IP Library › Granted Patent US 7,067,529

Granted Patent B2

US 7,067,529 · App. 10/827,514 · Granted Jun 27, 2006

Glutamine fructose-y-phosphate amidotransferase (GFAT) inhibitors

Assignee: Hoffmann-La Roche Inc.

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 7,067,529
App. No.: 10/827,514
Granted: Jun 27, 2006
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Compounds of formula I are provided as well as pharmaceutically acceptable salts and esters thereof, wherein the substituents are as disclosed in the specification. The compounds have utility for the treatment of type 2 diabetes mellitus.

Claims (201)

1. A compound of formula (I):

wherein

R 1 is -lower alkyl, —CH 2 -aryl, -cycloalkyl, —(CH 2 ) 3 —OC(═O)CH 3 , -lower alcohol, -lower alkyl-R 10 , —CH 2 COOH, or —CH 2 CH 2 OCH 2 CH 3 ;

R 2 is -lower alkyl, —CH 2 -aryl, -lower alcohol, —CH 2 C(═O)NH 2 , or -lower alkyl-R 10 , wherein at least one of R 1 or R 2 is —CH 3 ;

R 3 is —COOH, -lower alkyl-COOH, -lower alcohol, —CH 2 OCH 3 , —CH 2 NH 2 , —CH 2 NHSO 2 R 11 , —C(═O)R 12 , —CNHCH 2 CH 2 —R 12 , —C(═NH)—R 12 , —(CH 2 ) n NHC(═O)R 13 , —(CH 2 ) m C(═O)N(R 15 )(R 16 ), —C(═NH)—R 17 , or —(CH 2 ) n —R 18 ;

R 4 is —H, -lower alkoxy, —O—C(R 7 R 8 )C(═O)R 19 , -halo, —SCH 3 , —C═CHC(═O)—R 10 , —CH 2 CH 2 C(═O)—R 10 , —O-lower alcohol, —OCH 2 CH(OH)CH 2 N═N + N − , —OCH 2 CH 2 OCH 2 CH 2 Cl, —NHC(═O)CH 2 —R 10 , —NHC(═O)CH 2 -lower alkyl, —O(CH 2 ) n -cycloalkyl, —O-lower alkene, or a 5 membered unsaturated heterocyclic ring containing one hetero atom which is S or O;

R 5 and R 6 are each independently —H, -halo or -lower alkoxy;

R 7 and R 8 are each independently —H or —CH 3 ,

R 10 is a 5 or 6 membered saturated heterocyclyl containing 1 or 2 heteroatoms, wherein each hetero atom is selected from N and O, and the group is bound to the remainder of the molecule at a ring N;

R 11 is —CF 3 , -lower alkyl, —CH 2 Cl, —CH 2 CF 3 , or —R 12 ;

R 12 is a 5 or 6 membered saturated substituted or unsubstituted heterocyclic ring containing one hetero atom which is selected from N, O, and S wherein the substituted ring is the heterocyclic ring substituted with —OH or -phenyl;

R 13 is -lower alkyl, -lower alkoxy, or —(CH 2 ) n R 14 ;

R 14 is a 5 or 6 membered saturated or unsaturated heterocyclic ring containing one or two hetero atoms which are selected from N and O;

R 15 is —H or —CH 3 ;

R 16 is —H, -lower alkyl, —C≡N, —OH, -lower alkoxy, or —CH 2 COOCH 2 CH 3 ;

R 17 is -lower alkoxy —NH 2 or —N-lower alkyl;

R 18 is a saturated or unsaturated 5 membered substituted or unsubstituted heterocyclic ring containing from 1 to 4 hetero atoms wherein the hetero atoms are selected from N, O and S, wherein the substituted ring is the heterocyclic ring which is substituted at one or two ring carbons with ═O, or substituted at a ring N with -lower alcohol or -lower alkyl;

R 19 is —OH, —NHCH(CH 3 ) 2 , —N(CH 3 )CH 2 -aryl, —N(CH 3 )-lower alkyl,

or 5 or 6 membered saturated substituted or an unsubstituted heterocyclyl containing 1 or 2 heteroatoms wherein each heteroatom is independently selected from N, O and S, wherein said substituted heterocyclyl is the heterocyclyl substituted with lower alkyl;

m is 0, 1 or 2;

n is 0 or 1;

and pharmaceutically acceptable salts and esters thereof.

