Multi-substituted pyrimidine derivatives with excellent kinase inhibitory activities
Disclosed are a novel pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a method for preparing the compound and a pharmaceutical use of the compound as an anticancer agent or a therapeutic agent for degenerative brain diseases. Specifically, the novel pyrimidine derivative compound has excellent inhibitory activities against kinase enzymes such as ARK5/NUAK1, ACK1, FLT3, JAK1, JAK2 and JAK2 (V617F) and thus is useful for treating and preventing leukemia, ovarian cancer, breast cancer, non-small cell carcinoma, colorectal cancer, glioma, and brain protein abnormalities such as Alzheimer's disease, progressive supranuclear palsy and frontotemporal dementia, that is, degenerative diseases caused by Tau deposition.
1. A novel pyrimidine derivative compound represented by the following Formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
wherein
R1 and R2 are each independently a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —C(O)—(C1-C6 alkyl), —C(O)—O—(C1-C6 alkyl) or —O—C(O)—(C1-C6 alkyl), or R1 and R2 are bonded together to form a 5-membered to 6-membered saturated or unsaturated ring, or R1 and R2 are bonded together to form a 5-membered to 6-membered saturated or unsaturated heteroring including one to four heteroatoms selected from nitrogen (N) and oxygen (O) atoms;
Het is a C6-C15 aryl group, a 5-membered to 14-membered heteraryl group including one to four heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms, or a 5-membered to 6-membered heterocyclic group including one or two heteroatoms selected from nitrogen (N) and oxygen (O) atoms;
A is a carbon (C) or nitrogen (N) atom; and
B is a C6-C15 aryl group, a 5-membered to 14-membered heteraryl group including one to four heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms, or a 5-membered to 6-membered heterocyclic group including one or two heteroatoms selected from nitrogen (N) and oxygen (O) atoms.
2. The compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein
R1 and R2 are each independently a hydrogen atom, methyl, ethyl, CF3, F, Cl or Br, or R1 and R2 are bonded together to form a 5-membered to 6-membered saturated or unsaturated ring, or R1 and R2 are bonded together to form a 5-membered to 6-membered saturated or unsaturated heteroring including one to four heteroatoms selected from nitrogen (N) and oxygen (O) atoms;
Het represents a tetrahydrofuranyl group, a furanyl group, a pyranyl group, a pyridinyl group or a phenyl group; and
B represents a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group or an amino group.
3. The compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein
R1 and R2 are each independently a hydrogen atom, methyl, CF3, F or Cl, or R1 and R2 are bonded together to form a 6-membered unsaturated ring, or R1 and R2 are bonded together to form a 6-membered saturated ring, or R1 and R2 are bonded together to form a 5-membered saturated ring;
Het represents a tetrahydrofuranyl group, a furanyl group or a phenyl group; and
B represents a pyrrolidinyl group, a piperidinyl group, or a dimethylamino group.
4. The compound, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is selected from the following compounds:
(Compound No. 1) 4-(furan-2-yl)methylamino-5-methyl-2-[4-{2-(pyrrolidin-1-yl) ethoxy}phenylamino]pyrimidine;
(Compound No. 2) 4-(furan-2-yl)methylamino-5-methyl-2-[4-{2-(piperidin-1-yl) ethoxy}phenylamino]pyrimidine;
(Compound No. 3) 4-(furan-2-yl)methylamino-5-methyl-2-[4-{2-(dimethylamino)ethoxy}phenylamino]pyrimidine;
(Compound No. 4) 4-(furan-2-yl)methylamino-5-methyl-2-[2-amino-5-{2-(pyrrolidin-1-yl)ethoxy}pyridine]pyrimidine;
(Compound No. 5) 5-chloro-4-(furan-2-yl)methylamino-2-[4-{2-(pyrrolidin-1-yl) ethoxy}phenylamino]pyrimidine;
(Compound No. 6) 5-chloro-4-(furan-2-yl)methylamino-2-[4-{2-(piperidin-1-yl) ethoxy}phenylamino]pyrimidine;
(Compound No. 7) 5-chloro-4-(furan-2-yl)methylamino-2-[4-{2-(dimethylamino)ethoxy}phenylamino]pyrimidine;
(Compound No. 8) 4-(tetrahydrofuran-2-yl)methylamino-5-methyl-2-[4-{2-(pyrrolidin-1-Methoxy}phenylamino]pyrimidine;
(Compound No. 9) 4-(tetrahydrofuran-2-yl)methylamino-5-methyl-2-[4-{2-(piperidin-1-yl)ethoxy}phenylamino]pyrimidine;
(Compound No. 10) 4-(tetrahydrofuran-2-yl)methylamino-5-methyl-2-[4-{2-(dimethylamino)ethoxy}phenylamino]pyrimidine;
(Compound No. 11) 5-chloro-4-(tetrahydrofuran-2-yl)methylamino-2-[4-{2-(pyrrolidin-1-Methoxy}phenylamino]pyrimidine;
