Quinazoline compound and medicine

Abstract

Provided is a quinazoline compound represented by general formula [1] and having an mPGES-1-inhibiting activity, or a pharmaceutically acceptable salt of the quinazoline compound, or a solvate of the quinazoline compound or the pharmaceutically acceptable salt. (In the formula, R1 represents -NR6R7, an alkoxy group, a cycloalkyl group, or an alkyl group; R2 represents an aryl group, a heteroaryl group, a chlorine atom, or a cycloalkyl group; R3 represents a halogen atom or an optionally substituted alkyl group; R4 represents a hydrogen atom or a halogen atom; R5 represents -SO2R8 or -COR8; and R8 represents an alkyl group, a cycloalkyl group, or a heteroaryl group.)

Description

Quinazoline compounds and medicines

[0001] The present invention relates to novel quinazoline compounds or pharmaceutically acceptable salts thereof.

[0002] Prostaglandins (PGs) are produced in large quantities at the site of inflammation and are involved in the progression of inflammation. Prostaglandin production begins with the release of arachidonic acid from membrane glycerophospholipids by phospholipase A2, followed by conversion of the released arachidonic acid to prostaglandin H2 (PGH2) by cyclooxygenase (COX). PGH2 is converted to prostaglandins, including prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α), prostaglandin D2 (PGD2), prostaglandin I2 (PGI2), and thromboxane A2 (TXA2). These prostaglandins are known to have various physiological or pathophysiological activities, including proinflammatory effects. PGE2, in particular, is known to act as an inflammation-inducing substance in acute and chronic inflammation, and to induce fever and hyperalgesia. Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors exert their anti-inflammatory effects by inhibiting the production of PGE2 through COX-1 and / or COX-2 inhibition. PGE2 synthase (PGES) is responsible for the final step in the synthesis pathway of the inflammatory mediator PGE2. Three subtypes of PGES are currently known: membrane-bound prostaglandin E synthase-1 (mPGES-1) (see, e.g., Non-Patent Document 1), mPGES-2 (see, e.g., Non-Patent Document 2), and cytosolic PGES (cPGES) (see, e.g., Non-Patent Document 3). Of these, mPGES-1, like COX-2, is primarily induced during inflammation and is deeply involved in PGE2 production in inflammatory lesions. On the other hand, cPGES is a constitutive PGES that coexists primarily with COX-1 and is involved in constitutive PGE2 production (see, e.g., Non-Patent Document 4). There are reports that mPGES-2 is associated with all COXs, and no consensus has been reached. Studies on mPGES-1-deficient mice suggest that mPGES-1 is involved in the progression of pathological conditions in various inflammation models, such as the acetic acid writhing model (see, for example, Non-Patent Document 5), arthritis models (see, for example, Non-Patent Documents 5 and 6), multiple sclerosis models (see, for example, Non-Patent Document 7), and fever models (see, for example, Non-Patent Document 8).Furthermore, because mPGES-1 inhibitors only inhibit COX-2-dependent PGE2 production, they are expected to have fewer side effects than NSAIDs or COX-2 inhibitors. The increased risk of cardiovascular events associated with COX-2 inhibitors is thought to be due to the enhancement of the coagulation system and vasoconstriction caused by the inhibition of COX-2-dependent PGI2 production (see Non-Patent Document 9). In contrast, because mPGES-1 inhibitors do not inhibit PGI2 production, they are thought not to increase the risk of cardiovascular events, which is a problem associated with COX-2 inhibitors (see Non-Patent Document 10).

[0003] Furthermore, it has been reported that mPGES-1 inhibitors inhibit the production of PGE2, which is involved in inflammation, and also enhance the production of PGI2, which has anti-inflammatory effects (see, for example, Non-Patent Document 28) (see, for example, Non-Patent Document 29). Based on this, mPGES-1 inhibitors are expected to have strong anti-inflammatory effects.

[0004] Furthermore, since it has been reported that PGE2 has a cell proliferation-promoting effect (see, for example, Non-Patent Document 30) and PGI2 has a cell proliferation-inhibiting effect (see, for example, Non-Patent Document 31), mPGES-1 inhibitors are expected to have a strong cell proliferation-inhibiting effect. Therefore, drugs that exhibit mPGES-1 inhibitory activity and can selectively suppress PGE2 production are useful for the treatment or prevention of diseases in which mPGES-1 is involved, such as inflammatory diseases and proliferative diseases. Although various compounds having mPGES-1 inhibitory activity are known (see, for example, Patent Documents 1 and 2), no compounds having a quinazoline skeleton are known.

[0005] Chinese Patent No. 105523996 International Publication No. 2023 / 127883

[0006] snowflakeら、sweet ANNASASIA,1999,96 72072250000ら、 THIS IS YOUR LIFE FIFA,2002,291,848 LIKELIGHTSら、BILIGHTS 2,2000,275,32774327 82Experienceら、2000 DY,2000,275,327833 292000ら、2000 Y,2004,279,33643 950000ら、2000, 2008,180,86618666らら、Azhirzhas SUSA,2009,106,2184 21812 YOUTHら、99 Thanksgiving,2003,6,117 118)などfingersら、sickness 2000,81,209 27000ら、200000 2,2006,116,1391139 666,2004,178 12,8138447000 2011,65(1) 7840000000000000 9,2008,62(6),3737 No,2011,59,208218 THIS IS YOUR LIFE,201 32(1),10000000000000.000 Y,2003,278(21),193 19405012,20123 1(24),244329526 6,2008,68(9),325132 LITERATURE THIS IS YOU ,2006,1003,145504145200 THIS THIS IS YOU,2006 ,103(31),11700011740 Emotions,2005,32(5),8 852000000000000000000 Y,2008,026,75466000 10,001,79(1),44842 12,188,4003410202000000000000000000000000000 The snow 100004,284,4 8199180000000000 Whether it's a smile,2005, 288, L1010-L1016 Arthritis Res. Ther. , 2011, 13, R6J. Immunol. , 2007, 178, 702-710J. Biol. Chem. , 2005, 280, 16579-16585J. Clin. Endocrinol. Metab. , 2003, 88, 4481-4487AM. J. Respir. Cell Mol. Biol. ,2002,26,194-201,

[0007] A primary object of the present invention is to provide a novel quinazoline compound or a pharmaceutically acceptable salt thereof. Another object of the present invention is to provide a pharmaceutical composition containing such a quinazoline compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0008] The present inventors have found that the novel quinazoline compounds or pharmaceutically acceptable salts thereof described below have excellent mPGES-1 inhibitory activity, and have completed the present invention.

[0009] The present invention can be embodied in the following items 1 to 45. Item 1. A compound represented by the following general formula [1]: [In the formula, R １ is an alkoxy, cycloalkyl, alkyl, or a group represented by the following general formula [2]: (In the formula, R ６ and R ７ are each independently hydrogen or optionally substituted alkyl, or R ６ and R ７ together with the nitrogen atom to which they are attached form an optionally substituted saturated cyclic amino; R ２ is aryl, heteroaryl, halogen or cycloalkyl, and ２ Each of the aryl, heteroaryl, and cycloalkyl in R is optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkoxy optionally substituted with 1 to 3 halogens, (2) cyano, (3) halogen, (4) alkyl optionally substituted with (i) 1 to 3 halogens, (ii) hydroxy, or (iii) alkoxy, and (5) alkylsulfonyl;３ is halogen or alkyl optionally substituted with 1 to 3 halogens; R ４ is hydrogen or halogen; R ５ is -SO ２ R ８ or -COR ８ and R ８ is alkyl, cycloalkyl or heteroaryl; R ８ The alkyl in R may be substituted with 1 to 3 groups independently selected from the group consisting of hydroxy, alkoxy, and halogen; ８ wherein cycloalkyl may be substituted with (1) hydroxy, or (2) alkyl optionally substituted with 1 to 3 halogen atoms, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0010] Item 2 R ６ and R ７ are each independently a hydrogen atom or an optionally substituted alkyl, or R ６ and R ７ together with the nitrogen atom to which they are attached form an optionally substituted saturated cyclic amino; R ２ is aryl, heteroaryl or cycloalkyl; R ２ Each of the aryl, heteroaryl, and cycloalkyl in R is optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkoxy optionally substituted with 1 to 3 halogens, (2) cyano, (3) halogen, (4) alkyl optionally substituted with (i) 1 to 3 halogens, (ii) hydroxy, or (iii) alkoxy, and (5) alkylsulfonyl; ３ is halogen or alkyl optionally substituted with 1 to 3 halogens; R ４ is a hydrogen atom or a halogen; R ５ is -SO ２ R ８ or -COR ８ and R ８is alkyl or cycloalkyl, R ８ The alkyl in R may be substituted with 1 to 3 groups independently selected from the group consisting of hydroxy, alkoxy, and halogen; ８ Item 2. The compound according to Item 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein cycloalkyl in the formula (I) is optionally substituted with (1) hydroxy, or (2) alkyl optionally substituted with 1 to 3 halogens.

[0011] Item 3 R ６ and R ７ are each independently a hydrogen atom or an optionally substituted alkyl; R ２ is aryl, heteroaryl or cycloalkyl; R ２ Each of the aryl, heteroaryl, and cycloalkyl in R is optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkoxy optionally substituted with 1 to 3 halogens, (2) cyano, (3) halogen, (4) alkyl optionally substituted with (i) 1 to 3 halogens, (ii) hydroxy, or (iii) alkoxy, and (5) alkylsulfonyl; ３ is halogen or alkyl optionally substituted with 1 to 3 halogens; R ４ is a hydrogen atom or a halogen; R ５ is -SO ２ R ８ or -COR ８ and R ８ is alkyl or cycloalkyl, R ８ The alkyl in R may be substituted with 1 to 3 groups independently selected from the group consisting of hydroxy, alkoxy, and halogen; ８ Item 2. The compound according to Item 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein cycloalkyl in the formula (I) is optionally substituted with (1) hydroxy, or (2) alkyl optionally substituted with 1 to 3 halogens.

[0012] Item 4 R ６and R ７ are each independently a hydrogen atom or an optionally substituted alkyl; R ２ is aryl, heteroaryl or cycloalkyl; R ２ the aryl in R is phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkoxy optionally substituted with 1 to 3 halogen atoms, (2) cyano, (3) a fluorine atom or a chlorine atom, (4) alkyl optionally substituted with 1 to 3 halogen atoms, and (5) methylsulfonyl; ２ The heteroaryl in the formula (I) is pyridyl or isoxazolyl optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkyl optionally substituted with 1 to 3 halogens, and (2) alkoxy optionally substituted with 1 to 3 halogens; and R ２ The cycloalkyl in ３－６ cycloalkyl; R ３ is halogen or alkyl optionally substituted with 1 to 3 halogens; R ４ is a hydrogen atom or a halogen; R ５ is -SO ２ R ８ or -COR ８ and R ８ is alkyl or cycloalkyl, R ８ The alkyl in １－６ alkyl, R ８ The cycloalkyl in ３－６ Item 2. The compound according to Item 1, wherein R is cycloalkyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0013] Item 5 R ６ and R ７ are each independently a hydrogen atom or an optionally substituted alkyl; R ２ is aryl or heteroaryl, R ２the aryl in R is phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkoxy optionally substituted with 1 to 3 halogen atoms, (2) cyano, (3) a fluorine atom or a chlorine atom, (4) alkyl optionally substituted with 1 to 3 halogen atoms, and (5) methylsulfonyl; ２ The heteroaryl in the formula (I) is pyridyl or isoxazolyl optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkyl optionally substituted with 1 to 3 halogens, and (2) alkoxy optionally substituted with 1 to 3 halogens; ３ is halogen or alkyl optionally substituted with 1 to 3 halogens; R ４ is a hydrogen atom; R ５ is -COR ８ and R ８ is alkyl or cycloalkyl, R ８ The alkyl in １－６ alkyl, R ８ The cycloalkyl in ３－６ Item 2. The compound according to Item 1, wherein R is cycloalkyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0014] Item 6 R ６ and R ７ Item 6. The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein at least one of:

[0015] Item 7 R ６ and R ７ Item 6. The compound according to any one of Items 1 to 5, wherein one of the groups represented by the formula (I) is hydrogen and the other is optionally substituted alkyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0016] Item 8 R ２Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein aryl in the formula (I) is phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkoxy optionally substituted with 1 to 3 halogens, and (2) alkyl optionally substituted with 1 to 3 halogens.

[0017] Item 9 R ８ The alkyl in １－６ Item 9. The compound according to any one of Items 1 to 8, wherein R is alkyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0018] Item 10 R ３ Item 10. The compound according to any one of Items 1 to 9, wherein is chlorine or trifluoroalkyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0019] Item 11 R ６ and R ７ and R 1 and R 2 are independently substituted or unsubstituted, or R 3 and R 4 are independently substituted or unsubstituted, or R 5 and R 6 are independently substituted or unsubstituted, or R 6 and R 7 are independently substituted or unsubstituted, or R 8 and R 9 are independently substituted or unsubstituted, or R 10 and R 11 and R 12 and R 13 and R 14 and R 15 are independently substituted or unsubstituted, or R 16 and R 17 and R 18 and R 19 and R 20 are independently substituted or unsubstituted, or R 20 and R 21 and R 22 and R 23 and R 24 and R 25.

[0020] Item 12. The compound according to Item 11, wherein the optionally substituted saturated cyclic amino is optionally substituted azetidinyl, optionally substituted pyrrolidyl, optionally substituted piperidyl, or optionally substituted morpholinyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0021] Item 13 R ６ and R ７ and the other is optionally substituted alkyl, wherein the optionally substituted alkyl is alkyl substituted with a saturated heterocyclic group, or a pharmaceutically acceptable salt thereof, or a solvate thereof, according to any one of Items 1 to 5.

[0022] Item 14. The compound according to Item 13, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the saturated heterocyclic group is optionally further substituted with hydroxy, alkoxy, alkoxycarbonyl or alkyl.

[0023] Item 15 R ３ Item 15. The compound according to any one of Items 11 to 14, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein is chlorine or trifluoroalkyl.

[0024] Item 16: A compound of the following Examples 1 to 226, or a pharmaceutically acceptable salt or solvate thereof.

[0025] Item 17. A pharmaceutical composition comprising the compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0026] Item 18. An mPGES-1 inhibitor comprising the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0027] Item 19. A method for inhibiting mPGES-1 activity, which comprises administering the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, to a subject in need thereof.

[0028] Item 20. The compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in inhibiting mPGES-1.

[0029] Item 21. Use of the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of an mPGES-1 inhibitor.

[0030] Item 22. A PGE2 production inhibitor comprising the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0031] Item 23. A method for inhibiting PGE2 production, which comprises administering the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, to a subject in need thereof.

[0032] Item 24. The compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in inhibiting PGE2 production.

[0033] Item 25. Use of the compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a PGE2 production inhibitor.

[0034] Item 26. A preventive or therapeutic agent for a disease involving mPGES-1, comprising the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0035] Item 27. A method for preventing or treating a disease involving mPGES-1, comprising administering the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, to a subject in need thereof.

[0036] Item 28. The compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the prevention or treatment of a disease involving mPGES-1.

[0037] Item 29. Use of the compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of an agent for preventing or treating a disease involving mPGES-1.

[0038] Item 30. A preventive or therapeutic agent for a disease involving PGE2, comprising the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0039] Item 31. A method for preventing or treating a disease involving PGE2, which comprises administering the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, to a subject in need thereof.

[0040] Item 32. The compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the prevention or treatment of a disease involving PGE2.

[0041] Item 33. Use of the compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of an agent for preventing or treating a disease involving PGE.

[0042] Item 34. A preventive or therapeutic agent for a disease for which an analgesic, anti-inflammatory or cell growth inhibitory effect is expected to be effective, comprising the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0043] Item 35. A method for preventing or treating a disease for which an analgesic effect, anti-inflammatory effect or cell growth inhibitory effect can be expected to be effective, comprising administering the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, to a subject in need thereof.

[0044] Item 36. The compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the prevention or treatment of a disease for which an analgesic, anti-inflammatory or cell growth inhibitory effect is expected to be effective.

[0045] Item 37. Use of the compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of a preventive or therapeutic agent for a disease which is expected to be effective due to its analgesic, anti-inflammatory or cell proliferation inhibitory effect.

[0046] Item 38. A compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in treating inflammatory bowel disease, irritable bowel syndrome, migraine, headache, lower back pain, lumbar spinal stenosis, herniated disc, temporomandibular joint disorder, cervicobrachial syndrome, cervical spondylosis, endometriosis, adenomyosis, premature labor, threatened premature labor, dysmenorrhea, overactive bladder, nocturia, interstitial cystitis, neurodegenerative disease, psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, neuralgia, complex regional pain syndrome, myofascial disorder, viral infection, or bacterial infection. Preventive or therapeutic agent for pain in fungal infections, burns, inflammation and pain after surgery, trauma, and tooth extraction, malignant tumors, atherosclerosis, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ossification of the ligaments, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound treatment, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids, prostatitis, and cancer.

[0047] Item 39. A method for treating inflammatory bowel disease, irritable bowel syndrome, migraine, headache, lower back pain, lumbar spinal stenosis, herniated disc, temporomandibular joint disorder, cervicobrachial syndrome, cervical spondylosis, endometriosis, adenomyosis, premature labor, threatened premature labor, dysmenorrhea, overactive bladder, nocturia, interstitial cystitis, neurodegenerative disease, psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, neuralgia, complex regional pain syndrome, myofascial disorder, or viral infection, comprising administering the compound according to any one of items 1 to 16 or a pharmaceutically acceptable salt thereof, or a solvate thereof, to a subject in need thereof. A method for preventing or treating pain in the following conditions: bowel disease, bacterial infections, fungal infections, burns, inflammation and pain after surgery, trauma, and tooth extraction, malignant tumors, atherosclerosis, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ossification of ligaments, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound treatment, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids, prostatitis, and cancer.