2. The compound according to claim 1 , wherein R 4 is —O-lower alkyl, —O—C(R 7 R 8 )C(═O)R 19 , -halo, —SCH 3 , —C═CHC(═O)—R 10 , —CH 2 CH 2 C(═O)—R 10 , —O-lower alcohol, —OCH 2 CH(OH)CH 2 N═N + N − , —OCH 2 CH 2 OCH 2 CH 2 Cl, —NHC(═O)CH 2 —R 10 , —NHC(═O)CH 2 -lower alkyl, —O(CH 2 ) n -cycloalkyl, —O-lower alkene, or a 5 membered unsaturated heterocyclic ring containing one hetero atom which is S or O.

3. The compound according to claim 1 , wherein R 4 , R 5 and R 6 are each —H, and R 1 and R 2 are each —CH 3 .

4. The compound according to claim 1 , wherein R 4 , R 5 and R 6 are each —H, and R 3 is —COOH.

5. The compound according to claim 1 , wherein the compound is selected from:

2-[6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinolin-4-yl]-acetamide (Example 8);

3-[1-(3-Isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-propionamid (Example 11);

(4-Aminomethyl-6,7-dimethoxy-isoquinolin-1-yl)-(3-isopropoxy-phenyl)-methanone (Example 13);

2-[1-(3-Isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetamide (Example 25);

(4-Aminomethyl-6,7-dimethoxy-isoquinolin-1-yl)-(2-fluoro-5-methoxy-phenyl)-methanone (Example 27);

1-(2,6-Difluoro-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (Example 33);

N-[1-(2,6-Difluoro-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-C,C,C-trifluoro-methanesulfonamide (Example 34);

6,7-Dimethoxy-1-[3-(3-oxo-3-pyrrolidin-1-yl-propenyl)-benzoyl]-isoquinoline-4-carboxylic acid (Example 35);

6,7-Dimethoxy-1-{3-[(1-phenyl-ethylcarbamoyl)-methoxy]-benzoyl}-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 39);

6,7-Dimethoxy-1-{3-[(1-phenyl-ethylcarbamoyl)-methoxy]-benzoyl}-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 42);

1-[3-(1-Isopropylcarbamoyl-1-methyl-ethoxy)-benzoyl]-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 47);

1-(3-Furan-2-yl-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 49);

6,7-Dimethoxy-1-(3-thiophen-3-yl-benzoyl)-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 50);

(2-Fluoro-5-isopropoxy-phenyl)-[4-(2-hydroxy-ethyl)-6,7-dimethoxy-isoquinolin-1-yl]-methanone (Example 53);

7-Benzyloxy-6-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (Example 62);

7-(2-Hydroxy-ethoxy)-6-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (Example 64);

7-Carbamoylmethoxy-6-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (Example 65);

6-Methoxy-1-(3-methoxy-benzoyl)-7-(2-pyrrolidin-1-yl-ethoxy)-isoquinoline-4-carboxylic acid hydrochloride (Example 66);

6-Benzyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (Example 67);

6-Cyclopentyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (Example 69);

6-(3-Acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (Example 70);

6-(3-Hydroxy-propoxy)-1-(3-isopropoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid; compound with trifluoroacetic acid (Example 71);

6-Carboxymethoxy-1-(3-isopropoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid (Example 73);

6-(3-Acetoxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid (Example 74);

1-(3-Ethoxy-benzoyl)-6-(2-ethoxy-ethoxy)-7-methoxy-isoquinoline-4-carboxylic acid (Example 76);

1-(3-Ethoxy-benzoyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carboxylic acid (Example 77);

6,7-Dimethoxy-1-(3-methylsulfanyl-benzoyl)-isoquinoline-4-carboxylic acid; compound with trifluoroacetic acid (Example 80);

1-(3-Ethoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboximidic acid ethyl ester, hydrochloride salt (Example 87A);

1-(3-Ethoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid amide, hydrochloride salt (Example 87B);

1-(3-Ethoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxamidine, trifluoroacetic acid salt (Example 88);

(3-Ethoxy-phenyl)-[4-(imino-morpholin-4-yl-methyl)-6,7-dimethoxy-isoquinolin-1-yl]-methanone, trifluoroacetic acid salt (Example 90);

