A medicament comprising a novel heteroaromatic amide derivative or a salt thereof

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

Technical Field

[0001] The present invention relates to a medicament comprising a compound or a salt thereof useful for treating or preventing diseases involving voltage-dependent sodium channel Nav1.7 (hereinafter referred to as Nav1.7).

Background Art

[0002] Voltage-dependent sodium channels (Nav) are present in excitable cells including nerve cells and cardiomyocytes in the central and peripheral nervous systems. Their role is to control the rising phase of action potentials generated by depolarization of the cell membrane potential and to be involved in the generation and propagation of electrical signals. Therefore, Nav is essential for maintaining the physiological functions of excitable 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), myotonia (Non-Patent Document 3), and chronic pain (Non-Patent Document 4). Nav is composed of an α subunit that forms an ion channel pore and a β subunit that functions auxiliarily. To date, at least nine types of α subunits have been known (Nav1.1 to Nav1.9). These subtypes are roughly classified into TTX-sensitive Nav (Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6, Nav1.7) inhibited by tetrodotoxin (TTX), which is a pufferfish poison, and TTX-resistant Nav (Nav1.5, Nav1.8, Nav1.9). It is known that many of Nav1.1, Nav1.2, and Nav1.3 are expressed in the central nervous system, many of Nav1.4 are expressed in skeletal muscle, many of Nav1.5 are expressed in myocardium, many of Nav1.6 are expressed in the nervous system, and many of Nav1.7, Nav1.8, and Nav1.9 are 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 the autonomic and sensory nerves. In recent years, it has been shown that mutations in the gene (SCN9A) encoding Nav1.7 change the pain threshold. That is, from the pedigree analysis of erythromelalgia showing flushing of the extremities and increased pain sensation in the peripheral limbs, it has been reported that a gain of function mutation has occurred in SCN9A (Non-Patent Document 6). Furthermore, from the pedigree analysis of congenital insensitivity to pain in which only pain sensation is lost despite normal other sensations, it has been reported that a loss of function mutation has occurred in SCN9A (Non-Patent Document 7).

[0003] From studies using anti-Nav1.7 antibodies (Non-Patent Document 8) and Nav1.7 inhibitory compounds (Non-Patent Document 9, Patent Documents 1 and 2), it is also known that inhibition of Nav1.7 shows an analgesic effect on nociceptive pain and neuropathic pain. Thus, since Nav1.7 is particularly suggested to be related to pain sensation, Nav1.7 inhibitors are considered useful as therapeutic or prophylactic agents for diseases accompanied by pain, particularly nociceptive pain and neuropathic pain.

[0004] Furthermore, the sensation of itching is transmitted by peripheral sensory nerves, and since Nav1.7 is distributed in the peripheral nervous system, it is considered that Nav1.7 is also involved in acute or chronic itching, and it is considered that an anti-itching effect (Non-Patent Document 7) on acute or chronic itching can be obtained by inhibiting Nav1.7.

[0005] Nav inhibitors are effective for the treatment of various disease states. For example, as subtype-nonspecific Nav inhibitors, lidocaine, a local anesthetic, mexiletine, an antiarrhythmic drug, carbamazepine, an antiepileptic drug, etc. are known.

[0006] Subtype-nonspecific Nav inhibitors are known to exhibit analgesic effects in clinical settings and are used as analgesics. However, since these subtype-nonselective Nav inhibitors also inhibit Nav1.5 expressed in the myocardium, there is a concern that they may have an adverse effect on cardiac function, which is particularly important in maintaining life. So far, there has been no clinically used selective Nav1.7 inhibitor.

[0007] From the above, a Nav1.7 inhibitor selective for Nav1.5 is considered to have less concern about side effects derived from Nav1.5 inhibition and to be very useful as a therapeutic or preventive agent for various pathological conditions accompanied by pain.

[0008] So far, various heteroaromatic amide derivatives having Nav1.7 inhibitory activity have been reported (Patent Documents 3 to 10).

[0009] In addition, Patent Documents 11 to 15 disclose various amide compounds having Nav1.7 inhibitory activity. For example, Patent Document 15 describes

[0010]

Chemical formula

[0011] Patent Document 16 describes a compound having an affinity for the KCNQ2 / 3 potassium channel and useful as an analgesic,

[0012]

Chemical formula

[0013] Patent Document 17 describes a compound having PDE4B inhibitory activity and effective for various diseases including pain,

[0014] [Chemical formula] A compound represented by (wherein each symbol is as defined in Patent Document 17) is described.

[0015] Non-Patent Document 10 describes a negative allosteric modulator of metabotropic glutamate receptor 5, and as a compound applicable to chronic pain,

[0016] [Chemical formula] A compound represented by (wherein each symbol is as defined in Non-Patent Document 10) is described. [Prior Art Documents] [Patent Documents]

[0017] [Patent Document 1] International Publication No. 2014 / 151472 [Patent Document 2] US Patent Publication No. 2014-8883840 [Patent Document 3] International Publication No. 2008 / 008020 [Patent Document 4] International Publication No. 2009 / 145720 [Patent Document 5] International Publication No. 2009 / 145721 [Patent Document 6] International Publication No. 2013 / 161928 [Patent Document 7] Japanese Unexamined Patent Application Publication No. 2014-101287 [Patent Document 8] International Publication No. 2015 / 119998 [Patent Document 9] International Publication No. 2016 / 117647 [Patent Document 10] International Publication No. 2008 / 130319 [Patent Document 11] International Publication No. 2008 / 130320 [Patent Document 12] International Publication No. 2008 / 130321 [Patent Document 13] International Publication No. 2008 / 130322 [Patent Document 14] International Publication No. 2008 / 130323 [Patent Document 15] International Publication No. 2012 / 039657 [Patent Document 16] US Patent Publication No. 2009 - 0186902 [Patent Document 17] International Publication No. 2017 / 145013 [Non - Patent Document]

[0018] [Non - Patent Document 1] Yogeeswari et al., Curr. Drug Targets 2004, 5(7), 589 - 602. [Non - Patent Document 2] Noble D., Proc Natl Acad Sci USA. 2002, 99(9):5755 - 5756. [Non - Patent Document 3] Cannon SC, Kidney Int. 2000, 57(3), 772 - 779. [Non - Patent Document 4] Wood, JN et al., J. Neurobiol. 2004, 61(1), 55 - 71. [Non - Patent Document 5] Catterall, WA et al., Pharmacol Rev. 2005, 57:397 - 409. [Non - Patent Document 6] Waxman, SG Neurology. 2007, 7, 69(6), 505 - 507. [Non - Patent Document 7] Cox et al., Nature 2006, 444, 894 - 898.

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Summary of the Invention

Problems to be Solved by the Invention

[0019] An object of the present invention is to provide a medicament comprising a novel compound having a Nav1.7 inhibitory action or a salt thereof.

Means for Solving the Problems

[0020] As a result of intensive studies to solve the above problems, the present inventors have found that a medicament comprising a novel heteroaromatic amide derivative represented by the following general formula (I) or a salt thereof has a Nav1.7 inhibitory action selective for Nav1.5, and have completed the present invention.

[0021] (0) The present invention relates to a medicament comprising a heteroaromatic amide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:

[0022]

Chemical Formula

[0023] [Chemical formula] (In the formula,[[]] Ring B is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring,[[]] L 1 is a single bond, -CR a3 R a4 -, -O-, -NR a1 -, -CR a3 R a4 O-, -OCR a3 R a4 -, -CH2CH2-, -CH=CH-, -C≡C-, or -CH2OCH2- (R a3 and R a4 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group.). R 8a , R 8b and R 8cEach independently represents a hydrogen atom, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyloxy group, a heterocycloalkyl group, a heterocycloalkyloxy group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group.} The group represented by R 4a , R 4b and R 4cis, independently of each other, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 haloalkyl group, an optionally substituted C1-C6 alkoxy group, an optionally substituted C1-C6 haloalkoxy group, an optionally substituted C1-C4 alkoxy-C1-C4 alkyl group, an optionally substituted C1-C4 haloalkoxy-C1-C4 alkyl group, an optionally substituted C1-C4 alkoxy-C1-C4 haloalkyl group, an optionally substituted C1-C4 haloalkoxy-C1-C4 haloalkyl group, an optionally substituted C1-C6 alkylcarbonyl group, an optionally substituted C1-C6 alkoxycarbonyl group, an optionally substituted C1-C6 alkylcarbonyloxy group, an optionally substituted C1-C6 haloalkylcarbonyl group, an optionally substituted C1-C6 haloalkoxycarbonyl group, an optionally substituted C1-C6 haloalkylcarbonyloxy group, an optionally substituted C3-C7 cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted C3-C7 cycloalkyloxy group, an optionally substituted heterocycloalkyloxy group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 alkenyloxy group, an optionally substituted C2-C6 alkenyloxy-C1-C4 alkyl group, an optionally substituted C2-C6 alkenyloxy-C1-C4 haloalkyl group, an optionally substituted C2-C6 alkynyl group, an optionally substituted C2-C6 alkynyloxy group, an optionally substituted C2-C6 alkynyloxy-C1-C4 alkyl group, an optionally substituted C2-C6 alkynyloxy-C1-C4 haloalkyl group, an optionally substituted C1-C4 alkoxy-C1-C4 alkoxy group, an optionally substituted C1-C4 haloalkoxy-C1-C4 alkoxy group, an optionally substituted C2-C6 alkenyloxy-C1-C4 alkoxy group, an optionally substituted C2-C6 alkynyloxy-C1-C4 alkoxy group, an optionally substituted C2-C6 alkenyloxy-C1-C4 haloalkoxy group,A C2-C6 alkynyloxy-C1-C4 haloalkoxy group which may be substituted, a C1-C6 alkylthio group which may be substituted, a C1-C6 haloalkylthio group which may be substituted, a C1-C4 alkylthio-C1-C4 alkyl group which may be substituted, a C1-C4 haloalkylthio-C1-C4 alkyl group which may be substituted, a C1-C4 alkylthio-C1-C4 haloalkyl group which may be substituted, a C1-C4 haloalkylthio-C1-C4 haloalkyl group which may be substituted, a pentafluorosulfanyl group, -(CH2), q NR b1 R b2 (R b1 and R b2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group, and q is 0, 1, 2, or 3.), or the general formula (I-B)

[0024]

Chemical formula

[0025]

Chemical formula

[0026] [Chemical formula] (wherein R 4d and R 4e are each independently a hydrogen atom, a halogen atom, or a C1-C4 alkyl group, or R 4d and R 4e may together with the carbon atom to which they are attached form a 3- to 7-membered monocyclic ring.). 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 form a single bond, -CH2-, -OCH2-, -CH2O-, -CH2S-, -SCH2-, -CH2NR e1 -, -NR e1 CH2-, -CH2CH2-, -NR e1 CO-, -CR e1 R e2 O-, or -OCR e1 R e2 -(where Re1 and R e2 is a hydrogen atom or a C1-C4 alkyl group.), and R 5a is a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C7 cycloalkyl group, a heterocycloalkyl group, a C3-C7 cycloalkyl-C1-C4 alkyl group, a heterocycloalkyl-C1-C4 alkyl group, or an aralkyl group, and R 6a and R 6b are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group, and n is 1 or 2. (ii) R 5a and R 6a together form -CH2-, -CH2CH2-, -CH2CR e1 R e2 -, -CR e1 R e2 CH2-, -CH2CH2CH2-, -CH2CH2O-, -CH2CH2CH2O- (R e1 and R e2 are as defined in (i) above.), and R 5b is a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group, R 5c and R 6b are a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, or alternatively, R 5c and R 6b together form -(CH2) t -, -O(CH2) t -, -(CH2) t O-, -(CH2) t O(CH2) u -, -(CH2) t NR e3 (CH2) u -, -(CH2)t CONR e3 (CH2) u - or -(CH2) t NR e3 CO(CH2) u to form (t and u are each independently 0, 1, 2, or 3, and R e3 is a hydrogen atom or a C1-C4 alkyl group.), and n is 1. (iii) R 5a is a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C7 cycloalkyl group, a heterocycloalkyl group, a C3-C7 cycloalkyl-C1-C4 alkyl group, a heterocycloalkyl-C1-C4 alkyl group, or an aralkyl group, and R 5b is a hydrogen atom or a C1-C4 alkyl group, R 5c is a hydrogen atom, a C1-C4 alkyl group, or a halogen atom, R 6a and R 6b are each independently a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C3-C7 cycloalkyl group, or a C1-C6 haloalkyl group, or alternatively, R 6a and R 6b together with the carbon atom to which they are attached form a 3- to 7-membered monocyclic ring, and n is 1 or 2. (iv) R 5a and R 5b together form -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-, and R 5c , R 6a and R 6b are each independently a hydrogen atom or a halogen atom, and n is 1 or 2. (v) R 6a and R 5ccombine to form -OCH2-, -CH2O-, -CH2S-, -SCH2-, -CH2NH-, -NHCH2-, or -CH2CH2-, 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 each independently a hydrogen atom, a halogen atom, or a C1-C4 alkyl group. ].

[0027] That is, the present invention includes the following inventions.

[0028] (1) A medicament comprising a heteroaromatic amide derivative represented by the general formula (I) or a salt thereof:

[0029]

Chemical formula

[0030] (2) In the general formula (I), Y 1 、Y 2 、Y 3 and Y 4 together are -OCH2CH2CH2-, -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2-, -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2-, -OCH2CH2CH2CH2-, -OCR 4a HCH2CH2CH2-, -OCR 4a R 4b CH2CH2CH2-, -OCH2CR 4a HCH2CH2-, -OCH2CR 4a R 4b CH2CH2-, -CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2CH2OCH2-, -CH2CR 4a HOCH2- -CH2CH2CH2CH2-, -CH2CR 4a HCH2CH2-, -CH2CR 4a R 4b CH2CH2-, -CH2CH2CR 4a HCH2-, -CH2CH2CR 4a R 4b CH2-, -CH2SCH2CH2-, -CH2SO2CH2CH2-, -NHCH2CH2CH2-, -NR 4c CH2CH2CH2-, -NR 4c CR4a HCH2CH2-、 -NHCR 4a HCH2CH2-、 -CH2NR 4c CH2CH2-、-CH2NR 4c CR 4a HCH2-、-CH2NHCR 4a HCH2-、 -CH2CH2NR 4c CH2-、-CH2CR 4a HNR 4c CH2-、 or, -CH2CR 4a forms HNHCH2- (R 4a 、R 4b 、R 4c is synonymous with the definition shown in the above (0).), R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or an optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring (provided that X 1 -X 2 is C-N, and Y 1 、Y 2 、Y 3 and Y 4 together form -OCH2CH2CH2-, -OCR 4a HCH2CH2-, or -OCR 4a R 4b CH2CH2-, then R 2 is a hydrogen atom.). The medicament according to the above (1), which comprises a heteroaromatic amide derivative or a salt thereof.

[0031] (3) In the general formula (I), X 1 -X 2 is C-N, Y 1 、Y 2 、Y 3 and Y 4 together form -OCH2CH2CH2-, -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2-, -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2-, -OCH2CH2CH2CH2-, -OCR 4a HCH2CH2CH2-, -OCH2CR 4a HCH2CH2- -CH2OCH2CH2-, -CH2OCH2CH2CH2- -CH2CR 4a HCH2CH2-, -CH2CR 4a R 4b CH2CH2-, -CH2CH2CR 4a HCH2- -NHCH2CH2CH2-, -NR 4c CR 4a HCH2CH2-, -NHCR 4a HCH2CH2-, or, -CH2NR 4c CH2CH2- is formed (R 4a , R 4b and R 4c are synonymous with the definitions shown in the above (0).), R 5a , R 5b , R 5c , R 6a , R 6b and n satisfy any one of the structures shown in (i) to (iii) in the above (0), the pharmaceutical according to the above (1) or (2) comprising a heteroaromatic amide derivative or a salt thereof.

[0032] (4) A pharmaceutical comprising a heteroaromatic amide derivative represented by the general formula (I) or a salt thereof:

[0033]

Chemical formula

[0034] (5) In the general formula (I), Y 1 , Y 2 , Y 3 and Y 4 are such that when they are together, -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2-, -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4bCH2-、 -OCH2CH2CH2CH2-、-OCR 4a HCH2CH2CH2-、-OCR 4a R 4b CH2CH2CH2-、 -OCH2CR 4a HCH2CH2-、-OCH2CR 4a R 4b CH2CH2-、 -CH2OCH2CH2-、-CH2OCH2CH2CH2-、-CH2CH2OCH2-、-CH2CR 4a HOCH2- -CH2CH2CH2CH2-、-CH2CR 4a HCH2CH2-、-CH2CR 4a R 4b CH2CH2-、 -CH2CH2CR 4a HCH2-、-CH2CH2CR 4a R 4b CH2-、 -CH2SCH2CH2-、-CH2SO2CH2CH2-、 -NHCH2CH2CH2-、-NR 4c CH2CH2CH2-、-NR 4c CR 4a HCH2CH2-、 -NHCR 4a HCH2CH2-、 -CH2NR 4c CH2CH2-、-CH2NR 4c CR 4a HCH2-、-CH2NHCR 4a HCH2-、 -CH2CH2NR 4c CH2-、-CH2CR 4a HNR 4c CH2-、 or, -CH2CR 4a to form HNHCH2- (R 4a 、R 4b and R 4c are as defined in said (0).), R 2is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or an optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring (provided that X 1 -X 2 is C-N, and Y 1 、Y 2 、Y 3 and Y 4 together form -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2-, when R 2 is a hydrogen atom.). The medicament according to (4) above, which consists of a heteroaromatic amide derivative or a salt thereof (provided that X 1 -X 2 is N-C, Y 1 、Y 2 、Y 3 and Y 4 together form -CH2CR 4a HCH2CH2-, R 2 is a hydrogen atom, R 4a is a group represented by the general formula (I-B), and when L 2 is a single bond, ring C is not a phenyl ring. Alternatively, when ring C is a phenyl ring, X 1 -X 2 is C-N.).

[0035] (6) In the general formula (I), X 1 -X 2 is C-N, Y 1 、Y 2 、Y 3 and Y 4 together form -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2-, -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2-, -OCH2CH2CH2CH2-, -OCR 4aHCH2CH2CH2-, -OCH2CR 4a HCH2CH2- -CH2OCH2CH2-, -CH2OCH2CH2CH2- -CH2CR 4a HCH2CH2-, -CH2CR 4a R 4b CH2CH2-, -CH2CH2CR 4a HCH2- -NHCH2CH2CH2-, -NR 4c CR 4a HCH2CH2-, -NHCR 4a HCH2CH2-, or -CH2NR 4c CH2CH2- is formed (R 4a R 4b and R 4c are synonymous with the definitions shown in said (0).), R 5a R 5b R 5c R 6a R 6b and n satisfy the configuration of (i) in said (0), the pharmaceutical according to said (4) or (5) comprising a heteroaromatic amide derivative or a salt thereof.

[0036] (7) General formula (I-E2):

[0037]

Chemical formula

[0038] (8) In the general formula (I-E2), X 1 -X 2 is C-N, Y 1 , Y 2 , Y 3 and Y 4 are such that, together, -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2-, -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2-, -OCH2CH2CH2CH2-, -OCR 4a HCH2CH2CH2-, -OCH2CR 4a HCH2CH2-, -CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2CR 4a HCH2CH2-, -CH2CR 4a R 4b CH2CH2-, -CH2CH2CR 4a HCH2-, -NHCH2CH2CH2-, -NR 4c CR 4a HCH2CH2-, -NHCR 4a HCH2CH2-, or, -CH2NR 4c CH2CH2- to form (R 4a , R 4b and R4c is synonymous with the definition shown in the above (0). The medicament according to the above (7), which is composed of a heteroaromatic amide derivative or a salt thereof (provided that X 1 -X 2 is C-N, and Y 1 , Y 2 , Y 3 and Y 4 together form -OCR 4a HCH2CH2- or -OCR 4a R 4b CH2CH2- is formed, R 2 is a hydrogen atom.).

[0039] (9) In the general formula (I-E2), Z 2 -Z 3 is -CH2O-, R 6a and R 6b are each independently a hydrogen atom, a fluorine atom, a hydroxyl group, or a methoxy group R 11a and R 11c are each a hydrogen atom, a medicament composed of a heteroaromatic amide derivative or a salt thereof according to the above (7) or (8).

[0040] (10) In the general formula (I-E2), X 1 -X 2 is C-N, Y 1 , Y 2 , Y 3 and Y 4 together form -OCR 4a HCH2CH2-, -OCR 4a HCH2-, -OCR 4a HCH2CH2CH2-, -CH2CR 4a HCH2CH2-, -NR 4c CR 4a HCH2CH2-, -NHCR 4aHCH2CH2- or -CH2NR 4c forms CH2CH2- and R 4a is a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkyl group optionally substituted with a hydroxyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group optionally substituted with a C1-C4 haloalkoxy group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 haloalkylcarbonyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyl group optionally substituted with a halogen atom or a C1-C4 haloalkyl group, a heterocycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 alkyl group optionally substituted with a halogen atom, a C2-C6 alkynyl group, a C2-C6 alkynyl group optionally substituted with a halogen atom or a methoxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, -(CH2) q NR b1 R b2 (q, R b1 and R b2 are as defined in (0) above. ), or general formula (I-B)

[0041]

Chemical formula

[0042] (11) In the general formula (I-E2), X 1 -X 2 is N-C, Y 1 , Y 2, Y 3 and Y 4 are such that when combined together, -CH2CR 4a HOCH2-, -CH2CR 4a HCH2CH2-, -CH2CR 4a R 4b CH2CH2-, -CH2CH2NR 4c CH2-, -CH2CR 4a HNR 4c CH2-, or, -CH2CR 4a form HNHCH2- (R 4a , R 4b and R 4c are as defined in said (0).), the medicament according to said (7) comprising a heteroaromatic amide derivative or a salt thereof (provided that Y 1 , Y 2 , Y 3 and Y 4 are such that when combined together, they form -CH2CR 4a HCH2CH2-, R 2 is a hydrogen atom, R 4a is a group represented by general formula (I-B), and when L 2 is a single bond, ring C is not a phenyl ring. Alternatively, when ring C is a phenyl ring, X 1 -X 2 is C-N.).

[0043] (12) In said general formula (I-E2), Z 2 -Z 3 is -CH2O-, R 6a , R 6b and R 11c are each a hydrogen atom, and R 11a is a hydrogen atom or a halogen atom, the medicament according to said (7) or (11) comprising a heteroaromatic amide derivative or a salt thereof.

[0044] (13) In said general formula (I-E2), X 1 -X 2is N-C, Y 1 , Y 2 , Y 3 and Y 4 which, together, -CH2CR 4a HOCH2-, -CH2CR 4a HCH2CH2-, -CH2CH2NR 4c CH2-, -CH2CR 4a HNR 4c CH2-, or -CH2CR 4a form HNHCH2-, R 4a and R 4c are each independently a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkyl group optionally substituted with a hydroxyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group optionally substituted with a C1-C4 haloalkoxy group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 haloalkylcarbonyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyl group optionally substituted with a halogen atom or a C1-C4 haloalkyl group, a heterocycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 alkyl group optionally substituted with a halogen atom, a C2-C6 alkynyl group, a C2-C6 alkynyl group optionally substituted with a halogen atom or a methoxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, -(CH2) q NR b1 Rb2 (q, R b1 and R b2 are synonymous with the definitions shown in the above (0)). Or, general formula (I-B)

[0045] [Chemical formula] {In the formula, ring C is C3-C7 cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, 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 - is (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 shown in the above (0).), R 9a , R 9b and R 9c are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 alkoxycarbonyl group, a heterocycloalkyloxy group, or -(CH2) s NR d1 R d2 (s, R d1 and R d2is synonymous with the definition shown in the above (0).) The medicament according to any one of the above (7), (11), and (12), which comprises a heteroaromatic amide derivative or a salt thereof.

[0046] (14) In the general formula (I-E2), R 11b is a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group which may be substituted with a dimethylaminocarbonyl group or a dimethylamino group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group which may be substituted with a halogen atom, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, -(CH2) p NR a1 R a2 (p, R a1 and R a2 are synonymous with the definition shown in the above (0).), or the general formula (I-A)

[0047]

Chemical formula

[0048] (15) The compound represented by the general formula (I-E2) (the asterisk (*) shown in the structural formula means that the steric configuration of the corresponding asymmetric carbon is single. The numerical value represents the number of the example. For the notations of "isomer A", "isomer B", "isomer C" and "isomer D", among the plurality of compounds indicated by the same example number, in the order of the isomers fractionated first by high performance liquid chromatography in the example, they are specified by the notations of "isomer A", "isomer B", "isomer C" and "isomer D".) is

[0049]

Chemical formula

[0050]

Chemical formula

[0051]

Chemical formula

[0052] [Chemistry] JPEG0007701162000021.jpg91154

[0053] [Chemistry] JPEG0007701162000023.jpg61152

[0054] [Chemistry]

[0055] [Chemistry] JPEG0007701162000026.jpg90167 JPEG0007701162000027.jpg1839

[0056] [Chemistry]

[0057] [Chemistry]

[0058] [Chemistry] The pharmaceutical according to (7) above, which comprises a heteroaromatic amide derivative or a salt thereof, any one of which is selected from the group consisting of:

[0059] (16) The pharmaceutical according to any one of (1) to (15) above, which is a prophylactic or therapeutic agent for diseases associated with the voltage-dependent sodium channel Nav1.7.

[0060] The medicament according to any one of (1) to (15) above, which is a prophylactic or therapeutic agent for diseases accompanied by pain, diseases accompanied by itching, or autonomic nerve-related diseases. The medicament according to any one of (1) to (15) above, which is a prophylactic or therapeutic agent for diseases accompanied by pain. The medicament according to any one of (1) to (15) above, which is an analgesic. The medicament according to any one of (1) to (15) above, 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 the medicaments (1) to (15) above for manufacturing a medicament for use in the prevention or treatment of pain. Use of a heteroaromatic amide derivative or a salt thereof contained in any one of the medicaments (1) to (15) above for manufacturing an analgesic. [Advantages of the Invention]

[0061] The medicament comprising the heteroaromatic amide derivative or a salt thereof of the present invention has a strong Nav1.7 inhibitory activity, and thus is useful as a therapeutic agent and / or prophylactic agent for various diseases related to Nav1.7. For example, it is useful as an analgesic for diseases accompanied by various pains. The medicament comprising the heteroaromatic amide derivative or a salt thereof of the present invention has less concern about side effects derived from Nav1.5, and is useful as a therapeutic agent and / or prophylactic agent for a wide range of pathological conditions involving Nav1.7. The compounds described in Patent Documents 3 to 15 are significantly different in structure from the heteroaromatic amide derivative or a salt thereof contained in the medicament of the present invention. In addition, Patent Documents 16, 17 and Non-Patent Document 10 do not describe sodium channels, and moreover, there is no description or suggestion about compounds having selectivity for Nav1.5 and having a selective Nav1.7 inhibitory action. [Modes for Carrying Out the Invention]

[0062] The present invention will be described in more detail below. First, the substituents that the heteroaromatic amide derivative or its salt contained in the medicine of the present invention may have will be described.

[0063] Specific examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. The "C1-C6 alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a tert-pentyl group, a 3-methylbutyl group (isopentyl group), a neopentyl group, an n-hexyl group, a 3,3-dimethylbutyl group, and the like. The "C1-C4 alkyl group" means a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, and the like. The "C1-C6 haloalkyl group" means an alkyl group in which one or more of the hydrogen atoms of the "C1-C6 alkyl group" are substituted with a halogen atom. Specific examples include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a 1-fluoroethyl group, a 1,1-difluoroethyl group, a 3,3,3-trifluoropropyl group, a 3,3-difluoropropyl group, a 2-fluoroisopropyl group, a 2,3,3,3-tetrafluoropropyl group, a 2,2,3,3-tetrafluoropropyl group, a 2,2,3,3,3-pentafluoropropyl group, a 1,1,2,2,3,3,3-heptafluoropropyl group, a 1,1,1,3,3,3-hexafluoroisopropyl group, a 4,4,4-trifluorobutyl group, a 2,2,3,4,4-pentafluorobutyl group, a 2,2,3,4,4,4-hexafluorobutyl group, a 2,2,3,3,4,4,4-heptafluorobutyl group, a 3,3-difluorobutyl group, a 3,3,3-trifluoro-2-(trifluoromethyl)-propyl group, a 3-fluoro-3-methylbutyl group, and the like. The term "C1-C4 haloalkyl group" means an alkyl group in which one or more of the hydrogen atoms of the above-mentioned "C1-C4 alkyl group" are substituted by halogen atoms.

[0064] The term "C1-C6 alkoxy group" means an alkoxy group in which the alkyl part has the same meaning as the above-mentioned "C1-C6 alkyl group". Specific examples include methoxy group, ethoxy group, 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 group, and the like. The term "C1-C4 alkoxy group" means an alkoxy group in which the alkyl part has the same meaning as the above-mentioned "C1-C4 alkyl group". The term "C1-C6 haloalkoxy group" means a haloalkoxy group in which the haloalkyl part has the same meaning as the above-mentioned "C1-C6 haloalkyl group". Specific examples include trifluoromethoxy group, difluoromethoxy 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 the like. The term "C1-C4 haloalkoxy group" means a haloalkoxy group in which the haloalkyl part has the same meaning as the above-mentioned "C1-C4 haloalkyl group".

[0065] The term "C1-C4 alkoxy-C1-C4 alkyl group" means a group in which the above-mentioned "C1-C4 alkoxy group" is substituted for the above-mentioned "C1-C4 alkyl group", and these can be bonded at all substitutable 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-ethoxyethyl group, isobutoxyethyl group, tert-butoxyethyl group, and the like. The term "C1-C4 haloalkoxy-C1-C4 alkyl group" refers to a group in which the "C1-C4 alkoxy group" is substituted for the "C1-C4 alkyl group", and these can be bonded at all substitutable positions. Specific examples include a trifluoromethoxymethyl group, a difluoromethoxymethyl group, a monofluoromethoxymethyl group, a 2,2,2-trifluoroethoxymethyl group, a 2,2-difluoroethoxymethyl group, a 3,3,3-trifluoropropoxymethyl group, a 4,4,4-trifluorobutoxymethyl group, a 1,1,1,3,3,3-pentafluoroisopropoxymethyl group, a 3,3,3-trifluoro-2-(trifluoromethyl)-propoxymethyl group, a 2-(trifluoromethoxy)ethyl group, a 2-(difluoromethoxy)ethyl group, a 2-(2’,2’,2’-trifluoroethoxy)ethyl group, a 2-(2’,2’-difluoroethoxy)ethyl group, a 2-(1’,1’,1’,3’,3’,3’-pentafluoroisopropoxy)ethyl group, a 3-(trifluoromethoxy)propyl group, a 3-(difluoromethoxy)propyl group, a 3-(2’,2’,2’-trifluoroethoxy)propyl group, a 3-(2’,2’-difluoroethoxy)propyl group, a 3-(1’,1’,1’,3’,3’,3’-pentafluoroisopropoxy)propyl group, and the like. The term "C1-C4 alkoxy-C1-C4 haloalkyl group" refers to a group in which the "C1-C4 alkoxy group" is substituted for the "C1-C4 haloalkyl group", and these can be bonded at all substitutable positions. Specific examples include an ethoxymonofluoromethyl group and the like. The term "C1-C4 haloalkoxy-C1-C4 haloalkyl group" refers to a group in which the "C1-C4 haloalkoxy group" is substituted for the "C1-C4 haloalkyl group", and these can be bonded at all substitutable positions.

[0066] The term "C1-C6 alkylcarbonyl group" means an alkylcarbonyl group in which the alkyl moiety is the "C1-C6 alkyl group", and specific examples include a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, and the like. The "C1-C6 alkoxycarbonyl group" means an alkoxycarbonyl group in which the alkoxy moiety is the above-mentioned "C1-C6 alkoxy group". Specific examples include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, a tert-butoxycarbonyl group, etc. The "C1-C6 alkylcarbonyloxy group" means an alkylcarbonyloxy group in which the alkylcarbonyl moiety is the above-mentioned "C1-C6 alkylcarbonyl group". Specific examples include a methylcarbonyloxy group, an ethylcarbonyloxy group, an n-propylcarbonyloxy group, etc. The "C1-C6 haloalkylcarbonyl group" means a haloalkylcarbonyl group in which the haloalkyl moiety is the above-mentioned "C1-C6 haloalkyl group". Specifically, a trifluoromethylcarbonyl group, etc. can be mentioned. The "C1-C6 haloalkoxycarbonyl group" means a haloalkoxycarbonyl group in which the haloalkoxy moiety is the above-mentioned "C1-C6 haloalkoxy group". The "C1-C6 haloalkylcarbonyloxy group" means a haloalkylcarbonyloxy group in which the haloalkylcarbonyl moiety is the above-mentioned "C1-C6 haloalkylcarbonyl group".

[0067] The "C3-C7 cycloalkyl group" represents a monocyclic saturated carbon ring group having 3 to 7 carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc.

[0068] The "monocyclic saturated heterocycle" is a 3- to 7-membered saturated monocyclic ring containing at least one oxygen atom, nitrogen atom or sulfur atom. Specific examples include aziridine, azetidine, pyrrolidine, piperidine, piperazine, azepane, oxetane, tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine, etc. "Heterocycloalkyl group" refers to a monocyclic saturated heterocyclic group, in which at least one carbon atom of the "C3-C7 cycloalkyl group" is replaced by an oxygen atom, a nitrogen atom or a sulfur atom. Specific examples of the "heterocycloalkyl group" include an azetidinyl group, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholino group, etc.

[0069] "C3-C7 cycloalkyloxy group" means a cycloalkyloxy group in which the cycloalkyl moiety is the "C3-C7 cycloalkyl group". "Heterocycloalkyloxy group" means a heterocycloalkyloxy group in which the heterocycloalkyl moiety is the "heterocycloalkyl group".

[0070] "C2-C6 alkenyl group" means a straight-chain or branched alkenyl group having one or more double bonds and having 2 to 6 carbon atoms. 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, etc. "C2-C6 alkenyloxy group" means an alkenyloxy group in which the alkenyl moiety is the "C2-C6 alkenyl group", and specific examples include a vinyloxy group, an allyloxy group, a 1-butenyloxy group, a 2-butenyloxy group, a 3-butenyloxy group, etc. "C2-C6 alkenyloxy-C1-C4 alkyl group" means a group in which the "C1-C4 alkyl group" is substituted by the "C2-C6 alkenyloxy group", and these can be bonded at all substitutable positions. For example, a vinyloxymethyl group, an allyloxymethyl group, etc. "C2-C6 alkenyloxy-C1-C4 haloalkyl group" means a group in which the "C1-C4 haloalkyl group" is substituted by the "C2-C6 alkenyloxy group", and these can be bonded at all substitutable positions.

[0071] The term "C2-C6 alkynyl group" means a linear or branched alkynyl group having 2 to 6 carbon atoms and one or more triple bonds. The position of the triple bond is not particularly limited. Specific examples include ethynyl group, 1-propynyl group, 2-propynyl group, 3-methyl-1-butynyl group, and the like. The term "C2-C6 alkynyloxy group" means an alkynyloxy group in which the alkynyl moiety is the above-mentioned "C2-C6 alkynyl group". The term "C2-C6 alkynyloxy-C1-C4 alkyl group" means a group in which the above-mentioned "C1-C4 alkyl group" is substituted with the above-mentioned "C2-C6 alkynyloxy group", and these can be bonded at all substitutable positions. The term "C2-C6 alkynyloxy-C1-C4 haloalkyl group" means a group in which the above-mentioned "C1-C4 haloalkyl group" is substituted with the above-mentioned "C2-C6 alkynyloxy group", and these can be bonded at all substitutable positions.

[0072] The term "C1-C4 alkoxy-C1-C4 alkoxy group" means a group in which the above-mentioned "C1-C4 alkoxy group" is substituted with the above-mentioned "C1-C4 alkoxy group", and these can be bonded at all substitutable positions. The term "C1-C4 haloalkoxy-C1-C4 alkoxy group" means a group in which the above-mentioned "C1-C4 alkoxy group" is substituted with the above-mentioned "C1-C4 haloalkoxy group", and these can be bonded at all substitutable positions. Specific examples include 2-(trifluoromethoxy)ethoxy group and the like. The term "C2-C6 alkenyloxy-C1-C4 alkoxy group" means a group in which the above-mentioned "C1-C4 alkoxy group" is substituted with the above-mentioned "C2-C6 alkenyloxy group", and these can be bonded at all substitutable positions. The term "C2-C6 alkynyloxy-C1-C4 alkoxy group" means a group in which the above-mentioned "C1-C4 alkoxy group" is substituted with the above-mentioned "C2-C6 alkynyloxy group", and these can be bonded at all substitutable positions. For example, allyloxymethoxy group and the like can be mentioned. The "C2-C6 alkenyloxy-C1-C4 haloalkoxy group" means a group in which the "C2-C6 alkenyloxy group" is substituted for the "C1-C4 haloalkoxy group", and they can be bonded at all substitutable positions. The "C2-C6 alkynyloxy-C1-C4 haloalkoxy group" means a group in which the "C2-C6 alkynyloxy group" is substituted for the "C1-C4 haloalkoxy group", and they can be bonded at all substitutable positions.

[0073] The "C1-C6 alkylthio group" means an alkylthio group in which the alkyl part is synonymous with the "C1-C6 alkyl group". Specific examples include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, and the like. The "C1-C4 alkylthio group" means an alkylthio group in which the alkyl part is synonymous with the "C1-C4 alkyl group". The "C1-C6 haloalkylthio group" means an alkylthio group in which one or more of the hydrogen atoms of the "C1-C6 alkylthio group" are substituted with halogen atoms. Specific examples include a trifluoromethylthio group, a 2,2,2-trifluoroethylthio group, and the like. The "C1-C4 haloalkylthio group" means an alkylthio group in which one or more of the hydrogen atoms of the "C1-C4 alkylthio group" are substituted with halogen atoms. The "C1-C4 alkylthio-C1-C4 alkyl group" means a group in which the "C1-C4 alkylthio group" is substituted for the "C1-C4 alkyl group", and they can be bonded at all substitutable positions. The "C1-C4 haloalkylthio-C1-C4 alkyl group" means a group in which the "C1-C4 haloalkylthio group" is substituted for the "C1-C4 alkyl group", and they can be bonded at all substitutable positions. Specific examples include a trifluoromethylthiomethyl group, a ((2’,2’,2’-trifluoroethyl)thio)methyl group, a 2-((trifluoromethyl)thio)ethyl group, a 2-((2’,2’,2’-trifluoroethyl)thio)ethyl group, and the like. The term "C1-C4 alkylthio-C1-C4 haloalkyl group" refers to a group in which the "C1-C4 alkylthio group" is substituted for the "C1-C4 haloalkyl group", and these can be bonded at all substitutable positions. The term "C1-C4 haloalkylthio-C1-C4 haloalkyl group" refers to a group in which the "C1-C4 haloalkylthio group" is substituted for the "C1-C4 haloalkyl group", and these can be bonded at all substitutable positions. The term "C1-C6 alkylsulfonyl group" refers to a group in which the sulfonyl group is substituted for the "C1-C6 alkyl group", and these can be bonded at all substitutable positions.

[0074] The term "C3-C7 cycloalkyl-C1-C4 alkyl group" refers to a group in which the "C3-C7 cycloalkyl group" is substituted for the "C1-C4 alkyl group", and these can be bonded at all substitutable positions. Specific examples include cyclopropylmethyl group and the like. The term "heterocycloalkyl-C1-C4 alkyl group" refers to a group in which the "heterocycloalkyl group" is substituted for the "C1-C4 alkyl group", and these can be bonded at all substitutable positions. Specific examples include oxetanylmethyl group, pyrrolidinylmethyl group, morpholinomethyl group and the like. The term "aralkyl group" refers to a group in which a phenyl group, a 5-membered heteroaryl group, or a 6-membered heteroaryl group is substituted for the "C1-C6 alkyl group". These can be bonded at all substitutable positions. Specific examples include benzyl group, phenethyl group and the like.

[0075] The term "5-membered heteroaryl" represents a 5-membered monocyclic aromatic heterocyclic ring containing one or more (for example, 1 to 4) heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atoms. Specific examples include pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, oxadiazole, triazole, tetrazole and the like. The "5-membered heteroaryl group" refers to the group of the aforementioned "5-membered heteroaryl", and specific examples include a pyrrolyl group (e.g., 2-pyrrolyl group), a furyl group (e.g., 3-furyl group), a thienyl group (e.g., 2-thienyl group), an imidazolyl group (e.g., 4-imidazolyl group), a pyrazolyl group (e.g., 3-pyrazolyl group), and the like. "6-Membered heteroaryl" refers to a 6-membered monocyclic aromatic heterocyclic ring containing one or more (e.g., 1 to 3) nitrogen atoms in addition to carbon atoms. Specific examples include pyridine, pyridazine, pyrimidine, pyrazine, triazine, and the like. The "6-membered heteroaryl group" refers to the group of the aforementioned "6-membered heteroaryl", and specific examples include a pyridyl group (e.g., 2-pyridyl group, 3-pyridyl group, 4-pyridyl group), a pyridazinyl group (e.g., 3-pyridazinyl group), a pyrimidinyl group (e.g., 5-pyrimidinyl group), a pyrazinyl group (e.g., 2-pyrazinyl group), and the like.

[0076] In this specification, the "monocyclic ring" includes, unless otherwise specified, all of a monocyclic saturated carbon ring, a monocyclic partially saturated carbon ring, a monocyclic unsaturated carbon ring, a monocyclic saturated heterocyclic ring, a monocyclic partially saturated heterocyclic ring, a monocyclic unsaturated heterocyclic ring, and an aromatic ring of a monocyclic ring. In this specification, the "bicyclic ring" includes, unless otherwise specified, all of a bicyclic saturated carbon ring, a bicyclic partially saturated carbon ring, a bicyclic unsaturated carbon ring, a bicyclic saturated heterocyclic ring, a bicyclic partially saturated heterocyclic ring, a bicyclic unsaturated heterocyclic ring, and an aromatic ring of a bicyclic ring.

[0077] Next, the meaning of the substituent accompanied by the term "optionally substituted" in this specification will be described. Note that "substitution" means that, unless otherwise specified, one or more hydrogen atoms at any position are substituted by an atom or a functional group other than a hydrogen atom. The medicament of the present invention is a medicament comprising a heteroaromatic amide derivative represented by the general formula (I) or a salt thereof. That is, the medicament of the present invention is either a heteroaromatic amide derivative represented by the general formula (I) or a salt thereof alone, or a pharmaceutical composition comprising these components and a pharmaceutically acceptable solid or liquid formulation carrier. The medicament of the present invention may also be a pharmaceutical composition optionally containing a component having pharmaceutical activity other than the heteroaromatic amide derivative represented by the general formula (I) or a salt thereof.

[0078] In the general formula (I) or the general formula (I-E2), R 2 The substituents of the "optionally substituted C1-C6 alkyl group", "optionally substituted C1-C6 haloalkyl group", "optionally substituted C2-C6 alkenyl group", "optionally substituted C2-C6 alkynyl group", and "optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring" in are a halogen atom, a cyano group, a carboxyl group, a carboxamide group, a hydroxyl group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C3-C7 cycloalkyl group, a heterocycloalkyl group, a C3-C7 cycloalkyloxy group, a heterocycloalkyloxy group, a C1-C4 alkylthio group, a C1-C4 haloalkylthio group, and -NR d1 R d2 (R d1 and R d2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group.) represents a substituent selected from the group consisting of. These may be substituted one or more at all substitutable positions.

[0079] In the general formula (I) or the general formula (I-E2), R 3a 、R 3b 、R 3c 、R 11b and R 11cIn the context of, "optionally substituted C1-C6 alkyl group", "optionally substituted C1-C6 haloalkyl group", "optionally substituted C1-C6 alkoxy group", "optionally substituted C1-C6 haloalkoxy group", "optionally substituted C1-C4 alkoxy-C1-C4 alkyl group", "optionally substituted C1-C4 haloalkoxy-C1-C4 alkyl group", "optionally substituted C1-C4 alkoxy-C1-C4 haloalkyl group", "optionally substituted C1-C4 haloalkoxy-C1-C4 haloalkyl group", "optionally substituted C1-C6 alkylcarbonyl group", "optionally substituted C1-C6 alkoxycarbonyl group", "optionally substituted C1-C6 alkylcarbonyloxy group", "optionally substituted C1-C6 haloalkylcarbonyl group", "optionally substituted C1-C6 haloalkoxycarbonyl group", "optionally substituted C1-C6 haloalkylcarbonyloxy group", "optionally substituted C3-C7 cycloalkyl group", "optionally substituted heterocycloalkyl group", "optionally substituted C3-C7 cycloalkyloxy group", "optionally substituted heterocycloalkyloxy group", "optionally substituted C2-C6 alkenyl group", "optionally substituted C2-C6 alkenyloxy group", "optionally substituted C2-C6 alkenyloxy-C1-C4 alkyl group", "optionally substituted C2-C6 alkenyloxy-C1-C4 haloalkyl group", "optionally substituted C2-C6 alkynyl group", "optionally substituted C2-C6 alkynyloxy group", "optionally substituted C2-C6 alkynyloxy-C1-C4 alkyl group", "optionally substituted C2-C6 alkynyloxy-C1-C4 haloalkyl group", "optionally substituted C1-C4 alkoxy-C1-C4 alkoxy group", "optionally substituted C1-C4 haloalkoxy-C1-C4 alkoxy group", "optionally substituted C2-C6 alkenyloxy-C1-C4 alkoxy group", "optionally substituted C2-C6 alkynyloxy-C1-C4 alkoxy group", "optionally substituted C2-C6 alkenyloxy-C1-C4 haloalkoxy group"The substituents of "optionally substituted C2-C6 alkynyloxy-C1-C4 haloalkoxy group", "optionally substituted C1-C6 alkylthio group", "optionally substituted C1-C6 haloalkylthio group", "optionally substituted C1-C4 alkylthio-C1-C4 alkyl group", "optionally substituted C1-C4 haloalkylthio-C1-C4 alkyl group", "optionally substituted C1-C4 alkylthio-C1-C4 haloalkyl group", "optionally substituted C1-C4 haloalkylthio-C1-C4 haloalkyl group", "optionally substituted C1-C6 alkylsulfonyl group" represent substituents selected from the group consisting of a halogen atom, a cyano group, a carboxyl group, a carboxamide group, a hydroxyl group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C3-C7 cycloalkyl group, a heterocycloalkyl group, a C3-C7 cycloalkyloxy group, a heterocycloalkyloxy group, a C1-C4 alkylthio group, a C1-C4 haloalkylthio group, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, an ethylmethylamino group, a (2,2,2-trifluoroethyl)amino group, a methyl(2,2,2-trifluoroethyl)amino group, an ethyl(2,2,2-trifluoroethyl)amino group, a bis(2,2,2-trifluoroethyl)amino group, a methylaminocarbonyl group, a dimethylaminocarbonyl group, an ethylaminocarbonyl group, a diethylaminocarbonyl group and an ethylmethylaminocarbonyl group. These can be substituted one or more at all possible substitution positions.,

[0080] In general formula (I) or general formula (I-E2), R 4a , R 4b or R 4cIn the case of, "optionally substituted C1-C6 alkyl group", "optionally substituted C1-C6 haloalkyl group", "optionally substituted C1-C6 alkoxy group", "optionally substituted C1-C6 haloalkoxy group", "optionally substituted C1-C4 alkoxy-C1-C4 alkyl group", "optionally substituted C1-C4 haloalkoxy-C1-C4 alkyl group", "optionally substituted C1-C4 alkoxy-C1-C4 haloalkyl group", "optionally substituted C1-C4 haloalkoxy-C1-C4 haloalkyl group", "optionally substituted C1-C6 alkylcarbonyl group", "optionally substituted C1-C6 alkoxycarbonyl group", "optionally substituted C1-C6 alkylcarbonyloxy group", "optionally substituted C1-C6 alkoxycarbonyloxy group", "optionally substituted C1-C6 haloalkylcarbonyl group", "optionally substituted C1-C6 haloalkoxycarbonyl group", "optionally substituted C1-C6 haloalkylcarbonyloxy group", "optionally substituted C3-C7 cycloalkyl group", "optionally substituted heterocycloalkyl group", "optionally substituted C3-C7 cycloalkyloxy group", "optionally substituted heterocycloalkyloxy group", "optionally substituted C2-C6 alkenyl group", "optionally substituted C2-C6 alkenyloxy group", "optionally substituted C2-C6 alkenyloxy-C1-C4 alkyl group", "optionally substituted C2-C6 alkenyloxy-C1-C4 haloalkyl group", "optionally substituted C2-C6 alkynyl group", "optionally substituted C2-C6 alkynyloxy group", "optionally substituted C2-C6 alkynyloxy-C1-C4 alkyl group", "optionally substituted C2-C6 alkynyloxy-C1-C4 haloalkyl group", "optionally substituted C1-C4 alkoxy-C1-C4 alkoxy group", "optionally substituted C1-C4 haloalkoxy-C1-C4 alkoxy group", "optionally substituted C2-C6 alkenyloxy-C1-C4 alkoxy group", "optionally substituted C2-C6 alkynyloxy-C1-C4 alkoxy group""Optionally substituted C2-C6 alkenyloxy-C1-C4 haloalkoxy group", "optionally substituted C2-C6 alkynyloxy-C1-C4 haloalkoxy group", "optionally substituted C1-C6 alkylthio group", "optionally substituted C1-C6 haloalkylthio group", "optionally substituted C1-C4 alkylthio-C1-C4 alkyl group", "optionally substituted C1-C4 haloalkylthio-C1-C4 alkyl group", "optionally substituted C1-C4 alkylthio-C1-C4 haloalkyl group", "optionally substituted C1-C4 haloalkylthio-C1-C4 haloalkyl group" substituents are halogen atoms, cyano groups, carboxyl groups, carboxamide groups, hydroxyl groups, C1-C4 alkyl groups, C1-C4 haloalkyl groups, C1-C4 alkoxy groups, C1-C4 haloalkoxy groups, C3-C7 cycloalkyl groups, heterocycloalkyl groups, C3-C7 cycloalkyloxy groups, heterocycloalkyloxy groups, C1-C4 alkylthio groups and C1-C4 haloalkylthio groups. These may be substituted one or more times at all substitutable positions.,

[0081] Next, in the heteroaromatic amide derivative of general formula (I) or general formula (I-E2) or a salt thereof contained in the pharmaceutical of the present invention, preferred atoms, substituents, and rings will be described below. As the above heteroaromatic amide derivative, a compound having at least one preferred atom, substituent, or ring is preferred, and a compound having a plurality of preferred atoms, substituents, or rings is more preferred.

