Pyrazolo[4,3-d]pyrimidines as phosphodiesterase inhibitors

1. A compound of formula (I)

wherein

R 1 is a cyclic group selected from R A , R B , R C and R D , each of which is optionally substituted with one or more R 7 groups;

R 2 is hydrogen or C 1 -C 2 alkyl;

R 3 and R 4 are each independently C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or C 3 -C 10 cycloalkyl, each of which is optionally substituted with one or more R 8 groups, or R E , which is optionally substituted with one or more R 9 groups, or hydrogen;

or —NR 3 R 4 forms R F , which is optionally substituted with one or more R 10 groups;

R 5 is selected from —Y—CO 2 R 15 and —Y—R 16 ;

R 6 , which may be attached at N 1 or N 2 , is C 1 -C 6 alkyl, C 1 -C 8 haloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is optionally substituted by C 1 -C 8 alkoxy, C 1 -C 6 haloalkoxy or a cyclic group selected from R J , R K , R L and R M , or R 6 is R N , C 3 -C 7 cycloalkyl or C 3 -C 7 halocycloalkyl, each of which is optionally substituted by C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy, or R 6 is hydrogen;

R 7 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 8 alkynyl, cycloalkyl, C 3 -C 10 halocycloalkyl, phenyl, OR 12 , OC(O)R 12 , NO 2 , NR 12 R 13 , NR 12 C(O)R 13 , NR 12 CO 2 R 14 , C(O)R 12 , CO 2 R 12 , CONR 12 R 13 or CN;

R 8 is halo, phenyl, C 1 -C 6 alkoxyphenyl, OR 12 , OC(O)R 12 , NO 2 , NR 12 R 13 , NR 12 C(O)R 13 , NR 12 CO 2 R 14 , C(O)R 12 , CO 2 R 12 , CONR 12 R 13 , CN, C 3 -C 8 cycloalkyl, R G or R H , the last two of which are optionally substituted with one or more R 9 groups;

R 9 is C 1 -C 8 alkyl, C 1 -C 6 haloalkyl or CO 2 R 12 ;

R 10 is halo, C 3 -C 10 cycloalkyl, C 3 -C 10 halocycloalkyl, phenyl, OR 12 , OC(O)R 12 , NO 2 , NR 12 R 13 , NR 12 C(O)R 13 , NR 12 CO 2 R 14 , C(O)R 12 , CO 2 R 13 , CONR 12 R 13 , CN, oxo, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, the last two of which are optionally substituted by R 11 ;

R 11 is phenyl, NR 12 R 13 or NR 12 CO 2 R 14 ;

R 12 and R 13 are each independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;

R 14 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;

R 15 is hydrogen or C 1 -C 6 alkyl optionally substituted with one or more groups selected from phenyl, halo, OH, C 1 -C 6 alkyloxy, NH 2 , NH(C 1 -C 6 alkyl) and N(C 1 -C 6 alkyl) 2 ;

R 16 is a carboxylic acid isostere selected from tetrazol-5-yl, 5-trifluoromethyl-1,2,4-triazol-3-yl, 5-(methylsulfonyl)-1,2,4-triazol-3-yl, 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, —SO 2 NHR 17 and —CONHR 18 ;

R 17 is selected from C 1 -C 6 alkyl, phenyl, —CO—(C 1 -C 6 alkyl) and —CO-phenyl;

R 18 is selected from —SO 2 —(C 1 -C 6 alkyl) and —SO 2 -phenyl;

R A and R J are each independently a C 3 -C 10 cycloalkyl or C 3 -C 10 cycloalkenyl group, each of which may be either monocyclic or, when there are an appropriate number of ring atoms, polycyclic and which may be fused to either

(a) a monocyclic aromatic ring selected from a benzene ring and a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur, or

(b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur;

R B and R K are each independently a phenyl or naphthyl group, each of which may be fused to

(a) a C 5 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl ring,

(b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur, or

(c) a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur;

R C , R L and R N are each independently a monocyclic or, when there are an appropriate number of ring atoms, polycyclic saturated or partly unsaturated ring system containing between 3 and 10 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, which ring may be fused to a C 5 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl group or a monocyclic aromatic ring selected from a benzene ring and a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur;

R D and R M are each independently a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulphur, which ring may further be fused to

(a) a second 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur;

(b) C 5 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl ring;

(c) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur; or

(d) a benzene ring;

R E , R F and R G are each independently a monocyclic or, when there are an appropriate number of ring atoms, polycyclic saturated ring system containing between 3 and 10 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur;

R H is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulphur; and

Y is a covalent bond, —CH 2 —O—CH 2 —, C 1 -C 6 alkylenyl or C 3 -C 7 cycloalkylenyl; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

2. A compound according to claim 1 wherein R A is a monocyclic C 3 -C 8 cycloalkyl group optionally substituted with one to three R 7 groups, or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

3. A compound according to claim 1 wherein R 1 is phenyl optionally substituted with one to three R 7 groups, or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

4. A compound according to claim 1 wherein R 1 is a monocyclic saturated or partly unsaturated ring system containing between 3 and 8 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, said ring being optionally substituted with one to three R 7 groups, or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

5. A compound according to claim 1 wherein R 1 is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulphur, said ring being optionally substituted with one to three R 7 groups, or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

6. A compound according to claim 5 wherein R 1 is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl, said furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidyl and pyrazinyl being optionally substituted with one to three R 7 groups, or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

7. A compound according to claim 6 wherein R 1 is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl, said pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidyl and pyrazinyl being optionally substituted with one to three R 7 groups, or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

8. A compound according to claim 1 wherein R 7 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OR 12 or CONR 12 R 13 , or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

9. A compound according to claim 8 wherein R 7 is halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxy or CONH(C 1 -C 3 alkyl), or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