[0048] Item 40: Inflammatory bowel disease, irritable bowel syndrome, migraine, headache, lower back pain, lumbar spinal stenosis, herniated disc, temporomandibular joint disorder, cervicobrachial syndrome, cervical spondylosis, endometriosis, adenomyosis, premature birth, threatened premature birth, dysmenorrhea, overactive bladder, nocturia, interstitial cystitis, neurodegenerative diseases, psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, neuralgia, complex regional pain syndrome, fascial disorders, viral infections, bacterial infections, fungal infections, burns, inflammation and pain after surgery, trauma and tooth extraction, malignant tumors, atherosclerosis, stroke, gout Item 17. The compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the prevention or treatment of pain in the following diseases: arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ossifying ligaments, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound treatment, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic disease, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids, prostatitis, or cancer.

[0049] Item 41 Inflammatory bowel disease, irritable bowel syndrome, migraine, headache, lower back pain, lumbar spinal stenosis, herniated disc, temporomandibular joint disorder, cervicobrachial syndrome, cervical spondylosis, endometriosis, adenomyosis, premature birth, threatened premature birth, dysmenorrhea, overactive bladder, nocturia, interstitial cystitis, neurodegenerative disease, psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, neuralgia, complex regional pain syndrome, fascial disorders, viral infections, bacterial infections, fungal infections, burns, inflammation and pain after surgery, trauma and tooth extraction, malignant tumors, atherosclerosis, stroke, gout, Item 17. Use of the compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of an agent for preventing or treating pain in arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ossifying ligaments, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound treatment, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic disease, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids, prostatitis, or cancer.

[0050] Item 42. A preventive or therapeutic agent for ankylosing spondylitis, comprising the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0051] Item 43. A method for preventing or treating ankylosing spondylitis, which comprises administering to a subject in need thereof the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0052] Item 44. The compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the prevention or treatment of ankylosing spondylitis.

[0053] Item 45. Use of the compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of an agent for the prophylaxis or treatment of ankylosing spondylitis.

[0054] Each term used in this specification will be explained in detail below.

[0055] "Halogen" includes, for example, fluorine, chlorine, bromine, and iodine.

[0056] Examples of "alkyl" include straight-chain or branched alkyl groups having 1 to 8 carbon atoms (C １－８ ), specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl. １－６ ) alkyl is preferred.

[0057] The alkyl portion of "alkylsulfonyl" can be the same as the above-mentioned "alkyl".

[0058] Examples of "alkoxy" include straight-chain or branched-chain alkoxy groups having 1 to 8 carbon atoms (C １－８) and specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, and n-octyloxy.

[0059] The alkoxy moiety of "alkoxycarbonyl" can be the same as the above-mentioned "alkoxy".

[0060] The term "aryl" includes, for example, monocyclic, bicyclic, or tricyclic rings having 6 to 14 carbon atoms (C ６－１４ Specific examples include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, and 10-phenanthryl.

[0061] R ２ As the aryl in the formula (I), phenyl is preferred.

[0062] Examples of "heteroaryl" include monocyclic or bicyclic aromatic heterocyclic groups having 5 to 10 ring atoms and 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen atoms in the ring. Specific examples include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazolyl), and the like. oxazolyl (for example, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (for example, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (for example, 1,3,4-oxadiazol-2-yl), thiazolyl (for example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isoxazolyl, isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), benzimidazolyl (e.g., 2-benzimidazolyl, 4- benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl), indazolyl (for example, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), isoquinolyl (for example, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl).

[0063] R ２ The heteroaryl in the above formula is preferably isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl) or pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl).

[0064] R ８ As the heteroaryl in the above, furyl (for example, 2-furyl, 3-furyl) is preferred.

[0065] Examples of the "saturated cyclic amino" include 3- to 8-membered saturated cyclic amino which may have one oxygen atom or one sulfur atom as a ring-constituting atom and one or two nitrogen atoms, and specific examples include 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, piperidino, 1-piperazinyl, 1-tetrahydropyrimidinyl, 4-morpholino, 4-thiomorpholino, and 1-homopiperazinyl.

[0066] Examples of "saturated heterocyclic groups" include saturated heterocyclic groups having one or two identical or different heteroatoms arbitrarily selected from the group consisting of nitrogen atoms, sulfur atoms, and oxygen atoms, and composed of 3 to 8 atoms. Preferably, saturated heterocyclic groups have one nitrogen atom or one oxygen atom and composed of 3 to 8 atoms are exemplified. Specific examples of saturated heterocyclic groups include oxiranyl, azetidinyl (e.g., 2-azetidinyl, 3-azetidinyl), pyrrolidinyl (e.g., 2-pyrrolidinyl, 3-pyrrolidinyl), piperidinyl (e.g., 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (e.g., 2-piperazinyl, 3-piperazinyl), morpholinyl (e.g., 2-morpholinyl, 3-morpholinyl), thiomorpholinyl (e.g., 2-thiomorpholinyl, 3-thiomorpholinyl), tetrahydrofuryl (2-tetrahydrofuryl, 3-tetrahydrofuryl), and tetrahydropyranyl (2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl). Preferred examples include 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-oxetanyl, 3-oxetanyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl.

[0067] Examples of "cycloalkyl" include cycloalkyl groups having 3 to 10 carbon atoms (C ３－１０) and monocyclic to tricyclic saturated hydrocarbon groups. ３－８ ), preferably 3 to 6 carbon atoms (C ３－６ ) and a monocyclic saturated hydrocarbon group is preferred. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl.

[0068] It is understood that the present invention encompasses all combinations of the substituents described herein. That is, the present invention encompasses all combinations of the substituents R １ , R ２ , R ３ , R ４ and R ５ The term "substituted" encompasses any combination of substituents independently selected from the groups described for each of the groups, and is not limited to the particular combinations specifically described herein.

[0069] The compound of the present invention has mPGES-1 inhibitory activity and can inhibit PGE2 production, and is therefore effective in preventing or treating diseases associated with mPGES-1 or PGE2 production.

[0070] The compound of the present invention can be produced from known compounds or easily synthesized intermediates, for example, by the methods described below, the Examples described later, or by known methods. In producing the compound of the present invention, if the raw material has a substituent that affects the reaction, the raw material is generally protected with an appropriate protecting group by a known method beforehand, and then the reaction is carried out. The protecting group can be removed by a known method after the reaction. Production Method 1 (In the formula, R １ , R ２ , R ３ , R ４ , R ５are as defined above.) This reaction is a condensation reaction between compound [3] and compound [4], and can be carried out by a method known per se for condensation reactions. The compound of the present invention can be produced by reacting compound [4] or a reactive derivative thereof with compound [3]. Examples of reactive derivatives of compound [4] include those commonly used in amide condensation reactions, such as acid halides (e.g., acid chlorides, acid bromides), mixed acid anhydrides, imidazolides, and activated amides. When compound [4] is used, the reaction can be carried out using a condensing agent in the presence or absence of a base at a temperature within the range of -20°C to 100°C. Examples of condensing agents that can be used in this reaction include 1,1'-oxalyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphonate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HATU"), and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate. Examples of bases that can be used include organic bases such as triethylamine, N,N-diisopropylethylamine (hereinafter referred to as "DIPEA"), N,N-dimethylaniline, pyridine, and 1,8-diazabicyclo[5,4,0]-7-undecene (hereinafter referred to as "DBU"). Usable solvents are not particularly limited as long as they are not involved in the reaction, and examples include ethers such as tetrahydrofuran (hereinafter referred to as "THF") and 1,4-dioxane, amides such as N,N-dimethylformamide (hereinafter referred to as "DMF") and N,N-dimethylacetamide (hereinafter referred to as "DMA"), nitriles such as acetonitrile and propionitrile, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and dichloromethane, and mixed solvents thereof. Furthermore, additives can be used as needed.Examples of additives that can be used include 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole. The amount of the condensing agent used is, for example, within a range of 1 to 3 times the molar amount per mole of compound [4]. The amount of the base used is, for example, within a range of 1 to 10 equivalents, preferably 1 to 4 equivalents, per mole of compound [4]. The reaction time varies depending on the starting compounds and reagents used, the reaction temperature, etc., but is usually within a range of 10 minutes to 24 hours.

[0071] Compound [4] can be produced, for example, according to a method described in the literature (for example, WO2011 / 048004).

[0072] Compound [3] can be produced, for example, by the method described in (I) or (II) below.

[0073] (I) In compound [3], R ２ is an aryl, heteroaryl, or cycloalkyl (the aryl, heteroaryl, or cycloalkyl may be substituted with one to three groups selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, monohalogenoalkyl, dihalogenoalkyl, trihalogenoalkyl, alkoxy, monohalogenoalkoxy, dihalogenoalkoxy, trihalogenoalkoxy, halogen, cyano, and alkylsulfonyl), (In the formula, R １ has the same meaning as above. １ represents a boronic acid group, a boronic ester group, zinc, or magnesium halide. ２ａrepresents an aryl, heteroaryl, or cycloalkyl, and the aryl, heteroaryl, or cycloalkyl may be substituted with one to three groups selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, monohalogenoalkyl, dihalogenoalkyl, trihalogenoalkyl, alkoxy, monohalogenoalkoxy, dihalogenoalkoxy, trihalogenoalkoxy, halogen, cyano, and alkylsulfonyl. n represents 1 or 2. [Step 1] This reaction is a cross-coupling reaction of compound [5] with compound [6], which is commercially available or can be prepared by a known method, and is carried out by a method known per se. For example, compound [5] and an organometallic reagent, such as a boron reagent such as various boronic acids, various zinc reagents, or various Grignard reagents, are reacted in a suitable solvent with tetrakis(triphenylphosphine)palladium (hereinafter referred to as "Pd(PPh ３ ) ４The reaction is carried out in the presence of a palladium catalyst such as methyl phosphino (DMPO), a copper catalyst such as copper iodide, a zinc reagent, an iron reagent, or the like, with the addition of a ligand such as 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf") and a base, if necessary, and using microwaves as needed. The solvent that can be used is not particularly limited as long as it is inert to the reaction, and examples thereof include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and THF, alcohols such as methanol, ethanol, and 1-butanol, amides such as DMF, DMA, and N-methyl-2-pyrrolidone (hereinafter referred to as "NMP"), water, and mixtures thereof. Examples of bases that can be used include alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, and cesium carbonate, alkali metal hydroxides such as sodium hydroxide, alkali metal phosphates such as potassium phosphate, organic bases such as triethylamine and DIPEA, and alkali metal halides such as lithium chloride and cesium fluoride. The amount of base used is within the range of 1 to 10 equivalents, preferably 1 to 4 equivalents, relative to compound [5]. The reaction temperature varies depending on the types of starting compounds and reagents used, but is usually within the range of 0 to 200°C, preferably 50 to 160°C. The reaction time varies depending on the types of starting compounds and reagents used, reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.

[0074] [Step 2] This reaction is a reduction reaction of an aromatic nitro compound to an aromatic amine and can be carried out by a conventional method. For example, this reaction can be achieved in a suitable solvent under a hydrogen gas atmosphere by catalytic reduction using compound [7] and a catalyst containing Raney nickel, palladium, rhodium, platinum, or the like; hydride reduction using lithium aluminum hydride, or the like; iron reduction using a reduced iron reagent and ammonium chloride, or the like; zinc reduction using zinc dust and acetic acid, or the like. Other methods include a method using a sulfide such as sodium hydrosulfite, or a reduction method using ammonium formate, hydrazine, or the like in the presence of a metal catalyst such as palladium-carbon. Examples of solvents are selected depending on the type of compound and the type of reagent used. Examples include toluene, THF, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, acetone, acetonitrile, DMF, alcohols such as methanol, ethanol, and tert-butanol, and water, and these can be used alone or in combination. The reaction temperature varies depending on the types of compounds and reagents used, but is usually within the range of 0°C to 300°C, preferably within the range of 20°C to 150°C.

[0075] (II) In the compound [3], R ２ is chlorine. (In the formula, R １ has the same meaning as above.)

[0076] This reaction is a reduction reaction of an aromatic nitro compound to an aromatic amine, and can be carried out in accordance with the method described in step 2 of the aforementioned production method of compound [3A].

[0077] Compound [5] can be produced, for example, by the following methods (I) to (III). (In the formula, R １ has the same meaning as above. １ When is alkoxy, X ２ represents sodium or potassium, R １ is a group represented by general formula [2], X ２ represents a hydrogen atom, R １ When is cycloalkyl or alkyl, X２ represents a boronic acid group, a boronic ester group, zinc, or magnesium halide. m represents 1 or 2.

[0078] (I) R １ is alkoxy. This reaction is a nucleophilic substitution reaction between commercially available compound [8] and commercially available compound [9], or compound [9] that can be prepared by known methods, and is carried out by known methods. This reaction is carried out in a suitable solvent or without a solvent, using an excess of the reagent, or in the presence of a base. Usable reaction solvents are not particularly limited as long as they are inert to the reaction, but examples include ethers such as THF, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; amides such as DMF and DMA; hydrocarbons such as benzene and toluene; and mixtures thereof. Usable bases include organic bases such as triethylamine, DIPEA, N,N-dimethylaniline, pyridine, and DBU; and inorganic bases such as potassium carbonate and sodium carbonate. The reaction temperature varies depending on the compounds and reagents used, but is usually carried out within the range of 0°C to 200°C. The reaction time varies depending on the raw materials used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.

[0079] (II) R １is a group represented by general formula [2]. This reaction is a nucleophilic substitution reaction between a commercially available compound [8] and a commercially available compound [9] or a compound that can be prepared by a known method, and is carried out by a known method. This reaction is carried out in an appropriate solvent or without a solvent, using an excess of reagents, or in the presence of a base. The reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction, and examples thereof include ethers such as THF, 1,4-dioxane, and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, amides such as DMF and DMA, hydrocarbons such as benzene and toluene, and mixtures thereof. Alternatively, the amine used in the reaction can be used in excess instead of a solvent. Examples of bases that can be used include organic bases such as triethylamine, DIPEA, N,N-dimethylaniline, pyridine, and DBU, and inorganic bases such as potassium carbonate and sodium carbonate. The reaction temperature varies depending on the types of compounds and reagents used, but is usually within the range of 0°C to 200°C. The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.

[0080] (III) R １ When is cycloalkyl or alkyl, this reaction is a cross-coupling reaction of a commercially available compound [8] with a commercially available compound [9] or a compound that can be prepared by a known method, and is carried out by a known method. For example, in a suitable solvent, compound [8] is reacted with a boron reagent such as various boronic acids, various zinc reagents, various Grignard reagents, etc., to form an organometallic reagent, such as Pd(PPh ３ ) ４The reaction is carried out in the presence of a palladium catalyst such as exemplified by (I), a copper catalyst such as copper iodide, a zinc reagent, an iron reagent, or the like, optionally with the addition of a phosphorus catalyst such as dppf and a base, and optionally with the use of microwaves. The solvent that can be used is not particularly limited as long as it is inert to the reaction, and examples thereof include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and THF, alcohols such as methanol, ethanol, and 1-butanol, amides such as DMF, DMA, and NMP, water, and mixtures thereof. Examples of bases that can be used include alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, and cesium carbonate, alkali metal hydroxides such as sodium hydroxide, alkali metal phosphates such as potassium phosphate, organic bases such as triethylamine and DIPEA, and alkali metal halides such as lithium chloride and cesium fluoride. The amount of base used is within the range of 1 to 10 equivalents, preferably 1 to 4 equivalents, relative to compound [8]. The reaction temperature varies depending on the types of raw material compounds and reagents used, but is usually within the range of 0° C. to 200° C., preferably within the range of 50° C. to 160° C. The reaction time varies depending on the types of raw material compounds and reagents used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.

[0081] Compound [8] can also be produced, for example, according to a method described in the literature (for example, J. Chem. Soc., 1948, 1759-1765).

[0082] Method 2 (In the formula, R １ , R ２ , R ３ , R ４ , R ５ has the same meaning as defined above.) This reaction is a condensation reaction of compound

[10] with compound

[11] , which is commercially available or can be prepared by a known method, and can also be carried out in accordance with the method described in the above-mentioned Production Method 1.

[0083] Compound

[10] can be produced, for example, by the following method. (In the formula, R １ , R ２ , R３ , R ４ has the same meaning as defined above. PG represents an amino-protecting group. [Step 1] This reaction is a condensation reaction of compound [3] and compound

[12] , and can be carried out in accordance with the method described in the above-mentioned Production Method 1.

[0084] [Step 2] This reaction is a deprotection reaction of the amino-protecting group in compound

[13] , and can be carried out in accordance with a method known per se for deprotection of an amino-protecting group. The amino-protecting group is not particularly limited as long as it does not affect the reaction. Examples include carbamates such as tert-butoxycarbonyl and benzyloxycarbonyl. In addition, protecting groups commonly used as amino-protecting groups as described in the literature (e.g., Green's Protective Groups in Organic Synthesis, Fourth Edition, A John Wiley & Sons, Inc., Publication) can also be used. The deprotection reaction can be carried out under acidic conditions using hydrochloric acid, Lewis acid, trifluoroacetic acid, or the like in a suitable solvent. Alternatively, deprotection can be carried out by hydrogenolysis in the presence of a catalyst such as palladium. Compound

[12] can be produced, for example, according to a method described in the literature (for example, WO2011 / 048004; Tetrahedron Letters, 1993, 34, 6263-6264).

