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

[TITLE OF THE INVENTION]: QUINAZOLINE COMPOUND AND MEDICINE [TECHNICAL FIELD]

[0001] The present invention relates to a novel quinazoline compound or a pharmaceutically acceptable salt thereof, or a solvate thereof. [BACKGROUND ART]

[0002] Prostaglandins (PGs) are produced in large amounts at the site of inflammation and are involved in the development of inflammation. The production of prostaglandins begins with the release of arachidonic acid from membrane glycerophospholipids by phospholipase A2, which is then converted 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 inflammation-inducing effects. In particular, PGE2 is known to induce inflammation in acute and chronic inflammation, as well as fever and hyperalgesia. Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors exhibit anti-inflammatory effects by suppressing the production of PGE2 based on COX-1 and / or COX-2 inhibition. PGE2 synthase (PGES) plays the role in the final step of the synthesis pathway of the inflammatory mediator PGE2. PGES is currently known to include three subtypes: membrane-bound prostaglandin E synthase-1 (mPGES-1) (e.g., see Non-Patent Document 1), mPGES-2 (e.g., see Non-Patent Document 2), and cytosolic PGES (cPGES) (e.g., see Non-Patent Document 3). Among them, mPGES-1, as same to COX-2, is mainly induced during inflammation and is closely involved in production of PGE2 in inflammatory lesions. In contrast, cPGES is a constitutive PGES that mainly coexists with COX-1 and is involved in the constant production of PGE2 (e.g., see Non-Patent Document 4). Regarding mPGES-2, it has been shown to be involved in both COXs and a certain viewpoint has not been obtained. Studies for mPGES-1 deficient mice have suggested that mPGES-1 is involved in the pathogenesis of various inflammatory models, such as the acetate rising model (e.g., see Non-Patent Document 5), arthritis models (e.g., see Non-Patent Documents 5 and 6), multiple sclerosis models (e.g., see Non-Patent Document 7), and fever models (e.g., see Non-Patent Document 8). Also, since mPGES-1 inhibitors only inhibit COX-2-dependent PGE2 production, various side effects are expected to be reduced compared to NSAIDs and COX-2 inhibitors. It is thought that the enhancement of the coagulation system and vasoconstriction caused by the inhibition of COX-2-depent PGI2 production may contribute to the increased risk of cardiovascular events due to COX-2 inhibitors (e.g., see Non-Patent Document 9). In contrast, mPGES-1 inhibitors do not inhibit PGI2 production and thus would not increase the risk of cardiovascular events which are problematic with COX-2 inhibitors (e.g., see Non-Patent Document 10).

[0003] Further, mPGES-1 inhibitors inhibit production of PGE2 which is involved in inflammation, while the production of PGI2, which has anti-inflammatory properties (e.g., see Non-Patent Document 28), is increased by them (e.g., see Non-Patent Document 29). Thus, mPGES-1 inhibitors are expected to have strong anti-inflammatory effects.

[0004] Additionally, since it is reported that PGE2 promotes cell proliferation (e.g., see Non-Patent Document 30) and PGI2 suppresses cell proliferation (e.g., see Non-Patent Document 31), mPGES-1 inhibitors are also expected to have a strong inhibitory effect on cell proliferation. Thus, agents that exhibit mPGES-1 inhibitory activity and can selectively inhibit production of PGE2 can be beneficial in the treatment or prevention of diseases involving mPGES-1, such as inflammatory diseases, and proliferative diseases.Although various compounds having mPGES-1 inhibitory activity are known (e.g., see Patent Documents 1 and 2), compounds having such activity and comprising an quinazoline skeleton are not known.[PRIOR ART DOCUMENTS][PATENT DOCUMENTS]

[0005] [Patent Document 1] CN105523996B[Patent Document 2] WO2023 / 127883A[NON-PATENT DOCUMENTS]

[0006] [Non-patent Document 1] Jakobsson et al. Proc. Natl. Acad. Sci. USA, 1999, 96, 7220-7225.[Non-patent Document 2] Tanikawa et al. Biochem.Biophys.Res. Commun. 2002, 291, 884-889.[Non-patent Document 3] Tanioka et al., J. Biol. Chem. 2000, 275, 32775-32782.[Non-patent Document 4] Murakami et al., J. Biol. Chem. 2000, 275, 32783-32792.[Non-patent Document 5] Kamei et al., J. Biol. Chem. 2004, 279, 33684-33695.[Non-patent Document 6] Kojima et al., J. Immunol., 2008, 180, 8361-8368[Non-patent Document 7] Kihara et al., Proc. Natl.Acad.Sci.USA, 2009, 106, 21807-21812[Non-patent Document 8] Engblom et al., Nat. Neurosci.,2003, 6, 1137-1138 [Non-patent Document 9] Foudi et al., Cardiovasc.Res.,2009,81, 269-277[Non-patent Document 10] Cheng et al., J.Clin. Invest., 2006, 116, 1391-1399[Non-patent Document 11] J.Immunol., 2007, 178(12), 8138-47[Non-patent Document 12] Biomed. Pharmacother., 2011, 65(1), 77-84[Non-patent Document 13] Acta. Med. Okayama, 2008, 62(6), 373-378[Non-patent Document 14] Glia, 2011, 59, 208-218[Non-patent Document 15] J. Burn. Care. Res., 2011, 32(1), 79-90[Non-patent Document 16] J. Biol. Chem., 2003, 278(21), 19396-19405[Non-patent Document 17] Oncogene, 2012, 31(24), 2943-2952[Non-patent Document 18] Cancer Res., 2008, 68(9), 3251-3259[Non-patent Document 19] Proc. Natl. Acad. Sci. USA, 2006, 103, 14507-14512[Non-patent Document 20] Proc. Natl. Acad. Sci. USA, 2006, 103(31), 11790-11795[Non-patent Document 21] J. Rheumatol., 2005, 32(5), 887-895[Non-patent Document 22] J. Pharmacol. Exp. Ther., 2008, 326, 754-763[Non-patent Document 23] Kidney Int., 2011, 79(1), 77-88[Non-patent Document 24] J. Immunol., 2012, 188, 4093-4102[Non-patent Document 25] Am. J. Physiol. Lung Cell Mol. Physiol., 2004, 287, L981-L991[Non-patent Document 26] Am. J. Physiol. Lung Cell Mol. Physiol., 2005, 288, L1010-L1016[Non-patent Document 27] Arthritis Res. Ther., 2011, 13, R6[Non-patent Document 28] J. Immunol., 2007, 178, 702-710[Non-patent Document 29] J. Biol. Chem., 2005, 280, 16579-16585[Non-patent Document 30] J. Clin. Endocrinol. Metab., 2003, 88, 4481-4487[Non-patent Document 31] AM. J. Respir. Cell Mol. Biol., 2002, 26, 194-201[SUMMARY OF INVENTION][PROBLEMS TO BE SOLVED BY THE INVENTION]

[0007] The main object of the present invention is providing a novel quinazoline compound or a pharmaceutically acceptable salt thereof. It is also the object of the present invention to provide a pharmaceutical composition comprising such a quinazoline compound or a pharmaceutically acceptable salt thereof as active ingredients.[MEANS OF SOLVING THE PROBLEMS]

[0008] The inventors found that quinazoline compounds, or pharmaceutically acceptable salts thereof, have excellent mPGES-1 inhibitory activity, as described below.

[0009] The present invention includes the following embodiments of clauses 1 to 45.Clause 1.A compound represented by the general formula [1][Chemical Formula 1]wherein,R1 is alkoxy, cycloalkyl, alkyl or a group represented by the general formula [2]:[Chemical Formula 2]wherein,R6 and R7 are each independently hydrogen or optionally substituted alkyl; orR6 and R7 together with the nitrogen which they are attached to form optionally substituted saturated cyclic amino;R2 is aryl, heteroaryl, halogen or cycloalkyl, wherein each of the aryl, heteroaryl and cycloalkyl in R2 is optionally substituted by 1 to 3 groups independently selected from the group consisting of:(1) alkoxy optionally substituted by 1 to 3 halogens,(2) cyano,(3) halogen,(4) alkyl optionally substituted by (i) 1 to 3 halogens, (ii) hydroxy or (iii) alkoxy, and(5) alkylsulfonyl;R3 is halogen, or alkyl optionally substituted by 1 to 3 halogens;R4 is hydrogen or halogen;R5 is -SO2R8 or -COR8, wherein the R8 is alkyl, cycloalkyl or heteroaryl;the alkyl in R8 is optionally substituted by 1 to 3 groups independently selected from hydroxy, alkoxy and halogen; andthe cycloalkyl in R8 is optionally substituted by:(1) hydroxy, or(2) alkyl optionally substituted by 1 to 3 halogens,or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0010] Clause 2The compound according to clause 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof,wherein:R6 and R7 are each independently hydrogen or optionally substituted alkyl; orR6 and R7 together with the nitrogen which they are attached to form optionally substituted saturated cyclic amino;R2 is aryl, heteroaryl or cycloalkyl, each of the aryl, heteroaryl and cycloalkyl in R2 is optionally substituted by 1 to 3 groups independently selected from the group consisting of:(1) alkoxy optionally substituted by 1 to 3 halogens,(2) cyano,(3) halogen,(4) alkyl optionally substituted by (i) 1 to 3 halogens, (ii) hydroxy or (iii) alkoxy, and(5) alkylsulfonyl;R3 is halogen or alkyl optionally substituted by 1 to 3 halogens;R4 is hydrogen or halogen;R5 is -SO2R8 or -COR8;R8 is alkyl or cycloalkyl,the alkyl in R8 is optionally substituted by 1 to 3 groups independently selected from the group consisting of hydroxy, alkoxy and halogen; andthe cycloalkyl in R8 is optionally substituted by:(1) hydroxy, or(2) alkyl optionally substituted by 1 to 3 halogens.

[0011] Clause 3The compound according to clause 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof,wherein:R6 and R7 are each independently, hydrogen or optionally substituted alkyl;R2 is aryl, heteroaryl or cycloalkyl, each of the aryl, heteroaryl and cycloalkyl is optionally substituted by 1 to 3 groups independently selected from the group consisting of:(1) alkoxy optionally substituted by 1 to 3 halogens,(2) cyano,(3) halogen,(4) alkyl optionally substituted by (i) 1 to 3 halogens, (ii) hydroxy or (iii) alkoxy; and(5) alkylsulfonyl;R3 is halogen or alkyl optionally substituted by 1 to 3 halogens;R4 is hydrogen or halogen;R5 is -SO2R8 or -COR8;R8 is alkyl or cycloalkyl,the alkyl in R8 is optionally substituted by 1 to 3 groups independently selected from the group consisting of hydroxy, alkoxy and halogen; andthe cycloalkyl in R8 is optionally substituted by:(1) hydroxy or(2) alkyl optionally substituted by 1 to 3 halogens.

[0012] Clause 4The compound according to clause 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof,wherein:R6 and R7 are each independently, hydrogen or optionally substituted alkyl;R2 is aryl, heteroaryl or cycloalkyl, the aryl in R2 is phenyl optionally substituted by 1 to 3 groups independently selected from the group consisting of:(1) alkoxy optionally substituted by 1 to 3 halogens,(2) cyano,(3) fluorine or chlorine,(4) (i) 1 to 3 halogens, (ii) hydroxy or (iii) alkyl optionally substituted alkoxy; and(5) alkylsulfonyl;the heteroaryl in R2is pyridyl or isoxazolyl, each of which is optionally substituted by 1 to 3 groups independently selected from the group consisting of;(1) alkyl optionally substituted by 1 to 3 halogens, and (2) alkoxy optionally substituted by 1 to 3 halogens;the cycloalkyl in R2is C3-6cycloalkyl;R3 is halogen or alkyl optionally substituted by 1 to 3 halogens;R4 is hydrogen or halogen;R5 is -SO2R8 or -COR8;R8 is alkyl or cycloalkyl the alkyl in R8 is C1-6alkyl; andthe cycloalkyl in R8 is C3-6cycloalkyl.

[0013] Clause 5The compound according to clause 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof,wherein:R6 and R7 are each independently, hydrogen or optionally substituted alkyl;R2 is aryl or heteroaryl, the aryl in R2 is phenyl optionally substituted by 1 to 3 groups independently selected from the group consisting of:(1) alkoxy optionally substituted by 1 to 3 halogens,(2) cyano,(3) fluorine or chlorine, (4) alkyl optionally substituted by 1 to 3 halogens, and (5) methylsulfonyl;the heteroaryl in R2 is pyridyl or isoxazolyl, each of which is optionally substituted by 1 to 3 groups independently selected from the group consisting of;(1) alkyl optionally substituted by 1 to 3 halogens, and(2) alkoxy optionally substituted by 1 to 3 halogens;R3 is halogen or alkyl optionally substituted by 1 to 3 halogens;R4 is hydrogen;R5 is -COR8;R8 is alkyl or cycloalkyl;the alkyl in R8 is C1-6alkyl; andthe cycloalkyl in R8 is C3-6cycloalkyl.

[0014] Clause 6The compound according to any of clauses 1-5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein at least one of R6 and R7 is hydrogen.

[0015] Clause 7The compound according to any of clauses 1-5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the one of R6 and R7 is hydrogen, and the other is optionally substituted alkyl.

[0016] Clause 8The compound according to any of clauses 1 to 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof,wherein:the aryl in R2 is phenyl optionally substituted by 1 to 3 groups independently selected from the group consisting of:(1) alkoxy optionally substituted by 1 to 3 halogens, and(2) alkyl optionally substituted by 1 to 3 halogens.

[0017] Clause 9The compound according to any one of clauses 1 to 8, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the alkyl in R8 is C1-6alkyl.

[0018] Clause 10The compound according to any one of clauses 1 to 9, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R3 is chlorine or trifluoroalkyl.

[0019] Clause 11A compound according to clause 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R6 and R7 together with the nitrogen which they are attached to form optionally substituted saturated cyclic amino.

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

[0021] Clause 13The compound according to any of clauses 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the one of R6 and R7 is hydrogen, the other is optionally substituted alkyl, and wherein the optionally substituted alkyl is alkyl substituted by saturated heterocyclic group.

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

[0023] Clause 15The compound according to any of clauses 11 to 14, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R3 is chlorine or trifluoroalkyl.

