IP Library › Granted Patent US 6,849,638

Granted Patent B2

US 6,849,638 · App. 10/136,575 · Granted Feb 1, 2005

4-AMINO-5,6-SUBSTITUTED THIOPHENO [2,3-D] PYRIMIDINES, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME, AND THEIR USE IN THE TREATMENT OR PREVENTION OF PDE7B-MEDIATED DISEASES AND CONDITIONS

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Quick Facts

Patent No.: US 6,849,638
App. No.: 10/136,575
Granted: Feb 1, 2005
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention relates to 4-amino-5,6-substituted thiopheno [2,3-d] pyrimidines, pharmaceutical compositions containing the same and their use to treat or prevent diseases and conditions mediated by the phosphodiesterase enzyme 7 B (PDE7 B ). Diseases and conditions mediated by PDE7 B include osteoporosis, osteopenia and asthma.

Claims (421)

1. A compound according to formula I:

wherein

R 1 and R 2 are independently selected from the group consisting of

hydrogen,

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O,

heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and R 4 -R 5 ,

or R 1 and R 2 combine to form, together with the nitrogen atom to which they are attached, a 5-7 membered saturated ring which may contain 1-2 additional heteroatoms selected from the group consisting of NH, NR 8 , S and O, or combine to form, together with the nitrogen atom to which they are attached, a 5-7 membered unsaturated ring which may contain 1-2 additional heteroatoms selected from the group consisting of N, S and O,

wherein said saturated or unsaturated ring may be substituted with 1-2 substituents selected from the group consisting of OH, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-7 carbon atoms, fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, halogen, haloalkyl of 1-2 carbon atoms and a number of halogen atoms up to the perhalo level, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, and R 9 -R 10 ;

or R 1 and R 2 combine to form, together with the nitrogen atom to which they are attached, an 8-10 membered bicyclic saturated ring;

R 3 is selected from the group consisting of NH, S, S(═O) 2 , and O;

with the proviso that R 3 is not NH when both R 1 and R 2 are methyl;

with the further proviso that R 1 is not butyl, phenyl, or benzyl when R 2 is hydrogen and R 3 is S or O;

R 4 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

C(═C),

S(═O) 2 , and

C(═O)O—;

R 5 is selected from

hydrogen,

OH,

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atom,

alkynyl of 2-8 carbon atoms,

alkoxy of 1-8 carbon atoms,

aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O,

heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, and

N—R 6 -R 7 ,

with the proviso that R 5 is not OH, alkoxy or N—R 6 -R 7 when R 4 is C(═O)O—, and with the further proviso that R 5 is not alkyl when R 4 is alkyl, alkenyl or alkynyl;

R 6 and R 7 are independently selected from

hydrogen,

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms, and

alkynyl of 2-8 carbon atoms,

or R 6 and R 7 combine together with the nitrogen atom to which they are attached to form a 5-7 membered, unsaturated ring which may contain 1-2 additional heteroatoms selected from N, S and O or to form a 5-7 membered, saturated ring which may contain 1-2 additional heteroatoms selected from NH, S and O;

R 8 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

R 11 -R 12 ,

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

heteroaryl of 4-11 carbon atoms and 1-2heteroatoms selected from N, S and O, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O;

R 9 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms, and

alkynyl of 2-8 carbon atoms,

R 10 is selected from

OH,

R 11 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms, and

alkynyl of 2-8 carbon atoms; and

R 12 is selected from

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein

R 3 is S(═O) 2 ; and

R 4 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl 2-8 carbon atoms,

C(═O) 2 , and

S(═O).

3. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

4. A compound according to formula II:

wherein

R 1 and R 2 are independently selected from the group consisting of

hydrogen,

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

R 3 is selected from the group consisting of:

hydrogen,

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

R 4 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl 2-8 carbon atoms,

C(═O),

S(═O) 2 , and

C(═O)O—;

R 5 is selected from

hydrogen,

OH,

alkyl of 1-8 carbon atoms,

alkenyl 2-8 carbon atoms,

alkynyl 2-8 carbon atoms,

alkoxy of 1-8 carbon atoms,

aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O,

heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, and

N—R 6 -R 7 ,

with the proviso that R 5 is not OH, alkoxy or N—R 6 -R 7 when R 4 C(═O)O—, and with the further proviso that R 5 is not alkyl when R 4 is alkyl, alkenyl or alkynyl;

R 6 and R 7 are independently selected from

hydrogen,

alkyl of 1-8 carbon atoms,

alkenyl of 2-4 carbon atoms, and

alkynyl of 2-8 carbon atoms,

R 8 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

R 12 -R 13 ,

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

R 9 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms, and

alkynyl of 2-8 carbon atoms;

R 10 is selected from

OH,

R 11 is benzyl which may be substituted with

alkyl of 1-6 carbon atoms,

alkenyl of 2-6 carbon atoms,

alkynyl of 2-6 carbon atoms,

halogen, and

R 14 -R 15 ;

R 12 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms, and

alkynyl of 2-8 carbon atoms;

R 13 is selected from

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon stunts and 1-2 heteroatoms selected from NH, S and O,

aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a member of halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and

R 14 is alkyl of 1-3 carbon atoms;

R 15 is cycloalkyl of 3-7 carbon atoms;

with the proviso that when R 3 is hydrogen,

R 1 and R 2 are independently selected from the group consisting of

hydrogen, with the further proviso that R 1 and R 2 are not both hydrogen,

alkyl of 1-8 carbon atoms, with the further proviso that R 1 and R 2 are not both ethyl,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

fully saturated heterocycle of 4-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, and

bornyl,

or R 1 and R 2 combine to form, together with the nitrogen atom to which they are attached,

an 8-10 membered bicyclic saturated ring;

and pharmaceutically acceptable salts thereof.