[0085] Method 3 (In the formula, R １ , R ２ , R ３ , R ４ , R ５ has the same meaning as above. ３represents a halogen.) This reaction is a coupling reaction of compound

[14] and compound

[15] using a palladium catalyst or a copper catalyst, and is carried out by a method known per se. The solvent that can be used is not particularly limited as long as it is inert to the reaction, and examples thereof include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and THF, amides such as DMF, DMA and NMP, water, and mixtures thereof. This reaction is carried out in the presence of a base at a temperature in the range of 20°C to 200°C, and if necessary, using microwaves. Examples of palladium catalysts that can be used include tris(dibenzylideneacetone)(chloroform)dipalladium(0), dichloro(diphenylphosphinoferrocene)palladium.dichloromethane (hereinafter referred to as "PdCl"), and the like. ２ (dppf) CH ２ Cl ２ "), and palladium(II) acetate. The amount of the palladium catalyst is suitably within the range of 0.001 to 0.3 moles per mole of compound

[14] . Examples of ligands for the palladium catalyst that can be used include dppf, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, and bis[2-(diphenylphosphino)phenyl]ether. Examples of copper catalysts that can be used include copper iodide. Examples of bases that can be used include alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, and cesium carbonate; alkali metal hydroxides such as sodium hydroxide; alkali metal phosphates such as potassium phosphate; organic bases such as triethylamine and DIPEA; and alkali metal halides such as lithium chloride and cesium fluoride. The amount of base used is, for example, within the range of 1 to 10 equivalents, preferably 1 to 4 equivalents, relative to compound

[14] . The reaction time varies depending on the types of raw materials used, the reaction temperature, and the like, but is usually within the range of 10 minutes to 24 hours.

[0086] Compound

[15] can be produced, for example, by subjecting compound [4] to a condensation reaction with ammonia according to a method known per se as a condensation reaction.

[0087] Alternatively, compound

[14] can also be produced, for example, according to the method described in (I) or (II) below.

[0088] (I) In compound

[14] , R ２ is chlorine. (In the formula, m, R １ , X ２ , X ３ has the same meaning as defined above.) This reaction can be carried out according to the method described in the above-mentioned production method of compound [5].

[0089] (II) In compound

[14] , R ２ is an aryl, heteroaryl, or cycloalkyl (the aryl or heteroaryl may be substituted with one to three groups selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, monohalogenoalkyl, dihalogenoalkyl, trihalogenoalkyl, alkoxy, monohalogenoalkoxy, dihalogenoalkoxy, trihalogenoalkoxy, halogen, cyano, and alkylsulfonyl), (In the formula, n, R １ , R ２ａ , X １ , X ３ has the same meaning as defined above.) This reaction is a cross-coupling reaction of compound [14A] with compound [6], which is commercially available or can be prepared by a known method, and can be carried out according to the method described in step 1 of the above-mentioned method for producing compound [3A].

[0090] Compound

[16] can be produced, for example, according to a method described in the literature (for example, J. Med. Chem., 2008, 7855-7865).

[0091] The compound of the present invention can be used as a medicine as it is, or can be used in the form of a pharmaceutically acceptable salt prepared by a known method. Examples of such salts include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and salts with organic acids such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid.

[0092] For example, the hydrochloride salt of the compound of the present invention can be obtained by dissolving the compound of the present invention in an alcoholic, ethyl acetate or diethyl ether solution of hydrogen chloride.

[0093] The compound of the present invention or a pharmaceutically acceptable salt thereof may take up solvent molecules to form a solvate when left in the air or recrystallized, and such solvates are also included in the salt of the present invention. Examples of such solvates include solvates with solvent molecules such as methanol, ethanol, isopropyl alcohol, butanol, dimethyl sulfoxide, and acetonitrile, and hydrates.

[0094] Of the compounds of the present invention, those having an asymmetric carbon atom include both optical isomers and mixtures thereof. Optical isomers can be produced, for example, by optical resolution of a racemate using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) by a known method, taking advantage of its basicity, or by using a pre-prepared optically active compound as a starting material. Alternatively, optical isomers can also be produced by optical resolution using a chiral column or asymmetric synthesis.

[0095] Furthermore, among the compounds of the present invention, those which can form tautomers include both the individual tautomers and mixtures thereof.

[0096] As shown in the test examples below, the compound of the present invention or a pharmaceutically acceptable salt thereof has mPGES-1 inhibitory activity. Furthermore, since the compound of the present invention or a pharmaceutically acceptable salt thereof has mPGES-1 inhibitory activity, it also has PGE2 production inhibitory action, analgesic action, and anti-inflammatory action.

[0097] Thus, one embodiment of the present invention provides an mPGES-1 inhibitor comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0098] Furthermore, in one embodiment of the present invention, there is provided a method of inhibiting mPGES-1 activity, comprising administering to a subject in need thereof a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0099] Furthermore, in one embodiment of the present invention, there is provided a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in inhibiting mPGES-1.

[0100] Furthermore, one embodiment of the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of an mPGES-1 inhibitor.

[0101] Furthermore, the compound of the present invention or a pharmaceutically acceptable salt thereof has mPGES-1 inhibitory activity and therefore inhibits PGE2 production. Therefore, one embodiment of the present invention provides a PGE2 production inhibitor comprising the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0102] Furthermore, in one embodiment of the present invention, there is provided a method for inhibiting PGE2 production, comprising administering to a subject in need thereof a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0103] Furthermore, one embodiment of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in inhibiting PGE2 production.

[0104] Furthermore, one embodiment of the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a PGE2 production inhibitor.

[0105] The compound of the present invention or a pharmaceutically acceptable salt thereof has mPGES-1 inhibitory activity and inhibits PGE2 production, and therefore can be used for the prevention or treatment of, for example, diseases associated with mPGES-1, diseases associated with PGE2, and diseases for which analgesic or anti-inflammatory effects are expected to be effective.

[0106] Therefore, one embodiment of the present invention provides an agent for preventing or treating a disease involving mPGES-1, which comprises the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0107] Furthermore, one embodiment of the present invention provides a method for preventing or treating a disease associated with mPGES-1, which comprises administering the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0108] Furthermore, one embodiment of the present invention provides the compound of the present invention or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a disease involving mPGES-1.

[0109] Furthermore, one embodiment of the present invention provides use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of an agent for the prophylaxis or treatment of a disease involving mPGES-1.

[0110] Furthermore, one embodiment of the present invention provides a preventive or therapeutic agent for a disease involving PGE2, which comprises the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0111] Furthermore, one embodiment of the present invention provides a method for preventing or treating a disease involving PGE2, which comprises administering the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0112] Furthermore, one embodiment of the present invention provides the compound of the present invention or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a disease involving PGE2.

[0113] Furthermore, one embodiment of the present invention provides use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of an agent for the prophylaxis or treatment of a disease involving PGE2.

[0114] Furthermore, one embodiment of the present invention provides a preventive or therapeutic agent for a disease that is expected to be effective due to its analgesic, anti-inflammatory or cell proliferation inhibitory effect, which contains the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0115] Furthermore, one embodiment of the present invention provides a method for preventing or treating a disease for which analgesic, anti-inflammatory or cell proliferation inhibitory effect can be expected to be effective, which method comprises administering the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0116] Furthermore, one embodiment of the present invention provides the compound of the present invention or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of diseases for which analgesic or anti-inflammatory effects are expected to be effective.

[0117] Furthermore, one embodiment of the present invention provides use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a preventive or therapeutic agent for a disease whose effectiveness can be expected due to its analgesic, anti-inflammatory or cell proliferation inhibitory effect.

[0118] Diseases to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied include diseases involving mPGES-1, such as inflammatory bowel disease (see, for example, Non-Patent Document 11), irritable bowel syndrome, migraine, headache, lower back pain, lumbar spinal canal stenosis, herniated disc, temporomandibular joint disorder, cervicobrachial syndrome, cervical spondylosis, endometriosis (see, for example, Non-Patent Document 12), adenomyosis, premature labor, threatened premature labor, dysmenorrhea, overactive bladder, nocturia (see, for example, Non-Patent Document 13), and interstitial cystitis. , neurodegenerative diseases (e.g., Alzheimer's disease, multiple sclerosis) (see, for example, Non-Patent Document 7), psoriasis, rheumatoid arthritis (see, for example, Non-Patent Document 5, Non-Patent Document 6), rheumatic fever, fibromyalgia, neuralgia (see, for example, Non-Patent Document 14), complex regional pain syndrome, fascial disorders, viral infections (e.g., influenza, colds, shingles, AIDS), bacterial infections, fungal infections, burns (see, for example, Non-Patent Document 15), and after surgery, trauma, and tooth extraction. Inflammation / pain, malignant tumors (e.g., colon cancer, breast cancer, lung cancer, prostate cancer, etc.) (see, for example, Non-Patent Documents 16, 17, and 18), atherosclerosis (see, for example, Non-Patent Document 19), stroke (see, for example, Non-Patent Document 20), gout, arthritis, osteoarthritis (see, for example, Non-Patent Documents 21 and 22), juvenile arthritis, ankylosing spondylitis, tenosynovitis, ossification of ligaments, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis (see, for example, Non-Patent Documents 23 and 24). Examples of the pain caused by the use of steroids include pain in the following diseases: conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, osteoporosis, asthma (see, for example, Non-Patent Document 24), chronic obstructive pulmonary disease (see, for example, Non-Patent Document 25), pulmonary fibrosis (see, for example, Non-Patent Document 26), allergic diseases (see, for example, Non-Patent Document 24), familial adenomatous polyposis (see, for example, Non-Patent Document 17), scleroderma (see, for example, Non-Patent Document 27), bursitis, uterine fibroids, prostatitis, and cancer.

[0119] As shown in the test examples described below, the compound of the present invention or a pharmaceutically acceptable salt thereof has an inhibitory effect on the progression of extremity arthritis in ankylosing spondylitis, and therefore can be used for the prevention or treatment of ankylosing spondylitis.

[0120] Therefore, one embodiment of the present invention provides an agent for preventing or treating ankylosing spondylitis, which comprises the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0121] Furthermore, one embodiment of the present invention provides a method for preventing or treating ankylosing spondylitis, comprising administering the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0122] Furthermore, in one embodiment of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of ankylosing spondylitis.

[0123] Furthermore, one embodiment of the present invention provides use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of an agent for the prophylaxis or treatment of ankylosing spondylitis.

[0124] "Subject" refers to a human or non-human animal having or suspected of having a disease associated with mPGES-1 or a disease associated with PGE2. In one embodiment of the invention, the subject is a mammal. In one embodiment of the invention, the subject is a human.

[0125] When the compound of the present invention or a pharmaceutically acceptable salt thereof is administered as a medicine, it is administered to mammals including humans as it is or as a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%, of the compound of the present invention or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable, non-toxic and inert carrier.

[0126] The carrier may be one or more conventional pharmaceutically acceptable solid, semi-solid, or liquid diluents, fillers, and other formulation auxiliaries. The pharmaceutical composition of the present invention is preferably administered in a dosage unit form. The pharmaceutical composition may be administered intramuscularly, orally, intravenously, topically (transdermally, by eye drop, intraperitoneally, intrapleurally, etc.), or rectally. The pharmaceutical composition of the present invention is administered in a dosage form suitable for these administration methods.

[0127] The pharmaceutical dosage is desirably adjusted taking into consideration the patient's condition, such as age, body weight, type and severity of disease, the route of administration, the type of compound of the present invention, whether or not it is a salt, and the type of salt, but typically, in the case of oral administration to an adult, the amount of the active ingredient of the compound of the present invention or a pharmaceutically acceptable salt thereof is within the range of 0.01 mg to 5 g per adult, preferably 1 mg to 500 mg per adult, per day. In some cases, a lower dose may be sufficient, or conversely, a higher dose may be required. Typically, the compound is administered once a day or in divided doses, or in the case of intravenous administration, it can be administered as a bolus or continuously for up to 24 hours.

[0128] The present invention will be described in more detail below with reference to examples, test examples, and formulation examples, but the present invention is not limited to these. The measurement conditions for high performance liquid chromatography mass spectrometry (LCMS) are as follows: Analytical equipment: ACUITY UPLC MS / PDA system (manufactured by Waters Corporation) Mass spectrometer: Waters 3100 MS detector Photodiode array detector: ACUITY PDA detector (210-400 nm) Column: Acuity BEH C １８ , 1.7 μm, 2.1 × 50 mm Flow rate: 0.5 mL / min Column temperature: 40 ° C Solvent; Solution A: 0.1% formic acid / H ２ Solution B: 0.1% formic acid / acetonitrile (v / v; the same applies below)

[0129] The observed mass spectrometry value [MS(m / z)] (MS: mass spectrometry) is expressed as m / z.

[0130] Example 1 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride [Step 1] Preparation of 7-nitroquinazoline-2,4(1H,3H)-dione To a solution of 2-amino-4-nitrobenzoic acid (5.0 g) in dichloromethane (45 mL), chlorosulfonyl isocyanate (5.25 mL) was added dropwise under ice-cooling, and the mixture was stirred overnight at room temperature. To this solution, a solution of triethylamine (8.80 mL) in dichloromethane (30 mL) was added dropwise under ice-cooling, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and saturated aqueous sodium bicarbonate (200 mL) was added to the residue under ice-cooling, followed by stirring. Methanol (100 mL) was then added and the mixture was stirred. The precipitate was collected by filtration and dried to obtain 4.42 g of the title compound as a pale yellow powder.

[0131] [Step 2] Preparation of 2,4-dichloro-7-nitroquinazoline Phosphorus oxychloride (45 mL) was added to a mixture of 7-nitroquinazoline-2,4(1H,3H)-dione (3.0 g) and phosphorus pentachloride (15.0 g), and the mixture was stirred at 130°C overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure using toluene azeotropy. To the residue were added ice water (300 mL) and saturated aqueous sodium bicarbonate (100 mL) under ice cooling, and the mixture was stirred for 1 hour. The precipitate was collected by filtration and dried to obtain 2.97 g of the title compound as a yellow powder.

[0132] [Step 3] Preparation of 2-chloro-N-methyl-7-nitroquinazolin-4-amine To a suspension of 2,4-dichloro-7-nitroquinazoline (2.02 g) in THF (20 mL), a 2N THF solution of methylamine (4.97 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. A 2N THF solution of methylamine (4.97 mL) was further added, and the mixture was stirred at room temperature for 2 hours. After removing the insoluble matter, the THF was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.65 g of the title compound as a yellow powder.

[0133] [Step 4] Preparation of N-methyl-7-nitro-2-[3-(trifluoromethyl)phenyl]quinazolin-4-amine. A suspension of 2-chloro-N-methyl-7-nitroquinazolin-4-amine (0.48 g), [3-(trifluoromethyl)phenyl]boronic acid (0.53 g), 1-butanol (3.0 mL), and saturated aqueous sodium bicarbonate (2.0 mL) in toluene (6.0 mL) was treated with Pd(PPh ３ ) ４ (0.17 g) was added at room temperature, and the mixture was stirred for 15 minutes and then at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.55 g of the title compound as a yellow powder.

[0134] [Step 5] N ４ To a suspension of N-methyl-7-nitro-2-[3-(trifluoromethyl)phenyl]quinazolin-4-amine (0.55 g) in THF (8 mL) and methanol (8 mL) were added saturated aqueous ammonium chloride solution (4 mL) and zinc (1.0 g) at room temperature, and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature and filtered through Celite, and the solvent was evaporated under reduced pressure. The residue was washed with water and methanol, collected by filtration, and dried to obtain 0.46 g of the title compound as an orange powder.

[0135] [Step 6] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride To a solution of 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoic acid (synthesized according to the method described in WO2011 / 048004) (0.324 g) in dichloromethane (5 mL), oxalyl chloride (0.22 mL) and DMF (1 drop) were added dropwise at room temperature, and the mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (2 mL), and this was added to N ４To a solution of 2-methyl-2-[3-(trifluoromethyl)phenyl]quinazoline-4,7-diamine (0.32 g) and DIPEA (0.21 mL) in THF (10 mL) was slowly added dropwise under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes, followed by the addition of saturated aqueous sodium bicarbonate and water, and extraction with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (0.38 g) as a yellow powder. This powder was suspended in THF (10 mL), and 2 M hydrogen chloride in methanol solution (0.37 mL) was added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated under reduced pressure. The resulting solid was washed with diethyl ether, filtered, and dried to give 0.36 g of the title compound as a white powder. MS (ESI+) m / z 570.3 (M+H) ＋

[0136] Example 2 2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(trifluoroacetyl)amino]methyl}benzamide To a solution of 2-chloro-5-[(2,2,2-trifluoroacetamido)methyl]benzoic acid (synthesized according to the method described in WO2011 / 048004) (0.19 g) in dichloromethane (2 mL), oxalyl chloride (0.127 mL) and DMF (1 drop) were added dropwise at room temperature, and the mixture was stirred for 60 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (1 mL). ４To a solution of 2-methyl-2-[3-(trifluoromethyl)phenyl]quinazoline-4,7-diamine (0.16 g) and DIPEA (0.104 mL) in THF (2 mL) was slowly added dropwise under ice-cooling. The reaction mixture was stirred under ice-cooling for 90 minutes, after which saturated aqueous sodium bicarbonate and water were added, followed by extraction with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.27 g of the title compound as a pale yellow powder. MS (ESI+) m / z 582.1 (M+H) ＋

[0137] Example 3 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide [Step 1] Preparation of 5-(aminomethyl)-2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide To a suspension of 2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(trifluoroacetyl)amino]methyl}benzamide (synthesized by the method described in Example 2) (0.27 g) in methanol (10 mL) and water (2.3 mL) was added potassium carbonate (0.32 g) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, methanol was added, and the mixture was vigorously stirred for 1 hour. The resulting precipitate was collected by filtration and dried to obtain 0.20 g of the title compound as a pale yellow powder.