[0024] Clause 16A compound selected from Examples 1 to 226, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

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

[0026] Clause 18An agent for inhibiting mPGES-1, which comprises the compound according to any of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

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

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

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

[0030] Clause 22An agent for inhibiting the production of PGE2, which comprises the compound according to any of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0031] Clause 23A method for inhibiting the production of PGE2, comprising administering the compound according to any of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject in need thereof.

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

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

[0034] Clause 26A preventive or therapeutic agent for a disease associated with mPGES-1, which comprises the compound according to any of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

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

[0036] Clause 28The compound according to any of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the prevention or treatment of a disease associated with mPGES-1.

[0037] Clause 29Use of the compound according to any of clauses 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 associated with mPGES-1.

[0038] Clause 30A preventive or therapeutic agent for a disease associated with PGE2, comprising the compound according to any of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0039] Clause 31A method for preventing or treating a disease associated with PGE2, comprising administering the compound according to any of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject in need thereof.

[0040] Clause 32The compound according to any of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the prevention or treatment of a disease associated with PGE2.

[0041] Clause 33Use of the compound according to any of clauses 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 associated with PGE2.

[0042] Clause 34A preventive or therapeutic agent for a disease for which analgesic, anti-inflammatory or cell proliferation suppressive effect can be expected to be effective, comprising the compound according to any one of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0043] Clause 35A method for preventing or treating a disease for which analgesic, anti-inflammatory or cell proliferation suppressive effect can be expected to be effective, comprising administering the compound according to any of clauses 1 to 16, or a pharmaceutical acceptable salt thereof, or a solvate thereof to a subject in need thereof.

[0044] Clause 36The compound according to any of clauses 1 to 16, or a pharmaceutical acceptable salt thereof, or a solvate thereof for use in the prevention or treatment of a disease for which analgesic, anti-inflammatory or cell proliferation suppressive effect can be expected to be effective.

[0045] Clause 37Use of the compound according to any of clauses 1 to 16, or a pharmaceutical acceptable salt thereof, or a solvate thereof to a subject in need thereof in the manufacture of a preventive or therapeutic agent for a disease for which analgesic, anti-inflammatory or cell proliferation suppressive effect can be expected to be effective.

[0046] Clause 38A preventive or therapeutic agent for a disease comprising the compound according to any of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the disease is inflammatory bowel disease, irritable bowel syndrome, migraine, headache, lumbago, lumbar spinal stenosis, herniated disc, temporomandibular disorder, cervico-omo-brachial 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 infections, bacterial infections, fungal infections, burn injury, postoperative, post-trauma, and post-tooth extraction inflammation and pain, malignant tumor, atherosclerosis, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, tenosynovitis, ankylosing spondylitis, ligament ossification, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids, prostatitis, or pain in cancer.

[0047] Clause 39A method for preventing or treating inflammatory bowel disease, irritable bowel syndrome, migraine, headache, lumbago, lumbar spinal stenosis, herniated disc, temporomandibular disorder, cervico-omo-brachial 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 infections, bacterial infections, fungal infections, burn injury, postoperative, post-trauma, and post-tooth extraction inflammation and pain, malignant tumor, atherosclerosis, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, tenosynovitis, ankylosing spondylitis, ligament ossification, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids, prostatitis, or pain in cancer, comprising administering the compound according to any of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject in need thereof.

[0048] Clause 40A compound according to any of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof for use in preventing or treating inflammatory bowel disease, irritable bowel syndrome, migraine, headache, lumbago, lumbar spinal stenosis, herniated disc, temporomandibular disorder, cervico-omo-brachial 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 infections, bacterial infections, fungal infections, burn injury, postoperative, post-trauma, and post-tooth extraction inflammation and pain, malignant tumor, atherosclerosis, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, tenosynovitis, ankylosing spondylitis, ligament ossification, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids, prostatitis, or pain in cancer.

[0049] Clause 41Use of the compound according to any of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof for use in the manufacture of a preventive or therapeutic agent for inflammatory bowel disease, irritable bowel syndrome, migraine, headache, lumbago, lumbar spinal stenosis, herniated disc, temporomandibular disorder, cervico-omo-brachial 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 infections, bacterial infections, fungal infections, burn injury, postoperative, post-trauma, and post-tooth extraction inflammation and pain, malignant tumor, atherosclerosis, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, tenosynovitis, ankylosing spondylitis, ligament ossification, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids, prostatitis, depression, neurogenic bladder, nocturnal polyuria, diurnal polyuria, nocturnal enuresis, central diabetes insipidus, nephrogenic diabetes insipidus, urinary incontinence, prostatic hyperplasia, chronic prostatitis, or pain in cancer.

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

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

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

[0053] Clause 45Use of the compound according to any of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof in the manufacture of a preventive or therapeutic agent for ankylosing spondylitis.

[0054] The detailed definitions of the terms used herein are as follows.

[0055] "Halogen" refers to a fluorine, a chlorine, a bromine, or an iodine.

[0056] "Alkyl" refers to, for example, a linear or branched alkyl chain having 1 to 8 carbons (C1-8). Specific examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl and the like. Especially, alkyl having 1 to 6 carbons (C1-6) is preferred.

[0057] Examples of alkyl moiety of "alkylsulfonyl" include the same "alkyl" as described above.

[0058] "Alkoxy" refers to, for example, a linear or branched alkoxy chain having 1 to 8 carbons (C1-8). Specific examples of "alkoxy" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy and the like.

[0059] Examples of alkoxy moiety of "alkoxycarbonyl" include the same "alkoxy" as described above.

[0060] "Aryl" refers to, for example, a mono-, bi-, or tricyclic aromatic hydrocarbon having 6 to 14 carbons (C6-14). Specific examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 10-phenanthryl and the like.

[0061] As an aryl in R2, phenyl is preferred.

[0062] "Heteroaryl" refers to a mono- or bicyclic aromatic heterocyclic group consisting of 5 to 10 ring atoms and having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen in the ring. Specific examples of "heteroaryl" 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-triazol-4-yl), tetrazolyl (e.g., 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, 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 (e.g., 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl).

[0063] As a heteroaryl in R2, isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl) or pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl) is preferred.

[0064] As a heteroaryl in R8, furyl (e.g., 2-furyl, 3-furyl) is preferred.

[0065] "Saturated cyclic amino" refers to, for example, a saturated cyclic amino group consisting of 3 to 8 ring atoms which may optionally have 1 oxygen or sulfur as a ring atom and has one or two nitrogen. Specifics example of "saturated cyclic amino" include 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, piperidino, 1-piperadinyl, 1-tetrahydropyrimidinyl, 4-morpholino, 4-thiomorpholino, and 1-homopiperazinyl.

[0066] "Saturated heterocyclic group" refers to, for example, a saturated heterocyclic group consisting of 3 to 8 ring atoms and having 1 or 2 heteroatoms optionally selected from the group consisting of nitrogen, sulfur and oxygen which may be identical or different. Preferably, it includes a saturated heterocyclic group consisting of 3 to 8 ring atoms and having 1 nitrogen or oxygen. Specific examples of "saturated heterocyclic group" 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). More preferably, the examples include 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-oxetanyl, 3-oxetanyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl.

[0067] "Cycloalkyl" refers to, for example, a mono-, bi- or tricyclic saturated hydrocarbon group having 3 to 10 carbons (C3-10). Especially, a monocyclic saturated hydrocarbon group having 3 to 8 carbons (C3-8), preferably 3 to 6 carbons (C3-6) is preferred. Specific examples of "cycloalkyl" 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 substituents described herein. That is, the present invention encompasses any combination of substituents independently selected from the groups listed for each of R1, R2, R3, R4 and R5 in the general formula [1] and is not limited to the specific combinations as described herein.[EFFECT OF INVENTION]

[0069] The compounds of the present invention exhibit mPGES-1 inhibitory activity and can inhibit production of PGE2, thus, they can be useful for treating and preventing diseases associated with mPGES-1 or production of PGE2.[DESCRIPTION OF EMBODIMENTS]

[0070] The compounds of the present invention can be prepared using known compounds or intermediates that can be easily synthesized, for example, according to the methods described below, the examples described below, or known methods. In the manufacture of the compounds of the present invention, if a material has a substituent that affects the reaction, the reaction is generally carried out after protecting the material with an appropriate protecting group by known methods in advance. The protecting group can be deprotected by known methods after the reaction.Preparing method 1[Chemical Formula 3]wherein, R1,R2,R3,R4,R5 is as defined above. This reaction is condensation of Compound [3] with Compound [4], and can be carried out as condensation reaction, according to a method known as such. By reacting Compound [3] with Compound [4] or a reactive derivative thereof, the compound of the present invention can be synthesized. Examples of a reactive derivative of Compound [4] include those usually used for a reaction for formation of amide condensation, for example, acid halide (e.g., acid chlorides, acid bromides), mixed acid anhydride, imidazolide, active amide, etc. When Compound [4] is used, the reaction can be carried out in range of -20 °C to 100 °C in the presence or absence of a base, using a condensing agent. Examples of condensing agent which can be used in this reaction include, e.g, 1,1’-oxalyl diimidazole, 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"), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate. Examples of base which can be used in this reaction include organic bases such as triethylamine, N,N-diisopropylethylamine (hereinafter, referred to as "DIPEA"), N,N-dimethylaniline, pyridine, 1,8-diazabicyclo[5,4,0]-7-undecene (hereinafter, "DBU"). The solvent which can be used is not limited as long as it is not involved in the reaction. Examples of solvent include ethers such as tetrahydrofuran (hereinafter, referred to as "THF"), 1,4-dioxane, amides such as N,N-dimethylformamide (hereinafter, referred to as "DMF") and N,N-dimethylacetoamide (hereinafter, referred to as "DMA"), nitriles such as acetonitrile and propionitrile, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and dichloromethane or mixture thereof. Also, additives can be used appropriately. Examples of the additives include, for example, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole. As for the amount of condensing agent to be used, for example, 1 to 3 mole ratios per mole of Compound [4] is preferred. The amount of base to be used is, for example, in the range of 1 to 10 equivalents, preferably 1 to 4 equivalents for Compound [4]. While the reaction time varies depending on the type of material and reagent to be used, reaction temperature, etc., the range from 10 minutes to 24 hours is usually suitable.

[0071] Compound [4] can be prepared, for example, according to the method described in references (e.g, WO2011 / 048004).

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

[0073] (I) Method for preparing compound represented by the following general formula [3A] which corresponds to Compound [3] wherein R2 is aryl, heteroaryl, or cycloalkyl (the aryl, heteroaryl, or cycloalkyl is optionally substituted by 1 to 3 groups selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, monohalogenoalkyl, dihalogenoalkyl, trihalogenoalkyl, alkoxy, monohalogenoalkoxy, dihalogenoalkoxy, trihalogenoalkoxy, halogen, cyano and alkylsulfonyl).[Chemical Formula 4]wherein, R1 is as defined above; X1 represents boronic acid group, boronic acid ester group, zinc, or magnesium halide; R2a represents aryl, heteroaryl or cycloalkyl, the aryl, heteroaryl, or cycloalkyl is optionally substituted by 1 to 3 groups selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, monohalogenoalkyl, dihalogenoalkyl, trihalogenoalkyl, alkoxy, monohalogenoalkoxy, dihalogenoalkoxy, trihalogenoalkoxy, halogen, cyano, and alkylsulfonyl; and n represents 1 or 2. [Step 1]This reaction is cross-coupling reaction of Compound [5] with Compound [6] which is commercially available or can be prepared using a known method, and the reaction can be carried out according to a method known as such. For Example, the reaction can be carried out in suitable solvent by reacting Compound [5] with a boron reagent such as a boronic acid, an organometallic reagent such as zinc reagent or Grignard reagent in the presence of a palladium reagent such as tetrakis(triphenylphosphine)palladium (hereinafter, referred to as "Pd(PPh3)4"), cupper reagent such as cupper iodide, zinc reagent, or iron reagent. A ligand such as 1,1’-bis(diphenyllphosphino)ferrocene (hereinafter, referred to as "dppf") or base can be added appropriately. Also, the reaction can be carried out under microwave condition, if necessary. The solvent which can be used is not limited as long as it is not involved in the reaction. Examples of solvent include hydrocarbons such as toluene or xylene, ethers such as 1,4-dioxane or THF, alcohols such as methanol, ethanol or 1-butanol, amides such as DMF, DMA or N-methyl-2-pyrrolidone (hereinafter, referred to as "NMP"), water, or mixture thereof. Examples of base which can be used include, for example, alkaline metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate, alkaline metal hydroxides such as sodium hydroxide, alkaline metal phosphates such as potassium phosphate, organic bases such as triethylamine or DIPEA, or alkaline metal halides such as lithium chloride or cesium fluoride. The amount of base to be used is, for example, in the range of 1 to 10 equivalents, preferably 1 to 4 equivalents for Compound [5]. While the reaction temperature varies depending on the type of material and reagent to be used, it is in the range from 0 to 200 °C, preferably 50 to 160 °C. While the reaction time varies depending on the type of material used, reaction temperature, etc., the range from 10 minutes to 24 hours is usually suitable.

[0074] [Step 2]This reaction is the reduction of aromatic nitro compound to aromatic amine and can be carried out by conventional methods. For example, this reaction can be achieved in suitable solvent under hydrogen atmosphere by subjecting Compound [7] to contact reduction using a catalyst comprising Raney-nickel, palladium, rhodium, platinum, etc.; hydride reduction using lithium aluminum hydride, etc.; iron reduction using a reducing iron reagent and ammonium chloride, etc.; zinc reduction using zinc powder and acetic acid, etc. Other methods include the use of sulfides such as sodium hydrosulfite, or reduction with ammonium formate or hydrazine in the presence of a metal catalyst such as palladium-carbon. While a solvent varies depending on a type of compound or reagent to be used, examples of solvent include, for example, toluene, THF, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, acetone, acetonitrile, DMF, or alcohols such as methanol, ethanol or tert-butanol, and water, which can be used alone or as mixture. While the reaction temperature varies depending on the type of compounds and reagents to be used, it is usually in the range from 0 to 300°C, preferably from 20 to 150°C.

[0075] (II) Method for preparing Compound represented by the following general formula [3B] (Compound 3B) which corresponds to Compound [3] having chlorine as R2[Chemical Formula 5]wherein, R1 is as defined above.

[0076] This reaction is the reduction of aromatic nitro compound to aromatic amine and can be carried out according to the method described in Step 2 of preparation of Compound [3A].

