WO2013013614A1 - 4-(3-heteroarylarylamino)quinazoline and 1-(3-heteroarylarylamino)isoquinoline as hedgehog pathway inhibitor and use thereof - Google Patents

Abstract

Provided is novel 4-(3-heteroarylarylamino)quinazoline and 1-(3-heteroarylarylamino)isoquinoline of formula I, wherein ring C, A, R, and R₂-R₁₀ are defined in the text. The compound of formula I is a Hedgehog pathway inhibitor.Therefore, the compound of the invention can be used for treating diseases resulting from abnormal Hedgehog activity, such as cancer.

Description

 4-(3-heteroarylarylamino)quinazoline and 1-(3-heteroarylarylamino)isoquinoline

 As a Hedgehog pathway inhibitor and its application

 [0001] The invention belongs to the field of medicinal chemistry. The present invention particularly relates to 4-(3-heteroarylarylamino)quinazoline and 1-(3-heteroarylarylamino)isoquinoline, and as a therapeutically effective hedgehog pathway inhibitor, and The application of cancer drugs. Background technique

[0002] The Hedgehog protein was originally a highly conserved family of proteins found in Drosophila, which plays a crucial role in embryonic development. The most studied mammalian homologous hedgehog proteins associated with humans include three genes, Sonic hedgehog (Shh), Indian hedgehog, and Desert hedgehog. Among them, Shh is not only important in embryonic development, but also has many evidences that it also plays an important role in the carcinogenic mechanisms of some cancers including basal cell carcinoma (Caro, I. and JA Low, Clin Cancer Res, 2010. 16(13) ): 3335- 9). Shh first synthesized a 45 kDa precursor protein in vivo and produced a 20 kDa N-terminal fragment by self-resection. This N-terminal fragment possesses all the biological activities known to date. Although the carcinogenic mechanism of Shh is not well understood, its function includes activation of the hedgehog information pathway within the cell. In addition to Shh, the main members of this information pathway include patched (PTCH), G-like protein and receptor oncogene smoothened (SM0), and transcription factor Gl i (Bale, AE and KP Yu, Hum Mol Genet, 2001. 10(7): 757-62). Mutation analysis of members of the hedgehog signaling pathway in basal cell carcinoma showed that most of the mutations occurred on PTCH-1 and SM0 (Von Hoff, DD, et al., N Engl J Med, 2009. 361(12): 1164-72) . PTCH-1 is a membrane protein with 12 membrane-penetrating structures, which is a direct acting receptor for Shh. In the absence of Shh, PTCH-1 interacts with SM0 to inhibit the biological viability of SM0. The combination of Shh and PTCH-1 causes PTCH-1 to leave SM0, freeing SM0 from the suppressed state. The Gl i transcription factor is controlled by SM0, which plays a switching role in gene transcription, and the main members include Gl il, Gl i2 and Gl i3. The entire hedgehog pathway plays a crucial role in the normal development of the embryo. Disturbing this information pathway will lead to severe fetal malformations, such as the natural teratogenic compound cyclopamine is a hedgehog inhibitor. Under normal conditions, the concentration of hedgehog protein in adults is very low. In the case of a low concentration of hedgehog protein, PTCH-1 binds to SM0 and inhibits its biological activity, so the entire pathway is in a state of no vitality or low vitality. When the cell secretes hedgehog protein Afterwards, the binding of the hedgehog protein to the PTCH-1 receptor causes it to detach from SM0, thereby losing the inhibition of SM0. SM0 further activates the transcription factor G1 i-1 to regulate gene transcription and cell growth. A growing body of evidence suggests that the majority of basal cell carcinomas are caused by mutations or other causes of excessive hedgehog signaling pathway activity. Therefore, inhibition of the activity of the excessive hedgehog signaling pathway may inhibit the growth of cancer cells to achieve treatment of basal cell carcinoma or other cancers caused by the same mechanism. A series of scientific and clinical trials have shown that hedgehog inhibitors are effective in treating a variety of cancers, including basal cell carcinoma. Recent clinical trial data show that the hedgehog inhibitor GDC-0449 is effective in the treatment of basal cell carcinoma and medulloblastoma (Lorusso PM. et al. Cl in Cancer Res. 2011; 17 (8): 2502-11), or by the same Other cancers caused by the mechanism, such as basal cell nevus syndrome (BCNS) (Goldberg LH. et al. Arch Dermatol. 2011 Mar 21·). In March 2012, the US FDA approved GDC-0449 as a new anticancer drug for the treatment of basal cell carcinoma, confirming that hedgehog pathway inhibitors can be used as new anticancer drugs. Biochemical studies have shown that the inhibition point of GDC-0449 is on SM0, inhibiting the viability of SM0 inhibits the activity of the whole hedgehog pathway, thus achieving anti-cancer purposes. In addition to basal cell carcinoma and medulloblastic cancer, many other cancers are also associated with the ultra-high activity of the hedgehog signaling pathway, including pancreatic cancer, intestinal cancer, rectal cancer, ovarian cancer, and prostate cancer. Blood cancer, etc. (De Smaele E. et al. Curr Op in Investig Drugs. 2010; 11 (6): 707- 18). Therefore, the prospect of developing hedgehog pathway inhibitors as novel anticancer drugs is very broad.

 [0003] Hedgehog signaling pathway activation is critical for the differentiation of mouse mesenchymal stem cells, C3H10T1/2, into osteoblasts. When C3H10T1/2 is differentiated into osteoblasts, the activity of intracellular alkaline phosphatase is greatly enhanced. Inhibition of the activity of the Hedgehog pathway leads to a decrease in the activity of intracellular alkaline phosphatase. Therefore, C3H10T1/2 is induced to differentiate into osteoblasts by activating Hedgehog signaling, and the activity of hedgehog pathway inhibitors is screened and assayed by measuring the activity of intracellular alkaline phosphatase (Peukert, S. and K. Miller-Moslin, ChemMedChem, 2010). 5(4): 500-12; Tremblay, MR, et al., J. Med. Chem., 2009, 52: 4400-18).

[0004] US20030144308 discloses 4-(phenylamino)quinazoline as a fructose 1,6-bisphosphatase inhibitor. Wherein Q = pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, furyl, quinolinyl, imidazolyl, Pyridyl, pyrimidinyl; T ¹ = hydrogen, methyl, ethyl, OR ¹⁰ , SR ¹⁰ , cyano, cyclopropyl, cyclobutyl, NH ₂ , NHR ¹⁰ , N (R ¹⁰ ) ₂ , NHNH ₂ , CHR ¹⁰ OH, CH ₂ R ¹⁰ , C0C3⁄4, CON (R ¹⁰ ) ₂ ; R ¹ , R ² , R ³ , R ⁴ = hydrogen, halogen, trifluoromethyl, 4-chloroalkyl, 4-chloroalkoxy R ⁵ , R ⁸ = hydrogen, fluorine, chlorine, hydroxyl, methyl; R ⁶ , R ⁷ = 4-chloroalkyl, 4-chloroalkoxy; R ⁹ = hydrogen, cyclopropyl, cyclobutyl , 4-chloroalkyl, (CH ₂ ) _m -Y ; R ¹⁰ = hydrogen, methyl, ethyl; m = 1, 2, 3, or 4; Y = fluorine, chlorine, bromine, hydroxyl, N (R ") ₂ , 1-nitromethylpiperazinyl, 3-thiazolidinyl, 4-thiomorpholinyl, 1-piperidinyl, 1-pyrrolidine Base, 4-morpholinyl, 1-imidazolyl, 4-chloroalkoxy, SR ¹¹ , SOR ¹¹ , S0 ₂ R ⁿ , C0 ₂ H, C0 ₂ (d_C ₄ )alkyl or C0N(R ⁿ ) ₂ ; R ¹¹ = hydrogen, 4-chloroalkyl, and the like.

W02004030672 discloses aminoquinazoline as a protein kinase B inhibitor and an anticancer drug. Wherein R and 3⁄4 = independently hydrogen, alkyl, hydroxy, alkoxy, halogen, N(R ₅ ) ₂ , N0 ₂ , CN, CH0, alkanol, CON(R ₅ ) ₂ , C0 ₂ R ₅ , Allyl, CH=CHC0 ₂ Rs, CH=CHCON(R ₅ ) ₂ , alkylsulfonyl, or substituted (unsubstituted) phenyl; and R ₃ = independently hydrogen, cycloalkyl, substituted Non-substituted) heterocyclic (alkyl), alkoxy (alkyl), amino (alkyl), aryl (alkyl), etc.; or NR ₂ R ₃ = substituted (unsubstituted) heterocyclic ring; R ₄ = aryl or substituted phenylthio; = hydrogen or alkyl; Y = NR ₅ (CH ₂ ) _m; m = 0-6; n = 1-6 and the like.

W09609294 discloses quinoline and quinazoline as protein tyrosine kinase inhibitors. Where X = nitrogen, CH; Y = W(CH ₂ ), (CH ₂ )W, W; W = 0, S(0) _m , substituted (unsubstituted) NH; R ¹ = NH ₂ , H, halogen , hydroxy, N0 ₂ , C0 ₂ H, CF ₃ , CF ₃ 0, ureido, etc.; R ⁴ = hydrogen, hydroxy, halogen, alkyl, alkoxy, sulfur-containing alkyl, cyano, nitro, trifluoro Methyl, etc.; n = 1-3; R ⁵ = hydrogen, halogen, trifluoromethyl, alkyl, alkoxy; R ⁶ = substituted hydroxy, and the like.

发明内容

Summary of the invention

[0001] As shown in Structural Formula I, Formula II, and Formula III, the present invention provides novel 4-(3-heteroarylarylamino)quinazolines and 1-(3-heteroarylarylamino)iso Quinoline acts as a hedgehog pathway inhibitor. The invention also provides a pharmaceutical composition comprising an effective amount of a compound of Formula I, Formula II or Formula III for use in the treatment of cancer.

 In one embodiment, the pharmaceutical composition may also contain one or more pharmaceutically acceptable carriers or diluents.

 In one embodiment, the pharmaceutical composition may further comprise at least one known anticancer drug or a pharmaceutically acceptable salt of the anticancer drug.

 The present invention also relates to a process for the preparation of the novel compounds of Structural Formula I, Formula II and Formula III. Detailed ways

 As shown in Formula I, Formula II and Formula III, the present invention finds novel 4-(3-heteroarylarylamino)quinazoline and 1-(3-heteroarylarylamino)isoquine The porphyrin acts as a hedgehog pathway inhibitor.

 A specific compound is a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof:

 Wherein ring c is a monocyclic or bicyclic nitrogen-containing heteroaryl group which may be substituted;

A is N or CR _{1 ;}

 R is hydrogen, . Alkyl, haloalkyl, aryl, carbocyclyl, heterocyclyl, heteroaryl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, carbocycloalkyl, heterocycloalkyl, Hydroxyalkyl, aminoalkyl, carboxyalkyl;

R-R _{10 is} independently hydrogen, halogen, amino group which may be substituted, alkoxy group. Alkyl, haloalkyl, aryl group which may be substituted, carbocyclic group, heterocyclic group, heteroaryl group, alkenyl group, alkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkoxy, aminoalkyl, alkoxyalkyl, carboxyalkyl , carboxy alkoxy, nitro, cyano, amide, aminocarbonyl, hydroxy, decyl, acyloxy, azido, carboxy, carbonyl amide, alkylsulfonyl, aminosulfonyl, disubstituted alkane An aminosulfonyl group, an alkylsulfinyl group, or an alkylthio group;

Wherein R ₃ and R ₄ together with the carbon to which they are attached form a 5- or 6-membered heterocyclic ring containing two oxygens. A preferred group of compounds of formula I wherein A is N. In another preferred group of compounds of formula I, ring C is a benzothiazolyl group which may be substituted, pyridyl, pyrazinyl, oxazolyl, oxadiazolyl, quinoxalinyl, pyrimidinyl, pyridazinyl,吲哚 , isodecyl, 3 fluorenyl, pyridazinyl, oxazolyl, fluorenyl, 4 quinazinyl, isoquinolinyl, quinolinyl, pyridazinyl, naphthyridinyl, acridinyl, Naphthalene, dinitro(hetero)phenyl, phenanthroline, phenazinyl, isothiazolyl, phenothiazine, isoxazolyl, furazinyl, phenoxazinyl, 1,2-benziso Oxazol-3-yl, imidazolyl, benzimidazolyl, 2-hydroxyindenyl, thiadiazide and 2-oxobenzimidazolyl. Another preferred group of compounds of formula I wherein ring C is a benzimidazol-2-yl group and a phenylimidazol-2-yl group which may be substituted.

 Specifically, a compound of II or a pharmaceutically acceptable salt or prodrug thereof:

 Wherein ring c is a monocyclic or bicyclic nitrogen-containing heteroaryl group which may be substituted;

 R is hydrogen, . Alkyl, haloalkyl, aryl, carbocyclyl, heterocyclyl, heteroaryl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, carbocycloalkyl, heterocycloalkyl, Hydroxyalkyl, aminoalkyl, carboxyalkyl;

R ₂ -R _{10 are} independently hydrogen, halogen, amino group which may be substituted, alkoxy group. Alkyl, haloalkyl, aryl group which may be substituted, carbocyclic group, heterocyclic group, heteroaryl group, alkenyl group, alkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkoxy, aminoalkyl, alkoxyalkyl, carboxyalkyl , carboxy alkoxy, nitro, cyano, amide, aminocarbonyl, hydroxy, decyl, acyloxy, azido, carboxy, carbonyl amide, alkylsulfonyl, aminosulfonyl, disubstituted alkane An aminosulfonyl group, an alkylsulfinyl group, or an alkylthio group;

Wherein R ₃ and together with the carbon to which they are attached form a 5- or 6-membered heterocyclic ring containing two oxygens.

 A group of preferred compounds of the invention is represented by a compound of formula Ilia or Illb or a pharmaceutically acceptable salt or prodrug thereof:

其中， B^ 0， S， 0^或 _{15 ;} B₂为 0， S， 0?₁₂或 NR_{16 ;} B₃为 0， S， 0?₁₃或 _{17 ;} B₄为 0， S， 0?₁₄或 _{18 ;}

Where B^ 0, S, 0^ or _15; B ₂ is 0, S, 0? ₁₂ or NR _16; B ₃ is 0, S, 0? ₁₃ or _17; B ₄ is 0, S, 0? ₁₄ Or _{18 ;}

 R is hydrogen, . Alkyl, haloalkyl, aryl, carbocyclyl, heterocyclyl, heteroaryl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, carbocycloalkyl, heterocycloalkyl, Hydroxyalkyl, aminoalkyl, carboxyalkyl;

R ₂ -R _{14 are} independently hydrogen, halogen, amino group which may be substituted, alkoxy group. Alkyl, haloalkyl, aryl group which may be substituted, carbocyclic group, heterocyclic group, heteroaryl group, alkenyl group, alkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkoxy, aminoalkyl, alkoxyalkyl, carboxyalkyl Base, carboxyalkoxy, nitro, cyano, amido, aminocarbonyl, hydroxy, decyl, acyloxy, azide, carboxy, hydroxyamido, alkylsulfonyl, aminosulfonyl, disubstituted alkane An aminoalkylsulfonyl group, an alkylsulfinyl group, or an alkylthio group; wherein R ₃ and together with the carbon to which they are attached form a 5- or 6-membered heterocyclic ring containing two oxygens;

R ₁₅ -R _{18 are} independently hydrogen, Cwo alkyl, haloalkyl, aryl, carbocyclyl, heterocyclyl, heteroaryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, Aryl alkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl; or

R _u or R ₁₅ and 1 ₁₂ or 1 ₁₆ , R ₁₂ or R ₁₆ and 1 ₁₃ or 1 ₁₇ , R ₁₃ or R ₁₇ and R ₁₄ or R ₁₈ , together with the attached carbon or nitrogen, form a substitutable 5- or 6-membered aryl or heteroaryl.

A preferred group of compounds of formula Ilia wherein R ₁₂ or R ₁₃ are aryl or heteroaryl groups which may be substituted.

 In a preferred group of compounds of formula I or II, ring C is a benzzimidazolyl, benzothiazolyl or pyridyl group which may be substituted, including but not limited to, for example, 1 benzo[t]imidazol-2-yl, benzene And [t] thiazol-2-yl, 2-pyridyl, 3-pyridyl and 4-pyridyl. The substituent on the ring C may be, for example, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a cyano group, an amino group, a heteroaryl group (e.g., morpholinyl group), an aryl group (e.g., an alkyl group). , alkoxy, halogen substituted phenyl) and the like.

 In a preferred group of compounds of formula I, II or Ilia, ring C or a BfB^ containing ring is a substituted benzimidazolyl group, for example, Ibenzo[t]imidazol-2-yl. The ring may be 1, 2 or 3 selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, heteroaryl (eg morpholinyl), aryl (eg phenyl) Substituted by a substituent.

In a preferred group of compounds of formula I, II or 111b, ring C or a ring containing _{-4 4} is a phenylimidazolyl group which may be substituted, including but not limited to 4-phenylimidazol-2-yl which may be substituted And 5-phenylimidazol-2-yl and the like. Substituents include, but are not limited to, 1, 2 or 3 groups selected from the group consisting of alkyl, alkoxy and halogen.

A preferred group of compounds of formula I, II, Ilia or 111b, or. It is preferably a halogen, an alkyl group or an alkoxy group. In a preferred group of compounds of the formula I, II, Ilia or 111b, R ₃ —R ₅ are each independently preferably 11, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylsulfonyl (for example methyl sulfonate). Acyl), nitro, amino, heteroaryl (e.g., morpholinyl), optionally substituted phenyl (e.g., haloalkyl substituted phenyl), and the like.

In a preferred group of compounds of formula I, II, Ilia or 111b, R ₃ , R ₅ and R ₉ are each independently H, halo, alkyl or alkoxy.

A preferred group of compounds of formula I, II, Ilia or 111b, wherein R ₄ is H, halo, alkyl, haloalkyl, haloalkoxy, alkylsulfonyl (eg methylsulfonyl), nitro, amino, hetero An aryl group (e.g., morpholinyl), or an optionally substituted phenyl group (e.g., a haloalkyl substituted phenyl group).

A preferred group of compounds of formula I, II, Ilia or Illb, the 1? ₇ and. Each is independently H, alkyl or halogen.

 A preferred group of compounds of formula I, II, Ilia or Illb is 11, alkoxy or alkyl.

A preferred group of compounds of formula I, II, Ilia or Illb in, R ₆ is H, alkyl, haloalkyl or amino.

 A preferred group of compounds of formula I, II, Ilia or Illb is 11, haloalkyl or alkyl.

In a preferred group of compounds of formula I, II, Ilia or 111b, R, R ₂ , R ₆ , R ₇ , R ₈ , R ₉ (or R ₁₍₎ ) are H; R ₁₀ (or R ₉ ) is Halogen or alkyl; R ₃ and each independently halogen, alkyl or alkoxy; halogen, alkyl, haloalkyl, haloalkoxy, alkylsulfonyl (eg methylsulfonyl), nitro, amino, A phenyl group, or a haloalkyl substituted phenyl group.

 In a preferred group of compounds of formula I, II, Ilia or Illb, the quinazoline or isoquinoline is substituted at the 6 and 8 positions, the substituent being selected from the group consisting of halogen, alkyl and alkoxy.

In a group of compounds of formula I, II, Ilia or 111b, R ₃ , R ₄ form a methylene dioxybenzene or cycloethylene dioxybenzene ring with the phenyl group to which they are attached.

