Pyrazolopyridine derivatives as inhibitors of β-Adrenergic receptor kinase 1

1. A compound of the formula (I)

wherein

R 1 is

H or

(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl group is unsubstituted or substituted by one or more OH, halogen or NH 2 groups;

R 2 is

phenyl,

(C 3 -C 10 )cycloalkyl group or

(C 4 -C 10 )heterocyclyl group,

each of which are unsubstituted or substituted independently by 1, 2 or 3 residues selected from

1) (C 1 -C 6 )alkyl,

2) (C 2 -C 6 )alkenyl,

3) (C 2 -C 6 )alkynyl,

4) (C 1 -C 6 )alkylene-COOH,

5) (C 1 -C 6 )alkylene-C(O)O—(C 1 -C 6 )alkyl,

6) (C 1 -C 6 )alkylene-C(O)NH 2 ,

7) (C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl,

8) (C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl,

9) (C 1 -C 6 )alkylene-OH,

10) (C 1 -C 6 )alkylene-NH 2 ,

11) (C 1 -C 6 )alkylene-NH—(C 1 -C 6 )alkyl,

12) (C 1 -C 6 )alkylene-N[(C 1 -C 6 )alkyl] 2 ,

13) CN,

14) COOH,

15) C(O)O—(C 1 -C 6 )alkyl,

16) C(O)NH 2 ,

17) C(O)NH—(C 1 -C 6 )alkyl,

18) C(O)N[(C 1 -C 6 )alkyl] 2 ,

19) C(O)—(C 1 -C 6 )alkyl,

20) halogen,

21) NH 2 ,

22) NH(C 1 -C 6 )alkyl,

23) N[(C 1 -C 6 )alkyl] 2 ,

24) NH—C(O)—(C 1 -C 6 )alkyl,

25) OH,

26) O—(C 1 -C 6 )alkyl,

27) O—(C 2 -C 6 )alkenyl,

28) O—(C 2 -C 6 )alkynyl,

29) O—(C 1 -C 6 )alkylene-C(O)OH,

30) O—(C 1 -C 6 )alkylene-C(O)O—(C 1 -C 6 )alkyl,

31) O—(C 1 -C 6 )alkylene-C(O)NH 2 ,

32) O—(C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl,

33) O—(C 1 -C 6 )alkylene-OH,

34) O—(C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl,

35) O—(C 1 -C 6 )alkylene-NH 2 ,

36) O—(C 1 -C 6 )alkylene-NH—(C 1 -C 6 )alkyl,

37) O—C(O)—(C 1 -C 6 )alkyl,

38) S—(C 1 -C 6 )alkyl,

39) S(O) 2 —(C 1 -C 4 )alkyl,

40) (C 6 -C 10 )aryl,

41) (C 4 -C 10 )heterocyclyl,

42) (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl,

43) (C 1 -C 6 )alkylene-(C 4 -C 10 )heterocyclyl,

44) (C 1 -C 6 )alkylene-O—(C 6 -C 10 )aryl,

45) (C 1 -C 6 )alkylene-O—(C 4 -C 10 )heterocyclyl,

46) O—(C 6 -C 10 )aryl,

47) O—(C 4 -C 10 )heterocyclyl,

48) O—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, and

49) O—(C 1 -C 6 )alkylene-(C 4 -C 10 )heterocyclyl,

wherein the (C 6 -C 10 )aryl and (C 4 -C 10 )heterocyclyl in residues 40) to 49) are each unsubstituted or substituted independently by 1, 2 or 3 residues selected from OH, halogen, NH 2 , O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, S(O) 2 —(C 1 -C 4 )alkyl or (C 3 -C 10 )cycloalkyl;

and/or is vicinally substituted by a residue of the formula —O—(CH 2 ) n —O—, wherein n is 1, 2 or 3 and wherein one or more hydrogen atoms may be replaced by halogen atoms; and

R 3 is

H,

(C 1 -C 6 )alkyl or O—(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is unsubstituted or substituted by OH, halogen, NH 2 , NH(C 1 -C 6 )alkyl or N[(C 1 -C 6 )alkyl] 2 , or

(C 3 -C 10 )cycloalkyl, which is unsubstituted or substituted by one or more fluoro atoms;

or a physiologically acceptable salt thereof.

2. The compound according to claim 1 , wherein

R 2 is phenyl or (C 4 -C 10 )heterocyclyl.

3. The compound according to claim 2 , wherein

R 1 is H; and

R 3 is H,

(C 1 -C 6 )alkyl, which is unsubstituted or substituted by OH, halogen, NH 2 , NH(C 1 -C 6 )alkyl or N[(C 1 -C 6 )alkyl] 2 , or

(C 3 -C 10 )cycloalkyl, which is unsubstituted or substituted by one or more fluoro atoms.

4. The compound according to claim 2 wherein

R 1 is H; and

R 3 is H.