[0082] Preferred Y 1 、Y 2 、Y 3 and Y 4 together form -OCH2CH2CH2-, -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2- -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2-, -OCH2CH2CH2CH2-, -OCR 4a HCH2CH2CH2-, -OCR 4a R 4b CH2CH2CH2- -OCH2CR 4a HCH2CH2-, -OCH2CR 4a R 4b CH2CH2- -CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2CH2OCH2-, -CH2CR 4a HOCH2- -CH2CH2CH2CH2-, -CH2CR 4a HCH2CH2-, -CH2CR 4a R 4b CH2CH2- -CH2CH2CR 4a HCH2-, -CH2CH2CR 4a R 4b CH2- -CH2SCH2CH2-, -CH2SO2CH2CH2- -NHCH2CH2CH2-, -NR 4c CH2CH2CH2-, -NR 4c CR 4a HCH2CH2- -NHCR 4a HCH2CH2- -CH2NR 4c CH2CH2-, -CH2NR 4c CR 4a HCH2-, -CH2NHCR 4a HCH2- -CH2CH2NR 4c CH2-, -CH2CR 4a HNR 4c CH2-, or -CH2CR 4a HNHCH2- when forming more preferred Y 1 , Y 2 , Y 3 and Y 4 are such that, when taken together -OCR 4a HCH2CH2-, -OCR 4a R4b CH2CH2- -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2- -OCH2CH2CH2CH2-, -OCR 4a HCH2CH2CH2-, -OCR 4a R 4b CH2CH2CH2- -OCH2CR 4a HCH2CH2-, -OCH2CR 4a R 4b CH2CH2- -CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2CH2OCH2-, -CH2CR 4a HOCH2- -CH2CH2CH2CH2-, -CH2CR 4a HCH2CH2-, -CH2CR 4a R 4b CH2CH2- -CH2CH2CR 4a HCH2-, -CH2CH2CR 4a R 4b CH2- -CH2SCH2CH2-, -CH2SO2CH2CH2- -NHCH2CH2CH2-, -NR 4c CH2CH2CH2-, -NR 4c CR 4a HCH2CH2- -NHCR 4a HCH2CH2- -CH2NR 4c CH2CH2-, -CH2NR 4c CR 4a HCH2-, -CH2NHCR 4a HCH2- -CH2CH2NR 4c CH2-, -CH2CR 4a HNR 4c CH2-, or -CH2CR 4a HNHCH2- when forming. Note that, for example, "Y 1 , Y2 , Y 3 and Y 4 together form -OCR 4a HCH2CH2-. " means that Y 1 is -O-, Y 2 is -CR 4a H-, Y 3 is -CH2-, Y 4 is -CH2-.

[0083] X 1 -X 2 When it is C-N (i.e., X 1 is a carbon atom and X 2 is a nitrogen atom).), preferred Y 1 , Y 2 , Y 3 and Y 4 together form -OCH2CH2CH2-, -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2-, -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2-, -OCH2CH2CH2CH2-, -OCR 4a HCH2CH2CH2-, -OCH2CR 4a HCH2CH2-, -CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2CR 4a HCH2CH2-, -CH2CR 4a R 4b CH2CH2-, -CH2CH2CR 4a HCH2-, -NHCH2CH2CH2-, -NR 4c CR 4a HCH2CH2-, -NHCR 4a HCH2CH2-, or -CH2NR 4c CH2CH2- when forming, In this case, more preferred Y 1, Y 2 , Y 3 and Y 4 are, when combined together, -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2-, -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2-, -OCH2CH2CH2CH2-, -OCR 4a HCH2CH2CH2-, -OCH2CR 4a HCH2CH2-, -CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2CR 4a HCH2CH2-, -CH2CR 4a R 4b CH2CH2-, -CH2CH2CR 4a HCH2-, -NHCH2CH2CH2-, -NR 4c CR 4a HCH2CH2-, -NHCR 4a HCH2CH2-, or, -CH2NR 4c CH2CH2- when formed, in which case, a more preferred Y 1 , Y 2 , Y 3 and Y 4 are, when combined together, -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2-, -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2-, -OCH2CH2CH2CH2-, -OCR 4a HCH2CH2CH2-, -OCH2CR 4a HCH2CH2-, -CH2CR 4a HCH2CH2-, -NR 4c CR 4aHCH2CH2-, -NHCR 4a HCH2CH2- or -CH2NR 4c CH2CH2- when forming In this case, more preferable Y 1 Y 2 Y 3 and Y 4 are such that when combined together, -OCR 4a HCH2CH2-, -OCR 4a HCH2- -OCR 4a HCH2CH2CH2-, -CH2CR 4a HCH2CH2- -NR 4c CR 4a HCH2CH2-, -NHCR 4a HCH2CH2- or -CH2NR 4c when forming CH2CH2- In this case, particularly preferable Y 1 Y 2 Y 3 and Y 4 are such that when combined together, -OCR 4a when forming HCH2CH2-. Also, in another aspect of the present invention in this case, particularly preferable Y 1 Y 2 Y 3 and Y 4 are such that when combined together, -CH2NR 4c when forming CH2CH2-.

[0084] X 1 -X 2 when X is N-C (i.e., when X 1 is a nitrogen atom and X 2 is a carbon atom.), preferable Y 1 Y 2 Y 3 and Y 4 are such that when combined together, -CH2CH2OCH2-, -CH2CR 4aHOCH2- -CH2CH2CH2CH2-, -CH2CR 4a HCH2CH2-, -CH2CR 4a R 4b CH2CH2- -CH2CH2NR 4c CH2-, -CH2CR 4a HNR 4c CH2-, or, -CH2CR 4a HNHCH2- when forming In this case, more preferred Y 1 Y 2 Y 3 and Y 4 are such that when combined together, -CH2CH2OCH2-, -CH2CR 4a HOCH2-, -CH2CR 4a HCH2CH2- -CH2CH2NR 4c CH2-, -CH2CR 4a HNR 4c CH2-, or, -CH2CR 4a HNHCH2- when forming In this case, even more preferred Y 1 Y 2 Y 3 and Y 4 are such that when combined together, -CH2CR 4a HOCH2-, -CH2CR 4a HCH2CH2-, -CH2CH2NR 4c CH2- -CH2CR 4a HNR 4c CH2-, or, -CH2CR 4a HNHCH2- when forming.

[0085] Z 1 is preferably a single bond, -CR 7a R 7b -, -O-, or, -S-, and more preferably a single bond.

[0086] Ring A is a monocyclic aromatic ring having 3 to 7 members or a bicyclic aromatic ring having 8 to 12 members, In one embodiment of the present invention, preferred Ring A is a monocyclic aromatic ring having 3 to 7 members. For example, in this case, Ring A is phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrazolyl, isothiazolyl, oxadiazyl, isoxazolyl, or thiadiazolyl. In this case, preferably, Ring A is phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, In this case, more preferably, Ring A is phenyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, In this case, still more preferably, Ring A is phenyl.

[0087] In one embodiment of the present invention, preferred Ring A is a bicyclic aromatic ring having 8 to 12 members, For example, in this case, Ring A is quinolinyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzimidazolyl, indolyl, isoindolyl, benzoxazolinyl, benzofuranyl, isobenzofuranyl, or indazolyl. In this case, preferably, Ring A is quinolinyl, benzimidazolyl, indolyl, or benzoxazolinyl, In this case, more preferably, Ring A is 8 - quinolinyl, 1 - benzimidazolyl, 3 - indolyl, or 2 - benzoxazolinyl.

[0088] R 1a and R 1bis, independently of each other, a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C3-C7 cycloalkyl group, a C1-C4 alkoxy-C1-C4 alkyl group, or a C1-C4 haloalkoxy-C1-C4 alkyl group, preferably, R 1a and R 1b are, independently of each other, a hydrogen atom, a halogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group, more preferably, R 1a and R 1b are, independently of each other, a hydrogen atom, or a halogen atom.

[0089] R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 haloalkyl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 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 an optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring, more preferably, R 2 is a hydrogen atom, or an optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring.

[0090] In one embodiment of the present invention, a preferred R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, or a cyano group, and in this case, a particularly preferred R 2 is a hydrogen atom.

[0091] Also, in another aspect of the present invention, when R 2 is an optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring, R 2A 3- to 7-membered monocyclic aromatic ring which may be substituted is preferred.

[0092] Also, in another aspect of the present invention, R 2 When it is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring which may be substituted, R 2 Is preferably a halogen atom, a cyano group, a carboxyl group, a carboxamide group, a hydroxyl group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C3-C7 cycloalkyl group, a heterocycloalkyl group, a C3-C7 cycloalkyloxy group, a heterocycloalkyloxy group, a C1-C4 alkylthio group, a C1-C4 haloalkylthio group, or -NR d1 R d2 (R d1 And R d2 Are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group.) A saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring which may be substituted, In this case, more preferably, R 2 Is a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, or -NR d1 R d2 (R d1 And R d2 Are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group.) An unsaturated 3- to 7-membered monocyclic ring which may be substituted.

[0093] Also, in another aspect of the present invention, R 2 When it is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring which may be substituted, R 2 Is preferably each a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or -NR d1 R d2 (R d1and R d2 is, independently of one another, a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group. ), phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrazolyl, isothiazolyl, oxadiazolyl, isoxazolyl, or thiadiazolyl, which may be substituted with In this case, R 2 is more preferably, each, a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or -NR d1 R d2 (R d1 and R d2 is, independently of one another, a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group. ), phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrazolyl, isothiazolyl, oxadiazolyl, isoxazolyl, or thiadiazolyl, which may be substituted with In this case, R 2 is even more preferably, each, a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or -NR d1 R d2 (R d1 and R d2 is, independently of one another, a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group. ), phenyl, pyrazolyl, triazolyl, pyridyl, or pyrazinyl, which may be substituted with In this case, R 2 is even more preferably, each, 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 d2is a methyl group, an ethyl group, a trifluoromethyl group, or a trifluoroethyl group. It may be substituted with a phenyl, pyrazolyl, or pyridyl group which may be substituted with

[0094] In another aspect of the present invention, preferred R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group which may be substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group, or Preferred R 2 is a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or -NR d1 R d2 (R d1 and R d2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group. It is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring which may be substituted with More preferred R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, or a cyano group, or More preferred R 2 is each a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or -NR d1 R d2 (R d1 and R d2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group. It is a phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, or thiadiazolyl which may be substituted with

[0095] R 3a 、R 3b and R 3cis preferably, each independently, a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with a heterocyclooxy group, a C1-C6 alkyl group substituted with a cyano group, a C1-C6 alkyl group substituted with a morpholino group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 alkyl group substituted with a dimethylamino group, a C1-C4 alkoxy-C1-C4 alkyl group substituted with a dimethylaminocarbonyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylcarbonyloxy group, a C1-C6 haloalkylcarbonyl group, a C1-C6 haloalkoxycarbonyl group, a C1-C6 haloalkylcarbonyloxy group, a C3-C7 cycloalkyl group, a heterocycloalkyl group, a C3-C7 cycloalkyloxy group, a heterocycloalkyloxy group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 haloalkyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group optionally substituted with a halogen atom, a C2-C6 alkynyloxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C2-C6 alkynyloxy-C1-C4 haloalkyl group, a C1-C4 alkoxy-C1-C4 alkoxy group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C2-C6 alkenyloxy-C1-C4 alkoxy group, a C2-C6 alkynyloxy-C1-C4 alkoxy group, a C2-C6 alkenyloxy-C1-C4 haloalkoxy group, a C2-C6 alkynyloxy-C1-C4 haloalkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, a C1-C4 alkylthio-C1-C4 haloalkyl group, a C1-C4 haloalkylthio-C1-C4 haloalkyl group,C1-C6 alkylsulfonyl group, -(CH2), p NR a1 R a2 (R a1 and R a2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group, and p is 0, 1, or 2. ), or general formula (I-A)

[0096]

Chemical formula

[0097] R 3a , R 3b and R 3c are more preferably each independently a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group optionally substituted with a dimethylaminocarbonyl group or a dimethylamino group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group optionally substituted with a halogen atom, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, -(CH2) p NR a1 R a2 (p, R a1 and R a2 are as defined in the above (0). ), or general formula (I-A)

[0098]

Chemical formula

[0099] More preferably, R 3a , R 3b and R 3c are each independently a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, -(CH2) p NR a1 R a2 (p is 1, and R a1 and R a2 are each independently a hydrogen atom, a methyl group, an ethyl group, or a 2,2,2-trifluoroethyl group.), or general formula (I-A)

[0100]

Chemical formula

[0101] More preferably, R 3a R 3b and R 3c are each independently a hydrogen atom, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group.

[0102] R 4a R 4b and R 4cis preferably, each independently, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkyl group which may be substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkyl group which may be substituted with a hydroxyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group which may be substituted with a C1-C4 haloalkoxy group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylcarbonyloxy group, a C1-C6 haloalkylcarbonyl group, a C1-C6 haloalkoxycarbonyl group, a C1-C6 haloalkylcarbonyloxy group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyl group which may be substituted with a halogen atom, a heterocycloalkyl group, a C3-C7 cycloalkyloxy group, a heterocycloalkyloxy group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 alkyl group which may be substituted with a halogen atom, a C2-C6 alkenyloxy-C1-C4 haloalkyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group which may be substituted with a halogen atom or a methoxy group, a C2-C6 alkynyloxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C2-C6 alkynyloxy-C1-C4 haloalkyl group, a C1-C4 alkoxy-C1-C4 alkoxy group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C2-C6 alkenyloxy-C1-C4 alkoxy group, a C2-C6 alkynyloxy-C1-C4 alkoxy group, a C2-C6 alkenyloxy-C1-C4 haloalkoxy group, a C2-C6 alkynyloxy-C1-C4 haloalkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group,A C1-C4 alkylthio-C1-C4 haloalkyl group, a C1-C4 haloalkylthio-C1-C4 haloalkyl group, a pentafluorosulfanyl group, -(CH2) q NR b1 R b2 (R b1 and R b2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group, and q is 0, 1, 2, or 3.), or a general formula (I-B)

[0103]

Chemical formula

[0104] R 4a , R 4b and R 4cis more preferably, each independently, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 alkyl group which may be substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkyl group which may be substituted with a hydroxyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group which may be substituted with a C1-C4 haloalkoxy group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 haloalkylcarbonyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyl group which may be substituted with a halogen atom or a C1-C4 haloalkyl group, a heterocycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 alkyl group which may be substituted with a halogen atom, a C2-C6 alkynyl group, a C2-C6 alkynyl group which may be substituted with a halogen atom or a methoxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, -(CH2) q NR b1 R b2 (q, R b1 and R b2 has the same meaning as the definition shown in the above (0).), or, general formula (I-B)

[0105]

Chemical formula

[0106] In one embodiment of the present invention, preferred R 4a , R 4b and R 4cis, independently of one another, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group which may be substituted with a C1-C4 haloalkoxy group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, or -(CH2) q NR b1 R b2 (q, R b1 and R b2 are as defined in (0) above.). More preferably, it is a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C4 alkoxy-C1-C4 alkyl group which may be substituted with a C1-C4 haloalkoxy group, a C1-C4 haloalkoxy-C1-C4 alkyl group, or a C1-C4 haloalkoxy-C1-C4 alkoxy group.

[0107] 4a R 4b and R 4c are groups represented by the general formula (I-B), R 4a R 4b and R 4c are the following formula

[0108]

Chemical formula

[0109]

Chemical formula

[0110]

Chemical formula

[0111]

Chemical formula

[0112]

Chem.

[0113]

Chem.

[0114]

Chem.

[0115]

Chem.

[0116] Also, in another aspect of the present invention, preferred R 4a , R 4b and R 4c are each independently a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group optionally substituted with a C1-C4 haloalkoxy group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, -(CH2) q NR b1 R b2 (q, R b1 and R b2 are as defined in (0) above. ), or the following formula

[0117]

Chemical formula

[0118]

Chemical formula

[0119] In each case where the configurations (i) to (v) in the above (0) are satisfied, R 5a , R 5b , R 5c , R 6a , R 6b and n will be further described.

[0120] R 5a , R 5b , R 5c , R 6a , R 6b and n, when the configuration of (i) in the above (0) is satisfied,[[]] R 5b and R 5c together form a single bond, -CH2O-, -CH2S-, -CH2NR e1 -, -CH2CH2-, or -CONR e1 -(R e1 and R e2 are as defined in the above (0).), and R 5a is a hydrogen atom or a C1-C6 alkyl group, and R 6a and R 6b are, independently of one another, a hydrogen atom, a fluorine atom, a hydroxyl group, or a methoxy group,[[]] a compound in which n is 1 or 2 is preferred.[[]] More preferably, R 5a , R 5b , R 5c , R 6a and R 6b are such that R 5b and R 5c together form -CH2O-, and R 5a , R 6a and R 6b are hydrogen atoms and n is 1 is preferred.[[]]

[0121] R 5a 、R 5b 、R 5c 、R 6a 、R 6b and when R and n satisfy the configuration of (ii) in the said (0), R 5a and R 6a together form -CH2-, -CH2CH2-, -CH2CR e1 R e2 -, -CH2CH2CH2-, -CH2CH2O-, -CH2CH2CH2O- (where R e1 and R e2 have the same meanings as those defined in the said (0).), and R 5b is a hydrogen atom or a C1-C4 alkyl group, R 5c and R 6b are a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C4 alkyl group, or a C1-C4 alkoxy group, Compounds where n is 1 are preferred. More preferably, R 5a , R 5b , R 5c , R 6a and R 6b are such that R 5a and R 6a together form -CH2CH2- or -CH2CH2O-, R 5b , R 5c and R 6b are hydrogen atoms, Compounds where n is 1 are preferred.

[0122] R 5a 、R 5b 、R 5c 、R 6a 、R 6b and when R and n satisfy the configuration of (iii) in the said (0), R 5a is a hydrogen atom, a C1-C6 alkyl group, a C3-C7 cycloalkyl group, or a heterocycloalkyl group, a C3-C7 cycloalkyl-C1-C4 alkyl group, and R5b and R 5c is a hydrogen atom, R 6a and R 6b are each independently a hydrogen atom, a halogen atom, or alternatively, R 6a and R 6b together with the carbon atom to which they are attached form a 3- to 7-membered monocyclic ring, and a compound in which n is 1 or 2 is preferred.

[0123] R 5a , R 5b , R 5c , R 6a , R 6b and n satisfy the configuration of (iv) in the above (0), R 5a and R 5b together form -CH2CH2- or -CH2CH2CH2-, and R 5c , R 6a and R 6b are hydrogen atoms, a compound in which n is 1 or 2 is preferred.

[0124] R 5a , R 5b , R 5c , R 6a , R 6b and n satisfy the configuration of (v) in the above (0), R 6a and R 5c together form -OCH2-, -CH2O-, or -CH2CH2-, 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 a compound in which n is 1 is preferred.

[0125] To further explain each case where the configurations (i) to (v) in the above (0) are satisfied, R 5a 、R 5b 、R 5c 、R 6a 、R 6b and n satisfy the configuration (i) in the above (0), a compound in which Z 1 is a single bond is preferred; R 5a 、R 5b 、R 5c 、R 6a 、R 6b and n satisfy the configuration (ii) in the above (0), a compound in which Z 1 is a single bond or -O- is preferred; R 5a 、R 5b 、R 5c 、R 6a 、R 6b and n satisfy the configuration (iii) in the above (0), a compound in which Z 1 is a single bond, -CR 7a R 7b - or -O- is preferred; R 5a 、R 5b 、R 5c 、R 6a 、R 6b and n satisfy the configuration (iv) in the above (0), a compound in which Z 1 is a single bond or -CR 7a R 7b - is preferred; and R 5a 、R 5b 、R 5c 、R 6a 、R 6b and n satisfy the configuration (v) in the above (0), a compound in which Z 1 is a single bond or -CR 7a R 7b - is preferred.

[0126] In one embodiment of the present invention, ring A of the compound represented by general formula (I) is phenyl, and Z 1 is a single bond, and R5a , R 5b , R 5c , R 6a , R 6b and n satisfy the configuration of (i) in the said (0), the following formula (I-E):

[0127] [Chemical formula] [In the formula, 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 shown in the said (0) (provided that 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-, -CH2CR 4a R 4b -, or -CH2CR 4a H- (R 4a , R 4b are synonymous with the definitions shown in the said (0).), Z 2 -Z 3 , R 5a , R 11a , R 11b , R 11c are synonymous with the definitions shown in the said (7).] A medicament comprising a heteroaromatic amide derivative represented by the formula or a salt thereof is preferred.

[0128] In the general formula (I-E), X 1 -X 2 , Y 1 , Y 2 , Y 3 , Y 4 , R1a , R 1b , R 2 The preferred substituents of R are as described above.

[0129] In general formula (I-E) or general formula (I-E2), Z 2 -Z 3 is preferably -CH2O-, -CH2S-, -CH2NR f1 -, -CH2CH2-, or -CONR f1 -(where R f1 and R f2 are a hydrogen atom or a C1-C4 alkyl group). More preferably, Z 2 -Z 3 forms -CH2O-.

[0130] In general formula (I), general formula (I-E), or general formula (I-E2), R 5a is more preferably a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C7 cycloalkyl group, or a heterocycloalkyl group, More preferably, R 5a is a hydrogen atom.

[0131] In general formula (I-E2), when Z 4 is C-R 11a , R 11a is preferably a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group, More preferably, R 11a is a hydrogen atom, a halogen atom, a cyano group, a C1-C6 alkyl group, or a C1-C6 haloalkyl group, Even more preferably, R 11a is a hydrogen atom.

[0132] In general formula (I-E2), R 11b is the R 3b in (0) above, and its preferred substituents are the preferred R 3b above. In the general formula (I-E2), R 11c is the R in the above (0) 3c and its preferred substituents are the above preferred R 3c .

[0133] Next, in the heteroaromatic amide derivative represented by the general formula (I), the general formula (I-E) or the general formula (I-E2) contained in the medicament of the present invention or a salt thereof, preferred combinations of atoms, substituents or rings will be described below.

[0134] In one embodiment of the present invention, in the compound having at least one of R 3a , R 3b and R 3c and R 4a , R 4b and R 4c , preferred combinations of these substituents are R 3a , R 3b and R 3c are each independently a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 alkyl group optionally substituted with a dimethylaminocarbonyl group or a dimethylamino group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group optionally substituted with a halogen atom, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, -(CH2) p NR a1 R a2 (p, R a1 and R a2 are as defined in the above (0).), or the general formula (I-A)

[0135] [Chemical formula] {In the formula, ring B is C3-C7 cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, L 1 is a single bond, -CH2-, -CH2O-, -OCH2-, -CH2CH2-, or -CH2OCH2-, R 8a R 8b and R 8c are each independently a hydrogen atom, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyloxy group, a heterocycloalkyl group, a heterocycloalkyloxy group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group.} It is a group represented by, and R 4a R 4b and R 4c may each independently be substituted with a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 haloalkoxy group-substituted C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, -(CH2) q NR b1 R b2 (q, R b1 and R b2 are as defined in (0) above. ), or the following formula

[0136] [Chemical formula] (wherein R 9a , R 9b and R 9c are substituents selected from the group consisting of those having the same meanings as defined in the above (0).), a combination.)

