Pyrimidine 5-carboxamide compounds, process for producing the same and use thereof

1. A compound of the formula

wherein

R 1 is a heterocycle having a skeleton consisting of 8 to 12 atoms including a nitrogen atom and optionally substituted by substituent(s) selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 7-16 aralkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-14 aryl, C 1-8 alkoxy, C 1-3 alkylenedioxy, hydroxy, halogen atom, amino, (di or mono-(C 1-5 alkyl)amino, (C 1-5 alkoxy-carbonyl)amino, (C 1-5 acyl)amino, (C 1-5 acyl)(C 1-5 alkyl)amino, C 1-5 alkylthio, nitrile, nitro, C 1-5 alkoxy-carbonyl, carboxyl, C 1-5 alkyl-carbonyloxy, oxo, thioxo, C 1-6 acyl group, sulfamoyl and (di or mono-C 1-5 alkyl)sulfamoyl;

X is an oxygen atom, NH or a sulfur atom optionally oxidized with 1 or 2 oxygens,

Y is a bond or a C 1-5 alkylene group,

R 2 is (1) a hydrogen atom, (2) a hydroxy group, (3) a C 1-5 alkoxy group, (4) a C 1-5 alkylthio group, (5) a carbocycle having 3 to 15 carbon atoms or (6) a heterocycle having a skeleton consisting of 3 to 15 atoms including 1 to 5 heteroatom(s),

provided that when Y is a bond, R 2 is a carbocycle having 3 to 15 carbon atoms or a heterocycle having a skeleton consisting of 3 to 15 atoms including 1 to 5 heteroatom(s) and;

one of R 3 and R 4 is a hydrogen atom or a group of the formula: —Z—R 5 (Z is a bond or C 1-10 alkylene group optionally having substituent(s) and R 5 is (1) a hydrogen atom, (2) a hydroxy group, (3) a (C 1-5 alkoxy group, (4) a nitrile group, (5) a (C 1-5 alkoxy-carbonyl group, (6) a carboxyl group, (7) a carbamoyl group, (8) a (mono or di-C 1-5 alkyl)carbamoyl group, (9) an amino group, (10) a (di or mono-C 1-5 alkyl)amino group, (11) a (C 1-5 alkoxy-carbonyl)amino group, (12) a C 1-5 alkylthio group, (13) a carbocycle having 3 to 15 carbon atoms or (14) a heterocycle having a skeleton consisting of 3 to 15 atoms including 1 to 5 heteroatom(s));

the other is a group of the formula: —Z—R 5 (Z and R 5 are as defined above);

or R 3 and R 4 may form, together with the adjacent nitrogen atom, a heterocycle having a skeleton consisting of 3 to 15 atoms, which heterocycle is attached by a secondary nitrogen atom constituting the heterocycle, wherein the above-mentioned heterocycle and a carbocycle having 3 to 15 carbon atoms are each optionally substituted by substituent(s) selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 7-16 aralkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-14 aryl, C 1-8 alkoxy, C 1-3 alkylenedioxy, hydroxy, halogen atom, amino, (di or mono-C 1-5 alkyl)amino, (C 1-5 alkoxy-carbonyl)amino, (C 1-5 acyl)amino, (C 1-5 acyl)(C 1-5 alkyl)amino, C 1-5 alkylthio, nitrile, nitro, C 1-5 alkoxy-carbonyl, carboxyl, (C 1-5 alkyl-carbonyloxy, oxo, thioxo, C 1-6 acyl group, sulfamoyl and (di or mono-C 1-5 alkyl)sulfamoyl,

or a salt thereof.

2. The compound of claim 1 , wherein X is NH or a sulfur atom optionally oxidized with 1 or 2 oxygens.

3. The compound of claim 1 , wherein Y is a C 2-5 alkylene group.

4. The compound of claim 1 , wherein Y is a C 1-5 alkylene group, R 2 is a hydroxy group, a C 1-5 alkoxy group or a C 1-5 alkylthio group.

5. The compound of claim 1 , wherein R 5 is (1) a non-aromatic carbocycle having 3 to 15 carbon atoms or (2) a non-aromatic heterocycle having a skeleton consisting of 3 to 15 atoms including 1 to 5 heteroatom(s).

6. The compound of claim 1 , wherein Z is a C 2-10 alkylene group optionally having substituent(s), and R 5 is a hydroxy group, a nitrile group, a C 1-5 alkoxy-carbonyl, a carboxyl group, a carbamoyl group, a (mono or di-C 1-5 alkyl)carbamoyl group, a (C 1-5 alkoxy-carbonyl)amino group or a C 1-5 alkylthio group.

