2-substituted aromatic ring-pyrimidine derivative and preparation and application thereof

2:

• The 2-substituted aromatic ring-pyrimidine derivative, and the optical isomer or the pharmaceutically acceptable salt or the solvate thereof, as recited in claim 1, wherein the 2-substituted aromatic ring-pyrimidine derivative has a structure as shown in a general formula II:
• wherein W, X, Y and Z are identical or different and are independently selected from N, C and O;
• B is selected from —NH,
• wherein B1 is selected from H, C1-4 alkyl, halogenated C1-4 alkyl, C1-4 alkoxy, and halogenated C1-4 alkoxy;
• R1 is selected from halogen atom, C1-6 alkyl, halogenated C1-6 alkyl, C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, C2-6 hydroxy substituted alkenyl, C2-6 alkynyl, C2-6 hydroxy substituted alkynyl, and an unsubstituted or substituted penta- or hexa- aromatic ring or aromatic heterocyclic ring, wherein the aromatic heterocyclic ring comprises 1 to 3 hetero atoms selected from O, N and S, substitution is mono-, di- or tri-substitution, and a substituent is Ra;
• Ra is selected from H, halogen, nitro, cyano, C1-3 alkyl, halogenated C1-3 alkyl, —C(═O)ORb, —C(═O)NHRb, —NHRb, —ORb, and —NHCORb;
• Rb is selected from H, C1-3 alkyl, halogenated C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, and C1-7 alkylamine;
• R2 is selected from H, —NHRc, —N(Rc)2, —ORc, and —SRc;
• Rc is selected from penta- to octa-aliphatic ring containing 1 to 3 heteroatoms selected from O and N, C1-7 alkyl, C1-7 hydroxyalkyl, C1-7 alkylamino, and C1-7 alkoxy;
• R3 is selected from halogen, nitro, cyano, C1-3 alkyl, halogenated C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, C1-3 alkylamino, and halogenated C1-3 alkylamino;
• R4 is selected from H, halogen, nitro, cyano, trifluoromethyl, C1-3 alkyl, C1-3 alkoxy, amide, substituted alkyl amide.

3:

• The 2-substituted aromatic ring-pyrimidine derivative, and the optical isomer or the pharmaceutically acceptable salt or the solvate thereof, as recited in claim 1, wherein the 2-substituted aromatic ring-pyrimidine derivative has a structure as shown in a general formula III:
• wherein W, X, Y and Z are identical or different and are independently selected from N and C;
• B is selected from —NH,
• wherein B1 is selected from H, C1-4 alkyl, halogenated C1-4 alkyl, C1-4 alkoxy, and halogenated C1-4 alkoxy;
• R1 is selected from halogen atom, C1-6 alkyl, halogenated C1-6 alkyl, C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, C2-6 hydroxy substituted alkenyl, C2-6 alkynyl, C2-6 hydroxy substituted alkynyl, and an unsubstituted or substituted penta- or hexa- aromatic ring or aromatic heterocyclic ring, wherein the aromatic heterocyclic ring comprises 1 to 3 hetero atoms selected from O, N and S, substitution is mono-, di- or tri-substitution, and a substituent is Ra;
• Ra is selected from H, halogen, nitro, cyano, C1-3 alkyl, halogenated C1-3 alkyl, —C(═O)ORb, —C(═O)NHRb, —NHRb, —ORb, and —NHCORb;
• Rb is selected from H, C1-3 alkyl, halogenated C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, and C1-7 alkylamine;
• R2 is selected from H, —NHRc, —N(Rc)2, —ORc, and —SRc;
• Rc is selected from penta- to octa-aliphatic ring containing 1 to 3 heteroatoms selected from O and N, C1-7 alkyl, C1-7 hydroxyalkyl, C1-7 alkylamino, and C1-7 alkoxy;
• R3 is selected from halogen, nitro, cyano, C1-3 alkyl, halogenated C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, C1-3 alkylamino, and halogenated C1-3 alkylamino;
• R4 is selected from H, halogen, nitro, cyano, trifluoromethyl, C1-3 alkyl, C1-3 alkoxy, amide, substituted alkyl amide.