5. The compound of claim 4 , wherein

R 4 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl 2-8 carbon atoms,

C(═O), and

S(═O) 2 ;

with the proviso that when R 3 is hydrogen,

R 1 and R 2 are independently selected from the group consisting of

hydrogen, with the further proviso that R 1 and R 2 are not both hydrogen,

alkyl of 3-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

fully saturated heterocycle of 4-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, and

bornyl,

or R 1 and R 2 combine to form, together with the nitrogen atom to which they are attached, an 8-10 membered bicyclic saturated ring.

6. A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable carrier.

7. A compound according to formula III:

wherein

R 1 and R 2 are independently selected from the group consisting of

hydrogen,

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

alkoxy of 1-8 carbon atoms,

cycloalkyl of 3-7 carbon atoms, fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

R 3 is selected from the group consisting of:

hydrogen,

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

R 4 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

C(═O),

S(═O) 2 , and

C(═O)O—;

R 5 is selected from

hydrogen,

OH,

alkyl of 1-8 carbon atoms,

alkenyl 2-8 carbon atoms,

alkynyl 2-8 carbon atoms,

alkoxy of 1-8 carbon atoms,

aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O,

heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, and

N—R 6 -R 7 ,

with the proviso that R 5 is not OH, alkoxy or N—R 6 -R 1 when R 4 is C(═O)O—, and with the further proviso that R 5 is not alkyl when R 4 is alkyl, alkenyl or alkynyl;

R 6 and R 7 are independently selected from

hydrogen,

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms, and

alkynyl of 2-8 carbon atoms,

R 8 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

R 12 -R 13 ,

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

R 9 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms, and

alkynyl of 2-8 carbon atoms;

R 10 is selected from

OH,

R 11 is benzyl which may be substituted with

alkyl of 1-6 carbon atoms,

alkenyl of 2-6 carbon atom;

alkynyl of 2-6 carbon atoms,

halogen, and

R 14 -R 15 ;

R 12 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms, and

alkynyl of 2-8 carbon atoms;

R 13 is selected from

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and

R 14 is alkyl of 1-3 carbon atoms;

R 15 is cycloalkyl of 3-7 carbon atoms;

with the proviso that when R 3 is hydrogen,

R 1 and R 2 are independently selected from the group consisting of

hydrogen, with the further proviso that only one of R 1 and R 2 may be hydrogen,

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

alkoxy of 1-8 carbon atoms,

cycloalkyl of 3-7 carbon atoms,

phenyl which may be substituted from one to five times with bromine, chlorine, CH 3 , CF 3 , and

R 4 -R 5 , with the further proviso that if R 4 is methyl then R 5 may not be a five membered ring that contains oxygen as one member of the ring and that if R 4 is ethyl then R 5 may not be substituted or unsubstituted phenyl,

R 1 and R 3 combine to form, together with the nitrogen atom to which they are attached, a 6-7 membered saturated ring which may contain 1-2 additional heteroatoms selected from the group consisting of NH, NR 8 , S, and O, or combine to form, together with the nitrogen atom to which they are attached, a 6-7 membered unsaturated ring which may contain 1-2 additional heteroatoms selected from the group consisting of N, S and O,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, halogen, haloalkyl of 1-2 carbon atoms and a number of halogen atoms up to the perhalo level, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, and R 9 -R 10 ;

and pharmaceutically acceptable salts thereof.

8. The compound of claim 7 wherein

R 4 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

C(═O), and

S(═O) 2 ;

with the proviso that when R 3 is hydrogen,

R 1 and R 2 are independently selected from the group consisting of

hydrogen, with the further proviso that only one of R 1 and R 2 may be hydrogen,

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

alkoxy of 1-8 carbon atoms,

cycloalkyl of 3-7 carbon atoms, and

phenyl which may be substituted from one to five times with bromine, chlorine, CH 3 , or CF 3 ;

R 1 and R 2 combine to form, together with the nitrogen atom to which they are attached, a 6-7 membered saturated ring which may contain 1-2 additional heteroatoms selected from the group consisting of NH, NR 8 , S, and O, or combine to form, together with the nitrogen atom to which they are attached, a 6-7 membered unsaturated ring which may contain 1-2 additional heteroatoms selected from the group consisting of N, S and O,

