Novel quinazoline derivatives and pharmaceutical composition comprising same

Abstract

The present invention relates to a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof. The compound according to the present invention can be effectively used for preventing or treating cancer or tumors. [Chemical formula 1] In chemical formula 1, R1 to R3, A, L and a are as defined in the specification.

Description

Novel quinazoline derivatives and pharmaceutical compositions containing the same

[0001] The present invention relates to a novel quinazoline derivative useful as an HSP47 inhibitor and a pharmaceutical composition comprising the same.

[0002]

[0003] Heat shock protein 47 (HSP47) is a molecule that plays a crucial role in the assembly and secretion of extracellular matrix proteins. This protein is primarily required to ensure proper folding and stability of collagen, and because of this function, HSP47 plays a crucial role in tissue repair and fibrosis.

[0004]

[0005] HSP47 plays a key role in the synthesis of collagen types I, II, III, IV, and V within living cells, and in particular, synthesizes and secretes collagen types I and II, which are highly associated with fibrotic diseases. This protein is localized to the lumen of the endoplasmic reticulum, where it binds to collagen and acts as a molecular chaperone involved in the maturation of collagen molecules. HSP47 is essential for the proper folding of procollagen. It is known to affect various collagen-mediated fibrotic diseases, and plays a major role in the aggravation of diseases mediated by collagen and fibroblasts, such as the liver, lungs, kidneys, and heart, as well as all organs where fibrosis occurs, and the metastasis of cancer.

[0006]

[0007] High expression of HSP47 protein has been confirmed in tissues from patients with various fibrotic diseases, including IPF, liver fibrosis, and keloids. This elevated expression exacerbates excessive collagen deposition in the extracellular matrix of tissues. Animal studies of various fibrotic diseases have demonstrated the association of HSP47 with fibrotic diseases through inhibition, confirming its potential as a therapeutic agent. These results confirm that downregulation and inhibition of HSP47 function attenuate the progression of fibrosis.

[0008]

[0009] In particular, HSP47 has been identified as a key player in the development of fibrotic diseases through Epithelial-Mesenchymal Transition (EMT) and Fibroblast-Mesenchymal Transition (FMT), which are crucial factors in the fibrotic process. EMT refers to the differentiation of epithelial cells into mesenchymal cells, and this process is important in various biological processes such as development, wound healing, tissue remodeling, and cancer metastasis. During EMT, cells lose the expression of epithelial markers (such as E-cadherin) and increase the expression of mesenchymal markers (such as N-cadherin and vimentin), ultimately producing extracellular matrix such as collagen. FMT is a process in which fibroblasts acquire the characteristics of mesenchymal cells, undergoing changes similar to EMT and ultimately producing extracellular matrix such as collagen. This collagen production in turn influences the amplification of upstream signals that induce fibrotic diseases, such as TGF-β, causing fibrosis in surrounding normal cells and acting as a positive feedback loop that further aggravates fibrosis.

[0010]

[0011] Furthermore, through its regulation of collagen and the extracellular matrix, HSP47 can influence cell motility and invasiveness. In various cancer studies, HSP47 has been frequently linked to tumor invasiveness and metastasis. These processes are interconnected and have profound effects on cell behavior and tissue dynamics. HSP47 is a key research topic not only in fibrotic diseases, but also in EMT and FMT, particularly in cancer research, tissue engineering, and regenerative medicine.

[0012]

[0013] Therefore, there is a need for the development of sustained small molecule inhibitors of HSP47 for the treatment of fibrotic diseases.

[0014]

[0015] Accordingly, the present inventors studied a pharmaceutical agent that could be useful in the treatment of fibrotic diseases and confirmed that the compound according to the present invention, described below, inhibits collagen synthesis through inhibition of HSP47 and suppresses fibrosis induced by representative lung fibroblasts and hepatic stellate cells. Through this, the present inventors confirmed that the HSP47 inhibitor according to the present invention can play a key role in the treatment of fibrotic diseases, thereby completing the present invention.

[0016]

[0017] The present invention provides a novel structural compound that can be usefully used in the treatment or prevention of fibrotic diseases, cancer or metabolic diseases.

[0018]

[0019] In addition, the present invention provides a pharmaceutical composition for preventing or treating fibrotic diseases, cancer or metabolic diseases, comprising the compound.

[0020]

[0021] To solve the above problem, the present invention provides a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof:

[0022] [Chemical Formula 1]

[0023]

[0024] In the above chemical formula 1,

[0025] R1 is each independently hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, or C 1-4 It is haloalkoxy,

[0026] a is an integer from 0 to 4,

[0027] If a is 2 or more, two or more R1s are identical or different,

[0028] A is a five-membered heteroaromatic ring containing one or two heteroatoms of N, O and S,

[0029] R2 is C 1-10 Alkyl, C 3-10 Cycloalkyl, C 6-12 Aryl, or C containing one or more heteroatoms of N, O and S 2-10 It is heteroaryl,

[0030] Here, R2 is unsubstituted or substituted with deuterium, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituted with one or more substituents selected from the group consisting of haloalkoxy,

[0031] L is a single bond, -N(R a )-C(R b )(R c )-, -N(R a )-C(R b )(R c )-OL a -, or -N(R a )-C(Rb )(R c )-N(R d )-L b -and,

[0032] L a and L b are each independently C 1-4 Alkylene, or C 1-4 It is haloalkylene,

[0033] R a Inland R d are each independently hydrogen, C 1-4 Alkyl, or C 1-4 Haloalkyl,

[0034] R b is R a or combines with R to form a double bond, or c It can combine with to form oxo(=O),

[0035] R3 is N(R4)(R5),

[0036] R4 and R5 are each independently hydrogen, C 1-10 Alkyl, or C 1-10 haloalkyl, or N atom, R4 and R5 are combined with each other to form a 5-membered or 6-membered heterocycloalkane ring containing at least one heteroatom of N, O and S,

[0037] Here, R3 is substituted or unsubstituted with one or more R,

[0038] However, when there are two or more Rs, the two or more Rs may be the same or different, but the two Rs may combine with each other to form oxo (=O).

[0039] R is -L c -L d -R' and

[0040] L c is a single bond, C 1-4 Alkylene, or C 1-4 It is haloalkylene,

[0041] L dis a single bond, -CO-, -COO-, -SO-, -SO2-, -CON(R e )-, -N(R f )-, or -N(R g )COO-and,

[0042] R e Inland R g are each independently hydrogen, C 1-4 Alkyl, or C 1-4 It is haloalkyl,

[0043] R' is hydrogen, halogen, cyano, hydroxy, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-10 Cycloalkyl, or tetrahydrofuranyl,

[0044] However, R2 is C 1-10 Alkyl or C 6-12 In the case of aryl, R3 is a 5- or 6-membered heterocycloalkane ring formed by the N atom, R4, and R5 bonding together.

[0045]

[0046] Preferably, each R1 can independently be hydrogen, chloro, fluoro, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, or ethoxy.

[0047] More preferably, each R1 can independently be hydrogen or methoxy.

[0048]

[0049] In the above chemical formula 1, a represents the number of substituents R1 and may be an integer from 0 to 4. Specifically, a may be 0, 1, or 2.

[0050]

[0051] Preferably, can be represented by any one of the following chemical formulas a1 to a3:

[0052] .

[0053]

[0054] Preferably, A may be a 5-membered heteroaromatic ring containing one or two heteroatoms of N and S. Specifically, A may be a 5-membered heteroaromatic ring containing one N, two N, one S, two S, or one N and one S each.

[0055] More preferably, A may be a pyrazole, thiazole, or thiophene ring.

[0056]

[0057] Preferably, the above chemical formula 1 can be represented by any one of the following chemical formulas 1-1 to 1-4:

[0058] [Chemical Formula 1-1]

[0059]

[0060] [Chemical Formula 1-2]

[0061]

[0062] [Chemical Formula 1-3]

[0063]

[0064] [Chemical Formula 1-4]

[0065]

[0066] In the above chemical formulas 1-1 to 1-4,

[0067] R1, a, R2, L and R3 are as defined above.

[0068]

[0069] Preferably, R2 is C 1-5 Alkyl, C 3-6 Cycloalkyl, C 6-12 Aryl, or C containing one or more heteroatoms of N, O and S 2-10It may be heteroaryl. Also, here, R2 is unsubstituted, or halogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 It may be substituted with one or more substituents selected from the group consisting of alkoxy.

[0070]

[0071] More preferably, R2 is methyl, ethyl, propyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridinyl,

[0072] The above R2 may be unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy and ethoxy.

[0073]

[0074] Preferably, L can be a single bond, -N=CH-, -N(CH3)-CO-, -N(CH3)-CO-NH-(CH2CH2)-, or -N(CH3)-CO-O-(CH2CH2)-.

[0075]

[0076] Also, R3 is N(R4)(R5),

[0077] R4 and R5 are each independently hydrogen, C 1-4 Alkyl, or C 1-4 It may be haloalkyl, or the N atom, R4 and R5 may be combined with each other to form a 5-membered or 6-membered heterocycloalkane ring containing at least one heteroatom selected from N, O and S.

[0078]

[0079] In addition, the above R3 is substituted or unsubstituted with one or more R, and when there are two or more R, the two or more R are the same or different from each other, and the two R can combine with each other to form oxo (=O).

[0080]

[0081] Also, the above R is -L c -L d -R'.

[0082] Here, L c can be a single bond, -CH2-, or -CH2-CH2-.

[0083] Also, L d is a single bond, -CO-, -COO-, -SO-, -SO2-, -CON(R e )-, -N(R f )-, or -N(R g )COO-and,

[0084] R e Inland R g may each independently be hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0085] Additionally, R' can be hydrogen, fluoro, chloro, cyano, hydroxy, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or tetrahydrofuranyl.

[0086]

[0087] Preferably, R4 and R5 are each independently hydrogen, or C 1-4 Alkyl, and the above C 1-4 Each alkyl may be independently unsubstituted or substituted with one or two substituents selected from the group consisting of fluoro, -N(CH3)2 and tetrahydrofuranyl.

[0088]

[0089] Preferably, R3 is a pyrrolidine, pyrrolidine-2-one, piperidine, piperazine, or morpholine ring formed by combining N atom, R4, and R5 with each other,

[0090] The above ring may be unsubstituted or substituted with one or two substituents selected from the group consisting of -CH2-NH2, -CH2-N(CH3)2, -CH2-NH-COO-(tert-butyl), -CO-CH3, -CO-NH2, -CO-NH(CH3), -CO-N(CH3)2, -SO-CH3, -SO2-CH3, -N(CH3)2, fluoro, chloro, cyano, hydroxy, methyl, ethyl and cyclopropyl.

[0091]

[0092] Preferably, R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl,

[0093] wherein R2 is unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy and ethoxy,

[0094] R3 is N(R4)(R5),

[0095] R4 and R5 are each independently hydrogen, methyl, ethyl, propyl, isopropyl, and wherein R4 and R5 are unsubstituted or substituted with one or two substituents selected from the group consisting of fluoro, -N(CH3)2, and tetrahydrofuranyl; or

[0096] N atom, R4 and R5 are bonded to each other to form a pyrrolidine, piperidine, piperazine or morpholine ring, which ring may be unsubstituted or substituted with one or two substituents selected from the group consisting of -CH2-NH2, -CH2-N(CH3)2, -CO-CH3, -CO-NH2, -CO-NH(CH3), -CO-N(CH3)2, -SO-CH3, -SO2-CH3, -N(CH3)2, fluoro, chloro, methyl, ethyl and cyclopropyl.

[0097]

[0098] Preferably, R2 is pyridinyl,

[0099] wherein R2 is unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy and ethoxy,

[0100] R3 is a piperidine ring formed by combining N atom, R4 and R5, and the ring may be unsubstituted or substituted with one or two substituents selected from the group consisting of -CO-NH2, -CO-NH(CH3) and -CO-N(CH3)2.

[0101]

[0102] Preferably, R2 is methyl, ethyl, propyl, butyl, isobutyl, or phenyl,

[0103] wherein R2 is unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy and ethoxy,

[0104] R3 is a pyrrolidine, pyrrolidine-2-one, piperidine, or piperazine ring formed by the N atom, R4, and R5 bonded to each other, and the ring may be unsubstituted or substituted with one or two substituents selected from the group consisting of -CH2-NH2, -CH2-N(CH3)2, -CH2-NH-COO-(tert-butyl), -CO-CH3, -CO-NH2, -CO-NH(CH3), -CO-N(CH3)2, -N(CH3)2, fluoro, chloro, cyano, hydroxy, methyl, ethyl, and cyclopropyl.

[0105]

[0106] Meanwhile, representative examples of compounds represented by the chemical formula 1 are as follows:

[0107] 1) 1-(4-(1-phenyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide,

[0108] 2) 2-(4-ethylpiperazin-1-yl)-4-(1-phenyl-1H-pyrazol-4-yl)quinazoline,

[0109] 3) 1-(4-(1-butyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide,

[0110] 4) 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-2-(4-ethylpiperazin-1-yl)quinazoline,

[0111] 5) 2-(4-cyclopropylpiperazin-1-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)quinazoline,

[0112] 6) 1-(4-(1-isobutyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide,

[0113] 7) 2-(4-ethylpiperazin-1-yl)-4-(1-isobutyl-1H-pyrazol-4-yl)quinazoline,

[0114] 8) 4-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(4-ethylpiperazin-1-yl)quinazoline,

[0115] 9) 1-(4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carbonitrile,

[0116] 10) 1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)piperidine-4-carboxamide,

[0117] 11)N-methyl-1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)piperidine-4-carboxamide,

[0118] 12) (S)-4-hydroxy-1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)pyrrolidin-2-one,

[0119] 13) (R)-4-hydroxy-1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)pyrrolidin-2-one,

[0120] 14) (S)-N,N-dimethyl-1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)pyrrolidin-3-amine,

[0121] 15) tert-butyl((1-(4-(1-butyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl)carbamate,

[0122] 16) (1-(4-(1-butyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidin-4-yl)methanamine,

[0123] 17) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide,

[0124] 18) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide,

[0125] 19) 1-(6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-4-yl)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide,

[0126] 20) 1-(6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide,

[0127] 21) 4-(1-cyclohexyl-1H-pyrazol-4-yl)-2-(4-ethylpiperazin-1-yl)-6,7-dimethoxyquinazoline,

[0128] 22) 4-(1-cyclohexyl-1H-pyrazol-4-yl)-2-(4-cyclopropylpiperazin-1-yl)-6,7-dimethoxyquinazoline,

[0129] 23) (S)-4-(1-cyclohexyl-1H-pyrazol-4-yl)-2-(3-fluoropyrrolidin-1-yl)-6,7-dimethoxyquinazoline,

[0130] 24) (S)-2-(3-fluoropyrrolidin-1-yl)-6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-4-yl)quinazoline,

[0131] 25) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)pyrrolidine-3-carboxamide,

[0132] 26) (R)-4-(1-cyclohexyl-1H-pyrazol-4-yl)-2-(3-fluoropyrrolidin-1-yl)-6,7-dimethoxyquinazoline,

[0133] 27) 1-(1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl)ethan-1-one,