 Preferred compounds of Formula I, Formula II and Formula III include, but are not limited to:

 /H3- (I benzo[t]imidazolium-2-yl)-4-chlorophenyl)-7-chloroquinazoline-4-amine;

 /H3- (l benzo[t]imidazolium-2-yl)-4-chlorophenyl)-7-methylazoline-4-amine;

 /H3- (l benzo[t]imidazolium-2-yl)-4-chlorophenyl)-7-trifluoromethylquinazoline-4-amine;

 /H3- (l benzo[t]imidazolium-2-yl)-4-chlorophenyl)-7-fluoroquinazoline-4-amine;

 /H3- (l benzo[t]imidazolium-2-yl)-4-chlorophenyl)-6,8-dichloroquinazoline-4-amine;

 /H3- (l benzo[t]imidazolium-2-yl)-4-chlorophenyl)-6--chloro-8-methylquinazoline-4-amine;

 /H3- (l benzo[t]imidazolium-2-yl)-4-chlorophenyl)-6,8-dibromoquinazolin-4-amine;

/H3- (l benzo[t]imidazolium-2-yl)-4-chlorophenyl)-8-bromo-6-methylquinazolin-4-amine; N~(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-6,7-dimethoxyquinazolin-4-amine;

N~(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-7-methoxyquinazolin-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-8-methoxyquinazolin-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-6-methoxyquinazolin-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-7-methanesulfonylquinazoline-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-8-chloroquinazoline-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine;

 (4-chloro-3-(pyridin-2-yl-8-chloroquinazolin-4-amine;

 (4-chloro-3-(pyridin-2-yl-6, 8-dimethoxyquinazolin-4-amine;

 (4-chloro-3-(pyridin-2-yl-7-chloroquinazolin-4-amine;

 (4-chloro-3-(pyridin-2-yl-7-methylquinazolin-4-amine;

 (4-chloro-3-(pyridin-2-yl-7-trifluoromethylquinazolin-4-amine;

 (4-chloro-3-(pyridin-2-yl-7-fluoroquinazolin-4-amine;

 (4-chloro-3-(pyridin-2-yl-6,7-dimethoxyquinazolin-4-amine;

N~(4-chloro-3-(6-fluoro-I benzo[t:imidazol-2-yl)phenyl)-6,8-dimethoxyquinazolin-4-amine; N~ (3 - (Benzo[t]thiazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine;

N~(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-5,7-dimethoxyisoquinolin-1-amine; H4-chloro-3-(pyridine- 2-yl)phenyl-5,7-dimethoxyisoquinolin-1-amine;

N~(3-(benzo[t]thiazol-2-yl)-4 chlorophenyl)-5,7-dimethoxyisoquinolin-1-amine;

N~(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-6,8-dimethoxy-2-methylquinazolin-4-amine; H4-chloro- 3-(pyridin-2-yl)phenyl-6,8-dimethoxy-2-methylquinazolin-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-7-nitroquinazolin-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-7-aminoquinazolin-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-6, 7, 8-trimethoxyquinazolin-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-6,8-diethoxyquinazolin-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-6,7,8-triethoxyquinazolin-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-6,8-dimethylquinazoline-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-6,7-methylenedioxyquinazolin-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-6,7-ethylenedioxyquinazolin-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-7-morpholinylquinazolin-4-amine;

N-(3-(I benzo[t]imidazol-2-yl-4-chlorophenyl)-7-(4-trifluoromethylphenyl)quinazolin-4-amine; Benzo[t]imidazol-2-yl)-phenyl)-6, 8-dimethoxyquinazolin-4-amine;

N-I benzo[t]imidazol-2-yl)-4-methylphenyl)-6, 8-dimethoxyquinazolin-4-amine;

N-i benzo[t]imidazol-2-yl)-4-fluorophenyl)-6,8-dimethoxyquinazolin-4-amine;

N-i benzo[t]imidazol-2-yl)-4-bromophenyl)-6,8-dimethoxyquinazolin-4-amine;

N-i benzo[t]imidazol-2-yl)-4-methoxyphenyl)-6, 8-dimethoxyquinazolin-4-amine; N-i benzo[t] Imidazolyl-2-yl)-2-methylphenyl)-6, 8-dimethoxyquinazolin-4-amine;

N-i benzo[t]imidazol-2-yl)-2-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine;

N-i benzo[t]imidazol-2-yl)-6-methylphenyl)-6,8-dimethoxyquinazolin-4-amine;

N-i benzo[t]imidazol-2-yl)-6--chlorophenyl)-6, 8-dimethoxyquinazoline-4-amine;

N-i benzo[t]imidazol-2-yl)-5-trifluoromethylphenyl)--6, 8-dimethoxyquinazolin-4-amine-N-i benzo[ t]imidazol-2-yl)-5-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine;

N- 7 methyl-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; N- 7 methoxy-I Benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; N- 7 chloro-I benzo[t]imidazole-2- -4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; N- 7-bromo-I benzo[t]imidazol-2-yl)-4-chlorophenyl -6, 8-dimethoxyquinazolin-4-amine; N- 7-isopropoxy-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8 -dimethoxyquinazolin-4-amine; N- 7-ethoxy-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquin Oxazolin-4-amine; N- 6-chloro-I benzo[£]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; N - 6-Methyl-I benzo[£]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; N- 6-bromo-I benzene And [t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; N- 6-methoxy-I benzo[t]imidazole- 2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; N- 6-trifluoromethyl-I benzo[t]imidazol-2-yl) 4-chlorophenyl) -6, 8-dimethoxyquinazolin-4-amine; N- 6-cyano-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethyl Oxyquinazolin-4-amine; N- 6-ethoxy-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline- 4-amine; N- 6-dimethylamino-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; N- 6-morpholinyl-I benzo[£]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; N- 6-isopropoxy -I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; N-I benzo[t]imidazol-2-yl -4-chlorophenyl)-6,8-dimethoxy-2-ethylquinazolin-4-amine; N-I benzo[t]imidazol-2-yl)-4-chlorophenyl -6, 8-dimethoxy-2-chloromethylquinazolin-4-amine; N-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8- Dimethoxy-2-fluoromethylquinazolin-4-amine; (3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-(dimethylaminomethyl)quinazolin-4-amine;

 /H3 methylbenzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine;

 Methylbenzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-methylquinazolin-4-amine; methylbenzo[t]imidazole -2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-(dimethylaminomethyl)quinazolin-4-amine

 -Phenyloxazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine;

 - (phenyl-1,3,4-oxadiazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine;

 Phenyl-I imidazolium-2-yl-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine;

 Phenyl-I imidazolyl-2-yl-4-chlorophenyl)-6,8-dichloroquinazoline-4-amine;

 Phenyl-I imidazolium-2-yl-4-chlorophenyl)-6,7-methylenedioxyquinazolin-4-amine;

 Phenyl-I imidazolium-2-yl-4-chlorophenyl)-6,7-dimethoxyquinazolin-4-amine;

 Phenyl-I imidazolyl-2-yl-4-chlorophenyl)-7-nitroquinazolin-4-amine;

 Phenyl-I imidazolyl-2-yl-4-chlorophenyl)-7-chloroquinazoline-4-amine;

 Phenyl-I imidazolium-2-yl-4-chlorophenyl)-6-chloro-8-methylquinazoline-4-amine;

 Phenyl-I imidazolium-2-yl-4-chlorophenyl)-8-bromo-6-methylquinazoline-4-amine;

 4-methylphenyl)-I imidazolyl-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine;

 4-methoxyphenyl)-I imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; 4-chlorophenyl)-I imidazole- 2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; 4-fluorophenyl)-I imidazol-2-yl)-4-chlorophenyl) 6, 8-dimethoxyquinazolin-4-amine; 3-chlorophenyl)-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline- 4-amine; 3-methoxyphenyl)-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; 3-fluorophenyl) -I imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; 2-methoxyphenyl)-I imidazol-2-yl)-4 -chloro-phenyl)-6,8-dimethoxyquinazolin-4-amine; 2-methylphenyl)-I imidazol-2-yl)-4-chlorophenyl)-6, 8- Dimethoxyquinazolin-4-amine;

 2-chlorophenyl)-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; 2-fluorophenyl)-I imidazole-2- -4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; quinoxalin-2-yl)-4-chlorophenyl)-6, 8-dimethoxy Quinazoline-4-amine;

 Quinoline-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline-4-amine;

/H3 I benzo[t]imidazol-2-yl)-4-chlorophenyl)-5-methyl-7-(4-trifluoromethylphenyl)quinazolin-4-amine; Medicinal salt or prodrug. [0010] As used herein, "alkyl" refers to the alkyl group itself or as part of another group, which is a straight or branched group of up to ten carbon atoms. Useful alkyl groups include straight or branched chains. An alkyl group, preferably a linear or branched d- ₆ alkyl group, more preferably an alkyl group. typical. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl.

 [0011] As used herein, "alkenyl" refers to an alkenyl group itself or as part of another group, which is a straight or branched chain containing from 2 to 10 carbon atoms, wherein at least one of the two carbon atoms in the chain contains one A group of double bonds. A preferred alkenyl group is an alkenyl group having 2 to 4 carbon atoms. Typical alkenyl groups include ethenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

 [0012] As used herein, "alkynyl" refers to an alkyne substantially or as part of another group, which is a straight or branched chain containing from 2 to 10 carbon atoms, wherein at least one of the two carbon atoms in the chain contains one The group of the 叁 bond. A preferred alkynyl group is an alkynyl group having 2 to 4 carbon atoms. Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.

Useful alkoxy groups include those substituted by alkyl groups, for example as described above. The alkyl-substituted oxy group is preferably substituted by the above C _M alkyl group (i.e., C _M alkoxy group), more preferably d- ₃ alkoxy group.

Useful alkylthio groups include any of the above. An alkyl group (preferably, a d- ₆ alkyl group, more preferably a d- ₃ alkyl group) substituted thio group, the alkyl group in the alkylthio group may be substituted. Also included are such alkylthio sulfoxides and sulfones.

Useful amino groups include -NH ₂ , -1 ₁₉ and - ₁₉ . , where R ₁₉ and. Yes. An alkyl group (preferably ( ₃ alkyl) or ( ₃ - ( ₈ -cycloalkyl, or R ₁₉ and. Forms a ring such as piperidine with N- or R ₁₉ and R ₂ . with N and with other groups) A ring such as piperazine is formed. The alkyl group and the ring may be substituted. For example, examples of the amino group include dimethylamino group and the like.

[0016] Herein, when substituted, an alkyl group, an alkoxy group, an alkylthio group, an alkenyl group, an alkynyl group, a cycloalkyl group, a carbocyclic ring, and a heterocyclic ring may be one or more (for example, 1, 2, 3) Or 4) substituents selected from the group consisting of halogen, hydroxy, carboxy, amino, amine, nitro, cyano, C _M acylamino, C _M acyloxy, d- ₆ alkoxy, aryl Oxyl, alkylthio, C ₆ -C ₁₍₎ aryl, C ₄ -C ₇ cycloalkyl, C ₂ -C ₆ alkenyl, Ce-Ci. Aryl (c ₂ -c ₆ ) alkenyl, Ce-Ci. Aryl (C ₂ -C ₆ ) alkynyl, saturated and unsaturated heterocyclic or heteroaryl. In a preferred embodiment, the alkoxy group may be substituted by one or more (e.g., 1 to 4 or 1 to 3 unequal) substituents selected from the group consisting of halogen, morpholinyl, and ammonia including alkylamines. And dialkylamines, and carboxy esters.

Herein, when substituted, an aryl group, an arylalkyl group, an arylalkenyl group, an arylalkynyl group, a heteroaryl group, and a heteroarylalkyl group may be one or more (for example, 1, 2) , 3 or 4) Substituents substituted from the following groups: halogen, C _M alkyl, methylenedioxy, dC ₆ haloalkyl, C ₆ -C _{1 ()} aryl, C ₄ -C ₇ ring Alkyl, C ₂ -C ₆ alkenyl, C ₂ -c ₆ alkynyl, c ₆ -c ₁₀ aryl ( Ci-C ₆ ) fluorenyl, c ₆ _c ₁₀ aryl ( c ₂ -c ₆ ) alkene Base, c ₆ _c ₁₀ aryl ( c ₂ -c ₆ ) alkyne , CfCe hydroxyalkyl, nitro, amino, amino, ureido, cyano, dC ₆ acylamino, hydroxy, decyl, d_C ₆ acyloxy, aminocarbonyl, azide, (^-(alkane) An oxy group, a carboxyl group, a di(d-)amino group, an alkylsulfonyl group, an arylsulfonyl group, a dialkylaminosulfonyl group or an alkylsulfinyl group.

 [0018] As used herein, "aryl" refers to a aryl group or as part of another group, and refers to a monocyclic, bicyclic or tricyclic aromatic group containing from 6 to 14 carbon atoms.

[0019] Useful aryl groups include C ₆ - ₁₄ aryl group, more preferably an aryl group. Typical ₍₆ - ₁₄ aryl groups include phenyl, naphthyl, phenanthryl, anthryl, indenyl, biphenyl, biphenylene, and Fuji.

[0020] The term "carbocycle" as used herein includes cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups are C ₃ - ₈ cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

 Useful partially saturated carbocyclic groups include cycloalkenyl groups such as cyclopentenyl, cycloheptenyl and cyclooctyl

Useful halogen or halogen groups include fluorine, chlorine, bromine and iodine.

[0023] As used herein, "arylalkyl" as used above includes any of a C ₆ -... ₁₄ aryl-substituted (^ alkyl aryl group is preferably an alkyl group (preferably an alkyl group of ₄ arylalkyl It is a benzyl group, a phenethyl group or a naphthylmethyl group.

₁₄ aryl group substituted - "arylalkenyl" includes any of the above C ₆ [0024] As used herein. Alkenyl group

. Cloth ^ £)

₁₄ aryl group substituted - "arylalkynyl" includes any of the above C ₆ [0025] As used herein. Alkynyl group

C _{2 -4} alkynyl).

As used herein, "aryloxy" includes an oxy group substituted by any of the above C _{6 -14} aryl groups, the aryl group of which may be substituted. Useful aryloxy groups include phenoxy and 4-methylphenoxy.

 [0027] As used herein, "arylalkoxy" includes substituted with any of the above aryl groups. The alkoxy group, the aryl group thereof may be substituted. Useful arylalkoxy groups include benzyloxy and phenylethoxy.

 Useful haloalkyl groups include those substituted by one or more fluorine, chlorine, bromine or iodine atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, ι , i-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl.

Useful acylamino (amido) is any d- ₆ acyl (alkanoyl) attached to an amine nitrogen, such as acetamido, chloroacetamido, propionamide, butanamide, pentanamide And hexanoamide groups, and aryl substituted C _M acylamino groups, such as benzamide groups.

[0030] A useful acyloxy group is any C _M acyl (alkanoyl) attached to oxygen (-0-), such as formyloxy, acetoxy, propionyloxy, butyryloxy, valeryl Oxyl and hexanoyloxy. [0031] As used herein, a heterocyclic ring refers to a saturated or partially saturated 3-7 membered monocyclic ring, or a 7-10 membered bicyclic ring system, which is selected from the group consisting of carbon atoms and optionally from the heteroatoms 0, N and S. It is composed of heteroatoms, wherein the hetero atom nitrogen and sulfur can be arbitrarily oxidized, the nitrogen can also be aminated aminally, and any of the above heterocycles defined in the bicyclic system are fused to the benzene ring. If the resulting compound is stable, then the heterocyclic ring may have a substituent on the carbon or nitrogen atom.

 Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indanyl, iso-dihydro Mercapto, quinuclidinyl, morpholinyl, heterochromyl, chromanyl, pyrazolidinyl and pyrazolinyl.

 As used herein, "heteroaromatic ring" means having 5 to 14 ring atoms and having 6, 10 or 14 π electrons are shared on the ring system. Further, the ring atoms contained are carbon atoms and optionally 1-3 hetero atoms from oxygen, nitrogen and sulfur.

 Useful heteroaryl groups include benzothiazolyl, thienyl, benzothienyl, benzo[2,3-6]thienyl, thioxyl, furyl, pyranyl, isobenzopyran Base, chromenyl, oxime, phenoxanthi inyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridine , pyrazinyl, pyrimidinyl, pyridazinyl, fluorenyl, isodecyl, 3H-fluorenyl, pyridazinyl, oxazolyl, fluorenyl, 4 quinazinyl, isoquinolinyl , quinolyl, pyridazinyl, naphthyridinyl, acridinyl, naphthyldiaza(hetero)phenyl, phenanthroline, phenazinyl, isothiazolyl, phenothiazine, isoxazolyl , furazolyl, phenoxazinyl, 1, 4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido[l,2-a]pyrimidin-4-one, four Hydrogenated five members [c]pyrazol-3-yl, imidazo[l,5-a]pyrimidinyl, 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-hydroxyindole, Thiazodiyl, oxazolyl, oxadiazolyl, Quinoxalinyl, and 2-oxo-benzimidazolyl. When the heteroaryl group contains a nitrogen atom in the ring, such a nitrogen atom may be in the form of an N-oxide such as a pyridyl N-oxide, a pyrazinyl N-oxide and a pyrimidinyl N-oxide.

 "Heteroaryloxy" as used herein, includes an oxy group substituted by any of the above heteroaryl groups, wherein the heteroaryl group may have a substituent. Useful heteroaryloxy groups include pyridyloxy, pyrazinyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy and phenylthiooxy.

 [0036] As used herein, "heteroarylalkoxy" refers to substituted by any of the above heteroaryl groups. An alkoxy group having a substituent on the heteroaryl group.

 Some of the compounds of the invention may exist as stereoisomers, including optical isomers. The present invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as the individual enantiomers which can be separated according to methods well known to those skilled in the art.

Examples of pharmaceutically acceptable salts include inorganic and organic acid salts such as hydrochlorides, hydrobromides, sulfates, citrates, lactates, tartrates, maleates, fumarates, Mandelic acid salt and oxalate; and alkali Inorganic and organic base salts formed by sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl glucosamine.

Examples of prodrugs of the compounds of the invention include simple esters of carboxylic acid containing compounds (for example esters obtained by condensation with ( ₄ alcohols) according to methods known in the art; esters of hydroxyl containing compounds (eg, ₆ esters obtained by acid or anhydrides such as succinic anhydride, fumaric anhydride and condensation) - by methods known in the art and d- ₄ carboxylic acids, C _3; imine compound containing an amino group (e.g., according to known in the art Method by imine obtained by condensation with ( ₄ aldehyde or ketone); carbamate of amino group-containing compound, such as Leu et al. (7: fed i3⁄4 _effl. 42:3623- 3628 (1999)) and Greenwald et al. (J. Med. Chem. 42: 3657-3667 (1999)) those esters; acetals or ketals of alcohol-containing compounds (for example by chloromethyl methyl ether or by methods known in the art) Those condensates obtained by condensation of chloromethyl ethyl ether).

The compounds of the invention can be prepared using methods known to those skilled in the art or by the novel methods of the invention. Specifically, the compound of the present invention having the formula I, formula II or formula III can be obtained as shown in the reaction examples in Reaction Scheme 1. 2-Chloro-5-nitrobenzoic acid is reacted with oxalyl chloride to give 2-chloro-5-nitrobenzoyl chloride. 2-Chloro-5-nitrobenzoyl chloride is reacted with o-phenylenediamine to give the product aminophenyl)-2-chloro-5-nitrobenzamide. Aminophenyl)-2-chloro-5-nitrobenzamide and glacial acetic acid are refluxed to give the product 2-(2-chloro-5-nitrophenyl)-Ibenzo[t]imidazole. 2-(2-Chloro-5-nitrophenyl)-I benzo[t]imidazole is heated under reflux with reduced iron powder and concentrated hydrochloric acid to give the intermediate 3-(l benzo[t]imidazol-2-yl) 4-chloroaniline. 2-Amino-3,5-dimethoxybenzoic acid and formamide are heated to give the product 6,8-dimethoxyquinazolin-4(3^)-one. 6, 8-Dimethoxyquinazolin-4 (3^)-one and P0C1 _{3 were} heated to give the intermediate 4-chloro-6, 8-dimethoxyquinazoline. 4-Chloro-6, 8-dimethoxyquinazoline and 3-(I benzo[£]imidazol-2-yl)-4-chloroaniline were heated in isopropanol to give the desired product /^(3 -(1 benzo[ _£ ]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine. Other compounds can be prepared in a similar manner. For example, by using 4,7-dichloroquinazoline instead of 4-chloro-6,8-dimethoxyquinazoline, A 3-(l benzo[£]imidazol-2-yl)-4-chloro can be synthesized. Phenyl)-7-chloroquinazolin-4-amine. Synthesis of chloro-3-(pyridin-2-yl) by using 4-chloro-3-(pyridin-2-yl)aniline instead of 3-(I benzo[t]imidazol-2-yl)-4-chloroaniline Phenyl)-6,8-dimethoxyquinazolin-4-amine. Synthesis of /H3-(5-fluoro-I benzo[d]imidazol-2-yl)-4-chlorophenyl)-6 by using 4-fluoro-1,2-phenylenediamine instead of o-phenylenediamine 8-Dimethoxyquinazolin-4-amine. Synthesis of 3-benzo[t] Thiazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine. Synthesis of Λ 3-(1 benzo[t]imidazolyl-2-yl)-4-methylphenyl by 2-methyl-5-nitrobenzoic acid instead of 2-chloro-5-nitrobenzoic acid -6, 8-dimethoxyquinazolin-4-amine. Synthesis of (5-phenyl) with 4-chloro-3-(5-(phenyloxazol-2-yl)aniline instead of 3-(I benzo[t]imidazol-2-yl)-4-chloroaniline Oxazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine. Substituting 4-chloro-3-(5-phenyl-I imidazol-2-yl)aniline for 3_(l benzo[t] Imidazolyl-2-yl)-4-chloroaniline, synthesizable (3-(5-phenyl-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline- 4-amine. Synthesis of (quinoxalin-2-yl) by 2-(2-chloro-5-aminophenyl)quinoxaline in place of 3-(I benzo[t]imidazol-2-yl)-4-chloroaniline 4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine.