1-(3-Ethoxy-benzoyl)-6,7-dimethoxy-N,N-dimethyl-isoquinoline-4-carboxamidine, trifluoroacetic acid salt (Example 91);

1-(3-Ethoxy-benzoyl)-6,7-dimethoxy-N,N-dimethyl-isoquinoline-4-carboxamidine, trifluoroacetic acid salt (Example 92);

rac-[3-(3-Azido-2-hydroxy-propoxy)-phenyl]-[6,7-dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-methanone, trifluoroacetic acid salt (Example 94);

(3-Cyclopentyloxy-4-methoxy-phenyl)-[6,7-dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-methanone, trifluoroacetic acid salt (Example 95);

(3-Allyloxy-phenyl)-[6,7-dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-methanone, trifluoroacetic acid salt (Example 97);

(3-But-2-enyloxy-phenyl)-[6,7-dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-methanone, trifluoroacetic acid salt (Example 98);

(3-Cyclopentyloxy-phenyl)-[6,7-dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-methanone, trifluoroacetic acid salt (Example 99);

(3-Cyclopropylmethoxy-phenyl)-[6,7-dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-methanone, trifluoroacetic acid salt (Example 100);

(3-Cycloheptyloxy-phenyl)-[6,7-dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-methanone, trifluoroacetic acid salt (Example 101);

1-(3-hydroxyethoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (Example 102);

1-{3-[2-(2-Chloro-ethoxy)-ethoxy]-benzoyl}-6,7-dimethoxy-isoquinoline-4-carboxylic acid, trifluoroacetic acid salt (Example 103);

1-(3,5-Dimethoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid, trifluoroacetic acid salt (Example 104);

6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (Example 106);

6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (2-cyano-ethyl)-amide (Example 107);

6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid hydroxyamide (Example 108);

6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid methoxy-amide (Example 109);

6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid methoxy-methyl-amide (Example 110);

(4-Hydroxymethyl-6,7-dimethoxy-isoquinolin-1-yl)-(3-isopropoxy-phenyl)-methanone (Example 111);

6,7-Dimethoxy-1-(3-methoxy-5-methyl-benzoyl)-isoquinoline-4-carboxylic acid (Example 112);

[4-(4-Hydroxy-4-phenyl-piperidine-1-carbonyl)-6,7-dimethoxy-isoquinolin-1-yl]-(3-methoxy-phenyl)-methanone (Example 113);

{[6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbonyl]-amino}-acetic acid ethyl ester (Example 114);

[4-(4-Hydroxy-piperidine-1-carbonyl)-6,7-dimethoxy-isoquinolin-1-yl]-(3-methoxy-phenyl)-methanone (Example 115);

6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid amide (Example 117);

(4-Hydroxymethyl-6,7-dimethoxy-isoquinolin-1-yl)-(3-methoxy-phenyl)-methanone (Example 118);

(6,7-Dimethoxy-4-methoxymethyl-isoquinolin-1-yl)-(3-methoxy-phenyl)-methanone (Example 119);

6,7-Dimethoxy-1-[3-(2-morpholin-4-yl-acetylamino)-benzoyl]-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 120);

6,7-Dimethoxy-1-[3-(2-pyrrolidin-1-yl-acetylamino)-benzoyl]-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 121); and

1-(3-Butyrylamino-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (Example 122).

6. A compound of formula (1),

wherein

R 1 and R 2 are each independently -lower alkyl or -lower alkyl-R 10 , wherein at least one of R 1 or R 2 is —CH 3 ;

R 3 is —COOH, -lower alkyl-COOH, —(CH 2 ) n NHC(═O)R 13 , —H 2 NHSO 2 R 11 , or —CH 2 ) n —R 18 ;

R 4 is -lower alkoxy or —OC(R 7 R 8 )C(═O)R 19 ;

R 5 and R 6 are each independently —H or -halo;

R 7 and R 8 are each independently —H or —CH 3 ,

R 10 is a 5 or 6 membered saturated heterocyclyl containing 1 or 2 heteroatoms, wherein each hetero atom is selected from N and O, and the group is bound to the remainder of the molecule at a ring N;

R 11 is —CF 3 , -lower alkyl, —CH 2 Cl, —CH 2 CF 3 , or —R 12 ;

R 13 is -lower alkyl, -lower alkoxy, or —(CH 2 ) n R 14 ;

R 14 is a 5 or 6 membered saturated or unsaturated heterocyclic ring containing one or two hetero atoms which are selected from N and O;

R 19 is —OH, —NHCH(CH 3 ) 2 , —N(CH 3 )CH 2 -aryl, —N(CH 3 )-lower alkyl,

m is 0, 1 or 2;

n is 0 or 1;

and pharmaceutically acceptable salts and esters thereof.