[0134] 28) 1-(6,7-dimethoxy-4-(5-phenylthiophen-2-yl)quinazolin-2-yl)piperidine-4-carboxamide,

[0135] 29) 1-(6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-3-yl)quinazolin-2-yl)piperidine-4-carboxamide,

[0136] 30) 1-(6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-3-yl)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide,

[0137] 31) 1-(6,7-dimethoxy-4-(2-phenylthiazol-5-yl)quinazolin-2-yl)piperidine-4-carboxamide,

[0138] 32) 1-(6,7-dimethoxy-4-(2-phenylthiazol-5-yl)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide,

[0139] 33) 1-(6,7-dimethoxy-4-(5-phenylthiophen-2-yl)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide,

[0140] 34) 1-(4-(1-cyclopentyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide,

[0141] 35) 1-(4-(1-Cyclopentyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide,

[0142] 36) 1-(4-(1-cyclobutyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide,

[0143] 37) 1-(4-(1-Cyclobutyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide,

[0144] 38) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylpyrrolidine-3-carboxamide,

[0145] 39) 1-(1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)pyrrolidin-3-yl)-N,N-dimethylmethanamine,

[0146] 40) 1-(4-(1-Cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl-N,N-dimethylpyrrolidine-3-carboxamide,

[0147] 41) 1-(4-(1-Cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl-N,N-dimethylpiperidine-4-carboxamide,

[0148] 42) 4-(1-Cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-N,N-dimethylquinazolin-2-amine,

[0149] 43) 4-(1-Cyclohexyl-1H-pyrazol-4-yl)-N-isopropyl-6,7-dimethoxy-N-methylquinazolin-2-amine,

[0150] 44) 4-(1-Cyclohexyl-1H-pyrazol-4-yl-N,N-diethyl-6,7-dimethoxyquinazolin-2-amine,

[0151] 45) 1-(6,7-dimethoxy-4-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide,

[0152] 46) 1-(6,7-dimethoxy-4-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide,

[0153] 47)N 1 -(4-(1-Cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N 2 ,N 2-Dimethylethane-1,2-diamine,

[0154] 48) 4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-N-((tetrahydrofuran-2-yl)methyl)quinazolin-2-amine,

[0155] 49) (1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl)methanamine,

[0156] 50) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-2-yl)piperidine-4-carboxamide,

[0157] 51) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide,

[0158] 52) 4-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-2-yl)piperazine-1-carboxamide,

[0159] 53) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6-methoxyquinazolin-2-yl)piperidine-4-carboxamide,

[0160] 54) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6-methoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide,

[0161] 55)N-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylmorpholine-4-carboxamide,

[0162] 56) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3-isopropyl-1,3-dimethylurea,

[0163] 57) (S)-N-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3-fluoro-N-methylpyrrolidine-1-carboxamide,

[0164] 58) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3,3-diethyl-1-methylurea,

[0165] 59) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3-(2,2-difluoroethyl)-1-methylurea,

[0166] 60) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3-(2-(dimethylamino)ethyl)-1-methylurea,

[0167] 61) 2-(Diethylamino)ethyl (4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)(methyl)carbamate,

[0168] 62) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-1-methylurea,

[0169] 63) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-1,3-dimethylurea,

[0170] 64) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-1,3,3-trimethylurea,

[0171] 65) (E)-N'-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N,N-dimethylformamide,

[0172] 66) 1-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide,

[0173] 67) 1-(6,7-dimethoxy-4-(1-(4-methoxycyclohexyl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide,

[0174] 68) 1-(4-(1-(2-chloro-4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide,

[0175] 69) 1-(6,7-dimethoxy-4-(1-((1s,4s)-4-methylcyclohexyl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide,

[0176] 70) 1-(6,7-dimethoxy-4-(1-((1r,4r)-4-methylcyclohexyl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide,

[0177] 71) 4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-2-(4-(methylsulfinyl)piperidin-1-yl)quinazoline, and

[0178] 72) 4-(1-Cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-2-(4-(methylsulfonyl)piperidin-1-yl)quinazoline.

[0179]

[0180] Meanwhile, the compound represented by the above chemical formula 1 can be understood as a concept encompassing all stereoisomers, mixtures of stereoisomers, and isotopic derivatives of the compound.

[0181]

[0182] Specifically, the "stereoisomers" of the compound may be understood to include all possible structures of diastereomers and enantiomers when the compound contains one or more chiral centers.

[0183]

[0184] Additionally, "isotopic derivatives" of the compound mean that one or more atoms in the compound are replaced with its naturally occurring or non-naturally occurring isotope. For example, isotopic derivatives of the compound include compounds in which at least one hydrogen in the compound is replaced with deuterium.

[0185]

[0186] Furthermore, the compounds of the present invention may exist in the form of salts, particularly pharmaceutically acceptable salts. As salts, any salt commonly used in the art, such as acid addition salts formed with pharmaceutically acceptable free acids, may be used without limitation. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, which has a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and wherein the side effects caused by the salt do not diminish the beneficial effects of the compound represented by Chemical Formula 1.

[0187]

[0188] As the above-mentioned acid, organic acids and inorganic acids can be used. As the inorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used. As the organic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used, but are not limited thereto. Preferably, the salt may be hydrochloride.

[0189]

[0190] Additionally, a pharmaceutically acceptable metal salt can be obtained by a conventional method using a base. For example, the compound represented by the above chemical formula 1 is dissolved in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, the undissolved compound salt is filtered, and the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. In this case, it is particularly preferable to prepare a sodium salt, a potassium salt, or a calcium salt as the metal salt.

[0191]

[0192] Other pharmaceutically unacceptable salts or solvates of the compound represented by chemical formula 1 can be used as intermediates in the production of the compound represented by chemical formula 1, a pharmaceutically acceptable salt, or solvate thereof.

[0193]

[0194] In addition, the compound represented by the above chemical formula 1 according to the present invention includes, without limitation, not only its pharmaceutically acceptable salt but also solvates such as possible hydrates that can be prepared therefrom or prodrugs thereof.

[0195]

[0196] The solvate of the compound represented by the above chemical formula 1 can be prepared from the compound represented by the chemical formula 1 using a method known in the art.

[0197]

[0198] Additionally, unless otherwise indicated, a "prodrug" of the above compound may be understood to refer to any derivative which can be hydrolyzed, oxidized or otherwise reacted under biological conditions (in vitro or in vivo) to provide the compound of the present invention, a stereoisomer thereof, a mixture of stereoisomers thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof.

[0199]

[0200] In addition, the compound represented by the above chemical formula 1 according to the present invention can be prepared in a crystalline or amorphous form, and when prepared in a crystalline form, can be optionally hydrated or solvated. The present invention may include not only stoichiometric hydrates of the compound represented by the above chemical formula 1, but also compounds containing various amounts of water. The solvates of the compound represented by the above chemical formula 1 according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

[0201]

[0202] In addition, the compound represented by the above chemical formula 1 can be prepared, for example, through the following reaction scheme 1.

[0203] [Reaction Formula 1]

[0204]

[0205] In the above reaction formula 1, the remainder except Z is as defined in the chemical formula 1 above, and Z is halogen, preferably bromo or chloro.

[0206]

[0207] The above step 1 is a step of producing a compound represented by the above chemical formula C by reacting a compound represented by the above chemical formula A with a compound represented by the above chemical formula B. The above reaction is preferably performed in the presence of a palladium catalyst and a base as a Suzuki-coupling reaction.

[0208]

[0209] The above step 2 is a step of producing a compound represented by the above chemical formula 1 by reacting a compound represented by the above chemical formula C with a compound represented by the above chemical formula D. The above reaction is preferably performed in the presence of a base through an amine substitution reaction, or in the presence of palladium, a ligand, and a base.

[0210]

[0211] The manufacturing method of each step described above is further specified in the examples described below.

[0212]

[0213] In addition, the present invention provides a pharmaceutical composition comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0214]

[0215] More specifically, the present invention can be understood as providing a pharmaceutical composition comprising a compound represented by the above chemical formula 1, a stereoisomer thereof, a mixture of stereoisomers thereof, an isotopic derivative thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient.

[0216]

[0217] In addition, the present invention provides a pharmaceutical composition for preventing or treating fibrotic diseases, cancer or metabolic diseases, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0218]

[0219] More specifically, the present invention can be understood as providing a pharmaceutical composition for treating or preventing fibrotic diseases, cancer or metabolic diseases through the inhibitory action of HSP47, using a compound represented by the above chemical formula 1, a stereoisomer thereof, a mixture of stereoisomers thereof, an isotopic derivative thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient.

[0220]

[0221] The above fibrotic diseases may be systemic sclerosis, multifocal fibrosing sclerosis, scleroderma graft-versus-host disease, renal systemic fibrosis, organ-specific fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, massive progressive fibrosis, Crohn's disease, keloids, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, adhesive capsulitis, etc. In addition, organ-specific fibrosis may be pulmonary fibrosis, pulmonary hypertension, cystic fibrosis, asthma, chronic obstructive pulmonary disease, liver fibrosis, renal fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), lymph node fibrosis, corneal fibrosis, fibrous cartilage, endometriosis, etc.

[0222]

[0223] The cancer may be a hematological cancer, extranodal marginal zone B-cell lymphoma, glioblastoma, lymphoplasmacytic lymphoma, acute myeloid leukemia, macroglobulinemia, B-cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, hairy cell leukemia, mantle cell lymphoma, glioblastoma, bladder cancer, pancreatic cancer, ovarian cancer, colon cancer, kidney cancer, stomach cancer, transitional cell carcinoma, carcinoid tumor, breast cancer, non-small cell lung cancer, or multiple myeloma.

[0224]

[0225] Cancer also includes non-solid tumors, such as blood cancers, wherein the cancer cells originate from the bone marrow. Blood cancers include leukemia, lymphoma, myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, T-cell malignancies, or B-cell malignancies. In particular, T-cell malignancies include mature T-cell lymphoma not otherwise classified, anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia, blastic natural killer cell lymphoma, platelet gamma-delta T-cell lymphoma, and lymphoblastic lymphoma. B-cell malignancies include, but are not limited to, chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, head and neck tumors, lymphoid marginal zone B-cell lymphoma, Burkitt's lymphoma, primary mediastinal B-cell lymphoma, immunoglobulin lymphoma, precursor B-lymphoblastic lymphoma, prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, intravascular large B-cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

[0226]

[0227] In some cases, it includes recurrent or refractory cancer, and the cancer is a solid tumor. Recurrent or refractory cancer includes adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, biliary tract cancer, bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, esophageal cancer, eye tumor, primary fallopian tube cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, malignant melanoma, oral cancer, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.

[0228]

[0229] The above metabolic diseases may include hypertension, arteriosclerosis, hyperlipidemia, non-alcoholic fatty liver disease, hyperinsulinemia, type 2 diabetes, and insulin resistance syndrome.

[0230]

[0231] The term "prevention" of the present invention means any act of inhibiting or delaying the occurrence, spread, and recurrence of the disease by administering the composition of the present invention, and "treatment" means any act of improving or beneficially changing the symptoms of the disease by administering the composition of the present invention.

[0232]

[0233] The pharmaceutical composition of the present invention can be formulated into oral or parenteral dosage forms according to standard pharmaceutical practice. These dosage forms may contain, in addition to the active ingredient, pharmaceutically acceptable additives such as carriers, adjuvants, or diluents.

[0234]

[0235] Suitable carriers include, but are not limited to, saline, polyethylene glycol, ethanol, vegetable oils, and isopropyl myristate, and diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine. In addition, the compounds of the present invention can be dissolved in oils, propylene glycol, or other solvents commonly used in the preparation of injectable solutions. In addition, the compounds of the present invention can be formulated as ointments or creams for topical action.

[0236]

[0237] The preferred dosage of the compound of the present invention varies depending on the patient's condition and body weight, the severity of the disease, the form of the drug, the route of administration, and the duration of administration, but can be appropriately selected by those skilled in the art. However, for desirable effects, the compound of the present invention is preferably administered at a daily dose of 0.0001 to 100 mg / kg (body weight), preferably 0.001 to 100 mg / kg (body weight). Administration may be administered orally or parenterally once daily or in divided doses.

[0238]

[0239] Depending on the administration method, the pharmaceutical composition may contain 0.001 to 99 wt%, preferably 0.01 to 60 wt%, of the compound of the present invention.

[0240]

[0241] The pharmaceutical composition according to the present invention can be administered to mammals, including rats, mice, livestock, and humans, via various routes. Any route of administration is conceivable, including oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine, or intracerebroventricular injection.

[0242]

[0243] Meanwhile, used in this specification means a bond that connects to another substituent.

[0244]

[0245] Additionally, in the present specification, the halogen group means fluoro, chloro, bromo, or iodo.

[0246]

[0247] Additionally, in the present specification, the alkyl group may be linear or branched. In one embodiment, the alkyl group has 1 to 10 carbon atoms. In another embodiment, the alkyl group has 1 to 4 carbon atoms. Specific examples of the above alkyl group include methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methylbutyl, 1-ethylbutyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethyl-propyl, 1,1-dimethylpropyl, hexyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, n-heptyl, isohexyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, octyl, n-octyl, tert-octyl, 1-methylheptyl, 2-ethylhexyl, Examples thereof include, but are not limited to, 2,4,4-trimethyl-1-pentyl, 2,4,4-trimethyl-2-pentyl, 2-propylpentyl, n-nonyl, 2,2-dimethylheptyl, or n-decyl. In addition, the description regarding the alkyl group may be applied to the haloalkyl group, except that at least one carbon of the alkyl group is substituted with a halogen group. In addition, the description regarding the alkyl group may be applied to the alkylene group, except that it is divalent.

[0248]

[0249] Additionally, in the present specification, the alkoxy group refers to an alkyl group singly bonded to oxygen, and may be linear or branched. According to one embodiment, the alkoxy group has 1 to 10 carbon atoms. According to another embodiment, the alkoxy group has 1 to 4 carbon atoms. Specific examples of the above alkoxy group include methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, butoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, 1-methylbutoxy, 1-ethylbutoxy, pentyloxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1-ethyl-propoxy, 1,1-dimethylpropoxy, hexyloxy, n-hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 4-methyl-2-pentyloxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, heptyloxy, n-heptyloxy, isohexyloxy, 1-methylhexyloxy, 2-methylhexyloxy, 3-methylhexyloxy, 4-methylhexyloxy, Examples thereof include, but are not limited to, 5-methylhexyloxy, octyloxy, n-octyloxy, tert-octyloxy, 1-methylheptyloxy, 2-ethylhexyloxy, 2,4,4-trimethyl-1-pentyloxy, 2,4,4-trimethyl-2-pentyloxy, 2-propylpentyloxy, n-nonyloxy, 2,2-dimethylheptyloxy, or n-decyloxy. In addition, the description regarding the alkoxy group may be applied to the haloalkoxy group, except that at least one carbon of the alkoxy group is replaced by a halogen group.