4:

• The 2-substituted aromatic ring-pyrimidine derivative, and the optical isomer or the pharmaceutically acceptable salt or the solvate thereof, as recited in claim 2, wherein the 2-substituted aromatic ring-pyrimidine derivative has a structure as shown in a general formula IV:
• wherein W, X, Y and Z are identical or different and are independently selected from N, C and O;
• R1 is selected from halogen atom, C1-6 alkyl, halogenated C1-6 alkyl, C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, C2-6 hydroxy substituted alkenyl, C2-6 alkynyl, C2-6 hydroxy substituted alkynyl, and an unsubstituted or substituted penta- or hexa- aromatic ring or aromatic heterocyclic ring, wherein the aromatic heterocyclic ring comprises 1 to 3 hetero atoms selected from O, N and S, substitution is mono-, di- or tri-substitution, and a substituent is Ra;
• Ra is selected from H, halogen, nitro, cyano, C1-3 alkyl, halogenated C1-3 alkyl, —C(═O)ORb, —C(═O)NHRb, —NHRb, —ORb, and —NHCORb;
• Rb is selected from H, C1-3 alkyl, halogenated C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, and C1-7 alkylamine;
• R2 is selected from H, —NHRc, —N(Rc)2, —ORc, and —SRc;
• Rc is selected from penta- to octa-aliphatic ring containing 1 to 3 heteroatoms selected from O and N, C1-7 alkyl, C1-7 hydroxyalkyl, C1-7 alkylamino, and C1-7 alkoxy;
• R3 is selected from halogen, nitro, cyano, C1-3 alkyl, halogenated C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, C1-3 alkylamino, and halogenated C1-3 alkylamino;
• R4 is selected from H, halogen, nitro, cyano, trifluoromethyl, C1-3 alkyl, C1-3 alkoxy, amide, substituted alkyl amide.

5:

• The 2-substituted aromatic ring-pyrimidine derivative, and the optical isomer or the pharmaceutically acceptable salt or the solvate thereof, as recited in claim 4, wherein the derivative is selected from:
• 5-(1-methyl-1H-pyrazol-4-yl)-N2-(3-methylpyrazol-5-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-(1-methyl-1H-pyrazol-4-yl)-N2-(5-methyloxazol-3-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-(thien-2-yl)-N2-(5-methylpyrazol-3-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-(thien-2-yl)-N2-(5-methyloxazol-3-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-(furan-2-yl)-N2-(5-methylpyrazol-3-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine, and
• 5-(furan-2-yl)-N2-(5-methyloxazol-3-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine.

6:

• The 2-substituted aromatic ring-pyrimidine derivative, and the optical isomer or the pharmaceutically acceptable salt or the solvate thereof, as recited in claim 3, wherein the 2-substituted aromatic ring-pyrimidine derivative has a structure as shown in a general formula V:
• wherein W, X, Y and Z are identical or different and are independently selected from N and C;
• R1 is selected from halogen atom, C1-6 alkyl, halogenated C1-6 alkyl, C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, C2-6 hydroxy substituted alkenyl, C2-6 alkynyl, C2-6 hydroxy substituted alkynyl, and an unsubstituted or substituted penta- or hexa- aromatic ring or aromatic heterocyclic ring, wherein the aromatic heterocyclic ring comprises 1 to 3 hetero atoms selected from O, N and S, substitution is mono-, di- or tri-substitution, and a substituent is Ra;
• Ra is selected from H, halogen, nitro, cyano, C1-3 alkyl, halogenated C1-3 alkyl, —C(═O)ORb, —C(═O)NHRb, —NHRb, —ORb, and —NHCORb;
• Rb is selected from H, C1-3 alkyl, halogenated C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, and C1-7 alkylamine;
• R2 is selected from H, —NHRc, —N(Rc)2, —ORc, and —SRc;
• Rc is selected from penta- to octa-aliphatic ring containing 1 to 3 heteroatoms selected from O and N, C1-7 alkyl, C1-7 hydroxyalkyl, C1-7 alkylamino, and C1-7 alkoxy;
• R3 is selected from halogen, nitro, cyano, C1-3 alkyl, halogenated C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, C1-3 alkylamino, and halogenated C1-3 alkylamino;
• R4 is selected from H, halogen, nitro, cyano, trifluoromethyl, C1-3 alkyl, C1-3 alkoxy, amide, substituted alkyl amide.

7:

• The 2-substituted aromatic ring-pyrimidine derivative, and the optical isomer or the pharmaceutically acceptable salt or the solvate thereof, as recited in claim 6, wherein the derivative is selected from:
• 5-phenyl-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-4-methyl)-2,4-diaminopyrimidine,
• 5-(3-fluorophenyl)-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-4-methyl)-2,4-diaminopyrimidine,
• 5-(1-methyl-1H-pyrazol-4-yl)-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-4-methyl)-2,4-diaminopyrimidine,
• 5-trifluoromethyl-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-4-methyl)-2,4-diaminopyrimidine,
• 5-(3-fluorophenyl)-N2-(2-cyanopyridin-5-yl)-N4-aminoethyl-2,4-diaminopyrimidine,
• 5-(1-methyl-1H-pyrazol-4-yl)-N2-(2-cyanopyridin-5-yl)-N4-aminoethyl-2,4-diaminopyrimidine,
• 5-(3-fluorophenyl)-N2-(2-cyanopyridin-5-yl)-N4-(2-morpholinethyl)-2,4-diaminopyrimidine,
• 5-(1-methyl-1H-pyrazol-4-yl)-N2-(2-cyanopyridin-5-yl)-N4-(2-morpholinethyl)-2,4-diaminopyrimidine,
• 5-(3-fluorophenyl)-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-(1-methyl-1H-pyrazol-4-yl)-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-(thien-2-yl)-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-(furan-2-yl)-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-(5-methoxycarbonylthiophen-2-yl)-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-(5-methoxycarbonylfuran-2-yl)-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-trifluoromethyl-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• (R)-5-(1-methyl-1H-pyrazol-4-yl)-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-3-yl)-2,4-diaminopyrimidine,
• (S)-5-(1-methyl-1H-pyrazol-4-yl)-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-3-yl)-2,4-diaminopyrimidine,
• (R)-5-trifluoromethyl-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-3-yl)-2,4-diamino pyrimidine,
• (R)-5-(1-methyl-1H-pyrazol-4-yl)-N-(2-cyanopyridin-5-yl)-4-(3-aminopiperidin-1-yl)-2-aminopyrimidine,
• 5-(3-fluorophenyl)-N2-(2-cyanopyrimidin-5-yl)-N4-(2-morpholinethyl)-2,4-diaminopyrimidine,
• 5-(1-methyl-1H-pyrazol-4-yl)-N2-(2-cyanopyrimidin-5-yl)-N4-(2-morpholinethyl)-2,4-diaminopyrimidine,
• 5-(1-methyl-1H-pyrazol-4-yl)-N2-(pyridazin-5-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-(1-methyl-1H-pyrazol-4-yl)-N2-(3-cyanopyridin-6-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-(1-methyl-1H-pyrazol-4-yl)-N2-(2-cyanopyrazin-5-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-bromo-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-(4-methylthiazol-2-yl)-N2-(2-cyanopyridin-5-yl)-N4-(piperidin-4-yl)-2,4-diaminopyrimidine,
• 5-bromo-N-(2-cyanopyridin-5-yl)-2-aminopyrimidine,
• 5-(2-aminophenyl)-N-(2-cyanopyridin-5-yl)-2-aminopyrimidine,
• 5-(2-(piperidin-4-yl)aminophenyl)-N-(2-cyanopyridin-5-yl)-2-aminopyrimidine,
• 5-(2-(piperidin-4-methyl)aminophenyl)-N-(2-cyanopyridin-5-yl)-2-aminopyrimidine, and
• pharmaceutically acceptable salts or solvates of the above compounds.

8:

• A preparation method of a 2-substituted aromatic ring-pyrimidine derivative, comprising steps of:
• method I:
• using 5-bromo-2,4-dichloropyrimidine as a starting material, substituting with an aliphatic amine group and an aromatic heterocyclic amine group in sequence, and obtaining a target compound by Suzuki coupling, followed by deprotecting a Boc protective group;
• method II:
• using 5-bromo-2,4-dichloropyrimidine as a starting material, substituting with an aliphatic amine group and aminating in sequence to obtain a 5-bromo-pyrimidine-2,4-diamine intermediate, and processing the intermediate with Suzuki coupling before reacting with a brominated aromatic heterocyclic compound to obtain a target compound, followed by deprotecting a Boc protective group;
• method III:
• using 5-bromo-2,4-dichloropyrimidine as a starting material, substituting with an aliphatic amine group and aminating in sequence to obtain a 5-bromo-pyrimidine-2,4-diamine intermediate, acting the intermediate with a brominated aromatic heterocyclic compound, and then processing with Suzuki coupling and deprotecting a Boc protective group to obtain a target compound;
• method IV:
• using 5-bromo-2-aminopyrimidine as a starting material, reacting with a brominated aromatic heterocyclic compound before Suzuki coupling, reductive amination and deprotecting a Boc protective group in sequence to obtain a target compound;
• or
• method V:
• using 5-trifluoromethyl-2,4-dichloropyrimidine as a starting material, substituting with an aliphatic amine group and aminating in sequence to obtain a 5-trifluoromethyl-pyrimidine-2,4-diamine intermediate, then acting the intermediate with a brominated aromatic heterocyclic compound to obtain a target compound and deprotecting a Boc protective group.