7. The compound of claim 1 , wherein Z is a methylene group optionally having substituent(s), and R 5 is a nitrile group, a C 1-5 alkoxy-carbonyl group, a carboxyl group, a carbamoyl group or a (mono or di-C 1-5 alkyl)carbamoyl group.

8. The compound of claim 1 , wherein the substituent(s) of the heterocycle and the carbocycle having 3 to 15 carbon atoms is selected from the group consisting of C 2-8 alkenyl, C 2-8 alkynyl, C 7-16 aralkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-14 aryl, C 1-3 alkylenedioxy, hydroxy, (C 1-5 alkoxy-carbonyl)amino, (C 1-5 acyl)amino, (C 1-5 acyl)(C 1-5 alkyl)amino, (C 1-5 alkylthio, nitrile, (C 1-5 alkoxy-carbonyl, carboxyl, (C 1-5 alkyl-carbonyloxy, oxo, thioxo, C 1-6 acyl group, sulfamoyl and (di or mono-C 1-5 alkyl)sulfamoyl.

9. The compound of claim 1 , wherein R 1 is 1-indolinyl optionally substituted by substituent(s) selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 7-16 aralkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-14 aryl, C 1-8 alkoxy, C 1-3 alkylenedioxy, hydroxy, halogen atom, amino, (di or mono-C 1-5 alkyl)amino, (C 1-5 alkoxy-carbonyl)amino, (C 1-5 acyl)amino, (C 1-5 acyl)(C 1-5 alkyl)amino, C 1-5 alkylthio, nitrile, nitro, C 1-5 alkoxy-carbonyl, carboxyl, C 1-5 alkyl-carbonyloxy, oxo, thioxo, C 1-6 acyl group, sulfamoyl and (di or mono-C 1-5 alkyl)sulfamoyl.

10. The compound of claim 1 , wherein R 2 is a carbocycle having 5 to 7 carbon atoms or a heterocycle having a skeleton consisting of 5 to 7 atoms including 1 or 2 heteroatom(s), which heterocycle is optionally substituted by substituent(s) selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 7-16 aralkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-14 aryl, C 1-8 alkoxy, C 1-3 alkylenedioxy, hydroxy, halogen atom, amino, (di or mono-C 1-5 alkyl)amino, (C 1-5 alkoxy-carbonyl)amino, (C 1-5 acyl)amino, (C 1-5 acyl)(C 1-5 alkyl)amino, C 1-5 alkylthio, nitrile, nitro, C 1-5 alkoxy-carbonyl, carboxyl, C 1-5 alkyl-carbonyloxy, oxo, thioxo, C 1-6 acyl group, sulfamoyl and (di or mono-C 1-5 alkyl)sulfamoyl.

11. The compound of claim 1 , wherein R 2 is phenyl optionally substituted by substituent(s) selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 7-16 aralkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-14 aryl, C 1-8 alkoxy, C 1-3 alkylenedioxy, hydroxy, halogen atom, amino, (di or mono-C 1-5 alkyl)amino, (C 1-5 alkoxy-carbonyl)amino, (C 1-5 acyl)amino, (C 1-5 acyl)(C 1-5 alkyl)amino, C 1-5 alkylthio, nitrile, nitro, C 1-5 alkoxy-carbonyl, carboxyl, C 1-5 alkyl-carbonyloxy, oxo, thioxo, C 1-6 acyl group, sulfamoyl and (di or mono-C 1-5 alkyl)sulfamoyl.

12. The compound of claim 1 , wherein X is an oxygen atom or NH, and Y is a C 1-3 alkylene group.

13. The compound of claim 1 , wherein X is an oxygen atom, and Y is a methylene group.

14. The compound of claim 1 , wherein R 3 is a hydrogen atom and R 4 is a group of the formula: —Z—R 5 .

15. The compound of claim 14 , wherein Z is a bond or a C 1-4 alkylene group, R 5 is a carbocycle having 5 to 8 carbon atoms or a heterocycle having a skeleton consisting of 5 to 11 atoms having 1 to 5 heteroatom(s), which heterocycle is optionally substituted by substituent(s) selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 7-16 aralkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-14 aryl, C 1-8 alkoxy, C 1-3 alkylenedioxy, hydroxy, halogen atom, amino, (di or mono-C 1-5 alkyl)amino, (C 1-5 alkoxy-carbonyl)amino, (C 1-5 acyl)amino, (C 1-5 acyl)(C 1-5 alkyl)amino, C 1-5 alkylthio, nitrile, nitro, C 1-5 alkoxy-carbonyl, carboxyl, C 1-5 alkyl-carbonyloxy, oxo, thioxo, C 1-6 acyl group, sulfamoyl and (di or mono-C 1-5 alkyl)sulfamoyl.