7. The compound according to claim 6 , wherein R 7 and R 8 are each —CH 3 .

8. The compound according to claim 6 , wherein R 10 is —CH 2 CH 2 — morpholinyl and the morpholinyl is bound at a ring N.

9. The compound according to claim 6 , wherein R 11 is —CF 3 .

10. The compound according to claim 6 , wherein R 19 is —NHCH(CH 3 ) 2 .

11. The compound according to claim 6 , wherein R 3 is —CH 2 ) n NHC(═O)R 13 , and n is 1.

12. The compound according to claim 6 , wherein R 3 is —(CH 2 ) n NHC(═O)R 13 , and R 13 is —CH 3 .

13. The compound according to claim 6 , wherein R 3 is —(CH 2 ) n —R 18 and R 18 is an unsaturated 5 membered substituted or unsubstituted heterocyclic ring containing from 2 to 4 hetero atoms which are each N, wherein the substituted ring is the heterocyclic ring which is substituted at a ring N with -lower alkyl or -lower alcohol, and n is 0.

14. The compound according to claim 13 , wherein R 18 is tetrazole or substituted tetrazole.

15. The compound according to claim 6 , wherein the compound is selected from

1-(2,6-Difluoro-3-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid;

1-(3-sec-Butoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid;

1-(3-Isopropoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid;

N-[1-(3-Isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-acetamide;

1-[3-(1-Isopropylcarbamoyl-1-methyl-ethoxy)-benzoyl]-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid;

C,C,C-Trifluoro-N-[1-(2-fluoro-5-methoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-methanesulfonamide;

6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid;

[6,7-Dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-(3-ethoxy-phenyl)-methanone; compound, trifluoroacetic acid salt;

2-[1-(2-Fluoro-5-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-4-methyl-pentanoic acid; compound with trifluoro-acetic acid;

N-[1-(3-Isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-nicotinamide;

[6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinolin-4-yl]-acetic acid;

1-(3-Butoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid;

1-(3-Ethoxy-benzoyl)-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-isoquinoline-4-carboxylic acid hydrochloride (Example 79);

C,C,C-Trifluoro-N-[1-(3-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-methanesulfonamide (Example 23);

6,7-Dimethoxy-1-[3-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzoyl]-isoquinoline-4-carboxylic acid (Example 1);

6,7-Dimethoxy-1-{3-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethoxy]-benzoyl}-isoquinoline-4-carboxylic acid (Example 2);

6,7-Dimethoxy-1-[3-(2-morpholin-4-yl-2-oxo-ethoxy)-benzoyl]-isoquinoline-4-carboxylic acid (Example 3);

1-{3-[(Benzyl-methyl-carbamoyl)-methoxy]-benzoyl}-6,7-dimethoxy-isoquinoline-4-carboxylic acid (Example 4);

1-{3-[2-(4-Benzyl-piperazin-1-yl)-2-oxo-ethoxy]-benzoyl}-6,7-dimethoxy-isoquinoline-4-carboxylic acid (Example 5);

1-(3-Carboxymethoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (Example 6);

N-[1-(3-Isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetamide (Example 12);

Pyrazine-2-carboxylic acid [1-(3-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-amide (Example 16);

N-[1-(3-Isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-2-pyridin-3-yl-acetamide (Example 17);

3H-Imidazole-4-carboxylic acid [1-(3-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-amide (Example 18);

N-[1-(3-Isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-isonicotinamide (Example 19);

Morpholine-4-carboxylic acid [1-(3-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-amide (Example 20);

N-[1-(3-Isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-methanesulfonamide (Example 21);

Ethanesulfonic acid [1-(3-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-amide (Example 22);

[1-(3-Isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid (Example 24);

1-(2-Fluoro-5-methoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (Example 26);

N-[1-(2-Fluoro-5-methoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-methanesulfonamide (Example 28);

1-(2-Fluoro-5-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (Example 30);