10. A compound according to claim 9 wherein R 7 is fluoro, methyl, ethyl, hydroxy, methoxy, propoxy or CONHMe, or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

11. A compound according to claim 1 selected from:

methyl 5-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylate,

methyl 1-(2-ethoxyethyl)-5-(N-isopropyl-N-methylamino)-7-(6-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylate,

ethyl 1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylate,

2-(dimethylamino)ethyl 5-dimethylamino-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylate,

1-(2-ethoxyethyl)-5-(N-methyl-N-propylamino)-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

5-(N-isopropyl-N-methylamino)-7-(4-methylpyridin-2-ylamino)-1-(2-propoxy-ethyl)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

7-(4,6-dimethylpyridin-2-ylamino)-1-(2-ethoxyethyl)-5-(N-isopropyl-N-methyl-amino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

5-(N-cyclobutyl-N-methylamino)-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-yl-amino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

1-(2-ethoxyethyl)-5-isopropylamino-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(2-methoxypyrimidin-4-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

3-[1-(2-ethoxyethyl)-5-(N-isopropyl-N-methylamino)-7-(4-methylpyridin-2-yl-amino)-1H-pyrazolo[4,3-d]pyrimidin-3-yl]-2H-1,2,4-oxadiazol-5-one,

3-[1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-3-yl]-2H-1,2,4-oxadiazol-5-one,

1-(2-ethoxyethyl)-7-(4-fluoro-3-methylphenylamino)-5-(N-isopropyl-N-methyl-amino)-1H-pyrazolo[4,3-d]-pyrimidine-3-carboxylic acid,

1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(4-fluoro-3-methylphenylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

7-(3,4-dimethylphenylamino)-1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

1-(2-(cyclopropylmethoxy)ethyl)-5-(N-isopropyl-N-methylamino)-7-(4-methyl-pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

1-(2-(cyclopropylmethoxy)ethyl)-5-(N-ethyl-N-methylamino)-7-(4-methyl-pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

1-(2-ethoxyethyl)-5-(N-isopropyl-N-methylamino)-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

1-(2-isopropoxyethyl)-5-(N-isopropyl-N-methylamino)-7-(4-methylpyridin-2-yl-amino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

N-[1-(2-ethoxyethyl)-5-(N-isopropyl-N-methylamino)-7-(4-methylpyridin-2-yl-amino)-1H-pyrazolo[4,3-d]pyrimidine-3-carbonyl]methanesulfonamide,

N-[1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carbonyl]methanesulfonamide,

N-[5-(Ethyl-methyl-amino)-1-[2-(3-fluoro-propoxy)-ethyl]-7-(4-methyl-pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carbonyl]-methanesulfonamide

N-[1-[2-(3-Fluoro-propoxy)-ethyl]-5-(isopropyl-methyl-amino)-7-(4-methyl-pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carbonyl]-methanesulfonamide

N-[5-Diethylamino-1-[2-(3-fluoro-propoxy)-ethyl]-7-(4-methyl-pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carbonyl]-methanesulfonamide

N-[5-Diethylamino-1-[2-(2,2-difluoro-ethoxy)-ethyl]-7-(4-methyl-pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carbonyl]-methanesulfonamide

N-[1-[2-(2,2-Difluoro-ethoxy)-ethyl]-5-(ethyl-methyl-amino)-7-(4-methyl-pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carbonyl]-methanesulfonamide, and

N-[1-[2-(2,2-Difluoro-ethoxy)-ethyl]-5-(isopropyl-methyl-amino)-7-(4-methyl-pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carbonyl]-methanesulfonamide, or

a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

12. A compound of formula (I-AA)

wherein

R 1 is a pyridinyl optionally substituted with one or more C 1 -C 6 alkyl groups;

R 3 and R 4 are each independently hydrogen or C 1 -C 6 alkyl;

R 5 is —CONHR 18 ;

R 6 is C 1 -C 8 alkyl optionally substituted by a substituent selected from the group consisting of —OH, C 3 -C 6 cycloalkyloxy, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy;

R 18 is selected from the group consisting of —SO 2 —(C 1 -C 6 alkyl) and —SO 2 -phenyl; or

a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

13. A compound according to claim 12 wherein R 1 is 2-pyridinyl substituted with one or more methyl, or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

14. A compound according to claim 12 wherein R 3 and R 4 are independently selected from the group consisting of methyl, ethyl, propyl, and isopropyl, or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

15. A compound according to claim 12 wherein R 18 is selected from the group consisting of —SO 2 CH 3 and —SO 2 CH 2 CH 3 , or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

16. A compound according to claim 12 wherein R 6 is ethyl, optionally substituted by a substituent selected from the group consisting of hydroxyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, difluoromethoxy, difluoroethoxy, difluoropropoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, and cyclobutyloxy, or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

17. A compound according to claim 12 wherein

R 1 pyridinyl is substituted with one or more methyl;

R 3 and R 4 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and isopropyl;

R 6 is ethyl, optionally substituted by a substituent selected from the group consisting of —OH, C 3 -C 6 cycloalkyloxy, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy; and

R 18 is selected from the group consisting of —SO 2 CH 3 , and —SO 2 CH 2 CH 3 , or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

18. A compound of formula (I-BB)

wherein

R 3 and R 4 are each independently selected from the group consisting of methyl, ethyl, and isopropyl;

R 6A is selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl, difluoroethyl, difluoropropyl, trifluoroethyl, and trifluoropropyl; and

R 18 is selected from the group consisting of —SO 2 CH 3 and —SO 2 CH 2 CH 3 , or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

20. A method of treating a disorder or condition in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer wherein said disorder or condition is hypertension.

21. A method according to claim 20 wherein the hypertension is essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis or renovascular hypertension.