5. The compound according to claim 2 wherein

R 1 is H;

R 2 is phenyl or

(C 4 -C 10 )heterocyclyl, which is (C 5 -C 10 )heteroaryl; and

R 3 is H.

6. The compound according to claim 1 wherein R 2 is (C 4 -C 10 )heterocyclyl, which is (C 5 -C 10 )heteroaryl.

7. The compound according to claim 1 wherein R 2 is (C 4 -C 10 )heterocyclyl, which is (C 5 -C 10 )heteroaryl selected from the group of benzofuranyl, indolyl, furanyl, pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidyl, quinolinyl, thienyl, tetrazolyl, and triazolyl.

8. A compound according to claim 1 wherein

R 2 is (C 4 -C 10 )heterocyclyl, which is (C 5 -C 10 )heteroaryl that is a group of the formula (II),

wherein

X is N—R 4 or O,

R 4 is H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkylene-phenyl or C(O)—(C 1 -C 4 )alkyl;

R 5 is

H,

(C 1 -C 4 )alkyl,

(C 2 -C 4 )alkenyl,

(C 2 -C 4 )alkynyl,

(C 1 -C 4 )alkylene-phenyl,

C(O)—(C 1 -C 4 )alkyl,

COOH,

C(O)O—(C 1 -C 4 )alkyl,

C(O)NH 2 ,

halogen,

OH,

O—(C 1 -C 4 )alkyl,

O—(C 1 -C 4 )alkylene-OH,

O—(C 1 -C 4 )alkylene-NH 2 ,

O—(C 1 -C 4 )alkylene-O—(C 1 -C 4 )alkyl,

O—(C 1 -C 4 )alkylene-phenyl,

O—(C 1 -C 4 )alkylene-(C 5 -C 6 )heterocyclyl,

O—(C 1 -C 4 )alkylene-C(O)OH,

O—(C 1 -C 4 )alkylene-C(O)O—(C 1 -C 6 )alkyl, or

O—(C 1 -C 4 )alkylene-C(O)NH 2 , and

m is 1 or 2,

furanyl,

pyridyl,

pyrrolyl which is unsubstituted or substituted by (C 1 -C 6 )alkyl, or

pyrazolyl which is unsubstituted or substituted by phenyl.

9. The compound according to claim 1 wherein

R 1 is H; and

R 2 is (C 5 -C 10 )heteroaryl group of the formula (II),

wherein

X is N—R 4 ,

R 4 is H, CH 3 , CH(CH 3 ) 2 , benzyl, C(═O)CH 3 , CH 2 CH═CH 2 or CH 2 C≡CH,

R 5 is H, CH 3 , OCH 3 , COOH, C(O)OCH 3 , C(O)NH 2 , O-benzyl, F, Cl, Br, OH, O(CH 2 ) 2 OH, O(CH 2 ) 2 OCH 3 , O(CH 2 ) 2 NH 2 , OCH 2 C(O)OH, OCH 2 C(O)NH 2 , OCH 2 C(O)O-(tert-butyl),

m is 1 or 2,

pyridyl;

furanyl;

pyrrolyl of the formula (VII)

wherein R 8 is H or (C 1 -C 6 )alkyl, or

pyrazolyl of the formula (VIIIa)

wherein R 9 is phenyl; and

R 3 is H.

10. Method for the preparation of a compound of a compound of the formula (I) as claimed in claim 1 , comprising

either

a) mixing the compounds of the following formulae (II), (III) and (IV)

in dichloroethane in the presence of an acid, heating the mixture to 50-120° C. and subsequently oxidizing the mixture to yield 1H-Pyrazolo[3,4-b]pyridine system (VI)

reacting compound (VI) with ammonia in methanol to yield a compound of the formula (I) wherein R 1 is hydrogen.

11. The method of claim 10 wherein the oxidizing is effected by exposure to air.

12. Method for the preparation of a compound of a compound of the formula (I) as claimed in claim 1 , comprising

either

a) mixing compounds of the following formulae (II), (III) and (V) in ethanol,

heating the mixture to 50-120° C., subsequently oxidizing the mixture to yield the 1H-Pyrazolo[3,4-b]pyridine acid derivative (VII)

b) exposing the compound (VI) according to claim 10 to a base to yield the compound (VII), and then alternatively

a) activating the compound (VII) with Boc 2 O and subsequently treating with NH 4 HCO 3 to yield a compound of the formula (I) wherein R 1 is hydrogen, or

b) reacting compound (VII) with dicyclohexyl-carbodiimide, EDC or HOBT and R 1 —NH 2 derivative (VIII) to yield a compound of the formula (I) wherein R 1 is an optionally substituted (C 1 -C 6 )alkyl group.

13. A pharmaceutical composition comprising an effective amount at least one compound of the formula (I) according to claim 1 or a physiologically acceptable salt thereof and physiologically tolerated excipients and carriers, and, where appropriate, further additives and/or other active ingredients.

14. A method of inhibiting Adrenergic receptor in a patient comprising administering to the patient at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof.