2.17 g, 2.85 mmol) in N, N-dimethylformamide solution (11.9 mL) in (R) -chroman- 3-Amine hydrochloride (440 mg, 2.37 mmol), N-methylmorpholine (783 μL, 7.11 mmol), 1-hydroxybenzotriazole monohydrate (436 mg, 2.84 mmol) and 1-ethyl-3- (3) -Dimethylaminopropyl) carbodiimide hydrochloride (545 mg, 2.84 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction solution to separate the layers, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to purify (R) -N- (chroman-3-yl) -6-hydroxyimidazole [1,2-a] pyridine-2-. Carboxamide (yield 470 mg, yield 64%) was obtained.

Process 3
In a solution of (R) -N- (chroman-3-yl) -6-hydroxyimidazo [1,2-a] pyridin-2-carboxamide (40.0 mg, 0.129 mmol) in N, N-dimethylformamide (1.29 mL). , Cesium carbonate (84.3 mg, 0.259 mmol) and isobutyl bromide (17 μL, 0.155 mmol) were added, and the mixture was stirred at room temperature for 40 hours. Water and ethyl acetate were added to the reaction solution to separate the layers, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to purify (R) -N- (chroman-3-yl) -6-isobutoxyimidazo [1,2-a] pyridine-2. -Carboxamide (yield 2.4 mg, yield 5.1%) was obtained.

Process 4
(R) -N- (Chroman-3-yl) -6-isobutoxyimidazo [1,2-a] Pyridine-2-carboxamide (2.4 mg, 0.0066 mmol) in tetrahydrofuran (130 μL), ethanol (130 μL) Platinum oxide (IV) (1.0 mg) was added to a mixed solution of acetic acid (3 μL), and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 3 hours. The reaction mixture was filtered through Celite, and then the solvent was distilled off under reduced pressure. Residue Purified by silica gel column chromatography, N-((R) -chroman-3-yl) -6-isobutoxy-5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxamide (Yield 1.0 mg, yield 41%) was obtained.

Reference example 16
Production of Ethyl 6-Nitroimidazole [1,2-a] Pyridine-2-carboxylate

Ethyl 6-nitroimidazole [1,2-] using 5-nitropyridine-2-amine instead of 5- (trifluoromethyl) pyridine-2-amine in the same manner as in step 1 of Example 1. a] Pyridine-2-carboxylate was obtained.

Reference example 17
Production of (R) -N- (Chroman-3-yl) -6-nitroimidazo [1,2-a] Pyridine-2-carboxamide

Ethyl 6- synthesized by the method described in Reference Example 16 in place of ethyl 6-hydroxyimidazole [1,2-a] pyridine-2-carboxylate in the same manner as in Step 1 and Step 2 of Example 41. Using nitroimidazole [1,2-a] pyridine-2-carboxylate, (R) -N- (chroman-3-yl) -6-nitroimidazole [1,2-a] pyridine-2-carboxamide Obtained.

Example 42
Production of 6- (benzylamino) -N-((R) -chroman-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxamide

Process 1
Substitute for (R) -N- (chroman-3-yl) -6- (1-hydroxycyclobutyl) imidazole [1,2-a] pyridine-2-carboxamide in the same manner as in step 2 of Example 35. In addition, 6-amino- was used with (R) -N- (chroman-3-yl) -6-nitroimidazole [1,2-a] pyridin-2-carboxamide synthesized by the method described in Reference Example 17. N-((R) -Chroman-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxamide was obtained.

Process 2
6-Amino-N-((R) -Chroman-3-yl) -5,6,7,8-Tetrahydroimidazo [1,2-a] Pyridine-2-carboxamide (45.1 mg, 0.144 mmol) in dichloromethane ( Benzaldehyde (29.4 μL, 0.289 mmol) and triethylamine (60.3 μL, 0.433 mmol) were added to the 722 μL) solution, and the mixture was stirred at room temperature for 4 hours. Water and chloroform were added to the reaction solution to separate them, and then the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. -N-((R) -Chroman-3-yl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-carboxamide (yield 10.3 mg, yield 18%) was obtained. ..

Process 3
Ice-cooled 6- (benzylideneamino) -N-((R) -chroman-3-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-carboxamide (10.0 mg,) Sodium borohydride (1.8 mg, 0.051 mmol) was added to a solution of 0.0250 mmol) in methanol (260 μL), and the mixture was stirred at room temperature for 2 hours. Water, saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the ice-cooled reaction solution to separate the solutions, and then the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography and 6- (benzylamino) -N-((R) -chroman-3-yl) -5,6,7,8- Tetrahydroimidazo [1,2-a] pyridine-2-carboxamide (yield 4.5 mg, yield 43%) was obtained.

Example 43
N-((R) -Chroman-3-yl) -6- (5-methylthiophen-2-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide Manufacturing

Process 1
In a solution of 6-bromoimidazo [1,2-a] pyrazine-2-carboxylic acid (1.00 g, 4.13 mmol) in N, N-dimethylformamide (20 mL), (R) -chroman-3-amine hydrochloride (R) 800 mg, 4.31 mmol), N-methylmorpholin (1.40 mL, 12.7 mmol), 1-hydroxybenzotriazole monohydrate (800 mg, 5.22 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Hydrochloride (1.00 mg, 5.22 mmol) was added and the mixture was stirred at room temperature for 16 hours. Water was added to the ice-cooled reaction solution, and the precipitated solid was collected by filtration and dried under reduced pressure to (R) -6-bromo-N- (chroman-3-yl) imidazo [1,2-a]. Pyrazine-2-carboxamide (yield 1.50 g, yield 97%) was obtained.

Process 2
(R) -6-bromo-N- (chroman-3-yl) imidazo [1,2-a] pyrazine-2-carboxamide (50.0 mg, 0.134 mmol), (5-methylthiophen-2-yl) boronic acid 1,4 of (30.0 mg, 0.211 mmol), cesium carbonate (90.0 mg, 0.276 mmol) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropyrazine (II) (5.0 mg, 0.0071 mmol) -A mixed suspension of dioxane (1 mL) and water (0.2 mL) was stirred under heating and reflux for 2 hours. Water and chloroform were added to the reaction solution to separate them, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to purify (R) -N- (chroman-3-yl) -6- (5-methylthiophen-2-yl) imidazo [1]. , 2-a] Pyrazine-2-carboxamide (yield 40.0 mg, yield 77%) was obtained.

Process 3
(R) -N- (chroman-3-yl) -6- (5-methylthiophen-2-yl) imidazo [1,2-a] pyrazine-2-carboxamide (35.0 mg, 0.0896 mmol) in tetrahydrofuran (1) 20% Palladium on Carbon (5.0 mg) was added to a mixed solution of (mL), ethanol (1 mL) and acetic acid (25 μL), and the mixture was stirred under pressure (about 3 atm), hydrogen atmosphere, and room temperature for 18 hours. .. The reaction mixture was filtered through Celite, and then the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the residue, and the liquids were separated. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -chroman-3-yl) -6- (5-methylthiophen-2-yl) -5,6,7,8-tetrahydroimidazole [1]. , 2-a] Pyrazine-2-carboxamide (yield 20.0 mg, yield 57%) was obtained.

Example 44
Production of N-((R) -Chroman-3-yl) -6- (3,4-difluorophenyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide

N-((R) -Chromane, using (3,4-difluorophenyl) boronic acid instead of (5-methylthiophen-2-yl) boronic acid in step 2 in the same manner as in Example 43. -3-yl) -6- (3,4-difluorophenyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine-2-carboxamide was obtained.

Example 45
N-((R) -Chroman-3-yl) -6- (3,4-difluorophenyl) -7-methyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2- Manufacture of carboxamide

N-((R) -chroman-3-yl) -6- (3,4-difluorophenyl) -5,6,7,8-tetrahydroimidazo synthesized by the method described in Example 44 [1,2- a] Add 37% aqueous formaldehyde solution (10 μL, 0.123 mmol) and sodium triacetoxyborohydride (30.0 mg, 0.142 mmol) to a solution of pyrazine-2-carboxamide (30.0 mg, 0.0731 mmol) in methanol (1 mL). , Stirred for 2 hours at room temperature. After concentrating the reaction solution under reduced pressure, water and chloroform were added and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -chroman-3-yl) -6- (3,4-difluorophenyl) -7-methyl-5,6,7,8-tetrahydroimidazole. [1,2-a] Pyrazine-2-carboxamide (yield 29.0 mg, yield 94%) was obtained.

Example 46
N-((R) -Chroman-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine- 2-Manufacture of carboxamide

Using (6- (trifluoromethyl) pyridin-2-yl) boronic acid instead of (5-methylthiophen-2-yl) boronic acid in step 2 in the same manner as in Example 43, N- ((R) -Chroman-3-yl) -6- (6- (Trifluoromethyl) Pyridine-2-yl) -5,6,7,8-Tetrahydroimidazo [1,2-a] Pyrazine-2- Carboxamide was obtained.

Example 47
N-((R) -Chroman-3-yl) -7-methyl-6-(6- (trifluoromethyl) pyridin-2-yl) -5,6,7,8-tetrahydroimidazole [1,2- a] Production of pyrazine-2-carboxamide

N-((R) -chroman-3-yl) -6- (5-methylthiophen-2-yl) -5,6,7,8-tetrahydroimidazole [1,2] in the same manner as in Example 45. -a] N-((R) -chroman-3-yl) -6- (6- (trifluoromethyl) pyridin-2-) synthesized by the method described in Example 46 instead of pyrazine-2-carboxamide. Il) -5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide with N-((R) -chroman-3-yl) -7-methyl-6-( 6- (Trifluoromethyl) Pyridine-2-yl) -5,6,7,8-Tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide was obtained.

Example 48
Production of 6-Phenyl-N- (3- (trifluoromethyl) phenethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide

Using 2- (3- (trifluoromethyl) phenyl) ethaneamine instead of (R) -chroman-3-amine hydrochloride in step 1 in the same manner as in Example 43, (5-methylthiophene in step 2). Using phenylboronic acid instead of -2-yl) boronic acid, 6-phenyl-N- (3- (trifluoromethyl) phenethyl) -5,6,7,8-tetrahydroimidazo [1,2- a] Pyrazine-2-carboxamide was obtained.

Example 49
Production of N-((R) -Chroman-3-yl) -6-isopentyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide

Process 1
(R) -6-bromo-N- (chroman-3-yl) imidazo [1,2-a] pyrazine-2-carboxamide (50.0 mg, 0.134 mmol) synthesized by the method described in step 2 of Example 43. 3-Methyl-1-butyne (0.10 mL, 0.98 mmol), triethylamine (0.10 mL, 0.72 mmol), copper (I) iodide (3.0 mg, 0.016 mmol) and bis (tri) in an acetonitrile (1 mL) solution of Phenylphosphine) Pyrazine (II) dichloride was added, and the mixture was stirred under heating and reflux for 2 hours. The reaction mixture was filtered through Celite, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and (R) -N- (chroman-3-yl) -6- (3-methyl-1-butin-1-yl) imidazole [1,2-a] pyrazine- 2-Carboxamide (yield 45.0 mg, yield 93%) was obtained.

Process 2
(R) -N- (chroman-3-yl) -6- (3-methyl-1-butin-1-yl) imidazo [1,2-a] pyrazine-2-carboxamide (45.0 mg, 0.125 mmol) Acetic acid (20 μL, 0.350 mmol) and 20% palladium hydroxide carbon (5.0 mg) are added to a mixed solution of ethanol (2.0 mL) and tetrahydrofuran (2.0 mL) under a hydrogen atmosphere (balloon pressure) for 18 hours at room temperature. Stirred. The reaction mixture was filtered through Celite, and then the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the residue, and the liquids were separated. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -chroman-3-yl) -6-isopentyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2- Carboxamide (yield 45.0 mg, yield 98%) was obtained.

Example 50
Production of N-((R) -Chroman-3-yl) -6-isopentyl-7-methyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide

N-((R) -chroman-3-yl) -6- (5-methylthiophen-2-yl) -5,6,7,8-tetrahydroimidazole [1,2] in the same manner as in Example 45. -a] N-((R) -chroman-3-yl) -6-isopentyl-5,6,7,8-tetrahydroimidazole synthesized by the method described in Example 49 instead of pyrazine-2-carboxamide. [1,2-a] Using pyrazine-2-carboxamide, N-((R) -chroman-3-yl) -6-isopentyl-7-methyl-5,6,7,8-tetrahydroimidazole [1] , 2-a] Pyrazine-2-carboxamide was obtained.

Example 51
Production of N-((R) -chroman-3-yl) -6- (2-cyclopentylethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide

N-((R) -chroman-3-yl) -6- (2-cyclopentyl) using ethynylcyclopentane instead of 3-methyl-1-butyne in step 1 in the same manner as in Example 49. Ethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide was obtained.

Example 52
N-((R) -Chroman-3-yl) -6- (2-Cyclopentylethyl) -7-Methyl-5,6,7,8-Tetrahydroimidazole [1,2-a] Pyrazine-2-carboxamide Manufacturing

N-((R) -chroman-3-yl) -6- (5-methylthiophen-2-yl) -5,6,7,8-tetrahydroimidazole [1,2] in the same manner as in Example 45. -a] N-((R) -chroman-3-yl) -6- (2-cyclopentylethyl) -5,6,7 synthesized by the method described in Example 51 instead of pyrazine-2-carboxamide. , 8-Tetrahydroimidazole [1,2-a] with pyrazine-2-carboxamide, N-((R) -chroman-3-yl) -6- (2-cyclopentylethyl) -7-methyl-5, 6,7,8-Tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide was obtained.

Example 53
Production of N-((R) -Chroman-3-yl) -6- (4-fluorophenethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide

N-((R) -chroman-3-yl) -6 using 1-ethynyl-4-fluorobenzene instead of 3-methyl-1-butyne in step 1 in the same manner as in Example 49. -(4-Fluorofenetyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide was obtained.

Example 54
N-((R) -Chroman-3-yl) -6- (4-fluorophenethyl) -7-methyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide Manufacturing

N-((R) -chroman-3-yl) -6- (5-methylthiophen-2-yl) -5,6,7,8-tetrahydroimidazole [1,2] in the same manner as in Example 45. -a] N-((R) -chroman-3-yl) -6- (4-fluorophenethyl) -5,6,7 synthesized by the method described in Example 53 instead of pyrazine-2-carboxamide. , 8-Tetrahydroimidazole [1,2-a] with pyrazine-2-carboxamide, N-((R) -chroman-3-yl) -6- (4-fluorophenethyl) -7-methyl-5, 6,7,8-Tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide was obtained.

Example 55
Production of N-((R) -Chroman-3-yl) -6- (3-phenylpropyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide

N-((R) -chroman-3-yl) using (2-propyne-1-yl) benzene instead of 3-methyl-1-butyne in step 1 in the same manner as in Example 49. -6- (3-Phenylpropyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide was obtained.

Example 56
Production of N-((R) -Chroman-3-yl) -6-phenyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide

Process 1
Ethyl 6-bromoimidazole [1,2-a] pyrazine-2-carboxylate (300 mg, 1.11 mmol), phenylboronic acid (271 mg, 0.222 mmol), cesium carbonate (724 mg, 2.22 mmol) and bis (di) A mixed suspension of -tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (39.3 mg, 0.0555 mmol) in 1,4-dioxane (11.1 mL) and water (1.1 mL) at 100 ° C. Stirred for 10 hours. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution to separate them, and then the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give ethyl 6-phenylimidazole [1,2-a] pyrazine-2-carboxylate (yield 296 mg, yield 100%). Obtained.

Process 2
To a solution of 6-phenylimidazo [1,2-a] pyridine-2-carboxylate (297 mg, 1.11 mmol) in ethanol (5.6 mL) was added 4 mol / L aqueous sodium hydroxide solution (556 μL, 2.22 mmol). The mixture was stirred at room temperature for 1 hour. After adding 2 mol / L hydrochloric acid (1.11 mL, 2.22 mmol) to the reaction mixture, the solvent was distilled off under reduced pressure. The operation of adding toluene to the residue and distilling off the solvent under reduced pressure was repeated 3 times, and 6-phenylimidazole [1,2-a] pyrazine-2-carboxylic acid (yield 384 mg, yield 100%) was added to 2 Obtained as a mixture with equivalent amounts of sodium chloride.

Process 3
HATU (59.6 mg) in an N, N-dimethylformamide (1 mL) suspension of 6-phenylimidazole [1,2-a] pyrazine-2-carboxylic acid (sodium chloride mixture) (30.0 mg, 0.125 mmol). , 0.157 mmol), N, N-diisopropylethylamine (90 μL, 0.53 mmol) and (R) -chroman-3-amine hydrochloride (23.3 mg, 0.126 mmol) were added and stirred at room temperature for 14 hours. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution to separate them, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to purify (R) -N- (chroman-3-yl) -6-phenylimidazole [1,2-a] pyrazine-2-. Carboxamide (yield 40.4 mg, yield 87%) was obtained.

Process 4
(R) -N- (chroman-3-yl) -6-phenylimidazole [1,2-a] pyrazine-2-carboxamide (40.0 mg, 0.108 mmol) in tetrahydrofuran (1.44 mL), ethanol (2.16 mL) and To a mixed solution of acetic acid (108 μL), 20% palladium hydroxide carbon (16.0 mg) was added, and the mixture was stirred under pressure (about 3 atm), hydrogen atmosphere, and room temperature for 3 hours. The reaction mixture was filtered through Celite, and then the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the residue, and the liquids were separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -chroman-3-yl) -6-phenyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2- Carboxamide (yield 27.7 mg, yield 69%) was obtained.

Example 57
Production of N-((R) -Chroman-3-yl) -7-Methyl-6-Phenyl-5,6,7,8-Tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide

N-((R) -chroman-3-yl) -6- (5-methylthiophen-2-yl) -5,6,7,8-tetrahydroimidazole [1,2] in the same manner as in Example 45. -a] N-((R) -chroman-3-yl) -6-phenyl-5,6,7,8-tetrahydroimidazole synthesized by the method described in Example 56 instead of pyrazine-2-carboxamide. [1,2-a] Using pyrazine-2-carboxamide, N-((R) -chroman-3-yl) -7-methyl-6-phenyl-5,6,7,8-tetrahydroimidazole [1] , 2-a] Pyrazine-2-carboxamide was obtained.

Reference example 18
Production of N-Phenethyl-6-Phenyl-5,6,7,8-Tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide

N-Phenyl-6-phenyl-5,6,7, using 2-phenylethaneamine instead of (R) -chroman-3-amine hydrochloride in step 3 in the same manner as in Example 56, 8-Tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide was obtained.

Example 58
Production of 7-Methyl-N-Phenethyl-6-Phenyl-5,6,7,8-Tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide

N-((R) -chroman-3-yl) -6- (5-methylthiophen-2-yl) -5,6,7,8-tetrahydroimidazo [1,2] in the same manner as in Example 45. -a] N-phenetyl-6-phenyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine-2 synthesized by the method described in Reference Example 18 instead of pyrazine-2-carboxamide. -Carboxamide was used to obtain 7-methyl-N-phenethyl-6-phenyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine-2-carboxamide.

Example 59
Production of N-((R) -Chroman-3-yl) -6-cyclopentyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide

Process 1
Ethyl 6- (1-cyclopenten-1-yl) imidazole [1,2-a] pyrazine, using 1-cyclopentenylboronic acid instead of phenylboronic acid, in a manner similar to step 1 of Example 56. -2-Carboxylate was obtained.

Process 2
In the same manner as in step 4 of Example 56, instead of (R) -N- (chroman-3-yl) -6-phenylimidazole [1,2-a] pyrazine-2-carboxamide, ethyl 6- ( 1-Cyclopenten-1-yl) imidazole [1,2-a] pyrazine-2-carboxylate with ethyl 6-cyclopentyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine- A 2-carboxylate was obtained.

Process 3
In the same manner as in Step 2 of Example 56, instead of 6-phenylimidazole [1,2-a] pyridin-2-carboxylate, ethyl 6-cyclopentyl-5,6,7,8-tetrahydroimidazole [1] , 2-a] pyrazine-2-carboxylate was used to give 6-cyclopentylimidazole [1,2-a] pyrazine-2-carboxylic acid as a mixture with 10 equivalents of sodium chloride.

Process 4
6-Cyclopentylimidazo [1,2-a] pyrazine-2-carboxylic acid (10 sodium chloride mixture) (80.0 g, 0.0976 mmol) in N, N-dimethylformamide solution (0.49 mL), (R) -chroman- 3-Amine hydrochloride (19.9 mg, 0.107 mmol), N-methylmorpholine (32.2 μL, 0.293 mmol), 1-hydroxybenzotriazole monohydrate (17.9 mg, 0.117 mmol) and 1-ethyl-3- (3) -Dimethylaminopropyl) carbodiimide hydrochloride (22.5 mg, 0.117 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, the precipitated solid was collected by filtration, and then dried under reduced pressure to N-((R) -chroman-3-yl) -6-cyclopentyl-5,6,7,8-tetrahydroimidazole. [1,2-a] Pyrazine-2-carboxamide (yield 14.0 mg, yield 39%) was obtained.

Reference example 19
Production of 6-Phenyl-5,6,7,8-Tetrahydroimidazole [1,2-a] pyrazine-2-carboxylic acid

Process 1
Described in Step 1 of Example 56 in the same manner as in Step 2 of Example 59, instead of ethyl 6- (1-cyclopenten-1-yl) imidazo [1,2-a] pyrazine-2-carboxylate. Ethyl 6-phenyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine using the ethyl 6-phenyl imidazole [1,2-a] pyrazine-2-carboxylate produced by the above method. -2-carboxylate was obtained.

Process 2
In the same manner as in Step 3 of Example 59, instead of ethyl 6-cyclopentyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine-2-carboxylate, ethyl 6-phenyl-5 , 6,7,8-Tetrahydroimidazo [1,2-a] pyrazine-2-carboxylate, 6-Phenyl-5,6,7,8-Tetrahydroimidazo [1,2-a] pyrazine-2 -Carboxylic acid was obtained as a mixture with 2 equivalents of sodium chloride.

Example 60
Production of (6-phenyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-yl) (3- (3- (trifluoromethyl) phenyl) pyrrolidine-1-yl) metanone

6-Phenyl-5,6 produced by the method described in Reference Example 19 in place of 6-cyclopentylimidazole [1,2-a] pyrazine-2-carboxylic acid in the same manner as in Step 4 of Example 59. , 7,8-Tetrahydroimidazo [1,2-a] pyrazine-2-carboxylic acid was used and 3- (3- (trifluoromethyl) phenyl) was used instead of (R) -chroman-3-amine hydrochloride. 6-Phenyl-5,6,7,8-Tetrahydroimidazole [1,2-a] pyrazine-2-yl) (3- (3- (trifluoromethyl) phenyl) pyrrolidine-1-yl using pyrrolidine ) Obtained Metanon.

Reference example 20
Production of 2- (3- (trifluoromethyl) phenyl) morpholine

参考例15と同様の方法で、工程1の1-ブロモ-2,4-ジフルオロベンゼンの代わりに、1-ブロモ-3-(トリフルオロメチル)ベンゼンを用いて、2-(3-(トリフルオロメチル)フェニル)モルホリンを得た。

In the same manner as in Reference Example 15, 2- (3- (trifluoromethyl) benzene was used instead of 1-bromo-2,4-difluorobenzene in step 1 by using 1-bromo-3- (trifluoromethyl) benzene. Methyl) phenyl) morpholine was obtained.

Example 61
Production of (6-phenyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-yl) (2-(3- (trifluoromethyl) phenyl) morpholino) metanone

In the same manner as in Example 60, instead of 3- (3- (trifluoromethyl) phenyl) pyrrolidine, 2- (3- (trifluoromethyl) phenyl) morpholine synthesized by the method described in Reference Example 20 was used. To obtain (6-phenyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine-2-yl) (2-(3- (trifluoromethyl) phenyl) morpholino) methanone. ..

Reference example 21
Production of 7-Methyl-6-Phenyl-5,6,7,8-Tetrahydroimidazole [1,2-a] pyrazine-2-carboxylic acid

Process 1
N-((R) -chroman-3-yl) -6- (5-methylthiophen-2-yl) -5,6,7,8-tetrahydroimidazo [1,2] in the same manner as in Example 45. -a] Ethyl 6-phenyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2 synthesized by the method described in step 1 of Reference Example 19 instead of pyrazine-2-carboxamide. Using -carboxylate, ethyl 7-phenyl-6-phenyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine-2-carboxylate was obtained.

Process 2
In the same manner as in step 2 of Reference Example 19, ethyl 7-phenyl-6 instead of ethyl 6-phenyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine-2-carboxylate. -Phenyl-5,6,7,8-Tetrahydroimidazole [1,2-a] Using pyrazine-2-carboxylate, 7-Methyl-6-Phenyl-5,6,7,8-Tetrahydroimidazole [1] , 2-a] Pyrazine-2-carboxylic acid was obtained.

Reference example 22
Production of 2- (3-morpholinophenyl) ethaneamine

Morpholine (174 μL, 2.00 mmol), 4,5-bis (diphenylphosphino) -9 in a 1,4-dioxane (1 mL) solution of 2- (3-bromophenyl) ethaneamine (100 mg, 0.500 mmol) , 9-Dioxaneten (29.0 mg, 0.0501 mmol), sodium t-butoxide (96.0 mg, 0.999 mmol) and tris (dibenzylideneacetone) dipalladium (0) (23.0 mg, 0.0251 mmol) at 100 ° C. 4 Stirred for hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain 2- (3-morpholinophenyl) ethaneamine (yield 34.6 mg, yield 34%).

Example 62
Production of 7-Methyl-N- (3-morpholinophenethyl) -6-phenyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide

7-Methyl-6-phenyl synthesized by the method described in Reference Example 21 in place of 6-phenylimidazole [1,2-a] pyrazine-2-carboxylic acid in the same manner as in step 3 of Example 56. Using -5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine-2-carboxylic acid, instead of (R) -chroman-3-amine hydrochloride, by the method described in Reference Example 22. Using the synthesized 2- (3-morpholinophenyl) ethaneamine, 7-methyl-N- (3-morpholinofenetyl) -6-phenyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine -2-Carboxamide was obtained.

Reference example 23
Production of 2- (azetidine-3-yloxy) -6- (trifluoromethyl) pyridine dihydrochloride

Process 1
Potassium t-butoxide (212 mg, 1.89 mmol) and 2-fluoro in an ice-cooled solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (218 mg, 1.26 mmol) in N-methylpyrrolidone (2.5 mL). -6- (Trifluoromethyl) pyridine (150 μL, 1.26 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction solution to separate the layers, and then the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography and tert-butyl 3-((6-trifluoromethyl) pyridin-2-yl) oxy) azetidine-1-carboxylate (yield). 352 mg (yield 88%) was obtained.

Process 2
4 mol / in a solution of tert-butyl 3-((6-trifluoromethyl) pyridine-2-yl) oxy) azetidine-1-carboxylate (350 mg, 1.10 mmol) in 1,4-dioxane (8 mL). A solution of L hydrogen chloride-1,4-dioxane (8.25 mL, 33.0 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure to give 2- (azetidine-3-yloxy) -6- (trifluoromethyl) pyridine dihydrochloride (yield 332 mg) as a crude product.

Example 63
(7-Methyl-6-Phenyl-5,6,7,8-Tetrahydroimidazole [1,2-a] pyrazine-2-yl) (3-((6- (Trifluoromethyl) pyridin-2-yl)) Manufacture of oxy) azetidine-1-yl) methanone

2- (Azetidine-3-yloxy) -6- (trifluoromethyl) pyridine synthesized by the method described in Reference Example 23 instead of 2- (3-morpholinophenyl) ethaneamine in the same manner as in Example 62. Using dihydrochloride, (7-methyl-6-phenyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-yl) (3-((6- (trifluoromethyl) ) Pyridine-2-yl) Oxy) Azetidine-1-yl) Metanone was obtained.

Example 64
Production of (R) -N- (Chroman-3-yl) -3-phenyl-5,6-dihydro-8H-imidazole [2,1-c] [1,4] oxazine-2-carboxamide

Process 1
N-Bromosuccinimide (25.7 mg) in a solution of 5,6-dihydro-8H-imidazole [2,1-c] [1,4] oxazine-2-carbaldehyde (20.0 mg, 0.131 mmol) in dichloromethane (1.3 mL). , 0.145 mmol) was added, and the mixture was stirred at room temperature for 20 hours. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and 3-bromo-5,6-dihydro-8H-imidazole [2,1-c] [1,4] oxazine-2-carbaldehyde (yield 20.8 mg, yield 69). %) Was obtained.

Process 2
3-Bromo-5,6-dihydro-8H-imidazo [2,1-c] [1,4] Oxazine-2-carbaldehyde (20.0 mg, 0.0866 mmol) in tert-butanol (1.7 mL) and water (0.87) 2-Methyl-2-butene (92 μL, 0.87 mmol), sodium dihydrogen phosphate (67.5 mg, 0.433 mmol) and 1.2 mol / L sodium chlorite aqueous solution (220 μL, 0.260 mmol) in a mixed solution of mL). ) Was added, and the mixture was stirred at room temperature for 3 hours. Saturated saline and chloroform were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to remove 3-bromo-5,6-dihydro-8H-imidazole [2,1-c] [1, 4] Oxazine-2-carboxylic acid (yield 11.2 mg, yield 52%) was obtained.

Process 3
In the same manner as in Step 1 of Example 16, instead of 5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylic acid, 3-bromo-5,6-dihydro-8H -Imidazo [2,1-c] [1,4] Using oxadin-2-carboxylic acid, (R) -3-bromo-N- (chroman-3-yl) -5,6-dihydro-8H- Imidazo [2,1-c] [1,4] oxadin-2-carboxamide was obtained.

Process 4
(R) -N- (chroman-3-yl) -3-iodo-5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2 in the same manner as in step 3 of Example 16. -Instead of carboxamide, (R) -3-bromo-N- (chroman-3-yl) -5,6-dihydro-8H-imidazole [2,1-c] [1,4] oxazine-2-carboxamide To obtain (R) -N- (chroman-3-yl) -3-phenyl-5,6-dihydro-8H-imidazole [2,1-c] [1,4] oxazine-2-carboxamide. rice field.

Example 65
(R) -N- (6-chlorochroman-3-yl) -3- (6-methoxypyridin-2-yl) -5,6-dihydro-8H-imidazole [2,1-c] [1,4 ] Production of oxazine-2-carboxamide

(R) -6-chlorochroman-3-amine hydrochloride synthesized by the method described in Reference Example 1 instead of (R) -chroman-3-amine hydrochloride in step 3 in the same manner as in Example 64. , And 6-methoxypyridin-2-boronic acid instead of phenylboronic acid in step 4, (R) -N- (6-chlorochroman-3-yl) -3- (6-methoxypyridin- 2-Il) -5,6-dihydro-8H-imidazo [2,1-c] [1,4] Oxazine-2-carboxamide was obtained.

Example 66
(R) -N- (6-chlorochroman-3-yl) -3- (pyridin-2-yl) -5,6-dihydro-8H-imidazole [2,1-c] [1,4] oxazine- 2-Manufacture of carboxamide

Process 1
3-Bromo-5,6-dihydro-8H-imidazole [2,1-c] [1,4] oxadin-2-carboxylic acid (50.0 mg, 0.202 mmol) synthesized by the method described in Step 2 of Example 64. ) To a suspension of toluene (2.0 mL) was added methanol (0.3 mL) and (trimethylsilyl) diazomethane (0.4 mL, 0.2 mmol), and the mixture was stirred at room temperature for 6 hours. After concentrating the reaction under reduced pressure, the residue was purified by silica gel column chromatography to purify methyl 3-bromo-5,6-dihydro-8H-imidazole [2,1-c] [1,4] oxazine-2. -Carboxylate (yield 37.0 mg, yield 70%) was obtained.

Process 2 to Process 5
Methyl instead of ethyl 3-iodo-5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylate in step 1 in the same manner as in steps 1 through 4 of Example 18. With 3-bromo-5,6-dihydro-8H-imidazole [2,1-c] [1,4] oxazine-2-carboxylate, (R) -N- (6-chlorochroman-3-yl) ) -3- (Pyridine-2-yl) -5,6-dihydro-8H-imidazole [2,1-c] [1,4] Oxazine-2-carboxamide was obtained.

Example 67 Synthesis
(R) -3- (pyridin-2-yl) -N- (6- (trifluoromethyl) chroman-3-yl) -5,6-dihydro-8H-imidazole [2,1-c] [1, 4] Production of oxazine-2-carboxamide

Example 18 instead of 3- (pyridin-2-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylic acid in the same manner as in step 4 of Example 18. Using 3- (pyridin-2-yl) -5,6-dihydro-8H-imidazole [2,1-c] [1,4] oxadin-2-carboxylic acid synthesized by the method described in step 4 of 66. , (R) -6- (Trifluoromethyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 43 was used instead of (R) -6-chlorochroman-3-amine hydrochloride. , (R) -3- (Pyridine-2-yl) -N- (6- (Trifluoromethyl) Chroman-3-yl) -5,6-Dihydro-8H-Imidazo [2,1-c] [1 , 4] Oxazine-2-carboxamide was obtained.

Example 68
Production of N-((R) -Chroman-3-yl) -5- (o-Truyl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] Pyridine-2-carboxamide

In the same manner as in Example 32, instead of the ethyl 6-bromoimidazo [1,2-a] pyridine-2-carboxylate in step 1, ethyl 5-bromopyrazolo [1,5-a] pyridin-2-carboxylate Using the rate, o-toluylboronic acid was used instead of the (2-methoxy-5- (trifluoromethyl) pyridin-3-yl) boronic acid in step 1 and 2- (2,4-difluoro) in step 4 was used. Using (R) -chroman-3-amine hydrochloride instead of phenyl) morpholine, N-((R) -chroman-3-yl) -5- (o-toluyl) -4,5,6, 7-Tetrahydropyrazolo [1,5-a] pyridine-2-carboxamide was obtained.

Example 69
(R) -N- (Chroman-3-yl) -3- (6-Methoxypyridin-2-yl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] Pyridine-2-carboxamide Manufacturing of

Process 1
In the same manner as in Step 1 of Example 16, 4,5,6,7-tetrahydropyrazolo instead of 5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylic acid. [1,5-a] Pyridine-2-carboxylic acid, (R) -N- (chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine -2-Carboxamide was obtained.

Process 2
(R) -N- (Chroman-3-yl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] Pyridine-2-carboxamide (163 mg, 0.548 mmol) in dichloromethane (5.5 mL) N-Bromosuccinimide (107 mg, 0.603 mmol) was added to the solution, and the mixture was stirred at room temperature for 72 hours. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and (R) -3-bromo-N- (chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-2. -Carboxamide (yield 192 mg, yield 93%) was obtained.

Process 3
(R) -N- (chroman-3-yl) -3-iodo-5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2 in the same manner as in step 3 of Example 16. -Instead of carboxamide, (R) -3-bromo-N- (chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-carboxamide was used. Using (6-methoxypyridin-2-yl) boronic acid instead of phenylboronic acid, (R) -N- (chroman-3-yl) -3- (6-methoxypyridin-2-yl)- 4,5,6,7-Tetrahydropyrazolo [1,5-a] Pyridine-2-carboxamide was obtained.

Reference example 24
Production of (R) -3-aminochroman-6-carbonitrile

Process 1
Acetonitrile (1.43 g, 5.23 mmol) of (R) -2,2,2-trifluoro-N- (6-formylroman-3-yl) acetamide synthesized by the method described in step 2 of Reference Example 3 ( Sodium azide (524 mg, 8.06 mmol) and trifluoromethanesulfonic acid (1.61 mL, 18.3 mmol) were added to the 52.3 mL) solution, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution, water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (R) -N- (6-cyanochroman-3-yl) -2,2,2-trifluoroacetamide (yield 1.40 g, yield 99%).

Process 2
A 4 mol / L sodium hydroxide aqueous solution (R) -N- (6-cyanochroman-3-yl) -2,2,2-trifluoroacetamide (1.40 g, 5.18 mmol) in a chloroform (13 mL) solution ( 13.0 mL, 51.8 mmol) was added, and the mixture was stirred at room temperature for 13 hours. Water and chloroform were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to remove (R) -3-aminochroman-6-carbonitrile (yield 505 mg, yield 56%). Got

Example 70
N-((R) -6-cyanochroman-3-yl) -5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2- Manufacture of carboxamide

Process 1
1,1,3,3-Tetramethylguanidine (3.03 mL, 24.2 mmol) and ethyl diethylphosphonoacetate (3.52 mL, 17.7 mmol) in a solution of 2-fluorobenzaldehyde (2.00 g, 16.1 mmol) in chloroform (32.2 mL). ) Was added, and the mixture was stirred at 50 ° C. for 4 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain ethyl 3- (2-fluorophenyl) acrylate (yield 2.98 g, yield 95%).

Process 2
20% Palladium on Carbon (539 mg) was added to a solution of ethyl 3- (2-fluorophenyl) acrylate (2.98 g, 15.3 mmol) in ethanol (76.7 mL), and under pressure (about 3 atm), under a hydrogen atmosphere. , Stirred at 50 ° C. for 3 hours. The reaction mixture was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain ethyl 3- (2-fluorophenyl) propanoate (yield 2.79 g, yield 93%).

Process 3
Lithium borohydride (774 mg, 35.5 mmol) was added to a solution of ethyl 3- (2-fluorophenyl) propanoate (2.79 g, 14.2 mmol) in tetrahydrofuran (71.1 mL), and the mixture was stirred at room temperature for 5 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3- (2-fluorophenyl) propan-1-ol (yield 2.17 g, yield 99%).

Process 4
Dichloromethane (70.4 mL) of 3- (2-fluorophenyl) propan-1-ol (2.17 g, 14.1 mmol) in a solution of cyanuric chloride (2.86 g, 15.5 mL) in N, N-dimethylformamide (3.3 mL). The solution was added and stirred at room temperature for 13 hours. Water and chloroform were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 1- (3-chloropropyl) -2-fluorobenzene (yield 2.00 g, yield 82%).

Process 5
N-Bromosuccinimide (2.27 g, 12.7 mmol) and 2,2'-azobis (2,2'-azobis) in a solution of 1- (3-chloropropyl) -2-fluorobenzene (2.00 g, 11.6 mmol) in carbon tetrachloride (39 mL). 2-Methylpropionitrile) (168 μL, 1.16 mmol) was added, and the mixture was stirred at 90 ° C. for 2 hours. Water and chloroform were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 1- (1-bromo-3-chloropropyl) -2-fluorobenzene (yield 2.36 g, 81% yield).

Process 6
Ethyl 5-hydroxy-1H-pyrazol-3-carboxylate (1.47 g, 1.47 g,) in a solution of 1- (1-bromo-3-chloropropyl) -2-fluorobenzene (2.36 g, 9.38 mmol) in acetonitrile (31.3 mL). 9.38 mmol) and potassium carbonate (3.89 g, 28.1 mmol) were added, and the mixture was stirred at 100 ° C. for 15 hours. After concentrating the reaction under reduced pressure, the residue was purified by silica gel column chromatography and ethyl 5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1, 3] Oxazine-2-carboxylate (yield 2.30 g, yield 84%) was obtained.

Process 7
Ethanol (15.8 mL) of ethyl 5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate (2.30 g, 7.92 mmol) A 4 mol / L aqueous sodium hydroxide solution (7.92 mL, 31.7 mmol) was added to the solution, and the mixture was stirred at room temperature for 24 hours. After adding 2 mol / L hydrochloric acid to the reaction mixture, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue, and the liquid was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium chloride, the solvent was evaporated under reduced pressure, and 5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1- b] [1,3] Oxazine-2-carboxylic acid (yield 1.80 g, yield 87%) was obtained as a mixture with 4 equivalents of sodium chloride.

Process 8
5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid (mixture of sodium tetrachloride) (36.1 mg, 0.138 mmol) HATU (48.0 mg, 0.126 mmol), N, N-diisopropylethylamine (99 μL, 0.57 mmol) and (R) -3-aminochroman-6-carbonitrile (20.0 mg, 20.0 mg,) in a suspension of dichloromethane (1.2 mL). 0.115 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography and N-((R) -6-cyanochroman-3-yl) -5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1- b] [1,3] Oxazine-2-carboxamide (yield 47.9 mg, yield 100%) was obtained.

Example 71
N-((R) -6-bromochroman-3-yl) -5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2- Manufacture of carboxamide

(R) -6-bromochroman-3-amine synthesized by the method described in Reference Example 2 instead of (R) -3-aminochroman-6-carbonitrile in step 8 in the same manner as in Example 70. Using hydrochloride, N-((R) -6-bromochroman-3-yl) -5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1, 3] Oxazine-2-carboxamide was obtained.

Example 72
N-((R) -6-cyanochroman-3-yl) -5- (2-cyanophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2- Manufacture of carboxamide

N-((R) -6-cyanochroman-3-yl) -5- (2-) using 2-formylbenzonitrile instead of 2-fluorobenzaldehyde in step 1 in the same manner as in Example 70. Cyanophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 73
N-((R) -6-cyanochroman-3-yl) -5- (2-methoxypyridin-4-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Production of oxazine-2-carboxamide

N-((R) -6-cyanochroman-3-yl) -5-(2) was used in the same manner as in Example 70, using 2-methoxyisonicotinaldehyde instead of 2-fluorobenzaldehyde in step 1. -Methoxypyridin-4-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 74
N-((R) -6-cyanochroman-3-yl) -5- (2-methoxypyridin-4-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Isomeric separation of oxazine-2-carboxamide

N-((R) -6-cyanochroman-3-yl) -5- (2-methoxypyridine-4-yl) -6,7-dihydro-5H-pyrazolo [5] synthesized by the method described in Example 73. , 1-b] [1,3] Oxazine-2-carboxamide (32.0 mg, 0.0742 mmol) was dissolved in ethanol (1.9 mL) and preparatively obtained by HPLC (column: CHIRALPAK IB, developing solvent: ethanol, flow rate: 8.0 mL). The mixture was subjected to isomer A (yield 8.3 mg, yield 26%) and isomer B (yield 10.6 mg, yield 33%).

Example 75
N-((R) -6-cyanochroman-3-yl) -5- (2-methoxypyridin-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Production of oxazine-2-carboxamide

N-((R) -6-cyanochroman-3-yl) -5- (2-) using 2-methoxynicotinaldehyde instead of 2-fluorobenzaldehyde in step 1 in the same manner as in Example 70. Methoxypyridine-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 76
N-((R) -6-ethylchroman-3-yl) -5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2 -Manufacture of carboxamide

In the same manner as in Example 70, instead of (R) -3-aminochroman-6-carboxamide in step 8, (R) -6-ethylchroman-3- was synthesized by the method described in Reference Example 5. Using amine hydrochloride, N-((R) -6-ethylchroman-3-yl) -5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [ 1,3] Oxazine-2-carboxamide was obtained.

Example 77
Production of N- (5-chlorochroman-3-yl) -5-phenyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

In the same manner as in Steps 6 to 8 of Example 70, instead of 1- (1-bromo-3-chloropropyl) -2-fluorobenzene in Step 6, (1-bromo-3-chloropropyl) benzene In place of (R) -3-aminochroman-6-carbonitrile in step 8, 5-chlorochroman-3-amine hydrochloride synthesized by the method described in Reference Example 4 was used, and N-( 5-Chlorochroman-3-yl) -5-phenyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Reference example 25
Production of 5- (trifluoromethoxy) chroman-3-amine hydrochloride

In the same manner as in Reference Example 4, 2-hydroxy-6- (trifluoromethoxy) benzaldehyde was used instead of 2-chloro-6-hydroxy-benzaldehyde in step 1, and 5- (trifluoromethoxy) chromane- 3-Amine hydrochloride was obtained.

Example 78
Production of 5-Phenyl-N- (5- (trifluoromethoxy) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

In the same manner as in Example 77, instead of 5-chlorochroman-3-amine hydrochloride, 5- (trifluoromethoxy) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 25 was used. , 5-Phenyl-N- (5- (trifluoromethoxy) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide rice field.

Reference example 26
Production of 2- (3-ethoxyphenyl) ethaneamine hydrochloride

Process 1
Di-tert-butyl dicarbonate (8.4 mL, 37 mL), triethylamine (8.15 mL, 58.6 mmol) and 4 in a solution of 2- (3-bromophenyl) ethaneamine (2.93 g, 14.6 mmol) in acetonitrile (50 mL). -Dimethylaminopyridine (90.0 mg, 0.737 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl N- (2- (3-bromophenyl) ethyl) -N-tert-butoxycarbonyl-carbamate (yield 4.90 g, yield 84%).

Process 2
Mixing tert-butyl N- (2- (3-bromophenyl) ethyl) -N-tert-butoxycarbonyl-carbamate (1.50 g, 3.75 mmol) with 1,4-dioxane (6 mL) and water (3 mL). In solution, potassium hydroxide (360 mg, 6.42 mmol), 2-di-tert-butylphosphino-2', 4', 6'-triisopropylbiphenyl (127 mg, 0.299 mmol) and tris (dibenzylideneacetone). Dipalladium (0) (137 mg, 0.150 mmol) was added and the mixture was stirred at 100 ° C. for 16 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl N-tert-butoxycarbonyl-N- (2- (3-hydroxyphenyl) ethyl) carbamate (yield 467 mg, 37% yield).

Process 3
tert-Butyl N-tert-butoxycarbonyl-N- (2- (3-hydroxyphenyl) ethyl) carbamate (96.0 mg, 0.285 mmol) in N, N-dimethylformamide (1 mL) solution with iodoethane (35 μL, 35 μL, 0.44 mmol) and potassium carbonate (78.0 mg, 0.564 mmol) were added, and the mixture was stirred at room temperature for 6 hours and then at 70 ° C. for 16 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl N-tert-butoxycarbonyl-N- (2- (3-ethoxyphenyl) ethyl) carbamate (yield 33.0 mg, yield 32%).

Process 4
4 mol / L hydrogen chloride in a solution of ice-cooled tert-butyl N-tert-butoxycarbonyl-N- (2- (3-ethoxyphenyl) ethyl) carbamate (33.0 mg, 0.0903 mmol) in dichloromethane (500 μL). A 1,4-dioxane solution (500 μL, 2 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain 2- (3-ethoxyphenyl) ethaneamine hydrochloride (yield 17.5 mg, yield 96%).

Example 79
Production of N- (3-ethoxyphenethyl) -5-phenyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

N- (3-ethoxyphenyl) ethaneamine hydrochloride synthesized by the method described in Reference Example 26 was used instead of 5-chlorochroman-3-amine hydrochloride in the same manner as in Example 77. (3-ethoxyphenethyl) -5-phenyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Reference example 27
Production of (R) -6- (pyridin-4-yl) chroman-3-amine

Process 1
(R) -2,2,2-trifluoro-N- (6-( Pyridine-4-yl) chroman-3-yl) acetamide was obtained.