[0250]

[0251] In addition, in the present specification, the cycloalkyl group is understood to mean a monovalent substituent derived from a saturated or unsaturated hydrocarbon ring compound that contains only carbon as a ring-forming atom and does not have aromaticity, and includes all of monocyclic rings, fused bicyclic rings, bridged bicyclic rings, spirocyclic rings, and condensed polycyclic rings. According to one embodiment, the cycloalkyl group has 3 to 10 carbon atoms. According to another embodiment, the cycloalkyl group has 3 to 8 carbon atoms. According to yet another embodiment, the cycloalkyl group has 3 to 7 carbon atoms. According to yet another embodiment, the cycloalkyl group has 3 to 6 carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl.

[0252]

[0253] In addition, in the present specification, the aryl group is understood to mean a monovalent substituent derived from a monocyclic or condensed polycyclic compound having aromaticity and containing only carbon as a ring-forming atom. According to one embodiment, the aryl group has 6 to 12 carbon atoms. According to another embodiment, the aryl group has 6 to 10 carbon atoms. Specific examples of the monocyclic aryl group include phenyl or biphenylyl, and the condensed polycyclic aryl group includes naphthyl.

[0254]

[0255] In addition, in the present specification, the heteroaryl group is understood to mean a monovalent substituent derived from a monocyclic or condensed polycyclic compound having aromaticity and including, in addition to carbon, one or more heteroatoms selected from N, O, and S as ring-forming atoms. According to one embodiment, the heteroaryl group has 2 to 10 carbon atoms. According to another embodiment, the heteroaryl group has 2 to 8 carbon atoms. According to yet another embodiment, the heteroaryl group has 2 to 6 carbon atoms. Specific examples of the heteroaryl group include, but are not limited to, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, and the like.

[0256]

[0257] In addition, in the present specification, the five-membered heteroaromatic ring is understood to mean a monocyclic aromatic compound including one or two heteroatoms selected from N, O, and S in addition to carbon among five ring-forming atoms. Specific examples of such five-membered heteroaromatic rings include, but are not limited to, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, and thiophene.

[0258]

[0259] In addition, in the present specification, the heterocycloalkane ring is understood to mean a monovalent substituent derived from a saturated or unsaturated ring compound that further includes one or more heteroatoms selected from N, O, and S in addition to carbon as a ring-forming atom, but does not have aromaticity, and encompasses all of a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, a spiro ring, and a condensed polycyclic ring. According to one embodiment, the heterocycloalkane ring has 2 to 8 carbon atoms. According to another embodiment, the heterocycloalkane ring has 2 to 5 carbon atoms. According to another embodiment, the heterocycloalkane ring has 3 to 5 carbon atoms. Specific examples of the above heterocycloalkane ring include, but are not limited to, pyrrolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, morpholine, thiomorpholine, oxazinane, thiazinane, etc.

[0260]

[0261] The compound represented by chemical formula 1 according to the present invention or a pharmaceutically acceptable salt thereof can be usefully used for the prevention or treatment of fibrotic diseases, cancer, or metabolic diseases.

[0262]

[0263] Hereinafter, preferred examples are presented to help understand the present invention, but the following examples are only to illustrate the present invention and the scope of the present invention is not limited to the following examples.

[0264]

[0265] Example 1: Preparation of 1-(4-(1-phenyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide

[0266]

[0267] (Step 1)

[0268] 2,4-Dichloroquinazoline (100 mg, 1.0 eq) was dissolved in 1,4-Dioxane / water (2 mL, 4:1). Potassium carbonate (208 mg, 3.0 eq), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (203 mg, 1.5 eq), and tetrakis(triphenylphosphine) palladium(0) (29 mg, 0.05 eq) were added, and the reaction mixture was microwaved at 110°C for 30 minutes. After completion of the reaction, NH4Cl aqueous solution was added, and the organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1:3) to obtain 2-chloro-4-(1-phenyl-1H-pyrazol-4-yl)quinazoline (yield 58%, 90 mg).

[0269]

[0270] (Step 2)

[0271] 2-Chloro-4-(1-phenyl-1H-pyrazol-4-yl)quinazoline (30 mg, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and then isonipecotamide (25 mg, 2.0 eq), sodium tert-butoxide (28 mg, 3.0 eq), tris(dibenzylideneacetone)dipalladium(0) (8.9 mg, 0.1 eq), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (9.3 mg, 0.2 eq) were added. The reaction mixture was concentrated to 110 oThe temperature was raised to C, and after 12 hours of reaction, when the reaction was complete, an aqueous NH4Cl solution was added. The organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate) to obtain the title compound (yield 9%, 3.4 mg).

[0272] 1 H NMR (500MHz, CDCl3): δ 8.57 (s, 1H), 8.33 (s, 1H), 8.15 (d, 1H), 7.83 (d, 2H), 7.75-7.65 (m, 2H), 7.55 (t, 2H), 7.41 (t, 1H), 7.27 (t, 1H), 5.54 (d, 2H), 5.13 (d, 2H), 3.08 (t, 2H), 2.52 (t, 1H), 2.08 (d, 2H), 1.85-1.78 (m, 2H)

[0273]

[0274] Example 2: Preparation of 2-(4-ethylpiperazin-1-yl)-4-(1-phenyl-1H-pyrazol-4-yl)quinazoline

[0275]

[0276] The title compound (9.6 mg, yield: 16%) was obtained in the same manner as in Example 1, except that 4-ethylpiperazine was used instead of isonipecotamide in step 2 of Example 1.

[0277] 1H NMR (500MHz, CDCl3): δ 8.55 (s, 1H), 8.34 (s, 1H), 8.14 (d, 1H), 7.83 (d, 2H), 7.70-7.65 (m, 2H), 7.54 (t, 2H), 7.39 (t, 1H), 7.27 (t, 1H), 4.08 (t, 4H), 2.61 (t, 4H), 2.55-2.50 (m, 2H), 1.18 (t, 3H)

[0278]

[0279] Example 3: Preparation of 1-(4-(1-butyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide

[0280]

[0281] The title compound (3.9 mg, yield: 5%) was obtained in the same manner as in Example 1, except that 1-butylpyrazole-4-boronic acid was used instead of 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 1.

[0282] 1 H NMR (500MHz, CDCl3): δ 8.15 (s, 1H), 8.11 (d, 1H), 8.07 (s, 1H), 7.67 (s, 2H), 7.25 (t, 1H), 5.56 (d, 2H), 5.11 (d, 2H), 4.26 (t, 2H), 3.08 (t, 2H), 2.51 (t, 1H), 2.07 (d, 2H), 2.00-1.95 (m, 2H), 1.85-1.75 (m, 2H), 1.47-1.40 (m, 2H), 1.02 (t, 3H)

[0283]

[0284] Example 4: Preparation of 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-2-(4-ethylpiperazin-1-yl)quinazoline

[0285]

[0286] The title compound (4.8 mg, yield: 14%) was obtained in the same manner as in Example 1, except that 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 1 and 4-ethylpiperazine was used instead of isonipecotamide in step 2.

[0287] 1 H NMR (500MHz, CDCl3): δ 8.26 (s, 1H), 8.16 (s, 1H), 8.10 (d, 1H), 7.69-7.64 (m, 2H), 7.24 (t, 1H), 5.67-5.64 (m, 1H), 4.06 (s, 4H), 3.62-3.48 (m, 2H), 2.61 (t, 4H), 2.55-2.50 (m, 2H), 1.80 (d, 3H), 1.24 (t, 3H), 1.18 (t, 3H)

[0288]

[0289] Example 5: Preparation of 2-(4-cyclopropylpiperazin-1-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)quinazoline

[0290]

[0291] The title compound (14.2 mg, yield: 21%) was obtained in the same manner as in Example 1, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 1 and 1-cyclopropylpiperazine was used instead of isonipecotamide in step 2.

[0292] 1 H NMR (500MHz, CDCl3): δ 8.22 (d, 1H), 8.05 (d, 1H), 7.70-7.64 (m, 2H), 7.25 (t, 1H), 4.89-4.83 (m, 2H), 4.00 (s, 4H), 2.76 (m, 4H), 1.68 (t, 1H), 0.52 (t, 4H)

[0293]

[0294] Example 6: Preparation of 1-(4-(1-isobutyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide

[0295]

[0296] The title compound (7.6 mg, yield: 7%) was obtained in the same manner as in Example 1, except that 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 1.

[0297] 1H NMR (500MHz, CDCl3): δ 8.15 (s, 1H), 8.09 (d, 1H), 8.04 (s, 1H), 7.69-7.61 (m, 2H), 7.24 (t, 1H), 5.56 (m, 2H), 5.10 (d, 2H), 4.06 (d, 2H), 3.06 (t, 2H), 2.50 (t, 1H), 2.40-2.30 (m, 1H), 2.07-2.04 (d, 2H), 1.84-1.75 (m, 2H), 1.03 (d, 6H)

[0298]

[0299] Example 7: Preparation of 2-(4-ethylpiperazin-1-yl)-4-(1-isobutyl-1H-pyrazol-4-yl)quinazoline

[0300]

[0301] The title compound (5 mg, yield: 13%) was obtained in the same manner as in Example 1, except that 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 1 and 1-ethylpiperazine was used instead of isonipecotamide in step 2.

[0302] 1 H NMR (500MHz, CDCl3): δ 8.14 (s, 1H), 8.11 (d, 1H), 8.04 (s, 1H), 7.68-7.61 (m, 2H), 7.23 (t, 1H), 4.11 (d, 6H), 2.60 (m, 4H), 2.54-2.50 (m, 2H), 2.37-2.31 (m, 1H), 1.18 (t, 3H), 1.01 (t, 6H)

[0303]

[0304] Example 8: Preparation of 4-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(4-ethylpiperazin-1-yl)quinazoline

[0305]

[0306] The title compound (5.8 mg, yield: 17%) was obtained in the same manner as in Example 1, except that 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 1 and 1-ethylpiperazine was used instead of isonipecotamide in step 2.

[0307] 1 H NMR (500MHz, CDCl3): δ 8.12 (d, 2H), 8.07 (d, 1H), 7.66-7.63 (m, 2H), 7.22 (t, 1H), 4.05 (s, 4H), 3.75-3.71 (m, 1H), 2.60 (t, 4H), 2.53-2.49 (m, 2H), 1.26 (s, 2H), 1.17 (t, 3H), 1.14 (t, 2H)

[0308]

[0309] Example 9: Preparation of 1-(4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carbonitrile

[0310]

[0311] The title compound (23.7 mg, yield: 26%) was obtained in the same manner as in Example 1, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 11 and 4-cyanopiperidine was used instead of isonipecotamide in step 2.

[0312] 1 H NMR (500MHz, CDCl3): δ 8.21 (d, 2H), 8.05 (d, 1H), 7.70 (t, 1H), 7.65 (t, 1H), 7.27 (t, 1H), 4.89-4.84 (m, 2H), 4.38-4.32 (m, 2H), 3.91-3.84 (m, 2H), 2.10-2.04 (m, 2H), 2.00-1.94 (m, 2H)

[0313]

[0314] Example 10: Preparation of 1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)piperidine-4-carboxamide

[0315]

[0316] The title compound (5.45 mg, yield: 12%) was obtained in the same manner as in Example 1, except that 5-phenylthiophene-2-boronic acid pinacol ester was used instead of 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 1.

[0317] 1H NMR (500MHz, CDCl3): δ 8.31 (d, 1H), 7.82 (d, 1H), 7.76 (d, 2H), 7.70-7.65 (m, 2H), 7.48-7.44 (m, 3H), 7.39 (t, 1H), 5.52 (d, 2H), 5.13 (d, 2H), 3.08 (t, 2H), 2.52 (t, 1H), 2.08 (m, 2H), 1.85-1.77 (m, 2H)

[0318]

[0319] Example 11: Preparation of N-methyl-1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)piperidine-4-carboxamide

[0320]

[0321] The title compound (13.28 mg, yield: 29%) was obtained in the same manner as in Example 1, except that 5-phenylthiophene-2-boronic acid pinacol ester was used instead of 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 1 and that piperidine-4-carboxylic acid methyl amide was used instead of isonipecotamide in step 2.

[0322] 1 H NMR (500MHz, CDCl3): δ 8.31 (d, 1H), 7.82 (d, 1H), 7.77 (d, 2H), 7.70-7.64 (m, 2H), 7.49-7.44 (m, 3H), 7.39 (t, 1H), 7.26 (d, 1H), 5.54 (s, 1H), 5.12 (d, 2H), 3.07 (t, 2H), 2.87 (t, 3H), 2.46 (t, 1H), 2.04 (d, 2H), 1.85-1.77 (m, 2H)

[0323]

[0324] Example 12: Preparation of (S)-4-hydroxy-1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)pyrrolidin-2-one

[0325]

[0326] The title compound (3.7 mg, yield: 11%) was obtained in the same manner as in Example 1, except that 5-phenylthiophene-2-boronic acid pinacol ester was used instead of 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 1 and (S)-(+)-4-hydroxy-2-pyrrolidinone was used instead of isonipecotamide in step 2.

[0327] 1 H NMR (500MHz, CDCl3): δ 8.52 (d, 1H), 7.92 (d, 1H), 7.88 (s, 2H), 7.76 (d, 2H), 7.57-7.53 (m, 1H), 7.51-7.45 (m, 3H), 7.40 (t, 1H), 5.94-5.89 (m, 1H), 5.82 (s, 1H), 4.05 (dd, 1H), 3.76 (dd, 1H), 3.00 (dd, 1H), 2.81 (dd, 1H)

[0328]

[0329] Example 13: Preparation of (R)-4-hydroxy-1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)pyrrolidin-2-one

[0330]

[0331] The title compound (3.8 mg, yield: 8%) was obtained in the same manner as in Example 1, except that 5-phenylthiophene-2-boronic acid pinacol ester was used instead of 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 1 and (R)-(+)-4-hydroxy-2-pyrrolidinone was used instead of isonipecotamide in step 2.

[0332] 1 H NMR (500MHz, CDCl3): δ 8.51 (d, 1H), 7.92 (d, 1H), 7.89-7.85 (s, 2H), 7.76 (d, 2H), 7.58-7.53 (m, 1H), 7.50-7.45 (m, 3H), 7.41 (t, 1H), 5.94-5.88 (m, 1H), 5.85 (s, 1H), 4.05 (dd, 1H), 3.74 (dd, 1H), 3.00 (dd, 1H), 2.80 (dd, 1H)

[0333]

[0334] Example 14: Preparation of (S)-N,N-dimethyl-1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)pyrrolidin-3-amine

[0335]

[0336] The title compound (13.8 mg, yield: 22%) was obtained in the same manner as in Example 1, except that 5-phenylthiophene-2-boronic acid pinacol ester was used instead of 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 1 and (S)-(-)-3-(dimethylamino)pyrrolidine was used instead of isonipecotamide in step 2.