[0138] [Step 2] Preparation of 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide. A solution of 2-methoxyacetyl chloride (0.007 mL) in THF (0.5 mL) was slowly added dropwise to a solution of 5-(aminomethyl)-2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (20 mg) and DIPEA (0.010 mL) in THF (1.5 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes, then water was added and the THF was evaporated under reduced pressure. Methanol / water (1 / 10) was added to the resulting residue and the mixture was vigorously stirred for 1 hour. The resulting precipitate was collected by filtration and dried to give 15 mg of the title compound as a pale yellow powder. MS (ESI+) m / z 558.2 (M+H) ＋

[0139] Example 4 2-chloro-5-{[(cyclopropylcarbonyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide The title compound was obtained as a white powder in the same manner as in Step 2 of Example 3, except that cyclopropylcarbonyl chloride was used instead of 2-methoxyacetyl chloride. MS (ESI+) m / z 554.2 (M+H) ＋

[0140] Example 5 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide The title compound was obtained as a white powder in the same manner as in Step 2 of Example 3, except that cyclopentylcarbonyl chloride was used instead of 2-methoxyacetyl chloride. MS (ESI+) m / z 582.3 (M+H) ＋

[0141] Example 6 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide The title compound was obtained as a white powder in the same manner as in Step 2 of Example 3, except that 3,3-dimethylbutanoyl chloride was used instead of 2-methoxyacetyl chloride. MS (ESI+) m / z 584.3 (M+H) ＋

[0142] Example 7 N-[4-chloro-3-({4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}carbamoyl)benzyl]furan-2-carboxamide The title compound was obtained as a white powder in the same manner as in Step 2 of Example 3, except that 2-furancarbonyl chloride was used instead of 2-methoxyacetyl chloride. MS (ESI+) m / z 580.2 (M+H) ＋

[0143] Example 8 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide A solution of cyclopropanesulfonyl chloride (9 mg) in THF (0.5 mL) was added dropwise to a solution of 5-(aminomethyl)-2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (synthesized by the method described in Example 3, Step 1) (20 mg) and DIPEA (0.010 mL) in THF (1.5 mL) under ice-cooling. After stirring at room temperature for 2 hours, a solution of cyclopropanesulfonyl chloride (9 mg) in THF (0.5 mL) and DIPEA (0.010 mL) were further added. After stirring overnight at room temperature, saturated aqueous sodium bicarbonate and water were added, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and powdered with ethyl acetate / n-hexane (2 / 1), filtered, and dried to obtain 13 mg of the title compound as a white powder. MS (ESI+) m / z 590.2 (M+H) ＋

[0144] Example 9 2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide To a solution of 5-(aminomethyl)-2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (synthesized by the method described in Example 3, Step 1) (20 mg), 1-(trifluoromethyl)cyclopropanecarboxylic acid (9 mg), and HATU (22 mg) in DMF (0.5 mL) was added DIPEA (0.010 mL), and the mixture was stirred at room temperature overnight. Water, a 2N aqueous sodium hydroxide solution, and saturated saline were added to the reaction solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered, and the solvent was evaporated under reduced pressure. The residue was triturated with methanol, filtered, and dried to give 15 mg of the title compound as a white powder. MS (ESI+) m / z 622.2 (M+H) ＋

[0145] Example 10 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide The title compound was obtained as a white powder in the same manner as in Example 9, except that 3-hydroxy-2,2-dimethylpropanecarboxylic acid was used instead of cyclopropanecarboxylic acid. MS (ESI+) m / z 586.2 (M+H) ＋

[0146] Example 11 2-chloro-5-{[(difluoroacetyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide DIPEA (0.010 mL) was added to a solution of 5-(aminomethyl)-2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (synthesized by the method described in Example 3, Step 1) (20 mg), difluoroacetic acid (0.008 mL), and HATU (22 mg) in DMF (0.5 mL), and the mixture was stirred overnight at room temperature. Water, a 2N aqueous sodium hydroxide solution, and saturated saline were added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, triturated with ethyl acetate / n-hexane (2 / 1), filtered, and dried to obtain 5 mg of the title compound as a pale yellow powder. MS (ESI+) m / z 564.2 (M+H) ＋

[0147] Example 12 2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(3,3,3-trifluoropropanoyl)amino]methyl}benzamide The title compound was obtained as a pale yellow powder by the same method as in Example 11, except that 3,3,3-trifluoropropanecarboxylic acid was used instead of difluoroacetic acid. MS (ESI+) m / z 596.2 (M+H) ＋

[0148] Example 13 2-chloro-N-[2-chloro-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide [Step 1] 2-chloro-N ４To a solution of 2-chloro-N-methyl-7-nitroquinazolin-4-amine (synthesized by the method described in Example 1, Step 3) (0.40 g) in THF (15 mL) and methanol (15 mL) was added 1% platinum + 0.1% copper-activated carbon (Degussa type CF105 R / W) (0.40 g), and the mixture was stirred under a hydrogen atmosphere (0.3 MPa) at 40°C for 6 hours. The reaction solution was filtered through Celite, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.27 g of the title compound as a pale yellow powder.

[0149] [Step 2] Preparation of 2-chloro-N-[2-chloro-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide ４ 2-chloro-N-methyl-2-[3-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 15 mg of methyl-quinazoline-4,7-diamine, 15 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 460.3 (M+H) ＋

[0150] Example 14 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride [Step 1] N ４ Preparation of 2-chloro-N-methyl-2-[4-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ A suspension of 20 mg of 4-methyl-quinazoline-4,7-diamine (synthesized by the method described in Step 1 of Example 13), 25 mg of [4-(trifluoromethyl)phenyl]boronic acid, 0.3 mL of 1-butanol, and 0.3 mL of saturated aqueous sodium bicarbonate in 0.6 mL of toluene was treated with Pd(PPh ３ ) ４(11 mg) was added at room temperature, and the mixture was stirred at 130 °C for 15 minutes using a microwave synthesizer. The reaction mixture was cooled to room temperature, dried over sodium sulfate, and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 20 mg of the title compound as a yellow powder.

[0151] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride To a solution of 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoic acid (synthesized according to the method described in WO2011 / 048004) (18 mg) in dichloromethane (0.3 mL), oxalyl chloride (0.012 mL) and DMF (1 drop) were added dropwise at room temperature, and the mixture was stirred for 15 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (0.5 mL), and this was added to N ４ To a solution of N-methyl-2-[4-(trifluoromethyl)phenyl]quinazoline-4,7-diamine (18 mg) and DIPEA (0.012 mL) in THF (1.0 mL) was slowly added dropwise under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes, after which saturated aqueous sodium bicarbonate and water were added, followed by extraction with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (22 mg) as a white powder. MS (ESI+) m / z 570.2 (M+H) ＋ This was suspended in ethyl acetate (2 mL), and 2M hydrogen chloride methanol solution (0.021 mL) was added dropwise. After stirring the reaction mixture at room temperature for 15 minutes, the solvent was evaporated under reduced pressure, and the resulting solid was washed with ethyl acetate, filtered, and dried to obtain 15 mg of the title compound as a white powder. Elemental analysis value: C ２９ H ２７ ClF ３ N ５ O ２HCl + 1.0H ２ Calculated values ​​as O: C: 55.78 H: 4.84 N: 11.22 Measured values: C: 55.51 H: 4.87 N: 11.04

[0152] Example 15 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide hydrochloride [Step 1] N ４

[0123] Preparation of N-methyl-2-[6-(trifluoromethyl)pyridin-3-yl]quinazoline-4,7-diamine ４ This gave 4,7-diamine-methyl-2-[6-(trifluoromethyl)pyridin-3-yl]quinazoline as a white powder.

[0153] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide hydrochloride. ４ -methyl-2-[4-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, ４ Using 26 mg of 6-methyl-2-[6-(trifluoromethyl)pyridin-3-yl]quinazoline-4,7-diamine, 14 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 571.2 (M+H) ＋

[0154] Example 16 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide hydrochloride [Step 1] N ４Preparation of N-methyl-2-[3-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine ４ This gave 3-methyl-2-[3-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine as a white powder.

[0155] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide hydrochloride. ４ -methyl-2-[4-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, ４ Using 31 mg of 3-methyl-2-[3-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine, 26 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 585.9 (M+H). ＋

[0156] Example 17 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(6-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride [Step 1] 2-(6-methoxypyridin-3-yl)-N ４ Preparation of 2-(6-methoxypyridin-3-yl)-N-methyl-quinazoline-4,7-diamine ４ -methyl-quinazoline-4,7-diamine was obtained as a pale yellow powder.

[0157] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(6-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride. ４2-(6-methoxypyridin-3-yl)-N-methyl-2-[4-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 30 mg of methyl-quinazoline-4,7-diamine, 18 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 533.3 (M+H) ＋

[0158] Example 18 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[2-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride [Step 1] N ４ Preparation of 2-chloro-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ A suspension of 2-methyl-quinazoline-4,7-diamine (25 mg), [2-(trifluoromethyl)phenyl]boronic acid (32 mg), 1-butanol (0.3 mL), saturated aqueous sodium bicarbonate (0.3 mL) in toluene (0.6 mL) was treated with Pd(PPh ３ ) ４ (13 mg) was added at room temperature, and the mixture was stirred at 150° C. for 15 minutes using a microwave synthesizer. The reaction mixture was cooled to room temperature and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 32 mg of the title compound as a yellow powder.

[0159] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[2-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride To a solution of 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoic acid (synthesized according to the method described in WO2011 / 048004) (33 mg) in dichloromethane (0.3 mL), oxalyl chloride (0.021 mL) and DMF (1 drop) were added dropwise at room temperature, and the mixture was stirred for 15 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (0.5 mL), and this was added to N ４To a solution of N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine (32 mg) and DIPEA (0.021 mL) in THF (1.0 mL) was slowly added dropwise under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes, then saturated aqueous sodium bicarbonate and water were added, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[2-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (16 mg) as a white powder. This was suspended in THF (2 mL), and 2 M hydrogen chloride solution in methanol (0.016 mL) was added dropwise. The reaction mixture was stirred at room temperature for 15 minutes, and the solvent was evaporated under reduced pressure. The resulting solid was washed with diethyl ether, filtered, and dried to give 12 mg of the title compound as a white powder. MS (ESI+) m / z 570.2 (M+H) ＋

[0160] Example 19 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-fluoro-3-methoxyphenyl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride [Step 1] 2-(2-fluoro-3-methoxyphenyl)-N ４ Preparation of 2-(2-fluoro-3-methoxyphenyl)-N-methyl-quinazoline-4,7-diamine ４ -methyl-quinazoline-4,7-diamine was obtained as a white powder.

[0161] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-fluoro-3-methoxyphenyl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride. ４2-(2-fluoro-3-methoxyphenyl)-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 29 mg of methyl-quinazoline-4,7-diamine, 17 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 550.2 (M+H) ＋

[0162] Example 20 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride [Step 1] 2-(2-fluorophenyl)-N ４ Preparation of 2-(2-fluorophenyl)-N-methyl-quinazoline-4,7-diamine ４ -methyl-quinazoline-4,7-diamine was obtained as a white powder.

[0163] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride. ４ 2-(2-fluorophenyl)-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 18 mg of methyl-quinazoline-4,7-diamine, 15 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 520.2 (M+H) ＋

[0164] Example 21 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(4-methoxyphenyl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride [Step 1] 2-(4-methoxyphenyl)-N ４Preparation of 2-(4-methoxyphenyl)-N-methyl-quinazoline-4,7-diamine ４ -methyl-quinazoline-4,7-diamine was obtained as a white powder.

[0165] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(4-methoxyphenyl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride. ４ 2-(4-methoxyphenyl)-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 20 mg of methyl-quinazoline-4,7-diamine, 21 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 532.5 (M+H) ＋

[0166] Example 22 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride [Step 1] 2-(2-methoxypyridin-3-yl)-N ４ Preparation of 2-(2-methoxypyridin-3-yl)-N-methyl-quinazoline-4,7-diamine ４ -methyl-quinazoline-4,7-diamine was obtained as a pale yellow powder.

[0167] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride. ４2-(2-methoxypyridin-3-yl)-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 16 mg of methyl-quinazoline-4,7-diamine, 12 mg of the title compound was obtained as a pale yellow powder. MS (ESI+) m / z 533.2 (M+H) ＋

[0168] Example 23 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylpyridin-4-yl)quinazolin-7-yl]benzamide hydrochloride [Step 1] N ４ Preparation of N-methyl-2-(2-methylpyridin-4-yl)quinazoline-4,7-diamine ４ This gave 4,7-diamine-methyl-2-(2-methylpyridin-4-yl)quinazoline as a pale yellow powder.

[0169] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylpyridin-4-yl)quinazolin-7-yl]benzamide hydrochloride. ４ 2-(2-methylpyridin-4-yl)-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 13 mg of methyl-quinazoline-4,7-diamine, 6 mg of the title compound was obtained as a yellow powder. MS (ESI+) m / z 517.3 (M+H) ＋

[0170] Example 24 2-chloro-N-[2-(3,4-dimethoxyphenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride [Step 1] 2-(3,4-dimethoxyphenyl)-N ４Preparation of 2-(3,4-dimethoxyphenyl)-N-methyl-quinazoline-4,7-diamine: ４ -methyl-quinazoline-4,7-diamine was obtained as a pale yellow powder.

[0171] [Step 2] Preparation of 2-chloro-N-[2-(3,4-dimethoxyphenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride. ４ 2-(3,4-dimethoxyphenyl)-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 22 mg of 4,7-methyl-quinazoline-4,7-diamine, 14 mg of the title compound was obtained as a pale yellow powder. MS (ESI+) m / z 562.3 (M+H) ＋

[0172] Example 25 2-chloro-N-[2-(3-cyanophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride [Step 1] Preparation of 3-(7-amino-4-(methylaminoquinazolin-2-yl)benzonitrile In the same manner as in Step 1 of Example 18, except that (3-cyanophenyl)boronic acid was used instead of [2-(trifluoromethyl)phenyl]boronic acid, 3-(7-amino-4-(methylaminoquinazolin-2-yl)benzonitrile was obtained as a white powder.

[0173] [Step 2] Preparation of 2-chloro-N-[2-(3-cyanophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride. ４Using 3-(7-amino-4-(methylaminoquinazolin-2-yl)benzonitrile (23 mg) instead of 2-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 22 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 527.3 (M+H) ＋

[0174] Example 26 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride [Step 1] 2-(5-methoxypyridin-3-yl)-N ４ Preparation of 2-(5-methoxypyridin-3-yl)-N-methyl-quinazoline-4,7-diamine ４ -methyl-quinazoline-4,7-diamine was obtained as a white powder.

[0175] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride. ４ 2-(5-methoxypyridin-3-yl)-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 11 mg of methyl-quinazoline-4,7-diamine, 9 mg of the title compound was obtained as a yellow powder. MS (ESI+) m / z 533.3 (M+H) ＋

[0176] Example 27 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride [Step 1] 2-(4-fluorophenyl)-N ４Preparation of 2-(4-fluorophenyl)-N-methyl-quinazoline-4,7-diamine ４ -methyl-quinazoline-4,7-diamine was obtained as a white powder.

[0177] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride. ４ 2-(4-fluorophenyl)-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 26 mg of methyl-quinazoline-4,7-diamine, 18 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 520.3 (M+H) ＋

[0178] Example 28 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride [Step 1] 2-(4-chlorophenyl)-N ４ 2-(4-chlorophenyl)-N-methyl-quinazoline-4,7-diamine was prepared in the same manner as in Step 1 of Example 18, except that (4-chlorophenyl)boronic acid was used instead of [2-(trifluoromethyl)phenyl]boronic acid. ４ -methyl-quinazoline-4,7-diamine was obtained as a white powder.

[0179] [Step 2] 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride N ４ 2-(4-chlorophenyl)-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４Using 22 mg of methyl-quinazoline-4,7-diamine, 11 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 536.3 (M+H) ＋

[0180] Example 29 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride [Step 1] 2-(2-methoxypyridin-4-yl)-N ４ Preparation of 2-(2-methoxypyridin-4-yl)-N-methyl-quinazoline-4,7-diamine ４ -methyl-quinazoline-4,7-diamine was obtained as a pale yellow powder.

[0181] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide hydrochloride. ４ 2-(2-methoxypyridin-4-yl)-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 20 mg of 4,7-methyl-quinazoline-4,7-diamine, 14 mg of the title compound was obtained as a pale yellow powder. MS (ESI+) m / z 533.3 (M+H) ＋

[0182] Example 30 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide hydrochloride [Step 1] N ４

[0123] Preparation of N-methyl-2-[4-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine４ This gave 4,7-diamine-methyl-2-[4-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine as a white powder.

[0183] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide ４ A mixture of 2-methyl-2-[4-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine (11.34 g), 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoic acid (11.89 g), N-ethyldiisopropylamine (11.74 mL), and NMP (68 mL) was stirred, and HATU (19.35 g) was added, followed by stirring at 60°C. After 16 hours, the reaction mixture was cooled to room temperature, and water and saturated aqueous sodium bicarbonate were added, followed by extraction with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residual solid was washed with ethyl acetate and then dried to obtain 18.4 g of the title compound as a white powder. MS (ESI+) m / z 586.3 (M+H) ＋

[0184] [Step 3] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide hydrochloride. To a suspension of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide (7.50 g) in THF (64 mL) was added 2N hydrochloric acid (7.04 mL), and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration and dried to obtain 7.66 g of the title compound as a white powder. Elemental analysis value: C ２９ H ２７ ClF ３ N ５ O ３ HCl + 1.0H ２ Calculated values ​​as O: C: 54.38 H: 4.72 N: 10.94 Measured values: C: 54.37 H: 4.74 N: 10.81

[0185] Example 31 2-chloro-N-[2-(3,4-dichlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-benzamide [Step 1] 2-(3,4-dichlorophenyl)-N ４ Preparation of 2-(3,4-dichlorophenyl)-N-methyl-quinazoline-4,7-diamine: ４ -methyl-quinazoline-4,7-diamine was obtained as a white powder.

[0186] [Step 2] Preparation of 2-chloro-N-[2-(3,4-dichlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-benzamide ４ 2-(3,4-dichlorophenyl)-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 24 mg of methyl-quinazoline-4,7-diamine, 11 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 570.3 (M+H) ＋

[0187] Example 32 N-[2-(4-tert-butylphenyl)-4-(methylamino)quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-benzamide hydrochloride [Step 1] 2-[4-(tert-butyl)phenyl]-N ４ Preparation of 2-[4-(tert-butyl)phenyl]-N-methyl-quinazoline-4,7-diamine ４ -methyl-quinazoline-4,7-diamine was obtained as a white powder.

[0188] [Step 2] Preparation of N-[2-(4-tert-butylphenyl)-4-(methylamino)quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-benzamide hydrochloride ４ 2-[4-(tert-butyl)phenyl]-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 25 mg of methyl-quinazoline-4,7-diamine, 12 mg of the title compound was obtained as a pale yellow powder. MS (ESI+) m / z 558.4 (M+H) ＋

[0189] Example 33 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[2-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide hydrochloride [Step 1] N ４ Preparation of N-methyl-2-[2-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine ４ This gave 4,7-diamine-methyl-2-[2-(trifluoromethoxy)phenyl]quinazoline as a white powder.

[0190] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[2-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide hydrochloride. ４ -methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, ４ Using 31 mg of 2-methyl-2-[2-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine, 15 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 586.3 (M+H) ＋

[0191] Example 34 N-{2-[2,4-bis(trifluoromethyl)phenyl]-4-(methylamino)quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride [Step 1] 2-[2,4-bis(trifluoromethyl)phenyl]-N ４ Preparation of 2-[2,4-bis(trifluoromethyl)phenyl]-N-methyl-quinazoline-4,7-diamine ４ -methyl-quinazoline-4,7-diamine was obtained as a white powder.

[0192] [Step 2] Preparation of N-{2-[2,4-bis(trifluoromethyl)phenyl]-4-(methylamino)quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride. ４ 2-[2,4-bis(trifluoromethyl)phenyl]-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 24 mg of methyl-quinazoline-4,7-diamine, 27 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 638.3 (M+H) ＋

[0193] Example 35 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{2-[2-fluoro-4-(trifluoromethyl)phenyl]-4-(methylamino)quinazolin-7-yl}benzamide hydrochloride [Step 1] 2-[2-fluoro-4-(trifluoromethyl)phenyl]-N ４ Preparation of 2-[2-fluoro-4-(trifluoromethyl)phenyl]-N-methyl-quinazoline-4,7-diamine ４-methyl-quinazoline-4,7-diamine was obtained as a white powder.

[0194] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{2-[2-fluoro-4-(trifluoromethyl)phenyl]-4-(methylamino)quinazolin-7-yl}benzamide hydrochloride. ４ 2-[2-fluoro-4-(trifluoromethyl)phenyl]-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 30 mg of methyl-quinazoline-4,7-diamine, 35 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 588.3 (M+H) ＋

[0195] Example 36 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(methylsulfonyl)phenyl]quinazolin-7-yl}benzamide hydrochloride [Step 1] N ４

[0123] Preparation of N-methyl-2-[4-(methylsulfonyl)phenyl]quinazoline-4,7-diamine ４ This gave 4,7-diamine-methyl-2-[4-(methylsulfonyl)phenyl]quinazoline-4,7-diamine as a white powder.

[0196] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(methylsulfonyl)phenyl]quinazolin-7-yl}benzamide hydrochloride. ４ 2-[4-(methylsulfonyl)phenyl]-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４Using 13 mg of 4,7-methyl-quinazoline-4,7-diamine, 14 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 580.4 (M+H) ＋

[0197] Example 37 2-chloro-N-[2-(3,5-dimethyl-1,2-oxazol-4-yl)-4-(methylamino)quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride [Step 1] 2-(3,5-dimethyl-1,2-oxazol-4-yl)-N ４ Preparation of 2-(3,5-dimethyl-1,2-oxazol-4-yl)-N-methyl-quinazoline-4,7-diamine: 2-(3,5-dimethyl-1,2-oxazol-4-yl)-N-methyl-quinazoline-4,7-diamine was prepared in the same manner as in Step 1 of Example 18, except that (3,5-dimethyl-1,2-oxazol-4-yl)boronic acid was used instead of [2-(trifluoromethyl)phenyl]boronic acid. ４ -methyl-quinazoline-4,7-diamine was obtained as a white powder.

[0198] [Step 2] Preparation of 2-chloro-N-[2-(3,5-dimethyl-1,2-oxazol-4-yl)-4-(methylamino)quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride. ４ 2-(3,5-dimethyl-1,2-oxazol-4-yl)-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 12 mg of methyl-quinazoline-4,7-diamine, 10 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 521.4 (M+H) ＋

[0199] Example 38 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{2-[3-(methoxymethyl)phenyl]-4-(methylamino)quinazolin-7-yl}benzamide hydrochloride [Step 1] 2-[3-(methoxymethyl)phenyl]-N ４Preparation of 2-[3-(methoxymethyl)phenyl]-N-methyl-quinazoline-4,7-diamine ４ -methyl-quinazoline-4,7-diamine was obtained as a white powder.

[0200] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{2-[3-(methoxymethyl)phenyl]-4-(methylamino)quinazolin-7-yl}benzamide hydrochloride. ４ 2-[3-(methoxymethyl)phenyl]-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 19 mg of methyl-quinazoline-4,7-diamine, 21 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 546.4 (M+H) ＋

[0201] Example 39 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{2-[4-(methoxymethyl)phenyl]-4-(methylamino)quinazolin-7-yl}benzamide hydrochloride [Step 1] 2-[4-(methoxymethyl)phenyl]-N ４ Preparation of 2-[4-(methoxymethyl)phenyl]-N-methyl-quinazoline-4,7-diamine ４ -methyl-quinazoline-4,7-diamine was obtained as a white powder.

[0202] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{2-[4-(methoxymethyl)phenyl]-4-(methylamino)quinazolin-7-yl}benzamide hydrochloride. ４2-[4-(methoxymethyl)phenyl]-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 17 mg of 4,7-methyl-quinazoline-4,7-diamine, 17 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 546.4 (M+H) ＋

[0203] Example 40 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-(3,4,5-trifluoromethylphenyl)quinazolin-7-yl}benzamide hydrochloride [Step 1] N ４ Preparation of N-methyl-2-(3,4,5-trifluoromethylphenyl)quinazoline-4,7-diamine ４ 4,5-trifluoromethylphenyl)quinazoline-4,7-diamine was obtained as a white powder.

[0204] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-(3,4,5-trifluoromethylphenyl)quinazolin-7-yl}benzamide hydrochloride. ４ 2-(3,4,5-trifluoromethylphenyl)-N-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine ４ Using 25 mg of methyl-quinazoline-4,7-diamine, 26 mg of the title compound was obtained as a pale yellow powder. MS (ESI+) m / z 556.4 (M+H) ＋

[0205] Example 41 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{2-[4-(hydroxymethyl)phenyl]-4-(methylamino)quinazolin-7-yl}benzamide hydrochloride [Step 1] Preparation of {4-[7-amino-4-(methylamino)quinazolin-2-yl]phenyl}methanol In the same manner as in Step 1 of Example 18, except that [4-(hydroxymethyl)phenyl]boronic acid was used instead of [2-(trifluoromethyl)phenyl]boronic acid, {4-[7-amino-4-(methylamino)quinazolin-2-yl]phenyl}methanol was obtained as a white powder.

[0206] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{2-[4-(hydroxymethyl)phenyl]-4-(methylamino)quinazolin-7-yl}benzamide hydrochloride. ４ Using {4-[7-amino-4-(methylamino)quinazolin-2-yl]phenyl}methanol (17 mg) instead of 4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 16 mg of the title compound was obtained as a pale yellow powder. MS (ESI+) m / z 532.4 (M+H). ＋

[0207] Example 42 2-chloro-N-[2-cyclopentyl-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride [Step 1] 2-Cyclopentyl-N ４ Preparation of 2-chloro-N-methyl-quinazoline-4,7-diamine ４ -methyl-quinazoline-4,7-diamine (synthesized by the method described in Example 13, Step 1) (42 mg), PdCl ２ (dppf) CH ２ Cl ２To a suspension of 16 mg of bromocyclopentylzinc and 6 mg of copper iodide in 1.5 mL of DMA, 0.5 M bromo(cyclopentyl)zinc (0.64 mL) was added at room temperature under an argon atmosphere, and the mixture was stirred at 90°C for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite. Water was added, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 47 mg of the title compound as a pale brown powder.

[0208] [Step 2] Preparation of 2-chloro-N-[2-cyclopentyl-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride. ４ -methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, ４ Using 21 mg of 4,7-methyl-quinazoline-4,7-diamine, 26 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 494.4 (M+H) ＋

[0209] Example 43 N-{4-(azetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride [Step 1] Preparation of 4-(azetidin-1-yl)-2-chloro-7-nitroquinazoline To a suspension of 2,4-dichloro-7-nitroquinazoline (synthesized by the method described in Example 1, Step 2) (900 mg) in THF (13 mL), DIPEA (2.55 mL) and azetidine hydrochloride (0.69 g) were added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. DIPEA (2.55 mL) and azetidine hydrochloride (0.69 g) were further added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 452 mg of the title compound as a yellow powder.

[0210] [Step 2] Preparation of 4-(azetidin-1-yl)-7-nitro-2-[3-(trifluoromethyl)phenyl]quinazoline. A suspension of 4-(azetidin-1-yl)-2-chloro-7-nitroquinazoline (200 mg), [3-(trifluoromethyl)phenyl]boronic acid (172 mg), 1-butanol (3.0 mL), and saturated aqueous sodium bicarbonate (1.5 mL) in toluene (3.0 mL) was treated with Pd(PPh) under an argon atmosphere. ３ ) ４ (87 mg) was added at room temperature, and the mixture was stirred for 15 minutes, followed by stirring at 100°C for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate was added, and extraction with ethyl acetate was performed. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 138 mg of the title compound as a yellow powder.

[0211] [Step 3] Preparation of 4-(azetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-amine To a suspension of 4-(azetidin-1-yl)-7-nitro-2-[3-(trifluoromethyl)phenyl]quinazoline (237 mg) in THF (15 mL) and methanol (10 mL) was added 5% palladium / carbon (70 mg), and the mixture was stirred under a hydrogen atmosphere (0.3 MPa) at room temperature for 4 hours. The reaction solution was filtered through Celite, and the solvent was evaporated under reduced pressure to give 214 mg of the title compound as a gray powder.

[0212] [Step 4] Preparation of N-{4-(azetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride To a solution of 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoic acid (synthesized according to the method described in WO2011 / 048004) (218 mg) in dichloromethane (8.0 mL) were added dropwise at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (8.0 mL). This solution was slowly added dropwise to a solution of 4-(azetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-amine (214 mg) and DIPEA (0.32 mL) in THF (12 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour, after which saturated aqueous sodium bicarbonate and water were added, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give N-{4-(azetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide (322 mg) as a yellow powder. This was suspended in methanol (5 mL), and 2M hydrogen chloride methanol solution (0.28 mL) was added dropwise. After stirring the reaction solution at room temperature for 1 hour, the solvent was evaporated under reduced pressure, and the residue was powdered with chloroform / n-hexane, filtered, and dried to obtain 298 mg of the title compound as a pale yellow powder. MS (ESI+) m / z 596.3 (M+H) ＋

[0213] Example 44 2-chloro-N-{4-(dimethylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride The title compound was obtained as a pale yellow powder by the same method as in Example 43, except that 50% aqueous dimethylamine was used instead of azetidine hydrochloride. MS (ESI+) m / z 584.4 (M+H) ＋

[0214] Example 45 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(pyrrolidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride The title compound was obtained as a white powder by the same method as in Example 43, except that pyrrolidine was used instead of azetidine hydrochloride. MS (ESI+) m / z 610.3 (M+H) ＋

[0215] Example 46 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-[(2-methoxyethyl)amino]-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride The title compound was obtained as a white powder by the same method as in Example 43, except that 2-methoxyethylamine was used instead of azetidine hydrochloride. MS (ESI+) m / z 614.3 (M+H) ＋

[0216] Example 47 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(ethylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride The title compound was obtained as a white powder by the same method as in Example 43, except that 70% aqueous ethylamine was used instead of azetidine hydrochloride. MS (ESI+) m / z 584.0 (M+H). ＋

[0217] Example 48 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(propan-2-ylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride The title compound was obtained as a white powder by the same method as in Example 43, except that isopropylamine was used instead of azetidine hydrochloride. MS (ESI+) m / z 598.3 (M+H) ＋

[0218] Example 49 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(morpholin-4-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride The title compound was obtained as a pale yellow powder by the same method as in Example 43, except that morpholine was used instead of azetidine hydrochloride. MS (ESI+) m / z 626.3 (M+H) ＋

[0219] Example 50 N-{4-amino-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-benzamide hydrochloride The title compound was obtained as a white powder by the same method as in Example 43, except that 25% aqueous ammonia was used instead of azetidine hydrochloride. MS (ESI+) m / z 556.3 (M+H) ＋

[0220] Example 51 tert-Butyl 3-{[(7-{[(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]quinazolin-4-yl)amino]methyl}azetidine-1-carboxylate The title compound was obtained as a white powder by the same method as in Example 43 (excluding the hydrochlorination procedure in Step 4), using tert-butyl 3-(aminomethyl)azetidine-1-carboxylate instead of azetidine hydrochloride. MS (ESI+) m / z 725.4 (M+H) ＋

[0221] Example 52 N-{4-[(azetidin-3-ylmethyl)amino]-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide dihydrochloride tert-butyl 3-{[(7-{[(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]quinazolin-4-yl)amino]methyl}azetidine-1-carboxylate (synthesized by the method described in Example 51) (43 mg) in dichloromethane (2.4 mL) was added dropwise with ice-cooling, followed by addition of thioanisole (0.06 mL) and trifluoroacetic acid (0.6 mL). The reaction mixture was stirred at room temperature for 2 hours, followed by addition of saturated aqueous sodium bicarbonate, and extraction with ethyl acetate / THF (1 / 1). The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give N-{4-[(azetidin-3-ylmethyl)amino]-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide (19 mg) as a white solid. This was dissolved in methanol (1 mL), and 2 M hydrogen chloride methanol solution (0.031 mL) was added dropwise. The reaction solution was stirred at room temperature for 1 hour, after which the solvent was evaporated under reduced pressure. The solid was triturated with methanol / diethyl ether, filtered, and dried to give 19 mg of the title compound as a white powder. MS (ESI+) m / z 625.3 (M+H) ＋

[0222] Example 53 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(3-methoxyazetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride [Step 1] Preparation of 1-(2-chloro-7-nitroquinazolin-4-yl)azetidin-3-ol To a solution of 3-hydroxyazetidine hydrochloride (89 mg) in THF (4.0 mL), DIPEA (0.28 mL) and 2,4-dichloro-7-nitroquinazoline (synthesized by the method described in Example 1, Step 2) (100 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. 3-Hydroxyazetidine hydrochloride (178 mg) and DIPEA (0.28 mL) were further added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 53 mg of the title compound as a yellow powder.

[0223] [Step 2] Preparation of 1-{7-nitro-2-[3-(trifluoromethyl)phenyl]quinazolin-4-yl}azetidin-3-ol. A suspension of 1-(2-chloro-7-nitroquinazolin-4-yl)azetidin-3-ol (52 mg), [3-(trifluoromethyl)phenyl]boronic acid (71 mg), 1-butanol (1.5 mL), and saturated aqueous sodium bicarbonate (0.7 mL) in toluene (1.5 mL) was treated with Pd(PPh) under an argon atmosphere. ３ ) ４ (21 mg) was added at room temperature, and the mixture was stirred for 15 minutes, followed by stirring at 80°C for 3 hours. The reaction mixture was cooled to room temperature, water was added, and extraction with ethyl acetate was performed. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 53 mg of the title compound as a yellow powder.

