Bicyclic substituted pyrimidine compounds
Disclosed are bicyclic group substituted pyrimidine compounds, pharmaceutical acceptable salts thereof or stereoisomers thereof. Also disclosed are preparation methods, pharmaceutical formulations, and pharmaceutical compositions of the compounds, and use of the compounds, pharmaceutical formulations, and pharmaceutical compositions for preparing a medicament for treating and/or preventing sexual dysfunction diseases and diseases with lower urinary tract symptoms.
1. A compound of Formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof:
wherein
R 1 is selected from the group consisting of saturated 6 to 7 membered N-containing fused heterocyclyl, 7 to 12 membered N-containing spiro heterocyclyl and 7 to 12 membered N-containing bridged heterocyclyl; each attached to pyrimidyl via nitrogen and optionally substituted with a substituent selected from the group consisting of halogen, cyano, amino, hydroxyl, C 1-6 alkyl, halo C 1-6 alkyl, hydroxyl C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 alkylcarbonyl and C 1-6 alkoxylcarbonyl, wherein the number of the substituent is 1 to 4;
R 2 is selected from the group consisting of hydrogen, hydroxyl, amino, cyano, C 1-6 alkylamino, di(C 1-6 alkyl)amino,C 1-6 alkyl, halo C 1-6 alkyl, hydroxyl C 1-6 alkyl and C 1-6 alkoxyl;
R 3 and R 4 are each independently selected from hydrogen and -M-R 7 ,
M is selected from a single bond and C 1-6 alkylene optionally substituted with substituent L 1 ,
R 7 is selected from 3 to 14 membered cyclic group optionally substituted with substituent L 2 ,
or R 3 and R 4 together with nitrogen attached to R 3 and R 4 form a 5 to 6 membered N-containing heterocyclyl optionally substituted with substituent L 3 ,
said substituents L 1 , L 2 and L 3 are selected from the group consisting of halogen, hydroxyl, cyano, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, oxo, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl and di(C 1-6 alkyl)phosphino, wherein the number of the substituent is 1 to 4;
R 5 and R 6 are each independently selected from hydrogen and -Q-R 8 ,
Q is selected from a single bond and C 1-6 alkylene optionally substituted with substituent L 4 ,
R 8 is selected from the group consisting of 6 to 14 membered aryls, 5 to 7 membered monocyclic heterocyclyl, 8 to 9 membered fused cyclyl and 8 to 9 membered fused heterocyclyl; each optionally substituted with substituent L 5 ,
said substituents L 4 and L 5 are selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, halo C 1-6 alkyl, carboxyl C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyl, halo C 1-6 alkoxyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, cyano, nitro, C 1-6 alkylcarbonyl, sulfonyl amino and C 1-6 alkyl sulfonyl amino, wherein the number of the substituent is 1 to 4.
2. The compound of claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 2 is selected from the group consisting of hydrogen, hydroxyl and methyl;
R 4 is hydrogen;
R 6 is hydrogen.
3. The compound of claim 2 or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
R 5 is -Q-R 8 ,
Q is selected from C 1-6 alkylene,
R 8 is selected from the group consisting of 6 to 10 membered aryls, 5 to 7 membered monocyclic heterocyclyl, 8 to 9 membered fused cyclyl and 8 to 9 membered fused heterocyclyl; each optionally substituted with substituent L 5 ,
said substituent L 5 is selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, halo C 1-6 alkyl, carboxyl C 1-6 alkyl, C 1-6 alkoxyl, halo C 1-6 alkoxyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, cyano, nitro, C 1-6 alkylcarbonyl, sulfonyl amino and C 1-6 alkyl sulfonyl amino, wherein the number of the substituent is 1 to 4.
4. The compound of claim 3 or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is selected from the group consisting of saturated 6 to 7 membered N-containing fused heterocyclyl, 7 to 12 membered N-containing spiro heterocyclyl and 7 to 12 membered N-containing bridged heterocyclyl; each attached to pyrimidyl via nitrogen and optionally substituted with a substituent selected from the group consisting of halogen, cyano, amino, hydroxyl, C 1-6 alkyl, halo C 1-6 alkyl, hydroxyl C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 alkylcarbonyl and C 1-6 alkoxylcarbonyl, wherein the number of the substituent is 1 to 4.
5. The compound of claim 4 or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is selected from the group consisting of saturated 6 to 7 membered N-containing fused heterocyclyl, 7 to 10 membered N-containing spiro heterocyclyl and 7 to 8 membered N-containing bridged heterocyclyl; each attached to pyrimidyl via nitrogen and optionally substituted with a substituent selected from the group consisting of halogen, cyano, amino, hydroxyl, C 1-6 alkyl, halo C 1-6 alkyl, hydroxyl C 1-6 alkyl and C 1-6 alkoxyl, wherein the number of the substituent is 1 to 4;
R 3 is -M-R 7 ,
M is selected from a single bond and C 1-6 alkylene,
R 7 is selected from the group consisting of phenyl, 5 to 7 membered monocyclic heterocyclyl, 4 to 7 membered cycloalkyl, 8 to 9 fused cyclyl, 7 to 10 membered spiro cyclyl, 7 to 10 membered bridged cyclyl, 7 to 10 membered spiro heterocyclyl and 7 to 10 membered bridged heterocyclyl; each optionally substituted with substituent L 2 ,
or R 3 and R 4 together with nitrogen attached to R 3 and R 4 form a 5 to 6 membered N-containing heterocyclyl optionally substituted with substituent L 3 ,
said substituents L 2 and L 3 are selected from the group consisting of halogen, hydroxyl, cyano, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, oxo, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo C 1-6 alkyl and C 1-6 alkoxyl, wherein the number of the substituent is 1 to 4;
R 5 is -Q-R 8 ,
Q is selected from methylene and ethylene,
R 8 is selected from the group consisting of phenyl, 5 to 7 membered monocyclic heterocyclyl, 8 to 9 membered fused cyclyl and 8 to 9 fused heterocyclyl; each optionally substituted with substituent L 5 ,
said substituent L 5 is selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl, methoxyl, ethoxyl, trifluoromethoxyl, dimethylamino and carboxylmethyl, wherein the number of the substituent is 1 to 4;
R 2 is hydrogen; R 4 is hydrogen; R 6 is hydrogen.
6. The compound of claim 5 or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 7 is selected from the group consisting of phenyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl, 2-oxo-azacycloheptanyl, 2-oxo-piperazinylfuranyl, dihydrothienyl, dihydropyrrolyl, dihydrooxazolyl, dihydropyrazolyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, pyrimidyl, pyridyl, pyrazinyl, oxazolyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, naphthyl, indolyl, benzimidazolyl, 2,3-dihydrobenzfuranyl, quinolinyl, benzo[d][1,3]-meta-dioxa-cyclopentenyl, 7 to 10 membered spiro cyclyl, 7 to 10 membered bridged cyclyl, 7 to 10 membered spiro heterocyclyl and 7 to 10 membered bridged heterocyclyl; each optionally substituted with substituent L 2 ,
or R 3 and R 4 together with nitrogen attached to R 3 and R 4 form a 5 to 6 membered N-containing heterocyclyl optionally substituted with substituent L 3 ,
said substituents L 2 and L 3 are selected from the group consisting of halogen, hydroxyl, cyano, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, oxo, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo C 1-6 alkyl and C 1-6 alkoxyl, wherein the number of the substituent is 1 to 4;
R 8 is selected from the group consisting of phenyl, 8 to 9 membered fused cyclyl and 8 to 9 fused heterocyclyl; each optionally substituted with substituent L 5 ,
said substituent L 5 is selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl, methoxyl, ethoxyl, trifluoromethoxyl, dimethylamino and carboxylmethyl, wherein the number of the substituent is 1 to 4.
7. The compound of claim 6 or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is selected from the group consisting of saturated 6 to 7 membered N-containing fused heterocyclyl, 7 to 10 membered N-containing spiro heterocyclyl and 7 to 8 membered N-containing bridged heterocyclyl; each attached to pyrimidyl via nitrogen and optionally substituted with a substituent selected from the group consisting of fluoro, chloro, amino, hydroxyl, C 1-6 alkyl and hydroxyl C 1-6 alkyl, wherein the number of the substituent is 1 to 2;
R 3 is -M-R 7 ,
M is selected from the group consisting of a single bond, methylene and ethylene,
R 7 is selected from the group consisting of cyclopentyl, cyclohexyl and cycloheptyl; each optionally substituted with substituent L 2 ,
said substituent L 2 is selected from the group consisting of fluoro, chloro, hydroxyl, amino, methylamino, dimethylamino, methyl, ethyl and methoxyl, wherein the number of the substituent is 1 to 2;
R 5 is -Q-R 8 ,
Q is selected from methylene and ethylene,
R 8 is phenyl optionally substituted with substituent L 5 ,
said substituent L 5 is selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl, methoxyl, ethoxyl and trifluoromethoxyl, wherein the number of the substituent is 1 to 4.