Process 2
In the same manner as in step 2 of Reference Example 24, instead of (R) -N- (6-cyanochroman-3-yl) -2,2,2-trifluoroacetamide, (R) -2,2,2 -Trifluoro-N- (6- (pyridin-4-yl) chroman-3-yl) acetamide was used to obtain (R) -6- (pyridin-4-yl) chroman-3-amine.

Example 80
5- (2-fluorophenyl) -N-((R) -6- (pyridin-4-yl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Production of oxazine-2-carboxamide

Instead of (R) -3-aminochroman-6-carboxamide in step 8, it was synthesized by the method described in Reference Example 27 in the same manner as in Example 70 (R) -6- (pyridine-4-). 5- (2-Fluorophenyl) -N-((R) -6- (pyridin-4-yl) chroman-3-yl) -6,7-dihydro-5H with yl) chroman-3-amine -Pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Reference example 28
Production of (R) -6- (pyridin-2-yl) chroman-3-amine dihydrochloride

Process 1
1,4 of (R) -N- (6-bromochroman-3-yl) -2,2,2, -trifluoroacetamide (500 mg, 1.54 mmol) synthesized by the method described in step 1 of Reference Example 2 -Dioxane (10 mL) solution with bis (pinacolato) diboron (800 mg, 3.15 mmol), potassium acetate (300 mg, 7.87 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) ) (100 mg, 0.14 mmol) was added, and the mixture was stirred at 90 ° C. for 15 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and (R) -2,2,2-trifluoro-N- (6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2). -Il) Chroman-3-yl) Acetamide (yield 570 mg, yield 100%) was obtained.

Process 2
(R) -2,2,2-trifluoro-N- (6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) chroman-3-yl) acetamide ( 200 mg, 0.539 mmol), 2-bromopyridine (130 mg, 0.823 mmol), cesium carbonate (350 mg, 1.07 mmol) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) A mixed suspension of (38.0 mg, 0.0537 mmol) 1,4-dioxane (2.5 mL) and water (0.5 mL) was stirred at 100 ° C. for 5 hours. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution to separate the layers. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and (R) -2,2,2-trifluoro-N- (6- (pyridin-2-yl) chroman-3-yl) acetamide (yield 82.0 mg, yield). 47%) was obtained.

Process 3
In the same manner as in step 3 of Reference Example 1, instead of (R) -N- (6-chlorochroman-3-yl) -2,2,2, -trifluoroacetamide, (R) -2,2 , 2-Trifluoro-N- (6- (pyridin-2-yl) chroman-3-yl) acetamide, (R) -6- (pyridin-2-yl) chroman-3-amine dihydrochloride Got

Example 81
5- (2-Fluorophenyl) -N-((R) -6- (pyridin-2-yl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Production of oxazine-2-carboxamide

Instead of (R) -3-aminochroman-6-carboxamide in step 8, it was synthesized by the method described in Reference Example 28 in the same manner as in Example 70 (R) -6- (pyridin-2-). Il) Chroman-3-amine dihydrochloride, 5- (2-fluorophenyl) -N-((R) -6- (pyridin-2-yl) chroman-3-yl) -6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 82
5- (2-fluorophenyl) -N-((R) -6- (hydroxymethyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Production of oxazine-2-carboxamide

Process 1
In the same manner as in Step 1 of Reference Example 3, instead of (R) -N- (6-bromochroman-3-yl) -2,2,2, -trifluoroacetamide, the method described in Example 71. Synthesized N-((R) -6-bromochroman-3-yl) -5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine- With 2-carboxamide, 5- (2-fluorophenyl) -N-((R) 6-vinyl chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Oxazine-2-carboxamide was obtained.

Process 2
In the same manner as in step 2 of Reference Example 3, instead of (R) -2,2,2-trifluoro-N- (6-vinylchroman-3-yl) acetamide, 5- (2-fluorophenyl) -N-((R) 6-vinyl chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] with oxazine-2-carboxamide, 5-( 2-Fluorophenyl) -N-((R) 6-formylroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide Obtained.

Process 3
5- (2-Fluorophenyl) -N-((R) 6-Methanolroman-3-yl) -6,7-Dihydro-5H-Pyrazolo [5,1-b] [1,3] Oxazine-2 -Sodium borohydride (12.6 mg, 0.332 mmol) was added to a solution of carboxamide (70.0 mg, 0.166 mmol) in methanol (1.66 mL), and the mixture was stirred at room temperature for 13 hours. Water and chloroform were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and 5- (2-fluorophenyl) -N-((R) -6- (hydroxymethyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [ 5,1-b] [1,3] Oxazine-2-carboxamide (yield 82.0 mg, yield 47%) was obtained.

Example 83
N-((R) -6- (ethoxymethyl) chroman-3-yl) -5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Production of oxazine-2-carboxamide

Process 1
5- (2-Fluorophenyl) -N-((R) -6- (hydroxymethyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5] synthesized by the method described in Example 82. , 1-b] [1,3] Oxazine-2-carboxamide (42.0 mg, 0.0992 mmol) in dichloromethane (1 mL) with triethylamine (41.4 μL, 0.298 mmol) and methanesulfonyl chloride (30.8 μL, 0.396 mmol). In addition, it was stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography, and N-((R) -6- (chloromethyl) chroman-3-yl) -5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [ 5,1-b] [1,3] Oxazine-2-carboxamide (yield 37.6 mg, yield 86%) was obtained.

Process 2
N-((R) -6- (chloromethyl) chroman-3-yl) -5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] To tetrahydrofuran (1.1 mL) of oxadin-2-carboxamide (12.5 mg, 0.0283 mmol) was added a solution of 2.9 mol / L sodium ethoxydo-ethanol solution (49 μL, 0.141 mmol) diluted with ethanol (556 μL). After stirring at room temperature for 7 hours, the mixture was stirred at 80 ° C. for 2 hours. Water and chloroform were added to the residue and the liquid was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to N-((R) -6- (ethoxymethyl) chroman-3-yl) -5-(. 2-Fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxamide (yield 9.3 g, yield 73%) was obtained.

Example 84
5- (2-Fluorophenyl) -N-((R) -6-(((Tetrahydro-2H-pyran-4-yl) oxy) methyl) chroman-3-yl) -6,7-dihydro-5H- Production of pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

Sodium hydride (60% in oil) (9.1 mg, 0.23 mmol) was added to a mixture of tetrahydro-4-pyranol (45.3 μL, 4.75 mmol) and tetrahydrofuran (900 μL), and the mixture was stirred for 10 minutes and then Example 83. N-((R) -6- (chloromethyl) chroman-3-yl) -5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5] synthesized by the method described in step 1 of , 1-b] [1,3] Oxazine-2-carboxamide (10.0 mg, 0.0226 mmol) was added, and the mixture was stirred at room temperature for 17 hours and at 80 ° C. for 20 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography to obtain a crude product. Ethyl acetate was added to the crude product, washed with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and 5- (2-fluorophenyl) -N-((R) -6-(((tetrahydro-2H-pyran-4-yl) oxy) methyl) chroman-3- Il) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (yield 4.6 mg, yield 40%) was obtained.

Example 85
Production of N-((R) -6-chlorochroman-3-yl) -5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

Process 1
Add imidazole (3.78 g, 55.5 mmol) and tert-butylchlorodiphenylsilane (2.90 mL, 11.3 mmol) to a solution of butane-1,3-diol (1.00 g, 11.1 mmol) in dichloromethane (37 mL) at room temperature. Stirred for 18 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 4-((tert-butyldiphenylsilyl) oxy) butan-2-ol (yield 3.77 g, yield 103%). rice field.

Process 2
Ethyl 5-hydroxy-1H-pyrazol-3-carboxylate (1.78 g, 1.78 g,) in a solution of 4-((tert-butyldiphenylsilyl) oxy) butane-2-ol (3.75 g, 11.4 mmol) in tetrahydrofuran (38 mL). 11.4 mmol), triphenylphosphine (3.89 g, 14.8 mmol) and diisopropyl-toluene solution of 1.9 mol / L azodicarboxylate (7.8 mL, 15 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, and ethyl 5-((4-((tert-butyldiphenylsilyl) oxy) butane-2-yl) oxy) -1H-pyrazole- A 3-carboxylate (yield 5.07 g, yield 95%) was obtained.

Process 3
In a solution of ethyl 5-((4-((tert-butyldiphenylsilyl) oxy) butane-2-yl) oxy) -1H-pyrazol-3-carboxylate (5.00 g, 10.7 mmol) in tetrahydrofuran (107 mL), A 1 mol / L tetrahydroammonium fluoride- tetrahydrofuran solution (53.6 mL, 53.6 mmol) was added and stirred at room temperature for 4 hours. After concentrating the reaction under reduced pressure, the residue was purified by silica gel column chromatography and ethyl 5-((4-hydroxybutane-2-yl) oxy) -1H-pyrazole-3-carboxylate (yield 1.36 g). , Yield 56%) was obtained.

Process 4
N, N-diisopropylethylamine (6.1 mL) in a solution of ethyl 5-((4-hydroxybutane-2-yl) oxy) -1H-pyrazol-3-carboxylate (1.35 g, 5.91 mmol) in dichloromethane (40 mL). , 35 mmol), carbon tetrabromide (3.92 g, 11.8 mmol) and triphenylphosphine (2.02 g, 7.70 mmol) were added and stirred at room temperature for 5 hours. After concentrating the reaction under reduced pressure, the residue was purified by silica gel column chromatography, ethyl 5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2. -Carboxylate (yield 1.02 g, yield 82%) was obtained.

Process 5
In the same manner as in Step 7 of Example 70, of ethyl 5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate. Instead, use ethyl 5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate and 5-methyl-6,7-dihydro-5H. -Pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid was obtained.

Process 6
Substitution of 5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid in the same manner as in step 8 of Example 70. In addition, 5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid was used to prepare (R) -3-aminochroman-6-carbonitrile. Instead, N-((R) -6-chlorochroman-3-yl) -5-yl was used using the (R) -6-chlorochroman-3-amine hydrochloride synthesized by the method described in Reference Example 1. Methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxamide was obtained.

Example 86
(S) -N-((R) -6-chlorochroman-3-yl) -5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2- Manufacture of carboxamide

In the same manner as in Example 85, (S) -butane-1,3-diol was used instead of butane-1,3-diol in step 1, and (S) -N-((R) -6). -Chlorochroman-3-yl) -5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 87
(R) -N-((R) -6-chlorochroman-3-yl) -5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2- Manufacture of carboxamide

In the same manner as in Example 85, (R) -butane-1,3-diol was used instead of butane-1,3-diol in step 1, and (R) -N-((R) -6). -Chlorochroman-3-yl) -5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 88
(S) -N-((R) -6-bromochroman-3-yl) -5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide Manufacturing of

In the same manner as in Example 85, (S) -butane-1,3-diol was used instead of butane-1,3-diol in step 1, and (R) -6-chlorochroman-3 in step 6 was used. -Instead of the amine hydrochloride, (R) -6-bromochroman-3-amine hydrochloride synthesized by the method described in Reference Example 2 was used, and (S) -N-((R) -6-bromochroman-). 3-Il) -5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 89
(R) -N-((R) -6-bromochroman-3-yl) -5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide Manufacturing of

In the same manner as in Example 85, (R) -butane-1,3-diol was used instead of butane-1,3-diol in step 1, and (R) -6-chlorochroman-3 in step 6 was used. -Instead of the amine hydrochloride, (R) -N-bromochroman-3-amine hydrochloride synthesized by the method described in Reference Example 2 was used, and (R) -N-((R) -6-bromochroman-). 3-Il) -5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 90
Production of N-((R) -6-chlorochroman-3-yl) -5-ethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

N-((R) -6-chlorochroman-3-yl) using pentane-1,3-diol instead of butane-1,3-diol in step 1 in the same manner as in Example 85. -5-Ethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 91
Production of N-((R) -6-cyanochroman-3-yl) -5-ethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

In the same manner as in Example 85, pentane-1,3-diol was used instead of butane-1,3-diol in step 1, and (R) -6-chlorochroman-3-amine hydrochloride in step 6 was used. Instead of (R) -3-aminochroman-6-carboxamide synthesized by the method described in Reference Example 24, N-((R) -6-cyanochroman-3-yl) -5-ethyl was used. -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 92
Isomeric separation of N-((R) -6-cyanochroman-3-yl) -5-ethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

N-((R) -6-cyanochroman-3-yl) -5-ethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] synthesized by the method described in Example 91. ] Oxazine-2-carboxamide (200 mg, 0.568 mmol) is dissolved in ethanol (52 mL) and subjected to HPLC preparative (column: CHIRALPAK IB, developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature). Isomeric A (yield 53.1 mg, yield 27%) and isomer B (yield 62.0 mg, yield 31%) were obtained.

Reference example 29
Production of (R) -6- (2-methoxypyrimidine-5-yl) chroman-3-amine

In the same manner as in Reference Example 27, 2-methoxypyrimidine-5-boronic acid was used instead of pyridine-4-ylboronic acid in step 1, and (R) -6- (2-methoxypyrimidine-5-yl) was used. ) Chroman-3-amine was obtained.

Example 93
5-Ethyl-N-((R) -6- (2-Methoxypyrimidine-5-yl) Chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 ] Production of oxazine-2-carboxamide

In the same manner as in Example 85, pentane-1,3-diol was used instead of butane-1,3-diol in step 1, and (R) -6-chlorochroman-3-amine hydrochloride in step 6 was used. 5-Ethyl-N-((R)- 6- (2-methoxypyrimidine-5-yl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 94
Production of N-((R) -6-cyanochroman-3-yl) -5-propyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

Using hexane-1,3-diol instead of butane-1,3-diol in step 1, N-((R) -6-cyanochroman-3-yl)-in the same manner as in Example 85. 5-propyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 95
Isomeric separation of N-((R) -6-cyanochroman-3-yl) -5-propyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

N-((R) -6-cyanochroman-3-yl) -5-propyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] synthesized by the method described in Example 94. ] Oxazine-2-carboxamide (24.2 mg, 0.066 mmol) is dissolved in ethanol (3 mL) and subjected to HPLC preparative (column: CHIRALPAK IB, developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature). Isomeric A (yield 11.1 mg, yield 46%) and isomer B (yield 11.0 mg, yield 46%) were obtained.

Reference example 30
Production of 4-cyclopropylbutane-1,3-diol

Process 1
2,2-Dimethyl-1,3-dioxane-4,6-dione (3.17 g, 22.0 mmol) and 1- (3- (3-) in a solution of 2-cyclopropyl acetic acid (2.00 g, 20.0 mmol) in tetrahydrofuran (50 mL). Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.21 g, 22.0 mmol) was added, and the mixture was stirred at room temperature for 26 hours. After distilling off the solvent under reduced pressure, ethyl acetate and 1 mol / L hydrochloric acid were added to the residue to separate the liquids. After drying the organic layer with sodium sulfate, the solvent was distilled off under reduced pressure, and 5- (2-cyclopropyl-1-hydroxy-ethylidene) -2,2-dimethyl-1,3-dioxane-4,6- Zeon (yield 4.39 g, yield 97%) was obtained.

Process 2
4-Methyl in a solution of 5- (2-cyclopropyl-1-hydroxy-ethylidene) -2,2-dimethyl-1,3-dioxane-4,6-dione (4.39 g, 19.4 mmol) in methanol (50 mL). Benzenesulfonic acid monohydrate (36.9 mg, 0.194 mmol) was added, and the mixture was stirred under heating and reflux for 16 hours. After allowing to cool to room temperature, the solvent was distilled off under reduced pressure to obtain methyl 4-cyclopropyl-3-oxo-butanoate (yield 2.97 g, yield 98%).

Process 3
Lithium borohydride (911 mg, 41.8 mmol) was added to a solution of ice-cooled methyl 4-cyclopropyl-3-oxo-butanoate (2.97 g, 19.0 mmol) in tetrahydrofuran (190 mL), and the mixture was stirred at 60 ° C. for 3 hours. bottom. The reaction mixture was ice-cooled, water and ethyl acetate were added, and the layers were separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 4-cyclopropylbutane-1,3-diol (yield 2.50 g, yield 101%).

Example 96
Production of N-((R) -6-cyanochroman-3-yl) -5-cyclopropylmethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

N- was used in the same manner as in Example 85, using 4-cyclopropylbutane-1,3-diol synthesized by the method described in Reference Example 30 instead of butane-1,3-diol in step 1. ((R) -6-cyanochroman-3-yl) -5-cyclopropylmethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 97
N-((R) -6-cyanochroman-3-yl) -5-cyclopropylmethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide isomers Body separation

N-((R) -6-cyanochroman-3-yl) -5-cyclopropylmethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1] synthesized by the method described in Example 96. , 3] Oxazine-2-carboxamide (20.8 mg, 0.055 mmol) was dissolved in ethanol (2.1 mL) and subjected to HPLC preparative (column: CHIRALPAK IB, developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature). Then, isomer A (yield 8.0 mg, yield 38%) and isomer B (yield 8.5 mg, yield 41%) were obtained.

Reference example 31
Production of Ethyl 5-((benzyloxy) Methyl) -6,7-Dihydro-5H-Pyrazolo [5,1-b] [1,3] Oxazine-2-carboxylate

In the same manner as in steps 1 to 4 of Example 85, 4- (benzyloxy) butane-1,3-diol was used instead of butane-1,3-diol in step 1 to form ethyl 5- (. Benzyloxy) methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate was obtained.

Example 98
5-((benzyloxy) methyl) -N-((R) -6-chlorochroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine- 2-Manufacture of carboxamide

Ethyl 5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate in step 5 in the same manner as in steps 5 and 6 of Example 85. Instead of, ethyl 5-((benzyloxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2- synthesized by the method described in Reference Example 31. Using carboxylate, 5-((benzyloxy) methyl) -N-((R) -6-chlorochroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [ 1,3] Oxazine-2-carboxamide was obtained.

Example 99
5-((benzyloxy) methyl) -N-((R) -6-cyanochroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2 -Manufacture of carboxamide

Ethyl 5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate in step 5 in the same manner as in steps 5 and 6 of Example 85. Instead of, ethyl 5-((benzyloxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2- synthesized by the method described in Reference Example 31. Using carboxylate, instead of (R) -6-chlorochroman-3-amine hydrochloride in step 6, (R) -3-aminochroman-6-carbonitrile synthesized by the method described in Reference Example 24 was used. Using 5-((benzyloxy) methyl) -N-((R) -6-cyanochroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 100
Production of N-((R) -6-cyanochroman-3-yl) -5- (propoxymethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

Process 1
Ethyl 5-((benzyloxy) methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate (12.4 g) synthesized by the method described in Reference Example 31 20% Palladium hydroxide carbon (2.59 mg) was added to a solution of 18.4 mmol) in ethanol (61 mL), and the reaction mixture was stirred under pressurized conditions (about 3 atm) under a hydrogen atmosphere at 40 ° C. for 23 hours. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b]. [1,3] Oxazine-2-carboxylate (yield 2.47 g, yield 59%) was obtained.

Process 2
Ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate (1.97 g, 8.71 mmol) in ethanol (44 mL) solution , 4 mol / L aqueous sodium hydroxide solution (8.7 mL, 35 mmol) was added, and the mixture was stirred at room temperature for 15 hours. After adding 2 mol / L hydrochloric acid to the reaction solution, the solvent was distilled off under reduced pressure, and 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxylic acid (yield 3.68 g, yield 98%) was obtained as a mixture with 4 equivalents of sodium chloride.

Process 3
5- (Hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid (mixture of sodium tetrachloride) (450 mg, 1.04 mmol), reference example (R) -3-aminochroman-6-carbonitrile (200 mg, 1.15 mmol), 1-hydroxybenzotriazole (169 mg, 1.25 mmol) and 1-ethyl-3- (3) synthesized by the method described in 24. To a suspension of -dimethylaminopropyl) carbodiimide hydrochloride (240 mg, 1.25 mmol) in dichloromethane (10 mL) was added 4-methylmorpholine (573 μL, 5.21 mmol), and the mixture was stirred at room temperature for 24 hours. 1 mol / L hydrochloric acid and chloroform were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b]. [1,3] Oxazine-2-carboxamide (yield 300 mg, yield 81%) was obtained.

Process 4
N-((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide ( Sodium hydride (60% in oil) and 1-iodopropane (136 μL, 1.39 mmol) were added to a solution of 330 mg, 0.931 mmol) of N, N-dimethylformamide (8.8 mL), and the mixture was stirred at 90 ° C. for 13 hours. bottom. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -6-cyanochroman-3-yl) -5- (propoxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b]. [1,3] Oxazine-2-carboxamide (yield 73.3 mg, yield 20%) was obtained.

Example 101
N-((R) -6-cyanochroman-3-yl) -5- (propoxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide Isomer separation

N-((R) -6-cyanochroman-3-yl) -5- (propoxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [ 1,3] Oxazine-2-carboxamide (150 mg, 0.378 mmol) is dissolved in ethanol (15 mL) and subjected to HPLC preparative (column: CHIRALPAK IB, developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature). Then, isomer A (yield 59.9 mg, yield 40%) and isomer B (yield 61.4 mg, yield 41%) were obtained.

Example 102
N-((R) -6-cyanochroman-3-yl) -5-((cyclopropylmethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine- 2-Manufacture of carboxamide

N-((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-] synthesized by the method described in step 3 of Example 100. b] [1,3] Sodium hydride (60% in oil) (179 mg, 4.48 mmol) in a solution of oxazine-2-carboxamide (397 mg, 1.12 mmol) in N, N-dimethylformamide (11.2 mL). In addition, it was stirred at room temperature for 10 minutes. Further, (bromomethyl) cyclopropane (215 μL, 2.24 mmol) was added, and the mixture was stirred at 90 ° C. for 16 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -6-cyanochroman-3-yl) -5-((cyclopropylmethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5, 1-b] [1,3] Oxazine-2-carboxamide (yield 136 mg, yield 30%) was obtained.

Example 103
N-((R) -6-cyanochroman-3-yl) -5-((cyclopropylmethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine- Isolation of 2-carboxamide

N-((R) -6-cyanochroman-3-yl) -5-((cyclopropylmethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1] synthesized by the method described in Example 102. -b] [1,3] Oxazine-2-carboxamide (134 mg, 0.328 mmol) was dissolved in ethanol (13 mL) and sorted by HPLC (column: CHIRALPAK IB, developing solvent: ethanol, flow velocity: 8.0 mL / min. , Room temperature) to obtain isomer A (yield 49.3 mg, yield 37%) and isomer B (yield 48.9 mg, yield 37%).

Example 104
N-((R) -6-cyanochroman-3-yl) -5-(((3-fluorobenzyl) oxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1, 3] Production of oxazine-2-carboxamide

N-((R) -6-cyanochroman-3-yl) -5-((((R) -6-cyanochroman-3-yl) -5-yl) was used in the same manner as in Example 100, using 3-fluorobenzylbromid instead of 1-iodopropane in step 4. 3-Fluorobenzyl) oxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 105
N-((R) -6-chlorochroman-3-yl) -5-(((6- (trifluoromethyl) pyridin-2-yl) methoxy) methyl) -6,7-dihydro-5H-pyrazolo [ 5,1-b] [1,3] Production of oxazine-2-carboxamide

In the same manner as in Example 100, instead of (R) -3-aminochroman-6-carboxamide in step 3, (R) -6-chlorochroman-3- was synthesized by the method described in Reference Example 1. N-((R) -6-chlorochroman-3-yl) using amine hydrochloride and 2- (bromomethyl) -6- (trifluoromethyl) pyridine instead of 1-iodopropane in step 4. ) -5-(((6- (Trifluoromethyl) Pyridine-2-yl) methoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2- Carboxamide was obtained.

Example 106
N-((R) -6-chlorochroman-3-yl) -5-((cyclopropylmethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine -2-Production of carboxamide

In the same manner as in Example 100, instead of (R) -3-aminochroman-6-carboxamide in step 3, (R) -6-chlorochroman-3- was synthesized by the method described in Reference Example 1. N-((R) -6-chlorochroman-3-yl) -5-((cyclopropylmethoxy) using amine hydrochloride and (bromomethyl) cyclopropane instead of 1-iodopropane in step 4 ) Methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Reference example 32
Production of (R) -5- (3-aminochroman-6-yl) picolinonitrile

In the same manner as in Reference Example 27, (6-cyanopyridine-3-yl) boronic acid was used instead of pyridine-4-ylboronic acid in step 1, and (R) -5- (3-aminochroman-) was used. 6-Il) Picolinonitrile was obtained.

Example 107
N-((R) -6- (6-cyanopyridin-3-yl) chroman-3-yl) -5-((cyclopropylmethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1 -b] [1,3] Production of oxazine-2-carboxamide

(R) -5- (3-Aminochroman) synthesized by the method described in Reference Example 32 instead of (R) -3-aminochroman-6-carboxamide in step 3 in the same manner as in Example 100. N-((R) -6- (6-cyanopyridine-3-yl) using -6-yl) picolinonitrile and using (bromomethyl) cyclopropane instead of 1-iodopropane in step 4. Chroman-3-yl) -5-((cyclopropylmethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxamide was obtained.

Reference example 33
Production of 5-((cyclopropylmethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid

Process 1
N-((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] in the same manner as in step 4 of Example 100. ] [1,3] Ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo synthesized by the method described in step 1 of Example 100 instead of oxazine-2-carboxamide [5,1- b] [1,3] Ethyl 5-((cyclopropylmethoxy) methyl) -6,7-dihydro with oxazine-2-carboxylate and (bromomethyl) cyclopropane instead of 1-iodopropane -5H-Pyrazolo [5,1-b] [1,3] Oxazine-2-carboxylate was obtained.

Process 2
In the same manner as in Step 2 of Example 100, instead of ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate. , Ethyl 5-((cyclopropylmethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] with oxazine-2-carboxylate, 5-((cyclopropylmethoxy) Methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Example 108
5-((Cyclopropylmethoxy) Methyl) -N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b ] [1,3] Production of oxazine-2-carboxamide

In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid, Using 5-((cyclopropylmethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid synthesized by the method described in Reference Example 33. , (R) -3-aminochroman-6-carbonitrile, instead of (R) -6- (2,2-difluoroethyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 48. Using 5-((cyclopropylmethoxy) methyl) -N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5, 1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 109
5-((Cyclopropylmethoxy) Methyl) -N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b ] [1,3] Isolation of oxazine-2-carboxamide

5-((Cyclopropylmethoxy) methyl) -N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -6,7-dihydro synthesized by the method described in Example 108 -5H-Pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (15.9 mg, 0.036 mmol) was dissolved in ethanol / n-hexane (50/50) mixed solvent (1 mL).
HPLC preparative (column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50/50, flow velocity: 8.0 mL / min, room temperature), isomer A (yield 3.6 mg, yield 23%) and isomer B (Yield 3.2 mg, yield 20%) was obtained.

Example 110
5-((Cyclopropylmethoxy) methyl) -N-((R) -6- (pyridin-2-yl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Production of oxazine-2-carboxamide

In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid, Using 5-((cyclopropylmethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid synthesized by the method described in Reference Example 33. , (R) -3-aminochroman-6-carbonitrile, instead of (R) -6- (pyridin-2-yl) chroman-3-amine dihydrochloride synthesized by the method described in Reference Example 28. Using 5-((cyclopropylmethoxy) methyl) -N-((R) -6- (pyridin-2-yl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1 -b] [1,3] Oxazine-2-carboxamide was obtained.

Example 111
5-((Cyclopropylmethoxy) methyl) -N-((R) -6- (pyridin-2-yl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Isomeric separation of oxazine-2-carboxamide

5-((Cyclopropylmethoxy) methyl) -N-((R) -6- (pyridin-2-yl) chroman-3-yl) -6,7-dihydro- synthesized by the method described in Example 110. 5H-Pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (12.0 mg, 0.026 mmol) was dissolved in ethanol (1 mL) and preparative by HPLC (column: CHIRALPAK IC, developing solvent: ethanol). , Flow velocity: 8.0 mL / min, room temperature) to obtain isomer A (yield 4.3 mg, yield 36%) and isomer B (yield 4.0 mg, yield 33%).

Reference example 34
Production of 4-((1-methylcyclopropyl) methoxy) butane-1,3-diol

Process 1
To a solution of (1-methylcyclopropyl) methanol (1.6 g, 19 mmol) in toluene (93 mL), an aqueous solution of 10 mol / L sodium hydroxide (46 mL, 460 mmol) and tetrabutylammonium hydrogensulfate (3.2 g, 9.4). After adding mmol) and stirring for 30 minutes, tertbutyl bromoacetate (3.3 mL, 22 mmol) was added, and the mixture was stirred for 3.5 hours. After separating the reaction solution, the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl 2-((1-methylcyclopropyl) methoxy) acetate (yield 3.6 g, yield 97%).

Process 2
Trifluoroacetic acid (14 mL) was added to a solution of tert-butyl 2-((1-methylcyclopropyl) methoxy) acetate (3.6 g, 18 mmol) in dichloromethane (45 mL), and the mixture was stirred at room temperature for 1.5 hours. After concentrating the reaction solution under reduced pressure, toluene was added, and the solvent was distilled off again under reduced pressure to obtain 2-((1-methylcyclopropyl) methoxy) acetic acid (yield 3.6 g, yield 100%). ..

Process 3
1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.8 g, 20) in a solution of 2-((1-methylcyclopropyl) methoxy) acetic acid (2.6 g, 18 mmol) in tetrahydrofuran (45 mL). mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (2.9 mg, 20 mmol) and N, N-dimethyl-4-aminopyridine (3.3 g, 27 mmol) and 2 at room temperature. Stirred for hours. After distilling off the solvent under reduced pressure, ethyl acetate and 1 mol / L hydrochloric acid were added to the residue.
The liquid was separated. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to remove 2,2-dimethyl-5-(2-((1-methylcyclopropyl) methoxy) acetyl) -1,3-dioxane-. 4,6-dione (yield 4.9 g, yield 100%) was obtained.

Process 4
2,2-Dimethyl-5-(2-((1-methylcyclopropyl) methoxy) acetyl) -1,3-dioxane-4,6-dione (4.9 g, 18 mmol) in methanol (91 mL). , 4-Methylbenzenesulfonic acid monohydrate (34 mg, 0.18 mmol) was added, and the mixture was stirred under heating and reflux for 5 hours. After allowing the reaction solution to cool to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and 2,2-dimethyl-5-(2-((1-methylcyclopropyl) methoxy) acetyl) -1,3-dioxane-4,6-dione (yield 1.8 g). , Yield 50%) was obtained.

Process 5
2,2-Dimethyl-5-(2-((1-methylcyclopropyl) methoxy) acetyl) -1,3-dioxane- in a solution of lithium aluminum hydride (313 mg, 8.24 mmol) in tetrahydrofuran (27 mL) 4,6-dione (550 mg, 2.75 mmol) was added, and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was ice-cooled, an aqueous potassium sodium tartrate solution was added, and the mixture was stirred for 30 minutes, and then ethyl acetate was added to separate the solutions. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4-((1-methylcyclopropyl) methoxy) butane-1,3-diol (yield 132 mg, yield 28%).

Example 112
N-((R) -6-cyanochroman-3-yl) -5-(((1-methylcyclopropyl) methoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Production of oxazine-2-carboxamide

4-((1-Methylcyclopropyl) methoxy) butane-1,3 synthesized by the method described in Reference Example 34 instead of butane-1,3-diol in step 1 in the same manner as in Example 85. Using -diol, instead of (R) -6-chlorochroman-3-amine hydrochloride in step 6, (R) -3-aminochroman-6-carboxamide synthesized by the method described in Reference Example 24 was used. Using N-((R) -6-cyanochroman-3-yl) -5-(((1-methylcyclopropyl) methoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b ] [1,3] Oxazine-2-carboxamide was obtained.

Example 113
N-((R) -6-cyanochroman-3-yl) -5-(((1-methylcyclopropyl) methoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Isomeric separation of oxazine-2-carboxamide

N-((R) -6-cyanochroman-3-yl) -5-(((1-methylcyclopropyl) methoxy) methyl) -6,7-dihydro-5H- synthesized by the method described in Example 112. Pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (12.3 mg, 0.029 mmol) was dissolved in ethanol (2 mL) and preparative by HPLC (column: CHIRALPAK IG, developing solvent: ethanol, flow velocity. : 8.0 mL / min, room temperature) to obtain isomer A (yield 1.5 mg, yield 12%) and isomer B (yield 1.8 mg, yield 15%).

Example 114
N-((R) -6-cyanochroman-3-yl) -5-((2,2,2-trifluoroethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [ 1,3] Production of oxazine-2-carboxamide

N-((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-] synthesized by the method described in step 3 of Example 100. b] [1,3] Tributylphosphine (28.2 μL, 0.113 mmol), 2,2,2-trifluoroethanol (40.6 μL) in a toluene (1.1 mL) solution of oxazine-2-carboxamide (20.0 mg, 0.0564 mmol) , 0.564 mmol) and 1,1'-(azodicarbonyl) dipiperidin (28.5 mg, 0.113 mmol) were added and stirred at 80 ° C. for 15 hours. The reaction mixture was purified by silica gel column chromatography and N-((R) -6-cyanochroman-3-yl) -5-((2,2,2-trifluoroethoxy) methyl) -6,7-dihydro- 5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 115
N-((R) -6-cyanochroman-3-yl) -5-((2,2,2-trifluoroethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [ 1,3] Isomeric separation of oxazine-2-carboxamide

N-((R) -6-cyanochroman-3-yl) -5-((2,2,2-trifluoroethoxy) methyl) -6,7-dihydro-5H synthesized by the method described in Example 114 -Pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (178 mg, 0.408 mmol) dissolved in ethanol (18 mL) and preparated by HPLC (column: CHIRALPAK IB, developing solvent: ethanol, The mixture was subjected to flow rate: 8.0 mL / min, room temperature) to obtain isomer A (yield 74.7 mg, yield 42%) and isomer B (yield 70.5 mg, yield 40%).

Example 116
N-((R) -6-cyanochroman-3-yl) -5-(((1,1,1,3,3,3-hexafluoropropan-2-yl) oxy) methyl)-6,7- Production of dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

N-((R)) using 1,1,1,3,3,3-hexafluoro-2-propanol instead of 2,2,2-trifluoroethanol in the same manner as in Example 114. -6-cyanochroman-3-yl) -5-(((1,1,1,3,3,3-hexafluoropropan-2-yl) oxy) methyl) -6,7-dihydro-5H-pyrazolo [ 5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 117
N-((R) -6-chlorochroman-3-yl) -5-((pyridin-2-yloxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 ] Production of oxazine-2-carboxamide

Process 1
In the same manner as in Step 3 of Example 100, (R) -6-chlorochroman-3- was synthesized by the method described in Reference Example 1 instead of (R) -3-aminochroman-6-carboxamide. Using amine hydrochloride, N-((R) -6-chlorochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1, 3] Oxazine-2-carboxamide was obtained.

Process 2
N-((R) -6-chlorochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide 2-Hydroxypyridine (7.8 mg, 0.082 mmol), triphenylphosphine (28.8 mg, 0.110 mmol) and diisopropyl-toluene solution of 1.9 mol / L azodicarboxylate in a solution of (20.0 mg, 0.0550 mg) in tetrahydrofuran (0.6 mL). (58 μL, 0.11 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was purified by silica gel column chromatography and N-((R) -6-chlorochroman-3-yl) -5-((pyridin-2-yloxy) methyl) -6,7-dihydro-5H-pyrazolo. [5,1-b] [1,3] Oxazine-2-carboxamide (yield 9.5 mg, yield 39%) was obtained.

Example 118
N-((R) -6-cyanochroman-3-yl) -5- (phenoxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide Manufacturing

N-((R) -6-chlorochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-" in the same manner as in step 2 of Example 117. b] [1,3] N-((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6 synthesized by the method described in Example 100 instead of oxazine-2-carboxamide. N-((R) -6- Cyanocroman-3-yl) -5- (phenoxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 119
N-((R) -6-cyanochroman-3-yl) -5-((phenylthio) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2- Manufacture of carboxamide

Process 1
N-((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-] synthesized by the method described in step 3 of Example 100. b] [1,3] N, N-diisopropylethylamine (291 μL, 1.69 mmol) and methanesulfonyl chloride (87.8 μL, 1.13) in a solution of oxazine-2-carboxamide (100 mg, 0.282 mmol) in dichloromethane (2.8 mL). mmol) was added, and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was purified by silica gel column chromatography and (2-(((R) -6-cyanochroman-3-yl) carbamoyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1, 3] Oxazine-5-yl) methylmethane sulfonate was obtained (yield 122 mg, yield 100%).

Process 2
(2-(((R) -6-cyanochroman-3-yl) carbamoyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-5-yl) methylmethanesulfonate Thiophenol (6.1 mg, 0.056 mmol) was added to a suspension of (20.0 mg, 0.0463 mmol) and cesium carbonate (45.2 mg, 0.139 mmol) in N, N-dimethylformamide (930 μL) for 4 hours at 80 ° C. Stirred. Water, ethyl acetate and n-hexane were added to the reaction mixture, and the layers were separated. The organic layer was washed with saturated brine, dried over saturated anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -6-cyanochroman-3-yl) -5-((phenylthio) methyl) -6,7-dihydro-5H-pyrazolo [5,1- b] [1,3] Oxazine-2-carboxamide (yield 18.2 mg, yield 88%) was obtained.

Example 120
N-((R) -6-chlorochroman-3-yl) -5-((pyridin-4-yloxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 ] Production of oxazine-2-carboxamide

Process 1
N-((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] in the same manner as in step 1 of Example 119. ] [1,3] N-((R) -6-chlorochroman-3-yl) -5- (hydroxymethyl) synthesized by the method described in step 1 of Example 117 instead of oxazine-2-carboxamide. )-6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] with oxazine-2-carboxamide, (2-(((R) -6-chlorochroman-3-yl)) Carbamoyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-5-yl) methylmethanesulfonate was obtained.

Process 2
In the same manner as in step 2 of Example 119, (2-(((R) -6-cyanochroman-3-yl) carbamoyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Instead of oxazine-5-yl) methylmethanesulfonate, (2-(((R) -6-chlorochroman-3-yl) carbamoyl) -6,7-dihydro-5H-pyrazolo [5,1] -b] [1,3] Oxazine-5-yl) Methylmethanesulfonate and 4-hydroxypyridine instead of thiophenol, N-((R) -6-chlorochroman-3-yl) -5-((Pyridine-4-yloxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 121
5-((benzyl (methyl) amino) methyl) -N- (R) -6-chlorochroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Production of oxazine-2-carboxamide

(2-(((R) -6-chlorochroman-3-yl) carbamoyl) -6,7-dihydro-5H-pyrazolo [5,1-b] synthesized by the method described in step 1 of Example 120. [1,3] N, N-diisopropylethylamine (39 μL, 0.227 mmol) and N- in a solution of oxazine-5-yl) methylmethanesulfonate (20.0 mg, 0.045) in N, N-dimethylformamide (0.5 mL). Methylbenzylamine (18 μL, 0.14 mmol) was added, and the mixture was stirred at 120 ° C. for 15 hours. Water, ethyl acetate and n-hexane were added to the reaction mixture, and the layers were separated. The organic layer was washed with saturated brine, dried over saturated anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to 5-((benzyl (methyl) amino) methyl) -N- (R) -6-chlorochroman-3-yl) -6,7-dihydro-5H-pyrazolo [ 5,1-b] [1,3] Oxazine-2-carboxamide (yield 6.2 mg, yield 29%) was obtained.

Example 122
N-((R) -6-chlorochroman-3-yl) -5- (morpholinomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide Manufacturing of

Process 1
N-((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] in the same manner as in step 1 of Example 119. ] [1,3] Instead of oxazine-2-carboxamide, ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo synthesized by the method described in step 1 of Example 100 [5,1- b] [1,3] Using oxazine-2-carboxylate, ethyl 5-(((methylsulfonyl) oxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1, 3] Oxazine-2-carboxylate was obtained.

Process 2
In the same manner as in Example 121, (2-(((R) -6-chlorochroman-3-yl) carbamoyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 ] Oxazine-5-yl) Methylmethane Instead of sulfonate, ethyl 5-(((methylsulfonyl) oxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine Ethyl 5- (morpholinomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] with -2-carboxylate and morpholine instead of N-methylbenzylamine Oxazine-2-carboxylate was obtained.

Process 3
In the same manner as in Step 2 of Example 100, instead of ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate. , Ethyl 5- (morpholinomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] with oxazine-2-carboxylate, 5- (morpholinomethyl) -6,7 -Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Process 4
In the same manner as in Step 4 of Example 1, instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid, 5-( Morphorinomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxylic acid was used instead of 6-fluorochroman-3-amine hydrochloride as a reference example. Using the (R) -6-chlorochroman-3-amine hydrochloride synthesized by the method described in 1, N-((R) -6-chlorochroman-3-yl) -5- (morpholinomethyl)- 6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Reference example 35
Production of Ethyl 5- (ethoxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxylate

Ethyl 5-(((methylsulfonyl) oxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-synthesized by the method described in step 1 of Example 122. A 2.9 mol / L sodium ethoxydo-ethanol solution (0.9 mL, 3 mmol) was added to a suspension of 2-carboxylate (160 mg, 0.526 mmol) in ethanol (5.2 mL), and the mixture was stirred at 80 ° C. for 15 hours. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried over saturated anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and ethyl 5- (ethoxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate (yield 23.4 mg). , Yield 18%) was obtained.

Example 123
5- (ethoxymethyl) -N-((R) -6- (pyridin-2-yl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 ] Production of oxazine-2-carboxamide

Ethyl 5- (morpholinomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2 in step 3 by the same method as in steps 3 and 4 of Example 122. -Instead of carboxylate, ethyl 5- (ethoxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2- synthesized by the method described in Reference Example 35. (R) -6- (pyridin-2-yl) chromane synthesized by the method described in Reference Example 28 using carboxylate instead of (R) -6-chlorochroman-3-amine hydrochloride in step 4. 5- (ethoxymethyl) -N-((R) -6- (pyridin-2-yl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo using -3-amine dihydrochloride [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 124
5- (ethoxymethyl) -N-((R) -6- (pyridin-2-yl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 ] Isolemination of oxazine-2-carboxamide

5- (ethoxymethyl) -N-((R) -6- (pyridine-2-yl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo synthesized by the method described in Example 123 [ 5,1-b] [1,3] Oxazine-2-carboxamide (15.4 mg, 0.036 mmol) was dissolved in ethanol / n-hexane (50/50) mixed solvent (1 mL) and preparatively prepared by HPLC (column: column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50/50, flow velocity: 15.0 mL / min, room temperature), isomer A (yield 3.4 mg, yield 22%) and isomer B (yield 3.3 mg, yield) The rate was 21%).

Example 125
N-((R) -6- (6-cyanopyridin-3-yl) chroman-3-yl) -5- (ethoxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [ 1,3] Production of oxazine-2-carboxamide

Ethyl 5- (morpholinomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2 in step 3 by the same method as in steps 3 and 4 of Example 122. -Ethyl 5- (ethoxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2- synthesized by the method described in Reference Example 35 instead of carboxylate. Using carboxylate, instead of (R) -6-chlorochroman-3-amine hydrochloride in step 4, (R) -5- (3-aminochroman-6-) synthesized by the method described in Reference Example 32. N-((R) -6- (6-cyanopyridine-3-yl) chroman-3-yl) -5- (ethoxymethyl) -6,7-dihydro-5H- with picolinonitrile Pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Reference example 36
Preparation of Ethyl 5-((2,2,2-Trifluoroethoxy) Methyl) -6,7-Dihydro-5H-Pyrazolo [5,1-b] [1,3] Oxazine-2-carboxylate

N-((R) -6-cyanochroman-3-yl) -5-hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1, in the same manner as in Example 114. 3] Instead of oxazine-2-carboxamide, ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1] synthesized by the method described in step 1 of Example 100. , 3] Using oxazine-2-carboxylate, ethyl 5-((2,2,2-trifluoroethoxy) methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] ] Oxazine-2-carboxylate was obtained.

Example 126
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5-((2,2,2-trifluoroethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Production of oxazine-2-carboxamide

Ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2 in step 2 by the same method as in step 2 and step 3 of Example 100. -Althyl 5-((2,2,2-trifluoroethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] synthesized by the method described in Reference Example 36 instead of carboxylate. ] [1,3] Using oxazine-2-carboxylate, instead of (R) -3-aminochroman-6-carbonitrile in step 3, (R) -6 was synthesized by the method described in Reference Example 48. N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5-((2,2,) with -(2,2-difluoroethyl) chroman-3-amine hydrochloride 2,2-Trifluoroethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 127
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5-((2,2,2-trifluoroethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Isomeric separation of oxazine-2-carboxamide

N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5-((2,2,2-trifluoroethoxy) methyl) synthesized by the method described in Example 126) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (16.1 mg, 0.034 mmol) in ethanol / n-hexane (50/50) mixed solvent (2 mL) ), Soaked in HPLC preparative (column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50/50, flow velocity: 8.0 mL / min, room temperature), and isomer A (yield 5.8 mg, yield 36). %) And isomer B (yield 5.7 mg, yield 35%) were obtained.

Example 128
5-((2,2,2-trifluoroethoxy) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl-6,7- Production of dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

Ethyl 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylate in step 3 by the same method as in steps 3 and 4 of Example 1. Instead of ethyl 5-((2,2,2-trifluoroethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1] synthesized by the method described in Reference Example 36. , 3] Using oxazine-2-carboxylate, instead of 6-fluorochroman-3-amine hydrochloride in step 4, (R) -6-((2,2) was synthesized by the method described in Reference Example 44. , 2-Trifluoroethoxy) methyl chroman-3-amine hydrochloride with 5-((2,2,2-trifluoroethoxy) methyl) -N- (R) -6-((2,2, 2-Trifluoroethoxy) methyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxamide was obtained.

Example 129
5-((2,2,2-trifluoroethoxy) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl-6,7- Isomeric isolation of dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

5-((2,2,2-trifluoroethoxy) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) synthesized by the method described in Example 128) Chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide dissolved in ethanol and preparated by HPLC (column: CHIRALPAK IC, developing solvent) : Ethanol / n-hexane = 50/50, flow velocity: 8.0 mL / min, room temperature) to obtain isomer A (yield 3.7 mg) and isomer B (yield 3.6 mg).

Example 130
N-((R) -6- (pyridin-2-yl) chroman-3-yl) -5-((2,2,2-trifluoroethoxy) methyl) -6,7-dihydro-5H-pyrazolo [ 5,1-b] [1,3] Production of oxazine-2-carboxamide

Ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2 in step 2 by the same method as in step 2 and step 3 of Example 100. -Instead of carboxylate, ethyl 5-((2,2,2-trifluoroethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] synthesized by the method described in Reference Example 36. ] [1,3] Using oxazine-2-carboxylate, instead of (R) -3-aminochroman-6-carbonitrile in step 3, (R) -6- was synthesized by the method described in Reference Example 28. N-((R) -6- (pyridin-2-yl) chroman-3-yl) -5-((2,2,) using (pyridine-2-yl) chroman-3-amine dihydrochloride 2-Trifluoroethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 131
N-((R) -6- (pyridin-2-yl) chroman-3-yl) -5-((2,2,2-trifluoroethoxy) methyl) -6,7-dihydro-5H-pyrazolo [ 5,1-b] [1,3] Isomeric separation of oxazine-2-carboxamide

N-((R) -6- (pyridin-2-yl) chroman-3-yl) -5-((2,2,2-trifluoroethoxy) methyl)-synthesized by the method described in Example 130. 6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (7.4 mg, 0.015 mmol) was dissolved in ethanol (1 mL) and sorted by HPLC (column: CHIRALPAK). The mixture was subjected to IC, developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature) to obtain isomer A (yield 3.0 mg, yield 41%) and isomer B (yield 2.4 mg, yield 32%).