[0077] Compound [5] can be prepared, for example, according to the following method (I) to (III).[Chemical Formula 6]wherein, R1 is as defined above; when R1 is alkoxy, X2 represents sodium or potassium; when R1 is a group represented by the general formula [2], X2 represents hydrogen; when R1 is cycloalkyl or alkyl, X2represents boronic acid group, boronic acid ester group, zinc, magnesium halide; m represents 1 or 2.

[0078] (I) In case R1 is alkoxyThis reaction is a nucleophilic substitution reaction of Compound [8] which is commercially available with Compound [9] which is commercially available or can be prepared using known methods, and the reaction can be carried out according to a method known as such. The reaction is carried out using excess amount of reagent, or in the presence of base with suitable solvent or without solvent. The solvent which can be used is not limited as long as it is not involved in the reaction. Examples of solvent include, for example, ethers such as THF, 1,4-dioxane or 1,2-dimethoxyethane, alcohols such as methanol or ethanol, amides such as DMF or DMA, hydrocarbons such as benzene or toluene, or mixture thereof. Examples of base to be used include, for example, organic bases such as triethylamine, DIPEA, N,N-dimethylaniline, pyridine or DBU, or inorganic bases such as potassium carbonate or sodium carbonate. While the reaction temperature varies depending on the type of compounds and reagents to be used, it is usually in the range from 0 °C to 200 °C. While the reaction time varies depending on the type of material used, reaction temperature, etc., the range from 30 minutes to 24 hours is usually suitable.

[0079] (II) In case R1 is a group represented by the general formula [2]This reaction is nucleophilic substitution reaction of Compound [8] which is commercially available with Compound [9] which is commercially available or can be prepared using known methods, and it can be carried out according to a method known as such. The reaction is carried out using excess amount of reagent, or in the presence of base with suitable solvent or without solvent. The solvent which can be used is not limited as long as it is not involved in the reaction. Examples of solvent include, for example, ethers such as THF, 1,4-dioxane or 1,2-dimethoxyethane, alcohols such as methanol or ethanol, amides such as DMF or DMA, hydrocarbons such as benzene or toluene, or mixture thereof. Also, excess amount of amine used in the reaction can be used as solvent. Examples of base to be used include, for example, organic bases such as triethylamine, DIPEA, N,N-dimethylaniline, pyridine or DBU, or inorganic bases such as potassium carbonate or sodium carbonate. While the reaction temperature varies depending on the type of compounds and reagents to be used, it is usually in the range from 0°C to 200 °C. While the reaction time varies depending on the type of material used, reaction temperature, etc., the range from 30 minutes to 24 hours is usually suitable.

[0080] (III) In case R1 is cycloalkyl or alkylThis reaction is cross-coupling reaction of Compound [8] which is commercially available with Compound [9] which is commercially available or can be prepared using a known method, and the reaction can be carried out according to a method known as such. For Example, the reaction can be carried out in suitable solvent by reacting Compound [8] with a boron reagent such as a boronic acid, an organometallic reagent such as zinc reagent or Grignard reagent in the presence of a palladium reagent such as Pd(PPh3)4, cupper reagent such as cupper iodide, zinc reagent, or iron reagent. A phosphate catalyst such as dppf or base can be added appropriately. Also, the reaction can be carried out under microwave condition, if necessary. The solvent which can be used is not limited as long as it is not involved in the reaction. Examples of solvent include, for example, hydrocarbons such as toluene or xylene, ethers such as 1,4-dioxane or THF, alcohols such as methanol, ethanol or 1-butanol, amides such as DMF, DMA or NMP, water, or mixture thereof. Examples of base which can be used include, for example, alkaline metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate, alkaline metal hydroxides such as sodium hydroxide, alkaline metal phosphates such as potassium phosphate, organic base such as triethylamine or DIPEA, or alkaline metal halides such as lithium chloride or cesium fluoride. As for the amount of base to be used is, for example, in the range of 1 to 10 equivalents, preferably 1 to 4 equivalents for Compound [8]. While the reaction temperature varies depending on the type of material and reagent to be used, it is in the range from 0 °C to 200 °C, preferably 50 °C to 160 °C. While the reaction time varies depending on the type of material and reagent to be used, reaction temperature, etc., the range from 10 minutes to 24 hours is usually suitable.

[0081] Also, Compound [8] can be prepared, for example, according to the method described in references (e.g, J. Chem. Soc., 1948, 1759-1765).

[0082] Preparing method 2[Chemical Formula 7]wherein, R1, R2, R3, R4, R5 is 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 it can be carried out according to the method described in Preparing method 1 above.

[0083] Compound

[10] can be prepared, for example, according to the following method.[Chemical Formula 8]wherein, R1,R2,R3,R4 is as defined above; PG is a protecting group of amino group. [Step 1] This reaction is condensation reaction of Compound [3] with Compound

[12] , and it can be carried out according to the method described in Preparing method 1 above.

[0084] [Step 2]This reaction is a deprotection reaction of a protecting group of amino group in Compound

[13] , and the reaction can be carried out as a deprotection reaction of a protecting group of amino group according to a method known as such. The protecting group which can be used is not limited as long as it is not involved in the reaction. Examples of protecting group include carbamates such as tert-butoxycarbonyl or benzyloxycarbonyl, and a protecting group generally used as a protecting group for amino group which is described in references (e.g, Green's Protective Groups in Organic Synthesis, Fourth Edition, A John Wiley & Sons, Inc., Publication) also can be used. As to conditions for deprotection, deprotection can be carried out under acidic condition such as hydrochronic acid, Lewis acid or trifluoroacetic acid in a suitable solvent. The deprotection can be carried out hydrogenolysis in the presence of catalyst such as palladium.Compound

[12] can be prepared according to methods described in references (e.g, WO2011 / 048004; Tetrahedron Letters, 1993, 34, 6263-6264.).

[0085] Preparing method 3[Chemical Formula 9]wherein, R1, R2, R3, R4, R5 is as defined above; X3 represents halogen. This reaction is cross-coupling reaction of Compound

[14] with Compound

[15] by using palladium or cupper catalyst, and the reaction can be carried out according to a method known as such. The solvent which can be used is not limited as long as it is not involved in the reaction. Examples of solvent include hydrocarbons such as toluene or xylene, ethers such as 1,4-dioxane or THF, amides such as DMF, DMA or NMP, water, or mixture thereof. Also, the reaction can be carried out in range from 20 °C to 200 °C, and it also can be carried out under microwave condition, if necessary. Examples of palladium catalyst to be used include, for example, tris(dibenzilideneacetone)(chloroform)dipalladium(0), dichloro(diphenyllphosphinoferrocene)palladium dichloromethane adduct (hereinafter, "PdCl2(dppf)･CH2Cl2"), or palladium acetate (II). As for the amount of the palladium catalyst is, in the range of 0.001 to 0.3 mol for Compound

[14] per mol. Examples of ligand for palladium catalyst ligand include, for example, dppf, 4,5-bis(diphenyllphosphino)-9,9’-dimethylxanthen, 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl, (±)-2,2’-bis(diphenyllphosphino)-1,1’-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenyllphosphino)phenyl]ether, etc. Also, the cupper catalyst which can be used include, for example, cupper iodide. Examples of base which can be used include, for example, alkaline metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate, alkaline metal hydroxides such as sodium hydroxide, alkaline metal phosphates such as potassium phosphate, organic base such as triethylamine or DIPEA, or alkaline metal halides such as lithium chloride or cesium fluoride. As for the amount of base to be used is, for example, in the range of 1 to 10 equivalents, preferably 1 to 4 equivalents for Compound

[14] . While the reaction time varies depending on the type of material used, reaction temperature, etc., the range from 10 minutes to 24 hours is usually suitable.

[0086] Compound

[15] can be prepared by condensation reaction of Compound [4] with ammonia, according to a method known as such.

[0087] Also, Compound

[14] can be prepared, for example, according to the following method (I) or (II).

[0088] (I) Method for preparing Compound represented by the following general formula [14A] (Compound [14A]) which corresponds to Compound

[14] having chlorine as R2[Chemical Formula 10]wherein, m, R1, X2, X3 is as defined above. This reaction can be carried out according to the method for preparing Compound [5] above.

[0089] (II) Method for preparing Compound [14B] which corresponds to Compound

[14] wherein R2 is aryl, heteroaryl or cycloalkyl (the aryl or heteroaryl is optionally substituted by 1 to 3 groups selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, monohalogenoalkyl, dihalogenoalkyl, trihalogenoalkyl, alkoxy, monohalogenoalkoxy, dihalogenoalkoxy, trihalogenoalkoxy, halogen, cyano and alkylsulfonyl).[Chemical Formula 11]wherein, n, R1, R2a, X1, X3 is as defined above. This reaction is cross-coupling reaction of Compound [14A] with Compound [6] which is commercially available or can be prepared using a known method, and it can be carried out according to the method described in Step 1 of preparation of Compound [3A].

[0090] Compound

[16] can be prepared, for example, according to methods described in references (e.g, J. Med. Chem., 2008, 7855-7865)｡

[0091] While the compounds of the present invention can be used as pharmaceuticals, the compounds can also be used in the form of pharmaceutically acceptable salts by known methods. Examples of such salts include a salt with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and a salt with organic acids such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid and methane sulfonic acid.

[0092] For example, a salt of compound with hydrochloric acid can be obtained by dissolving a compound in alcoholic solution, ethyl acetate solution or diethyl ether solution of hydrogen chloride.

[0093] The compounds of the present invention or pharmaceutically acceptable salts thereof may form a solvate by incorporating solvent molecules when left in air or recrystallized. Such a solvate is within the scope of the salt of the present invention. Examples of solvate include a solvate with molecules of methanol, ethanol, isopropyl alcohol, butanol, dimethyl sulfoxide, acetonitrile, etc., and a hydrate.

[0094] Some of the compounds of the present invention which have an asymmetric carbon includes each optical isomer and mixture of each of optical isomer in the present invention. The optical isomers can be prepared, for example, by means of optical resolution from the racemate thereof according to a known method using an optically active acid (e.g., tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphor sulfonic acid, etc.), utilizing its basicity, or by using an optically active compound prepared in advance as a starting material. In addition, the optical isomers may also be prepared by optical resolution using a chiral column or by asymmetric synthesis.

[0095] The compound of the present invention which can form a tautomer or mixture thereof are also encompassed in the present invention.

[0096] Also, the compound of the present invention or a pharmaceutically acceptable salt thereof has mPGES-1 inhibitory activity, as shown in the test examples below. Further, a compound of the present invention or a pharmaceutically acceptable salt thereof have mPGES-1 inhibitory activity, thus, it has inhibitory effect on production of PGE2, or analgesic or anti-inflammatory effect.

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

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

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

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

[0101] Still furthermore, the compounds of the present invention or a pharmaceutically acceptable salt thereof has mPGES-1 inhibitory activity and inhibits the production of PGE2. Thus, one embodiment of the present invention provides an inhibitor of the production of PGE2, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof.

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

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

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

[0105] A compound of the present invention, or a pharmaceutically acceptable salt thereof has mPGES-1 inhibitory activity and inhibits the production of PGE2, thus, it can be used, for example, for preventing or treating a disease associated with mPGES-1 or PGE2, or a disease for which analgesic or anti-inflammatory effect can be expected to be effective.

[0106] Thus, one embodiment of the present invention provides a preventive or therapeutic agent for a disease involving mPGES-1, comprising the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0107] Further, one embodiment of the present invention provides a method for preventing or treating a disease associated with mPGES-1, comprising administering the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0108] Still furthermore, one embodiment of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in preventing or treating a disease associated with mPGES-1.

[0109] Still 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 preventive or therapeutic agent for a disease associated with mPGES-1.

[0110] Still furthermore, one embodiment of the present invention provides a preventive or therapeutic agent for a disease associated with PGE2, comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0111] Still furthermore, one embodiment of the present invention provides a method for preventing or treating a disease associated with PGE2, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0112] Still furthermore, one embodiment of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease associated with PGE2

[0113] Still 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 preventive or therapeutic agent for a disease associated with PGE2.

[0114] Still furthermore, one embodiment of the present invention provides a preventive or therapeutic agent for a disease, which is expected to be effective due to an analgesic, anti-inflammatory or cell proliferation suppressive effect, comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof.

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

[0116] Still furthermore, one embodiment of the present invention provides a compound of the present invention, or a pharmaceutical acceptable salt thereof, for use in preventing or treating a disease for which analgesic or anti-inflammatory effect can be expected to be effective.

[0117] Still furthermore, one embodiment of the present invention provides use of a compound of the present invention, or a pharmaceutical acceptable salt thereof in the manufacture of a preventive or therapeutic agent for a disease which analgesic, anti-inflammatory or cell proliferation suppressive effect can be expected to be effective.

[0118] Examples of diseases to which the compounds of the present invention or pharmaceutically acceptable salts thereof can be applied include a disease involving mPGES-1, such as inflammatory bowel disease (e.g, see Non-patent Document 11), irritable bowel syndrome, migraine, headache, lumbago, lumbar spinal stenosis, herniated disc, temporomandibular disorder, cervico-omo-brachial syndrome, cervical spondylosis, endometriosis (e.g, see Non-patent Document 12), adenomyosis, premature labor, threatened premature labor, dysmenorrhea, overactive bladder, nocturia (e.g, see Non-patent Document 13), interstitial cystitis, neurodegenerative disease (e.g, see Alzheimer's disease, multiple sclerosis) (e.g, see Non-patent Document 7), psoriasis, rheumatoid arthritis (e.g, see Non-patent Document 5, Non-patent Document 6), rheumatic fever, fibromyalgia, neuralgia (e.g, Non-patent Document 14), complex regional pain syndrome, myofascial disorders, viral infections (e.g, influenza, cold, shingles, AIDS), bacterial infections, fungal infections, burn injury (e.g, see Non-patent Document 15), postoperative, post-trauma, and post-tooth extraction inflammation and pain, malignant tumors (e.g, colon cancer, breast cancer, lung cancer, prostate cancer) (e.g, see Non-patent Document 16, Non-patent Document 17, Non-patent Document 18), atherosclerosis (e.g, Non-patent Document 19), stroke (e.g, see Non-patent Document 20), gout, arthritis, osteoarthritis (e.g, see Non-patent Document 21, Non-patent Document 22), juvenile arthritis, ankylosing spondylitis, tenosynovitis, ligament ossification, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis (e.g, see Non-patent Document 23), conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, osteoporosis, asthma (e.g, see Non-patent Document 24), chronic obstructive pulmonary disease (e.g, see Non-patent Document 25), pulmonary fibrosis (e.g., see Non-patent Document 26), allergic diseases (e.g., see Non-patent Document 24), familial adenomatous polyposis (e.g, see Non-patent Document 17), scleroderma (e.g, see Non-patent Document 27), bursitis, uterine fibroid, prostatitis, or pain in cancer.

