Heterocyclic substituted pyrimidine compound
The present invention pertains to the field of medical technology, and particularly relates to a heterocyclic substituted pyrimidine compound represented by General Formula (I) and its pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the description, the present invention also relates to a preparation method of the compound, a pharmaceutical composition containing the compound, and a use of the compound and the pharmaceutical composition in preparation of a medicine for enhancing a cGMP signal transduction function or a medicine for treating or preventing sexual dysfunction and diseases with lower urinary tract symptoms.
1. A compound of Formula (I), and its pharmaceutically acceptable salts or stereoisomers thereof:
wherein
R 1 represents 6-7-membered nitrogen-containing hetero fused ring group, 7-12-membered nitrogen-containing hetero spiro ring group, or 7-12-membered nitrogen-containing hetero bridged ring group, each of which is linked to pyrimidine ring via N and is unsubstituted or substituted with 1-4 substituents, wherein
the substituents are selected from halogen atoms, cyano, amino, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl or C 1-6 alkoxycarbonyl;
R 2 represents hydrogen atom, hydroxy, amino, cyano, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkyl, haloC 1-6 alkyl, hydroxy C 1-6 alkyl or C 1-6 alkoxy;
R 3 and R 4 each independently represent hydrogen atom or -M-R 7 , wherein
M represents a single bond, or C 1-6 alkylidene, represented by —(CH 2 ) t — (t is an integer from 1 to 6), unsubstituted or substituted with 1-4 substituents, and
R 7 represents a cyclic group other than adamantyl, which is unsubstituted or substituted with 1-4 substituents,
or R 3 and R 4 together with the nitrogen atom to which they link form a 5-7-membered nitrogen-containing hetero ring group unsubstituted or substituted with 1-4 substituents, wherein
the substituents are selected from halogen atoms, hydroxy, cyano, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, oxo, C 1-6 alkyl, hydroxyC 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl or di(C 1-6 alkyl)phosphino; and
R 5 represents hydrogen atom or -Q-R 8 , wherein
Q represents a single bond, or C 1-6 alkylidene, represented by —(CH 2 ) t — (t is an integer from 1 to 6), unsubstituted or substituted with 1-4 substituents, and
R 8 represents 6-14-membered aryl, 5-7-membered heteromonocyclic group or 6-14-membered fused ring group, each of which is unsubstituted or substituted with 1-4 substituents, wherein
the substituents are selected from halogen atoms, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, carboxylC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-8 alkoxy, haloC 1-8 alkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, cyano, nitro, C 1-6 alkylcarbonyl, sulfonylamino or C 1-6 alkylsulfonylamino.
2. The compound according to claim 1 , and its pharmaceutically acceptable salts or stereoisomers thereof:
wherein R 2 represents hydrogen atom, hydroxy or methyl; and R 4 represents hydrogen atom.
3. The compound according to claim 2 , and its pharmaceutically acceptable salts or stereoisomers thereof:
wherein R 5 represents -Q-R 8 , wherein
Q is selected from C 1-6 alkylidene, represented by —(CH 2 ) t — (t is an integer from 1 to 6, unsubstituted or substituted with 1-3 substituents, and
R 8 is selected from 6-14-membered aryl, 5-7-membered heteromonocyclic group or 6-14-membered fused ring group, each of which is unsubstituted or substituted with 1-3 substituents, wherein
the substituents are selected from halogen atoms, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, carboxylC 1-6 alkyl, C 1-8 alkoxy, haloC 1-8 alkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, cyano, nitro, C 1-6 alkylcarbonyl, sulfonylamino or C 1-6 alkylsulfonylamino.
4. The compound according to claim 3 , and its pharmaceutically acceptable salts or stereoisomers thereof:
wherein
R 1 is selected from 6-7-membered nitrogen-containing hetero fused ring group, 7-10-membered nitrogen-containing hetero spiro ring group, or 7-8-membered nitrogen-containing hetero bridged ring group, each of which is linked to pyrimidine ring via N and is unsubstituted or substituted with 1-3 substituents, wherein
the substituents are selected from halogen atoms, cyano, amino, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl or C 1-6 alkoxy;
R 3 is selected from -M-R 7 , wherein
M represents a single bond or C 1-6 alkylidene, represented by —(CH 2 ) t — (t is an integer from 1 to 6, unsubstituted or substituted with 1-4 substituents, and
R 7 is selected from phenyl, 5-7-membered heteromonocyclic group, 4-7-membered cycloalkyl, 6-14-membered fused ring group, 7-10-membered spiro ring group, or 7-10-membered bridged ring group other than adamantyl, each of which is unsubstituted or substituted with 1-3 substituents,
or
R 3 and R 4 together with the nitrogen atom to which they link form a 5-6-membered nitrogen-containing hetero ring group, which is unsubstituted or substituted, wherein
the substituents are selected from halogen atoms, hydroxy, cyano, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, oxo, C 1-6 alkyl, hydroxyC 1-6 alkyl, haloC 1-6 alkyl or C 1-6 alkoxy; and
R 5 represents -Q-R 8 , wherein
Q is selected from methylidene, represented by —CH 2 —, unsubstituted or substituted with 1-2 substituents, or ethylidene unsubstituted or substituted with 1-3 substituents, and
R 8 is selected from phenyl, 5-7-membered heteromonocyclic group, or 6-14-membered fused ring group, each of which is unsubstituted or substituted with 1-3 substituents, wherein
the substituents are selected from C 1-3 alkyl, fluorine, chlorine, methoxy, ethoxy, trifluoromethoxy, dimethylamino or carboxymethyl.