8. The compound of claim 6 or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is selected from the group consisting of saturated 6 to 7 membered N-containing fused heterocyclyl and 7 to 10 membered N-containing spiro heterocyclyl; each attached to pyrimidyl via nitrogen and optionally substituted with a substituent selected from the group consisting of fluoro, chloro, amino, hydroxyl, C 1-6 alkyl and hydroxyl C 1-6 alkyl, wherein the number of the substituent is 1 to 2;
R 3 is -M-R 7 ,
M is selected from the group consisting of a single bond, methylene and ethylene,
R 7 is selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, 2-oxo-azacycloheptanyl, 2-oxo-piperazinylfuranyl and 7 to 10 membered spiro cyclyl; each optionally substituted with substituent L 2 ,
or R 3 and R 4 together with nitrogen attached to R 3 and R 4 form piperidinyl, piperazinyl or morpholinyl; each optionally substituted with substituent L 3 ,
said substituents L 2 and L 3 are selected from the group consisting of fluoro, chloro, hydroxyl, amino, methylamino, dimethylamino, oxo, trifluoromethyl, methyl, ethyl and methoxyl, wherein the number of the substituent is 1 to 2;
R 5 is -Q-R 8 ,
Q is selected from methylene and ethylene,
R 8 is phenyl optionally substituted with substituent L 5 ,
said substituent L 5 is selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl, methoxyl, ethoxyl and trifluoromethoxyl, wherein the number of the substituent is 1 to 4.
9. The compound of claim 6 or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is selected from the group consisting of saturated 6 to 7 membered N-containing fused heterocyclyl, 7 to 10 membered N-containing spiro heterocyclyl and 7 to 8 membered N-containing bridged heterocyclyl; each attached to pyrimidyl via nitrogen and optionally substituted with a substituent selected from the group consisting of fluoro, chloro, amino, hydroxyl, C 1-6 alkyl and hydroxyl C 1-6 alkyl, wherein the number of the substituent is 1 to 2;
R 3 is -M-R 7 ,
M is selected from the group consisting of a single bond, methylene and ethylene,
R 7 is selected from the group consisting of phenyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, pyrimidyl, pyridyl, pyrazinyl, oxazolyl, naphthyl, indolyl, quinolinyl and 7 to 10 membered bridged cyclyl; each optionally substituted with substituent L 2 ,
or R 3 and R 4 together with nitrogen attached to R 3 and R 4 form piperidinyl, piperazinyl or morpholinyl; each optionally substituted with substituent L 3 ,
said substituents L 2 and L 3 are selected from the group consisting of fluoro, chloro, hydroxyl, amino, methylamino, dimethylamino, oxo, trifluoromethyl, methyl, ethyl and methoxyl, wherein the number of the substituent is 1 to 2;
R 5 is -Q-R 8 ,
Q is selected from methylene and ethylene,
R 8 is selected from the group consisting of phenyl and 8 to 9 membered fused cyclyl; each optionally substituted with L 5 ,
said substituent L 5 is selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl, methoxyl, ethoxyl and trifluoromethoxyl, wherein the number of the substituent is 1 to 4.
10. The compound of claim 6 or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is selected from the group consisting of
R 3 is selected from the group consisting of
or R 3 and R 4 together with nitrogen attached to R 3 and R 4 form
R 5 is selected from the group consisting of
11. The compound of claim 10 or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is selected from the group consisting of
R 3 is selected from the group consisting of
or R 3 and R 4 together with nitrogen attached to R 3 and R 4 form
R 5 is selected from the group consisting of
12. The compound of claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound is selected from
13. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 1 and one or more pharmaceutical carrier and/or diluent.
14. The pharmaceutical composition according to claim 13 , further comprising one or more second therapeutically active agents selected from the group consisting of vasodilator, prostaglandin E1, prostacyclin, α-adrenoreceptor blocker, mixed α, β-blocker, α-blocker, 5α-reductase inhibitor, α2-adrenoreceptor blocker, ACE inhibitor, NEP inhibitor, central dopaminergic agent, vasoactive intestinal peptide, calcium channel blocker, thiazines and the mixture thereof.
15. A method for treating in a subject a disease selected from the group consisting of diseases with lower urinary tract symptoms, hypertension, pulmonary hypertension, erectile dysfunction, and prostatic hyperplasia, comprising the step of administrating the compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 1 , or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt or a stereoisomer thereof to the subject.
16. The method of claim 15 , wherein said disease is selected from the group consisting of erectile dysfunction and benign prostatic hyperplasia.