[1-(2-Fluoro-5-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid (Example 31);

2-[1-(2-Fluoro-5-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-propionic acid (Example 32);

6,7-Dimethoxy-1-[3-(3-oxo-3-pyrrolidin-1-yl-propyl)-benzoyl]-isoquinoline-4-carboxylic acid (Example 36);

1-[3-(Isopropylcarbamoyl-methoxy)-benzoyl]-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 37);

6,7-Dimethoxy-1-[3-(2-oxo-2-thiomorpholin-4-yl-ethoxy)-benzoyl]-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 38);

1-{3-[(Ethyl-methyl-carbamoyl)-methoxy]-benzoyl}-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 40);

6,7-Dimethoxy-1-{3-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethoxy]-benzoyl}-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 41);

1-(3-Isobutoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 43);

1-[3-(1,1-Dimethyl-2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzoyl]-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 45);

1-(3-Butoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (Example 48);

2-[1-(3-Isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-[1,2,4]oxadiazolidine-3,5-dione; compound with trifluoro-acetic acid (Example 51);

3-[1-(3-Isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-thiazolidine-2,4-dione; compound with trifluoro-acetic acid (Example 52);

2-[1-(2-Fluoro-5-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-4-methyl-pentanoic acid; compound with trifluoro-acetic acid (Example 54);

1-(2,6-Difluoro-3-methoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 55);

[6,7-Dimethoxy-4-(1H-tetrazol-5-ylmethyl)-isoquinolin-1-yl]-(2-fluoro-5-methoxy-phenyl)-methanone (Example 57);

7-Butoxy-6-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (Example 63);

6-Butoxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (Example 68);

1-(3-Isopropoxy-benzoyl)-7-methoxy-6-(2-pyrrolidin-1-yl-ethoxy)-isoquinoline-4-carboxylic acid hydrochloride (Example 72);

6-(3-Acetoxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid hydrochloride (Example 75);

1-(3-Ethoxy-benzoyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carboxylic acid (Example 78);

1-(3-Ethoxy-benzoyl)-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-isoquinoline-4-carboxylic acid hydrochloride (Example 79);

[1-(3-sec-Butoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid; 1:1 trifluoro-acetic acid (Example 81);

1-(3-Ethoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (Example 84);

(3-Ethoxy-phenyl)-{4-[1-(2-hydroxy-ethyl)-1H-tetrazol-5-yl]-6,7-dimethoxy-isoquinolin-1-yl}-methanone, trifluoroacetic acid salt (Example 85A);

(3-Ethoxy-phenyl)-{4-[2-(2-hydroxy-ethyl)-1H-tetrazol-5-yl]-6,7-dimethoxy-isoquinolin-1-yl}-methanone, trifluoroacetic acid salt (Example 85B);

[6,7-Dimethoxy-4-(1-methyl-1H-tetrazol-5-yl)-isoquinolin-1-yl]-(3-ethoxy-phenyl)-methanone, trifluoroacetic acid salt (Example 86);

[4-(4,5-Dihydro-1H-imidazol-2-yl)-6,7-dimethoxy-isoquinolin-1-yl]-(3-ethoxy-phenyl)-methanone, trifluoroacetic acid salt (Example 89);

[6,7-Dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-[3-(2-hydroxy-ethoxy)-phenyl]-methanone, trifluoroacetic acid salt (Example 93);

[6,7-Dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-(3-isopropoxy-phenyl)-methanone, trifluoroacetic acid salt (Example 96);

N-[1-(3-sec-Butoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-C,C,C-trifluoro-methanesulfonamide (Example 105);

(6,7-Dimethoxy-4-pyrrolidin-1-ylmethyl-isoquinolin-1-yl)-(3-methoxy-phenyl)-methanone (Example 116);

N-[6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinolin-4-yl]-acetamide, hydrochloride salt (Example 123);

[6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinolin-4-yl]-carbamic acid methyl ester; compound with trifluoro-acetic acid (Example 124);

C-Chloro-N-[1-(3-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-methanesulfonamide, hydrochloride salt (Example 125);

Thiophene-2-sulfonic acid [1-(3-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-amide (Example 126); and

2,2,2-Trifluoro-ethanesulfonic acid [1-(3-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-amide (Example 127).

16. The compound according to claim 15 , wherein the compound is selected from