[0137] 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-E) or the general formula (I-E2), R 11a and R 11b and R 11c , preferred combinations of these substituents are R 11a is a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group, and R 11b and R 11c are each independently a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 alkyl group optionally substituted with a dimethylaminocarbonyl group or a dimethylamino group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group optionally substituted with a halogen atom, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, -(CH2) p NR a1 R a2 (p, R a1 and R a2 have the same meanings as defined in the above (0).), or the general formula (I-A)

[0138] [Chemical formula] {In the formula, ring B is C3-C7 cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, L 1 is a single bond, -CH2-, -CH2O-, -OCH2-, -CH2CH2-, or -CH2OCH2-, R 8a , R 8b and R 8c are each independently a hydrogen atom, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyloxy group, a heterocycloalkyl group, a heterocycloalkyloxy group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group.} It is a group represented by, and R 4a , R 4b and R 4c may each independently be a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group optionally substituted with a C1-C4 haloalkoxy group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, -(CH2) q NR b1 R b2 (q, R b1 and R b2 are as defined in (0) above. ), or the following formula

[0139] [Chemistry] (In the formula, R 9a , R 9b and R 9c are substituents selected from the group consisting of those having the same meaning as the definitions shown in the above (0).) is a combination.

[0140] In one embodiment of the present invention, in a compound having at least one of R 4a , R 4b and R 4c and R 2 , a preferred combination of these substituents is R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, or a cyano group, and R 4a , R 4b and R 4cis, independently of one another, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 alkyl group which may be substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkyl group which may be substituted with a hydroxyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group which may be substituted with a C1-C4 haloalkoxy group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 haloalkylcarbonyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyl group which may be substituted with a halogen atom or a C1-C4 haloalkyl group, a heterocycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 alkyl group which may be substituted with a halogen atom, a C2-C6 alkynyl group, a C2-C6 alkynyl group which may be substituted with a halogen atom or a methoxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, -(CH2) q NR b1 R b2 (q, R b1 and R b2 has the same meaning as the definition shown in the above (0).), or the general formula (I-B)

[0141]

Chemical formula

[0142] In one embodiment of the present invention, in the compound having Z 2 -Z 3 and R 6a and R 6b and R 11a , R 11b and R 11c , the preferred combination of these substituents is Z 2 -Z 3 is -CH2O-, -CH2S-, -CH2NR f1 -, -CH2CH2-, or -CONR f1 - (R f1 and R f2 are a hydrogen atom or a C1-C4 alkyl group.). R 6a and R 6b are each independently a hydrogen atom, a fluorine atom, a hydroxyl group, or a methoxy group, R 11a is a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group, R 11b and R 11c are each independently a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 alkyl group optionally substituted with a dimethylaminocarbonyl group or a dimethylamino group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group optionally substituted with a halogen atom, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, -(CH2) p NR a1 R a2 (p, R a1 and R a2 are as defined in (0) above. ), or the general formula (I-A)

[0143]

Chemical formula

[0144] Next, preferred compounds of the heteroaromatic amide derivative represented by the general formula (I) or the general formula (I-E2) contained in the medicine of the present invention will be described.

[0145] 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 the heteroaromatic amide derivative or a salt thereof contained in the medicine described in (1) to (15) above.

[0146] 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 "derivatives". Any "derivative" also includes its pharmaceutically acceptable salt, and one compound may belong to a plurality of "derivatives".

[0147] (a) type derivative: X in the general formula (I) or the general formula (I-E2) 1 -X 2 is C-N, and Y 1 is -O-, which is a group of compounds, specifically, 2,3-dihydropyrazolo[5,1-b]oxazole derivatives, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine derivatives, 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxepine derivatives, etc. (b) type derivative: X in general formula (I) or general formula (I-E2) 1 -X 2 is C-N, and Y 1 is -CH2-, and the group of compounds is, specifically, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine derivatives, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine derivatives, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine derivatives, etc. (c)-type derivatives: X in general formula (I) or general formula (I-E2) 1 -X 2 is N-C, and Y 1 is -CH2-, and the group of compounds is, specifically, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine derivatives, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine derivatives, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine derivatives, etc. (d)-type derivatives: R in general formula (I) or general formula (I-E2) 2 is a heteroaromatic amide derivative which is an optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring

[0148] Next, each "derivative" will be described separately to show the compounds of preferred embodiments. Any compound included therein is a concept including its optically active form and also includes its pharmaceutically acceptable salts.

[0149] Preferred (a)-type derivatives included in general formula (I) or general formula (I-E2) contained in the medicament of the present invention are the following compounds.

[0150] a1) The following general formula (I-F):

[0151]

Chemical formula

[0152] a2) The following general formula (I-G)

[0153]

Chemical formula

[0154] a3) In the general formula (I-G), Y 2 , Y 3 and Y 4 when taken together, -CR 4a HCH2CH2-, -CR 4a R 4b CH2CH2-, -CH2CH2-, -CR 4a HCH2-, -CR 4a R 4b CH2-, -CH2CH2CH2CH2-, -CR 4a HCH2CH2CH2-, or -CH2CR 4a HCH2CH2- (R 4a , R 4b are as defined in (0) above.), the heteroaromatic amide derivative or a salt thereof according to a1) above.

[0155] a4) In the general formula (I-G), Z 2 -Z 3 is -CH2O-, -CH2S-, -CH2NR f1 -, -CH2CH2-, or -CONR f1 - (R f1 and R f2is synonymous with the definition shown in the above (7).), R 5a 、R 6a and R 6b are hydrogen atoms, the heteroaromatic amide derivative or a salt thereof according to the above a2) or a3).

[0156] a5) The heteroaromatic amide derivative or a salt thereof according to any one of the above a2) to a4), in the general formula (I-G), Z 2 -Z 3 is -CH2O-, R 11a is a hydrogen atom, a halogen atom, a cyano group, a C1-C6 alkyl group, or a C1-C6 haloalkyl group, R 11b and R 11c are each independently a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 alkyl group optionally substituted with a dimethylaminocarbonyl group or a dimethylamino group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group optionally substituted with a halogen atom, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, -(CH2) p NR a1 R a2 (p, R a1 and R a2 are synonymous with the definition shown in the above (0).), or the general formula (I-A)

[0157]

Chemical formula

[0158] a6) A heteroaromatic amide derivative or a salt thereof according to any one of a2) to a5) above, wherein in the general formula (I-G), R 4ais a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 alkyl group which may be substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkyl group which may be substituted with a hydroxyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group which may be substituted with a C1-C4 haloalkoxy group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 haloalkylcarbonyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyl group which may be substituted with a halogen atom or a C1-C4 haloalkyl group, a heterocycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 alkyl group which may be substituted with a halogen atom, a C2-C6 alkynyl group, a C2-C6 alkynyl group which may be substituted with a halogen atom or a methoxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, -(CH2) q NR b1 R b2 (q, R b1 and R b2 are as defined in (0) above. ), or the general formula (I-B)

[0159] [Chemical formula] {In the formula, Ring C is C3-C7 cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, 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 (CR10c 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 - is (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 shown in the said (0).), R 9a , R 9b and R 9c are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 alkoxycarbonyl group, a heterocycloalkyloxy group, or -(CH2) s NR d1 R d2 (s, R d1 and R d2 are synonymous with the definitions shown in the said (0).).}, A heteroaromatic amide derivative or a salt thereof.

[0160] a7) A heteroaromatic amide derivative or a salt thereof according to any one of a2) to a6) above, wherein in the general formula (I-G), Y 2 , Y 3 and Y 4 together are -CR4a to form HCH2CH2-, R 4a is a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group optionally substituted with a C1-C4 haloalkoxy group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, -(CH2) q NR b1 R b2 (q, R b1 and R b2 are as defined in (0) above. ), or the following formula

[0161]

Chemical formula

[0162] [Chemical formula] {In the formula, ring B is C3-C7 cycloalkyl, morpholino, phenyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, L 1 is a single bond, R 8a R 8b and R 8c are each independently a hydrogen atom, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group.} It is a group represented by a heteroaromatic amide derivative or a salt thereof.

[0163] a8) The compound represented by the general formula (I-F) or the general formula (I-G) (the meanings of the numbers and asterisks (*) are as defined in (15) above).

[0164] [Chemical formula]

[0165] [Chemical formula] JPEG0007701162000061.jpg93152

[0166] [Chemical formula]

[0167] [Chemical formula] JPEG0007701162000064.jpg89153

[0168] [Chemical formula] JPEG0007701162000066.jpg61152

[0169]

Chem.

[0170] Preferred (b) - type derivatives included in the general formula (I) or general formula (I - E2) contained in the pharmaceutical of the present invention are the following compounds.

[0171] b1) General formula (I - H):

[0172]

Chem.

[0173] b2) General formula (I-I)

[0174]

Chemical formula

[0175] b3) In the general formula (I-I), Y 2 、Y 3 and Y 4 are such that, when taken together, -OCH2CH2-, -OCH2CH2CH2-, -CR 4a HCH2CH2-, -CR 4a R 4b CH2CH2-, -CH2CR 4a HCH2-, or -NR 4c CH2CH2- is formed (R 4a 、R 4b and R 4c are as defined in the above (0).), the heteroaromatic amide derivative or a salt thereof described in the above b2).

[0176] b4) The heteroaromatic amide derivative or a salt thereof according to b2) or b3), wherein in the general formula (I-I), Z 2 -Z 3 is -CH2O-, -CH2S-, -CH2NR f1 -, -CH2CH2-, or -CONR f1 - (R f1 and R f2 are as defined in the above (7).), R 5a 、R 6a and R 6b are hydrogen atoms, a heteroaromatic amide derivative or a salt thereof.

[0177] b5) The compound represented by the general formula (I-H) or the general formula (I-I) (the meaning of the numbers is as defined in the above (15)) is

[0178]

Chemical formula

[0179] Preferred (c) - type derivatives included in the general formula (I) or general formula (I - E2) contained in the pharmaceutical of the present invention are the following compounds.

[0180] c1) General formula (I - J):

[0181]

Chemical formula

[0182] c2) General formula (I-K)

[0183]

Chemical formula

[0184] c3) The heteroaromatic amide derivative or a salt thereof according to c2), wherein in the general formula (I-K), Y 2 、Y 3 and Y 4 together form -CR 4a HOCH2-, -CR 4a HCH2CH2-, -CH2NR 4c CH2-, -CR 4a HNR 4c CH2-, or -CR 4a HNHCH2- (R 4a and R 4c are as defined in (0) above.), a heteroaromatic amide derivative or a salt thereof.

[0185] c4) The heteroaromatic amide derivative or a salt thereof according to c2) or c3), wherein in the general formula (I-K), Z 2 -Z 3 is -CH2O-, -CH2S-, -CH2NR f1 -, -CH2CH2-, or -CONR f1 - (R f1 and R f2 are as defined in (7) above.), R 5a 、R 6a and R 6b are hydrogen atoms, a heteroaromatic amide derivative or a salt thereof.

[0186] c5) The compound represented by the general formula (I-J) or the general formula (I-K) (the meaning of the numbers is as defined in (15) above) is

[0187]

Chemical formula

[0188] Preferred (d) - type derivatives included in the general formula (I) or general formula (I - E2) contained in the medicine of the present invention are the following compounds.

[0189] d1) General formula (I):

[0190]

Chemical formula

[0191] d2) General formula (I-E2):

[0192] [Chemical formula] [In the formula, R 1a , R 1b , R 6a , R 6b has the same meaning as the definition shown in the above (0), Z 2 -Z 3 , Z 4 , R 5a , R 11b , R 11c has the same meaning as the definition shown in the above (7), R 2 is an optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring,[[]] Y 1 , Y 2 , Y 3 and Y 4 together form -OCH2CH2CH2-, -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2- -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2-, -OCH2CH2CH2CH2-, -OCR 4a HCH2CH2CH2-, -OCR 4a R 4b CH2CH2CH2-, -OCH2CR 4a HCH2CH2-, -OCH2CR 4a R 4b CH2CH2-, -CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2CH2OCH2-, -CH2CR 4a HOCH2- -CH2CH2CH2CH2-, -CH2CR 4a HCH2CH2-, -CH2CR4a R 4b CH2CH2-, -CH2CH2CR 4a HCH2-, -CH2CH2CR 4a R 4b CH2-, -CH2SCH2CH2-, -CH2SO2CH2CH2-, -NHCH2CH2CH2-, -NR 4c CH2CH2CH2-, -NR 4c CR 4a HCH2CH2-, -NHCR 4a HCH2CH2-, -CH2NR 4c CH2CH2-, -CH2NR 4c CR 4a HCH2-, -CH2NHCR 4a HCH2-, -CH2CH2NR 4c CH2-, -CH2CR 4a HNR 4c CH2-, or, -CH2CR 4a HNHCH2- to form (R 4a 、R 4b and R 4c are synonymous with the definitions given in said (0).), X 1 -X 2 is N-C or C-N (provided that in the case of C-N, Y 1 、Y 2 、Y 3 and Y 4 together do not form -OCH2CH2CH2-, -OCR 4a HCH2CH2-, or, -OCR 4a R 4b CH2CH2-.). A heteroaromatic amide derivative represented by [] or a salt thereof.

[0193] d3) The heteroaromatic amide derivative or a salt thereof according to d2) above, wherein in the general formula (I-E2), Z 2 -Z 3 is -CH2O-, -CH2S-, -CH2NR f1-, -CH2CH2-, or -CONR f1 - where (R f1 and R f2 are as defined in (7) above.). R 5a , R 6a and R 6b are hydrogen atoms, a heteroaromatic amide derivative or a salt thereof.

[0194] d4) In the heteroaromatic amide derivative or a salt thereof according to any one of d2) to d3) above, in the general formula (I-E2), R 2 is each independently a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or -NR d1 R d2 (R d1 and R d2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group). Optionally substituted with phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, or thiadiazolyl, a heteroaromatic amide derivative or a salt thereof.

[0195] d5) A heteroaromatic amide derivative or a salt thereof according to any one of d3) to d4) above, in the general formula (I-E2), R 2 is each independently a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or -NR d1 R d2 (R d1 and R d2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group). Optionally substituted with phenyl, pyrazolyl, triazolyl, pyridyl, or pyrazinyl, a heteroaromatic amide derivative or a salt thereof.

[0196] d6) Any one of the heteroaromatic amide derivatives or salts thereof according to d3) to d5), wherein in the general formula (I-E2), R 2 is each 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 trifluoromethyl group, or a trifluoroethyl group.) and may be substituted with phenyl, pyrazolyl, or pyridyl, which is a heteroaromatic amide derivative or a salt thereof.

[0197] d7) The compound represented by the general formula (I) or the general formula (I-E2) (the meaning of the numbers is as defined in (15) above) is

[0198]

Chemical formula

[0199] Next, another embodiment of the present invention will be described. The present invention also includes, for example, the following inventions.

[0200] 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 6b and n have the same meanings as defined in (0) above, Y 1 , Y 2 , Y 3 and Y 4 are each independently a single bond, -CH2-, -CH2CH2-, -CR 4a R 4b-, -CR 4a H-, -CR 4b H-, -CH2CR 4a R 4b -, -CH2CR 4a H-, -NR 4c -, -NH-, -S-, -SO2-, or -O-, R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group, or R 2 is a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or -NR d1 R d2 (R d1 and R d2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group.) is an optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring, R 3a 、R 3b and R 3cis, independently of each other, a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, a C1-C6 alkyl group, a heterocyclooxy-substituted C1-C6 alkyl group, a C1-C6 alkyl group substituted with a cyano group, a C1-C6 alkyl group substituted with a morpholino group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 alkyl group substituted with a dimethylamino group, a C1-C4 alkoxy-C1-C4 alkyl group substituted with a dimethylaminocarbonyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylcarbonyloxy group, a C1-C6 haloalkylcarbonyl group, a C1-C6 haloalkoxycarbonyl group, a C1-C6 haloalkylcarbonyloxy group, a C3-C7 cycloalkyl group, a heterocycloalkyl group, a C3-C7 cycloalkyloxy group, a heterocycloalkyloxy group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 haloalkyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group optionally substituted with a halogen atom, a C2-C6 alkynyloxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C2-C6 alkynyloxy-C1-C4 haloalkyl group, a C1-C4 alkoxy-C1-C4 alkoxy group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C2-C6 alkenyloxy-C1-C4 alkoxy group, a C2-C6 alkynyloxy-C1-C4 alkoxy group, a C2-C6 alkenyloxy-C1-C4 haloalkoxy group, a C2-C6 alkynyloxy-C1-C4 haloalkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, a C1-C4 alkylthio-C1-C4 haloalkyl group, a C1-C4 haloalkylthio-C1-C4 haloalkyl group,C1-C6 alkylsulfonyl group, -(CH2), p NR a1 R a2 (R a1 and R a2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group, and p is 0, 1, or 2.), or general formula (I-A)

[0201] [Chemical formula] {In the formula, ring B, L 1 , R 8a , R 8b , R 8c are as defined in the above (0).} is a group represented by, R 4a , R 4b and R 4cis, independently of each other, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkyl group optionally substituted with a hydroxyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylcarbonyloxy group, a C1-C6 haloalkylcarbonyl group, a C1-C6 haloalkoxycarbonyl group, a C1-C6 haloalkylcarbonyloxy group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyl group optionally substituted with a halogen atom, a heterocycloalkyl group, a C3-C7 cycloalkyloxy group, a heterocycloalkyloxy group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 alkyl group optionally substituted with a halogen atom, a C2-C6 alkenyloxy-C1-C4 haloalkyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group optionally substituted with a halogen atom or a methoxy group, a C2-C6 alkynyloxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C2-C6 alkynyloxy-C1-C4 haloalkyl group, a C1-C4 alkoxy-C1-C4 alkoxy group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C2-C6 alkenyloxy-C1-C4 alkoxy group, a C2-C6 alkynyloxy-C1-C4 alkoxy group, a C2-C6 alkenyloxy-C1-C4 haloalkoxy group, a C2-C6 alkynyloxy-C1-C4 haloalkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, a C1-C4 alkylthio-C1-C4 haloalkyl group, a C1-C4 haloalkylthio-C1-C4 haloalkyl group, a pentafluorosulfanyl group, -(CH2)q NR b1 R b2 (R b1 and R b2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group, and q is 0, 1, 2, or 3.), or the general formula (I-B)

[0202]

Chemical formula

[0203]

Chemical formula

[0204] A2) In the general formula (I), Y 1 , Y 2 , Y 3 and Y 4 together are -OCH2CH2CH2-, -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2- -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2- -OCH2CH2CH2CH2-, -OCR 4a HCH2CH2CH2-, -OCR 4a R 4b CH2CH2CH2- -OCH2CR 4a HCH2CH2-, -OCH2CR 4a R 4b CH2CH2- -CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2CH2OCH2-, -CH2CR 4a HOCH2- -CH2CH2CH2CH2-, -CH2CR 4a HCH2CH2-, -CH2CR 4a R 4b CH2CH2- -CH2CH2CR 4a HCH2-, -CH2CH2CR 4a R 4b CH2- -CH2SCH2CH2-, -CH2SO2CH2CH2- -NHCH2CH2CH2-, -NR 4c CH2CH2CH2-, -NR 4c CR 4a HCH2CH2- -NHCR4a HCH2CH2-、 -CH2NR 4c CH2CH2-、-CH2NR 4c CR 4a HCH2-、-CH2NHCR 4a HCH2-、 -CH2CH2NR 4c CH2-、-CH2CR 4a HNR 4c CH2-、 or, -CH2CR 4a forms HNHCH2- (R 4a 、R 4b and R 4c are synonymous with the definitions shown in said A1).), R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, or a cyano group, or R 2 is each, independently, a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or -NR d1 R d2 (R d1 and R d2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group.).) may be substituted with phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, or thiadiazolyl (provided that X 1 -X 2 is C-N, and Y 1 、Y 2 、Y 3 and Y 4 together form -OCH2CH2CH2-, -OCR 4a HCH2CH2-, or -OCR 4a R 4b CH2CH2-, then R 2 is a hydrogen atom.). The medicament according to said A1) comprising a heteroaromatic amide derivative or a salt thereof.

[0205] A3) In the general formula (I), X 1 -X 2 is C-N, Y 1 Y 2 Y 3 and Y 4 together form -OCH2CH2CH2-, -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2-, -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2-, -OCH2CH2CH2CH2-, -OCR 4a HCH2CH2CH2-, -OCH2CR 4a HCH2CH2-, -CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2CR 4a HCH2CH2-, -CH2CR 4a R 4b CH2CH2-, -CH2CH2CR 4a HCH2-, -NHCH2CH2CH2-, -NR 4c CR 4a HCH2CH2-, -NHCR 4a HCH2CH2-, or -CH2NR 4c CH2CH2- (where R 4a R 4b and R 4c are as defined in A1) above).), R 5a R 5b R 5c R 6a R 6b and n satisfy any one of the structures shown in (i) to (iii) in (0) above, a pharmaceutical comprising a heteroaromatic amide derivative or a salt thereof as described in A1) or A2) above.

[0206] A4) In the general formula (I), X 1 -X 2 、Z 1 、ring A, R 1a 、R 1b has the same meaning as the definition shown in the above (0), Y 1 、Y 2 、Y 3 and Y 4 each independently represents a single bond, -CH2-, -CH2CH2-, -CR 4a R 4b -, -CR 4a H-, -CR 4b H-, -CH2CR 4a R 4b -, -CH2CR 4a H-, -NR 4c -, -NH-, -S-, -SO2-, or -O-, R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group, or R 2 is a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or -NR d1 R d2 (R d1 and R d2 each independently represents a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group.) is an optionally substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring, R 3a 、R 3b and R 3cis, independently of each other, a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, a C1-C6 alkyl group, a heterocyclooxy-substituted C1-C6 alkyl group, a C1-C6 alkyl group substituted with a cyano group, a C1-C6 alkyl group substituted with a morpholino group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 alkyl group substituted with a dimethylamino group, a C1-C4 alkoxy-C1-C4 alkyl group substituted with a dimethylaminocarbonyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylcarbonyloxy group, a C1-C6 haloalkylcarbonyl group, a C1-C6 haloalkoxycarbonyl group, a C1-C6 haloalkylcarbonyloxy group, a C3-C7 cycloalkyl group, a heterocycloalkyl group, a C3-C7 cycloalkyloxy group, a heterocycloalkyloxy group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 haloalkyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group optionally substituted with a halogen atom, a C2-C6 alkynyloxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C2-C6 alkynyloxy-C1-C4 haloalkyl group, a C1-C4 alkoxy-C1-C4 alkoxy group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C2-C6 alkenyloxy-C1-C4 alkoxy group, a C2-C6 alkynyloxy-C1-C4 alkoxy group, a C2-C6 alkenyloxy-C1-C4 haloalkoxy group, a C2-C6 alkynyloxy-C1-C4 haloalkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, a C1-C4 alkylthio-C1-C4 haloalkyl group, a C1-C4 haloalkylthio-C1-C4 haloalkyl group,C1-C6 alkylsulfonyl group, -(CH2), p NR a1 R a2 (R a1 and R a2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group, and p is 0, 1, or 2.), or general formula (I-A)

[0207] [Chemical formula] {In the formula, ring B, L 1 , R 8a , R 8b , R 8c are synonymous with the definitions shown in the above (0).} is a group represented by R 4a , R 4b and R 4cis, independently of one another, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkyl group optionally substituted with a hydroxyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylcarbonyloxy group, a C1-C6 haloalkylcarbonyl group, a C1-C6 haloalkoxycarbonyl group, a C1-C6 haloalkylcarbonyloxy group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyl group optionally substituted with a halogen atom, a heterocycloalkyl group, a C3-C7 cycloalkyloxy group, a heterocycloalkyloxy group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 alkyl group optionally substituted with a halogen atom, a C2-C6 alkenyloxy-C1-C4 haloalkyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group optionally substituted with a halogen atom or a methoxy group, a C2-C6 alkynyloxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C2-C6 alkynyloxy-C1-C4 haloalkyl group, a C1-C4 alkoxy-C1-C4 alkoxy group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C2-C6 alkenyloxy-C1-C4 alkoxy group, a C2-C6 alkynyloxy-C1-C4 alkoxy group, a C2-C6 alkenyloxy-C1-C4 haloalkoxy group, a C2-C6 alkynyloxy-C1-C4 haloalkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, a C1-C4 alkylthio-C1-C4 haloalkyl group, a C1-C4 haloalkylthio-C1-C4 haloalkyl group, a pentafluorosulfanyl group, -(CH2)q NR b1 R b2 (R b1 and R b2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group, and q is 0, 1, 2, or 3.), or the general formula (I-B)

[0208]

Chemical formula

[0209]

Chemical formula

[0210] A5) In the general formula (I), Y 1 , Y 2 , Y 3 and Y 4 together form -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2-, -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2-, -OCH2CH2CH2CH2-, -OCR 4a HCH2CH2CH2-, -OCR 4a R 4b CH2CH2CH2-, -OCH2CR 4a HCH2CH2-, -OCH2CR 4a R 4b CH2CH2-, -CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2CH2OCH2-, -CH2CR 4a HOCH2- -CH2CH2CH2CH2-, -CH2CR 4a HCH2CH2-, -CH2CR4a R 4b CH2CH2-, -CH2CH2CR 4a HCH2-, -CH2CH2CR 4a R 4b CH2-, -CH2SCH2CH2-, -CH2SO2CH2CH2-, -NHCH2CH2CH2-, -NR 4c CH2CH2CH2-, -NR 4c CR 4a HCH2CH2-, -NHCR 4a HCH2CH2-, -CH2NR 4c CH2CH2-, -CH2NR 4c CR 4a HCH2-, -CH2NHCR 4a HCH2-, -CH2CH2NR 4c CH2-, -CH2CR 4a HNR 4c CH2-, or, -CH2CR 4a forms HNHCH2- (R 4a 、R 4b and R 4c is synonymous with the definition shown in said A4).), R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, or a cyano group, or R 2 is each independently a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or -NR d1 R d2 (R d1 and R d2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group).) may be substituted, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, or thiadiazolyl (provided that X 1-X 2 is C-N, and Y 1 Y 2 Y 3 and Y 4 when these together form -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2-, R 2 is a hydrogen atom. ), the pharmaceutical according to A4) above, which is composed of a heteroaromatic amide derivative or a salt thereof (provided that X 1 -X 2 is N-C, Y 1 Y 2 Y 3 and Y 4 when these together form -CH2CR 4a HCH2CH2-, R 2 is a hydrogen atom, R 4a is a group represented by the general formula (I-B), and L 2 when is a single bond, ring C is not a phenyl ring. Or, when ring C is a phenyl ring, X 1 -X 2 is C-N.).

