IP Library › Granted Patent US 12698277
Granted Patent B2
US 12698277 · App. 18/100,782 · Granted Aug 4, 2026

2-polysubstituted aromatic ring-pyrimidine derivatives, preparation and medical application thereof

Inventors: Tao Liu (Hangzhou, CN); Jia Li (Shanghai, CN); Yongzhou Hu (Hangzhou, CN); Yubo Zhou (Shanghai, CN); Xiaowu Dong (Hangzhou, CN); Anhui Gao (Shanghai, CN); Pinrao Song (Hangzhou, CN); Peipei Wang (Shanghai, CN); Lexian Tong (Hangzhou, CN); Xiaobei Hu (Shanghai, CN); Mingbo Su (Shanghai, CN)
Assignees: ZHEJIANG UNIVERSITY; SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES
C07D413/14A61P35/00A61P35/02C07D401/14C07D405/14C07D409/14C07D417/14
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Quick Facts
Patent No.
US 12698277
App. No.
18/100,782
Granted
Aug 4, 2026
Kind
B2
Abstract

The present invention provides a 2-polysubstituted aromatic ring-pyrimidine derivative and an optical isomer thereof, or a pharmaceutically acceptable salt or solvate thereof, the compound, and an optical isomer thereof or a pharmaceutically thereof acceptable salts or solvates can be used in the preparation of anti-tumor drugs. The invention designs and synthesizes a series of novel small molecule Chk1 inhibitors by using N-substituted pyridin-2-aminopyrimidine obtained by structure-based virtual screening as a lead compound, and carries out Chk1 kinase inhibitory activity test. The experiment confirmed that said compounds possess potent anticancer activity, Chk1 kinase inhibitory activity, and are promising Chk1 inhibitors, and can be used as new cancer therapeutic drugs, which can be applied to treat solid tumors or hematologic tumors related to proliferative disease of human or animal. The 2-polysubstituted aromatic ring-pyrimidine derivatives provided by the present invention has the structure of the formula I.

Claims (62)

1 . A 2-polysubstituted aromatic ring-pyrimidine derivative, wherein the compound is selected from the group consisting of:

5-phenyl-N-(2-cyano-3-(piperidin-3-oxy)pyridin-5-yl)-2-aminopyrimidine;

5-(3-fluorophenyl)-N-(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2-aminopyrimidine;

5-(4-fluorophenyl)-N-(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2-aminopyrimidine;

5-(3-methoxyphenyl)-N-(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2-aminopyrimidine;

5-(4-methoxyphenyl)-N-(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2-aminopyrimidine;

5-(pyridin-3-yl)-N-(2-cyano-3-(piperidin-3-oxy)pyridin-5-yl)-2-aminopyrimidine;

5-(pyridin-4-yl)-N-(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2-aminopyrimidine;

5-(thien-2-yl)-N-(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2-aminopyrimidine;

5-(furan-2-yl)-N-(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2-aminopyrimidine;

5-trifluoromethyl-N-(2-cyano-3-(piperidin-3-oxy)pyridin-5-yl)-2-aminopyrimidine;

(R)-5-(1-methyl-1H-pyrazol-4-yl)-N-(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2-aminopyrimidine;

(S)-5-(1-Methyl-1H-pyrazol-4-yl)-N-(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2-aminopyrimidine;

4-methoxy-5-(3-fluorophenyl)-N-(2-cyano-3-(piperidin-4-methyl)oxypyridin-5-yl)-2-aminopyrimidine;

4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-N-(2-cyano-3-(piperidin-4-methyl)oxypyridin-5-yl)-2-aminopyrimidine;

4-methoxy-5-(3-fluorophenyl)-N-(2-cyano-3-(2-dimethylaminoethoxy)pyridin-5-yl)-2-aminopyrimidine;

4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-N-(2-cyano-3-(2-dimethylaminoethoxy)pyridine-5-yl)-2-aminopyrimidine;

4-methoxy-5-trifluoromethyl-N-(2-cyano-3-(piperidin-4-methyl)oxypyridin-5-yl)-2-aminopyrimidine;

N 4 -methyl-5-phenyl-N 2 -(2-cyano-3-(piperidin-3-oxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(3-fluorophenyl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(4-fluorophenyl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(2-fluorophenyl)-N 2 -(2-cyano-3-(piperidin-3-oxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(3-methoxyphenyl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(4-methoxyphenyl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(2,4-dimethoxyphenyl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(pyridin-3-yl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(pyridin-4-yl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(thien-2-yl)-N 2 -(2-cyano-3-(piperidin-3-oxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(furan-2-yl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(5-chloro-furan-2-yl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(5-methoxycarbonylthien-2-yl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(1-methyl-1H-pyrazol-4-yl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(1-methyl-1H-pyrazol-5-yl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-trifluoromethyl-N 2 -(2-cyano-3-(piperidin-3-oxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(1-methyl-1H-pyrazol-4-yl)-N 2 -(2-cyano-3-(piperidin-4-methyl)oxypyridin-5-yl)-2,4-diaminopyrimidine;