5. The compound according to claim 4 , and its pharmaceutically acceptable salts or stereoisomers thereof:
wherein
R 1 is selected from 6-7-membered nitrogen-containing hetero fused ring group, 7-10-membered nitrogen-containing hetero spiro ring group, or 7-8-membered nitrogen-containing hetero bridged ring group, each of which is linked to pyrimidine ring via N and is unsubstituted or substituted with 1-3 substituents, wherein
the substituents are selected from halogen atoms, cyano, amino, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl or C 1-6 alkoxy;
R 2 represents hydrogen atom, hydroxy or methyl;
R 4 is selected from hydrogen atom;
R 3 is selected from -M-R 7 , wherein
M represents a single bond or C 1-6 alkylidene, represented by —(CH 2 ) t — (t is an integer from 1 to 6), unsubstituted or substituted with 1-2 substituents, and
R 7 is selected from phenyl, 5-7-membered heteromonocyclic group, 4-7-membered cycloalkyl, 8-10-membered fused ring group, or 7-10-membered spiro ring group, each of which is unsubstituted or substituted with 1-3 substituents,
or
R 3 and R 4 together with the nitrogen atom to which they link form a 5-6-membered nitrogen-containing hetero ring group, which is unsubstituted or substituted, wherein
the substituents are selected from halogen atoms, hydroxy, cyano, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, oxo, C 1-6 alkyl, hydroxy C 1-6 alkyl, haloC 1-6 alkyl or C 1-6 alkoxy; and
R 5 represents -Q-R 8 , wherein
Q is selected from methylidene, represented by —CH 2 —, or ethylidene, represented by —CH 2 CH 2 —, unsubstituted or substituted with 1-2 substituents, and
R 8 is selected from phenyl, 5-7-membered heteromonocyclic group, or 8-10-membered fused ring group, each of which is unsubstituted or substituted with 1-3 substituents, wherein
the substituents are selected from C 1-3 alkyl, fluorine, chlorine, methoxy, ethoxy, trifluoromethoxy, dimethylamino or carboxymethyl.
6. The compound according to claim 5 , and its pharmaceutically acceptable salts or stereoisomers thereof:
wherein
R 1 is selected from a group consisting of:
R 2 is hydrogen atom;
R 4 is hydrogen atom;
R 3 is selected from a group consisting of:
or
R 3 and R 4 together with the nitrogen atom to which they link form:
and
R 5 is selected from a group consisting of:
7. The compound according to claim 6 , and its pharmaceutically acceptable salts or stereoisomers thereof:
wherein
R 1 is selected from a group consisting of:
R 2 is hydrogen atom;
R 3 is selected from a group consisting of:
R 4 is hydrogen atom; and
R 5 is selected from a group consisting of:
8. The compound according to claim 7 , and its pharmaceutically acceptable salts or stereoisomers thereof:
wherein
R 1 is selected from a group consisting of:
R 2 is hydrogen atom;
R 3 is selected from a group consisting of:
R 4 is hydrogen atom;
R 5 is selected from a group consisting of:
9. The compound according to claim 8 , and its pharmaceutically acceptable salts or stereoisomers thereof:
wherein R 1 is selected from a group consisting of:
R 2 is hydrogen atom;
R 3 is selected from a group consisting of:
R 4 is hydrogen atom; and
R 5 is selected from a group consisting of:
10. The compound according to claim 9 , and its pharmaceutically acceptable salts or stereoisomers thereof, which is selected from:
11. A pharmaceutical preparation comprising the compound according to claim 1 , pharmaceutically acceptable salts or stereoisomers thereof, in conjunction with one or more pharmaceutically acceptable carriers.
12. A method for inhibiting PDE-5 activity or enhancing cGMP signal transduction comprising contacting the compound of Formula (I) according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, with a cell.
13. A method of treating erectile dysfunction or female sexual dysfunction comprising administering an effective amount of the compound of Formula (I) according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need thereof.