[0211] A6) In the general formula (I) above, X 1 -X 2 is C-N, Y 1 Y 2 Y 3 and Y 4 when these together form -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2-, -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2-, -OCH2CH2CH2CH2-, -OCR 4a HCH2CH2CH2-, -OCH2CR 4a HCH2CH2-, -CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2CR 4a HCH2CH2-, -CH2CR 4a R 4b CH2CH2-, -CH2CH2CR 4a HCH2-, -NHCH2CH2CH2-, -NR 4c CR 4a HCH2CH2-, -NHCR 4a HCH2CH2-, or, -CH2NR 4c CH2CH2- is formed (R 4a R 4b R 4c is synonymous with the definition shown in said A4).), R 5a R 5b R 5c R 6a R 6b and n satisfies the configuration of (i) of said (0), the pharmaceutical according to said A4) or A5) comprising a heteroaromatic amide derivative or a salt thereof.

[0212] A7) In the general formula (I-E), X 1 X 2 R 1a R 1b are synonymous with the definitions shown in said (0), Y 1 Y 2 Y 3 and Y 4 are each independently a single bond, -CH2-, -CH2CH2-, -CR 4a R 4b -, -CR 4a H-, -CR 4b H-, -CH2CR 4a R 4b -, -CH2CR 4a H-, -NR 4c -, -NH-, -S-, -SO2-, or, -O-, Z 2 -Z 3 is -CH2-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -CH2NRf1 -, -NR f1 CH2-, -CH2CH2-, -CONR f1 -, -NR f1 CO-, -OCR f1 R f2 -, or, -CR f1 R f2 is O- (R f1 and R f2 are each a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group.). R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group, or R 2 is a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or -NR d1 R d2 (R d1 and R d2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group.)-substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring, R 4a , R 4b and R 4cis, independently of each other, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkyl group optionally substituted with a hydroxyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylcarbonyloxy group, a C1-C6 haloalkylcarbonyl group, a C1-C6 haloalkoxycarbonyl group, a C1-C6 haloalkylcarbonyloxy group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyl group optionally substituted with a halogen atom, a heterocycloalkyl group, a C3-C7 cycloalkyloxy group, a heterocycloalkyloxy group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 alkyl group optionally substituted with a halogen atom, a C2-C6 alkenyloxy-C1-C4 haloalkyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group optionally substituted with a halogen atom or a methoxy group, a C2-C6 alkynyloxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C2-C6 alkynyloxy-C1-C4 haloalkyl group, a C1-C4 alkoxy-C1-C4 alkoxy group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C2-C6 alkenyloxy-C1-C4 alkoxy group, a C2-C6 alkynyloxy-C1-C4 alkoxy group, a C2-C6 alkenyloxy-C1-C4 haloalkoxy group, a C2-C6 alkynyloxy-C1-C4 haloalkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, a C1-C4 alkylthio-C1-C4 haloalkyl group, a C1-C4 haloalkylthio-C1-C4 haloalkyl group, a pentafluorosulfanyl group, -(CH2)q NR b1 R b2 (R b1 and R b2 are each independently a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group, and q is 0, 1, 2, or 3.), or the general formula (I-B)

[0213]

Chemical formula

[0214]

Chemical formula

[0215] [Chemical formula] {In the formula, ring B, L 1 , R 8a , R 8b , R 8c are as defined in (0) above.} is a group represented by (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-, -CH2CR 4a R 4b -, -CH2CR 4a H-, or -NR 4c -.), a pharmaceutical comprising a heteroaromatic amide derivative or a salt thereof.

[0216] A8) In the general formula (I-E), X 1 -X 2 is C-N, Y 1 , Y 2 , Y 3 and Y 4 are such that together they are -OCR 4a HCH2CH2-, -OCR 4a R 4b CH2CH2-, -OCH2CH2-, -OCR 4a HCH2-, -OCR 4a R 4b CH2-, -OCH2CH2CH2CH2-, -OCR 4a HCH2CH2CH2-, -OCH2CR 4a HCH2CH2-, -CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2CR 4a HCH2CH2-, -CH2CR 4a R 4b CH2CH2-, -CH2CH2CR 4a HCH2-, -NHCH2CH2CH2-, -NR 4c CR 4a HCH2CH2-, -NHCR 4a HCH2CH2-, or, -CH2NR 4c form CH2CH2- (R 4a 、R 4b 、R 4c is synonymous with the definition shown in A7).), The medicament according to A7) above, which consists of a heteroaromatic amide derivative or a salt thereof (provided that X 1 -X 2 is C-N, and Y 1 、Y 2 、Y 3 and Y 4 together form -OCR 4a HCH2CH2- or -OCR 4a R 4b When forming CH2CH2-, R 2 is a hydrogen atom.).

[0217] A9) In the general formula (I-E), Z 2 -Z 3 is -CH2O-, R 6a 、R 6b 、R 11a and R 11c are each a hydrogen atom, a medicament according to A7) or A8) above, which consists of a heteroaromatic amide derivative or a salt thereof.

[0218] In the general formula (I-E), X 1 -X 2 is C-N, Y 1 Y 2 Y 3 and Y 4 together form -OCR 4a HCH2CH2-, -OCR 4a HCH2-, -OCR 4a HCH2CH2CH2-, -CH2CR 4a HCH2CH2-, -NR 4c CR 4a HCH2CH2-, -NHCR 4a HCH2CH2-, or -CH2NR 4c CH2CH2- to form R 4ais a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 alkyl group which may be substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkyl group which may be substituted with a hydroxyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 haloalkylcarbonyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyl group which may be substituted with a halogen atom or a C1-C4 haloalkyl group, a heterocycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 alkyl group which may be substituted with a halogen atom, a C2-C6 alkynyl group, a C2-C6 alkynyl group which may be substituted with a halogen atom or a methoxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, -(CH2) q NR b1 R b2 (q, R b1 and R b2 have the same meanings as defined in the above (0).), or the general formula (I-B)

[0219] [Chemical formula] (wherein, ring C is C3-C7 cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, L2 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 - is (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 shown in the above (0).), R 9a , R 9b and R 9c are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 alkoxycarbonyl group, a heterocycloalkyloxy group, or -(CH2) s NR d1 R d2 (s, R d1 and R d2 are synonymous with the definitions shown in the above (0).).}, The medicament according to any one of A7) to A9) above, comprising a heteroaromatic amide derivative or a salt thereof.

[0220] Next, another embodiment of the present invention will be described. The present invention also includes, for example, the following inventions.

[0221] B1) In the general formula (I), X 1 -X 2 , Z 1 , ring A, R 1a , R 1b are synonymous with the definitions shown in the above (0), Y 1 , Y 2 , Y3 and Y 4 is, independently of one another, a single bond, -CH2-, -CH2CH2-, -CR 4a R 4b -, -CR 4a H-, -CR 4b H-, -CH2CR 4a R 4b -, -CH2CR 4a H-, -NR 4c -, -NH-, -S-, -SO2-, or -O-, and R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group which may be substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group, or R 2 is a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or -NR d1 R d2 (R d1 and R d2 are, independently of one another, a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group.)-substituted saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring, and R 3a , R 3b and R 3cis independently a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 alkyl group optionally substituted with a dimethylaminocarbonyl group or a dimethylamino group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group optionally substituted with a halogen atom, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, -(CH2) p NR a1 R a2 (p, R a1 and R a2 has the same meaning as the definition shown in the above (0).), or the general formula (I-A)

[0222] [Chemical formula] (wherein ring B is C3-C7 cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, L 1 is a single bond, -CH2-, -CH2O-, -OCH2-, -CH2CH2-, or -CH2OCH2- R 8a R 8b and R 8cis, independently of one another, a hydrogen atom, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyloxy group, a heterocycloalkyl group, a heterocycloalkyloxy group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group.}, and is a group represented by R 4a , R 4b and R 4c are, independently of one another, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 alkyl group which may be substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkyl group which may be substituted with a hydroxyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 haloalkylcarbonyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyl group which may be substituted with a halogen atom or a C1-C4 haloalkyl group, a heterocycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 alkyl group which may be substituted with a halogen atom, a C2-C6 alkynyl group, a C2-C6 alkynyl group which may be substituted with a halogen atom or a methoxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, -(CH2) q NR b1 R b2 (q, R b1 and R b2 are as defined in (0) above.), or the general formula (I-B)

[0223] [Chemical formula] [wherein, ring C is C3-C7 cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, 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 (CR10g 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 - wherein (R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , r1, r2, r3, r4 and R c are as defined in (0) above.). R 9a , R 9b and R 9c are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 alkoxycarbonyl group, a heterocycloalkyloxy group, or -(CH2) s NR d1 R d2 (s, R d1 and R d2 are as defined in (0) above.). R 5a , R 5b , R 5c , R 6a , R 6band n satisfies either (i) or (ii) of the above (0) (provided that when 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 do not form -CH2NR 4a HCH2CH2-. ), a pharmaceutical comprising a heteroaromatic amide derivative or a salt thereof (provided that when R 2 is a hydrogen atom, Y 1 , Y 2 , Y 3 , or at least one of Y 4 is -CR 4a R 4b -, -CR 4a H-, -CH2CR 4a R 4b -, -CH2CR 4a H-, or -NR 4c -. ).

[0224] B2) In the general formula (I), R 3a , R 3b and R 3c are each independently a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C2-C6 alkynyl group, a C2-C6 alkynyl group, -(CH2) p NR a1 R a2 (p is 1, and R a1 and R a2 are each independently a hydrogen atom, a methyl group, an ethyl group, or a 2,2,2-trifluoroethyl group. ), or the general formula (I-A)

[0225]

Chemical formula

[0226] B3) In the general formula (I), R 4a R 4b and R 4c are each independently a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, -(CH2) q NR b1 R b2 (q, R b1 and R b2 are as defined in (0) above. ), or the following formula

[0227] [Chemical formula] (In the formula, R 9a R 9b and R 9c are as defined in (0) above. ) The medicament according to B1) or B2) above, which is a substituent selected from the group consisting of a heteroaromatic amide derivative or a salt thereof.

[0228] B4) In the general formula (I-E), X 1 、X 2 、R 1a 、R 1b are synonymous with the definitions shown in the above (0), Y 1 、Y 2 、Y 3 and Y 4 are each independently a single bond, -CH2-, -CH2CH2-, -CR 4a R 4b -, -CR 4a H-, -CR 4b H-, -CH2CR 4a R 4b -, -CH2CR 4a H-, -NR 4c -, -NH-, -S-, -SO2-, or -O-, Z 2 -Z 3 is -CH2-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -CH2NR f1 -, -NR f1 CH2-, -CH2CH2-, -CONR f1 -, -NR f1 CO-, -OCR f1 R f2 -, or -CR f1 R f2 O- (R f1 and R f2 are a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group.). R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group, or R 2 is a halogen atom, a cyano group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group or -NR d1 R d2 (R d1 and R d2is, independently of one another, a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group. It is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring which may be substituted with (), R 4a , R 4b and R 4c are, independently of one another, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 alkyl group which may be substituted with a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkyl group which may be substituted with a hydroxyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 haloalkyl group, a C1-C4 haloalkoxy-C1-C4 haloalkyl group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 haloalkylcarbonyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyl group which may be substituted with a halogen atom or a C1-C4 haloalkyl group, a heterocycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkenyloxy group, a C2-C6 alkenyloxy-C1-C4 alkyl group, a C2-C6 alkenyloxy-C1-C4 alkyl group which may be substituted with a halogen atom, a C2-C6 alkynyl group, a C2-C6 alkynyl group which may be substituted with a halogen atom or a methoxy group, a C2-C6 alkynyloxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, -(CH2) q NR b1 R b2 (q, R b1 and R b2 are as defined in (0) above.), or of general formula (I-B)

[0229]

Chemical formula

[0230]

Chemical formula

[0231] B5) In the general formula (I-E), R 11b and R 11c are each independently a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, -(CH2) p NR a1 Ra2 (p is 1, R a1 and R a2 are each independently a hydrogen atom, a methyl group, an ethyl group, or a 2,2,2-trifluoroethyl group.), or the general formula (I-A)

[0232]

Chemical formula

[0233] B6) In the general formula (I-E), R 4a , R 4b and R 4c are each independently a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy-C1-C4 alkyl group, a C1-C4 alkylthio-C1-C4 alkyl group, a C1-C4 haloalkylthio-C1-C4 alkyl group, -(CH2) q NR b1 R b2 (q, R b1 and R b2 are as defined in (0) above.), or the following formula

[0234]

Chemical formula

[0235] The salt of the compound represented by the general formula (I) is preferably a pharmacologically acceptable salt. The "pharmacologically acceptable salt" is not particularly limited as long as it is a pharmacologically acceptable salt, but includes inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc., organic carboxylates such as acetate, oxalate, fumarate, maleate, malonate, citrate, succinate, lactate, tartrate, malate, etc., aromatic carboxylates such as salicylate, benzoate, etc., organic sulfonates such as methanesulfonate, tosylate, benzenesulfonate, etc., alkali metal salts such as lithium salt, sodium salt, potassium salt, etc., alkaline earth metal salts such as calcium salt, magnesium salt, etc.

[0236] In the compound represented by the general formula (I), when an asymmetric carbon is present, any of its racemate, diastereoisomers and individual optically active forms are included in the pharmaceutical of the present invention, and when geometric isomers are present, any of the (E) form, (Z) form and their mixture are included in the pharmaceutical of the present invention.

[0237] In the compound represented by the general formula (I), when solvates such as hydrates are present, they are also included in the pharmaceutical of the present invention.

[0238] Next, the compound represented by the general formula (I) can be produced by various methods. For example, it can be produced by appropriately combining the methods shown below, methods similar to the following production methods, or synthetic methods well-known to those skilled in the art. All of the starting materials and reaction reagents used in these syntheses are either commercially available or can be produced from commercially available compounds according to methods well-known to those skilled in the art. Also, extraction, purification, etc. may be performed by the treatments carried out in ordinary organic chemistry experiments. Further, for all of the following steps, the order of the steps to be carried out can be appropriately changed.

[0239] The compound represented by the general formula (I) can be produced, for example, by the method shown in the following Reaction Scheme-1. <Reaction Scheme-1>

[0240] [Chem.] [In the formula, for 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, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 and Z 1 are as defined for the general formula (I) in (0) above.]

[0241] (Step 1) In Process 1, the compound represented by the general formula (2) and the compound represented by the general formula (3) are subjected to a condensation reaction using a condensing agent in the presence or absence of a base to produce the compound represented by the general formula (I). Examples of the condensing agent include N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, propylphosphonic anhydride (cyclic trimer), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), and the like. Examples of the base include organic bases such as 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]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,1,3,3-tetramethylguanidine, or 1,8-diazabicyclo[5.4.0]-7-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; ketones such as acetone and methyl ethyl ketone; aromatic hydrocarbons such as toluene; and mixed solvents thereof. A reaction reagent such as 1-hydroxybenzotriazole (HOBt) may be added as necessary. 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 1 hour to 24 hours is preferred.

[0242] Also, the compound represented by the general formula (I) can be produced by inducing the compound represented by the general formula (2) into a reaction intermediate using an activator for the carboxyl group and then reacting it with the compound represented by the general formula (3). Examples of the activator for the carboxyl group include thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosgene, triphosgene, 1,1'-carbonyldiimidazole, ethyl chloroformate, 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; nitriles such as acetonitrile and propionitrile; 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 1 hour to 24 hours is preferred.

[0243] Among the compounds represented by the general formula (2) in the above Reaction Formula -1, the compounds represented by the general formulas (2-a) and (2-b) can be produced, for example, by the method shown in the following Reaction Formula -2. <Reaction Formula -2>

[0244]

Chemical Formula

[0245] (Step 2) In Step 2, the compound represented by the general formula (4) can be produced by subjecting the compound represented by the general formula (4) and the compound represented by the general formula (5) to a cyclization reaction in the presence or absence of a base. Examples of the base include inorganic bases such as potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; and organic bases such as 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]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). An additive may be allowed to coexist in order to smoothly carry out the reaction. Examples of the additive include potassium iodide, sodium iodide, tetrabutylammonium iodide, potassium bromide, sodium bromide, tetrabutylammonium bromide, 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; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; 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 1 hour to 24 hours is preferable.

[0246] In addition, the compound represented by the general formula (6) obtained in this step 2 can be prepared by reacting various organometallic compounds (e.g., boronic acid derivatives, etc.), which are well-known methods to those skilled in the art, in the co-presence of a palladium catalyst and a base, and R 4a the halogen atom (chlorine atom, bromine atom or iodine atom) of can be converted into an optionally substituted C1-C6 alkyl group or an optionally substituted saturated or unsaturated 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 appropriately after a subsequent step as long as it does not affect the subsequent steps. For example, by reacting the compound represented by the general formula (6) in a mixed solvent of 1,4-dioxane and water with a boronic acid derivative such as phenylboronic acid and a palladium catalyst such as bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) and a base such as cesium carbonate, R 4a the halogen atom (chlorine atom, bromine atom or iodine atom) of can be converted into a substituent such as a phenyl group. Examples of the palladium catalyst include: metallic palladium such as palladium-carbon and palladium black; organic palladium salts such as tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium acetate, palladium chloride-1,1'-bis(diphenylphosphino)ferrocene, or bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); and polymer-immobilized organic palladium complexes such as polymer-supported bis(acetato)triphenylphosphine palladium(II) and polymer-supported di(acetato)dicyclohexylphenylphosphine palladium(II). These palladium catalysts may be used in combination. The addition amount of the palladium catalyst is usually 1 to 50 mol%, preferably 5 to 20 mol%, based on the compound represented by the general formula (6). Examples of the base include inorganic bases such as potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride, or organic bases such as 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]nona-5-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 examples of additives include: trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphines such as triphenylphosphine and tritolylphosphine; trialkylphosphites such as trimethyl phosphite, triethyl phosphite and tributyl phosphite; tricycloalkylphosphites such as tricyclohexyl phosphite; triarylphosphites such as triphenyl phosphite; imidazolium salts such as 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride; diketones such as acetylacetone and octafluoroacetylacetone; amines such as trimethylamine, triethylamine, tripropylamine, triisopropylamine and tributylamine; 1,1'-bis(diphenylphosphino)ferrocene; 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; 2-dicyclohexylphosphino-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. Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; 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 1 hour to 24 hours is preferred.

[0247] In addition, 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 are reacted with a palladium catalyst and a copper catalyst in the presence of a base to convert the halogen atom of R 4a into an optionally substituted alkynyl group. This reaction may be carried out after the completion of step 2, and may be carried out appropriately after a subsequent step as long as it does not affect the subsequent steps. For example, the compound represented by the general formula (6) is reacted in acetonitrile with an alkyne derivative such as phenylacetylene, a palladium catalyst such as dichlorobis(triphenylphosphine)palladium, a copper catalyst such as copper iodide, and a base such as triethylamine to convert the halogen atom (chlorine atom, bromine atom or iodine atom) of R 4a into a substituent such as a phenylalkynyl group. Examples of the base include inorganic bases such as 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, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; organic bases such as 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]nona-5-ene, 1,4-diazabicyclo[2.2.2]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 addition amount of the palladium catalyst 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. The addition amount of the copper catalyst is usually 1 to 50 mol%, preferably 5 to 20 mol%, based on the compound represented by the general formula (6). Examples of the reaction solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, and 1,4-dioxane; and aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide, 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 1 hour to 24 hours is preferred.

[0248] In addition, the compound represented by the general formula (6) obtained in this step 2 can be converted into an alkoxy group which may be substituted on the hydroxyl group of R by reacting various alkyl halides, which is a method well known to those skilled in the art, in the presence of a base. 4a This reaction may be carried out after the completion of step 2, and may be carried out appropriately after a subsequent step as long as it does not affect the subsequent steps. For example, by reacting the 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 can be converted into an alkoxy group such as an ethoxy group. Examples of the base include inorganic bases such as 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, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; and organic bases such as 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]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Examples of the reaction solvent include, but are not limited to, 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, and 1,4-dioxane; and aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. 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 1 hour to 24 hours is preferred.

[0249] (Step 3) In Step 3, the compound represented by the general formula (6) can be subjected to a catalytic reduction reaction in the presence of a transition metal catalyst and hydrogen to produce the compound represented by the general formula (7). Examples of the transition metal catalyst include palladium carbon, palladium hydroxide, Raney nickel, and platinum oxide. The addition amount of the transition metal catalyst is usually 5 times by weight or less, preferably 0.01 to 0.5 times by weight, based on 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, and examples include alcohols such as methanol and ethanol; esters such as methyl acetate and ethyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; protic polar solvents such as acetic acid; water; and mixed solvents thereof. The reaction temperature is not particularly limited and is usually from 0°C to 80°C, and the reaction is carried out under normal pressure or under pressure. The reaction time is not particularly limited, and preferably from 1 hour to 24 hours.

[0250] (Step 4) In Step 4, the compound represented by the general formula (7) can be hydrolyzed in the presence of a base or an acid to produce the compound represented by the general formula (2-a). Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, etc., 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, etc. The reaction solvent is appropriately selected according to the type of the base or acid used, etc., and examples include ethers such as tetrahydrofuran and 1,4-dioxane; nitriles such as acetonitrile and propionitrile; aromatic hydrocarbons such as benzene, toluene, and xylene; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; alcohols such as methanol, ethanol, and 2-propanol; water; 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 preferably from 1 hour to 48 hours.

[0251] (Step 5) Step 5 is a step of reacting the compound in which Y 3a in the compound represented by the general formula (7) is NH with the compound represented by the general formula (8) or the compound represented by the general formula (9) to produce the compound represented by the general formula (10).

[0252] Among the compounds represented by the general formula (7), a compound in which Y 3a is NH and a compound represented by the general formula (8) are reacted in the presence or absence of a base to produce a compound represented by the general formula (10). Examples of the base include inorganic bases such as 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, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; organic bases such as 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]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). An additive may be allowed to coexist in order to carry out the reaction smoothly. Examples of the additive include potassium iodide, sodium iodide, tetrabutylammonium iodide, potassium bromide, sodium bromide, tetrabutylammonium bromide, 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; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; 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 1 hour to 24 hours is preferred.