[0119] As shown in the test examples below, since the compound of the present invention or a pharmaceutically acceptable salt thereof has suppressive effect on acroarthritis in ankylosing spondylitis, it can be used for preventing or treating ankylosing spondylitis.

[0120] Thus, one embodiment of the present invention provides a preventive or therapeutic agent for ankylosing spondylitis comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.

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

[0122] Further, one embodiment of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in preventing or treating ankylosing spondylitis.

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

[0124] The term "subject" refers to a human or non-human animal that has or is suspected of having a disease involving mPGES-1 or PGE2. In one embodiment of the present invention, the subject is a mammal. In one embodiment of the present invention, the subject is a human.

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

[0126] The carrier may be one or more of pharmaceutically acceptable solid, semi-solid or liquid diluents, fillers, and other auxiliaries for formulations. The pharmaceutical composition according to the present invention is preferably administered in a unit dosage form. The pharmaceutical composition can be administered by tissue administration, oral administration, intravenous administration, local administration (transdermal administration, eye drops, intraperitoneal cavity, intrathoracic cavity, etc.), or transrectally. The composition according to the present invention is administered in dosage forms suitable for these modes of administration.

[0127] The dose as a pharmaceutical is preferably adjusted taking into consideration the conditions such as age, weight, type and severity of disease of the patient, administration route, type of the compound of the present invention, whether or not it is a salt, and the type of the salt. In general, as an active ingredient, the amount of a compound of the present invention or a pharmaceutically acceptable salt thereof for adult, in the case of oral administration, is suitably within a range of 0.01 mg to 5 g / day / adult, preferably 1 mg to 500 mg / day / adult. In some cases, lower amount may be sufficient or higher amount may be required. Usually, the dosage can be administered once a day or can be divided and administered several times a day, or in the case of intravenous administration, the dosage can be administered rapidly or sustainably within 24 hours.[EXAMPLES]

[0128] The present invention is described in more detail with reference to, but is not limited to, the following Examples, Test Examples and Formulation Examples.The measurement conditions for high performance liquid chromatography-mass spectrometry; LCMS are as follows.Instrument: ACUITY UPLC MS / PDA System (Waters)Mass Spectrometer: Waters 3100 MS detectorPhotodiode array detector: ACUITY PDA detector (210 to 400 nm)Column: Acuity BEH C18, 1.7 μm, 2.1 x 50 mmFlow rate: 0.5 mL / minColumn temperature: 40°CSolvent;A: 0.1% formic acid / H2O(v / v; the same applies below)B: 0.1% formic acid / acetonitrile

[0129] Also, the observed value of mass spectrometry [MS(m / z)](MS: mass spectrometry) is expressed in 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)-dioneTo a solution of 2-amino-4-nitrobenzoic acid (5.0g) in dichloromethane (45 mL) was added chlorosulfonyl isocyanate (5.25 mL) dropwise under ice-cooling, then the mixture was stirred at room temperature for overnight. A solution of triethylamine (8.80 mL) in dichloromethane (30 mL) was added dropwise thereto under ice-cooling, then the mixture was stirred at room temperature for overnight. The solvent was removed under reduced pressure, and saturated aqueous solution of sodium bicarbonate (200 mL) was added to the residue and the mixture was stirred, methanol (100 mL) was added thereto, and then the mixture was stirred. The precipitate was filtered and dried to afford 4.42 g of the title compound as pale yellow powder.

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

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

[0133] [Step 4] Preparation of N-methyl-7-nitro-2-[3-(trifluoromethyl)phenyl]quinazolin-4-amineUnder Ar atmosphere, to a suspension of 2-chloro-N-methyl-7-nitroquinazolin-4-amine (0.48g), [3-(trifluoromethyl)phenyl]boronic acid (0.53g), 1-butanol (3.0 mL) and saturated sodium bicarbonate solution (2.0 mL) in toluene (6.0 mL) was added Pd(PPh3)4 (0.17g) at room temperature, and the mixture was stirred for 15 minutes and further stirred for 3 hours at 100 °C. The reaction mixture was cooled to room temperature, filtered through celite, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 0.55 g of the title compound as yellow powder.

[0134] [Step 5] Preparation of N4-methyl-2-[3-(trifluoromethyl)phenyl]quinazoline-4,7-diamineTo a suspension of N-methyl-7-nitro-2-[3-(trifluoromethyl)phenyl]quinazolin-4-amine (0.55g) in THF (8 mL) and methanol (8 mL) were added saturated ammonium chloride solution (4 mL), zinc (1.0g) at room temperature, and the mixture was stirred for 1 hour at 60 °C. The reaction mixture was cooled to room temperature, filtered through celite, then the solvent was removed under reduced pressure. The residue was washed with water, methanol, and then filtered, dried to afford 0.46 g of the title compound as 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 hydrochlorideTo a solution of 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoic acid (prepared according to the method described in WO2011 / 048004) (0.324g) in dichloromethane (5 mL) were added oxalyl chloride (0.22 mL) and DMF (one drop) dropwise at room temperature, and the mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (2 mL) and the solution was slowly added dropwise to N4-methyl-2-[3-(trifluoromethyl)phenyl]quinazoline-4,7-diamine (0.32g), DIPEA (0.21 mL) in THF (10 mL). After the reaction mixture was stirred for 30 minutes under ice-cooling, saturated sodium bicarbonate solution and water were added thereto, and then the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (0.38g) was obtained as yellow powder. This was suspended in THF (10 mL), and 2M hydrogen chloride in methanol (0.37 mL) was added under ice-cooling. After the reaction solution was stirred for 1 hour at room temperature, solvent was removed under reduced pressure and resulting solid was washed with diethyl ether, filtered, and then dried to afford, 0.36g of the title compound as 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}benzamideTo a solution of 2-chloro-5-[(2,2,2-trifluoroacetoamide)methyl]benzoic acid (prepared according to the method described in WO2011 / 048004) (0.19g) in dichloromethane (2 mL) were added oxalyl chloride (0.127 mL) and DMF (one drop) 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). The solution was added to a solution of N4-methyl-2-[3-(trifluoromethyl)phenyl]quinazoline-4,7-diamine (0.16g) and DIPEA (0.104 mL) in THF (2 mL) under ice-cooling. The reaction mixture was stirred for 90 minutes under ice-cooling, and saturated sodium bicarbonate and water were added thereto, then the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 0.27 g of the title compound as 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}benzamideTo a suspension of 2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-5-{[(trifluoroacetyl)amino]methyl}benzamide (prepared according to the method described in Example 2) (0.27g) in methanol(10 mL) and water (2.3 mL) was added potassium carbonate (0.32g) at room temperature, and the mixture was stirred for 3 hours at 60 °C. The reaction mixture was cooled to room temperature and methanol was added thereto, then the mixture was stirred vigorously for 1 hour. The obtained precipitate was filtered and dried to afford 0.20 g of the title compound as pale yellow powder.

[0138] [Step 2] Preparation of 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamideUnder ice-cooling, 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) was added dropwise 2-methoxyacetylchloride (0.007 mL) in THF (0.5 mL). The reaction mixture was stirred for 30 minutes under ice-cooling, and water was poured, the THF was removed under reduced pressure. Methanol / water(1 / 10) was added to the resulting residue and the mixture was stirred vigorously for 1 hour. The obtained precipitate was filtered and dried to afford 15 mg of the title compound as 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}benzamideAccording to the method described in Step 2 of Example 3, using cyclopropylcarbonyl chloride instead of 2-methoxyacetylchloride, the title compound was obtained as white powder.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}benzamideAccording to the method described in Step 2 of Example 3, using cyclopentylcarbonyl chloride instead of 2-methoxyacetylchloride, the title compound was obtained as white powder.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}benzamideAccording to the method described in Step 2 of Example 3,using 3,3-dimethylbutanoylchloride instead of 2-methoxyacetylchloride, the title compound was obtained as white powder.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-carboxamideAccording to the method described in Step 2 of Example 3, using 2-furancarbonyl chloride instead of 2-methoxyacetylchloride, the title compound was obtained as white powder.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}benzamideA 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 (prepared according to the method described in Step 1 of Example 3) (20 mg) and DIPEA (0.010 mL) in THF (1.5 mL) under ice-cooling. After the mixture was stirred for 2 hours at room temperature, cyclopropanesulfonyl chloride (9 mg) in THF (0.5 mL) and DIPEA (0.010 mL) were added thereto. After the reaction was stirred overnight at room temperature, aqueous saturated sodium bicarbonate and water were added, and then the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography and powderized in ethyl acetate / n-hexane (2 / 1), filtered, dried to afford 13 mg of the title compound as 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]benzamideTo a solution of 5-(aminomethyl)-2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (prepared according to the method described in Step 1 of Example 3) (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 overnight at room temperature. Water, 2N aqueous sodium hydroxide and saturated saline were added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was powderized in methanol, filtered, dried to afford 15 mg of the title compound as 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}benzamideAccording to the method described in Example 9, using 3-hydroxy-2,2-dimethylpropanecarboxylic acid instead of cyclopropanecarboxylic acid, the title compound was obtained as white powder.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}benzamideTo a solution of 5-(aminomethyl)-2-chloro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (prepared according to the method described in Step 1 of Example 3) (20 mg), difluoroacetic acid (0.008 mL) and HATU(22 mg) in DMF (0.5 mL) was added DIPEA (0.010 mL), and the mixture was stirred overnight at room temperature. Water, 2N aqueous sodium hydroxide and saturated saline were added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, and powderized in ethyl acetate / n-hexane (2 / 1), filtered, dried to afford 5 mg of the title compound as 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}benzamideAccording to the method described in Example 11, using 3,3,3-trifluoropropanecarboxylic acid instead of difluoroacetic acid, the title compound was obtained as pale yellow powder.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] Preparation of 2-chloro-N4-methyl-quinazoline-4,7-diamineTo a solution of 2-chloro-N-methyl-7-nitroquinazolin-4-amine (prepared according to the method described in Step 3 of Example 1) (0.40g) in THF (15 mL) and methanol (15 mL) was added 1% platinum + 0.1% copper-activated carbon (Degussa type, CF105 R / W) (0.40g), the mixture was stirred for 6 hours at 40 °C under hydrogen atmosphere (0.3 MPa). The reaction solution was filtered through celite, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 0.27 g of title compound as pale yellow powder.