16. The compound of claim 1 , wherein R 1 is a group selected from

—X—Y—R 2 is a group selected from

and —NR 3 R 4 is a group selected from

17. The compound of claim 1 , wherein R 1 is a group selected from

—X—Y—R 2 is a group selected from

and —NR 3 R 4 is a group selected from

18. The compound of claim 1 , wherein R 1 is a group selected from the group consisting of

—X—Y—R 2 is a group selected from the group consisting of

and —NR 3 R 4 is a group selected from the group consisting of

19. The compound of claim 1 , wherein when Z is a C 2-10 alkylene group optionally having substituent(s), R 5 is a hydrogen atom, a hydroxy group, a C 1-5 alkoxy group, a nitrile group, a C 1-5 alkoxy-carbonyl, a carboxyl group, a carbamoyl group, a (mono or di-C 1-5 alkyl)carbamoyl group, an amino group, a (di or mono-C 1-5 alkyl)amino group, a (C 1-5 alkoxy-carbonyl)amino group, a C 1-5 alkylthio group, a carbocycle having 3 to 15 carbon atoms, or a heterocycle having a skeleton consisting of 3 to 15 atoms including 1 to 5 heteroatom(s) or when Z is a methylene group optionally having substituents, R 5 is a nitrile group, a C 1-5 alkoxy-carbonyl group, a carboxyl group, a carbamoyl group, a (mono or di-C 1-5 alkyl)carbamoyl group, a carbocycle having 3 to 15 carbon atoms, or a heterocycle having a skeleton consisting of 3 to atoms including 1 to 5 heteroatom(s).