 Reaction scheme 1

 Similarly, the compounds of the present invention can be prepared as shown in the reaction examples in Reaction Scheme 2. 3, 5-Dimethoxybenzoic acid and oxalyl chloride are reacted. Then, it was reacted with 2,2-dimethoxyethylamine in triethylamine and dichloromethane to obtain 3,5-dimethoxy-(dimethoxymethyl)-benzamide. The reaction of 3,5-dimethoxy-(dimethoxymethyl)-benzamide with concentrated sulfuric acid gives 5,7-dimethoxyisoquinolin-1-(2^)one. The 5,7-dimethoxyisoquinoline-1-(2^) ketone is reacted with phosphorus oxychloride at 100 C to give 1-chloro-5,7-dimethoxyisoquinoline. 1-Chloro-5,7-dimethoxyisoquinoline is reacted with 3-(1 benzo[]imidazol-2-yl)-4-chloroaniline in isopropanol and concentrated hydrochloric acid to give the desired product N~ (3 - (l benzo[ ]imidazol-2-yl)-4-chlorophenyl)-5,7-dimethoxyisoquinolin-1-amine. Other compounds can be prepared in a similar manner. For example, 4-chloro-3-(pyridin-2-yl)aniline can be used in place of 3-(I benzo[]imidazol-2-yl)-4-chloroaniline to synthesize chloro-3-(pyridin-2-yl) Phenyl)-5,7-dimethoxyisoquinolin-1-amine. Synthesis of ΛΚ3-(benzo[]thiazole with 3-(benzo[]thiazol-2-yl)-4-chloroaniline instead of 3-(I benzo[]imidazol-2-yl)-4-chloroaniline -2-yl) 4-chlorophenyl)-5,7-dimethoxyisoquinolin-1-amine.

 Reaction scheme 2

Similarly, the compounds of the present invention can be prepared as shown in the reaction examples in Reaction Scheme 3. 2-Amino-3,5-dimethoxybenzoic acid was reacted with acetic anhydride to 135 °C. Then add ammonia water and react at 135 ° C. 6, 8-dimethoxy-2-methylquinazolin-4 (3-keto. 6, 8-dimethoxy-2-methylquinazolin-4 (3^-ketone with trichloroox Phosphine reaction gives 4-chloro-6, 8-dimethoxy-2-methylquinazoline. 4-Chloro-6, 8-dimethoxy-2-methylquinazoline and

3-(I benzo[t]imidazol-2-yl)-4-chloroaniline is reacted in isopropanol to give the desired product A 3- (l benzo[t]imidazol-2-yl)-4-chloro Phenyl)-6,8-dimethoxy-2-methylquinazolin-4-amine. Other compounds can be prepared in a similar manner. For example, 4-chloro-3-(pyridin-2-yl)aniline can be used in place of 3-(I benzo[t]imidazol-2-yl)-4-chloroaniline to synthesize chloro-3-(pyridine-2- Phenyl)-6,8-dimethoxy-2-methylquinazolin-4-amine. By using propionic anhydride instead of acetic anhydride, (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-ethylquinazoline-

4-amine. In addition, 3, 5-dimethoxybenzoic acid is reacted with chloroacetonitrile in 1,4-dioxane to give 6,8-dimethoxy-2-chloromethylquinazoline-4 (3 - Ketone. This compound is reacted with phosphorus oxychloride to give 4-chloro-6, 8-dimethoxy-2-chloromethylquinazoline. This compound is 3-(l benzo[d]imidazole-2- Reaction of 4-chloroaniline in isopropanol to give the desired product (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxy-2-chloro Methyl quinazolin-4-amine. Similarly, (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-fluoromethylquinazoline can be synthesized by using fluoroacetonitrile instead of chloroacetonitrile. 4-amine.

 An important aspect of the present invention is the discovery that the compounds of Formula I, Formula II and Formula III (including Formulas Ilia and IHb, the same below) are hedgehog pathway inhibitors. Thus, these compounds are useful in the treatment of a variety of clinical conditions, such as cancer, caused by abnormalities in hedgehog activity.

 The present invention also encompasses methods of treating an animal with an effective amount of a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or prodrug thereof. Wherein the method of treatment is used to treat various conditions (i.e., hedgehog mediated diseases) caused by abnormal hedgehog activity, such as cancer.

[0045] Herein, various disorders or hedgehog-mediated diseases caused by abnormal hedgehog activity include cancer, including but not limited to basal cell carcinoma, medulloblastoma, basal cell nevus syndrome (BCNS), liver cancer, black Neoplasms, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, Testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant Carcinoid cancer, choriocarcinoma, mycosis fungoides, head or neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tumor disease, Thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical Hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocytosis, adrenocortical carcinoma, skin cancer, and prostate cancer. Preferably, the disease is basal cell carcinoma, medulloblastic carcinoma or basal cell nevus syndrome.

 In practicing the methods of treatment of the present invention, an effective amount of a pharmaceutical formulation is administered to a patient having one or more of these conditions. The pharmaceutical preparations contain a therapeutically effective concentration of a compound of formula I, formula II or formula I II, formulated for oral, intravenous, topical or topical administration for the treatment of cancer and other diseases. The amount administered is an amount effective to ameliorate or eliminate one or more conditions. For the treatment of a particular disease, an effective amount is a dose sufficient to ameliorate or otherwise alleviate the symptoms associated with the disease. Such a dose may be administered as a single dose or may be administered in accordance with an effective therapeutic regimen. The amount administered may cure the disease, but administration is usually to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired improvement in symptoms.

 The invention also relates to the use of a compound of the formula I, formula II or formula I I I for the manufacture of a medicament for the treatment or prevention of a disease caused by an abnormality in hedgehog activity. The disease caused by the abnormality of the hedgehog activity includes cancer. In a preferred embodiment, the disease is selected from the group consisting of cancer. In a more preferred embodiment, the disease is selected from the group consisting of basal cell carcinoma, medulloblastic carcinoma, and basal cell nevus syndrome. In other preferred embodiments, the medicament may also contain other known anticancer agents including, but not limited to, the various known anticancer agents described herein.

 [0048] In another embodiment there is provided a pharmaceutical composition comprising a compound of Formula I, Formula II or Formula I I I, or a pharmaceutically acceptable salt thereof, as a hedgehog pathway inhibitor, and a pharmaceutically acceptable carrier.

Another embodiment of the invention relates to a pharmaceutical composition effective for treating cancer comprising a compound of Formula I, Formula II or Formula I II as a hedgehog pathway inhibitor, or a pharmaceutically acceptable salt or prodrug thereof, It is used in combination with at least one known anticancer drug or a pharmaceutically acceptable salt of an anticancer drug. Known anticancer drugs that can be used in combination therapy for cancer include, but are not limited to, DNA damage chemotherapeutic anticancer drugs, including alkylating agents such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide , temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin and carboplatin; topoisomerase I preparations such as camptothecin, irinotecan and topotecan; topoisomerase II inhibitors such as doxorubicin, epirubicin, aclarithromycin, mitoxantrone, el l iptinium, and temtopip; RNA/DNA antimetabolites such as 5-azapine, gemcitabine, 5 - Fluorine urinary and methotrexate; DNA antimetabolites such as 5-fluoro-2, -deoxyuridine, fludarabine, nelarabine ara-C thioguanine, pralatrexate pemetrexed, hydroxyurea And thioguanine; anti-mitotic agents such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel and docetaxel; antibodies such as campath, Panitumumab, Ofatumumab, Avastin, Herceptin and Rituxan; kinase inhibitors such as i Matinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, dexamethasone and everolimus; HDAC inhibition Agents such as vorinostat and romic p _S in. Other known anticancers for anticancer combination therapy Drugs include tamoxifen, letrozole, fulvestrant, mitogu _azone , octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, _salidol and lenalidomide.

 In carrying out the methods of the invention, the compounds of the invention may be administered as a single pharmaceutical composition with at least one known anti-cancer drug. Alternatively, the compounds of the invention may be administered separately from at least one known anticancer drug. In one embodiment, the compound of the invention is administered at about the same time as at least one known anticancer drug, i.e., all drugs are administered simultaneously or sequentially, as long as the compound achieves a therapeutic concentration in the blood simultaneously. In another embodiment, the compound of the invention and at least one known anticancer drug are administered according to a respective dosage regimen as long as the compound reaches a therapeutic concentration in the blood.

 Another embodiment of the present invention is a bioconjugate of the compound which is effective for inhibiting tumors. This bioconjugant capable of inhibiting tumors consists of the compound with a therapeutic antibody such as Herceptin or Rituxan, or an auxin such as DGF or NGF, or a cytokine such as interleukin 2 or 4, or any A molecular composition that binds to the cell surface. The antibody and other molecules are capable of delivering the compound to its target, making it an effective anticancer drug. This bioconjugate can also increase the anticancer effect of medically active antibodies such as Herceptin or Rituxan.

 Another embodiment of the present invention relates to a pharmaceutical composition effective for inhibiting tumors, comprising a compound of Formula I, Formula II or Formula III as a hedgehog pathway inhibitor, or a pharmaceutically acceptable salt or prodrug thereof, Combined with radiation therapy. In this embodiment, the compounds of the invention may be administered at the same time or at different times as the radiation therapy.

 Another embodiment of the present invention relates to a pharmaceutical composition effective for post-operative treatment of cancer, comprising Formula I, Formula II or Formula III as a hedgehog pathway inhibitor, or a pharmaceutically acceptable salt thereof or Prodrug. The present invention also relates to a method of treating a cancer in a mammal by surgically removing the tumor and then using the pharmaceutical composition of the present invention.

 The pharmaceutical composition of the present invention may also contain the bioconjugate of the present invention as an active ingredient, and the bioconjugate may be, for example, a compound of the formula I, II or III of the present invention as described above. The formation of antibodies for medical action. Pharmaceutically acceptable carriers can also be included in the pharmaceutical compositions.

The pharmaceutical composition of the present invention includes all of the pharmaceutical preparations of the present invention in an amount effective to achieve their intended purpose. While the needs of each individual are different, one skilled in the art can determine the optimal dosage for each portion of the pharmaceutical formulation. In general, the compound, or a pharmaceutically acceptable salt thereof, is administered orally to a mammal daily, in an amount of from about 0.0025 to 50 mg/kg body weight. Preferably, it is about 0.01 to 10 mg per kg orally. If a known anticancer drug is also administered, the dose should be effective to achieve its intended purpose. The optimal dosage of these known anticancer drugs is well known to those skilled in the art. 1至十毫克的化合物的化合物。 [0056] The unit oral dose may comprise from about 0.01 to 50 mg, preferably from about 0.1 to 10 mg of the compound of the invention. The unit dose may be administered one or more times per day, one or more tablets, each tablet containing from about 0.1 to 50 mg, conveniently about 0.25 to 10 mg of the compound of the present invention or a solvate thereof.

 01至100毫克。 [0057] In the external preparation, the concentration of the compound may be about 0.01 to 100 mg per gram of the carrier.

 The compounds of the invention can be administered as unprocessed pharmaceuticals. The compounds of the invention may also be administered as part of a suitable pharmaceutical formulation containing a pharmaceutically acceptable carrier (including adjuvants, adjuvants). These pharmaceutically acceptable carriers facilitate the processing of the compounds into pharmaceutically acceptable pharmaceutical preparations. The preferred pharmaceutical preparations, especially those of the oral and preferred modes of administration, such as tablets, troches and capsules, and solutions suitable for injection or oral administration, containing from about 0.01% to about 99%, preferably from about 0. 25% to 75% of active compound and excipients.

 The scope of the invention also includes non-toxic pharmaceutically acceptable salts of the compounds of the invention. The acid addition salt is formed by mixing a non-toxic pharmaceutically acceptable acid solution and a solution of the compound of the present invention. The acid is, for example, hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid or the like. The base addition salt is formed by mixing a non-toxic pharmaceutically acceptable base solution and a solution of the compound of the present invention. The base is, for example, sodium hydroxide, potassium hydroxide, hydrogen choline, sodium carbonate, Tris, N-methyl-glucosamine or the like.

 The pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compound of the present invention. The most important of these mammals are human and veterinary animals, although the invention is not intended to be so limited.

 The pharmaceutical preparation of the present invention can be administered by any route to achieve its intended purpose. For example, it can be administered parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, transdermally, intranasally, intrathecally, intracranically, nasally or externally. Alternatively or in parallel, it can be administered orally. The dosage of the drug will be determined by the age of the patient, the health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

 The pharmaceutical preparations of the invention can be made in a known manner. For example, it is manufactured by conventional mixing, granulating, tableting, dissolving, or freeze drying processes. In the manufacture of oral formulations, the mixture can be selectively milled in combination with the solid adjuvant and the active compound. If necessary or necessary, after adding appropriate amounts of auxiliaries, the granule mixture is processed to obtain a tablet or tablet core.

Suitable excipients are, in particular, fillers, such as sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, These include corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone. If necessary, a disintegrating agent such as the above-mentioned starch, and carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added. Adjuvants are especially flow regulators and lubricants, for example, silica, talc, stearates, such as calcium magnesium stearate, Stearic acid or polyethylene glycol. If desired, the tablet core can be provided with a suitable coating that is resistant to gastric juice. For this purpose, a concentrated sugar solution can be applied. This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture. For the preparation of a gastric juice resistant coating, a suitable cellulose solution such as cellulose acetate phthalic acid or hydroxypropyl methylcellulose phthalic acid can be used. A dye or pigment can be added to the coating of the tablet or tablet core. For example, a combination for identifying or for characterizing the dose of an active ingredient.

 Other orally available pharmaceutical preparations include pressure-bonded capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer such as glycerin or sorbitol. The pressure-bonded capsules may contain the active compound in the form of granules mixed with a filler such as lactose, a binder such as a starch, a lubricant such as talc or magnesium stearate, and a stabilizer. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid such as a fat or liquid paraffin, to which a stabilizer may be added.

 Formulations suitable for parenteral administration include aqueous solutions of the active compounds, such as solutions of aqueous salts and basic solutions. In addition, an oily injection suspension of the appropriate active compound may be employed. Suitable lipophilic solvents or vehicles include oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate, triglycerides or polyethylene glycol 400, cremophor, or cyclodextrin. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Suspension stabilizers may also be included.

The external preparation of the present invention can be formulated into an oil, a cream, an emulsion, an ointment or the like by a preferably suitable carrier. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular alcohols (greater than C _12). Preferred carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants, as well as agents which impart color or aroma, if desired, may also be included. Further, these external preparations may contain a transdermal penetration enhancer. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

 The cream is preferably prepared by mixing a mixture of mineral oil, self-emulsifying beeswax and water with an active ingredient dissolved in a small amount of oil such as almond oil. A typical example of a cream includes about 40 parts water, 20 parts beeswax, 40 parts mineral oil and 1 part almond oil.

 The ointment may be formulated by mixing a vegetable oil containing an active ingredient such as almond oil and warm soft paraffin, and then cooling the mixture. A typical ointment example includes about 30% by weight of almond oil and 70% by weight of white soft paraffin.

The present application also relates to the use of a compound of the formula I, II or II II according to the invention for the preparation of a composition (for example a pharmaceutical composition) for inhibiting hedgehog activity. The following examples are illustrative and not limiting of the methods and formulations of the present invention. Others will be apparent to those skilled in the art, and appropriate modifications and improvements to the various conditions and parameters that are commonly encountered in clinical practice are within the spirit and scope of the invention. Example

 General description

 The reagents used are all of a commercial quality. The solvents were dried and purified according to standard methods. Mass spectrometry data was determined using an electrospray single quadrupole mass spectrometer (Platform II, Agilent 6110). The hydrogen spectrum was determined by a Brilcker AMX 300 mega NMR at 300K. Chemical shifts were recorded as TML as an internal standard (0.0 ppm) from the low field in ppm and coupling constants/values in Hertz. Example 1

 (2-aminophenyl)-2-chloro-5-nitrobenzamide

 a) Add 2-chloro-5-nitrobenzoic acid (8.06 g, 40 mmol) and dry dichloromethane (40 mL) to a 100 mL three-neck reaction flask, stir until completely dissolved, and add the grass at 0 °C. The acid chloride (3.6 mL, 42 mmol) was added dropwise two portions of DMF and stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give 2-chloro-5-nitrobenzoyl chloride, which was used directly for the next step.

b) Add o-phenylenediamine (4.3 g, 40 mmol), triethylamine (8.3 mL, 60 mmol) and anhydrous tetrahydrofuran (120 mL) to a 250 mL reaction flask, cool to 0 ° C and add the above A solution of 2-chloro-5-nitrobenzoyl chloride and anhydrous tetrahydrofuran (30 mL) was obtained. The title product (6.8 g, 58%) 3⁄4匪R (DMS0-t ₆ ): 9.88 (brs: 1H), 9.58 (d, J= 2.7 Hz, 1H), 9.29 (dd, = 9· 0 and 2· 7 Hz, 1H), 7.84 (d, J 9.0 Hz, 1H), 7.23 (d, = 6.9 Hz, 1H), 6.96—6.94 (m, 1H), 6.74 (d, J= 7.2 Hz: 1H), 6.59-6.54 (m, 1H), 5.00 ( Brs, 2H). MS: m/z 292.1 [M+H] +. Example 2

 72-(2-Chloro-5-nitrophenyl)-I benzo[t]imidazole

To a 500 mL reaction flask was added aminophenyl)-2-chloro-5-nitrobenzamide (5.9 g, 20 mmol) and glacial acetic acid (220 mL). After cooling to room temperature, water (300 mL) was added, and a precipitate was obtained, which was filtered, washed with a little ice water, washed with anhydrous diethyl ether and dried to give the desired product as white solid (4.20 g, 77 %). 3⁄4 匪R (DMS0-t ₆ ): 12.99 (brs, 1H), 8.75 (d, J = 2.7 Hz, 1H), 8.33 (dd, = 9· 0 and 2·7 Hz, 1H), 7.96 (d, = 9.0 Hz, 1H), 7.75 (d, J 7.8 Hz, 1H), 7.62 (d, = 7.2 Hz, 1H), 7.32—7.23 (m, 2H). MS: m/z 274.1

[M+H] +. Example 3

 3-(I benzo[t]imidazol-2-yl)-4-chloroaniline

 Add 2-(2-chloro-5-nitrophenyl)-I benzo[£]imidazole (2.0 g, 7.3 mmol), reduced iron powder (1.23 g, 22 mmol), concentrated hydrochloric acid to a 100 mL reaction flask. (3 mL) and ethanol (30 mL) were heated to reflux for 5 hours. After cooling to room temperature, the mixture was adjusted to pH 11 with EtOAc (EtOAc) (EtOAc) The extract was washed with EtOAc (EtOAc m. MS: m/z 244.1 [M+H] +. Example 4

 4-chloro-3-(6-fluoro-I phenyl [t]imidazol-2-yl)aniline

This compound was obtained by a synthesis method similar to that described in Examples 1-3, and the starting materials were 4-fluoro-1,2-phenylenediamine and 2-chloro-4-nitrobenzoyl chloride. MS: m/z 262.1 [M+H] ⁺ . Example 5

 7-chloroquinazoline -4 (3^)-one

 2-Amino-4-chlorobenzoic acid (1 g, 5.83 mmol) and 1.5 mL of formamide were added to a 25 mL vial, and heated to 170 ° C under a protective atmosphere for 5 hours. After cooling to room temperature, a solid precipitated. After filtration, the cake was washed with ethanol and dried to give a white solid title product (0.59 g, 55.7 %). MS: m/z 181.10 [M+H] +. Example 6

 4,7-dichloroquinazoline

A mixture of 7-chloroquinazolin-4 (3^)-one (0.27 g, 1.48 mmol) and P0C1 ₃ (3 mL) was heated to 140 ° C and stirred overnight under N ₂ . After cooling to room temperature, P0C1 _{3 was} evaporated under reduced pressure. To the residue was added ethyl acetate, washed with saturated aqueous NaHC0 ₃ pH adjusted to 5.0. The ethyl acetate layer was concentrated and evaporated to dryness crystals crystals crystals MS: m/z 201.10 [M+H] +. Example 7

 2-(2-chloro-5-nitrophenyl)pyridine

 Add 20 mL of ethylene glycol dimethyl ether to a 50 mL round bottom flask, then the compound 2-chloro-5-nitrophenylboronic acid (300 mg, 1.49 mmol), 2-bromopyridine (235 mg, 1.49 mmol), (Triphenylphosphine) palladium (52 mg, 44.7 mmol), and potassium carbonate (412 mg, 3.0 mmol) were added in portions and refluxed overnight under nitrogen. The reaction mixture was cooled to room temperature, filtered and evaporated to dryness crystals crystals MS: m/z 234.2 [M+H] +. Example 8