[0149] [Step 2] Preparation of 2-chloro-N-[2-chloro-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamideAccording to the method described in Step 6 of Example 1, using 2-chloro-N4-methyl-quinazoline-4,7-diamine (15 mg) instead of N4-methyl-2-[3-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 15 mg of the title compound was obtained as 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] Preparation of N4-methyl-2-[4-(trifluoromethyl)phenyl]quinazoline-4,7-diamineTo a suspension of 2-chloro-N4-methyl-quinazoline-4,7-diamine (prepared according to the method described in Step 1 of Example 13) (20 mg), [4-(trifluoromethyl)phenyl]boronic acid (25 mg), 1-butanol (0.3 mL) and saturated sodium bicarbonate (0.3 mL) in toluene (0.6 mL), , Pd(PPh3)4 (11 mg) was added under Ar atmosphere at room temperature. The mixture was stirred for 15 minutes at 130 °C in a microwave reactor. The reaction mixture was cooled to room temperature, dried over sodium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 20 mg of the title compound as 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 hydrochlorideTo a solution of 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoic acid (prepared according to the method described in WO2011 / 048004) (18 mg) in dichloromethane (0.3 mL) was added oxalyl chloride (0.012 mL) and DMF (one drop) dropwise at room temperature and the mixture was stirred for 15 minutes. The reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in dichloromethane (0.5 mL), and the solution was slowly added dropwise to a solution of N4-methyl-2-[4-(trifluoromethyl)phenyl]quinazoline-4,7-diamine (18 mg), DIPEA (0.012 mL) in THF (1.0 mL). After the reaction mixture was stirred for 30 minutes under ice cooling, aqueous saturated sodium bicarbonate and water were added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (22 mg) as white powder. MS (ESI+) m / z 570.2 (M+H)+The obtained compound was suspended in ethyl acetate (2 mL), and 2M hydrogen chloride in methanol (0.021 mL) was added thereto. After the reaction solution was stirred for 15 minutes at room temperature, solvent was removed under reduced pressure, and the resulting solid was washed with ethyl acetate, filtered, dried to afford 15 mg of the title compound as white powder.Elemental analysis value as C29H27ClF3N5O2･HCl + 1.0H2OCalculated % C: 55.78 H: 4.84 N: 11.22Measured % 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] Preparation of N4-methyl-2-[6-(trifluoromethyl)pyridin-3-yl]quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 14, using [6-(trifluoromethyl)pyridin-3-yl]boronic acid instead of [4-(trifluoromethyl)phenyl]boronic acid, N4-methyl-2-[6-(trifluoromethyl)pyridin-3-yl]quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 14, using N4-methyl-2-[6-(trifluoromethyl)pyridin-3-yl]quinazoline-4,7-diamine (26 mg) instead of N4-methyl-2-[4-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 14 mg of the title compound was obtained as 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] Preparation of N4-methyl-2-[3-(trifluoromethoxy)phenyl]quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 14, using [3-(trifluoromethoxy)phenyl]boronic acid instead of [4-(trifluoromethyl)phenyl]boronic acid, N4-methyl-2-[3-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 14, using N4-methyl-2-[3-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine (31 mg) instead of N4-methyl-2-[4-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 26 mg of the title compound was obtained as 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] Preparation of 2-(6-methoxypyridin-3-yl)-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 14, using (6-methoxypyridin-3-yl)boronic acid instead of [4-(trifluoromethyl)phenyl]boronic acid, 2-(6-methoxypyridin-3-yl)-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 14, using 2-(6-methoxypyridin-3-yl)-N4-methyl-quinazoline-4,7-diamine (30 mg) instead of N4-methyl-2-[4-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 18 mg of the title compound was obtained as 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] Preparation of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamineTo a suspension of 2-chloro-N4-methyl-quinazoline-4,7-diamine (25 mg), [2-(trifluoromethyl)phenyl]boronic acid (32 mg), 1-butanol (0.3 mL) and saturated sodium bicarbonate(0.3 mL) in toluene (0.6 mL) was added Pd(PPh3)4 (13 mg) at room temperature under Ar atmosphere, and the mixture was stirred for 15 minutes at 150 °C using microwave reactor. After the reaction solution was cooled to room temperature and dried over sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 32 mg of the title compound as 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 hydrochlorideTo a solution of 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoic acid(prepared according to the method described in WO2011 / 048004) (33 mg) in dichloromethane (0.3 mL) were added oxalyl chloride (0.021 mL), DMF (one drop) dropwise at room temperature, and the mixture was stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (0.5 mL), and the solution slowly was added dropwise to a solution of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine (32 mg) and DIPEA (0.021 mL) in THF (1.0 mL) under ice-cooling. After the reaction mixture was stirred for 30 minutes under ice-cooling, aqueous saturated sodium bicarbonate and water were added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[2-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (16 mg) as white powder. The compound was suspended in THF (2 mL), and 2M hydrogen chloride in methanol (0.016 mL) was added dropwise thereto. After the reaction solution stirred for 15 minutes at room temperature, the solvent was removed under reduced pressure. The resulting solid was washed with diethyl ether, filtered, and dried to afford 12 mg of the title compound as 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] Preparation of 2-(2-fluoro-3-methoxyphenyl)-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using (2-fluoro-3-methoxyphenyl)boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-(2-fluoro-3-methoxyphenyl)-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-(2-fluoro-3-methoxyphenyl)-N4-methyl-quinazoline-4,7-diamine (29 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 17 mg of the title compound was obtained as 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] Preparation of 2-(2-fluorophenyl)-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using (2-fluorophenyl)boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-(2-fluorophenyl)-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-(2-fluorophenyl)-N4-methyl-quinazoline-4,7-diamine (18 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 15 mg of the title compound was obtained as 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] Preparation of 2-(4-methoxyphenyl)-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using (4-methoxyphenyl)boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid 2-(4-methoxyphenyl)-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-(4-methoxyphenyl)-N4-methyl-quinazoline-4,7-diamine (20 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 21 mg of the title compound was obtained as 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] Preparation of 2-(2-methoxypyridin-3-yl)-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using (2-methoxypyridin-3-yl)boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-(2-methoxypyridin-3-yl)-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-(2-methoxypyridin-3-yl)-N4-methyl-quinazoline-4,7-diamine (16 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 12 mg of the title compound was obtained as 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] Preparation of N4-methyl-2-(2-methylpyridin-4-yl)quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using (2-methylpyridin-4-yl)boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, N4-methyl-2-(2-methylpyridin-4-yl)quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, 2-(2-methylpyridin-4-yl)-N4-methyl-quinazoline-4,7-diamine (13 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 6 mg of the title compound was obtained as 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] Preparation of 2-(3,4-dimethoxyphenyl)-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using (3,4-dimethoxyphenyl)boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-(3,4-dimethoxyphenyl)-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-(3,4-dimethoxyphenyl)-N4-methyl-quinazoline-4,7-diamine (22 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 14 mg of the title compound was obtained as 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)benzonitrileAccording to the method described in Step 1 of Example 18, using (3-cyanophenyl)boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 3-(7-amino-4-(methylaminoquinazolin-2-yl)benzonitrile was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 3-(7-amino-4-(methylaminoquinazolin-2-yl)benzonitrile (23 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 22 mg of the title compound was obtained as 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] Preparation of 2-(5-methoxypyridin-3-yl)-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using (5-methoxypyridin-3-yl)boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-(5-methoxypyridin-3-yl)-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-(5-methoxypyridin-3-yl)-N4-methyl-quinazoline-4,7-diamine (11 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 9 mg of the title compound was obtained as 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] Preparation of 2-(4-fluorophenyl)-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using (4-fluorophenyl)boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-(4-fluorophenyl)-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-(4-fluorophenyl)-N4-methyl-quinazoline-4,7-diamine (26 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 18 mg of the title compound was obtained as 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)-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using (4-chlorophenyl)boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-(4-chlorophenyl)-N4-methyl-quinazoline-4,7-diamine was obtained as white powder.

[0179] [Step 2] 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-(4-chlorophenyl)-N4-methyl-quinazoline-4,7-diamine (22 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 11 mg of the title compound was obtained as 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] Preparation of 2-(2-methoxypyridin-4-yl)-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using (2-methoxypyridin-4-yl)boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-(2-methoxypyridin-4-yl)-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-(2-methoxypyridin-4-yl)-N4-methyl-quinazoline-4,7-diamine (20 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 14 mg of the title compound was obtained as 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] Preparation of N4-methyl-2-[4-(trifluoromethoxy)phenyl]quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using [4-(trifluoromethoxy)phenyl]boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, N4-methyl-2-[4-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine was obtained as 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}benzamideTo a stirred mixture of N4-methyl-2-[4-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine (11.34g), 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoic acid (11.89g), N-ethyldiisopropylamine (11.74 mL) and NMP(68 mL) was added HATU(19.35g), and the mixture was stirred at 60 °C. After 16 hours, the reaction solution was cooled to room temperature, water and aqueous saturated sodium bicarbonate were added, and then the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, saturated saline in this order, dried over anhydrous sodium sulfate, and then concentrated. The residual solid was washed with ethyl acetate, and dried to afford 18.4 g of the title compound as 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 hydrochlorideTo a suspension of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide (7.50g) in THF (64 mL)was added 2N hydrochlonic acid (7.04 mL), and the mixture was stirred for 3 hours at room temperature. The precipitated solid was filtered and dried to afford 7.66 g of the title compound as white powder.Elemental analysis value as C29H27ClF3N5O3･HCl + 1.0H2OCalculated % C:54.38 H:4.72 N:10.94Measured % 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] Preparation of 2-(3,4-dichlorophenyl)-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using (3,4-dichlorophenyl)boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-(3,4-dichlorophenyl)-N4-methyl-quinazoline-4,7-diamine was obtained as 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}-benzamideAccording to the method described in Step 2 of Example 18, using 2-(3,4-dichlorophenyl)-N4-methyl-quinazoline-4,7-diamine (24 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 11 mg of the title compound was obtained as 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] Preparation of 2-[4-(tert-butyl)phenyl]-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using [4-(tert-butyl)phenyl]boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-[4-(tert-butyl)phenyl]-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-[4-(tert-butyl)phenyl]-N4-methyl-quinazoline-4,7-diamine (25 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 12 mg of the title compound was obtained as 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] Preparation of N4-methyl-2-[2-(trifluoromethoxy)phenyl]quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using [2-(trifluoromethoxy)phenyl]boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, N4-methyl-2-[2-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using N4-methyl-2-[2-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine (31 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 15 mg of the title compound was obtained as 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] Preparation of 2-[2,4-bis(trifluoromethyl)phenyl]-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using [2,4-bis(trifluoromethyl)phenyl]boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-[2,4-bis(trifluoromethyl)phenyl]-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-[2,4-bis(trifluoromethyl)phenyl]-N4-methyl-quinazoline-4,7-diamine (24 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 27 mg of the title compound was obtained as 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] Preparation of 2-[2-fluoro-4-(trifluoromethyl)phenyl]-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using [2-fluoro-4-(trifluoromethyl)phenyl]boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-[2-fluoro-4-(trifluoromethyl)phenyl]-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-[2-fluoro-4-(trifluoromethyl)phenyl]-N4-methyl-quinazoline-4,7-diamine (30 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 35 mg of the title compound was obtained as 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] Preparation of N4-methyl-2-[4-(methylsulfonyl)phenyl]quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using [4-(methylsulfonyl)phenyl]boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, N4-methyl-2-[4-(methylsulfonyl)phenyl]quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-[4-(methylsulfonyl)phenyl]-N4-methyl-quinazoline-4,7-diamine (13 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 14 mg of the title compound was obtained as 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] Preparation of 2-(3,5-dimethyl-1,2-oxazol-4-yl)-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using (3,5-dimethyl-1,2-oxazol-4-yl)boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-(3,5-dimethyl-1,2-oxazol-4-yl)-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-(3,5-dimethyl-1,2-oxazol-4-yl)-N4-methyl-quinazoline-4,7-diamine (12 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 10 mg of the title compound was obtained as 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] Preparation of 2-[3-(methoxymethyl)phenyl]-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using [3-(methoxymethyl)phenyl]boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-[3-(methoxymethyl)phenyl]-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-[3-(methoxymethyl)phenyl]-N4-methyl-quinazoline-4,7-diamine (19 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 21 mg of the title compound was obtained as 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] Preparation of 2-[4-(methoxymethyl)phenyl]-N4-methyl-quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using [4-(methoxymethyl)phenyl]boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, 2-[4-(methoxymethyl)phenyl]-N4-methyl-quinazoline-4,7-diamine was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-[4-(methoxymethyl)phenyl]-N4-methyl-quinazoline-4,7-diamine (17 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 17 mg of the title compound was obtained as 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-trifluorophenyl)quinazolin-7-yl}benzamide hydrochloride[Step 1] Preparation of N4-methyl-2-(3,4,5-trifluorophenyl)quinazoline-4,7-diamineAccording to the method described in Step 1 of Example 18, using (3,4,5-trifluorophenyl)boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, N4-methyl-2-(3,4,5-trifluorophenyl)quinazoline-4,7-diamine was obtained as white powder.

[0204] [Step 2] Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-(3,4,5-trifluorophenyl)quinazolin-7-yl}benzamide hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-(3,4,5-trifluorophenyl)-N4-methyl-quinazoline-4,7-diamine (25 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 26 mg of the title compound was obtained as 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}methanolAccording to the method described in Step 1 of Example 18, using [4-(hydroxymethyl)phenyl]boronic acid instead of [2-(trifluoromethyl)phenyl]boronic acid, {4-[7-amino-4-(methylamino)quinazolin-2-yl]phenyl}methanol was obtained as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using {4-[7-amino-4-(methylamino)quinazolin-2-yl]phenyl}methanol (17 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 16 mg of the title compound was obtained as 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] Preparation of 2-cyclopentyl-N4-methyl-quinazoline-4,7-diamineUnder Ar atmosphere, to a suspension of 2-chloro-N4-methyl-quinazoline-4,7-diamine (prepared according to the method described in Step 1 of Example 13) (42 mg), PdCl2(dppf)･CH2Cl2(16 mg) and cupper iodide (6 mg)in DMA(1.5 mL) was added, 0.5M bromo(cyclopentyl)zinc in THF (0.64 mL) at room temperature, and the mixture was stirred for 2 hours at 90 °C. The reaction solution was cooled to room temperature, filtered through celite, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 47 mg of the title compound as 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 hydrochlorideAccording to the method described in Step 2 of Example 18, using 2-cyclopentyl-N4-methyl-quinazoline-4,7-diamine (21 mg) instead of N4-methyl-2-[2-(trifluoromethyl)phenyl]quinazoline-4,7-diamine, 26 mg of the title compound was obtained as 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-nitroquinazolineTo a suspension of 2,4-dichloro-7-nitroquinazoline (prepared according to the method described in Step 2 of Example 1) (900 mg) in THF (13 mL) were added DIPEA (2.55 mL) and azetidine hydrochloride (0.69g) under ice-cooling, and the mixture was stirred for 2 hours at room temperature. DIPEA (2.55 mL) and azetidine hydrochloride (0.69g) were further added thereto, and the mixture was stirred for 2 hours at room temperature. To the reaction solution was added aqueous saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 452 mg of the title compound was obtained as yellow powder.

[0210] [Step 2] Preparation of 4-(azetidin-1-yl)-7-nitro-2-[3-(trifluoromethyl)phenyl]quinazolineTo 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 aqueous saturated sodium bicarbonate (1.5 mL) in toluene (3.0 mL) was added Pd(PPh3)4 (87 mg) at room temperature under Ar atmosphere, and the mixture was stirred for 15 minutes, and further stirred for 3 hours at 100 °C. The reaction mixture was cooled to room temperature, aqueous saturated sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound 138mg was obtained as yellow powder.

[0211] [Step 3] Preparation of 4-(azetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazoline-7-amineTo 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 for 4 hours at room temperature under hydrogen atmosphere (0.3MPa). The reaction solution was filtered through celite, then solvent was removed under reduced pressure to afford 214 mg of the title compound as grey 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 hydrochlorideTo a solution of 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoic acid(prepared according to the method described in WO2011 / 048004) (218 mg) in dichloromethane (8.0 mL) were added oxalyl chloride (0.137 mL) and DMF (0.0062 mL) dropwise at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (8.0 mL), and the solution was slowly added dropwise to a solution of 4-(azetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazoline-7-amine (214 mg) and DIPEA (0.32 mL) in THF (12 mL) under ice-cooling. After the reaction mixture was cooled for 1 hour under ice-cooling, aqueous saturated sodium bicarbonate and water were added, and then the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford N-{4-(azetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide (322 mg) was obtained as yellow powder. The compound was suspended in methanol (5 mL), and 2M hydrogen chloride in methanol (0.28 mL) was added dropwise thereto. After the reaction solution was stirred for 1 hour at room temperature, solvent was removed under reduced pressure. The residue was powderized in chloroform / n-hexane, filtered, and dried to afford 298 mg of the title compound as 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 hydrochlorideAccording to the method described in Example 43, using 50% aqueous dimethylamine instead of azetidine hydrochloride, the title compound was obtained as pale yellow powder.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 hydrochlorideAccording to the method described in Example 43, using pyrrolidine instead of azetidine hydrochloride, the title compound was obtained as white powder.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 hydrochlorideAccording to the method described in Example 43, using 2-methoxyethylamine instead of azetidine hydrochloride, the title compound was obtained as white powder.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 hydrochlorideAccording to the method described in Example 43, using 70% aqueous ethylamine instead of azetidine hydrochloride, the title compound was obtained as white powder.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 hydrochlorideAccording to the method described in Example 43, using isopropylamine instead of azetidine hydrochloride, the title compound was obtained as white powder.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 hydrochlorideAccording to the method described in Example 43, using morpholine instead of azetidine hydrochloride, the title compound was obtained as pale yellow powder.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 hydrochlorideAccording to the method described in Example 43, using 25% aqueous ammonia instead of azetidine hydrochloride, the title compound was obtained as white powder.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}azetidin-1-carboxylateAccording to the method described in Example 43 (except the process to prepare hydrochloride in Step 4), using tert-butyl 3-(aminomethyl)azetidin-1-carboxylate instead of azetidine hydrochloride, the title compound was obtained as white powder.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 dihydrochlorideTo a suspension of tert-butyl 3-{[(7-{[(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]quinazolin-4-yl)amino]methyl}azetidin-1-carboxylate (according to the method described in Example 51) (43 mg) in dichloromethane (2.4 mL) was added thioanisole (0.06 mL) and trifluoroacetic acid (0.6 mL) dropwise under ice-cooling. After the reaction mixture was stirred for 2 hours at room temperature, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate / THF (1 / 1). The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford N-{4-[(azetidin-3-ylmethyl)amino]-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}-2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide (19 mg) was obtained as white solid. The solid was dissolved in methanol (1 mL), and 2M hydrogen chloride in methanol (0.031 mL) was added dropwise. After the reaction solution was stirred for 1 hour at room temperature, it was powderized in methanol / diethyl ether, filtered and dried to afford 19mg of the title compound as 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-olTo a solution of 3-hydroxyazetidine hydrochloride (89 mg) in THF (4.0 mL) was added DIPEA (0.28 mL) and 2,4-dichloro-7-nitroquinazoline (prepared according to the method described in Step 2 of Example 1) (100 mg) under ice-cooling, and the mixture was stirred for 1 hour at room temperature. 3-hydroxyazetidine hydrochloride (178 mg) and DIPEA (0.28 mL)were added thereto and the mixture was further stirred for 1 hour at room temperature. Aqueous saturated sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 53mg of the title compound as yellow powder.