Example 132
N-((R) -6- (6-cyanopyridine-3-yl) chroman-3-yl) -5-((2,2,2-trifluoroethoxy) methyl) -6,7-dihydro-5H -Manufacture of pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

Ethyl 5- (morpholinomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2 in step 3 in the same manner as in steps 3 and 4 of Example 122. -Instead of carboxylate, ethyl 5-((2,2,2-trifluoroethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] synthesized by the method described in Reference Example 36. ] [1,3] Using oxazine-2-carboxylate, instead of (R) -6-chlorochroman-3-amine hydrochloride in step 4, (R)-synthesized by the method described in Reference Example 32. N-((R) -6- (6-cyanopyridine-3-yl) chroman-3-yl) -5-((2) using 5- (3-aminochroman-6-yl) picolinonitrile , 2,2-Trifluoroethoxy) Methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Reference example 37
Production of 5-((trifluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid

Process 1
Ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylate (3.00) synthesized by the method described in step 1 of Example 100. Silver trifluoromethanesulfonate (6.81 g, 26.5 mmol), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2,2,2] in a solution of g, 13.3 mmmol) in ethyl acetate (66 mL). ] Octanebis (tetrafluoroborate) (7.05 g, 19.9 mmol), potassium fluoride (2.31 g, 39.8 mmol), 2-fluoropyridine (2.3 mL, 27 mmol) and (trifluoromethyl) trimethylsilane (3.9 mL, 3.9 mL,) 26 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and ethyl 5-((trifluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate. (Yield 1.49 g, yield 38%) was obtained.

Process 2
In the same manner as in Step 2 of Example 100, instead of ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate. , Ethyl 5-((trifluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] with oxazine-2-carboxylate, 5-((trifluoro) Methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Example 133
N-((R) -6-cyanochroman-3-yl) -5-((trifluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine- 2-Manufacture of carboxamide

5-((Trifluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid (4) synthesized by the method described in Reference Example 37. Sodium chloride mixture) (267 mg, 0.534 mmol), (R) -3-aminochroman-6-carbonitrile (140 mg, 0.804 mmol) synthesized by the method described in Reference Example 24, 1-hydroxybenzotriazole (123). 4-Methylmorpholine (5-methylmorpholine) in N, N-dimethylformamide (5 mL) suspension of mg, 0.804 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (154 mg, 0.804 mmol). 353 μL, 3.21 mmol) was added, and the mixture was stirred at 40 ° C. for 15 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -6-cyanochroman-3-yl) -5-((trifluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5, 1-b] [1,3] Oxazine-2-carboxamide (yield 182 mg, yield 81%) was obtained.

Example 134
NR) -6-cyanochroman-3-yl) -5-((trifluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide Isomeric separation

N-((R) -6-cyanochroman-3-yl) -5-((trifluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1] synthesized by the method described in Example 133. -b] [1,3] Oxazine-2-carboxamide (20 mg) dissolved in ethanol (2 mL) and preparative by HPLC (column: CHIRALPAK IB, developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature) And isomer A (yield 9.4 mg, yield 47%) and isomer B (yield 8.2 mg, yield 41%) were obtained.

Example 135
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5-((trifluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b ] [1,3] Production of oxazine-2-carboxamide

In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid, Using 5-((trifluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid synthesized by the method described in Reference Example 37. , (R) -3-Aminochroman-6-Carboxamide, instead of (R) -6- (2,2-difluoroethyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 48. Using N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5-((trifluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5, 1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 136
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5-((trifluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b ] [1,3] Isolation of oxazine-2-carboxamide

N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5-((trifluoromethoxy) methyl) -6,7-dihydro synthesized by the method described in Example 135 -5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide is dissolved in ethanol and preparative by HPLC (column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50/50, flow velocity. : 8.0 mL / min, room temperature) to obtain isomer A (yield 4.0 mg) and isomer B (yield 3.2 mg).

Reference example 38
5-((Difluoromethoxy) Methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxylic acid

Process 1
Ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate (600) synthesized by the method described in step 1 of Example 100. A suspension of mg, 2.65 mmmol) and copper (I) iodide (152 mg, 0.798 mmol) in acetonitrile (13 mL) was heated to 50 ° C. and 2,2-difluoro-2- (fluorosulfonyl) acetic acid (0.41). mL, 4.0 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hours. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution to separate the layers, and then the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography and ethyl 5-((difluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1. , 3] Oxazine-2-carboxylate (yield 520 mg, yield 71%) was obtained.

Process 2
In the same manner as in Step 2 of Example 100, instead of ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate. , Ethyl 5-((difluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] with oxazine-2-carboxylate, 5-((difluoromethoxy) Methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Example 137
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5-((difluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Production of oxazine-2-carboxamide

In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid, Using 5-((difluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid synthesized by the method described in Reference Example 38, Instead of (R) -3-aminochroman-6-carbonitrile, (R) -6- (2,2-difluoroethyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 48 was used. N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5-((difluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1- b] [1,3] Oxazine-2-carboxamide was obtained.

Example 138
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5-((difluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Isomeric separation of oxazine-2-carboxamide

N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5-((difluoromethoxy) methyl) -6,7-dihydro- synthesized by the method described in Example 137. 5H-Pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (15.7 mg, 0.035 mmol) was dissolved in ethanol / n-hexane (50/50) mixed solvent (4 mL), and the amount of HPLC was added. (Column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50/50, flow velocity: 12.0 mL / min, room temperature), isomer A (yield 5.6 mg, yield 36%) and isomer B (yield) 5.7 mg, yield 36%) was obtained.

Example 139
5-((difluoromethoxy) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [ 5,1-b] [1,3] Production of oxazine-2-carboxamide

In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid, Using 5-((difluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid synthesized by the method described in Reference Example 38, (R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3 synthesized by the method described in Reference Example 44 instead of (R) -3-aminochroman-6-carbonitrile -Using amine hydrochloride, 5-((difluoromethoxy) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -6, 7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxamide was obtained.

Example 140
5-((difluoromethoxy) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [ 5,1-b] [1,3] Isomeric separation of oxazine-2-carboxamide

5-((Difluoromethoxy) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl)-synthesized by the method described in Example 139. 6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (21.2 mg, 0.0431 mmol) in ethanol / n-hexane (50/50) mixed solvent (1 mL) Soaked in HPLC preparative (column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50/50, flow velocity: 8.0 mL / min, room temperature) and subjected to isomer A (yield 3.6 mg, yield 17%). ) And isomer B (yield 3.7 mg, yield 17%).

Example 141
N-((R) -6- (2-difluoromethoxy) ethyl) chroman-3-yl) -5-((difluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Production of oxazine-2-carboxamide

In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid, Using 5-((difluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid synthesized by the method described in Reference Example 38, Instead of (R) -3-aminochroman-6-carbonitrile, (R) -6-(2- (difluoromethoxy) ethyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 45 was used. Using N-((R) -6- (2-difluoromethoxy) ethyl) chroman-3-yl) -5-((difluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1 -b] [1,3] Oxazine-2-carboxamide was obtained.

Example 142
N-((R) -6- (2-difluoromethoxy) ethyl) chroman-3-yl) -5-((difluoromethoxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Isomeric separation of oxazine-2-carboxamide

N-((R) -6- (2-difluoromethoxy) ethyl) chroman-3-yl) -5-((difluoromethoxy) methyl) -6,7-dihydro- synthesized by the method described in Example 141. 5H-Pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (15.2 mg, 0.032 mmol) was dissolved in ethanol / n-hexane (50/50) mixed solvent (1 mL), and the amount was HPLC. (Column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50/50, flow velocity: 8.0 mL / min, room temperature), isomer A (yield 7.1 mg, yield 47%) and isomer B (yield) 7.4 mg (yield 49%) was obtained.

Reference example 39
Ethyl 5- (2- (benzyloxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxylate production

In the same manner as in steps 1 to 4 of Example 85, 5- (benzyloxy) pentane-1,3-diol was used instead of butane-1,3-diol in step 1 to form ethyl 5- (. 2- (Benzyloxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate was obtained.

Reference example 40
Production of 5- (2- (trifluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid

Process 1
Ethyl 5-((benzyloxy) methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate in the same manner as in Step 1 of Example 100. Instead, ethyl 5- (2- (benzyloxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2 synthesized by the method described in Reference Example 39. -Ethyl 5- (2-hydroxyethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate was obtained using -carboxylate.

Process 2, process 3
Ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2 in step 1 in the same manner as in steps 1 and 2 of Reference Example 37. -Use ethyl 5- (2-hydroxyethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate instead of -carboxylate, 5- (2- (Trifluoromethoxy) Ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid was obtained as a mixture with 2 equivalents of sodium chloride. ..

Example 143
N-((R) -6-cyanochroman-3-yl) -5-(2- (trifluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Production of oxazine-2-carboxamide

Reference Example 40 instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid in the same manner as in step 4 of Example 1. 5- (2- (Trifluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid synthesized by the method described in N-((R) -6- Cyanochroman-3-yl) -5- (2- (trifluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxamide was obtained.

Example 144
N-((R) -6-cyanochroman-3-yl) -5- (2- (trifluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Isomeric separation of oxazine-2-carboxamide

N-((R) -6-cyanochroman-3-yl) -5-(2- (trifluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5] synthesized by the method described in Example 143. , 1-b] [1,3] Oxazine-2-carboxamide (9.9 mg) was dissolved in ethanol (2.1 mL) and prepared by HPLC (column: CHIRALPAK IB, developing solvent: ethanol, flow velocity: 8.0 mL / min, The mixture was subjected to isomer A (yield 4.4 mg, yield 44%) and isomer B (yield 4.1 mg, yield 41%).

Reference example 41
Production of 5- (2- (difluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid

Ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2 in step 1 in the same manner as in steps 1 and 2 of Reference Example 38. -Ethyl 5- (2-hydroxyethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] synthesized by the method described in Step 1 of Reference Example 40 instead of carboxylate. ] With oxazine-2-carboxylate, 5- (2- (difluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid Was obtained as a mixture with 2 equivalents of sodium chloride.

Example 145
N-((R) -6-cyanochroman-3-yl) -5- (2- (difluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine -2-Production of carboxamide

Reference Example 41 instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid in the same manner as in step 4 of Example 1. 5- (2- (Difluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid synthesized by the method described in 6 N-((R) -6-cyanochroman) was used instead of -fluorochroman-3-amine hydrochloride using (R) -3-aminochroman-6-carboxamide synthesized by the method described in Reference Example 24. -3-yl) -5- (2- (difluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 146
N-((R) -6-cyanochroman-3-yl) -5- (2- (difluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine -2- Carboxamide isomer separation

N-((R) -6-cyanochroman-3-yl) -5-(2- (difluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,] synthesized by the method described in Example 145. 1-b] [1,3] Oxazine-2-carboxamide (20.5 mg, 0.049 mmol) is dissolved in ethanol (10 mL) and preparative by HPLC (column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50). The mixture was subjected to / 50, flow rate: 20.0 mL / min, room temperature) to obtain isomer A (yield 8.2 mg, yield 40%) and isomer B (yield 9.4 mg, yield 46%).

Example 147
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5- (2- (difluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1- b] [1,3] Production of oxazine-2-carboxamide

Reference Example 41 instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid in the same manner as in step 4 of Example 1. Using 5- (2- (difluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid synthesized by the method described in 6 N- using (R) -6- (2,2-difluoroethyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 48 instead of -fluorochroman-3-amine hydrochloride. ((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5- (2- (difluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 148
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5- (2- (difluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1- b] [1,3] Isomeric separation of oxazine-2-carboxamide

N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5-(2- (difluoromethoxy) ethyl) -6,7- synthesized by the method described in Example 147. Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide (20.8 mg, 0.049 mmol) was dissolved in ethanol (2.1 mL) and preparatively prepared by HPLC (column: CHIRALPAK IC, developing solvent). : Ethanol / n-hexane = 50/50, flow velocity: 20.0 mL / min, room temperature) and isomer A (yield 6.8 mg, yield 33%) and isomer B (yield 7.4 mg, yield 36%). Obtained.

Example 149
5- (2- (difluoromethoxy) ethyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -6,7-dihydro-5H- Production of pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

Reference Example 41 instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid in the same manner as in step 4 of Example 1. Using 5- (2- (difluoromethoxy) ethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid synthesized by the method described in 6 -(R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 44 instead of fluorochroman-3-amine hydrochloride 5-(2- (Difluoromethoxy) ethyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxamide was obtained.

Example 150
5- (2- (difluoromethoxy) ethyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -6,7-dihydro-5H- Isomeric isolation of pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

5- (2- (difluoromethoxy) ethyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl synthesized by the method described in Example 149. )-6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (21.3 mg, 0.042 mmol) was dissolved in ethanol (2.1 mL) and preparated by HPLC (column). : CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50/50, flow velocity: 20.0 mL / min, room temperature), isomer A (yield 8.3 mg, yield 39%) and isomer B (yield 7.3 mg,) The yield was 34%).

Example 151
N-((R) -6-chlorochroman-3-yl) -5-(((2,2,2-trifluoroethyl) amino) methyl)-6,7-dihydro-5H-pyrazolo [5,1 -b] [1,3] Production of oxazine-2-carboxamide

Process 1
N-((R) -6-chlorochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1] synthesized by the method described in step 1 of Example 117. -b] [1,3] Sodium carbonate (208 mg, 2.48 mmol) and des-martin peryodinane (699 mg, 1.65) in a solution of oxazine-2-carboxamide (200 mg, 0.550 mmol) in dichloromethane (5.5 mL). mmol) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried over saturated anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -6-chlorochroman-3-yl) -5-formyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Oxazine-2-carboxamide (yield 85.7 mg, yield 43%) was obtained.

Process 2
N-((R) -6-chlorochroman-3-yl) -5-formyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (40.1 mg) , 0.111 mmol) in dichloromethane (1.1 mL) solution with 2,2,2-trifluoroethylamine (13 μL, 0.17 mmol), sodium triacetoxyborohydride (70.5 mg, 0.333 mmol) and acetic acid (6 μL, 0.1 mL). mmol) was added, and the mixture was stirred at room temperature for 20 hours. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried over saturated anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -6-chlorochroman-3-yl) -5-(((2,2,2-trifluoroethyl) amino) methyl) -6, 7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide (yield 6.4 mg, yield 13%) was obtained.

Example 152
N-((R) -6-chlorochroman-3-yl) -5-(((2,2,2-trifluoroethyl) amino) methyl)-6,7-dihydro-5H-pyrazolo [5,1 -b] [1,3] Isolation of oxazine-2-carboxamide

N-((R) -6-chlorochroman-3-yl) -5-(((2,2,2-trifluoroethyl) amino) methyl) -6,7 synthesized by the method described in Example 151. -Dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (19.1 mg, 0.0429 mmol) was dissolved in ethanol (1.9 mL) and sorted by HPLC (column: CHIRALPAK IB, developed. Solvent: ethanol, flow velocity: 8.0 mL / min, room temperature) to obtain isomer A (yield 8.8 mg, yield 46%) and isomer B (yield 6.6 mg, yield 35%).

Reference example 42
Production of 5-((3,3-difluoropyrrolidin-1-yl) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid

5-((3,3-difluoropyrrolidine-1-yl) methyl) using 3,3-difluoropyrrolidine hydrochloride instead of morpholine in step 2 in the same manner as in steps 2 and 3 of Example 122. )-6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Example 153
N-((R) -6-chlorochroman-3-yl) -5-((3,3-difluoropyrrolidin-1-yl) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b ] [1,3] Production of oxazine-2-carboxamide and isolation of isomers

Process 1
In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid, 5-((3,3-difluoropyrrolidin-1-yl) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine synthesized by the method described in Reference Example 42 Using -2-carboxylic acid, instead of (R) -3-aminochroman-6-carbonitrile, (R) -6-chlorochroman-3-amine hydrochloride synthesized by the method described in Reference Example 1 was used. Using N-((R) -6-chlorochroman-3-yl) -5-((3,3-difluoropyrrolidin-1-yl) methyl) -6,7-dihydro-5H-pyrazolo [5, 1-b] [1,3] Oxazine-2-carboxamide was obtained.

Process 2
N-((R) -6-chlorochroman-3-yl) -5-((3,3-difluoropyrrolidin-1-yl) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b ] [1,3] Oxazine-2-carboxamide (7.6 mg, 0.017 mmol) is dissolved in ethanol (1 mL) and preparative by HPLC (column: CHIRALPAK IC, developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature. ), And isomer A (yield 2.4 mg, yield 32%) and isomer B (yield 1.9 mg, yield 25%) were obtained.

Example 154
5-((3,3-difluoropyrrolidine-1-yl) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -6, Production of 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide and isolation of isomers

Process 1
In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid, 5-((3,3-difluoropyrrolidin-1-yl) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine synthesized by the method described in Reference Example 42 (R) -6-((2,2,2-tri) synthesized by the method described in Reference Example 44 using -2-carboxylic acid instead of (R) -3-aminochroman-6-carboxamide. 5-((3,3-difluoropyrrolidin-1-yl) methyl) -N-((R) -6-((2,2,2)) using fluoroethoxy) methyl) chroman-3-amine hydrochloride -Trifluoroethoxy) methyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxamide was obtained.

Process 2
5-((3,3-difluoropyrrolidine-1-yl) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -6, 7-Dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (12.5 mg, 0.024 mmol) was dissolved in ethanol (1 mL) and sorted by HPLC (column: CHIRALPAK IC, The developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature) was applied to obtain isomer A (yield 3.7 mg, yield 30%) and isomer B (yield 3.8 mg, yield 30%).

Example 155
N-((R) -6-cyanochroman-3-yl) -5-(((trifluoromethyl) thio) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 ] Production of oxazine-2-carboxamide

((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] synthesized by the method described in step 3 of Example 93. [1,3] Trifluoromethanethiol silver (I) (53.0 mg, 0.254 mmol) and tetrabutylammonium iodide (281 mmol) in a toluene (1.4 mL) suspension of oxazine-2-carboxamide (30.0 mg, 0.0847 mmol). mg, 0.761 mmol) was added, and the mixture was stirred at 120 ° C. for 2 hours. Water and ethyl acetate were added to the reaction solution to separate the layers, and then the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to N-((R) -6-cyanochroman-3-yl) -5-(((trifluoromethyl) thio) methyl). -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide (yield 4.3 mg, yield 12%) was obtained.

Example 156
N-((R) -6-cyanochroman-3-yl) -5-(((trifluoromethyl) thio) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 ] Isolemination of oxazine-2-carboxamide

N-((R) -6-cyanochroman-3-yl) -5-(((trifluoromethyl) thio) methyl) -6,7-dihydro-5H-pyrazolo [ 5,1-b] [1,3] Oxazine-2-carboxamide (22.3 mg, 0.051 mmol) is dissolved in ethanol (3 mL) and preparative by HPLC (column: CHIRALPAK IB, developing solvent: ethanol, flow velocity: 8.0. The mixture was subjected to mL / min (room temperature) to obtain isomer A (yield 7.8 mg, yield 35%) and isomer B (yield 8.1 mg, yield 36%).

Example 157
N-((R) -6-chlorochroman-3-yl) -5- (difluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide Manufacturing of

N-((R) -6-chlorochroman-3-yl) -5-formyl-6,7-dihydro-5H-pyrazolo [5,1-b] synthesized by the method described in step 1 of Example 151. [1,3] N, N-diethylaminosulfur trifluoride (21 μL, 0.16 mmol) was added to a solution of oxazine-2-carboxamide (14.0 mg, 0.039 mmol) in dichloromethane (0.4 mL), and the mixture was stirred at room temperature for 30 minutes. bottom. The reaction mixture was purified by silica gel column chromatography and N-((R) -6-chlorochroman-3-yl) -5- (difluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b]. ] [1,3] Oxazine-2-carboxamide (yield 4.3 mg, yield 29%) was obtained.

Example 158
N-((R) -6-chlorochroman-3-yl) -5- (difluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide Isomer separation

N-((R) -6-chlorochroman-3-yl) -5- (difluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] synthesized by the method described in Example 157. [1,3] Oxazine-2-carboxamide (20.9 mg, 0.0545 mmol) is dissolved in ethanol (2.1 mL) and preparative by HPLC (column: CHIRALPAK IB, developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature). And isomer A (yield 8.3 mg, yield 40%) and isomer B (yield 5.4 mg, yield 26%) were obtained.

Example 159
N-((R) -6-bromochroman-3-yl) -5- (difluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide Manufacturing

Process 1
Lithium borohydride (4.34 g, 199 mmol) was added to a solution of ethyl 4,4-difluoro-3-oxo-butanoate (10.0 g, 60.2 mmol) in tetrahydrofuran (300 mL), and the mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 4,4-difluorobutane-1,3-diol (yield 3.37 g, yield 44%).

Process 2
Imidazole (346 mg, 5.08 mmol) and tert-butylchlorodiphenylsilane (263 μL, 1.01 mmol) in a solution of 4,4-difluorobutane-1,3-diol (128 mg, 1.02 mmol) in dichloromethane (3.4 mL). Was added, and the mixture was stirred at room temperature for 6 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography and 4- (tert-butyl (diphenyl) silyl) oxy-1,1-difluoro-butan-2-ol (yield 299 mg,). Yield 81%) was obtained.

Process 3
Ethyl 5-hydroxy-1H-pyrazol-3 in a solution of 4- (tert-butyl (diphenyl) silyl) oxy-1,1-difluoro-butane-2-ol (100 mg, 0.274 mmol) in tetrahydrofuran (1.0 mL). -Carboxylate (42.8 mg, 0.274 mmol), triphenylphosphine (93.6 mg, 0.357 mmol) and diisopropyl-toluene solution of 1.9 mol / L azodicarboxylate (190 μL, 0.36 mmol) were added and stirred at room temperature for 13 hours. The reaction mixture was purified by silica gel column chromatography and ethyl 5- (3- (tert-butyl (diphenylsilyl) oxy) -1- (difluoromethyl) propoxy) -1H-pyrazole-3-carboxylate (yield 33.3 mg,). Yield 24%) was obtained.
Process 4
In a solution of ethyl 5- (3- (tert-butyl (diphenylsilyl) oxy) -1- (difluoromethyl) propoxy) -1H-pyrazol-3-carboxylate (9.16 g, 18.2 mmol) in tetrahydrofuran (180 mL). A 1 mol / L tetrahydroammonium fluoride-tetrahydrofuran solution (37 mL, 37 mmol) was added and stirred at room temperature for 1 hr. After concentrating the reaction under reduced pressure, the residue was purified by silica gel column chromatography and ethyl 5- (1- (difluoromethyl) -3-hydroxy-propoxy) -1H-pyrazole-3-carboxylate (yield 4.75). g, yield 99%) was obtained.
Process 5
N, N-diisopropylethylamine (363) in a solution of ethyl 5- (1- (difluoromethyl) -3-hydroxy-propoxy) -1H-pyrazol-3-carboxylate (93.0 mg, 5.91 mmol) in dichloromethane (3.5 mL). mL, 2.11 mmol), carbon tetrabromide (233 mg, 0.703 mmol) and triphenylphosphine (120 mg, 0.703 mmol) were added and stirred at room temperature for 22 hours. 1 mol / L hydrochloric acid and chloroform were added, and the liquids were separated. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. Ethyl 5- (difluoromethyl) -6,7-dihydro-5H-pyrazolo [5] , 1-b] [1,3] Oxazine-2-carboxylate was obtained as a mixture with triphenylphosphine oxide (219 mg).
Process 6
Ethyl 5- (difluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] A mixture of oxazine-2-carboxylate and triphenylphosphine oxide (213 mg) in ethanol (1.7) A 4 mol / L aqueous sodium hydroxide solution (346 μL, 1.38 mmol) was added to the (mL) solution, and the mixture was stirred at room temperature for 1 hour. After adding 2 mol / L hydrochloric acid and toluene and distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography and 5- (difluoromethyl) -6,7-dihydro-5H-pyrazolo [5, 1-b] [1,3] Oxazine-2-carboxylic acid (20.1 mg) was obtained.

Process 7
In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid, Using 5- (difluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid, (R) -3-aminochroman-6-carbonitrile Instead of using (R) -6-bromochroman-3-amine hydrochloride synthesized by the method described in Reference Example 2, N-((R) -6-bromochroman-3-yl) -5-( Difluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Reference example 43
Production of (R) -6- (trifluoromethyl) chroman-3-amine hydrochloride

Process 1
A solution of (R) -N- (chroman-3-yl) -2,2,2-trifluoroacetamide (2.50 g, 16.3 mmol) in acetonitrile (26 mL) synthesized by the method described in step 1 of Reference Example 1. Para-toluenesulfonic acid monohydrate (2.13 g, 11.2 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. Further, a solution of N-iodosuccinimide (2.52 g, 11.2 mmol) in acetonitrile (40 mL) was added, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution, a saturated aqueous sodium thiosulfate solution and ethyl acetate were added to the reaction solution to separate them, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After adding n-hexane and ethyl acetate to the residue and dissolving by heating, the mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration to give (R) -2,2,2-trifluoro-N- (6-iodochroman-3-yl) acetamide (yield 1.19 g, yield 32%).

Process 2
Copper iodide in a solution of (R) -2,2,2-trifluoro-N- (6-iodochroman-3-yl) acetamide (1.19 g, 3.21 mmol) in N, N-dimethylformamide (100 mL). (I) (0.73 g, 3.8 mmol) and methyl 2,2-difluoro-2- (fluorosulfonyl) acetate (2.04 mL, 16 mmol) were added, and the mixture was stirred at 120 ° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, filtered through Celite, and ethyl acetate, n-hexane and saturated aqueous sodium hydrogen carbonate solution were added to separate the solutions. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (R) -2,2,2-trifluoro-N- (6- (trifluoromethyl) chroman-3-yl). Acetamide (yield 949 mg, yield 95%) was obtained.

Process 3
2 mol / L water in a solution of (R) -2,2,2-trifluoro-N- (6- (trifluoromethyl) chroman-3-yl) acetamide (133 mg, 0.425 mmol) in methanol (1.1 mL). Aqueous sodium oxide solution (1.1 mL, 2.2 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water and chloroform were added to the reaction solution to separate the layers, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, a 4 mol / L hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure to obtain ((R) -6- (trifluoromethyl) chroman-3-amine hydrochloride (yield 93.8 mg, yield 87%).

Example 160
5- (Difluoromethyl) -N-((R) -6- (trifluoromethyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine -2-Production of carboxamide

5- (Difluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid (51.5 mg) synthesized by the method described in step 6 of Example 159. , 0.236 mmol), (R) -6- (trifluoromethyl) chroman-3-amine hydrochloride (72.0 mg, 0.284 mmol), 1-hydroxybenzotriazole (43.4 mg,) synthesized by the method described in Reference Example 43. 4-Methylmorpholine (158 μL, 1.44) in N, N-dimethylformamide (787 μL) solution of 0.283 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (54.5 mg, 0.284 mmol). mmol) was added, and the mixture was stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and 5- (difluoromethyl) -N-((R) -6- (trifluoromethyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5]. , 1-b] [1,3] Oxazine-2-carboxamide (yield 91.1 mg, yield 93%) was obtained.

Example 161
5- (difluoromethyl) -N-((R) -6- (trifluoromethyl) chroman-3-yl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine- Isolation of 2-carboxamide

5- (Difluoromethyl) -N-((R) -6- (trifluoromethyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5, 1-b] [1,3] Oxazine-2-carboxamide (14.7 mg, 0.035 mmol) is dissolved in ethanol (7 mL) and preparative by HPLC (column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50). The mixture was subjected to / 50, flow rate: 20.0 mL / min, room temperature) to obtain isomer A (yield 6.2 mg, yield 42%) and isomer B (yield 5.2 mg, yield 35%).

Reference example 44
Production of (R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-amine hydrochloride

Process 1
(R) -2,2,2-trifluoro-N- (6-methanolroman-3-yl) acetamide (3.89 g, 14.2 mmol) synthesized by the method described in Step 2 of Reference Example 3 ice-cooled. Sodium borohydride (1.08 g, 28.5 mmol) was added to a solution of methanol (70 mL), and the mixture was stirred under ice-cooling for 15 minutes. 1 mol / L hydrochloric acid and chloroform were added to the reaction solution, and the mixture was separated. Was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to purify (R) -2,2,2-trifluoro-N- (6- (hydroxymethyl). ) Chroman-3-yl) acetamide (yield 2.34 g, yield 60%) was obtained.

Process 2
Tributylphosphine (908 μL, 908 μL, in a toluene (18 mL) solution of (R) -2,2,2-trifluoro-N- (6- (hydroxymethyl) chromane-3-ylacetamide (500 mg, 1.82 mmol)). 3.64 mmol), 2,2,2-trifluoroethanol (1.3 mL, 18 mmol) and 1,1'-(azodicarbonyl) dipiperidin (919 mg, 3.64 mmol) were added and stirred at 80 ° C. for 1 hr. The reaction solution was allowed to cool to room temperature, water and ethyl acetate were added, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Purified by silica gel column chromatography, (R) -2,2,2-trifluoro-N- (6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) acetamide (yield 409) mg, yield 63%) was obtained.

Process 3
In the same manner as in step 3 of Reference Example 1, instead of (R) -N- (6-chlorochroman-3-yl) -2,2,2, -trifluoroacetamide, (R) -2,2 , 2-Trifluoro-N-(6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) acetamide with (R) -6-((2,2,2-) Trifluoroethoxy) methylchroman-3-amine hydrochloride was obtained.

Example 162
5- (Difluoromethyl) -N-((R) -6-((trifluoroethoxy) methyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1, 3] Production of oxazine-2-carboxamide

In the same manner as in Example 159, instead of (R) -6-bromochroman-3-amine hydrochloride in step 4, (R) -6-((2,2) was synthesized by the method described in Reference Example 44. , 2-Trifluoroethoxy) methyl) chroman-3-amine hydrochloride, 5- (difluoromethyl) -N-((R) -6-((trifluoroethoxy) methyl) chroman-3-yl) -6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 163
5- (Difluoromethyl) -N-((R) -6-((trifluoroethoxy) methyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1, 3] Isomeric separation of oxazine-2-carboxamide

5- (Difluoromethyl) -N-((R) -6-((trifluoroethoxy) methyl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo synthesized by the method described in Example 162. [5,1-b] [1,3] Oxazine-2-carboxamide (18.0 mg, 0.039 mmol) was dissolved in ethanol (9 mL) and preparative by HPLC (column: CHIRALPAK IC, developing solvent: ethanol / n- Hexane = 50/50, flow velocity: 20.0 mL / min, room temperature) to obtain isomer A (yield 8.6 mg, yield 48%) and isomer B (yield 7.9 mg, yield 44%).

Reference example 45
Production of (R) -6- (2- (difluoromethoxy) ethyl) chroman-3-amine hydrochloride

Process 1
Ice-cooled (R) -2,2,2-trifluoro-N- (6-vinylchroman-3-yl) acetamide (1.45 g, 5.35 mmol) synthesized by the method described in Step 1 of Reference Example 3 To a solution of tetrahydrofuran (27 mL) was added a solution of 0.9 mol / L boron-tetrahydrofuran in tetrahydrofuran (15 mL, 14 mmol) and stirred at room temperature for 1 hr. The reaction mixture was ice-cooled, water and sodium perborate (2.47 g, 16.1 mmol) were added, and the mixture was further stirred at room temperature for 2.5 hours. Water and ethyl acetate were added to the reaction solution to separate the layers, and then the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to purify (R) -2,2,2-trifluoro-N- (6- (2-hydroxyethyl) chroman-3-yl). ) Acetamide (yield 1.20 g, yield 77%) was obtained.

Process 2
(R) -2,2,2-trifluoro-N- (6- (2-hydroxyethyl) chroman-3-yl) acetamide (1.19 g, 4.11 mmol) and copper (I) iodide (235 mg, 1.23) A suspension of acetonitrile (21 mL) of mmol) was heated to 50 ° C., 2,2-difluoro-2- (fluorosulfonyl) acetic acid (1.10 g, 6.17 mmol) was added, and the mixture was stirred at 50 ° C. for 3 hours. Water and ethyl acetate were added to the reaction solution to separate the layers, and then the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography and (R) -N- (6- (2- (difluoromethoxy) ethyl) chroman-3-yl) -2,2, 2-Trifluoroacetamide (yield 710 mg, yield 51%) was obtained.

Process 3
In the same manner as in step 3 of Reference Example 1, instead of (R) -N- (6-chlorochroman-3-yl) -2,2,2, -trifluoroacetamide, (R) -N-( With 6-(2- (difluoromethoxy) ethyl) chroman-3-yl) -2,2,2-trifluoroacetamide, (R) -6-(2- (difluoromethoxy) ethyl) chroman-3- Amine hydrochloride was obtained.

Example 164
N-((R) -6- (2- (difluoromethoxy) ethyl) chroman-3-yl) -5- (difluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Production of oxazine-2-carboxamide

(R) -6- (2- (difluoro) synthesized by the method described in Reference Example 45 instead of (R) -6-bromochroman-3-amine hydrochloride in step 4 in the same manner as in Example 159. N-((R) -6- (2- (difluoromethoxy) ethyl) chroman-3-yl) -5- (difluoromethyl) -6,7 with methoxy) ethyl) chroman-3-amine hydrochloride -Dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 165
N-((R) -6- (2- (difluoromethoxy) ethyl) chroman-3-yl) -5- (difluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Isomeric separation of oxazine-2-carboxamide

N-((R) -6-(2- (difluoromethoxy) ethyl) chroman-3-yl) -5- (difluoromethyl) -6,7-dihydro-5H- synthesized by the method described in Example 164. Pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (25.5 mg, 0.058 mmol) was dissolved in ethanol (2.6 mL) and preparatively prepared by HPLC (column: CHIRALPAK IB N-5, developing solvent: The mixture was subjected to ethanol, flow rate: 20.0 mL / min, room temperature) to obtain isomer A (yield 10.1 mg, yield 40%) and isomer B (yield 9.8 mg, yield 38%).

Reference example 46
N-((R) -6-chlorochroman-3-yl) -5- (2-hydroxypropan-2-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 ] Oxazine-2-carboxamide and 5-acetyl-N-((R) -6-chlorochroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine -2-Production of carboxamide

Process 1
N-((R) -6-chlorochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo synthesized by the method described in step 1 of Example 117 ice-cooled [ 5,1-b] [1,3] Oxazine-2-carboxamide (668 mg, 1.84 mmol) in acetone (9.2 mL) solution with 2 mol / L chromium trioxide-sulfuric acid aqueous solution (2.8 mL, 5.6 mmol). In addition, it was stirred at room temperature for 6 hours. Isopropanol was added to the reaction solution, and the mixture was filtered through Celite. Water and ethyl acetate were added to the filtrate, and the mixture was separated. The organic layer was washed with saturated brine, dried over saturated anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and 2-(((R) -6-chlorochroman-3-yl) carbamoyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1, 3] Oxazine-5-carboxylic acid (yield 314 mg, yield 45%) was obtained.

Process 2
2-(((R) -6-chlorochroman-3-yl) carbamoyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-5-carboxylic acid (150 mg) , 0.397 mmol) in toluene (4 mL), methanol (0.6 mL, 10 mmol) and 0.6 mol / L (trimethylsilyl) diazomethane-n-hexane solution (1 mL, 0.6 mmol) at room temperature. Stirred for 30 minutes. The reaction mixture was purified by silica gel column chromatography, and methyl 2-(((R) -6-chlorochroman-3-yl) carbamoyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Oxazine-5-carboxylate (yield 33.3 mg, yield 21%) was obtained.

Process 3
Methyl 2-(((R) -6-chlorochroman-3-yl) carbamoyl) cooled to -78 ° C-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin- A 3 mol / L methylmagnesium bromide-diethyl ether solution (0.40 mL, 1.2 mmol) was added to a solution of 5-carboxylate (48.9 mg, 0.125 mmol) in tetrahydrofuran (1.3 mL), and the mixture was stirred for 20 minutes. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over saturated anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -6-chlorochroman-3-yl) -5- (2-hydroxypropan-2-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (yield 9.3 mg, yield 19%) and 5-acetyl-N- ((R) -6-chlorochroman-3-yl) -6 , 7-Dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (yield 38.3 mg, yield 82%) was obtained.

Example 166
N-((R) -6-chlorochroman-3-yl) -5- (2-fluoropropane-2-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 ] Production of oxazine-2-carboxamide

N-((R) -6-chlorochroman-3-yl) -5-formyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] in the same manner as in Example 157. ] N-((R) -6-chlorochroman-3-yl) -5- (2-hydroxypropan-2-yl)-synthesized by the method described in Reference Example 46 instead of oxazine-2-carboxamide. N-((R) -6-chlorochroman-3-yl) -5-(with 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide 2-Fluoropropan-2-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 167
N-((R) -6-chlorochroman-3-yl) -5- (1,1-difluoroethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine -2-Production of carboxamide

N-((R) -6-chlorochroman-3-yl) -5-formyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] in the same manner as in Example 157. ] Instead of oxazine-2-carboxamide, 5-acetyl-N-((R) -6-chlorochroman-3-yl) -6,7-dihydro-5H-pyrazolo synthesized by the method described in Reference Example 46. [5,1-b] [1,3] With oxazine-2-carboxamide, N-((R) -6-chlorochroman-3-yl) -5- (1,1-difluoroethyl) -6 , 7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 168
N-((R) -6-chlorochroman-3-yl) -5- (3-hydroxypentane-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 ] Production of oxazine-2-carboxamide

Methyl 2-(((R) -6-chlorochroman-3-yl) carbamoyl) -6,7-dihydro-5H-pyrazolo [5,1-b] synthesized by the method described in step 2 of Reference Example 46. [1,3] Titanium (IV) isopropoxide (31 μL, 0.10 mmol) was added to a solution of oxazine-5-carboxylate in tetrahydrofuran (1.7 mL), and the mixture was stirred for 30 minutes and then 1 mol / L ethylmagnesium bromide-. A tetrahydrofuran solution (0.4 mL, 0.4 mmol) was added, and the mixture was stirred at room temperature for 6 hours. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and N-((R) -6-chlorochroman-3-yl) -5- (3-hydroxypentane-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (yield 5.8 mg, yield 16%) was obtained.

Example 169
N-((R) -6-chlorochroman-3-yl) -5- (trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2- Manufacture of carboxamide

Process 1
In the same production method as in Step 1 of Example 85, 4-((tert-butyl) was used instead of butane-1,3-diol using 4,4,4-trifluorobutane-1,3-diol. Diphenylsilyl) oxy) -1,1,1-trifluorobutane-2-ol was obtained.

Process 2
Ice-cooled 4-((tert-butyldiphenylsilyl) oxy) -1,1,1-trifluorobutane-2-ol (563 mg, 1.47 mmol) in acetonitrile (2 mL) solution in pyridine (186 μL, 2.31) After adding mmol) and trifluoromethanesulfonic anhydride (226 μL, 1.34 mmol) and stirring for 30 minutes, ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (200 mg, 1.28 mmol) and potassium carbonate (266 mg, 266 mmol). mg, 1.92 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was purified by silica gel column chromatography, and ethyl 5-((4-((tert-butyldiphenylsilyl) oxy) -1,1,1-trifluorobutane-2-yl) oxy) -1H-pyrazole- 3-carboxylate (113 mg, 17%) was obtained.

Process 3
In the same manner as in Step 3 of Example 85, instead of ethyl 5-((4-((tert-butyldiphenylsilyl) oxy) butane-2-yl) oxy) -1H-pyrazol-3-carboxylate, Ethyl 5-((4-((tert-butyldiphenylsilyl) oxy) -1,1,1-trifluorobutane-2-yl) oxy) -1H-pyrazole-3-carboxylate, ethyl 5- ((1,1,1-Trifluoro-4-hydroxybutane-2-yl) oxy) -1H-pyrazol-3-carboxylate was obtained.

Process 4
In the same manner as in step 4 of Example 85, instead of ethyl 5-((4-hydroxybutan-2-yl) oxy) -1H-pyrazole-3-carboxylate, ethyl 5-((1,1,1,1) Ethyl 5- (trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5, using 1-trifluoro-4-hydroxybutane-2-yl) oxy) -1H-pyrazole-3-carboxylate 1-b] [1,3] Oxazine-2-carboxylate was obtained.

Process 5
In the same manner as in Step 5 of Example 85, instead of ethyl 5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate, ethyl 5 -(Trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] with oxazine-2-carboxylate, 5- (trifluoromethyl) -6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Process 6
In the same manner as in Step 6 of Example 85, instead of 5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid, 5-( Trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] with oxazine-2-carboxylic acid (sodium tetrachloride mixture), N-((R) -6 -Chlorochroman-3-yl) -5- (trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 170
N-((R) -6-chlorochroman-3-yl) -5- (trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2- Isomeric separation of carboxamide

N-((R) -6-chlorochroman-3-yl) -5- (trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] synthesized by the method described in Example 169. ] [1,3] Oxazine-2-carboxamide (10.0 mg, 0.125 mmol) is dissolved in ethanol (2 mL) and preparative by HPLC (column: CHIRALPAK IA, developing solvent: ethanol, flow rate: 8.0 mL / min, room temperature. ), And isomer A (yield 1.9 mg, yield 19%) and isomer B (yield 2.3 mg, yield 23%) were obtained.

Example 171
N-((R) -6-bromochroman-3-yl) -5- (trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide Manufacturing of

In the same manner as in Example 169, instead of (R) -6-chlorochroman-3-amine hydrochloride in step 6, (R) -6-bromochroman-3- was synthesized by the method described in Reference Example 2. Using amine hydrochloride, N-((R) -6-bromochroman-3-yl) -5- (trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1, 3] Oxazine-2-carboxamide was obtained.

Reference example 47
Production of 6- (trifluoromethyl) chroman-3-amine hydrochloride

In the same manner as in Reference Example 4, 2-hydroxy-5- (trifluoromethyl) benzaldehyde was used instead of 2-chloro-6-hydroxy-benzaldehyde in step 1, and 6- (trifluoromethyl) chromane- 3-Amine hydrochloride was obtained.

Reference example 48
Production of (R) -6- (2,2-difluoroethyl) chroman-3-amine hydrochloride

Process 1
(R) -2,2,2-trifluoro-N- (6- (2-hydroxyethyl) chroman-3-yl) acetamide (1.20 g, 4.15 mmol) synthesized by the method described in step 1 of Reference Example 45. ), Sodium hydrogen carbonate (1.39 g, 16.5 mmol) and des-martin peryodinane (3.52 g, 8.30 mmol) were added to a solution of dichloromethane (21 mL), and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction solution to separate the layers, and then the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (R) -2,2,2-trifluoro-N- (6- (2-oxoethyl chroman-3-yl)). Acetamide (yield 906 mg, yield 76%) was obtained.

Process 2
In ice-cold (R) -2,2,2-trifluoro-N- (6- (2-oxoethylchroman-3-yl) acetamide (906 mg, 3.16 mmol) in dichloromethane (16 mL), three. Fluorinated N, N-diethylaminosulfur (1.3 mL, 9.8 mmol) was added, and the mixture was stirred as it was for 30 minutes. Saturated sodium hydrogen carbonate aqueous solution and chloroform were added to the reaction solution to separate the solutions, and then the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to (R) -N- (6- (2,2-difluoroethyl) chroman-3-yl) -2,2, 2-Trifluoroacetamide (yield 716 mg, yield 73%) was obtained.

Process 3
In the same manner as in step 3 of Reference Example 1, instead of (R) -N- (6-chlorochroman-3-yl) -2,2,2, -trifluoroacetamide, (R) -N-( With 6- (2,2-difluoroethyl) chroman-3-yl) -2,2,2-trifluoroacetamide, (R) -6- (2,2-difluoroethyl) chroman-3-amine hydrochloride I got salt.

Example 172
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5- (trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Production of oxazine-2-carboxamide

In the same manner as in Example 169, instead of (R) -6-chlorochroman-3-amine hydrochloride in step 6, (R) -6- (2,2) was synthesized by the method described in Reference Example 48. N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5- (trifluoromethyl) -6,7 with -difluoroethyl) chroman-3-amine hydrochloride -Dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 173
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5- (trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Isomeric separation of oxazine-2-carboxamide

N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -5- (trifluoromethyl) -6,7-dihydro-5H- synthesized by the method described in Example 172. Pyrazolo [5,1-b] [1,3] oxadin-2-carboxamide (10.1 mg, 0.010 mmol) was dissolved in ethanol / n-hexane (50/50) mixed solvent (5 mL) and preparative by HPLC (5 mL). Column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50/50, flow velocity: 8.0 mL / min, room temperature), isomer A (yield 3.9 mg, yield 39%) and isomer B (yield 3.9 mg) , Yield 39%) was obtained.

Example 174
N-((R) -6- (6-cyanopyridin-3-yl) chroman-3-yl) -5- (trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Production of oxazine-2-carboxamide

Synthesized by the method described in Example 171 in the same manner as in Step 1 of Reference Example 27, instead of (R) -N- (6-bromochroman-3-yl) -2,2,2-trifluoroacetamide. N-((R) -6-bromochroman-3-yl) -5- (trifluoromethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxamide , And instead of pyridine-4-ylboronic acid, 6-cyanopyridine-3-ylboronic acid was used to use N-((R) -6- (6-cyanopyridine-3-yl) chroman-3-yl). ) -5- (Trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 175
N-((R) -6- (6-Methylpyridine-3-yl) chroman-3-yl) -5- (trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Production of oxazine-2-carboxamide

Using (6-methoxypyridin-3-yl) boronic acid instead of (6-cyanopyridine-3-yl) boronic acid in the same manner as in Example 174, N-((R) -6-( 6-Methylpyridine-3-yl) Chroman-3-yl) -5- (trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide Got

Example 176
N-((R) -6- (2-Methoxypyrimidine-5-yl) chroman-3-yl) -5- (trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Production of oxazine-2-carboxamide

Using (2-methoxypyrimidine-5-yl) boronic acid instead of (6-cyanopyridin-3-yl) boronic acid in the same manner as in Example 174, N-((R) -6-( 2-Methoxypyrimidine-5-yl) Chroman-3-yl) -5- (trifluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide Got

Example 177
(R) -N- (6-Chlorochroman-3-yl) -5,5-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide Manufacturing

Process 1
In the same production method as in Step 1 of Example 85, 3-methylbutane-1,3-diol was used instead of butane-1,3-diol, and 4-((tert-butyldiphenylsilyl) oxy)-. 2-Methylbutane-2-ol was obtained.