[0337] 1 H NMR (500MHz, CDCl3): δ 8.31 (d, 1H), 7.82 (d, 1H), 7.75 (d, 2H), 7.70-7.67 (m, 2H), 7.48-7.43 (m, 3H), 7.38 (t, 1H), 7.25-7.22 (m, 1H), 4.19 (t, 1H), 4.07 (t, 1H), 3.75-3.69 (m, 1H), 3.52 (t, 1H), 2.92 (s, 1H), 2.41 (s, 6H), 2.33-2.29 (m, 1H), 2.06-1.98 (m, 1H)

[0338]

[0339] Example 15: Preparation of tert-butyl ((1-(4-(1-butyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl)carbamate

[0340]

[0341] (Step 1)

[0342] 2,4-Dichloroquinazoline (100 mg, 1.0 eq) was dissolved in 1,4-dioxane / water (2 mL, 4:1). Potassium carbonate (208 mg, 3.0 eq), 1-butylpyrazole-4-boronic acid (126 mg, 1.5 eq), and tetrakis(triphenylphosphine) palladium(0) (29 mg, 0.05 eq) were added, and the reaction mixture was microwaved at 110°C for 30 minutes. After completion of the reaction, an aqueous NH4Cl solution was added, and the organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1:3) to obtain 4-(1-butyl-1H-pyrazol-4-yl)-2-chloroquinazoline (yield 56%, 80 mg).

[0343]

[0344] (Step 2)

[0345] 4-(1-butyl-1H-pyrazol-4-yl)-2-chloroquinazoline (40 mg, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and tert-butyl N-(piperidin-4-ylmethyl)carbamate (60 mg, 2.0 eq), sodium tert-butoxide (40 mg, 3.0 eq), tris(dibenzylideneacetone)dipalladium(0) (12.7 mg, 0.1 eq), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (13 mg, 0.2 eq) were added. The reaction mixture was heated to 110°C and reacted for 12 hours. Once the reaction was complete, an aqueous NH4Cl solution was added. The organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1:3) to obtain the title compound (yield 28%, 18.3 mg).

[0346] 1 H NMR (500MHz, CDCl3): δ 8.13 (s, 1H), 8.09 (d, 1H), 8.06 (s, 1H), 7.67-7.61 (m, 2H), 7.20 (t, 1H), 5.08 (d, 2H), 4.67 (s, 1H), 4.26 (t, 2H), 3.09 (t, 2H), 2.96 (t, 2H), 2.00-1.94 (m, 2H), 1.86 (d, 2H), 1.48 (s, 9H), 1.45-1.40 (m, 1H), 1.34-1.25 (m, 2H), 1.01 (t, 3H)

[0347]

[0348] Example 16: Preparation of (1-(4-(1-butyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidin-4-yl)methanamine

[0349]

[0350] Tert-Butyl ((1-(4-(1-butyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl)carbamate (15 mg, 1.0 eq) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (10 μL, 3.0 eq) was added. After the reaction was allowed to react for 4 hours, the starting material disappeared, and the solvent was removed under reduced pressure. The obtained residue was basified by adding 1 N aqueous NaOH solution, and the organic layer was separated using water and dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (yield 78%, 9.1 mg).

[0351] 1 H NMR (500MHz, CDCl3): δ 8.13 (s, 1H), 8.09 (d, 1H), 8.06 (s, 1H), 7.65-7.61 (m, 2H), 7.22-7.18 (m 1H), 5.09 (d, 2H), 4.25 (t, 2H), 2.99-2.95 (t, 2H), 2.66 (d, 2H), 1.99-1.94 (m, 2H), 1.91 (d, 2H), 1.69-1.61 (m, 2H), 1.46-1.41 (m, 2H), 1.00 (s, 3H)

[0352]

[0353] Example 17: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide

[0354]

[0355] (Step 1)

[0356] 2,4-dichloro-6,7-dimethoxyquinazoline (50 mg, 1.0 eq) was dissolved in 1,4-dioxane / water (2 mL, 4:1). Potassium carbonate (80 mg, 3.0 eq), 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (80 mg, 1.5 eq), and tetrakis(triphenylphosphine) palladium(0) (11 mg, 0.05 eq) were added, and the reaction mixture was microwaved at 110°C for 30 minutes. After completion of the reaction, an aqueous NH4Cl solution was added, and the organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1:1) to obtain 2-chloro-4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazoline (yield 50%, 35 mg).

[0357]

[0358] (Step 2)

[0359] 2-Chloro-4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazoline (20 mg, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and N-methylpiperidine-4-carboxamide (14 mg, 2.0 eq), sodium tert-butoxide (14.6 mg, 3.0 eq), tris(dibenzylideneacetone)dipalladium(0) (4.6 mg, 0.1 eq), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (4.8 mg, 0.2 eq) were added. The reaction mixture was heated to 110°C and reacted for 12 hours. Once the reaction was complete, an aqueous NH4Cl solution was added. The organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate only) to obtain the title compound 28 (yield 33%, 7.9 mg).

[0360] 1 H NMR (500MHz, CDCl3): δ 8.08 (d, 2H), 7.41 (s, 1H), 7.00 (s, 1H), 5.55 (s, 1H), 5.38 (d, 2H), 4.23 (t, 1H), 4.03 (s, 3H), 3.97 (s, 3H), 2.98 (t, 2H), 2.85 (d, 3H), 2.40 (t, 1H), 2.88 (d, 2H), 1.98 (t, 4H), 1.88-1.74 (m, 4H), 1.55-1.45 (m, 3H), 1.37-1.29 (m, 1H)

[0361]

[0362] Example 18: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide

[0363]

[0364] The title compound (6.8 mg, yield: 14%) was obtained in the same manner as in Example 17, except that isonipecotamide was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0365] 1 H NMR (500MHz, CDCl3): δ 8.09 (d, 2H), 7.41 (s, 1H), 7.01 (s, 1H), 5.54 (d, 2H), 5.04 (d, 2H), 4.24 (t, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.01 (t, 2H), 2.47 (t, 1H), 2.30 (d, 2H), 2.06 (d, 2H), 1.99 (d, 2H), 1.88-1.75 (m, 4H), 1.54-1.46 (m, 3H), 1.37-1.29 (m, 1H)

[0366]

[0367] Example 19: Preparation of 1-(6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-4-yl)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide

[0368]

[0369] The title compound (4.8 mg, yield: 11%) was obtained in the same manner as in Example 17, except that 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 17.

[0370] 1H NMR (500MHz, CDCl3): δ 8.55 (s, 1H), 8.29 (s, 1H), 7.81 (d, 2H), 7.54 (t, 2H), 7.40 (s, 2H), 7.04 (s, 1H), 5.56 (s, 1H), 5.06 (d, 2H), 4.05 (s, 3H), 3.98 (s, 3H), 2.99 (t, 2H), 2.85 (d, 3H), 2.41 (t, 1H), 2.02 (d, 2H), 1.84-1.75 (m, 2H)

[0371]

[0372] Example 20: Preparation of 1-(6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide

[0373]

[0374] The title compound (7.6 mg, yield: 17%) was obtained in the same manner as in Example 17, except that 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 17 and that isonipecotamide was used instead of N-methylpiperidine-4-carboxamide in step 2.

[0375] 1 H NMR (500MHz, CDCl3): δ 8.54 (s, 1H), 8.30 (s, 1H), 7.80 (d, 2H), 7.54 (t, 2H), 7.40 (t, 2H), 7.04 (s, 1H), 5.55 (s, 2H), 5.06 (d, 2H), 4.05 (s, 3H), 3.98 (s, 3H), 3.03 (t, 2H), 2.50 (t, 1H), 2.05 (d, 2H), 1.84-1.76 (m, 2H)

[0376]

[0377] Example 21: Preparation of 4-(1-cyclohexyl-1H-pyrazol-4-yl)-2-(4-ethylpiperazin-1-yl)-6,7-dimethoxyquinazoline

[0378]

[0379] The title compound (10.1 mg, yield: 17%) was obtained in the same manner as in Example 17, except that 1-ethylpiperazine was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0380] 1 H NMR (500MHz, CDCl3): δ 8.09 (d, 2H), 7.41 (s, 1H), 7.01 (s, 1H), 4.27-4.19 (m, 1H), 4.03 (s, 3H), 3.99 (s, 4H), 3.96 (s, 3H), 2.60 (s, 4H), 2.54-2.49 (m, 2H), 2.29 (d, 2H), 1.98 (d, 2H), 1.87-1.77 (m, 3H), 1.53-1.45 (m, 2H), 1.36-1.28 (m, 1H), 1.17 (t, 3H)

[0381]

[0382] Example 22: Preparation of 4-(1-cyclohexyl-1H-pyrazol-4-yl)-2-(4-cyclopropylpiperazin-1-yl)-6,7-dimethoxyquinazoline

[0383]

[0384] The title compound (18.2 mg, yield: 30%) was obtained in the same manner as in Example 17, except that 1-cyclopropylpiperazine was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0385] 1H NMR (500MHz, CDCl3): δ 8.10 (d, 2H), 7.41 (s, 1H), 7.02 (s, 1H), 4.23 (t, 1H), 4.04 (s, 3H), 3.97 (s, 3H), 3.95 (s, 4H), 2.76 (s, 4H), 2.29 (d, 2H), 1.98 (d, 2H), 1.88-1.77 (m, 3H), 1.69 (s, 1H), 1.54-1.45 (m, 2H), 1.37-1.29 (m, 1H), 0.54 (t, 4H)

[0386]

[0387] Example 23: Preparation of (S)-4-(1-cyclohexyl-1H-pyrazol-4-yl)-2-(3-fluoropyrrolidin-1-yl)-6,7-dimethoxyquinazoline

[0388]

[0389] The title compound (4.4 mg, yield: 8%) was obtained in the same manner as in Example 17, except that (S)-(+)-3-fluoropyrrolidine hydrochloride was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0390] 1 H NMR (500MHz, CDCl3): δ 8.12 (d, 2H), 7.43 (s, 1H), 7.07 (s, 1H), 5.47 (d, 1H), 4.27-4.19 (m, 1H), 4.17-4.02 (m, 2H), 4.04 (s, 3H), 3.98 (s, 3H), 4.01-3.79 (m, 2H), 2.46-2.37 (m, 1H), 2.31 (d, 2H), 2.25-2.13 (m, 1H), 1.98 (d, 2H), 1.88-1.79 (m, 3H), 1.54-1.47 (m, 2H), 1.34 (t, 1H)

[0391]

[0392] Example 24: Preparation of (S)-2-(3-fluoropyrrolidin-1-yl)-6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-4-yl)quinazoline

[0393]

[0394] The title compound (10.3 mg, yield: 12%) was obtained in the same manner as in Example 17, except that 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 17 and (S)-(+)-3-fluoropyrrolidine hydrochloride was used instead of N-methylpiperidine-4-carboxamide in step 2.

[0395] 1 H NMR (500MHz, CDCl3): δ 8.56 (s, 1H), 8.32 (s, 1H), 7.83 (d, 2H), 7.55 (t, 2H), 7.43-7.39 (m, 2H), 7.11 (s, 1H), 5.48 (d, 1H), 4.22-4.12 (m, 2H), 4.07 (s, 3H), 3.99 (s, 3H), 3.95-3.82 (m, 2H), 2.44 (t, 1H), 2.28-2.12 (m, 1H)

[0396]

[0397] Example 25: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)pyrrolidine-3-carboxamide

[0398]

[0399] The title compound (2.7 mg, yield: 4%) was obtained in the same manner as in Example 17, except that pyrrolidine-3-carboxamide was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0400] 1 H NMR (500MHz, CDCl3): δ 8.11 (s, 2H), 7.44 (s, 1H), 5.79 (t, 2H), 4.24 (t, 1H), 4.16-4.11 (m, 2H), 4.06 (s, 3H), 4.04-3.79 (m, 2H), 3.97 (s, 3H), 3.19-3.12 (m, 1H), 2.36 (t, 2H), 2.30 (d, 2H), 2.00 (d, 2H), 1.87-1.77 (m, 3H), 1.55-1.46 (m, 2H), 1.35 (m, 1H)

[0401]

[0402] Example 26: Preparation of (R)-4-(1-cyclohexyl-1H-pyrazol-4-yl)-2-(3-fluoropyrrolidin-1-yl)-6,7-dimethoxyquinazoline

[0403]

[0404] The title compound (8.4 mg, yield: 23%) was obtained in the same manner as in Example 17, except that (R)-(+)-3-fluoropyrrolidine hydrochloride was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0405] 1H NMR (500MHz, CDCl3): δ 8.11 (d, 2H), 7.42 (s, 1H), 7.07 (s, 1H), 5.46 (d, 1H), 4.23 (t, 1H), 4.19-4.01 (m, 2H), 4.05 (s, 3H), 3.97 (s, 3H), 3.94-3.79 (m, 2H), 2.41 (t, 1H), 2.30 (d, 2H), 2.24-2.09 (m, 1H), 1.98 (d, 2H), 1.88-1.78 (m, 3H), 1.54-1.46 (m, 2H), 1.34 (t, 1H)

[0406]

[0407] Example 27: Preparation of 1-(1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl)ethan-1-one

[0408]

[0409] The title compound (3.7 mg, yield: 5%) was obtained in the same manner as in Example 17, except that 1-(piperidin-4-yl)ethanone hydrochloride was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0410] 1 H NMR (500MHz, CDCl3): δ 8.10 (d, 2H), 7.41 (s, 1H), 7.05 (s, 1H), 4.99 (d, 2H), 4.23 (t, 1H), 4.04 (s, 3H), 3.97 (s, 3H), 3.04 (s, 2H), 2.63 (t, 1H), 2.30 (d, 2H), 2.23 (s, 3H), 2.05-1.96 (m, 4H), 1.88-1.79 (m, 3H), 1.74-1.68 (m, 2H), 1.54-1.46 (m, 2H), 1.34 (t, 1H)

[0411]

[0412] Example 28: Preparation of 1-(6,7-dimethoxy-4-(5-phenylthiophen-2-yl)quinazolin-2-yl)piperidine-4-carboxamide

[0413]

[0414] The title compound (10 mg, yield: 8%) was obtained in the same manner as in Example 17, except that 5-phenylthiophene-2-boronic acid pinacol ester was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 17 and that isonipecotamide was used instead of N-methylpiperidine-4-carboxamide in step 2.

[0415] 1 H NMR (500MHz, CDCl3): δ 7.74 (dd, 3H), 7.59 (s, 1H), 7.47-7.48 (m, 3H), 7.37 (t, 1H), 7.08 (s, 1H), 5.58 (d, 2H), 5.06 (d, 2H), 4.05 (s, 3H), 4.00 (s, 3H), 3.05 (t, 2H), 2.50 (t, 1H), 2.06 (d, 2H), 1.85-1.76 (m, 2H)

[0416]

[0417] Example 29: Preparation of 1-(6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-3-yl)quinazolin-2-yl)piperidine-4-carboxamide

[0418]

[0419] The title compound (2.2 mg, yield: 3%) was obtained in the same manner as in Example 28, except that 1-phenyl-1H-pyrazole-3-boronic acid pinacol ester was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 17 and that isonipecotamide was used instead of N-methylpiperidine-4-carboxamide in step 2.

[0420] 1 H NMR (500MHz, CDCl3): δ 8.85 (s, 1H), 8.08 (s, 1H), 7.86 (d, 2H), 7.54 (t, 2H), 7.38 (s, 2H), 7.07 (s, 1H), 5.57 (s, 1H), 5.11 (d, 2H), 4.07 (s, 6H), 3.06 (s, 2H), 2.86 (d, 3H), 2.44 (t, 1H), 2.50 (d, 2H), 1.87-1.79 (m, 2H)

[0421]

[0422] Example 30: Preparation of 1-(6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-3-yl)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide

[0423]

[0424] The title compound (1.8 mg, yield: 2%) was obtained in the same manner as in Example 17, except that 1-phenyl-1H-pyrazole-3-boronic acid pinacol ester was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 17.