[0223] [Step 2] Preparation of 1-{7-nitro-2-[3-(trifluoromethyl)phenyl]quinazolin-4-yl}azetidin-3-olTo 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), saturated sodium bicarbonate(0.7 mL) in toluene (1.5 mL)was added Pd(PPh3)4(21 mg) at room temperature under Ar atmosphere, and the mixture was stirred for 15 minutes and further stirred for 3 hours at 80 °C. The reaction mixture was cooled to room temperature, water was added thereto, ant the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 53mg of the title compound as yellow powder.

[0224] [Step 3] Preparation of 4-(3-methoxyazetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazoline-7-amineTo 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. After the reaction mixture was stirred for 15 minutes under ice-cooling, methyl iodide (0.0055 mL) was added dropwise. The reaction solution was stirred for 1 hour at room temperature, aqueous saturated aqueous ammonium chloride was added thereto, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The resulting residue was dissolved in methanol (5 mL) and THF (5 mL), 5% palladium / carbon (20 mg) was added thereto, and the mixture was stirred for 4 hours at room temperature under hydrogen atmosphere(0.3 MPa). The reaction solution was filtered through celite, then solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 7.3mg of the title compound as obtained as 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 hydrochlorideAccording to the method described in Step 4 of Example 43, using 4-(3-methoxyazetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazoline-7-amine (7.3 mg) instead of 4-(azetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazoline-7-amine, 8.6mg of the title compound was obtained as 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]quinazolineTo a solution of 1-{7-nitro-2-[3-(trifluoromethyl)phenyl]quinazolin-4-yl}azetidin-3-ol(prepared according to the method described in Step 2 of Example 53) (27 mg) in DMF (3.0 mL) were added imidazole (14 mg) and tert-butyldimethylsilylchloride (15 mg) under ice-cooling, and the mixture was stirred for 2 hours at room temperature. Additional imidazole (14 mg) and tert-butyldimethylsilyl chloride (15 mg) were added, and the mixture was stirred overnight at room temperature. To the reaction solution was added water, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 24mg of the title compound as 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}benzamideAccording to the method described in Steps 3 and 4 of Example 43, using 4-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-7-nitro-2-[3-(trifluoromethyl)phenyl]quinazoline instead of 4-(azetidin-1-yl)-7-nitro-2-[3-(trifluoromethyl)phenyl]quinazoline, the title compound was obtained as 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 hydrochlorideTo 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 1M tetrabutylammonium fluoride in THF (0.042 mL) dropwise, and the mixture was stirred for 1 hour at room temperature. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(3-hydroxyazetidin-1-yl)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide (16 mg). The compound was dissolved in methanol (0.5 mL), and 2M hydrogen chloride in methanol (0.015 mL) was added dropwise thereto. After the reaction solution was stirred for 0.5 hour at room temperature. the solvent was removed under reduced pressure, powderized in methanol / diethyl ether, filtered, dried to afford 8.4mg of the title compound as white powder.MS (ESI+) m / z 612.3 (M+H)+

[0229] Example 55: Preparation of 2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-(4-{[(1-methylazetidin-3-yl)methyl]amino}-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl)benzamide dihydrochlorideAccording to the method described in Example 43, using (1-methylazetidin-3-yl)-methanamine instead of azetidine hydrochloride, the title compound was obtained as white powder.MS (ESI+) m / z 639.4 (M+H)+

[0230] Example 56: Preparation of 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-nitroquinazolineTo a suspension of 2,4-dichloro-7-nitroquinazoline (prepared according to the method described in Step 2 of Example 1) (50 mg) in methanol (2.0 mL) added sodium methoxide (33 mg), and the mixture was stirred for 2 hours at room temperature. To the reaction solution was added saturated aqueous ammonium chloride, the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 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 hydrochlorideAccording to the method described in Steps 2, 3 and 4 of Example 43, using 2-chloro-4-methoxy-7-nitroquinazoline instead of 4-(azetidin-1-yl)-2-chloro-7-nitroquinazoline, the title compound was obtained as pale yellow powder.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-nitroquinazolineTo a suspension of 2,4-dichloro-7-nitroquinazoline (prepared according to the method described in Step 2 of Example 1) (100 mg) in ethanol (4.0 mL) was added sodium ethoxide (139 mg), and the mixture was stirred for 3 hours at room temperature. To the reaction solution was added saturated aqueous ammonium chloride, the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 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 hydrochlorideAccording to the method described in Steps 2, 3 and 4 of Example 43, using 2-chloro-4-ethoxy-7-nitroquinazoline instead of 4-(azetidin-1-yl)-2-chloro-7-nitroquinazoline, the title compound was obtained as pale yellow powder.MS (ESI+) m / z 585.3 (M+H)+

[0234] Example 58: Preparation of 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-nitroquinazolineTo a suspension of2,4-dichloro-7-nitroquinazoline (prepared according to the method described in Step 2 of Example 1) (200 mg), cyclopropylboronic acid (85 mg), potassium phosphate (434 mg) in THF (8.0 mL) was added PdCl2(dppf)･CH2Cl2 (66 mg) at room temperature under Ar atmosphere, and the mixture was stirred for 15 minutes and further stirred 1 hour at 90 °C. The reaction mixture was cooled to room temperature, purified by silica gel column chromatography to afford 100 mg of the title compound as pale yellow powder.

[0235] [Step 2] Preparation of 2-chloro-4-cyclopropylquinazoline-7-amineTo a solution of 2-chloro-4-cyclopropyl-7-nitroquinazoline (95 mg) in THF (10 mL) and methanol (15 mL) was added 1% platinum + 0.1% cupper-activated carbon (Degussa type CF105 R / W) (50 mg), and the mixture was stirred under hydrogen atmosphere (0.3 MPa) for 6 hours at room temperature. The reaction solution was filtered through celite, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 57 mg of the title compound as 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 hydrochlorideAccording to the method described in Example 14, using 2-chloro-4-cyclopropylquinazoline-7-amine instead of 2-chloro-N4-methyl-quinazoline-4,7-diamine the title compound was obtained as pale-yellow powder.

[0237] Example 59: Preparation of 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-nitroquinazolineUnder Ar atmosphere, to a suspension of 2,4-dichloro-7-nitroquinazoline (prepared according to the method describe in Step 2 of Example 1) (200 mg), methylboronic acid (49 mg) and potassium phosphate (434 mg) in THF (2.0 mL) was added PdCl2(dppf)･CH2Cl2(66 mg) at room temperature, and the mixture was stirred for 15 minutes and further stirred for 1 hour at 90 °C. After the reaction solution was cooled to room temperature, it was purified by silica gel column chromatography, and 21 mg of the title compound was obtained as 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 hydrochlorideAccording to the method described in Steps 2, 3 and 4 of Example 43, using 2-chloro-4-methyl-7-nitroquinazoline instead of 4-(azetidin-1-yl)-2-chloro-7-nitroquinazoline, the title compound was obtained as pale yellow powder.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-(cyclopropanecarboxamidemethyl)-2,6-difluorobenzoic acidCyclopropanecarboxamide (8.50g) was suspended in 37% aqueous formaldehyde (8.92g), and , potassium carbonate (1.38g) was added thereto at room temperature, and then the mixture was stirred at 40 °C for 1 hour. The reaction solution was concentrated under the reduced pressure at the extent not to precipitate potassium carbonate. Ethyl acetate was added to the solution and the resulting precipitate was filtered and dried to afford N-(hydroxymethyl)cyclopropanecarboxamide (8.40g) as white solid. To a mixture of N-(hydroxymethyl)cyclopropanecarboxamide (2.76g) and 2,6-difluorobenzoic acid (1.72g) was added sulfuric acid (15 mL) and the mixture was stirred for 20 hours at 60 °C. To the reaction mixture was added water (80 mL) under ice-cooling, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 0.80 g of the title compound as yellow powder.

[0240] [Step 2] Preparation of 3-{[(cyclopropanecarbonyl)amino]methyl}-2,6-difluoro-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamideTo a solution of N4-methyl-2-[3-(trifluoromethyl)phenyl]quinazoline-4,7-diamine (prepared according to the method described in Step 5 of Example 1) (28 mg), 3-(cyclopropanecarboxamidemethyl)-2,6-difluorobenzoic acid (45 mg) and HATU (67 mg) in DMF (1.5 mL) was added DIPEA (0.030 mL), and the mixture was stirred for 2 days at 50 °C. 3-(Cyclopropanecarboxamidemethyl)-2,6-difluorobenzoic acid (45 mg), HATU(67 mg), DIPEA (0.030 mL) were further added thereto, and the mixture was stirred for 3 days at 50 °C. To the reaction solution were added water, 2N aqueous sodium hydroxide, saturated saline, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, then the solvent was removed under reduced pressure. After the residue was powderized in ethyl acetate / n-hexane (2 / 1), the powder was filtered, dried to afford 10 mg of the title compound as 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 hydrochlorideAccording to the method described in Steps 2, 3 and 4 of Example 43, using [4-(trifluoromethyl)phenyl]boronic acid instead of [3-(trifluoromethyl)phenyl]boronic acid, the title compound was obtained as white powder.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 hydrochlorideAccording to the method described in Example 14, using 2-chloro-4-cyclopropylquinazoline-7-amine (prepared according to the method described in Step 2 of Example 58) instead of 2-chloro-N4-methyl-quinazoline-4,7-diamine, the title compound was obtained as 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)benzamideTo a stirred mixture of N4-methyl-2-[4-(trifluoromethoxy)phenyl]quinazoline-4,7-diamine (5.0g), 5-[(2,2-dimethylpropanoylamino)methyl]-2-(trifluoromethyl)benzoic acid (5.9g), N-ethyldiisopropylamine (5.2 mL) and NMP (30 mL) was added HATU (8.53g), and the mixture was stirred at 70 °C. After 16 hours, the reaction solution was cooled to room temperature. To the solution were added water and saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, saturated saline in this order, dried over anhydrous sodium sulfate, and then concentrated. The residual solid was washed with ethyl acetate, and dried to afford 6.72 g of the title compound as 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}benzamideAccording to the method described in Steps 1 and 2 of Example 14, 22 mg of the title compound was obtained as 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}benzamideAccording to the method described in Steps 1 and 2 of Example 30, 18.4 g of the title compound was obtained as 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 hydrochlorideAccording to the method described in Step 1 of Example 63, 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide was obtained. to a suspension of 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide (6.72g) in THF (36 mL) was added 2N hydrochronic acid (5.97 mL), and the mixture was stirred at room temperature. After 5 hours, the precipitate was filtered, washed with ethyl acetate, and dried to afford 6.07g of the title compound was obtained as white solid.Elemental analysis value as C30H27F6N5O3･HCl + 1.0H2OCalculated % C:53.46 H:4.49 N:10.39Measured % 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 methanesulfonateN,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 (20.00g) ,which was obtained according to the method described in Example 65, and the mixture was stirred at room temperature to make solution. Methane sulfonic acid (2.33 mL) was added followed by ethyl acetate (400.00 mL) dropwise, the mixture was stirred overnight at room temperature. The precipitated white solid was filtered, washed with ethyl acetate (40.00 mL) and dried to afford 20.04g of the title compound as white solid.Elemental analysis value as C29H27ClF3N5O3･MeSO3H + 0.5H2OCalculated % C:52.14 H:4.67 N:10.13Measured % C:52.28 H:4.49 N:10.10

[0248] The compounds described in the following Examples 68 to 149 were prepared by reacting and treating the corresponding starting compounds in the same manner as in Example 1 (except the conversion to hydrochloride salt 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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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]benzamideMS (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]benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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]benzamideMS (ESI+) m / z 545 (M+H)+

[0260] Example 79: 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamideMS (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]benzamideMS (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]benzamideMS (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]benzamideMS (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]benzamideMS (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]benzamideMS (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]benzamideMS (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}benzamideMS (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)benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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]benzamideMS (ESI+) m / z 553 (M+H)+

[0274] Example 93: 2-chloro-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(methoxyacetyl)amino]methyl}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (ESI+) m / z 591 (M+H)+

[0283] Example 102: 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamideMS (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)benzamideMS (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)benzamideMS (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)benzamideMS (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)benzamideMS (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}benzamideMS (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}benzamideMS (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]benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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)benzamideMS (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]benzamideMS (ESI+) m / z 534 (M+H)+

[0297] Example 116: 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamideMS (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]benzamideMS (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)benzamideMS (ESI+) m / z 520 (M+H)+

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

[0301] Example 120: 2-chloro-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamideMS (ESI+) m / z 536 (M+H)+