Process 2
1.6 mol / L n-butyllithium-n- in a solution of ice-cooled 4-((tert-butyldiphenylsilyl) oxy) -2-methylbutane-2-ol (300 mg, 0.876 mmol) in tetrahydrofuran (5 mL). A hexane solution (550 μL, 0.88 mmol) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was ice-cooled, chlorodiphenylphosphine (160 μL, 0.873 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, hexane and ethyl acetate were added, and the mixture was filtered. The filtrate was concentrated under reduced pressure. Prepare a solution of the residue in dichloromethane (1 mL) and make dichloromethane of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (164 mg, 1.05 mmol) and 2,6-dimethylbenzoquinone (143 mg, 1.05 mmol). 3 mL) After addition to the solution, the mixture was stirred at room temperature for 18 hours. Water and chloroform were added to the reaction solution, and the layers were separated. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and ethyl 5-((4-((tert-butyldiphenylsilyl) oxy) -2-methylbutane-2-yl) oxy-1H-pyrazole-3-carboxylate (yield 30.1). mg, yield 7.2%) was obtained.

Process 3
In the same manner as in Step 3 of Example 85, instead of ethyl 5-((4-((tert-butyldiphenylsilyl) oxy) butane-2-yl) oxy) -1H-pyrazole-3-carboxylate, Ethyl 5-((4-((tert-butyldiphenylsilyl) oxy) -2-methylbutan-2-yl) oxy-1H-pyrazole-3-carboxylate, ethyl 5-((4-hydroxy-2) -Methylbutane-2-yl) oxy) -1H-pyrazole-3-carboxylate was obtained.

Process 4
In the same manner as in Step 4 of Example 85, instead of ethyl 5-((4-hydroxybutane-2-yl) oxy) -1H-pyrazole-3-carboxylate, ethyl 5-((4-hydroxy-) 2-Methylbutane-2-yl) Oxy) -1H-Pyrazole-3-carboxylate with ethyl 5,5-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 ] Oxazine-2-carboxylate was obtained.

Process 5
In the same manner as in Step 5 of Example 85, instead of ethyl 5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate, ethyl 5 , 5-Dimethyl-6,7-dihydro-5H-Pyrazolo [5,1-b] [1,3] With oxazine-2-carboxylate, 5,5-dimethyl-6,7-dihydro-5H- Pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Process 6
In the same manner as in step 6 of Example 85, instead of 5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid, 5,5 -Dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] with oxazine-2-carboxylic acid, (R) -N- (6-chlorochroman-3-yl) -5,5-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide was obtained.

Example 178
Production of (R) -N- (6-cyanochroman-3-yl) -5,5-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide

(R) -3-Aminochroman-6 synthesized by the method described in Reference Example 24 instead of (R) -6-chlorochroman-3-amine hydrochloride in Step 6 in the same manner as in Example 177. -Using carboxamide, (R) -N- (6-cyanochroman-3-yl) -5,5-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 179
(R) -N- (6- (6-cyanopyridin-3-yl) chroman-3-yl) -5,5-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Production of oxazine-2-carboxamide

In the same manner as in Example 177, instead of (R) -6-chlorochroman-3-amine hydrochloride in step 6, (R) -5- (3-amino) was synthesized by the method described in Reference Example 32. Chroman-6-yl) using picolinonitrile, (R) -N- (6- (6-cyanopyridin-3-yl) chroman-3-yl) -5,5-dimethyl-6,7-dihydro -5H-Pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide was obtained.

Example 180
(R) -N- (6-Cyanochroman-3-yl) -6', 7'-dihydrospiro [cyclobutane-1,5'-pyrazolo [5,1-b] [1,3] oxazine-2'- Manufacture of carboxamide

In the same manner as in Example 177, 1- (2-hydroxyethyl) cyclobutanol was used instead of 3-methylbutane-1,3-diol in step 1, and (R) -6-chlorochroman in step 6 was used. Instead of 3-amine hydrochloride, (R) -3-aminochroman-6-carboxamide synthesized by the method described in Reference Example 24 was used, and (R) -N- (6-cyanochroman-3-yl) was used. ) -6', 7'-Dihydrospiro [cyclobutane-1,5'-pyrazolo [5,1-b] [1,3] oxazine-2'-carboxamide was obtained.

Example 181
Production of N-((R) -Chroman-3-yl) -2-phenyl-2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide

Using (1,2-dibromoethyl) benzene instead of 1- (1-bromo-3-chloropropyl) -2-fluorobenzene in step 6 in the same manner as in steps 6 to 8 of Example 70. , N-((R) -Chroman-3-yl)-using (R) -chroman-3-amine hydrochloride instead of (R) -3-aminochroman-6-carboxamide in step 8. 2-Phenyl-2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Example 182
Production of N-((R) -6-cyanochroman-3-yl) -2-phenyl-2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide

Using (1,2-dibromoethyl) benzene instead of 1- (1-bromo-3-chloropropyl) -2-fluorobenzene in step 6 in the same manner as in steps 6 to 8 of Example 70. N-((R) -6-cyanochroman-3-yl) -2-phenyl-2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Example 183
N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2- (trifluoromethyl) -2,3-dihydropyrazolo [5,1- b] Production of oxazole-6-carboxamide

In the same manner as in Example 169, 3,3,3-trifluoropropane-1,2-diol was used instead of 4,4,4-trifluorobutane-1,3-diol in step 1. (R) -6-((2,2,2-trifluoroethoxy) methyl) synthesized by the method described in Reference Example 44 instead of 6 (R) -6-chlorochroman-3-amine hydrochloride. N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2- (trifluoromethyl) -2 with chroman-3-amine hydrochloride , 3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained.

Example 184
N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2- (trifluoromethyl) -2,3-dihydropyrazolo [5,1- b] Isolation of oxazole-6-carboxamide

N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2- (trifluoromethyl) -2, synthesized by the method described in Example 183. 3-Dihydropyrazolo [5,1-b] oxazole-6-carboxamide (15.8 mg, 0.034 mmol) was dissolved in ethanol (3 mL) and preparated by HPLC (column: CHIRALPAK IB, developing solvent: ethanol, flow velocity: The mixture was subjected to 8.0 mL / min, room temperature) to obtain isomer A (yield 3.4 mg, yield 22%) and isomer B (yield 3.2 mg, yield 20%).

Reference example 49
Production of 3- (Cyclopropylmethoxy) Propane-1,2-diol

Process 1
Sodium hydride (60% in oil) (908 mg) in a solution of methanol (1.50 g, 11.3 mmol) in N, N-dimethylformamide (57 mL) (2,2-dimethyl-1,3-dioxolan-4-yl). , 22.7 mmol) was added, and the mixture was stirred for 10 minutes, then (bromomethyl) cyclopropane (1.6 mL, 17 mmol) was added, and the mixture was stirred at 70 ° C. for 15 hours. The reaction mixture was allowed to cool to room temperature, and then water and ethyl acetate were added to separate the solutions. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4- (cyclopropylmethoxymethyl) -2,2-dimethyl-1,3-dioxolane (yield 1.31 g, yield 62%).

Process 2
To a solution of 4- (cyclopropylmethoxymethyl) -2,2-dimethyl-1,3-dioxolane (1.31 g, 7.03 mmol) in ethanol (35 mL) was added 2 mol / L hydrochloric acid (8.8 mL, 18 mmol). The mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to remove 3- (cyclopropylmethoxy) propane-1,2-diol (yield 955 mg, yield 93%). ) Was obtained.

Reference example 50
Production of 2-((cyclopropylmethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid

3- (Cyclopropylmethoxy) propane-1,3 synthesized by the method described in Reference Example 49 in place of butane-1,3-diol in step 1 in the same manner as in steps 1 to 5 of Example 85. 2- ((Cyclopropylmethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid was obtained using 2-diol.

Example 185
2-((Cyclopropylmethoxy) Methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) Methyl) Chroman-3-yl) -2,3-dihydropyrazolo [5 , 1-b] Production of oxazole-6-carboxamide

In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid, Using 2-((cyclopropylmethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in Reference Example 50, (R) -3- Instead of aminochroman-6-carbonitrile, (R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 44 was used. 2-((Cyclopropylmethoxy) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained.

Example 186
2-((Cyclopropylmethoxy) Methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) Methyl) Chroman-3-yl) -2,3-dihydropyrazolo [5 , 1-b] Isolation of oxazole-6-carboxamide

2-((Cyclopropylmethoxy) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) synthesized by the method described in Example 185) -2,3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (17.7 mg, 0.037 mmol) was dissolved in an ethanol / n-hexane (50/50) mixed solvent (1 mL) for HPLC minutes. (Column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50/50, flow velocity: 8.0 mL / min, room temperature), isomer A (yield 5.7 mg, yield 32%) and isomer B (yield) 4.4 mg, yield 25%) was obtained.

Reference example 51
Production of Ethyl 2-((benzyloxy) Methyl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxylate

Ethyl 2-((benzyl) was used in the same manner as in Steps 1 to 4 of Example 85, using 3-benzyloxypropane-1,2-diol instead of butane-1,3-diol in Step 1. Oxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate was obtained.

Example 187
2-((2,2,2-trifluoroethoxy) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2,3 -Production of dihydropyrazolo [5,1-b] oxazole-6-carboxamide

Process 1
Ethyl 5-((benzyloxy) methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate in the same manner as in Step 1 of Example 100. Instead, ethyl 2 is used with ethyl 2-((benzyloxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate synthesized by the method described in Reference Example 51. -(Hydroxymethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate was obtained.

Process 2
N-((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1] in the same manner as in Example 114. , 3] Ethyl 2- (hydroxymethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate instead of oxazine-2-carboxamide. , 2,2-Trifluoroethoxy) Methyl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxylate was obtained.

Process 3
In the same manner as in Step 2 of Example 100, instead of ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate. , Ethyl 2-((2,2,2-trifluoroethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] with oxazole-6-carboxylate, 2-((2,2) , 2-Trifluoroethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Process 4
In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid, Using 2-((2,2,2-trifluoroethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid, (R) -3-aminochroman-6 -Instead of carboxamide, 2-(R) -6-((2,2,2-trifluoroethoxy) methyl) chromane-3-amine hydrochloride synthesized by the method described in Reference Example 44 was used. ((2,2,2-trifluoroethoxy) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2,3-dihydro Pyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Example 188
2-((2,2,2-trifluoroethoxy) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2,3 -Isomer separation of dihydropyrazolo [5,1-b] oxazole-6-carboxamide

2-((2,2,2-trifluoroethoxy) methyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) synthesized by the method described in Example 187) Chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide was dissolved in a mixed solvent of tert-butyl methyl ether / ethanol (90/1) (1 mL) and HPLC. Preparative (column: CHIRALPAK IA, developing solvent: tert-butylmethyl ether / ethanol = 90/10, flow velocity: 8.0 mL / min, room temperature), isomer A (yield 4.1 mg) and isomer B (yield 4.1 mg) ) Was obtained.

Example 189
N-((R) -6- (2- (difluoromethoxy) ethyl) chroman-3-yl) -2-((2,2,2-trifluoroethoxy) methyl) -2,3-dihydropyrazolo [ 5,1-b] Production of oxazole-6-carboxamide

The method described in Reference Example 45 in place of (R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-amine hydrochloride in the same manner as in Step 4 of Example 187. N-((R) -6-(2- (difluoromethoxy) ethyl) chroman-3 using the (R) -6-(2- (difluoromethoxy) ethyl) chroman-3-amine hydrochloride synthesized in -Il) -2-((2,2,2-trifluoroethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained.

Example 190
N-((R) -6- (2- (difluoromethoxy) ethyl) chroman-3-yl) -2-((2,2,2-trifluoroethoxy) methyl) -2,3-dihydropyrazolo [ 5,1-b] Isolation of oxazole-6-carboxamide

N-((R) -6-(2- (difluoromethoxy) ethyl) chroman-3-yl) -2-((2,2,2-trifluoroethoxy) methyl) synthesized by the method described in Example 189. ) -2,3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (21.3 mg, 0.043 mmol) was dissolved in ethanol / n-hexane (50/50) mixed solvent (1 mL) and HPLC. Preparative (column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50/50, flow velocity: 8.0 mL / min, room temperature), isomer A (yield 9.2 mg, yield 43%) and isomer B (yield 9.2 mg) The yield was 5.7 mg and the yield was 27%).

Reference example 52
Production of (R) -6- (2,2,2-trifluoroethyl) chroman-3-amine hydrochloride

Process 1
Tetrahydrofuran (1.0 g, 3.7 mmol) of (R) -2,2,2-trifluoro-N- (6-formylroman-3-yl) acetamide synthesized by the method described in Step 2 of Reference Example 3 ( To a 20 mL) solution was added (trifluoromethyl) trimethylsilane (2.2 mL, 15 mmol) and cesium fluoride (1.7 g, 11 mmol), and the mixture was stirred at room temperature for 15 hours. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Tetrahydrofuran (20 mL) and a 1 mol / L tetrabutylammonium fluoride-tetrahydrofuran solution were added to the residue, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to 2,2,2-trifluoro-N-((3R) -6- (2,2,2-trifluoro-1-hydroxyethyl) chroman-3-yl). Acetamide (yield 0.68 g, yield 54%) was obtained.

Process 2
2,2,2-Trifluoro-N-((3R) -6- (2,2,2-trifluoro-1-hydroxyethyl) chroman-3-yl) acetamide (0.68 g, 2.0 mmol) in dichloromethane ( To a 20 mL) solution was added di (imidazol-1-yl) methanthione (0.56 g, 3.1 mmol) and N, N-dimethyl-4-aminopyridine (31 mg, 0.25 mmol), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography to obtain O- (2,2,2-trifluoro-1-((R) -3- (2,2,2-trifluoroacetamide) chromane). -6-Il) Ethyl 1H-imidazol-1-carbonitrile (yield 0.68 g, yield 75%) was obtained.

Process 3
O- (2,2,2-trifluoro-1-((R) -3- (2,2,2-trifluoroacetamide) chroman-6-yl) ethyl 1H-imidazol-1-carbonitrile (600 mg) Tributylstannan (0.70 mL, 2.7 mmol) and benzoyl peroxide (160 mg, 0.66 mmol) were added to a solution of (1.32 mmol) in toluene (3 mL), and the mixture was stirred at 100 ° C. for 2 hours. The reaction solution was silica gel column chroma. Purified by doography, 2,2,2-trifluoro-N-((3R) -6- (2,2,2-trifluoroethyl) chroman-3-yl) acetamide (yield 300 mg, yield 69) %) Was obtained.

Process 4
In the same manner as in step 3 of Reference Example 1, instead of (R) -N- (6-chlorochroman-3-yl) -2,2,2, -trifluoroacetamide, 2,2,2-tri Fluoro-N-((3R) -6- (2,2,2-trifluoroethyl) chroman-3-yl) acetamide with (R) -6- (2,2,2-trifluoroethyl) Chroman-3-amine hydrochloride was obtained.

Example 191
2-((2,2,2-trifluoroethoxy) methyl) -N-((R) -6- (2,2,2-trifluoroethyl) chroman-3-yl) -2,3-dihydropyra Production of Zoro [5,1-b] Oxazole-6-Carboxamide

The method described in Reference Example 52 in place of (R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-amine hydrochloride in the same manner as in Step 4 of Example 187. 2-((2,2,2-trifluoroethoxy) methyl) -N- using the (R) -6- (2,2,2-trifluoroethyl) chroman-3-amine hydrochloride synthesized in ((R) -6- (2,2,2-trifluoroethyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained.

Example 192
2-((2,2,2-trifluoroethoxy) methyl) -N-((R) -6- (2,2,2-trifluoroethyl) chroman-3-yl) -2,3-dihydropyra Isomeric isolation of Zoro [5,1-b] oxazole-6-carboxamide

2-((2,2,2-trifluoroethoxy) methyl) -N-((R) -6- (2,2,2-trifluoroethyl) chroman-3 synthesized by the method described in Example 191. -Il) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (10.0 mg, 0.021 mmol) was dissolved in ethanol (0.8 mL) and sorted by HPLC (column: CHIRALPAK IB, developed. Solvent: ethanol, flow velocity: 8.0 mL / min, room temperature) to obtain isomer A (yield 3.0 mg, yield 30%) and isomer B (yield 3.5 mg, yield 35%).

Reference example 53
Production of (R) -6- (5-methylpyrazine-2-yl) chroman-3-amine

Process 1
(R) -2,2,2-trifluoro-N- (6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) synthesized by the method described in step 1 of Reference Example 28 -2-yl) chroman-3-yl) acetamide (600 mg, 1.62 mmol), 2-bromo-5-methylpyrazine (336 mg, 1.94 mmol), cesium carbonate (1.00 g, 3.07 mmol) 1,4- Xantphos Pd G3 (15.0 mg, 0.0158 mmol) was added to a suspension of dioxane (20 mL), and the mixture was stirred at 125 ° C. for 4 hours. Water and ethyl acetate were added to the reaction solution to separate the layers, and then the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and (R) -2,2,2-trifluoro-N- (6- (5-methylpyrazine-2-yl) chroman-3-yl) acetamide (yield 224 mg). , Yield 41%) was obtained.

Process 2
In the same manner as in step 3 of Reference Example 1, instead of (R) -N- (6-chlorochroman-3-yl) -2,2,2, -trifluoroacetamide, (R) -2,2 , 2-Trifluoro-N- (6- (5-methylpyrazine-2-yl) chroman-3-yl) using acetamide, (R) -6- (5-methylpyrazine-2-yl) chroman- 3-Amin was obtained.

Example 193
N-((R) -6- (5-methylpyrazine-2-yl) chroman-3-yl) -2-((2,2,2-trifluoroethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] Production of oxazole-6-carboxamide

The method described in Reference Example 53 in place of (R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-amine hydrochloride in the same manner as in Step 4 of Example 187. N-((R) -6- (5-methylpyrazine-2-yl) -2-yl) using the (R) -6- (5-methylpyrazine-2-yl) chroman-3-amine synthesized in ((2,2,2-trifluoroethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Example 194
N-((R) -6- (5-methylpyrazine-2-yl) -2-((2,2,2-trifluoroethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] ] Isolemination of oxazole-6-carboxamide

N-((R) -6- (5-methylpyrazine-2-yl) -2-((2,2,2-trifluoroethoxy) methyl) -2,3 synthesized by the method described in Example 193. -Dihydropyrazolo [5,1-b] oxazole-6-carboxamide (20.0 mg, 0.041 mmol) was dissolved in ethanol (1.5 mL) and preparative by HPLC (column: CHIRALPAK IB N-5, developing solvent: ethanol, The flow rate was 16.0 mL / min, room temperature) to obtain isomer A (yield 5.1 mg, yield 26%) and isomer B (yield 5.5 mg, yield 28%).

Reference example 54
Production of 2-((trifluoromethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid

In the same manner as in Reference Example 37, instead of ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate in step 1. , 2-(( Trifluoromethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Example 195
N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2-((trifluoromethoxy) methyl) -2,3-dihydropyrazolo [5 , 1-b] Production of oxazole-6-carboxamide

In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylic acid, Using 2-((trifluoromethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in Reference Example 54, (R) -3- Instead of aminochroman-6-carbonitrile, (R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 44 was used. N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2-((trifluoromethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained.

Example 196
N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2-((trifluoromethoxy) methyl) -2,3-dihydropyrazolo [5 , 1-b] Isolation of oxazole-6-carboxamide

N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2-((trifluoromethoxy) methyl) synthesized by the method described in Example 195. -2,3-Dihydropyrazolo [5,1-b] oxazole-6-carboxamide (20.8 mg, 0.042 mmol) was dissolved in a mixed solvent of tert-butyl methyl ether / ethanol (90/10) (2 mL). It was subjected to HPLC preparative (column: CHIRALPAK IA, developing solvent: tert-butylmethyl ether / ethanol = 90/10, flow velocity: 8.0 mL / min, room temperature), and isomer A (yield 6.2 mg, yield 30%) and Isomeric B (yield 6.4 mg, yield 31%) was obtained.

Example 197
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -2-((trifluoromethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole -6-Manufacture of carboxamide

In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazole-2-carboxylic acid, Using 2-((trifluoromethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in Reference Example 54, (R) -3- N-((( R) -6- (2,2-difluoroethyl) chroman-3-yl) -2-((trifluoromethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide Got

Example 198
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -2-((trifluoromethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole -Separation of carboxamide isomers

N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -2-((trifluoromethoxy) methyl) -2,3-dihydro synthesized by the method described in Example 197. Pyrazolo [5,1-b] oxazole-6-carboxamide (13.4 mg, 0.030 mmol) was dissolved in ethanol / n-hexane (50/50) mixed solvent (1 mL) and preparative by HPLC (column: CHIRALPAK IC). , Developing solvent: ethanol / n-hexane = 50/50, flow velocity: 8.0 mL / min, room temperature), isomer A (yield 5.1 mg, yield 38%) and isomer B (yield 4.7 mg, yield 35) %) Was obtained.

Example 199
N-((R) -6-cyanochroman-3-yl) -2-(((2,2,2-trifluoroethyl) thio) methyl) -2,3-dihydropyrazolo [5,1-b] Production of oxazole-6-carboxamide

In the same manner as in steps 2 to 4 of Example 187, 2,2,2-trifluoroethanethiol was used instead of 2,2,2-trifluoroethanol in step 2, and (R) in step 4 was used. Instead of -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-amine hydrochloride, (R) -3-aminochroman-6-carbo was synthesized by the method described in Reference Example 24. Using nitrile, N-((R) -6-cyanochroman-3-yl) -2-(((2,2,2-trifluoroethyl) thio) methyl) -2,3-dihydropyrazolo [5 , 1-b] Oxazole-6-carboxamide was obtained.

Example 200
N-((R) -6-cyanochroman-3-yl) -2-(((2,2,2-trifluoroethyl) thio) methyl) -2,3-dihydropyrazolo [5,1-b] Isolation of oxazole-6-carboxamide

N-((R) -6-cyanochroman-3-yl) -2-(((2,2,2-trifluoroethyl) thio) methyl) -2,3- synthesized by the method described in Example 199. Dihydropyrazolo [5,1-b] oxazole-6-carboxamide (10.4 mg, 0.078 mmol) was dissolved in ethanol (1 mL) and sorted by HPLC (column: CHIRALPAK IB N-5, developing solvent: ethanol, flow velocity. : 8.0 mL / min, room temperature) to obtain isomer A (yield 3.4 mg, yield 33%) and isomer B (yield 3.5 mg, yield 34%).

Example 201
Production of N-((R) -6-cyanochroman-3-yl) -2- (2- (cyclopropylmethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide

Process 1
Tetrabutylammonium bromide (16.4 mg, 0.0509 mmol), 4-benzyloxybutane-1,3-diol (100 mg, 0.510 mmol) and (bromomethyl) cyclopropane in a 4 mol / L sodium hydroxide aqueous solution (1 mL). (0.15 mL, 1.6 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hours. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution to separate them. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1-benzyloxy-4- (cyclopropylmethoxy) butan-2-ol (yield 58 mg, yield 45%).

Process 2
In the same manner as in Step 85, 1-benzyloxy-4- (cyclopropylmethoxy) butan-2-ol was used instead of 4-((tert-butyldiphenylsilyl) oxy) butane-2-ol. It was used to obtain ethyl 5- (1-benzyloxymethyl) -3- (cyclopropylmethoxy) propoxy) -1H-pyrazol-3-carboxylate.

Process 3
Ethyl 5- (1-benzyloxymethyl) -3- (cyclopropylmethoxy) propoxy) -1H-pyrazol-3-carboxylate (1.3 g, 3.3 mmol) in ethanol (50 mL) solution with 5% palladium carbon ( 0.71 g) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere (balloon pressure). The reaction mixture was filtered through Celite, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and ethyl 5- (3- (cyclopropylmethoxy) -1- (hydroxymethyl) propoxy) -1H-pyrazol-3-carboxylate (yield 0.91 g, yield 91%). Got

Process 4
N, N-diisopropyl in a solution of ethyl 5- (3- (cyclopropylmethoxy) -1- (hydroxymethyl) propoxy) -1H-pyrazol-3-carboxylate (0.91 g, 3.1 mmol) in dichloromethane (20 mL). Ethylamine (3.1 mL, 18 mmol), carbon tetrabromide (3.0 g, 9.0 mmol) and triphenylphosphine (1.6 g, 6.1 mmol) were added, and the mixture was stirred at room temperature for 15 hours. After concentrating the reaction under reduced pressure, the residue was purified by silica gel column chromatography and ethyl 5- (1- (bromomethyl) -3- (cyclopropylmethoxy) propoxy) -1H-pyrazol-3-carboxylate ( Yield 0.42 g, yield 38%) was obtained.

Process 5
Ethyl 5- (1- (bromomethyl) -3- (cyclopropylmethoxy) propoxy) -1H-pyrazol-3-carboxylate (0.42 g, 1.2 mmol) in N, N-dimethylformamide (12 mL) solution with carbonate Potassium (0.40 g, 2.9 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water and chloroform were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and ethyl 2- (2- (cyclopropylmethoxy) ethyl) -2,3-dihydropyrazolo [5,1, b] oxazole-6-carboxylate (yield 195 mg, Yield 60%) was obtained.

Process 6
Ethyl 5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylate in the same manner as in step 5 of Example 85. Instead, use ethyl 2- (2- (cyclopropylmethoxy) ethyl) -2,3-dihydropyrazolo [5,1, b] oxazole-6-carboxylate to use 2- (2- (cyclopropylmethoxy) methoxy. ) Ethyl) -2,3-dihydropyrazolo [5,1-b] oxazol-6-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Process 7
In the same manner as in Step 4 of Example 1, instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid, 2-( Reference Example 24 using 2- (cyclopropylmethoxy) ethyl) -2,3-dihydropyrazolo [5,1, b] oxazole-6-carboxylic acid instead of 6-fluorochroman-3-amine hydrochloride N-((R) -6-cyanochroman-3-yl) -2- (2- (cyclopropylmethoxy)) using (R) -3-aminochroman-6-carbonitrile synthesized by the method described in 1. Ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Example 202
N-((R) -6-cyanochroman-3-yl) -2- (2- (cyclopropylmethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide isomers Body separation

N-((R) -6-cyanochroman-3-yl) -2- (2- (cyclopropylmethoxy) ethyl) -2,3-dihydropyrazolo [5,1] synthesized by the method described in Example 201. -b] Oxazole-6-carboxamide (19.0 mg, 0.047 mmol) was dissolved in ethanol (1 mL) and subjected to HPLC preparative (column: CHIRALPAK IB, developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature). Then, isomer A (yield 7.5 mg, yield 39%) and isomer B (yield 6.7 mg, yield 35%) were obtained.

Example 203
2- (2- (Cyclopropylmethoxy) Ethyl) -N-((R) -6- (2-Methoxypyrimidine-5-yl) Chroman-3-yl) -2,3-dihydropyrazolo [5,1 -b] Production of oxazole-6-carboxamide

(R) -6- (2-Methoxypyrimidine-5-) synthesized by the method described in Reference Example 29 instead of (R) -3-aminochroman-6-carbonitrile in the same manner as in Example 201. 2-(2- (Cyclopropylmethoxy) ethyl) -N-((R) -6- (2-methoxypyrimidine-5-yl) chroman-3-yl)-with yl) chroman-3-amine 2,3-Dihydropyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Example 204
2- (2- (Cyclopropylmethoxy) Ethyl) -N-((R) -6- (2-Methoxypyrimidine-5-yl) Chroman-3-yl) -2,3-dihydropyrazolo [5,1 -b] Isomeric isolation of oxazole-6-carboxamide

2- (2- (Cyclopropylmethoxy) ethyl) -N-((R) -6- (2-methoxypyrimidin-5-yl) chroman-3-yl) -2 synthesized by the method described in Example 203. , 3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (22.0 mg, 0.045 mmol) dissolved in ethanol (7 mL) and preparated by HPLC (column: CHIRALPAK IB, developing solvent: ethanol, flow velocity. : 8.0 mL / min, room temperature) to obtain isomer A (yield 6.4 mg, yield 29%) and isomer B (yield 8.5 mg, yield 39%).

Reference example 55
Production of 2- (2- (2,2,2-trifluoroethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid

Process 1 and process 2
In the same manner as in steps 1 to 2 of Example 85, 4- (benzyloxy) butane-1,3-diol was used instead of butane-1,3-diol in step 1 to form ethyl 5- (. (1- (benzyloxy) -4-((tert-butyldiphenylsilyl) oxy) butane-2-yl) oxy) -1H-pyrazol-3-carboxylate was obtained.

Process 3
Ethyl 5-((benzyloxy) methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylate in the same manner as in Step 1 of Example 100. Instead, use ethyl 5-((1- (benzyloxy) -4-((tert-butyldiphenylsilyl) oxy) butane-2-yl) oxy) -1H-pyrazol-3-carboxylate to make ethyl 5 -((4-((tert-Butyldiphenylsilyl) oxy) -1-hydroxybutane-2-yl) oxy) -1H-pyrazol-3-carboxylate was obtained.

Process 4
In the same manner as in step 4 of Example 85, instead of ethyl 5-((4-hydroxybutane-2-yl) oxy) -1H-pyrazol-3-carboxylate, ethyl 5-((4-((((- Ethyl 2-(2-((tert-butyldiphenylsilyl) oxy) ethyl with tert-butyldiphenylsilyl) oxy) -1-hydroxybutane-2-yl) oxy) -1H-pyrazol-3-carboxylate ) -2,3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxylate was obtained.

Process 5
In the same manner as in Step 3 of Example 85, instead of ethyl 5-((4-((tert-butyldiphenylsilyl) oxy) butane-2-yl) oxy) -1H-pyrazol-3-carboxylate, Ethyl 2-(2-((tert-butyldiphenylsilyl) oxy) ethyl) -2,3-hydropyrazolo [5,1-b] with oxazole-6-carboxylate, ethyl 2- (2-hydroxyethyl) -2,3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxylate was obtained.

Process 6
N-((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1] in the same manner as in Example 114. , 3] Ethyl 2- (2-hydroxyethyl) -2,3-hydropyrazolo [5,1-b] oxazole-6-carboxylate instead of oxazine-2-carboxamide. (2,2,2-trifluoroethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxylate was obtained.

Process 7
Ethyl 5- (2-fluorophenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate in the same manner as in step 7 of Example 70. Instead, using ethyl 2- (2- (2,2,2-trifluoroethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate, 2-( 2- (2,2,2-trifluoroethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Reference example 56
Production of (R) -6- (1-methyl-1H-pyrazol-3-yl) chroman-3-amine hydrochloride

In the same manner as in Reference Example 53, 3-iodo-1-methyl-pyrazole was used instead of 2-bromo-5-methylpyrazine in step 2, and Ruphos Pd G3 was used instead of Xantphos Pd G3. R) -6- (1-Methyl-1H-pyrazole-3-yl) chroman-3-amine hydrochloride was obtained.

Example 205
N-((R) -6- (1-methyl-1H-pyrazol-3-yl) chroman-3-yl) -2- (2- (2,2,2-trifluoroethoxy) ethyl) -2, Production of 3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide

In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazole-2-carboxylic acid, 2- (2- (2,2,2-trifluoroethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in Reference Example 55. Instead of (R) -3-aminochroman-6-carbonitrile, (R) -6- (1-methyl-1H-pyrazol-3-yl) chroman- was synthesized by the method described in Reference Example 56. Using 3-amine, N-((R) -6- (1-methyl-1H-pyrazol-3-yl) chroman-3-yl) -2- (2- (2,2,2-trifluoro) Ethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Example 206
N-((R) -6- (1-methyl-1H-pyrazol-3-yl) chroman-3-yl) -2- (2- (2,2,2-trifluoroethoxy) ethyl) -2, Isolation of 3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide

N-((R) -6- (1-methyl-1H-pyrazol-3-yl) chroman-3-yl) -2- (2- (2,2,2) synthesized by the method described in Example 205 -Trifluoroethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (21.5 mg, 0.044 mmol) was dissolved in ethanol (1.5 mL) and sorted by HPLC (column: column: CHIRALPAK IB N-5, developing solvent: ethanol, flow velocity: 16.0 mL / min, room temperature), isomer A (yield 6.5 mg, yield 30%) and isomer B (yield 5.5 mg, yield 26%). Obtained.

Example 207
N-((R) -6- (pyridin-2-yl) chroman-3-yl) -2- (2- (2,2,2-trifluoroethoxy) ethyl) -2,3-dihydropyrazolo [ 5,1-b] Production of oxazole-6-carboxamide and isolation of isomers

Process 1
In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazole-2-carboxylic acid, 2- (2- (2,2,2-trifluoroethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in Reference Example 55. (R) -6- (Pyridine-2-yl) chroman-3-amine dihydrochloride synthesized by the method described in Reference Example 28 instead of (R) -3-aminochroman-6-carbonitrile. N-((R) -6- (pyridin-2-yl) chroman-3-yl) -2- (2- (2,2,2-trifluoroethoxy) ethyl) -2,3- Dihydropyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Process 2
N-((R) -6- (pyridine-2-yl) chroman-3-yl) -2- (2- (2,2,2-trifluoroethoxy) ethyl) -2,3-dihydropyrazolo [ 5,1-b] Oxazole-6-carboxamide (15.0 mg, 0.031 mmol) was dissolved in ethanol (1 mL) and sorted by HPLC (column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50/50, The flow rate was 12.0 mL / min, room temperature) to obtain isomer A (yield 5.0 mg, yield 33%) and isomer B (yield 4.5 mg, yield 30%).

Reference example 57
Production of 2- (2- (trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid

In the same manner as in Reference Example 37, instead of ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate in step 1. , 2- (2-Hydroxyethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate synthesized by the method described in step 5 of Reference Example 55. (2- (Trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid was obtained.

Example 208
Production of N-((R) -6-cyanochroman-3-yl) -2- (2- (trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide

Reference Example 57 instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid in the same manner as in Step 4 of Example 1. 2- (2- (Trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in the above, 6-fluorochroman-3- N-((R) -6-cyanochroman-3-yl)-using the (R) -3-aminochroman-6-carbonitrile synthesized by the method described in Reference Example 24 instead of the amine hydrochloride. 2- (2- (Trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Example 209
N-((R) -6-cyanochroman-3-yl) -2- (2- (trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide isomers Body separation

N-((R) -6-cyanochroman-3-yl) -2- (2- (trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1] synthesized by the method described in Example 208. -b] Oxazole-6-carboxamide (15 mg, 0.036 mmol) was dissolved in ethanol (3 mL) and subjected to HPLC preparative (column: CHIRALPAK IB, developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature). Then, isomer A (yield 6.5 mg, yield 43%) and isomer B (yield 6.0 mg, yield 40%) were obtained.

Example 210
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -2- (2- (trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b ] Production of oxazole-6-carboxamide

Reference Example 57 instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid in the same manner as in Step 4 of Example 1. 2- (2- (Trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in the above, 6-fluorochroman-3- N-((R) -6 -(2,2-difluoroethyl) chroman-3-yl) -2- (2- (trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide rice field.

Example 211
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -2- (2- (trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b ] Isolemination of oxazole-6-carboxamide

N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -2- (2- (trifluoromethoxy) ethyl) -2,3 synthesized by the method described in Example 210 -Dihydropyrazolo [5,1-b] oxazole-6-carboxamide (13.0 mg, 0.028 mmol) was dissolved in ethanol (1 mL) and preparative by HPLC (column: CHIRALPAK IB N-5, developing solvent: ethanol, The flow rate was 8.0 mL / min, room temperature) to obtain isomer A (yield 4.5 mg, yield 35%) and isomer B (yield 4.0 mg, yield 31%).

Example 212
N-((R) -6- (1-methyl-1H-pyrazol-3-yl) chroman-3-yl) -2- (2- (trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [ 5,1-b] Production of oxazole-6-carboxamide

Reference Example 57 instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid in the same manner as in step 4 of Example 1. 2- (2- (Trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in the above, 6-fluorochroman-3- N-((R) was used instead of the amine hydrochloride using (R) -6- (1-methyl-1H-pyrazol-3-yl) chroman-3-amine synthesized by the method described in Reference Example 56. ) -6- (1-Methyl-1H-pyrazol-3-yl) chroman-3-yl) -2- (2- (trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b ] Oxazole-6-carboxamide was obtained.

Example 213
N-((R) -6- (1-methyl-1H-pyrazol-3-yl) chroman-3-yl) -2- (2- (trifluoromethoxy) ethyl) -2,3-dihydropyrazolo [ 5,1-b] Isolation of oxazole-6-carboxamide

N-((R) -6- (1-methyl-1H-pyrazol-3-yl) chroman-3-yl) -2- (2- (trifluoromethoxy) ethyl synthesized by the method described in Example 212. ) -2,3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (190 mg, 0.398 mmol) dissolved in ethanol (2.5 mL) and preparated by HPLC (column: CHIRALPAK IC, developing solvent: Ethanol / n-hexane = 50/50, flow velocity: 8.0 mL / min, room temperature) to obtain isomer A (yield 69.0 mg, yield 36%) and isomer B (yield 61.0 mg, yield 32%). rice field.

Reference example 58
Production of 2- (2- (difluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid

In the same manner as in Reference Example 38, instead of ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate in step 1. , 2- (2-Hydroxyethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate synthesized by the method described in step 5 of Reference Example 55. (2- (Difluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid was obtained.

Example 214
2- (2- (difluoromethoxy) ethyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2,3-dihydropyrazolo [ 5,1-b] Production of oxazole-6-carboxamide

Reference Example 58 instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid in the same manner as in step 4 of Example 1. 6-Fluorochroman-3-amine using 2- (2- (difluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in 1. Instead of the hydrochloride salt, 2-((2,2,2-trifluoroethoxy) methyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 44 was used. 2- (Difluoromethoxy) ethyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1 -b] Oxazole-6-carboxamide was obtained.

Example 215
2- (2- (difluoromethoxy) ethyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2,3-dihydropyrazolo [ 5,1-b] Isolation of oxazole-6-carboxamide

2- (2- (difluoromethoxy) ethyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl synthesized by the method described in Example 214 ) -2,3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (10 mg, 0.020 mmol) dissolved in ethanol (4 mL) and preparated by HPLC (column: CHIRALPAK IC, developing solvent: The mixture was subjected to ethanol, flow velocity: 8.0 mL / min, room temperature) to obtain isomer A (yield 3.8 mg, yield 38%) and isomer B (yield 3.7 mg, yield 37%).

Example 216
2- (2- (difluoromethoxy) ethyl) -N-((R) -6- (2-difluoromethoxy) ethyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] Production of oxazole-6-carboxamide

Reference Example 58 instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid in the same manner as in step 4 of Example 1. 6-Fluorochroman-3-amine using 2- (2- (difluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in 1. Instead of the hydrochloride salt, 2- (2- (difluoromethoxy) ethyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 45 was used. ) Ethyl) -N-((R) -6- (2-difluoromethoxy) ethyl) Chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained. ..

Example 217
2- (2- (difluoromethoxy) ethyl) -N-((R) -6- (2-difluoromethoxy) ethyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] Isolation of oxazole-6-carboxamide

2- (2- (Difluoromethoxy) ethyl) -N-((R) -6- (2-difluoromethoxy) ethyl) chroman-3-yl) -2,3- synthesized by the method described in Example 216. Dihydropyrazolo [5,1-b] oxazole-6-carboxamide (6.4 mg, 0.014 mmol) was dissolved in ethanol (4 mL) and preparative by HPLC (column: CHIRALPAK IC, developing solvent: ethanol, flow velocity: 8.0 mL). After exposure to / min (room temperature), isomer A (yield 2.8 mg, yield 44%) and isomer B (yield 2.4 mg, yield 38%) were obtained.

Example 218
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -2- (2- (difluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] Production of oxazole-6-carboxamide

Reference Example 58 instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid in the same manner as in step 4 of Example 1. 6-Fluorochroman-3-amine using 2- (2- (difluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in 1. N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -2- (2- (difluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Example 219
N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -2- (2- (difluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] Isolation of oxazole-6-carboxamide

N-((R) -6- (2,2-difluoroethyl) chroman-3-yl) -2- (2- (difluoromethoxy) ethyl) -2,3- synthesized by the method described in Example 218. Dihydropyrazolo [5,1-b] oxazole-6-carboxamide (10.0 mg, 0.023 mmol) was dissolved in ethanol (3 mL) and preparative by HPLC (column: CHIRALPAK IC, developing solvent: ethanol, flow velocity: 8.0 mL). The mixture was subjected to isomer A (yield 3.8 mg, yield 38%) and isomer B (yield 3.7 mg, yield 37%).

Reference example 59
Production of (R) -6- (1-methyl-1H-pyrazol-4-yl) chroman-3-amine hydrochloride

In the same manner as in Reference Example 53, 4-bromo-1-methyl-pyrazole was used instead of 2-bromo-5-methylpyrazine in step 2, and Ruphos Pd G3 was used instead of Xantphos Pd G3. R) -6- (1-Methyl-1H-pyrazole-4-yl) chroman-3-amine was obtained.

Example 220
2- (2- (Difluoromethoxy) ethyl) -N-((R) -6- (1-methyl-1H-pyrazol-4-yl) chroman-3-yl) -2,3-dihydropyrazolo [5 , 1-b] Production of oxazole-6-carboxamide

Reference Example 58 instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid in the same manner as in step 4 of Example 1. 6-Fluorochroman-3-amine using 2- (2- (difluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in 1. Instead of the hydrochloride salt, 2- (2- (2- (2-( Difluoromethoxy) ethyl) -N-((R) -6- (1-methyl-1H-pyrazol-4-yl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] oxazole -6-Carboxamide was obtained.

Example 221
2- (2- (Difluoromethoxy) ethyl) -N-((R) -6- (1-methyl-1H-pyrazol-4-yl) chroman-3-yl) -2,3-dihydropyrazolo [5 , 1-b] Isolation of oxazole-6-carboxamide

2- (2- (Difluoromethoxy) ethyl) -N-((R) -6- (1-methyl-1H-pyrazole-4-yl) chroman-3-yl) synthesized by the method described in Example 220) -2,3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (6.2 mg, 0.013 mmol) was dissolved in ethanol (1.8 mL) and preparatively prepared by HPLC (column: CHIRALPAK IB, developing solvent: ethanol). , Flow rate: 10.0 mL / min, room temperature) to obtain isomer A (yield 2.0 mg, yield 32%) and isomer B (yield 1.8 mg, yield 29%).

Reference example 60
Production of (R) -6- (pyrazine-2-yl) chroman-3-amine hydrochloride

In the same manner as in Reference Example 53, 2-iodopyrazine was used instead of 2-bromo-5-methylpyrazine in step 2, and Ruphos Pd G3 was used instead of Xantphos Pd G3, (R) -6- (Pyrazine-2-yl) chroman-3-amine hydrochloride was obtained.

Example 222
2- (2- (difluoromethoxy) ethyl) -N-((R) -6- (pyrazine-2-yl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] oxazole -6-Manufacture of carboxamide

Reference Example 58 instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid in the same manner as in step 4 of Example 1. 6-Fluorochroman-3-amine using 2- (2- (difluoromethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in 1. 2- (2- (Difluoromethoxy) ethyl ) -N-((R) -6- (pyrazine-2-yl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained.

Example 223
2- (2- (difluoromethoxy) ethyl) -N-((R) -6- (pyrazine-2-yl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] oxazole -Separation of carboxamide isomers

2- (2- (Difluoromethoxy) ethyl) -N-((R) -6- (pyrazine-2-yl) chroman-3-yl) -2,3-dihydro synthesized by the method described in Example 222 Pyrazolo [5,1-b] oxazole-6-carboxamide (5.6 mg, 0.012 mmol) was dissolved in ethanol (4 mL) and preparatively dispensed by HPLC (column: CHIRALPAK IC, developing solvent: ethanol, flow velocity: 16.0 mL / The mixture was subjected to isomer A (yield 2.5 mg, yield 45%) and isomer B (yield 2.4 mg, yield 43%).

Reference example 61
Production of 1- (benzyloxy) -4- (2,2-difluoroethoxy) butane-2-ol

Process 1
To a solution of 4-benzyloxybutane (1.00 mg, 5.10 mmol) in tetrahydrofuran (10.2 mL), add N, N-dimethylformamide (10.2 mL) and sodium hydride (60% in oil) (367 mg, 9.17 mmol). After stirring at room temperature for 20 minutes. A solution of 2,2-difluoroethyl 4-methanebenzenesulfonate (1.44 mg, 6.11 mmol) in tetrahydrofuran (1 mL) was added, and the mixture was stirred at 85 ° C. for 1 hr. After allowing to cool to room temperature, saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution to separate the solutions. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 1- (benzyloxy) -4- (2,2-difluoroethoxy) butan-2-ol (yield 370 mg, yield 28%).

Reference example 62
Production of 2- (2- (2,2-difluoroethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid

Synthesized by the method described in Reference Example 61 in place of 1-benzyloxy-4- (cyclopropylmethoxy) butane-2-ol in Step 2 in the same manner as in Steps 2 to 6 of Example 2011 -(Benzyloxy) -4- (2,2-difluoroethoxy) butane-2-ol with 2- (2- (2,2-difluoroethoxy) ethyl) -2,3-dihydropyrazolo [5 , 1-b] Oxazole-6-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Example 224
2- (2- (2,2-difluoroethoxy) ethyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2,3- Production and Isolation of Dihydropyrazolo [5,1-b] Oxazole-6-Carboxamide

Process 1
In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid, Using 2- (2- (2,2-difluoroethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in Reference Example 62, ( R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3- ((2,2,2-trifluoroethoxy) methyl) synthesized by the method described in Reference Example 44 instead of R) -3-aminochroman-6-carbonitrile 2-(2- (2,2-difluoroethoxy) ethyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman 3-yl using amine hydrochloride ) -2,3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained.

Process 2
2- (2- (2,2-difluoroethoxy) ethyl) -N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2,3- Dihydropyrazolo [5,1-b] oxazole-6-carboxamide (14.0 mg, 0.028 mmol) was dissolved in ethanol (1 mL) and preparative by HPLC (column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = The mixture was subjected to 50/50, flow rate: 8.0 mL / min, room temperature) to obtain isomer A (yield 4.5 mg, yield 32%) and isomer B (yield 4.0 mg, yield 29%).

Example 225
N-((R) -6-chlorochroman-3-yl) -2-(2-((2,2,2-trifluoroethyl) amino) ethyl) -2,3-dihydropyrazolo [5,1 -b] Production of oxazole-6-carboxamide

Process 1
N-((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] in the same manner as in step 1 of Example 119. ] [1,3] Ethyl 2- (2-hydroxyethyl) -2,3-dihydropyrazolo synthesized by the method described in step 5 of Reference Example 55 instead of oxazine-2-carboxamide [5,1- b] Ethyl 2- (2-((methylsulfonyl) oxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate is obtained using oxazole-6-carboxylate. rice field.