[0425] 1H NMR (500MHz, CDCl3): δ 8.85 (s, 1H), 8.08 (s, 1H), 7.85 (d, 2H), 7.54 (t, 2H), 7.39 (s, 2H), 7.07 (s, 1H), 5.56 (d, 2H), 5.10 (d, 2H), 4.08 (s, 6H), 3.09 (s, 2H), 2.52 (t, 1H), 2.09 (d, 2H), 1.85 (d, 2H)

[0426]

[0427] Example 31: Preparation of 1-(6,7-dimethoxy-4-(2-phenylthiazol-5-yl)quinazolin-2-yl)piperidine-4-carboxamide

[0428]

[0429] The title compound (2.7 mg, yield: 2%) was obtained in the same manner as in Example 17, except that 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 17 and that isonipecotamide was used instead of N-methylpiperidine-4-carboxamide in step 2.

[0430] 1 H NMR (500MHz, CDCl3): δ 8.50 (s, 1H), 8.09 (d, 2H), 7.53 (s, 4H), 7.07 (s, 1H), 5.55 (d, 2H), 5.03 (s, 2H), 4.08 (s, 3H), 4.01 (s, 3H), 3.09 (s, 2H), 2.52 (s, 1H), 2.06 (s, 2H), 1.82 (s, 2H)

[0431]

[0432] Example 32: Preparation of 1-(6,7-dimethoxy-4-(2-phenylthiazol-5-yl)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide

[0433]

[0434] The title compound (6.7 mg, yield: 6%) was obtained in the same manner as in Example 17, except that 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 17.

[0435] 1 H NMR (500MHz, CDCl3): δ 8.48 (s, 1H), 8.09 (d, 2H), 7.52 (m, 4H), 7.09 (s, 1H), 5.58 (s, 1H), 5.03 (d, 2H), 4.06 (s, 3H), 4.00 (s, 3H), 3.03 (t, 2H), 2.87 (d, 3H), 2.43 (t, 1H), 2.03 (d, 2H), 1.85-1.78 (m, 2H)

[0436]

[0437] Example 33: Preparation of 1-(6,7-dimethoxy-4-(5-phenylthiophen-2-yl)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide

[0438]

[0439] The title compound (9 mg, yield: 8%) was obtained in the same manner as in Example 17, except that 5-phenylthiophene-2-boronic acid pinacol ester was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 17.

[0440] 1 H NMR (500MHz, CDCl3): δ 7.75 (dd, 3H), 7.59 (s, 1H), 7.47-7.44 (m, 3H), 7.38 (t, 1H), 7.09 (s, 1H), 5.60 (s, 1H), 5.06 (d, 2H), 4.05 (s, 3H), 4.00 (s, 3H), 3.03 (t, 2H), 2.85 (d, 3H), 2.42 (t, 1H), 2.03 (d, 2H), 1.84-1.77 (m, 2H)

[0441]

[0442] Example 34: Preparation of 1-(4-(1-cyclopentyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide

[0443]

[0444] The title compound (14 mg, yield: 19%) was obtained in the same manner as in Example 17, except that 1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 17 and that isonipecotamide was used instead of N-methylpiperidine-4-carboxamide in step 2.

[0445] 1H NMR (500 MHz, CDCl3): δ 8.10 (d, 2H), 7.40 (s, 1H), 7.04 (s, 1H), 5.58 (d, 2H), 5.04 (d, 2H), 4.78 (t, 1H), 4.04 (s, 3H), 3.96 (s, 3H), 3.01 (t, 2H), 2.47 (t, 1H), 2.29-2.24 (m, 2H), 2.18-2.12 (m, 2H), 2.05 (d, 2H), 1.96 (t, 2H), 1.82-1.75 (m, 2H)

[0446]

[0447] Example 35: Preparation of 1-(4-(1-cyclopentyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide

[0448]

[0449] The title compound (4.5 mg, yield: 6%) was obtained in the same manner as in Example 17, except that 1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 17.

[0450] 1 H NMR (500MHz, CDCl3): δ 8.10 (d, 2H), 7.40 (s, 1H), 7.07 (s, 1H), 5.57 (s, 1H), 5.05 (d, 2H), 4.78 (t, 1H), 4.04 (s, 3H), 3.96 (s, 3H), 2.99 (s, 2H), 2.87 (d, 3H), 2.41 (t, 1H), 2.29-2.25 (m, 2H), 2.18-2.13 (m, 2H), 2.02-1.96 (m, 4H), 1.82-1.76 (m, 4H)

[0451]

[0452] Example 36: Preparation of 1-(4-(1-cyclobutyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide

[0453]

[0454] The title compound (8.8 mg, yield: 19%) was obtained in the same manner as in Example 17, except that 1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 17 and that isonipecotamide was used instead of N-methylpiperidine-4-carboxamide in step 2.

[0455] 1 H NMR (500MHz, CDCl3): δ 8.11 (d, 2H), 7.39 (s, 1H), 7.05 (s, 1H), 5.57 (d, 2H), 5.04 (d, 2H), 4.94-4.87 (m, 1H), 4.04 (s, 3H), 3.96 (s, 3H), 3.03 (t, 2H), 2.72-2.64 (m, 2H), 2.62-2.56 (m, 2H), 2.48 (t, 1H), 2.06 (d, 2H), 2.01-1.89 (m, 2H), 1.83-1.76 (m, 2H)

[0456]

[0457] Example 37: Preparation of 1-(4-(1-cyclobutyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide

[0458]

[0459] The title compound (4.4 mg, yield: 10%) was obtained in the same manner as in Example 17, except that 1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 17.

[0460] 1 H NMR (500MHz, CDCl3): δ 8.11 (d, 2H), 7.39 (s, 1H), 7.03 (s, 1H), 5.57 (s, 2H), 5.04 (d, 2H), 4.89 (t, 1H), 4.04 (s, 3H), 3.96 (s, 3H), 2.98 (t, 2H), 2.86 (d, 3H), 2.72-2.64 (m, 2H), 2.61-2.56 (m, 2H), 2.40 (t, 1H), 2.02-1.90 (m, 4H), 1.83-1.75 (m, 2H)

[0461]

[0462] Example 38: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylpyrrolidine-3-carboxamide

[0463]

[0464] The title compound (9.7 mg, yield: 13%) was obtained in the same manner as in Example 17, except that N-methylpyrrolidine-3-carboxamide was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0465] 1H NMR (500MHz, CDCl3): δ 8.10 (s, 2H), 7.42 (s, 1H), 7.11 (s, 1H), 5.77 (s, 1H), 4.23 (t, 1H), 4.08-3.99 (m, 2H), 4.03 (s, 3H), 3.96 (s, 3H), 3.92-3.87 (m, 1H), 3.77-3.73 (m, 1H), 3.05 (t, 1H), 2.87 (d, 3H), 2.36-2.27 (m, 4H), 2.01-1.96 (m, 2H), 1.87-1.79 (m, 3H), 1.53-1.46 (m, 2H), 1.36-1.30 (m, 1H)

[0466]

[0467] Example 39: Preparation of 1-(1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)pyrrolidin-3-yl)-N,N-dimethylmethanamine

[0468]

[0469] The title compound (4.4 mg, yield: 6%) was obtained in the same manner as in Example 17, except that N,N-dimethyl-1-(pyrrolidin-3-yl)methanamine was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0470] 1H NMR (500MHz, CDCl3): δ 8.10 (s, 2H), 7.42 (s, 1H), 7.04 (s, 1H), 4.23 (t, 1H), 4.02-3.99 (m, 2H), 4.03 (s, 3H), 3.96 (s, 3H), 3.91 (t, 1H), 3.70-3.65 (m, 1H), 3.45-3.39 (m, 1H), 2.61-2.56 (m, 1H), 2.49 (s, 2H), 2.38 (s, 6H), 2.29 (d, 2H), 2.25-2.19 (m, 1H), 1.98 (d, 2H), 1.89-1.79 (m, 3H), 1.54-1.46 (m, 2H), 1.35 (t, 1H)

[0471]

[0472] Example 40: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N,N-dimethylpyrrolidine-3-carboxamide

[0473]

[0474] The title compound (8.9 mg, yield: 12%) was obtained in the same manner as in Example 17, except that N,N-dimethylpyrrolidine-3-carboxamide was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0475] 1H NMR (500MHz, CDCl3): δ 8.10 (s, 2H), 7.42 (s, 1H), 7.09 (s, 1H), 4.23 (t, 1H), 4.15 (t, 1H), 4.04 (s, 3H), 4.03-4.00 (m, 1H), 3.96 (s, 3H), 3.89-3.73 (m, 2H), 3.42 (t, 1H), 3.17 (s, 3H), 3.02 (s, 3H), 2.39 (t, 1H), 2.29 (d, 3H), 1.98 (d, 2H), 1.87-1.78 (m, 3H), 1.53-1.45 (m, 2H), 1.37-1.31 (m, 1H)

[0476]

[0477] Example 41: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N,N-dimethylpiperidine-4-carboxamide

[0478]

[0479] The title compound (5.9 mg, yield: 8%) was obtained in the same manner as in Example 17, except that N,N-dimethylpiperidine-4-carboxamide was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0480] 1 H NMR (500MHz, CDCl3): δ 8.09 (d, 2H), 7.41 (s, 1H), 7.01 (s, 1H), 5.05 (d, 2H), 4.23 (t, 1H), 4.04 (s, 3H), 3.96 (s, 3H), 3.14 (s, 3H), 2.99 (s, 3H), 2.81 (s, 1H), 2.29 (d, 2H), 1.99 (d, 3H), 1.91-1.79 (m, 8H), 1.54-1.46 (m, 2H), 1.34 (t, 1H)

[0481]

[0482] Example 42: Preparation of 4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-N,N-dimethylquinazolin-2-amine

[0483]

[0484] The title compound (7.8 mg, yield: 13%) was obtained in the same manner as in Example 17, except that dimethyl amine was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0485] 1 H NMR (500MHz, CDCl3): δ 8.11 (d, 2H), 7.41 (s, 1H), 6.98 (s, 1H), 4.23 (t, 1H), 4.05 (s, 3H), 3.97 (s, 3H), 3.34 (s, 6H), 2.30 (d, 2H), 1.98 (d, 2H), 1.88-1.79 (m, 3H), 1.54-1.46 (m, 2H), 1.34 (t, 1H)

[0486]

[0487] Example 43: Preparation of 4-(1-cyclohexyl-1H-pyrazol-4-yl)-N-isopropyl-6,7-dimethoxy-N-methylquinazolin-2-amine

[0488]

[0489] The title compound (1.9 mg, yield: 3%) was obtained in the same manner as in Example 17, except that N-methyl-isopropyl amine was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0490] 1H NMR (500 MHz, CDCl3): δ 8.10 (d, 2H), 7.40 (s, 1H), 7.00 (s, 1H), 5.34 (t, 1H), 4.24 (t, 1H), 4.04 (s, 3H), 3.96 (s, 3H), 3.13 (s, 3H), 2.30 (d, 2H), 1.99 (d, 2H), 1.88-1.79 (m, 3H), 1.55-1.47 (m, 2H), 1.34 (t, 1H), 1.26 (t, 6H), 1.25-1.20 (m, 2H)

[0491]

[0492] Example 44: Preparation of 4-(1-cyclohexyl-1H-pyrazol-4-yl)-N,N-diethyl-6,7-dimethoxyquinazolin-2-amine

[0493]

[0494] The title compound (7.3 mg, yield: 11%) was obtained in the same manner as in Example 17, except that diethylamine was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0495] 1 H NMR (500MHz, CDCl3): δ 8.10 (d, 2H), 7.39 (s, 1H), 6.98 (s, 1H), 4.23 (t, 1H), 4.04 (s, 3H), 3.96 (s, 3H), 3.81-3.77 (m, 4H), 2.29 (d, 2H), 1.99 (d, 2H), 1.89-1.79 (m, 3H), 1.54-1.46 (m, 2H), 1.38-1.24 (m, 6H), 1.34 (t, 1H)

[0496]

[0497] Example 45: Preparation of 1-(6,7-dimethoxy-4-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide

[0498]

[0499] The title compound (11.9 mg, yield: 10%) was obtained in the same manner as in Example 17, except that 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1 of Example 17 and that isonipecotamide was used instead of N-methylpiperidine-4-carboxamide in step 2.

[0500] 1 H NMR (500 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.58 (d, 2H), 8.09 (d, 2H), 7.47 (s, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 7.00 (s, 1H), 6.80 (s, 1H), 4.88 (d, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 2.96 (t, 2H), 1.84 (d, 2H), 1.55 (d, 2H)

[0501]

[0502] Example 46: Preparation of 1-(6,7-dimethoxy-4-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide

[0503]

[0504] The title compound (8.7 mg, yield: 7%) was obtained in the same manner as in Example 17, except that 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyrazol-1-yl]pyridine was used instead of 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and isonipecotamide was used instead of N-methylpiperidine-4-carboxamide.

[0505] 1 H NMR (500MHz, CD3OD): δ 9.18 (s, 1H), 9.02 (s, 1H), 8.58 (d, 1H), 8.40 (d, 2H), 7.65 (dd, 1H), 7.42 (s, 1H), 7.04 (s, 1H), 4.64 (s, 2H), 3.99 (s, 3H), 3.96 (s, 3H), 3.03 (t, 2H), 2.58 (t, 1H), 1.95 (d, 2H), 1.79-1.71 (m, 2H)

[0506]

[0507] Example 47:N 1 -(4-(1-Cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N 2 ,N 2 - Manufacture of dimethylethane-1,2-diamine

[0508]

[0509] The title compound (3.8 mg, yield: 6%) was obtained in the same manner as in Example 17, except that N,N-Dimethylethylenediamine was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0510] 1H NMR (500MHz, CDCl3): δ 8.14 (d, 2H), 7.44 (s, 1H), 7.03 (s, 1H), 5.88 (s, 1H), 5.37 (s, 1H), 4.23 (t, 1H), 4.05 (s, 3H), 3.97 (s, 3H), 3.86 (s, 2H), 3.01 (s, 2H), 2.62 (s, 6H), 2.28 (d, 2H), 2.10-1.96 (m, 2H), 1.87-1.79 (m, 3H), 1.54-1.46 (m, 2H), 1.42-1.33 (m, 1H)

[0511]

[0512] Example 48: Preparation of 4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-N-((tetrahydrofuran-2-yl)methyl)quinazolin-2-amine

[0513]

[0514] The title compound (3.4 mg, yield: 7%) was obtained in the same manner as in Example 17, except that (+ / -)-tetrahydrofurfurylamine was used instead of N-methylpiperidine-4-carboxamide in step 2 of Example 17.