[0302] Example 121: 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamideMS (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)benzamideMS (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}benzamideMS (ESI+) m / z 550 (M+H)+

[0305] Example 124: 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(cyclopentylcarbonyl)amino]methyl}benzamideMS (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]benzamideMS (ESI+) m / z 588 (M+H)+

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

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

[0309] Example 128: 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamideMS (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]benzamideMS (ESI+) m / z 554 (M+H)+

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

[0312] Example 131: 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamideMS (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]benzamideMS (ESI+) m / z 518 (M+H)+

[0314] Example 133: 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]benzamideMS (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]benzamideMS (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}benzamideMS (ESI+) m / z 550 (M+H)+

[0317] Example 136: 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(cyclopentylcarbonyl)amino]methyl}benzamideMS (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]benzamideMS (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)benzamideMS (ESI+) m / z 536 (M+H)+

[0320] Example 139: 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(methoxyacetyl)amino]methyl}benzamideMS (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}benzamideMS (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)benzamideMS (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]benzamideMS (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]benzamideMS (ESI+) m / z 568 (M+H)+

[0325] Example 144: 2-chloro-5-{[(methoxyacetyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamideMS (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]benzamideMS (ESI+) m / z 532 (M+H)+

[0327] Example 146: 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamideMS (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]benzamideMS (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]benzamideMS (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]benzamideMS (ESI+) m / z 521 (M+H)+

[0331] The compounds described in the following Examples 150 to 226 were prepared by reacting and treating the corresponding starting compounds in the same manner as in Example 43 (except the conversion to hydrochloride salt 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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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]benzamideMS (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]benzamideMS (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]benzamideMS (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]benzamideMS (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]benzamideMS (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)benzamideMS (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)benzamideMS (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)benzamideMS (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)benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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)benzamideMS (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)benzamideMS (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)benzamideMS (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)benzamideMS (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)benzamideMS (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}benzamideMS (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}benzamideMS (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]benzamideMS (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)benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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)benzamideMS (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}benzamideMS (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}benzamideMS (ESI+) m / z 558 (M+H)+

[0384] Example 202: N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamideMS (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)benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (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)benzamideMS (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}benzamideMS (ESI+) m / z 542 (M+H)+

[0391] Example 209: N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamideMS (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]benzamideMS (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)benzamideMS (ESI+) m / z 528 (M+H)+

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

[0395] Example 213: N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamideMS (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}benzamideMS (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}benzamideMS (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]benzamideMS (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)benzamideMS (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}benzamideMS (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}benzamideMS (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)benzamideMS (ESI+) m / z 596 (M+H)+

[0403] Example 221: N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamideMS (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}benzamideMS (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]benzamideMS (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}benzamideMS (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}benzamideMS (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}benzamideMS (ESI+) m / z 573 (M+H)+

[0409] Also, the following compounds 1 to 74 are prepared according to any of 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}benzamide2. 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide3. 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)--N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide4. 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide5. 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide6. 2-chloro-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide7. 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide8. 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide9. 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}benzamide10. 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide11. 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}benzamide12. 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(6-methoxypyridin-4-yl)-4-(methylamino)quinazolin-7-yl]benzamide13. 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(4-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide14. 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-(trifluoromethyl)benzamide15. N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide16. N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide17. N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide18. N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide19. N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide20. N-{4-(azetidin-1-yl)-2-[3-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide21. N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide22. N-{4-(azetidin-1-yl)-2-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide23. N-{4-(azetidin-1-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide24. N-[4-(azetidin-1-yl)-2-(6-methoxypyridin-4-yl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide25. N-[4-(azetidin-1-yl)-2-(4-fluorophenyl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide26. N-{4-(azetidin-1-yl)-2-[4-(trifluoromethoxy)phenyl]quinazolin-7-yl}-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide27. 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-{4-(methylamino)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide28. 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(2-fluorophenyl)-4-(methylamino)quinazolin-7-yl]benzamide29. 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide30. 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(methoxyacetyl)amino]methyl}benzamide31. 2-chloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide32. 2,6-dichloro-N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide33. N-[2-(4-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide34. 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-phenylquinazolin-7-yl]-2-(trifluoromethyl)benzamide35. 2-chloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide36. 2,6-dichloro-N-[2-(2-chlorophenyl)-4-(methylamino)quinazolin-7-yl]-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide37. 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide38. 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide39. 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]benzamide40. 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[4-(methylamino)-2-(2-methylphenyl)quinazolin-7-yl]-2-(trifluoromethyl)benzamide41. 2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide42. 2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide43. 2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide44. 2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}-N-[2-((5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide45. 2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]benzamide46. 5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-[2-(5-methoxypyridin-3-yl)-4-(methylamino)quinazolin-7-yl]-2-(trifluoromethyl)benzamide47. N-{4-(azetidin-1-yl)-2-[4-(trifluoromethyl)phenyl]quinazolin-7-yl}-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide48. N-[4-(azetidin-1-yl)-2-(2-fluorophenyl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide49. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3,3-dimethylbutanoyl)amino]methyl}benzamide50. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide51. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide52. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide53. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide54. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide55. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide56. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide57. N-[4-(azetidin-1-yl)-2-(4-chlorophenyl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide58. N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide59. N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide60. N-[4-(azetidin-1-yl)-2-phenylquinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide61. N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide62. N-[4-(azetidin-1-yl)-2-(2-chlorophenyl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide63. N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide64. N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide65. N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide66. N-[4-(azetidin-1-yl)-2-(2-methylphenyl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}-2-(trifluoromethyl)benzamide67. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-{[(cyclopentylcarbonyl)amino]methyl}benzamide68. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-[({[1-(trifluoromethyl)cyclopropyl]carbonyl}amino)methyl]benzamide69. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-({[(1-hydroxycyclopropyl)carbonyl]amino}methyl)benzamide70. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-{[(methoxyacetyl)amino]methyl}benzamide71. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-{[(3-hydroxy-2,2-dimethylpropanoyl)amino]methyl}benzamide72. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2-chloro-5-{[(cyclopropylsulfonyl)amino]methyl}benzamide73. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-2,6-dichloro-3-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide74. N-[4-(azetidin-1-yl)-2-(5-methoxypyridin-3-yl)quinazolin-7-yl]-5-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide

[0410] The chemical formulas of the compounds of Examples 1 to 226 are shown in Tables 1 to 11.[Table 1]ExampleFormulaExampleFormulaExampleFormula181529163101741118512196132071421 [Table 2]ExampleFormulaExampleFormulaExampleFormula222936233037243138253239263340273441283542 [Table 3]ExampleFormulaExampleFormulaExampleFormula435057445158455259465360475461485562495663 [Table 4]ExampleFormulaExampleFormulaExampleFormula647178657279667380677481687582697683707784 [Table 5]ExampleFormulaExampleFormulaExampleFormula859299869310087941018895102899610390971049198105 [Table 6]ExampleFormulaExampleFormulaExampleFormula106113120107114121108115122109116123110117124111118125112119126 [Table 7]ExampleFormulaExampleFormulaExampleFormula127134141128135142129136143130137144131138145132139146133140147 [Table 8]ExampleFormulaExampleFormulaExampleFormula148155162149156163150157164151158165152159166153160167154161168 [Table 9]ExampleFormulaExampleFormulaExampleFormula169176183170177184171178185172179186173180187174181188175182189 [Table 10]ExampleFormulaExampleFormulaExampleFormula190197204191198205192199206193200207194201208195202209196203210 [Table 11]ExampleFormulaExampleFormulaExampleFormula211218225212219226213220  214221  215222  216223  217224   

[0411] Test Example 1: Inhibitory activity for mPGES-1A microsome preparation of mPGES-1 was prepared from CHO-K1 cells transiently transfected with a plasmid encoding human mPGES-1cDNA. The microsome preparation was diluted with potassium phosphate buffer (pH 7.4) containing reduced glutathione. The test compound in DMSO or DMSO alone was added so that the final concentration of DMSO was 1%, followed by incubation at 4 ℃ for 20 minutes. Then, the enzymatic reaction was initiated by the addition of a solution of PGH2 substrate at a final concentration of 1 μM and incubated for 60 seconds at 4 ℃. The reaction was terminated by the addition of ferric chloride and a solution of citrate to a final concentration of 5 mg / mL and 250mM, respectively. The formed PGE2 was quantified using a HTRF kit (Cisbio International product catalog #62P2APEC). A solution without test compound was used as a positive control, and a solution without 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. Then, IC50 value was measured by calculating the ratio of PGE2 production inhibition at the final concentration of 10nM of the test compound, or using standard methods.

[0412] Test Example 2: Test for inhibition of PGE2 and PGF2α production using A549 cells100 μL of RPMI medium containing 10% FBS and human A549 cells was seeded in a 96-well plate at 2 × 104 human A549 cells per well and incubated overnight. The medium was removed and washed with phosphate-buffered saline, and then the test compound in DMSO or RPMI medium containing 3% FBS and DMSO was added so that the final concentration of DMSO was 0.1%. After incubation for 60 minutes, IL-1β (5 ng / well) was added to each well. After incubation for 24 h at 37℃, PGE2 in the medium was quantified using an HTRF kit (Cisbio International Products Product Catalog #62P2APEC) and PGF2α was quantified using an EIA kit (Cayman Chemical Company Product Catalog #516011). A solution without test compound was used as a positive control, and a solution without test compound and IL-1β was used as a negative control. 100% activity was defined as the PGE2 and PGE2α production in the positive control minus the PGE2 and PGE2α production in the negative control. Then, IC50 value was measured by using standard methods. The results of Test Examples 1 and 2 are shown in Tables 12 to 14 (In tables, "-" indicates not implemented).

[0413] [Table 12]ExampleInhibitory effect on mPGES-1IC50(nM)Inhibition of production of PGE2 in A549 cellsIC50(nM)ExampleInhibitory effect on mPGES-1IC50(nM)Inhibition of production of PGE2 in A549 cellsIC50(nM)11.01.51341.71.625.5-359.41.0310.447.73631.642.240.710.4378.612157.69.2382.42.969.415.3392.81.4739.335.2409.51.8810.352.04123.110190.51.4420.816.0103.281.4433.12.71127.3101442.531.8122.326.4453.64.5136.56100469.85.3146.41.2470.82.31513.0483.92.21611.2491.78.6174.15.15016.86.2181.816.6511.01.8197.512.95222.1114200.15.2530.71.1210.72.2546.09.92210.13525598.698.5233.835.4562.89.62446.819.05754.02.52546.610.8581.02.42612.245.35928.87.0270.53.7603.912.5281.42.36178.60.42915.92.8622.21.2301.01.0639.92.3314.01.064--324.61.765--3310.349.4661.10.9   67-- 

[0414] [Table 13]ExampleInhibition of mPGES-1(%)Inhibition of production of PGE2 in A549 cellsIC50(nM)10nM72576.273717.374832.375842.3766119.480931.682683.9956818.899834.31018645.8106911.0109710.9112511.5113802.5114771.51167627.3117779.9118561030124522.9126568.5128882.51308516.71338362.41368824.0137779.9139540.314055269143793.51455226714662298148718.3151565.4156843.3 

[0415] [Table 14]ExampleInhibition of mPGES-1(%)Inhibition of production of PGE2 in A549 cellsIC50(nM)10nM162862.0168867.31726017.1178703.31806283.1181800.3183512.31855144.21866629.4188540.9190599.7191742.1192713.0193852.8194701.5195796.8196725.7197831.9198822.92016527.42086327.3209839.9210841.92118233.72136017.62165811.9 

[0416] Test Example 3: in vivo spondylarthritis model in mouseThe inflammatory agent zymosan was dissolved in sterile saline and administered intraperitoneally to SKG / Jcl mice under SPF conditions. The Dosage was 3 mg zymosan / 500 μL per mouse.One week after administration of zymosan, the mice were evaluated for acroarthritis and assigned to each group based on acroarthritis clinical score and body weight.The assigned individuals began receiving oral administration of vehicle or compound (twice a day) for 42 consecutive days.The day on which the allocation was performed was designated as day 0, and thereafter, the clinical scores for acroarthritis were measured every 7 days (at 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 values were used.The clinical score of acroarthritis for each individual was calculated by scoring the swelling of each interphalangeal joint of the front (hind) limbs and the carpal (foot) joints for each limb, and adding up the scores for all limbs (normal score 0 to maximum score 5.8: The first toe of the forelimb is excluded from the subject of evaluation. Table 15).

[0417] Test Example 4: in vivo spondylarthritis model in mouseThe inflammatory agent zymosan was dissolved in sterile saline and administered intraperitoneally to SKG / Jcl mice under SPF conditionsThe Dosage was 3 mg zymosan / 500 μL per mouse.Two weeks after administration of zymosan, the mice were evaluated for acroarthritis once a week, and mice with 0.5 or higher acroarthritis clinical score were assigned to the treatment group.The assigned individuals began receiving oral administration of vehicle or compound (twice a day) for 28 or 42 consecutive days.The day on which the onset of the symptom was confirmed was designated as day 0, and thereafter, the clinical scores for acroarthritis were measured every 7 days (in cases of daily administration for 28 days, the acroarthritis clinical score was measured on days 7, 14, 21, and 28, and in cases of daily administration for 42 days, the acroarthritis clinical score was 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 values were used.The clinical score of acroarthritis for each individual was calculated by scoring the swelling of each interphalangeal joint of the front (hind) limbs and the carpal (foot) joints for each limb, and adding up the scores for all limbs (normal score 0 to maximum score 5.8: The first toe of the forelimb is excluded from the subject of evaluation. Table 15).[Table 15]JointScore and corresponding findingsInterphalangeal joints of fore (hind) limbsScore 0：No abnormalityScore 0.1：Redness and swelling of one interphalangeal jointMaximum Score: Interphalangeal joint scores of the front (hind) limbs (front limbs: 2 limbs, 4 joints for each, and hind limbs: 2 limbs, 5 joints for each) are summed up (up to 1.8).WristScore 0：No abnormalityScore 0.5：No constriction at the wrist jointScore 1：More convex compared to score 0.5Maximum Score: 1 / 1 wrist joint, up to 2（2 limbs in total）AnkleScore 0：No abnormalityScore 0.5：The Achilles tendon insertion is at an obtuse angle and no depression around the Achilles tendon is found.Score 1：More convex compared to score 0.5Maximum Score: 1 / 1 ankle joint, up to 2（2 limbs in total） 

[0418] As described in Test Examples 1 and 2, a compound of the present invention or a pharmaceutically acceptable salt thereof exhibits high inhibitory activity for mPGES-1, and inhibits the production of PGE2. Also, a compound of the present invention or a pharmaceutically acceptable salt thereof exhibits suppressive effect on the progress of acroarthritis in in vivo mouse spondylarthritis model in Test Examples 3 and 4.