[0253] Among the compounds represented by the general formula (7), a compound in which Y 3a is NH and a compound represented by the general formula (9) are subjected to a reductive alkylation reaction using a reducing agent in the presence or absence of an acid or a base to produce a compound represented by the general formula (10). Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, or DBU, etc. Examples of the acid to be used include formic acid, acetic acid, propionic acid, isobutyric acid, hexanoic acid, p-toluenesulfonic acid, benzoic acid, etc. Examples of the reducing agent to be used include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, dimethylamine borane, triethylamine borane, trimethylamine borane, tert-butylamine borane, N,N-diethylaniline borane, 2-picoline borane, etc. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but examples include aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as methanol, ethanol, and 2-propanol; 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, and 1,4-dioxane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; 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 1 hour to 24 hours is preferred.

[0254] (Step 6) In Step 6, a compound represented by the general formula (2-b) can be produced by hydrolyzing the compound represented by the general formula (10) in the presence of a base or an acid by the same method as described in Step 4 of Reaction Scheme-1.

[0255] 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 shown in the following reaction formula -3. <Reaction formula -3>

[0256]

Chemical formula

[0257] The protecting group represented by P is not particularly limited as long as it is generally used as a protecting group for a hydroxyl group. Examples include: lower alkyl groups such as a methyl group; lower alkoxyalkyl groups such as a methoxymethyl group and an ethoxyethyl group; an optionally substituted benzyl group (substituents include a nitro group, a lower alkoxy group, etc.); a lower alkoxycarbonyl group; a halogeno lower alkoxycarbonyl group; an optionally substituted benzyloxycarbonyl group (substituents include a nitro group, a lower alkoxy group, etc.); acyl groups such as an acetyl group and a benzoyl group; a triphenylmethyl group; a tetrahydropyranyl group; trisubstituted silyl groups such as a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a triisopropylsilyl group, a dimethylhexylsilyl group, and a t-butyldiphenylsilyl group, etc.

[0258] (Step 7) In Step 7, the compound represented by the general formula (13) can be produced by reacting the compound represented by the general formula (11) and the compound represented by the general formula (12) with an azodicarboxylic acid derivative and a phosphine derivative. Examples of the azodicarboxylic acid derivative include ethyl azodicarboxylate, isopropyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine, and the like. Examples of the phosphine derivative include triphenylphosphine, tri-n-butylphosphine, and the like. Further, instead of the azodicarboxylic acid derivative and the phosphine derivative, the same reaction can be carried out using a phosphorane reagent such as cyanomethylene tributylphosphorane or cyanomethylene trimethylphosphorane. The reaction solvent is not particularly limited as long as it is a neutral solvent, and examples thereof include tetrahydrofuran, toluene, or 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 1 hour to 24 hours is preferable.

[0259] 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, the compound represented by the general formula (13) can also be produced by reacting it with the compound represented by the general formula (11) in the presence of a base. Examples of the conversion reagent to the leaving group include thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, carbon tetrabromide, dimethyl bromosulfonium bromide, thionyl bromide, phosphorus triiodide, p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like. Examples of bases include the following: inorganic bases such as 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, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; organic bases such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Examples of reaction solvents include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; and mixed solvents thereof, 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 1 hour to 24 hours is preferred.

[0260] (Step 8) In Step 8, a compound represented by the general formula (13) can be subjected to a deprotection reaction to produce a compound represented by the general formula (14). Such a deprotection reaction may be carried out according to methods well known to those skilled in the art (for example, the methods described in "Protective Groups in Organic Synthesis (Third Edition, 1999)" by Green and Wuts).

[0261] (Project 9) In Project 9, the compound represented by the general formula (16) can be 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. Examples of the base include inorganic bases such as 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, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; and organic bases such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Examples of the halogenating agent include carbon tetrachloride, carbon tetrabromide, hexachloroacetone, hexabromoacetone, triphosgene, lithium bromide, methyl iodide, bromine, iodine, and the like. Examples of the phosphine derivative include triphenylphosphine, tri-n-butylphosphine, 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; nitriles such as acetonitrile and propionitrile; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; 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 1 hour to 24 hours is preferable.

[0262] (Project 10) In Project 10, the compound represented by the general formula (11) and the compound represented by the general formula (15) can be subjected to a cyclization reaction in the presence or absence of a base to produce the compound represented by the general formula (16). Examples of the base include inorganic bases such as 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, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; and organic bases such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholine, pyridine, 4-N,N-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). An additive may be allowed to coexist to smoothly carry out the reaction. Examples of the additive include potassium iodide, sodium iodide, tetrabutylammonium iodide, potassium bromide, sodium bromide, tetrabutylammonium bromide, 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; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; 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 1 hour to 24 hours is preferred.

[0263] (Step 11) In Step 11, the compound represented by the general formula (16) can be hydrolyzed in the presence of a base or an acid by a method similar to the method described in Step 4 of Reaction Formula -1 to produce the compound represented by the general formula (2-c).

[0264] 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) can be produced, for example, by the method shown in the following Reaction Formula -4. <Reaction Formula -4>

[0265] [Chemical formula] [In the formula, R 4a is as defined for the general formula (I) in the above (O). Each R alk is independently an alkyl group having 1 to 8 carbon atoms, P is a protecting group, LG is a leaving group (for example, a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group, etc.), Hal is a halogen atom, and Y 3a is a single bond, methylene, or ethylene.]

[0266] Examples of the protecting group represented by P include the following: lower alkyl groups such as methyl group; lower alkoxyalkyl groups such as methoxymethyl group and ethoxyethyl group; optionally substituted benzyl groups (examples of the substituent include nitro group and lower alkoxy group); lower alkoxycarbonyl groups; halogeno lower alkoxycarbonyl groups; optionally substituted benzyloxycarbonyl groups (examples of the substituent include nitro group and lower alkoxy group); acyl groups such as acetyl group and benzoyl group; triphenylmethyl group; tetrahydropyranyl group; trisubstituted silyl groups such as trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, triisopropylsilyl group, dimethylhexylsilyl group, and t-butyldiphenylsilyl group, etc.

[0267] (Step 12) In Step 12, a compound represented by the general formula (19) can be produced by reacting a compound represented by the general formula (17) with a compound represented by the general formula (18) in the presence of zinc. Examples of the reaction solvent include 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 dimethyl sulfoxide; and mixed solvents thereof, but are not limited thereto. An additive may be coexisted to smoothly carry out the reaction, and examples of the additive 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 1 hour to 24 hours is preferable. Further, zinc powder and the compound represented by the general formula (18) can be treated in advance and used in the reaction as a Reformatsky reagent.

[0268] (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, etc. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as methanol, ethanol, and 2-propanol; ethers such as diethyl ether, tetrahydrofuran, and 1,4-dioxane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; 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 1 hour to 24 hours is preferred.

[0269] (Step 14) In Step 14, the compound represented by the general formula (12-a) can be produced by subjecting the compound represented by the general formula (20-a) or the general formula (20-b) to a protective reaction of the primary hydroxyl group. Such a protective reaction may be carried out according to methods well known to those skilled in the art (for example, the methods described in "Protective Groups in Organic Synthesis (Third Edition, 1999)" by Green and Wuts).

[0270] (Step 15) In Process 15, the primary and secondary hydroxyl groups of the compound represented by the general formula (20-a) are converted into leaving groups such as a halogen atom or a substituted sulfonyloxy group in the presence of a sulfonylating agent and a base, whereby 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. Examples of the base include the following: inorganic bases such as 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, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; organic bases such as 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]nona-5-ene, 1,4-diazabicyclo[2.2.2]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, and examples thereof include halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene, xylene; nitriles such as acetonitrile, propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide; and mixed solvents thereof. The reaction temperature is not particularly limited and is carried out at 0°C to 120°C. The reaction time is not particularly limited, and 1 hour to 24 hours is preferred.

[0271] Also, the compound represented by the general formula (15-a) can also be produced 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. Examples of the halogenating agent include carbon tetrachloride, carbon tetrabromide, hexachloroacetone, hexabromoacetone, triphosgene, lithium bromide, methyl iodide, bromine, iodine, and the like. Examples of the phosphine derivative include triphenylphosphine, tri-n-butylphosphine, and the like. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene, and xylene; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; and mixed solvents thereof. 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 1 hour to 24 hours is preferred.

[0272] (Step 16) In Step 16, the compound represented by the general formula (22) can be produced by reacting the compound represented by the general formula (17) with the compound represented by the general formula (21) in the presence of a base. Examples of the base include inorganic bases such as 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, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; organic bases such as 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]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,1,3,3-tetramethylguanidine. Examples of the reaction solvent include 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, and 1,4-dioxane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; and mixed solvents thereof, but are not limited thereto. 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 1 hour to 24 hours is preferred.

[0273] (Step 17) In Step 17, a compound represented by the general formula (22) can be subjected to a catalytic reduction reaction in the presence of a transition metal catalyst and hydrogen to produce a compound represented by the general formula (23). Examples of the transition metal catalyst include palladium carbon, palladium hydroxide, Raney nickel, and platinum oxide. The addition amount of the transition metal catalyst is usually 5 times by weight or less, preferably 0.01 to 0.5 times by weight, based on 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 include: alcohols such as methanol and ethanol; esters such as methyl acetate and ethyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; protic polar solvents such as acetic acid; water; and mixed solvents thereof. The reaction temperature is not particularly limited and is usually 0°C to 80°C, and the reaction is carried out under normal pressure or under pressure. The reaction time is not particularly limited, and 1 hour to 24 hours is preferred.

[0274] (Step 18) In Step 18, in the same manner as the method described in Step 13 of Reaction Scheme -4, an ester of a compound represented by the general formula (23) can be reduced to an alcohol using a reducing agent to produce a compound represented by the general formula (24).

[0275] (Step 19) In Step 19, in the same manner as the method described in Step 15 of Reaction Scheme -4, the hydroxyl group of the compound represented by the general formula (24) can be converted to a leaving group such as a halogen atom or a substituted sulfonyloxy group in the presence of a sulfonylating agent and a base to produce a compound represented by the general formula (25). Among the compounds represented by the general formula (25), the compound in which LG is a chlorine atom can also be produced by reacting the compound represented by the general formula (24) with a chlorinating agent in the presence or absence of a formamide derivative. Examples of the formamide derivative used include N,N-dimethylformamide. 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 include: halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene, and xylene; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; 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 1 hour to 24 hours is preferred.

[0276] (Step 20) In Step 20, among the compounds represented by the general formula (25), when R 4a is a partially saturated or unsaturated 3- to 7-membered monocyclic ring or a partially saturated or unsaturated 7- to 12-membered bicyclic ring, the compound represented by the general formula (15-a) can be produced by reacting a halogenating agent in the presence of a radical initiator. Examples of the radical initiator include azobis compounds such as 2,2'-azobis(isobutyronitrile) (AIBN) and 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile); and peroxides such as benzoyl peroxide and di-tert-butyl peroxide. Examples of the halogenating agent to be used include chlorine, N-chlorosuccinimide, bromine, N-bromosuccinimide, sodium bromoisocyanurate, dibromoisocyanuric acid, 1,3-dibromo-5,5-dimethylhydantoin, iodine, and N-iodosuccinimide. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and examples include: halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride; aromatic hydrocarbons having an electron-withdrawing group on the aromatic ring such as monochlorobenzene, monobromobenzene, and nitrobenzene; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; 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 1 hour to 24 hours is preferred.

[0277] (Step 21) In Step 21, among the compounds represented by the general formula (26), when R 4a is a compound having a partially saturated or unsaturated 3- to 7-membered monocyclic ring or a partially saturated or unsaturated 7- to 12-membered bicyclic ring, and a compound represented by the general formula (27) are reacted with a palladium catalyst and a copper catalyst in the presence of a base, a compound represented by the general formula (28) can be produced. 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 addition amount of the palladium catalyst 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. The addition amount of the copper catalyst is usually 1 to 50 mol%, preferably 5 to 20 mol%, based on the compound represented by the general formula (26). Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, and 1,4-dioxane; and aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. 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 1 hour to 24 hours is preferred.

[0278] (Step 22) In Step 22, a compound represented by the general formula (28) can be subjected to a catalytic reduction reaction in the presence of a transition metal catalyst and hydrogen by a method similar to the method described in Step 17 of Reaction Scheme - 4 to produce a compound represented by the general formula (23).

[0279] Among the compounds represented by the general formula (2) in the Reaction Scheme - 1, the compound represented by the general formula (2 - d) can be produced, for example, by the method shown in the following Reaction Scheme - 5. <Reaction Scheme - 5>

[0280] [Chemical formula] [In the formula, R 4c is as defined for the general formula (I) in (0) above. Also, R alk is an alkyl group having 1 to 8 carbon atoms, P is a protecting group, LG is a leaving group (for example, a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p - toluenesulfonyloxy group, etc.), and Y 3a is methylene or ethylene.]

[0281] 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. Examples thereof include a tert-butoxycarbonyl (Boc) group, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac) group, trifluoroacetyl group, benzyl (Bn) group, 4-methoxybenzyl (PMB) group, and the like.

[0282] (Step 23) In Step 23, a compound represented by the general formula (29) and a 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, whereby a compound represented by the general formula (31) can be produced. Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, potassium hexamethyldisilazane, triethylamine, diisopropylethylamine, or DBU. Examples of the acid to be used include formic acid, acetic acid, propionic acid, isobutyric acid, hexanoic acid, p-toluenesulfonic acid, or benzoic acid. Examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, dimethylamine borane, triethylamine borane, trimethylamine borane, tert-butylamine borane, N,N-diethylaniline borane, or 2-picoline borane. 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; 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, and 1,4-dioxane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; 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 1 hour to 24 hours is preferred.

[0283] (Step 24) In Step 24, by subjecting the compound represented by the general formula (31) and the compound represented by the general formula (32) to a cyclization reaction in the presence or absence of a base in the same manner as the method described in Step 10 of Reaction Formula -3, the compound represented by the general formula (33) can be produced.

[0284] (Step 25) In Step 25, by reacting the compound represented by the general formula (29) and the compound represented by the general formula (34) in the presence or absence of a base, the compound represented by the general formula (35) can be produced. Examples of the base include the following: inorganic bases such as 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, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; organic bases such as 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]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). An additive may coexist to smoothly carry out the reaction. Examples of the additive include potassium iodide, sodium iodide, tetrabutylammonium iodide, potassium bromide, sodium bromide, tetrabutylammonium bromide, and the like. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; 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 1 hour to 24 hours is preferred.

[0285] (Step 26) In Step 26, in the same manner as the method described in Step 23 of Reaction Scheme -5, a compound represented by the general formula (35) and a 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, whereby a compound represented by the general formula (36) can be produced.

[0286] (Step 27) In Step 27, in the same manner as the method described in Step 9 of Reaction Scheme -3, a compound represented by the general formula (36) is reacted with a halogenating agent and a phosphine derivative in the presence or absence of a base to produce a compound represented by the general formula (33).

[0287] (Step 28) In Step 28, a compound represented by the general formula (37) is subjected to a deprotection reaction to produce a compound represented by the general formula (38). Such a deprotection reaction may be carried out according to methods well known to those skilled in the art (for example, the methods described in "Protective Groups in Organic Synthesis (Third Edition, 1999)" by Green and Wuts).

[0288] (Step 29) In Step 29, a compound represented by the general formula (38) can be reacted with a compound represented by the general formula (8) or a compound represented by the general formula (9) by a method similar to the method described in Step 5 of Reaction Scheme - 2 to produce a compound represented by the general formula (33).

[0289] (Step 30) In Step 30, a compound represented by the general formula (33) can be hydrolyzed in the presence of a base or an acid by a method similar to the method described in Step 4 of Reaction Scheme - 2 to produce a compound represented by the general formula (2 - d).

[0290] Among the compounds represented by the general formula (2) in the Reaction Scheme - 1, the compound represented by the general formula (2 - e) can be produced, for example, by the method shown in the following Reaction Scheme - 6. [Reaction Scheme - 6]

[0291] [Chemical Formula] [wherein, R 1a , R 1b , X 1 , X 2 , Y 1 , Y 2 , Y 3 and Y 4 are as defined for the general formula (I) in (0) above. R alk is an alkyl group having 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 attached and the boron atom to which that oxygen atom is attached form an optionally substituted non - aromatic heterocyclic ring, R 2a is an optionally substituted partially saturated or unsaturated 3 - to 7 - membered monocyclic ring, Hal is a halogen atom (e.g., chlorine atom, bromine atom, iodine atom).

[0292] (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). Examples of the halogenating agent include chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, and the like. For this reaction, an appropriate acid such as acetic acid, trifluoroacetic acid, or hydrochloric acid may be added. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; 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 1 hour to 24 hours is preferred.

[0293] (Step 32) In Step 32, the compound represented by the general formula (42) can be produced by allowing the compound represented by the general formula (41) to act on the compound represented by the general formula (40) in the coexistence of a palladium catalyst and a base. Examples of the palladium catalyst include the following: metallic palladium such as palladium-carbon and palladium black; organic palladium salts such as tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium acetate, palladium chloride-1,1'-bis(diphenylphosphino)ferrocene, or bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); and polymer-immobilized organic palladium complexes such as polymer-supported bis(acetato)triphenylphosphine palladium(II) and polymer-supported di(acetato)dicyclohexylphenylphosphine palladium(II). These may be used in combination. The addition amount of the palladium catalyst is usually 1 to 50 mol%, preferably 5 to 20 mol%, based on the compound represented by the general formula (40). Examples of the base include the following: 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-undecene (DBU). Additives may coexist to carry out the reaction smoothly, and examples of the additives include: trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphines such as triphenylphosphine and tritolylphosphine; trialkylphosphites such as trimethyl phosphite, triethyl phosphite and tributyl phosphite; tricycloalkylphosphites such as tricyclohexyl phosphite; triarylphosphites such as triphenyl phosphite; imidazolium salts such as 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride; diketones such as acetylacetone and octafluoroacetylacetone; amines such as trimethylamine, triethylamine, tripropylamine, triisopropylamine and tributylamine; 1,1'-bis(diphenylphosphino)ferrocene; 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; 2-dicyclohexylphosphino-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. Examples of the reaction solvent include, but are not limited to, 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 dimethyl sulfoxide; 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 1 hour to 24 hours is preferred.

[0294] (Step 33) In Step 33, the compound represented by the general formula (42) can be hydrolyzed in the presence of a base or an acid by a method similar to the method described in Step 4 of Reaction Formula -2 to produce the compound represented by the general formula (2-e).

[0295] 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 shown in the following Reaction Formula -7. (Reaction Formula -7)

[0296] [Chemical formula] [In the formula, R 3a , R 3b , R 3c are as defined for the general formula (I) in (0) above. Ring A 1 is a 3- to 7-membered monocyclic aromatic ring, R alk is an alkyl group having 1 to 8 carbon atoms, and P is a protecting group.]

[0297] 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. Examples thereof include a tert-butoxycarbonyl (Boc) group, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac) group, trifluoroacetyl group, benzyl (Bn) group, 4-methoxybenzyl (PMB) group, and the like.

[0298] (Step 34) In Step 34, the compound represented by the general formula (45) can be produced by reacting the compound represented by the general formula (43) with the compound represented by the general formula (44) in the presence of a base. Examples of the base include inorganic bases such as 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, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; and organic bases such as 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]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,1,3,3-tetramethylguanidine. Examples of the reaction solvent include 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, and 1,4-dioxane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; and mixed solvents thereof. The reaction solvent is not limited thereto. 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 1 hour to 24 hours is preferred.

[0299] (Step 35) In Step 35, a compound represented by the general formula (46) can be produced by subjecting a 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, and platinum oxide. The addition amount of the transition metal catalyst is usually 5 times by weight or less, preferably 0.01 to 0.5 times by weight, relative to 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 include: alcohols such as methanol and ethanol; esters such as methyl acetate and ethyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; protic polar solvents such as acetic acid; water; and mixed solvents thereof. The reaction temperature is not particularly limited and is usually from 0 °C to 80 °C, and is carried out under normal pressure or under pressure. The reaction time is not particularly limited, and 1 hour to 24 hours is preferred.

[0300] (Step 36) In Step 36, the ester of the compound represented by the general formula (46) can be reduced to an alcohol using a reducing agent to produce the compound represented by the general formula (47). Examples of the reducing agent include lithium aluminum hydride, sodium borohydride, lithium borohydride, and borane. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as methanol, ethanol, and 2-propanol; ethers such as diethyl ether, tetrahydrofuran, and 1,4-dioxane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; 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 1 hour to 24 hours is preferred.

[0301] (Step 37) In Step 37, the compound represented by the general formula (47) can be reacted with an azodicarboxylic acid derivative and a phosphine derivative to produce the compound represented by the general formula (48). Examples of the azodicarboxylic acid derivative include ethyl azodicarboxylate, isopropyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine, and the like. Examples of the phosphine derivative include triphenylphosphine, tri-n-butylphosphine, and the like. Alternatively, instead of the azodicarboxylic acid derivative and the phosphine derivative, a phosphorane reagent such as cyanomethylene tributylphosphorane or cyanomethylene trimethylphosphorane can be used to carry out the same reaction. The reaction solvent is not particularly limited as long as it is a neutral solvent, and examples thereof include tetrahydrofuran, toluene, or 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 1 hour to 24 hours is preferred.

[0302] (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 a deprotection reaction may be carried out according to a method well known to those skilled in the art (for example, the method described in "Protective Groups in Organic Synthesis (Third Edition, 1999)" by Green and Wuts).

[0303] Among the compounds represented by the general formula (3) in the Reaction Scheme-1, the compound represented by the general formula (3-b) can be produced, for example, by the method shown in the following Reaction Scheme-8. <Reaction Scheme-8>

[0304] [In the formula, Ring A, R [wherein, Ring A, R3a and R 3b and R 3c are as defined for the general formula (I) in (0) above. Hal is a halogen atom (for example, a chlorine atom, a bromine atom, an iodine atom), M is MgBr, MgCl, Li, ZnBr, or ZnCl, P is a protecting group, and Q is a single bond, methylene, ethylene, or an oxygen atom.]

[0305] 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. Examples include a tert-butoxycarbonyl (Boc) group, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac) group, trifluoroacetyl group, benzyl (Bn) group, 4-methoxybenzyl (PMB) group, and the like.

[0306] (Step 39) In Step 39, a compound represented by the general formula (52) can be produced by reacting a compound represented by the general formula (49) with a compound represented by the general formula (51). Examples of the compound represented by the general formula (51) include a lithium reagent prepared by halometal exchange using a base such as normal butyllithium, sec-butyllithium, tert-butyllithium, etc. with a compound represented by the general formula (50); a Grignard reagent prepared by magnesium, isopropylmagnesium bromide, or isopropylmagnesium chloride, etc.; a zinc reagent prepared by activated zinc, zinc bromide, or zinc chloride, etc. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but tetrahydrofuran, diethyl ether, 1,4-dioxane, or dimethoxyethane, etc. are preferred. 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 1 hour to 24 hours is preferred.

[0307] (Step 40) In Step 40, a compound represented by the general formula (53) can be produced by reacting a compound represented by the general formula (52) with a trialkylsilane 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 preferred. The reaction temperature is not limited and is usually carried out at 0°C to 50°C. The reaction time is not particularly limited, and 1 hour to 24 hours is preferred.

[0308] (Step 41) In Step 41, a compound represented by the general formula (3-b) can be produced by subjecting a compound represented by the general formula (53) to a deprotection reaction. Such a deprotection reaction may be carried out according to methods well known to those skilled in the art (for example, the methods described in "Protective Groups in Organic Synthesis (Third Edition, 1999)" by Green and Wuts).

[0309] Among the compounds represented by the general formula (3) in the Reaction Scheme-1, the compound represented by the general formula (3-c) can be produced, for example, by the method shown in the following Reaction Scheme-9. <Reaction Scheme-9>

[0310] [In the formula, Ring A, R , R 3a , R 3b , R 3c are as defined for the general formula (I) in the above (0). m is 0, 1, or 2, Hal is a halogen atom (for example, a fluorine atom, a chlorine atom, or a bromine atom), P is a protecting group, and Z 1a is O, S, or NH.]

[0311] 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. Examples include a tert-butoxycarbonyl (Boc) group, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac) group, trifluoroacetyl group, benzyl (Bn) group, 4-methoxybenzyl (PMB) group, and the like.

[0312] (Step 42) In Step 42, the compound represented by the general formula (54) and the compound represented by the general formula (55) can be reacted in the presence or absence of a base to produce the compound represented by the general formula (56). Examples of the base include inorganic bases such as 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, potassium fluoride, potassium hexamethyldisilazane, or sodium hydride; and organic bases such as 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]nona-5-ene, 1,4-diazabicyclo[2.2.2]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, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; 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 1 hour to 24 hours is preferred.