[0515] 1 H NMR (500MHz, CDCl3): δ 8.09 (d, 2H), 7.43 (s, 1H), 7.07 (s, 1H), 4.27-4.18 (m, 1H), 4.18-4.06 (m, 2H), 4.05 (s, 3H), 3.98 (s, 3H), 3.85-3.77 (m, 2H), 3.69 (s, 1H), 2.29 (d, 2H), 2.13-2.02 (m, 2H), 1.99-1.94 (m, 2H), 1.87-1.75 (m, 3H), 1.54-1.47 (m, 2H), 1.38-1.29 (m, 1H)

[0516]

[0517] Example 49: Preparation of (1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl)methanamine

[0518]

[0519] (Step 1)

[0520] 2,4-dichloro-6,7-dimethoxyquinazoline (800 mg, 1.0 eq) was dissolved in 1,4-dioxane / water (12 mL, 4:1). Potassium carbonate (1.2 g, 2.5 eq), 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.06 g, 1.1 eq), and tetrakis(triphenylphosphine) palladium(0) (201 mg, 0.05 eq) were added, and the reaction mixture was microwaved at 120°C for 1 hour. After completion of the reaction, NH4Cl aqueous solution was added, and the organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1:1) to obtain 2-chloro-4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazoline (yield 24%, 312 mg).

[0521]

[0522] (Step 2)

[0523] 2-Chloro-4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazoline (30 mg, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and tert-butyl N-(piperidin-4-ylmethyl)carbamate (35 mg, 2.0 eq) and triethylamine (34 μL, 3.0 eq) were added. The reaction mixture was heated to 110°C, and after 12 hours of reaction, the reaction was confirmed to be complete, and the mixture was concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1:1) to obtain tert-butyl((1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl)methyl)carbamate (yield 36%, 16 mg).

[0524]

[0525] (Step 3)

[0526] tert-Butyl((1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl)methyl)carbamate (16 mg, 1.0 eq) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (20 μL, 10.0 eq) was added. After the reaction was allowed to react for 4 hours, the starting material disappeared, and the solvent was removed under reduced pressure. The obtained residue was basified by adding 1 N aqueous NaOH solution, and the organic layer was separated using water and dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (yield 62%, 8.1 mg).

[0527] 1H NMR (500MHz, CDCl3): δ 8.08 (s, 2H), 7.39 (s, 1H), 6.98 (s, 1H), 5.05 (d, 2H), 4.21 (t, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.68 (m, 2H), 2.97 (t, 2H), 2.81 (d, 2H), 2.67 (d, 2H), 2.07-2.01 (m, 1H), 1.97 (d, 4H), 1.86-1.76 (m, 5H), 1.52-1.44 (m, 2H), 1.34-1.29 (m, 1H)

[0528]

[0529] Example 50: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-2-yl)piperidine-4-carboxamide

[0530]

[0531] (Step 1)

[0532] 2,4-dichloro-7-methoxyquinazoline (100 mg, 1.0 eq) was dissolved in 1,4-dioxane / water (4 mL, 4:1), and potassium carbonate (120 mg, 2.0 eq), 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (120 mg, 1.0 eq), and tetrakis(triphenylphosphine) palladium(0) (25 mg, 0.05 eq) were added, and the reaction mixture was microwaved at 110 oThe reaction was carried out at C for 1 hour. After completion of the reaction, NH4Cl aqueous solution was added, and the organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1:3) to obtain 2-chloro-4-(1-cyclohexyl-1H-pyrazol-4-yl)-7-methoxyquinazoline (yield 70.2%, 105 mg).

[0533]

[0534] (Step 2)

[0535] 2-Chloro-4-(1-cyclohexyl-1H-pyrazol-4-yl)-7-methoxyquinazoline (30 mg, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and isonipecotamide (22 mg, 2.0 eq) and triethylamine (20 μL, 2.0 eq) were added. The reaction mixture was heated to 110°C and reacted for 12 hours. After confirming the completion of the reaction, the residue obtained by concentration under reduced pressure was purified by column chromatography (ethyl acetate: hexane = 1:1) to obtain the title compound (yield 15.8%, 6 mg).

[0536] 1 H NMR (500MHz, CDCl3): δ 8.08 (d, 2H), 7.99 (d, 1H), 7.00 (s, 1H), 6.87 (d, 1H), 5.58 (d, 2H), 5.09 (d, 2H), 4.23 (t, 1H), 3.94 (s, 3H), 3.06 (t, 2H), 2.49 (t, 1H), 2.29 (d, 2H), 2.07 (d, 2H), 1.98 (d, 2H), 1.85-1.78 (m, 5H), 1.53-1.45 (m, 2H), 1.33 (t, 1H)

[0537]

[0538] Example 51: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide

[0539]

[0540] The title compound (30.9 mg, yield: 7%) was obtained in the same manner as in Example 50, except that N-methylpiperidine-4-carboxamide was used instead of isonipecotamide in step 2 of Example 50.

[0541] 1 H NMR (500MHz, CDCl3): δ 8.08 (d, 2H), 7.99 (d, 1H), 6.96 (s, 1H), 6.86 (d, 1H), 5.56 (s, 1H), 5.09 (d, 2H), 4.23 (t, 1H), 3.95 (s, 3H), 3.01 (t, 2H), 2.86 (d, 3H), 2.41 (t, 1H), 2.29 (d, 2H), 1.98 (t, 4H), 1.87-1.75 (m, 5H), 1.53-1.45 (m, 2H), 1.36-1.29 (m, 1H)

[0542]

[0543] Example 52: Preparation of 4-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-2-yl)piperazine-1-carboxamide

[0544]

[0545] The title compound (5.1 mg, yield: 9%) was obtained in the same manner as in Example 50, except that piperazine-1-carboxylic acid amide hydrochloride was used instead of isonipecotamide in step 2 of Example 50.

[0546] 1H NMR (500MHz, CDCl3): δ 8.09 (d, 2H), 8.02 (d, 1H), 6.98 (s, 1H), 6.90 (d, 1H), 4.65 (s, 2H), 4.24 (t, 1H), 4.05 (s, 4H), 3.96 (s, 3H), 3.57 (s, 4H), 2.28 (d, 2H), 1.99 (d, 2H), 1.88-1.78 (m, 3H), 1.53-1.45 (m, 2H), 1.34 (t, 1H)

[0547]

[0548] Example 53: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6-methoxyquinazolin-2-yl)piperidine-4-carboxamide

[0549]

[0550] (Step 1)

[0551] 2,4-dichloro-6-methoxy-quinazoline (100 mg, 1.0 eq) was dissolved in 1,4-dioxane / water (4 mL, 4:1). Potassium carbonate (120 mg, 2.0 eq), 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (120 mg, 1.0 eq), and tetrakis(triphenylphosphine) palladium(0) (25 mg, 0.05 eq) were added, and the reaction mixture was microwaved at 110°C for 1 hour. After completion of the reaction, NH4Cl aqueous solution was added, and the organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1:3) to obtain 2-chloro-4-(1-cyclohexyl-1H-pyrazol-4-yl)-6-methoxyquinazoline (yield 85.5%, 98 mg).

[0552]

[0553] (Step 2)

[0554] 2-Chloro-4-(1-cyclohexyl-1H-pyrazol-4-yl)-6-methoxyquinazoline (30 mg, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and isonipecotamide (22 mg, 2.0 eq) and triethylamine (20 μL, 2.0 eq) were added. The reaction mixture was heated to 110°C and reacted for 12 hours. After confirming the completion of the reaction, the residue obtained by concentrating under reduced pressure was purified by column chromatography (ethyl acetate: hexane = 1:1) to obtain the title compound (yield 13.8%, 6 mg).

[0555] 1H NMR (500MHz, CDCl3): δ 8.14 (d, 2H), 7.66 (s, 1H), 7.46 (s, 1H), 7.39 (d, 1H), 5.55 (d, 2H), 5.04 (d, 2H), 4.24 (t, 1H), 3.90 (s, 3H), 3.05 (t, 2H), 2.49 (t, 1H), 2.30 (d, 2H), 2.07 (d, 2H), 1.99 (d, 2H), 1.89-1.77 (m, 5H), 1.54-1.46 (m, 2H), 1.35 (t, 1H)

[0556]

[0557] Example 54: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6-methoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide

[0558]

[0559] The title compound (20.6 mg, yield: 8%) was obtained in the same manner as in Example 53, except that N-methylpiperidine-4-carboxamide was used instead of isonipecotamide in step 2 of Example 53.

[0560] 1 H NMR (500MHz, CDCl3): δ 8.13 (d, 2H), 7.59 (s, 1H), 7.46 (s, 1H), 7.39 (d, 1H), 5.53 (s, 1H), 5.05 (d, 2H), 4.24 (t, 1H), 3.89 (s, 3H), 2.99 (t, 2H), 2.86 (d, 3H), 2.40 (t, 1H), 2.30 (d, 2H), 1.99 (t, 4H), 1.89-1.75 (m, 5H), 1.54-1.46 (m, 2H), 1.35 (t, 1H)

[0561]

[0562] Example 55: Preparation of N-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylmorpholine-4-carboxamide

[0563]

[0564] (Step 1)

[0565] 2,4-dichloro-6,7-dimethoxyquinazoline (600 mg, 1.0 eq) was dissolved in 1,4-dioxane / water (4 mL, 4:1). Potassium carbonate (960 mg, 3.0 eq), 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (831 mg, 1.3 eq), and tetrakis(triphenylphosphine) palladium(0) (133 mg, 0.05 eq) were added, and the reaction mixture was microwaved at 120°C for 1 hour. After completion of the reaction, an aqueous NH4Cl solution was added, and the organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1:3) to obtain 2-chloro-4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazoline (yield 50.1%, 433 mg).

[0566]

[0567] (Step 2)

[0568] 2-Chloro-4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazoline (270 mg, 1.0 eq) was dissolved in tetrahydrofuran (6 mL), and methylamine in MeOH (3 mL) was added thereto. The reaction mixture was stirred in a sealed tube at 90°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (methylene chloride: methanol = 20:1) to obtain 4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-N-methylquinazolin-2-amine (yield 45.1%, 120 mg).

[0569]

[0570] (Step 3)

[0571] 4-(1-Cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-N-methylquinazolin-2-amine (35 mg, 1.0 eq) was dissolved in dichloromethane (2 mL), and 4-morpholinecarbonyl chloride (28 mg, 2.0 eq) and N,N-diisopropylethylamine (40 μL, 2.0 eq) were added. The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (methylene chloride: methanol = 20:1) to obtain the title compound (yield 21.8%, 10 mg).

[0572] 1H NMR (500MHz, CDCl3): δ 8.13 (d, 2H), 7.49 (s, 1H), 7.12 (s, 1H), 4.29-4.20 (m, 1H), 4.07 (s, 3H), 4.01 (s, 3H), 3.73-3.67 (m, 4H), 3.55 (s, 4H), 3.47 (s, 3H), 2.29 (d, 2H), 1.99 (d, 2H), 1.88-1.79 (m, 3H), 1.56-1.45 (m, 2H), 1.37-1.30 (m, 1H)

[0573]

[0574] Example 56: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3-isopropyl-1,3-dimethylurea

[0575]

[0576] (Step 1)

[0577] 4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-N-methylquinazolin-2-amine (50 mg, 1.0 eq) was dissolved in acetonitrile (2 mL), and 4-nitrophenyl chloroformate (35 mg, 1.3 eq) and potassium carbonate (37 mg, 2 eq) were added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, an aqueous NH4Cl solution was added, and the organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained by concentration under reduced pressure was purified by column chromatography (ethyl acetate: hexane = 1:1) to obtain 4-nitrophenyl(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)(methyl)carbamate (yield 91.9%, 66 mg).

[0578]

[0579] (Step 2)

[0580] 4-Nitrophenyl(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)(methyl)carbamate (33 mg, 1.0 eq) was dissolved in acetonitrile / DMF 1:1 (2 mL), to which N-methylisopropylamine (10 μL, 1.0 eq) and potassium carbonate (27 mg, 3 eq) were added, and the reaction mixture was reacted at 40°C for 4 h. After completion of the reaction, NH4Cl aqueous solution was added, and the organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained by concentration under reduced pressure was purified by column chromatography (methylene chloride: methanol = 20:1) to obtain the title compound (yield 62.6%, 18.1 mg).

[0581] 1 H NMR (500MHz, CDCl3): δ 8.09 (d, 2H), 7.47 (s, 1H), 7.09 (s, 1H), 5.32 (s, 1H), 4.22 (t, 1H), 4.06 (s, 3H), 4.00 (s, 3H), 3.44 (s, 3H), 2.78 (s, 3H), 2.27 (d, 2H), 1.98 (d, 2H), 1.84-1.76 (m, 3H), 1.54-1.45 (m, 2H), 1.35-1.28 (m, 1H), 1.20 (d, 6H),

[0582]

[0583] Example 57: Preparation of (S)-N-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3-fluoro-N-methylpyrrolidine-1-carboxamide

[0584]

[0585] The title compound (16.2 mg, yield: 12%) was obtained in the same manner as in Example 56, except that (s)-(+)-3-fluoropyrrolidine hydrochloride was used instead of N-methylisopropylamine in step 2 of Example 56.

[0586] 1 H NMR (500MHz, CDCl3): δ 8.13 (d, 2H), 7.53 (s, 1H), 7.15 (s, 1H), 7.34 (t, 1H), 4.22 (t, 1H), 4.07 (s, 3H), 4.02 (s, 3H), 3.92-3.68 (m, 2H), 3.68-3.54 (m, 2H), 3.56 (s, 3H), 2.26 (d, 2H), 1.98 (d, 2H), 1.85-1.76 (m, 3H), 1.54-1.45 (m, 2H), 1.36-1.28 (m, 1H)

[0587]

[0588] Example 58: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3,3-diethyl-1-methylurea

[0589]

[0590] The title compound (7.2 mg, yield: 4%) was obtained in the same manner as in Example 56, except that diethylcarbamoyl chloride was used instead of N-methylisopropylamine in step 2 of Example 56.

[0591] 1H NMR (500MHz, CDCl3): δ 8.10 (d, 2H), 7.48 (s, 1H), 7.11 (s, 1H), 4.22 (t, 1H), 4.07 (s, 3H), 3.99 (s, 3H), 3.43 (s, 3H), 3.22-3.17 (m, 4H), 2.28 (d, 2H), 1.98 (d, 2H), 1.79 (t, 3H), 1.53-1.46 (m, 2H), 1.36-1.27 (m, 1H), 1.13 (t, 6H)

[0592]

[0593] Example 59: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3-(2,2-difluoroethyl)-1-methylurea

[0594]

[0595] The title compound (18 mg, yield: 18%) was obtained in the same manner as in Example 56, except that 2,2-difluoroethylamine was used instead of N-methylisopropylamine in step 2 of Example 56.

[0596] 1 H NMR (500MHz, CDCl3): δ 11.02 (s, 1H), 8.13 (s, 2H), 7.52 (s, 1H), 7.14 (s, 1H), 6.02 (t, 1H), 4.26 (t, 1H), 4.09 (s, 3H), 4.04 (s, 3H), 3.87 (t, 2H), 3.71 (s, 3H), 2.30 (d, 2H), 1.99 (d, 2H), 1.89-1.79 (m, 3H), 1.55-1.47 (m, 2H), 1.36 (t, 1H)

[0597]

[0598] Example 60: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3-(2-(dimethylamino)ethyl)-1-methylurea

[0599]

[0600] The title compound (17.4 mg, yield: 12%) was obtained in the same manner as in Example 56, except that N,N-dimethylethylenediamine was used instead of N-methylisopropylamine in step 2 of Example 56.