Process 2
Dimethyl sulfoxide (1.6 mL) of ethyl 2- (2-((methylsulfonyl) oxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate (100 mg, 0.329 mmol) Sodium azide (32.1 mg, 0.494 mmol) was added to the solution, and the mixture was stirred at 90 ° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, water, ethyl acetate and n-hexane were added, and the layers were separated. The organic layer was washed with saturated brine, dried over saturated anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and ethyl 2- (2-azidoethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate (yield 82.0 mg, yield 99%). Got

Process 3
20% Palladium on Carbon (22.9) in Ethanol (1.6 mL) Solution of Ethyl 2- (2-Azidoethyl) -2,3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxylate (82.0 mg, 0.326 mmol) mg) was added, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere (balloon pressure). After filtering the reaction solution through Celite, the solvent was distilled off under reduced pressure, and ethyl 2- (2-aminoethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate (yield 72). mg, yield 98%) was obtained.

Process 4
N, N-diisopropyl in a solution of ethyl 2- (2-aminoethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate (40.0 mg, 0.178 mmol) in acetonitrile (0.95 mL) Ethylamine (0.13 mL, 0.76 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (55 μL, 0.38 mmol) were added, and the mixture was stirred at 70 ° C. for 3 hours. After concentrating the reaction under reduced pressure, the residue was purified by silica gel column chromatography, ethyl 2-(2 ((2,2,2-trifluoroethyl) amino) ethyl) -2,3-dihydropyrazolo. [5,1-b] Oxazole-6-carboxylate (yield 24.0 mg, yield 44%) was obtained.

Step 5 and step 6
Ethyl 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylate in step 3 in the same manner as in steps 3 to 4 of Example 1. Instead of ethyl 2-(2 ((2,2,2-trifluoroethyl) amino) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate, step N-((R)- 6-Chlorochroman-3-yl) -2- (2-((2,2,2-trifluoroethyl) amino) ethyl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6- Carboxamide was obtained.

Example 226
N-((R) -6-chlorochroman-3-yl) -2-(2-((2,2,2-trifluoroethyl) amino) ethyl) -2,3-dihydropyrazolo [5,1 -b] Isolation of oxazole-6-carboxamide

N-((R) -6-chlorochroman-3-yl) -2-(2-((2,2,2-trifluoroethyl) amino) ethyl) -2 synthesized by the method described in Example 225. , 3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (8.6 mg, 0.019 mmol) dissolved in ethanol and preparated by HPLC (column: CHIRALPAK IB N-5, developing solvent: ethanol / n- Hexane = 50/50, flow velocity: 8.0 mL / min, room temperature) to obtain isomer A (yield 1.3 mg, yield 15%) and isomer B (yield 2.9 mg, yield 34%).

Reference example 63
Production of (R) -6-methylchroman-3-amine hydrochloride

In the same manner as in Reference Example 27, methylboronic acid was used instead of pyridine-4-ylboronic acid in Step 1 to obtain (R) -6-methylchroman-3-amine hydrochloride.

Example 227
N-((R) -6-methylchroman-3-yl) -2-(2-((2,2,2-trifluoroethyl) amino) ethyl) -2,3-dihydropyrazolo [5,1 -b] Production of oxazole-6-carboxamide

(R) -6-methylchroman-3 synthesized by the method described in Reference Example 63 instead of (R) -6-chlorochroman-3-amine hydrochloride in the same manner as in step 6 of Example 225. -With amine hydrochloride, N-((R) -6-methylchroman-3-yl) -2-(2-((2,2,2-trifluoroethyl) amino) ethyl) -2,3 -Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained.

Example 228
N-((R) -6-methylchroman-3-yl) -2-(2-((2,2,2-trifluoroethyl) amino) ethyl) -2,3-dihydropyrazolo [5,1 -b] Isolation of oxazole-6-carboxamide

N-((R) -6-methylchroman-3-yl) -2-(2-((2,2,2-trifluoroethyl) amino) ethyl) -2 synthesized by the method described in Example 227. , 3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (7.9 mg, 0.019 mmol) dissolved in ethanol and preparated by HPLC (column: CHIRALPAK IB N-5, developing solvent: ethanol / n- Hexane = 50/50, flow velocity: 8.0 mL / min, room temperature) to obtain isomer A (yield 1.9 mg, yield 24%) and isomer B (yield 2.5 mg, yield 32%).

Example 229
2-(2-((2,2,2-trifluoroethyl) amino) ethyl) -N-((R) -6- (trifluoromethyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] Production of oxazole-6-carboxamide

(R) -6- (trifluoromethyl) synthesized by the method described in Reference Example 43 instead of (R) -6-chlorochroman-3-amine hydrochloride in the same manner as in Step 6 of Example 225. ) Chroman-3-amine hydrochloride, 2-(2-((2,2,2-trifluoroethyl) amino) ethyl) -N-((R) -6- (trifluoromethyl) chroman- 3-Il) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained.

Example 230
2-(2-((2,2,2-trifluoroethyl) amino) ethyl) -N-((R) -6- (trifluoromethyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] Isolation of oxazole-6-carboxamide

2-(2-((2,2,2-trifluoroethyl) amino) ethyl) -N-((R) -6- (trifluoromethyl) chromato-3-" synthesized by the method described in Example 229. Il) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (9.5 mg, 0.020 mmol) dissolved in ethanol and preparative by HPLC (column: CHIRALPAK IC, developing solvent: ethanol / n -Hexane = 50/50, flow velocity: 8.0 mL / min, room temperature) to obtain isomer A (yield 1.9 mg, yield 20%) and isomer B (yield 2.5 mg, yield 26%).

Example 231
N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2-(2-((2,2,2-trifluoroethyl) amino) ethyl )-2,3-Dihydropyrazolo [5,1-b] Oxazole-6-Carboxamide production

In the same manner as in step 6 of Example 225, instead of (R) -6-chlorochroman-3-amine hydrochloride, it was synthesized by the method described in Reference Example 44 ((R) -6-((2). N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl, using 2,2,2-trifluoroethoxy) methyl) chroman-3-amine hydrochloride ) -2- (2-((2,2,2-trifluoroethyl) amino) ethyl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained.

Example 232
N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2-(2-((2,2,2-trifluoroethyl) amino) ethyl )-2,3-Dihydropyrazolo [5,1-b] Oxazole-6-Carboxamide isomer separation

N-((R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -2- (2-((2,2) , 2-Trifluoroethyl) Amino) Ethyl) -2,3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (7.5 mg, 0.014 mmol) dissolved in ethanol (1 mL) for HPLC minutes (Column: CHIRALPAK IB N-5, developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature), isomer A (yield 2.1 mg, yield 28%) and isomer B (yield 2.1 mg, yield). 28%) was obtained.

Reference example 64
Production of 2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid

Process 1
Ethyl 2-(2-((methylsulfonyl) oxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate synthesized by the method described in Step 1 of Example 225 ( Sodium iodide (349 mg, 2.32 mmol), N, N-diisopropylethylamine (593 μL, 3.45 mmol) and 3,3-difluoro in a solution of 70 mg, 0.23 mmol) in N, N-dimethylformamide (2 mL). Azetidine hydrochloride (298 mg, 2.30 mmol) was added, and the mixture was stirred at 90 ° C. for 15 hours. The reaction mixture was allowed to cool to room temperature, and then water and ethyl acetate were added to separate the solutions. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and ethyl 2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6. -Carboxylate (yield 58.6 mg, yield 85%) was obtained.

Process 2
In the same manner as in Step 3 of Example 1, instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylate, ethyl 2- Using (2- (3,3-difluoroazetidine-1-yl) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate, 2- (2- (3,3,) 3-Difluoroazetidine-1-yl) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Example 233
N-((R) -6-chlorochroman-3-yl) -2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -2,3-dihydropyrazolo [5,1- b] Production of oxazole-6-carboxamide

In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid, 2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in Reference Example 64. Using an acid, instead of (R) -3-aminochroman-6-carboxamide, using (R) -6-chlorochroman-3-amine hydrochloride synthesized by the method described in Reference Example 1, N -((R) -6-chlorochroman-3-yl) -2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -2,3-dihydropyrazolo [5,1-b ] Oxazole-6-carboxamide was obtained.

Example 234
N-((R) -6-chlorochroman-3-yl) -2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -2,3-dihydropyrazolo [5,1- b] Isomeric separation of oxazole-6-carboxamide

N-((R) -6-chlorochroman-3-yl) -2-(2- (3,3-difluoroazetidine-1-yl) ethyl) -2, synthesized by the method described in Example 233. 3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide is dissolved in ethanol and subjected to HPLC preparative (column: CHIRALPAK IB N-5, developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature). Then, isomer A (yield 5.0 mg) and isomer B (yield 5.0 mg) were obtained.

Example 235
2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -N-((R) -6- (trifluoromethyl) chroman-3-yl) -2,3-dihydropyrazolo [ 5,1-b] Production of oxazole-6-carboxamide

(R) -6- (trifluoromethyl) chromane- was synthesized by the method described in Reference Example 43 instead of (R) -6-chlorochroman-3-amine hydrochloride in the same manner as in Example 233. 2-(2- (3,3-difluoroazetidine-1-yl) ethyl) -N-((R) -6- (trifluoromethyl) chroman-3-yl) using 3-amine hydrochloride -2,3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained.

Example 236
2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -N-((R) -6- (trifluoromethyl) chroman-3-yl) -2,3-dihydropyrazolo [ 5,1-b] Isolation of oxazole-6-carboxamide

2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -N-((R) -6- (trifluoromethyl) chroman-3-yl) synthesized by the method described in Example 235. ) -2,3-Dihydropyrazolo [5,1-b] Oxazole-6-carboxamide is dissolved in ethanol and sorted by HPLC (column: CHIRALPAK IB N-5, developing solvent: ethanol, flow velocity: 8.0 mL / min. , Room temperature) to obtain isomer A (yield 4.0 mg) and isomer B (yield 3.3 mg).

Example 237
2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -N-((R) -6- (2- (difluoromethoxy) ethyl) chroman-3-yl) -2,3- Production of dihydropyrazolo [5,1-b] oxazole-6-carboxamide

(R) -6- (2- (difluoromethoxy) synthesized by the method described in Reference Example 45 instead of (R) -6-chlorochroman-3-amine hydrochloride in the same manner as in Example 233. 2-(2- (3,3-difluoroazetidine-1-yl) ethyl) -N-((R) -6- (2- (difluoromethoxy)) using ethyl) chroman-3-amine hydrochloride Ethyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Example 238
2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -N-((R) -6- (2- (difluoromethoxy) ethyl) chroman-3-yl) -2,3- Isomeric isolation of dihydropyrazolo [5,1-b] oxazole-6-carboxamide

2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -N-((R) -6- (2- (difluoromethoxy) ethyl) chromato synthesized by the method described in Example 237. -3-yl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (5.0 mg, 0.010 mmol) was dissolved in ethanol and sorted by HPLC (column: CHIRALPAK IB N-5, The developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature) gave isomer A (yield 1.4 mg, yield 28%) and isomer B (yield 1.3 mg, yield 26%).

Reference example 65
Production of (R) -6- (2- (trifluoromethoxy) ethyl) chroman-3-amine hydrochloride

Process 1
(R) -2,2,2-trifluoro-N- (6- (2-hydroxyethyl) chroman-3-yl) acetamide (570 mg, 1.97 mmol) synthesized by the method described in Step 1 of Reference Example 45. ) In a solution of ethyl acetate (9.9 mL), silver trifluoromethanesulfonate (1.01 g, 3.93 mmol), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2,2,2] octanebis (2,2,2) Tetrafluoroborate) (1.05 g, 2.96 mmol), potassium fluoride (344 mg, 5.92 mmol), 2-fluoropyridine (0.34 mL, 4.0 mmol) and (trifluoromethyl) trimethylsilane (0.58 mL, 3.9 mmol) In addition, it was stirred at room temperature for 15 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and (R) -2,2,2-trifluoro-N- (6- (2- (trifluoromethoxy) ethyl) chroman-3-yl) acetamide (yield 413 mg). , Yield 59%) was obtained.

Process 2
In the same manner as in step 3 of Reference Example 1, instead of (R) -N- (6-chlorochroman-3-yl) -2,2,2, -trifluoroacetamide, (R) -2,2 , 2-Trifluoro-N-(6- (2- (trifluoromethoxy) ethyl) chroman-3-yl) acetamide with (R) -6-(2- (trifluoromethoxy) ethyl) chroman- 3-Amine hydrochloride was obtained.

Example 239
2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -N-((R) -6- (2- (trifluoromethoxy) ethyl) chroman-3-yl) -2,3 -Production of dihydropyrazolo [5,1-b] oxazole-6-carboxamide

(R) -6- (2- (trifluoromethoxy) synthesized by the method described in Reference Example 65 instead of (R) -6-chlorochroman-3-amine hydrochloride in the same manner as in Example 233. ) Ethyl) Chroman-3-amine hydrochloride with 2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -N-((R) -6- (2- (trifluoro) Methoxy) ethyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Example 240
2- (2- (3,3-difluoroazetidine-1-yl) ethyl) -N-((R) -6- (2- (trifluoromethoxy) ethyl) chroman-3-yl) -2,3 -Isomer separation of dihydropyrazolo [5,1-b] oxazole-6-carboxamide

2-(2- (3,3-difluoroazetidine-1-yl) ethyl) -N-((R) -6- (2- (trifluoromethoxy) ethyl) synthesized by the method described in Example 239) Chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (6.8 mg, 0.013 mmol) was dissolved in ethanol and sorted by HPLC (column: CHIRALPAK IB N-5). , The developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature) to obtain isomer A (yield 3.2 mg, yield 47%) and isomer B (yield 1.7 mg, yield 25%).

Reference example 66
Production of 2- (2- (3,3-difluoropyrrolidin-1-yl) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid

In the same manner as in Reference Example 64, 2- (2- (3,3-difluoropyrrolidine-1) was used instead of 3,3-difluoroazetidine hydrochloride in Step 1. -Il) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Example 241
2- (2- (3,3-difluoropyrrolidin-1-yl) ethyl) -N-((R) -6- (2,2,2-trifluoroethyl) chroman-3-yl) -2,3 -Dihydropyrazolo [5,1-b] Oxazole-6-Carboxamide production and isomer separation

Process 1
In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazole-2-carboxylic acid, 2- (2- (3,3-difluoropyrrolidin-1-yl) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in Reference Example 66. (R) -6- (2,2,2-trifluoroethyl) chroman-3 synthesized by the method described in Reference Example 52 instead of (R) -3-aminochroman-6-carbonitrile using -With amine hydrochloride, 2- (2- (3,3-difluoropyrrolidin-1-yl) ethyl) -N-((R) -6- (2,2,2-trifluoroethyl) chromane- 3-Il) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained.

Process 2
2- (2- (3,3-difluoropyrrolidin-1-yl) ethyl) -N-((R) -6- (2,2,2-trifluoroethyl) chroman-3-yl) -2,3 -Dihydropyrazolo [5,1-b] oxazole-6-carboxamide (16.9 mg, 0.034 mmol) was dissolved in ethanol (1 mL) and sorted by HPLC (column: CHIRALPAK IB N-5, developing solvent: ethanol, The flow rate was 8.0 mL / min, room temperature) to obtain isomer A (yield 6.2 mg, yield 37%) and isomer B (yield 5.2 mg, yield 31%).

Reference example 67
Production of 2- (2- (4,4-difluoropiperidine-1-yl) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid

2-(2- (4,4-difluoropiperidine-1), using 4,4-difluoropiperidin hydrochloride instead of 3,3-difluoroazetidine hydrochloride in step 1 in the same manner as in Reference Example 64. -Il) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Example 242
2- (2- (4,4-difluoropiperidin-1-yl) ethyl) -N-((R) -6- (trifluoromethyl) chroman-3-yl) -2,3-dihydropyrazolo [5 , 1-b] Production of oxazole-6-carboxamide and isolation of isomers

Process 1
In the same manner as in Step 3 of Example 100, instead of 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazole-2-carboxylic acid, 2- (2- (4,4-difluoropiperidin-1-yl) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid synthesized by the method described in Reference Example 67. Instead of (R) -3-aminochroman-6-carbonitrile, (R) -6- (trifluoromethyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 43 was used. 2- (2- (4,4-difluoropiperidin-1-yl) ethyl) -N-((R) -6- (trifluoromethyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained.

Process 2
2- (2- (4,4-difluoropiperidin-1-yl) ethyl) -N-((R) -6- (trifluoromethyl) chroman-3-yl) -2,3-dihydropyrazolo [5 , 1-b] Oxazole-6-carboxamide (15.1 mg, 0.030 mmol) was dissolved in ethanol (1 mL) and sorted by HPLC (column: CHIRALPAK IB N-5, developing solvent: ethanol, flow velocity: 8.0 mL / min. , Room temperature) to obtain isomer A (yield 3.2 mg, yield 21%) and isomer B (yield 2.9 mg, yield 19%).

Example 243
N-((R) -6-cyanochroman-3-yl) -2-(((2,2,2-trifluoroethyl) thio) ethyl) -2,3-dihydropyrazolo [5,1-b] Production of oxazole-6-carboxamide

Reference in place of ethyl 2- (hydroxymethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate in step 2 in the same manner as in steps 2 through 4 of Example 187. Using the ethyl 2- (2-hydroxyethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate synthesized by the method described in step 5 of Example 55, 2,2,2 -Use 2,2,2-trifluoroethanethiol instead of trifluoroethanol and use (R) -6-((2,2,2-trifluoroethoxy) methyl) chroman-3-amine hydrochloride in step 4. Using (R) -3-aminochroman-6-carbonitrile synthesized by the method described in Reference Example 24 instead of the salt, N-((R) -6-cyanochroman-3-yl) -2- (((2,2,2-Trifluoroethyl) thio) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Example 244
N-((R) -6-cyanochroman-3-yl) -2-(((2,2,2-trifluoroethyl) thio) ethyl) -2,3-dihydropyrazolo [5,1-b] Isolation of oxazole-6-carboxamide

N-((R) -6-cyanochroman-3-yl) -2-(((2,2,2-trifluoroethyl) thio) ethyl) -2,3- synthesized by the method described in Example 243. Dihydropyrazolo [5,1-b] oxazole-6-carboxamide (31.8 mg, 0.070 mmol) was dissolved in ethanol (1.5 mL) and preliminarily prepared by HPLC (column: CHIRALPAK IB, developing solvent: ethanol, flow velocity: 8.0 mL). The mixture was subjected to isomer A (yield 12.3 mg, yield 39%) and isomer B (yield 12.5 mg, yield 39%).

Example 245
N-((R) -6-cyanochroman-3-yl) -2- (3- (2,2,2-trifluoroethoxy) propyl) -2,3-dihydropyrazolo [5,1-b] oxazole -6-Manufacture of carboxamide

Process 1
Silver (I) oxide (8.0 g, 35 mmol) and benzyl bromide (11.8 mL) in a solution of 5- (hydroxymethyl) tetrahydrofuran-2-one (5.0 g, 43 mmol) in N, N-dimethylformamide (42 mL). , 99.4 mmol) was added, and the mixture was stirred at room temperature for 48 hours. Water and ethyl acetate were added to the reaction solution to separate the layers, and then the organic layer was washed with water and saturated brine. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 5- (benzyloxymethyl) tetrahydrofuran-2-one (yield 4.8 g, yield 54%).

Process 2
To a solution of 5- (benzyloxymethyl) tetrahydrofuran-2-one (4.8 g, 23 mmol) in tetrahydrofuran (78 mL) was added a solution of 0.9 mol / L borane-tetrahydrofuran in tetrahydrofuran (90 mL, 15 mmol) at room temperature. Stirred for 2 hours. The reaction mixture was concentrated to obtain 5-benzyloxypentane-1,4-diol (yield 3.0 g, yield 62%).

Process 3 to Process 7
In the same manner as in Steps 1 to 5 of Reference Example 55, 5-benzyloxypentane-1,4-diol was used instead of 4- (benzyloxy) butane-1,3-diol in Step 1 and ethyl was used. 2- (3-Hydroxypropyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate was obtained.

Process 8
Ethyl 2- (2- (2,2,2-trifluoroethoxy) ethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6- in the same manner as in step 7 of Reference Example 55. Use ethyl 2- (3-hydroxypropyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate instead of carboxylate, 2- (3-hydroxypropyl) -2, 3-Dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Process 9
In the same manner as in Step 4 of Example 1, instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid, 2-( The method described in Reference Example 24 using 3-hydroxypropyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid instead of 6-fluorochroman-3-amine hydrochloride. N-((R) -6-cyanochroman-3-yl) -2- (3-hydroxypropyl) -2,3-dihydro using (R) -3-aminochroman-6-carbonitrile synthesized in Pyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Process 10
N-((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1] in the same manner as in Example 114. , 3] N-((R) -6-cyanochroman-3-yl) -2- (3-hydroxypropyl) -2,3-dihydropyrazolo [5,1-b] instead of oxazine-2-carboxamide N-((R) -6-cyanochroman-3-yl) -2-(3- (2,2,2-trifluoroethoxy) propyl) -2,3-dihydropyra with oxazole-6-carboxamide Zoro [5,1-b] oxazole-6-carboxamide was obtained.

Example 246
N-((R) -6-cyanochroman-3-yl) -2- (3- (2,2,2-trifluoroethoxy) propyl) -2,3-dihydropyrazolo [5,1-b] oxazole -Separation of carboxamide isomers

N-((R) -6-cyanochroman-3-yl) -2-(3- (2,2,2-trifluoroethoxy) propyl) -2,3-dihydro synthesized by the method described in Example 245 Pyrazolo [5,1-b] oxazole-6-carboxamide (26.7 mg, 0.059 mmol) was dissolved in ethanol (6 mL) and sorted by HPLC (column: CHIRALPAK IB N-5, developing solvent: ethanol, flow velocity: The mixture was subjected to 8.0 mL / min, room temperature) to obtain isomer A (yield 11.3 mg, yield 42%) and isomer B (yield 10.6 mg, yield 40%).

Example 247
Production of N-((R) -6-cyanochroman-3-yl) -2- (3- (trifluoromethoxy) propyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide And isomer separation

Process 1 to Process 2
Ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2 in step 1 in the same manner as in steps 1 to 2 of Reference Example 37. -Instead of carboxylate ethyl 2- (3-hydroxypropyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate synthesized by the method described in Step 7 of Example 245. It was used to obtain 2- (3- (trifluoromethoxy) propyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid.

Process 3
In the same manner as in Step 4 of Example 1, instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid, 2-( Reference Example 24 using 3- (trifluoromethoxy) propyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid instead of 6-fluorochroman-3-amine hydrochloride N-((R) -6-cyanochroman-3-yl) -2- (3- (trifluoromethoxy)) using (R) -3-aminochroman-6-carbonitrile synthesized by the method described in 1. Propyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Process 4
N-((R) -6-cyanochroman-3-yl) -2- (3- (trifluoromethoxy) propyl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (126) mg, 0.289 mmol) was dissolved in ethanol (12 mL) and subjected to HPLC preparative (column: CHIRALPAK IB N-5, developing solvent: ethanol, flow velocity: 8.0 mL / min, room temperature) and isomer A (yield 57.7). mg, yield 46%) and isomer B (yield 52.5 mg, yield 42%) were obtained.

Example 248
Production of N-((R) -6-cyanochroman-3-yl) -2- (3- (difluoromethoxy) propyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide Isomeric separation

Process 1 to Process 2
Ethyl 5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2 in step 1 in the same manner as in steps 1 to 2 of Reference Example 38. -Instead of carboxylate ethyl 2- (3-hydroxypropyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate synthesized by the method described in Step 7 of Example 245. It was used to obtain 2- (3- (difluoromethoxy) propyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid.

Process 3
In the same manner as in Step 4 of Example 1, instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid, 2-( In Reference Example 24, 3- (difluoromethoxy) propyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid was used instead of 6-fluorochroman-3-amine hydrochloride. N-((R) -6-cyanochroman-3-yl) -2- (3- (difluoromethoxy) propyl) using (R) -3-aminochroman-6-carbonitrile synthesized by the method described. -2,3-Dihydropyrazolo [5,1-b] Oxazole-6-Carboxamide was obtained.

Process 4
N-((R) -6-cyanochroman-3-yl) -2- (3- (difluoromethoxy) propyl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (12.1 mg) , 0.029 mmol) is dissolved in ethanol (4 mL) and subjected to HPLC preparative (column: CHIRALPAK IB N-5, developing solvent: ethanol, flow rate: 8.0 mL / min, room temperature) and isomer A (yield 4.3 mg). , Yield 36%) and isomer B (Yield 3.8 mg, Yield 31%).

Example 249
(R) -7- (1H-Pyrazole-5-yl) -N- (6- (trifluoromethyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6 -Manufacture of carboxamide

Process 1
Ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (1.2 g, 7.7 mmol) and potassium carbonate (3.2 g, 23 mmol) in a solution of 1,2-dibromoethane (1.5 g, 8.1 mmol) in acetonitrile (15 mL) ) Was added, the tube was sealed, and the mixture was stirred at 110 ° C. for 15 hours. The reaction mixture was allowed to cool to room temperature, filtered, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate (yield 890 mg, yield 64%).

Process 2
N-((R) -chroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-in the same manner as in Example 14. Ethyl 7,3-iodo-2,3-dihydropyrazolo [5,1-b] with ethyl 2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate instead of 2-carboxamide Oxazole-6-carboxylate was obtained.

Process 3 to Process 4
Ethyl 3- (pyridin-2-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2-yl in step 3 in the same manner as in steps 3 to 4 of Example 18. Ethyl 7-iodo-2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate was used instead of carboxylate, and (R) -6-chlorochroman-3-amine hydrochloride in step 4 was used. Instead of (R) -6- (trifluoromethyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 43, (R) -7-iodo-N- (6- (tri) Fluoromethyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide was obtained.

Process 5
(R) -7-iodo-N- (6- (trifluoromethyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxamide (13.4 mg, 0.028 mmol) ) In n-butanol (1 mL) solution with 1H-pyrazole-5-ylboronic acid (6.3 mg, 0.056 mmol), triethylamine (16 μL, 0.11 mmol) and bis (di-tert-butyl (4-dimethylaminophenyl)). Phosphine) dichloropalladium (II) (2.0 mg, 0.0028 mmol) was added, and the mixture was stirred at 130 ° C. for 1 hr under microwave irradiation. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and (R) -7- (1H-pyrazole-5-yl) -N- (6- (trifluoromethyl) chroman-3- Il) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide (yield 3.6 mg, yield 31%) was obtained.

Reference example 68
Production of Ethyl 2,2-Dimethyl-2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxylate

Process 1
Cesium carbonate (3.1 g, 9.5 mmol), tert-butyl 2-bromo- in a solution of ethyl 5-hydroxy-1H-pyrazol-3-carboxylate (1.2 g, 7.7 mmol) in N, N-dimethylformamide (21 mL). 2-Methyl-propanoate (2.1 g, 9.4 mmol) and tetrabutylammonium iodide (236 mg. 0.639 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction solution to separate the layers. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and ethyl 5-((1- (tert-butoxy) -2-methyl-1-oxopropan-2-i) oxy) -1H-pyrazole-3-carboxylate (yield). 1.41 g, yield 74%) was obtained.

Process 2
4 mol / L chloride to ethyl 5-((1- (tert-butoxy) -2-methyl-1-oxopropane-2-i) oxy) -1H-pyrazole-3-carboxylate (1.41 g, 4.71 mmol) A hydrogen-ethyl acetate solution (8 mL) was added, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure to obtain 2-((3- (ethoxycarbonyl) -1H-pyrazole-5-yl) oxy) -2-methylpropionic acid (yield 1.14 g, yield 100%).

Process 3
1 mol / L borane-tetrahydrofuran complex in 2-((3- (ethoxycarbonyl) -1H-pyrazol-5-yl) oxy) -2-methylpropionic acid (1.14 g, 4.71 mmol) solution in tetrahydrofuran (23.5 mL) Tetrahydrofuran solution (11.3 mL, 11.3 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After adding methanol to the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 5- (2-hydroxy-1,1-dimethyl-ethoxy) -1H-pyrazole-3-carboxylate (yield 821 mg, yield 76%).

Process 4
Ethyl 5- (2-hydroxy-1,2) instead of ethyl 5-((4-hydroxybutane-2-yl) oxy) -1H-pyrazole-3-carboxylate in the same manner as in step 4 of Example 85. Ethyl 2,2-dimethyl-2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate was obtained using 1-dimethyl-ethoxy) -1H-pyrazole-3-carboxylate.

Example 250
(R) -2,2-dimethyl-7- (1H-pyrazole-5-yl) -N- (6- (trifluoromethyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1 -b] Production of oxazole-6-carboxamide

In the same manner as in Steps 2 to 5 of Example 249, instead of the ethyl 2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate in Step 2, the method described in Reference Example 68. Using the synthesized ethyl 2,2-dimethyl-2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate, (R) -2,2-dimethyl-7- (1H-pyrazole-) 5-Il) -N- (6- (trifluoromethyl) chroman-3-yl) -2,3-dihydropyrazolo [5,1-b] Oxazole-6-carboxamide was obtained.

Example 251
Production of N-((R) -6-cyanochroman-3-yl) -5-phenyl-5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine-2-carboxamide

N-((R)) using 4-chlorobutylbenzene instead of 1- (3-chloropropyl) -2-fluorobenzene in step 5 in the same manner as in steps 5 to 8 of Example 70. -6-Cyanochroman-3-yl) -5-phenyl-5,6,7,8-Tetrahydropyrazolo [5,1-b] [1,3] Oxazepine-2-carboxamide was obtained.

Example 252
N-((R) -6-cyanochroman-3-yl) -6- (trifluoromethoxy) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] Oxazepine-2 -Manufacture of carboxamide

Process 1
In the same manner as in Step 1 of Example 85, 1- (benzyloxy) -4-(( tert-Butyldiphenylsilyl) oxy) butane-2-ol was obtained.

Process 2
Ethyl 5-((benzyloxy) methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxadin-2-carboxylate in the same manner as in Step 1 of Example 100. Instead, use 1- (benzyloxy) -4-((tert-butyldiphenylsilyl) oxy) butane-2-ol to add 4-((tert-butyldiphenylsilyl) oxy) butane-1,2-diol. Obtained.

Process 3
4-((tert-Butyldiphenylsilyl) oxy) butane-1,2-diol (2.00 g, 5.81 mmol) in dichloromethane (24 mL) solution with p-toluenesulfonic acid (55 mg, 0.29 mmol) and 4- Methoxybenzaldehyde (2.37 g, 17.4 mmol) was added, and the mixture was stirred at room temperature for 1 hr. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction solution to separate the layers. After washing the organic layer with saturated brine and distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to purify tert-butyl (2- (2- (4-methoxyphenyl) -1,3-). Dioxolane-4-yl) ethoxy) diphenylsilane (yield 1.76 g, yield 66%) was obtained.

Process 4
Dichloromethane (20 mL) solution of tert-butyl (2- (2- (4-methoxyphenyl) -1,3-dioxolan-4-yl) ethoxy) diphenylsilane (1.76 g, 3.80 mmol) cooled to -78 ° C. A 1 mol / L diisobutylaluminum hydride / n-hexane solution (5.33 mL, 5.33 mmol) was added to the mixture, and the mixture was stirred for 15 minutes and then heated to 0 ° C. An aqueous solution of potassium sodium tartrate and chloroform were added to the reaction solution to separate them, and then the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and 4- (tert-butyl (diphenyl) silyl) oxy-2-((4-methoxyphenyl) methoxy) butane-1-ol (yield 427 mg, yield 24%). Got

Process 5 to Process 6
In the same manner as in steps 2 to 3 of Example 85, 4- (tert-butyl (diphenyl) silyl) oxy instead of 4-((tert-butyldiphenylsilyl) oxy) butan-2-ol in step 2 Ethyl 5- (4-hydroxy-2-((4-methoxybenzyl) oxy) butoxy) -1H-pyrazol-3-carboxy with -2-((4-methoxyphenyl) methoxy) butane-1-ol Got a rate.

Process 7
Tri-N-butyl in a toluene (15 mL) solution of ethyl 5- (4-hydroxy-2-((4-methoxybenzyl) oxy) butoxy) -1H-pyrazole-3-carboxylate (274 mg, 0.752 mmol) Phosphine (376 μL, 1.51 mmol) and 1,1'-(azodicarbonyl) dipiperidine (379 mg, 1.50 mmol) were added and stirred at 80 ° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and ethyl 6-((4-methoxybenzyl) oxy) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine-2. -Carboxylate (yield 198 mg, yield 76%) was obtained.

Process 8
Ethyl 5-((benzyloxy) methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate in the same manner as in Step 1 of Example 100. Ethyl 6-((4-methoxybenzyl) oxy) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine-2-carboxylate instead -Hydroxy-5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine-2-carboxylate was obtained.

Steps 9 to 11
Ethyl 6-hydroxy-instead of ethyl 2- (3-hydroxypropyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate in step 1 in the same manner as in Example 247. N-((R) -6-cyanochroman-3-yl) -6 with 5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine-2-carboxylate -(Trifluoromethoxy) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] Oxazepine-2-carboxamide was obtained.

Example 253
N-((R) -6-cyanochroman-3-yl) -6- (trifluoromethoxy) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] Oxazepine-2 -Carboxamide isomer separation

N-((R) -6-cyanochroman-3-yl) -6- (trifluoromethoxy) -5,6,7,8-tetrahydropyrazolo [5,1-] synthesized by the method described in Example 252. b] [1,3] Oxazepine-2-carboxamide (13.1 mg, 0.031 mmol) was dissolved in ethanol / n-hexane (50/50) mixed solvent (4 mL) and preparative by HPLC (column: CHIRALPAK IC, developing solvent). : Ethanol / n-hexane = 50/50, flow velocity: 8.0 mL / min, room temperature) and isomer A (yield 4.7 mg, yield 36%) and isomer B (yield 5.2 mg, yield 40%). Obtained.

Example 254
N-((R) -6-cyanochroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1 , 3] Production of oxazepine-2-carboxamide

Process 1
N-((R) -6-cyanochroman-3-yl) -5- (hydroxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1, in the same manner as in Example 114. 3] Using 1- (benzyloxy) -4-((tert-butyldiphenylsilyl) oxy) butan-2-ol synthesized by the method described in step 1 of Example 252 instead of oxazine-2-carboxamide. , (4- (benzyloxy) -3- (2,2,2-trifluoroethoxy) butoxy) (tert-butyl) diphenylsilane was obtained.

Process 2
In the same manner as in step 2 of Example 252, instead of 1- (benzyloxy) -4-((tert-butyldiphenylsilyl) oxy) butane-2-ol, (4- (benzyloxy) -3-( Using 2,2,2-trifluoroethoxy) butoxy) (tert-butyl) diphenylsilane, 4- (tert-butyldiphenylsilyl) oxy) -2- (2,2,2-trifluoroethoxy) butane- I got 1-all.

Process 3 to process 5
In the same manner as in Steps 5 to 7 of Example 252, instead of 4- (tert-butyl (diphenyl) silyl) oxy-2-((4-methoxyphenyl) methoxy) butane-1-ol in Step 5. Ethyl 6- (2,2,2-trifluoroethoxy) -5 with 4- (tert-butyldiphenylsilyl) oxy) -2- (2,2,2-trifluoroethoxy) butane-1-ol , 6,7,8-Tetrahydropyrazolo [5,1-b] [1,3] Oxazepine-2-carboxylate was obtained.

Process 6 to process 7
Ethyl 6- (trifluoromethoxy) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] in step 10 in the same manner as in steps 10 to 11 of Example 252. Ethyl 6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine-2 instead of oxazepine-2-carboxylate Using -carboxylate, N-((R) -6-cyanochroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydropyrazolo [5 , 1-b] [1,3] Oxazepine-2-carboxamide was obtained.

Example 255
N-((R) -6-cyanochroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1 , 3] Isomeric separation of oxazepine-2-carboxamide

N-((R) -6-cyanochroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydropyra synthesized by the method described in Example 254. Zoro [5,1-b] [1,3] Oxazepine-2-carboxamide (7.2 mg, 0.016 mmol) dissolved in ethanol (4 mL) and preparative by HPLC (column: CHIRALPAK IC, developing solvent: ethanol / n- Hexane = 50/50, flow velocity: 8.0 mL / min, room temperature) to obtain isomer A (yield 3.1 mg, yield 43%) and isomer B (yield 3.1 mg, yield 43%).

Example 256
N-((R) -6-chlorochroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydropyrazolo [5,1-b] [ 1,3] Production of oxazepine-2-carboxamide (isomer A and isomer B)

6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] synthesized by the method described in step 6 of Example 254. Oxazepine-2-carboxylic acid (sodium tetrachloride mixture) (26.0 mg, 0.0591 mmol), (R) -6-chlorochroman-3-amine (14.1 mg, 0.0768 mmol), 1-hydroxybenzotriazole (14.2 mg, 0.0927) 4-Methylmorpholine (41 μL, 41 μL, in N, N-dimethylformamide (0.5 mL) suspension of mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (17.8 mg, 0.0929 mmol). 0.373 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and the diastereomers were separated and N-((R) -6-chlorochroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5, 6,7,8-Tetrahydropyrazolo [5,1-b] [1,3] Oxazepine-2-carboxamide (isomer A) (yield 2.7 mg, yield 10%) and N-((R) -6- Chromarochroman-3-yl) -6- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] Oxazepine-2-carboxamide (Isomer B) (yield 2.9 mg, yield 11%) was obtained.

Example 257
6- (2,2,2-trifluoroethoxy) -N-((R) -6- (trifluoromethyl) chroman-3-yl) -5,6,7,8-tetrahydropyrazolo [5,1 -b] [1,3] Production of oxazepine-2-carboxamide and isolation of isomers

Process 1
(R) -6- (trifluoromethyl) chromane-3 synthesized by the method described in Reference Example 43 instead of (R) -6-chlorochroman-3-amine hydrochloride in the same manner as in Example 256. -With amine hydrochloride, 6- (2,2,2-trifluoroethoxy) -N-((R) -6- (trifluoromethyl) chroman-3-yl) -5,6,7,8 -Tetrahydropyrazolo [5,1-b] [1,3] Oxazepine-2-carboxamide was obtained.

Process 2
6- (2,2,2-trifluoroethoxy) -N-((R) -6- (trifluoromethyl) chroman-3-yl) -5,6,7,8-tetrahydropyrazolo [5,1] -b] [1,3] Dissolve oxazepine-2-carboxamide (10 mg) in ethanol (4 mL) and perform HPLC preparative (column: CHIRALPAK IC, developing solvent: ethanol / n-hexane = 50/50, flow velocity: The mixture was subjected to 8.0 mL / min, room temperature) to obtain isomer A (yield 1.7 mg, yield 17%) and isomer B (yield 1.5 mg, yield 15%).

Example 258
(R) -3- (1H-pyrazole-5-yl) -N- (6- (trifluoromethyl) chroman-3-yl) -5,6,7,8-tetrahydropyrazolo [5,1-b ] [1,3] Production of oxazepine-2-carboxamide

Process 1
Potassium carbonate (2.66 g, 19.2 mmol) and 1,4-dibromobutane (804 μL, 6.73 mmol) in a solution of ethyl 5-hydroxy-1H-pyrazol-3-carboxylate (1.00 g, 6.40 mmol) in acetonitrile (13 mL). ) Was added, and after sealing, the mixture was stirred at 100 ° C. for 15 hours. The reaction mixture was allowed to cool to room temperature, filtered, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and ethyl 5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine-2-carboxylate (yield 574 mg, yield 43%). ) Was obtained.

Process 2
N-((R) -chroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-in the same manner as in Example 14. Ethyl 3-iodo-5,6,7 with ethyl 5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine-2-carboxylate instead of 2-carboxamide , 8-Tetrahydropyrazolo [5,1-b] [1,3] Oxazepine-2-carboxylate was obtained.

Process 3 to Process 4
Ethyl 3- (pyridin-2-yl) -5,6,7,8-tetrahydroimidazole [1,2-a] pyridin-2- in step 3 in the same manner as in steps 3 to 4 of Example 18. Use ethyl 3-iodo-5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine-2-carboxylate instead of carboxylate, and use (R) -6 in step 4. -(R) -3- (trifluoromethyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 43 was used instead of chlorochroman-3-amine hydrochloride. Iodo-N- (6- (trifluoromethyl) chroman-3-yl) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine-2-carboxamide was obtained. ..

Process 5
(R) -3-iodo-N- (6- (trifluoromethyl) chroman-3-yl) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine- 1H-pyrazole-5-ylboronic acid (8.8 mg, 0.079 mmol), triethylamine (22 μL, 0.16 mmol) and bis (di-tert) in an n-butanol (800 μL) solution of 2-carboxamide (20 mg, 0.039 mmol). -Butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (2.8 mg, 0.0040 mmol) was added, and the mixture was stirred at 120 ° C. for 1 hr under microwave irradiation. The reaction mixture is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, and (R) -3- (1H-pyrazole-5-yl) -N- (6- (trifluoromethyl) chroman-3- Il) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine-2-carboxamide (yield 13.6 mg, yield 77%) was obtained.

Example 259
(R) -3- (1H-Pyrazole-5-yl) -N- (6- (trifluoromethyl) chroman-3-yl) -6,7-dihydro-4H-pyrazolo [5,1-c] [ 1,4] Production of oxazine-2-carboxamide

Process 1 to Process 4
Substitute for ethyl 5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine-2-carboxylate in step 2 in the same manner as in steps 2 through 5 of Example 258. With ethyl 6,7-dihydro-4H-pyrazolo [5,1-c] [1,4] oxazine-2-carboxylate, (R) -3- (1H-pyrazol-5-yl) -N -(6- (Trifluoromethyl) chroman-3-yl) -6,7-dihydro-4H-pyrazolo [5,1-c] [1,4] oxazine-2-carboxamide was obtained.

Example 260
(R) -3- (Pyridine-2-yl) -N- (6- (Trifluoromethyl) Chroman-3-yl) -6,7-Dihydro-4H-Pyrazolo [5,1-c] [1, 4] Production of oxazine-2-carboxamide

Performed in the same manner as in Steps 1 to 2 of Example 18 in place of ethyl 3-iodo-5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylate in Step 1. (R) -3-iodo-N- (6-trifluoromethyl) chroman-3-yl) -6,7-dihydro-4H-pyrazolo [5,1- c] [1,4] Using oxazine-2-carboxamide, (R) -3- (pyridin-2-yl) -N- (6- (trifluoromethyl) chroman-3-yl-6,7- Dihydro-4H-pyrazolo [5,1-c] [1,4] oxadin-2-carboxamide was obtained.

Example 261
(R) -N- (6-chlorochroman-3-yl) -5- (3,3,3-trifluoropropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine -2-Production of carboxamide

Process 1
Ethyl 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate (600 mg, 3.07 mmol) in dichloromethane (30 mL) solution of 3,3,3-trifluoropropanol (689 mg, 6.15 mmol) and sodium triacetoxyborohydride (3.26 g, 15.4 mmol) were added, and the mixture was stirred at 40 ° C. for 4 hours. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction solution, and the layers were separated. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and ethyl 5- (3,3,3-trifluoropropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate. (Yield 876 mg, yield 98%) was obtained.

Process 2
Ethyl 5 instead of ethyl 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine-2-carboxylate in the same manner as in Step 3 of Example 1. -(3,3,3-trifluoropropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] with pyrazine-2-carboxylate, 5- (3,3,3- Trifluoropropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

Process 3
In the same manner as in step 4 of Example 1, instead of 6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-2-carboxylic acid, 5-( 3,3,3-Trifluoropropyl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] Pyrazine-2-carboxylic acid was used instead of 6-fluorochroman-3-amine hydrochloride. In addition, using the (R) -6-chlorochroman-3-amine hydrochloride synthesized by the method described in Reference Example 1, (R) -N- (6-chlorochroman-3-yl) -5-( 3,3,3-trifluoropropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide was obtained.

Example 262
N- (5-chlorochroman-3-yl) -5- (3,3,3-trifluoropropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide Manufacturing of

5-Chlorochroman-3-amine hydrochloride synthesized by the method described in Reference Example 4 instead of (R) -6-chlorochroman-3-amine hydrochloride in step 3 in the same manner as in Example 261. N- (5-chlorochroman-3-yl) -5- (3,3,3-trifluoropropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine -2-Carboxamide was obtained.

Reference example 69
Ethyl 5- (2-Cyclopropylethyl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] Production of pyrazine-2-carboxylate

Ethyl 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate (90.0 mg, 0.461 mmol) in N, N-dimethylformamide (2.3 mL) solution in N, N- Diisopropylethylamine (39 μL, 2.3 mmol) and 2-bromoethylcyclopropane (82.4 mg, 0.553 mmol) were added, and the mixture was stirred at 80 ° C. for 1 hr. Water and chloroform were added to the reaction solution, and the layers were separated. The organic layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and ethyl 5- (2-cyclopropylethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate (yield 68.9 mg). , Yield 57%) was obtained.

Example 263
(R) -N- (6-chlorochroman-3-yl) -5- (2-cyclopropylethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide Manufacturing of

Ethyl 5- (3,3,3-trifluoropropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] in step 2 in the same manner as in steps 2 and 3 of Example 261. ] Ethyl 5- (2-cyclopropylethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] synthesized by the method described in Reference Example 69 instead of pyrazine-2-carboxylate. Using pyrazine-2-carboxylate, (R) -N- (6-chlorochroman-3-yl) -5- (2-cyclopropylethyl) -4,5,6,7-tetrahydropyrazolo [1] , 5-a] Pyrazine-2-carboxamide was obtained.

Example 264
5- (2-Cyclopropylethyl) -N- (6- (trifluoromethyl) chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide Manufacturing of

Ethyl 5- (3,3,3-trifluoropropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] in step 2 in the same manner as in steps 2 and 3 of Example 261. ] Ethyl 5- (2-cyclopropylethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] synthesized by the method described in Reference Example 69 instead of pyrazine-2-carboxylate. 6- (trifluoromethyl) chroman-3 synthesized by the method described in Reference Example 47 using pyrazine-2-carboxylate instead of (R) -6-chlorochroman-3-amine hydrochloride in step 3. -Using amine hydrochloride, 5- (2-cyclopropylethyl) -N- (6- (trifluoromethyl) chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5 -a] Pyrazine-2-carboxamide was obtained.

Reference example 70
Production of Ethyl 5- (2-Cyclobutoxyethyl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate

Ethyl 5- (2-cyclobutoxyethyl) -4,5,6,7-tetrahydropyrazolo [1, using 2-bromoethoxycyclobutane instead of bromoethylcyclopropane in the same manner as in Reference Example 69. 5-a] Pyrazine-2-carboxylate was obtained.