[0313] (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 a deprotection reaction may be carried out according to methods well known to those skilled in the art (for example, the methods described in "Protective Groups in Organic Synthesis (Third Edition, 1999)" by Green and Wuts, etc.).

[0314] In the above production method, the starting material, intermediate, or final product can also be derived into another compound included in the present invention by appropriately converting its functional group. The conversion of the functional group can be carried out by methods well known to those skilled in the art (for example, the methods described in "Comprehensive Organic Transformations (1989)" by R.C. Larock, etc.).

[0315] The compound represented by the general formula (I) produced by the above-described method may be isolated and purified as a free compound, its salt, its hydrate, various solvates such as ethanol solvate, or a crystalline polymorphic substance. The pharmaceutically acceptable salt of the compound of the present invention can be produced by a conventional salt formation reaction. Isolation and purification may be carried out by applying chemical operations such as extraction fractionation, crystallization, and various fractional chromatographies.

[0316] In addition, the optically active substance can be obtained as a stereochemically pure isomer by selecting an appropriate starting compound or by conventional optical resolution from a racemate. For example, when optically resolving a racemate using a chiral column, it may be carried out according to a method known to those skilled in the art (see, for example, "Separation of Optical Isomers" (Quarterly Chemical Reviews No. 6, 1989, edited by The Chemical Society of Japan, The Chemical Society of Japan Press)). Also, various chiral columns are commercially available, and an appropriate one may be selected as appropriate. Preferably, CHIRALPAK IA, CHIRALPK IB, CHIRALPAK IC, etc. manufactured by Daicel Corporation can be mentioned.

[0317] The heteroaromatic amide derivative or a salt thereof contained in the pharmaceutical of the present invention may have an optical isomer, a stereoisomer, a tautomer, and / or a geometric isomer, but the pharmaceutical of the present invention includes all possible isomers including these and mixtures thereof. Similarly, the raw materials and intermediates for synthesizing the compounds contained in the pharmaceutical of the present invention may also have an optical isomer, a stereoisomer, a tautomer, and / or a geometric isomer, but the raw materials and intermediates used for producing the pharmaceutical of the present invention include all of these.

[0318] The prodrug of the compound contained in the pharmaceutical of the present invention can be produced, for example, by substituting an appropriate functional group present in the heteroaromatic amide derivative or a salt thereof with a protecting group according to a method known to those skilled in the art (such as the method described in "Design of Prodrugs" by H. Bundgaard (Elsevuer, 1985)).

[0319] The compound or its salt contained in the medicament of the present invention selectively inhibits Nav1.7 against Nav1.5, so there is less concern about side effects derived from Nav1.5, and it acts very effectively on a wide range of pathological conditions involving Nav1.7. There are various pathological conditions involving Nav1.7, but the compound or its salt of the present invention is effective, for example, in the treatment or prevention of pain. More specifically, the compound or its salt of the present invention is particularly useful in the treatment or prevention of acute pain, chronic pain, nociceptive pain, neuropathic pain, and headache. In addition, the compound or its salt contained in the medicament of the present invention is particularly useful in the treatment or prevention of acute or chronic pruritus and autonomic nervous system-related diseases.

[0320] Nociceptive pain is pain caused by tissue damage or a strong stimulus that may cause damage, and includes the following types of pain: Perioperative pain; persistent postoperative pain; post-traumatic pain; inflammatory pain; cancer-related pain; pain associated with osteoarthritis; herpes zoster pain; renal colic; bladder pain; visceral pain; toothache; pain after tooth extraction; pain associated with heart disease; pain associated with pancreatitis; pain related to contusion and strain; back pain; pain associated with musculoskeletal disorders, and pain associated with rheumatoid arthritis. Inflammatory pain includes pain associated with pathological conditions related to the following inflammatory factors: Rheumatoid arthritis; interstitial cystitis; skin diseases (e.g., sunburn, burns, eczema, dermatitis, or psoriasis); eye diseases (e.g., glaucoma, retinitis, retinopathy, uveitis, or acute disorders of eye tissues); lung diseases (e.g., asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, respiratory distress syndrome, or farmer's lung); conditions associated with infections such as influenza or colds; gastrointestinal diseases (e.g., aphthous ulcers, irritable bowel syndrome, inflammatory bowel syndrome, atopic gastritis, functional gastrointestinal disorders, gastroesophageal reflux syndrome, Crohn's disease, ileitis, or ulcerative colitis); dysmenorrhea; organ transplantation; vascular diseases; periarteritis nodosa; thyroiditis; aplastic anemia; Hodgkin's disease; scleroderma; myasthenia gravis; systemic lupus erythematosus; Behçet's disease; Sjogren's syndrome; nephrotic syndrome; polymyositis; gingivitis; and febrile diseases. Cancer-related pain includes pain associated with tumors and pain associated with cancer therapies. Pain associated with musculoskeletal disorders includes myalgia, fibromyalgia, polymyositis, suppurative myositis, and temporomandibular myofascial pain. Back pain includes pain due to intervertebral disc herniation, lumbar spinal joints, sacroiliac joints, paravertebral muscle groups, or abnormalities of the posterior longitudinal ligament. Chronic arthropathy includes rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, and juvenile arthritis.

[0321] Neuropathic pain is pain caused by injury or disease that has damaged the nervous system, and neuropathic pain includes many disorders resulting from a variety of causes. Neuropathic pain includes, but is not limited to, the following types of pain: Peripheral neuropathic pain; central neuropathic pain; postherpetic neuralgia; diabetic neuropathy; trigeminal neuralgia; nonspecific low back pain; cancerous neuropathic pain; pain associated with Parkinson's disease; pain associated with multiple sclerosis; HIV-related neuropathic pain; sciatica; complex regional pain syndrome; spinal stenosis; carpal tunnel syndrome; phantom limb pain; pain after stroke; pain associated with spinal cord injury; pain associated with epilepsy; pain associated with spasm; pain associated with vitamin deficiency; familial acroparesthesia; primary acroparesthesia; paroxysmal extreme pain disorder; orofacial pain; and burning mouth syndrome, pain resulting from toxins or chronic inflammatory conditions. These neuropathic pains include spontaneous pain, sensory disturbances and paresthesia, hyperesthesia, high sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), painful sensation to non-noxious stimuli (dynamic, static, thermal, or cold allodynia), or analgesia.

[0322] Headache includes migraine, cluster headache, tension-type headache, mixed headache, headache associated with vascular disorders, secondary headache, and autonomic headache.

[0323] Itching includes itching associated with skin diseases, drug rash, kidney dialysis-related pruritus, ocular pruritus, aural pruritus, itching due to insect bites, opioid-induced pruritus, itching associated with infections such as viruses, cutaneous lymphoma, and neuropathic itching.

[0324] Autonomic nerve-related diseases include autonomic neuropathy, nervous gastritis, irritable bowel syndrome, Meniere's disease, hyperventilation syndrome, and autonomic neuropathy. However, the above-mentioned diseases through the action of Nav1.7 are illustrative, and the diseases are not limited to those described above.

[0325] The medicament of the present invention is composed of a novel heteroaromatic amide derivative or its salt alone, or is mixed with a pharmacologically acceptable solid or liquid pharmaceutical carrier, and can be prepared by conventional methods in the art. Examples of the pharmacologically acceptable solid or liquid pharmaceutical carrier include: For example, excipients, binders, disintegrants, disintegration aids, fluidizing agents, lubricants, stabilizers, coating agents, plasticizers, brightening agents, bases, emulsifiers, thickeners, suspending agents, dispersants, solvents, solubilizers, solubilization aids, surfactants, antioxidants, buffers, isotonic agents, pH regulators, preservatives, antiseptics, fragrances, colorants, sweeteners, flavoring agents, and other additives.

[0326] The medicament of the present invention can be administered orally or parenterally to mammals (for example, humans, monkeys, cows, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice, etc.). Examples of dosage forms for administering the medicament of the present invention include: For example, tablets (including sugar-coated tablets and film-coated tablets), capsules, granules, powders, oral liquids, syrups, oral jellies, buccal tablets, buccal liquids, buccal sprays, buccal semi-solid agents, injections, dialysis agents, inhalants, eye drops, eye ointments, ear drops, nasal drops, suppositories, rectal semi-solid agents, enemas, vaginal tablets, vaginal suppositories, external solid agents, external liquids (including liniments and lotions), sprays, ointments, creams, gels, and patches, etc. In addition, other drugs may be formulated in the medicament of the present invention as necessary.

[0327] When the medicament of the present invention is administered orally, the dosage form is not particularly limited as long as it is a dosage form used as a pharmaceutical composition for oral administration. For example, it can be prepared into dosage forms such as tablets, capsules, granules, syrups, etc. When preparing the medicament of the present invention consisting of these dosage forms, those of each dosage form can be carried out by conventional methods in the art. Also, the dosage and the number of administrations of the medicament of the present invention are not limited, and can be determined and / or adjusted in consideration of the age and weight of the subject to be administered. For example, when orally administering to an adult patient, usually, the amount of the compound or its salt of the present invention, which is the active ingredient, administered at one time can be administered at a normal frequency so that it is about 0.001 mg to about 1000 mg per 1 kg of body weight.

Examples

[0328] The features of the present invention will be further specifically described below 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 without departing from the gist of the present invention. Therefore, the scope of the present invention should not be construed as being limited by the specific examples shown below.

[0329] Shown below 1 The 1H-NMR spectra were measured using deuterated chloroform (CDCl3), deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) as solvents and tetramethylsilane (TMS) as an internal standard, with a JNM-ECA400 type spectrometer (400 MHz, manufactured by JEOL Ltd.) or an AVANCEIII HD400 type (400 MHz, manufactured by Bruker BioSpin). The measurement results of chemical shifts were shown as δ values in ppm, and the J values of coupling constants were shown 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 electrospray ionization method with Exactive (manufactured by Thermo Fisher Scientific). The chemical structural formulas and physical property values of the compounds in each example are shown in the following table.

[0330] In each example, each abbreviation has the following meaning. Ac: Acetyl ADDP: 1,1'-(Azodicarbonyl)dipiperidine (A ta (Phos)2PdCl2: Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Bn: Benzyl Boc: tert-Butoxycarbonyl BPO: Benzoyl peroxide Bu: Butyl CAN: Cerium(IV) ammonium nitrate DAST: N,N-Diethylaminosulfur trifluoride DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene 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-Azabenzotriazol-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-Azanoradamantane N-Oxyl p: para Ph: Phenyl PTSA: p-Toluenesulfonic acid TBAB: Tetrabutylammonium bromide TBA-HS: Tetrabutylammonium hydrogensulfate 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) methanesulfonate TBDPS: tert-Butyldiphenylsilyl tert: tertiary (third grade) 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) methanesulfonate The asterisk (*) shown in the structural formula in the examples means that the configuration of the corresponding asymmetric carbon is single. For the notations of "isomer A", "isomer B", "isomer C" and "isomer D", among the multiple compounds indicated by the same example number, they are specified in the order of "isomer A", "isomer B", "isomer C" and "isomer D" from the isomers first separated by high performance liquid chromatography in the examples.

[0331] Example 1 Preparation of N-(6-fluorochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0332]

Chemical formula

[0333] Step 1 Ethyl bromopyruvate (776 μL, 6.18 mmol) was added to a mixed solution of 5-(trifluoromethyl)pyridin-2-amine (835 mg, 5.15 mmol) in 1,2-dimethoxyethane (12.9 mL) and methanol (12.9 mL), and the mixture was stirred at 80 °C for 14 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography to obtain ethyl 6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (yield 557 mg, yield 42%).

[0334] Step 2 To a mixed solution of ethyl 6-(trifluoromethyl)imidazo[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 hydroxide on carbon (2.43 g) was added, and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere at about 3 atmospheres pressure. After filtering the reaction solution through celite, the solvent was distilled off under reduced pressure. Toluene was added to the residue, and the solvent was distilled off under reduced pressure to obtain ethyl 6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate (yield 6.42 g) as a crude product.

[0335] Step 3 To a solution of ethyl 6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate (6.42 g, 24.5 mmol) in ethanol (49 mL), 4 mol / L aqueous sodium hydroxide 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 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 to obtain 6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid (yield 11.2 g, 98% yield) as a mixture with 4 equivalents of sodium chloride.

[0336] Step 4 A suspension of 6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid (sodium chloride mixture) (30.0 mg, 0.0641 mmol) in N,N-dimethylformamide (641 μL) was added with 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), and stirred at 40 °C for 6 hours. After adding water and ethyl acetate to the reaction mixture and separating the layers, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain N-(6-fluorochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (yield 17.9 mg, yield 73%).

[0337] Reference Example 1 Production of (R)-6-chlorochroman-3-amine hydrochloride

[0338]

Chemical Structure

[0339] Step 1 To a suspension of (R)-chroman-3-amine hydrochloride (200 mg, 1.08 mmol) in dichloromethane (11 mL) were added N,N-diisopropylethylamine (555 μL, 3.23 mmol) and trifluoroacetic anhydride (180 μL, 1.29 mmol), and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography to obtain (R)-N-(chroman-3-yl)-2,2,2-trifluoroacetamide (yield 245 mg, yield 93%).

[0340] Step 2 To a solution of (R)-N-(chroman-3-yl)-2,2,2-trifluoroacetamide (4.00 g, 16.3 mmol) in acetonitrile (100 mL) was added N-chlorosuccinimide (2.60 g, 19.5 mmol), and the mixture was stirred at 70 °C for 6 hours. After adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to the reaction mixture and separating the layers, 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%).

[0341] Step 3 To a solution of (R)-N-(6-chlorochroman-3-yl)-2,2,2-trifluoroacetamide (297 mg, 1.06 mmol) in chloroform (2.7 mL) was added 4 mol / L aqueous sodium hydroxide solution (2.7 mL, 10.8 mmol), and the mixture was stirred at room temperature for 17 hours. After adding water and chloroform to the reaction mixture and separating the layers, 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 the ethyl acetate solution of the purified compound was added 4 mol / L hydrogen chloride-ethyl acetate solution, and the precipitated solid was collected by filtration to obtain (R)-6-chlorochroman-3-amine hydrochloride (yield 60.9 mg, yield 67%).

[0342] Example 2 Production and isomer separation of N-((R)-6-chlorochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0343]

Chemical formula

[0344] Step 1 A suspension of 6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid (sodium chloride mixture) (128 mg, 0.273 mmol), synthesized by the method described in Step 3 of Example 1, in N,N-dimethylformamide (2.27 mL) was added with HATU (95.0 mg, 0.250 mmol), N,N-diisopropylethylamine (195 μL, 1.14 mmol) and (R)-6-chlorochroman-3-amine hydrochloride (50.0 mg, 0.227 mmol), synthesized by the method described in Reference Example 1, and stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was purified by silica gel column chromatography to obtain 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%).

[0345] Step 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) was dissolved in ethanol (20 mL) and subjected to preparative HPLC (column: CHIRALPAK IB, eluent: ethanol / n-hexane = 50 / 50, flow rate: 5.0 mL / min, room temperature) to obtain isomer A (yield 16.8 mg, yield 34%) and isomer B (yield 14.3 mg, yield 29%).

[0346] 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)

[0347]

Chemical Structure

[0348] To a solution of N-((R)-6-chlorochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (isomer A) (50.0 mg, 0.125 mmol) synthesized by the method described in Example 2 in N,N-dimethylformamide (1.3 mL) were added sodium hydride (60% in oil) (12.5 mg, 0.313 mmol) and iodomethane (11.7 μL, 0.188 mmol), and the mixture was stirred at 80 °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 anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain N-((R)-6-chlorochroman-3-yl)-N-methyl-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (isomer A) (yield 24.4 mg, 47% yield).

[0349] 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)

[0350]

Chemical formula

[0351] In the same manner as in Example 3, instead of N-((R)-6-chlorochroman-3-yl)-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-a]pyridine-2-carboxamide (isomer B) synthesized by the method described in Example 2 was used to obtain N-((R)-6-chlorochroman-3-yl)-N-methyl-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (isomer B).

[0352] Reference Example 2 Production of (R)-6-bromochroman-3-amine hydrochloride

[0353]

Chemical formula

[0354] Step 1 To a solution of (R)-N-(chroman-3-yl)-2,2,2-trifluoroacetamide (6.46 g, 26.3 mmol) in acetonitrile (132 mL) was added N-bromosuccinimide (5.16 g, 29.0 mmol), and the mixture was stirred at room temperature for 22 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography to obtain (R)-N-(6-bromochroman-3-yl)-2,2,2-trifluoroacetamide (yield 8.47 g, 99% yield).

[0355] Step 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-(6-bromochroman-3-yl)-2,2,2-trifluoroacetamide was used to obtain (R)-6-bromochroman-3-amine hydrochloride.

[0356] Example 5 Production of N-((R)-6-bromochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0357]

Chemical formula

[0358] Reference Example 3 Production of (R)-6-(difluoromethyl)chroman-3-amine hydrochloride

[0359]

Chemical formula

[0360] Step 1 A mixed suspension of (R)-N-(6-bromochroman-3-yl)-2,2,2,-trifluoroacetamide (6.47 g, 20.0 mmol), potassium vinyltrifluoroborate (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) in 1,4-dioxane (167 mL) and water (33 mL) was stirred at 100 °C for 15 hours. After adding water and ethyl acetate to the reaction solution and separating the layers, 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 (R)-2,2,2-trifluoro-N-(6-vinylchroman-3-yl)acetamide (yield 3.03 g, yield 56%).

[0361] Step 2 (R)-2,2,2-Trifluoro-N-(6-vinylchroman-3-yl)acetamide (3.03 g, 11.2 mmol) was added to a 1,4-dioxane solution, followed by the addition of water (37 mL), 2,6-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). The mixture was stirred at room temperature for 3 hours. 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 evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain (R)-2,2,2-trifluoro-N-(6-formylchroman-3-yl)acetamide (yield 2.56 g, yield 84%).

[0362] Step 3 (R)-2,2,2-Trifluoro-N-(6-formylchroman-3-yl)acetamide (1.45 g, 5.31 mmol) was added with N,N-diethylaminosulfur trifluoride (2.8 mL, 21.2 mmol), and the mixture was stirred at room temperature for 5 days. The reaction mixture was diluted with dichloromethane, dropped into a mixture of chloroform and water, and then separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (R)-N-(6-(difluoromethyl)chroman-3-yl)-2,2,2-trifluoroacetamide (yield 1.11 g, yield 71%).

[0363] Step 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.

[0364] Example 6 Preparation of N-((R)-6-(difluoromethyl)chroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0365]

Chemical formula

[0366] In the same manner as in Example 1, using (R)-6-(difluoromethyl)chroman-3-amine hydrochloride synthesized by the method described in Reference Example 3 instead of 6-fluorochroman-3-amine hydrochloride in Step 4, N-((R)-6-(difluoromethyl)chroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide was obtained.

[0367] Example 7 Isomer separation of N-((R)-6-(difluoromethyl)chroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0368]

Chemical formula

[0369] N-((R)-6-(difluoromethyl)chroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (50.0 mg, 0.120 mmol) synthesized by the method described in Example 6 was dissolved in ethanol (20 mL) and subjected to preparative HPLC (column: CHIRALPAK IB, eluent: ethanol / n-hexane = 50 / 50, flow rate: 10.0 mL / min, room temperature) to obtain isomer A (yield 24.4 mg, 49%) and isomer B (yield 21.4 mg, 43%).

[0370] Reference Example 4 Production of 5-chlorochroman-3-amine hydrochloride

[0371] [Chemical formula]

[0372] Step 1 To a solution of ice-cooled N-(tert-butoxycarbonyl)-2-phosphonoglycine trimethyl (2.30 g, 7.73 mmol) in tetrahydrofuran (30 mL), a solution of 2-chloro-6-hydroxy-benzaldehyde (1.10 g, 7.03 mmol) and 1,1,3,3-tetramethylguanidine (970 μL, 7.73 mmol) in tetrahydrofuran (30 mL) was added, and the mixture was stirred at room temperature for 18 hours. Water and ethyl acetate were added to the reaction solution, and liquid separation was performed. 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 methyl 2-((tert-butoxycarbonyl)amino)-3-(2-chloro-6-hydroxyphenyl)acrylate (yield 2.05 g, yield 89%).

[0373] Step 2 To a solution of ice-cooled methyl 2-((tert-butoxycarbonyl)amino)-3-(2-chloro-6-hydroxyphenyl)acrylate (2.05 g, 6.25 mmol) in tetrahydrofuran (60 mL), 3 mol / L 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 liquid separation was performed. 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 (1-(2-chloro-6-hydroxyphenyl)-3-hydroxypropyl)carbamate (yield 220 mg, yield 12%).

[0374] Step 3 To a solution of tert-butyl (1-(2-chloro-6-hydroxyphenyl)-3-hydroxypropyl)carbamate (218 mg, 0.722 mmol) in tetrahydrofuran (2 mL) were added triphenylphosphine (246 mg, 0.939 mmol) and diisopropyl azodicarboxylate (186 μL, 0.939 mmol), 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, 86%).

[0375] Step 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), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain 5-chlorochroman-3-amine hydrochloride (yield 129 mg, 97%).

[0376] Example 8 Preparation of N-(5-chlorochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0377]

Chemical formula

[0378] In the same manner as in Example 1, using 5-chlorochroman-3-amine hydrochloride synthesized by the method described in Reference Example 4 instead of 6-fluorochroman-3-amine hydrochloride in Step 4, N-(5-chlorochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide was obtained.

[0379] Example 9 Preparation of N-(5-bromochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (isomer A, enantiomeric mixture) and (isomer B, enantiomeric mixture)

[0380]

Chem.

[0381] In the same manner as in Example 1, using 5-bromochroman-3-amine hydrochloride instead of 6-fluorochroman-3-amine hydrochloride in Step 4, N-(5-bromochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide was obtained. Further, the diastereomers were separated by silica gel column chromatography to obtain N-(5-bromochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (isomer A, enantiomeric mixture) and N-(5-bromochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (isomer B, enantiomeric mixture).

[0382] Example 10 Preparation of N-(5-cyclopropylchroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0383]

Chem.

[0384] N-(5-Bromochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (50.0 mg, 0.113 mmol) synthesized by the method described in Example 9 and cyclopropylboronic acid (14.5 mg, 0.169 mmol) were added to a mixed solution of 1,4-dioxane (833 μL) and water (133 μL). Cesium carbonate (73.3 mg, 0.225 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7.9 mg, 0.011 mmol) were added thereto, and the mixture was stirred at 140 °C for 1 hour under microwave irradiation. Water and ethyl acetate were added to the reaction solution, and liquid separation was performed. 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 to obtain N-(5-cyclopropylchroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (yield 20.9 mg, yield 46%).

[0385] Reference Example 5 Production of (R)-6-ethylchroman-3-amine hydrochloride

[0386]

Chemical formula

[0387] Step 1 To a solution 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 in ethanol (10.9 mL) was added 20% palladium hydroxide on carbon (38.3 mg), and the mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere (balloon pressure). After the reaction solution was filtered 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%).

[0388] Step 2 In the same manner as in Step 3 of Reference Example 1, (R)-6-ethylchroman-3-amine hydrochloride was obtained using (R)-N-(6-ethylchroman-3-yl)-2,2,2-trifluoroacetamide instead of (R)-N-(6-chlorochroman-3-yl)-2,2,2-trifluoroacetamide.

[0389] Example 11 Production of N-((R)-6-ethylchroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0390] [Chemical formula]

[0391] In the same manner as in Example 1, N-((R)-6-ethylchroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide was obtained using (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.

[0392] Reference Example 6 Production of 6-bromochroman-3-amine hydrochloride

[0393] [Chemical formula]

[0394] In the same manner as in Reference Example 4, 6-bromochroman-3-amine hydrochloride was obtained using 5-bromo-2-hydroxy-benzaldehyde instead of 2-chloro-6-hydroxy-benzaldehyde in Step 1.

[0395] Example 12 Production of N-(6-bromochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0396]

Chemical formula

[0397] In the same manner as in Example 1, instead of the 6-fluorochroman-3-amine hydrochloride in Step 4, 6-bromochroman-3-amine hydrochloride synthesized by the method described in Reference Example 6 was used to obtain N-(6-bromochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide.