 4-chloro-3-(pyridin-2-yl)aniline

 Add 15 mL of ethanol and 10 mL of water to a 50 mL round bottom flask, then compound 2-(2-chloro-5-nitrophenyl)pyridine (110 mg, 0.47 mmol), iron powder (131 mg, 2.34 mmol) It was added in one portion with ammonium chloride (13 mg, 0.24 mmol) and the reaction was reacted at 70 °C for 3 hours. Ethanol was evaporated and the aqueous extracted with ethyl acetate (30 mL×3). The combined organic layers were dried with anhydrous sodium sulfate and evaporated MS: m/z 205.2 [M+H] +. Example 9

 3, 5-dimethoxy (dimethoxymethyl)-benzamide

Add 3,5-dimethoxybenzoic acid (2 g, 0.011 mol) and dichloromethane (20 mL) to a 50 mL vial and add oxalyl chloride (2.09 g, 0.0165 mol, 1.5 eq) with stirring. The mixture was heated at room temperature for 3 hours, and the solvent and excess oxalyl chloride were distilled off under reduced pressure. Add 2,2-dimethoxyethylamine (1.154 g, 0.011 mol), triethylamine (2.78 mL, 0.0274 mol, 2.5 eq), and dichloromethane (20 mL) to a 100 mL two-neck bottle. The ice water bath was cooled to 5 V, and the prepared acid chloride was slowly added by a syringe. After the addition was completed, it was naturally allowed to react to room temperature for 16 hours. The solvent was evaporated, and the residue was poured into 30 mL of iced water and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with EtOAc EtOAc m. _3⁄4 NMR (CDC1 ₃ ): 6.89 (d, J = 2.1 Hz, 2H), 6.58 (s, 1H), 6.27 (brs, 1H), 4.78 (t, = 5.4 Hz, 1H), 3.83 (s, 6H) , 3.59 (t, = 5.4 Hz, 2H), 3.43 (s, 6H). Example 10

5,7-dimethoxyisoquinoline-1-{20) ketone Add 3,5-dimethoxy-fluorenyldimethoxymethyl)-benzamide (0.5 g, 1.86 mmol) and concentrated sulfuric acid (2 mL) to a 25 mL vial and react at 50 °C for 3 days. . The reaction solution was slowly poured onto 30 g of crushed ice with stirring, and then 30 mL of ethyl acetate was added. After the layers were separated, the organic layer was washed with water and dried over anhydrous sodium sulfate. After concentration, the title compound was obtained as a yellow solid (0.366 g, 95%). MS: m/z 206.1 [M+H] ⁺ . Example 11

 1-chloro-5,7-dimethoxyisoquinoline

5,7-Dimethoxyisoquinolin-1-(2)one (0.3 g, 1.41 mmol) and phosphorus oxychloride (15 mL) were added to a 25 mL vial and allowed to react at 100 °C overnight. After the reaction solution was cooled, most of the solvent was evaporated under reduced pressure, and the residue was slowly poured on crushed ice with stirring, and a solid precipitated. After filtration, the filter cake was washed with water and dried to give a pale yellow solid object product (0.28 g, 85 %). _3⁄4 NMR (CDC1 ₃ ): 8.16 (d, = 5.4 Hz, 1H), 7.89 (d, J 5.4 Hz, 1H), 7.07 (s, 1H), 6.97 (d, = 2.1 Hz, 1H), 3.99 (s , 3H), 3.95 (s, 3H). MS: m/z 224.1 [M+H]+. Example 12

 6, 8-dimethoxy-2-methylquinazoline-4 (3-ketone)

2-amino-3,5-dimethoxybenzoic acid (0.40 g, 2.03 mmol) in a solution of acetic anhydride (5 mL) was heated to 135 ° C under N ₂ protection. After stirring for 3 hours, the solvent was evaporated to dryness under reduced pressure. To the residue was added 10 mL of aqueous ammonia, and the mixture was stirred at 135 ° C for 4 hours. After cooling to room temperature, the precipitate was filtered, washed sequentially with water and methanol, and the filter cake was dried to give a pale yellow solid object product (0.29 g, 64.7 %). MS: m/z 221.2 [M+H] ⁺ . Example 13

 4-chloro-6, 8-dimethoxy-2-methylquinazoline

This compound was obtained by a synthesis method similar to that described in Example 6, and the starting material was 6, 8-dimethoxy-2-methylquinazoline-4(3^)-one. MS: m/z 221.2 [M+H] ⁺ . Example 14

N~(3-(I benzo[£]imidazol-2-yl)-4-chlorophenyl)-7-chloroquinazolin-4-amine to 4,7-dichloroquinazoline (4L 2 mg, 0.205 Add 3-benzo[t]imidazol-2-yl)-4-chloroaniline (52.3 mg, 0.214 mmol) to isopropyl isopropanol (10 mL), heat to 120 °C, stir under overnight. The product was precipitated, filtered, and washed with ethyl acetate. 14. 4%). 3⁄4 NMR (DMS0-t _tf ): 10. 31 (brs, 1H), 8. 70—8. 65 (m, 2H), 8. 49 (d, J 2. 1 Hz, 1H), 8. 20- 8. 16 (m, 1H), 7. 88 (s, 1H), 7. 78 (d, J 8. 4, 1H), 7. 72- 7. 66 (m, 3H), 7. 30-7 . 27 (m, 2H). MS: m/z 407. 1 [M+H] +. The following compounds were prepared in analogy to the synthetic procedure described in Example 14, starting from 3-(I benzo[t]imidazol-2-yl)-4-chloroaniline and the corresponding substituted 4-chloroquinazole. Porphyrin. Example 15

N~(3-(I benzo[£]imidazol-2-yl)-4-chlorophenyl)-7-methylquinazolin-4-amine 3⁄4 NMR (DMS0-t _tf ): 10. 66 ( Brs, 1H), 8. 77 (s, 1H), 8. 60 (d, = 8. 4 Hz, 1H),

8. 46 (d, = 2. 4 Hz, 1H), 8. 11 (dd, = 8· 7 and 2· 4 Hz, 1Η), 7. 72 (d, = 8. 7 Hz, 1H), 7 67-7. 60 (m, 4H), 7. 28-7. 25 (m, 2H), 2. 55 (s, 3H). MS: m/z 386. 2

[M+H] +. Example 16

(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-trifluoromethylquinazolin-4-amine 3⁄4 NMR (DMS0-t _tf ): 10. 39 ( Brs, 1H), 8. 85 (d, = 8. 7 Hz, 1H), 8. 77 (s, 1H), 8. 50 (d, J 1. 8 Hz, 1H), 8. 19 (dd, = 8· 7 and 2· 4 Hz, 1H), 8. 14 (s, 1H), 8. 01 (d, = 9. 9 Hz, 1H), 7. 72 (d, = 8. 7 Hz, 1H ), 7. 69-7. 66 (m, 2H), 7. 30-7. 27 (m, 2H). MS: m/z 440. 2 [M+H] +. Example 17

(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-fluoroquinazolin-4-amine 3⁄4 NMR (DMS0-t _tf ): 10. 65 (brs, 1H ), 8. 81-8. 75 (m, 2H), 8. 47 (d, J = 2. 7 Hz, 1H), 8. 11 (dd, = 8. 9 and 2. 6 Hz, 1H), 7. 75-7. 68 (m, 4H), 7. 60 (dd, = 9·8 and 2. 6 Hz, 1H), 7. 34-7. 31 (m, 2H). MS: m/z 390. 2 [M+H] +. Example 18

Λ^-(3-(I benzo[£]imidazol-2-yl)-4-chlorophenyl)-6,8-dichloroquinazolin-4-amine 3⁄4 NMR (DMS0-t _tf ): 10. 37 (brs, 1H), 8. 80 (d, = 1. 8 Hz, 1H), 8. 74 (s, 1H), 8. 58 (d, J = 2. 7 Hz, 1H), 8. 22 (d, J = 2Λ Hz, 1H), 8. 18 (dd, = 9· 0 and 2· 7 Hz, 1H), 7. 80-7. 77 (m , 3H), 7. 47-7. 44 (m, 2H). MS: m/z 440. 1 [M+H] +.

 Example 19

N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6-chloro-8-methylquinazolin-4-amine 3⁄4 NMR (DMS0-t _tf ): 10. 41 (brs, 1H), 8. 73 (s, 1H), 8. 68 (s, 1H), 8. 56 (d, J = 2. 1 Hz, 1H), 8. 19 (dd, = 8· 7 and 2· 0 Hz, 1Η), 7. 85 (s, 1H), 7. 77-7. 74 (m, 3H), 7. 42-7. 39 (m, 2H), 2. 61 (s, 3H). MS: m/z 420. 3 [M+H] +.

 Example 20

N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dibromoquinazolin-4-amine 3⁄4 NMR (DMS0-t _tf ): 10. 38 (brs, 1H), 8. 97 (d, = 1. 5 Hz, 1H), 8. 74 (s, 1H), 8. 57 (d, = 2. 4 Hz, 1H), 8. 44 ( d, = 1. 8 Hz, 1H), 8. 18 (dd, = 8· 7 and 2· 4 Hz, 1H), 7. 79-7. 77 (m, 3H), 7. 46—7. 43 (m, 2H). MS: m/z 530. 0 [M+H] +.

 Example 21

 (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-8-bromo-6-methylquinazoline-4-amine

3⁄4 NMR (DMS0-t _tf ): 10. 36 (brs, 1H), 8. 68 (s, 1H), 8. 60 (d, = 2. 4 Hz, 1H): 8. 50 (s, 1H) , 8. 19 (dd, = 9· 0 and 2· 4 Hz, 1Η), 8. 14 (s, 1H), 7. 81—7. 76 (m: 3H), 7. 48-7. 45 ( m, 2H), 2. 52 (s, 3H). MS: m/z 464. 2 [M+H] +.

 Example 22

N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,7-dimethoxyquinazolin-4-amine 3⁄4 匪R (DMS0-t _tf ) : 11. 67 (brs, 1H), 8. 87 (s, 1H), 8. 41—8. 39 (m, 2H), 8. 06

(dd, = 8. 7 and 1. 8 Hz, 1H), 7. 83 (d, = 8. 7 Hz, 1H), 7. 76-7. 73 (m, 2H), 7. 39-7. 36 (m, 3H), 4. 03 (s, 3H), 3. 99 (s, 3H). MS: m/z 432. 3 [M+H] +.

 Example 23

(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-methoxyquinazolin-4-amine 3⁄4 NMR (DMS0-t _tf ): 11.30 (brs, 1H), 8.86 (s, 1H), 8.76 (d, = 9.3 Hz, 1H), 8.39 (d, J = 2Λ Hz, 1H), 8.01 (dd, = 8· 7 and 2· 4 Hz, 1H), 7.76 (d, = 8.7 Hz, 1H), 7.69-7.66 (m, 2H), 7.48 (dd, = 9· 2 and 2· 0 Hz, 1H), 7.31-7.29 (m, 3H), 3.97 (s, 3H). MS: m/z 402.2 [M+H] +.

 Example 24

 (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-8-methoxyquinazoline-4-amine

3⁄4 NMR (DMS0-t _tf ): 10.60 (brs, 1H), 8.69 (s, 1H), 8.44 (d, = 1.5 Hz, 1H), 8.20 (d, = 8.4 Hz, 1H), 8.09 (dd, J 8.4 and 0·9 Hz, 1H), 7.72—7· 65 (m, 4H), 7.49 (d, = 7.8 Hz, 1H), 7.27—7.24 (m, 2H), 3.99 (s, 3H). MS: m/z 402.2

[M+H] +.

 Example 25

N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6-methoxyquinazolin-4-amine 3⁄4 NMR (DMS0-t _tf ): 11.60 (brs , 1H), 8.90 (s, 1H), 8.44 (d, = 2.4 Hz, 1H),

8.39 (s, 1H), 8. 10 (dd, = 9· 0 and 2· 4 Hz, 1Η), 7.92 (d, = 9.3 Hz, 1H), 7.84 (d, = 8.7 Hz, 1H), 7.77— 7.72 (m, 3H), 7.37-7.35 (m, 2H), 4.02 (s, 3H). MS: m/z 402.3 [M+H] +.

 Example 26

N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-methanesulfonylquinazolin-4-amine 3⁄4 NMR (DMS0-t _tf ): 11. 13 (brs, 1H), 9. 14 (d, = 8.7 Hz, 1H), 8.97 (s, 1H), 8.69 (d, = 2.4 Hz, 1H), 8.44 (d, = 1.8 Hz, 1H), 8.34— 8· 28 (m, 2H), 7.94— 7.88 (m, 3H), 7.58-7.55 (m, 2H), 3.51 (s, 3H). MS: m/z 450.2 [M+H] +.

 Example 27

N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-8-chloroquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 10.46 (brs, 1H) , 8.76 (s, 1H), 8.67—8· 59 (m, 2H), 8.23— 8. 19 (m, 1H), 8. 11-8.09 (m, 1H), 7.80-7.69 (m, 4H), 7.47-7.45 (m, 2H). MS: m/z 407. 1 [M+H] +. N~(3-(I benzo[£]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine

3⁄4 NMR (DMS0-t ₆ ): 12. 73 (brs, 1H), 9. 79 (s, 1H), 8. 49 (s, 1H), 8. 44 (d, J = 2. 4 Hz, 1H ), 8. 23 (dd, = 9· 0 and 2· 4 Hz, 1Η), 7. 72—7. 57 (m, 3H), 7. 54 (d, J = 1. 5 Hz, 1H), 7. 26-7. 22 (m, 2H), 6. 96 (d, = 1. 5 Hz, 1H), 3. 95 (s, 3H), 3. 91 (s, 3H). MS: m/z 432· 1 [Μ+Η] +. Example 29

 (4-Chloro-3-(pyridin-2-yl)phenyl)-8-chloroquinazolin-4-amine In a 25 mL round bottom flask was added 10 mL of isopropanol, then the compound 4-chloro-3- ( Pyridin-2-yl)aniline (30 mg,

0. 15 mmol) and 4, 8-dichloroquinazoline (29 mg, 0.15 mmol) were added in one portion. The reaction mixture was reacted at 130 ° C for 6 hr. 3⁄4 NMR (DMS0-d ₆ ): 10. 29 (brs, 1H), 8. 73-8. 66 (m, 3H), 8. 15-8. 09 (m, 2H), 8. 05 (d, J = 7. 5 Hz, 1H), 7. 94 (t, = 7. 8 Hz, 1H), 7. 72 (d, = 7. 8 Hz, 1H), 7. 64-7. 58 (m, 2H), 7. 48-7. 43 (m, 1H). MS: m/z 367. 1 [M+H] +. The following compound was prepared using a synthetic procedure analogous to that described in Example 29, starting from 4-chloro-3-(pyridin-2-yl)aniline and the corresponding substituted 4-chloroquinazoline. Example 30

(4-Chloro-3-(pyridin-2-yl)phenyl)-6,8-dimethoxyquinazolin-4-amine _3⁄4 NMR (CD ₃ 0D): 8. 68-8· 66 (m , 1H), 8. 48 (s, 1H), 8. 05-7· 97 (m, 3H), 7. 75 (d, = 7. 8 Hz, 1H), 7. 58 (d, = 8. 7 Hz, 1H), 7. 53-7. 48 (m, 1H), 7. 40 (d, J = 1. 2 Hz, 1H), 6. 99 (d, = 1. 5 Hz, 1H), 4. 03 (s, 3H), 4. 02 (s, 3H). MS: m/z 393. 2 [M+H] +. Example 31

 (4-chloro-3-(pyridin-2-yl)phenyl)-7-chloroquinazoline-4-amine

3⁄4匪R (DMS0-t _tf ): 10. 08 (brs, 1H), 8. 70 (d, = 5. 1 Hz, 1H), 8. 62-8· 59 (m, 2H), 8. 10 -8. 06 (m, 2H), 7. 92 (t, = 7. 8 Hz, 1H), 7. 84 (d, = 2. 1 Hz, 1H),

28 7.73-7.69 (m, 2H), 7.59 (d, = 9.3 Hz, 1H), 7.48-7.41 (m, 1H). MS: m/z 367.1

[M+H] +. Example 32

 (4-chloro-3-(pyridin-2-yl)phenyl)-7-methylquinazoline-4-amine

匪R (DMS0-t _tf ): 11.53 (brs, 1H), 8.91 (s, 1H), 8.77-8.70 (m, 2H), 8.01 = 2.4 Hz, 1H), 7.97-7.88 (m, 2H), 7.75 -7· 67 (m, 4H), 7.48 ■ 7.43 (m, 1H), s, 3H). MS: m/z 347.1 [M+H] +. Example 33

(4-Chloro-3-(pyridin-2-yl)phenyl)-7-trifluoromethylquinazolin-4-amine 3⁄4 NMR (DMS0-t _tf ): 11.27 (brs, 1H), 9.00 (d , = 8.7 Hz, 1H), 8.92 (s, 1H), 8.74 (d, = 4.5 Hz, 1H), 8.21 (s, 1H), 8.14—8.08 (m, 2H), 8.02—7.96 (m, 2H) , 7.77 (d, = 8.1 Hz, 1H), 7.69 (d, = 8.7 Hz, 1H), 7.53-7.48 (m, 1H). MS: m/z 401.1 [M+H] +. Example 34

 (4-chloro-3-(pyridin-2-yl)phenyl)-7-fluoroquinazoline-4-amine

3⁄4 NMR (DMS0-t _tf ): 11.42 (brs, 1H), 8.95—8.89 (m, 2H), 8.72 (d, = 4.2 Hz, 1H), 8.02 (d, J 2.Ί Hz, 1H), 7.99 -7.90 (m, 2H), 7.81-7.65 (m, 4H), 7.50- 7.45 (m, 1H). MS: m/z 351.2 [M+H] +. Example 35

(4-Chloro-3-(pyridin-2-yl)phenyl)-6,7-dimethoxyquinazolin-4-amine _3⁄4 NMR (CD ₃ 0D): 8.65 (d, = 4.2 Hz, 1H ), 8.44 (s, 1H), 8.01 (d, J 2.Ί Hz, lH), 7.96-7.93 (m, 2H), 7.78 (s, 1H), 7.72 (d, = 8.8 Hz, 1H), 7.53 (d, J = 9.0 Hz, lH), 7.48 (t, = 6.6 Hz, 1H), 7.16 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H). MS: m/z 393.2 [M+H] +. Example 36

N~(4-Chloro-3-(6-fluoro-I benzo[t]imidazol-2-yl)phenyl)-6,8-dimethoxyquinazolin-4-amine This compound was prepared in a similar manner to the synthetic method of Example 14 described, starting from 4-chloro-3-(6-fluoro-benzo[t]imidazol-2-yl)aniline and 4-chloro-6. , 8-dimethoxyquinazoline. 3⁄4 NMR (DMS0_t ₆ ): 12. 23 (brs, 1H), 8. 75 (s, 1H), 8. 43 (d, J = 2Λ Hz, 1H), 8. 23 (s, 1H), 8. 08 (dd, J = 8. 7 and 2. 7 Hz, 1H), 7. 83 (d, = 8. 7 Hz, 1H), 7. 75 (dd, = 9. 0 and 4. 8 Hz, 1H ), 7. 56 (dd, J 9. 0 and 2. 4 Hz, 1H), 7. 32 (d, = 1. 8 Hz, 1H), 7. 29-7. 21 (m, 1H), 4 . 07 (s, 3H), 4. 03 (s, 3H). MS: m/z 450. 3 [M+H] +. Example 37

(3-(Benzo[t]thiazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine The present compound is applied similarly to the described Example 14 Prepared by the synthesis method, the starting materials are 2-(2-chloro-5-aminophenyl)-benzo[t]thiazole and 4-chloro-6, 8-dimethoxyquinazoline. 3⁄4 NMR (DMS0-t ₆ ): 9. 82 (brs, 1H), 8. 67 (d, J = 2. 7 Hz, 1H), 8. 50 (s, 1H), 8. 28 (dd, = 8·6 and 2·6 Hz, 1H), 8. 22 (d, = 8. 1 Hz, 1H), 8. 14 (d, = 7. 8 Hz, 1H), 7. 71 (d, = 9 . 0 Hz, 1H), 7. 63-7. 52 (m, 3H), 6. 96 (d, J = 2. 1 Hz, 1H), 3. 95 (s, 3H), 3. 91 (s , 3H). MS: m/z 449. 2 [M+H] +. Example 38