Example 265
(R) -5- (2-Cyclobutoxyethyl) -N- (6- (trifluoromethyl) chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine -2-Production of carboxamide

Ethyl 5- (3,3,3-trifluoropropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] in step 2 in the same manner as in steps 2 and 3 of Example 261. ] Instead of pyrazine-2-carboxylate, ethyl 5- (2-cyclobutoxyethyl) -4,5,6,7-tetrahydropyrazolo synthesized by the method described in Reference Example 70 [1,5-a] (R) -6- (trifluoromethyl) synthesized by the method described in Reference Example 43 using pyrazine-2-carboxylate instead of (R) -6-chlorochroman-3-amine hydrochloride in step 3. Using chroman-3-amine hydrochloride, (R) -5- (2-cyclobutoxyethyl) -N- (6- (trifluoromethyl) chroman-3-yl) -4,5,6,7- Tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide was obtained.

Example 266
(R) -5- (2-Cyclobutoxyethyl) -N- (6-((2,2,2-trifluoroethoxy) methyl) chroman-3-yl) -4,5,6,7-tetrahydropyra Production of Zoro [1,5-a] pyrazine-2-carboxamide

Ethyl 5- (3,3,3-trifluoropropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] in step 2 in the same manner as in steps 2 and 3 of Example 261. ] Instead of pyrazine-2-carboxylate, ethyl 5- (2-cyclobutoxyethyl) -4,5,6,7-tetrahydropyrazolo synthesized by the method described in Reference Example 70 [1,5-a] It was synthesized using pyrazine-2-carboxylate by the method described in Reference Example 44 instead of (R) -6-chlorochroman-3-amine hydrochloride in step 3 ((R) -6-((2, 2,,). With 2,2-trifluoroethoxy) methyl) chroman-3-amine hydrochloride, (R) -5- (2-cyclobutoxyethyl) -N- (6-((2,2,2-trifluoro) Ethoxy) methyl) chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide was obtained.

Example 267
(R) -3- (Pyrazine-2-yl) -5- (2,2,2-trifluoroethyl) -N- (6- (trifluoromethyl) chroman-3-yl) -4,5,6 , 7-Tetrahydropyrazolo [1,5-a] Production of pyrazine-2-carboxamide

Process 1
Ethyl 5- (2,2,2-trifluoroethyl) -4 using 2,2,2-trifluoroethyl trifluoromethanesulfonate instead of 2-bromoethylcyclopropane in the same manner as in Reference Example 69. , 5,6,7-Tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate was obtained.

Process 2
Ethyl 5- (2,2,) instead of 5,6-dihydro-8H-imidazo [2,1-c] [1,4] oxazine-2-carbaldehyde in the same manner as in step 1 of Example 64. 2-Trifluoroethyl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] with pyrazine-2-carboxylate, ethyl 3-bromo-5- (2,2,2-tri) Fluoroethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate was obtained.

Process 3 to Process 6
Ethyl 3-iodo-5,6,7,8-tetrahydroimidazole [1,2-a] pyridine-2-carboxylate in step 1 in the same manner as in steps 1 to 4 of Example 18. Using 3-bromo-5- (2,2,2-trifluoroethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate, (R) in step 4 ) -6- (Trifluoromethyl) chroman-3-amine hydrochloride synthesized by the method described in Reference Example 43 instead of 6-chlorochroman-3-amine hydrochloride, (R) -3- (Pyrazine-2-yl) -5- (2,2,2-trifluoroethyl) -N- (6- (trifluoromethyl) chroman-3-yl) -4,5,6,7- Tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide was obtained.

Example 268
Production of (R) -N- (6-cyanochroman-3-yl) -5- (4-fluorobenzyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide

Process 1
HATU in a solution of 5- (tert-butoxycarbonyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylic acid (120 mg, 0.449 mmol) in dichloromethane (3 mL). (188 mg, 0.494 mmol), N, N-diisopropylethylamine (386 μL, 2.24 mmol) and (R) -3-aminochroman-6-carbonitrile (104 mg, 0.494 mmol) synthesized by the method described in Reference Example 24. mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was purified by silica gel column chromatography and (R) -tert-butyl 2-((6-cyanochroman-3-yl) carbamoyl) -6,7-dihydropyrazolo [1,5-a] pyrazine-5. (4H) -carboxylate (yield 210 mg) was obtained.

Process 2
(R) -tert-Butyl 2-((6-cyanochroman-3-yl) carbamoyl) -6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylate (210 mg, 0.496) A 4 mol / L hydrogen chloride-ethyl acetate solution (8.0 mL, 32 mmol) was added to a solution of ethyl acetate (8 mL) in mmol), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and (R) -N- (6-cyanochroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide hydrochloride (Yield 178 mg, yield 100%) was obtained.

Process 3
N, N of (R) -N- (6-cyanochroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide (15.0 mg, 0.0417 mmol) To a solution of -dimethylformamide (208 μL), add N, N-diisopropylethylamine (36 μL, 0.21 mmol) and 1- (bromomethyl) -4-fluorobenzene (15.8 mg, 0.0834 mmol), and stir at 100 ° C. for 12 hours. bottom. Water and chloroform were added to the reaction solution, and the layers were separated. The organic layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and (R) -N- (6-cyanochroman-3-yl) -5- (4-fluorobenzyl) -4,5,6,7-tetrahydropyrazolo [1, 5-a] Pyrazine-2-carboxamide (yield 16.0 mg, yield 89%) was obtained.

Example 269
Production of (R) -N- (6-cyanochroman-3-yl) -5- (4-fluorophenethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide

(R) -N- (6) using 1- (2-bromoethyl) -4-fluorobenzene instead of 1- (bromomethyl) -4-fluorobenzene in step 3 in the same manner as in Example 268. -Cyanochroman-3-yl) -5- (4-fluorophenethyl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] Pyrazine-2-carboxamide was obtained.

Example 270
Production of (R) -N- (6-cyanochroman-3-yl) -5-isobutyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide

In the same manner as in Example 268, 1-bromo-2-methylpropane was used instead of 1- (bromomethyl) -4-fluorobenzene in step 3, and (R) -N- (6-cyanochroman-3) was used. -Il) -5-isobutyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide was obtained.

Example 271
Production of (R) -N- (6-cyanochroman-3-yl) -5-cyclopentyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide

(R) -N- (6-cyanochroman-3-yl) -5 using bromocyclopentane instead of 1- (bromomethyl) -4-fluorobenzene in step 3 in the same manner as in Example 268. -Cyclopentyl-4,5,6,7-Tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide was obtained.

Example 272
(R) -5- (2- (tert-butoxy) ethyl) -N- (6- (difluoromethyl) chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a ] Production of pyrazine-2-carboxamide

(R) -6- (difluoromethyl) chromane synthesized by the method described in Reference Example 3 instead of (R) -3-aminochroman-6-carboxamide in step 1 in the same manner as in Example 268. Using -3-amine hydrochloride and using 2- (2-bromoethoxy) -2-methylpropane instead of 1- (bromomethyl) -4-fluorobenzene in step 3, (R) -5-( 2- (tert-butoxy) ethyl) -N- (6- (difluoromethyl) chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide Obtained.

Reference example 71
Production of (R) -N- (6-chlorochroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide hydrochloride

In the same manner as in Step 1 and Step 2 of Example 268, (R) -6 was synthesized by the method described in Reference Example 1 instead of (R) -3-aminochroman-6-carboxamide in Step 1. -With chlorochroman-3-amine hydrochloride, (R) -N- (6-chlorochroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine- 2-Carboxamide was obtained.

Example 273
(R) -N- (6-chlorochroman-3-yl) -5-((6-methoxypyridin-2-yl) methyl) -4,5,6,7-tetrahydropyrazolo [1,5-a ] Production of pyrazine-2-carboxamide

In the same manner as in step 3 of Example 268, (R) -N- (6-cyanochroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2- (R) -N- (6-chlorochroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] synthesized by the method described in Reference Example 71 instead of carboxamide. Using pyrazine-2-carboxamide hydrochloride and using 2- (bromomethyl) -6-methoxypyridine instead of 1- (bromomethyl) -4-fluorobenzene, (R) -N- (6-chlorochroman-) 3-Il) -5-((6-methoxypyridin-2-yl) methyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide was obtained.

Example 274
(R) -N- (6-chlorochroman-3-yl) -5- (2- (pyridin-2-yloxy) ethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] Production of pyrazine-2-carboxamide

Process 1
It was synthesized by the method described in Reference Example 71 instead of ethyl 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate in the same manner as in Reference Example 69 (R). )-N- (6-Chlorochroman-3-yl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] Pyrazine-2-carboxamide hydrochloride using 2-bromoethylcyclopropane Instead, using 2-iodoethanol, (R) -N- (6-chlorochroman-3-yl) -5- (2-hydroxyethyl) -4,5,6,7-tetrahydropyrazolo [1] , 5-a] Pyrazine-2-carboxamide was obtained.

Process 2
(R) -N- (6-chlorochroman-3-yl) -5- (2-hydroxyethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide ( In a mixed solution of 30 mg, 0.080 mmol) of toluene (1.1 mL) and tetrahydrofuran (1.1 mL), 2-hydroxypyridine (11 μL, 0.16 mmol), tributylphosphine (40 μL, 0.16 mmol) and 1,1'- (Azodicarbonyl) dipiperidine (40 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was purified by silica gel column chromatography, and (R) -N- (6-chlorochroman-3-yl) -5- (2- (pyridin-2-yloxy) ethyl) -4,5,6,7 -Tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide was obtained.

Example 275
(R) -N- (Chroman-3-yl) -3-Phenyl-5- (2,2,2-trifluoroethyl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] Production of pyrazine-2-carboxamide

Process 1
Using (R) -chroman-3-amine hydrochloride instead of (R) -3-aminochroman-6-carbonitrile in the same manner as in step 1 of Example 268, (R) -tert- Butyl 2- (chroman-3-ylcarbamoyl) -6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylate was obtained.

Process 2
In the same manner as in Step 2 of Example 69, of (R) -N- (chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-2-carboxamide. Instead, use (R) -tert-butyl 2- (chroman-3-ylcarbamoyl) -6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylate (R). ) -tert-Butyl 3-bromo-2- (chroman-3-ylcarbamoyl) -6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylate was obtained.

Process 3
(R) -N- (chroman-3-yl) -3-iodo-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2 in the same manner as in step 3 of Example 16. -Instead of carboxamide, (R) -tert-butyl 3-bromo-2- (chroman-3-ylcarbamoyl) -6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxy Using the rate, (R) -tert-butyl 2- (chroman-3-ylcarbamoyl) -3-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylate Got

Process 4
In the same manner as in Step 2 of Example 268, (R) -tert-butyl 2-((6-cyanochroman-3-yl) carboxamide) -6,7-dihydropyrazolo [1,5-a] pyrazine- Instead of 5 (4H) -carboxylate, (R) -tert-butyl 2- (chroman-3-ylcarbamoyl) -3-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazine-5 Using (4H) -carboxylate, (R) -N- (chroman-3-yl) -3-phenyl-4, 5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2- Carboxamide hydrochloride was obtained.

Process 5
In the same manner as in Reference Example 69, instead of ethyl 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate, (R) -N- (chroman-3-yl) ) -3-Phenyl-4, 5,6,7-Tetrahydropyrazolo [1,5-a] Pyrazine-2-carboxamide hydrochloride was used instead of 2-bromoethylcyclopropane, 2,2,2- Trifluoroethyl Trifluoromethanesulfonate, (R) -N- (chroman-3-yl) -3-phenyl-5- (2,2,2-trifluoroethyl) -4,5,6,7- Tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide was obtained.

Reference example 72
Production of (R) -N- (chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide hydrochloride

In the same manner as in Step 1 and Step 2 of Example 268, instead of (R) -3-aminochroman-6-carboxamide in Step 1, (R) -chroman-3-amine hydrochloride was used. (R) -N- (chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide hydrochloride was obtained.

Example 276
Production of (R) -N- (Chroman-3-yl) -5- (2-Phenylacetyl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide

The method according to HATU (36.9 mg, 0.0971 mmol), N, N-diisopropylethylamine (64 μL, 0.37 mmol) and Reference Example 72 in a solution of 2-phenylacetic acid (15.0 mg, 0.110 mmol) in dichloromethane (1 mL). (R) -N- (chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide hydrochloride (25.0 mg, 0.0747 mmol) synthesized in In addition, it was stirred at room temperature for 65 hours. The reaction mixture was purified by silica gel column chromatography, and (R) -N- (chroman-3-yl) -5- (2-phenylacetyl) -4,5,6,7-tetrahydropyrazolo [1,5- a] Pyrazine-2-carboxamide (yield 30.5 mg, yield 98%) was obtained.

Example 277
(R) -N- (Chroman-3-yl) -5-((3- (Trifluoromethyl) Phenyl) Sulfonyl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] Pyrazine- 2-Manufacture of carboxamide

(R) -N- (chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide hydrochloride synthesized by the method described in Reference Example 72 ( To a solution of 20.0 mg, 0.0597 mmol) in dichloromethane (1 mL) was added 3- (trifluoromethyl) benzenesulfonyl chloride (19.0 mg, 0.0777 mmol) and N, N-diisopropylethylamine (51 μL, 0.30 mmol) at room temperature. Was stirred for 65 hours. The reaction mixture was purified by silica gel column chromatography, and (R) -N- (chroman-3-yl) -5-((3- (trifluoromethyl) phenyl) sulfonyl) -4,5,6,7-tetrahydro Pyrazolo [1,5-a] pyrazine-2-carboxamide was obtained.

Example 278
Production of (R) -N- (6-cyanochroman-3-yl) -5- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide

Process 1
2-Iodine ethanol (750 μL, 9.62 mmol) was added to 4-fluoroaniline (1.39 mL, 14.4 mmol), and the mixture was stirred at 100 ° C. for 15 hours. A 2 mol / L aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture, and the layers were separated. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-((4-fluorophenyl) amino) ethanol (yield 980 mg, yield 66%).

Process 2
2-((4-Fluorophenyl) amino) ethanol (554 mg, 3.57 mmol) in a solution of ethyl 5-formyl-1H-pyrazol-3-carboxylate (500 mg, 2.97 mmol) in dichloromethane (29.7 mL), tri. Sodium acetoxyborohydride (3.15 g, 14.9 mmol) and acetic acid (170 μL, 2.97 mmol) were added, and the mixture was stirred at 30 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue, and the mixture was separated. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was washed with a mixed solvent of ethyl acetate and n-hexane and ethyl 5-(((4-fluorophenyl) (2-hydroxyethyl) amino) methyl) -1H-pyrazole-3-carboxylate (yield 681 mg). , Yield 75%) was obtained.

Process 3
In the same manner as in step 4 of Example 85, instead of ethyl 5-((4-hydroxybutane-2-yl) oxy) -1H-pyrazole-3-carboxylate, ethyl 5-(((4-fluoro) Ethyl 5- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5] with phenyl) (2-hydroxyethyl) amino) methyl) -1H-pyrazole-3-carboxylate -a] Pyrazine-2-carboxylate was obtained.

Process 4
In the same manner as in Step 5 of Example 85, instead of ethyl 5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate, ethyl 5 -(4-Fluorophenyl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] with pyrazine-2-carboxylate, 5- (4-fluorophenyl) -4,5,6 , 7-Tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate was obtained as a mixture with 4 equivalents of sodium chloride.

Process 5
In the same manner as in Step 1 of Example 268, instead of 5- (tert-butoxycarbonyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylic acid, 5 -(4-Fluorophenyl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] Pyrazine-2-carboxylate with (R) -N- (6-Cyanochroman-3) -Il) -5- (4-fluorophenyl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] Pyrazine-2-carboxamide was obtained.

Reference example 73
Production of (R) -6- (pyridin-3-yl) chroman-3-amine dihydrochloride

(R) -6- (Pyridine-3-yl) chroman-3-amine using pyridine-3-ylboronic acid instead of pyridine-4-ylboronic acid in step 1 in the same manner as in Reference Example 27. Dihydrochloride was obtained.

Example 279
(R) -5- (4-fluorophenyl) -N- (6- (pyridin-3-yl) chroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] Production of pyrazine-2-carboxamide

In the same manner as in Example 278, instead of (R) -3-aminochroman-6-carboxamide in step 5, (R) -6- (pyridin-3-) was synthesized by the method described in Reference Example 73. (Il) using chroman-3-amine dihydrochloride, (R) -5- (4-fluorophenyl) -N- (6- (pyridin-3-yl) chroman-3-yl) -4,5, 6,7-Tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide was obtained.

Example 280
(R) -N- (6-chlorochroman-3-yl) -5- (5-cyanopyridin-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine- 2-Manufacture of carboxamide

(R) -N- (6-chlorochroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide synthesized by the method described in Reference Example 71. Cesium carbonate (20.9 mg, 0.108 mmol) and 6-chloropyridin-3-carboxamide (15.0 mg, 0.108 mmol) were added to a solution of hydrochloride (20.0 mg, 0.0542 mmol) in dimethylsulfoxide (271 μL), and microwaved. Under irradiation, the mixture was stirred at 130 ° C. for 1 hour. A saturated aqueous solution of ammonium chloride, water and chloroform were added to the reaction solution, and the layers were separated. The organic layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and (R) -N- (6-chlorochroman-3-yl) -5- (5-cyanopyridin-2-yl) -4,5,6,7-tetrahydro. Pyrazolo [1,5-a] pyrazine-2-carboxamide (yield 16.0 mg, yield 68%) was obtained.

Example 281
Production of (R) -5- (tert-butyl) -N- (6-chlorochroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide

Process 1
2-Methylpropan-2-amine (196 mg, 2.68 mmol) and tri of ethyl 5-formyl-1H-pyrazole-3-carboxylate (150 mg, 0.892 mmol) in a solution of 1,2-dichloroethane (5 mL) Sodium acetoxyborohydride (945 mg, 4.46 mmol) was added, and the mixture was stirred at 80 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue, and the mixture was separated. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 5-((tert-butylamino) methyl) -1H-pyrazole-3-carboxylate (yield 186 mg, yield 92%).

Process 2
Potassium carbonate (46.0 mg, 0.333 mmol) and 1,2 in a solution of ethyl 5-((tert-butylamino) methyl) -1H-pyrazol-3-carboxylate (30.0 mg, 0.133 mmol) in acetonitrile (1 mL). -Dibromoethane (17.2 μL, 0.200 mmol) was added, and the mixture was stirred at 90 ° C. for 3 hours. The reaction mixture was purified by silica gel column chromatography and ethyl 5- (tert-butyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate (yield 18.8 mg, yield). A rate of 56%) was obtained.

Process 3
In the same manner as in Step 4 of Example 278, instead of ethyl 5- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate, Ethyl 5- (tert-butyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] with pyrazine-2-carboxylate, 5- (tert-butyl) -4,5,6 , 7-Tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate was obtained as a mixture with 4 equivalents of sodium chloride.

Process 4
5- (3,3,3-trifluoropropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylic acid in the same manner as in step 3 of Example 261. Instead of 5- (tert-butyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate, (R) -5- (tert -Butyl) -N- (6-chlorochroman-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide was obtained.

Example 282
(R) -N- (6-cyanochroman-3-yl) -5- (1- (4-fluorophenyl) cyclopropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine -2-Production of carboxamide

In the same manner as in Example 281, 1- (4-fluorophenyl) cyclopropaneamine hydrochloride was used instead of 2-methylpropan-2-amine in step 1, and (R) -6-chloro in step 4. Using (R) -3-aminochroman-6-carboxamide synthesized by the method described in Reference Example 24 instead of chroman-3-amine hydrochloride, (R) -N- (6-cyanochroman-3) -Il) -5- (1- (4-fluorophenyl) cyclopropyl) -4,5,6,7-Tetrahydropyrazolo [1,5-a] Pyrazine-2-carboxamide was obtained.

Example 283
(R) -N- (6-chlorochroman-3-yl) -5-(1- (trifluoromethyl) cyclopropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine -2-Production of carboxamide

Process 1
To a solution of ethyl 5-formyl-1H-pyrazol-3-carboxylate (500 mg, 2.97 mmol) in ethanol (5.9 mL), add a 4 mol / L sodium hydroxide aqueous solution (3 mL, 12 mmol) at 50 ° C. Stirred for 3 hours. After adding 2 mol / L hydrochloric acid (98.0 mL, 98.0 mmol) of the reaction solution, the solvent was distilled off under reduced pressure. The operation of adding toluene to the residue and distilling off the solvent under reduced pressure was repeated 3 times, and 5-formyl-1H-pyrazole-3-carboxylic acid (yield 1.1 g, yield 99%) was combined with 4 equivalents of sodium chloride. Obtained as a mixture of.

Process 2
In the same manner as in Step 2 of Example 41, 5-formyl-1H-pyrazole-3-carboxylic acid was used instead of 6-hydroxyimidazole [1,2-a] pyridine-2-carboxylic acid (R). )-Chroman-3-amine hydrochloride was replaced with (R) -6-chlorochroman-3-amine hydrochloride synthesized by the method described in Reference Example 1 and (R) -N- (6-). Chlorochroman-3-yl) -5-formyl-1H-pyrazole-3-carboxamide was obtained.

Process 3
In the same manner as in Step 2 of Example 278, instead of ethyl 5-formyl-1H-pyrazole-3-carboxylate, (R) -N- (6-chlorochroman-3-yl) -5-formyl- With 1H-pyrazole-3-carboxamide and with 1- (trifluoromethyl) cyclopropaneamine hydrochloride instead of 2-((4-fluorophenyl) amino) ethanol, (R) -N- (6) -Chlorochroman-3-yl) -5-(((1- (trifluoromethyl) cyclopropyl) amino) methyl) -1H-pyrazole-3-carboxamide was obtained.

Process 4
In the same manner as in Step 2 of Example 281, instead of ethyl 5-((tert-butylamino) methyl) -1H-pyrazole-3-carboxylate, (R) -N- (6-chlorochroman-3) -Il) -5-(((1- (Trifluoromethyl) cyclopropyl) amino) methyl) -1H-pyrazole-3-carboxamide, (R) -N- (6-chlorochroman-3-yl) ) -5- (1- (Trifluoromethyl) cyclopropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide was obtained.

Example 284
(R) -N- (6-chlorochroman-3-yl) -5-(1- (2,2,2-trifluoroethyl) cyclopropyl) -4,5,6,7-tetrahydropyrazolo [1 , 5-a] Production of pyrazine-2-carboxamide

In the same manner as in Example 283, 1- (2,2,2-trifluoroethyl) cyclopropaneamine hydrochloride was used instead of 1- (trifluoromethyl) cyclopropaneamine hydrochloride in step 3. (R) -N- (6-Chlorochroman-3-yl) -5- (1- (2,2,2-trifluoroethyl) cyclopropyl) -4,5,6,7-Tetrahydropyrazolo [1 , 5-a] Pyrazine-2-carboxamide was obtained.

Example 285
(R) -N- (6-chlorochroman-3-yl) -5- (2- (pyridin-2-yl) propan-2-yl) -4,5,6,7-tetrahydropyrazolo [1, 5-a] Production of pyrazine-2-carboxamide

In the same manner as in Example 283, instead of 1- (trifluoromethyl) cyclopropaneamine hydrochloride in step 3, 2- (pyridin-2-yl) propan-2-amine hydrochloride was used (R). ) -N- (6-Chlorochroman-3-yl) -5- (2- (pyridin-2-yl) propan-2-yl) -4,5,6,7-Tetrahydropyrazolo [1,5- a] Pyrazine-2-carboxamide was obtained.

Reference example 74
Production of 1- (2-methoxypyridin-4-yl) cyclopropaneamine

Titanium (IV) isopropoxide (500 μL, 1.65 mmol) and 1 mol / L ethylmagnesium bromide- tetrahydrofuran solution (200 mg, 1.49 mmol) in ice-cooled 2-methoxypyridine-4-carbonitrile (200 mg, 1.49 mmol). 3.3 mL, 3.3 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was ice-cooled, boron trifluoride diethyl ether complex (0.37 mL, 3.0 mmol) was added, and the mixture was stirred at room temperature for 1 hr. A 1 mol aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was filtered through Celite. Ethyl acetate was added to the filtrate, and the mixture was separated, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1- (2-methoxypyridin-4-yl) cyclopropaneamine (yield 76.5 mg, yield 31%).

Example 286
(R) -N- (6-cyanochroman-3-yl) -5- (1- (2-methoxypyridin-4-yl) cyclopropyl) -4,5,6,7-tetrahydropyrazolo [1,5 -a] Production of pyrazine-2-carboxamide

(R) -3-Aminochroman-6 synthesized by the method described in Reference Example 24 instead of (R) -6-chlorochroman-3-amine hydrochloride in Step 2 in the same manner as in Example 283. 1- (2-methoxypyridin-4-yl) cyclopropaneamine synthesized by the method described in Reference Example 74 using carboxamide instead of 1- (trifluoromethyl) cyclopropaneamine hydrochloride in step 3. With (R) -N- (6-cyanochroman-3-yl) -5- (1- (2-methoxypyridin-4-yl) cyclopropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] Pyrazine-2-carboxamide was obtained.

Example 287
Production of N-((R) -Chroman-3-yl) -5-Phenyl-4,5,6,7-Tetrahydropyrazolo [1,5-a] pyrimidin-2-carboxamide

In the same manner as in steps 6 to 8 of Example 70, (1-bromo-3-chloropropyl) benzene was used instead of 1- (1-bromo-3-chloropropyl) -2-fluorobenzene in step 6. Using methyl 5-amino-1H-pyrazole-3-carboxylate instead of ethyl 5-hydroxy-1H-pyrazol-3-carboxylate in step 6, (R) -3-aminochroman-6 in step 8 was used. -Using (R) -chroman-3-amine hydrochloride instead of carbonitrile, N-((R) -chroman-3-yl) -5-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] Pyrimidine-2-carboxamide was obtained.

Example 288
N-((R) -6-chlorochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] Pyridine-2-carboxamide (isomer A) ) Manufacture of hydrochloride

N-((R) -6-chlorochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazo synthesized by the method described in Example 2 [1,2- a] After adding 4 mol / L hydrogen chloride-ethyl acetate solution (1 mL, 4 mmol) to ethyl acetate solution (1 mL) of pyridine-2-carboxamide (isomer A) (170 mg, 0.425 mmol), Stirred for 10 minutes. The solvent was distilled off under reduced pressure, and N-((R) -6-chlorochroman-3-yl) -6- (trifluoromethyl) -5,6,7,8-tetrahydroimidazole [1,2-a] ] Pyridine-2-carboxamide (isomer A) hydrochloride (yield 185 mg, yield 100%) was obtained.

Example 289
5- (2-Fluorophenyl) -N-((R) -6- (pyridin-2-yl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Production of oxazine-2-carboxamide hydrochloride

5- (2-Fluorophenyl) -N-((R) -6- (pyridin-2-yl) chroman-3-yl) -6,7-dihydro-5H- synthesized by the method described in Example 81. Pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide (123 mg, 0.261 mmol) in ethyl acetate solution (1 mL) in 4 mol / L hydrogen chloride-ethyl acetate solution (131 μL, 0.523) mmol) was added and stirred. The solvent was distilled off under reduced pressure, and 5- (2-fluorophenyl) -N-((R) -6- (pyridin-2-yl) chroman-3-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-2-carboxamide hydrochloride (yield 115 mg, yield 87%) was obtained.

Example 290
(R) -N- (6-cyanochroman-3-yl) -5- (4-fluorobenzyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide hydrochloride Manufacturing of

(R) -N- (6-cyanochroman-3-yl) -5- (4-fluorobenzyl) -4,5,6,7-tetrahydropyrazolo [1,5] synthesized by the method described in Example 268. -a] A 4 mol / L hydrogen chloride-ethyl acetate solution (141 μL, 0.563 mmol) was added to an ethyl acetate solution (2 mL) of pyrazine-2-carboxamide (122 mg, 0.283 mmol), and the mixture was stirred. n-Hexane (2 mL) was added, and the precipitated solid was collected by filtration and dried under reduced pressure to (R) -N- (6-cyanochroman-3-yl) -5- (4-fluorobenzyl)-. 4,5,6,7-Tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide hydrochloride (yield 96.4 mg, yield 73%) was obtained.

The table below shows the chemical structural formulas and instrumental analysis data of the compounds synthesized in Examples 1 to 287. In the table below, the asterisk (*) shown in the structural formula means that the corresponding asymmetric carbon has a single solid. Unless otherwise noted, "Example" in the table refers to the compound intended for production in each Example, for example, the data of Example 1 is the compound intended for production in Example 1. Means the data of.

The compound of Example 291 was synthesized from the compound of Example 9 by the same method as in Step 1 of Reference Example 3.

The compound of Example 292 was synthesized from the compound of Example 9 by the same method as in Steps 1 to 3 of Reference Example 3.

The compound of Example 293 was synthesized from the compound of Example 9 by the same method as in Step 1 of Reference Example 3.

The compound of Example 294 was synthesized from the compound of Example 293 by the scheme shown in the figure below.

The compound of Example 295 was synthesized in the same manner as in Example 11.

The compound of Example 296 was synthesized from the compound synthesized in Step 1 of Example 294 by the scheme shown in the figure below.

The compound of Example 297 was synthesized from the compound synthesized in Step 2 of Example 296 by the scheme shown in the figure below.

The compound of Example 298 was synthesized by the same method as that described in Examples 1 and 3.

The compound of Example 299 was synthesized in the same manner as in Example 15.

The compound of Example 300 was synthesized from the compound synthesized in Example 14 by the scheme shown in the figure below.

The compound of Example 301 was synthesized from the compound synthesized in Example 14 by the same method as in Example 29.

The compound of Example 302 was synthesized from the compound synthesized in Example 14 by the same method as in Step 2 of Reference Example 3.

The compound of Example 303 was synthesized in the same manner as in Example 16.

The compound of Example 304 was synthesized in the same manner as in Example 16.

The compound of Example 305 was synthesized by the same method as described in Example 18 and Reference Example 43.

The compound of Example 306 was synthesized by the same method as described in Example 18 and Reference Example 65.

The compound of Reference Example 75 (shown in the figure below) was synthesized by the same method as in Example 26.

The compound of Example 307 was synthesized from the compound synthesized in Reference Example 75 by the scheme shown in the figure below.

The compound of Example 308 was synthesized in the same manner as in Example 307.

The compound of Example 309 was synthesized in the same manner as in Example 307.

The compound of Example 310 was synthesized in the same manner as in Example 307.

The compound of Example 311 was synthesized in the same manner as in Example 307.

The compound of Example 312 was synthesized by the same method as that described in Example 307 and Example 102.

The compound of Example 313 was synthesized from the compound synthesized in Reference Example 75 by the following scheme.

The compound of Example 314 was synthesized in the same manner as in Example 27.

The compound of Example 315 was synthesized in the same manner as in Example 26.

The compound of Example 316 was synthesized in the same manner as in Example 26.

The compound of Example 317 was synthesized in the same manner as in Example 29.

The compound of Example 318 was synthesized in the same manner as in Example 30.

The compound of Example 319 was synthesized by the same method as described in Example 41, Example 168 and Example 157.

The compound of Example 320 was synthesized by the same method as described in Examples 29 and 157.

The compound of Example 321 was synthesized in the same manner as in Example 41.

The compound of Example 322 was synthesized from the compound synthesized in Step 1 of Example 42 by the scheme shown in the figure below.

The compound of Example 323 was synthesized in the same manner as in Example 62.

The compound of Example 324 was synthesized in the same manner as in Example 43.

The compound of Example 325 was synthesized by the same method as that described in Step 3 of Examples 62 and 41.

The compound of Example 326 was synthesized by the same method as described in Examples 43 and 45.

The compound of Example 327 was synthesized in the same manner as in Example 325.

The compound of Example 328 was synthesized in the same manner as in Example 49.

The compound of Reference Example 76 (3- (2-chlorophenyl) -3-fluoropyrrolidine hydrochloride) was synthesized by the scheme shown in the figure below.

The compound of Example 329 was synthesized from the compound of Reference Example 21 and the compound of Reference Example 76 in the same manner as in Step 3 of Example 56.

The compound of Example 330 was synthesized in the same manner as in Example 62.

The compound of Example 331 was synthesized in the same manner as in Example 62.

The compound of Example 332 was synthesized by the same method as that described in Reference Example 18, Example 58 and Example 3.

The compound of Example 333 was synthesized by the same method as described in Examples 59 and 45.

The compound of Reference Example 77 (shown in the figure below) was synthesized in the same manner as in Reference Example 4.

The compound of Example 334 was synthesized from the compound of Reference Example 21 and the compound of Reference Example 77 by the same method as in Step 3 of Example 100.

The compound of Example 335 was synthesized by the same method as described in Examples 43 and 45.

The compound of Example 336 was synthesized in the same manner as in Example 43.

The compound of Example 337 was synthesized in the same manner as in Example 43.

The compound of Reference Example 78 ((R) -N- (chroman-3-yl) -3-phenyl-5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine-2-carboxamide) is shown in the figure below. It was synthesized according to the scheme of.

The compound of Example 338 was synthesized from the compound of Reference Example 78 in the same manner as in Reference Example 69.

The compound of Example 339 was synthesized from the compound of Reference Example 78 by the same method as in Step 1 of Reference Example 1.

The compound of Reference Example 79 (6-phenyl-5,6-dihydro-8H-imidazole [2,1-c] [1,4] oxazine-2-carboxylic acid) was synthesized according to the scheme shown in the figure below.

実施例340の化合物は、参考例79の化合物から、実施例100の工程3と同様の方法で合成した。

The compound of Example 340 was synthesized from the compound of Reference Example 79 by the same method as in Step 3 of Example 100.

The compound of Example 341 was synthesized by the same method as described in Example 64 and Reference Example 24.

The compound of Reference Example 80 (shown in the figure below) was synthesized by the same method as that described in Steps 1 and 4 of Reference Example 3.

The compound of Example 342 was synthesized by the same method as described in Example 66 and Reference Example 80.

The compound of Example 343 was synthesized by the same method as described in Example 66 and Reference Example 52.

The compound of Example 344 was synthesized by the same method as described in Example 64 and Reference Example 1.

The compound of Example 345 was synthesized by the same method as described in Example 64 and Reference Example 43.

The compound of Example 346 was synthesized by the same method as described in Example 64 and Reference Example 43.

The compound of Example 347 was synthesized in the same manner as in Example 69.

The compound of Example 348 was synthesized by the same method as described in Example 69 and Reference Example 1.

The compound of Example 349 was synthesized in the same manner as in Example 70.

The compound of Example 350 was synthesized in the same manner as in Example 70.

The compound of Example 351 was synthesized in the same manner as in Example 70.

The compound of Example 352 was synthesized in the same manner as in Example 70.

The compound of Example 353 was synthesized in the same manner as in Example 70.

The compound of Example 354 was synthesized in the same manner as in Example 70.

The compound of Example 355 was synthesized in the same manner as in Example 70.

The compound of Example 356 was synthesized in the same manner as in Example 70.

The compound of Example 357 was synthesized from the compound of Example 71 by the same method as in Step 1 of Reference Example 27.

The compound of Example 358 was synthesized by the same method as described in Example 70 and Reference Example 1.

The compounds of Example 359 and Example 360 were obtained by dividing the compounds of Example 70.

The compound of Example 361 was synthesized from the compound of Example 82 in the same manner as in Steps 2 to 3 of Example 296.

The compound of Example 362 was synthesized by the same method as described in Example 70 and Reference Example 1.

The compound of Example 363 was synthesized in the same manner as in Example 70.

The compound of Example 364 was synthesized by the same method as described in Example 70 and Reference Example 24.

The compound of Example 365 was synthesized in the same manner as in Example 361.

The compound of Example 366 was synthesized by the same method as described in Example 70 and Reference Example 24.

The compound of Example 367 was synthesized by the same method as described in Example 70 and Reference Example 1.

The compound of Example 368 was synthesized from the compound of Example 82 in the same manner as in Step 2 of Example 296 and Step 1 of Example 122.

The compound of Example 369 was synthesized from the compound of Example 82 in the same manner as in Steps 2 to 3 of Example 296.

The compound of Example 370 was synthesized from the compound of Example 82 by the same method as in Steps 2 to 3 of Example 296.

The compound of Example 371 was synthesized by the same method as described in Example 70 and Reference Example 1.

The compound of Example 372 was synthesized by the same method as described in Example 70 and Reference Example 24.

The compound of Example 373 was synthesized by the same method as described in Example 169 and Reference Example 24.

The compound of Example 374 was obtained by dividing the compound of Example 373.

The compound of Example 375 was synthesized by the same method as described in Example 169 and Reference Example 73.

The compound of Example 376 was synthesized by the same method as described in Example 169 and Reference Example 23.

The compound of Example 377 was synthesized from the compound of Example 171 in the same manner as in Step 1 of Reference Example 27.

The compound of Example 378 was synthesized from the compound of Example 171 in the same manner as in Step 1 of Reference Example 27.

The compound of Example 379 was synthesized from the compound synthesized in Step 1 of Example 120 by the scheme shown in the figure below.

The compound of Example 380 was synthesized from the compound of Example 171 in the same manner as in Step 1 of Reference Example 27.

The compound of Example 381 was synthesized from the compound synthesized in Step 1 of Example 117 by the same method as in Example 157.

The compound of Example 382 was synthesized from the compound of Example 171 in the same manner as in Step 1 of Reference Example 27.

The compound of Example 383 was synthesized by the same method as described in Example 177 and Reference Example 28.

The compound of Example 384 was synthesized by the same method as described in Reference Example 34, Example 85 and Reference Example 24.

The compound of Reference Example 81 (6,6-difluoro-5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid) is prepared according to the scheme shown in the figure below. , Synthesized.

The compound of Example 385 was synthesized from the compound of Reference Example 81 and the compound of Reference Example 1 by the same method as in Step 3 of Example 100.

The compound of Example 386 was synthesized from the compound synthesized in Step 3 of Example 100 by the scheme shown in the figure below.

The compound of Reference Example 82 (1-cyclopropylpropane-1,3-diol) was synthesized by the scheme shown in the figure below.

The compound of Example 387 was synthesized from the compound of Reference Example 82 by the same method as described in Example 159 and Reference Example 1.

The compound of Example 388 was synthesized by the same method as described in Reference Example 82, Example 159 and Reference Example 24.

The compound of Example 389 was synthesized in the same manner as in Example 85.

The compound of Reference Example 83 (5-((tert-butyldiphenylsilyl) oxy) -1-phenylpent-1-in-3-ol) was synthesized by the scheme shown in the figure below.

The compound of Example 390 was synthesized from the compound of Reference Example 83 by the same method as described in Example 85 and Reference Example 24.

The compound of Example 391 was synthesized from the compound of Example 171 by the same method as described in Examples 82 and 83.

The compound of Example 392 was synthesized from the compound of Example 171 by the same method as that described in Step 2 of Examples 82 and 117.

The compound of Example 393 was synthesized by the same method as described in Example 85 and Reference Example 24.

The compound of Example 394 was synthesized by the same method as described in Reference Example 83, Example 85 and Reference Example 24.

The compound of Example 395 was synthesized by the same method as described in Reference Example 82, Example 159 and Reference Example 1.

The compound of Example 396 was synthesized from the compound of Example 171 by the same method as in Step 1 of Reference Example 3.

The compound of Example 397 was synthesized from the compound of Example 396 by the same method as described in Step 1 of Reference Example 45 and Step 2 of Reference Example 44.

The compound of Reference Example 84 ((R) -6- (3-methoxy-3-ethylbut-1-in-1-yl) chroman-3-amine) is shown in the figure below from the compound synthesized in Step 1 of Reference Example 2. It was synthesized according to the scheme of.

The compound of Example 398 was synthesized by the same method as described in Example 169 and Reference Example 84.

The compound of Example 399 was synthesized in the same manner as in Example 391.

The compound of Example 400 was synthesized from the compound of Example 398 by the same method as in Step 2 of Example 1.

The compound of Example 401 was synthesized by the same method as described in Example 169, Reference Example 45 and Example 122.

The compound of Example 402 was synthesized by the same method as described in Reference Example 83, Example 85 and Reference Example 43.

The compound of Example 403 was synthesized by the same method as described in Example 177 and Reference Example 65.

The compound of Example 404 was synthesized by the same method as that described in Reference Example 83, Example 85, Reference Example 3 and Reference Example 1.

The compound of Example 405 was synthesized from the compound synthesized in Step 6 of Example 159 and the compound of Reference Example 80 in the same manner as in Step 8 of Example 70.

The compound of Reference Example 85 was synthesized by the same method as that described in Reference Example 83, Example 85 and Reference Example 1.

The compounds of Example 406 and Example 407 were obtained by dividing the compound of Reference Example 85.

The compound of Example 408 was synthesized by the same method as described in Example 85 and Reference Example 24.

The compound of Example 409 was synthesized in the same manner as in Example 157.

The compound of Example 410 was synthesized in the same manner as in Example 100.

The compound of Example 411 was synthesized by the same method as described in Example 117 and Reference Example 24.

The compound of Example 412 was synthesized in the same manner as in Example 114.

The compound of Example 413 was synthesized by the same method as described in Example 100 and Reference Example 1.

The compound of Example 414 was synthesized by the same method as described in Example 100 and Reference Example 28.

The compound of Example 415 was synthesized from the compound synthesized in Step 1 of Example 117 by the same method as in Step 1 to Step 2 of Example 122.

Compound of Reference Example 86 (2,3,5,6,6', 7'-hexahydrospiro [pyran-4,5'-pyrazolo [5,1-b] [1,3] oxazine] -2'- Carboxylic acid) was synthesized by the following scheme.

The compound of Example 416 was synthesized from the compound of Reference Example 86 and the compound of Reference Example 1 in the same manner as in Step 8 of Example 70.

The compound of Example 417 was synthesized from the compound synthesized in Step 1 of Example 386 by the scheme shown in the figure below.

The compound of Example 418 was synthesized from the compound synthesized in Step 3 of Example 100 by the scheme shown in the figure below.

The compound of Reference Example 87 (5- (hydroxymethyl) -5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid) is the scheme shown in the figure below. Was synthesized by.

The compound of Example 419 was synthesized from the compound of Reference Example 87 by the same method as in Steps 3 to 4 of Example 100.

The compound of Example 420 was synthesized from the compound of Reference Example 37 and the compound of Reference Example 1 in the same manner as in Example 133.

The compound of Example 421 was synthesized from the compound of Reference Example 37 and the compound of Reference Example 32 in the same manner as in Example 133.

The compound of Example 422 was synthesized in the same manner as in Example 114.

The compounds of Example 423 and Example 424 were obtained by dividing the compounds of Example 422.

The compound of Example 425 was synthesized by the same method as that described in Step 1 of Example 100, Reference Example 2 and Reference Example 27.

The compound of Example 426 was synthesized in the same manner as in Example 425.

The compound of Example 427 was synthesized in the same manner as in Example 425.

The compound of Example 428 was synthesized in the same manner as in Example 425.

The compound of Example 429 was synthesized in the same manner as in Example 425.

The compound of Example 430 was synthesized in the same manner as in Example 425.

The compound of Example 431 was synthesized in the same manner as in Example 425.

The compound of Example 432 was synthesized from the compound of Reference Example 36 and the compound of Reference Example 43 in the same manner as in Steps 5 to 6 of Example 85.

The compound of Example 433 was synthesized from the compound of Reference Example 41 and the compound of Reference Example 43 in the same manner as in Step 6 of Example 85.

The compound of Example 434 was synthesized by the same method as described in Reference Example 49, Example 85 and Reference Example 24.

The compound of Example 435 was synthesized by the same method as described in Example 434 and Reference Example 60.

The compound of Example 436 was synthesized from the compound of Reference Example 36 by the same method as described in Steps 5 to 6 of Reference Example 84 and Example 85.

The compound of Example 437 was synthesized by the same method as described in Example 384 and Reference Example 48.

The compound of Example 438 was synthesized by the same method as described in Example 384 and Reference Example 44.

The compound of Example 439 was synthesized by the same method as described in Example 384, Example 157 and Reference Example 24.

The compound of Example 440 was synthesized by the same method as described in Example 122 and Reference Example 44.

The compound of Example 441 was synthesized from the compound of Reference Example 36 and the compound of Reference Example 52 by the same method as described in Steps 5 to 6 of Example 85.

The compound of Example 442 was synthesized from the compound of Reference Example 36 and the compound of Reference Example 1 by the same method as described in Steps 5 to 6 of Example 85.

The compound of Example 443 was synthesized in the same manner as in Example 98.

The compound of Example 444 was synthesized by the same method as described in Examples 85 and 69.

The compound of Example 445 was synthesized by the same method as described in Example 183 and Reference Example 2.

The compound of Example 446 was synthesized from the compound synthesized in Reference Example 68 by the same method as described in Example 249 and Reference Example 1.

The compound of Example 447 was synthesized by the same method as described in Example 183 and Reference Example 65.

The compound of Example 448 was synthesized from the compound synthesized in Step 1 of Example 187 by the same method as in Example 225.

The compound of Reference Example 88 (ethyl 2- (1,1-difluoro-2-hydroxyethyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylate) is the step of Reference Example 81. From the compound synthesized in 4, it was synthesized by the scheme shown in the figure below.

The compound of Example 449 was synthesized from the compound of Reference Example 88 by the same method as that described in Step 6 of Reference Example 33 and Example 85.

The compound of Example 450 was synthesized from the compound synthesized in Step 1 of Example 187 by the same method as described in Step 2 of Example 117 and Steps 2 to 3 of Example 100.

The compound of Example 451 was synthesized from the compound synthesized in Step 5 of Reference Example 55 by the same method as described in Steps 5 to 6 of Reference Example 35 and Example 85.

The compound of Example 452 was synthesized from the compound synthesized in Step 1 of Example 187 by the same method as described in Example 225 and Reference Example 24.

The compound of Example 453 was synthesized from the compound synthesized in Step 1 of Reference Example 187 by the same method as described in Steps 5 to 6 of Reference Example 35 and Example 85.

The compound of Example 454 was synthesized from the compound of Reference Example 50 by the same method as in Step 3 of Example 100.

The compound of Example 455 was synthesized by the same method as described in Example 451 and Reference Example 24.

The compound of Example 456 was synthesized from the compound of Reference Example 55 and the compound of Reference Example 60 by the same method as in Step 3 of Example 100.

The compound of Example 457 was synthesized by the same method as described in Example 243 and Reference Example 56.

The compound of Example 458 is obtained from the compound synthesized in Step 1 of Example 187 by the same method as described in Step 1, Reference Example 64, Reference Example 43 and Step 3 of Example 100 of Example 225. Synthesized.

The compound of Example 459 was synthesized by the same method as described in Example 187 and Reference Example 48.

The compound of Example 460 was synthesized by the same method as described in Example 203 and Reference Example 59.

The compound of Example 461 was synthesized by the same method as described in Example 203 and Reference Example 56.

The compound of Example 462 was synthesized by the same method as that described in Step 3 of Reference Example 38, Reference Example 65 and Example 100.

The compound of Example 463 was synthesized by the same method as described in Example 185 and Reference Example 80.

The compound of Example 464 was synthesized by the same method as that described in Step 3 of Reference Example 49, Reference Example 50, Reference Example 24 and Example 100.

The compound of Example 465 was synthesized by the same method as described in Reference Example 49, Example 85 and Reference Example 24.