[0419] Formulation Example 1Tablet (Oral drug)in one tablet (80 mg);Compound of Example 15.0mgCorn starch46.6mgCrystalline cellulose24.0 mgMethyl cellulose4.0 mgMagnesium stearate0.4 mgThe mixed powder in the above ratio is compressed into tablets by the known method to make oral tablets.

[0420] [Other Example]Evaluation ItemsIn Test Examples 3 and 4, the clinical score of acroarthritis was measured. However, the examples are not limited thereto. For example, histological scores may be measured as described in the literature (ARTHRITIS & RHEUMATOLOGY, Vol. 67, No. 4, April 2015, pp 893-902). For example, the test tissues of the left and right forelimbs, left and right hindlimbs, fingers of left and right hindlimbs, vertebrae and tail of a mouse are excised, fixed in 10% neutral buffered formalin fixative, decalcified in 10% EDTA decalcifying solution, embedded in paraffin and sectioned. The samples are then stained with hematoxylin and eosin. Note that the animal species for which the histological score is measured is not limited to mice, and the test tissues are not limited to the left and right forelimbs, left and right hindlimbs, fingers of left and right hindlimbs, vertebrae and tail, and can be selected arbitrarily. Furthermore, the concentration of the fixative can be adjusted as appropriate as long as it can fix the test tissue, and the concentration of the decalcifying solution can be adjusted as appropriate as long as it can decalcify the test tissue.

[0421] Histological evaluation of periarticular inflammation, cartilage necrosis, bone erosion and necrosis, and inflammation / pannus in the joint cavity can be performed, for example, by 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). Tables 16 to 19 show examples of the scoring system, but the present invention is not limited thereto and can be modified as appropriate.[Table 16]ScorePeriarticular Inflammation0No1Minimal infiltration of inflammatory cells in the synovium and periarticular tissues of affected joints.2Mild infiltration which is limited to affected joints in the forelimbs.3Moderate infiltration with moderate edema except in the spine. In the forelimbs, it is limited to the invasion at affected joints.4Infiltration with edema in almost all area5Severe diffuse infiltration [Table 17]ScoreCartilage necrosis0No1Minimal to mild loss of toluidine blue staining, and no evident loss of chondrocyte or collagen destruction in the affected joints.2Mild loss of toluidine blue staining with local mild (superficial) loss of chondrocyte and / or collagen destruction in affected joints.3Multifocal moderate loss of chondrocyte (deep to middle part) and / or moderate loss of toluidine blue staining with collagen destruction in affected joints.4Marked loss of toluidine blue staining with marked loss of multifocal chondrocyte and / or collagen destruction in most joints.5Severe diffuse loss of toluidine blue staining with multifocal severe loss of chondrocyte and / or collagen destruction in all joints. [Table 18]ScoreBone Erosion and Necrosis0No1Small areas of marginal zone / periosteal resorption2Many areas of marginal zone / periosteal resorption, which are easily visible at low magnification, and mild overall cortical and medullary bone resorption.3Marked resorption of medullary cancellous and cortical bone and some medullary cancellous bone loss without full-thickness cortical defect, whose lesions are visible at low magnification.4Defect of whole layer in cortical bone, often with distortion of the contours of the remaining cortical surface, and significant loss of medullary bone.5Defect of whole layer in cortical bone and destruction of all articular structures [Table 19]ScoreInflammation / Pannus in the Joint Cavity0No1Mild infiltration of panniculus into the marginal cartilage and subchondral bone.2Mild destruction of cortical and medullary bone in the affected joints and mild invasion of the marginal zone.3Moderate infiltration with moderate hard tissue destruction in the affected joint.4Marked infiltration affecting most joints with extensive destruction of joint structures.5Severe infiltration with total or near total destruction of articular structures, affecting all joints. 

[0422] Histological evaluation of periosteal reaction (osteogenesis) and inflammation of Achilles tendon (attachment) can be performed, for example, by 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 the scoring system, but the present invention is not limited thereto and can be modified as appropriate.[Table 20]ScorePeriosteal reaction (Osteogenesis)0AbsencepPresence [Table 21]ScorePeriosteal reaction (Osteogenesis)0No1Minimal2Mild3Moderate4Marked5Severe diffuse 

[0423] Histological evaluation of intervertebral disc disorder and excessive tissue formation can be performed, for example, by 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 the scoring system, but the present invention is not limited to thereto and can be modified as appropriate. [Table 22]ScoreIntervertebral Disc Disorder0No150% or less250% or more3Overall destruction of intervertebral disc / Necrotic intervertebral disc only [Table 23]ScoreExcessive Tissue Formation0No1Infiltration and / or expansion of mesenchymal cells2Moderate formation of fibrocartilage (less than 50% relative to the original area of intervertebral disc)3Wide formation of fibrocartilage (50% or more relative to the original area of intervertebral disc) 

[0424] In addition, X-ray photography can be used as another method for evaluation. For example, in X-ray photography of bones and joints, narrowing and fusion of the joint space due to loss of articular cartilage, dislocation, fracture, osteoporosis, and bony ankylosis may be observed and scored as evaluation items. In addition, X-ray photography can be performed using an X-ray apparatus, an X-ray CT apparatus, a PET-CT apparatus, etc.

[0425] Profiles of CompoundsRegarding the profiles of the compounds described in the Examples, but not limited to, mPGES-1 inhibitory activity and PGE2 production inhibitory activity were measured. For example, in addition to measuring mPGES-1 inhibitory activity and PGE2 production inhibitory activity, a compound may be profiled by measuring the half-life and the like. For example, the half-life can be measured by the following method. Each administration solution (each of which contains a test compound) is administered at 1 mg / mL / kg to male rats under fasting conditions via the jugular vein or tail vein. Their blood is collected at the point of 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and (24) hours after administration. The collected blood is immediately centrifuged, and the plasma drug concentration of the supernatant is measured by LC-MS / MS. The dosage and timing of blood collection can be modified as appropriate.[Industrial Applicability]

[0426] Since a compound of the present invention or a pharmaceutically acceptable salt thereof has inhibitory activity for mPGES-1, it would be useful as preventive or therapeutic agent for, inflammatory bowel disease, irritable bowel syndrome, migraine, headache, lumbago, lumbar spinal stenosis, herniated disc, temporomandibular disorder, cervico-omo-brachial syndrome, cervical spondylosis, endometriosis, adenomyosis, premature labor, threatened premature labor, dysmenorrhea, overactive bladder, nocturia, interstitial cystitis, neurodegenerative disease(e.g, Alzheimer's disease, multiple sclerosis), psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, neuralgia,, complex regional pain syndrome, myofascial disorders, viral infections (e.g, influenza, cold, shingles, AIDS), bacterial infections, fungal infections, burn injury, postoperative, post-trauma, and post-tooth extraction inflammation and pain, malignant tumor (e.g, colon cancer, breast cancer, lung cancer, prostate cancer, etc.), atherosclerosis, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ligament ossification, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroid, prostatitis, or pain in cancer. 

Claims

1. A compound represented by the general formula [1]:[Chemical Formula 1]wherein,R1 is alkoxy, cycloalkyl, alkyl or a group represented by the general formula [2]:[Chemical Formula 2]wherein,R6 and R7 are each independently hydrogen or optionally substituted alkyl; orR6 and R7 together with the nitrogen which they are attached to form optionally substituted saturated cyclic amino;R2 is aryl, heteroaryl , halogen or cycloalkyl, wherein each of the aryl, heteroaryl and cycloalkyl in R2 is optionally substituted by 1 to 3 groups independently selected from the group consisting of:(1) alkoxy optionally substituted by 1 to 3 halogens,(2) cyano,(3) halogen,(4) alkyl optionally substituted by (i) 1 to 3 halogens, (ii) hydroxy or (iii) alkoxy, and(5) alkylsulfonyl;R3 is halogen, or alkyl optionally substituted by 1 to 3 halogens;R4 is hydrogen or halogen;R5 is -SO2R8 or -COR8, wherein the R8 is alkyl, cycloalkyl or heteroaryl;the alkyl in R8 is optionally substituted by 1 to 3 groups independently selected from hydroxy, alkoxy and halogen; andthe cycloalkyl in R8 is optionally substituted by:(1) hydroxy, or(2) alkyl optionally substituted by 1 to 3 halogens,or a pharmaceutically acceptable salt thereof, or a solvate thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof,wherein:R6 and R7 are each independently hydrogen or optionally substituted alkyl; orR6 and R7 together with the nitrogen which they are attached to form optionally substituted saturated cyclic amino;R2 is aryl, heteroaryl or cycloalkyl, wherein each of the aryl, heteroaryl and cycloalkyl in R2 is optionally substituted by 1 to 3 groups independently selected from the group consisting of:(1) alkoxy optionally substituted by 1 to 3 halogens,(2) cyano,(3) halogen,(4) alkyl optionally substituted by (i) 1 to 3 halogens, (ii) hydroxy or (iii) alkoxy, and(5) alkylsulfonyl;R3 is halogen or alkyl optionally substituted by 1 to 3 halogens;R4 is hydrogen or halogen;R5 is -SO2R8 or -COR8;R8 is alkyl or cycloalkyl,the alkyl in R8 is optionally substituted by 1 to 3 groups independently selected from the group consisting of hydroxy, alkoxy and halogen; andthe cycloalkyl in R8 is optionally substituted by:(1) hydroxy or(2) alkyl optionally substituted by 1 to 3 halogens.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof,wherein:R6 and R7 are each independently, hydrogen or optionally substituted alkyl;R2 is aryl, heteroaryl or cycloalkyl, wherein each of the aryl, heteroaryl and cycloalkyl in R2 is optionally substituted by 1 to 3 groups independently selected from the group consisting of:(1) alkoxy optionally substituted by 1 to 3 halogens,(2) cyano,(3) halogen,(4) alkyl optionally substituted by (i) 1 to 3 halogens, (ii) hydroxy or (iii) alkoxy; and(5) alkylsulfonyl;R3 is halogen or alkyl optionally substituted by 1 to 3 halogens;R4 is hydrogen or halogen;R5 is -SO2R8 or -COR8;R8 is alkyl or cycloalkyl,the alkyl in R8 is optionally substituted by 1 to 3 groups independently selected from the group consisting of hydroxy, alkoxy and halogen; andthe cycloalkyl in R8 is optionally substituted by:(1) hydroxy or(2) alkyl optionally substituted by 1 to 3 halogens.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof,wherein:R6 and R7 are each independently, hydrogen or optionally substituted alkyl;R2 is aryl, heteroaryl or cycloalkyl, the aryl in R2 is phenyl which is optionally substituted by 1 to 3 groups independently selected from the group consisting of:(1) alkoxy optionally substituted by 1 to 3 halogens,(2) cyano,(3) fluorine or chlorine,(4) alkyl optionally substituted by 1 to 3 halogens, and(5) methylsulfonyl;the heteroaryl in R2is pyridyl or isoxazolyl, each of which is optionally substituted by 1 to 3 groups independently selected from the group consisting of:(1) alkyl optionally substituted by 1 to 3 halogens, and (2) alkoxy optionally substituted by 1 to 3 halogens;the cycloalkyl in R2is C3-6cycloalkyl;R3 is halogen or alkyl optionally substituted by 1 to 3 halogens;R4 is hydrogen or halogen;R5 is -SO2R8 or -COR8;R8 is alkyl or cycloalkyl the alkyl in R8 is C1-6alkyl; andthe cycloalkyl in R8 is C3-6cycloalkyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof,wherein:R6 and R7 are each independently, hydrogen or optionally substituted alkyl;R2 is aryl or heteroaryl, the aryl in R2 is phenyl which is optionally substituted by 1 to 3 groups independently selected from the group consisting of:(1) alkoxy optionally substituted by 1 to 3 halogens,(2) cyano,(3) fluorine or chlorine, (4) alkyl optionally substituted by 1 to 3 halogens, and (5) methylsulfonyl;the heteroaryl in R2 is pyridyl or isoxazolyl, each of which is optionally substituted by 1 to 3 groups independently selected from the group consisting of;(1) alkyl optionally substituted by 1 to 3 halogens, and(2) alkoxy optionally substituted by 1 to 3 halogens;R3 is halogen or alkyl optionally substituted by 1 to 3 halogens;R4 is hydrogen;R5 is -COR8;R8 is alkyl or cycloalkyl;the alkyl in R8 is C1-6alkyl; andthe cycloalkyl in R8 is C3-6cycloalkyl.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein at least one of R6 and R7 is hydrogen.

7. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the one of R6 and R7 is hydrogen, and the other is optionally substituted alkyl.

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, or a solvate thereof, whereinthe aryl in R2 is phenyl optionally substituted by 1 to 3 groups independently selected from the group consisting of:(1) alkoxy optionally substituted by 1 to 3 halogens, and(2) alkyl optionally substituted by 1 to 3 halogens.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the alkyl in R8 is C1-6alkyl.

10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R3 is chlorine or trifluoroalkyl.

11. A compound selected from 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) 2-chloro-5-{[(cyclopropylcarbonyl)amino]methyl}-N-{4-(methylamino)-2-[3-(trifluoromethyl)phenyl]quinazolin-7-yl}benzamide,(5) 2-chloro-5-{[(cyclopentylcarbonyl)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-trifluorophenyl)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}azetidin-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 methane sulfonate,(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,(151) 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, and(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 1-11, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

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

14. An agent for inhibiting the production of PGE2, comprising the compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

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

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

17. A preventive or therapeutic agent for a disease, comprising the compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the disease is inflammatory bowel disease, irritable bowel syndrome, migraine, headache, lumbago, lumbar spinal stenosis, herniated disc, temporomandibular disorder, cervico-omo-brachial 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 disorders, viral infections, bacterial infections, fungal infections, burn injury, postoperative, post-trauma, and post-tooth extraction inflammation and pain, malignant tumors, atherosclerosis, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ligament ossification, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroid, prostatitis, or pain in cancer. 

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