9. A pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically acceptable carrier.

10. A compound according to the formula IV:

wherein

R 1 and R 2 are independently selected from the group consisting of

hydrogen,

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

aryl of 6-12 carbon atoms which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O,

or R 1 and combine to form, together with the nitrogen atom to which they are attached, a 5-7 membered saturated ring which may contain 1-2 additional heteroatoms selected from the group consisting of NH, NR 8 , S and O, or combine to form, together with the nitrogen atom to which they are attached, a 5-7 membered unsaturated ring which may contain 1-2 additional heteroatoms selected from the group consisting of N, S and O,

R 3 is selected from the group consisting of:

hydrogen,

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

R 4 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl 2-8 carbon atoms,

C(═O),

S(═O) 2 , and

C(═O)O—;

R 5 is selected from

hydrogen,

OH,

alkyl of 1-8 carbon atoms,

alkenyl 2-8 carbon atoms,

alkynyl 2-8 carbon atoms,

alkoxy of 1-8 carbon atoms,

aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O,

heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, and

N—R 6 -R 7 ,

with the proviso that R 5 is not OH, alkoxy or N—R 6 -R 7 when R 4 is C(═O)O—, that R 5 is not alkyl when R 4 is alkyl, alkenyl or alkynyl, and that R 5 is not a 6-membered fully saturated heterocycle having four carbon atoms and NH and O as heteroatoms when R 4 is CH 2 ;

R 6 and R 7 are independently selected from

hydrogen,

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms, and

alkynyl of 2-8 carbon atoms,

R 8 is selected from

alkyl of 4-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

R 12 -R 13 ,

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

R 9 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms, and

alkynyl of 2-8 carbon atoms;

R 10 is selected from

OH,

R 11 is selected from benzyl which may be substituted with

alkyl of 1-6 carbon atoms,

alkenyl of 2-6 carbon atoms,

alkynyl of 2-6 carbon atoms,

halogen, and

R 14 R 15 ;

R 12 is selected from

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms, and

alkynyl of 2-8 carbon atoms;

R 13 is selected from

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

R 14 is alkyl of 1-3 carbon atoms;

R 15 is cycloalkyl of 3-7 carbon atoms;

with the proviso that when R 3 is hydrogen,

R 1 and R 2 are independently selected from

hydrogen, with the further proviso that only one of R 1 and R 2 may be hydrogen,

CH 2 —CH 2 —N(CH 2 CH 3 ) 2 ,

CH 2 —CH 2 SCH 3 ,

bornyl, and

or R 1 and R 2 combine to form, together with the nitrogen atom to which they are attached, a six membered saturated ring which may contain 1-2 sulfur atoms,

wherein said ring may be substituted with 1-2 substituents selected from the group consisting of alkyl of 2-8 carbon atoms, OH, CH 2 OH;

or R 1 and R 2 combine to form, together with the nitrogen atom to which they are attached, a five membered saturated ring which also contains 1-2 sulfur atoms,

or R 1 and R 2 combine to form, together with the nitrogen atom to which they are attached, an 8-10 membered bicyclic saturated ring;

with the further proviso that when R 3 is methyl,

R 1 and R 2 are independently selected from the group consisting of

hydrogen,

alkyl of 1-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

cycloalkyl of 3-7 carbon atoms, and

bornyl;

with the further proviso that when R 3 is hydrogen or C 2 -C 4 alkyl, then R 1 and R 2 may not combine to form a morpholino, piperidino, or piperazinyl group;

and pharmaceutically acceptable salts thereof.

11. The compound of claim 10 , wherein

R 3 is selected from the group consisting of:

alkyl of 2-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl of 2-8 carbon atoms,

cycloalkyl of 3-7 carbon atoms,

fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

R 4 is selected from

alkyl of 2-8 carbon atoms,

alkenyl of 2-8 carbon atoms,

alkynyl 2-8 carbon atoms,

C(═O), and

S(═O) 2 ,

with the proviso that when R 3 is C 2 -C 4 alkyl, then R 1 and R 2 may not combine to form a morpholino, piperidino, or piperazinyl group.

12. A pharmaceutical composition comprising the compound of claim 10 and a pharmaceutically acceptable carrier.

Assignments (5)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 1, 2013

From: BAYER PHARMA AKTIENGESELLSCHAFT

To: BAYER INTELLECTUAL PROPERTY GMBH

Reel/Frame 029908/0437 →

MERGER Recorded Jan 12, 2010

From: BAYER HEALTHCARE AG

To: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT

Reel/Frame 023769/0122 →

NUNC PRO TUNC ASSIGNMENT Recorded Dec 4, 2009

From: BAYER PHARMACEUTICALS CORPORATION

To: BAYER HEALTHCARE AG

Reel/Frame 023605/0562 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 3, 2004

From: BAYER CORPORATION

To: BAYER PHARMACEUTICALS CORPORATION

Reel/Frame 015104/0137 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 7, 2002

From: STOLLE, ANDREAS; BIERER, DONALD E.; CHEN, YUANWEI; FAN, DONGPING; HART, BARRY; MONAHAN, MARY KATHERINE; SCOTT, WILLIAM J.

To: BAYER CORPORATION

Reel/Frame 013160/0294 →