[0224] [Step 3] Preparation of 4-(3-methoxyazetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-amine. To a solution of 1-{7-nitro-2-[3-(trifluoromethyl)phenyl]quinazolin-4-yl}azetidin-3-ol (23 mg) in DMF (1.0 mL) was added sodium hydride (3.5 mg) under ice-cooling. The reaction mixture was stirred for 15 minutes under ice-cooling, and then methyl iodide (0.0055 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of saturated aqueous ammonium chloride solution and extraction with diethyl ether. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was dissolved in methanol (5 mL) and THF (5 mL), and 5% palladium on carbon (20 mg) was added. The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere (0.3 MPa). The reaction mixture was filtered through Celite, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 7.3 mg of the title compound as a yellow powder.

[0225] [Step 4] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(3-methoxyazetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride In the same manner as in Step 4 of Example 43, except that 4-(3-methoxyazetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-amine (7.3 mg) was used instead of 4-(azetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-amine, 8.6 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 626.3 (M+H) ＋

[0226] Example 54 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(3-hydroxyazetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride [Step 1] Preparation of 4-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-7-nitro-2-[3-(trifluoromethyl)phenyl]quinazoline To a solution of 1-{7-nitro-2-[3-(trifluoromethyl)phenyl]quinazolin-4-yl}azetidin-3-ol (synthesized by the method described in Example 53, Step 2) (27 mg) in DMF (3.0 mL) were added imidazole (14 mg) and tert-butyldimethylsilyl chloride (15 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Imidazole (14 mg) and tert-butyldimethylsilyl chloride (15 mg) were further added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with diethyl ether was performed. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 24 mg of the title compound as a yellow powder.

[0227] [Step 2] Preparation of N-(4-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl)-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide In the same manner as in Steps 3 and 4 of Example 43, except that 4-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-7-nitro-2-[3-(trifluoromethyl)phenyl]quinazoline was used in place of 4-(azetidin-1-yl)-7-nitro-2-[3-(trifluoromethyl)phenyl]quinazoline, the title compound was obtained as a pale yellow powder.

[0228] [Step 3] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(3-hydroxyazetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride. To a solution of N-(4-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl)-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide (20 mg) in THF (0.3 mL) was added dropwise 1 M tetrabutylammonium fluoride THF solution (0.042 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and extraction with ethyl acetate was performed. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(3-hydroxyazetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (16 mg). This was dissolved in methanol (0.5 mL), and 2M hydrogen chloride methanol solution (0.015 mL) was added dropwise. The reaction solution was stirred at room temperature for 0.5 hours, and then the solvent was evaporated under reduced pressure. The residue was triturated with methanol / diethyl ether, filtered, and dried to give 8.4 mg of the title compound as a white powder. MS (ESI+) m / z 612.3 (M+H) ＋

[0229] Example 55 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-(4-{[(1-methylazetidin-3-yl)methyl]amino}-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl)benzamide dihydrochloride The title compound was obtained as a white powder by the same method as in Example 43, except that (1-methylazetidin-3-yl)-methanamine was used instead of azetidine hydrochloride. MS (ESI+) m / z 639.4 (M+H) ＋

[0230] Example 56 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-methoxy-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride [Step 1] Preparation of 2-chloro-4-methoxy-7-nitroquinazoline Sodium methoxide (33 mg) was added to a suspension of 2,4-dichloro-7-nitroquinazoline (synthesized by the method described in Example 1, Step 2) (50 mg) in methanol (2.0 mL), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 27 mg of the title compound.

[0231] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-methoxy-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride. The title compound was obtained as a pale yellow powder by a method similar to that of Steps 2, 3, and 4 of Example 43, except that 2-chloro-4-methoxy-7-nitroquinazoline was used instead of 4-(azetidin-1-yl)-2-chloro-7-nitroquinazoline. MS (ESI+) m / z 571.3 (M+H). ＋

[0232] Example 57 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-ethoxy-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride [Step 1] Preparation of 2-chloro-4-ethoxy-7-nitroquinazoline Sodium ethoxide (139 mg) was added to a suspension of 2,4-dichloro-7-nitroquinazoline (synthesized by the method described in Example 1, Step 2) (100 mg) in ethanol (4.0 mL), and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 20 mg of the title compound.

[0233] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-ethoxy-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride. The title compound was obtained as a pale yellow powder by a method similar to that of Steps 2, 3, and 4 of Example 43, except that 2-chloro-4-ethoxy-7-nitroquinazoline was used instead of 4-(azetidin-1-yl)-2-chloro-7-nitroquinazoline. MS (ESI+) m / z 585.3 (M+H). ＋

[0234] Example 58 2-chloro-N-{4-cyclopropyl-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride [Step 1] Preparation of 2-chloro-4-cyclopropyl-7-nitroquinazoline A suspension of 2,4-dichloro-7-nitroquinazoline (synthesized by the method described in Example 1, Step 2) (200 mg), cyclopropylboronic acid (85 mg), and potassium phosphate (434 mg) in THF (8.0 mL) was treated with PdCl under an argon atmosphere. ２ (dppf) CH ２ Cl ２ (66 mg) was added at room temperature, and the mixture was stirred for 15 minutes and then stirred for 1 hour at 90° C. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography to obtain 100 mg of the title compound as a pale yellow powder.

[0235] [Step 2] Preparation of 2-chloro-4-cyclopropylquinazolin-7-amine To a solution of 2-chloro-4-cyclopropyl-7-nitroquinazoline (95 mg) in THF (10 mL) and methanol (15 mL), 1% platinum + 0.1% copper-activated carbon (Degussa type CF105 R / W) (50 mg) was added, and the mixture was stirred under a hydrogen atmosphere (0.3 MPa) at room temperature for 6 hours. The reaction solution was filtered through Celite, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 57 mg of the title compound as a pale yellow powder.

[0236] [Step 3] Preparation of 2-chloro-N-{4-cyclopropyl-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride. ４ Using 2-chloro-4-cyclopropylquinazolin-7-amine instead of 4,7-methyl-quinazoline-4,7-diamine gave the title compound as a pale yellow powder. MS (ESI+) m / z 581.3 (M+H). ＋

[0237] Example 59 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-methyl-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride [Step 1] Preparation of 2-chloro-4-methyl-7-nitroquinazoline A suspension of 2,4-dichloro-7-nitroquinazoline (synthesized by the method described in Example 1, Step 2) (200 mg), methylboronic acid (49 mg), and potassium phosphate (434 mg) in THF (2.0 mL) was treated with PdCl under an argon atmosphere. ２ (dppf) CH ２ Cl ２ (66 mg) was added at room temperature, and the mixture was stirred for 15 minutes, and then stirred for 1 hour at 90° C. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography to obtain 21 mg of the title compound as a pale yellow powder.

[0238] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-methyl-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide hydrochloride. The title compound was obtained as a pale yellow powder by a method similar to that of Steps 2, 3, and 4 of Example 43, except that 2-chloro-4-methyl-7-nitroquinazoline was used instead of 4-(azetidin-1-yl)-2-chloro-7-nitroquinazoline. MS (ESI+) m / z 555.3 (M+H). ＋

[0239] Example 60 3-{[(cyclopropanecarbonyl)amino]methyl}-2,6-difluoro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide [Step 1] Preparation of 3-(cyclopropanecarboxamidomethyl)-2,6-difluorobenzoic acid Cyclopropanecarboxamide (8.50 g) was suspended in 37% aqueous formaldehyde solution (8.92 g), and potassium carbonate (1.38 g) was added at room temperature, followed by stirring for 1 hour at 40° C. The reaction solution was concentrated under reduced pressure to an extent that potassium carbonate no longer precipitated, and ethyl acetate was added. The resulting precipitate was collected by filtration and dried to give N-(hydroxymethyl)cyclopropanecarboxamide (8.40 g) as white crystals. To a mixture of N-(hydroxymethyl)cyclopropanecarboxamide (2.76 g) and 2,6-difluorobenzoic acid (1.72 g), sulfuric acid (15 mL) was added and stirred at 60°C for 20 hours. Water (80 mL) was added to the reaction mixture under ice-cooling, and extraction with ethyl acetate was performed. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.80 g of the title compound as a yellow powder.

[0240] [Step 2] Preparation of 3-{[(cyclopropanecarbonyl)amino]methyl}-2,6-difluoro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide ４To a solution of 28 mg of 3-methyl-2-[3-(trifluoromethyl)phenyl]quinazoline-4,7-diamine (synthesized by the method described in Example 1, Step 5), 45 mg of 3-(cyclopropanecarboxamidomethyl)-2,6-difluorobenzoic acid, and 67 mg of HATU in 1.5 mL of DMF, DIPEA (0.030 mL) was added and the mixture was stirred at 50°C for 2 days. 45 mg of 3-(cyclopropanecarboxamidomethyl)-2,6-difluorobenzoic acid, 67 mg of HATU, and 0.030 mL of DIPEA were further added, and the mixture was stirred at 50°C for 3 days. Water, a 2N aqueous sodium hydroxide solution, and saturated saline were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered, and the solvent was evaporated under reduced pressure. The residue was triturated with ethyl acetate / n-hexane (2 / 1), filtered, and dried to obtain 10 mg of the title compound as a white powder. MS (ESI+) m / z 556.3 (M+H) ＋

[0241] Example 61 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride The title compound was obtained as a white powder by a method similar to that in Steps 2, 3, and 4 of Example 43, except that [4-(trifluoromethyl)phenyl]boronic acid was used instead of [3-(trifluoromethyl)phenyl]boronic acid. MS (ESI+) m / z 596.3 (M+H) ＋

[0242] Example 62 2-chloro-N-{4-cyclopropyl-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochloride In the same manner as in Example 14, 2-chloro-N ４ Using 2-chloro-4-cyclopropylquinazolin-7-amine (synthesized by the method described in Step 2 of Example 58) instead of 4,7-methyl-quinazoline-4,7-diamine, the title compound was obtained as a pale yellow powder. MS (ESI+) m / z 581.3 (M+H). ＋

[0243] Example 63 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide N ４ A mixture of 5-methyl-2-[4-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine (5.0 g), 5-[(2,2-dimethylpropanoylamino)methyl]-2-(trifluoromethyl)benzoic acid (5.9 g), N-ethyldiisopropylamine (5.2 mL), and NMP (30 mL) was stirred, and HATU (8.53 g) was added and stirred at 70°C. After 16 hours, the reaction mixture was cooled to room temperature, and water and saturated aqueous sodium bicarbonate were added, followed by extraction with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residual solid was washed with ethyl acetate and dried to obtain 6.72 g of the title compound as a white powder. MS (ESI+) m / z 620.3 (M+H) ＋

[0244] Example 64 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide In a similar manner to that described in Steps 1 and 2 of Example 14, 22 mg of the title compound was obtained as a white powder. MS (ESI+) m / z 570.2 (M+H) ＋

[0245] Example 65 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide In a similar manner to that described in Steps 1 and 2 of Example 30, 18.4 g of the title compound was obtained as a white powder. MS (ESI+) m / z 586.3 (M+H) ＋

[0246] Example 66: 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide hydrochloride. 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide was obtained in the same manner as in Example 63, Step 1. To a suspension of this 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide (6.72 g) in THF (36 mL) was added 2N hydrochloric acid (5.97 mL), and the mixture was stirred at room temperature. After 5 hours, the precipitate was collected by filtration, washed with ethyl acetate, and dried to obtain 6.07 g of the title compound as a white solid. ３０ H ２７ F ６ N ５ O ３ HCl + 1.0H ２ Calculated values ​​as O: C: 53.46 H: 4.49 N: 10.39 Measured values: C: 53.50 H: 4.35 N: 10.30

[0247] Example 67 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide methanesulfonate

[0043] N,N-Dimethylformamide (200.00 mL) was added to 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide (20.00 g) obtained by a method similar to that of Example 65, and the mixture was stirred at room temperature to form a solution. Methanesulfonic acid (2.33 mL) and then ethyl acetate (400.00 mL) were added dropwise, and the mixture was stirred at room temperature overnight. The precipitated white solid was collected by filtration, washed with ethyl acetate (40.00 mL), and dried to obtain 20.04 g of the title compound as a white solid. Elemental analysis value C２９ H ２７ ClF ３ N ５ O ３ ・MeSO ３ H + 0.5H ２ Calculated values ​​as O: C: 52.14 H: 4.67 N: 10.13 Measured values: C: 52.28 H: 4.49 N: 10.10

[0248] The compounds described in the following Examples 68 to 149 were produced by reacting and treating the corresponding starting compounds in the same manner as in Example 1 (excluding the hydrochloride salt formation procedure in Step 6 of Example 1).

[0249] Example 68 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 600 (M+H) ＋

[0250] Example 69 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 600 (M+H) ＋

[0251] Example 70 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide MS (ESI+) m / z 585 (M+H) ＋

[0252] Example 71 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide MS (ESI+) m / z 585 (M+H) ＋

[0253] Example 72 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide MS (ESI+) m / z 547 (M+H) ＋

[0254] Example 73 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide MS (ESI+) m / z 534 (M+H) ＋

[0255] Example 74 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 598 (M+H) ＋

[0256] Example 75 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 598 (M+H) ＋

[0257] Example 76 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide MS (ESI+) m / z 583 (M+H) ＋

[0258] Example 77 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide MS (ESI+) m / z 583 (M+H) ＋

[0259] Example 78 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide MS (ESI+) m / z 545 (M+H) ＋

[0260] Example 79 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide MS (ESI+) m / z 534 (M+H) ＋

[0261] Example 80 2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 638 (M+H) ＋

[0262] Example 81 2-chloro-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 638 (M+H) ＋

[0263] Example 82 2-chloro-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 623 (M+H) ＋

[0264] Example 83 2-chloro-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 623 (M+H) ＋

[0265] Example 84 2-chloro-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 585 (M+H) ＋

[0266] Example 85 2-chloro-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 572 (M+H) ＋

[0267] Example 86 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 586 (M+H) ＋

[0268] Example 87 2-chloro-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide MS (ESI+) m / z 520 (M+H) ＋

[0269] Example 88 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 574 (M+H) ＋

[0270] Example 89 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 574 (M+H) ＋

[0271] Example 90 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide MS (ESI+) m / z 559 (M+H) ＋

[0272] Example 91 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide MS (ESI+) m / z 559 (M+H) ＋

[0273] Example 92 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide MS (ESI+) m / z 553 (M+H) ＋

[0274] Example 93 2-chloro-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(methoxyacetyl)amino]methyl}benzamide MS (ESI+) m / z 508 (M+H) ＋

[0275] Example 94 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 602 (M+H) ＋

[0276] Example 95 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 602 (M+H) ＋

[0277] Example 96 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide MS (ESI+) m / z 587 (M+H) ＋

[0278] Example 97 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide MS (ESI+) m / z 587 (M+H) ＋

[0279] Example 98 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 606 (M+H) ＋

[0280] Example 99 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 606 (M+H) ＋

[0281] Example 100 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide MS (ESI+) m / z 591 (M+H) ＋

[0282] Example 101 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide MS (ESI+) m / z 591 (M+H) ＋

[0283] Example 102 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide MS (ESI+) m / z 540 (M+H) ＋

[0284] Example 103 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide MS (ESI+) m / z 620 (M+H) ＋

[0285] Example 104 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide MS (ESI+) m / z 605 (M+H) ＋

[0286] Example 105 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]-2-(trifluoromethyl)benzamide MS (ESI+) m / z 567 (M+H) ＋

[0287] Example 106 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-2-(trifluoromethyl)benzamide MS (ESI+) m / z 554 (M+H) ＋

[0288] Example 107 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 584 (M+H) ＋

[0289] Example 108 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 582 (M+H) ＋

[0290] Example 109 2-chloro-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 622 (M+H) ＋

[0291] Example 110 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 570 (M+H) ＋

[0292] Example 111 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 558 (M+H) ＋

[0293] Example 112 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 586 (M+H) ＋

[0294] Example 113 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide MS (ESI+) m / z 590 (M+H) ＋

[0295] Example 114 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide MS (ESI+) m / z 604 (M+H) ＋

[0296] Example 115 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide MS (ESI+) m / z 534 (M+H) ＋

[0297] Example 116 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide MS (ESI+) m / z 532 (M+H) ＋

[0298] Example 117 2-chloro-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 572 (M+H) ＋

[0299] Example 118 2-chloro-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide MS (ESI+) m / z 520 (M+H) ＋

[0300] Example 119 2-chloro-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(methoxyacetyl)amino]methyl}benzamide MS (ESI+) m / z 508 (M+H) ＋

[0301] Example 1209 2-chloro-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide MS (ESI+) m / z 536 (M+H) ＋

[0302] Example 121 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide MS (ESI+) m / z 540 (M+H) ＋

[0303] Example 122 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-2-(trifluoromethyl)benzamide MS (ESI+) m / z 554 (M+H) ＋

[0304] Example 123 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide MS (ESI+) m / z 550 (M+H) ＋

[0305] Example 124 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide MS (ESI+) m / z 548 (M+H) ＋

[0306] Example 125 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 588 (M+H) ＋

[0307] Example 126 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide MS (ESI+) m / z 556 (M+H) ＋

[0308] Example 127 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamide MS (ESI+) m / z 516 (M+H) ＋

[0309] Example 128 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamide MS (ESI+) m / z 514 (M+H) ＋

[0310] Example 129 2-chloro-N-[4-(methylamino)-2-phenylquinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 554 (M+H) ＋

[0311] Example 130 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamide MS (ESI+) m / z 502 (M+H) ＋

[0312] Example 131 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamide MS (ESI+) m / z 490 (M+H) ＋

[0313] Example 132 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamide MS (ESI+) m / z 518 (M+H) ＋

[0314] Example 133 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamide MS (ESI+) m / z 522 (M+H) ＋

[0315] Example 134 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamide MS (ESI+) m / z 536 (M+H) ＋

[0316] Example 135 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide MS (ESI+) m / z 550 (M+H) ＋

[0317] Example 136 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide MS (ESI+) m / z 548 (M+H) ＋

[0318] Example 137 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 588 (M+H) ＋

[0319] Example 138 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide MS (ESI+) m / z 536 (M+H) ＋

[0320] Example 139 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(methoxyacetyl)amino]methyl}benzamide MS (ESI+) m / z 524 (M+H) ＋

[0321] Example 140 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide MS (ESI+) m / z 552 (M+H) ＋

[0322] Example 141 N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide MS (ESI+) m / z 570 (M+H) ＋

[0323] Example 142 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide MS (ESI+) m / z 530 (M+H) ＋

[0324] Example 143 2-chloro-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 568 (M+H) ＋

[0325] Example 1443 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide MS (ESI+) m / z 504 (M+H) ＋

[0326] Example 145 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide MS (ESI+) m / z 532 (M+H) ＋

[0327] Example 146 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide MS (ESI+) m / z 536 (M+H) ＋

[0328] Example 147 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide MS (ESI+) m / z 547 (M+H) ＋

[0329] Example 148 2-chloro-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 585 (M+H) ＋

[0330] Example 149 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide MS (ESI+) m / z 521 (M+H) ＋

[0331] The compounds described in the following Examples 150 to 226 were produced by reacting and treating the corresponding starting compounds in the same manner as in Example 43 (excluding the hydrochloride salt formation procedure in Step 4 of Example 43).