(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-5,7-dimethoxyisoquinolin-1-amine 3-(I benzo[£]imidazole -2-yl)-4-chloroaniline (0.11 g, 0. 447 mmol), 1-chloro-5,7-dimethoxyisoquinoline (0·1 g, 0. 447 mmol), Propanol (10 mL) and concentrated hydrochloric acid (ΙΟ μ ί) were added to a 25 mL single-mouth bottle and refluxed for 18 hours. The solvent was evaporated to dryness crystals crystals crystals crystal crystals 3⁄4 NMR (DMSO-1 ₆ ): 10. 71 (brs, 1H), 8. 38 (d, J 2. 4 Hz, 1H), 7. 99-7. 95 (m, 1H), 7. 88- 7· 74 (m, 4H), 7. 69 (d, = 6. 6 Hz, 1H), 7. 48-7. 43 (m, 3H), 7. 07 (s, 1H), 3. 99 ( s, 6H). MS: m/z 431. 2 [M+H] +. Example 39

(4-Chloro-3-(pyridin-2-yl)phenyl)-5,7-dimethoxyisoquinolin-1-amine 5 mL of isopropanol in a 25 mL round bottom flask, then compound 4 -Chloro-3-(pyridin-2-yl)aniline (30 mg, 0.15 mmol) and 1-chloro-5,7-dimethoxyisoquinoline (36 mg, 0.16 mmol) . The reaction mixture was reacted at 100 ° C for 12 hours, and evaporated to dryness. _3⁄4 NMR (CDC1 ₃ ): 8. 74 (d, = 4. 2 Hz, 1H), 8. 01 (d, J = 5. 7 Hz, 1H), 7. 95 (d, J = 7. 5 Hz, 1H), 7.85-7.78 (m, 2H), 7.67 (s, 1H), 7.49-7.45 (m, 2H), 7.32-7.31 (m, 1H), 6.71-6.68 (m, 2H), 5.37 ( Brs, 1H), 3.99 (s, 3H), 3.96 (s, 3H). MS: m/z 392.2 [M+H] +. Example 40

(3-(Benzo[t]thiazol-2-yl)-4-chlorophenyl)-5,7-dimethoxyisoquinolin-1-amine The compound was applied in a similar manner to that described in Example 39. The synthesis method is carried out, and the starting materials are 1-chloro-5,7-dimethoxyisoquinoline and 2-(2-chloro-5-aminophenyl)-benzo[t]thiazole. _3⁄4 NMR (CDC1 ₃ ): 8.25 (s, 1H), 8. 14-8. 11 (m, 2H), 8.00—7.96 (m, 2H), 7.53-7.49 (m, 4H), 6.77 (s, 1H ), 6.69 (s, 1H), 3.99 (s, 6H). MS: m/z 448.2 [M+H] +. Example 41

N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-methylquinazolin-4-amine Prepared by the synthetic method described in Example 14, starting materials were 3-(I benzo[t]imidazol-2-yl)-4-chloroaniline and 4-chloro-6,8-dimethoxy 2-methylquinazoline. 3⁄4 匪R (DMS0-t _tf ): 11.38 (brs, 1H) , 8.39 (d, J 2. Ί Hz, 1H), 8. 12 (dd, = 8· 7 and 2· 7 Hz, 1H),

7.89 (s, 1H), 7.78 (d, = 8.7 Hz, 1H), 7.69—7· 66 (m, 2H), 7.30—7· 27 (m, 3H), 4.08 (s, 3H), 4.00 (s , 3H), 2.66 (s, 3H). MS: m/z 446.3 [M+H] +. Example 42

N~(4-Chloro-3-(pyridin-2-yl)phenyl)-6,8-dimethoxy-2-methylquinazolin-4-amine The present compound is applied similarly to the examples described. The synthesis method of 29 was carried out, and the starting materials were 4-chloro-3-(pyridine-2-yl)aniline and 4-chloro-6,8-dimethoxy-2-methylquinazoline. 3⁄4 NMR (DMS0_t ₆ ): 10. 14 (brs, 1H),

8.70 (d, = 4.5 Hz, 1H), 8. 19 (dd, J 9·3 and 2·1 Hz, 1Η), 8.08 (d, = 2.4 Hz: 1H), 7.92 (td, = 7.5 and 1· 5 Hz, 1H), 7.70 (d, = 7.8 Hz, 1H), 7.66-7.63 (m,

1H), 7.57 (d, = 8.7 Hz, 1H), 7.45-7.41 (m, 1H), 6.95 (s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 2.60 (s, 3H) . MS: m/z 407.2 [M+H] +. Example 43

N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-nitroquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 10. 92 (brs, 1H), 9. 00 (d, = 9. 3 Hz, 1H), 8. 84 (s, 1H), 8. 59-8. 58 ( m, 2H), 8. 46 (dd, = 9· 0 and 2· 4 Hz, 1H), 8. 21 (dd, = 8· 7 and 2· 7 Hz, 1H), 7. 84-7. 79 (m, 3H), 7. 49-7. 46 (m, 2H). MS: m/z 417. 2 [M+H] +. Example 44

N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-aminoquinazolin-4-amine will be SnCl ₂ 3⁄40 (0. 13 g, 0. 56 mmol Add to (3_(I benzo[t]imidazolium-2-yl)-4-chlorophenyl)-7-nitroquinazolin-4-amine (58.6 mg, 0.14 mmol) in methanol Solution (10 mL). The reaction was heated to 70 ° C and stirred under N ₂ overnight. After the temperature was lowered to room temperature, the solvent was evaporated to dryness. The residue was washed with a mixed solution of ethyl acetate and methanol: dissolving (101), was added solid N _a HC0 ₃ was adjusted to pH 5.0. Filtration, the filtrate was concentrated to dryness to give the title compound (55.1 mg, 97.6%). 3⁄4匪R (DMSO- : 12. 76 (brs, 1H), 9. 76 (s, 1H), 8. 47 (d, J 2. Ί Hz, 1H), 8. 39 (s, 1H), 8 32 (d, = 9. 0 Hz, 1H), 8. 18 (dd, = 8· 7 and 2·7 Hz, 1H), 7. 72-7· 69 (m, 1H), 7. 62- 7· 59 (m, 2H), 7. 25-7· 20 (m, 2H), 6. 93 (dd, = 9· 0 and 2· 1 Hz, 1H), 6. 73 (d, J = 2Λ Hz, 1H), 6. 14 (s, 2H) MS: m/z 387. 2 [M+H] +. The following compounds were obtained using a synthetic procedure similar to that described in Examples 5, 6 and 14. The starting materials were substituted 2-aminobenzoic acid, formamide and 3-(l benzo[t]imidazol-2-yl)-4-chloroaniline.

 A 3- (l benzo[£]imidazol-2-yl)-4-chlorophenyl)-6, 7, 8-trimethoxyquinazoline-4-amine

3⁄4 NMR (DMS0-t ₆ ): 11. 57 (brs, 1H), 8. 76 (s, 1H), 8. 41 (d, J = 2Λ Hz, 1H), 8. 26 (s, 1H), 8. 07 (dd, = 8· 7 and 2·7 Hz, 1H), 7. 81 (d, = 8. 7 Hz, 1H), 7. 73-7. 70 (m, 2H), 7. 35 —7. 32 (m, 2H), 4. 07 (s, 3H), 4. 02 (s, 6H). MS: m/z 462. 4 [M+H] +. Example 46

N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-diethoxyquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 12. 72 (s, 1H), 9. 67 (s, 1H), 8. 51 (s, 1H), 8. 45 (d, J 2. 7 Hz, 1H), 8. 24 (dd, J 8 · 7 and 2· 4 Hz, 1Η), 7. 72—7· 59 (m, 3H), 7. 48 (d, J = 2. 1 Hz, 1H), 7. 28-7. 23 (m, 2H), 6. 94 (d, J = 2Λ Hz, 1H), 4. 23—4. 13 (m, 4H) 1. 46 -1. 40 (m, 6H). MS: m/z 460. 4 [M+H] +. Example 47

 A 3- (l benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 7, 8-triethoxyquinazolin-4-amine

_3⁄4 NMR (CD ₃ 0D): 8. 51 (s, 1H), 8. 31 (d, J = 2Λ Hz, 1H), 8. 04 (dd, = 8. 9 and 2. 6 Hz, 1Η), 7. 64-7. 61 (m, 4Η), 7. 33-7. 30 (m, 2H), 4. 31-4. 22 (m, 4H), 1. 56-1. 51 (m, 3H ), 1. 46-1. 40 (m, 6H). MS: m/z 504. 2 [M+H] +. Example 48

N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethylquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 12 81 (s, 1H), 10. 02 (s, 1H), 8. 63 (s, 1H), 8. 54 (d, J 2. 4 Hz, 1H), 8. 37 (s, 1H), 8. 26 (dd, J 8. 9 and 2. 6 Hz, 1Η), 7. 72—7· 59 (m, 4H) 7. 30-7. 20 (m, 2H), 2. 59 (s, 3H), 2. 50 (s, 3H). MS: m/z 400. 3 [M+H] +. Example 49

 N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,7-methylenedioxyquinazoline-4-amine

 3⁄4 NMR (DMSO-t^): 11. 28 (s, 1H), 8. 83 (s, 1H), 8. 40-8. 39 (m, 2H), 8. 06 (dd, = 8· 7 And 2·4 Hz, 1H), 7. 83-7. 75 (m, 3H), 7. 43-7. 39 (m, 3H), 6. 38 (s, 2H). MS: m/z 416. 1 [M+H] +. Example 50

 N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,7-ethylenedioxyquinazoline-4-amine

3⁄4 NMR (DMS0-t ₆ ): 11. 30 (brs, 1H), 8. 82 (s, 1H), 8. 48-8. 40 (m, 2H), 8. 05 (dd, = 8· 9 And 2· 0 Hz, 1H), 7. 78-7· 69 (m, 3H), 7. 39-7· 32 (m, 3H), 4. 50-4· 46 (m, 4H). MS: m/z 430. 1 [M+H] +. Example 51

N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-morpholinylquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 11. 48 (brs, 1H), 8. 84-8. 71 (m, 2H), 8. 38 (s, 1H), 8. 03

(d, = 7. 8 Hz, 1H), 7. 84 (d, = 8. 7 Hz, 1H), 7. 78-7. 71 (m, 2H), 7. 67-7. 64 (m, 1H), 7.43-7.42 (m, 2H), 7.03-7.02 (m, 1H), 3.79-3.77 (m, 4H), 3.51-3.49

(m, 4H). MS: m/z 457. 1 [M+H] +. Example 52

 Ι ~ (3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-(4-trifluoromethylphenyl)quinazoline-4-amine

3⁄4匪R (DMS0-t ₆ ): 12.77 (s, 1H), 10. 18 (s, 1H), 8.76 (d, = 8.7 Hz, 1H), 8.72 (s, 1H), 8.54 (d, = 2.7) Hz, 1H), 8.26 (dd, = 8· 9 and 2· 6 Hz, 1H), 8. 17-8.09 (m, 4H), 7.91 (d, = 8.4 Hz, 2H), 7.74-7.68 (m, 2H), 7.62-7.59 (m, 1H), 7.31-7.21 (m, 2H). MS: m/z 516. 1 [M+H] +. The following compounds were prepared in a similar manner to the synthesis methods described in Examples 1 to 3 and 14, and the starting materials were unsubstituted or substituted 5-nitrobenzoic acid, o-phenylenediamine, acetic acid and 4-chloro-6. , 8-dimethoxyquinazoline (synthesis method is similar to the described examples 5 and 6, starting materials are 2-amino-3,5-dimethoxybenzoic acid and formamide). Example 53

 N~(3-(I benzo[£]imidazol-2-yl)-phenyl)-6, 8-dimethoxyquinazoline-4-amine

 3⁄4 NMR (DMSO-t^): 11.91 (s, 1H), 8.74-8.70 (m, 2H), 8.23 (d, = 7.8 Hz, 1H), 8.08 (s, 1H), 7.97 (d, = 8. 1 Hz, 1H), 7.75-7.73 (m, 3H), 7.45-7.31 (m, 2H), 7.29 (s, 1H), 4.06 (s, 3H), 4.02 (s, 3H). MS: m/z 398.2 [M+H] +. Example 54

 (I benzo[t]imidazol-2-yl)-4-methylphenyl)-6, 8-dimethoxyquinazoline-4-amine

3⁄4 NMR (DMS0-t ₆ ): 11.53 (brs, 1H), 8.67 (s, 1H), 8. 19 (s, 1H), 7.96 (s, 1H), 7.86 (d, = 8.4 Hz, 1H), 7.80—7· 65 (m, 2H), 7.56 (d, = 8.4 Hz, 1H), 7.45-7.30 (m, 2H), 7.27 (s, 1H), 4.05 (s, 3H), 4.01 (s, 3H) ), 2.63 (s, 3H). MS: m/z 412.4 [M+H] +. Example 55

 N~(3-(I benzo[t]imidazol-2-yl)-4-fluorophenyl)-6, 8-dimethoxyquinazoline-4-amine

3⁄4 NMR (DMS0-t ₆ ): 12.57 (s, 1H), 9.69 (s, 1H), 8.62 (dd, = 6·6 and 2·7 Hz,

1H), 8.47 (s, 1H), 8.22-8. 17 (m, 1H), 7.71-7.68 (m, 2H), 7.61-7.59 (m, 2H), 7.51-7.44 (m, 2H), 6.95 (s, 1H), 3.96 (s, 3H), 3.91 (s, 3H). MS: m/z 416.4

[M+H] +.

 Example 56

 (I benzo[t]imidazol-2-yl)-4-bromophenyl)-6,8-dimethoxyquinazoline-4-amine

3⁄4 NMR (DMS0-t ₆ ): 10.85 (brs, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 8.03-8· 00 (m, 1H), 7.99-7.90 (m, 1H), 7.74 (s, 1H), 7.68-7.64 (m, 2H), 7.31-7.28 (m, 2H), 7.19 (s, 1H), 4.01 (s, 3H), 3.99 (s, 3H). MS: m/z 476.3 [M+H] +.

 Example 57

 N~(3-(I benzo[t]imidazol-2-yl)-4-methoxyphenyl)-6, 8-dimethoxyquinazoline-4-amine

3⁄4 NMR (DMS0-t ₆ ): 9.78 (brs, 1H), 8.64 (d, J = 2.7 Hz, 1H), 8.46 (s, 1H), 8.13 (dd, = 9.3 and 2.7 Hz, 1H), 7.66- 7.63 (m, 2H), 7.55-7.54 (m, 1H), 7.32 (d, = 9.0 Hz, 1H), 7.22-7.19 (m, 2H), 6.98 (s, 1H), 4.07 (s, 3H), 3.97 (s, 3H), 3.94 (s, 3H). MS: m/z 428.2 [M+H] +.

 Example 58

 N~(3-(I benzo[t]imidazol-2-yl)-2-methylphenyl)-6, 8-dimethoxyquinazoline-4-amine

3⁄4 NMR (DMS0-t ₆ ): 11.54 (brs, 1H), 8.61 (s, 1H), 7.89-7.85 (m, 1H), 7.83- 7.78 (m, 1H), 7.73-7.70 (m, 2H), 7.59-7.57 (m, 2H), 7.36-7.32 (m, 3H), 4.07 (s, 3H), 4.00 (s, 3H), 2.43 (s, 3H). MS: m/z 412.4 [M+H] +.

 Example 59

N~(3-(I benzo[t]imidazol-2-yl)-2-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 9.08 (s, 1H), 7.91 (d, = 7.8 Hz, 1H), 7.40-7.28 (m, 7.08 (d, = 2.1 Hz, 1H), 6.93 (t, = 7.8 Hz, 1H), 6.75 (dd, = 8· 0 and

Hz, 1H), 6.58 (dd, = 7· 5 and 1.2 Hz, 1H), 6.40 (d, = 2.4 Hz, 1H), 4.00

3H), 3.67 (s, 3H). MS: m/z 432.3 [M+H] +.

 Example 60

N~(3-(I benzo[t]imidazol-2-yl)-6-methylphenyl)-6,8-dimethoxyquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 11. 18 (brs, 1H), 8. 34 (s, 1H), 8. 20-8. 13 (m, 2H), 7. 83 (s, 1H), 7 65-7. 58 (m, 3H), 7. 34—7· 32 (m, 1H), 7. 25—7· 23 (m, 2H), 4. 04 (s, 3H), 3. 99 (s, 3H), 2. 30 (s, 3H). MS: m/z 412. 4 [M+H] +. Example 61

N~(3-(I benzo[t]imidazol-2-yl)-6-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 11. 94 (brs, 1H), 8. 64 (s, 1H), 8. 44 (s, 1H), 8. 31 (d, J = 8. 4 Hz, 1H), 7. 91-7. 88 (m, 2H), 7. 66-7. 63 (m, 2H), 7. 30-7. 27 (m, 3H), 4. 06 (s, 3H), 4. 00 (s, 3H). MS: m/z 432. 3 [M+H] +. Example 62

N~(3-(I benzo[t]imidazol-2-yl)-5-trifluoromethylphenyl)-6, 8-dimethoxyquinazolin-4-amine 3⁄4匪R (DMS0- t ₆ ): 11. 13 (brs, 1H), 8. 96 (s, 1H), 8. 79 (s, 1H), 8. 44-8. 40 (m, 2H), 7. 78 (s, 1H), 7. 67-7. 66 (m, 2H), 7. 31-7. 27 (m, 3H), 4. 05 (s, 3H), 4. 02 (s, 3H). MS: m/z 466. 4 [M+H] +. Example 63

N~(3-(I benzo[t]imidazol-2-yl)-5-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine 3⁄4 匪R (DMS0-t ₆ ) : 11. 45 (brs, 1H), 8. 82 (s, 1H), 8. 62 (s, 1H), 8. 20-8. 15 (m, 2H), 7. 89 (s, 1H), 7. 70-7· 67 (m, 2H), 7. 32-7· 30 (m, 3H), 4. 07 (s, 3H), 4. 03 (s, 3H). MS: m/z 432. 3 [M+H] +. The following compounds were prepared in a similar manner to the synthesis methods of Examples 1 to 3 and Example 14 described above, starting from 2-chloro-5-nitrobenzoic acid, substituted o-phenylenediamine, acetic acid and 4-chloro -6, 8-dimethoxyquinazoline.