[0601] 1 H NMR (500MHz, CDCl3): δ 10.81 (s, 1H), 8.17 (d, 2H), 7.49 (s, 1H), 7.18 (s, 1H), 4.25 (t, 1H), 4.09 (s, 3H), 4.02 (s, 3H), 3.69 (s, 3H), 3.62 (m, 2H), 2.66 (s, 2H), 2.42 (s, 6H), 2.30 (d, 2H), 1.99 (d, 2H), 1.90-1.78 (m, 3H), 1.55-1.48 (m, 2H), 1.35 (t, 1H)

[0602]

[0603] Example 61: Preparation of 2-(diethylamino)ethyl (4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)(methyl)carbamate

[0604]

[0605] The title compound (4.3 mg, yield: 5%) was obtained in the same manner as in Example 56, except that 2-diethylaminoethanol hydrochloride was used instead of N-methylisopropylamine in step 2 of Example 56.

[0606] 1H NMR (500 MHz, CDCl3): δ 8.18 (d, 2H), 7.57 (s, 1H), 7.29 (s, 1H), 4.39 (s, 2H), 4.25 (t, 1H), 4.08 (s, 3H), 4.04 (s, 3H), 3.56 (s, 3H), 2.89 (s, 2H), 2.66 (s, 4H), 2.29 (d, 2H), 1.99 (d, 2H), 1.88-1.79 (m, 3H), 1.55-1.47 (m, 2H), 1.34 (t, 1H), 1.05 (s, 6H)

[0607]

[0608] Example 62: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-1-methylurea

[0609]

[0610] The title compound (3.2 mg, yield: 2%) was obtained in the same manner as in Example 56, except that ammonia was used instead of N-methylisopropylamine in step 2 of Example 56.

[0611] 1 H NMR (500MHz, CDCl3): δ 10.24 (s, 1H), 8.13 (d, 2H), 7.51 (s, 1H), 7.15 (s, 1H), 4.26 (t, 1H), 4.09 (s, 3H), 4.03 (s, 3H), 3.71 (s, 3H), 2.31 (d, 2H), 2.01 (d, 2H), 1.90-1.80 (m, 3H), 1.56-1.48 (m, 2H), 1.35 (t, 1H)

[0612]

[0613] Example 63: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-1,3-dimethylurea

[0614]

[0615] The title compound (15.9 mg, yield: 18%) was obtained in the same manner as in Example 56, except that methylamine was used instead of N-methylisopropylamine in step 2 of Example 56.

[0616] 1 H NMR (500MHz, CDCl3): δ 10.42 (s, 1H), 8.13 (d, 2H), 7.49 (s, 1H), 7.11 (s, 1H), 4.26 (t, 1H), 4.09 (s, 3H), 4.02 (s, 3H), 3.70 (s, 3H), 3.03 (s, 3H), 2.31 (d, 2H), 1.99 (d, 2H), 1.89-1.80 (m, 3H), 1.56-1.48 (m, 2H), 1.35 (t, 1H)

[0617]

[0618] Example 64: Preparation of 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-1,3,3-trimethylurea

[0619]

[0620] The title compound (12.4 mg, yield: 17%) was obtained in the same manner as in Example 56, except that dimethyl amine was used instead of N-methylisopropylamine in step 2 of Example 56.

[0621] 1 H NMR (500MHz, CDCl3): δ 8.12 (d, 2H), 7.49 (s, 1H), 7.14 (s, 1H), 4.23 (t, 1H), 4.07 (s, 3H), 4.00 (s, 3H), 3.47 (s, 3H), 3.02 (s, 6H), 2.29 (d, 2H), 1.98 (d, 2H), 1.86-1.78 (m, 3H), 1.55-1.47 (m, 2H), 1.35 (t, 1H)

[0622]

[0623] Example 65: Preparation of (E)-N'-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N,N-dimethylformamide

[0624]

[0625] (Step 1)

[0626] 2,4-Dichloro-6,7-dimethoxyquinazoline (600 mg, 1.0 eq) was dissolved in 1,4-dioxane / water (4 mL, 4:1). Potassium carbonate (960 mg, 3.0 eq), 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (831 mg, 1.3 eq), and tetrakis(triphenylphosphine) palladium(0) (133 mg, 0.05 eq) were added, and the reaction mixture was microwaved at 120°C for 1 hour. After completion of the reaction, NH4Cl aqueous solution was added, and the organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1:3) to obtain 2-chloro-4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazoline (yield 50.1%, 433 mg).

[0627]

[0628] (Step 2)

[0629] 2-Chloro-4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazoline (145 mg, 1.0 eq) was dissolved in ethanol (6 mL), and an aqueous solution of ammonia (2.5 mL) was added thereto. The reaction mixture was concentrated in a sealed tube at 110 oThe reaction was carried out for 16 hours at C. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain 4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-amine (yield 87.3%, 120 mg) without purification, and the next reaction was carried out.

[0630]

[0631] (Step 3)

[0632] 4-(1-Cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-amine (30 mg, 1.0 eq) was dissolved in toluene (2 mL). N,N-dimethylformamide dimethyl acetal (960 mg, 3.0 eq) and 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10 μL, 1.1 eq) were added, and the reaction mixture was microwaved at 90°C for 2 hours. After completion of the reaction, the residue obtained by concentration under reduced pressure was purified by column chromatography (methylene chloride: methanol = 20:1) to obtain the title compound (yield 22.5%, 7.8 mg).

[0633] 1 H NMR (500MHz, CDCl3): δ 8.82 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.51 (s, 1H), 7.34 (s, 1H), 4.23 (t, 1H), 4.06 (s, 3H), 3.99 (s, 3H), 3.24 (s, 3H), 3.22 (s, 3H), 2.29 (d, 2H), 1.98 (d, 2H), 1.86-1.77 (m, 3H), 1.54-1.45 (m, 2H), 1.36-1.29 (t, 1H)

[0634]

[0635] Example 66: Preparation of 1-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide

[0636]

[0637] (Step 1)

[0638] 2,4-Dichloro-6,7-dimethoxyquinazoline (80 mg, 1.0 eq) was dissolved in 1,4-dioxane / water (2.5 mL, 4:1). Potassium carbonate (106.6 mg, 2.5 eq), 4-pyrazole boronic acid pinacol ester (65 mg, 1.1 eq), and tetrakis(triphenylphosphine) palladium(0) (17.8 mg, 0.05 eq) were added, and the reaction mixture was microwaved at 120°C for 1 hour. After completion of the reaction, NH4Cl aqueous solution was added, and the organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1:1) to obtain 2-chloro-6,7-dimethoxy-4-(1H-pyrazol-4-yl)quinazoline (yield 22.3%, 20 mg).

[0639]

[0640] (Step 2)

[0641] 2-Chloro-6,7-dimethoxy-4-(1H-pyrazol-4-yl)quinazoline (20 mg, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and isonipecotamide (9 mg, 1.0 eq) and triethylamine (20 μL, 2.0 eq) were added. The reaction mixture was reacted at 110°C for 16 h. After completion of the reaction, the residue obtained by concentration under reduced pressure was purified by column chromatography (methylene chloride: methanol = 20:1) to obtain 1-(6,7-dimethoxy-4-(1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide (yield 53.2%, 14 mg).

[0642]

[0643] (Step 3)

[0644] 1-(6,7-Dimethoxy-4-(1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide (50 mg, 1.0 eq) was dissolved in N,N-dimethylformamide (2 mL). 4-fluoro-iodo-benzene (10 μL, 0.9 eq), copper iodide (2.4 mg, 0.1 eq), L-proline (0.27 mg, 0.2 eq), and cesium carbonate (85 mg, 2 eq) were added, and the reaction mixture was reacted at 110°C for 16 h. After completion of the reaction, the residue obtained by concentration under reduced pressure was purified by column chromatography (methylene chloride: methanol = 20:1) to obtain the title compound (yield 1.9%, 1.2 mg).

[0645] 1H NMR (500MHz, CDCl3): δ 8.48 (s, 1H), 8.29 (s, 1H), 7.80 (dd, 2H), 7.40 (s, 1H), 7.25 (t, 1H), 5.54 (d, 2H), 5.05 (s, 2H), 4.07 (s, 3H), 3.98 (s, 3H), 3.07 (s, 2H), 2.50 (s, 1H), 2.06 (d, 2H), 1.82 (s, 2H)

[0646]

[0647] Example 67: Preparation of 1-(6,7-dimethoxy-4-(1-(4-methoxycyclohexyl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide

[0648]

[0649] 1-(6,7-Dimethoxy-4-(1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxyamide (50 mg, 1.0 eq) was dissolved in acetonitrile (2 mL), to which cesium carbonate (85 mg, 2 eq) and 4-methoxycyclohexyl methanesulfonate (32 mg, 1.2 eq) were added, and the reaction mixture was reacted at 100°C for 16 hours. After completion of the reaction, the residue obtained by concentration under reduced pressure was purified by column chromatography (methylene chloride: methanol = 20:1) to obtain the title compound (yield 5.3%, 3.4 mg).

[0650] 1H NMR (500MHz, CDCl3): δ 8.12 (d, 2H), 7.39 (s, 1H), 7.07 (s, 1H), 5.54 (d, 2H), 5.04 (d, 2H), 4.28 (t, 1H), 4.04 (s, 3H), 3.97 (s, 3H), 3.43 (s, 3H), 3.02 (s, 2H), 2.48 (t, 1H), 2.33 (t, 4H), 2.18 (t, 1H), 2.08-1.93 (m, 2H), 1.91-1.77 (m, 2H), 1.52-1.44 (m, 2H)

[0651]

[0652] Example 68: Preparation of 1-(4-(1-(2-chloro-4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide

[0653]

[0654] The title compound (2.9 mg, yield: 2%) was obtained in the same manner as in Example 66, except that 3-chloro-4-fluoro benzotrifluoride was used instead of 4-fluoro-iodo-benzene in step 3 of Example 66.

[0655] 1 H NMR (500MHz, CDCl3): δ 8.64 (s, 1H), 8.38 (s, 1H), 7.95 (d, 1H), 7.89 (s, 1H), 7.75 (d, 1H), 7.41 (s, 1H), 7.07 (s, 1H), 5.53 (d, 2H), 5.05 (d, 2H), 4.07 (s, 3H), 3.99 (s, 3H), 3.05 (s, 2H), 2.50 (s, 1H), 2.06 (d, 2H), 1.87-1.74 (m, 2H)

[0656]

[0657] Example 69: Preparation of 1-(6,7-dimethoxy-4-(1-((1s,4s)-4-methylcyclohexyl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide

[0658]

[0659] The title compound (1 mg, yield: 1%) was obtained in the same manner as in Example 67, except that trans-4-methylcyclohexyl methanesulfonate was used instead of 4-methoxycyclohexyl methanesulfonate.

[0660] 1 H NMR (500MHz, CDCl3): δ 8.13 (d, 2H), 7.42 (s, 1H), 7.07 (s, 1H), 5.53 (d, 2H), 5.05 (d, 2H), 4.32 (t, 1H), 4.05 (s, 3H), 3.97 (s, 3H), 3.05 (s, 2H), 2.50 (s, 1H), 2.31-2.25 (m, 2H), 2.07-2.01 (m, 6H), 1.93-1.79 (m, 1H), 1.76-1.71 (m, 4H), 1.05 (d, 3H)

[0661]

[0662] Example 70: Preparation of 1-(6,7-dimethoxy-4-(1-((1r,4r)-4-methylcyclohexyl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide

[0663]

[0664] The title compound (4.3 mg, yield: 1%) was obtained in the same manner as in Example 67, except that cis-4-methylcyclohexyl methanesulfonate was used instead of 4-methoxycyclohexyl methanesulfonate.

[0665] 1 H NMR (500MHz, CDCl3): δ 8.09 (d, 2H), 7.42 (s, 1H), 7.07 (s, 1H), 5.53 (d, 2H), 5.05 (s, 2H), 4.22 (t, 1H), 4.06 (s, 3H), 3.98 (s, 3H), 3.19 (t, 1H), 3.06 (s, 1H), 2.53 (s, 1H), 2.30 (d, 2H), 2.09-2.04 (m, 4H), 1.96-1.80 (m, 6H), 1.01 (d, 3H)

[0666]

[0667] Examples 71 and 72: Preparation of 4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-2-(4-(methylsulfinyl)piperidin-1-yl)quinazoline and 4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-2-(4-(methylsulfonyl)piperidin-1-yl)quinazoline

[0668]

[0669] (Step 1)

[0670] 2,4-dichloro-6,7-dimethoxyquinazoline (800 mg, 1.0 eq) was dissolved in 1,4-dioxane / water (15 mL, 4:1). Potassium carbonate (106.6 g, 2.5 eq), 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (938 mg, 1.1 eq), and tetrakis(triphenylphosphine) palladium(0) (178 mg, 0.05 eq) were added, and the reaction mixture was microwaved at 120°C for 1 hour. After completion of the reaction, NH4Cl aqueous solution was added, and the organic layer was separated using water and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1:1) to obtain 2-chloro-4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazoline (yield 13.9%, 100 mg).

[0671]

[0672] (Step 2)

[0673] 2-Chloro-4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazoline (100 mg, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and 4-methylthiopiperidine hydrochloride (67 mg, 1.5 eq) and triethylamine (0.11 mL, 3.0 eq) were added, and the reaction mixture was stirred at 110 oThe reaction was carried out at C for 16 hours. After completion of the reaction, the residue obtained by concentration under reduced pressure was purified by column chromatography (ethyl acetate: hexane = 1:1) to obtain 4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-2-(4-(methylthio)piperidin-1-yl)quinazoline (yield 78.2%, 100 mg).

[0674]

[0675] (Step 3)

[0676] 4-(1-Cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-2-(4-(methylthio)piperidin-1-yl)quinazoline (100 mg, 1.0 eq) was dissolved in dichloromethane (2 mL), and 3-chloroperbenzoic acid (47 mg, 1.0 eq) was added. The reaction was carried out at 0℃ for 1 hour. The reaction was terminated by adding aqueous NaHCO3 solution, and the organic layer was separated using water and dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (methylene chloride: methanol = 20:1) to obtain the title compound 71 (yield 6.3%, 6.4 mg) and compound 72 (yield 3.2%, 3.4 mg).

