KR20060136457A - Pyrrole-derivatives as factor Xa inhibitors - Google Patents

Abstract

The present invention relates to compounds of formula (I) and (Ia).

Formula I

Formula Ia

In the above formulas I and Ia,

R ⁰ , R ¹ , R 3, R 4, R 22, Q, V, G and M have the meanings set forth in the claims.

Compounds of formulas (I) and (Ia) are valuable pharmacologically active compounds. They exhibit strong antithrombotic effects and are suitable for the treatment and prevention of cardiovascular disorders such as, for example, thromboembolic diseases or restenosis. These are reversible inhibitors of the blood coagulation enzyme factor Xa (FXa) and / or factor VIIa (FVIIa), and in general there is an undesired activity of factor Xa and / or factor VIIa or factor Xa and / or factor for treatment or prevention Inhibition of VIIa can be used in conditions where it is necessary. The invention also relates to a process for the preparation of the compounds of the formulas (I) and (Ia), in particular the use thereof as an active ingredient of a medicament and a pharmaceutical preparation comprising the same.

Blood coagulation, FXa, FVIIa, fibrinolysis, antithrombosis

Description

Pyrrole-derivatives as factor Xa inhibitors

The present invention relates to compounds of formula (I) and (Ia).

In the above formulas I and Ia,

R ⁰ , R ¹ , R 3, R 4, R 22, Q, V, G and M have the meanings described below.

Compounds of formulas (I) and (Ia) are valuable pharmacologically active compounds. They exhibit strong antithrombotic effects and are suitable for the treatment and prevention of cardiovascular disorders such as, for example, thromboembolic diseases or restenosis. These are reversible inhibitors of the blood coagulation enzyme factor Xa (FXa) and / or factor VIIa (FVIIa), and in general there is an undesired activity of factor Xa and / or factor VIIa or factor Xa and / or factor for treatment or prevention Inhibition of VIIa can be used in conditions where it is necessary. The invention also relates to a process for the preparation of the compounds of the formulas (I) and (Ia), in particular its use as an active ingredient of a medicament and a pharmaceutical preparation comprising the same.

Normal hemostasis is the result of a complex balance in the process of initiation, formation and clot dissolution. In the absence of damage and blood loss, the complex interaction between blood cells, specific plasma proteins and blood vessel surfaces maintains the flow of blood (EP-A-987274). Many distinct diseases described are associated with abnormal hemostasis. For example, local thrombus formation due to rupture of atherosclerotic plaques is a major cause of acute myocardial infarction and unstable angina. Treatment of closed coronary thrombi by thrombolytic or percutaneous angioplasty can be achieved by acute thrombolytic reclosure of the diseased vessel.

There is a continuing need for safe and effective therapeutic anticoagulants to limit or prevent thrombus formation. It is most desirable to develop coagulation inhibitors that do not directly inhibit thrombin but inhibit other stages of the coagulation cascade, such as factor Xa and / or factor VIIa activity. Currently, inhibitors of factor Xa are believed to have a lower risk of bleeding than thrombin inhibitors (A. E. P. Adang & J. B. M. Rewinkel, Drugs of the Future 2000, 25, 369-383). Low molecular weight factor Xa-specific blood coagulation inhibitors that are effective but do not cause unwanted side effects are described, for example, in WO-A-95 / 29189. However, in addition to effective factor Xa-specific blood coagulation inhibitors, these inhibitors additionally have additional beneficial properties such as stability in plasma and liver and selectivity for other serine proteases not intended for inhibition such as thrombin. It is preferable. There is a continuing need for another low molecular weight factor Xa-specific blood clotting inhibitor that is not only effective but also has the advantages described above.

Factor VIIa / tissue factor catalyst using proteins such as monoclonal antibody (WO-A-92 / 06711) or chloromethyl ketone inactivated factor VIIa (WO-A-96 / 12800, WO-A-97 / 47651) Specific inhibition of the complex is a very effective means for controlling thrombus formation due to thrombotic complications associated with acute arterial injury or bacterial sepsis. There is also experimental evidence demonstrating that inhibition of factor VIIa / tissue factor activity inhibits restenosis after balloon angioplasty. The bleeding studies were performed in non-baboons, with the inhibition of factor VIIa / tissue factor complexes having the widest, safest window on the therapeutic effect and risk of bleeding risk of any anticoagulant approach tested, including thrombin, platelet, and factor Xa inhibition. Indicated. Certain inhibitors of factor VIIa are already known. For example, EP-A-987274 discloses compounds containing tripeptide units that inhibit factor VIIa. However, the property profile of these compounds is still not ideal, and there is a continuing need for other low molecular weight blood clotting inhibitors that inhibit factor VIIa.

The present invention satisfies this need by providing novel compounds of formulas (I) and (Ia), which are preferred agents which exhibit good factor Xa and / or factor VIIa inhibitory activity and have high bioavailability.

Accordingly, the present invention relates to compounds of formulas (I) and (Ia), all stereoisomeric forms thereof, mixtures thereof in any proportion and physiologically acceptable salts thereof.

Formula I

Formula Ia

In the above formulas I and Ia,

R ⁰ is

1) monocyclic or bicyclic 6 to 14 membered aryl, wherein the aryl is independently mono-, di- or tri-substituted with R 8,

2) monocyclic or bisy selected from the group pyridinyl, pyrimidinyl, indolyl, isoindoleyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, benzothiophene, quinazolinyl and phenylpyridyl 4-15 membered heterocyclyl, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R8; or

3) monocyclic or bicyclic 4 to 15 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the heterocyclyl is unsubstituted or independently of one another Mono-, di- or tri-substituted and further substituted with monocyclic or bicyclic 4 to 15 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, Wherein heterocyclyl is unsubstituted or independently of one another is mono-, di-, or tri-substituted with R 8),

R8 is

1) halogen,

2) -NO ₂ ,

3) -OH,

4) -O-CF ₃

5) aryl monocyclic or bicyclic 6- to 14-membered (wherein aryl is independently from each other halogen or -O- (C ₁ -C ₈₎ - is a substituted mono-, di- or tri-alkyl),

6)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -OH or methoxy moieties,

_{7) -O- (C 1 -C 8} ) - alkyl (wherein alkyl is optionally substituted mono-, di or tri halogen, NH _2, -OH or a methoxy residue is optionally substituted independently from each other),

8) -SO ₂ -CH ₃ or

9) -SO ₂ -CF ₃ ,

Provided that when R ⁰ is a monocyclic or bicyclic 6 to 14 membered aryl, R 8 is at least one halogen or —O— (C ₁ -C ₈ ) -alkyl moiety,

Q is-(C ₀ -C ₂ ) -alkylene-C (O) -NR ^10- , -NR ¹⁰ -C (O) -NR ^10- , -NR ¹⁰ -C (O)-,-(C ₁ -C ₆ ) -alkylene,-(CH ₂ ) _m -NR ¹⁰ -C (O) -NR ^10- (CH ₂ ) _n - _, -(CH ₂ ) _m -NR ¹⁰ -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _m -S- (CH ₂ ) _n -,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _m -SO _2- NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO ₂ -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -CH (OH)-(CH ₂ ) _n -,-(CH ₂ ) _m -OC (O) -NR ^10- (CH ₂ ) _n -,-(C ₂ -C ₃ ) -alkylene-O- (C ₀ -C ₃ ) -alkylene-,-(C ₂ -C ₃ ) -alkylene-S (O)-,-(C ₂ -C ₃ ) -alkylene- S (O) ₂ -,-(CH ₂ ) _m -NR ¹⁰ -C (O) -O- (CH ₂ ) _n -,-(C ₂ -C ₃ ) -alkylene-S (O) ₂ -NH -(R ¹⁰ )-,-(C ₂ -C ₃ ) -alkylene-N (R ¹⁰ )-or-(C ₀ -C ₃ ) -alkylene-C (O) -O- (CH ₂ ) _m -ego,

Wherein R ¹⁰ is as defined below, n and m are the same or different integers, independently of one another, 0, 1, 2, 3, 4, 5 or 6, and-(CH ₂ ) _m -or-(CH ₂ ) _n The alkylene moiety formed by-is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -NH ₂ or -OH, or-(C ₃ -C ₆ ) -cycloalkylene, wherein cycloalkylene Are unsubstituted or independently of each other mono-, di- or tri-substituted with halogen, -NH ₂ or -OH,

R ¹ is a hydrogen atom, — (C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or substituted 1-3 times with R 13; - (C ₁ -C ₃₎ - alkylene ^{-C (O) -NH-R 0} , - (C 1 -C 3) - alkylene -C (O) -OR ^10, monocyclic or bicyclic 6 To 14 membered aryl, wherein the aryl is independently mono-, di- or tri-substituted with R 8, wherein R 8 is as described; Monocyclic or bicyclic 4 to 15 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen; - (C ₁ -C ₃₎ - _{perfluoroalkyl-alkylene, - (C 1 -C 3)} - alkylene _{-S (O) - (C 1} -C 4) - alkyl, - (C ₁ -C ₃₎ - alkylene _{-S (O) 2 - (C} 1 -C 3) - _{alkyl, - (C 1 -C 3)} - alkylene _{-S (O) 2 -N (R} 4 ') -R 5', - (C ₁ -C ₃ ) -alkylene-O- (C ₁ -C ₄ ) -alkyl,-(C ₀ -C ₃ ) -alkylene- (C ₃ -C ₈ ) -cycloalkyl or-(C ₀ -C ₃ ) -alkylene-het wherein het is a 3-7 membered cyclic moiety containing one, two, three or four or more heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic moiety is a substitution Or mono-, di-, or tri-substituted with R 14 independently of one another;

R ^{4 '} and R ^5' are the same or different independently from each other, and are a hydrogen atom or-(C ₁ -C ₄ ) -alkyl,

R ¹ and R 22 together with the atoms bonded to them may form a 6-8 membered cyclic group containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic group Are unsubstituted or independently of each other mono-, di-, or tri-substituted with R 14,

R ¹ -NV can form a 4-8 membered cyclic group containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic groups are unsubstituted or independently of one another Mono-, di- or tri-substituted with R 14,

R 14 is halogen, —OH, ═O, — (C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₄ ) -alkoxy, -NO ₂ ,-(C ₀ -C ₄ ) -alkyl-C (O ) -OR ¹⁸ , -CN,-(C ₀ -C ₄ ) -alkyl-N (R ¹⁸ ) -R ²¹ ,-(C ₀ -C ₄ ) -alkyl-OR ¹⁸ ,-(C ₀ -C ₄ ) -Alkyl-het,-(C ₀ -C ₈ ) -alkyl-SO _2- (C ₁ -C ₄ ) -alkyl,-(C ₀ -C ₈ ) -alkyl-SO _2- (C ₁ -C ₃ ) -Perfluoroalkyl,-(C ₀ -C ₈ ) -alkyl-SO ₂ -N (R ¹⁸ ) -R ²¹ , -C (O) -NH- (C ₁ -C ₈ ) -alkyl, -C ( O) -N - [(-C ₁ C ₈₎ - alkyl] _2, -NR ¹⁸ -C (O) -NH- (-C ₁ C ₈₎ - _{alkyl, -C (O) -NH 2,} -SR and - [alkyl _{(C 1 -C 8) -]} 2, 18 , or -NR ¹⁸ -C (O) -NH

Wherein R ¹⁸ and R ²¹ independently of one another are a hydrogen atom,-(C ₁ -C ₃ ) -perfluoroalkyl or-(C ₁ -C ₆ ) -alkyl,

V is

1) a 3 to 7 membered cyclic moiety containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic moieties are unsubstituted or independently of each other mono-, di- or tri- Is substituted) or

2) monocyclic or bicyclic 4 to 15 membered heterocyclyl, wherein the heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

G is a direct bond,-(CH ₂ ) _m -NR ¹⁰ -SO ₂ -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -CH (OH)-(CH ₂ ) _n -,-(CH ₂ ) _m -,-(CH ₂ ) _m -O- (CH ₂ ) _n -,-(CH ₂ ) _m -C (O) -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -C (O) -NR ^10- (CH ₂ ) _n - _, -(CH ₂ ) _m -NR ¹⁰ -C (O)-( CH ₂ ) _n -,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -,-(CH ₂ ) -S- (CH ₂ ) _n -,-(CH ₂ ) _m -SO _2- NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -,-(CH ₂ ) _m -OC ( O) -NR ^10- (CH ₂ ) _n -or-(CH ₂ ) _m -NR ¹⁰ -C (O) -O- (CH ₂ ) _n- ,

n and m are independently of each other the same or different integers 0, 1, 2, 3, 4, 5 or 6,

M is

1) hydrogen atom,

2)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another substituted, di- or tri-substituted by R 14,

3) -C (O) -N (R11) -R12,

4)-(CH ₂ ) _m -NR ¹⁰ ,

5) 6-14 membered aryl, wherein aryl is unsubstituted or independently of one another mono-, di- or tri-substituted by R14,

6) monocyclic or bicyclic 4-15 membered heterocyclyl, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

7)-(C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 14 or

8) 3 to 7 membered cyclic moieties containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic moieties are unsubstituted or independently of each other mono-, di- or tri- Substituted, wherein R14 is as described),

R3, R4 and R22 are the same or different independently from each other,

1) hydrogen atom,

2) halogen,

3)-(C ₁ -C ₄ ) -alkyl wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

_{4) - (C 1 -C 3} ) - alkyl, perfluoroalkyl,

5) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 13,

6)-(C ₀ -C ₄ ) -alkylene-O-R 19, where R 19 is a) a hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another Mono-, di-, or tri-substituted); c) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13; d) -CF ₃ or e) -CHF ₂ ],

7) -NO ₂ ,

8) -CN,

9) -SO _s -R ¹¹ (where s is 1 or 2),

10) -SO _t -N (R ¹¹ ) -R ¹² , where t is 1 or 2,

11)-(C ₀ -C ₄ ) -alkylene-C (O) —R ¹¹ ,

12)-(C ₀ -C ₄ ) -alkylene-C (O) —OR ¹¹ ,

13)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹² ,

14)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹² ,

15) -NR ¹⁰ -SO ₂ -R ¹⁰ ,

16) -SR ¹⁰ ,

17)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O)-(C ₁ -C ₄ ) -alkyl,

18) -C (O) -O-C (R15, R16) -O-C (O) -R17,

19)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O) -O- (C ₁ -C ₆ ) -alkyl,

20) -C (O) -O-C (R15, R16) -O-C (O) -O-R17,

21)-(C ₀ -C ₄ ) -alkylene- (C ₆ -C ₁₄ ) -aryl, wherein aryl is independently mono-, di-, or tri-substituted with R 13,

22)-(C ₀ -C ₄ ) -alkylene- (C ₄ -C ₁₅ ) -heterocyclyl, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

23)-(C ₀ -C ₄ ) -alkylene- (C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

24)-(C ₀ -C ₄ ) -alkylene-het wherein het is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

25)-(C ₀ -C ₄ ) -alkylene-O-CH _2- (C ₁ -C ₃ ) -perfluoroalkylene-CH ₂ -O- (C ₀ -C ₄ ) -alkyl,

26) -SO _w -N (R ¹¹ ) -R ¹³ , where w is 1 or 2,

27)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹³ ,

28)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹³ or

29)

로부터의 잔기(여기서 Me은 메틸이거나, 2개의 -OR19 잔기가 인근 원자에 결합되는 경우, 이들에 결합된 원자와 함께 치환되지 않거나 R13으로 1, 2, 3 또는 4회 치환되는 5 또는 6원의 환을 형성할 수 있다)이고,

Residues from Me, wherein Me is methyl or a 5 or 6 membered moiety that is unsubstituted or substituted 1, 2, 3 or 4 times with Can form a ring),

R11 and R12 are the same or different independently from each other,

1) hydrogen atom,

2)-(C ₁ -C ₆ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

3)-(C ₀ -C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,

4) -SO _t -R ¹⁰ (where t is 1 or 2),

5)-(C ₀ -C ₆ ) -alkyl- (C ₆ -C ₁₄ ) -aryl, wherein alkyl and aryl are not substituted independently of one another or are mono-, di-, or tri-substituted with R 13,

_{6) - (C 1 -C 3} ) - alkyl, perfluoroalkyl,

7) -OR ¹⁷ or

8)-(C ₀ -C ₆ ) -alkyl- (C ₄ -C ₁₅ ) -heterocyclyl, wherein alkyl and heterocyclyl are unsubstituted independently or mono-, di- or tri-substituted with R 13 ,

R11 and R12 together with the nitrogen atom bonded thereto form a 4 to 8 membered monocyclic heterocyclic ring which may contain one or two identical or different ring heteroatoms selected from oxygen, sulfur and nitrogen in addition to nitrogen Wherein the heterocyclic ring is unsubstituted or independently of one another is mono-, di- or tri-substituted with R 13,

R4 and R22 of formula (I) and formula (Ia) may together with the carbon atoms bonded to them form a phenyl moiety,

R13 is halogen, -NO ₂ , -CN, = O, -OH, -CF ₃ , -C (O) -OR ¹⁰ , -C (O) -N (R ¹⁰ ) -R ²⁰ , -N (R ¹⁰ ) -R ²⁰ ,-(C ₃ -C ₈ ) -cycloalkyl,-(C ₀ -C ₃ ) -alkylene-OR ¹⁰ , -Si- (CH ₃ ) ₃ , -N (R ¹⁰ ) -S ( O) _u -R ¹⁰ (where u is 1 or 2), -SR ¹⁰ , -SO _r -R ¹⁰ (where r is 1 or 2), -S (O) _v -N (R ¹⁰ ) -R ²⁰ , where v is 1 or 2, -C (O) -R ¹⁰ ,-(C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₈ ) -alkoxy, phenyl, phenyloxy-, -O -CF ₃ ,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R 15, R 16) -OC (O) -R 17,-(C ₁ -C ₄ ) -alkoxyphenyl,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R 15, R 16) -OC (O) -O-R 17,-(C ₁ -C ₃ ) -perfluoroalkyl, -O-R 15, -NH- C (O) -NH-R ¹⁰ , -NH-C (O) -OR ¹⁰ or

로부터의 잔기이고,

Residues from,

R ¹⁰ and R ²⁰ independently of one another are hydrogen,-(C ₁ -C ₆ ) -alkyl,-(C ₀ -C ₄ ) -alkyl-OH,-(C ₀ -C ₄ ) -alkyl-O- (C ₁ -C ₄ ) -acyl or-(C ₁ -C ₃ ) -perfluoroalkyl,

R 15 and R 16 are independently of each other hydrogen or — (C ₁ -C ₆ ) -alkyl, a 3-6 membered carbocyclic ring which is unsubstituted or substituted one to three times with R ¹⁰ with a carbon atom bonded thereto; Can form

R17 is-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl-OH,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₆ ) -alkyl,- (C ₃ -C ₈ ) -cycloalkyl,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₈ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,-(C _1- C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted 1, 2 or 3 times with -OH, -O- (C ₁ -C ₄ ) -alkyl or R ¹⁰ is.

2) The present invention also

R ⁰ is

1) monocyclic or bicyclic 6 to 14 membered aryl, wherein the aryl is independently mono-, di- or tri-substituted with R 8,

2) monocyclic selected from the group benzothiophene, indazolyl, indolyl, isoindoleyl, isoquinolyl, phenylpyridyl, phthalazinyl, pyridyl, pyridinyl, pyrimidinyl, quinazolinyl and quinolyl Or bicyclic 4-15 membered heterocyclyl, wherein the heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 8; or

3) monocyclic or bicyclic 4 to 15 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the heterocyclyl is unsubstituted or independently of one another Mono-, di- or tri-substituted and further substituted with monocyclic or bicyclic 4 to 15 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, Wherein heterocyclyl is unsubstituted or independently of one another is mono-, di-, or tri-substituted with R 8),

R8 is

1) halogen,

2) -NO ₂ ,

3) -OH,

4) -O-CF ₃

5) aryl monocyclic or bicyclic 6- to 14-membered (wherein aryl is independently from each other halogen or -O- (C ₁ -C ₈₎ - is a substituted mono-, di- or tri-alkyl),

6)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -OH or methoxy moieties,

_{7) -O- (C 1 -C 8} ) - alkyl (wherein alkyl is optionally substituted mono-, di or tri halogen, NH _2, -OH or a methoxy residue is optionally substituted independently from each other),

8) -SO ₂ -CH ₃ or

9) -SO ₂ -CF ₃ ,

Provided that when R ⁰ is a monocyclic or bicyclic 6 to 14 membered aryl, R 8 is at least one halogen or —O— (C ₁ -C ₈ ) -alkyl moiety,

Q is-(C ₀ -C ₂ ) -alkylene-C (O) -NR ^10- , -NR ¹⁰ -C (O) -NR ^10- , -NR ¹⁰ -C (O)-,-(C ₁ -C ₆ ) -alkylene,-(CH ₂ ) _m -NR ¹⁰ -C (O) -NR ^10- (CH ₂ ) _n - _, -(CH ₂ ) _m -NR ¹⁰ -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _m -S- (CH ₂ ) _n -,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _m -SO _2- NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO ₂ -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -CH (OH)-(CH ₂ ) _n -,-(CH ₂ ) _m -OC (O) -NR ^10- (CH ₂ ) _n -,-(C ₂ -C ₃ ) -alkylene-O- (C ₀ -C ₃ ) -alkylene-,-(C ₂ -C ₃ ) -alkylene-S (O)-,-(C ₂ -C ₃ ) -alkylene- S (O) ₂ -,-(CH ₂ ) _m -NR ¹⁰ -C (O) -O- (CH ₂ ) _n -,-(C ₂ -C ₃ ) -alkylene-S (O) ₂ -NH -(R ¹⁰ )-,-(C ₂ -C ₃ ) -alkylene-N (R ¹⁰ )-or-(C ₀ -C ₃ ) -alkylene-C (O) -O- (CH ₂ ) _m -ego,

Wherein R ¹⁰ is as defined below, n and m are the same or different integers, independently of one another, 0, 1, 2, 3, 4, 5 or 6, and-(CH ₂ ) _m -or-(CH ₂ ) _n The alkylene moiety formed by-is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -NH ₂ or -OH, or-(C ₃ -C ₆ ) -cycloalkylene, wherein cycloalkylene Are unsubstituted or independently of each other mono-, di- or tri-substituted with halogen, -NH ₂ or -OH,

R ¹ is a hydrogen atom, — (C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or substituted 1-3 times with R 13; - (C ₁ -C ₃₎ - alkylene ^{-C (O) -NH-R 0} ; — (C ₁ -C ₃ ) -alkylene-C (O) —O—R 15; Monocyclic or bicyclic 6 to 14 membered aryl, wherein the aryl is independently mono-, di- or tri-substituted with R 8, wherein R 8 is as described; Monocyclic or bicyclic 4 to 15 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen; - (C ₁ -C ₃₎ - perfluoroalkyl alkylene; - (C ₁ -C ₃₎ - alkylene _{-S (O) - (C 1} -C 4) - alkyl; - (C ₁ -C ₃₎ - alkylene _{-S (O) 2 - (C} 1 -C 3) - alkyl; - (C ₁ -C ₃₎ - alkylene _{-S (O) 2 -N (R} 4 ') -R 5'; - (C ₁ -C ₃₎ - alkylene -O- (C ₁ -C ₄₎ - alkyl; -(C ₀ -C ₃ ) -alkylene- (C ₃ -C ₈ ) -cycloalkyl or-(C ₀ -C ₃ ) -alkylene-het, where het is unsubstituted or independently substituted with R 14 , Di- or tri-substituted),

R ^{4 '} and R ^5' are the same as or different from each other independently and are a hydrogen atom or-(C ₁ -C ₄ ) -alkyl,

R ¹ and R 22 together with the atoms bonded thereto may form a 6 to 8 membered cyclic group containing at least 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where cyclic The group is unsubstituted or independently of one another substituted, di- or tri-substituted by R 14,

R ¹ -NV may form a 4 to 8 membered cyclic group containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic groups are unsubstituted or independently of one another Mono-, di- or tri-substituted with R 14,

R 14 is halogen, —OH, ═O, — (C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₄ ) -alkoxy, -NO ₂ ,-(C ₀ -C ₄ ) -alkyl-C (O ) -OR ¹⁸ , -CN,-(C ₀ -C ₄ ) -alkyl-N (R ¹⁸ ) -R ²¹ ,-(C ₀ -C ₄ ) -alkyl-OR ¹⁸ ,-(C ₀ -C ₄ ) -Alkyl-het,-(C ₀ -C ₈ ) -alkyl-SO _2- (C ₁ -C ₄ ) -alkyl,-(C ₀ -C ₈ ) -alkyl-SO _2- (C ₁ -C ₃ ) -Perfluoroalkyl,-(C ₀ -C ₈ ) -alkyl-SO ₂ -N (R ¹⁸ ) -R ²¹ , -C (O) -NH- (C ₁ -C ₈ ) -alkyl, -C ( _{O) -N - [(C 1} -C 8) - ^{_{alkyl] 2, -NR 18 -C (O}} ) -NH- (C 1 -C 8) - _{alkyl, -C (O) -NH 2,} -SR and - [alkyl _{(C 1 -C 8) -]} 2, 18 , or -NR ¹⁸ -C (O) -NH

Wherein R ¹⁸ and R ²¹ independently of one another are a hydrogen atom,-(C ₁ -C ₃ ) -perfluoroalkyl or-(C ₁ -C ₆ ) -alkyl,

V

1) a 3 to 7 membered cyclic moiety containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic moieties are unsubstituted or independently of each other mono-, di- or tri- Is substituted) or

2) monocyclic or bicyclic 4 to 15 membered heterocyclyl, wherein the heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

G is a direct bond,-(CH ₂ ) _m -NR ¹⁰ -SO ₂ -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -CH (OH)-(CH ₂ ) _n -,-(CH ₂ ) _m -,-(CH ₂ ) _m -O- (CH ₂ ) _n - _, -(CH ₂ ) _m -C (O) -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -C (O) -NR ^10- (CH ₂ ) _n - _, -(CH ₂ ) _m -NR ¹⁰ -C (O)-( CH ₂ ) _n -,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -,-(CH ₂ ) -S- (CH ₂ ) _n -,-(CH ₂ ) _m -SO _2- NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -,-(CH ₂ ) _m -OC ( O) -NR ^10- (CH ₂ ) _n -or-(CH ₂ ) _m -NR ¹⁰ -C (O) -O- (CH ₂ ) _n- ,

n and m are independently the same or different integers 0, 1, 2, 3, 4, 5 or 6

M

1) hydrogen atom,

2)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

3) -C (O) -N (R11) -R12,

4)-(CH ₂ ) _m -NR ¹⁰ ,

5)-(C ₆ -C ₁₄ ) -aryl, wherein aryl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

6)-(C ₄ -C ₁₅ ) -heterocyclyl, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

7)-(C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 14 or

8) a 3 to 7 membered cyclic moiety containing one, two, three or four or more heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic moiety is unsubstituted or independently of one another mono-, di-substituted or Trimethylated, wherein R14 is as described),

R3, R4 and R22 are the same as or different from each other independently,

1) hydrogen atom,

2) halogen,

3)-(C ₁ -C ₄ ) -alkyl wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

_{4) - (C 1 -C 3} ) - alkyl, perfluoroalkyl,

5) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 13,

6)-(C ₀ -C ₄ ) -alkylene-O-R 19, where R 19 is a) a hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another Mono-, di-, or tri-substituted); c) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13; d) -CF ₃ or e) -CHF ₂ ],

7) -NO ₂ ,

8) -CN,

9) -SO _s -R ¹¹ (where s is 1 or 2),

10) -SO _t -N (R ¹¹ ) -R ¹² , where t is 1 or 2,

11)-(C ₀ -C ₄ ) -alkylene-C (O) —R ¹¹ ,

12)-(C ₀ -C ₄ ) -alkylene-C (O) —OR ¹¹ ,

13)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹² ,

14)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹² ,

15) -NR ¹⁰ -SO ₂ -R ¹⁰ ,

16) -SR ¹⁰ ,

17)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O)-(C ₁ -C ₄ ) -alkyl,

18) -C (O) -O-C (R15, R16) -O-C (O) -R17,

19)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O) -O- (C ₁ -C ₆ ) -alkyl,

20) -C (O) -O-C (R15, R16) -O-C (O) -O-R17,

21)-(C ₀ -C ₄ ) -alkylene- (C ₆ -C ₁₄ ) -aryl, wherein aryl is independently mono-, di-, or tri-substituted with R 13,

22)-(C ₀ -C ₄ ) -alkylene- (C ₄ -C ₁₅ ) -heterocyclyl, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

23)-(C ₀ -C ₄ ) -alkylene- (C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

24)-(C ₀ -C ₄ ) -alkylene-het wherein het is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

25)-(C ₀ -C ₃ ) -alkylene-O-CH _2- (C ₁ -C ₃ ) -perfluoroalkylene-CH ₂ -O- (C ₀ -C ₃ ) -alkyl,

26) -SO _w -N (R ¹¹ ) -R ¹³ , where w is 1 or 2,

27)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹³ ,

28)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹³ or

29)

로부터의 잔기(여기서 Me은 메틸이거나, 2개의 -OR19 잔기가 인근 원자에 결합되는 경우, 이들에 결합된 원자와 함께 치환되지 않거나 R13으로 1, 2, 3 또는 4회 치환되는 5 또는 6원의 환을 형성할 수 있다)이고,

Residues from Me, wherein Me is methyl or a 5 or 6 membered moiety that is unsubstituted or substituted 1, 2, 3 or 4 times with Can form a ring),

R11 and R12 are the same or different independently from each other,

1) hydrogen atom,

2)-(C ₁ -C ₆ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

3)-(C ₀ -C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,

4) -SO _t -R ¹⁰ (where t is 1 or 2),

5)-(C ₀ -C ₆ ) -alkyl- (C ₆ -C ₁₄ ) -aryl, wherein alkyl and aryl are not substituted independently of one another or are mono-, di-, or tri-substituted with R 13,

_{6) - (C 1 -C 3} ) - alkyl, perfluoroalkyl,

7) -OR ¹⁷ or

8)-(C ₀ -C ₆ ) -alkyl- (C ₄ -C ₁₅ ) -heterocyclyl, wherein alkyl and heterocyclyl are unsubstituted independently or mono-, di- or tri-substituted with R 13 ,

R 11 and R 12 together with the nitrogen atom bonded thereto form a 4 to 8 membered monocyclic heterocyclic ring which may contain, in addition to nitrogen, one or two identical or different ring heteroatoms selected from oxygen, sulfur and nitrogen. Wherein the heterocyclic ring is unsubstituted or independently of one another is mono-, di- or tri-substituted with R 13,

R4 and R22 of formula (I) and formula (Ia) may together with the carbon atoms bonded to them form a phenyl moiety,

R13 is halogen, -NO ₂ , -CN, = O, -OH, -CF ₃ , -C (O) -OR ¹⁰ , -C (O) -N (R ¹⁰ ) -R ²⁰ , -N (R ¹⁰ ) -R ²⁰ ,-(C ₃ -C ₈ ) -cycloalkyl,-(C ₀ -C ₃ ) -alkylene-OR ¹⁰ , -Si- (CH ₃ ) ₃ , -N (R ¹⁰ ) -S ( O) _u -R ¹⁰ (where u is 1 or 2), -SR ¹⁰ , -SO _r -R ¹⁰ (where r is 1 or 2), -S (O) _v -N (R ¹⁰ ) -R ²⁰ , where v is 1 or 2, -C (O) -R ¹⁰ ,-(C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₈ ) -alkoxy, phenyl, phenyloxy-, -O -CF ₃ ,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R 15, R 16) -OC (O) -R 17,-(C ₁ -C ₄ ) -alkoxyphenyl,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R 15, R 16) -OC (O) -O-R 17,-(C ₁ -C ₃ ) -perfluoroalkyl, -O-R 15, -NH- C (O) -NH-R ¹⁰ , -NH-C (O) -OR ¹⁰ or

로부터의 잔기이고,

Residues from,

R ¹⁰ and R ²⁰ are independently of each other hydrogen, — (C ₁ -C ₆ ) -alkyl or — (C ₁ -C ₃ ) -perfluoroalkyl,

R 15 and R 16 are independently of each other hydrogen or — (C ₁ -C ₆ ) -alkyl, a 3-6 membered carbocyclic ring which is unsubstituted or substituted one to three times with R ¹⁰ with a carbon atom bonded thereto; Can form

R17 is-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl-OH,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₆ ) -alkyl,- (C ₃ -C ₈ ) -cycloalkyl,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₈ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,-(C _1- C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted 1, 2 or 3 times with -OH; A compound of formula (I) which is —O— (C ₁ -C ₄ ) -alkyl or R ¹⁰ , all stereoisomeric forms thereof, mixtures thereof in any proportion and physiologically acceptable salts thereof.

3) Therefore, the present invention

R ⁰ is

1) monocyclic or bicyclic 6 to 14 membered aryl selected from the group phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, wherein aryl is independently mono-, di- or tri-substituted by R8 ),

2) group benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophenyl, cinnolinyl, chromanyl, indazolyl, indolyl, isochromenyl, iso Indolyl, isoquinolinyl, phenylpyridyl, phthalazinyl, pterridinyl, furinyl, pyridinyl, pyridimidazolyl, pyridopyridinyl, pyridopyrimidinyl, pyrimidinyl, quinazolinyl , Heterocyclyl selected from quinolyl, quinoxalinyl or 1,4,5,6-tetrahydropyridazinyl, wherein the heterocyclyl is unsubstituted or independently of one another mono-, di- or trisubstituted by R8; or

3) heterocyclyl, where heterocyclyl is a group acridinyl, azabenzimidazolyl, azaspirodecanyl, azefinyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzothio Furanyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromaenyl, Cinnaolinyl, decahydrocinnolinyl, 4,5-diohydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 6H-1,5, 2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, Indolinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromenyl, isoindazolyl, isoindolinyl, isoindolinyl, isoquinolinyl, Isothiazolyl, isothiazolidinyl, isothiazolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopiperazinyl, morpholinyl, naphthyridinyl, octahydrodin Isoquinolinyl, oxdiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1 , 2-oxathipanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl, 1,4-oxazinyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4- Oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, phenantridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxatiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, Pterridinyl, furinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyrimididazolyl, pyridothiazolyl, pyridinyl, pyridyl, Pyrimidinyl, pyrrolidinyl, pyrrolidinyl , Pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolininyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroqui Nolinyl, 1,4,5,6-tetrahydropyridazinyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3 -Thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1,3- Thiazinyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thiazolidinyl, thiazolinyl, thienyl, thientanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thi Tanyl, thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3 -Triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazole And greater chrysanthemate is selected from carbonyl, where the heterocyclyl is optionally substituted mono-, di- or tri-substituted independently with unsubstituted or R8 together,

Group acridinyl, azabenzimidazolyl, azaspirodecanyl, azepineyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, Benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydrocinolinyl, 4 , 5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 6H-1,5,2-diothiazinyl, dihydrofuro [2 , 3-b] -tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolinyl, indolyl, 3H-indolyl , Isobenzofuranyl, isochromenyl, isodazolyl, isoindolinyl, isoindoleyl, isoquinolinyl, isothiazolyl, isothiazolidinyl, isothiazole Linyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopipiperazinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadizolyl, 1,2 , 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathipanyl, 1,2-oxa Thiolanyl, 1,4-oxazepanyl, 1,4-oxazinyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolinyl, oxa Zolyl, phenantridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxatiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, putridinyl, furinyl, pyranyl, pyrazinyl , Pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrroli Nil, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolininyl, quinoxalinyl, quinuclininyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 1,4,5,6-tetrahydropyridazinyl, tetrahydropyridinyl , Tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- Thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thia Zolidinyl, thiazolinyl, thienyl, thiethanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiethanyl, thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2 , 3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl As heterocyclyl selected from 1,3,4-triazolyl and xanthenyl Substituted and in which a heterocyclyl is unsubstituted or independently substituted with one optionally substituted with R8, disubstituted or trisubstituted with each other),

R8 is

1) halogen,

2) -NO ₂ ,

3) -OH,

4) -O-CF ₃

5) aryl monocyclic or bicyclic 6- to 14-membered (wherein aryl is independently from each other halogen or -O- (C ₁ -C ₈₎ - is a substituted mono-, di- or tri-alkyl),

6)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -OH or methoxy moieties,

_{7) -O- (C 1 -C 8} ) - alkyl (wherein alkyl is optionally substituted mono-, di or tri halogen, NH _2, -OH or a methoxy residue is optionally substituted independently from each other),

8) -SO ₂ -CH ₃ or

9) -SO ₂ -CF ₃ ,

Provided that when R ⁰ is a monocyclic or bicyclic 6 to 14 membered aryl, R 8 is at least one halogen or —O— (C ₁ -C ₈ ) -alkyl moiety,

Q is-(C ₀ -C ₂ ) -alkylene-C (O) -NR ^10- , -NR ¹⁰ -C (O) -NR ^10- , -NR ¹⁰ -C (O)-,-(C ₁ -C ₆ ) -alkylene,-(CH ₂ ) _m -NR ¹⁰ -C (O) -NR ^10- (CH ₂ ) _n - _, -(CH ₂ ) _m -NR ¹⁰ -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _m -S- (CH ₂ ) _n -,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _m -SO _2- NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO ₂ -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -CH (OH)-(CH ₂ ) _n -,-(CH ₂ ) _m -OC (O) -NR ^10- (CH ₂ ) _n -,-(C ₂ -C ₃ ) -alkylene-O- (C ₀ -C ₃ ) -alkylene-,-(C ₂ -C ₃ ) -alkylene-S (O)-,-(C ₂ -C ₃ ) -alkylene- S (O) ₂ -,-(CH ₂ ) _m -NR ¹⁰ -C (O) -O- (CH ₂ ) _n -,-(C ₂ -C ₃ ) -alkylene-S (O) ₂ -NH -(R ¹⁰ )-,-(C ₂ -C ₃ ) -alkylene-N (R ¹⁰ )-or-(C ₀ -C ₃ ) -alkylene-C (O) -O- (CH ₂ ) _m -ego,

Wherein R ¹⁰ is as defined below, n and m are the same or different integers, independently of one another, 0, 1, 2, 3, 4, 5 or 6, and-(CH ₂ ) _m -or-(CH ₂ ) _n The alkylene moiety formed by-is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -NH ₂ or -OH, or-(C ₃ -C ₆ ) -cycloalkylene, wherein cycloalkylene Are unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -NH ₂ or -OH,

R ¹ is a hydrogen atom, — (C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or substituted 1-3 times with R 13; - (C ₁ -C ₃₎ - alkylene ^{-C (O) -NH-R 0} , - (C 1 -C 3) - alkylene -C (O) -O-R15; Aryl residues selected from the group phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, wherein aryl is independently mono-, di- or tri-substituted with R 8, wherein R 8 is as described; Monocyclic or bicyclic 4-15 membered heterocyclyl as described; - (C ₁ -C ₃₎ - _{perfluoroalkyl-alkylene, - (C 1 -C 3)} - alkylene _{-S (O) - (C 1} -C 4) - alkyl, - (C ₁ -C ₃₎ - alkylene _{-S (O) 2 - (C} 1 -C 3) - _{alkyl, - (C 1 -C 3)} - alkylene _{-S (O) 2 -N (R} 4 ') -R 5'; - (C ₁ -C ₃₎ - alkylene -O- (C ₁ -C ₄₎ - _{alkyl, - (C 0 -C 3)} - alkylene - (C ₃ -C ₈₎ - cycloalkyl, or - (C _0- C ₃ ) -alkylene-het, where het is the group azepine, azetidine, aziridine, azirin, 1,4-diazaphane, 1,2-diazepine, 1,3-diazepine, 1, 4-diazepines, diaziridine, diazirine, dioxazole, dioxazine, dioxol, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, Isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazolin, isoxazolidine, 2-isoxazolin, ketopiperazine, morpholine, 1,4-oxazepan, 1,2- Oxathipan, 1,2-oxathiolane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxaziridine, oxirane, piperazine, piperidine, pyran , Pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, tiadi Gin thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine, thiazolin, thienyl, thiethane, thio Morpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole A moiety selected from: wherein het is unsubstituted or independently of one another is mono-, di-, or tri-substituted with R 14),

R ^{4 '} and R ^5' are the same as or different from each other independently and are a hydrogen atom or-(C ₁ -C ₄ ) -alkyl,

R ¹ and R 22 together with the atoms bonded thereto are a group azocans, azocan-2-ones, 1,2-diazepines, 1,3-diazepines, 1,4-diazepines, [1,4] Diazocans, [1,2] diazocan-3-ones, [1,3] diazocan-2-ones, dioxazines, [1,4] dioxokanes, dioxoles, ketopiperazines, morpholines, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxocan, oxocan-2-one, piperazine, piperidine, pyran, pyrazine, pyridazine, pyrimidine or 5, Can form a 6-8 membered cyclic moiety selected from 6,7,8-tetrahydro-1H-azosin-2-one, wherein the cyclic groups are unsubstituted or mono-substituted or substituted with R14 independently of one another; Or trisubstituted,

R ¹ -NV groups azepine, azetidine, dioxazole, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazoline Dean, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazolin, isoxazolidine, 2-isoxazolin, ketopiperazine, morpholine, oxazole, piperazine, piperidine , Pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole , Thiazolidine, thiazolin, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1, A 4-8 membered cyclic group selected from 2,4-triazole, wherein the cyclic group is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

R 14 is halogen, —OH, ═O, — (C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₄ ) -alkoxy, -NO ₂ ,-(C ₀ -C ₄ ) -alkyl-C (O ) -OR ¹⁸ , -CN,-(C ₀ -C ₄ ) -alkyl-N (R ¹⁸ ) -R ²¹ ,-(C ₀ -C ₄ ) -alkyl-OR ¹⁸ ,-(C ₀ -C ₄ ) -Alkyl-het, where het is azetidine, azetidinone, piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, 1,2,3-triazine, 1,2,4- Triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine, ketopiperazine, 1,4-oxazepan, oxazole, isoxazole, isoxazolidine, 2-isoxazolin, morpholine, thia Sol, isothiazole, thiadiazole or thiomorpholine); -(C ₀ -C ₈ ) -alkyl-SO _2- (C ₁ -C ₄ ) -alkyl,-(C ₀ -C ₈ ) -alkyl-SO _2- (C ₁ -C ₃ ) -perfluoroalkyl ,-(C ₀ -C ₈ ) -alkyl-SO ₂ -N (R ¹⁸ ) -R ²¹ , -C (O) -NH- (C ₁ -C ₈ ) -alkyl, -C (O) -N- [(C ₁ -C ₈₎ - ^{_{alkyl] 2, -NR 18 -C (O}} ) -NH- (C 1 -C 8) - _{alkyl, -C (O) -NH 2,} -SR 18 or -NR ¹⁸ -C (O) -NH - [( C 1 -C 8) - alkyl] _2, wherein R ¹⁸ and R ²¹ independently represent a hydrogen atom, each - (C ₁ -C ₃₎ - perfluoroalkyl, or - (C ₁ -C ₆ ) -alkyl,

V is a group aridinyl, azaindole (1H-pyrrolopyridine), azabenzimidazolyl, azaspirodecanyl, azepineyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzo Thiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl , Cinnalinel, decahydrocinolinyl, 1,4-diazepane, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxole Nil, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromenyl, isoindazolyl, isoindolinyl, isoindolinyl, isoquinolinyl, Isothiazolyl, isothiazolidinyl, isothiazolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopiperazinyl, morpholinyl, naphthyridinyl, octahydrodin Isoquinolinyl, oxdiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1 , 2-oxathipanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl, 1,4-oxazinyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4- Oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, phenantridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxatiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, Pterridinyl, furinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyrimididazolyl, pyridothiazolyl, pyridinyl, pyridyl, Pyrimidinyl, pyrrolidinyl, pyrrolidinyl , Pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolininyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisocinnolinyl, tetrahydrocinnoline Neyl, 1,4,5,6-tetrahydropyridazinyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3- Thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1,3-thia Genyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thiazolidinyl, thiazolinyl, thienyl, thietanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiethananyl , Thiomorpholinyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1 Selected from 2,5-triazolyl, 1,3,4-triazolyl and xanthenyl And interrogating heterocyclyl (wherein heterocyclyl is optionally substituted mono-, di- or tri-substituted independently with unsubstituted or R14 with each other),

G is a direct bond,-(CH ₂ ) _m -NR ¹⁰ -SO ₂ -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -CH (OH)-(CH ₂ ) _n -,-(CH ₂ ) _m -,-(CH ₂ ) _m -O- (CH ₂ ) _n - _, -(CH ₂ ) _m -C (O) -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -C (O) -NR ^10- (CH ₂ ) _n - _, -(CH ₂ ) _m -NR ¹⁰ -C (O)-( CH ₂ ) _n -,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -,-(CH ₂ ) -S- (CH ₂ ) _n -,-(CH ₂ ) _m -SO _2- NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -,-(CH ₂ ) _m -OC ( O) -NR ^10- (CH ₂ ) _n -or-(CH ₂ ) _m -NR ¹⁰ -C (O) -O- (CH ₂ ) _n- ,

n and m are, independently from each other, the same or different integers 0, 1, 2, 3, 4, 5 or 6,

M

1) hydrogen atom,

2)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

3) -C (O) -N (R11) -R12,

4)-(CH ₂ ) _m -NR ¹⁰ ,

5)-(C ₆ -C ₁₄ ) -aryl, wherein aryl is as described and aryl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

6)-(C ₄ -C ₁₅ ) -heterocyclyl, wherein heterocyclyl is as described and is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14 or

7)-(C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

R3, R4 and R22 are the same as or different from each other independently,

1) hydrogen atom,

2) halogen,

3)-(C ₁ -C ₄ ) -alkyl wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

_{4) - (C 1 -C 3} ) - alkyl, perfluoroalkyl,

5) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 13,

6)-(C ₀ -C ₄ ) -alkylene-O-R 19, where R 19 is a) a hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another Mono-, di-, or tri-substituted); c) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R13); d) -CF ₃ or e) -CHF ₂ ],

7) -NO ₂ ,

8) -CN,

9) -SO _s -R ¹¹ (where s is 1 or 2),

10) -SO _t -N (R ¹¹ ) -R ¹² , where t is 1 or 2,

11)-(C ₀ -C ₄ ) -alkylene-C (O) —R ¹¹ ,

12)-(C ₀ -C ₄ ) -alkylene-C (O) —OR ¹¹ ,

13)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹² ,

14)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹² ,

15) -NR ¹⁰ -SO ₂ -R ¹⁰ ,

16) -SR ¹⁰ ,

17)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O)-(C ₁ -C ₄ ) -alkyl,

18) -C (O) -O-C (R15, R16) -O-C (O) -R17,

19)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O) -O- (C ₁ -C ₆ ) -alkyl,

20) -C (O) -O-C (R15, R16) -O-C (O) -O-R17,

21)-(C ₀ -C ₄ ) -alkylene- (C ₆ -C ₁₄ ) -aryl, wherein aryl is independently mono-, di-, or tri-substituted with R 13,

22)-(C ₀ -C ₄ ) -alkylene- (C ₄ -C ₁₅ ) -heterocyclyl, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

23)-(C ₀ -C ₄ ) -alkylene- (C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

24)-(C ₀ -C ₄ ) -alkylene-het wherein het is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

25)-(C ₀ -C ₃ ) -alkylene-O-CH _2- (C ₁ -C ₃ ) -perfluoroalkylene-CH ₂ -O- (C ₀ -C ₃ ) -alkyl,

26) -SO _w -N (R ¹¹ ) -R ¹³ , where w is 1 or 2,

27)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹³ ,

28)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹³ or

29)

로부터의 잔기(여기서 Me은 메틸이거나, 2개의 -OR19 잔기가 인근 원자에 결합되는 경우, 이들에 결합된 원자와 함께 R13으로 1, 2, 3 또는 4회 치환되는 1,3-디옥솔 환 또는 2,3-디하이드로-[1,4]디옥신 환을 형성할 수 있다)이고,

Residues from Me, wherein Me is methyl or a 1,3-dioxol ring substituted one, two, three or four times with R 13 with the atoms bonded thereto when two -OR 19 residues are bonded to an adjacent atom, or 2,3-dihydro- [1,4] dioxin ring can be formed),

R11 and R12 are the same or different independently from each other,

1) hydrogen atom,

2)-(C ₁ -C ₆ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

3)-(C ₀ -C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,

4) -SO _t -R ¹⁰ (where t is 1 or 2),

5)-(C ₀ -C ₆ ) -alkyl- (C ₆ -C ₁₄ ) -aryl, wherein alkyl and aryl are not substituted independently of one another or are mono-, di-, or tri-substituted with R 13,

_{6) - (C 1 -C 3} ) - alkyl, perfluoroalkyl,

7) -OR ¹⁷ or

8)-(C ₀ -C ₆ ) -alkyl- (C ₄ -C ₁₅ ) -heterocyclyl, wherein alkyl and heterocyclyl are as described and are not independently substituted with each other or are mono-, di- or tri-substituted with R 13 Is substituted), or

R11 and R12 together with the nitrogen atom bonded to them group azepine, azetidine, dioxazole, dioxazine, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4 Diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazolin, isoxazolidine, 2-isoxazoline, ketopipera Gin, morpholine, [1,4] oxazepan, 1,4-oxazinyl, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine , Pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazolin, thiomorpholine, thiophene, 1,2,3 A heterocyclic ring selected from -triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, wherein Heterocyclic rings are unsubstituted Or it is mono- substituted, disubstituted or trisubstituted independently of one another by R13,

R4 and R22 of formula (I) and formula (Ia) may together with the carbon atoms bonded to them form a phenyl moiety,

R13 is halogen, -NO ₂ , -CN, = O, -OH, -CF ₃ , -C (O) -OR ¹⁰ , -C (O) -N (R ¹⁰ ) -R ²⁰ , -N (R ¹⁰ ) -R ²⁰ ,-(C ₃ -C ₈ ) -cycloalkyl,-(C ₀ -C ₃ ) -alkylene-OR ¹⁰ , -Si- (CH ₃ ) ₃ , -N (R ¹⁰ ) -S ( O) _u -R ¹⁰ (where u is 1 or 2), -SR ¹⁰ , -SO _r -R ¹⁰ (where r is 1 or 2), -S (O) _v -N (R ¹⁰ ) -R ²⁰ , where v is 1 or 2, -C (O) -R ¹⁰ ,-(C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₈ ) -alkoxy, phenyl, phenyloxy-, -O -CF ₃ ,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R 15, R 16) -OC (O) -R 17,-(C ₁ -C ₄ ) -alkoxyphenyl,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R 15, R 16) -OC (O) -O-R 17,-(C ₁ -C ₃ ) -perfluoroalkyl, -O-R 15, -NH- C (O) -NH-R ¹⁰ , -NH-C (O) -OR ¹⁰ or

로부터의 잔기(여기서 Me는 메틸이고, R¹⁰ 및 R²⁰은 서로 독립적으로 수소, -(C₁-C₆)-알킬, -(C₀-C₄)-알킬-OH, -(C₀-C₄)-알킬-O-(C₁-C₄)-아킬 또는 -(C₁-C₃)-퍼플루오로알킬이다)이고,

Residues from where Me is methyl and R ¹⁰ and R ²⁰ independently of one another are hydrogen,-(C ₁ -C ₆ ) -alkyl,-(C ₀ -C ₄ ) -alkyl-OH,-(C _0- C ₄₎ - alkyl, -O- (C ₁ -C ₄₎ - ahkil or - (C ₁ -C ₃₎ - it is perfluoroalkyl), and

R 15 and R 16 are independently of each other hydrogen, — (C ₁ -C ₆ ) -alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein each ring is unsubstituted or substituted 1 to 3 times with R ¹⁰ ,

R17 is-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl-OH,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₆ ) -alkyl,- (C ₃ -C ₈ ) -cycloalkyl,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₈ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,-(C _1- C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted 1, 2 or 3 times with -OH; -O- (C ₁ -C ₄₎ - alkyl, or R ¹⁰ of the compound, all stereoisomeric forms thereof, of formula I, relates to the acceptable salts thereof, and mixtures thereof in any proportion of the physiologically.

4) The present invention also

R ⁰ is

1) monocyclic or bicyclic 6 to 14 membered aryl selected from the group phenyl, naphthyl, biphenyl, anthryl or fluorenyl, wherein the aryl is independently mono-, di- or tri-substituted with R8; ,

2) group benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophenyl, cinnolinyl, chromanyl, indazolyl, indolyl, isochromenyl, iso Indolyl, isoquinolinyl, phenylpyridyl, phthalazinyl, pterridinyl, furinyl, pyridinyl, pyridimidazolyl, pyridopyridinyl, pyridopyrimidinyl, pyrimidinyl, quinazolinyl Heterocyclyl selected from quinolyl, quinoxalinyl or 1,4,5,6-tetrahydropyridazinyl, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R8 or

3) group azabenzimidazolyl, benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, 2-furyl, 3 -Furyl, imidazolyl, indolyl, indazolyl, isochromenyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, phthalazinyl, pterridinyl, furinyl, pyrazinyl , Pyrazolyl, pyridazinyl, pyridimidazolyl, pyridopyridinyl, pyridopyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrrolyl; Heterocyclyl selected from 2-pyrrolyl, 3-pyrrolyl, quinolinyl, quinazolinyl, quinoxalinyl, tetrazolyl, thiazolyl, 2-thienyl or 3-thienyl, wherein the group acridinyl, Azabenzimidazolyl, azaspirodecanyl, azepinyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benz Triazolyl, Benztetrazolyl, Benzisoxazolyl, Benzisothiazolyl, Carbazolyl, 4aH-carbazolyl, Carbolinyl, Chromanil, Chromenyl, Cynolinyl, Decahydrocinnolinyl, 4,5-dihydro Oxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] -Tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolinyl, indolyl, 3H-phosphoryl Reel, isobenzofuranyl, isochromenyl, isodazolyl, isoindolinyl, isoindolinyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isothiazolidinyl, isothiazolinyl, isox Sazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopiperazinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadizolyl, 1,2,3 Oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathipanyl, 1,2-oxathiola Neyl, 1,4-oxazepanyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, phenantridinyl, phenanthrolinyl, Phenazinyl, phenothiazinyl, phenoxatiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, putridinyl, furinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazin Zolyl, pyridazinyl, pyridooxazole Pyridimidazolyl, pyridothiazolyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl , 4H-quinolininyl, quinoxalinyl, quinuclininyl, tetrahydrofuranyl, tetrahydroisocinnolinyl, tetrahydrocinnolinyl, 1,4,5,6-tetrahydropyridazinyl, tetrahydropyridinyl , Tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- Thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thia Zolidinyl, thiazolinyl, thienyl, thiethanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiethanyl, thiomorpholinyl, thiophenyl, thiopyranyl, 1,2,3-tria Genyl, 1,2,3-triazolyl, Further substituted with heterocyclyl selected from 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, wherein Heterocyclyl is unsubstituted or independently from each other mono-, di- or tri-substituted by R8),

R8 is

One) Fluorine, chlorine or bromine,

2) -NO ₂ ,

3) -OH,

4) -O-CF ₃

5) aryl monocyclic or bicyclic 6- to 14-membered (wherein aryl is independently from each other halogen or -O- (C ₁ -C ₈₎ - is a substituted mono-, di- or tri-alkyl),

6)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -OH or methoxy moieties,

_{7) -O- (C 1 -C 8} ) - alkyl (wherein alkyl is optionally substituted mono-, di or tri halogen, NH _2, -OH or a methoxy residue is optionally substituted independently from each other),

8) -SO ₂ -CH ₃ or

9) -SO ₂ -CF ₃ ,

Provided that when R ⁰ is aryl or heterocyclyl as described, R 8 is at least one halogen or —O— (C ₁ -C ₈ ) -alkyl moiety,

Q is-(C ₀ -C ₂ ) -alkylene-C (O) -NR ^10- , -NR ¹⁰ -C (O) -NR ^10- , -NR ¹⁰ -C (O)-,-(C ₁ -C ₆ ) -alkylene or-(C ₀ -C ₃ ) -alkylene-C (O) -O- (C ₀ -C ₂ ) -alkylene,

R ¹ is a hydrogen atom, — (C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or substituted 1-3 times with R 13; - (C ₁ -C ₃₎ - alkylene ^{-C (O) -NH-R 0} , - (C 1 -C 3) - alkylene -C (O) -O-R15, - (C 1 -C 3 ) perfluoroalkyl _{alkylene, - (C 1 -C 3)} - alkylene -S (O) - (C ₁ -C ₄₎ - _{alkyl, - (C 1 -C 3)} - alkylene -S (O ) _2- (C ₁ -C ₃ ) -alkyl,-(C ₁ -C ₃ ) -alkylene-S (O) ₂ -N (R ^{4 ′} ) -R ⁵ ,-(C ₁ -C ₃ )- alkylene -O- (C ₁ -C ₄₎ - _{alkyl, - (C 0 -C 3)} - alkylene - (C ₃ -C ₈₎ - cycloalkyl, or - (C ₀ -C ₃₎ - alkylene- het (where het is the group azepine, azetidine, aziridine, azirin, 1,4-diazepane, 1,2-diazepines, 1,3-diazepines, 1,4-diazepines, diaziridine, Diazirin, Dioxazole, Dioxazine, Dioxol, 1,3-dioxolene, 1,3-dioxolane, Furan, Imidazole, Imidazoline, Imidazolidine, Isothiazole, Isothiazolidine, Isothiazoline, isoxazole, isoxazolin, isoxazolidine, 2-isoxazolin, ketopiperazine, morpholine, 1,2-oxathipan, 1,2-oxathiolane, 1,4-oxa Engraving, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxaziridine, jade Silane, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetra Gin, tetrazole, thiadiazine thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine, thiazolin, Thienyl, thiethane, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1 , 2,4-triazole, wherein het is unsubstituted or independently of each other mono-substituted, substituted or trisubstituted with R14),

R ^{4 '} and R ^5' are the same as or different from each other independently and are a hydrogen atom or-(C ₁ -C ₄ ) -alkyl,

R ¹ -NV is a group azepine, azetidine, 1,4-diazepane, dioxazole, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, Imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazolin, ketopiperazine, morpholine, 1, 4-oxazepan, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydro Pyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazolin, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5- To form a 4 to 8 membered cyclic group selected from triazine, 1,2,3-triazole or 1,2,4-triazole, wherein the cyclic group is unsubstituted or independently monovalent to R14, Di- or tri-substituted And,

R14 is fluorine, chlorine, bromine, iodine, -OH, = O, - ( C 1 -C 8) - _{alkyl, - (C 1 -C 4)} - _{alkoxy, -NO 2, -C (O)} -OH, -CN, -NH ₂ , -C (O) -O- (C ₁ -C ₄ ) -alkyl,-(C ₀ -C ₄ ) -alkyl-SO _2- (C ₁ -C ₄ ) -alkyl,- (C ₀ -C ₈ ) -alkyl-SO ₂ -N (R ¹⁸ ) -R ²¹ , -C (O) -NH- (C ₁ -C ₈ ) -alkyl, -C (O) -N-[( C ₁ -C ₈ ) -alkyl] ₂ , -NR ¹⁸ -C (O) -NH- (C ₁ -C ₈ ) -alkyl, -C (O) -NH ₂ , -SR ¹⁸ or -NR ¹⁸ -C (O) -NH - [(C 1 -C 8) - Al skill] _2, wherein R ¹⁸ and R ²¹ independently represent a hydrogen atom, each - (C ₁ -C ₃₎ - perfluoroalkyl, or - ( C ₁ -C ₆ ) -alkyl,

V is azaindole (1H-pyrrolopyridine), azepine, azetidine, aziridine, azirin, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4- Diazepine, Diaziridine, Diazirin, Dioxazole, Dioxazine, Dioxol, 1,3-dioxolene, 1,3-dioxolane, Furan, Imidazole, Imidazoline, Imidazolidine, Isothia Sol, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazolin, ketopiperazine, morpholine, 1,2-oxathipan, 1,2-oxa Thiolane, 1,4-oxazepan, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxaziridine, oxirane, piperazine, piperidine, pyran, pyrazine , Pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiadiazine, thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazoli , Thiazoline, thienyl, thiethane, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3- Heterocyclyl moiety selected from triazole or 1,2,4-triazole, as described, wherein het is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

G is a direct bond,-(CH ₂ ) _m -NR ¹⁰ -SO ₂ -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -CH (OH)-(CH ₂ ) _n -,-(CH ₂ ) _m -,-(CH ₂ ) _m -O- (CH ₂ ) _n - _, -(CH ₂ ) _m -C (O) -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -C (O) -NR ^10- (CH ₂ ) _n - _, -(CH ₂ ) _m -NR ¹⁰ -C (O)-( CH ₂ ) _n -,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -,-(CH ₂ ) -S- (CH ₂ ) _n -,-(CH ₂ ) _m -SO _2- NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -,-(CH ₂ ) _m -OC ( O) -NR ^10- (CH ₂ ) _n -or-(CH ₂ ) _m -NR ¹⁰ -C (O) -O- (CH ₂ ) _n- ,

n and m are independently the same or different integers 0, 1, 2, 3, 4, 5 or 6

M

1) hydrogen atom,

2)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

3) -C (O) -N (R11) -R12,

4)-(CH ₂ ) _m -NR ¹⁰ ,

5) phenyl or naphthyl, wherein phenyl or naphthyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 14,

6) heterocyclyl, where heterocyclyl is azepan, azepin, 1,4-diazepan, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, isothia Sol, isoxazole, isoxazolidine, 2-isoxazolin, ketomorpholine, ketopiperazine, morpholine, oxazole, [1,4] -oxazepan, piperazine, piperazinone, piperidine , Piperidinone, pyrazine, pyridazine, pyridazinone, pyridine, pyridone, pyrimidine, pyrrolidine, pyrrolidinone, tetrahydropyran, 1,4,5,6-tetrahydropyridazinyl, tetrazine , Tetrazole, thiadiazole, thiazole, thiophene, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3 -A residue selected from the group derivable from a triazole or 1,2,4-triazole, wherein the heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R14) or

7)-(C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

R3, R4 and R22 are the same as or different from each other independently,

1) hydrogen atom,

2) halogen,

3)-(C ₁ -C ₄ ) -alkyl wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

_{4) - (C 1 -C 3} ) - alkyl, perfluoroalkyl,

5) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 13,

6)-(C ₀ -C ₄ ) -alkylene-O-R 19, wherein R 19 is a) a hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another Mono-, di-, or tri-substituted); c) phenyl, wherein phenyl is unsubstituted or independently of one another mono, di or trisubstituted by R 13; d) -CF ₃ or e) CHF ₂ ],

7) -CN,

8)-(C ₀ -C ₄ ) -alkylene- (C ₄ -C ₁₅ ) -heterocyclyl, wherein heterocyclyl is as described and is unsubstituted or independently of one another mono, di or trisubstituted by R 13 do),

9) -SO _s -R ¹¹ (where s is 1 or 2),

10) -SO _t -N (R ¹¹ ) -R ¹² , where t is 1 or 2,

11)-(C ₀ -C ₄ ) -alkylene-C (O) —R ¹¹ ,

12)-(C ₀ -C ₄ ) -alkylene-C (O) —OR ¹¹ ,

13)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹² ,

14)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹² ,

15) -NR ¹⁰ -SO ₂ -R ¹⁰ ,

16)-(C ₀ -C ₄ ) -alkylene-het, wherein het is as described and is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

17)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O)-(C ₁ -C ₄ ) -alkyl,

18) -C (O) -O-C (R15, R16) -O-C (O) -R17,

19)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O) -O- (C ₁ -C ₆ ) -alkyl,

20) -C (O) -O-C (R15, R16) -O-C (O) -O-R17,

21)-(C ₀ -C ₄ ) -alkylene- (C ₆ -C ₁₄ ) -aryl, wherein aryl is as described and independently of one another mono-, di- or tri-substituted with R 13,

22)-(C ₀ -C ₄ ) -alkylene- (C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

23)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl,

24)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl,

25)-(C ₀ -C ₃ ) -alkylene-O-CH _2- (C ₁ -C ₃ ) -perfluoroalkylene-CH ₂ -OH,

26) -SO _w -N (R ¹¹ ) -R ¹³ , where w is 1 or 2,

27)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹³ ,

28)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹³ or

29)

로부터의 잔기(여기서 Me은 메틸이거나, 2개의 -OR19 잔기가 인근 원자에 결합되는 경우, 이들에 결합된 원자와 함께 R13으로 1, 2, 3 또는 4회 치환되는 1,3-디옥솔 환 또는 2,3-디하이드로-[1,4]디옥신 환을 형성할 수 있다)이고,

Residues from Me, wherein Me is methyl or a 1,3-dioxol ring substituted one, two, three or four times with R 13 with the atoms bonded thereto when two -OR 19 residues are bonded to an adjacent atom, or 2,3-dihydro- [1,4] dioxin ring can be formed),

R11 and R12 are the same or different independently from each other,

1) hydrogen atom,

2)-(C ₁ -C ₆ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

3)-(C ₀ -C ₆ ) -alkyl- (C ₆ -C ₁₄ ) -aryl, wherein aryl is as described herein wherein alkyl and aryl are unsubstituted independently or mono-, di- or tri-substituted with R 13 do),

4) -OR ¹⁷ or

5)-(C ₀ -C ₆ ) -alkyl- (C ₄ -C ₁₅ ) -heterocyclyl, wherein alkyl and heterocyclyl are as described and are not substituted independently of one another or are mono-, di- or tri-substituted with R 13 Is substituted), or

R11 and R12 together with the nitrogen atom bonded to them are a group azepine, azetidine, 1,4-diazepane, dioxazole, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4 Diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazolin, isoxazolidine, 2-isoxazoline, ketopipera Gin, morpholine, [1,4] oxazepan, 1,4-oxazepine, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, Pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazolin, thiomorpholine, 1,2,3-triazine, May form a ring selected from 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, which may be unsubstituted or independently of one another Mono, di or Trisubstituted,

R4 and R22 of formula (I) and formula (Ia) may together with the carbon atoms bonded to them form a phenyl moiety,

R13 is fluorine, chlorine, bromine, iodine, -NO ₂ , -CN, = O, -OH, -CF ₃ , -C (O) -OR ¹⁰ , -C (O) -N (R ¹⁰ ) -R ²⁰ , -N (R ¹⁰ ) -R ²⁰ ,-(C ₀ -C ₃ ) -alkylene-OR ¹⁰ , -Si- (CH ₃ ) ₃ , -N (R ¹⁰ ) -S (O) ₂ -R ¹⁰ , -SR ¹⁰ , -SO ₂ -R ¹⁰ , -S (O) ₂ -N (R ¹⁰ ) -R ²⁰ , -C (O) -R ¹⁰ ,-(C ₁ -C ₈ ) -alkyl,-( C ₁ -C ₈ ) -alkoxy, phenyl, phenyloxy-, -O-CF ₃ ,-(C ₁ -C ₃ ) -perfluoroalkyl,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R15, R16) -OC (O) -R17,-(C ₁ -C ₄ ) -alkoxyphenyl,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R15, R16)- O-C (O) -O-R17, -O-R15, -NH-C (O) -NH-R ¹⁰ , -NH-C (O) -OR ¹⁰ or

로부터의 잔기(여기서 Me은 메틸이고, R¹⁰ 및 R²⁰은 서로 독립적으로 수소, -(C₁-C₆)-알킬, -(C₀-C₄)-알킬-OH, -(C₀-C₄)-알킬-O-(C₁-C₄)-아킬 또는 -(C₁-C₃)-퍼플루오로알킬이다)이고,

Residues from wherein Me is methyl and R ¹⁰ and R ²⁰ independently of one another are hydrogen,-(C ₁ -C ₆ ) -alkyl,-(C ₀ -C ₄ ) -alkyl-OH,-(C _0- C ₄₎ - alkyl, -O- (C ₁ -C ₄₎ - ahkil or - (C ₁ -C ₃₎ - it is perfluoroalkyl), and

R 15 and R 16 are independently of each other hydrogen or — (C ₁ -C ₆ ) -alkyl, or together form a ring selected from the group cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein each ring is unsubstituted or R Substituted 1 to 3 times with ¹⁰ ,

R17 is-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl-OH,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₆ ) -alkyl,- (C ₃ -C ₈ ) -cycloalkyl,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₈ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,-(C _1- C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted 1, 2 or 3 times with -OH; -O- (C ₁ -C ₄₎ - alkyl, or R ¹⁰ of the compound, all stereoisomeric forms thereof, of formula I, to a pipe for acceptable salts thereof and mixtures thereof in any proportion of the physiologically.