(Compound No. 12) 5-chloro-4-(tetrahydrofuran-2-yl)methylamino-2-[4-{2-(piperidin-1-yl)ethoxy}phenylamino]pyrimidine;
(Compound No. 13) 5-chloro-4-(tetrahydrofuran-2-yl)methylamino-2-[4-{2-(dimethylamino)ethoxy}phenylamino]pyrimidine;
(Compound No. 14) 4-benzylmethylamino-5-methyl-2-[4-{2-(pyrrolidin-1-yl) ethoxy}phenylamino]pyrimidine;
(Compound No. 15) 4-benzylmethylamino-5-methyl-2-[4-{2-(piperidin-1-yl) ethoxy}phenylamino]pyrimidine;
(Compound No. 16) 4-benzylmethylamino-5-methyl-2-[4-{2-(dimethylamino) ethoxy}phenylamino]pyrimidine;
(Compound No. 17) 5-chloro-4-benzylmethylamino-2-[4-{2-(pyrrolidin-1-yl) ethoxy}phenylamino]pyrimidine;
(Compound No. 18) 5-chloro-4-benzylmethylamino-2-[4-{2-(piperidin-1-yl) ethoxy}phenylamino]pyrimidine;
(Compound No. 19) 5-chloro-4-benzylmethylamino-2-[4-{2-(dimethylamino) ethoxy}phenylamino]pyrimidine;
(Compound No. 20) 4-(furan-2-yl) methylamino-5-fluoro-2-[4-{2-(pyrrolidin-1-yl)ethoxy}phenylamino]pyrimidine;
(Compound No. 21) 4-(furan-2-yl) methylamino-5-trifluoromethyl-2-[4-{2-(pyrrolidin-1-Methoxy}phenylamino]pyrimidine;
(Compound No. 22) 4-(furan-2-yl)methylamino-2-[4-{2-(pyrrolidin-1-yl) ethoxy}phenylamino]quinazoline;
(Compound No. 23) 4-(furan-2-yl)methylamino-2-[4-{2-(pyrrolidin-1-yl) ethoxy}phenylamino]-5,6,7,8-tetrahydroquinazoline;
(Compound No. 24) 4-(furan-2-yl)methylamino-2-[4-{2-(pyrrolidin-1-yl) ethoxy}phenylamino]-6,7-dihydro-5H-cyclopenta[d]pyrimidine;
(Compound No. 25) 4-((S)-tetrahydrofuran-2-yl) methylamino-5-methyl-2-[4-{2-(pyrrolidin-1-yl]ethoxy}phenylamino]pyrimidine; and
(Compound No. 26) 5-chloro-4-((S)-tetrahydrofuran-2-yl) methylamino-2-[4-{2-(pyrrolidin-1-yl]ethoxy}phenylamino]pyrimidine.
5. A pharmaceutical composition for treating, preventing or palliating cancer comprising, as an active ingredient, the compound according to claim 1 .
6. A pharmaceutical composition for treating, preventing or palliating a degenerative brain disease comprising, as an active ingredient, the compound according to claim 1 .
7. A pharmaceutical composition for treating, preventing or palliating an immunological disease comprising, as an active ingredient, the compound according to claim 1 .
8. A pharmaceutical composition for treating, preventing or palliating an inflammatory disease comprising, as an active ingredient, the compound according to claim 1 .
9. The pharmaceutical composition according to claim 5 , wherein the cancer comprises one or more of ovarian cancer, non-small cell carcinoma, colorectal cancer, glioma, breast cancer, esophageal cancer, lung cancer, uterine cancer, pancreatic cancer, prostate cancer and blood cancer.
10. The pharmaceutical composition according to claim 6 , wherein the degenerative brain disease comprises one or more of Alzheimer's disease, Parkinson's disease, Lewy body dementia and frontotemporal dementia.
11. A pharmaceutical composition for treating, preventing or palliating cancer comprising, as an active ingredient, the compound according to claim 2 .
12. A pharmaceutical composition for treating, preventing or palliating cancer comprising, as an active ingredient, the compound according to claim 3 .
13. A pharmaceutical composition for treating, preventing or palliating cancer comprising, as an active ingredient, the compound according to claim 4 .
14. A pharmaceutical composition for treating, preventing or palliating a degenerative brain disease comprising, as an active ingredient, the compound according to claim 2 .
15. A pharmaceutical composition for treating, preventing or palliating a degenerative brain disease comprising, as an active ingredient, the compound according to claim 3 .
16. A pharmaceutical composition for treating, preventing or palliating a degenerative brain disease comprising, as an active ingredient, the compound according to claim 4 .
17. A pharmaceutical composition for treating, preventing or palliating an immunological disease comprising, as an active ingredient, the compound according to claim 2 .
18. A pharmaceutical composition for treating, preventing or palliating an immunological disease comprising, as an active ingredient, the compound according to claim 3 .
19. A pharmaceutical composition for treating, preventing or palliating an immunological disease comprising, as an active ingredient, the compound according to claim 4 .
20. A pharmaceutical composition for treating, preventing or palliating an inflammatory disease comprising, as an active ingredient, the compound according to claim 2 .