[0677]

[0678] #71

[0679] 1H NMR (500MHz, CDCl3): δ 8.10 (d, 2H), 7.42 (s, 1H), 7.03 (s, 1H), 5.12 (t, 2H), 4.25 (t, 1H), 4.04 (s, 3H), 3.97 (s, 3H), 3.11 (s, 2H), 2.87 (t, 1H), 2.61 (s, 3H), 2.29 (d, 4H), 1.99 (d, 2H), 1.89-1.74 (m, 4H), 1.55-1.47 (m, 3H), 1.37-1.32 (m, 1H)

[0680]

[0681] #72

[0682] 1 H NMR (500 MHz, CDCl3): δ 8.10 (d, 2H), 7.43 (s, 1H), 7.02 (s, 1H), 5.24 (d, 2H), 4.25 (t, 1H), 4.05 (s, 3H), 3.98 (s, 3H), 3.15 (t, 1H), 3.01 (s, 2H), 2.88 (s, 3H), 2.30 (d, 4H), 1.99 (d, 2H), 1.88-1.80 (m, 4H), 1.54-1.46 (d, 3H), 1.35 (t, 1H)

[0683]

[0684] Experimental Example 1: HSP47 Inhibitory Activity Test

[0685] For each of the compounds manufactured in the above examples and the comparative example compounds, HSP47 inhibitory activity tests were conducted as follows.

[0686]

[0687] HSP47 inhibitory activity was measured using a reagent that selectively detects collagen. 100 ng of collagen (Collagen from calf skin, C9791, Sigma-Aldrich) was shaken to induce aggregation, then 1 μg of HSP47 (Daewoong Pharmaceutical) was treated to alleviate collagen aggregation through HSP47-collagen binding and increase collagen detection value. Then, 100 μM of the compound to be evaluated was additionally treated to decrease the detection value. This method was used to calculate the inhibition percent and quantify the inhibitory activity. Specifically, the experiment was performed with shaking at 34°C for 2 hours, followed by analysis by Enzyme-Linked Immunosorbent Assay (ELISA) using TMB (3,3',5,5'-tetramethylbenzidine) as a substrate. The evaluation was performed with a minimum of duplicates to ensure the reliability of the results.

[0688]

[0689] The inhibitory activity of each compound was classified into A, B, and C as follows, and is shown in Table 1 below.

[0690] A: Denatured collagen assay, more than 120% inhibition at 100uM

[0691] B: Denatured collagen assay, 90-120% inhibition at 100uM

[0692] C: Denatured collagen assay, less than 90% inhibition at 100uM

[0693]

[0694] 실시예번호% inhibition at 100 uM(Denatured Collagen assay)실시예번호% inhibition at 100 uM(Denatured Collagen assay)실시예번호% inhibition at 100 uM(Denatured Collagen assay)1C26B51C2B27B52C3C28B53B4C29C54B5C30C55C6C31C56A7C32C57A8C33C58A9C34B59C10A35A60B11C36C61C12C37B62C13C38A63C14C39A64C15C40A65C16A41A66B17A42A67C18A43C68C19A44C69A20B45C70A21B46C71A22A47C72A23A48A24B49B25A50B

Claims

A compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, R1 is each independently hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, or C 1-4 It is haloalkoxy, a is an integer from 0 to 4, If a is 2 or more, two or more R1s are identical or different, A is a five-membered heteroaromatic ring containing one or two heteroatoms of N, O and S, R2 is C 1-10 Alkyl, C 3-10 Cycloalkyl, C 6-12 Aryl, or C containing one or more heteroatoms of N, O and S 2-10 It is heteroaryl, Here, R2 is unsubstituted or substituted with deuterium, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituted with one or more substituents selected from the group consisting of haloalkoxy, L is a single bond, -N(R a )-C(R b )(R c )-, -N(R a )-C(R b )(R c )-OL a -, or -N(R a )-C(R b )(R c )-N(R d )-L b -and, L a and L b are each independently C 1-4 Alkylene, or C 1-4 It is haloalkylene, R a Inland R d are each independently hydrogen, C 1-4 Alkyl, or C 1-4 Haloalkyl, R b is R a or combines with R to form a double bond, or c It can combine with to form oxo(=O), R3 is N(R4)(R5), R4 and R5 are each independently hydrogen, C 1-10 Alkyl, or C 1-10 haloalkyl, or N atom, R4 and R5 are combined with each other to form a 5-membered or 6-membered heterocycloalkane ring containing at least one heteroatom of N, O and S, Here, R3 is substituted or unsubstituted with one or more R, However, when there are two or more Rs, the two or more Rs may be the same or different, but the two Rs may combine with each other to form oxo (=O). R is -L c -L d -R', L c is a single bond, C 1-4 Alkylene, or C 1-4 It is haloalkylene, L d is a single bond, -CO-, -COO-, -SO-, -SO2-, -CON(R e )-, -N(R f )-, or -N(R g )COO-and, R e Inland R g are each independently hydrogen, C 1-4 Alkyl, or C 1-4 It is haloalkyl, R' is hydrogen, halogen, cyano, hydroxy, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-10 Cycloalkyl, or tetrahydrofuranyl, However, R2 is C 1-10 Alkyl or C 6-12 In the case of aryl, R3 is a 5- or 6-membered heterocycloalkane ring formed by the N atom, R4, and R5 bonding together. In the first paragraph, R1 is each independently hydrogen or methoxy, A compound, or a pharmaceutically acceptable salt thereof. In the first paragraph, is represented by any one of the following chemical formulas a1 to a3, A compound, or a pharmaceutically acceptable salt thereof: . In the first paragraph, A is a 5-membered heteroaromatic ring containing one or two heteroatoms of N and S, A compound, or a pharmaceutically acceptable salt thereof. In the first paragraph, A is a pyrazole, thiazole, or thiophene ring, A compound, or a pharmaceutically acceptable salt thereof. In the first paragraph, The above chemical formula 1 is represented by any one of the following chemical formulas 1-1 to 1-4, A compound, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1-1] [Chemical Formula 1-2] [Chemical Formula 1-3] [Chemical Formula 1-4] In the above chemical formulas 1-1 to 1-4, R1, a, R2, L and R3 are as defined in paragraph 1. In the first paragraph, R2 is methyl, ethyl, propyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridinyl, wherein R2 is unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy and ethoxy. A compound, or a pharmaceutically acceptable salt thereof. In the first paragraph, L is a single bond, -N=CH-, -N(CH3)-CO-, -N(CH3)-CO-NH-(CH2CH2)-, or -N(CH3)-CO-O-(CH2CH2)-, A compound, or a pharmaceutically acceptable salt thereof. In the first paragraph, R4 and R5 are each independently hydrogen, or C 1-4 It is alkyl, C above 1-4 Alkyl is each independently unsubstituted or substituted with one or two substituents selected from the group consisting of fluoro, -N(CH3)2 and tetrahydrofuranyl. A compound, or a pharmaceutically acceptable salt thereof. In the first paragraph, R3 is a pyrrolidine, pyrrolidine-2-one, piperidine, piperazine, or morpholine ring formed by combining N atom, R4, and R5, wherein the ring is unsubstituted or substituted with one or two substituents selected from the group consisting of -CH2-NH2, -CH2-N(CH3)2, -CH2-NH-COO-(tert-butyl), -CO-CH3, -CO-NH2, -CO-NH(CH3), -CO-N(CH3)2, -SO-CH3, -SO2-CH3, -N(CH3)2, fluoro, chloro, cyano, hydroxy, methyl, ethyl and cyclopropyl. A compound, or a pharmaceutically acceptable salt thereof. In the first paragraph, R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R2 is unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy and ethoxy, R3 is N(R4)(R5), R4 and R5 are each independently hydrogen, methyl, ethyl, propyl, isopropyl, and wherein R4 and R5 are unsubstituted or substituted with one or two substituents selected from the group consisting of fluoro, -N(CH3)2, and tetrahydrofuranyl; or N atom, R4 and R5 are combined with each other to form a pyrrolidine, piperidine, piperazine, or morpholine ring, said ring being unsubstituted or substituted with one or two substituents selected from the group consisting of -CH2-NH2, -CH2-N(CH3)2, -CO-CH3, -CO-NH2, -CO-NH(CH3), -CO-N(CH3)2, -SO-CH3, -SO2-CH3, -N(CH3)2, fluoro, chloro, methyl, ethyl and cyclopropyl. A compound, or a pharmaceutically acceptable salt thereof. In the first paragraph, R2 is pyridinyl, wherein R2 is unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy and ethoxy, R3 is a piperidine ring formed by combining N atom, R4 and R5, and the ring is unsubstituted or substituted with one or two substituents selected from the group consisting of -CO-NH2, -CO-NH(CH3) and -CO-N(CH3)2. A compound, or a pharmaceutically acceptable salt thereof. In the first paragraph, R2 is methyl, ethyl, propyl, butyl, isobutyl, or phenyl, wherein R2 is unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy and ethoxy, R3 is a pyrrolidine, pyrrolidine-2-one, piperidine, or piperazine ring formed by the combination of N atom, R4, and R5, which ring is unsubstituted or substituted with one or two substituents selected from the group consisting of -CH2-NH2, -CH2-N(CH3)2, -CH2-NH-COO-(tert-butyl), -CO-CH3, -CO-NH2, -CO-NH(CH3), -CO-N(CH3)2, -N(CH3)2, fluoro, chloro, cyano, hydroxy, methyl, ethyl, and cyclopropyl. A compound, or a pharmaceutically acceptable salt thereof. In the first paragraph, The compound represented by the above chemical formula 1 is 1) 1-(4-(1-phenyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide, 2) 2-(4-ethylpiperazin-1-yl)-4-(1-phenyl-1H-pyrazol-4-yl)quinazoline, 3) 1-(4-(1-butyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide, 4) 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-2-(4-ethylpiperazin-1-yl)quinazoline, 5) 2-(4-cyclopropylpiperazin-1-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)quinazoline, 6) 1-(4-(1-isobutyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide, 7) 2-(4-ethylpiperazin-1-yl)-4-(1-isobutyl-1H-pyrazol-4-yl)quinazoline, 8) 4-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(4-ethylpiperazin-1-yl)quinazoline, 9) 1-(4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carbonitrile, 10) 1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)piperidine-4-carboxamide, 11)N-methyl-1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)piperidine-4-carboxamide, 12) (S)-4-hydroxy-1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)pyrrolidin-2-one, 13) (R)-4-hydroxy-1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)pyrrolidin-2-one, 14) (S)-N,N-dimethyl-1-(4-(5-phenylthiophen-2-yl)quinazolin-2-yl)pyrrolidin-3-amine, 15) tert-butyl((1-(4-(1-butyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl)carbamate, 16) (1-(4-(1-butyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidin-4-yl)methanamine, 17) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide, 18) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide, 19) 1-(6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-4-yl)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide, 20) 1-(6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide, 21) 4-(1-cyclohexyl-1H-pyrazol-4-yl)-2-(4-ethylpiperazin-1-yl)-6,7-dimethoxyquinazoline, 22) 4-(1-cyclohexyl-1H-pyrazol-4-yl)-2-(4-cyclopropylpiperazin-1-yl)-6,7-dimethoxyquinazoline, 23) (S)-4-(1-cyclohexyl-1H-pyrazol-4-yl)-2-(3-fluoropyrrolidin-1-yl)-6,7-dimethoxyquinazoline, 24) (S)-2-(3-fluoropyrrolidin-1-yl)-6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-4-yl)quinazoline, 25) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)pyrrolidine-3-carboxamide, 26) (R)-4-(1-cyclohexyl-1H-pyrazol-4-yl)-2-(3-fluoropyrrolidin-1-yl)-6,7-dimethoxyquinazoline, 27) 1-(1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl)ethan-1-one, 28) 1-(6,7-dimethoxy-4-(5-phenylthiophen-2-yl)quinazolin-2-yl)piperidine-4-carboxamide, 29) 1-(6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-3-yl)quinazolin-2-yl)piperidine-4-carboxamide, 30) 1-(6,7-dimethoxy-4-(1-phenyl-1H-pyrazol-3-yl)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide, 31) 1-(6,7-dimethoxy-4-(2-phenylthiazol-5-yl)quinazolin-2-yl)piperidine-4-carboxamide, 32) 1-(6,7-dimethoxy-4-(2-phenylthiazol-5-yl)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide, 33) 1-(6,7-dimethoxy-4-(5-phenylthiophen-2-yl)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide, 34) 1-(4-(1-cyclopentyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide, 35) 1-(4-(1-Cyclopentyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide, 36) 1-(4-(1-cyclobutyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide, 37) 1-(4-(1-Cyclobutyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide, 38) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylpyrrolidine-3-carboxamide, 39) 1-(1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)pyrrolidin-3-yl)-N,N-dimethylmethanamine, 40) 1-(4-(1-Cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl-N,N-dimethylpyrrolidine-3-carboxamide, 41) 1-(4-(1-Cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl-N,N-dimethylpiperidine-4-carboxamide, 42) 4-(1-Cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-N,N-dimethylquinazolin-2-amine, 43) 4-(1-Cyclohexyl-1H-pyrazol-4-yl)-N-isopropyl-6,7-dimethoxy-N-methylquinazolin-2-amine, 44) 4-(1-Cyclohexyl-1H-pyrazol-4-yl-N,N-diethyl-6,7-dimethoxyquinazolin-2-amine, 45) 1-(6,7-dimethoxy-4-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide, 46) 1-(6,7-dimethoxy-4-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide, 47)N 1 -(4-(1-Cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N 2 ,N 2 -Dimethylethane-1,2-diamine, 48) 4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-N-((tetrahydrofuran-2-yl)methyl)quinazolin-2-amine, 49) (1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl)methanamine, 50) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-2-yl)piperidine-4-carboxamide, 51) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide, 52) 4-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-7-methoxyquinazolin-2-yl)piperazine-1-carboxamide, 53) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6-methoxyquinazolin-2-yl)piperidine-4-carboxamide, 54) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6-methoxyquinazolin-2-yl)-N-methylpiperidine-4-carboxamide, 55)N-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N-methylmorpholine-4-carboxamide, 56) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3-isopropyl-1,3-dimethylurea, 57) (S)-N-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3-fluoro-N-methylpyrrolidine-1-carboxamide, 58) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3,3-diethyl-1-methylurea, 59) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3-(2,2-difluoroethyl)-1-methylurea, 60) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-3-(2-(dimethylamino)ethyl)-1-methylurea, 61) 2-(Diethylamino)ethyl (4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)(methyl)carbamate, 62) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-1-methylurea, 63) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-1,3-dimethylurea, 64) 1-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-1,3,3-trimethylurea, 65) (E)-N'-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)-N,N-dimethylformamide, 66) 1-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide, 67) 1-(6,7-dimethoxy-4-(1-(4-methoxycyclohexyl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide, 68) 1-(4-(1-(2-chloro-4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-6,7-dimethoxyquinazolin-2-yl)piperidine-4-carboxamide, 69) 1-(6,7-dimethoxy-4-(1-((1s,4s)-4-methylcyclohexyl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide, 70) 1-(6,7-dimethoxy-4-(1-((1r,4r)-4-methylcyclohexyl)-1H-pyrazol-4-yl)quinazolin-2-yl)piperidine-4-carboxamide, 71) 4-(1-cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-2-(4-(methylsulfinyl)piperidin-1-yl)quinazoline, and 72) 4-(1-Cyclohexyl-1H-pyrazol-4-yl)-6,7-dimethoxy-2-(4-(methylsulfonyl)piperidin-1-yl)quinazoline Any one selected from the group consisting of, A compound, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for the prevention or treatment of fibrotic diseases, cancer or metabolic diseases, comprising a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, as an active ingredient.

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