5) The present invention also

R ⁰ is

1) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R8,

2) group benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophenyl, cinnolinyl, chromanyl, indazolyl, indolyl, isochromenyl, iso Indolyl, isoquinolinyl, phenylpyridyl, phthalazinyl, pterridinyl, furinyl, pyridinyl, pyridimidazolyl, pyridopyridinyl, pyridopyrimidinyl, pyrimidinyl, quinazolinyl , Heterocyclyl selected from quinolyl, quinoxalinyl or 1,4,5,6-tetrahydropyridazinyl, wherein the heterocyclyl is unsubstituted or independently of one another mono-, di- or trisubstituted by R8; or

3) group pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furyl, 2-furyl, 3-furyl; Thienyl, 2-thienyl, 3-thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl Heterocyclyl selected from: wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 8, a group pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furyl, 2-furyl, 3-furyl; thienyl, 2-thienyl, 3-thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, Further substituted with a residue selected from thiadiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl, wherein the residues are unsubstituted or independently substituted, substituted or trisubstituted with R8) ,

R8 is

One) F, Cl, Br or J,

2)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -OH or methoxy moieties; or

_{3) -O- (C 1 -C 4} ) - alkyl (wherein alkyl is optionally substituted mono-, di- or tri-halogen or a methoxy residue is optionally substituted independently from each other), and

Provided that when R ⁰ is aryl or heterocyclyl as described, R 8 is at least one halogen or —O— (C ₁ -C ₈ ) -alkyl moiety,

Q is -C (O) -, - ( C 1 -C 6) - _{alkylene, - (C 0 -C 2)} - alkylene -C (O) -NR ¹⁰ - or - (C ₀ -C ₃₎ -Alkylene-C (O) -O- (C ₀ -C ₂ ) -alkylene,

R ¹ is a hydrogen atom,-(C ₁ -C ₂ ) -alkyl,-(C ₁ -C ₃ ) -alkylene-C (O) -NH-R 0,-(C ₁ -C ₃ ) -perfluoro Alkylene,-(C ₁ -C ₃ ) -alkylene-C (O) -OR ¹⁵ ,-(C ₁ -C ₃ ) -alkylene-S (O) _2- (C ₁ -C ₃ ) -alkyl or - (C ₁ -C ₃₎ - alkylene _{-S (O) 2 -N (R} 4 ') -R 5' ( wherein R ^{4 'and} R ^5' are each independently the same or different and represent a hydrogen atom or -(C ₁ -C ₄ ) -alkyl),

R ¹ -NV is a group azetidine, azetidinone, piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, 1,2,3-triazine, 1,2,4-triazine , 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,4-diazepane, 1,2-diazepine, 1, 3-diazepine, 1,4-diazepine, azepine, ketopiperazine, 1,4-oxazepan, oxazole, isoxazole, isoxazolidine, 2-isoxazolin, morpholine, thiazole, A 4-7 membered cyclic group selected from isothiazole, thiadiazole or thiomorpholine, wherein the cyclic group is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

R14 is fluorine, chlorine, -OH, = O,-(C ₁ -C ₈ ) -alkyl, -C (O) -OH, -CN, -NH ₂ , -C (O) -O- (C _1- C ₄ ) -alkyl, -C (O) -NH- (C ₁ -C ₈ ) -alkyl, -C (O) -N-[(C ₁ -C ₈ ) -alkyl] ₂ , -C (O) -NH ₂ or -N (R ¹⁸ ) -R ²¹ , wherein R ¹⁸ and R ²¹ are independently of each other a hydrogen atom,-(C ₁ -C ₃ ) -perfluoroalkyl or-(C ₁ -C ₄ )- Alkyl),

V is azaindole (1H-pyrrolopyridine), aziridine, aziline, azetidine, azetidinone, 1,4-diazepane, pyrrole, pyrrolidine, pyridonyl, imidazole, pyrazole, 1, 2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5 Triazine, tetrazine, tetrazole, azepine, diazirine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, pyridazine, piperidine, piperazine, pyrrolidinone , Ketopiperazine, furan, pyran, dioxol, 1,4-oxazepan, oxazole, isoxazole, 2-isoxazolin, isoxazolidine, morpholine, oxirane, oxaziridine, 1,3 Dioxolene, 1,3-dioxolane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxaziridine, thiophene, thiopyran, thiethane, thiazole, isothia Sol, isothiazoline, isothiazolidine, 1,2-oxathiolane, thiadiazole, thiopyran, 1,2-thiazine, 1,3-thiazole, 1,3-thiazine, 1,4- Thiazine, thiadiazine It is alkylthio, and know from a group containing a compound derived from a morpholine cyclic heteroatom selected moiety, wherein the heterocyclyl moiety is optionally substituted monosubstituted, disubstituted or trisubstituted by R14 is optionally substituted independently from each other,

G is a direct bond,-(CH ₂ ) _m -or-(CH ₂ ) _m -NR ^10- ,

m is an integer 0, 1, 2, 3 or 4,

M

1) hydrogen atom,

2) heterocyclyl, where heterocyclyl is azepan, azepin, 1,4-diazepan, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, isothia Sol, isoxazole, isoxazolidine, 2-isoxazolin, ketomorpholine, ketopiperazine, morpholine, oxazole, [1,4] -oxazepan, piperazine, piperazinone, piperidine , Piperidinone, pyrazine, pyridazine, pyridazinone, pyridine, pyridone, pyrimidine, pyrrolidine, pyrrolidinone, tetrahydropyran, 1,4,5,6-tetrahydropyridazinyl, tetra Gin, tetrazole, thiadiazole, thiazole, thiomorpholine, thiophene, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2, A residue selected from the group derivable from 3-triazole or 1,2,4-triazole, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14),

3)-(C ₁ -C ₆ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

4) (C ₃ -C ₆ ) -cycloalkyl or

5) -C (O) -N (R ¹¹ ) -R ¹² ,

R3, R4 and R22 are the same as or different from each other independently,

1) hydrogen atom,

2) halogen,

3)-(C ₁ -C ₄ ) -alkyl wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

_{4) - (C 1 -C 3} ) - alkyl, perfluoroalkyl,

5) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 13,

6)-(C ₀ -C ₄ ) -alkylene-O-R 19, wherein R 19 is a) a hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another Mono-, di-, or tri-substituted); c) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13; d) -CF ₃ or e) CHF ₂ ],

7) -CN,

8) -NR ¹⁰ -SO ₂ -R ¹⁰ ,

9) -SO _s -R ¹¹ (where s is 1 or 2),

10) -SO _t -N (R ¹¹ ) -R ¹² , where t is 1 or 2,

11)-(C ₀ -C ₄ ) -alkylene-C (O) —R ¹¹ ,

12)-(C ₀ -C ₄ ) -alkylene-C (O) —OR ¹¹ ,

13)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹² ,

14)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹² ,

15)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O)-(C ₁ -C ₄ ) -alkyl,

16) -C (O) -O-C (R15, R16) -O-C (O) -R17,

17)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O) -O- (C ₁ -C ₆ ) -alkyl,

18) -C (O) -O-C (R15, R16) -O-C (O) -O-R17,

19)-(C ₀ -C ₄ ) -alkylene- (C ₃ -C ₆ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

20)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl,

21)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl,

22)-(C ₀ -C ₃ ) -alkylene-O-CH _2- (C ₁ -C ₃ ) -perfluoroalkylene-CH ₂ -OH,

23) -SO _w -N (R ¹¹ ) -R ¹³ , wherein w is 1 or 2,

24)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹³ ,

25)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹³ or

26)

로부터의 잔기(여기서 Me은 메틸이거나, 2개의 -OR19 잔기가 인근 원자에 결합되는 경우, 이들에 결합된 원자와 함께 R13으로 1, 2, 3 또는 4회 치환되는 1,3-디옥솔 환 또는 2,3-디하이드로-[1,4]디옥신 환을 형성할 수 있다)이고,

Residues from Me, wherein Me is methyl or a 1,3-dioxol ring substituted one, two, three or four times with R 13 with the atoms bonded thereto when two -OR 19 residues are bonded to an adjacent atom, or 2,3-dihydro- [1,4] dioxin ring can be formed),

R ¹¹ and R ¹² together with the nitrogen atom bonded thereto are a group azepine, azetidine, 1,4-diazepane, dioxazole, dioxazine, 1,2-diazepine, 1,3-diazepine, 1 , 4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazolin, isoxazolidine, 2-isoxazolin, ke Topiperazine, morpholine, [1,4] -oxazepan, 1,4-oxazepine, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, Pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazolin, thiomorpholine, thiophene, 1,2 Can form a ring selected from, 3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, Wherein the rings are unsubstituted or independently of each other R13 A mono-, di- or tri-substituted,

R4 and R22 of formula (I) and formula (Ia) may together with the carbon atoms bonded to them form a phenyl moiety,

R 13 is fluorine, chlorine, -NO ₂ , -CN, = O, -OH, -CF ₃ , -C (O) -OR ¹⁰ , -C (O) -N (R ¹⁰ ) -R ²⁰ , -N ( R ¹⁰ ) -R ²⁰ ,-(C ₀ -C ₃ ) -alkylene-OR ¹⁰ , -Si- (CH ₃ ) ₃ , -N (R ¹⁰ ) -S (O) ₂ -R ¹⁰ , -SR ¹⁰ , -SO ₂ -R ¹⁰ , -S (O) ₂ -N (R ¹⁰ ) -R ²⁰ , -C (O) -R ¹⁰ ,-(C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₈ ) -alkoxy, phenyl, phenyloxy-, -O-CF ₃ ,-(C ₁ -C ₃ ) -perfluoroalkyl, -NH-C (O) -NH-R ¹⁰ ,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R 15, R 16) -OC (O) -R 17,-(C ₁ -C ₄ ) -alkoxyphenyl,-(C ₀ -C ₄ ) -alkyl-C (O ) -OC (R15, R16) -OC (O) -O-R17, -O-R15, -NH-C (O) -OR ¹⁰ or

로부터의 잔기(여기서 Me은 메틸이고, R¹⁰ 및 R²⁰은 서로 독립적으로 수소, -(C₁-C₆)-알킬, -(C₀-C₄)-알킬-OH, -(C₀-C₄)-알킬-O-(C₁-C₄)-아킬 또는 -(C₁-C₃)-퍼플루오로알킬이다)이고,

Residues from wherein Me is methyl and R ¹⁰ and R ²⁰ independently of one another are hydrogen,-(C ₁ -C ₆ ) -alkyl,-(C ₀ -C ₄ ) -alkyl-OH,-(C _0- C ₄₎ - alkyl, -O- (C ₁ -C ₄₎ - ahkil or - (C ₁ -C ₃₎ - it is perfluoroalkyl), and

R 15 and R 16 are independently of each other hydrogen or — (C ₁ -C ₆ ) -alkyl, or together form a ring selected from the group cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein each ring is unsubstituted or R Substituted 1 to 3 times with ¹⁰ ,

R17 is-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl-OH,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₆ ) -alkyl,- (C ₃ -C ₈ ) -cycloalkyl,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₈ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,-(C _1- C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted 1, 2 or 3 times with -OH; -O- (C ₁ -C ₄₎ - alkyl, or R ¹⁰ of the compound, all stereoisomeric forms thereof, of formula I, relates to the acceptable salts thereof, and mixtures thereof in any proportion of the physiologically.

6) The present invention also

R ⁰ is

1) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R8,

2) group indolyl, isoindoleyl, benzofuranyl, benzothiophenyl, 1,3-benzodioxolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl , Chrominyl, isochromenyl, cinnaolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrimididazolyl, pyridopyridinyl, pyridopyrimidinyl, pyridinyl, furinyl and pterridinyl Heterocyclyl selected from: wherein heterocyclyl is unsubstituted or independently of one another mono-, di-, or trisubstituted with R 8; or

3) group pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furyl, 2-furyl, 3-furyl; Thienyl, 2-thienyl, 3-thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl Heterocyclyl selected from: wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 8, a group pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furyl, 2-furyl, 3-furyl; thienyl, 2-thienyl, 3-thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, Further substituted with a moiety selected from thiadiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl, wherein the residues are unsubstituted or independently substituted, substituted or trisubstituted with R8) ,

R8 is

1) F, Cl, Br or J,

2)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -OH or methoxy moieties; or

_{3) -O- (C 1 -C 4} ) - alkyl (wherein alkyl is optionally substituted mono-, di- or tri-halogen or a methoxy residue is optionally substituted independently from each other), and

Provided that when R ⁰ is aryl or heterocyclyl as described, R 8 is at least one halogen or —O— (C ₁ -C ₈ ) -alkyl moiety,

Q is —C (O) —, —C (O) —O-methylene, — (C ₁ -C ₄ ) -alkylene or — (C ₀ -C ₂ ) -alkylene-C (O) —NR ¹⁰ -ego,

R ¹ is a hydrogen atom or — (C ₁ -C ₂ ) -alkyl,

R ¹ -NV is a group piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, 1,2,3-triazine, 1,2,4-triazine, 1,3,5- Triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine 4-7 membered cyclic group selected from ketopiperazine, oxazole, isoxazole, isoxazolidine, 2-isoxazolin, morpholine, thiazole, isothiazole, thiadiazole or thiomorpholine Wherein the cyclic groups are unsubstituted or are independently mono-, di-, or tri-substituted with R 14,

R 14 is fluoro, chlorine,-(C ₁ -C ₄ ) -alkyl or -NH ₂ ,

V is azaindolyl (1H-pyrrolopyridyl), azetidine, azepine, aziridine, azirin, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4 Diazepine, diazirine, 1,3-dioxolane, dioxazole, furan, imidazole, isoquinoline, isothiazole, isothiazolidine, isothiazoline, isoxazole, 2-isoxazolin, isoxa Zolidine, ketopiperazine, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, 1,2-oxathiolane, piperidine, pyran, pyrazine, Pyrazole, pyridazine, piperazine, pyridine, pyridone, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, quinazoline, quinoline, tetrazine, tetrazole, thiadiazine, 1,2-thiazine, 1 , 3-thiazine, 1,4-thiazine, 1,3-thiazole, thiethane, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,2,4-triazine Hetero yarns selected from the group containing compounds derived from 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole Is an cyclyl moiety wherein the heterocyclyl moiety is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14,

G is a direct bond,-(CH ₂ ) _m -or-(CH ₂ ) _m -NR ^10- ,

m is an integer 0, 1, 2, 3 or 4,

M

1) hydrogen atom,

2) heterocyclyl, where heterocyclyl is 1,4-diazepane, ketomorpholine, thiophene, pyridazone, piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, pyrido Nyl, imidazole, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2, 4-triazole, tetrazine, tetrazole, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine, ketopiperazine, oxazole, isoxazole, isoxazolidine , 2-isoxazolin, morpholine, thiazole, isothiazole, tetrahydropyran, 1,4,5,6-tetrahydropyridazinyl, thiadiazole or thiomorpholine Moiety wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14),

3)-(C ₁ -C ₆ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 14; or

4) (C ₃ -C ₆ ) -cycloalkyl,

R3, R4 and R22 are the same as or different from each other independently,

1) hydrogen atom,

2) halogen,

3)-(C ₁ -C ₄ ) -alkyl wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

_{4) - (C 1 -C 3} ) - alkyl, perfluoroalkyl,

5) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 13,

6)-(C ₀ -C ₄ ) -alkylene-O-R 19, where R 19 is a) a hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another Mono-, di-, or tri-substituted); c) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13; d) -CF ₃ or e) -CHF ₂ ],

7) -CN,

8) -NR ¹⁰ -SO ₂ -R ¹⁰ ,

9) -SO _s -R ¹¹ (where s is 1 or 2),

10) -SO _t -N (R ¹¹ ) -R ¹² , where t is 1 or 2,

11)-(C ₀ -C ₄ ) -alkylene-C (O) —R ¹¹ ,

12)-(C ₀ -C ₄ ) -alkylene-C (O) —OR ¹¹ ,

13)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹² ,

14)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹² ,

15)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O)-(C ₁ -C ₄ ) -alkyl,

16) -C (O) -O-C (R15, R16) -O-C (O) -R17,

17)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O) -O- (C ₁ -C ₆ ) -alkyl,

18) -C (O) -O-C (R15, R16) -O-C (O) -O-R17,

19)-(C ₀ -C ₃ ) -alkylene- (C ₃ -C ₆ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

20)-(C ₀ -C ₄ ) -alkylene- (C ₃ -C ₆ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

21)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl,

22)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl,

23)-(C ₀ -C ₃ ) -alkylene-O-CH _2- (C ₁ -C ₃ ) -perfluoroalkylene-CH ₂ -OH,

24) -SO _w -N (R ¹¹ ) -R ¹³ , wherein w is 1 or 2,

25)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹³ ,

26)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹³ or

27)

로부터의 잔기(여기서 Me은 메틸이다)이고,

Is a residue from where Me is methyl

R11 and R12 are the same or different independently from each other,

1) hydrogen atom,

2)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

3)-(C ₀ -C ₆ ) -alkyl- (C ₃ -C ₆ ) -cycloalkyl,

4) -OR ¹⁷ or

5)-(C ₀ -C ₆ ) -alkyl- (C ₄ -C ₁₅ ) -heterocyclyl, wherein alkyl and heterocyclyl are unsubstituted independently or mono-, di- or tri-substituted with R 13, wherein Heterocyclyl is a group azetidine, cyclopropyl, cyclobutyl, 4,5-dihydro-oxazole, imidazolidine, morpholine, (1,4) -oxazepan, oxazolidine, piperidine, pipepe Razine, pyrrolidine, tetrahydrothiophene, thiazolidine or thiomorpholine);

The groups azetidine, cyclopropyl, cyclobutyl, 4,5-dihydro-oxazole, imidazolidine, morpholine, (1,4) -oxaze plates, with R 11 and R 12 together with the nitrogen atoms bonded thereto; To form a heterocyclic ring selected from 1,4-oxazepine, oxazolidine, piperidine, piperazine, pyrrolidine, tetrahydrothiophene, thiazolidine or thiomorpholine,

R4 and R22 of formula (I) and formula (Ia) may together with the carbon atoms bonded to them form a phenyl moiety,

R13 is fluorine, -CN, = O, -OH, -CF ₃ , -C (O) -OR ¹⁰ , -C (O) -N (R ¹⁰ ) -R ²⁰ , -N (R ¹⁰ ) -R ²⁰ ,-(C ₃ -C ₆ ) -cycloalkyl,-(C ₀ -C ₃ ) -alkylene-OR ¹⁰ , -Si- (CH ₃ ) ₃ , -SR ¹⁰ , -SO ₂ -R ¹⁰ ,-( C ₁ -C ₃ ) -perfluoroalkyl or

로부터의 잔기(여기서 Me은 메틸이고, R¹⁰ 및 R²⁰은 서로 독립적으로 수소, -(C₁-C₄)-알킬 또는 -(C₁-C₃)-퍼플루오로알킬이다)이고,

Residue from where Me is methyl and R ¹⁰ and R ²⁰ are independently of each other hydrogen,-(C ₁ -C ₄ ) -alkyl or-(C ₁ -C ₃ ) -perfluoroalkyl,

R ¹⁵ and R ¹⁶ are independently of each other hydrogen or-(C ₁ -C ₄ ) -alkyl, or together form a ring selected from the group cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein each ring is unsubstituted Or substituted one to three times with R ¹⁰ ,

R17 is-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl-OH,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₆ ) -alkyl,- (C ₃ -C ₈ ) -cycloalkyl,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₈ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,-(C _1- C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted 1, 2 or 3 times with -OH; -O- (C ₁ -C ₄₎ - alkyl, or R ¹⁰ of the compound, all stereoisomeric forms thereof, of formula I, relates to the acceptable salts thereof, and mixtures thereof in any proportion of the physiologically.

7) The present invention also

R ⁰ is

1) phenyl, wherein phenyl is unsubstituted or independently of one another mono- or di-substituted by R8,

2) pyridyl, wherein pyridyl is unsubstituted or independently of one another mono- or di-substituted by R8; or

3) heterocyclyl selected from the group thienyl, thiadiazolyl, isoxazolyl and thiazolyl, where heterocyclyl is substituted with a residue selected from the group thienyl, 2-thienyl and 3-thienyl, wherein the residue is Unsubstituted or independently of each other mono- or di-substituted by R8),

R8 is F, Cl, Br, -O-CH ₃ or -O-CF ₃ ,

Q is -C (O)-, -C (O) -O-methylene, -CH ₂ -C (O) -NH-, methylene or ethylene,

R ¹ is a hydrogen atom,

R ¹ -NV may form a 4-8 membered cyclic group selected from the groups azetidine, pyrrolidine, piperidine and piperazine,

R14 is fluorine, chlorine, methyl, ethyl or -NH ₂ ,

V is azaindolyl (1H-pyrrolopyridyl), azetidine, 1,4-diazepane, isoxazole, isoquinoline, piperazine, piperidine, pyrazine, pyridazine, pyrimidine, pyrrolidine, quina Heterocyclyl selected from the group containing compounds derived from sleepy, quinoline or tetrahydropyran, wherein the heterocyclyl moieties are unsubstituted or independently substituted or substituted with R14,

G is a direct bond,-(CH ₂ ) _m -or-(CH ₂ ) _m -NR ^10- ,

m is an integer 0, 1 or 2,

M is a hydrogen atom, (C ₂ -C ₄ ) -alkyl, isopropyl, azepanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, ketomorpholinyl, morpholinyl, [1,4 ] Oxazepanyl, piperidinyl, piperidonyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidyl, pyrrolidinyl, 1,4,5,6-tetrahydropyridazinyl or tetrahydropyra Nil, wherein the residues are unsubstituted or independently substituted or substituted with R 14,

R3, R4 and R22 are the same as or different from each other independently,

1) hydrogen atom,

2) fluorine, chlorine, bromine, iodine,

3)-(C ₁ -C ₄ ) -alkyl wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

_{4) - (C 1 -C 3} ) - alkyl, perfluoroalkyl,

5) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 13,

6)-(C ₀ -C ₂ ) -alkylene-O-R 19, wherein R 19 is a) a hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another Mono-, di-, or tri-substituted); c) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13; d) -CF ₃ or e) -CHF ₂ ],

7) -NO ₂ ,

8) -NR ¹⁰ -SO ₂ -R ¹⁰ ,

9) -SO _s -R ¹¹ (where s is 1 or 2),

10) -SO _t -N (R ¹¹ ) -R ¹² , where t is 1 or 2,

11)-(C ₀ -C ₄ ) -alkylene-C (O) —R ¹¹ ,

12)-(C ₀ -C ₄ ) -alkylene-C (O) —OR ¹¹ ,

13)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹² ,

14)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹² ,

15)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O)-(C ₁ -C ₄ ) -alkyl,

16) -C (O) -O-C (R15, R16) -O-C (O) -R17,

17)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O) -O- (C ₁ -C ₆ ) -alkyl,

18) -C (O) -O-C (R15, R16) -O-C (O) -O-R17,

19)-(C ₀ -C ₃ ) -alkylene-phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

20) pyridinyl, wherein pyridinyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R13,

21) thiazolyl, wherein thiazolyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R13,

22)-(C ₀ -C ₄ ) -alkylene- (C ₃ -C ₆ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

23)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl,

24)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl,

25)-(C ₀ -C ₃ ) -alkylene-O-CH _2- (C ₁ -C ₃ ) -perfluoroalkylene-CH ₂ -OH or

26)

로부터의 잔기(여기서 Me은 메틸이다)이고,

Is a residue from where Me is methyl

R11 and R12 are the same or different independently from each other,

1) hydrogen atom,

2)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13,

3)-(C ₀ -C ₆ ) -alkyl-phenyl,

4) -OR ¹⁷ or

5)-(C ₀ -C ₆ ) -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are unsubstituted independently or mono-, di- or tri-substituted with R 13, wherein the heterocyclyl is a group azetidine, Imidazolidine, morpholine, (1,4) -oxazepan or piperidine);

R11 and R12 together with the nitrogen atom bonded to them group azetidine, imidazolidine, morpholine, (1,4) -oxazepan, 1,4-oxazepine, piperazine, piperidine, pyrrolidine Or form a ring selected from thiomorpholine,

R 13 is fluorine, chlorine, -CN, = O, -OH, -CF ₃ , -C (O) -OR ¹⁰ , -C (O) -N (R ¹⁰ ) -R ²⁰ , -N (R ¹⁰ )- R ²⁰ ,-(C ₃ -C ₆ ) -cycloalkyl,-(C ₀ -C ₃ ) -alkylene-OR ¹⁰ , -Si- (CH ₃ ) ₃ , -SR ¹⁰ , -SO ₂ -R ¹⁰ , - (C ₁ -C ₄₎ - _{alkyl, - (C 1 -C 3)} - perfluoroalkyl or

로부터의 잔기(여기서 Me은 메틸이고, R¹⁰ 및 R²⁰은 서로 독립적으로 수소, -(C₁-C₄)-알킬 또는 -(C₁-C₃)-퍼플루오로알킬이다)이고,

Residue from where Me is methyl and R ¹⁰ and R ²⁰ are independently of each other hydrogen,-(C ₁ -C ₄ ) -alkyl or-(C ₁ -C ₃ ) -perfluoroalkyl,

R ¹⁵ and R ¹⁶ are independently of each other hydrogen or-(C ₁ -C ₄ ) -alkyl, or together form a ring selected from the group cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein each ring is unsubstituted Or substituted one to three times with R ¹⁰ ,

R17 is-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl-OH,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₆ ) -alkyl,- (C ₃ -C ₈ ) -cycloalkyl,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₈ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,-(C _1- C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted 1, 2 or 3 times with -OH; -O- (C ₁ -C ₄₎ - alkyl, or R ¹⁰ of the compound, all stereoisomeric forms thereof, of formula I, relates to the acceptable salts thereof, and mixtures thereof in any proportion of the physiologically.

The invention also

1- [5- (5-Chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1 H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide,

1- (3-methoxy-benzyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide,

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amides,

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidine-4- Yl) -amide,

1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4- (perhydro-1,4-oxazepin-4-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropyl Piperidin-4-yl) -amide,

1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -5- (perhydro-1,4-oxazepin-4-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropyl Piperidin-4-yl) -amide,

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (perhydro-1,4-oxazepine-4-carbonyl) -1H-pyrrole-2 Carboxylic acid (1-isopropylpiperidin-4-yl) -amide,

3- [1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -2,4 -Dimethyl-1H-pyrrol-3-yl] -propionic acid,

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid benzyl ester,

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid methyl ester,

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid,

1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid benzyl ester,

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid benzyl ester,

1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide,

1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid methyl ester,

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid methyl ester,

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid,

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (3-methoxy-azetidine-1-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide,

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1H-pyrrole-2,5-dicarboxylic acid 2-[(1-isopropylpiperidine-4- Yl) -amide] 5-[(2-methoxyethyl) -amide],

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1H-pyrrole-2,5-dicarboxylic acid 2-[(1-isopropylpiperidine-4- Il) -amide] 5-[(2-methoxyethyl) -methylamide],

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5-phenyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -Amide or

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-4- (perhydro-1,4-oxazepine-4-sulfonyl) A compound of Formula (I) and (Ia) which is -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide.

In general, the meaning of any group, moiety, heteroatom, number, etc. that may occur one or more times in the compounds of Formulas (I) and (Ia) is independent of the meaning of any other occurrence of group, moiety, heteroatom, number, and the like. All group residues, heteroatoms, numbers, etc., which may occur more than once in the compounds of Formulas (I) and (Ia) may be the same or different.

As used herein, the term alkyl is broadly understood to mean hydrocarbon residues which may be linear, ie straight or branched. Examples of "-(C ₁ -C ₈ ) -alkyl" or "-(C ₁ -C ₈ ) -alkylene" are methyl, methylene, ethyl, ethylene, propyl, propylene, butyl, butylene, pentyl, pentylene , Hexyl, heptyl or octyl, n-isomer of all these residues, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, iso 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, such as hexyl, secondary-butyl, tBu, tert-pentyl, secondary-butyl, tert-butyl or tert-pentyl Containing alkyl moiety. The term "-(C ₀ -C ₆ ) -alkyl" or "-(C ₀ -C ₈ ) -alkylene" refers to a hydrocarbon containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms Residues. The term "-C ₀ -alkyl" or "-C ₀ -alkylene" is a covalent bond.

Examples of — (C ₃ -C ₈ ) -cycloalkyl cyclic alkyl moieties are 3, 4, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, which may be saturated and / or unsaturated Cycloalkyl moieties containing 5, 6, 7, or 8 ring carbon atoms. For example, unsaturated cyclic alkyl groups such as cyclopentenyl or cyclohexenyl and unsaturated cycloalkyl groups may be bonded via any carbon atom.

The term “monocyclic or bicyclic 6 to 14 membered aryl” or “(C ₆ -C ₁₄ ) -aryl” is understood to mean an aromatic hydrocarbon radical containing 6 to 14 carbon atoms in the ring. Examples of-(C ₆ -C ₁₄ ) -aryl radicals are phenyl, naphthyl, for example 1-naphthyl and 2-naphthyl, biphenylyl, for example 2-biphenylyl, 3 -Biphenylyl and 4-biphenylyl, anthryl or fluorenyl. Biphenylyl radicals, naphthyl radicals and, in particular, phenyl radicals are preferred aryl radicals.

The term “mono- or bicyclic 4-15 membered heterocyclyl” or “(C ₄ -C ₁₅ ) -heterocyclyl” means that at least one of the 4 to 15 ring carbon atoms is nitrogen, oxygen or sulfur, such as It means a heterocycle replaced by a heteroatom. Examples are acridinyl, azaindole (1H-pyrrolopyridinyl), azabenzimidazolyl, azaspirodecanyl, azepineyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzo Thiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl , Cinnalinel, decahydrocinolinyl, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 6H-1,5 , 2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl , Indolinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromenyl, isodazolyl, isoindolinyl, isoindolinyl, isoquinolinyl (benzimidazolyl) , Isothiazolyl, isothiazolidinyl, isothiazolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopiperazinyl, morpholinyl, naphthyridinyl, octa Hydroisoquinolinyl, oxdiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathipanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl, 1,4-oxazinyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4 Oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, oxetanyl, oxocanyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxatiinyl, phenoxazinyl, phthalazinyl , Piperazinyl, piperidinyl, putridinyl, furinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyrimididazolyl, pyrido Thiazolyl, pyridinyl, pyridyl, pyrimidinyl, pyrrole Lidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolininyl, quinoxalinyl, quinuclininyl, tetrahydrofuranyl, tetrahydroisoiso Quinolinyl, tetrahydroquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1, 2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1 , 3-thiazinyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thiazolidinyl, thiazolinyl, thienyl, thietanyl, thienothiazolyl, thienooxazolyl, thienoimida Zolyl, thietanyl, thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1, 2,3-triazolyl, 1,2,3-triazole , 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and greater than a carbonyl chrysanthemate.

Benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnaolinyl, 2-furyl, 3-furyl; Imidazolyl, indolyl, indazolyl, isochromenyl, isoindoleyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, phthalazinyl, putridinyl, furinyl, pyrazinyl, pyrazolyl , Pyridazinyl, pyridimidazolyl, pyridopyridinyl, pyridopyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrrolyl; Preference is given to heterocyclyls such as 2-pyrrolyl, 3-pyrrolyl, quinolinyl, quinazolinyl, quinoxalinyl, tetrazolyl, thiazolyl, 2-thienyl and 3-thienyl.

Also,

가 바람직하다.

Is preferred.

The term "het" or "three to seven membered cyclic moieties containing one, two, three or four or more heteroatoms" means azepine, azetidine, aziridine, azirin, 1,4 diazephan, 1, 2-diazepines, 1,3-diazepines, 1,4-diazepines, diaziridines, diazirines, dioxazoles, dioxazines, dioxoles, 1,3-dioxolenes, 1,3-dioxolanes, Furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazolin, isoxazolidine, 2-isoxazolin, ketomorpholine, ke Topiperazine, morpholine, 1,2-oxathipan, 1,2-oxathiolane, 1,4-oxazepan, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, Oxazole, oxaziridine, oxetane, oxirane, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroli Dinon, pyrroline, tetrahydrofuran, tetrahydropyran, tetraha Dropyridine, tetrazine, tetrazole, thiadiazine thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine , Thiazoline, thienyl, thiethane, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3- It refers to a structure of a heterocycle that can be derived from compounds such as triazoles or 1,2,4-triazoles.

The term “R ¹ -NV may form a 4-8 membered cyclic group” or “R ¹¹ and R ¹² together with the nitrogen atom bonded thereto are the same or different selected from oxygen, sulfur and nitrogen in addition to the nitrogen atom Capable of forming a 4-8 membered monocyclic heterocyclic ring which may contain 1 or 2 heteroatoms "means azepan, azepin, azetidine, dioxazole, dioxazine, 1,4- Diazepan, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isox Azoles, isoxazolins, isoxazolidines, 2-isoxazolines, ketopiperazines, morpholines, [1,4] oxazanes, oxazoles, piperazine, piperidine, pyrazine, pyrazoles, pyrazolines , Pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, Azole, thiadiazole, thiazolidine, thiazolin, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3- It refers to a structure of a heterocycle that can be derived from compounds such as triazoles or 1,2,4-triazoles.

The term “R ¹⁵ and R ¹⁶ may form a 3-6 membered carbocyclic ring with carbon atoms bonded thereto” may be derived from compounds such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl It means a structure.

The term “R ¹ and R 22 together with the atoms bonded to them may form a 6-8 membered cyclic group containing at least 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen” Azocan, azocan-2-one, cycloheptyl cyclohexyl, cyclooctane, cyclooctene, 1,4-diazepane, 1,2-diazepines, 1,3-diazepines, 1,4-diazepines, [ 1,4] diazocan, [1,2] diazocan-3-one, [1,3] diazocan-2-one, dioxazine, [1,4] dioxocan, dioxol, ketopiperazine , Morpholine, 1,4-oxazepan, 1,2-diazepines, 1,3-diazepines, 1,4-diazepines, [1,4] diazocans, [1,2] diazocan-3- On, [1,3] diazokane-2-one, dioxazine, [1,4] dioxocan, dioxol, ketopiperazine, morpholine, 1,2-oxathiphan, 1,2-jade Photo, 1,3-oxazine, 1,4-oxazine, [1,4] oxazocan, [1,3] oxazocan-2-one, oxocan, oxocan-2-one, phenyl, piperazine , Piperidine, pyran, pyrazine, pyridazine, pyrimidine, 5, It refers to a structure of a heterocycle that can be derived from compounds such as 6,7,8-tetrahydro-1H-azosin-2-one or thiomorpholine.

The fact that many of the heterocycle names listed above are chemical names of unsaturated or aromatic ring systems does not mean that 4 to 15 membered mono- or polycyclic groups can be derived only from the corresponding unsaturated ring systems. The name herein is provided only to describe ring systems in terms of ring size and position relative to the number of heteroatoms. As described above, the 4-15 membered mono- or polycyclic group may be saturated or partially unsaturated or aromatic, and thus, in addition to the heterocycles listed above, optionally, partially or fully hydrated. All their homologues and their higher unsaturated homologues. Examples of fully or partially hydrogenated homologs of the above-listed heterocycles from which this group can be derived are pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, piperidine , 1,3-dioxolane, 2-imidazoline, imidazolidine, 4,5-dihydro-1,3-oxazole, 1,3-oxazolidine, 4,5-dihydro-1, 3-thiazole, 1,3-thiazolidine, perhydro-1,4-dioxane, piperazine, perhydro-1,4-oxazine (= morpholine), perhydro-1,4-thiazine (= Thiomorpholine), perhydroazepine, indolin, isoindolin, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline and the like can be mentioned.

The term "(C ₁ -C ₃₎ - perfluoroalkyl" is _{-CF 3, -CHF 2, -CH 2} F, -CHF-CF 3, -CHF-CHF 2, -CHF-CH 2 F, -CH ₂ -CF ₃ , -CH ₂ -CHF ₂ , -CH ₂ -CH ₂ F, -CF ₂ -CF ₃ , -CF ₂ -CHF ₂ , -CF ₂ -CH ₂ F, -CH ₂ -CHF-CF ₃ , -CH ₂ -CHF-CHF ₂ , -CH ₂ -CHF-CH ₂ F, -CH ₂ -CH ₂ -CF ₃ , -CH ₂ -CH ₂ -CHF ₂ , -CH ₂ -CH ₂ -CH ₂ F , -CH ₂ -CF ₂ -CF ₃ , -CH ₂ -CF ₂ -CHF ₂ , -CH ₂ -CF ₂ -CH ₂ F, -CHF-CHF-CF ₃ , -CHF-CHF-CHF ₂ , -CHF -CHF-CH ₂ F, -CHF-CH ₂ -CF ₃ , -CHF-CH ₂ -CHF ₂ , -CHF-CH ₂ -CH ₂ F, -CHF-CF ₂ -CF ₃ , -CHF-CF _2- CHF ₂ , -CHF-CF ₂ -CH ₂ F, -CF ₂ -CHF-CF ₃ , -CF ₂ -CHF-CHF ₂ , -CF ₂ -CHF-CH ₂ F, -CF ₂ -CH ₂ -CF ₃ , -CF ₂ -CH ₂ -CHF ₂ , -CF ₂ -CH ₂ -CH ₂ F, -CF ₂ -CF ₂ -CF ₃ , -CF ₂ -CF ₂ -CHF ₂ or -CF ₂ -CF ₂ -CH Partially or wholly fluorinated alkyl-residues that can be derived from residues such as _2F . The term “(C ₁ -C ₃ ) -perfluoroalkylene” refers to —CF ₂ —, —CHF—, —CHF—CHF ₂ —, —CHF—CHF—, —CH ₂ —CF ₂ —, —CH ₂ -CHF-, -CF ₂ -CF _2- , -CF ₂ -CHF-, -CH ₂ -CHF-CF _2- , -CH ₂ -CHF-CHF-, -CH ₂ -CH ₂ -CF ₂ -,- CH ₂ -CH ₂ -CHF, -CH ₂ -CF ₂ -CF _2- , -CH ₂ -CF ₂ -CHF-, -CHF-CHF-CF _2- , -CHF-CHF-CHF-, -CHF-CH ₂ -CF _2- , -CHF-CH ₂ -CHF-, -CHF-CF ₂ -CF _2- , -CHF-CF ₂ -CHF-, -CF ₂ -CHF-CF _2- , -CF ₂ -CHF- To be derived from residues such as CHF-, -CF ₂ -CH ₂ -CF _2- , -CF ₂ -CH ₂ -CHF-, -CF ₂ -CF ₂ -CF _2- , or -CF ₂ -CF ₂ -CHF Partially or wholly fluorinated alkylene-residue. Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or iodine, particularly preferably chlorine or iodine.

The optically active carbon atoms present in the compounds of formula (I) or formula (I ') may have an R configuration or an S configuration independently of one another. The compounds of formula (I) may exist in the form of pure enantiomers or pure diastereomeric or enantiomers and / or mixtures of diastereomers, for example racemic forms. The present invention relates to a mixture of pure diastereomers and diastereomers as well as mixtures of pure enantiomers and enantiomers. The present invention includes mixtures of two or more stereoisomers of Formulas I and Ia, which include mixtures of stereoisomers in any proportion. When the compounds of formulas (I) and (Ia) may exist as E isomers or Z isomers (or cis isomers or trans isomers), the present invention relates to both pure E isomers and pure Z isomers and to any proportion of E / Z mixtures. . The present invention also includes all tautomeric forms of the compounds of Formulas I and Ia. Diastereomers comprising E / Z isomers can be separated into individual isomers, for example, using chromatography. The racemates can be separated into two enantiomers by conventional methods, for example by chromatography on chiral or by cleavage, for example by crystallization of diastereomeric salts obtained with optically active acids or bases. Stereochemically single compounds of formula (I) or formula (I ') may also be obtained using stereochemically single starting materials or using stereoselective reactions.

Physiologically acceptable salts of the compounds of formulas (I) and (Ia) are physiologically acceptable nontoxic salts, in particular pharmaceutically usable salts. Such salts of compounds of formula (I) containing acidic groups such as carboxyl group COOH include, for example, alkali or alkaline earth metal salts such as sodium salts, potassium salts, magnesium salts and calcium salts; Salts with physiologically acceptable quaternary ammonium such as tetramethylammonium or tetraethylammonium; And acid addition salts with ammonia and physiologically acceptable organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, ethanolamine or tris- (2-hydroxyethyl) amine . Basic groups contained in the compounds of formulas (I) and (Ia), for example amino groups or guanidino groups, include acid addition salts such as inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; Or acid addition salts with sulfonic acids and organic carboxylic acids such as formic acid, acetic acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. . In addition, compounds of formulas (I) and (Ia) containing both basic and acidic groups, such as guanidino groups and carboxyl groups, may also exist as zwitterions (betaines), which are included in the present invention.

Salts of the compounds of formulas (I) and (Ia) may be prepared by conventional methods known to those skilled in the art, for example by combining the compounds of formulas (I) and (Ia) with inorganic or organic acids or bases in a solvent or dispersion, or by cation From other salts by exchange or anion exchange. The invention is also not suitable for use directly in medicaments because of its low physiological tolerance, but for example for the preparation of intermediates or physiologically acceptable salts for the delivery of further chemical modifications of the compounds of formulas (I) and (Ia). All salts of the compounds of formulas I and Ia suitable as starting materials are included. The invention further encompasses adducts with all solvates of the compounds of formulas (I) and (Ia), for example hydrates or alcohols. The present invention also includes derivatives and modifiers of compounds of Formulas (I) and (Ia), such as prodrugs, protected forms, and other physiologically acceptable derivatives, as well as active metabolites of compounds of Formulas (I) and (Ia). In particular, the present invention relates to prodrugs and protected forms of compounds of Formulas (I) and (Ia) which may be converted into compounds of Formulas (I) and (Ia) under physiological conditions. Suitable prodrugs of compounds of Formulas (I) and (Ia), ie, chemically modified derivatives of compounds of Formulas (I) and (Ia), having properties that are enhanced in a preferred manner with respect to solubility, bioavailability or duration of action, are known in the art It is known to the skilled person. More details related to prodrugs can be found in standard literature, for example, in Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115-130; or H. Bundgaard, Drugs of the Future 16 (1991) 443. Prodrugs suitable for compounds of Formulas (I) and (Ia) are especially acyl prodrugs; Carbamate prodrugs of acylable nitrogen-containing groups such as amino groups and guanidino groups; And amide prodrugs of carboxylic acid groups which may be present in ester prodrugs and compounds of formulas (I) and (Ia). In acyl prodrugs and carbamate prodrugs, one or more hydrogen atoms on the nitrogen atoms of this group, for example one or two, are acyl groups, or carbamate, preferably-(C ₁ -C ₆ ) -alkyl Replace with an oxycarbonyl group. Acyl and carbamate groups suitable for acyl prodrugs and carbamate prodrugs include, for example, R ^p1 is hydrogen, (C ₁ -C ₁₈ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl, (C ₃ -C ₈₎ - cycloalkyl, - (C ₁ -C ₄₎ - alkyl _{-, (C 6 -C 14)} - _{aryl, Het-, (C 6 -C 14} ) - aryl - (C ₁ -C ₄₎ -alkyl- or Het- (C ₁ -C ₄₎ - alkyl - a, R ^p2 is a group, which means R ^p1 except hydrogen R ^p1 -CO- and R ^p2 O-CO-.

Particularly preferred compounds of formula (I) and formula (I ') comprise two or more residues as described in the preferred compounds of formula (I) and formula (I') above, or which may have one or more of the general definitions or specific indications of the residues given in the definitions of the preferred compounds. It is things that have. Preferred definitions of residues and all possible combinations of definitions given in specific indications are expressly the subject matter of the present invention.

In addition, with respect to all preferred compounds of formulas (I) and (Ia), all stereoisomeric forms and mixtures thereof and physiologically acceptable salts thereof, as well as prodrugs thereof, are expressly subject to the present invention. Similarly, in all preferred compounds of Formulas (I) and (Ia), all residues present at least once in a molecule may be independent of one another, and may be the same or different.

Compounds of formulas (I) and (Ia) are known in nature and can be prepared using methods and techniques that are obvious to those skilled in the art. Starting materials or building blocks for use in general synthetic methods that can be used to prepare compounds of Formulas (I) and (Ia) are readily available to those skilled in the art. In many cases they are commercially available or described in the literature. If not, they can be prepared from precursor compounds which can be used as readily as the methods described in the literature or the methods described herein.

Compounds of formulas (I) and (Ia) are known in nature and can be prepared using methods and techniques that are obvious to those skilled in the art. Starting materials or building blocks for use in general synthetic methods that can be used to prepare compounds of Formulas (I) and (Ia) are readily available to those skilled in the art. In many cases they are commercially available or described in the literature. If not, they can be prepared from precursor compounds which can be used as readily as the methods described in the literature or the methods described herein.

In general, compounds of formula (I) and formula (I ') can be prepared by the process of convergent synthesis, for example, by linking two or more fragments that can be resynthesically derived from formula (I) and formula (I'). More specifically, suitably substituted starting pyrrole derivatives can be used as building blocks in the preparation of compounds of formulas (I) and (Ia). If not commercially available, these pyrrole derivatives may be prepared according to known standard methods for the formation of pyrrole ring systems. By selecting suitable precursor molecules, such pyrrole synthesis allows the introduction of various substituents into various positions of the pyrrole system, which can be chemically modified to finally be a molecule of formula (I) and (Ia) with the desired substitution pattern. As a comprehensive overview of a number of descriptions and literature references for pyrrole chemistry and synthetic methods for the preparation thereof, see CW Bird, "Comprehensive Heterocyclic Chemistry" Vol. 4, CW Bird and GWH Cheeseman, eds., Pergamon Press, Oxford, 1984; RJ Sundberg, "Comprehensive Heterocyclic Chemistry II" Vol. 2, A. Katritzky, Ch. Rees, E. Scriven, eds., Elsevier 1996; A. Gossauer, Houben-Weyl, "Methoden der Organischen Chemie" (Methods of Organic Chemistry), Thieme, Stuttgart, Germany 1994, Vol. E6a "Hetarene I"; DM Ketcha, Progress in Heterocyclic Chemistry 2002, 14, 114-138; DM Ketcha, Progress in Heterocyclic Chemistry 2001, 13, 111-129; DM Ketcha, Progress in Heterocyclic Chemistry 2000, 12, 114-133; DS Black, Science of Synthesis 2002, 9, 441-552; D. van Leusen, AM van Leusen, Organic Reactions 2001, 57, 417-666; VF Ferreira et al., Org. Prep. Proced. Int. 2001, 33, 411-454.

If starting pyrrole derivatives are not commercially available and must be synthesized, they can be prepared, for example, according to the known pyrrole synthesis mentioned above. In the following, particularly interesting methods are listed and briefly referred to in the aspects of the present invention, but these are standard methods which are comprehensively discussed in the literature and are known to those skilled in the art. Although not always clearly indicated, positional isomers may occur in certain cases during the synthesis of the reactions mentioned below. Even when such mixtures are not positional isomers, they can be separated using modern separation techniques such as, for example, preparative HPLC.

Examples for some common methods:

1) Preparation of pyrrole from □ -dicarbonyl compound, □ -halocarbonyl compound and amine (Hantzsch synthesis):

A. Hantzsch, Ber. Dtsch. Chem. Ges. 1890, 23, 1474

2) pyrrole (Paal-Knorr synthesis) from 1,4-diketo compound and amino compound:

a) W. J. Thomson and C. A. Buhr, J. Org. Chem. 1983, 48, 2769

b) H. Stetter and R. Lauterbach, Liebigs Ann. Chem. 1962, 655, 20

3) Pyrrole (Knorr synthesis) from □ -aminocarbonyl compounds and activated ketones:

a) H. Ogoshi et al., Tetrahedron Lett. 1983, 24, 929

b) J. V. Cooney, E. J. Beal and R. N. Hazlett, Org. Prep. Proced. Int. 1983, 15, 292

c) J. M. Hamby and J. C. Hodges, heterocycle 1993, 35, 843

4) 2-hydroxypyrrole can be obtained by intramolecular aldol condensation of □ -acylamino ketones:

a) T. Kato, M. Sato and T. Yoshida, Chem. Pharm. Bull. 1971, 19, 292

b) R. L. Wineholt, E. Wyss and J. A. Moore, J. Org. Chem. 1966, 31, 48

5) Synthesis of 2-aminopyrrole:

M. T. Cocco et al., Farmaco Ed. Sci. 1988, 43, 103

6) 2,5-unsubstituted pyrrole:

A. M. van Leusen et al., Tetrahedron Lett. 1972, 5337

7) Reaction of 1,3-dicarbonyl compound and glycine ester to form pyrrole-2-ester:

a) S. Mataka et al., synthesis 1982, 157

b) G. H. Walizei and E. Breitmaier, synthesis 1989, 337

c) H. K. Hombrecher and G. Horter, synthesis 1990, 389

In addition, in order to obtain the desired substitution in the pyrrole ring systems of the formulas (I) and (Ia), functional groups introduced into the ring system during pyrrole synthesis can be chemically modified. In particular, the groups present in the pyrrole ring system can be modified in various reactions, thus obtaining the desired residues. For example, pyrrole containing hydrogen atoms in the 2- or 3-position can also be obtained by saponifying the pyrrole containing esters at each position, followed by dicarboxylation. Alkyl- or hydroxymethyl groups bound to the pyrrole core, as well as formyl groups, are known to those skilled in the art by various oxidation reactions, such as various functional groups, for example corresponding carboxylic or carboxylic esters. You can switch. In addition, the nitrile group bound to the pyrrole ring can be converted to the desired acid, for example, under acidic or basic conditions. In addition, carboxylic acid groups and acetic acid groups at 2-, 3-, 4- and 5-positions can be converted into their counterparts in general for chain extension of carboxylic acids. Halogen atoms can be introduced, for example, in 2-position, 3-position, 4-position and 5-position according to methods as described in the literature. For fluolation of pyrrole, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate) ("selectfluoro") can be used [ See J. Wang and AI Scott, J. Chem. Soc., Chem. Commun. 1995, 2399]. However, if desired, other suitable fluorination reagents, such as xenon difluoride, may also be used (J. Wang and AI Scott, Tetrahedron 1994, 50, 6181). Chlorination, bromination or iodide of pyrrole can be accomplished by reaction with halogen elements or using NCS, NBS or NIS and many other reagents known to those skilled in the art. Suitable precursors are also described, for example, in HJ Anderson and S.-F. Lee, Can. J. Chem. 1965, 43, 409; HM Gilow, DE Burton, J. Org. Chem. 1981, 46, 2221; S. Petruso et al., J. Heterocycl. Chem. 1990, 27, 1209; M. D'Auria et al., J. Chem. Soc., Perkin Trans. 1 1997, 2369. Depending on the reaction conditions, reagents, stoichiometry and substitution pattern, halogen is introduced at the 2-position and / or 3-position and / or 4-position and / or 5-position. Various substituents can be introduced into the heterocyclic nucleus by metallization by selective halogen / metal exchange or by selective hydrogen / metal exchange and subsequent reaction of a wide range of electrophiles. JA Ganske et al., J. Org. Chem. 1989, 54, 4801; D. Monti and G. Sleiter, Gazz. Chim. Ital. 1990, 120, 587; A. Furstner, R. Singer and P. Knochel, Tetrahedron Lett. 1994, 35, 1047; A. Minato et al., Tetrahedron Lett. 1981, 22, 5319]. Halogen or hydroxy groups (via triplate or nonaplate), or primary amines (if their diazonium salts) present in the pyrrole structure, for example directly or after interconversion to the corresponding tin or boronic acid, for example , Transition metals, mainly palladium or nickel catalysts or copper salts and, for example, -CN, -CF ₃ , -C ₂ F ₅ , ethers, acids, amides, amines, mediated using reagents described in the following references: And various other functional groups such as alkyl- or aryl groups. F. Diederich, P. Stang, "Metal-catalyzed Cross-coupling Reactions", Wiley-VCH, 1998; or M. Beller, C. Bolm, "Transition Metals for Organic Synthesis", Wiley-VCH, 1998; J. Tsuji, "Palladium Reagents and Catalysts", Wiley, 1996; J. Hartwig, Angew. Chem. 1998, 110, 2154; In B. Yang, S. Buchwald, J. Organomet. Chem. 1999, 576, 125; T. Sakamoto, K. Ohsawa, J. Chem. Soc. Perkin Trans I 1999, 2323; D. Nichols, S. Frescas, D. Marona-Lewicka, X. Huang, B. Roth, G. Gudelsky, J. Nash, J. Med. Chem. 1994, 37, 4347; P. Lam, C. Clark, S. Saubern, J. Adams, M. Winters, D. Chan, A. Combs, Tetrahedron Lett. 1998, 39, 2941; D. Chan, K. Monaco, R. Wang, M. Winters, Tetrahedron Lett. 1998, 39, 2933; V. Farina, V. Krishnamurthy, W. Scott, "The Stille Reaction", Wiley, 1994; F. Qing et al., J. Chem. Soc. Perkin Trans. I 1997, 3053; S. Buchwald et al., J. Am. Chem Soc. 2001, 123, 7727; S. Buchwald et al., Organic Lett. 2002, 4, 581; T. Fuchikami et al., Tetrahedron Lett. 1991, 32, 91; Q. Chen et al., Tetrahedron Lett. 1991, 32, 7689].

For example, nitro groups can be reduced to amino groups using various reducing agents such as sulfides, dithionites, complex hydrides or by catalytic hydrogenation. Reduction of the nitro group may also be carried out in a subsequent step of the synthesis of the compounds of formulas I and Ia, and reduction of the nitro group to the amino group is also carried out, for example, with a group such as a cyano group and hydrogen sulfide At the time of hydrogenation of a group or group, it may occur simultaneously with the reaction carried out on another functional group. In order to introduce or derive the residues R ^1a and R ^1b of the formula (2), the amino group is a standard method of alkylation, for example, by reaction with (substituted) alkyl halides or reduction amination of carbonyl compounds. According to the standard method of acylation, for example by reaction with activated carboxylic acid derivatives such as acid chlorides, anhydrides, activated esters, or with carboxylic acids in the presence of an activator, It can be modified according to the standard method of sulfonylation by reaction with sulfonyl chloride.

The ester group present in the pyrrole nucleus can be hydrolyzed to the corresponding carboxylic acid (or sometimes substituted or unsubstituted benzyl ester is modified to the corresponding carboxylic acid by the hydrogenation process), and then the activity is respectively amide or alcohol. It can be reacted with amines or alcohols under standard conditions to yield. Ester groups present in the pyrrole nucleus can be converted to other esters by transesterification. Carboxylic acids bound to suitable pyrrole nuclei are also alkylated to yield esters. After ether groups present in the pyrrole nucleus, such as benzyloxy groups or other easily cleaved ether groups, are cleaved to obtain hydroxy groups, various agents, such as etherification agents or hydroxy groups, may be substituted for other groups. It can be reacted with an activator which can be replaced. Sulfur-containing groups can be reacted equally.

During the synthesis process for modifying groups R ⁸⁷ or R ^{8 ′} of Formulas 2 and 3 bound to a pyrrole ring system using parallel synthesis, various reactions can be very useful, including, for example, palladium, nickel or copper. have. Such reactions are described, for example, in F. Diederich, P. Stang, "Metal-catalyzed Cross-coupling Reactions", Wiley-VCH, 1998; or M. Beller, C. Bolm, "Transition Metals for Organic Synthesis", Wiley-VCH, 1998; J. Tsuji, "Palladium Reagents and Catalysts", Wiley, 1996; J. Hartwig, Angew. Chem. 1998, 110, 2154; In B. Yang, S. Buchwald, J. Organomet. Chem. 1999, 576, 125; P. Lam, C. Clark, S. Saubern, J. Adams, M. Winters, D. Chan, A. Combs, Tetrahedron Lett. 1998, 39, 2941; D. Chan, K. Monaco, R. Wang, M. Winters, Tetrahedron Lett. 1998, 39, 2933; J. Wolfe, H. Tomori, J. Sadight, J. Yin, S. Buchwald, J. Org. Chem. 2000, 65, 1158; V. Farina, V. Krishnamurthy, W. Scott, "The Stille Reaction", Wiley, 1994; S. Buchwald et al., J. Am. Chem. Soc. 2001, 123, 7727; S. Buchwald et al., Org. Lett. 2002, 4, 581.

In addition, the above reactions for the conversion of functional groups are generally described in organic chemistry [M. Smith, J. March, "March's Advanced Organic Chemistry", Wiley-VCH, 2001 and in treatises like Houben-Weyl, " Methoden der Organischen Chemie "(Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart, Germany, or" Organic Reactions ", John Wiley & Sons, New York, or RC Larock," Comprehensive Organic Transformations ", Wiley-VCH, 2 ^nd ed 1999, B. Trost, I. Fleming (eds.) "Comprehensive Organic Synthesis", Pergamon, 1991; A. Katritzky, C. Rees, E. Scriven, "Comprehensive Heterocyclic Chemistry II", Elsevier Science, 1996, and extensively describes reactions and primary source literature. Due to the fact that the functional group in this case is linked to the pyrrole ring, in particular the specific means for applying the reaction conditions or for selecting a particular reagent from the various reagents that can be used in principle for the conversion reaction and otherwise achieving the desired conversion It may be necessary in some cases to take and use, for example, protection group techniques. However, in finding suitable reaction modifications, the reaction conditions in this case do not cause any problems for those skilled in the art. The structural atoms present in the moiety at the 1 position of the pyrrole ring in the compounds of formulas (I) and (Ia) and the COR ^{8 ′} group present in the residues at the 2 and / or 3/4 and / or 5-position of the pyrrole ring are described below. Parallel synthesis methodologies, such as methodologies, can be used to introduce pyrrole derivatives, starting materials obtainable as described by successive reaction steps, using procedures well known to those skilled in the art.

As the compound of the formula (2), for example, the residue R ^{8 '} which can be introduced by condensation of the corresponding carboxylic acid of the formula (2) with the compound of the formula HR ^8' , ie, the amine of the formula HN (R ^{1 '} ) -VGM It provides a compound of. Thus, the obtained compound of formula 3 may comprise a final group already aimed at, i.e., group R ^{8 '} wherein R ⁸⁷ is selected from the group -N (R ¹ ) -VGM and Residues or residues R ^{8 ′} and residues R ⁸⁷ in the compound of Formula 3, which may be R ⁰ -Q-, or optionally subsequently obtained, are each represented by residues -N (R ¹ ) -VGM and residues R ⁰ -Q- In turn, the desired compounds of formulas (I) and (Ia) can be provided.

Thus, the residues R ^{8 ′} and residues R ^{1 ′} and ^' -VGM included herein may have an explicit meaning for R ¹ and -VGM, respectively, or may also be functional at residue R ^1' and residue -VGM. The group may also exist in the form of a group which can subsequently be converted to the final group R ¹ and the group -VGM. Functional groups may be present in the form of prodrug groups or derivatives, for example in protective form. In the course of the preparation of the compounds of the formulas (I) and (Ia), each is usually in the form of a prodrug group which can subsequently be converted to the desired functional group by a protecting group to suit the synthetic problem, or temporarily as a block functional group. It is advantageous or necessary to introduce into functional groups which reduce or prevent unwanted or side reactions in the synthesis step. This strategy is known to a person skilled in the art [see: for example, TW Greene and PGM Wuts, " Protective Groups in Organic Synthesis" 3 rd ed, Wiley, 1999, or P. Kocienski, "Protecting Groups" Thieme , 1994]. Examples of prodrug groups include cyano groups and nitro groups. The cyano group may be modified to an aminomethyl group by a carboxylic acid derivative or reduction in a subsequent step, or the nitro group may be modified to an amino group by reduction such as a catalytic hydration reaction. In addition, the protecting group can have the same meaning as the solid phase and can be decomposed from the solid phase normal phase for removal of the protecting group. The use of this technique is known to those skilled in the art (K. Burgess (ed.), "Solid Phase Organic Synthesis" New York, Wiley, 2000). For example, the phenolic hydroxy group can be linked to a trityl-polystyrene resin that acts as a protecting group, and the molecule is degraded from the resin by treatment with TFA at the end of the synthesis.

Residue R ⁸⁷ in the compound of Formula 2 and compound 3 is finally the group -QR ⁰ (as defined above) present in the desired target molecule of Formulas I and Ia, or subsequently the functional group is in a protective form Or R ⁸⁷ may be a hydrogen atom or a protecting group for the nitrogen atom of the pyrrole ring, or a group which may be transformed into a prodrug group or derivative of group -QR ⁰ , for example group -QR ⁰ . Similarly, residues R ^1a and R ^1b of Formulas 2 and 3 have corresponding definitions of R ⁴ and R ³ as defined above in Formulas I and Ia, but for the synthesis of compounds of Formulas I and Ia Can in principle also be present in the step of condensation of the compound of formula 2 with the compound of formula HR ^{8 ′, so that} the compound of formula 3 is provided in the form of prodrug groups or in protective form.

Residues R ⁸⁶ in the compound of formula 2, which may be the same or different, may be, for example, hydroxy or (C ₁ -C ₄ ) -alkoxy, ie group COR ⁸⁶ present in the compound of formula 2 For example free carboxylic acids or esters thereof, such as alkyl esters which may be group COR ^{8 ′} in the compounds of formulas (I) and (Ia). Group COR ⁸⁶ may also be other activated derivatives of carboxylic acids capable of forming amides, esters or thioesters with compounds of the formula HR ^{8 ′} . Groups COR ⁸⁶ are, for example, acid chlorides, activated esters, for example substituted phenyl esters or N-hydroxysuccinimides or hydroxybenzotriazole esters, azolides, for example imidazoli de, an azide or a mixed anhydride, for example, derivatives are all of the formula HR ^{8 'under} a carbonic acid ester or sulfonic Foshan and may be an anhydride mixture, the standard conditions, which may be prepared from the carboxylic acid by standard procedures It may react with amines, alcohols or mercaptans. The carboxylic acid group COOH represented by COR ⁸⁶ in the compound of formula (2) can be obtained from ester groups introduced into the pyrrole system during pyrrole synthesis, for example, by standard hydrogenation procedures. It can also be obtained, for example, by hydrolysis of nitriles introduced into the pyrrole system during pyrrole synthesis.

Compounds of formulas (I) and (Ia) in which the group COR ^{8 '} is an ester group are also conventional esterification reactions, such as, for example, the reaction of acids with alcohols under acid catalysts, or the alkylation of salts of carboxylic acids with electrophiles such as alkyl halides, By transesterification from other esters can be prepared from compounds of formula 2 wherein COR ⁸⁶ is a carboxylic acid group. Compounds of formulas (I) and (Ia) in which group COR ^{8 '} is an amide group can be prepared by conventional amination reactions from compounds of formula (2) in which amines and COR ⁸⁶ are carboxylic acid groups or esters thereof. Particularly for the preparation of the amides, compounds of formula (2) wherein COR ⁸⁶ is a carboxylic acid group can be condensed under standard conditions with compounds of formula (HR ^{8 ')} , which are amines, by the usual coupling reagents used in peptide synthesis. Such coupling reagents are, for example, carbodiimi such as dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDCI) or diisopropylcarbodiimide mid; Carbonyldiazoles such as carbonyldiimidazole (CDI) and similar reagents; Propylphosphonic anhydride, O-((cyano- (ethoxycarbonyl) -methylene) amino) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TOTU), diethylphosphoryl Cyanide (DEPC), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) or bis- (2-oxo-3-oxazolidinyl) -phosphoryl chloride (BOP-Cl) and many others.

Residues -QR ⁰ present in the pyrrole of formulas (I) and (Ia), residues R ⁸⁷ present in the pyrrole of formula (2), or residues -QR ⁰ or R ⁸⁷ present in the form of a protecting group or precursor group are preliminary, for example, If not already introduced during the synthesis of the pyrrole nucleus, these residues may, for example, undergo N-alkylation, reductive amination, N-arylation, N-acylation or N-sulfonylation of the ring nitrogen atoms of the heterocycle. Can be introduced at the 1-position of the pyrrole system by conventional literature methods known to those skilled in the art. N-alkylation of a ring nitrogen atom is, for example, in terms of surface conditions, preferably in the presence of a base such as K ₂ CO ₃ , Cs ₂ CO ₃ , NaH, KOH or KO ^t Bu, of formula LG-QR ⁰ or of formula R Can be carried out using an alkylated compound of ^87- LG, wherein in this case the atoms of group Q or group R ⁸⁷ bonded to the group LG are aliphatic carbon atoms of the alkyl moiety, and LG is a leaving group, for example, Halogen, such as chlorine, bromine or iodine, or sulfonyloxy groups such as tosyloxy, mesyloxy or trifluoromethylsulfonyloxy. LG can be, for example, a hydroxy group achieved by known Mitsunobu reactions with conventional activators to achieve alkylation reactions.

For the preparation of compounds in which A is a direct bond and the aromatic is directly bonded at the 1-position of the imidazole system, conventional arylation procedures can be used. For example, aryl fluorides such as alkyl fluorobenzoate or 4-fluorophenyl methyl sulfone can be used as the arylating agent. Such a process is described, for example, in M. Yamada et al. J. Med. Chem. 1996, 39, 596; J. Ohmori et al. J. Med. Chem. 1996, 39, 3971. Alternatively, a wide range of substituted aryl iodide, brominated aryl or aryl triflate can be found, for example, in P. Cozzi et al. Farmaco 1987, 42, 205; P. Unangst, D. Connor, R. Stabler, R. Weikert, J. Heterocycl. Chem. 1987, 24, 811; G. Tokmakov, I. Grandberg, Tetrahedron 1995, 51, 2091; D. Old, M. Harris, S. Buchwald, Org. Lett. 2000, 2, 1403, G. Mann, J. Hartwig, M. Driver, C. Fernandez-Rivas, J. Am. Chem. Soc. 1998, 120, 827; J. Hartwig, M. Kawatsura, S. Hauk, K. Shaughnessy, L. J. Org. Chem. 1999, 64, 5575; S. Buchwald et al., J. Am. Chem. Soc. 2001, 123, 7727, may be provided as an arylating agent at the 1-position of the heterocyclic nitrogen of the copper salt or palladium mediated reaction. In addition, such arylation is described, for example, in W. Mederski, M. Lefort, M. Germann, D. Kux, Tetrahedron 1999, 55, 12757; J. Collman et al., J. Org. Chem. 2001, 66, 7892 can be achieved according to the reaction of a wide range of substituted aryl boronic acid as described. Preferred methods include, but are not limited to, those described in the Examples.

Compounds of the invention are serine protease inhibitors that inhibit the activity of blood coagulation enzyme factor Xa and / or factor VIIa. In particular, they are very active inhibitors of factor Xa. These are certain serine protease inhibitors that do not inhibit the activity of other proteases that do not substantially require inhibition. For factor Xa inhibition, preferred embodiments of the present invention have Ki <1 mM for factor Xa inhibition and preferably (the same concentration) as measured in the assay described below, with or without incident factor VIIa inhibition. Including inhibitors), which do not substantially inhibit the activity of fibrinolysis and other proteases involved in coagulation, where inhibition is not required. The compounds of the present invention inhibit factor Xa catalytic activity either directly in the prothrombinase complex or as soluble structural units, or indirectly by inhibiting the collection of factor Xa into the prothrombinase complex.

As inhibitors of Factor Xa and / or Factor VIIa, the compounds of Formulas I and Ia, physiologically acceptable salts thereof, and their prodrugs generally do not serve or aim for the activity of Factor Xa and / or Factor VIIa. Treatment and prophylaxis of conditions which may have an undesired range or which may be advantageously affected by inhibiting or reducing the activity of Factor Xa and / or Factor VIIa, or inhibiting Factor Xa and / or Factor VIIa or decreasing their activity It is suitable for the prevention, alleviation or treatment required by a physician. Since inhibition of factor Xa and / or factor VIIa affects blood coagulation and fibrinolysis, the compounds of Formulas I and Ia and physiologically acceptable salts thereof and their prodrugs generally reduce blood coagulation, or Treatment and prevention of conditions in which the activity of the blood coagulation system plays a role and has an undesired range or may be advantageously affected by reducing blood coagulation, or the prevention, slowing down of the activity required by the physician to reduce the activity of the blood coagulation system. Suitable for shoes or treatment. Thus, a specific subject of the present invention is to reduce or inhibit unwanted blood coagulation, particularly in individuals by administering an effective amount of a compound of Formulas I and Ia or a physiologically acceptable salt thereof or a prodrug thereof and a pharmaceutical formulation thereof. will be.

The invention also inhibits the compounds of Formulas (I) and (Ia) and / or physiologically acceptable salts and / or prodrugs thereof, and Factor Xa and / or Factor VIIa for use as a medicament (or drug), Agents for affecting blood coagulation, inflammatory response or fibrinolysis, or for treating or preventing diseases mentioned above or below, for example, for treating or preventing cardiovascular disease, thromboembolism or restenosis. To the use of the compounds of formulas (I) and (Ia) and / or physiologically acceptable salts thereof and / or their prodrugs for the preparation of these compounds. The invention also relates to inhibiting factor Xa and / or factor VIIa, to affect blood coagulation or fibrinolysis, or to treat or prevent diseases mentioned above or below, for example, cardiovascular diseases, Including the use of the compounds of Formulas (I) and (Ia) and / or physiologically acceptable salts and / or their prodrugs thereof for use in treating or preventing thromboembolism or restenosis, and methods of such treatment and prevention It relates to a method of pursuing a purpose. The invention also relates to compounds of the formulas (I) and (Ia) and / or physiologically acceptable thereof, in addition to conventional pharmaceutically acceptable carriers, ie one or more pharmaceutically acceptable carrier materials or excipients and / or auxiliary substances or additives. A pharmaceutical formulation (or pharmaceutical composition) containing an effective amount of one or more salts and / or prodrugs thereof.

The invention also relates to disease states, such as aberrant thrombus formation, acute myocardial infarction, unstable angina, thromboembolism, thromboembolism or acute vascular obstruction (PTCA), transient ischemic attack, stroke, intermittent treatment associated with percutaneous vascular dilatation. Laparation or coronary or peripheral artery bypass surgery, stenosis, restenosis after cardiac or venous angioplasty, maintenance of vascular access for long-term hemodialysis patients, pathological thrombus formation in the veins of the lower abdomen, knee or hip surgery, pulmonary thrombus It relates to the treatment of disseminated intravascular coagulation that occurs in the vascular system during embolism or septic shock, viral infection or cancer disease. Compounds of the invention can also be used to reduce the inflammatory response. Examples of specific diseases in which the compounds of formulas (I) and (Ia) may be used for treatment and prevention include cardiac disease, myocardial infarction, angina, vascular restenosis, restenosis after angioplasty, such as PTCA, adult respiratory distress syndrome, multi-organ Dysfunction and disseminated intravascular coagulation disease. Examples of related complications associated with surgery are thrombosis such as deep veins and proximal venous thrombosis that can occur after surgery.

The compounds of formulas (I) and (Ia), physiologically acceptable salts thereof and their prodrugs may be administered to animals, preferably mammals, especially humans, as agents for treatment or prophylaxis. They may be administered on their own or in the form of mixtures mixed with one another or in the form of pharmaceutical preparations which allow for digestive or parenteral administration.

The agent may be administered orally, for example, in the form of pills, tablets, lacquer tablets, epidermal tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. However, administration may also be parenterally, for example intravenously, intramuscularly or subcutaneously, for example rectally in the form of suppositories, in the form of injection or infusion solutions, microcapsules, implants or rods, or For example, it may be performed transdermally or topically in the form of ointments, solutions or tinctures, or in other ways in the form of aerosols or nasal sprays.

The pharmaceutical preparations according to the invention are prepared in a manner known per se and are familiar to those skilled in the art, and the compound (s) of Formulas I and Ia and / or physiologically acceptable salts thereof and In addition to their prodrugs, pharmaceutically acceptable inert inorganic and / or organic carriers are used. To prepare pills, tablets, epidermal tablets and hard gelatin capsules, it is possible to use, for example, lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts and the like. Carriers of soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils and the like. Suitable carriers for the preparation of solutions such as injection solutions or emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils and the like. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. Pharmaceutical formulations generally contain about 0.5 to 90% by weight of the compounds of Formulas I and Ia and / or physiologically acceptable salts and / or prodrugs thereof. The amount of active ingredient of Formulas (I) and (Ia) and / or physiologically acceptable salts and / or prodrugs thereof in the pharmaceutical formulations is generally from 0.5 to about 1000 mg, preferably from about 1 to about 500 mg.

In addition to the active ingredients of Formulas (I) and (Ia) and / or their physiologically acceptable salts and / or prodrugs and carrier materials, pharmaceutical preparations may contain additives such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers , Emulsifiers, preservatives, sweeteners, colorants, seasonings, fragrances, thickeners, diluents, buffers, solvents, solubilizers, preparations for achieving the depot effect, salts for changing the osmotic pressure, coatings or antioxidants can do. They may also contain two or more compounds of Formulas (I) and (Ia) and / or physiologically acceptable salts thereof and / or prodrugs thereof. If the pharmaceutical formulation contains two or more compounds of formulas (I) and (Ia), the selection of the individual compounds may be aimed at the specific gross pharmacological profile of the pharmaceutical formulation. For example, highly potent compounds with shorter durations of action may be combined with lower potency long acting compounds. The flexibility afforded for the selection of substituents in the compounds of Formulas (I) and (Ia) selects such desired compounds by controlling in large quantities over the biological and physicochemical properties of the compounds. Moreover, in addition to one or more compounds of Formulas (I) and (Ia) and / or physiologically acceptable salts and / or prodrugs thereof, the pharmaceutical formulation may also contain one or more other therapeutically or prophylactically active ingredients.

When using compounds of formulas (I) and (Ia), the dosage can vary widely and, as is commonly known to physicians, to suit the individual's condition in the case of each individual. This depends, for example, on the particular compound to be used, the nature and severity of the disease to be treated, the manner and plan of administration, whether the disease to be treated is acute or chronic, or whether prevention has been carried out. Suitable dosages can be constructed using clinical approaches that are well known in the medical arts. In general, the daily dosage for achieving a desired result in an adult weighing about 75 kg is 0.01 mg / kg to 100 mg / kg, preferably 0.1 mg / kg to 50 mg / kg, in particular 0.1 mg / kg to 10 mg / kg (mg in kg of body weight in each case). The daily dose may be administered several times, for example in two, three or four times, especially when administered in relatively large quantities. As usual, it may need to deviate above or below the indicated daily dosage, depending on the individual's behavior.

Compounds of formulas (I) and (Ia) may also be used as anticoagulants outside of the individual. For example, an effective amount of a compound of the present invention may be contacted with a freshly extracted blood sample to prevent coagulation of the blood sample. In addition, the compounds of the formulas (I) and (Ia) and salts thereof are used for diagnostic purposes, for example in in vitro diagnostics, and can be used as adjuvants in biochemical investigations. For example, compounds of Formulas (I) and (Ia) can be used in the assay to confirm the presence of Factor Xa and / or Factor VIIa or to separate Factor Xa and / or Factor VIIa into substantially purified form. Compounds of the invention may be labeled, for example, with radioisotopes, and then the compounds labeled and bound to Factor Xa and / or Factor VIIa are detected using routine methods useful for detecting specific labels. . Thus, the compounds of Formulas (I) and (Ia) or salts thereof can be used as probes to detect the location or amount of Factor Xa and / or Factor VIIa activity in vivo, in vitro or ex vivo.

Furthermore, the compounds of formulas (I) and (Ia) are for preparing other compounds, in particular other pharmaceutically active ingredients, which may be obtained from compounds of formulas (I) and (Ia), for example by introduction of substituents or by modification of functional groups. It can be used as a synthetic intermediate.

General synthetic procedures for preparing compounds useful in the present invention are shown in the examples given below. Both descriptions and practical methods of various aspects of the invention have been described appropriately. The following examples are merely intended to illustrate the invention, not to limit the scope or spirit thereof. Those skilled in the art will readily understand that known variations of the conditions and methods described in the examples can be used to synthesize the compounds of the present invention.

It is understood that changes which do not substantially affect the activity of the various embodiments of the present invention are included in the inventions described herein. Accordingly, the following examples are intended to illustrate the invention and not to limit it.

In the final stage of compound synthesis, when an acid such as trifluoroacetic acid or acetic acid is used, for example trifluoroacetic acid is used to remove the tBu group, or the compound is subjected to a post-treatment method such as freezing Depending on the details of the drying process, in some cases, when purified by chromatography using an eluent containing such an acid, the compound is in the form of a salt of the acid used, for example acetic acid salt or trifluoroacetic acid. Partially or completely obtained in the form of salts or hydrochloride salts.

Abbreviations used:

NEt ₃ triethyl amine

Bu ₄ NI tetra-n-butylammonium iodide

Cs ₂ CO ₃ Cesium Carbonate

DCM dichloromethane

DIEA ethyldiisopropylamine

DME 1,2-dimethoxyethane

DMF N, N-dimethylformamide

EDCI N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide

HATU [dimethylamino-([1,2,3] triazolo [4,5-b] pyridin-3-yloxy) -methylene] -dimethylammonium hexafluorophosphate

HOAt 1-hydroxy-7-azabenzotriazole ([1,2,3] triazolo [4,5-b] pyridin-1-ol)

HPLC high performance liquid chromatography

LiOH Lithium Hydroxide

MeOH Methanol

MTBE tert-butyl methyl ether (2-methoxy-2-methylpropane)

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

NIS N-iodosuccinimide

POCl ₃ phosphorus oxychloride

PyBroP Bromotripyrrolidinophosphonium Hexafluorophosphate

TFA trifluoroacetic acid

THF tetrahydrofuran

Example 1:

1- [5- (5-Chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1 H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide

(i) 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1 H-pyrrole-2-carboxylic acid ethyl ester

To a solution of 1H-pyrrole-2-carboxylic acid ethyl ester (70 mg) in MeCN 3-bromomethyl-5- (5-chlorothiophen-2-yl) -isoxazole (139 mg), Cs ₂ CO ₃ (180 mg), Bu ₄ NI (2 mg) and hexa-n-decyltri-n-butyl phosphonium bromide (10 mg) were added. After the mixture was stirred at 60 ° C. for 4 hours, it was cooled to room temperature and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over anhydrous MgSO ₄ and concentrated in vacuo to give 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1H-pyrrole-2-carboxylic acid Ethyl ester (169 mg) was obtained, which was used directly in the next step.

MS (ESI &lt; + &gt;): m / e = 337 [M + H] ⁺ , chloro pattern.

(ii) 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1 H-pyrrole-2-carboxylic acid

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1H-pyrrole-2- in MeOH / THF / H ₂ O (3: 1: 1, 5 mL) LiOH monohydrate (100 mg) was added to a carboxylic acid ethyl ester (135 mg) solution. After the mixture was refluxed for 2 hours, it was cooled to room temperature and concentrated. The mixture was acidified by addition of 1N aqueous KHSO ₄ solution and extracted with ethyl acetate. The combined organic phases were dried (MgSO ₄ ) and concentrated in vacuo to afford crude 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1H-pyrrole-2-carboxylic acid (148 mg) was obtained and used directly in the next step.

MS (ESI-): m / e = 307 [M ⁻ H] ⁻ , chloro pattern.

(iii) 1- [5- (5-Chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1 H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl)- amides

HOAt (27 mg), EDCI hydro to 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1H-pyrrole-2-carboxylic acid (62 mg) in DCM (5 mL) Chloride (38 mg) and DIEA (106 μl) were added. The mixture was stirred for 30 minutes at room temperature. 1-isopropylpiperidin-4-ylamine dihydrochloride (47 mg) and DME (1 mL) were added and stirring continued for 16 h at room temperature. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC. Fractions containing product were evaporated to yield 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidine- 66 mg of 4-yl) -amide were obtained as its trifluoroacetate salt.

MS (ESI &lt; + &gt;): m / e = 433 [M + H] ⁺ , chloro pattern.

Example 2:

1- (3-methoxy-benzyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide

According to the method of Example 1, in step (i), 3-bromomethyl-5- (5-chlorothiophen-2-yl) -isoxazole was replaced with 1-bromomethyl-3-methoxy-benzene , HPLC purification of the crude reaction mixture of 1- (3-methoxy-benzyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide with trifluoroacetate salt thereof Separated.

MS (ESI &lt; + &gt;): m / e = 356 [M + H] ⁺ .

Example 3:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amides

1- [5- (5-chlorothiophene, according to the method of Example 1 in which 1H-pyrrole-2-carboxylic acid ethyl ester was replaced with 4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester in step (i). -2-yl) -isoxazol-3-ylmethyl] -4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -de after HPLC purification of the crude reaction mixture, It was separated into its trifluoroacetate salt.

MS (ESI &lt; + &gt;): m / e = 478 [M + H] ⁺ , chloro pattern.

Example 4:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidine-4- Yl) -amide

According to the method of Example 1, wherein in step (i) the 1H-pyrrole-2-carboxylic acid ethyl ester was replaced with 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 1- [5- (5-chloro Thiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -de of the crude reaction mixture After HPLC purification, it was separated into its trifluoroacetate salt.

MS (ESI &lt; + &gt;): m / e = 461 [M + H] ⁺ , chloro pattern.

Example 5:

1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4- (perhydro-1,4-oxazepin-4-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropyl Piperidin-4-yl) -amide

(i) 4-formyl-1H-pyrrole-2-carboxylic acid methyl ester and 5-formyl-1H-pyrrole-2-carboxylic acid methyl ester:

Both formyl-pyrrole derivatives were prepared by the methods described in C. Schmuck, Tetrahedron 2001, 57, 3063. To DMF (1.61 g) POCl _{3 (} 3.37 g) was added dropwise at 0 ° C. under Ar. The mixture was allowed to warm to room temperature and then diluted with DCM (11 mL). 1 H-pyrrole-2-carboxylic acid methyl ester (2.51 g) in DCM (11 mL) was added dropwise. After the mixture was refluxed for 30 minutes, it was cooled to 10 ° C. and quenched with a solution of potassium acetate (10.8 g) in water (28 mL). The phases were separated and the aqueous phase was extracted with MTBE. The combined organic phases were washed with saturated aqueous K ₂ CO ₃ solution and concentrated in vacuo. The residue was purified by flash column chromatography on silica (ethyl acetate / heptane 1: 5) to give 4-formyl-1H-pyrrole-2-carboxylic acid methyl ester (589 mg) and 5-formyl-1H-pyrrole-2- Carboxylic acid methyl ester (1.60 g) was obtained as a solid.

(ii) 1H-pyrrole-2,4-dicarboxylic acid 2-methyl ester:

To a solution of 4-formyl-1H-pyrrole-2-carboxylic acid methyl ester (589 mg) in acetone / water (50 mL, 1: 1) was added dropwise KMnO ₄ in acetone / water (70 mL, 1: 1) in 1 hour. It was. The mixture was stirred for 3 hours at room temperature before it was poured into NaHSO ₃ (10% in 1N HCl, 100 mL). The resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with water and extracted with 2N K ₂ CO ₃ aqueous solution. The basic aqueous phase was acidified with 2N HCl and extracted with ethyl acetate. The combined organic phases were dried (MgSO ₄ ) and concentrated in vacuo to give 1H-pyrrole-2,4-dicarboxylic acid 2-methyl ester (530 mg), which was used directly in the next step.

(iii) 4-([1,4] oxapanane-4-carbonyl) -1H-pyrrole-2-carboxylic acid ethyl ester:

To 1H-pyrrole-2,4-dicarboxylic acid 2-methyl ester (291 mg) in DCM (18 mL) was added [1,4] oxazepan hydrochloride (236 mg), PyBroP (802 mg) and DIEA (878 μl). . The mixture was stirred for 3 hours at room temperature, then washed with saturated aqueous NaHCO ₃ and 1N HCl. The organic phase was dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on flash silica (ethyl acetate) to afford 4-([1,4] oxazepan-4-carbonyl) -1H-pyrrole-2-carboxylic acid ethyl ester (533 mg). Although present in trace amounts of phosphine oxide obtained from the coupling agent, this material was used directly in the next step.

(iv) 4-([1,4] oxazepan-4-carbonyl) -1 H-pyrrole-2-carboxylic acid:

To the solution of the ester (434 mg) in ethanol (16 mL) was added 1N NaOH (1.82 mL). The mixture was stirred for 2 days at room temperature, concentrated, acidified with 2N HCl and extracted with ethyl acetate. The combined organic phases were dried over anhydrous MgSO ₄ and concentrated in vacuo to afford crude 4-([1,4] oxazepan-4-carbonyl) -1H-pyrrole-2-carboxylic acid (293 mg) which was then Used directly in the step.

(v) 4-([1,4] oxazepan-4-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide:

To this carboxylic acid (293 mg) in DCM (10 mL) was added HOAt (167 mg), EDCI hydrochloride (236 mg) and DIEA (627 μL). The mixture was stirred for 30 minutes at room temperature. 1-isopropylpiperidin-4-ylamine dihydrochloride (265 mg) was added and stirring continued for 16 hours at room temperature. The reaction mixture was washed with 2N NaOH and concentrated. The residue was purified by flash column chromatography on silica (ethyl acetate / MeOH / NEt ₃ 20: 2: 1) to give 4-([1,4] oxazepan-4-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide (72 mg) was obtained.

MS (ESI &lt; + &gt;): m / e = 363 [M + H] ⁺ .

(vi) 1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4- (perhydro-1,4-oxazepine-4-carbonyl) -1H-pyrrole-2-carboxylic acid (1 -Isopropylpiperidin-4-yl) -amide:

To pyrrole (72 mg) in anhydrous DMF (2.5 mL) was added NaH (20 mg, 60% in mineral oil). The mixture was stirred for 30 minutes at room temperature. A solution of 2-bromo-N- (5-chloropyridin-2-yl) -acetamide (49 mg) in DMF (0.5 mL) was added dropwise and stirring continued at room temperature for 5 hours. The mixture was quenched by the dropwise addition of acetic acid and then concentrated. The residue was purified by preparative HPLC. Fractions containing product were evaporated to yield 1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4- (perhydro-1,4-oxazepine-4-carbonyl) -1H-pyrrole- 11 mg of 2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide were obtained as its trifluoroacetate salt.

MS (ESI &lt; + &gt;): m / e = 531 [M + H] ⁺ , chloro pattern.

Example 6:

1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -5- (perhydro-1,4-oxazepin-4-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropyl Piperidin-4-yl) -amide

(i) 1H-pyrrole-2,5-dicarboxylic acid 2-methyl ester was prepared according to the method described in step (ii) of Example 5 using 5-formyl-1H-pyrrole-2-carboxylic acid.

(ii) 5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid ethyl ester:

To this carboxylic acid (845 mg) in DCM (50 mL) was added HOAt (680 mg), EDCI hydrochloride (960 mg) and DIEA (2.55 mL). The mixture was stirred for 30 minutes at room temperature. 1-isopropylpiperidin-4-ylamine dihydrochloride (1.08 g) was added and stirred for 16 hours at room temperature. The reaction mixture was washed with saturated aqueous KHCO ₃ solution and water and concentrated in vacuo to afford 1.05 g of 5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid ethyl ester, which was It was used directly in the next step.

(iii) Sodium 5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylate:

The ester was dissolved in ethanol (33 mL) and 1N NaOH (3.58 mL). The solution was stirred for 2 days at room temperature and concentrated in vacuo to afford crude sodium 5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylate (1.05 g), It was used without further purification.

(iv) 5-([1,4] oxazepan-4-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide is used as the carboxylate and [1, 4] Prepared by coupling mediated carbodiimide according to step (v) of Example 5 using oxazane hydrochloride as reagent.

(v) 1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -5- (perhydro-1,4-oxazepine-4-carbonyl) -1H-pyrrole-2-carboxylic acid (1 -Isopropylpiperidin-4-yl) -amide:

In step (vi) 4-([1,4] oxazepan-4-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide is replaced with 5-([1 , 4] oxapanane-4-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide according to the method of Example 5, followed by 1-[(5 -Chloropyridin-2-ylcarbamoyl) -methyl] -5- (perhydro-1,4-oxazepine-4-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidine-4 -Yl) -amide was separated into its trifluoroacetate salt after HPLC purification of the crude reaction mixture.

MS (ESI &lt; + &gt;): m / e = 531 [M + H] ⁺ , chloro pattern.

Example 7:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (perhydro-1,4-oxazepine-4-carbonyl) -1H-pyrrole-2 -Carboxylic acid (1-isopropylpiperidin-4-yl) -amide

Replace 2-bromo-N- (5-chloropyridin-2-yl) -acetamide with 3-bromomethyl-5- (5-chlorothiophen-2-yl) -isoxazole in step (v) According to the method of Example 6, 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (perhydro-1,4-oxazepine-4- Carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide was separated by trifluoroacetate salt thereof after HPLC purification of the crude reaction mixture.

MS (ESI &lt; + &gt;): m / e = 560 [M + H] ⁺ , chloro pattern.

Example 8:

3- [1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -2,4 -Dimethyl-1H-pyrrol-3-yl] -propionic acid

(i) 4- (2-methoxycarbonylethyl) -3,5-dimethyl-1H-pyrrole-2-carboxylic acid:

4- (2-methoxycarbonylethyl) -3,5-dimethyl-1H-pyrrole-2-carboxylic acid benzyl ester (390 mg, 1.24 mmol) was dissolved in anhydrous MeOH (20 mL). The solution was drained and rinsed several times under argon. 120 mg of palladium on charcoal (10%) was added, the mixture was again drained and rinsed several times with argon. Finally argon was exchanged with hydrogen (balloons filled with hydrogen) and the mixture was stirred for 3 hours at room temperature. The reaction mixture was filtered through celite and the filter residue was washed with MeOH (150 mL). The filtrate was concentrated in vacuo to give pure 4- (2-methoxycarbonylethyl) -3,5-dimethyl-1H-pyrrole-2-carboxylic acid as a colorless solid (263 mg).

MS (ESI ⁻ ): m / e = 225 [M ⁻ H] ⁻ .

(ii) 3- [5- (1-isopropylpiperidin-4-ylcarbamoyl) -2,4-dimethyl-1H-pyrrol-3-yl] -propionic acid methyl ester

263 mg (1.17 mmol) of 4- (2-methoxycarbonylethyl) -3,5-dimethyl-1H-pyrrole-2-carboxylic acid were dissolved in DMF (10 mL). 488.4 mg (1.28 mmol) of HATU and DIEA (224 mL) were added and the resulting mixture was stirred at room temperature for 45 minutes. 276.3 mg (1.28 mmol) of 1-isopropylpiperidin-4-ylamine dihydrochloride and 448 mL of DIEA were added. The reaction mixture was stirred overnight, then it was concentrated. The residue was diluted with DCM and washed with saturated NaHCO ₃ solution and brine. The organic phase was dried over MgSO ₄ and concentrated. Pure 3- [5- (1-isopropylpiperidin-4-ylcarbamoyl) -2,4-dimethyl-1H-pyrrole-3 with preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% formic acid) -Yl] -propionic acid methyl ester (166 mg) was obtained as a colorless amorphous material.

MS (ESI ⁺ ): m / e = 351 [M + H] ⁺ .

(iii) 3- [1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl)- 2,4-dimethyl-1H-pyrrol-3-yl] -propionic acid methyl ester

55 mg (0.16 mmol) of 3- [5- (1-isopropylpiperidin-4-ylcarbamoyl) -2,4-dimethyl-1H-pyrrol-3-yl] -propionic acid methyl ester (DMF) (5 mL) In water. Then, 103 mg (2 equivalents) of Cs ₂ CO ₃ and 65.8 mg (1.5 equivalents) of 3-bromomethyl-5- (5-chlorothiophen-2-yl) -isoxazole were added, and the resulting mixture was added for 4 hours. Stir at 80 ° C for. Because of the low conversion, 206 mg (4 equivalents) of Cs ₂ CO ₃ was added and stirring continued at 80 ° C. for 7 hours. The reaction mixture was acidified by addition of acetic acid and concentrated. The residue was purified by preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% formic acid) 3- [1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl ] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -2,4-dimethyl-1H-pyrrol-3-yl] -propionic acid methyl ester (34 mg) was obtained as a colorless amorphous material.

MS (ESI ⁺ ): m / e = 548 [M + H] ⁺ , chloro pattern.

(iv) 3- [1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl)- 2,4-dimethyl-1H-pyrrol-3-yl] -propionic acid

3- [1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarba in MeOH (4 mL) Moyl) -2,4-dimethyl-1H-pyrrole-3-yl] -propionic acid methyl ester was added to 34 mg (0.06 mmol) of 1M LiOH aqueous solution (0.3 mL), and the obtained mixture was stirred at 60 ° C for 5 hours. The mixture was acidified by addition of 1M HCl-solution (pH ˜5) and concentrated under reduced pressure. Final purification by preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% formic acid) to give pure 3- [1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl]- 5- (1-Isopropylpiperidin-4-ylcarbamoyl) -2,4-dimethyl-1H-pyrrol-3-yl] -propionic acid was obtained as a colorless amorphous material. The product was obtained as its hydroformitate (11 mg).