The compound of Example 466 was synthesized from the compound of Reference Example 55 and the compound of Reference Example 48 by the same method as in Step 3 of Example 100.

The compound of Example 467 was synthesized by the same method as described in Example 465 and Reference Example 60.

The compound of Example 468 was synthesized from the compound of Reference Example 50 and the compound of Reference Example 29 by the same method as in Step 3 of Example 100.

The compound of Example 469 was synthesized from the compound of Reference Example 50 and the compound of Reference Example 1 by the same method as in Step 3 of Example 100.

The compound of Example 470 was synthesized by the same method as described in Reference Example 49, Example 85 and Reference Example 24.

The compound of Example 471 was synthesized by the same method as described in Reference Example 49, Example 85 and Reference Example 48.

The compound of Example 472 was synthesized by the same method as described in Reference Example 49, Example 85 and Reference Example 44.

The compound of Example 473 was synthesized by the same method as described in Reference Example 49, Example 85 and Reference Example 59.

The compound of Example 474 was synthesized by the same method as described in Reference Example 49, Example 85 and Reference Example 60.

The compound of Example 475 was synthesized by the same method as described in Reference Example 49, Example 85 and Reference Example 53.

The compounds of Example 476 and Example 477 were synthesized by the same method as described in Example 241 and Reference Example 43.

The compound of Example 478 was synthesized by the same method as described in Step 1 and Reference Example 48 of Example 224.

The compound of Example 479 was synthesized by the same method as that described in Step 1 and Reference Example 52 of Example 224.

The compound of Example 480 was synthesized by the same method as described in Example 251 and Reference Example 1.

The compound of Example 481 was synthesized by the same method as described in Example 258 and Reference Example 1.

The compound of Example 482 was synthesized by the same method as described in Example 254 and Reference Example 44.

The compound of Reference Example 89 (4-((tert-butyldiphenylsilyl) oxy) -2- (trifluoromethyl) butane-1-ol) was synthesized by the scheme shown in the figure below.

The compound of Example 483 was synthesized from the compound of Reference Example 89 by the same method as described in Steps 2 to 6 and Reference Example 24 of Example 85.

The compound of Example 484 was synthesized in the same manner as in Example 259.

The compound of Example 485 was synthesized in the same manner as in Example 259.

The compound of Example 486 was synthesized by the same method as described in Example 16 and Reference Example 43.

The compound of Example 487 was synthesized from the compound of Reference Example 72 by the same method as in Step 1 of Example 266.

The compound of Example 488 was synthesized from the compound of Reference Example 72 by the same method as in Step 1 of Example 266.

The compound of Example 489 was synthesized by the same method as described in Example 487 and Reference Example 24.

The compound of Example 490 was synthesized from the compound of Reference Example 72 by the same method as in Step 1 of Example 266.

The compound of Example 491 was synthesized by the same method as described in Example 263 and Reference Example 24.

The compound of Example 492 was synthesized by the same method as described in Example 268 and Reference Example 3.

The compound of Example 493 was synthesized from the compound of Reference Example 71 by the same method as in Step 1 of Example 266.

The compound of Example 494 was synthesized from the compound of Reference Example 71 by the same method as described in Reference Example 69 and Example 157.

The compound of Example 495 was synthesized by the same method as that described in Steps 2 to 3 of Reference Example 69, Example 157 and Example 261.

The compound of Example 496 was synthesized by the same method as that described in Steps 2 to 3 of Reference Example 69 and Example 261.

The compound of Example 497 was synthesized in the same manner as in Example 268.

The compound of Example 498 was synthesized in the same manner as in Example 268.

The compound of Example 499 was synthesized in the same manner as in Example 269.

The compound of Example 500 was synthesized in the same manner as in Example 283.

The compound of Example 501 was synthesized in the same manner as in Example 283.

The compound of Example 502 was synthesized by the same method as described in Example 283 and Reference Example 24.

The compound of Example 503 was synthesized by the same method as described in Example 283 and Reference Example 24.

The compound of Example 504 was synthesized from the compound of Reference Example 69 by the same method as described in Steps 2 to 3 and Reference Example 48 of Example 261.

The compound of Example 505 was synthesized from the compound of Reference Example 69 by the same method as described in Steps 2 to 3 and Reference Example 44 of Example 261.

The compound of Example 506 was synthesized by the same method as described in Example 261 and Reference Example 43.

The compound of Example 507 was synthesized by the same method as described in Example 261 and Reference Example 44.

The compound of Example 508 was synthesized in the same manner as in Example 278.

The compound of Example 509 was synthesized by the same method as described in Example 275 and Reference Example 1.

The compound of Example 510 was synthesized in the same manner as in Example 276.

The compound of Example 511 was synthesized in the same manner as in Example 277.

The compound of Example 512 was synthesized by the same method as described in Example 64 and Reference Example 43.

The compound of Example 513 was synthesized in the same manner as in Example 259.

The compound of Example 514 was synthesized in the same manner as in Example 259.

The compound of Example 515 was synthesized by the same method as described in Example 259 and Reference Example 1.

The compound of Reference Example 90 (3- (6-ethylpyridin-2-yl) -6,7-dihydro-4H-pyrazolo [5,1-c] [1,4] oxazine-2-carboxylic acid) was carried out. From the compound synthesized in step 1 of Example 259, it was synthesized by the scheme shown in the figure below.

The compound of Example 516 was synthesized from the compound of Reference Example 90 in the same manner as in Step 3 of Example 100.

The compound of Example 517 was synthesized in the same manner as in Example 259.

The compound of Example 518 was synthesized in the same manner as in Example 259.

The compound of Example 519 was synthesized from the compound of Example 514 by the scheme shown in the figure below.

The compound of Example 520 was synthesized from the compound of Example 519 in the same manner as in Example 114.

The compound of Example 521 was synthesized from the compound of Example 519 by the scheme shown in the figure below.

The compound of Example 522 was synthesized from the compound synthesized in Step 2 of Example 519 by the scheme shown in the figure below.

The compound of Example 523 was synthesized from the compound of Example 519 by the scheme shown in the figure below.

The compound of Reference Example 91 (3- (6-methylpyridine-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-2-carboxylic acid) is prepared according to the scheme shown in the figure below. , Synthesized.

The compound of Example 524 was synthesized from the compound of Reference Example 91 and the compound of Reference Example 43 in the same manner as in Step 3 of Example 100.

The compound of Example 525 was synthesized by the same method as that described in Step 3 of Reference Example 91, Reference Example 44 and Example 100.

The compound of Example 526 was synthesized by the scheme shown in the figure below.

The compound of Example 527 was synthesized from the compound synthesized in Step 2 of Example 519 by the same method as in Step 1 of Reference Example 52.

The compound of Example 528 was synthesized by the same method as described in Steps 1 to 3 of Example 259 and Example 260.

The compound of Reference Example 92 ((3S) -3-amino-6- (trifluoromethyl) chroman-4-ol (isomer A and isomer B)) was synthesized by the scheme shown in the figure below.

The compound of Example 529 was synthesized from the compound synthesized in Step 1 of Example 259 and the compound of Reference Example 92 (isomer A) by the same method as described in Steps 2 to 4 of Example 259. ..

The compound of Example 530 was synthesized from the compound synthesized in Step 3 of Example 259 by the scheme shown in the figure below.

The compound of Example 531 was synthesized from the compound synthesized in Step 3 of Example 259 by the scheme shown in the figure below.

The compound of Example 532 was synthesized by the same method as described in Reference Example 34, Example 85 and Reference Example 24.

The compound of Example 533 was synthesized by the same method as described in Reference Example 34, Example 85 and Reference Example 43.

The compound of Reference Example 93 (5- (difluoromethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylic acid (isomer A and isomer B)) is From the compound synthesized in step 5 of Example 159, it was synthesized by the scheme shown in the figure below.

The compounds of Example 534 (isomer A and isomer B) were synthesized from the compound of Reference Example 93 (isomer A) and the compound of Reference Example 92 (isomer A) in the same manner as in Step 6 of Example 85.

The compound of Example 535 was synthesized from the compound of Example 534 (isomer A) according to the scheme shown in the figure below.

The compound of Example 536 was synthesized from the compound of Example 534 (isomer A) in the same manner as in Example 114.

The compound of Example 537 was synthesized from the compound synthesized in Step 7 of Example 70 by the same method as in Step 3 of Example 100.

The compound of Reference Example 94 (1-((2,4-dihydroxybutoxy) methyl) cyclopropane-1-carbonitrile) was synthesized by the scheme shown in the figure below.

The compound of Example 538 was synthesized from the compound of Reference Example 94 by the same method as described in Example 85.

The compound of Reference Example 95 (ethyl 6-((benzyloxy) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxylate) is the scheme shown in the figure below. Was synthesized by.

The compound of Example 539 was synthesized from the compound of Reference Example 95 by the same method as described in Example 100 and Reference Example 43.

The compound of Example 540 was synthesized by the same method as described in Reference Example 34, Example 169 and Reference Example 24.

The compound of Example 541 was synthesized by the same method as described in Example 449 and Reference Example 24.

The compound of Example 542 was synthesized from the compound of Reference Example 37 by the same method as in Step 3 of Example 100.

The compound of Reference Example 96 (4-((tert-butyldiphenylsilyl) oxy) -2-methylbutane-1-ol) was synthesized by the scheme shown in the figure below.

The compound of Example 543 was synthesized from the compound of Reference Example 96 by the same method as described in Example 85 and Reference Example 44.

The compound of Example 544 was synthesized from the compound of Example 534 by the scheme shown in the figure below.

The compound of Example 545 was synthesized in the same manner as in Example 543.

The compound of Example 546 was synthesized from the compound of Example 534 (isomer A) in the same manner as in Step 1 of Reference Example 37.

The compounds of Example 547 (isomer A and isomer B) were obtained by dividing the compounds of Example 540.

Compound of Reference Example 97 (6-(((2,2,2-trifluoroethyl) amino) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2 -Carboxylic acid) was synthesized from the compound of Reference Example 95 by the scheme shown in the figure below.

The compound of Example 548 was synthesized from the compound of Reference Example 95 in the same manner as in Step 6 of Example 85.

The compound of Reference Example 98 (6- (trifluoromethyl) -3,4-dihydro-2H-pyrano [3,2-b] pyridin-3-amine hydrochloride) was synthesized by the scheme shown in the figure below.

The compound of Example 549 was synthesized by the same method as described in Example 90 and Reference Example 98.

The compound of Example 550 was synthesized from the compound synthesized in Step 7 of Example 70 and the compound of Reference Example 98 in the same manner as in Step 8 of Example 70.

The compound of Example 551 was synthesized from the compound of Reference Example 93 (isomer A) in the same manner as in Step 6 of Example 85.

The compounds of Example 552 (isomer A and isomer B) were obtained by dividing the compounds of Example 532.

The compound of Example 553 was synthesized by the same method as described in Example 538 and Reference Example 43.

The compounds of Example 554 (isomer A and isomer B) were obtained by dividing the compounds of Example 553.

Compound of Reference Example 99 (6-((2,2,2-trifluoroethoxy) methyl) -5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine-2- Carboxylic acid) was synthesized according to the scheme shown in the figure below.

The compound of Example 555 was synthesized from the compound of Reference Example 99 by the same method as in Step 3 of Example 100.

The compound of Example 556 was synthesized from the compound of Reference Example 99 and the compound of Reference Example 43 in the same manner as in Step 3 of Example 100.

The compound of Example 557 was synthesized from the compound of Reference Example 99 and the compound of Reference Example 48 by the same method as in Step 3 of Example 100.

The compound of Example 558 was synthesized from the compound of Reference Example 33 and the compound of Reference Example 92 (isomer A) in the same manner as in Step 8 of Example 70.

The compound of Example 559 was synthesized from the compound of Reference Example 33 and the compound of Reference Example 92 (isomer B) in the same manner as in Step 8 of Example 70.

The compound of Example 560 was synthesized from the compound of Reference Example 50 and the compound of Reference Example 92 (isomer A) in the same manner as in Step 8 of Example 70.

The compound of Example 561 was synthesized from the compound of Reference Example 36 and the compound of Reference Example 92 (isomer A) in the same manner as in Steps 7 to 8 of Example 70.

The compound of Example 562 was obtained by dividing a compound synthesized by the same method as that described in Steps 3 to 5, Example 169 and Reference Example 24 of Reference Example 34.

The compounds of Example 563 (isomer A and isomer B) were obtained by dividing the compounds of Example 538.

The compound of Reference Example 100 (2-((tetrahydro-2H-pyran-4-yl) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid) is according to the scheme shown in the figure below. , Synthesized.

The compound of Example 564 was synthesized from the compound of Reference Example 100 and the compound of Reference Example 48 by the same method as in Step 8 of Example 70.

The compound of Example 565 was synthesized from the compound of Reference Example 100 and the compound of Reference Example 24 in the same manner as in Step 8 of Example 70.

The compound of Reference Example 101 ((R) -6-iodochroman-3-amine) was synthesized from the compound synthesized in Step 1 of Reference Example 1 by the scheme shown in the figure below.

The compound of Example 566 was synthesized from the compound of Reference Example 93 (isomer A) and the compound of Reference Example 101 in the same manner as in Step 8 of Example 70.

The compound of Example 567 was synthesized by the same method as described in Reference Example 34, Example 85 and Reference Example 48.

The compound of Example 568 was synthesized from the compound of Example 534 (isomer B) in the same manner as in Example 535.

The compound of Example 569 was synthesized from the compound synthesized in Step 3 of Example 187 and the compound of Reference Example 92 (isomer A) by the same method as described in Step 8 of Example 70 and Example 535. bottom.

The compound of Example 570 was synthesized from the compound of Reference Example 36 and the compound of Reference Example 92 (isomer A) by the same method as described in Steps 7 to 8 and Example 535 of Example 70.

The compound of Example 571 was synthesized from the compound of Reference Example 33 in the same manner as in Step 8 of Example 70.

The compounds of Example 572 (isomer A and isomer B) were obtained by dividing the compounds of Example 555.

The compound of Example 573 was synthesized in the same manner as in Example 70.

The compound of Example 574 was synthesized from the compound of Reference Example 36 and the compound of Reference Example 4 in the same manner as in Steps 5 to 6 of Example 85.

The compounds of Example 575 (isomer A and isomer B) were obtained by dividing the compounds of Example 559.

The compounds of Example 576 (isomer A and isomer B) were obtained by dividing the compounds of Example 560.

The compounds of Example 577 (isomer A and isomer B) were obtained by dividing the compounds of Example 565.

The compound of Reference Example 102 (2-((cyclopropylmethoxy) methyl) -2,3-dihydroimidazole [2,1-b] oxazole-6-carboxylic acid) was synthesized by the scheme shown in the figure below.

The compound of Example 578 was synthesized from the compound of Reference Example 102 and the compound of Reference Example 1 by the same method as in Step 8 of Example 70.

The compounds of Example 579 (isomer A and isomer B) are the same as those described in Step 8 and Example 114 of Example 70 from the compound of Reference Example 93 (isomer A) and the compound of Reference Example 92 (isomer A). , Synthesized in the same way.

The compound of Reference Example 103 (shown in the figure below) was synthesized from the compound synthesized in Step 1 of Example 259 in the same manner as in Reference Example 91.

The compound of Example 580 was synthesized from the compound of Reference Example 103 and the compound of Reference Example 92 (isomer A) in the same manner as in Step 3 of Example 100.

The compound of Example 581 was synthesized from the compound of Reference Example 90 and the compound of Reference Example 92 (isomer A) in the same manner as in Step 3 of Example 100.

The compound of Example 582 was synthesized from the compound synthesized in Step 8 of Example 252 by the scheme shown in the figure below.

The compound of Example 583 was synthesized by the same method as that described in Steps 3 to 5, Example 85 and Reference Example 43 of Reference Example 34.

The compound of Example 584 was synthesized by the same method as that described in Steps 3 to 5, Example 85 and Reference Example 1 of Reference Example 34.

The compound of Example 585 was synthesized by the same method as described in Step 3 to Step 5, Example 85 and Reference Example 24 of Reference Example 34.

The compound of Example 586 was synthesized by the same method as described in Steps 3 to 5, Example 85 and Reference Example 48 of Reference Example 34.

The compound of Example 587 was synthesized by using the compound of Reference Example 92 (isomer A) in the same manner as in the method described in Example 199.

The compound of Example 588 was synthesized from the compound of Reference Example 55 and the compound of Reference Example 92 (isomer A) in the same manner as in Step 8 of Example 70.

The compound of Example 589 was synthesized from the compound of Reference Example 55 and the compound of Reference Example 92 (isomer B) in the same manner as in Step 8 of Example 70.

The compounds of Example 590 (isomer A and isomer B) were obtained by dividing the compounds of Example 564.

The compound of Reference Example 104 (shown in the figure below) was synthesized from the compound synthesized in Step 7 of Example 245 by the same method as described in Step 7 of Examples 114 and 70.

The compound of Example 591 was synthesized from the compound of Reference Example 104 and the compound of Reference Example 92 (isomer A) in the same manner as in Step 8 of Example 70.

The compound of Example 592 was synthesized from the compound of Reference Example 104 and the compound of Reference Example 92 (isomer B) in the same manner as in Step 8 of Example 70.

The compound of Example 593 was synthesized from the compound of Reference Example 92 (isomer A) in the same manner as in Example 268.

The compound of Example 594 was synthesized from the compound of Reference Example 92 (isomer A) by the same method as described in Examples 268 and 261.

The compound of Example 595 was synthesized from the compound synthesized in Step 6 of Example 201 and the compound of Reference Example 92 (isomer A) in the same manner as in Step 8 of Example 70.

The compound of Example 596 was synthesized from the compound synthesized in Step 6 of Example 201 and the compound of Reference Example 92 (isomer B) in the same manner as in Step 8 of Example 70.

The compounds of Example 597 (isomer A and isomer B) were obtained by dividing the compounds of Example 569.

The compounds of Example 598 (isomer A and isomer B) were obtained by dividing the compounds of Example 570.

The compound of Example 599 was synthesized by the same method as that of Example 90 using the compound of Reference Example 92 (isomer B).

The compounds of Example 600 (isomer A and isomer B) were obtained by dividing the compounds of Example 588.

The compounds of Example 601 (isomer A and isomer B) were obtained by dividing the compounds of Example 557.

The compounds of Example 602 (isomer A and isomer B) were obtained by dividing a compound synthesized from the compound of Reference Example 99 and the compound of Reference Example 44 in the same manner as in Step 3 of Example 100.

The compounds of Example 603 (isomer A and isomer B) were obtained by dividing the compounds of Example 591.

The compound of Reference Example 105 was synthesized from the compound synthesized in Step 2 of Example 245 by the scheme shown in the figure below.

The compound of Reference Example 106 (shown in the figure below) was synthesized from the compound of Reference Example 105 by the same method as described in Steps 5 to 8 of Example 245.

The compound of Example 604 (isomer A and isomer B) is obtained by dividing a compound synthesized by the same method as that described in Step 8 of Example 70 using the compound of Reference Example 106 and the compound of Reference Example 24. I got it

The compound of Example 605 was synthesized from the compound of Reference Example 100 and the compound of Reference Example 44 by the same method as that described in Step 8 of Example 70.

The compound of Reference Example 107 (shown in the figure below) was synthesized by the same method as described in Steps 3 to 5 of Reference Example 34 and Steps 1 to 5 of Example 85.

The compound of Example 606 was synthesized from the compound of Reference Example 107 and the compound of Reference Example 44 by the same method as that described in Step 8 of Example 70.

The compound of Example 607 was synthesized by using the compound of Reference Example 106 and the compound of Reference Example 92 (isomer A) in the same manner as in Step 8 of Example 70.

The compounds of Example 608 (isomer A and isomer B) were obtained by dividing the compounds of Example 607.

The compound of Example 609 was synthesized by using the compound of Reference Example 106 and the compound of Reference Example 92 (isomer B) in the same manner as in Step 8 of Example 70.

The compounds of Example 610 (isomer A and isomer B) were obtained by dividing the compounds of Example 609.

The compound of Reference Example 108 (shown in the figure below) was synthesized in the same manner as the compound of Reference Example 107.

The compound of Example 611 was synthesized from the compound of Reference Example 108 and the compound of Reference Example 1 by the same method as that described in Step 8 of Example 70.

The compound of Example 612 was synthesized from the compound of Reference Example 108 and the compound of Reference Example 43 by the same method as that described in Step 8 of Example 70.

The compound of Example 613 was synthesized from the compound of Reference Example 108 and the compound of Reference Example 92 (isomer A) according to the scheme shown in the figure below.

The compound of Example 614 was synthesized from the compound of Reference Example 108 and the compound of Reference Example 92 (isomer B) in the same manner as in Example 613.

The compounds of Example 615 (isomer A and isomer B) were obtained by dividing the compounds of Example 606.

The compounds of Example 616 (isomer A and isomer B) were obtained by dividing the compounds of Example 592.

The compound of Reference Example 109 ((3S) -3-amino-4-fluorochroman-6-carbonitrile) was synthesized by the scheme shown in the figure below.

The compounds of Example 617 (isomer A, isomer B, isomer C and isomer D) were synthesized from the compounds of Reference Example 33 and the compounds of Reference Example 109 in the same manner as in Step 8 of Example 70. The compound was obtained by partitioning.

The compound of Reference Example 110 (6-bromo-2-((cyclopropylmethoxy) methyl) -2-methyl-2,3-dihydropyrazolo [5,1-b] oxazole) was synthesized by the scheme shown in the figure below. ..

The compound of Reference Example 111 (shown in the figure below) was synthesized from the compound of Reference Example 110 by the same method as described in Steps 8 to 10 of Reference Example 79.

The compound of Example 618 was synthesized from the compound of Reference Example 111 and the compound of Reference Example 24 by the same method as that described in Step 8 of Example 70.

The compound of Example 619 was synthesized from the compound of Reference Example 111 and the compound of Reference Example 48 by the same method as described in Step 8 of Example 70.

The compound of Reference Example 112 (shown in the figure below) was synthesized by the same method as described in Steps 3 to 5 of Reference Example 34 and Steps 1 to 5 of Example 85.

The compound of Example 620 was synthesized from the compound of Reference Example 112 (isomers A) and the compound of Reference Example 43 by the same method as described in Step 8 of Example 70.

The compound of Example 621 was synthesized from the compound of Example 588 in the same manner as in Example 535.

The compounds of Example 622 (isomer A and isomer B) were obtained by dividing the compounds of Example 605.

The compound of Reference Example 113 (shown in the figure below) was synthesized by the same method as that described in Reference Example 100.

The compound of Example 623 was synthesized from the compound of Reference Example 113 and the compound of Reference Example 24 by the same method as that described in Step 8 of Example 70.

The compound of Reference Example 114 (4-((tert-butyldiphenylsilyl) oxy) -1- (2,2-difluoroethoxy) butane-2-ol) was synthesized by the scheme shown in the figure below.

The compound of Reference Example 115 (shown in the figure below) was synthesized from the compound of Reference Example 114 by the same method as described in Steps 2 to 5 of Example 85.

The compound of Example 624 was synthesized from the compound of Reference Example 115 and the compound of Reference Example 92 (isomer B) by the same method as that described in Step 8 of Example 70 and Step 2 of Example 613.

The compound of Example 625 is obtained from the compound of Reference Example 70 and the compound of Reference Example 92 (isomer A) in the same manner as in the methods described in Steps 7 to 8 of Example 70 and Step 2 of Example 613. Synthesized.

The compound of Reference Example 116 (shown in the figure below) was synthesized in the same manner as in Reference Example 4.

The compound of Example 626 was synthesized from the compound synthesized in Step 5 of Example 169 and the compound of Reference Example 116 in the same manner as in Step 8 of Example 70.

The compound of Example 627 was synthesized from the compound of Reference Example 36 and the compound of Reference Example 116 by the same method as described in Steps 7 to 8 of Example 70.

The compound of Example 628 was synthesized from the compound of Reference Example 104 and the compound of Reference Example 116 by the same method as that described in Step 8 of Example 70.

The compound of Example 629 was synthesized from the compound of Reference Example 55 and the compound of Reference Example 116 in the same manner as in Step 8 of Example 70.

The compound of Example 630 was synthesized from the compound of Reference Example 108 and the compound of Reference Example 44 by the same method as that described in Step 8 of Example 70.

The compound of Example 631 was synthesized from the compound of Reference Example 112 (isomers A) and the compound of Reference Example 44 by the same method as described in Step 8 of Example 70.

The compound of Example 632 was synthesized from the compound of Reference Example 89 by the same method as described in Steps 2 to 6 and Reference Example 44 of Example 85.

The compound of Example 633 was synthesized from the compound of Reference Example 89 by the same method as described in Steps 2 to 6 and Reference Example 48 of Example 85.

The compound of Example 634 was synthesized from the compound of Reference Example 99 and the compound of Reference Example 92 (isomer A) by the same method as that described in Step 8 of Example 70 and Step 2 of Example 613.

The compound of Example 635 was synthesized from the compound of Reference Example 115 and the compound of Reference Example 44 by the same method as that described in Step 8 of Example 70.

The compounds of Example 636 (isomer A and isomer B) were obtained by dividing the compounds of Example 595.

The compound of Reference Example 117 (shown in the figure below) was synthesized by using the compound of Reference Example 92 (isomer A) in the same manner as in Steps 1 to 2 of Example 268.

The compound of Example 637 was synthesized from the compound of Reference Example 117 by the same method as that described in Step 1 of Example 261 and Step 2 of Example 613.

The compound of Example 638 was synthesized from the compound of Reference Example 112 (isomers B) and the compound of Reference Example 44 by the same method as described in Step 8 of Example 70.

The compound of Example 639 was synthesized from the compound synthesized in Step 6 of Example 201 and the compound of Reference Example 116 in the same manner as in Step 8 of Example 70.

The compound of Example 640 was synthesized from the compound of Reference Example 106 and the compound of Reference Example 116 by the same method as described in Step 8 of Example 70.

The compounds of Example 641 (isomer A and isomer B) were obtained by dividing the compounds of Example 587.

The compound of Example 642 was synthesized from the compound of Reference Example 117 by the same method as that described in Step 2 of Reference Example 69 and Example 613.

The compound of Example 643 was synthesized from the compound of Reference Example 117 in the same manner as in Reference Example 637.

The compound of Reference Example 118 (shown in the figure below) was synthesized by the same method as in Step 1 of Example 267.

The compound of Example 644 was synthesized from the compound of Reference Example 118 and the compound of Reference Example 43 by the same method as described in Steps 7 to 8 of Example 70.

The compound of Example 645 is synthesized from the compound of Reference Example 118 and the compound of Reference Example 92 (isomer B) by the same method as described in Steps 2 to 3 of Example 100 and Step 2 of Example 613. bottom.

The compound of Reference Example 119 (shown in the figure below) was synthesized by using the compound of Reference Example 92 (isomer B) in the same manner as in Steps 1 to 2 of Example 268.

The compound of Example 646 was synthesized from the compound of Reference Example 119 by the same method as that described in Step 2 of Reference Example 69 and Example 613.

The compound of Example 647 was synthesized from the compound of Reference Example 119 by the same method as that described in Step 1 of Example 261 and Step 2 of Example 613.

The compound of Example 648 was synthesized from the compound synthesized in Step 5 of Example 169 and the compound of Reference Example 109 in the same manner as in Step 8 of Example 70.

The compound of Example 649 was synthesized from the compound of Reference Example 89 by the same method as described in Steps 2 to 6 of Example 85 and Reference Example 109.

The compound of Example 650 was synthesized from the compound synthesized in Step 6 of Example 201 and the compound of Reference Example 109 in the same manner as in Step 8 of Example 70.

The compound of Reference Example 120 (shown in the figure below) was synthesized in the same manner as the compound of Reference Example 107.

The compound of Example 651 was synthesized from the compound of Reference Example 120 and the compound of Reference Example 44 in the same manner as in Step 8 of Example 70.

The compound of Example 652 was synthesized from the compound of Reference Example 117 in the same manner as in Reference Example 69.

The compound of Example 653 was synthesized by the same method as described in Example 268 and Reference Example 43.

The compound of Example 654 was synthesized from the compound of Example 652 by the same method as that described in Step 2 of Example 613.

The compound of Example 655 was synthesized by the same method as described in Reference Example 82, Example 159 and Reference Example 44.

The compound of Reference Example 121 (shown in the figure below) is the same method as that described in Steps 1 and 3 of Reference Example 1 and Step 2 of Example 613 from the compound synthesized in Step 3 of Reference Example 92. Synthesized with.

The compound of Example 656 was synthesized by the scheme shown in the figure below using the compound synthesized in step 8 of Example 252 and the compound of Reference Example 121.

The compound of Reference Example 122 (2-((2- (2,2,2-trifluoroethoxy) ethoxy) methyl) -2,3-dihydropyrazolo [5,1-b] oxazole-6-carboxylic acid) is , Was synthesized from the compound synthesized in step 1 of Example 187 by the scheme shown in the figure below.

The compound of Example 657 was synthesized from the compound of Reference Example 122 and the compound of Reference Example 43 in the same manner as in Step 3 of Example 100.

The compound of Example 658 was synthesized from the compound of Reference Example 122 and the compound of Reference Example 1 by the same method as in Step 3 of Example 100.

The compound of Example 659 was synthesized from the compound of Reference Example 122 and the compound of Reference Example 24 by the same method as in Step 3 of Example 100.

The compound of Example 660 was synthesized from the compound of Reference Example 122 and the compound of Reference Example 92 (isomer A) in the same manner as in Step 3 of Example 100.

The compound of Example 661 was synthesized from the compound of Reference Example 122 and the compound of Reference Example 44 in the same manner as in Step 3 of Example 100.

The compound of Reference Example 123 (shown in the figure below) was synthesized from the compound synthesized in Step 1 of Example 100 by the same method as that of Reference Example 122.

The compound of Example 662 was synthesized from the compound of Reference Example 123 and the compound of Reference Example 1 by the same method as in Step 8 of Example 70.

The compound of Example 663 was synthesized from the compound of Reference Example 123 and the compound of Reference Example 43 in the same manner as in Step 8 of Example 70.

The compound of Example 664 was synthesized from the compound of Reference Example 123 and the compound of Reference Example 24 in the same manner as in Step 8 of Example 70.

The compound of Example 665 was synthesized from the compound of Reference Example 123 and the compound of Reference Example 92 (isomer B) by the same method as that described in Step 8 of Example 70 and Step 2 of Example 613.

The compound of Example 666 was synthesized by the same method as described in Example 268 and Reference Example 43.

The compound of Example 667 was synthesized from the compound of Reference Example 118 and the compound of Reference Example 44 by the same method as described in Steps 7 to 8 of Example 70.

The compound of Example 668 was synthesized from the compound of Reference Example 120 and the compound of Reference Example 48 by the same method as in Step 8 of Example 70.

The compound of Example 669 was synthesized by the same method as described in Example 268 and Reference Example 43.

The compound of Example 670 was synthesized from the compound of Reference Example 119 by the same method as that described in Step 1 of Example 261 and Step 2 of Example 613.

The compound of Example 671 was synthesized from the compound of Reference Example 119 by the same method as that described in Step 2 of Reference Example 69 and Example 613.

The compound of Example 672 was synthesized from the compound of Reference Example 119 by the same method as that described in Step 2 of Reference Example 69 and Example 613.

The compound of Example 673 was synthesized from the compound of Reference Example 119 by the same method as that described in Step 2 of Reference Example 69 and Example 613.

The compound of Example 674 was synthesized by the same method as described in Reference Example 82, Example 159 and Reference Example 48.

The compound of Example 675 was synthesized from the compound of Reference Example 122 and the compound of Reference Example 92 (isomer B) in the same manner as in Step 3 of Example 100.

The compound of Example 676 was synthesized from the compound of Example 660 by the same method as that described in Step 2 of Example 613.

The compound of Example 677 was synthesized from the compound of Reference Example 117 in the same manner as in Reference Example 69.

The compound of Example 678 was synthesized from the compounds of Reference Example 117 and Example 119 by the same method as that described in Step 2 of Reference Example 69 and Example 613.

The compound of Example 679 is the same as the method described in Step 8 of Example 70 and Step 2 of Example 613 from the compound synthesized in Step 6 of Example 254 and the compound of Reference Example 92 (isomer B). Synthesized by the method.

The compound of Reference Example 124 (shown in the figure below) was synthesized from the compound synthesized in Step 8 of Example 252 in the same manner as in Reference Example 122.

The compound of Example 680 was synthesized from the compound of Reference Example 124 and the compound of Reference Example 43 in the same manner as in Step 8 of Example 70.

The compound of Example 681 was synthesized from the compound of Reference Example 124 and the compound of Reference Example 92 (isomer A) in the same manner as in Step 8 of Example 70.

The compound of Example 682 was synthesized from the compound of Reference Example 124 and the compound of Reference Example 1 by the same method as in Step 8 of Example 70.

The compound of Example 683 was synthesized from the compound of Reference Example 99 and the compound of Reference Example 92 (isomer A) by the same method as that described in Step 3 of Example 100 and Step 2 of Example 613.

The table below shows the chemical structural formulas and instrumental analysis data of the compounds synthesized in Examples 291 to 683.

Test Example 1: Evaluation of human Nav1.7 inhibitory activity A cell line in which human Nav1.7 and human Navβ1 subunit were stably expressed in HEK293A cells was used. Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, 600 μg / ml geneticin, and 2 μg / ml Blastsaidin S was used as a culture medium in a T175 flask in an environment of _{37 ° C and 5% CO 2.} Was cultured in. When the 60-80% confluence was reached, the cells were detached to prepare a cell suspension of ^{approximately 0.5-5.0x10 6 cells / mL.} The amount of current through human Nav1.7 was recorded at room temperature using a fully automatic patch clamp device QPatch16X (Sophion Biosciences, Inc.). The extracellular fluid is 145 mM NaCl, 4 mM KCl, 1 mM MgCl ₂ , 2 mM CaCl ₂ , 10 mM Glucose, 10 mM 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid (HEPES), pH 7. 4 was used. As the intracellular solution, 135 mM CsF, 1/5 mM glycol ether diamine tetraacetic acid (EGTA) / CsOH, 10 mM HEPES, 10 mM NaCl, and pH 7.3 were used. The test compound was dissolved in dimethyl sulfoxide (DMSO) and diluted with extracellular fluid so that the DMSO concentration at the time of measurement was 0.1%.

The current response was acquired at a sampling frequency of 25 kHz and noise was removed with a 3 kHz lowpass filter. The holding potential was -100 mV. Leakage current correction was performed by applying a -120 mV step pulse prior to the test pulse. The following test pulses were given to examine the inhibitory effect of the test compound. That is, after applying a depolarizing pulse of -10 mV for 50 ms, it was fixed at -120 mV for 500 ms. Approximately 30-40% of the channels were held at the inactivating potential for 15 seconds, then fixed again at -120 mV for 100 milliseconds, and finally a depolarized pulse of -10 mV was applied for 50 milliseconds. Test pulses were given before and after the addition of the test compound.
The inhibitory effect of the test compound was determined based on the amount of inward current generated by the second depolarization pulse, and the 50% inhibitory concentration (IC ₅₀ ) was calculated from the concentration response curve. The IC ₅₀ values of inhibitory action of the test compounds are shown in Table 89-98.
Compounds with IC ₅₀ values less than 1 [mu] M are indicated by the letter "A", compounds having an IC ₅₀ value of less than 10 [mu] M are indicated by the letter "B".
Unless otherwise specified, "Example" in the table refers to the compound intended for production in each Example. For example, the evaluation result of Example 1 is the purpose of production in Example 1. It means the evaluation result of the compound.

Test Example 2: Evaluation of human Nav1.5 inhibitory activity A cell line in which human Nav1.5 was stably expressed in HEK293 cells was used. DMEM supplemented with 15% fetal bovine serum, 500 μg / ml geneticillin, 100 units / ml penicillin, 100 μg / ml streptomycin, and 20 mM HEPES as a culture medium in a T175 flask in an environment of _{37 ° C and 5% CO 2.} Cultured in. Upon reaching 60-80% confluence, ^{a cell suspension of approximately 0.5-5.0x10 6} cells / mL was prepared. The amount of current through human Nav1.5 was recorded at room temperature using the fully automatic patch clamp device QPatch16X. As the extracellular fluid, 145 mM NaCl, 4 mM KCl, 1 mM MgCl ₂ , 2 mM CaCl ₂ , 10 mM Glucose, 10 mM HEPES, and pH 7.4 were used. As the intracellular solution, 135 mM CsF, 1/5 mM EGTA / CsOH, 10 mM HEPES, 10 mM NaCl, pH 7.3 was used. The test compound was dissolved in DMSO and diluted with extracellular fluid so that the DMSO concentration at the time of measurement was 0.1%.

The current response was acquired at a sampling frequency of 25 kHz and noise was removed with a 3 kHz lowpass filter. The holding potential was -80 mV. Leakage current correction was performed by applying a -100 mV step pulse prior to the test pulse. To investigate the inhibitory effect of the test compound on human Nav1.5, test pulses mimicking the action potentials of cardiomyocytes were given 20 times in a row. Test pulses were given before and after the addition of the test compound.

The inhibitory effect of the test compound was determined based on the amount of inward current generated by the 20th depolarization pulse, and the 50% inhibitory concentration (IC ₅₀ ) was calculated from the concentration response curve.
The IC ₅₀ values of inhibitory action of the test compounds are shown in Table 89-98.
Compounds with IC ₅₀ values less than 1 [mu] M are indicated by the letter "A", 1 compounds with an IC ₅₀ value of less than [mu] M or 3 [mu] M are indicated by the letter "B", 3 [mu] M or IC ₅₀ values Compounds with are indicated by the letter "C".

Test Example 3: Effect on acute pain
Six-week-old male ICR mice were used in the study. The test compound was orally administered at 1-10 mg / kg and the mice were acclimatized in a clear observation cage for 60 minutes. The mice were mildly restrained without anesthesia, and 20 μL of 80 μg / mL (0.8% ethanol-saline) capsaicin solution was injected subcutaneously into the right hind limb and footpad of the mouse. The mice were returned to the observation cage, and the reaction time was measured for 5 minutes immediately after that, showing the pain-related behavior (licking, shaking) occurring in the right hind limb.
The suppression rate of the test compound was determined by the following formula.
Inhibition rate of test compound (%) = 100 x [1- (reaction time of test compound administration group / reaction time of vehicle control group)]
The effects of the test compounds on acute pain are shown in Table 99 below. Compounds showing an inhibition rate of 30% or more are indicated by the letter "A", and compounds exhibiting an inhibition rate of 20% or more and less than 30% are indicated by the letter "B", and the inhibition rate is 10% or more and less than 20%. Is indicated by the letter "C".

Test Example 4: Effect on neuropathic pain
Five-week-old male ICR mice were used in the study. Under isoflurane anesthesia, an incision was made in the skin and muscles to expose the 6th lumbar vertebrae and the right transverse process was removed. The fifth spinal nerve was dissected from the surrounding tissue and cut, and then the incision site was sutured.
The 50% pain threshold of the footpad is determined by von Frey filament (0.008 g, 0.02 g, 0.04 g, 0.07 g, 0.16 g), referring to the method of Chaplan SR et al. (J Neurosci Methods 1994, 53: 55-63). It was measured using 0.4 g and 0.6 g). First, the scaffold was placed in a measuring case on the grid, acclimatized until the animal settled, and then 0.07 g of filament was pressed against the footpad for about 3 seconds. When escape behavior was observed, stimulation was given using a filament with a stimulus intensity one step lower, and conversely, when no escape behavior was observed, a filament with a stimulus intensity one step higher was used. By repeating this operation, the results for a total of 6 times were recorded starting from 2 times before and after the change in the presence or absence of escape behavior, and the 50% pain threshold was calculated by the following formula.
50% pain threshold (g) = (10 ^{[Xf + κδ]} / 10000)
Xf is the stimulus intensity value (log value) of the filament used last, κ is the value derived from the pattern of the presence or absence of escape behavior for 6 times, and δ is the stimulus intensity (log value) between the filaments used in the test. The average value of the difference (0.365 here).
Animals showing a 50% pain threshold of the affected limb and footpad of 0.16 g or more before the operation and 0.08 g or less after 1 week after the operation were used for evaluation of the test substance as allodynia-developing animals.
The compounds of the present invention, for example, isomer A of Example 70 and Example 103, isomer A of Example 134, isomer A of Example 161, 288 of Example, and 290 of Example 290 are each compound of 10 mg / kg or less. A single oral dose increased the pain threshold by 50%, demonstrating an anti-allodynic effect.

The heteroaromatic amide derivative represented by the general formula (I), the general formula (IE) or the general formula (I-E2) of the present invention or a salt thereof has a strong Nav1.7 inhibitory activity and has a strong Nav1.7 inhibitory activity. Since the Nav1.5 inhibitory activity is reduced, Nav1.7 is useful as an active ingredient of a therapeutic agent and / or a preventive agent for various related diseases, and there is little concern about side effects derived from Nav1.5. For example, the heteroaromatic amide derivative of the present invention or a salt thereof is useful as an analgesic for various painful diseases.

Claims (22)

General formula (I):

[In the equation, X ¹ −X ² is N−C or C−N,
Y ¹ , Y ² , Y ³ and Y ⁴ are independently single-bonded, −CH ₂ −, _{−CH 2} CH ₂ −, −CR ^4a R ^4b −, −CR ^4a H−, −CR ^4b H, respectively. −, −CH ₂ CR ^4a R ^4b −, −CH ₂ CR ^4a H−, −NR ^4c −, _{−NH−, −S−, −SO 2−} , or −O−,
Z ¹ is a single bond, −CR ^7a R ^7b −, ^{−O−, −S−, −NH−, −NR 7a} −, −NR ^7a CH ₂ −, −CH ₂ NR ^7a −, −CO−, or , −SO ₂₋ ,
Ring A is a 3- to 7-membered monocyclic aromatic ring or an 8- to 12-membered bicyclic aromatic ring.
R ^1a and R ^1b are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, C _1- C ₄ haloalkoxy group, C _3- C ₇ cycloalkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, or C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group.
R ² is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted C _1- C ₆ alkyl group, an optionally substituted C ₁ -C ₆ haloalkyl group, an optionally substituted C. _{A 2-} C ₆ alkenyl group, an optionally substituted C _2- C ₆ alkynyl group, or an optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring.
R ^3a , R ^3b and R ^3c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, and optionally substituted C _1- C ₆ alkyl. Group, _{optionally substituted C 1-} C ₆ haloalkyl group, _{optionally substituted C 1} -C ₆ alkoxy group, optionally substituted C ₁ -C ₆ haloalkoxy group, optionally substituted good C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₆ alkylcarbonyl group, optionally substituted which may C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted C ₁ -C ₆ alkylcarbonyloxy group, an optionally substituted C ₁ -C ₆ haloalkylcarbonyl group, optionally C ₁ substituted -C ₆ haloalkoxycarbonyl group, optionally substituted C ₁ -C ₆ haloalkylcarbonyloxy _{group, optionally substituted C 3} -C ₇ cycloalkyl group, optionally substituted heterocycloalkyl group, which may be substituted C ₃ -C ₇ cycloalkyl group, an optionally substituted heterocycloalkyl group, optionally substituted C ₂ -C ₆ alkenyl group, an optionally substituted C ₂ -C ₆ Alkoxy Oxy Group, May Be Substituted C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, _{May Be Substituted C 2} -C ₆ Alkoxy Oxy-C ₁ -C ₄ Halo Alkoxy Group , May be substituted C ₂ -C ₆ alkylyl group, optionally substituted C ₂ -C ₆ alkylyloxy group, optionally substituted C ₂ -C ₆ alkylyloxy -C ₁ -C ₄ alkyl Group, _{optionally substituted C 2-} C ₆ alkynyloxy-C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₄ alkoxy-C ₁ -C ₄ alkoxy group, optionally substituted Good C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ Alkoxy groups, optionally substituted C _2- C ₆ alkenyloxy -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkenyloxy -C _1- C ₄ haloalkoxy group, optionally substituted C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ haloalkoxy group, optionally substituted C ₁ -C ₆ alkylthio group, optionally substituted Good C ₁ -C ₆ haloalkylthio groups, optionally substituted C ₁ -C ₄ alkylthio-C ₁ -C ₄ alkyl groups, _{optionally substituted C 1} -C ₄ haloalkylthio-C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl group, an optionally substituted C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl groups, substituted May be C _{1 -C 6} alkylsulfonyl group,-(CH ₂ ) _p NR ^a1 R ^a2 (R ^a1 and R ^a2 are independent hydrogen atoms, C ₁ -C ₄ alkyl groups, or C _1- It is a C ₄ haloalkyl group, where p is 0, 1, or 2. ) Or general formula (IA)

{In the formula,
Ring B is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring.
L ¹ represents a single ^{bond, -CR a3 R a4 -, -} O -, - NR a1 -, - CR a3 R a4 O -, - OCR a3 R a4 -, - CH 2 CH 2 -, - CH = CH- , -C ≡ C-, or -CH ₂ OCH _2- (R ^a3 and R ^a4 are independent hydrogen atoms, C _{1 -C 4} alkyl groups, or C ₁ -C ₄ haloalkyl groups, respectively. ),
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₃ -C ₇ cycloalkyloxy group, heterocycloalkyl group, heterocycloalkyloxy group, C _2- C ₆ alkoxy group, or C _2- It is a C ₆ alkylyl group. } Is a group represented by
R ^4a , R ^4b , and R ^4c are independent halogen atoms, cyano groups, cyanomethyl groups, formyl groups, nitro groups, carboxamide groups, hydroxyl groups, and optionally substituted C _1- C ₆ alkyl groups. , May be substituted C ₁ -C ₆ haloalkyl group, _{may be substituted C 1} -C ₆ alkoxy group, may be substituted C ₁ -C ₆ haloalkoxy group, may be substituted C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkoxy - C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₄ haloalkoxy-C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₆ alkylcarbonyl group, optionally substituted good C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted C ₁ -C ₆ alkylcarbonyloxy group, an optionally substituted C ₁ -C ₆ haloalkylcarbonyl group, optionally substituted C ₁ - C ₆ haloalkoxycarbonyl group, optionally substituted C _1- C ₆ haloalkylcarbonyloxy _{group, optionally substituted C 3-} C ₇ cycloalkyl group, optionally substituted heterocycloalkyl group, substituted which may be C ₃ -C ₇ cycloalkyl group, an optionally substituted heterocycloalkyl group, optionally substituted C ₂ -C ₆ alkenyl group, optionally substituted C ₂ - C ₆ Alkoxyoxy groups, optionally substituted C ₂ -C ₆ Alkoxyoxy-C ₁ -C ₄ alkyl groups, optionally substituted C ₂ -C ₆ Alkoxyoxy-C ₁ -C ₄ haloalkyl groups, C _2- C ₆ Alkoxyyl Group May Be Substituted, C ₂ -C ₆ Alkinyl Oxy Group May Be Substituted, C ₂ -C ₆ Alkinyl Oxy-C ₁ -C ₄ Alkoxy Group May Be Substitutable , May be substituted C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ haloalkyl group, may be substituted C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkoxy group, may be substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ Alkoxy groups, optionally substituted C ₂ -C ₆ Alkenyloxy -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkenyloxy -C ₁ - C ₄ haloalkoxy group, optionally substituted C _2- C ₆ alkynyloxy-C ₁ -C ₄ haloalkoxy group, optionally substituted C ₁ -C ₆ alkylthio group, optionally substituted C _1- C ₆ haloalkylthio groups, optionally substituted C ₁ -C ₄ alkylthio-C ₁ -C ₄ alkyl groups, _{optionally substituted C 1} -C ₄ haloalkylthio-C ₁ -C ₄ alkyl groups , optionally substituted C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl group, an optionally substituted C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group, pentafluorosulfanyl group, - (CH ₂ ) _q NR ^b1 R ^b2 (R ^b1 and R ^b2 are independently hydrogen atoms, C _1- C ₄ alkyl groups, or C ₁ -C ₄ haloalkyl groups, where q is 0, 1 , 2, or 3. ) Or general formula (IB)

{In the formula,
Ring C is a saturated, partially saturated, or unsaturated 3- to 7-membered monocyclic ring, or a saturated, partially saturated, or unsaturated 7 to 12-membered bicyclic ring.
L ² is a single bond, -CH = CH-, -C ≡ C ^{-,-(CR 10a R 10b} ) _r1 (CR ^10c R ^10d ) _r2 (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- , -(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 O (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CONR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 S (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO ₂ (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO ₂ NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- or
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c SO ₂ (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4-
(R ^c is a hydrogen atom, a C _1- C ₄ alkyl group, or a C ₁ -C ₄ haloalkyl group.
R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^10f , R ^10g , R ^10h are independently hydrogen atom, halogen atom, C _1- C ₄ alkyl group, or C ₃ -C. ₇ cycloalkyl group,
R ^10a and R ^10b may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
R ^10c and R ^10d may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
R ^10e and R ^10f may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
R ^10g and R ^10h may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
r1, r2, r3 and r4 are independently 0, 1 or 2 respectively. ),
R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, formyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ Alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy- C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyl group, C _3- C ₇ cycloalkyl group, heterocycloalkyl group, C _3- C ₇ cycloalkyloxy group, heterocycloalkyloxy group, C ₂ -C ₆ alkoxy group,-(CH ₂ ) _s NR ^d1 R ^d2 (R ^d1 and R ^d2 are independent hydrogen atoms, C, respectively. _{It is a 1-} C ₄ alkyl group or a C _1- C ₄ haloalkyl group, and s is 0, 1, or 2), or the general formula (IC).