20. (i) (RS)-2-(2,3-Dihydro-1H-indol-1-yl)-4-[(4-methoxybenzyl)oxy]-N-(2-oxo-3-azepanyl)-5-pyrimidinecarboxamide, (ii) 2-(2,3-dihydro-1H-indol-1-yl)-4-[(4-methoxybenzyl)oxy]-N-[(5-methyl-2-pyrazinyl)methyl]-5-pyrimidinecarboxamide, (iii) 2-(2,3-dihydro-1H-indol-1-yl)-4-[(4-methoxybenzyl)oxy]-N-(2-pyridinylmethyl)-5-pyrimidinecarboxamide, (iv) (RS)-4-(1,3-benzodioxol-5-ylmethoxy)-2-(2,3-dihydro-1H-indol-1-yl)-N-(2-oxo-3-azepanyl)-5-pyrimidinecarboxamide, (v) 4-(1,3-benzodioxol-5-ylmethoxy)-2-(2,3-dihydro-1H-indol-1-yl)-N-(2-pyridinylmethyl)-5-pyrimidinecarboxamide, (vi) 2-(2,3-dihydro-1H-indol-1-yl)-4-[(3-fluoro-4-methoxybenzyl)oxy]-N-(2-pyridinylmethyl)-5-pyrimidinecarboxamide, (vii) 2-(2,3-dihydro-1H-indol-1-yl)-4-[(3-fluoro-4-methoxybenzyl)oxy]-N-(2-oxo-3-azepanyl)-5-pyrimidinecarboxamide, (viii) 2-(2,3-dihydro-1H-indol-1-yl)-4-[(3-fluoro-4-methoxybenzyl)oxy]-N-[(5-methyl-2-pyrazinyl)methyl]-5-pyrimidinecarboxamide, (ix) 4-[(3-chloro-4-methoxybenzyl)oxy]-2-(2,3-dihydro-1H-indol-1-yl)-N-(2-pyridinylmethyl)-5-pyrimidinecarboxamide, (x) 4-[(3-chloro-4-methoxybenzyl)oxy]-2-(2,3-dihydro-1H-indol-1-yl)-N-(2-oxo-3-azepanyl)-5-pyrimidinecarboxamide, (xi) 4-[(3-chloro-4-methoxybenzyl)oxy]-2-(2,3-dihydro-1H-indol-1-yl)-N-[(5-methyl-2-pyrazinyl)methyl]-5-pyrimidinecarboxamide, (xii) (rac)-4-[(4-methoxybenzyl)oxy]-2-(2-methyl-2,3-dihydro-1H-indol-1-yl)-N-(2-oxo-3-azepanyl)-5-pyrimidinecarboxamide, (xiii) 2-(2,3-dihydro-1H-indol-1-yl)-4-[(4-methoxybenzyl)oxy]-N-[(3 S)-2-oxoazepanyl]-5-pyrimidinecarboxamide, (xiv) 2-(2,3-dihydro-1H-indol-1-yl)-4-[(4-methoxybenzyl)oxy]-N-[(3R)-2-oxoazepanyl]-5-pyrimidinecarboxamide, (xv) 4-(1,3-benzodioxol-5-ylmethoxy)-2-(2,3-dihydro-1H-indol-1-yl)-4-[(4-methoxybenzyl)oxy]-N-[(3S)-2-oxoazepanyl]-5-pyrimidinecarboxamide, (xvi) 2-(2,3-dihydro-1H-indol-1-yl)-4-[(3-fluoro-4-methoxybenzyl)oxy]-N-[(3S)-2-oxoazepanyl]-5-pyrimidinecarboxamide, (xvii) 4-[(3-chloro-4-methoxybenzyl)oxy]-2-(2,3-dihydro-1H-indol-1-yl)-N-[(3 S)-2-oxoazepanyl]-5-pyrimidinecarboxamide, (xviii) 4-[(4-methoxybenzyl)oxy]-2-[(2RS)-2-methyl-2,3-dihydro-1H-indol-1-yl]-N-[(3S)-2-oxoazepanyl]-5-pyrimidinecarboxamide, (xix) 4-[(4-methoxybenzyl)oxy]-2-[(2RS)-2-methyl-2,3-dihydro-1H-indol-1-yl]-N-[(3R)-2-oxoazepanyl]-5-pyrimidinecarboxamide, (xx) 4-[(4-methoxybenzyl)oxy]-2-[(2R)-2-methyl-2,3-dihydro-1H-indol-1-yl]-N-[(3 S)-2-oxoazepanyl]-5-pyrimidinecarboxamide, (xxi) 4-[(4-methoxybenzyl)oxy]-2-[(2R)-2-methyl-2,3-dihydro-1H-indol-1-yl]-N-[(3R)-2-oxoazepanyl]-5-pyrimidinecarboxamide, (xxii) 2-[(2R)-2-methyl-2,3-dihydro-1H-indol-1-yl]-4-[(3-fluoro-4-methoxybenzyl)oxy]-N-[(3S)-2-oxoazepanyl]-5-pyrimidinecarboxamide, (xxiii) 4-[(3-chloro-4-methoxybenzyl)oxy]-2-[(2R)-2-methyl-2,3-dihydro-1H-indol-1-yl]-N-[(3 S)-2-oxoazepanyl]-5-pyrimidinecarboxamide, (xxiv) 4-[(4-methoxybenzyl)oxy]-2-[(2S)-2-methyl-2,3-dihydro-1H-indol-1-yl]-N-[(3S)-2-oxoazepanyl]-5-pyrimidinecarboxamide or (xxv) 4-[(4-methoxybenzyl)oxy]-2-[(2S)-2-methyl-2,3-dihydro-1H-indol-1-yl]-N-[(3R)-2-oxoazepanyl]-5-pyrimidinecarboxamide.

21. A prodrug of the compound of the formula

wherein

R 1 is a heterocycle having a skeleton consisting of 8 to 12 atoms including a nitrogen atom and optionally substituted by substituent(s) selected from the group consisting of C 1-8 alkyl C 2-8 alkenyl, C 2-8 alkynyl, C 7-16 aralkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-14 aryl, C 1-8 alkoxy, C 1-3 alkylenedioxy, hydroxy, halogen atom, amino, (di or mono-C 1-5 alkyl)amino, (C 1-5 alkoxy-carbonyl)amino, (C 1-5 acyl)amino, (C 1-5 acyl)(C 1-5 alkyl)amino, C 1-5 alkylthio, nitrile, nitro, C 1-5 alkoxy-carbonyl, carboxyl, C 1-5 alkyl-carbonyloxy, oxo, thioxo, C 1-6 acyl group, sulfamoyl and (di or mono-(C 1-5 alkyl)sulfamoyl;

X is an oxygen atom, NH or a sulfur atom optionally oxidized with 1 or 2 oxygens,