Example 64

 N~(3-(7-Methyl-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazoline-4-amine

3⁄4 NMR (DMS0-t ₆ ): 11. 64 (brs, 1H), 8. 69 (s, 1H), 8. 35 (s, 1H), 8. 10 (d, J

= 8. 7 Hz, 1H), 8. 03 (s, 1H), 7. 81 (d, = 8. 7 Hz, 1H), 7. 52 (d, = 7. 8 Hz, 1H), 7. 30-7. 20 (m, 2H), 7. 14 (d, J = 7. 2 Hz, 1H), 4. 04 (s, 3H), 4. 02 (s, 3H),

2. 59 (s, 3H). MS: m/z 446. 4 [M+H] +. Example 65

 N-(3-(7-Methoxy-IH-benzo[d]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine 1H MR (DMSO-i ): 11.97 (brs, IH), 8.74 (s, IH), 8.39 (s, IH), 8.20-8.00 (m, 2H), 7.84 (d, J = 8.7 Hz, IH), 7.45- 7.20 (m, 3H), 7.60 (d, J = 8.4 Hz, IH), 4.07 (s, 3H), 4.02 (s, 3H), 4.00 (s, 3H). MS: m/z 462.4 [M+H]+. Example 66

 N-(3-(7-Chloro-IH-benzo[d]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazoline-4-amine

1H MR (DMSO-i ): 11.69 (brs, IH), 8.75 (s, IH), 8.31 (d, J = 2.4 Hz, IH), 8.06 (dd, J = 8.9 and 2.6 Hz, IH), 7.97 ( s, IH), 7.81 (d, J = 9.0 Hz, IH), 7.61 (d, J = 7.8 Hz, IH), 7.40-7.20 (m _: 3H), 4.07 (s, 3H), 4.02 (s, 3H) ). MS: m/z 466.3 [M+H]+. Example 67

 N-(3-(7-Bromo-IH-benzo[d]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazoline-4-amine

1H MR (DMSO- ₆ ): 12.00 (s, IH), 8.75 (s, IH), 8.31 (s, IH), 8.10-8.04 (m, 2H), 7.81 (d J = 8.4 Hz, IH), 7.66 (d, J = 7.8 Hz, IH), 7.50 (d, J = 7.5 Hz, IH), 7.32-7.23 (m, 2H), 4.07 (s, 3H), 4.02 (s, 3H). MS: m/z 512.3 [M+H] +. Example 68

 N-(3-(7-Isopropoxy-IH-benzo[d]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine 1H MR (DMSO-i ): 11.69 (brs, IH), 8.73 (s, IH), 8.33 (d, J = 2.1 Hz, IH), 8.06 (dd, J = 8.7 and 2.1 Hz, IH), 7.99 ( s, IH), 7.81 (d, J = 9.0 Hz, IH), 7.40-7.15 (m, 3H), 6.88-6.85 (m, IH), 5.01-4.93 (m, IH), 4.06 (s, 3H) , 4.02 (s, 3H), 1.50-1.20 (m, 6H). MS: m/z 490.3 [M+H] +. Example 69

N-(3-(7-ethoxy-IH-benzo[d]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine 1H MR (DMSO-i ): 11.92 (brs, IH), 8.74 (s, IH), 8.37 (d, J = 2.7 Hz, IH), 8.20-8.00 (m, 2H), 7.83 (d, J = 9.0 Hz, (I, IH) , J = 6.9 Hz, 3H). MS: m/z 476.2 [M+H]+. Example 70

 N-(3-(6-Chloro-IH-benzo[d]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazoline-4-amine

 1H MR (DMSO-i ): 11.86 (brs, IH), 8.74 (s, IH), 8.39 (d, J = 2.4 Hz, IH), 8.06-8.02 (m, 2H), 7.79 (d, J = 8.7 Hz, IH), 7.72-7.66 (m, 2H), 7.33-7.29 (m, 2H), 4.06 (s, 3H), 4.01 (s, 3H). MS: m/z 466.4 [M+H]+. Example 71

N-(3-(6-Methyl-IH-benzo[d]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine 1H MR ( DMSO-i ): 11.49 (brs, IH), 8.70 (s, IH), 8.42 (s, IH), 8.08 (d, J = 8.7 Hz, 1H) _: 7.95 (s, IH), 7.79 (d, J = 8.4 Hz, IH), 7.60 (d, J = 8.1 Hz, IH), 7.50 (s, IH), 7.25 (s, IH), 7.18 (d, J = 7.8 Hz, IH), 4.04 (s, 3H) ), 4.01 (s, 3H), 2.50 (s, 3H). MS: m/z 446.4 [M+H]+. Example 72

 N-(3-(6-Bromo-IH-benzo[d]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazoline-4-amine

 1H MR (DMSO-i ): 11.95 (s, IH), 8.75 (s, IH), 8.39 (d, J = 2.4 Hz, IH), 8.08-8.03 (m, 2H), 7.90 (s, IH), 7.82 (d, J = 8.7 Hz, IH), 7.67 (d, J = 8.4 Hz, IH), 7.46 (dd, J = 8.7 and 1.5 Hz, IH), 7.33 (s, IH), 4.07 (s, 3H) ), 4.02 (s, 3H). MS: m/z 510.3 [M+H] +. Example 73

N-(3 -(6-Methoxy-IH-benzo[d]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine 1H MR (DMSO- ₆ ): 11.35 (brs, IH), 8.71 (s, IH), 8.39 (s, IH), 8.03 (d, J = 8.7 Hz, 1H) _: 7.90-7.70 (m, 2H), 7.60 ( d, J = 8.4 Hz, IH), 7.28 (s, IH), 7.17 (s, IH), 6.96 (d, J = 8.1 Hz, IH), 4.05 (s, 3H), 4.01 (s, 3H), 3.83 (s, 3H). MS: m/z 462.4 [M+H]+. Example 74

N-(3-(6-trifluoromethyl-IH-benzo[d]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine 1H MR (DMSO-i ): 11.66 (brs, IH), 8.74 (s, IH), 8.40 (d, J = 2.4 Hz, IH), 8.15-7.92 (m, 3H), 7.90-7.70 (m, 2H) , 7.60 (d, J = 8.4 Hz, IH), 7.30 (s, IH), 4.06 (s, 3H), 4.01 (s, 3H). MS: m/z 500.3 [M+H] +. Example 75 N-(3-(6-Cyano-1H-benzo[d]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine 1H MR ( DMSO-i ): 11.61 (brs, 1H), 8.74 (s, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.94 (s, 1H), 7.89-7.72 (m, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 4.06 (s, 3H), 4.01 (s, 3H). MS: m/z 457.3 [M+H]+.

Example 76

N~(3-(6-ethoxy-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine 3⁄4 NMR ( DMS0-t ₆ ): 11.39 (brs, 1H), 8.71 (s, 1H), 8.41 (d, J= 2.7 Hz, 1H),

8.07 (dd, = 8.7 and 2.4, 1H), 7.91 (s, 1H), 7.81 (d, = 8.7 Hz, 1H), 7.61

(d, = 9.0 Hz, 1H), 7.27 (s, 1H), 7.16 (d, J = 2.1 Hz, 1H), 6.97 (dd, J

8.7 and 2· 1 Hz, 1H), 4.13-4.08 (m, 2H), 4.05 (s, 3H), 4.01 (s, 3H), 1.40 (t, J

= 6.9 Hz, 3H). MS: m/z 476.4 [M+H] +.

Example 77

Λ^-(3-(6-Dimethylamino-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 11.01 (brs, 1H), 8.66 (s, 1H), 8.43 (d, J = 2Λ Hz, 1H),

8.08 (dd, = 8.7 and 2.4, 1H), 7.81-7.78 (m, 2H), 7.65 (d, = 9.0 Hz, 1H),

7.21-7.13 (m, 3H), 4.02 (s, 3H), 4.00 (s, 3H), 3.05 (s, 6H). MS: m/z 475.4

[M+H] +.

Example 78

N~(3-(6-morpholinyl-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine 3⁄4 NMR ( DMS0-t ₆ ): 10.84 (brs, 1H), 8.63 (s, 1H), 8.42 (d, J= 2.7 Hz, 1H),

8.09 (dd, = 8.7 and 2.7, 1H), 7.77-7.72 (m, 2H), 7.57 (d, = 9.6 Hz, 1H),

7.16-7.10 (m, 3H), 4.00 (s, 3H), 3.99 (s, 3H), 3.81—3.78 (m, 4H), 3.17—3.13

(m, 4H). MS: m/z 517.2 [M+H] +.

Example 79

N~(3-(6-Isopropoxy-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine 3⁄4 NMR (DMSO-t^): 11. 79 (brs, 1H), 8. 70 (s, 1H), 8. 44 (d, J = 2. 7 Hz, 1H), 8. 12-8. 07 (m, 2H), 7. 78 (d, = 8. 7 Hz, 1H), 7. 60 (d, = 8. 7 Hz, 1H), 7. 24 (d, J = 2. 1 Hz, 1H ), 7. 18 (d, J = 2. 1 Hz, 1H), 6. 96 (dd, = 8· 9 and 2· 6 Hz, 1H), 4. 69-4. 61 (m, 1H), 4. 04 (s, 3H), 4. 02 (s, 3H), 1. 31 (d, = 6. 0 Hz,

6H). MS: m/z 490. 2 [M+H] +. Example 80

(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-ethylquinazolin-4-amine is applied in a similar manner as described The synthesis methods of Examples 12, 6 and 14 were carried out, and the starting materials were 2-amino-3,5-dimethoxybenzoic acid, propionic anhydride and 3-(I benzo[£]imidazol-2-yl. ) 4-chloroaniline. 3⁄4 NMR (DMS0-d ₆ ) : 11. 46 (brs, 1H), 8. 52 (d, = 8. 7 Hz, 1H), 8. 14 (dd, = 8· 7 and 2· 4 Hz, 1Η ), 7. 94 (s, 1H), 7. 79 (d, = 8. 7 Hz, 1H), 7. 69—7· 66 (m, 2H), 7. 30—7· 27 (m, 3H) ), 4. 08 (s, 3H), 4. 01 (s, 3H), 2. 99 (q, J ΊΛ Hz, 2H), 1. 28 (t, = 7. 5 Hz, 3H). MS: m/z 460. 4 [M+H] +. Example 81

 Λ^-((33--((II Benzobenzo[[tt]]imimidazole--22--yl))-44--chlorochlorophenylphenyl))-66,, 88--dimethoxymethoxy--22-chlorochloromethylmethyl quinazolinazoline--44--amine amine aa)) 66,, 88--dimethoxymethoxy Base--22--chlorochloromethylmethyl quinazolinazoline--44 ((33^^))-ketoone:: 22-aminoamino--33,, 55- - Dimethylmethoxyphenebenzoic acid ((11.. 0000 gg,, 44.. 7744 mmmmooll)) solution of chlorochloroacetonitrile nitrile (( 00.. 66 mmLL)) plus Add 11,44-dioxyoxocyclohexane ring solution ((44 mmLL)) into HHCC11, add heat to the heat

2200 5500 ° ° CC,, stir and stir for 2244 hours, a solid solid precipitated out. . After cooling to room temperature at room temperature, add ethyl ether ether ((3300 mmLL)), continue to stir and stir for 3300 minutes, filter, wash with ethyl ether ether Polyester, the filter cake will be dried and dried to obtain the target product of the rose red red solid color solid target ((11.. 1133 gg,, 9933.. 77%%)). . MMSS :: mm//zz 225555.. 33 [[MM++HH]] ++. .

Bb)) 44--chlorochloro--66,, 88--dimethoxymethoxy- 22--chlorochloromethylmethylquinazolinazoline:: should be applied similarly to According to the synthesis method of Example 66 described in the description, the starting material is 66, 88-dimethoxymethoxy- -22--Chlorochloromethylmethyl quinazolinazoline--44 ((33^^))-keto ketone. . MMSS :: mm//zz 227744.. 33 [[MM++HH]] ⁺⁺ . .

实施例 82 2255 cc)) ((II benzobenzo[[££]]imimidazole--22--yl))-44--chlorochlorophenylphenyl))--66,, 88-- Dimethylmethoxyoxy--22--chlorochloromethylmethyl quinazolinazoline--44--amine amine:: should be applied similar to what is described in the description The starting material method of the example 1144 was prepared, and the starting material was 44-chlorochloro--66, 88-dimethoxymethoxy--22. -Chlorochloromethylmethyl quinazolinazoline and 33--((II benzobenzo[[tt]]imimidazole--22--yl))-44--chlorochloride Phenylaniline. . 3⁄43⁄4 匪匪RR ((DDMMSS00--tt ₆₆ )):: 1100.. 6600 ((bbrrss,, 11HH)),, 88.. 6666 ((ss,, 11HH)),, 88.. 3344 ((dd ,, == 99.. 00 HHzz,, 11HH)),, 77.. 8811--77.. 7788 ((mm,, 33HH)),, 77.. 7744 ((ss,, 11HH)),, 77.. 5500--77.. 4477 ((mm,, 22HH)),, 77.. 0088 ((ss,, 11HH)),, 44.. 7766 ((ss,, 22HH)),, 33. . 9977 ((ss,, 33HH)),, 33.. 9966 ((ss,,,

Example 82

N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-fluoromethylquinazolin-4-amine is similar to The synthetic method of Example 81 was carried out to prepare the starting material as 2-amino-3,5-dimethoxybenzoic acid, fluoroacetonitrile and 3-(l benzo[£]imidazol-2-yl)- 4-chloroaniline. 3⁄4 NMR (DMS0-£ ₆ ): 10.40 (brs, 1H), 8.58 (d, J = 2.7 Hz, 1H), 8.35 (dd, = 9· 0 and 2·7 Hz, 1H), 7.82- 7.78 (m , 3H), 7.68 (s, 1H), 7.49-7.46 (m, 2H), 7.07 (s, 1H), 5.51 (s, 1H), 5.35 (s, 1H), 3.98 (s, 3H), 3.96 ( s, 3H). MS: m/z 464.4 [M+H] +. Example 83

N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-(dimethylaminomethyl)quinazoline_4_ Amine 6,6-dimethoxy-2-(dimethylaminomethyl)quinazolin-4(3^)-one: dimethylamine hydrochloride at 0 ° C

(0.27 g, 3.3 mmol) In a mixture with THF (3 mL), NaOH (0.13 g, 3.30 mmol) and 1 drop of 4M NaOH solution were added and stirred for 30 min. The resulting solution was added to a round bottom flask containing 6,8-dimethoxy-2-chloromethylquinazolin-4(3^)-one (Example 81a, 0.30 g, 1.18 mmol). The mixture was heated to 50 ° C, stirred for 2 hours, and the reaction solution was clarified. After cooling to room temperature, the solvent was distilled off, to the residue was added ethyl acetate and saturated NaHC0 ₃ solution, separated, ethyl acetate layer was dried over anhydrous N¾S0 _4, and concentrated to give the desired product after drying as a pale yellow solid (0.15 g, 47.8%). MS: m/z 264.35 [M+H] +.

b) 4-Chloro-6,8-dimethoxy-2-(dimethylaminomethyl)quinazoline: Prepared using a synthesis similar to that described in Example 6, starting material 6,8 -Dimethoxy-2-(dimethylaminomethyl)quinazolin-4(3^)-one. Grayish yellow solid (0.11 g, 67.9%). MS: m/z 282.3 [M+H] +.

c) N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-(dimethylaminomethyl)quinazoline- 4-Amine: Prepared using a synthetic procedure analogous to that described in Example 14, starting material 4-chloro-6, 8-dimethoxy-2-(dimethylaminomethyl)quinazoline and 3 - (l benzo[t]imidazol-2-yl)-4-chloroaniline. 3⁄4 NMR (DMS0-t ₆ ): 12.75 (brs, 1H), 10.06 (s, 1H), 8.43 (s, 1H), 8.19 (d, = 8.7 Hz, 1H), 7.69-7.60 (m, 4H), 7.28—7· 25 (m, 2H), 7.04 (s, 1H), 4.45 (s, 2H),

3.98 (s, 3H), 3.95 (s, 3H), 2.97 (s, 6H). MS: m/z 489.5 [M+H] +. Example 84

N~(3-(1-methylbenzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine a) 2-(2 -Chloro-5-nitrophenyl)-1-methylbenzo[£]imidazole: Add 2_(2_chloro-5-nitrophenyl)-Ibenzo[t]imidazole to a 100 mL vial (0.80 g, 2.93 mmol), anhydrous tetrahydrofuran (50 mL), stirring. Cool to 5 ° C and then add 60% sodium hydride (0.23 g, 5.87 mmol) in portions. After the addition, the nitrogen was protected, and the mixture was stirred at room temperature for 2 hours. Methyl iodide (1.83 g, 5.87 mmol) was slowly added dropwise to the reaction mixture. Stir at room temperature overnight. Water (50 mL) was added to the reaction mixture, and the THF was evaporated. The aqueous phase was extracted with dichloromethane (100 mL x 2). The combined organic phases were washed with EtOAc EtOAc EtOAc (EtOAc) MS: m/z 288.3 [M+H] ⁺ .

b) 3-(l-Methylbenzo[t]imidazol-2-yl)-4-chloroaniline: Prepared using a synthetic procedure analogous to that described in Example 8, starting material 2-(2- Chloro-5-nitrophenyl)-1-methylbenzo[t]imidazole. Yellow solid (0.18 g, 92.0%). MS: m/z 258.3 [M+H] +.

c) Λ 3-(1-Methylbenzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine: Application similar to that described The synthesis method of Example 14 was carried out, and the starting material was 3-(1-methylbenzo[t]imidazol-2-yl)-

4-Chloroaniline and 4-chloro-6, 8-dimethoxyquinazoline. 3⁄4 NMR (DMS0_t ₆ ): 11.57 (brs, 1H), 8.70 (s, 1H), 8.19-8.10 (m, 2H), 7.98 (s, 1H), 7.83-7· 72 (m, 3H), 7.37- 7· 34 (m,

2H), 7.24 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.74 (s, 3H). MS: m/z 446.4 [M+H] +. The following compound was prepared using a synthetic procedure similar to that described in Example 14, starting from 3-(1-methylbenzo[t]imidazol-2-yl)-4-chloroaniline (Example 84b) and Corresponding to 4-chloro-6, 8-dimethoxy-2-methylquinazoline or 4-chloro-6, 8-dimethoxy-2-(dimethylaminomethyl)quinazoline. Example 85

N~(3-(1-methylbenzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-methylquinazolin-4-amine 3⁄4匪R (DMS0-t ₆ ): 11.68 (brs, 1H), 8.17—8.12 (m, 2H), 8.02 (d, = 2.1 Hz, 1H), 7.82 (d, = 8.7 Hz, 1H), 7.75—7.68 (m, 2H), 7.41—7.27 (m, 3H), 4.07 (s, 3H), 3.99 (s, 3H), 3.75 (s, 3H), 2.66 (s, 3H). MS: m/z 460.2 [M+H] +. Example 86

 N~(3-(1-methylbenzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-(dimethylaminomethyl)quinazoline -

4-amine

3⁄4 NMR (DMS0-t ₆ ): 10.08 (s, 1H), 8.22 (dd, J 9· 0 and 2·7 Hz, 1H), 8.10 (d, J 2.Ί Hz, 1H), 7.73-7.65 ( m, 3H), 7.59 (d, J = 2Λ Hz, 1H), 7.38-7.37 (m, 2H), 7.03 (d, J = 2Λ Hz, 1H), 4.36 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.72 (s, 3H), 2.89 (s, 6H). MS: m/z 503.3 [M+H] +. Example 87

 (3-(5-Phenyloxazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine a) 2-chloro-5-nitro-oxime 2-oxo-2-phenylethyl)benzamide: 2-nitroacetophenone hydrochloride (0.86 g, 5 mmol), 2-chloro-5-nitrate was added to a 25 mL two-necked flask under nitrogen. Benzoic acid (1 g, 5 mmol), 2-(7-aza-I benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (HATU, 2.85 g, 7.5 mmol) and DCM (20 mL). The mixture was cooled to EtOAc. EtOAc (EtOAc, EtOAc. The reaction solution was evaporated to dryness, and the solvent was evaporated, and then, 10 ml of water, and ethyl acetate (50 mL×3). The organic layer was washed with EtOAc EtOAc (EtOAc) The title product (0.9 g, 60%) was obtained by column chromatography ( petroleum ether / ethyl acetate (3:1). MS: m/z 319.3 [M+H] +.

b) 2-(2-Chloro-5-nitrophenyl)-5-phenyloxazole: Add 2-chloro-4-nitrate to a 25 mL three-necked flask equipped with a reflux cold-cold tube under nitrogen atmosphere protection at room temperature Base-oxime 2-oxo-2-phenylethyl)aniline (0.5 g, 1.5 mmol), hexachloroethane

(0.7 g, 3 mmol), triphenylphosphine (0.8 g, 3 mmol) and dichloromethane (10 mL), then triethylamine (0.4 g, 3 mmol). . After cooling, the reaction solution was evaporated to dryness, and then, solvent was evaporated, and then, 10 ml of water was added, and ethyl acetate (50 mL x 3) was used for extraction. 1N hydrochloric acid solution for organic layer

(50 mL×2), washed with EtOAc EtOAc m. The title product (300 mg, 64%) was obtained by column chromatography ( petroleum ether / ethyl acetate 2:1). MS: m/z

301.2 [M+H] +.

c) 4-Chloro-3-(5-(phenyloxazol-2-yl)aniline: Prepared using a synthetic procedure analogous to that described in Example 44, starting material 2-(2-chloro-5) - nitrophenyl)-5-phenyloxazole MS: m/z 271.2 [M+H] ⁺ .

d) (5-Phenyloxazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine: A synthetic method similar to that described in Example 14 was applied. The starting material is 4-chloro-3-(5-(phenyloxazol-2-yl)aniline and 4-chloro-

6,8-Dimethoxyquinazoline. 3⁄4 匪R (DMS0-t ₆ ): 11.60 (brs, 1H), 8.76 (s, 1H), 8.55 (d, = 2.4 Hz, 1H), 8.02 (dd, = 8· 9 and 2· 6 Hz, 1Η ), 7.96—7· 93 (m, 2H), 7.86-7.78 (m, 3H), 7.55-7.50 (m, 2H), 7.45-7.42 (m, 1H), 7.31 (d, = 1.5 Hz, 1H) , 4.07 (s, 3H), 4.02 (s, 3H). MS: m/z 459.4 [M+H] +. Example 88 (3-(5-(phenyl-1,3,4-oxadiazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine is similar to The synthetic method of Example 87 was carried out to prepare starting materials of 2-chloro-5-nitrobenzoic acid, benzoylhydrazine, and 4-chloro-6,8-dimethoxyquinazoline. NMR (DMS0-t ₆ ): 9. 82 (s, 1H), 8. 63 (d, = 2. 4 Hz, 1H), 8. 54 (s, 1H), 8. 29 (dd, = 9· 0 and 2· 4 Hz, 1Η), 8. 15-8. 09 (m, 2H), 7. 75 (d, = 9. 0 Hz, 1H), 7. 68—7. 65 (m, 3H) , 7. 49 (d, = 1. 8 Hz, 1H), 6. 99 (d, = 2. 1 Hz, 1H), 3. 97 (s, 3H), 3. 93 (s, 3H). MS : m/z 460. 4 [M+H] +. Example 89

 N~(3-(5-phenyl-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine a) 2-(2-chloro- 5-nitrophenyl)-5-phenyl-I imidazole: 2-chloro-4-nitro-oxime 2-oxo-2 was added to a 25 mL single-necked flask equipped with a reflux cold-cold tube under nitrogen atmosphere. -Phenylethyl)aniline (Example 87a, 1. 5 g, 5 mmol), ammonium acetate (7.2 g, 100 mmol) and 5 mL of acetic acid, and the mixture was heated to reflux overnight. After cooling, 50 mL of water was added, and a solid was precipitated. The precipitated solid was collected by filtration and dried in vacuo to give the desired product (300 mg, 20%). MS: m/z 300. 2 [M+H] +.

b) 4-Chloro-3-(5-phenyl-I imidazol-2-yl)aniline: Prepared using a synthetic procedure analogous to that described in Example 44, starting material 2-(2-chloro-5) -Nitrophenyl)-5-phenyl-I imidazole. Concentrated under reduced pressure to obtain the target crude product

(150 mg), used in the next step without further purification. MS: m/z 270. 1 [M+H] ⁺ .

c) (5-Phenyl-I imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine: a synthetic method applied to the described Example 14. The starting materials were obtained as 4-chloro-3-(5-phenyl-I imidazol-2-yl)aniline and 4-chloro-6, 8-dimethoxyquinazoline. 3⁄4 匪R (DMSO-t^): 12. 31 (brs, 1H), 8. 73 (s, 1H), 8. 40-8. 14 (m, 4H), 7. 94-7· 89 (m , 3H), 7. 52-7· 32 (m, 4H), 4. 07 (s, 3H), 4. 03 (s, 3H). MS: m/z 458. 4 [M+H] +. The following compound was obtained by a synthesis method similar to that described in Example 14, starting from 4-chloro-3-

(5-Phenyl-I imidazolyl-2-yl)phenylamine and the corresponding substituted 4-chloroquinazoline. Example 90

N~(3-(5-Phenyl-I imidazol-2-yl)-4-chlorophenyl)-6,8-dichloroquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 12. 52 (brs, 1H), 10. 18 (s. 1H), 8. 76—8. 73 (m, 2H), 8. 31

(d, = 2. 4 Hz, 1H), 8. 20 (d, = 2. 1 Hz, 1H), 8. 10 (dd, = 8· 7 and 2· 7 Hz, 1H), 7. 86-7. 77 (m, 3H), 7. 64 (d, = 8. 7 Hz, 1H), 7. 38 (t, J ΊΛ Hz, 2H) 7. 25-7. 20 (m, 1H). MS: m/z 468. 1 [M+H] +.