[0398] Example 13 Production of N-((R)-6-methoxychroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0399]

Chemical formula

[0400] Step 1 A solution of N-(6-bromochroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (50.0 mg, 0.113 mmol) synthesized by the method described in Example 12 in 1,4-dioxane (1.0 mL) was added with water (500 μL), 85 w / w% potassium hydroxide (12.6 mg, 0.191 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylphenyl (4.8 mg, 0.011 mmol), and tris(dibenzylideneacetone)palladium(0) (5.2 mg, 0.0056 mmol), and the mixture was stirred at 120 °C for 1 hour under microwave irradiation. Water and ethyl acetate were added to the reaction solution, and liquid separation was performed. 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 to obtain N-(6-hydroxychroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (yield 34.5 mg, yield 80%).

[0401] Step 2 To a solution of N-(6-hydroxychroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (15.0 mg, 0.0393 mmol) in N,N-dimethylformamide (787 μL) were added cesium carbonate (25.6 mg, 0.0787 mmol) and methyl iodide (3.7 μL, 0.0590 mmol), and the mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added to the reaction solution, and liquid separation was performed. 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 to obtain 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%).

[0402] Reference Example 7 Production of N-((R)-chroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0403]

Chemical formula

[0404] Example 14 Production of N-((R)-chroman-3-yl)-3-iodo-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0405]

Chemical formula

[0406] To a solution of N-((R)-chroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (79.7 mg, 0.218 mmol) synthesized by the method described in Reference Example 7 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 liquid separation was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain N-((R)-chroman-3-yl)-3-iodo-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (yield 97.5 mg, yield 91%).

[0407] Example 15 Production of N-((R)-chroman-3-yl)-3-(6-methoxypyridin-2-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0408] [Chemical formula]

[0409] N-((R)-Chroman-3-yl)-3-iodo-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (30.0 mg, 0.0611 mmol) and 6-methoxypyridine-2-boronic acid (18.7 mg, 0.122 mmol) were added to a mixed solution of 1,4-dioxane (500 μL) and water (100 μL). Cesium carbonate (39.8 mg, 0.122 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.3 mg, 0.0061 mmol) were added thereto, and the mixture was stirred at 140 °C for 1 hour 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 evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain N-((R)-chroman-3-yl)-3-(6-methoxypyridin-2-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (yield 9.4 mg, yield 33%).

[0410] Example 16 Production of (R)-N-(chroman-3-yl)-3-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0411] [Chemical formula]

[0412] Step 1 In the same manner as in Step 2 of Example 1, (R)-6-bromo-N-(chroman-3-yl)imidazo[1,2-a]pyridine-2-carboxamide synthesized by the method described in Reference Example 9 was used instead of ethyl 6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate to obtain (R)-N-(chroman-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide.

[0413] Step 2 In the same manner as in Example 14, (R)-N-(chroman-3-yl)-3-iodo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide was obtained using (R)-N-(chroman-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide instead of N-((R)-chroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide.

[0414] Step 3 In the same manner as in Example 15, (R)-N-(chroman-3-yl)-3-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide was obtained using (R)-N-(chroman-3-yl)-3-iodo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide instead of N-((R)-chroman-3-yl)-3-iodo-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide and using phenylboronic acid instead of 6-methoxypyridine-2-boronic acid.

[0415] Example 17 Production of (R)-N-(6-chlorochroman-3-yl)-3-(6-methoxypyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0416]

Chemical formula

[0417] Step 1 In the same manner as in Example 14, using ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate instead of N-((R)-chroman-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide, ethyl 3-iodo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate was obtained.

[0418] Step 2 In the same manner as in Example 15, using ethyl 3-iodo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate instead of N-((R)-chroman-3-yl)-3-iodo-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide, ethyl 3-(6-methoxypyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate was obtained.

[0419] Step 3 In the same manner as in Step 3 of Example 1, using ethyl 3-(6-methoxypyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate instead of ethyl 6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate, 3-(6-methoxypyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

[0420] Step 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, and instead of 6-fluorochroman-3-amine hydrochloride, (R)-6-chlorochroman-3-amine hydrochloride synthesized by the method described in Reference Example 1 was used to obtain (R)-N-(6-chlorochroman-3-yl)-3-(6-methoxypyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide.

[0421] Example 18 Production of (R)-N-(6-chlorochroman-3-yl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0422]

Chemical formula

[0423] Step 1 In the same manner as in Step 2 of Example 17, instead of 6-methoxypyridine-2-boronic acid, 6-(chloropyridin-2-yl)boronic acid was used to obtain ethyl 3-(6-chloropyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate.

[0424] Step 2 To a solution of ethyl 3-(6-chloropyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate (1.05 g, 3.43 mmol) in tetrahydrofuran (10 mL) were added ethanol (10 mL), acetic acid (1.8 mL) and 20% palladium hydroxide on carbon (0.72 g). The mixture was stirred at 50 °C for 2 h under a hydrogen atmosphere (balloon pressure). After filtering the reaction mixture through celite, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 3-(pyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate (yield 900 g, 97% yield).

[0425] Step 3 In the same manner as in Step 3 of Example 1, using ethyl 3-(pyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate instead of ethyl 6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate, 3-(pyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid was obtained as a mixture with 4 equivalents of sodium chloride.

[0426] Step 4 3-(Pyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid (sodium chloride mixture) (15 mg, 0.031 mmol), (R)-6-chlorochroman-3-amine hydrochloride (6.9 mg, 0.031 mmol) synthesized by the method described in Reference Example 1, 1-hydroxybenzotriazole (7.2 mg, 0.047 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.0 mg, 0.047 mmol) were suspended in dichloromethane (1 mL). To this suspension, 4-methylmorpholine (21 μL, 0.19 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (R)-N-(6-chlorochroman-3-yl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (yield 8.0 mg, yield 62%).

[0427] Reference Example 8 Production of 3-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid

[0428] [Chemical Structure]

[0429] 3-(1H-Pyrazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid was obtained in the same manner as in Steps 2 to 3 of Example 17, using 1H-pyrazol-5-ylboronic acid instead of 6-methoxypyridine-2-boronic acid in Step 2.

[0430] Example 19 Production of (R)-3-(1H-pyrazol-5-yl)-N-(6-(trifluoromethyl)chroman-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0431] [Chem.]

[0432] In the same manner as in Step 4 of Example 18, using 3-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid synthesized by the method described in Reference Example 8 instead of 3-(pyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid, and using (R)-6-(trifluoromethyl)chroman-3-amine hydrochloride synthesized by the method described in Reference Example 43 instead of (R)-6-chlorochroman-3-amine hydrochloride, (R)-3-(1H-pyrazol-5-yl)-N-(6-(trifluoromethyl)chroman-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide was obtained.

[0433] Example 20 Production of (R)-3-(1H-pyrazol-5-yl)-N-(6-((2,2,2-trifluoroethoxy)methyl)chroman-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0434] [Chem.]

[0435] In the same manner as in Step 4 of Example 18, using 3-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid synthesized by the method described in Reference Example 8 instead of 3-(pyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid, and using (R)-6-((2,2,2-trifluoroethoxy)methyl)chroman-3-amine hydrochloride synthesized by the method described in Reference Example 44 instead of (R)-6-chlorochroman-3-amine hydrochloride, (R)-3-(1H-pyrazol-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.

[0436] Example 21 Production of (R)-N-(6-chlorochroman-3-yl)-3-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0437]

Chemical formula

[0438] In the same manner as in Example 17, using 1H-pyrazole-5-boronic acid instead of 6-methoxypyridine-2-boronic acid in Step 2, (R)-N-(6-chlorochroman-3-yl)-3-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide was obtained.

[0439] Example 22 Production of 3-phenyl-N-(3-(trifluoromethyl)phenethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

[0440]

Chemical formula

[0441] In the same manner as in Example 17, phenylboronic acid was used instead of 6-methoxypyridine-2-boronic acid in Step 2, and 2-(3-(trifluoromethyl)phenyl)ethanamine was used instead of (R)-6-chlorochroman-3-amine hydrochloride in Step 4 to obtain 3-phenyl-N-(3-(trifluoromethyl)phenethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide.

[0442] Reference Example 9 Production ...

Claims

1. General formula (I-E2): 【Chemical 1】 [wherein, X 1 -X 2 is N-C or C-N, Y1, Y2, Y3 and Y4 together form -OCH2CH2CH2-, -OCR4aHCH2CH2-, -OCR4aR4bCH2CH2-, -OCH2CH2-, -OCR4aHCH2-, -OCR4aR4bCH2-, -OCH2CH2CH2CH2-, -OCR4aHCH2CH2CH2-, -OCR4aR4bCH2CH2CH2-, -OCH2CR4aHCH2CH2-, -OCH2CR4aR4bCH2CH2-, -CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2CH2OCH2-, -CH2CR4aHOCH2- -CH2CH2CH2CH2-, -CH2CR4aHCH2CH2-, -CH2CR4aR4bCH2CH2-, -CH2CH2CR4aHCH2-, -CH2CH2CR4aR4bCH2-, -CH2SCH2CH2-, -CH2SO2CH2CH2-, -NHCH2CH2CH2-, -NR4cCH2CH2CH2-, -NR4cCR4aHCH2CH2-, -NHCR4aHCH2CH2-, -CH2NR4cCH2CH2-, -CH2NR4cCR4aHCH2-, -CH2NHCR4aHCH2-, -CH2CH2NR4cCH2-, -CH2CR4aHNR4cCH2-, or -CH2CR4aHNHCH2-, and R 1a and R 1b each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a 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, and 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 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 each independently a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 6 haloalkyl group, an optionally substituted C 1 -C 6 alkoxy group, an optionally substituted C 1 -C 6 haloalkoxy group, an optionally substituted C 1 -C 4 alkoxy-C 1 -C 4 alkyl group, an optionally substituted C 1 -C 4 haloalkoxy-C 1 -C 4 alkyl group, an optionally substituted C 1 -C 4 alkoxy-C 1 -C 4 haloalkyl group, an optionally substituted C 1 -C 4 haloalkoxy-C 1 -C 4 haloalkyl group, an optionally substituted C 1 -C 6 alkylcarbonyl group, an 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 haloalkoxycarbonyl group, an optionally substituted C 1 -C 6 haloalkylcarbonyloxy group, an optionally substituted C 3 -C 7 Cycloalkyl group, optionally substituted heterocycloalkyl group, optionally substituted C 3 -C 7 Cycloalkyloxy group, optionally substituted heterocycloalkyloxy group, optionally substituted C 2 -C 6 Alkenyl group, optionally substituted C 2 -C 6 Alkenyloxy group, optionally substituted C 2 -C 6 Alkenyloxy-C 1 -C 4 Alkyl group, optionally substituted C 2 -C 6 Alkenyloxy-C 1 -C 4 Haloalkyl 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, optionally substituted C 1 -C 4 Haloalkoxy-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 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 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, 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 each independently a hydrogen atom, C 1 -C 4 alkyl group, or C 1 -C 4 haloalkyl group, and q is 0, 1, 2, or 3. ), or general formula (I-B) 【Chemical 2】 {wherein ring C is a saturated, partially saturated, or unsaturated monocyclic ring having 3 to 7 members, or a saturated, partially saturated, or unsaturated bicyclic ring having 7 to 12 members, 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 - and is (R c is a hydrogen atom, C 1 -C 4 alkyl group, or C 1 -C 4 haloalkyl group, and R 10a 、R 10b 、R 10c 、R 10d 、R 10e 、R 10f 、R 10g 、R 10h are each independently a hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, or a C 3 -C 7 cycloalkyl group, R 10a and R 10b may together with the carbon atom to which they are attached form a 3- to 7-membered monocyclic ring, R 10c and R 10d may together with the carbon atom to which they are attached form a monocyclic ring of 3 to 7 members, R 10e and R 10f may together with the carbon atom to which they are attached form a monocyclic ring of 3 to 7 members, R 10g and R 10h may together with the carbon atom to which they are attached form a 3- to 7-membered monocyclic ring, r1, r2, r3 and r4 are each independently 0, 1, or 2.) R 9a 、R 9b and R 9c each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a 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 alkenyl group, -(CH 2 ) s NR d1 R d2 (R d1 and R d2 each independently represents a hydrogen atom, C 1 -C 4 alkyl group, or C 1 -C 4 haloalkyl group, and s is 0, 1, or 2.), or general formula (I-C) [Chemical Formula 3] {wherein Ring D is a 3- to 7-membered monocyclic ring which 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. L 3 is a single bond or an oxygen atom.} is a group represented by} or R 4a and R 4b may together with the carbon atom to which they are attached form a 3- to 7-membered monocyclic ring, or R 4a and R 4b together form the general formula (I-D): 【Chemical Formula 4】 may be formed (R 4d and R 4e are each independently a hydrogen atom, a halogen atom, or a C 1 -C 4 alkyl group, or R 4d and R 4e may together with the carbon atom to which they are attached form a 3- to 7-membered monocyclic ring. (However, when R2 is a hydrogen atom, at least one of Y1, Y2, Y3, or Y4 is -CR4aR4b-, -CR4aH-, -CH2CR4aR4b-, or -CH2CR4aH-.). Z 2 - Z 3 is -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- (wherein R f1 and R f2 are a hydrogen atom, a C 1 -C 4 alkyl group, or a 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 an aralkyl group, R 6a 、 and R 6b are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano 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, Z 4 is C-R 11a or a nitrogen atom, and R 11a is a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a 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 alkenyl group, C 2 -C 6 alkenyloxy group, C 2 -C 6 alkynyl group, or C 2 -C 6 alkynyloxy group, and R 11b and R 11c each independently represents a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a hydroxyl group, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 6 haloalkyl group, an optionally substituted C 1 -C 6 alkoxy group, an optionally substituted C 1 -C 6 haloalkoxy group, an optionally substituted C 1 -C 4 alkoxy-C 1 -C 4 alkyl group, an optionally substituted C 1 -C 4 haloalkoxy-C 1 -C 4 alkyl group, an optionally substituted C 1 -C 4 alkoxy-C 1 -C 4 haloalkyl group, an optionally substituted C 1 -C 4 haloalkoxy-C 1 -C 4 haloalkyl group, an optionally substituted C 1 -C 6 alkylcarbonyl group, an 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 haloalkoxycarbonyl group, an optionally substituted C 1 -C 6 haloalkylcarbonyloxy group, an optionally substituted C 3 -C 7 Cycloalkyl group, optionally substituted heterocycloalkyl group, optionally substituted C 3 -C 7 Cycloalkyloxy group, optionally substituted heterocycloalkyloxy group, optionally substituted C 2 -C 6 Alkenyl group, optionally substituted C 2 -C 6 Alkenyloxy group, optionally substituted C 2 -C 6 Alkenyloxy-C 1 -C 4 Alkyl group, optionally substituted C 2 -C 6 Alkenyloxy-C 1 -C 4 Haloalkyl 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, optionally substituted C 1 -C 4 Haloalkoxy-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 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 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, optionally substituted C 1 -C 4 Haloalkylthio-C 1 -C 4 Haloalkyl group, optionally substituted C 1 -C 6 Alkylsulfonyl group, -(CH 2 ) p NR a1 R a2 (R a1 and R a2 are each independently a hydrogen atom, C 1 -C 4 alkyl group, or C 1 -C 4 haloalkyl group, and p is 0, 1, or 2), or a general formula (I-A) [Chemical Formula 5] {wherein, ring B is a saturated, partially saturated or unsaturated 3- to 7-membered monocyclic ring, L 1 is 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 -(where R a3 and R a4 are each independently a hydrogen atom, a C 1 -C 4 alkyl group, or a C 1 -C 4 haloalkyl group). R 8a 、 R 8b and R 8c each independently represents a hydrogen atom, a halogen atom, a cyano group, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 haloalkoxy group, a C 3 -C 7 cycloalkyl group, a C 3 -C 7 cycloalkyloxy group, a heterocycloalkyl group, a heterocycloalkyloxy group, a C 2 -C 6 alkenyl group, or a C 2 -C 6 alkynyl group. It is a group represented by {}.] a medicament comprising a heteroaromatic amide derivative represented by the formula or a salt thereof, or a medicament comprising a heteroaromatic amide derivative selected from the group consisting of compounds represented by the following formula or a salt thereof [Chemical Formula 6] 。

2. In the general formula (I-E2), X 1 -X 2 is C-N, Y 1 、Y 2 、Y 3 and Y 4 are such that, when combined, -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 to form (R 4a , R 4b and R 4c are synonymous with the definitions given in claim 1.). The pharmaceutical according to claim 1, which comprises a heteroaromatic amide derivative or a salt thereof (provided that X 1 -X 2 is C-N, and Y 1 Y 2 Y 3 and Y 4 are such that, when taken together, -OCR 4a HCH 2 CH 2 -or -OCR 4a R 4b CH 2 CH 2 When forming -, R 2 is a hydrogen atom.).

3. In the general formula (I-E2), Z 2 -Z 3 is -CH 2 O-, and R 6a and R 6b are each independently a hydrogen atom, a fluorine atom, a hydroxyl group or a methoxy group, R 11a and R 11c is each a hydrogen atom, a pharmaceutical according to claim 1 or claim 2 comprising a heteroaromatic amide derivative or a salt thereof.

4. In the general formula (I-E2), X 1 -X 2 is C-N, Y 1 、Y 2 、Y 3 and Y 4 are such that, when combined, -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 - to form R 4a is a halogen atom, a hydroxyl group, a cyano group, C 1 -C 6 alkyl group, C 1 -C 6 alkyl group, C 1 -C 6 haloalkyl 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 which may be substituted with 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 C 1 -C 4 haloalkyl group which may be substituted with C 3 -C 7 cycloalkyl group, heterocycloalkyl group, C 2 -C 6 alkenyl group, C 2 -C 6 alkenyloxy group, C 2 -C 6 alkenyloxy-C 1 -C 4 an alkyl group, C which may be substituted with a halogen atom 2 -C 6 alkenyloxy-C 1 -C 4 an alkyl group, C 2 -C 6 an alkynyl group, C which may be substituted with a halogen atom or a methoxy group 2 -C 6 an alkynyl group, C 2 -C 6 alkynyloxy-C 1 -C 4 an alkyl group, C 1 -C 4 haloalkoxy-C 1 -C 4 an alkoxy group, C 1 -C 6 an alkylthio group, C 1 -C 6 a haloalkylthio group, C 1 -C 4 alkylthio-C 1 -C 4 an alkyl group, C 1 -C 4 haloalkylthio-C 1 -C 4 an alkyl group, -(CH 2 ) q NR b1 R b2 (q, R b1 and R b2 are synonymous with the definitions shown in claim 1.), or the general formula (I-B) 【Chemical Formula 7】 {wherein, Ring C is C 3 -C 7 cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, 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 - is (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 claim 1.). R 9a 、R 9b and R 9c are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 haloalkoxy group, a C 1 -C 6 alkoxycarbonyl group, a heterocycloalkyloxy group, or -(CH 2 ) s NR d1 R d2 (where s, R d1 and R d2 are as defined in claim 1).).} is, The medicament according to any one of claims 1 to 3, comprising a heteroaromatic amide derivative or a salt thereof.

5. In the general formula (I-E2), X 1 -X 2 is N-C, Y 1 、Y 2 、Y 3 and Y 4 are such that, when combined, -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 -to form (R 4a ,R 4b and R 4c are synonymous with the definitions given in claim 1.). The medicament according to claim 1, which comprises a heteroaromatic amide derivative or a salt thereof (provided that 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 (I-B), and when L 2 is a single bond, ring C is not a phenyl ring.).

6. In the general formula (I-E2), Z 2 -Z 3 is -CH 2 O-, and R 6a 、 R 6b 、 and R 11c are each a hydrogen atom, R 11a The pharmaceutical according to claim 1 or claim 5, which comprises a heteroaromatic amide derivative or a salt thereof, wherein R is a hydrogen atom or a halogen atom.

7. In the general formula (I-E2), X 1 -X 2 is N-C, Y 1 、 Y 2 、 Y 3 and Y 4 are such that, when combined, -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 to form, R 4a and R 4c each independently represents a halogen atom, a hydroxyl group, a cyano group, C 1 -C 6 an alkyl group, a C 1 -C 6 alkyl group which may be substituted with a hydroxyl group, C 1 -C 6 a haloalkyl group, a C 1 -C 6 haloalkyl group, C 1 -C 6 an alkoxy group, C 1 -C 6 a haloalkoxy group, C 1 -C 4 a C which may be substituted with a haloalkoxy group 1 -C 4 an alkoxy-C 1 -C 4 alkyl group, C 1 -C 4 a haloalkoxy-C 1 -C 4 alkyl group, C 1 -C 4 an alkoxy-C 1 -C 4 haloalkyl group, C 1 -C 4 a haloalkoxy-C 1 -C 4 haloalkyl group, C 1 -C 6 an alkylcarbonyl group, C 1 -C 6 an alkoxycarbonyl group, C 1 -C 6 a haloalkylcarbonyl group, C 3 -C 7 a cycloalkyl group, a halogen atom or a C 1 -C 4 a C which may be substituted with a haloalkyl group 3 -C 7 a cycloalkyl group, a heterocycloalkyl group, C 2 -C 6 an alkenyl group, C 2 -C 6 an alkenyloxy group, C 2 -C 6 Alkenyloxy-C 1 -C 4 An alkyl group, C which may be substituted with a halogen atom 2 -C 6 Alkenyloxy-C 1 -C 4 An alkyl group, C 2 -C 6 An alkynyl group, C which may be substituted with a halogen atom or a methoxy group 2 -C 6 An alkynyl group, C 2 -C 6 Alkynyloxy-C 1 -C 4 An alkyl group, C 1 -C 4 Haloalkoxy-C 1 -C 4 An alkoxy group, C 1 -C 6 An alkylthio group, C 1 -C 6 A haloalkylthio group, C 1 -C 4 Alkylthio-C 1 -C 4 An alkyl group, C 1 -C 4 Haloalkylthio-C 1 -C 4 An alkyl group,-(CH 2 ) q NR b1 R b2 (q, R b1 and R b2 are as defined in claim 1.), or the general formula (I-B) [Chemical 8] {wherein, Ring C is C 3 -C 7 cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, 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 is (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 claim 1.). R 9a 、R 9b and R 9c are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a 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 6 alkoxycarbonyl group, heterocycloalkyloxy group, or -(CH 2 ) s NR d1 R d2 (s, R d1 and R d2 are as defined in claim 1. ).} is, The medicament according to any one of claims 1, 5, and 6, comprising a heteroaromatic amide derivative or a salt thereof.

8. In the general formula (I-E2), R 11b is a hydrogen atom, a halogen atom, a cyano group, a cyanomethyl group, a formyl group, a nitro group, a carboxamide group, a 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 which may be substituted with a dimethylaminocarbonyl group or a dimethylamino group 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 alkenyl group, C 2 -C 6 alkynyl group, C which may be substituted with a halogen atom 2 -C 6 alkynyl 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 a2 are as defined in claim 1. ), or the general formula (I-A) 【Chemical Formula 9】 {wherein, Ring B is C 3 -C 7 cycloalkyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, L 1 is a single bond, -CH 2 -, -CH 2 O-, -OCH 2 -, -CH 2 CH 2 -, or, -CH 2 OCH 2 - and R 8a 、 R 8b and R 8c are each independently a hydrogen atom, a halogen atom, a 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 alkenyl group, or C 2 -C 6 alkynyl group.} A medicament according to any one of claims 1 to 7, which is a group represented by, and is composed of a heteroaromatic amide derivative or a salt thereof.

9. The following formula (the asterisk (*) shown in the structural formula means that the configuration of the corresponding asymmetric carbon is single.) 【Chemical Formula 10】 【Chemical 11】 【Chem.】 【Chemical Formula 12】 【Chemical 13】 【Chem.】 【Chemical Formula 14】 【Chem.】 【Chemical Formula 15】 【Chemical 16】 【Chem.】 【Chem.】 【Chemical 17】 【Chemical 18】 【Chemical 19】 【Chemical 20】 A medicament comprising a heteroaromatic amide derivative selected from the group consisting of compounds represented by the formula or a salt thereof.

10. The medicament according to claim 1, which is a prophylactic or therapeutic agent for diseases related to voltage-dependent sodium channel Nav1.

7.

11. The medicament according to claim 1, which is a prophylactic or therapeutic agent for diseases accompanied by pain, diseases accompanied by itching, and autonomic nerve-related diseases.

12. The medicament according to claim 1, which is a prophylactic or therapeutic agent for diseases accompanied by pain.

13. The medicament according to claim 1, which is an analgesic.

14. The medicament according to claim 1, which is a prophylactic or therapeutic agent for nociceptive pain or neuropathic pain.

15. Use of a heteroaromatic amide derivative or a salt thereof contained in the medicament according to claim 1 for manufacturing a medicament for use in the prevention or treatment of pain.

16. Use of a heteroaromatic amide derivative or a salt thereof contained in the pharmaceutical of claim 1 for producing an analgesic agent.

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