Y is a bond or a C 1-5 alkylene group,

R 2 is (1) a hydrogen atom, (2) a hydroxy group, (3) a C 1-5 alkoxy group, (4) a C 1-5 alkylthio group, (5) a carbocycle having 3 to 15 carbon atoms or (6) a heterocycle having a skeleton consisting of 3 to 15 atoms including 1 to 5 heteroatom(s),

provided that when Y is a bond, R 2 is a carbocycle having 3 to 15 carbon atoms or a heterocycle having a skeleton consisting of 3 to 15 atoms including 1 to 5 heteroatom(s) and;

one of R 3 and R 4 is a hydrogen atom or a group of the formula: —Z—R 5 (Z is a bond or C 1-10 alkylene group optionally having substituent(s) and R 5 is (1) a hydrogen atom, (2) a hydroxy group, (3) a C 1-5 alkoxy group, (4) a nitrile group, (5) a C 1-5 alkoxy-carbonyl group, (6) a carboxyl group, (7) a carbamoyl group, (8) a (mono or di-C 1-5 alkyl)carbamoyl group, (9) an amino group, (10) a (di or mono-C 1-5 alkyl)amino group, (11) a (C 1-5 alkoxy-carbonyl)amino group, (12) a C 1-5 alkylthio group, (13) a carbocycle having 3 to 15 carbon atoms or (14) a heterocycle having a skeleton consisting of 3 to 15 atoms including 1 to 5 heteroatom(s));

the other is a group of the formula: —Z—R 5 (Z and R 5 are as defined above);

or R 3 and R 4 may form, together with the adjacent nitrogen atom, a heterocycle having a skeleton consisting of 3 to 15 atoms, which heterocycle is attached by a secondary nitrogen atom constituting the heterocycle, wherein the above-mentioned heterocycle and a carbocycle having 3 to 15 carbon atoms are each optionally substituted by substituent(s) selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 7-16 aralkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-14 aryl, C 1-8 alkoxy, C 1-3 alkylenedioxy, hydroxy, halogen atom, amino, (di or mono-C 1-5 alkyl)amino, (C 1-5 alkoxy-carbonyl)amino, (C 1-5 acyl)amino, (C 1-5 acyl)(C 1-5 alkyl)amino, C 1-5 alkylthio, nitrile, nitro, C 1-5 alkoxy-carbonyl, carboxyl, C 1-5 alkyl-carbonyloxy, oxo, thioxo, C 1-6 acyl group, sulfamoyl and (di or mono-C 1-5 alkyl)sulfamoyl,

or a salt thereof;

which is selected from the group consisting of (1) a prodrug wherein an amino group of said compound is acylated, alkylated or phosphorylated; (2) a prodrug wherein a hydroxy group of said compound is acylated, alkylated, phosphorylated or borated; and (3) a prodrug wherein an esterified or amidated carboxyl group of said compound is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified or methylamidated.

22. A production method of the compound of claim 1 , which comprises reacting a compound of the formula

wherein L 1 is a leaving group and other symbols are as defined in claim 1 , or a salt thereof, with an amine compound of the formula

R 3 R 4 NH

wherein R 3 and R 4 are as defined in claim 1 .

23. A production method of the compound of claim 1 , which comprises reacting a compound of the formula

wherein L 2 is a leaving group and other symbols are as defined in claim 1 , or a salt thereof, with a compound of the formula

R 1 —H

wherein R 1 is as defined in claim 1 .

24. A production method of the compound of claim 1 , which comprises reacting a compound of the formula

wherein L 3 is a leaving group and other symbols are as defined in claim 1 , or a salt thereof, with a compound of the formula

R 2 —Y—X 1 —H

wherein R 2 and Y are as defined in claim 1 and X 1 is an oxygen atom, a nitrogen atom optionally substituted by a hydrocarbon group having 1 to 5 carbon atom(s) or a sulfur atom, and if desired, subjecting the resulting compound to oxidation.

25. A production method of the compound of claim 1 , which comprises reacting a compound of the formula

wherein symbols are as defined in claim 1 , X 1 is an oxygen atom, a nitrogen atom optionally substituted by a hydrocarbon group having 1 to 5 carbon atom(s) or a sulfur atom, or a salt thereof, with a compound of the formula

R 2 —Y-L 4

wherein R 2 and Y are as defined in claim 1 and L 4 is a leaving group, and if desired, subjecting the resulting compound to oxidation.

26. A pharmaceutical composition comprising a compound of the formula

wherein symbols are as defined in claim 1 , or a salt thereof or a prodrug of claim 21 .

27. A method for inhibiting cGMP-PDE V which comprises administering an effective amount of the compound of claim 1 or a prodrug of claim 21 thereof to a mammal in need thereof.

28. A method for the treatment of pulmonary hypertension or disorders of male genital function in a mammal, which comprises administering an effective amount of the compound of claim 1 or a prodrug of claim 21 thereof to a mammal in need thereof.