 Example 91

 N~(3-(5-phenyl-I imidazolyl-2-yl)-4-chlorophenyl)-6,7-methylenedioxyquinazoline-4-amine

3⁄4 NMR (DMS0-t ₆ ): 12. 42 (brs, 1H), 9. 58 (s, 1H), 8. 48 (s, 1H), 8. 26 (d, J = 1. 5 Hz, 1H ), 8. 08 (dd, = 8· 7 and 2· 4 Hz, 1Η), 8. 02 (s, 1H), 7. 85 (d, J

6. 9 Hz, 2H), 7. 75-7. 72 (m, 1H), 7. 57 (d, = 8. 7 Hz, 1H), 7. 37 (t, = 7. 8 Hz, 2H) , 7. 23-7. 19 (m, 2H), 6. 38 (s, 2H). MS: m/z 442. 1 [M+H] +.

 Example 92

N~(3-(5-Phenyl-I imidazol-2-yl)-4-chlorophenyl)-6,7-dimethoxyquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 11. 58 (brs, 1H), 8. 85 (s, 1H), 8. 37 (s, 1H), 8. 29 (d, J = 2. 4 Hz, 1H), 8. 13 (s, 1H ), 8. 02 (dd, = 8· 7 and 2· 4 Hz, 1H), 7. 87 (d, J

7. 5 Hz, 2H), 7. 81 (d, = 8. 7 Hz, 1H), 7. 47 (t, J = 7. 7 Hz, 2H), 7. 38-7. 34 (m, 2H ), 4. 02 (s, 3H), 3. 99 (s, 3H). MS: m/z 458. 2 [M+H] +.

 Example 93

(3-(5-Phenyl-I imidazol-2-yl)-4-chlorophenyl)-7-nitroquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 10. 79 (brs, 1H), 8. 99 (d, = 9. 0 Hz, 1H), 8. 82 (s, 1H),

8. 57 (d, = 2. 4 Hz, 1H), 8. 49-8· 43 (m, 2H), 8. 24-8· 18 (m, 2H), 7. 92 (d, J = 7 5 Hz, 2H), 7. 82 (d, = 9. 0 Hz, 1H), 7. 52 (t, J = 7. 5 Hz, 2H), 7. 44—7. 39 (m, 1H) . MS: m/z 443. 2 [M+H] +.

 Example 94

 N~(3-(5-phenyl-I imidazolyl-2-yl)-4-chlorophenyl)-7-chloroquinazoline-4-amine

3⁄4 NMR (DMS0-t ₆ ): 10. 81 (brs, 1H), 8. 80-8. 77 (m, 2H), 8. 43 (d, = 2. 1 Hz, 1H), 8. 15- 8. 12 (m, 2H), 7. 93-7. 88 (m, 5H), 7. 50 (t, = 7. 8 Hz, 2H), 7. 41- 7. 36 (m, 1H). MS: m/z 434. 1 [M+H] +.

Example 95 N~(3-(5-Phenyl-I imidazol-2-yl)-4-chlorophenyl)-6-chloro-8-methylquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 12. 45 (brs, 1H), 10. 00 (s, 1H), 8. 71 (s, 1H), 8. 62 (d, = 2. 1 Hz, 1H), 8. 35 (d, J = 2. 7 Hz, 1H), 8. 17 (dd, = 8· 7 and 2·7 Hz, 1H), 7. 89-7. 87 (m, 2H), 7. 82-7· 80 (m, 2H), 7. 62 (d, = 9. 0 Hz, 1H), 7. 38 (t, J = 7. 5 Hz, 2H), 7. 24-7. 20 (m, 1H), 2. 63 (s, 3H). MS: m/z 446. 1 [M+H] +. Example 96

N~(3-(5-phenyl-1 imidazol-2-yl)-4-chlorophenyl)-8-bromo-6-methylquinazolin-4-amine 3⁄4匪R (DMS0-t ₆ ) : 12. 45 (brs, 1H), 10. 05 (s, 1H), 8. 68 (s, 1H), 8. 45 (s, 1H), 8. 33 (d, J 2. Ί Hz, 1H ), 8. 16—8. 12 (m, 2H), 7. 89 (d, J Ί. 2 Hz, 2H), 7. 81 (d, = 1. 8 Hz, 1H), 7. 61 (d , = 8. 7 Hz, 1H), 7. 38 (t, J = 7. 5 Hz, 2H),

7. 25-7. 22 (m, 1H), 2. 54 (s, 3H). MS: m/z 492. 1 [M+H] +. The following compounds were prepared in a similar manner to the synthetic procedures described in Examples 87a and 89, starting from 2-chloro-5-nitrobenzoic acid, corresponding substituted 2-aminoacetophenone hydrochloride, ammonium acetate. And 4-chloro-6, 8-dimethoxyquinazoline. Example 97

N~(3-(5-(4-methylphenyl)-1)imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine 3⁄4 NMR ( DMS0-t ₆ ): 11. 62 (brs, 1H), 8. 68 (s, 1H), 8. 29 (d, = 2. 1 Hz, 1H),

8. 09-7. 93 (m, 3H), 7. 80 (d, = 8. 7 Hz, 1H), 7. 73 (d, = 7. 8 Hz, 2H), 7. 28- 7. 27 (m, 3H), 4. 02 (s, 3H), 3. 98 (s, 3H), 2. 31 (s, 3H). MS: m/z 472. 1

[M+H] +. Example 98

N~(3-(5-(4-Methoxyphenyl)-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 11. 08 (brs, 1H), 8. 67 (s, 1H), 8. 33 (d, = 1. 2 Hz, 1H), 8. 04 (dd, = 9. 3 And 2. 1 Hz, 1Η), 7. 94 (s, 1H), 7. 82-7. 77 (m, 4H), 7. 22 (s, 1H), 7. 02 (d, = 8. 4 Hz, 2H), 4. 03 (s, 3H), 4. 00 (s, 3H), 3. 35 (s, 3H). MS: m/z 488. 1 [M+H] +. Example 99

 N~(3-(5-(4-chlorophenyl)-I imidazolyl-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline-4-amine

3⁄4 匪R (DMS0-t ₆ ): 8. 71 (s, 1H), 8. 25 (s, 1H), 7. 97-7. 87 (m, 4H), 7. 81-7. 72 (m , 2H), 7. 48 (d, J = 7. 5 Hz, 2H), 7. 27 (s, 1H), 4. 05 (s, 3H), 4. 04 (s, 3H). S : m/z 492. 1 [M+H] +.

 Example 100

 N~(3-(5-(4-fluorophenyl)-I imidazolyl-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline-4-amine

3⁄4 NMR (DMS0-t ₆ ): 11. 53 (brs, 1H), 8. 72 (s, 1H), 8. 29 (s, 1H), 8. 00-7. 89 (m, 5H), 7 80 (d, = 9. 0 Hz, 1H), 7. 32—7. 26 (m, 3H), 4. 05 (s, 3H), 4. 01 (s, H). MS: m/z 476. 1 [M+H] +.

 Example 101

 N~(3-(5-(3-chlorophenyl)-I imidazolyl-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline-4-amine

 3⁄4 NMR (DMSO-t^): 8. 62 (s, 1H), 8. 25 (d, J 2. Ί Hz, 1H), 8. 04—8. 01 (m, H), 7. 94 ( d, J Ί. 2 Hz, 2H), 7. 84—7· 73 (m, 2H), 7. 68 (d, = 8. 7 Hz, 1H), . 45 (t, = 8. 1 Hz, 1H), 7. 30 (d, = 9. 3 Hz, 1H), 7. 16 (s, 1H), 4. 00 (s, H), 3. 99 (s, 3H). MS: m/z 492. 1 [M+H] +.

 Example 102

N~(3-(5-(3-methoxyphenyl)-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine 3⁄4 匪R (DMS0-t ₆ ): 11. 94 (brs, 1H), 8. 72 (s, 1H), 8. 34 (s, 1H), 8. 21 (s, 1H): . 12-8. 07 (m, 2H), 7. 83 (d, = 8. 7 Hz, 1H), 7. 51-7. 47 (m, 2H), 7. 39 (t, J . 0 Hz, 1H), 7. 31 (s, 1H), 6. 93 (d, = 6. 3 Hz, 1H), 4. 06 (s, 3H), 4. 02 (s, H), 3. 82 (s, 1H). MS: m/z 488. 2 [M+H] +.

 Example 103

 N~(3-(5-(3-fluorophenyl)-I imidazolyl-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline-4-amine

3⁄4 NMR (DMS0-t ₆ ): 11. 59 (brs, 1H), 8. 73 (s, 1H), 8. 26 (s, 1H), 8. 04-7. 95 (m: H), 7 78-7. 71 (m, 3H), 7. 49-7. 42 (m, 1H), 7. 30 (s, 1H), 7. 13-7. 08 (m, 1H), . 06 ( s, 3H), 4. 01 (s, 3H). MS: m/z 476. 3 [M+H] +. Example 104

N~(3-(5-(2-methoxyphenyl)-I imidazol-2-yl)-4-chloro-phenyl)-6, 8-dimethoxyquinazolin-4-amine 3⁄4 NMR (DMS0-t ₆ ): 12. 30 (brs, 1H), 8. 73 (s, 1H), 8. 40-8. 30 (m, 2H), 8. 01- 7. 94 (m, 2H ), 7. 89—7. 86 (m, 2H), 7. 43 (t, = 7. 8 Hz, 1H), 7. 31 (s, 1H), 7. 20 (d, = 8. 1 Hz) , 1H), 7. 10 (t, J ΊΛ Hz, 1H), 4. 06 (s, 3H), 4. 03 (s, 3H), 3. 96 (s, 3H). MS: m/z 488. 2 [M+H] +. Example 105

 N~(3-(5-(2-methylphenyl)-1 imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine 3⁄4 NMR ( MeOD): 8. 70 (s, 1H), 8. 42 (d, = 2. 4 Hz, 1H), 8. 11 (dd, = 8. 7 and 2. 7 Hz, 1H), 7. 89- 7. 86 (m, 2H), 7. 71 (d, = 2. 1 Hz, 1H), 7. 57 (d, = 6. 9 Hz, 1H), 7. 43-7. 36 (m, 3H ), 7. 32 (d, = 2. 1 Hz, 1H), 4. 15 (s, 3H), 4. 07 (s, 3H), 2. 51 (s, 3H). MS: m/z 472. 1 [M+H] +. Example 106

N~(3-(5-(2-chlorophenyl)-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine 3⁄4 NMR (DMS0 -t ₆ ): 12. 63 (brs, 1H), 9. 69 (s, 1H), 8. 48 (s, 1H), 8. 27 (d, J = 3. 0 Hz, 1H), 8. 17 (dd, = 8· 0 and 1. 7 Hz, 1H), 8. 11 (dd, = 8· 7 and 2·7 Hz, 1Η), 7. 88 (d, J = 2Λ Hz, 1H), 7. 62 (d, = 8. 7 Hz, 1H), 7. 50-7. 47 (m, 2H),

7. 39-7. 36 (m, 1H), 7. 27-7. 25 (m, 1H), 6. 94 (s, 1H), 3. 93 (s, 3H), 3. 90 (s, 3H). MS: m/z 492. 1 [M+H] +. Example 107

N~(3-(5-(2-fluorophenyl)-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine 3⁄4 NMR (DMS0 -t ₆ ): 11. 85 (brs, 1H), 8. 74 (s, 1H), 8. 29 (d, = 1. 8 Hz, 1H),

8. 08-7. 96 (m, 3H), 7. 80—7· 70 (m, 2H), 7. 35—7· 32 (m, 4H), 4. 07 (s, 3H), 4. 02 (s, 3H). MS: m/z 476. 1 [M+H] +. Example 108

(3-(quinoxalin-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine a) 2-(2-Chloro-5-nitrophenyl)quinoxaline: To a 50 mL flask was added 2-bromoquinoxaline (100 mg, 0.48 mmol), 2-chloro-5-nitrophenylboronic acid (106 mg, 0.52 mmol), potassium carbonate (132 mg, 0.96 mmol) and 10 mL anhydrous ethylene glycol dimethyl ether. After stirring for 10 min, tetratriphenylphosphine palladium (28 mg, 0.024 mmol), argon Heat under reflux under protection. It was cooled to room temperature, filtered, and the filter cake was washed with water and dried to give the desired product (100 mg, 73.0%). MS: m/z 286.2 [M+H] +.

b) 2-(2-Chloro-5-aminophenyl)quinoxaline: Using a synthetic procedure analogous to that described in Example 3, the starting material was 2-(2-chloro-5-nitrobenzene Base) quinoxaline. MS: m/z 256.1 [M+H] ⁺ .

c) (quinoxalin-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine: prepared using a synthetic method similar to that described in Example 14, The starting materials were 2-(2-chloro-5-aminophenyl)quinoxaline and 4-chloro-6, 8-dimethoxyquinazoline. 3⁄4 NMR (MeOD): 9.26 (s, 1H), 8.49 (s, 1H), 8.26 (d, = 2.7 Hz 1H), 8.21-8.12 (m, 3H), 7.94-7.91 (m, 2H), 7.66 ( d, = 8.7 Hz, 1H), 7.38 (d, J = 2. Ί Hz, 1H), 6.99 (d, J = 2. Ί Hz, 1H), 4.58 (s, 3H), 4.01 (s, 3H) . MS: m/z 444. l [M+H] +. Example 109

 N~(3-(quinolin-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline-4-amine

 Using a synthetic procedure analogous to that described in Example 108, the starting materials were 2-bromoquinoline, 2-chloro-5-nitrophenylboronic acid and 4-chloro-6, 8-dimethoxyquinazole. Porphyrin. 3⁄4匪R (MeOD): 8.49-8.44 (m, 2H), 8.12- 8.01 (m, 2H), 7.84-7.81 (m, 2H), 7.77-7.61 (m, 2H), 7.40 (d, J 1.8 Hz , 1H), 7.02 (d, = 2.1 Hz, 1H), 4.03 (s, 3H), 4.00 (s, 3H). MS: m/z 443.3 [M+H] +. Example 110

 N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-5-methyl-7-(4-trifluoromethylphenyl)quinazolin-4-amine a) 5-Methyl-7-bromoquinolin-4(3^)-one: Prepared using a synthetic procedure analogous to that described in Example 5, starting material 2-methyl-4-bromo-6 -Aminobenzoic acid and formamide. Light yellow solid (0.27 g, 86.3 %). MS: m/z 239.0 [M+H]+.

b) 5-Methyl-7-(4-(trifluoromethyl)phenyl)quinolin-4(3^)-one: Add 5-methyl-7-bromoquinoline to a 100 mL round bottom flask -4 (3^)-ketone (0.20 g, 0.84 mmol), 4-(trifluoromethyl)benzeneboronic acid (0.24 g, 1.26 mmol), cesium carbonate (0.55 g, 1.68 mmol), tetrakis(triphenylphosphine) Palladium (77.65 mg, 0.07 mmol), water (3 mL) and dioxane (30 mL). The reaction solution was cooled to room temperature, concentrated, and ethyl acetate (50 mL) and brine (30 mL) was added and stirred for 1 hour. The organic phase was dried over anhydrous sodium sulfate (MgSO4). MS: m/z 305.2 [M+H] +.

c) 4-Chloro-5-methyl-7-(4-(trifluoromethyl)phenyl)quinoline: To a 25 mL round bottom flask was added 5-methyl-7-(4-(trifluoromethyl) Phenyl)quinoline-4(3^)-one (50.0 mg, 0.16 mmol), /^ diethylaniline (95.5 mg, 0.64 mmol), toluene (3 mL), phosphorus oxychloride (3 mL), Protected with nitrogen and heated to reflux for 48 hours. The reaction solution was cooled to room temperature, concentrated, ethyl acetate (60 mL) and 10% aqueous citric acid (30 mL) was added, and the mixture was stirred for 30 minutes, the organic phase was separated, and the organic phase was washed once with saturated aqueous sodium hydrogen carbonate. The residue was dried over sodium sulfate, filtered, and evaporated. MS: m/z 323.1 [M+H] +.

d) (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6-methyl-8-(4-(trifluoromethyl)phenyl)quinazolin-4-amine: Using a synthetic procedure similar to that described in Example 14, the starting materials were 3-(I benzo[t]imidazol-2-yl)-4-chloroaniline and 4-chloro-5-methyl-7. -(4-(Trifluoromethyl)phenyl)quinoline. Light yellow solid (7.1 mg, 22.2%). 3⁄4 NMR (DMSO— ₁₆ ): 9.09—9.07 (m, 1H), 8.61—8.58 (m, 1H), 8.31- 8.30 (m, 1H), 8.07 (d, = 7.8 Hz, 2H), 7.97-7 · 88 (m, 4H), 7.67-7· 64 (m, 3H), 7.27-7.24 (m, 2H), 3.07 (s, 3H). MS: m/z 530.2 [M+H] +. Example 111

 Detection of osteogenic differentiation induced by C3H10T1/2 cells (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine and its analogue inhibition Hedgehog signaling pathway-activated mouse mesenchymal stem cells C3H10T1/2 (C3H/10T1/2, Clone 8 mouse embryonic fibroblasts, Chinese Academy of Sciences cell bank) induced by hedgehog pathway to differentiate into osteoblasts, while intracellular Alkaline phosphatase expression is a loyal sign in this differentiation process. This process can be used as a means of detecting the activity of hedgehog pathway inhibitors.

The healthy growth period C3H10T1/2 cells were plated at 10,000 cells per well in a 96-well cell culture dish one day before the test. The cells were cultured overnight in growth medium DMEM (Hyclone) containing 10% fetal calf serum (FBS, Hyclone) at 37 ° C and 5% C0 ₂ . The test day was equipped with induction medium and inhibitor as follows: Reference compound and test compound were serially diluted to a concentration of 7 compounds with DMS0 at 1:3 and 1:10, and the eighth was a blank DMSO control. Ten-fold dilutions were prepared by mixing 10 μM DMS0 dilution with 90 μL fresh complete growth medium. In addition, a pre-packed 1 mM hedgehog pathway activator SAG (Yang, H. et al. J. Biol. Chem. 2009, 284, 20876-84) was added to the DMS0 mother liquor at a ratio of 1:1000 to 10% FBS. In the DMEM growth medium, the concentration of SAG was 1 μΜ, and the concentration of DMS0 was 0.1%. Take out from the incubator Cells, remove the medium, add 180 μΐ per well to the medium containing 1 μΜ activator SAG and immediately add 20 μM diluted 10 times of the reference compound or test compound solution. The concentration of the test compound is between 10 μΜ and 1 ηΜ. between. The cells were returned to the incubator for further 5 days.