[0332] Example 150 N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide MS (ESI+) m / z 626 (M+H) ＋

[0333] Example 151 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide MS (ESI+) m / z 626 (M+H)＋

[0334] Example 152 N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide MS (ESI+) m / z 611 (M+H) ＋

[0335] Example 153 N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide MS (ESI+) m / z 611 (M+H) ＋

[0336] Example 154 N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide MS (ESI+) m / z 573 (M+H) ＋

[0337] Example 155 N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide MS (ESI+) m / z 560 (M+H) ＋

[0338] Example 156 N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide MS (ESI+) m / z 624 (M+H) ＋

[0339] Example 157 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide MS (ESI+) m / z 624 (M+H) ＋

[0340] Example 158 N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide MS (ESI+) m / z 609 (M+H) ＋

[0341] Example 159 N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide MS (ESI+) m / z 609 (M+H) ＋

[0342] Example 160 N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide MS (ESI+) m / z 571 (M+H) ＋

[0343] Example 161 N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide MS (ESI+) m / z 558 (M+H) ＋

[0344] Example 162 N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 664 (M+H) ＋

[0345] Example 163 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 664 (M+H) ＋

[0346] Example 164 N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 649 (M+H) ＋

[0347] Example 165 N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 649 (M+H) ＋

[0348] Example 166 N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 598 (M+H) ＋

[0349] Example 167 N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide MS (ESI+) m / z 612 (M+H) ＋

[0350] Example 168 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide MS (ESI+) m / z 612 (M+H) ＋

[0351] Example 169 N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide MS (ESI+) m / z 597 (M+H) ＋

[0352] Example 170 N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide MS (ESI+) m / z 546 (M+H) ＋

[0353] Example 171 N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide MS (ESI+) m / z 600 (M+H) ＋

[0354] Example 172 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-({[(methoxyacetyl)amino]methyl}benzamide MS (ESI+) m / z 600 (M+H) ＋

[0355] Example 173 N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide MS (ESI+) m / z 585 (M+H) ＋

[0356] Example 174 N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide MS (ESI+) m / z 585 (M+H) ＋

[0357] Example 175 N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide MS (ESI+) m / z 547 (M+H) ＋

[0358] Example 176 N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide MS (ESI+) m / z 534 (M+H) ＋

[0359] Example 177 N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide MS (ESI+) m / z 628 (M+H) ＋

[0360] Example 178 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide MS (ESI+) m / z 628 (M+H) ＋

[0361] Example 179 N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide MS (ESI+) m / z 613 (M+H) ＋

[0362] Example 180 N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide MS (ESI+) m / z 613 (M+H) ＋

[0363] Example 181 N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide MS (ESI+) m / z 562 (M+H) ＋

[0364] Example 182 N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide MS (ESI+) m / z 632 (M+H) ＋

[0365] Example 183 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide MS (ESI+) m / z 632 (M+H) ＋

[0366] Example 184 N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide MS (ESI+) m / z 617 (M+H) ＋

[0367] Example 185 N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide MS (ESI+) m / z 617 (M+H) ＋

[0368] Example 186 N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide MS (ESI+) m / z 566 (M+H) ＋

[0369] Example 187 N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide MS (ESI+) m / z 646 (M+H) ＋

[0370] Example 188 N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide MS (ESI+) m / z 631 (M+H) ＋

[0371] Example 189 N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide MS (ESI+) m / z 631 (M+H) ＋

[0372] Example 190 N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide MS (ESI+) m / z 593 (M+H) ＋

[0373] Example 191 N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide MS (ESI+) m / z 580 (M+H) ＋

[0374] Example 192 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide MS (ESI+) m / z 610 (M+H) ＋

[0375] Example 193 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide MS (ESI+) m / z 608 (M+H) ＋

[0376] Example 194 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 648 (M+H) ＋

[0377] Example 195 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide MS (ESI+) m / z 596 (M+H) ＋

[0378] Example 196 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide MS (ESI+) m / z 584 (M+H) ＋

[0379] Example 197 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide MS (ESI+) m / z 612 (M+H) ＋

[0380] Example 198 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide MS (ESI+) m / z 616 (M+H) ＋

[0381] Example 199 N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide MS (ESI+) m / z 630 (M+H) ＋

[0382] Example 200 N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide MS (ESI+) m / z 560 (M+H) ＋

[0383] Example 201 N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide MS (ESI+) m / z 558 (M+H) ＋

[0384] Example 2022 N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 598 (M+H) ＋

[0385] Example 203 N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide MS (ESI+) m / z 546 (M+H) ＋

[0386] Example 204 N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide MS (ESI+) m / z 534 (M+H) ＋

[0387] Example 205 N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide MS (ESI+) m / z 562 (M+H) ＋

[0388] Example 206 N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide MS (ESI+) m / z 566 (M+H) ＋

[0389] Example 207 N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide MS (ESI+) m / z 580 (M+H) ＋

[0390] Example 208 N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide MS (ESI+) m / z 542 (M+H) ＋

[0391] Example 209 N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide MS (ESI+) m / z 540 (M+H) ＋

[0392] Example 210 N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 580 (M+H) ＋

[0393] Example 211 N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide MS (ESI+) m / z 528 (M+H) ＋

[0394] Example 212 N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide MS (ESI+) m / z 516 (M+H)＋

[0395] Example 213 N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide MS (ESI+) m / z 548 (M+H) ＋

[0396] Example 214 N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide MS (ESI+) m / z 576 (M+H) ＋

[0397] Example 215 N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide MS (ESI+) m / z 574 (M+H) ＋

[0398] Example 216 N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 614 (M+H) ＋

[0399] Example 217 N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide MS (ESI+) m / z 562 (M+H) ＋

[0400] Example 218 N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide MS (ESI+) m / z 550 (M+H) ＋

[0401] Example 219 N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide MS (ESI+) m / z 582 (M+H) ＋

[0402] Example 220 N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide MS (ESI+) m / z 596 (M+H) ＋

[0403] Example 220 N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide MS (ESI+) m / z 556 (M+H) ＋

[0404] Example 222 N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide MS (ESI+) m / z 554 (M+H) ＋

[0405] Example 223 N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide MS (ESI+) m / z 594 (M+H) ＋

[0406] Example 224 N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide MS (ESI+) m / z 530 (M+H) ＋

[0407] Example 225 N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide MS (ESI+) m / z 558 (M+H) ＋

[0408] Example 226 N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide MS (ESI+) m / z 573 (M+H) ＋

[0409] The compounds described in the following 1. to 74. are prepared according to any of the methods described in Examples 1 to 67 above. 1. 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide 2. 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide 3. 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide 4. 2-Chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide 5. 2-Chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide 6. 2-Chloro-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide 7. 1. 2-Chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide 8. 2,6-Dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide 9. 2,6-Dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide 10. 2,6-Dichloro-3-{[(2,10. 2,6-Dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide 11. 2,6-Dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide 12. 2,6-Dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide 13. 13. 2,6-Dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide 14. 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide 15. N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide 16. 16. N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide 17. N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide 18. N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide 19. N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide 20. N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide 21. N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide 22. 22. N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide 23. N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide 24. N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide 25. 26. N-{4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide 26. N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide 27. 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide 28. 2,6-dichloro-3-{[(2,2-Dimethylpropanoyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide 29. 2-Chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide 30. 2-Chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(methoxyacetyl)amino]methyl}benzamide 31. 2-Chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide 32. 31. 2,6-Dichloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide 32. 2,6-Dichloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide 33. N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide 34. 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]-2-(trifluoromethyl)benzamide 35. 2-Chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide 36. 36. 2,6-Dichloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide 37. 2-Chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide 38. 2-Chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide 39. 2,6-Dichloro-3-{[(2,2-Dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide 40. 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]-2-(trifluoromethyl)benzamide 41. 2-Chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide 42. 2-Chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide 43. 43. 2-Chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide 2-Chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[2-((5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide 45. 2,6-Dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide 46. 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]-2-(trifluoromethyl)benzamide 47. 47. N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide 48. N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide 49. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide 50. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide 51. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide 52. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide 53. 53. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide 54. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide 55. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide 56. 56. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide 57. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide 58. N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide 59. 60. N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide 61. N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide 62. N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide 63. N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide 64. 64. N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide 65. N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide 66. N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide 67. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide 68. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide 69. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide 70. 70. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide 71. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide 72. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide 73. 73. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide 74. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide

[0410] The structural formulas of Examples 1 to 226 are shown in Tables 1 to 11.

[0411] Test Example 1: mPGES-1 Inhibitory Activity Test. mPGES-1 microsome preparations were prepared from CHO-K1 cells transiently transfected with a plasmid encoding human mPGES-1 cDNA. The prepared mPGES-1 microsome preparation was diluted with reduced glutathione-containing potassium phosphate buffer (pH 7.4), and a DMSO solution of the test compound or DMSO was added to a final DMSO concentration of 1%. The mixture was then incubated at 4°C for 20 minutes. The enzyme reaction was then initiated by adding a solution of PGH2 substrate adjusted to a final concentration of 1 μM, followed by incubation at 4°C for 60 seconds. The reaction was terminated by adding ferric chloride and citrate solutions to final concentrations of 5 mg / mL and 250 mM, respectively. The amount of PGE2 formed was quantified using an HTRF kit (Cisbio International, product catalog #62P2APEC). A solution without the test compound was used as a positive control, and a solution without the test compound and microsome preparation was used as a negative control. 100% activity was defined as the PGE2 production in the positive control minus the PGE2 production in the negative control. The PGE2 production inhibition rate at a final concentration of 10 nM of the test compound was then calculated, or the IC50 value was measured using standard methods.

[0412] Test Example 2: Test for inhibition of PGE2 and PGF2α production using A549 cells. 2 x 10 human A549 cells were placed in each well of a 96-well plate. ４Human A549 cells were seeded in 100 μL of RPMI medium containing 10% FBS and incubated overnight. The medium was then removed and washed with phosphate-buffered saline. A DMSO solution of the test compound or RPMI medium containing 3% FBS plus DMSO was added to the wells, with a final DMSO concentration of 0.1%. After 60 minutes of incubation, IL-1β (5 ng / well) was added. After 24 hours of incubation at 37°C, PGE2 in the medium was quantified using an HTRF kit (Cisbio International, product catalog #62P2APEC) and PGF2α was quantified using an EIA kit (Cayman Chemical Company, product catalog #516011). A solution without the test compound served as a positive control, and a solution without the test compound and IL-1β served as a negative control. 100% activity was defined as the PGE2 and PGF2α production in the positive control minus the PGE2 and PGF2α production in the negative control. IC50 values ​​were then measured using standard methods. The results of Test Examples 1 and 2 are shown in Tables 12 to 14 (in the tables, "-" indicates that the test was not performed).

[0413]

[0414]

[0415]

[0416] Test Example 3: In Vivo Mouse Spondyloarthritis Model. The inflammation-causing substance, zymosan, was dissolved in sterile saline and administered intraperitoneally to SKG / Jcl mice under an SPF environment. The administration volume was 3 mg zymosan / 500 μL per mouse. One week after zymosan administration, the mice were evaluated for limb arthritis and assigned to a group based on their limb arthritis clinical score and body weight. The assigned mice began oral administration of vehicle or compound (twice daily) for 42 consecutive days. The day of assignment was designated day 0, and limb arthritis clinical scores were measured every seven days thereafter (days 7, 14, 21, 28, 35, and 42). Measurements were performed by three independent evaluators in a blinded manner across all groups, and the mean values ​​were used. The clinical score for limb arthritis of each individual was calculated by scoring the swelling of each interphalangeal joint and carpal (foot) joint of each forelimb (hindlimb) and adding up the scores for all limbs (normal: 0 points, maximum 5.8 points; the great toe of the forelimb was excluded from the evaluation; Table 15).

[0417] Test Example 4: In Vivo Mouse Spondyloarthritis Model. The inflammation-causing substance, zymosan, was dissolved in sterile saline and intraperitoneally administered to SKG / Jcl mice under an SPF environment. The administration volume was 3 mg zymosan / 500 μL per mouse. Starting two weeks after zymosan administration, mice were evaluated for limb arthritis once a week, and mice with a limb arthritis clinical score of 0.5 or higher were assigned to a pediatric group. These mice were then orally administered vehicle or compound twice daily for 28 or 42 days. The day onset of symptoms was defined as day 0, and limb arthritis clinical scores were measured every 7 days thereafter. (For the 28-day daily administration, limb arthritis clinical scores were measured on days 7, 14, 21, and 28; for the 42-day daily administration, limb arthritis clinical scores were measured on days 7, 14, 21, 28, 35, and 42.) Measurements were performed independently by three evaluators in a blinded manner for all groups, and the average value was used. The clinical score for limb arthritis of each individual was calculated by scoring the swelling of each interphalangeal joint and carpal (foot) joint of each forelimb (hindlimb) and adding up the total score for all limbs (normal: 0 points, maximum 5.8 points; the great toe of the forelimb was excluded from the evaluation; Table 15).

[0418] As described in Test Examples 1 and 2, the compound of the present invention or a pharmaceutically acceptable salt thereof exhibits high mPGES-1 inhibitory activity and inhibits the production of PGE2. Furthermore, the compound of the present invention or a pharmaceutically acceptable salt thereof exhibits an inhibitory effect on the progression of limb arthritis in an in vivo mouse spondyloarthritis model of Test Examples 3 and 4.

[0419] Formulation Example 1 Tablets (oral tablets) Formulation per 80 mg tablet: Compound of the present invention of Example 1 5.0 mg Corn starch 46.6 mg Microcrystalline cellulose 24.0 mg Methylcellulose 4.0 mg Magnesium stearate 0.4 mg The powder mixture in this proportion is compressed into tablets by a conventional method to give oral tablets.

[0420] [Other Examples] Evaluation Items In Test Examples 3 and 4, limb arthritis clinical scores were measured, but Examples are not limited thereto. For example, histological scores may be measured as described in a literature article (ARTHRITIS & RHEUMATOLOGY, Vol. 67, No. 4, April 2015, pp. 893-902). For example, test tissues from the left and right forelimbs, left and right hindlimbs, left and right hind digits, spine, and tail vertebrae of a mouse were excised, fixed in 10% neutral buffered formalin fixative, decalcified in 10% EDTA decalcifying solution, embedded in paraffin, and sectioned. The samples were then stained with hematoxylin and eosin. Note that the animal species used to measure histological scores are not limited to mice, and the test tissues are not limited to the left and right forelimbs, left and right hindlimbs, left and right hind digits, spine, and tail vertebrae; any tissue can be selected. Furthermore, the concentration of the fixative can be adjusted as appropriate as long as it can fix the tissue to be examined, and the concentration of the decalcification solution can be adjusted as appropriate as long as it can decalcify the tissue to be examined.

[0421] Histological evaluation of periarticular inflammation, cartilage necrosis, bone erosion and necrosis, and inflammation / pannus within the joint cavity can be performed, for example, using a scoring system created with reference to the literature (Banda NK et al. 2009. Targeted Inhibition of the Complement Alternative Pathway with Complement Receptor 2 and Factor H Attenuates Collagen Antibody-Induced Arthritis in Mice). Examples of scoring systems are shown in Tables 16 to 19, but the systems are not limited to these and can be modified as appropriate.

[0422] Histological evaluation of the periosteal reaction (neosteogenesis) and inflammation of the Achilles tendon (enthesis) can be performed, for example, using a scoring system created with reference to the literature (uutu M, et al. 2012. β-glucan triggers spondylarthritis and Crohn's disease-like ileitis in SKG mice. Arthritis Rheum. 64, 2211-22 (2012)). Tables 20 and 21 show examples of scoring systems, but the system is not limited to these and can be modified as appropriate.