{In the formula,
Ring D may be substituted with a halogen atom, a hydroxyl group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, or a C _1- C _{4 haloalkoxy group.} , A 3- to 7-membered monocyclic ring,
L ³ is a single bond or an oxygen atom. }. Is a group represented by} or
R ^4a and R ^4b may combine with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring, or
R ^4a and R ^4b together have the general formula (ID):

(R ^4d and R ^4e are independent hydrogen atoms, halogen atoms, or C _1- C ₄ alkyl groups, or R ^4d and R ^4e are carbon atoms to which they are bonded. Together with, a 3- to 7-membered monocyclic ring may be formed.),
R ^5a , R ^5b , R ^5c , R ^6a , R ^6b , and n satisfy any one of the following configurations (i) to (v) {(i) R ^5b and R ^5c Together, single bond, −CH ₂ −, −OCH ₂ −, −CH ₂ O−, −CH ₂ S−, −SCH ₂ −, −CH ₂ NR ^e1 −, −NR ^e1 CH ₂ −, − _{CH 2 CH 2 -, - NR} e1 CO -, - CR e1 R e2 O-, or, -OCR ^e1 R ^e2 - to form (R ^e1 and R ^e2 is a hydrogen atom, or, C ₁ -C ₄ alkyl It is the basis.) And
R ^5a is a hydrogen atom, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, C ₃ -C ₇ cycloalkyl-C ₁ -C ₄ Alkyl group, heterocycloalkyl-C _1- C ₄ alkyl group, or aralkyl group, and
R ^6a and R ^6b are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, or C. _{It is a 1-} C ₄ haloalkoxy group and
n is 1 or 2.
(ii) R ^5a and R ^6a _{together, -CH 2 -, - CH 2} CH 2 -, - CH 2 CR e1 R e2 -, - CR e1 R e2 CH 2 -, - CH 2 CH 2 CH ₂ −, −CH ₂ CH ₂ O−, −CH ₂ CH ₂ CH ₂ O− are formed (R ^e1 and R ^e2 are synonymous with the definitions shown in (i) above), and
R ^5b is a hydrogen atom, a C _1- C ₄ alkyl group, or a C ₁ -C ₄ haloalkyl group.
^Are R 5c and R ^6b hydrogen atom, halogen atom, hydroxyl group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, C ₁ -C ₄ haloalkoxy group? ,
Alternatively, R ^5c and R ^6b together,-(CH ₂ ) _t- , -O (CH ₂ ) _t -,-(CH ₂ ) _t O-,-(CH ₂ ) _t O (CH ₂₎ ) _U -,-(CH ₂ ) _t NR ^e3 (CH ₂ ) _u -,-(CH ₂ ) _t CONR ^e3 (CH ₂ ) _u- or-(CH ₂ ) _t NR ^e3 CO (CH ₂ ) _u- (T and u are 0, 1, 2, or 3, respectively, and R ^e3 is a hydrogen atom or C _1- C ₄ alkyl group), and
n is 1.
(iii) R ^5a is a hydrogen atom, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, C ₃ -C ₇ cycloalkyl-C ₁ -C ₄ alkyl group, heterocycloalkyl -C ₁ -C ₄ alkyl group, or aralkyl group and
R ^5b is a hydrogen atom or a C _1- C ₄ alkyl group,
R ^5c is a hydrogen atom, a C _1- C ₄ alkyl group, or a halogen atom.
Whether R ^6a and R ^6b are independently hydrogen atoms, halogen atoms, C _1- C ₆ alkyl groups, C ₃ -C ₇ cycloalkyl groups, or C _1- C ₆ haloalkyl groups, respectively.
Alternatively, R ^6a and R ^6b together with the carbon atoms to which they bond form a 3- to 7-membered monocyclic ring, and
n is 1 or 2.
(iv) R ^5a and R ^5b together form −CH ₂ CH ₂ −, −CH ₂ CH ₂ CH ₂ −, or −CH ₂ CH ₂ CH ₂ CH ₂ −, and
R ^5c , R ^6a and R ^6b are independent hydrogen atoms or halogen atoms, respectively, and
n is 1 or 2.
(v) R ^6a and R ^5c _{together, -OCH 2 -, - CH 2} O-, -CH 2 S -, - SCH 2 -, - CH 2 NH -, - NHCH 2 -, or - CH ₂ CH ₂ − is formed and
R ^5a and R ^5b are hydrogen atoms and
R ^6b is a hydrogen atom or a halogen atom, and
n is 1. },
R ^7a and R ^7b are independently hydrogen atoms, halogen atoms, or C _1- C ₄ alkyl groups (where X ^1- X ² is N-C and Y ¹ , Y ² , Y ³ and Y ⁴ together form −CH ₂ CR ^4a HCH ₂ CH ₂ −, where R ² is a hydrogen atom and R ^4a is a group represented by the general formula (IB). And when L ² is a single bond, ring C is not a phenyl ring.) ] Represented by a heteroaromatic amide derivative or a salt thereof. In the general formula (I),
Y ¹ , Y ² , Y ³ and Y ⁴ together,
−OCH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ −, −OCR ^4a R ^4b CH ₂ CH ₂ −,
−OCH ₂ CH ₂ −, −OCR ^4a HCH ₂ −, −OCR ^4a R ^4b CH ₂ −,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCR ^4a R ^4b CH ₂ CH ₂ CH ₂ −,
−OCH ₂ CR ^4a HCH ₂ CH ₂ −, −OCH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −, −CH ₂ CH ₂ OCH ₂ −, −CH ₂ CR ^4a HOCH ₂ −
−CH ₂ CH ₂ CH ₂ CH ₂ −, −CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
−CH ₂ CH ₂ CR ^4a HCH ₂ −, −CH ₂ CH ₂ CR ^4a R ^4b CH ₂ −,
−CH ₂ SCH ₂ CH ₂ −, −CH ₂ SO ₂ CH ₂ CH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −, −NHCR ^4a HCH ₂ CH ₂ −,
−CH ₂ NR ^4c CH ₂ CH ₂ −, −CH ₂ NR ^4c CR ^4a HCH ₂ −, −CH ₂ NHCR ^4a HCH ₂ −,
−CH ₂ CH ₂ NR ^4c CH ₂ −, −CH ₂ CR ^4a HNR ^4c CH ₂ −, or −CH ₂ CR ^4a HNHCH ₂ − (R ^4a , R ^4b , R ^4c are claimed in claim 1). Synonymous with the definition given.),
R ² is a hydrogen atom, halogen atom, hydroxyl group, cyano group, or a saturated, partially saturated, or unsaturated 3- to 7-membered monocyclic ring that may be substituted (where X ¹ −X ^2). There is a C-N, ^{and, Y 1, Y 2, Y} 3 and Y ⁴ is, they _{together, -OCH 2 CH 2 CH 2 -} , - OCR 4a HCH 2 CH 2 -, or, _{^{-OCR 4a R 4b CH 2 CH 2}} -. when forming a, R ² is a hydrogen atom), a medicament according to claim 1 comprising a heteroaromatic amide derivative or a salt thereof. In the general formula (I), X ¹ − X ² is C − N, and
Y ¹ , Y ² , Y ³ and Y ⁴ together,
−OCH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ −, −OCR ^4a R ^4b CH ₂ CH ₂ −, −OCH ₂ CH ₂ −,
_{^{-OCR 4a HCH 2 -, - OCR}} 4a R 4b CH 2 -,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCH ₂ CR ^4a HCH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −,
−CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −, −CH ₂ CH ₂ CR ^4a HCH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −, −NHCR ^4a HCH ₂ CH ₂ − or −CH ₂ NR ^4c CH ₂ CH ₂ − (R ^4a , R ^4b) , R ^4c is synonymous with the definition given in claim 1.),
A ^{heteroaromatic amide derivative or a heteroaromatic amide derivative in which R 5a} , R ^5b , R ^5c , R ^6a , R ^6b , and n satisfy any one of the configurations shown in (i) to (iii) in claim 1. The medicament according to claim 1 or 2, which comprises the salt. General formula (I):

[In the equation, X ¹ −X ² is N−C or C−N,
Y ¹ , Y ² , Y ³ and Y ⁴ are independently single-bonded, −CH ₂ −, _{−CH 2} CH ₂ −, −CR ^4a R ^4b −, −CR ^4a H−, −CR ^4b H, respectively. −, −CH ₂ CR ^4a R ^4b −, −CH ₂ CR ^4a H−, −NR ^4c −, _{−NH−, −S−, −SO 2−} , or −O−,
Z ¹ is a single bond, −CR ^7a R ^7b −, ^{−O−, −S−, −NH−, −NR 7a} −, −NR ^7a CH ₂ −, −CH ₂ NR ^7a −, −CO−, or , −SO ₂₋ ,
Ring A is a 3- to 7-membered monocyclic aromatic ring or an 8- to 12-membered bicyclic aromatic ring.
R ^1a and R ^1b are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, C _1- C ₄ haloalkoxy group, C _3- C ₇ cycloalkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, or C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group.
R ² is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted C _1- C ₆ alkyl group, an optionally substituted C ₁ -C ₆ haloalkyl group, an optionally substituted C. _{A 2-} C ₆ alkenyl group, an optionally substituted C _2- C ₆ alkynyl group, or an optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring.
R ^3a , R ^3b and R ^3c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, and optionally substituted C _1- C ₆ alkyl. Group, _{optionally substituted C 1-} C ₆ haloalkyl group, _{optionally substituted C 1} -C ₆ alkoxy group, optionally substituted C ₁ -C ₆ haloalkoxy group, optionally substituted good C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₆ alkylcarbonyl group, optionally substituted which may C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted C ₁ -C ₆ alkylcarbonyloxy group, an optionally substituted C ₁ -C ₆ haloalkylcarbonyl group, optionally C ₁ substituted -C ₆ haloalkoxycarbonyl group, optionally substituted C ₁ -C ₆ haloalkylcarbonyloxy _{group, optionally substituted C 3} -C ₇ cycloalkyl group, optionally substituted heterocycloalkyl group, which may be substituted C ₃ -C ₇ cycloalkyl group, an optionally substituted heterocycloalkyl group, optionally substituted C ₂ -C ₆ alkenyl group, an optionally substituted C ₂ -C ₆ Alkoxy Oxy Group, May Be Substituted C ₂ -C ₆ Alkoxy Oxy-C ₁ -C ₄ Alkoxy Group, _{May Be Substituted C 2} -C ₆ Alkoxy Oxy-C ₁ -C ₄ Halo Alkoxy Group , May be substituted C ₂ -C ₆ alkylyl group, optionally substituted C ₂ -C ₆ alkylyloxy group, optionally substituted C ₂ -C ₆ alkylyloxy -C ₁ -C ₄ alkyl Group, _{optionally substituted C 2-} C ₆ alkynyloxy-C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₄ alkoxy-C ₁ -C ₄ alkoxy group, optionally substituted Good C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ Alkoxy groups, optionally substituted C _2- C ₆ alkenyloxy -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkenyloxy -C _1- C ₄ haloalkoxy group, optionally substituted C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ haloalkoxy group, optionally substituted C ₁ -C ₆ alkylthio group, optionally substituted Good C ₁ -C ₆ haloalkylthio groups, optionally substituted C ₁ -C ₄ alkylthio-C ₁ -C ₄ alkyl groups, _{optionally substituted C 1} -C ₄ haloalkylthio-C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl group, an optionally substituted C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl groups, substituted May be C _{1 -C 6} alkylsulfonyl group,-(CH ₂ ) _p NR ^a1 R ^a2 (R ^a1 and R ^a2 are independent hydrogen atoms, C ₁ -C ₄ alkyl groups, or C _1- It is a C ₄ haloalkyl group, where p is 0, 1, or 2. ) Or general formula (IA)

{In the formula,
Ring B is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring.
L ¹ represents a single ^{bond, -CR a3 R a4 -, -} O -, - NR a1 -, - CR a3 R a4 O -, - OCR a3 R a4 -, - CH 2 CH 2 -, - CH = CH- , -C ≡ C-, or -CH ₂ OCH _2- (R ^a3 and R ^a4 are independent hydrogen atoms, C _{1 -C 4} alkyl groups, or C ₁ -C ₄ haloalkyl groups, respectively. ),
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₃ -C ₇ cycloalkyloxy group, heterocycloalkyl group, heterocycloalkyloxy group, C _2- C ₆ alkoxy group, or C _2- It is a C ₆ alkylyl group. } Is a group represented by
R ^4a , R ^4b and R ^4c are independently halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxylxamide group, hydroxyl group, optionally substituted C _1- C ₆ alkyl group, substituted. is optionally C ₁ -C ₆ haloalkyl group, an optionally substituted C ₁ -C ₆ alkoxy group, optionally substituted C ₁ -C ₆ haloalkoxy group, an optionally C ₁ substituted -C ₄ alkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₆ alkylcarbonyl group, optionally substituted C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted C ₁ -C ₆ alkylcarbonyloxy group, an optionally substituted C ₁ -C ₆ haloalkylcarbonyl group, an optionally substituted C ₁ -C _{6 Alkoxycarbonyl group optionally substituted, C 1-} C ₆ haloalkylcarbonyloxy _{group optionally substituted, C 3-} C ₇ cycloalkyl group optionally substituted, heterocycloalkyl group optionally substituted, substituted May be C _{3 -C 7} cycloalkyloxy groups, optionally substituted heterocycloalkyloxy groups, optionally substituted C ₂ -C ₆ alkoxy groups, optionally substituted C ₂ -C ₆ Alkoxyoxy groups, optionally substituted C ₂ -C ₆ alkoxyoxy-C ₁ -C ₄ alkyl groups, optionally substituted C ₂ -C ₆ alkoxyoxy -C ₁ -C ₄ haloalkyl groups, substituted May be C ₂ -C ₆ Alkoxy Group, May Be Substituted C ₂ -C ₆ Alkoxy Group, May Be Substituted C ₂ -C ₆ Alkinyl Oxy-C ₁ -C ₄ Alkoxy Group, Substituted May be C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ haloalkyl group, may be substituted C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy group, may be substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ Alkoxy groups, optionally substituted C ₂ -C _{6 Alkoxy} Niruokishi -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ haloalkoxy groups, optionally substituted C _2- C ₆ alkynyloxy-C ₁ -C ₄ haloalkoxy groups, optionally substituted C ₁ -C ₆ alkylthio groups, optionally substituted C ₁ -C ₆ haloalkylthio group, optionally substituted C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, _{optionally substituted C 1} -C ₄ haloalkylthio -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl group, an optionally substituted C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group, pentafluorosulfanyl group, - ( CH ₂ ) _q NR ^b1 R ^b2 (R ^b1 and R ^b2 are independently hydrogen atoms, C _1- C ₄ alkyl groups, or C ₁ -C ₄ haloalkyl groups, where q is 0, 1, 2 or 3. ) Or general formula (IB)

{In the formula,
Ring C is a saturated, partially saturated, or unsaturated 3- to 7-membered monocyclic ring, or a saturated, partially saturated, or unsaturated 7 to 12-membered bicyclic ring.
L ² is a single bond, -CH = CH-, -C ≡ C ^{-,-(CR 10a R 10b} ) _r1 (CR ^10c R ^10d ) _r2 (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- , -(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 O (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CONR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 S (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO ₂ (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO ₂ NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- or
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c SO ₂ (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4-
(R ^c is a hydrogen atom, a C _1- C ₄ alkyl group, or a C ₁ -C ₄ haloalkyl group.
R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^10f , R ^10g , R ^10h are independently hydrogen atom, halogen atom, C _1- C ₄ alkyl group, or C ₃ -C. ₇ cycloalkyl group,
R ^10a and R ^10b may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
R ^10c and R ^10d may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
R ^10e and R ^10f may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
R ^10g and R ^10h may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
r1, r2, r3 and r4 are independently 0, 1 or 2 respectively. ),
R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, formyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ Alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy- C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyl group, C _3- C ₇ cycloalkyl group, heterocycloalkyl group, C _3- C ₇ cycloalkyloxy group, heterocycloalkyloxy group, C ₂ -C ₆ alkoxy group,-(CH ₂ ) _s NR ^d1 R ^d2 (R ^d1 and R ^d2 are independent hydrogen atoms, C, respectively. _{It is a 1-} C ₄ alkyl group or a C _1- C ₄ haloalkyl group, and s is 0, 1, or 2), or the general formula (IC).

{In the formula,
Ring D may be substituted with a halogen atom, a hydroxyl group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, or a C _1- C _{4 haloalkoxy group.} , A 3- to 7-membered monocyclic ring,
L ³ is a single bond or an oxygen atom. }. Is a group represented by} or
R ^4a and R ^4b may combine with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring, or
R ^4a and R ^4b together have the general formula (ID):

(R ^4d and R ^4e are independent hydrogen atoms, halogen atoms, or C _1- C ₄ alkyl groups, or R ^4d and R ^4e are carbon atoms to which they are bonded. Together with, a 3- to 7-membered monocyclic ring may be formed.) (However, if R ² is a hydrogen atom, at least ^{Y 1} , Y ² , Y ³ , or Y ⁴ one ^{is, -CR 4a R 4b -, -} CR 4a H -, - CH 2 CR 4a R 4b -, or a -CH ₂ CR ^4a H-),.
R ^5a , R ^5b , R ^5c , R ^6a , R ^6b , and n satisfy either of the following configurations (i) or (ii) {(i) R ^5b and R ^5c together. , Single bond, −CH ₂ −, −OCH ₂ −, −CH ₂ O−, −CH ₂ S−, −SCH ₂ −, −CH ₂ NR ^e1 −, −NR ^e1 CH ₂ −, −CH ₂ CH ₂ ^{-, - NR e1 CO -,} - CR e1 R e2 O-, or -OCR ^e1 R ^e2 - to form (R ^e1 and R ^e2 is a hydrogen atom, or a C ₁ -C ₄ alkyl group. ),And,
R ^5a is a hydrogen atom, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, C ₃ -C ₇ cycloalkyl-C ₁ -C ₄ Alkyl group, heterocycloalkyl-C _1- C ₄ alkyl group, or aralkyl group, and
R ^6a and R ^6b are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, or C. _{It is a 1-} C ₄ haloalkoxy group and
n is 1 or 2.
(ii) R ^5a and R ^6a _{together, -CH 2 -, - CH 2} CH 2 -, - CH 2 CR e1 R e2 -, - CR e1 R e2 CH 2 -, - CH 2 CH 2 CH ₂ −, −CH ₂ CH ₂ O−, −CH ₂ CH ₂ CH ₂ O− are formed (R ^e1 and R ^e2 are synonymous with the definitions shown in (i) above), and
R ^5b is a hydrogen atom, a C _1- C ₄ alkyl group, or a C ₁ -C ₄ haloalkyl group.
^Are R 5c and R ^6b hydrogen atom, halogen atom, hydroxyl group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, C ₁ -C ₄ haloalkoxy group? ,
Alternatively, R ^5c and R ^6b together,-(CH ₂ ) _t- , -O (CH ₂ ) _t -,-(CH ₂ ) _t O-,-(CH ₂ ) _t O (CH ₂₎ ) _U -,-(CH ₂ ) _t NR ^e3 (CH ₂ ) _u -,-(CH ₂ ) _t CONR ^e3 (CH ₂ ) _u- or-(CH ₂ ) _t NR ^e3 CO (CH ₂ ) _u- (T and u are 0, 1, 2, or 3, respectively, and R ^e3 is a hydrogen atom or C _1- C ₄ alkyl group), and
n is 1. }
(However, if R ^5a , R ^5b , R ^5c , R ^6a , R ^6b , and n satisfy the configuration of (ii) above, then Y ¹ , Y ² , Y ³ and Y ⁴ are combined. −CH ₂ NR ^4a HCH ₂ CH ₂ − is not formed.),
R ^7a and R ^7b are independently hydrogen atoms, halogen atoms, or C _1- C ₄ alkyl groups. ]
A drug comprising a heteroaromatic amide derivative represented by or a salt thereof. In the general formula (I),
Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a R 4b CH 2 CH 2 -,
−OCH ₂ CH ₂ −, −OCR ^4a HCH ₂ −, −OCR ^4a R ^4b CH ₂ −,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCR ^4a R ^4b CH ₂ CH ₂ CH ₂ −,
−OCH ₂ CR ^4a HCH ₂ CH ₂ −, −OCH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −, −CH ₂ CH ₂ OCH ₂ −, −CH ₂ CR ^4a HOCH ₂ −
−CH ₂ CH ₂ CH ₂ CH ₂ −, −CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
−CH ₂ CH ₂ CR ^4a HCH ₂ −, −CH ₂ CH ₂ CR ^4a R ^4b CH ₂ −,
−CH ₂ SCH ₂ CH ₂ −, −CH ₂ SO ₂ CH ₂ CH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −,
−NHCR ^4a HCH ₂ CH ₂ −,
−CH ₂ NR ^4c CH ₂ CH ₂ −, −CH ₂ NR ^4c CR ^4a HCH ₂ −, −CH ₂ NHCR ^4a HCH ₂ −,
−CH ₂ CH ₂ NR ^4c CH ₂ −, −CH ₂ CR ^4a HNR ^4c CH ₂ −, or −CH ₂ CR ^4a HNHCH ₂ − (R ^4a , R ^4b and R ^4c are claimed in claim 4). Synonymous with the definition given.),
R ² is a hydrogen atom, halogen atom, hydroxyl group, cyano group, or a saturated, partially saturated, or unsaturated 3- to 7-membered monocyclic ring that may be substituted (where X ¹ −X ^2). There is a C-N, ^{and, Y 1, Y 2, Y} 3 and Y ⁴ is, they _{^{together, -OCR 4a HCH 2 CH 2 -}} , - OCR 4a R 4b CH 2 CH 2 - and When forming, R ² is a hydrogen atom.),
The medicament according to claim 4, which comprises a heteroaromatic amide derivative or a salt thereof (where X ^1- X ² is NC, and Y ¹ , Y ² , Y ³ and Y ⁴ are combined, When −CH ₂ CR ^4a HCH ₂ CH ₂ − is formed, R ² is a hydrogen atom, R ^4a is a group represented by the general formula (IB), and L ² is a single bond, ring C Is not a phenyl ring.) In the general formula (I), X ¹ − X ² is C − N, and
Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a R 4b CH 2 CH 2 -, - OCH 2 CH 2 -,
_{^{-OCR 4a HCH 2 -, - OCR}} 4a R 4b CH 2 -,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCH ₂ CR ^4a HCH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −,
−CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −, −CH ₂ CH ₂ CR ^4a HCH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −, −NHCR ^4a HCH ₂ CH ₂ − or −CH ₂ NR ^4c CH ₂ CH ₂ − (R ^4a , R ^4b) And R ^4c are synonymous with the definitions given in claim 4),.
Claim 4 or claim 5 comprising a heteroaromatic amide derivative or a salt thereof, wherein R ^{5a , R 5b} , R ^5c , R ^6a , R ^{6b, and n satisfy the constitution (i) in claim 4.} The medicine described in. General formula (I-E2):

[In the equation, X ¹ −X ² is N−C or C−N,
Y ¹ , Y ² , Y ³ and Y ⁴ are independently single-bonded, −CH ₂ −, _{−CH 2} CH ₂ −, −CR ^4a R ^4b −, −CR ^4a H−, −CR ^4b H, respectively. −, −CH ₂ CR ^4a R ^4b −, −CH ₂ CR ^4a H−, −NR ^4c −, _{−NH−, −S−, −SO 2−} , or −O−,
Z ² −Z ³ is −CH ₂ −, −OCH ₂ −, −CH ₂ O−, −SCH ₂ −, −CH ₂ S−, −CH ₂ NR ^f1 −, −NR ^f1 CH ₂ −, −CH ₂ CH ₂ −, −CONR ^f1 −, −NR ^f1 CO −, −OCR ^f1 R ^f2 −, or −CR ^f1 R ^f2 O − (R ^f1 and R ^f2 are hydrogen atoms, C ₁ -C ₄ Alkyl group or C _1- C ₄ haloalkyl group),
R ^1a and R ^1b are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, C _1- C ₄ haloalkoxy group, C _3- C ₇ cycloalkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, or C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group.
R ² is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted C _1- C ₆ alkyl group, an optionally substituted C ₁ -C ₆ haloalkyl group, an optionally substituted C. _{A 2-} C ₆ alkenyl group, an optionally substituted C _2- C ₆ alkynyl group, or an optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring.
R ^4a , R ^4b and R ^4c are independently halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxylxamide group, hydroxyl group, optionally substituted C _1- C ₆ alkyl group, substituted. is optionally C ₁ -C ₆ haloalkyl group, an optionally substituted C ₁ -C ₆ alkoxy group, optionally substituted C ₁ -C ₆ haloalkoxy group, an optionally C ₁ substituted -C ₄ alkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₆ alkylcarbonyl group, optionally substituted C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted C ₁ -C ₆ alkylcarbonyloxy group, an optionally substituted C ₁ -C ₆ haloalkylcarbonyl group, an optionally substituted C ₁ -C _{6 Alkoxycarbonyl group optionally substituted, C 1-} C ₆ haloalkylcarbonyloxy _{group optionally substituted, C 3-} C ₇ cycloalkyl group optionally substituted, heterocycloalkyl group optionally substituted, substituted May be C _{3 -C 7} cycloalkyloxy groups, optionally substituted heterocycloalkyloxy groups, optionally substituted C ₂ -C ₆ alkoxy groups, optionally substituted C ₂ -C ₆ Alkoxyoxy groups, optionally substituted C ₂ -C ₆ alkoxyoxy-C ₁ -C ₄ alkyl groups, optionally substituted C ₂ -C ₆ alkoxyoxy -C ₁ -C ₄ haloalkyl groups, substituted May be C ₂ -C ₆ Alkoxy Group, May Be Substituted C ₂ -C ₆ Alkoxy Group, May Be Substituted C ₂ -C ₆ Alkinyl Oxy-C ₁ -C ₄ Alkoxy Group, Substituted May be C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ haloalkyl group, may be substituted C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy group, may be substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ Alkoxy groups, optionally substituted C ₂ -C _{6 Alkoxy} Niruokishi -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ haloalkoxy groups, optionally substituted C _2- C ₆ alkynyloxy-C ₁ -C ₄ haloalkoxy groups, optionally substituted C ₁ -C ₆ alkylthio groups, optionally substituted C ₁ -C ₆ haloalkylthio group, optionally substituted C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, _{optionally substituted C 1} -C ₄ haloalkylthio -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl group, an optionally substituted C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group, pentafluorosulfanyl group, - ( CH ₂ ) _q NR ^b1 R ^b2 (R ^b1 and R ^b2 are independently hydrogen atoms, C _1- C ₄ alkyl groups, or C ₁ -C ₄ haloalkyl groups, where q is 0, 1, 2 or 3. ) Or general formula (IB)

{In the formula,
Ring C is a saturated, partially saturated, or unsaturated 3- to 7-membered monocyclic ring, or a saturated, partially saturated, or unsaturated 7 to 12-membered bicyclic ring.
L ² is a single bond, -CH = CH-, -C ≡ C ^{-,-(CR 10a R 10b} ) _r1 (CR ^10c R ^10d ) _r2 (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- , -(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 O (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CONR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 S (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO ₂ (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO ₂ NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- or
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c SO ₂ (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4-
(R ^c is a hydrogen atom, a C _1- C ₄ alkyl group, or a C ₁ -C ₄ haloalkyl group.
R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^10f , R ^10g , R ^10h are independently hydrogen atom, halogen atom, C _1- C ₄ alkyl group, or C ₃ -C. ₇ cycloalkyl group,
R ^10a and R ^10b may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
R ^10c and R ^10d may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
R ^10e and R ^10f may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
R ^10g and R ^10h may be combined with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring.
r1, r2, r3 and r4 are independently 0, 1 or 2 respectively. ),
R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, formyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ Alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy- C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyl group, C _3- C ₇ cycloalkyl group, heterocycloalkyl group, C _3- C ₇ cycloalkyloxy group, heterocycloalkyloxy group, C ₂ -C ₆ alkoxy group,-(CH ₂ ) _s NR ^d1 R ^d2 (R ^d1 and R ^d2 are independent hydrogen atoms, C, respectively. _{It is a 1-} C ₄ alkyl group or a C _1- C ₄ haloalkyl group, and s is 0, 1, or 2), or the general formula (IC).

{In the formula,
Ring D may be substituted with a halogen atom, a hydroxyl group, a C _1- C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, or a C _1- C _{4 haloalkoxy group.} , A 3- to 7-membered monocyclic ring,
L ³ is a single bond or an oxygen atom. }. Is a group represented by} or
R ^4a and R ^4b may combine with the carbon atoms to which they bond to form a 3- to 7-membered monocyclic ring, or
R ^4a and R ^4b together have the general formula (ID):

(R ^4d and R ^4e are independent hydrogen atoms, halogen atoms, or C _1- C ₄ alkyl groups, or R ^4d and R ^4e are carbon atoms to which they are bonded. Together with, a 3- to 7-membered monocyclic ring may be formed.),
R ^5a is a hydrogen atom, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, C ₃ -C ₇ cycloalkyl-C ₁ -C ₄ Alkyl group, heterocycloalkyl-C _1- C ₄ alkyl group, or aralkyl group,
R ^6a and R ^6b are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ alkoxy group, or C. ₁ -C ₄ haloalkoxy group,
Z ⁴ is a CR ^11a or nitrogen atom
R ^11a is a hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group. , C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl group, C ₃ -C ₇ cycloalkyl group, C _2- C ₆ Alkoxy Group, C _2- C ₆ Alkoxy Oxy Group, C _2- C ₆ Alkinyl Group, or C _2- C ₆ Alkoxy Oxy Group.
R ^11b and R ^11c are independently hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxylxamide group, hydroxyl group, optionally substituted C _1- C ₆ alkyl group, substituted. is optionally C ₁ -C ₆ haloalkyl group, an optionally substituted C ₁ -C ₆ alkoxy group, optionally substituted C ₁ -C ₆ haloalkoxy group, an optionally C ₁ substituted -C ₄ alkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl group, _{optionally substituted C 1} -C ₆ alkylcarbonyl group, optionally substituted C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted C ₁ -C ₆ alkylcarbonyloxy group, an optionally substituted C ₁ -C ₆ haloalkylcarbonyl group, an optionally substituted C ₁ -C _{6 Alkoxycarbonyl group optionally substituted, C 1-} C ₆ haloalkylcarbonyloxy _{group optionally substituted, C 3-} C ₇ cycloalkyl group optionally substituted, heterocycloalkyl group optionally substituted, substituted May be C _{3 -C 7} cycloalkyloxy groups, optionally substituted heterocycloalkyloxy groups, optionally substituted C ₂ -C ₆ alkoxy groups, optionally substituted C ₂ -C ₆ Alkoxyoxy groups, optionally substituted C ₂ -C ₆ alkoxyoxy-C ₁ -C ₄ alkyl groups, optionally substituted C ₂ -C ₆ alkoxyoxy -C ₁ -C ₄ haloalkyl groups, substituted May be C ₂ -C ₆ Alkoxy Group, May Be Substituted C ₂ -C ₆ Alkoxy Group, May Be Substituted C ₂ -C ₆ Alkinyl Oxy-C ₁ -C ₄ Alkoxy Group, Substituted May be C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ haloalkyl group, may be substituted C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy group, may be substituted C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ Alkoxy groups, optionally substituted C ₂ -C ₆ a Rukeniruokishi -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ alkoxy groups, optionally substituted C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ Haloalkoxy groups, optionally substituted C _2- C ₆ alkynyloxy-C ₁ -C ₄ haloalkoxy groups, optionally substituted C ₁ -C ₆ alkylthio groups, optionally substituted C ₁ -C ₆ haloalkylthio groups, optionally substituted C ₁ -C ₄ alkylthio-C ₁ -C ₄ alkyl groups, _{optionally substituted C 1} -C ₄ haloalkylthio-C ₁ -C ₄ alkyl groups, optionally substituted C ₁ -C ₄ alkylthio -C ₁ -C ₄ haloalkyl group, an optionally substituted C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ haloalkyl group, an optionally substituted C ₁ -C ₆ Alkoxysulfonyl Group,-(CH ₂ ) _p NR ^a1 R ^a2 (R ^a1 and R ^a2 are independent hydrogen atoms, C ₁ -C ₄ alkyl groups, or C ₁ -C ₄ haloalkyl, respectively. Is the basis and
p is 0, 1, or 2. ) Or general formula (IA)

{In the formula,
Ring B is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring.
L ¹ represents a single ^{bond, -CR a3 R a4 -, -} O -, - NR a1 -, - CR a3 R a4 O -, - OCR a3 R a4 -, - CH 2 CH 2 -, - CH = CH- , -C ≡ C-, or -CH ₂ OCH _2- (R ^a3 and R ^a4 are independent hydrogen atoms, C _{1 -C 4} alkyl groups, or C ₁ -C ₄ haloalkyl groups, respectively. ),
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₃ -C ₇ cycloalkyloxy group, heterocycloalkyl group, heterocycloalkyloxy group, C _2- C ₆ alkoxy group, or C _2- It is a C ₆ alkylyl group. } (However, if R ² is a hydrogen atom, at least one of ^{Y 1} , Y ² , Y ³ , or Y ^{4 is −CR 4a} R ^4b −, ^{−CR 4a} H−. , -CH ₂ CR ^4a R ^4b- , or -CH ₂ CR ^4a H-). ]
A drug comprising a heteroaromatic amide derivative represented by or a salt thereof. In the general formula (I-E2),
X ¹ −X ² is C −N,
Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a R 4b CH 2 CH 2 -, - OCH 2 CH 2 -,
_{^{-OCR 4a HCH 2 -, - OCR}} 4a R 4b CH 2 -,
−OCH ₂ CH ₂ CH ₂ CH ₂ −, −OCR ^4a HCH ₂ CH ₂ CH ₂ −, −OCH ₂ CR ^4a HCH ₂ CH ₂ −,
−CH ₂ OCH ₂ CH ₂ −, −CH ₂ OCH ₂ CH ₂ CH ₂ −,
−CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −, −CH ₂ CH ₂ CR ^4a HCH ₂ −,
−NHCH ₂ CH ₂ CH ₂ −, −NR ^4c CR ^4a HCH ₂ CH ₂ −, −NHCR ^4a HCH ₂ CH ₂ − or −CH ₂ NR ^4c CH ₂ CH ₂ − (R ^4a , R ^4b) And R ^4c are synonymous with the definitions given in claim 7),.
The medicament according to claim 7, which comprises a heteroaromatic amide derivative or a salt thereof (where X ^1- X ² is C-N, and Y ¹ , Y ² , Y ³ and Y ⁴ are these. When combined to form −OCR ^4a HCH ₂ CH ₂ − or −OCR ^4a R ^4b CH ₂ CH ₂ −, R ² is a hydrogen atom). In the general formula (I-E2),
Z ² −Z ³ is −CH ₂ O−,
A claim consisting of a heteroaromatic amide derivative or a salt thereof, in which ^{R 6a} and R ^6b are independently hydrogen atoms, fluorine atoms, hydroxyl groups or methoxy groups, and R ^11a and R ^{11c are hydrogen atoms, respectively.} The medicament according to claim 7 or claim 8. In the general formula (I-E2),
X ¹ −X ² is C −N,
Y ¹ , Y ² , Y ³ and Y ⁴ together,
_{^{-OCR 4a HCH 2 CH 2 -,}} - OCR 4a HCH 2 -,
−OCR ^4a HCH ₂ CH ₂ CH ₂ −, −CH ₂ CR ^4a HCH ₂ CH ₂ −,
Forming −NR ^4c CR ^4a HCH ₂ CH ₂ −, −NHCR ^4a HCH ₂ CH ₂ −, or −CH ₂ NR ^4c CH ₂ CH ₂ −
R ^4a is substituted with halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, optionally substituted with hydroxyl group C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, substituted with hydroxyl group. May be _{substituted with C 1} -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ haloalkoxy group C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkylcarbonyl group, C ₃ -C ₇ cycloalkyl group, halogen atom or C ₁ -C ₄ haloalkyl group in optionally substituted C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ Alkoxy group, optionally substituted with halogen atom C _2- C ₆ Alkoxyoxy-C ₁ -C ₄ Alkoxy group, C _2- C ₆ Alkoxy group, optionally substituted with halogen atom or methoxy group C _2- C ₆ alkoxy group, C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkoxy group, C ₁ -C ₆ alkylthio group, C _1- C ₆ haloalkylthio group, C ₁ -C ₄ alkylthio -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkylthio -C ₁ -C ₄ alkyl group,-(CH ₂ ) _q NR ^b1 R ^b2 (q, R ^b1 and R ^b2 are synonymous with the definitions given in claim 7) or general formula (IB).

{In the formula,
Ring C is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ² is a single bond, -CH = CH-, -C ≡ C ^{-,-(CR 10a R 10b} ) _r1 (CR ^10c R ^10d ) _r2 (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- , -(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 O (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 S (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- or
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- and (R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^{10f, R 10g, R 10h,} r1, r2, r3, r4 and R ^c have the same meanings as defined indicated in claim 7.)
R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, respectively. C ₁ -C ₆ haloalkoxy group, C ₁ -C ₆ alkoxycarbonyl group, heterocycloalkyloxy group, or-(CH ₂ ) _s NR ^d1 R ^d2 (s, R ^d1 and R ^d2 are in claim 7). It is synonymous with the definition given.) },
The medicament according to any one of claims 7 to 9, which comprises a heteroaromatic amide derivative or a salt thereof. In the general formula (I-E2),
X ¹ −X ² is N − C,
Y ¹ , Y ² , Y ³ and Y ⁴ together,
−CH ₂ CR ^4a HOCH ₂ −, −CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CR ^4a R ^4b CH ₂ CH ₂ −,
-CH ₂ CH ₂ NR ^4c CH ₂ −, −CH ₂ CR ^4a HNR ^4c CH ₂ −, or −CH ₂ CR ^4a HNHCH ₂ − (R ^4a , R ^4b and R ^4c are claimed in claim 7). Synonymous with the definition given.),
The medicament according to claim 7, which comprises a heteroaromatic amide derivative or a salt thereof (provided that Y ¹ , Y ² , Y ³ and Y ⁴ are combined to form −CH ₂ CR ^4a HCH ₂ CH ₂ −. , R ² is a hydrogen atom, R ^4a is a group represented by the general formula (IB), and L ² is a single bond, then ring C is not a phenyl ring.) In the general formula (I-E2),
Z ² −Z ³ is −CH ₂ O−,
R ^6a , R ^6b , and R ^11c are hydrogen atoms, respectively.
The medicament according to claim 7 or claim 11, wherein R ^{11a comprises} a heteroaromatic amide derivative or a salt thereof, which is a hydrogen atom or a halogen atom. In the general formula (I-E2),
X ¹ −X ² is N − C,
Y ¹ , Y ² , Y ³ and Y ⁴ together,
−CH ₂ CR ^4a HOCH ₂ −, −CH ₂ CR ^4a HCH ₂ CH ₂ −, −CH ₂ CH ₂ NR ^4c CH ₂ −,
Forming −CH ₂ CR ^4a HNR ^4c CH ₂ − or −CH ₂ CR ^4a _{HNHCH 2} −
R ^4a and R ^4c may be independently substituted with halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, hydroxyl group, C _1- C ₆ alkyl group, C _1- C ₆ haloalkyl, respectively. It may be substituted with a group or a hydroxyl group. It may be substituted with a C _1- C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or a C _1- C ₄ haloalkoxy group. C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl groups, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl groups, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ Alkoxy-C ₁ -C ₄ Haloalkyl groups, C ₁ -C ₆ alkylcarbonyl groups, C ₁ -C ₆ alkoxycarbonyl groups, C ₁ -C ₆ haloalkylcarbonyl groups, C ₃ -C ₇ cycloalkyl groups, halogen atoms or C ₁ -C ₄ optionally substituted with a haloalkyl group C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ Alkoxyoxy-C _1- C ₄ Alkoxy group, optionally substituted with halogen atom C ₂ -C ₆ Alkoxyoxy-C ₁ -C ₄ Alkoxy group, C _2- C ₆ Alkinyl group, halogen atom or methoxy group in optionally substituted C ₂ -C ₆ alkynyl group, C ₂ -C ₆ alkynyloxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkoxy groups, C ₁ - C ₆ Alkoxy Group, C ₁ -C ₆ Halo Alkoxy Group, C ₁ -C ₄ Alkoxy-C ₁ -C ₄ Alkoxy Group, C ₁ -C ₄ Halo Alkoxy-C ₁ -C ₄ Alkoxy Group,-(CH ₂ ) _q NR ^b1 R ^b2 (q, R ^b1 and R ^b2 are synonymous with the definitions given in claim 7), or the general formula (IB).

{In the formula,
Ring C is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, lyazolyl, pyridyl, pyrazinyl, pyridadinyl, or pyrimidinyl. And
L ² is a single bond, -CH = CH-, -C ≡ C ^{-,-(CR 10a R 10b} ) _r1 (CR ^10c R ^10d ) _r2 (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- , -(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 O (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 NR ^c (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 CO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- ,
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 S (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- or
-(CR ^10a R ^10b ) _r1 (CR ^10c R ^10d ) _r2 SO (CR ^10e R ^10f ) _r3 (CR ^10g R ^10h ) _r4- and (R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^{10f, R 10g, R 10h,} r1, r2, r3, r4 and R ^c have the same meanings as defined indicated in claim 7.)
R ^9a , R ^9b and R ^9c are independently hydrogen atom, halogen atom, hydroxyl group, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, respectively. C ₁ -C ₆ haloalkoxy group, C ₁ -C ₆ alkoxycarbonyl group, heterocycloalkyloxy group, or-(CH ₂ ) _s NR ^d1 R ^d2 (s, R ^d1 and R ^d2 are in claim 7). It is synonymous with the definition given.) },
The medicament according to any one of claims 7, 11, and 12, which comprises a heteroaromatic amide derivative or a salt thereof. In the general formula (I-E2),
R ^11b is a hydrogen atom, halogen atom, cyano group, cyanomethyl group, formyl group, nitro group, carboxamide group, hydroxyl group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group. , C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, optionally substituted with dimethylaminocarbonyl group or dimethylamino group C ₁ -C ₄ alkoxy -C ₁ - C ₄ alkyl group, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ haloalkoxy -C ₁ -C ₄ haloalkyl Group, C _1- C ₆ Alkoxy carbonyl group, C ₂ -C ₆ Alkoxy group, C ₂ -C ₆ Alkoxy group, C ₂ -C ₆ Alkoxy group optionally _{substituted with halogen atom, C 1} -C _{6 Alkoxy group} Group, C ₁ -C ₆ haloalkylthio group,-(CH ₂ ) _p NR ^a1 R ^a2 (p, R ^a1 and R a ² are synonymous with the definitions given in claim 7), or the general formula. (IA)

{In the formula,
Ring B is C _3- C ₇ cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, frill, thienyl, imidazolyl, pyrazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, pyrazil, tetrazolyl, pyridyl, pyrazil. , Pyridadinyl, or pyrimidinyl,
L ¹ represents a single _{bond, -CH 2 -, - CH 2} O -, - OCH 2 -, - CH 2 CH 2 -, or, -CH ₂ OCH ₂ - and is,
R ^8a , R ^8b and R ^8c are independently hydrogen atom, halogen atom, cyano group, C _1- C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₃ -C ₇ cycloalkyloxy group, heterocycloalkyl group, heterocycloalkyloxy group, C _2- C ₆ alkoxy group, or C _2- It is a C ₆ alkylyl group. The medicament according to any one of claims 7 to 13, which comprises a heteroaromatic amide derivative or a salt thereof, which is a group represented by. The compound represented by the general formula (I-E2) (the asterisk (*) shown in the structural formula means that the corresponding asymmetric carbon has a single solid).

The medicament according to claim 7, which comprises a heteroaromatic amide derivative or a salt thereof. The medicament according to any one of claims 1 to 15, which is a prophylactic or therapeutic agent for a disease related to voltage-gated sodium channel Nav1.7. The medicament according to any one of claims 1 to 15, which is a prophylactic or therapeutic agent for a disease associated with pain, a disease associated with pruritus, and an autonomic nerve-related disease. The medicament according to any one of claims 1 to 15, which is a prophylactic or therapeutic agent for a painful disease. The medicament according to any one of claims 1 to 15, which is an analgesic. The medicament according to any one of claims 1 to 15, which is a prophylactic or therapeutic agent for nociceptive pain or neuropathic pain. Use of a heteroaromatic amide derivative or a salt thereof contained in any one of claims 1 to 15 for producing a drug for use in the prevention or treatment of pain. Use of a heteroaromatic amide derivative or a salt thereof contained in any one of claims 1 to 15 for producing an analgesic.