 After five days, the activity of alkaline phosphatase in the cells was measured, and the detection methods included the following:

1) Configure the substrate reaction solution:

Solution Α: Configure 0.5 mM MgCl ₂ solution (Sigma Prod. No. M- 0250) for use.

 Solution B: A 1 M solution of diethanolamine was placed. Take 10. 51 g of diethanolamine (Sigma Prod. No. D-

8885) Dissolve in 80 mL of double distilled water, adjust the pH to 9. 8 (37 °C) with 5 M HCl, and finally make up to 100 mL.

 Solution C: 3.71 mg p-NPP (molecular weight 371. 14) was added to 10 mL of double distilled water to a final concentration of 1 mM, which was fully dissolved.

 Substrate reaction solution: Add 250 μM solution Α and 200 μM solution C to 10 mL of Solution B and mix.

 2) Detection of intracellular alkaline phosphatase activity:

 The cell culture dish was taken out, the supernatant was discarded, and the cells were washed twice with PBS, and 20 μM of the lysate was added per well (0.2%).

Triton solution), after shaking for 30 min at room temperature, add 80 μM of substrate reaction solution to each well. Put in the VariSkan Flash microplate reader and read 0D ₄ . ₅ absorbance values as background readings. The dish was then placed back in the 37 ° C incubator for 30 min and scanned again to read 0D ₄ . ₅ absorption value.

data processing:

0D ₄ read with 30 min. ₅ Readings minus background readings and data analysis using GraphPad's Prism 5. The logarithmized concentration of the compound is 0D ₄ representing the activity of alkaline phosphatase. ₅ Readings were plotted and the curve equation was fitted to the IC ₅ with the following equation. Value, Y (0D _{4. 5} readings) = minimum reading + (maximum reading - minimum reading) I (1+10~ (log compound concentration - LogIC ₅ .)).

Calculated IC ₅ . Values refer to the inhibitory activity of specific compounds on the hedgehog pathway, summarized in Table 1. Table 1. IC ₅ of the inhibitory activity of compounds on the hedgehog pathway. value

IC₅„ (nM) 80 〉10000 1249 2257 2761 1243 1898 实施例 35 36 37 38 39 40 41

IC ₅ „ (nM) 80 〉10000 1249 2257 2761 1243 1898 Example 35 36 37 38 39 40 41

IC ₅ „ (nM) 3283 90 〉10000 251 652 361 1 46 Example 42 43 44 45 46 47 48

IC ₅ „ (nM) 937 3389 4721 134 148 351 6178 Example 49 50 51 52 53 54 55

IC ₅ „ (nM) 〉10000 1 197 646 96 〉10000 237 494 Example 56 57 58 59 60 61 62

IC ₅ „ (nM) 93 5363 〉10000 〉10000 1258 〉10000 〉10000 Example 63 64 65 66 67 68 69

IC ₅ „ (nM) 〉 10000 123 668 127 173 1447 〉 10000 Example 70 71 72 73 74 75 76

IC ₅ „ (nM) 1 17 74 95 80 142 〉 10000 52 Example 77 78 79 80 81 82 83

IC ₅ „ (nM) 64 125 42 83 613 57 130 Example 84 85 86 87 88 89 90

IC ₅ „ (nM) 52 45 1006 〉 10000 496 65 709 Example 91 92 93 94 95 96 97

IC ₅ „ (nM) 1945 226 1 196 2344 〉10000 255 96

IC ₅ „ (nM) 98 99 100 101 102 103 104 Example 102 327 47 715 882 163 〉10000 Example 105 106 107 108 109 1 10 GDC- 0449

IC ₅ „ (nM) 702 1370 316 528 1394 439 56 Example NVP- LDE225

IC ₅ „ (nM) 75

Thus, the compounds of the invention exhibit an inhibitory effect on the hedgehog pathway, wherein A 3-( l benzo[ t ]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline- 4-amine (Example 28) and its analogs showed a strong inhibitory effect on the hedgehog pathway. While the invention has been fully described, it will be understood by those skilled in the art that the invention may be practiced in the scope of the broad and equivalent conditions, formulations and other parameters without departing from the scope of the invention. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety herein.

Claims

a compound of formula I, or

Wherein ring C is a monocyclic or bicyclic nitrogen-containing heteroaryl group which may be substituted; A is N or CR _{1 ;}  R is hydrogen, . Alkyl, haloalkyl, aryl, carbocyclyl, heterocyclyl, heteroaryl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, carbocycloalkyl, heterocycloalkyl, Hydroxyalkyl, aminoalkyl, carboxyalkyl; R-R _{10 is} independently hydrogen, halogen, amino group which may be substituted, alkoxy group. Alkyl, haloalkyl, aryl group which may be substituted, carbocyclic group, heterocyclic group, heteroaryl group, alkenyl group, alkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkoxy, aminoalkyl, alkoxyalkyl, carboxyalkyl , carboxy alkoxy, nitro, cyano, amide, aminocarbonyl, hydroxy, decyl, acyloxy, azido, carboxy, carbonyl amide, alkylsulfonyl, aminosulfonyl, disubstituted alkane An aminosulfonyl group, an alkylsulfinyl group, or an alkylthio group;  Wherein, and together with the carbon to which they are attached, a 5- or 6-membered heterocyclic ring containing two oxygens may be formed.  2. The compound of claim 1 wherein A is N.  3. The compound of claim 1, wherein ring C is a benzothiazolyl group which may be substituted, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, fluorenyl, isodecyl, 3 fluorenyl, fluorene Azinyl, carbazolyl, fluorenyl, 4 quinazinyl, isoquinolinyl, quinolinyl, pyridazinyl, naphthyridinyl, acridinyl, naphthalene, diazide, phenyl, phenanthrene Orolinyl, phenazinyl, isothiazolyl, phenothiazine, isoxazolyl, furazinyl, phenoxazinyl, 1,2-benzisoxazole-3-yl, imidazolyl, benzimidazole Base, 2-hydroxyindenyl, thiadiazepine, oxazolyl, oxadiazolyl, quinoxalinyl, and 2-oxobenzimidazolyl. 4. A compound of formula II, or a pharmaceutically acceptable salt or prodrug thereof:

Wherein ring c is a monocyclic or bicyclic nitrogen-containing heteroaryl group which may be substituted;  R is hydrogen, Cwo alkyl, haloalkyl, aryl, carbocyclyl, heterocyclyl, heteroaryl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, carbocycloalkyl, Heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl; R ₂ -R. Independently hydrogen, halogen, amino acid which can be substituted, alkoxy, or. Alkyl, haloalkyl, aryl group which may be substituted, carbocyclic group, heterocyclic group, heteroaryl group, alkenyl group, alkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxydecyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl , carboxy alkoxy, nitro, cyano, amide, aminocarbonyl, hydroxy, decyl, acyloxy, azido, carboxy, carbonyl amide, alkylsulfonyl, aminosulfonyl, disubstituted alkane An aminosulfonyl group, an alkylsulfinyl group, or an alkylthio group; Wherein R ₃ and together with the carbon to which they are attached form a 5- or 6-membered heterocyclic ring containing two oxygens.  The compound of claim 1, wherein ring C is pyridin-2-yl, phenylimidazolyl-2-yl or benzoimidazole-2-yl which may be substituted.  6. Formula III

Wherein, 8 ₁ is 0, S, 0^ or _15; B ₂ is 0, S, 0? ₁₂ or _16; B ₃ is 0, S, 0? ₁₃ or _17; B ₄ is 0, S, 0? ₁₄ Or _{18 ;} R is hydrogen, . Alkyl, haloalkyl, aryl, carbocyclyl, heterocyclyl, heteroaryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl , heteroarylalkenyl, heteroarylalkynyl, carbocyclic fluorenyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl; R ₂ -R _{14 are} independently hydrogen, halogen, amino group which may be substituted, alkoxy group. Alkyl, haloalkyl, aryl group which may be substituted, carbocyclic group, heterocyclic group, heteroaryl group, alkenyl group, alkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkoxy, aminoalkyl, alkoxyalkyl, carboxyalkyl Base, carboxyalkoxy, nitro, cyano, amido, aminocarbonyl, hydroxy, decyl, acyloxy, azide, carboxy, hydroxyamido, alkylsulfonyl, aminosulfonyl, disubstituted alkane An aminoalkylsulfonyl group, an alkylsulfinyl group, or an alkylthio group; wherein R ₃ and together with the carbon to which they are attached form a 5- or 6-membered heterocyclic ring containing two oxygens; R ₁₅ -R _{18 are} independently hydrogen. Alkyl, haloalkyl, aryl, carbocyclyl, heterocyclyl, heteroaryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl , heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl; or Or R ₁₅ and R ₁₂ or R ₁₆ , R ₁₂ or R ₁₆ and R ₁₃ or R ₁₃ or R ₁₆ and R ₁₄ or R ₁₇ , R ₁₄ or R ₁₇ and R ₁₅ or R ₁₈ together with the attached carbon or nitrogen Forming a 5- or 6-membered aryl or heteroaryl group.  7. The compound of claim 1, 4 or 6, wherein the compound is selected from the group consisting of:  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-chloroquinazoline-4-amine;  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-methylquinazoline-4-amine;  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-trifluoromethylquinazoline-4-amine;  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-fluoroquinazoline-4-amine;  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dichloroquinazoline-4-amine;  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6-chloro-8-methylquinazoline-4-amine;  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dibromoquinazolin-4-amine;  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-8-bromo-6-methylquinazoline-4-amine;  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,7-dimethoxyquinazoline-4-amine;  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-methoxyquinazolin-4-amine;  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-8-methoxyquinazolin-4-amine;  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6-methoxyquinazolin-4-amine;  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-methanesulfonylquinazoline-4-amine;  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-8-chloroquinazoline-4-amine;  /H3- (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine;  (4-chloro-3-(pyridin-2-yl)phenyl)-8-chloroquinazoline-4-amine;  N~(4-chloro-3-(pyridin-2-yl)phenyl)-6, 8-dimethoxyquinazolin-4-amine; N~(4-chloro-3-(pyridin-2-yl)phenyl)-7-chloroquinazolin-4-amine; N~(4-chloro-3-(pyridin-2-yl)phenyl)-7-methylquinazolin-4-amine;  N-(4-chloro-3-(pyridin-2-yl)phenyl)-7-trifluoromethylquinazoline-4-amine;  N-(4-chloro-3-(pyridin-2-yl)phenyl)-7-fluoroquinazoline-4-amine;  N-(4-chloro-3-(pyridin-2-yl)phenyl)-6,7-dimethoxyquinazolin-4-amine;  N-(4--chloro-3-(6-fluoro-I benzo[t]imidazol-2-yl)phenyl)-6,8-dimethoxyquinazolin-4-amine; N-(3- -(benzo[t]thiazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine;  N-(3- - (l benzo[£]imidazol-2-yl)-4-chlorophenyl)-5,7-dimethoxyisoquinolin-1-amine; N-(4-chloro-3-(pyridin-2-yl)phenyl)-5,7-dimethoxyisoquinolin-1-amine;  N-(3- -(benzo[t]thiazol-2-yl)-4-chlorophenyl)-5,7-dimethoxyisoquinolin-1-amine;  N-(3- - (l benzo[£]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxy-2-methylquinazoline-4-amine N-(4-chloro-3-(pyridin-2-yl)phenyl)-6,8-dimethoxy-2-methylquinazolin-4-amine;  N-(3- -(I benzo[£]imidazol-2-yl)-4-chlorophenyl)-7-nitroquinazolin-4-amine;  N-(3- -(I benzo[£]imidazol-2-yl)-4-chlorophenyl)-7-aminoquinazolin-4-amine;  N-(3- -(I benzo[£]imidazol-2-yl)-4-chlorophenyl)-6, 7, 8-trimethoxyquinazolin-4-amine; N-(3- -(I benzo[£]imidazol-2-yl)-4-chlorophenyl)-6,8-diethoxyquinazolin-4-amine; N-(3- -(I benzo[£]imidazol-2-yl)-4-chlorophenyl)-6, 7, 8-triethoxyquinazolin-4-amine; N-(3- -(I benzo[£]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethylquinazoline-4-amine;  N-(3- -(I benzo[£]imidazol-2-yl)-4-chlorophenyl)-6,7-methylenedioxyquinazolin-4-amine; N-(3- -(I benzo[£]imidazol-2-yl)-4-chlorophenyl)-6,7-ethylenedioxyquinazoline-4-amine; N-(3- -(I benzo[£]imidazol-2-yl)-4-chlorophenyl)-7-morpholinylquinazoline-4-amine;  N-(3- -(I benzo[£]imidazol-2-yl)-4-chlorophenyl)-7-(4-trifluoromethylphenyl)quinazoline-4-amine; N-(3- -(I benzo[£]imidazol-2-yl)-phenyl)-6, 8-dimethoxyquinazoline-4-amine;  N-(3- -(I benzo[£]imidazol-2-yl)-4-methylphenyl)-6,8-dimethoxyquinazolin-4-amine; N-(3- -(I benzo[£]imidazol-2-yl)-4-fluorophenyl)-6,8-dimethoxyquinazolin-4-amine; N-(3- -(I benzo[£]imidazol-2-yl)-4-bromophenyl)-6,8-dimethoxyquinazolin-4-amine; N-(3- -(I benzo[£]imidazol-2-yl)-4-methoxyphenyl)-6,8-dimethoxyquinazolin-4-amine; N-(3- -(I benzo[£]imidazol-2-yl)-2-methylphenyl)-6,8-dimethoxyquinazolin-4-amine; N-(3- -(I benzo[£]imidazol-2-yl)-2-chlorophenyl)-6, 8-dimethoxyquinazoline-4-amine; N-(3- -(I benzo[£]imidazol-2-yl)-6-methylphenyl)-6,8-dimethoxyquinazolin-4-amine; N-(3- -(I benzo[£]imidazol-2-yl)-6-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; N-(3- -(I benzo[£]imidazol-2-yl)-5-trifluoromethylphenyl)-6, 8-dimethoxyquinazolin-4-amine; Λ^(3-Benzo[t]imidazol-2-yl)-5-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; Λ^ (3- 7-methyl- I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine;  Λ^(3- 7-Methoxy-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; Λ^ ( 3- 7-chloro-I benzo[£]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine;  Λ^(3- 7-Bromo-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine;  Λ^(3- 7-Isopropoxy-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; Λ^ (3- 7-ethoxy-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; Λ^ (3- 6-chloro-I benzo[£]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine;  Λ^(3- 6-Methyl-Ibenzo[£]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazoline-4-amine;  Λ^(3- 6-Bromo-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline-4-amine;  Λ^(3- 6-Methoxy-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; Λ^ ( 3- 6-trifluoromethyl-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6-8-dimethoxyquinazolin-4-amine; Λ^ (3- 6 -cyano-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine;  Λ^(3- 6-ethoxy-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; Λ^ ( 3- 6-dimethylamino-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6 8-dimethoxyquinazolin-4-amine; Λ^ (3- 6- Morpholinyl-I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; Λ^(3- 6-isopropoxy -I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6-8-dimethoxyquinazolin-4-amine; Λ^(3-I benzo[t]imidazole-2 -yl)-4-chlorophenyl)-6,8-dimethoxy 2-ethylquinazolin-4-amine;  Λ^(3- I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxy 2-chloromethylquinazolin-4-amine; Λ^ (3 - I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy 2-fluoromethylquinazolin-4-amine; Λ^ (3-I benzo) [t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy 2-(dimethylaminomethyl)quinazoline- 4-amine;  Λ^(3- 1-Methylbenzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazoline-4-amine;  Λ^(3- 1-Methylbenzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-methylquinazolin-4-amine; ^ (3- 1-Methylbenzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-(dimethylaminomethyl)quinazoline-4 -amine;  Λ^(3- 5-Phenyloxazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline-4-amine;  Λ^(3- 5-(phenyl-1,3,4-oxadiazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine;  Λ^(3- 5-Phenyl-I imidazolyl-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline-4-amine;  Λ^(3- 5-Phenyl-Iimidazol-2-yl)-4-chlorophenyl)-6,8-dichloroquinazoline-4-amine; Λ^(3- 5-Phenyl-Iimidazol-2-yl)-4-chlorophenyl)-6,7-methylenedioxyquinazolin-4-amine; N~(3-(5-phenyl-I imidazol-2-yl)-4-chlorophenyl)-6,7-dimethoxyquinazolin-4-amine; N~ (3- (5- phenyl-I imidazol-2-yl)-4-chlorophenyl)-7-nitroquinazolin-4-amine;  N~(3-(5-phenyl-I imidazolyl-2-yl)-4-chlorophenyl)-7-chloroquinazoline-4-amine;  N~(3-(5-phenyl-I imidazolyl-2-yl)-4-chlorophenyl)-6-chloro-8-methylquinazoline-4-amine;  N~(3-(5-phenyl-1 imidazolyl-2-yl)-4-chlorophenyl)-8-bromo-6-methylquinazoline-4-amine;  N~(3-(5-(4-methylphenyl)-1)imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine; N~ (3-(5-(4-methoxyphenyl)-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; N~ ( 3-(5-(4-chlorophenyl)-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; N~(3-( 5-(4-fluorophenyl)-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine;  (5-(3-Chlorophenyl)-1 imidazolidin-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; N~(3-(5-(3-methoxyphenyl)-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; N ~ (3-(5-(3-Fluorophenyl)-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; N~ (3 -(5-(2-Methoxyphenyl)-I imidazol-2-yl)-4-chloro-phenyl)-6, 8-dimethoxyquinazolin-4-amine; N~ (3 - (5-(2-methylphenyl)-1 imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; (5-(2- Chlorophenyl)-1 imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; N~(3-(5-(2-fluorophenyl)-I imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine; N~ ( 3-(quinoxalin-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazolin-4-amine;  N~(3-(quinolin-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline-4-amine;  N~(3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-5-methyl-7-(4-trifluoromethylphenyl)quinazolin-4-amine ;  Or a pharmaceutically acceptable salt or prodrug thereof.  8. Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment of a hedgehog mediated disease. 9. The use of claim 8, wherein the disease is basal cell carcinoma, medulloblastic carcinoma, basal cell nevus syndrome (BCNS), liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute Lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder Carcinoma, chronic leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head or Cervical cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tumor, thyroid cancer, esophageal cancer, malignant Hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocytosis, adrenocortical carcinoma, skin cancer or prostate cancer.  10. The use of claim 9, wherein the medicament further comprises at least one known anticancer drug, or a pharmaceutically acceptable salt of the anticancer drug. 11. The use of claim 10, wherein the anticancer drug is selected from the group consisting of busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin , mitomycin c, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarithromycin, mitoxantrone, el l iptinimiK Mingtuop, 5-aza-cell, gemcitabine, 5-fluorouridine, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, ara_C, thioguanine吟, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel docetaxel, campath Panitumumab Ofatumumab Avastin Herceptin, Rituxan, imatinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, special cancer, according to Vimot, vorino, romic psiru tamoxifen, letrozole, Fulvestrant, mit ₀ gua _ZO ne, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, thalidomide or lenalidomide.  12. The use of claim 9, wherein the medicament is used in combination with radiation therapy.  A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier. 14. The pharmaceutical composition according to claim 13, wherein the composition further comprises at least one known anticancer drug, or a pharmaceutically acceptable salt of the anticancer drug. The pharmaceutical composition according to claim 14, wherein the composition further comprises at least one anticancer drug selected from the group consisting of busulfan, melphalan, chlorambucil, cyclophosphamide, and isocyclic phosphorus Amide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan and topotecan, doxorubicin, epirubicin, ar Clarithromycin, mitoxantrone, el l iptinimiK temtopip, 5-aza-cell, gemcitabine, 5-fluorouridine, cysteine, 5-fluoro-2'-deoxyuridine, Fludarabine, nelarabine, ara_C, thioguanine, pral _a tr _exa t _e , pemetrexed, hydroxyurea, _thioguanine , colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, campath Panitumumab Ofatumumab Avastin Herceptin, Rituxan, imatinib, gefitinib, erlotinib, lapatinib, _S orafenib, sunitinib, Nigeria Rotitanib, dasatinib, pazopanib, special cancer, everolimus, volt Rino, romic psin, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, salidol or lenalidomide.