[0423] Histological evaluation of intervertebral disc damage and excessive tissue formation can be performed, for example, using a scoring system created with reference to the literature (Tseng HW et al. 2016. Inflammation-driven bone formation in a mouse model of ankylosing spondylitis: sequential not parallel processes). Tables 22 and 23 show examples of scoring systems, but the system is not limited to these and can be modified as appropriate.

[0424] X-ray imaging can also be used as another evaluation method. For example, in X-ray imaging of bones and joints, narrowing and fusion of the joint space due to loss of articular cartilage, dislocation, fracture, osteoporosis, and bony stiffness can be observed and scored as evaluation items. X-ray imaging can also be performed using an X-ray device, X-ray CT device, PET-CT device, etc.

[0425] Compound Profiles In the compound profiles described in the examples, mPGES-1 inhibitory activity and PGE2 production inhibitory activity were measured, but the present invention is not limited to these. For example, in addition to measuring mPGES-1 inhibitory activity and PGE2 production inhibitory activity, compounds may be profiled by measuring half-life, etc. For example, half-life can be measured as follows. Male rats are administered each administration solution (each containing a test compound) at 1 mg / mL / kg via the jugular or tail vein under fasting conditions, and blood samples are collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and (24) time points after administration. The collected blood is immediately centrifuged, and the plasma drug concentration in the supernatant is measured by LC-MS / MS. The dose and timing of blood collection can be modified as appropriate.

[0426] The compound of the present invention or a pharmaceutically acceptable salt thereof exhibits mPGES-1 inhibitory activity and is therefore particularly useful in the treatment of inflammatory bowel disease, irritable bowel syndrome, migraine, headache, lower back pain, lumbar spinal canal stenosis, herniated disc, temporomandibular joint disorder, cervicobrachial syndrome, cervical spondylosis, endometriosis, adenomyosis, premature labor, threatened premature labor, dysmenorrhea, overactive bladder, nocturia, interstitial cystitis, neurodegenerative diseases (e.g., Alzheimer's disease, multiple sclerosis), psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, neuralgia, complex regional pain syndrome, fascial disorders, viral infections (e.g., influenza, cold, shingles, AIDS), bacterial The composition is useful as a preventive or therapeutic agent for pain caused by sexually transmitted diseases, fungal infections, burns, inflammation and pain after surgery, trauma and tooth extraction, malignant tumors (e.g., colon cancer, breast cancer, lung cancer, prostate cancer, etc.), atherosclerosis, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ossification of the ligaments, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound treatment, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids, prostatitis and cancer.

Claims

1. The following general formula [1]: [In the formula, R １ is an alkoxy, cycloalkyl, alkyl, or a group represented by the following general formula [2]: (In the formula, R ６ and R ７ are each independently hydrogen or optionally substituted alkyl, or R ６ and R ７ together with the nitrogen atom to which they are attached form an optionally substituted saturated cyclic amino; R ２ is aryl, heteroaryl, halogen or cycloalkyl, and ２ Each of the aryl, heteroaryl, and cycloalkyl in R is optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkoxy optionally substituted with 1 to 3 halogens, (2) cyano, (3) halogen, (4) alkyl optionally substituted with (i) 1 to 3 halogens, (ii) hydroxy, or (iii) alkoxy, and (5) alkylsulfonyl; ３ is halogen or alkyl optionally substituted with 1 to 3 halogens; R ４ is hydrogen or halogen; R ５ is -SO ２ R ８ or -COR ８ and R ８ is alkyl, cycloalkyl or heteroaryl; R ８ The alkyl in R may be substituted with 1 to 3 groups independently selected from the group consisting of hydroxy, alkoxy, and halogen; ８ wherein cycloalkyl may be substituted with (1) hydroxy, or (2) alkyl optionally substituted with 1 to 3 halogen atoms, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

2. R ６ and R ７ are each independently a hydrogen atom or an optionally substituted alkyl, or R ６ and R ７ together with the nitrogen atom to which they are attached form an optionally substituted saturated cyclic amino; R ２ is aryl, heteroaryl or cycloalkyl; R ２ Each of the aryl, heteroaryl, and cycloalkyl in R is optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkoxy optionally substituted with 1 to 3 halogens, (2) cyano, (3) halogen, (4) alkyl optionally substituted with (i) 1 to 3 halogens, (ii) hydroxy, or (iii) alkoxy, and (5) alkylsulfonyl; ３ is halogen or alkyl optionally substituted with 1 to 3 halogens; R ４ is a hydrogen atom or a halogen; R ５ is -SO ２ R ８ or -COR ８ and R ８ is alkyl or cycloalkyl, R ８ The alkyl in R may be substituted with 1 to 3 groups independently selected from the group consisting of hydroxy, alkoxy, and halogen; ８ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein cycloalkyl in the formula (I) is optionally substituted with: (1) hydroxy, or (2) alkyl optionally substituted with 1 to 3 halogens.

3. R ６ and R ７ are each independently a hydrogen atom or an optionally substituted alkyl; R ２ is aryl, heteroaryl or cycloalkyl; R ２ Each of the aryl, heteroaryl, and cycloalkyl in R is optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkoxy optionally substituted with 1 to 3 halogens, (2) cyano, (3) halogen, (4) alkyl optionally substituted with (i) 1 to 3 halogens, (ii) hydroxy, or (iii) alkoxy, and (5) alkylsulfonyl; ３ is halogen or alkyl optionally substituted with 1 to 3 halogens; R ４ is a hydrogen atom or a halogen; R ５ is -SO ２ R ８ or -COR ８ and R ８ is alkyl or cycloalkyl, R ８ The alkyl in R may be substituted with 1 to 3 groups independently selected from the group consisting of hydroxy, alkoxy, and halogen; ８ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein cycloalkyl in the formula (I) is optionally substituted with: (1) hydroxy, or (2) alkyl optionally substituted with 1 to 3 halogens.

4. R ６ and R ７ are each independently a hydrogen atom or an optionally substituted alkyl; R ２ is aryl, heteroaryl or cycloalkyl; R ２ the aryl in R is phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkoxy optionally substituted with 1 to 3 halogen atoms, (2) cyano, (3) a fluorine atom or a chlorine atom, (4) alkyl optionally substituted with 1 to 3 halogen atoms, and (5) methylsulfonyl; ２ The heteroaryl in the formula (I) is pyridyl or isoxazolyl optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkyl optionally substituted with 1 to 3 halogens, and (2) alkoxy optionally substituted with 1 to 3 halogens; and R ２ The cycloalkyl in ３－６ cycloalkyl; R ３ is halogen or alkyl optionally substituted with 1 to 3 halogens; R ４ is a hydrogen atom or a halogen; R ５ is -SO ２ R ８ or -COR ８ and R ８ is alkyl or cycloalkyl, R ８ The alkyl in １－６ alkyl, R ８ The cycloalkyl in ３－６ 2. The compound of claim 1, wherein R is cycloalkyl; or a pharmaceutically acceptable salt thereof, or a solvate thereof.

5. R ６ and R ７ are each independently a hydrogen atom or an optionally substituted alkyl; R ２ is aryl or heteroaryl, R ２ the aryl in R is phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkoxy optionally substituted with 1 to 3 halogen atoms, (2) cyano, (3) a fluorine atom or a chlorine atom, (4) alkyl optionally substituted with 1 to 3 halogen atoms, and (5) methylsulfonyl; ２ The heteroaryl in the formula (I) is pyridyl or isoxazolyl optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkyl optionally substituted with 1 to 3 halogens, and (2) alkoxy optionally substituted with 1 to 3 halogens; ３ is halogen or alkyl optionally substituted with 1 to 3 halogens; R ４ is a hydrogen atom; R ５ is -COR ８ and R ８ is alkyl or cycloalkyl, R ８ The alkyl in １－６ alkyl, R ８ The cycloalkyl in ３－６ 2. The compound of claim 1, wherein R is cycloalkyl; or a pharmaceutically acceptable salt thereof, or a solvate thereof.

6. R ６ and R ７ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein at least one of: is hydrogen.

7. R ６ and R ７ The compound according to any one of claims 1 to 5, wherein one of is hydrogen and the other is optionally substituted alkyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

8. R ２ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the aryl in the formula (I) is phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of: (1) alkoxy optionally substituted with 1 to 3 halogens, and (2) alkyl optionally substituted with 1 to 3 halogens.

9. R ８ The alkyl in １－６ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R is alkyl.

10. R ３ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein is chlorine or trifluoroalkyl.

11. A compound according to any one of the following (1) to (296) or a pharmaceutically acceptable salt thereof, or a solvate thereof: (1) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (2) 2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(trifluoroacetyl)amino]methyl}benzamide, (3) 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (4) (5) 2-chloro-5-{[(cyclopropylcarbonyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (6) 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (7) N-[4-chloro-3-({4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}carbamoyl)benzyl]furan-2-carboxamide, (8) 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (9) 2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (10) 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide,(11) 2-chloro-5-{[(difluoroacetyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (12) 2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(3,3,3-trifluoropropanoyl)amino]methyl}benzamide, (13) 2-chloro-N-[2-chloro-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (14) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (15) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide, (16) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (17) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(6-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (18) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[2-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (19) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-fluoro-3-methoxyphenyl)-4-(methylamino)quinazolin-7-yl]benzamide, (20) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide,(21) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(4-methoxyphenyl)-4-(methylamino)quinazolin-7-yl]benzamide, (22) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (23) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylpyridin-4-yl)quinazolin-7-yl]benzamide, (24) 2-chloro-N-[2-(3,4-dimethoxyphenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (25) 2-chloro-N-[2-(3-cyanophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (26) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (27) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide, (28) 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (29) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (30) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (31) 2-chloro-N-[2-(3,4-dichlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-benzamide,(32) N-[2-(4-tert-butylphenyl)-4-(methylamino)quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-benzamide, (33) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[2-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (34) N-{2-[2,4-bis(trifluoromethyl)phenyl]-4-(methylamino)quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (35) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{2-[2-fluoro-4-(trifluoromethyl)phenyl]-4-(methylamino)quinazolin-7-yl}benzamide, (36) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(methylsulfonyl)phenyl]quinazolin-7-yl}benzamide, (37) 2-chloro-N-[2-(3,5-dimethyl-1,2-oxazol-4-yl)-4-(methylamino)quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (38) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{2-[3-(methoxymethyl)phenyl]-4-(methylamino)quinazolin-7-yl}benzamide, (39) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{2-[4-(methoxymethyl)phenyl]-4-(methylamino)quinazolin-7-yl}benzamide, (40) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-(3,4,5-trifluoromethylphenyl)quinazolin-7-yl}benzamide, (41) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{2-[4-(hydroxymethyl)phenyl]-4-(methylamino)quinazolin-7-yl}benzamide,(42) 2-chloro-N-[2-cyclopentyl-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (43) N-{4-(azetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (44) 2-chloro-N-{4-(dimethylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (45) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(pyrrolidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (46) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-[(2-methoxyethyl)amino]-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (47) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(ethylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (48) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(propan-2-ylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (49) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(morpholin-4-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (50) N-{4-amino-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-benzamide, (51) tert-butyl 3-{[(7-{[(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]quinazolin-4-yl)amino]methyl}azetidine-1-carboxylate,(52) N-{4-[(azetidin-3-ylmethyl)amino]-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (53) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(3-methoxyazetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (54) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(3-hydroxyazetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (55) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-(4-{[(1-methylazetidin-3-yl)methyl]amino}-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl)benzamide, (56) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-methoxy-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (57) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-ethoxy-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (58) 2-chloro-N-{4-cyclopropyl-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (59) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-methyl-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (60) 3-{[(cyclopropanecarbonyl)amino]methyl}-2,6-difluoro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (61) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide,(62) 2-chloro-N-{4-cyclopropyl-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (63) 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide, (64) 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (65) 2-Chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide (66) 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide hydrochloride (67) 2-Chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide methanesulfonate (68) 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (69) 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (70) 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide, (71) 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide,(72) 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (73) 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide, (74) 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (75) 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (76) 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide, (77) 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide, (78) 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (79) 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide, (80) 2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (81) 2-chloro-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide,(82) 2-chloro-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (83) 2-chloro-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (84) 2-chloro-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (85) 2-chloro-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (86) 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (87) 2-chloro-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (88) 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (89) 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide (90) 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide, (91) 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide,(92) 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (93) 2-chloro-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(methoxyacetyl)amino]methyl}benzamide, (94) 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (95) 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (96) 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide, (97) 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide, (98) 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (99) 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (100) 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide, (101) 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide,(102) 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide, (103) 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide, (104) 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide, (105) 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]-2-(trifluoromethyl)benzamide, (106) 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-2-(trifluoromethyl)benzamide, (107) 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (108) 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (109) 2-chloro-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (110) 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (111) 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide,(112) 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (113) 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (114) 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide, (115) 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide, (116) 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide, (117) 2-chloro-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (118) 2-chloro-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (119) 2-chloro-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(methoxyacetyl)amino]methyl}benzamide, (120) 2-chloro-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (121) 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide,(122) 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-2-(trifluoromethyl)benzamide, (123) 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide, (124) 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide, (125) 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (126) 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide, (127) 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamide, (128) 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamide, (129) 2-chloro-N-[4-(methylamino)-2-phenylquinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (130) 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamide, (131) 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamide, (132) 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamide,(133) 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamide, (134) 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamide, (135) 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide, (136) 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide, (137) 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (138) 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (139) 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(methoxyacetyl)amino]methyl}benzamide, (140) 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (141) N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide, (142) 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide, (143) 2-chloro-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide,(144) 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide, (145) 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide, (146) 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide, (147) 2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (148) 2-chloro-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (149) 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (150) N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide, (15147) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide, (152) N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide, (153) N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide,(154) N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide, (155) N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide, (156) N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide, (157) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide, (158) N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide, (159) N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide, (160) N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide, (161) N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide, (162) N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (163) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide,(164) N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (165) N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (166) N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (167) N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (168) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (169) N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (170) N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (171) N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide, (172) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-({[(methoxyacetyl)amino]methyl}benzamide,(173) N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide, (174) N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide, (175) N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide, (176) N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide, (177) N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (178) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (179) N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (180) N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (181) N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide,(182) N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide, (183) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide, (184) N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide, (185) N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide, (186) N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide, (187) N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide, (188) N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide, (189) N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide, (190) N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide,(191) N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide, (192) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide, (193) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide, (194) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (195) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (196) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide, (197) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (198) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide, (199) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide,(200) N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide, (201) N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide, (202) N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (203) N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (204) N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide, (205) N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (206) N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide, (207) N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide, (208) N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide, (209) N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide,(210) N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (211) N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (212) N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide, (213) N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide, (214) N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide, (215) N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide, (216) N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (217) N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (218) N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide, (219) N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide,(220) N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide, (221) N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide, (222) N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide, (223) N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (224) N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide, (225) N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (226) N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide, (227) 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (228) 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide, (229) 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide,(230) 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (231) 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (232) 2-chloro-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (233) 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (234) 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (235) 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide, (236) 2,6-Dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide, (237) 2,6-Dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide, (238) 2,6-Dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (239) 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide,(240) 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide, (241) N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (242) N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (243) N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (244) N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (245) N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide, (246) N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (247) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (248) N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide,(249) N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (250) N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (251) N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (252) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide, (253) 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide, (254) 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide, (255) 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (256) 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(methoxyacetyl)amino]methyl}benzamide, (257) 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (258) 2,6-dichloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide,(259) N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide, (260) 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]-2-(trifluoromethyl)benzamide, (261) 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide, (262) 2,6-Dichloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (263) 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide, (264) 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide, (265) 2,6-Dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide, (266) 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]-2-(trifluoromethyl)benzamide, (267) 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (268) 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide,(269) 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (270) 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[2-((5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (271) 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide, (272) 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]-2-(trifluoromethyl)benzamide, (273) N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (274) N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (275) N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide, (276) N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide, (277) N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (278) N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide,(279) N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide, (280) N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (281) N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide, (282) N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (283) N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide, (284) N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (285) N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (286) N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide, (287) N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (288) N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide,(289) N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (290) N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide, (291) N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (292) N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide, (293) N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide, (294) N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide, (295) N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide, (296) N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide, (297) N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide, (298) N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide,(299) N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide, (300) N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

13. An mPGES-1 inhibitor comprising the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

14. A PGE2 production inhibitor comprising the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

15. A preventive or therapeutic agent for a disease involving mPGES-1, comprising the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

16. A preventive or therapeutic agent for a disease involving PGE2, comprising the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

17. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the treatment of inflammatory bowel disease, irritable bowel syndrome, migraine, headache, lower back pain, lumbar spinal stenosis, herniated disc, temporomandibular joint disorder, cervicobrachial syndrome, cervical spondylosis, endometriosis, adenomyosis, premature labor, threatened premature labor, dysmenorrhea, overactive bladder, nocturia, interstitial cystitis, neurodegenerative disease, psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, neuralgia, complex regional pain syndrome, myofascial disorder, viral infection, or bacterial infection. Preventive or therapeutic agent for pain in fungal infections, burns, inflammation and pain after surgery, trauma, and tooth extraction, malignant tumors, atherosclerosis, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ossification of the ligaments, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound treatment, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids, prostatitis, and cancer.

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