(R)-N 4 -methyl-5-(1-methyl-1H-pyrazol-4-yl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridine-5-yl)-2,4-diaminopyrimidine;

(S)-N 4 -methyl-5-(1-methyl-1H-pyrazol-4-yl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridine-5-yl)-2,4-diaminopyrimidine;

(R)-N 4 -methyl-5-trifluoromethyl-N 2 -(2-cyano-3-(piperidin-3-oxy)pyridin-5-yl)-2,4-diaminopyrimidine;

(S)-N 4 -methyl-5-trifluoromethyl-N 2 -(2-cyano-3-(piperidin-3-oxy)pyridin-5-yl)-2,4-diaminopyrimidine;

(R)-N 4 -methyl-5-(1-methyl-1H-pyrazol-4-yl)-N 2 -(2-cyano-3-(pyrrolidin-3-oxy)pyridin-5-yl)-2,4-diaminopyrimidine;

(S)-N 4 -methyl-5-(1-methyl-1H-pyrazol-4-yl)-N 2 -(2-cyano-3-(pyrrolidin-3-oxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(1-methyl-1H-pyrazol-4-yl)-N 2 -(2-cyano-3-(piperidin-4-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(1-methyl-1H-pyrazol-4-yl)-N 2 -(2-cyano-3-(2-dimethylaminoethoxy)pyridine-5-yl)-2,4-diaminopyrimidine;

(R)-3-((1-(dimethylamino)propan-2-yl)oxy)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino)pyrimidin-2-yl)amino)picolinonitrile;

(S)-3-((1-(dimethylamino)propan-2-yl)oxy)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino)pyrimidin-2-yl)amino)picolinonitrile;

5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino)pyrimidin-2-yl)amino)-3-((1-methylpiperidin-4-yl)oxy)picolinonitrile;

N 4 -methyl-5-trifluoromethyl-N 2 -(2-cyano-3-(N-methylpiperidin-4-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

N 4 -methyl-5-(4-methylthiazol-2-yl)-N 2 -(2-cyano-3-(piperidin-3-yloxy)pyridin-5-yl)-2,4-diaminopyrimidine;

and a pharmaceutically acceptable salt thereof.

2 . A method for treating a tumor, comprising administering an effective amount of a composition to a subject in need thereof, wherein the tumor is breast cancer, lung cancer, prostate cancer, gastric cancer, colon cancer, rectal cancer, kidney cancer, pancreatic cancer, leukemia, neuroblastoma, glioma, head and neck cancer, ovarian cancer, myeloma, melanoma, or non-Hodgkin's lymphoma; and the composition comprises a 2-polysubstituted aromatic ring-pyrimidine derivative according to claim 1 , an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

3 . A 2-polysubstituted aromatic ring-pyrimidine derivative of formula V:

and an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein:

W, X, Y and Z are the same or different and are each independently selected from N or C;

R 1 is selected from C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 3-6 cycloalkyl group, halogenated C 3-6 cycloalkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 hydroxy substituted alkenyl, C 2-6 alkynyl, C 2-6 hydroxy substituted alkynyl, unsubstituted or substituted 5- or 6-membered aromatic or aromatic heterocyclic ring, said aromatic heterocyclic ring comprising 1 to 3 hetero atoms selected from O, N and S, the substitution being a mono-, di- or tri-substitution, said substituent being selected from the group consisting of Ra:

Ra is selected from H, halogen, nitro, cyano, C 1-3 alkyl, halogenated C 1-3 alkyl, —C(═O)OR b , —C(═O)NHR b , —NHR b , —OR b and —NHCOR b ; R b is selected from H, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, and C 1-7 alkylamine;

R 2 is selected from the group consisting of H, —NHRc, —N(Rc) 2 , —ORc, and —SRc; Rc is selected from the group consisting of C 1-7 alkyl, halogenated C 1-7 alkyl, C 1-7 hydroxyalkyl, C 1-7 alkylamino group, and C 1-7 alkoxy group;

R 3 is selected from the group consisting of H, halogen, nitro, cyano, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 alkylamino, and halogenated C 1-3 alkylamino group:

L 1 is selected from O, S, or NH;

m=0-2;

R 4 is selected from the group consisting of C 1-7 alkylamino, halogenated C 1-7 alkylamino, and unsubstituted 5- to 8-membered nitrogen-containing aliphatic heterocyclic ring;

R 5 is selected from the group consisting of halogen, nitro, cyano, trifluoromethyl, C 1-3 alkyl, C 1-3 alkoxy, amide, and substituted alkyl amide.

4 . The 2-polysubstituted aromatic ring-pyrimidine derivative of formula V according to claim 3 , wherein R 4 is selected from unsubstituted 5- to 8-membered nitrogen-containing aliphatic heterocyclic ring.