MS (ESI ⁺ ): m / e = 534 [M + H] ⁺ , chloro pattern.

Example 9:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid benzyl ester

(i) 5-formyl-1H-pyrrole-2-carboxylic acid benzyl ester and 4-formyl-1H-pyrrole-2-carboxylic acid benzyl ester:

POCl ₃ (12.45 g) was added dropwise to DMF (5.93 g) at 0 ° C. The mixture was warmed to rt, diluted with DCM (40 mL) and cooled back to 0 ° C. 1H-pyrrole-2-carboxylic acid benzyl ester in DCM (40 mL) (15.00 g, prepared by applying the method of J. Barry, G. Bram and A. Petit, Heterocycles 1985, 23, 875-880). ) Solution was added dropwise at a rate such that the concentration of the reaction mixture did not increase above 0 ° C. The reaction was heated at reflux for 30 minutes and then cooled to 10 ° C. A solution of sodium acetate (28 g) in water (90 mL) was added carefully. After stirring for 15 minutes, the two phases obtained were separated and the aqueous phase was washed with DCM (3 x 75 mL). The combined organic phases were washed with saturated Na ₂ CO ₃ solution and brine, dried over MgSO ₄ and concentrated. The residue was purified by flash column chromatography on silica (ethyl acetate / heptane 1: 2) to give 5-formyl-1H-pyrrole-2-carboxylic acid benzyl ester (8.0 g) and 4-formyl-1H-pyrrole-2. -Carboxylic acid benzyl ester (4.0 g) was obtained.

(ii) 1H-pyrrole-2,5-dicarboxylic acid monobenzyl ester:

Sodium dihydrogen phosphate (6.28 g), sodium chloride (9.47 g) and isobu in a solution of 5-formyl-1H-pyrrole-2-carboxylic acid benzyl ester (8.0 g) in n-butanol (300 mL) and water (112 mL) Ten (58 g) was added. The mixture was stirred at rt for 20 h and then concentrated. The residue was purified by flash column chromatography on silica (DCM / MeOH 15: 1 to 1: 1) to afford 10.0 g of 1H-pyrrole-2,5-dicarboxylic acid monobenzyl ester.

(iii) 5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid benzyl ester:

A few drops of DMF were added to the acid (1.72 g) in DCM (35 mL) followed by the slow addition of oxalyl chloride (1.34 g). The mixture was added at reflux for 3 hours and then concentrated. To the resulting acid chloride solution in THF was added 1-isopropylpiperidin-4-ylamine (1.00 g) and NEt ₃ (3.89 mL) in THF (35 mL). The resulting mixture was stirred at rt for 20 h and then concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO ₃ solution. The phases were separated and the organic phase was washed with saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ and concentrated. Preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA) afforded 5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid benzyl ester (287 mg). .

(iv) 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole 2-carboxylic acid benzyl ester:

To a solution of 5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid benzyl ester (20 mg) in DMF (1 mL) was added Cs ₂ CO ₃ (71 mg). The mixture was stirred for 30 minutes at room temperature. 3-bromomethyl-5- (5-chlorothiophen-2-yl) -isoxazole (15 mg) was added and stirring continued for 20 hours at room temperature, then the mixture was filtered. The filtrate was directly preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA). Pure 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2 -Carboxylic acid benzyl ester (15 mg) was obtained as its trifluoroacetate salt.

MS (ESI ⁺ ): m / e = 567 [M + H] ⁺ , chloro pattern.

Example 10:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid methyl ester

The product was obtained by transesterification of the product of step (iv) of Example 9: The crude reaction mixture of step (iv) of Example 9 was triturated with MeOH for several minutes, after which it was filtered and concentrated. 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1 after preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA) of the residue -Isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid methyl ester was obtained as its trifluoroacetate salt.

MS (ESI ⁺ ): m / e = 491 [M + H] ⁺ , chloro pattern.

Example 11:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidine-4- in 5 mL of THF / water (3: 1) The LiOH (9 mg) mixture was stirred in a solution of ylcarbamoyl) -1H-pyrrole-2-carboxylic acid methyl ester (Example 10, 30 mg) at 45 ° C. for 2 hours, then cooled to room temperature, acidified with TFA, Concentrated. 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1 after preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA) of the residue -Isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid was obtained.

MS (ESI ⁺ ): m / e = 477 [M + H] ⁺ , chloro pattern.

Example 12:

1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid benzyl ester

(i) 1H-pyrrole-2,4-dicarboxylic acid 2-benzyl ester:

According to the method of step (ii) of example 9, 1H-pyrrole-2,4-dicarboxylic acid 2-benzyl ester was obtained by oxidizing 4-formyl-1H-pyrrole-2-carboxylic acid benzyl ester.

(ii) 4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid benzyl ester:

The title compound was prepared according to the method of step (iii) of Example 9 by replacing 1H-pyrrole-2,5-dicarboxylic acid monobenzyl ester with 1H-pyrrole-2,4-dicarboxylic acid 2-benzyl ester.

(iii) 1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid benzyl ester:

Cs ₂ CO ₃ (176 mg) was added to a solution of 4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid benzyl ester (50 mg) in DMF ( ₂ mL), followed by 2 Bromo-N- (5-chloropyridin-2-yl) -acetamide (34 mg) was added. The mixture was stirred at rt for 20 h and then it was filtered. The filtrate was directly preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA). Pure 1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid benzyl ester (28.5 mg ) Was obtained as its trifluoroacetate salt.

MS (ESI ⁺ ): m / e = 538 [M + H] ⁺ , chloro pattern.

Example 13:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid benzyl ester

This compound was replaced with 2-bromo-N- (5-chloropyridin-2-yl) -acetamide with 3-bromomethyl-5- (5-chlorothiophen-2-yl) -isoxazole Prepared according to the method of Example 12. This was obtained as a trifluoroacetate salt thereof after preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA).

MS (ESI ⁺ ): m / e = 567 [M + H] ⁺ , chloro pattern.

Example 14:

1-[(5-Chloropyridin-2-ylcarbamoyl) -methyl] -4-nitro-1 H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide

(i) 4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide:

To 4-nitro-1H-pyrrole-2-carboxylic acid (200 mg) in DCM (10 mL) was added DIEA (436 μL), HATU (487 mg) and 1-isopropylpiperidin-4-ylamine (182 mg). . The mixture was stirred for 1 h at rt before it was concentrated. The residue was purified by preparative HPLC to give 4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide as its trifluoroacetate salt (50 mg).

(ii) 1-[(5-Chloropyridin-2-ylcarbamoyl) -methyl] -4-nitro-1 H-pyrrol-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide:

To a solution of 4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide trifluoroacetate salt (30 mg) in DMF (4 mL) was added Cs ₂ CO ₃ (70 mg). Was added. The mixture was stirred for 30 minutes at room temperature, then 2-bromo-N- (5-chloropyridin-2-yl) -acetamide (27 mg) was added. Stirring was continued at room temperature for 20 hours. The mixture was filtered and directly preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA) to 1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4-nitro-1H-pyrrole 2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide (15 mg) was obtained as its trifluoroacetate salt.

MS (ESI ⁺ ): m / e = 449 [M + H] ⁺ , chloro pattern.

Example 15:

1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid methyl ester

The product was obtained by transesterifying the product of Example 12: The crude reaction mixture of Example 12 was triturated with MeOH for several minutes, after which it was filtered and concentrated. Preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA) followed by 1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4- (1-isopropylpiperidine- 4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid methyl ester was obtained as its trifluoroacetate salt.

MS (ESI ⁺ ): m / e = 462 [M + H] ⁺ , chloro pattern.

Example 16:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid methyl ester

The product was obtained by transesterifying the product of Example 13: The crude reaction mixture of Example 12 was triturated with MeOH for several minutes, after which it was filtered and concentrated. 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4- (1 after preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA) of the residue -Isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid methyl ester was obtained as its trifluoroacetate salt.

MS (ESI ⁺ ): m / e = 491 [M + H] ⁺ , chloro pattern.

Example 17:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4- (1-isopropylpiperidine-4- in 15 mL of THF / water (3: 1) LiOH monohydrate (50 mg) was added to a solution of ilcarbamoyl) -1H-pyrrole-2-carboxylic acid methyl ester (Example 16, 60 mg). The mixture was stirred for 2 h at 45 ° C., then it was cooled to rt, acidified with TFA and concentrated. After HPLC purification of the crude product (CH ₃ CN / H ₂ O gradient + 0.05% TFA), 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4- ( 1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid (33 mg) was obtained.

MS (ESI ⁺ ): m / e = 477 [M + H] ⁺ , chloro pattern.

Example 18:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (3-methoxy-azetidine-1-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide

1- [5- (5-Chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl)-in DCM (2 mL) To a 1 H-pyrrole-2-carboxylic acid (Example 17, 9 mg) solution was added HATU (7.2 mg), DIEA (13 μl) and 3-methoxy-azetidine. The mixture was stirred at rt for 1 h and then concentrated. The residue was purified by preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA) 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (3-methoxy-azetidine-1-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide (4.3 mg) was obtained as its trifluoroacetate salt. It was.

MS (ESI ⁺ ): m / e = 546 [M + H] ⁺ , chloro pattern.

Example 19:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1H-pyrrole-2,5-dicarboxylic acid 2-[(1-isopropylpiperidine-4- Yl) -amide] 5-[(2-methoxyethyl) -amide]

This compound was prepared according to the method of Example 18 in which 3-methoxy-azetidine was replaced with 2-methoxyethylamine. After HPLC purification of the crude product (CH ₃ CN / H ₂ O gradient + 0.05% TFA), 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1H-pyrrole -2,5-dicarboxylic acid 2-[(1-isopropylpiperidin-4-yl) -amide] 5-[(2-methoxyethyl) -amide] was obtained as its trifluoroacetate salt.

MS (ESI ⁺ ): m / e = 534 [M + H] ⁺ , chloro pattern.

Example 20:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1H-pyrrole-2,5-dicarboxylic acid 2-[(1-isopropylpiperidine-4- Yl) -amide] 5-[(2-methoxyethyl) -methylamide]

This compound was prepared according to the method of Example 18, wherein 3-methoxy-azetidine was replaced with (2-methoxyethyl) -methylamine. 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1H-pyrrole-2,5-dicarboxylic acid 2-[(1-isopropylpiperidine-4- Il) -amide] 5-[(2-methoxyethyl) -methylamide] was obtained as trifluoroacetate salt thereof after HPLC purification (CH ₃ CN / H ₂ O gradient + 0.05% TFA) of the crude product. .

MS (ESI ⁺ ): m / e = 548 [M + H] ⁺ , chloro pattern.

Example 21:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5-phenyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amides

(i) 5-phenyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide:

DIEA (1.67 mL) was added to 1-isopropylpiperidin-4-ylamine (350 mg) in DCM (15 mL), followed by HATU (935 mg) and 5-phenyl-1H-pyrrole-2-carboxylic acid (461 mg). Was added. The mixture was stirred for 1 h at rt, then washed twice with saturated aqueous NaHCO ₃ , dried over MgSO ₄ and concentrated to crude crude 5-phenyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidine 4-yl) -amide was obtained, which was used directly in the next step.

(ii) 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5-phenyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidine-4 -Yl) -amides:

Cs ₂ CO ₃ (105 mg) was added to a solution of 5-phenyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide (50 mg) in DMF (2 mL). The mixture was stirred for 30 minutes at room temperature. 3-bromomethyl-5- (5-chlorothiophen-2-yl) -isoxazole (45 mg) was added and stirring continued for 3 hours at room temperature. The mixture was filtered and directly preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA) gave 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl]- 5-phenyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide (15 mg) was obtained as its trifluoroacetate salt.

MS (ESI ⁺ ): m / e = 509 [M + H] ⁺ , chloro pattern.

Example 22:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-4- (perhydro-1,4-oxazepine-4-sulfonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide

(i) 3,5-dimethyl-4-([1,4] oxazepan-4-sulfonyl) -1H-pyrrole-2-carboxylic acid ethyl ester:

DIEA (2.70 mL) was added to [1,4] oxazepan hydrochloride (400 mg) in DCM (45 mL), followed by 4-chlorosulfonyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester ( 1.05 g) was added. The mixture was stirred for 1 hour at room temperature, then water was added and the two phases obtained were separated. The organic phase was washed twice with saturated aqueous NaHCO ₃ , dried over MgSO ₄ and concentrated to crude 3,5-dimethyl-4-([1,4] oxazepan-4-sulfonyl) -1H-pyrrole-2 -Carboxylic acid ethyl ester (970 mg) was obtained, which was used directly in the next step.

(ii) 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-4-([1,4] oxazepan-4-sulfonyl ) -1H-pyrrole-2-carboxylic acid ethyl ester:

Cs ₂ CO ₃ (197 mg) in a solution of 3,5-dimethyl-4-([1,4] oxazepan-4-sulfonyl) -1H-pyrrole-2-carboxylic acid ethyl ester (100 mg) in DMF (5 mL) Was added. The mixture was stirred for 30 minutes at room temperature, then 3-bromomethyl-5- (5-chlorothiophen-2-yl) -isoxazole (84 mg) was added. After continuing stirring at room temperature for 20 hours, the mixture was filtered and directly purified by preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA) to 1- [5- (5-chlorothiophen-2-yl) -Isoxazol-3-ylmethyl] -3,5-dimethyl-4-([1,4] oxapanane-4-sulfonyl) -1H-pyrrole-2-carboxylic acid ethyl ester (100 mg) was obtained.

(iii) 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-4-([1,4] oxazepan-4-sulfonyl ) -1H-pyrrole-2-carboxylic acid:

[5- (5-Chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-4-([1,4] oxa in 20 mL of THF / water (3: 1) LiOH monohydrate (200 mg) was added to a solution of platen-4-sulfonyl) -1H-pyrrole-2-carboxylic acid ethyl ester (100 mg), and the mixture was stirred at 45 ° C. for 2 hours, and stirred at 60 ° C. for 6 hours. It was then cooled to rt, concentrated, acidified to pH 2 with 2M HCl and extracted with DCM (3 × 30 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated to crude 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-4- ( [1,4] oxazepan-4-sulfonyl) -1H-pyrrole-2-carboxylic acid (80 mg) was obtained and used directly in the next step.

(iv) 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-4- (perhydro-1,4-oxazepine-4- Sulfonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-4-([1,4] oxazapan-4 in DCM (5 mL) To the sulfonyl) -1H-pyrrole-2-carboxylic acid (80 mg) was added DIEA (110 μl), HATU (61 mg) and 1-isopropylpiperidin-4-ylamine (23 mg). The mixture was stirred for 1 h at rt before it was concentrated. The residue was purified by preparative HPLC to give 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-4- (perhydro-1,4- Oxazepine-4-sulfonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide was obtained as its trifluoroacetate salt (90 mg).

MS (ESI ⁺ ): m / e = 623 [M + H] ⁺ , chloro pattern.

Example 23:

4-Bromo-1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpy) Ferridin-4-yl) -amide

(i) 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid:

To a 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (900 mg) was added a 10 ml solution of boron tribromide (1M) in DCM. The mixture was stirred at rt for 16 h and then heated at reflux for 5 h. After the reaction was completed, anhydrous boron tribromide (1.5 mL) was added dropwise and reflux continued for 3 hours. After cooling to room temperature, the mixture was poured onto ice cubes and extracted with DCM. The combined organic phases were filtered through a diatomaceous earth plug and concentrated under reduced pressure to afford crude 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1.2 g), which was used directly in the next step. It was.

(ii) 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide:

To 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (570 mg) in DCM (15 mL) DIEA (2.11 g), HATU (994 mg) and 1-isopropylpiperidin-4-yl Amine (372 mg) was added. The mixture was stirred for 16 h at rt before it was concentrated. The residue was purified by preparative HPLC to afford 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide (65 mg), which was then Used directly in the step.

(iii) 4-bromo-1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1- Isopropylpiperidin-4-yl) -amides:

Solution of 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide (33 mg) in a mixture of DMF (2 mL) and DCM (2 mL) To Cs ₂ CO ₃ (62 mg) was added. The mixture was stirred for 30 min at rt, then 3-bromomethyl-5- (5-chlorothiophen-2-yl) -isoxazole (84 mg) was added. The mixture was stirred at rt for 1 h. Cs ₂ CO ₃ (62 mg) was added and stirred at rt for 48 h, then the mixture was filtered and concentrated. The residue was purified by preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA) to 4-bromo-1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-Dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide was obtained as its trifluoroacetate salt (9 mg).

MS (ESI ⁺ ): m / e = 539 [M + H] ⁺ , chloro pattern.

Example 24:

4-Bromo-1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amides

(i) 4-bromo-1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester:

Cs ₂ CO ₃ (912 mg) was added to a solution of 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (492 mg) in DMF (5 mL). The mixture was stirred for 30 minutes at room temperature before 2-bromo-N- (5-chloropyridin-2-yl) -acetamide (499 mg) was added. After continuing stirring at room temperature for 2 hours, the mixture was filtered and concentrated. The residue was purified by preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA) to 4-bromo-1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -3,5-dimethyl- 1H-pyrrole-2-carboxylic acid ethyl ester (220 mg) was obtained.

(ii) 4-bromo-1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid:

220 mg of the ester was added dropwise to anhydrous boron tribromide (1.5 mL). The mixture was refluxed for 8 hours. Additional boron tribromide (1.5 mL) was added dropwise and continued for 3 hours, after which the mixture was poured on crushed ice and cooled to room temperature. The phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to afford crude 4-bromo-1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -3,5- Dimethyl-1H-pyrrole-2-carboxylic acid (200 mg) was obtained and used directly in the next step.

(iii) 4-bromo-1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1- Isopropylpiperidin-4-yl) -amides:

To the crude acid (200 mg) in DCM (2 mL) was added DIEA (33 mg), HATU (49 mg) and 1-isopropylpiperidin-4-ylamine (18 mg). The mixture was stirred for 16 h at rt before it was concentrated. The residue was purified by preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA) to 4-bromo-1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-Dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide was obtained as its trifluoroacetate salt (19 mg).

MS (ESI ⁺ ): m / e = 510 [M + H] ⁺ , chloro pattern.

Example 25:

1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4-formyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpy Ferridin-4-yl) -amide

(i) 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4-formyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester:

Cs ₂ CO ₃ (6.51 g) was added to 4-formyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.60 g) in DMF (26 mL). The mixture was stirred for 30 minutes at room temperature before 3-bromomethyl-5- (5-chlorothiophen-2-yl) -isoxazole (3.71 g) was added. Stirring was continued at room temperature for 2 hours. Water was added and the phases separated. The aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried (MgSO ₄ ) and concentrated under reduced pressure to afford crude 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4 -Formyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (4.20 g) was obtained and used directly without purification in the next step.

(ii) 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4-formyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid:

To the ester solution in a THF (7.5 mL) and water (2.5 mL) mixture was added lithium hydroxide monohydrate (55 mg). The mixture was stirred at 60 ° C. for 2 hours. Additional lithium hydroxide monohydrate (60 mg) was added and the mixture was refluxed for 4 hours. After cooling to rt, the mixture was concentrated, acidified to pH 3 with 2N HCl and extracted with ethyl acetate. The combined organic phases were washed with brine, dried (MgSO ₄ ) and concentrated under reduced pressure to afford crude 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4- Formyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (100 mg) was obtained and used directly in the next step.

(iii) 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4-formyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1- Isopropylpiperidin-4-yl) -amides:

To the acid (100 mg) in DCM (2 mL) was added DIEA (142 mg), HATU (104 mg) and 1-isopropylpiperidin-4-ylamine (39 mg). The mixture was stirred for 2 h at rt before it was concentrated. The residue was purified by preparative HPLC (CH ₃ CN / H ₂ O gradient + 0.05% TFA) to give 1- [5-(-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4-formyl- 3,5-Dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide was obtained as its trifluoroacetate salt (101 mg).

MS (ESI ⁺ ): m / e = 489 [M + H] ⁺ , chloro pattern.

Pharmacological test

The ability of the compounds of Formulas (I) and (Ia) to inhibit Factor Xa or Factor VIIa, or other enzymes such as thrombin, plasmin or trypsin, results in 50% enzymatic activity associated with the inhibition constant Ki, i.e. It can be evaluated by measuring the concentration of the compound of. Purified enzyme was used for colorimetric analysis. The concentration of inhibitor causing a 50% decrease in the rate of substrate hydrolysis is plotted after plotting the relative rate of the hydrolysis reaction (as compared to the uninhibited control) against the log of the concentrations of the compounds of Formulas I and Ia. It was measured by regression. To calculate the inhibition constant Ki, IC50 values were corrected for competition with the substrate using the following equation (I).

Ki = IC50 / {1+ (substrate concentration / Km)}

In Equation 1 above,

Km is described in Chen and Prusoff, Biochem. Pharmacol. 22 (1973), 3099-3108; I. H. Segal, Enzyme Kinetics, 1975, John Wiley & Sons, New York, 100-125.

a) factor Xa analysis

In assays to determine inhibition of factor Xa activity, TBS-PEG buffer (50 mM Tris-HCl, pH 7.8, 200 mM NaCl, 0.05% (w / v) PEG-8000, 0.02% (w / v) NaN ₃ ) Was used. IC50 is derived from human factor Xa in TBS-PEG in a suitable well of a Costar half area microtiter plate [Enzyme Research Laboratories, Inc .; South Bend, Indiana] 25 μl, 40 μl of compound at various concentrations to be diluted in 10% (v / v) DMSO in TBS-PEG (uncontrolled control) or 10% (v / v) DMSO in TBS-PEG, And by combining the substrate S-2765 (N (α) -benzyloxycarbonyl-D-Arg-Gly-L-Arg-p-nitroanilide in TBS-PEG (Kabi Pharmacia, Inc .; Franklin, Ohio) The assay was performed by preincubation of the compounds of formulas (I) and (Ia) with enzyme for 10 minutes, after which the assay was initiated by addition to the substrate to obtain a final volume of 100 μL. Was measured by the change in absorbance at 405 nm using the Bio-tek instrument kinetic plate reader (Ceres UV900HDi) at 25 ° C. (typically 1.5 minutes after substrate addition) during the linear portion of the time course. 0.5 M and substrate concentration was 140 μM.

b) Factor VIIa Analysis

Inhibitory activity towards factor VIIa / tissue factor activity is measured essentially using colorimetric analysis, as previously described in JA Ostrem et al., Biochemistry 37 (1998) 1053-1059, which is incorporated herein by reference. It became. Kinetic analysis was performed at 25 ° C. in a half area microtiter plate (Costar Corp., Cambridge, Massachusetts) using an kinetic plate reader (Molecular Devices Spectramax 250). Conventional assay human Factor VIIa 25㎕ and 10% DMSO / TBS-PEG buffer (50mM Tris, 15mM NaCl, 5mM CaCl 2, 0.05% PEG 8000, pH 8.15) inhibitor dilutions 40㎕ with TF (5nM in the formulation and 10 nM, each final concentration). After 15 minutes of the preculture period, the assay was initiated by adding 35 μl of chromogenic substrate S-2288 (D-Ile-Pro-Arg-p-nitroanilide, Pharmacia Hepar Inc., final concentration of 500 μl). Table 1 shows the results (inhibition constant Ki (FXa) for suppressing factor Xa).

Example Ki (FXa) [μM] Example Ki (FXa) [μM] Example Ki (FXa) [μM] One 0.077 10 0.007 19 0.088 2 8.06 11 0.294 20 0.057 3 0.043 12 34.88 21 0.005 4 0.011 13 9.576 22 0.112 5 0.081 14 0.059 23 0.005 6 0.902 15 41.285 24 0.011 7 0.249 16 1.439 25 0.024 8 0.152 17 8.99 9 0.997 18 0.036

Claims (12)

Compounds of Formulas (I) and (Ia), all stereoisomeric forms thereof, mixtures thereof in any proportion and physiologically acceptable salts thereof. Formula I

Formula Ia

In the above formulas I and Ia, R ⁰ is 1) monocyclic or bicyclic 6 to 14 membered aryl, wherein the aryl is independently mono-, di- or tri-substituted with R 8, 2) monocyclic or bisy selected from the group pyridinyl, pyrimidinyl, indolyl, isoindoleyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, benzothiophene, quinazolinyl and phenylpyridyl 4-15 membered heterocyclyl, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R8; or 3) monocyclic or bicyclic 4 to 15 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the heterocyclyl is unsubstituted or independently of one another Mono-, di- or tri-substituted and further substituted with monocyclic or bicyclic 4 to 15 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, Wherein heterocyclyl is unsubstituted or independently of one another is mono-, di-, or tri-substituted with R 8), R8 is 1) halogen, 2) -NO ₂ , 3) -OH, 4) -O-CF ₃ 5) aryl monocyclic or bicyclic 6- to 14-membered (wherein aryl is independently from each other halogen or -O- (C ₁ -C ₈₎ - is a substituted mono-, di- or tri-alkyl), 6)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -OH or methoxy moieties, _{7) -O- (C 1 -C 8} ) - alkyl (wherein alkyl is optionally substituted mono-, di or tri halogen, NH _2, -OH or a methoxy residue is optionally substituted independently from each other), 8) -SO ₂ -CH ₃ or 9) -SO ₂ -CF ₃ , Provided that when R ⁰ is a monocyclic or bicyclic 6 to 14 membered aryl, R 8 is at least one halogen or —O— (C ₁ -C ₈ ) -alkyl moiety, Q is-(C ₀ -C ₂ ) -alkylene-C (O) -NR ^10- , -NR ¹⁰ -C (O) -NR ^10- , -NR ¹⁰ -C (O)-,-(C ₁ -C ₆ ) -alkylene,-(CH ₂ ) _m -NR ¹⁰ -C (O) -NR ^10- (CH ₂ ) _n - _, -(CH ₂ ) _m -NR ¹⁰ -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _m -S- (CH ₂ ) _n -,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _m -SO _2- NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO ₂ -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -CH (OH)-(CH ₂ ) _n -,-(CH ₂ ) _m -OC (O) -NR ^10- (CH ₂ ) _n -,-(C ₂ -C ₃ ) -alkylene-O- (C ₀ -C ₃ ) -alkylene-,-(C ₂ -C ₃ ) -alkylene-S (O)-,-(C ₂ -C ₃ ) -alkylene- S (O) ₂ -,-(CH ₂ ) _m -NR ¹⁰ -C (O) -O- (CH ₂ ) _n -,-(C ₂ -C ₃ ) -alkylene-S (O) ₂ -NH -(R ¹⁰ )-,-(C ₂ -C ₃ ) -alkylene-N (R ¹⁰ )-or-(C ₀ -C ₃ ) -alkylene-C (O) -O- (CH ₂ ) _m -ego, Wherein R ¹⁰ is as defined below, n and m are the same or different integers, independently of one another, 0, 1, 2, 3, 4, 5 or 6, and-(CH ₂ ) _m -or-(CH ₂ ) _n The alkylene moiety formed by-is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -NH ₂ or -OH, or-(C ₃ -C ₆ ) -cycloalkylene, wherein cycloalkyl Lene is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -NH ₂ or -OH, R ¹ is a hydrogen atom, — (C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or substituted 1-3 times with R 13; - (C ₁ -C ₃₎ - alkylene ^{-C (O) -NH-R 0} , - (C 1 -C 3) - alkylene -C (O) -OR ^10, monocyclic or bicyclic 6 To 14 membered aryl, wherein the aryl is independently mono-, di- or tri-substituted with R 8, wherein R 8 is as described; Monocyclic or bicyclic 4 to 15 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen; - (C ₁ -C ₃₎ - _{perfluoroalkyl-alkylene, - (C 1 -C 3)} - alkylene _{-S (O) - (C 1} -C 4) - alkyl, - (C ₁ -C ₃₎ - alkylene _{-S (O) 2 - (C} 1 -C 3) - _{alkyl, - (C 1 -C 3)} - alkylene _{-S (O) 2 -N (R} 4 ') -R 5', - (C ₁ -C ₃ ) -alkylene-O- (C ₁ -C ₄ ) -alkyl,-(C ₀ -C ₃ ) -alkylene- (C ₃ -C ₈ ) -cycloalkyl or-(C ₀ -C ₃ ) -alkylene-het wherein het is a 3-7 membered cyclic moiety containing one, two, three or four or more heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic moiety is a substitution Or mono-, di-, or tri-substituted with R 14 independently of one another; R ^{4 '} and R ^5' are the same or different independently from each other and are a hydrogen atom or-(C ₁ -C ₄ ) -alkyl, R ¹ and R 22 together with the atoms bonded to them may form a 6-8 membered cyclic group containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic group Are unsubstituted or independently of each other mono-, di-, or tri-substituted with R 14, R ¹ -NV can form a 4-8 membered cyclic group containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic groups are unsubstituted or independently of one another Mono-, di- or tri-substituted with R 14, R 14 is halogen, —OH, ═O, — (C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₄ ) -alkoxy, -NO ₂ ,-(C ₀ -C ₄ ) -alkyl-C (O ) -OR ¹⁸ , -CN,-(C ₀ -C ₄ ) -alkyl-N (R ¹⁸ ) -R ²¹ ,-(C ₀ -C ₄ ) -alkyl-OR ¹⁸ ,-(C ₀ -C ₄ ) -Alkyl-het,-(C ₀ -C ₈ ) -alkyl-SO _2- (C ₁ -C ₄ ) -alkyl,-(C ₀ -C ₈ ) -alkyl-SO _2- (C ₁ -C ₃ ) -Perfluoroalkyl,-(C ₀ -C ₈ ) -alkyl-SO ₂ -N (R ¹⁸ ) -R ²¹ , -C (O) -NH- (C ₁ -C ₈ ) -alkyl, -C ( O) -N - [(-C ₁ C ₈₎ - alkyl] _2, -NR ¹⁸ -C (O) -NH- (-C ₁ C ₈₎ - _{alkyl, -C (O) -NH 2,} -SR and - [alkyl _{(C 1 -C 8) -]} 2, 18 , or -NR ¹⁸ -C (O) -NH Wherein R ¹⁸ and R ²¹ independently of one another are a hydrogen atom,-(C ₁ -C ₃ ) -perfluoroalkyl or-(C ₁ -C ₆ ) -alkyl, V is 1) a 3 to 7 membered cyclic moiety containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic moieties are unsubstituted or independently of each other mono-, di- or tri- Is substituted) or 2) monocyclic or bicyclic 4 to 15 membered heterocyclyl, wherein the heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, G is a direct bond,-(CH ₂ ) _m -NR ¹⁰ -SO ₂ -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -CH (OH)-(CH ₂ ) _n -,-(CH ₂ ) _m -,-(CH ₂ ) _m -O- (CH ₂ ) _n -,-(CH ₂ ) _m -C (O) -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -C (O) -NR ^10- (CH ₂ ) _n - _, -(CH ₂ ) _m -NR ¹⁰ -C (O)-( CH ₂ ) _n -,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -,-(CH ₂ ) -S- (CH ₂ ) _n -,-(CH ₂ ) _m -SO _2- NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -,-(CH ₂ ) _m -OC ( O) -NR ^10- (CH ₂ ) _n -or-(CH ₂ ) _m -NR ¹⁰ -C (O) -O- (CH ₂ ) _n- , n and m are independently of each other the same or different integers 0, 1, 2, 3, 4, 5 or 6, M is 1) hydrogen atom, 2)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, 3) -C (O) -N (R11) -R12, 4)-(CH ₂ ) _m -NR ¹⁰ , 5) 6-14 membered aryl, wherein aryl is unsubstituted or independently of one another mono-, di- or tri-substituted by R14, 6) monocyclic or bicyclic 4-15 membered heterocyclyl, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, 7)-(C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 14 or 8) 3 to 7 membered cyclic moieties containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic moieties are unsubstituted or independently of each other mono-, di- or tri- Substituted, wherein R14 is as described), R3, R4 and R22 are the same or different independently from each other, 1) hydrogen atom, 2) halogen, 3)-(C ₁ -C ₄ ) -alkyl wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, _{4) - (C 1 -C 3} ) - alkyl, perfluoroalkyl, 5) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 13, 6)-(C ₀ -C ₄ ) -alkylene-O-R 19, where R 19 is a) a hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another Mono-, di-, or tri-substituted); c) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13; d) -CF ₃ or e) -CHF ₂ ], 7) -NO ₂ , 8) -CN, 9) -SO _s -R ¹¹ (where s is 1 or 2), 10) -SO _t -N (R ¹¹ ) -R ¹² , where t is 1 or 2, 11)-(C ₀ -C ₄ ) -alkylene-C (O) —R ¹¹ , 12)-(C ₀ -C ₄ ) -alkylene-C (O) —OR ¹¹ , 13)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹² , 14)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹² , 15) -NR ¹⁰ -SO ₂ -R ¹⁰ , 16) -SR ¹⁰ , 17)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O)-(C ₁ -C ₄ ) -alkyl, 18) -C (O) -O-C (R15, R16) -O-C (O) -R17, 19)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O) -O- (C ₁ -C ₆ ) -alkyl, 20) -C (O) -O-C (R15, R16) -O-C (O) -O-R17, 21)-(C ₀ -C ₄ ) -alkylene- (C ₆ -C ₁₄ ) -aryl, wherein aryl is independently mono-, di-, or tri-substituted with R 13, 22)-(C ₀ -C ₄ ) -alkylene- (C ₄ -C ₁₅ ) -heterocyclyl, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 23)-(C ₀ -C ₄ ) -alkylene- (C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 24)-(C ₀ -C ₄ ) -alkylene-het wherein het is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 25)-(C ₀ -C ₄ ) -alkylene-O-CH _2- (C ₁ -C ₃ ) -perfluoroalkylene-CH ₂ -O- (C ₀ -C ₄ ) -alkyl, 26) -SO _w -N (R ¹¹ ) -R ¹³ , where w is 1 or 2, 27)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹³ , 28)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹³ or 29)

Residues from Me, wherein Me is methyl or a 5 or 6 membered moiety that is unsubstituted or substituted 1, 2, 3 or 4 times with Can form a ring), R11 and R12 are the same or different independently from each other, 1) hydrogen atom, 2)-(C ₁ -C ₆ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 3)-(C ₀ -C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, 4) -SO _t -R ¹⁰ (where t is 1 or 2), 5)-(C ₀ -C ₆ ) -alkyl- (C ₆ -C ₁₄ ) -aryl, wherein alkyl and aryl are not substituted independently of one another or are mono-, di-, or tri-substituted with R 13, _{6) - (C 1 -C 3} ) - alkyl, perfluoroalkyl, 7) -OR ¹⁷ or 8)-(C ₀ -C ₆ ) -alkyl- (C ₄ -C ₁₅ ) -heterocyclyl, wherein alkyl and heterocyclyl are unsubstituted independently or mono-, di- or tri-substituted with R 13 , R11 and R12 together with the nitrogen atom bonded thereto form a 4 to 8 membered monocyclic heterocyclic ring which may contain one or two identical or different ring heteroatoms selected from oxygen, sulfur and nitrogen in addition to nitrogen Wherein the heterocyclic ring is unsubstituted or independently of one another is mono-, di- or tri-substituted with R 13, R4 and R22 of formula (I) and formula (Ia) may together with the carbon atoms bonded to them form a phenyl moiety, R13 is halogen, -NO ₂ , -CN, = O, -OH, -CF ₃ , -C (O) -OR ¹⁰ , -C (O) -N (R ¹⁰ ) -R ²⁰ , -N (R ¹⁰ ) -R ²⁰ ,-(C ₃ -C ₈ ) -cycloalkyl,-(C ₀ -C ₃ ) -alkylene-OR ¹⁰ , -Si- (CH ₃ ) ₃ , -N (R ¹⁰ ) -S ( O) _u -R ¹⁰ (where u is 1 or 2), -SR ¹⁰ , -SO _r -R ¹⁰ (where r is 1 or 2), -S (O) _v -N (R ¹⁰ ) -R ²⁰ , where v is 1 or 2, -C (O) -R ¹⁰ ,-(C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₈ ) -alkoxy, phenyl, phenyloxy-, -O -CF ₃ ,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R 15, R 16) -OC (O) -R 17,-(C ₁ -C ₄ ) -alkoxyphenyl,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R 15, R 16) -OC (O) -O-R 17,-(C ₁ -C ₃ ) -perfluoroalkyl, -O-R 15, -NH- C (O) -NH-R ¹⁰ , -NH-C (O) -OR ¹⁰ or

Residues from, R ¹⁰ and R ²⁰ independently of one another are hydrogen,-(C ₁ -C ₆ ) -alkyl,-(C ₀ -C ₄ ) -alkyl-OH,-(C ₀ -C ₄ ) -alkyl-O- (C ₁ -C ₄ ) -acyl or-(C ₁ -C ₃ ) -perfluoroalkyl, R 15 and R 16 are independently of each other hydrogen or — (C ₁ -C ₆ ) -alkyl, a 3-6 membered carbocyclic ring which is unsubstituted or substituted one to three times with R ¹⁰ with a carbon atom bonded thereto; Can form R17 is-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl-OH,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₆ ) -alkyl,- (C ₃ -C ₈ ) -cycloalkyl,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₈ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,-(C _1- C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted 1, 2 or 3 times with -OH, -O- (C ₁ -C ₄ ) -alkyl or R ¹⁰ is. The method of claim 1, R ⁰ is 1) monocyclic or bicyclic 6 to 14 membered aryl, wherein the aryl is independently mono-, di- or tri-substituted with R 8, 2) monocyclic selected from the group benzothiophene, indazolyl, indolyl, isoindoleyl, isoquinolyl, phenylpyridyl, phthalazinyl, pyridyl, pyridinyl, pyrimidinyl, quinazolinyl and quinolyl Or bicyclic 4-15 membered heterocyclyl, wherein the heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 8; or 3) monocyclic or bicyclic 4 to 15 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein heterocyclyl is unsubstituted or independently of one another Mono-, di- or tri-substituted with R 8 and further substituted with monocyclic or bicyclic 4-15 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen and Wherein heterocyclyl is unsubstituted or independently of one another is mono-, di-, or tri-substituted with R 8), R8 is 1) halogen, 2) -NO ₂ , 3) -OH, 4) -O-CF ₃ 5) aryl monocyclic or bicyclic 6- to 14-membered (wherein aryl is independently from each other halogen or -O- (C ₁ -C ₈₎ - is a substituted mono-, di- or tri-alkyl), 6)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -OH or methoxy moieties, _{7) -O- (C 1 -C 8} ) - alkyl (wherein alkyl is optionally substituted mono-, di or tri halogen, NH _2, -OH or a methoxy residue is optionally substituted independently from each other), 8) -SO ₂ -CH ₃ or 9) -SO ₂ -CF ₃ , Provided that when R ⁰ is a monocyclic or bicyclic 6 to 14 membered aryl, R 8 is at least one halogen or —O— (C ₁ -C ₈ ) -alkyl moiety, Q is-(C ₀ -C ₂ ) -alkylene-C (O) -NR ^10- , -NR ¹⁰ -C (O) -NR ^10- , -NR ¹⁰ -C (O)-,-(C ₁ -C ₆ ) -alkylene,-(CH ₂ ) _m -NR ¹⁰ -C (O) -NR ^10- (CH ₂ ) _n - _, -(CH ₂ ) _m -NR ¹⁰ -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _m -S- (CH ₂ ) _n -,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _m -SO _2- NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO ₂ -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -CH (OH)-(CH ₂ ) _n -,-(CH ₂ ) _m -OC (O) -NR ^10- (CH ₂ ) _n -,-(C ₂ -C ₃ ) -alkylene-O- (C ₀ -C ₃ ) -alkylene-,-(C ₂ -C ₃ ) -alkylene-S (O)-,-(C ₂ -C ₃ ) -alkylene- S (O) ₂ -,-(CH ₂ ) _m -NR ¹⁰ -C (O) -O- (CH ₂ ) _n -,-(C ₂ -C ₃ ) -alkylene-S (O) ₂ -NH -(R ¹⁰ )-,-(C ₂ -C ₃ ) -alkylene-N (R ¹⁰ )-or-(C ₀ -C ₃ ) -alkylene-C (O) -O- (CH ₂ ) _m -ego, Wherein R ¹⁰ is as defined below, n and m are the same or different integers, independently of one another, 0, 1, 2, 3, 4, 5 or 6, and-(CH ₂ ) _m -or-(CH ₂ ) _n The alkylene moiety formed by-is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -NH ₂ or -OH, or-(C ₃ -C ₆ ) -cycloalkylene, wherein cycloalkylene Are unsubstituted or independently of each other mono-, di- or tri-substituted with halogen, -NH ₂ or -OH, R ¹ is a hydrogen atom, — (C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or substituted 1-3 times with R 13; - (C ₁ -C ₃₎ - alkylene ^{-C (O) -NH-R 0} ; — (C ₁ -C ₃ ) -alkylene-C (O) —O—R 15; Monocyclic or bicyclic 6 to 14 membered aryl, wherein the aryl is independently mono-, di- or tri-substituted with R 8, wherein R 8 is as described; Monocyclic or bicyclic 4 to 15 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen; - (C ₁ -C ₃₎ - perfluoroalkyl alkylene; - (C ₁ -C ₃₎ - alkylene _{-S (O) - (C 1} -C 4) - alkyl; - (C ₁ -C ₃₎ - alkylene _{-S (O) 2 - (C} 1 -C 3) - alkyl; - (C ₁ -C ₃₎ - alkylene _{-S (O) 2 -N (R} 4 ') -R 5'; - (C ₁ -C ₃₎ - alkylene -O- (C ₁ -C ₄₎ - alkyl; -(C ₀ -C ₃ ) -alkylene- (C ₃ -C ₈ ) -cycloalkyl or-(C ₀ -C ₃ ) -alkylene-het, where het is unsubstituted or independently substituted with R 14 , Di- or tri-substituted), R ^{4 '} and R ^5' are the same as or different from each other independently and are a hydrogen atom or-(C ₁ -C ₄ ) -alkyl, R ¹ and R 22 together with the atoms bonded thereto may form a 6 to 8 membered cyclic group containing at least 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where cyclic The group is unsubstituted or independently of one another substituted, di- or tri-substituted by R 14, R ¹ -NV may form a 4 to 8 membered cyclic group containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic groups are unsubstituted or independently of one another Mono-, di- or tri-substituted with R 14, R 14 is halogen, —OH, ═O, — (C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₄ ) -alkoxy, -NO ₂ ,-(C ₀ -C ₄ ) -alkyl-C (O ) -OR ¹⁸ , -CN,-(C ₀ -C ₄ ) -alkyl-N (R ¹⁸ ) -R ²¹ ,-(C ₀ -C ₄ ) -alkyl-OR ¹⁸ ,-(C ₀ -C ₄ ) -Alkyl-het,-(C ₀ -C ₈ ) -alkyl-SO _2- (C ₁ -C ₄ ) -alkyl,-(C ₀ -C ₈ ) -alkyl-SO _2- (C ₁ -C ₃ ) -Perfluoroalkyl,-(C ₀ -C ₈ ) -alkyl-SO ₂ -N (R ¹⁸ ) -R ²¹ , -C (O) -NH- (C ₁ -C ₈ ) -alkyl, -C ( _{O) -N - [(C 1} -C 8) - ^{_{alkyl] 2, -NR 18 -C (O}} ) -NH- (C 1 -C 8) - _{alkyl, -C (O) -NH 2,} -SR and - [alkyl _{(C 1 -C 8) -]} 2, 18 , or -NR ¹⁸ -C (O) -NH Wherein R ¹⁸ and R ²¹ independently of one another are a hydrogen atom,-(C ₁ -C ₃ ) -perfluoroalkyl or-(C ₁ -C ₆ ) -alkyl, V 1) a 3 to 7 membered cyclic moiety containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic moieties are unsubstituted or independently of each other mono-, di- or tri- Is substituted) or 2) monocyclic or bicyclic 4 to 15 membered heterocyclyl, wherein the heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, G is a direct bond,-(CH ₂ ) _m -NR ¹⁰ -SO ₂ -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -CH (OH)-(CH ₂ ) _n -,-(CH ₂ ) _m -,-(CH ₂ ) _m -O- (CH ₂ ) _n - _, -(CH ₂ ) _m -C (O) -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -C (O) -NR ^10- (CH ₂ ) _n - _, -(CH ₂ ) _m -NR ¹⁰ -C (O)-( CH ₂ ) _n -,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -,-(CH ₂ ) -S- (CH ₂ ) _n -,-(CH ₂ ) _m -SO _2- NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -,-(CH ₂ ) _m -OC ( O) -NR ^10- (CH ₂ ) _n -or-(CH ₂ ) _m -NR ¹⁰ -C (O) -O- (CH ₂ ) _n- , n and m are independently the same or different integers 0, 1, 2, 3, 4, 5 or 6 M 1) hydrogen atom, 2)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, 3) -C (O) -N (R11) -R12, 4)-(CH ₂ ) _m -NR ¹⁰ , 5)-(C ₆ -C ₁₄ ) -aryl, wherein aryl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, 6)-(C ₄ -C ₁₅ ) -heterocyclyl, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, 7)-(C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 14 or 8) a 3 to 7 membered cyclic moiety containing one, two, three or four or more heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic moiety is unsubstituted or independently of one another mono-, di-substituted or Trimethylated, wherein R14 is as described), R3, R4 and R22 are the same as or different from each other independently, 1) hydrogen atom, 2) halogen, 3)-(C ₁ -C ₄ ) -alkyl wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, _{4) - (C 1 -C 3} ) - alkyl, perfluoroalkyl, 5) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 13, 6)-(C ₀ -C ₄ ) -alkylene-O-R 19, where R 19 is a) a hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another Mono-, di-, or tri-substituted); c) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13; d) -CF ₃ or e) -CHF ₂ ], 7) -NO ₂ , 8) -CN, 9) -SO _s -R ¹¹ (where s is 1 or 2), 10) -SO _t -N (R ¹¹ ) -R ¹² , where t is 1 or 2, 11)-(C ₀ -C ₄ ) -alkylene-C (O) —R ¹¹ , 12)-(C ₀ -C ₄ ) -alkylene-C (O) —OR ¹¹ , 13)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹² , 14)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹² , 15) -NR ¹⁰ -SO ₂ -R ¹⁰ , 16) -SR ¹⁰ , 17)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O)-(C ₁ -C ₄ ) -alkyl, 18) -C (O) -O-C (R15, R16) -O-C (O) -R17, 19)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O) -O- (C ₁ -C ₆ ) -alkyl, 20) -C (O) -O-C (R15, R16) -O-C (O) -O-R17, 21)-(C ₀ -C ₄ ) -alkylene- (C ₆ -C ₁₄ ) -aryl, wherein aryl is independently mono-, di-, or tri-substituted with R 13, 22)-(C ₀ -C ₄ ) -alkylene- (C ₄ -C ₁₅ ) -heterocyclyl, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 23)-(C ₀ -C ₄ ) -alkylene- (C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 24)-(C ₀ -C ₄ ) -alkylene-het wherein het is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 25)-(C ₀ -C ₃ ) -alkylene-O-CH _2- (C ₁ -C ₃ ) -perfluoroalkylene-CH ₂ -O- (C ₀ -C ₃ ) -alkyl, 26) -SO _w -N (R ¹¹ ) -R ¹³ , where w is 1 or 2, 27)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹³ , 28)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹³ or 29)

Residues from Me, wherein Me is methyl or a 5 or 6 membered moiety that is unsubstituted or substituted 1, 2, 3 or 4 times with Can form a ring), R11 and R12 are the same or different independently from each other, 1) hydrogen atom, 2)-(C ₁ -C ₆ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 3)-(C ₀ -C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, 4) -SO _t -R ¹⁰ (where t is 1 or 2), 5)-(C ₀ -C ₆ ) -alkyl- (C ₆ -C ₁₄ ) -aryl, wherein alkyl and aryl are not substituted independently of one another or are mono-, di-, or tri-substituted with R 13, _{6) - (C 1 -C 3} ) - alkyl, perfluoroalkyl, 7) -OR ¹⁷ or 8)-(C ₀ -C ₆ ) -alkyl- (C ₄ -C ₁₅ ) -heterocyclyl, wherein alkyl and heterocyclyl are unsubstituted independently or mono-, di- or tri-substituted with R 13 , R 11 and R 12 together with the nitrogen atom bonded thereto form a 4 to 8 membered monocyclic heterocyclic ring which may contain, in addition to nitrogen, one or two identical or different ring heteroatoms selected from oxygen, sulfur and nitrogen. Wherein the heterocyclic ring is unsubstituted or independently of one another is mono-, di- or tri-substituted with R 13, R4 and R22 of formula (I) and formula (Ia) may together with the carbon atoms bonded to them form a phenyl moiety, R13 is halogen, -NO ₂ , -CN, = O, -OH, -CF ₃ , -C (O) -OR ¹⁰ , -C (O) -N (R ¹⁰ ) -R ²⁰ , -N (R ¹⁰ ) -R ²⁰ ,-(C ₃ -C ₈ ) -cycloalkyl,-(C ₀ -C ₃ ) -alkylene-OR ¹⁰ , -Si- (CH ₃ ) ₃ , -N (R ¹⁰ ) -S ( O) _u -R ¹⁰ (where u is 1 or 2), -SR ¹⁰ , -SO _r -R ¹⁰ (where r is 1 or 2), -S (O) _v -N (R ¹⁰ ) -R ²⁰ , where v is 1 or 2, -C (O) -R ¹⁰ ,-(C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₈ ) -alkoxy, phenyl, phenyloxy-, -O -CF ₃ ,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R 15, R 16) -OC (O) -R 17,-(C ₁ -C ₄ ) -alkoxyphenyl,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R 15, R 16) -OC (O) -O-R 17,-(C ₁ -C ₃ ) -perfluoroalkyl, -O-R 15, -NH- C (O) -NH-R ¹⁰ , -NH-C (O) -OR ¹⁰ or

Residues from, R ¹⁰ and R ²⁰ are independently of each other hydrogen, — (C ₁ -C ₆ ) -alkyl or — (C ₁ -C ₃ ) -perfluoroalkyl, R 15 and R 16 are independently of each other hydrogen or — (C ₁ -C ₆ ) -alkyl, a 3-6 membered carbocyclic ring which is unsubstituted or substituted one to three times with R ¹⁰ with a carbon atom bonded thereto; Can form R17 is-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl-OH,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₆ ) -alkyl,- (C ₃ -C ₈ ) -cycloalkyl,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₈ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,-(C _1- C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted 1, 2 or 3 times with -OH; A compound of Formula I and Ia, which is -O- (C ₁ -C ₄ ) -alkyl or R ¹⁰ . The method according to claim 1 or 2, R ⁰ is 1) monocyclic or bicyclic 6 to 14 membered aryl selected from the group phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, wherein aryl is independently mono-, di- or tri-substituted by R8 ), 2) group benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophenyl, cinnolinyl, chromanyl, indazolyl, indolyl, isochromenyl, iso Indolyl, isoquinolinyl, phenylpyridyl, phthalazinyl, pterridinyl, furinyl, pyridinyl, pyridimidazolyl, pyridopyridinyl, pyridopyrimidinyl, pyrimidinyl, quinazolinyl , Heterocyclyl selected from quinolyl, quinoxalinyl or 1,4,5,6-tetrahydropyridazinyl, wherein the heterocyclyl is unsubstituted or independently of one another mono-, di- or trisubstituted by R8; or 3) heterocyclyl, where heterocyclyl is a group acridinyl, azabenzimidazolyl, azaspirodecanyl, azefinyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzothio Furanyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromaenyl, Cinnolinyl, decahydrocinnolinyl, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 6H-1,5, 2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl , Indolinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromenyl, isodazolyl, isoindolinyl, isoindolinyl, isoquinolinyl, Isothiazolyl, isothiazolidinyl, isothiazolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopiperazinyl, morpholinyl, naphthyridinyl, octahydrodin Isoquinolinyl, oxdiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1 , 2-oxathipanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl, 1,4-oxazinyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4- Oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, phenantridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxatiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, Pterridinyl, furinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyrimididazolyl, pyridothiazolyl, pyridinyl, pyridyl, Pyrimidinyl, pyrrolidinyl, pyrrolidinyl , Pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolininyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroqui Nolinyl, 1,4,5,6-tetrahydropyridazinyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3 -Thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1,3- Thiazinyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thiazolidinyl, thiazolinyl, thienyl, thientanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thi Tanyl, thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3 -Triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazole And greater chrysanthemate is selected from carbonyl, where the heterocyclyl is optionally substituted mono-, di- or tri-substituted independently with unsubstituted or R8 together, Group acridinyl, azabenzimidazolyl, azaspirodecanyl, azepineyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, Benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydrocinolinyl, 4 , 5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 6H-1,5,2-diothiazinyl, dihydrofuro [2 , 3-b] -tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolinyl, indolyl, 3H-indolyl , Isobenzofuranyl, isochromenyl, isodazolyl, isoindolinyl, isoindoleyl, isoquinolinyl, isothiazolyl, isothiazolidinyl, isothiazole Linyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopipiperazinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadizolyl, 1,2 , 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathipanyl, 1,2-oxa Thiolanyl, 1,4-oxazepanyl, 1,4-oxazinyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolinyl, oxa Zolyl, phenantridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxatiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, putridinyl, furinyl, pyranyl, pyrazinyl , Pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrroli Nil, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolininyl, quinoxalinyl, quinuclininyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 1,4,5,6-tetrahydropyridazinyl, tetrahydropyridinyl , Tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- Thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thia Zolidinyl, thiazolinyl, thienyl, thiethanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiethanyl, thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2 , 3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl As heterocyclyl selected from 1,3,4-triazolyl and xanthenyl Substituted and in which a heterocyclyl is unsubstituted or independently substituted with one optionally substituted with R8, disubstituted or trisubstituted with each other), R8 is 1) halogen, 2) -NO ₂ , 3) -OH, 4) -O-CF ₃ 5) aryl monocyclic or bicyclic 6- to 14-membered (wherein aryl is independently from each other halogen or -O- (C ₁ -C ₈₎ - is a substituted mono-, di- or tri-alkyl), 6)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -OH or methoxy moieties, _{7) -O- (C 1 -C 8} ) - alkyl (wherein alkyl is optionally substituted mono-, di or tri halogen, NH _2, -OH or a methoxy residue is optionally substituted independently from each other), 8) -SO ₂ -CH ₃ or 9) -SO ₂ -CF ₃ , Provided that when R ⁰ is a monocyclic or bicyclic 6 to 14 membered aryl, R 8 is at least one halogen or —O— (C ₁ -C ₈ ) -alkyl moiety, Q is-(C ₀ -C ₂ ) -alkylene-C (O) -NR ^10- , -NR ¹⁰ -C (O) -NR ^10- , -NR ¹⁰ -C (O)-,-(C ₁ -C ₆ ) -alkylene,-(CH ₂ ) _m -NR ¹⁰ -C (O) -NR ^10- (CH ₂ ) _n - _, -(CH ₂ ) _m -NR ¹⁰ -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _m -S- (CH ₂ ) _n -,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _m -SO _2- NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO ₂ -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -CH (OH)-(CH ₂ ) _n -,-(CH ₂ ) _m -OC (O) -NR ^10- (CH ₂ ) _n -,-(C ₂ -C ₃ ) -alkylene-O- (C ₀ -C ₃ ) -alkylene-,-(C ₂ -C ₃ ) -alkylene-S (O)-,-(C ₂ -C ₃ ) -alkylene- S (O) ₂ -,-(CH ₂ ) _m -NR ¹⁰ -C (O) -O- (CH ₂ ) _n -,-(C ₂ -C ₃ ) -alkylene-S (O) ₂ -NH -(R ¹⁰ )-,-(C ₂ -C ₃ ) -alkylene-N (R ¹⁰ )-or-(C ₀ -C ₃ ) -alkylene-C (O) -O- (CH ₂ ) _m -ego, Wherein R ¹⁰ is as defined below, n and m are the same or different integers, independently of one another, 0, 1, 2, 3, 4, 5 or 6, and-(CH ₂ ) _m -or-(CH ₂ ) _n The alkylene moiety formed by-is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -NH ₂ or -OH, or-(C ₃ -C ₆ ) -cycloalkylene, wherein cycloalkylene Are unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -NH ₂ or -OH, R ¹ is a hydrogen atom, — (C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or substituted 1-3 times with R 13; - (C ₁ -C ₃₎ - alkylene ^{-C (O) -NH-R 0} , - (C 1 -C 3) - alkylene -C (O) -O-R15; Aryl residues selected from the group phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, wherein aryl is independently mono-, di- or tri-substituted with R 8, wherein R 8 is as described; Monocyclic or bicyclic 4-15 membered heterocyclyl as described; - (C ₁ -C ₃₎ - _{perfluoroalkyl-alkylene, - (C 1 -C 3)} - alkylene _{-S (O) - (C 1} -C 4) - alkyl, - (C ₁ -C ₃₎ - alkylene _{-S (O) 2 - (C} 1 -C 3) - _{alkyl, - (C 1 -C 3)} - alkylene _{-S (O) 2 -N (R} 4 ') -R 5'; - (C ₁ -C ₃₎ - alkylene -O- (C ₁ -C ₄₎ - _{alkyl, - (C 0 -C 3)} - alkylene - (C ₃ -C ₈₎ - cycloalkyl, or - (C _0- C ₃ ) -alkylene-het, where het is the group azepine, azetidine, aziridine, azirin, 1,4-diazaphane, 1,2-diazepine, 1,3-diazepine, 1, 4-diazepines, diaziridine, diazirine, dioxazole, dioxazine, dioxol, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, Isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazolin, isoxazolidine, 2-isoxazolin, ketopiperazine, morpholine, 1,4-oxazepan, 1,2- Oxathipan, 1,2-oxathiolane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxaziridine, oxirane, piperazine, piperidine, pyran , Pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, tiadi Azine thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine, thiazolin, thienyl, thiethane, thio Morpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole A moiety selected from: wherein het is unsubstituted or independently of one another is mono-, di-, or tri-substituted with R 14), R ^{4 '} and R ^5' are the same as or different from each other independently and are a hydrogen atom or-(C ₁ -C ₄ ) -alkyl, R ¹ and R 22 together with the atoms bonded thereto are a group azocan, azocan-2-one, 1,2-diazepines, 1,3-diazepines, 1,4-diazepines, [1,4] dia Zokanes, [1,2] diazocan-3-ones, [1,3] diazocan-2-ones, dioxazines, [1,4] dioxokanes, dioxols, ketopiperazines, morpholines, 1 , 2-oxazine, 1,3-oxazine, 1,4-oxazine, oxocan, oxocan-2-one, piperazine, piperidine, pyran, pyrazine, pyridazine, pyrimidine or 5,6 Can form a 6-8 membered cyclic moiety selected from, 7,8-tetrahydro-1H-azosin-2-one, wherein the cyclic groups are unsubstituted or independently of each other mono-, di-substituted or Trisubstituted, R ¹ -NV groups azepine, azetidine, dioxazole, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazoline Dean, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazolin, isoxazolidine, 2-isoxazolin, ketopiperazine, morpholine, oxazole, piperazine, piperidine , Pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole , Thiazolidine, thiazolin, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1, A 4-8 membered cyclic group selected from 2,4-triazole, wherein the cyclic group is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, R 14 is halogen, —OH, ═O, — (C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₄ ) -alkoxy, -NO ₂ ,-(C ₀ -C ₄ ) -alkyl-C (O ) -OR ¹⁸ , -CN,-(C ₀ -C ₄ ) -alkyl-N (R ¹⁸ ) -R ²¹ ,-(C ₀ -C ₄ ) -alkyl-OR ¹⁸ ,-(C ₀ -C ₄ ) -Alkyl-het, where het is azetidine, azetidinone, piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, 1,2,3-triazine, 1,2,4- Triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,4-diazepane, 1,2-diazepines, 1,3-diazepine, 1,4-diazepine, azepine, ketopiperazine, 1,4-oxazepan, oxazole, isoxazole, isoxazolidine, 2-isoxazolin, morpholine, thia Sol, isothiazole, thiadiazole or thiomorpholine); -(C ₀ -C ₈ ) -alkyl-SO _2- (C ₁ -C ₄ ) -alkyl,-(C ₀ -C ₈ ) -alkyl-SO _2- (C ₁ -C ₃ ) -perfluoroalkyl ,-(C ₀ -C ₈ ) -alkyl-SO ₂ -N (R ¹⁸ ) -R ²¹ , -C (O) -NH- (C ₁ -C ₈ ) -alkyl, -C (O) -N- [(C ₁ -C ₈₎ - ^{_{alkyl] 2, -NR 18 -C (O}} ) -NH- (C 1 -C 8) - _{alkyl, -C (O) -NH 2,} -SR 18 or -NR ¹⁸ -C (O) -NH - [( C 1 -C 8) - alkyl] _2, wherein R ¹⁸ and R ²¹ independently represent a hydrogen atom, each - (C ₁ -C ₃₎ - perfluoroalkyl, or - (C ₁ -C ₆ ) -alkyl, V is a group aridinyl, azaindole (1H-pyrrolopyridine), azabenzimidazolyl, azaspirodecanyl, azepineyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzo Thiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl , Cinnalinel, decahydrocinolinyl, 1,4-diazepane, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxole Nil, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromenyl, isoindazolyl, isoindolinyl, isoindolinyl, isoquinolinyl, Isothiazolyl, isothiazolidinyl, isothiazolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopiperazinyl, morpholinyl, naphthyridinyl, octahydrodin Isoquinolinyl, oxdiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1 , 2-oxathipanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl, 1,4-oxazinyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4- Oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, phenantridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxatiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, Pterridinyl, furinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyrimididazolyl, pyridothiazolyl, pyridinyl, pyridyl, Pyrimidinyl, pyrrolidinyl, pyrrolidinyl , Pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolininyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisocinnolinyl, tetrahydrocinnoline Neyl, 1,4,5,6-tetrahydropyridazinyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3- Thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1,3-thia Genyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thiazolidinyl, thiazolinyl, thienyl, thietanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiethananyl , Thiomorpholinyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1 Selected from 2,5-triazolyl, 1,3,4-triazolyl and xanthenyl And interrogating heterocyclyl (wherein heterocyclyl is optionally substituted mono-, di- or tri-substituted independently with or not been R14 each other), G is a direct bond,-(CH ₂ ) _m -NR ¹⁰ -SO ₂ -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -CH (OH)-(CH ₂ ) _n -,-(CH ₂ ) _m -,-(CH ₂ ) _m -O- (CH ₂ ) _n - _, -(CH ₂ ) _m -C (O) -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -C (O) -NR ^10- (CH ₂ ) _n - _, -(CH ₂ ) _m -NR ¹⁰ -C (O)-( CH ₂ ) _n -,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -,-(CH ₂ ) -S- (CH ₂ ) _n -,-(CH ₂ ) _m -SO _2- NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -,-(CH ₂ ) _m -OC ( O) -NR ^10- (CH ₂ ) _n -or-(CH ₂ ) _m -NR ¹⁰ -C (O) -O- (CH ₂ ) _n- , n and m are, independently from each other, the same or different integers 0, 1, 2, 3, 4, 5 or 6, M 1) hydrogen atom, 2)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, 3) -C (O) -N (R11) -R12, 4)-(CH ₂ ) _m -NR ¹⁰ , 5)-(C ₆ -C ₁₄ ) -aryl, wherein aryl is as described and aryl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, 6)-(C ₄ -C ₁₅ ) -heterocyclyl, wherein heterocyclyl is as described and is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14 or 7)-(C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, R3, R4 and R22 are the same as or different from each other independently, 1) hydrogen atom, 2) halogen, 3)-(C ₁ -C ₄ ) -alkyl wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, _{4) - (C 1 -C 3} ) - alkyl, perfluoroalkyl, 5) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 13, 6)-(C ₀ -C ₄ ) -alkylene-O-R 19, where R 19 is a) a hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another Mono-, di-, or tri-substituted); c) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R13); d) -CF ₃ or e) -CHF ₂ ], 7) -NO ₂ , 8) -CN, 9) -SO _s -R ¹¹ (where s is 1 or 2), 10) -SO _t -N (R ¹¹ ) -R ¹² , where t is 1 or 2, 11)-(C ₀ -C ₄ ) -alkylene-C (O) —R ¹¹ , 12)-(C ₀ -C ₄ ) -alkylene-C (O) —OR ¹¹ , 13)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹² , 14)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹² , 15) -NR ¹⁰ -SO ₂ -R ¹⁰ , 16) -SR ¹⁰ , 17)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O)-(C ₁ -C ₄ ) -alkyl, 18) -C (O) -O-C (R15, R16) -O-C (O) -R17, 19)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O) -O- (C ₁ -C ₆ ) -alkyl, 20) -C (O) -O-C (R15, R16) -O-C (O) -O-R17, 21)-(C ₀ -C ₄ ) -alkylene- (C ₆ -C ₁₄ ) -aryl, wherein aryl is independently mono-, di-, or tri-substituted with R 13, 22)-(C ₀ -C ₄ ) -alkylene- (C ₄ -C ₁₅ ) -heterocyclyl, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 23)-(C ₀ -C ₄ ) -alkylene- (C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 24)-(C ₀ -C ₄ ) -alkylene-het wherein het is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 25)-(C ₀ -C ₃ ) -alkylene-O-CH _2- (C ₁ -C ₃ ) -perfluoroalkylene-CH ₂ -O- (C ₀ -C ₃ ) -alkyl, 26) -SO _w -N (R ¹¹ ) -R ¹³ , where w is 1 or 2, 27)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹³ , 28)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹³ or 29)

Residue from Me, wherein Me is methyl or a 1,3-dioxol ring which is substituted one, two, three or four times with R 13 together with the atoms bonded thereto when two -OR 19 moieties are bonded to adjacent atoms; Or 2,3-dihydro- [1,4] dioxine ring), R11 and R12 are the same or different independently from each other, 1) hydrogen atom, 2)-(C ₁ -C ₆ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 3)-(C ₀ -C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, 4) -SO _t -R ¹⁰ (where t is 1 or 2), 5)-(C ₀ -C ₆ ) -alkyl- (C ₆ -C ₁₄ ) -aryl, wherein alkyl and aryl are not substituted independently of one another or are mono-, di-, or tri-substituted with R 13, _{6) - (C 1 -C 3} ) - alkyl, perfluoroalkyl, 7) -OR ¹⁷ or 8)-(C ₀ -C ₆ ) -alkyl- (C ₄ -C ₁₅ ) -heterocyclyl, wherein alkyl and heterocyclyl are as described and are not independently substituted with each other or are mono-, di- or tri-substituted with R 13 Is substituted), or R11 and R12 together with the nitrogen atom bonded to them group azepine, azetidine, dioxazole, dioxazine, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4 Diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazolin, isoxazolidine, 2-isoxazolin, ketopipera Gin, morpholine, [1,4] oxazepan, 1,4-oxazinyl, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine , Pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazolin, thiomorpholine, thiophene, 1,2,3 A heterocyclic ring selected from -triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, wherein Heterocyclic rings are unsubstituted Or mono-, di-, or tri-substituted with R13 independently of each other, R4 and R22 of formula (I) and formula (Ia) may together with the carbon atoms bonded to them form a phenyl moiety, R13 is halogen, -NO ₂ , -CN, = O, -OH, -CF ₃ , -C (O) -OR ¹⁰ , -C (O) -N (R ¹⁰ ) -R ²⁰ , -N (R ¹⁰ ) -R ²⁰ ,-(C ₃ -C ₈ ) -cycloalkyl,-(C ₀ -C ₃ ) -alkylene-OR ¹⁰ , -Si- (CH ₃ ) ₃ , -N (R ¹⁰ ) -S ( O) _u -R ¹⁰ (where u is 1 or 2), -SR ¹⁰ , -SO _r -R ¹⁰ (where r is 1 or 2), -S (O) _v -N (R ¹⁰ ) -R ²⁰ , where v is 1 or 2, -C (O) -R ¹⁰ ,-(C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₈ ) -alkoxy, phenyl, phenyloxy-, -O -CF ₃ ,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R 15, R 16) -OC (O) -R 17,-(C ₁ -C ₄ ) -alkoxyphenyl,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R 15, R 16) -OC (O) -O-R 17,-(C ₁ -C ₃ ) -perfluoroalkyl, -O-R 15, -NH- C (O) -NH-R ¹⁰ , -NH-C (O) -OR ¹⁰ or

Residues from where Me is methyl and R ¹⁰ and R ²⁰ independently of one another are hydrogen,-(C ₁ -C ₆ ) -alkyl,-(C ₀ -C ₄ ) -alkyl-OH,-(C _0- C ₄₎ - alkyl, -O- (C ₁ -C ₄₎ - ahkil or - (C ₁ -C ₃₎ - it is perfluoroalkyl), and R 15 and R 16 are independently of each other hydrogen, — (C ₁ -C ₆ ) -alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein each ring is unsubstituted or substituted 1 to 3 times with R ¹⁰ , R17 is-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl-OH,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₆ ) -alkyl,- (C ₃ -C ₈ ) -cycloalkyl,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₈ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,-(C _1- C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted 1, 2 or 3 times with -OH; A compound of Formula I and Ia, which is -O- (C ₁ -C ₄ ) -alkyl or R ¹⁰ . The method according to any one of claims 1 to 3, R ⁰ is 1) monocyclic or bicyclic 6 to 14 membered aryl selected from the group phenyl, naphthyl, biphenyl, anthryl or fluorenyl, wherein the aryl is independently mono-, di- or tri-substituted with R8; , 2) group benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophenyl, cinnolinyl, chromanyl, indazolyl, indolyl, isochromenyl, iso Indolyl, isoquinolinyl, phenylpyridyl, phthalazinyl, pterridinyl, furinyl, pyridinyl, pyridimidazolyl, pyridopyridinyl, pyridopyrimidinyl, pyrimidinyl, quinazolinyl , Heterocyclyl selected from quinolyl, quinoxalinyl or 1,4,5,6-tetrahydropyridazinyl, wherein the heterocyclyl is unsubstituted or independently of one another mono-, di- or trisubstituted by R8; or 3) group azabenzimidazolyl, benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, 2-furyl, 3 -Furyl, imidazolyl, indolyl, indazolyl, isochromenyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, phthalazinyl, pterridinyl, furinyl, pyrazinyl , Pyrazolyl, pyridazinyl, pyridimidazolyl, pyridopyridinyl, pyridopyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrrolyl; Heterocyclyl selected from 2-pyrrolyl, 3-pyrrolyl, quinolinyl, quinazolinyl, quinoxalinyl, tetrazolyl, thiazolyl, 2-thienyl or 3-thienyl, wherein the group acridinyl, Azabenzimidazolyl, azaspirodecanyl, azepinyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benz Triazolyl, Benztetrazolyl, Benzisoxazolyl, Benzisothiazolyl, Carbazolyl, 4aH-carbazolyl, Carbolinyl, Chromanil, Chromenyl, Cynolinyl, Decahydrocinnolinyl, 4,5-dihydro Oxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] -Tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolinyl, indolyl, 3H-phosphoryl Doryl, isobenzofuranyl, isochromenyl, isodazolyl, isoindolinyl, isoindolinyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isothiazolidinyl, isothiazolinyl, isox Sazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopiperazinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadizolyl, 1,2,3- Oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathipanyl, 1,2-oxathiolanyl , 1,4-oxazepanyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, phenantridinyl, phenanthrolinyl, phena Genyl, Phenothiazinyl, Phenoxatiinyl, Phenoxazinyl, Phtharazinyl, Piperazinyl, Piperidinyl, Pterridinyl, Furinyl, Pyranyl, Pyrazinyl, Pyrazolidinyl, Pyrazolinyl, Pyrazolyl , Pyridazinyl, pyridooxazole Pyridimidazolyl, pyridothiazolyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl , 4H-quinolininyl, quinoxalinyl, quinuclininyl, tetrahydrofuranyl, tetrahydroisocinnolinyl, tetrahydrocinnolinyl, 1,4,5,6-tetrahydropyridazinyl, tetrahydropyripy Diyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5 -Thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, Thiazolidinyl, thiazolinyl, thienyl, thiethanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiethanyl, thiomorpholinyl, thiophenyl, thiopyranyl, 1,2,3- Triazinyl, 1,2,3-triazolyl Further substituted with heterocyclyl selected from 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, Wherein heterocyclyl is unsubstituted or independently of one another is mono-, di-, or tri-substituted with R 8), R8 is One) Fluorine, chlorine or bromine, 2) -NO ₂ , 3) -OH, 4) -O-CF ₃ 5) aryl monocyclic or bicyclic 6- to 14-membered (wherein aryl is independently from each other halogen or -O- (C ₁ -C ₈₎ - is a substituted mono-, di- or tri-alkyl), 6)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -OH or methoxy moieties, _{7) -O- (C 1 -C 8} ) - alkyl (wherein alkyl is optionally substituted mono-, di or tri halogen, NH _2, -OH or a methoxy residue is optionally substituted independently from each other), 8) -SO ₂ -CH ₃ or 9) -SO ₂ -CF ₃ , Provided that when R ⁰ is aryl or heterocyclyl as described, R 8 is at least one halogen or —O— (C ₁ -C ₈ ) -alkyl moiety, Q is-(C ₀ -C ₂ ) -alkylene-C (O) -NR ^10- , -NR ¹⁰ -C (O) -NR ^10- , -NR ¹⁰ -C (O)-,-(C ₁ -C ₆ ) -alkylene or-(C ₀ -C ₃ ) -alkylene-C (O) -O- (C ₀ -C ₂ ) -alkylene, R ¹ is a hydrogen atom, — (C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or substituted 1-3 times with R 13; - (C ₁ -C ₃₎ - alkylene ^{-C (O) -NH-R 0} , - (C 1 -C 3) - alkylene -C (O) -O-R15, - (C 1 -C 3 ) perfluoroalkyl _{alkylene, - (C 1 -C 3)} - alkylene -S (O) - (C ₁ -C ₄₎ - _{alkyl, - (C 1 -C 3)} - alkylene -S (O ) _2- (C ₁ -C ₃ ) -alkyl,-(C ₁ -C ₃ ) -alkylene-S (O) ₂ -N (R ^{4 ′} ) -R ⁵ ,-(C ₁ -C ₃ )- alkylene -O- (C ₁ -C ₄₎ - _{alkyl, - (C 0 -C 3)} - alkylene - (C ₃ -C ₈₎ - cycloalkyl, or - (C ₀ -C ₃₎ - alkylene- het (where het is the group azepine, azetidine, aziridine, azirin, 1,4-diazepane, 1,2-diazepines, 1,3-diazepines, 1,4-diazepines, diaziridine, Diazirin, Dioxazole, Dioxazine, Dioxol, 1,3-dioxolene, 1,3-dioxolane, Furan, Imidazole, Imidazoline, Imidazolidine, Isothiazole, Isothiazolidine, Isothiazoline, isoxazole, isoxazolin, isoxazolidine, 2-isoxazolin, ketopiperazine, morpholine, 1,2-oxathipan, 1,2-oxathiolane, 1,4-oxa Engraving, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxaziridine, jade Silane, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetra Gin, tetrazole, thiadiazine thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine, thiazolin, Thienyl, thiethane, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1 , A residue selected from 2,4-triazole, wherein het is unsubstituted or independently of each other mono-, di- or tri-substituted with R14), R ^{4 '} and R ^5' are the same as or different from each other independently and are a hydrogen atom or-(C ₁ -C ₄ ) -alkyl, R ¹ -NV is a group azepine, azetidine, 1,4-diazepane, dioxazole, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, Imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazolin, ketopiperazine, morpholine, 1, 4-oxazepan, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydro Pyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazolin, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5- To form a 4 to 8 membered cyclic group selected from triazine, 1,2,3-triazole or 1,2,4-triazole, wherein the cyclic group is unsubstituted or independently monovalent to R14, Di- or tri-substituted And, R14 is fluorine, chlorine, bromine, iodine, -OH, = O, - ( C 1 -C 8) - _{alkyl, - (C 1 -C 4)} - _{alkoxy, -NO 2, -C (O)} -OH, -CN, -NH ₂ , -C (O) -O- (C ₁ -C ₄ ) -alkyl,-(C ₀ -C ₄ ) -alkyl-SO _2- (C ₁ -C ₄ ) -alkyl,- (C ₀ -C ₈ ) -alkyl-SO ₂ -N (R ¹⁸ ) -R ²¹ , -C (O) -NH- (C ₁ -C ₈ ) -alkyl, -C (O) -N-[( C ₁ -C ₈ ) -alkyl] ₂ , -NR ¹⁸ -C (O) -NH- (C ₁ -C ₈ ) -alkyl, -C (O) -NH ₂ , -SR ¹⁸ or -NR ¹⁸ -C (O) -NH - [(C 1 -C 8) - alkyl] _2, wherein R ¹⁸ and R ²¹ independently represent a hydrogen atom, each - (C ₁ -C ₃₎ - perfluoroalkyl, or - (C _1- C ₆ ) -alkyl, V is azaindole (1H-pyrrolopyridine), azepine, azetidine, aziridine, azirin, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4- Diazepine, Diaziridine, Diazirin, Dioxazole, Dioxazine, Dioxol, 1,3-dioxolene, 1,3-dioxolane, Furan, Imidazole, Imidazoline, Imidazolidine, Isothia Sol, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazolin, ketopiperazine, morpholine, 1,2-oxathipan, 1,2-oxa Thiolane, 1,4-oxazepan, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxaziridine, oxirane, piperazine, piperidine, pyran, pyrazine , Pyrazole, pyrazoline, pyrazole ridine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiadiazine, thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazoli Dean, thiazolin, thienyl, thiethane, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3 A heterocyclyl moiety selected from -triazole or 1,2,4-triazole, as described, wherein het is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, G is a direct bond,-(CH ₂ ) _m -NR ¹⁰ -SO ₂ -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -CH (OH)-(CH ₂ ) _n -,-(CH ₂ ) _m -,-(CH ₂ ) _m -O- (CH ₂ ) _n - _, -(CH ₂ ) _m -C (O) -NR ^10- (CH ₂ ) _n -,-(CH ₂ ) -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -C (O) -NR ^10- (CH ₂ ) _n - _, -(CH ₂ ) _m -NR ¹⁰ -C (O)-( CH ₂ ) _n -,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -,-(CH ₂ ) -S- (CH ₂ ) _n -,-(CH ₂ ) _m -SO _2- NR ^10- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -SO _2- (CH ₂ ) _n -,-(CH ₂ ) _m -NR ¹⁰ -,-(CH ₂ ) _m -OC ( O) -NR ^10- (CH ₂ ) _n -or-(CH ₂ ) _m -NR ¹⁰ -C (O) -O- (CH ₂ ) _n- , n and m are independently the same or different integers 0, 1, 2, 3, 4, 5 or 6 M 1) hydrogen atom, 2)-(C ₁ -C ₈ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, 3) -C (O) -N (R11) -R12, 4)-(CH ₂ ) _m -NR ¹⁰ , 5) phenyl or naphthyl, wherein phenyl or naphthyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 14, 6) heterocyclyl, where heterocyclyl is azepan, azepin, 1,4-diazepan, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, isothia Sol, isoxazole, isoxazolidine, 2-isoxazolin, ketomorpholine, ketopiperazine, morpholine, oxazole, [1,4] -oxazepan, piperazine, piperazinone, piperidine , Piperidinone, pyrazine, pyridazine, pyridazinone, pyridine, pyridone, pyrimidine, pyrrolidine, pyrrolidinone, tetrahydropyran, 1,4,5,6-tetrahydropyridazinyl, tetrazine , Tetrazole, thiadiazole, thiazole, thiophene, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3 -A residue selected from the group derivable from a triazole or 1,2,4-triazole, wherein the heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R14) or 7)-(C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, R3, R4 and R22 are the same as or different from each other independently, 1) hydrogen atom, 2) halogen, 3)-(C ₁ -C ₄ ) -alkyl wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, _{4) - (C 1 -C 3} ) - alkyl, perfluoroalkyl, 5) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 13, 6)-(C ₀ -C ₄ ) -alkylene-O-R 19, wherein R 19 is a) a hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another Mono-, di-, or tri-substituted); c) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13; d) -CF ₃ or e) CHF ₂ ], 7) -CN, 8)-(C ₀ -C ₄ ) -alkylene- (C ₄ -C ₁₅ ) -heterocyclyl, wherein heterocyclyl is as described and is unsubstituted or independently of one another mono, di or trisubstituted by R 13 do), 9) -SO _s -R ¹¹ (where s is 1 or 2), 10) -SO _t -N (R ¹¹ ) -R ¹² , where t is 1 or 2, 11)-(C ₀ -C ₄ ) -alkylene-C (O) —R ¹¹ , 12)-(C ₀ -C ₄ ) -alkylene-C (O) —OR ¹¹ , 13)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹² , 14)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹² , 15) -NR ¹⁰ -SO ₂ -R ¹⁰ , 16)-(C ₀ -C ₄ ) -alkylene-het, wherein het is as described and is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 17)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O)-(C ₁ -C ₄ ) -alkyl, 18) -C (O) -O-C (R15, R16) -O-C (O) -R17, 19)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O) -O- (C ₁ -C ₆ ) -alkyl, 20) -C (O) -O-C (R15, R16) -O-C (O) -O-R17, 21)-(C ₀ -C ₄ ) -alkylene- (C ₆ -C ₁₄ ) -aryl, wherein aryl is as described and independently of one another mono-, di- or tri-substituted with R 13, 22)-(C ₀ -C ₄ ) -alkylene- (C ₃ -C ₈ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 23)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl, 24)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl, 25)-(C ₀ -C ₃ ) -alkylene-O-CH _2- (C ₁ -C ₃ ) -perfluoroalkylene-CH ₂ -OH, 26) -SO _w -N (R ¹¹ ) -R ¹³ , where w is 1 or 2, 27)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹³ , 28)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹³ or 29)

Residues from Me, wherein Me is methyl or a 1,3-dioxol ring substituted one, two, three or four times with R 13 with the atoms bonded thereto when two -OR 19 residues are bonded to an adjacent atom, or 2,3-dihydro- [1,4] dioxin ring can be formed), R11 and R12 are the same or different independently from each other, 1) hydrogen atom, 2)-(C ₁ -C ₆ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 3)-(C ₀ -C ₆ ) -alkyl- (C ₆ -C ₁₄ ) -aryl, wherein aryl is as described herein wherein alkyl and aryl are unsubstituted independently or mono-, di- or tri-substituted with R 13 do), 4) -OR ¹⁷ or 5)-(C ₀ -C ₆ ) -alkyl- (C ₄ -C ₁₅ ) -heterocyclyl, wherein alkyl and heterocyclyl are as described and are not substituted independently of one another or are mono-, di- or tri-substituted with R 13 Is substituted), or R11 and R12 together with the nitrogen atom bonded to them are a group azepine, azetidine, 1,4-diazepane, dioxazole, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4 Diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazolin, isoxazolidine, 2-isoxazoline, ketopipera Gin, morpholine, [1,4] oxazepan, 1,4-oxazepine, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, Pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazolin, thiomorpholine, 1,2,3-triazine, May form a ring selected from 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, which may be unsubstituted or independently of one another Mono, di or Trisubstituted, R4 and R22 of formula (I) and formula (Ia) may together with the carbon atoms bonded to them form a phenyl moiety, R13 is fluorine, chlorine, bromine, iodine, -NO ₂ , -CN, = O, -OH, -CF ₃ , -C (O) -OR ¹⁰ , -C (O) -N (R ¹⁰ ) -R ²⁰ , -N (R ¹⁰ ) -R ²⁰ ,-(C ₀ -C ₃ ) -alkylene-OR ¹⁰ , -Si- (CH ₃ ) ₃ , -N (R ¹⁰ ) -S (O) ₂ -R ¹⁰ , -SR ¹⁰ , -SO ₂ -R ¹⁰ , -S (O) ₂ -N (R ¹⁰ ) -R ²⁰ , -C (O) -R ¹⁰ ,-(C ₁ -C ₈ ) -alkyl,-( C ₁ -C ₈ ) -alkoxy, phenyl, phenyloxy-, -O-CF ₃ ,-(C ₁ -C ₃ ) -perfluoroalkyl,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R15, R16) -OC (O) -R17,-(C ₁ -C ₄ ) -alkoxyphenyl,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R15, R16)- OC (O) -O-R17, -O-R15, -NH-C (O) -NH-R ¹⁰ , -NH-C (O) -OR ¹⁰ or

Residues from wherein Me is methyl and R ¹⁰ and R ²⁰ independently of one another are hydrogen,-(C ₁ -C ₆ ) -alkyl,-(C ₀ -C ₄ ) -alkyl-OH,-(C _0- C ₄₎ - alkyl, -O- (C ₁ -C ₄₎ - ahkil or - (C ₁ -C ₃₎ - it is perfluoroalkyl), and R 15 and R 16 are independently of each other hydrogen or — (C ₁ -C ₆ ) -alkyl, or together form a ring selected from the group cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein each ring is unsubstituted or R Substituted 1 to 3 times with ¹⁰ , R17 is-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl-OH,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₆ ) -alkyl,- (C ₃ -C ₈ ) -cycloalkyl,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₈ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,-(C _1- C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted 1, 2 or 3 times with -OH; A compound of Formula I and Ia, which is -O- (C ₁ -C ₄ ) -alkyl or R ¹⁰ . The method according to any one of claims 1 to 4, R ⁰ is 1) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R8, 2) group benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophenyl, cinnolinyl, chromanyl, indazolyl, indolyl, isochromenyl, iso Indolyl, isoquinolinyl, phenylpyridyl, phthalazinyl, pterridinyl, furinyl, pyridinyl, pyridimidazolyl, pyridopyridinyl, pyridopyrimidinyl, pyrimidinyl, quinazolinyl , Heterocyclyl selected from quinolyl, quinoxalinyl or 1,4,5,6-tetrahydropyridazinyl, wherein the heterocyclyl is unsubstituted or independently of one another mono-, di- or trisubstituted by R8; or 3) group pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furyl, 2-furyl, 3-furyl; Thienyl, 2-thienyl, 3-thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl Heterocyclyl selected from: wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 8, a group pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furyl, 2-furyl, 3-furyl; thienyl, 2-thienyl, 3-thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, Further substituted with a residue selected from thiadiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl, wherein the residues are unsubstituted or independently substituted, substituted or trisubstituted with R8) , R8 is One) F, Cl, Br or J, 2)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -OH or methoxy moieties; or _{3) -O- (C 1 -C 4} ) - alkyl (wherein alkyl is optionally substituted mono-, di- or tri-halogen or a methoxy residue is optionally substituted independently from each other), and Provided that when R ⁰ is aryl or heterocyclyl as described, R 8 is at least one halogen or —O— (C ₁ -C ₈ ) -alkyl moiety, Q is -C (O) -, - ( C 1 -C 6) - _{alkylene, - (C 0 -C 2)} - alkylene -C (O) -NR ¹⁰ - or - (C ₀ -C ₃₎ -Alkylene-C (O) -O- (C ₀ -C ₂ ) -alkylene, R ¹ is a hydrogen atom,-(C ₁ -C ₂ ) -alkyl,-(C ₁ -C ₃ ) -alkylene-C (O) -NH-R 0,-(C ₁ -C ₃ ) -perfluoro Alkylene,-(C ₁ -C ₃ ) -alkylene-C (O) -OR ¹⁵ ,-(C ₁ -C ₃ ) -alkylene-S (O) _2- (C ₁ -C ₃ ) -alkyl or - (C ₁ -C ₃₎ - alkylene _{-S (O) 2 -N (R} 4 ') -R 5' ( wherein R ^{4 'and} R ^5' are each independently the same or different and represent a hydrogen atom or -(C ₁ -C ₄ ) -alkyl), R ¹ -NV is a group azetidine, azetidinone, piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, 1,2,3-triazine, 1,2,4-triazine , 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,4-diazepane, 1,2-diazepine, 1, 3-diazepine, 1,4-diazepine, azepine, ketopiperazine, 1,4-oxazepan, oxazole, isoxazole, isoxazolidine, 2-isoxazolin, morpholine, thiazole, A 4-7 membered cyclic group selected from isothiazole, thiadiazole or thiomorpholine, wherein the cyclic group is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, R14 is fluorine, chlorine, -OH, = O,-(C ₁ -C ₈ ) -alkyl, -C (O) -OH, -CN, -NH ₂ , -C (O) -O- (C _1- C ₄ ) -alkyl, -C (O) -NH- (C ₁ -C ₈ ) -alkyl, -C (O) -N-[(C ₁ -C ₈ ) -alkyl] ₂ , -C (O) -NH ₂ or -N (R ¹⁸ ) -R ²¹ , wherein R ¹⁸ and R ²¹ are independently of each other a hydrogen atom,-(C ₁ -C ₃ ) -perfluoroalkyl or-(C ₁ -C ₄ )- Alkyl), V is azaindole (1H-pyrrolopyridine), aziridine, aziline, azetidine, azetidinone, 1,4-diazepane, pyrrole, pyrrolidine, pyridonyl, imidazole, pyrazole, 1, 2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5- Triazine, tetrazine, tetrazole, azepine, diazirine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, pyridazine, piperidine, piperazine, pyrrolidinone, Ketopiperazine, furan, pyran, dioxol, 1,4-oxazepan, oxazole, isoxazole, 2-isoxazolin, isoxazolidine, morpholine, oxirane, oxaziridine, 1,3- Dioxolene, 1,3-dioxolane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxaziridine, thiophene, thiopyran, thiethane, thiazole, isothiazole , Isothiazoline, isothiazolidine, 1,2-oxathiolane, thiadiazole, thiopyran, 1,2-thiazine, 1,3-thiazole, 1,3-thiazine, 1,4-thia Jean, thiadiazine, Is a heterocyclic moiety selected from the group containing a compound derived from thiomorpholine, wherein the heterocyclyl moieties are unsubstituted or independently of each other mono-, di- or tri-substituted with R 14, G is a direct bond,-(CH ₂ ) _m -or-(CH ₂ ) _m -NR ^10- , m is an integer 0, 1, 2, 3 or 4, M 1) hydrogen atom, 2) heterocyclyl, where heterocyclyl is azepan, azepin, 1,4-diazepan, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, isothia Sol, isoxazole, isoxazolidine, 2-isoxazolin, ketomorpholine, ketopiperazine, morpholine, oxazole, [1,4] -oxazepan, piperazine, piperazinone, piperidine , Piperidinone, pyrazine, pyridazine, pyridazinone, pyridine, pyridone, pyrimidine, pyrrolidine, pyrrolidinone, tetrahydropyran, 1,4,5,6-tetrahydropyridazinyl, tetrazine , Tetrazole, thiadiazole, thiazole, thiomorpholine, thiophene, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3 -Triazole or a residue selected from the group derivable from 1,2,4-triazole, wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R14), 3)-(C ₁ -C ₆ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14, 4) (C ₃ -C ₆ ) -cycloalkyl or 5) -C (O) -N (R ¹¹ ) -R ¹² , R3, R4 and R22 are the same as or different from each other independently, 1) hydrogen atom, 2) halogen, 3)-(C ₁ -C ₄ ) -alkyl wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, _{4) - (C 1 -C 3} ) - alkyl, perfluoroalkyl, 5) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 13, 6)-(C ₀ -C ₄ ) -alkylene-O-R 19, where R 19 is a) a hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another Mono-, di-, or tri-substituted); c) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13; d) -CF ₃ or e) CHF ₂ ], 7) -CN, 8) -NR ¹⁰ -SO ₂ -R ¹⁰ , 9) -SO _s -R ¹¹ (where s is 1 or 2), 10) -SO _t -N (R ¹¹ ) -R ¹² , where t is 1 or 2, 11)-(C ₀ -C ₄ ) -alkylene-C (O) —R ¹¹ , 12)-(C ₀ -C ₄ ) -alkylene-C (O) —OR ¹¹ , 13)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹² , 14)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹² , 15)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O)-(C ₁ -C ₄ ) -alkyl, 16) -C (O) -O-C (R15, R16) -O-C (O) -R17, 17)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O) -O- (C ₁ -C ₆ ) -alkyl, 18) -C (O) -O-C (R15, R16) -O-C (O) -O-R17, 19)-(C ₀ -C ₄ ) -alkylene- (C ₃ -C ₆ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 20)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl, 21)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl, 22)-(C ₀ -C ₃ ) -alkylene-O-CH _2- (C ₁ -C ₃ ) -perfluoroalkylene-CH ₂ -OH, 23) -SO _w -N (R ¹¹ ) -R ¹³ , wherein w is 1 or 2, 24)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹³ , 25)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹³ or 26)

Residues from Me, wherein Me is methyl or a 1,3-dioxol ring substituted one, two, three or four times with R 13 with the atoms bonded thereto when two -OR 19 residues are bonded to an adjacent atom, or 2,3-dihydro- [1,4] dioxin ring can be formed), R ¹¹ and R ¹² together with the nitrogen atom bonded thereto are a group azepine, azetidine, 1,4-diazepane, dioxazole, dioxazine, 1,2-diazepine, 1,3-diazepine, 1 , 4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazolin, isoxazolidine, 2-isoxazolin, ke Topiperazine, morpholine, [1,4] -oxazepan, 1,4-oxazepine, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, Pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazolin, thiomorpholine, thiophene, 1,2 Can form a ring selected from, 3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, Wherein the rings are unsubstituted or independently of each other R13 A mono-, di- or tri-substituted, R4 and R22 of formula (I) and formula (Ia) may together with the carbon atoms bonded to them form a phenyl moiety, R 13 is fluorine, chlorine, -NO ₂ , -CN, = O, -OH, -CF ₃ , -C (O) -OR ¹⁰ , -C (O) -N (R ¹⁰ ) -R ²⁰ , -N ( R ¹⁰ ) -R ²⁰ ,-(C ₀ -C ₃ ) -alkylene-OR ¹⁰ , -Si- (CH ₃ ) ₃ , -N (R ¹⁰ ) -S (O) ₂ -R ¹⁰ , -SR ¹⁰ , -SO ₂ -R ¹⁰ , -S (O) ₂ -N (R ¹⁰ ) -R ²⁰ , -C (O) -R ¹⁰ ,-(C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₈ ) -alkoxy, phenyl, phenyloxy-, -O-CF ₃ ,-(C ₁ -C ₃ ) -perfluoroalkyl, -NH-C (O) -NH-R ¹⁰ ,-(C ₀ -C ₄ ) -alkyl-C (O) -OC (R 15, R 16) -OC (O) -R 17,-(C ₁ -C ₄ ) -alkoxyphenyl,-(C ₀ -C ₄ ) -alkyl-C (O ) -OC (R15, R16) -OC (O) -O-R17, -O-R15, -NH-C (O) -OR ¹⁰ or

Residues from wherein Me is methyl and R ¹⁰ and R ²⁰ independently of one another are hydrogen,-(C ₁ -C ₆ ) -alkyl,-(C ₀ -C ₄ ) -alkyl-OH,-(C _0- C ₄₎ - alkyl, -O- (C ₁ -C ₄₎ - ahkil or - (C ₁ -C ₃₎ - it is perfluoroalkyl), and R 15 and R 16 are independently of each other hydrogen or — (C ₁ -C ₆ ) -alkyl, or together form a ring selected from the group cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein each ring is unsubstituted or R Substituted 1 to 3 times with ¹⁰ , R17 is-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl-OH,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₆ ) -alkyl,- (C ₃ -C ₈ ) -cycloalkyl,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₈ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,-(C _1- C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted 1, 2 or 3 times with -OH; A compound of Formula I and Ia, which is -O- (C ₁ -C ₄ ) -alkyl or R ¹⁰ . The method according to any one of claims 1 to 5, R ⁰ is 1) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R8, 2) group indolyl, isoindoleyl, benzofuranyl, benzothiophenyl, 1,3-benzodioxolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl , Chrominyl, isochromenyl, cinnaolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrimididazolyl, pyridopyridinyl, pyridopyrimidinyl, pyridinyl, furinyl and pterridinyl Heterocyclyl selected from: wherein heterocyclyl is unsubstituted or independently of one another mono-, di-, or trisubstituted with R 8; or 3) group pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furyl, 2-furyl, 3-furyl; Thienyl, 2-thienyl, 3-thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridazinyl and pyra Heterocyclyl selected from genyl, wherein the heterocyclyl is unsubstituted or independently of each other mono-, di- or tri-substituted with R8 and is a group pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl , 2-pyrrolyl, 3-pyrrolyl, furyl, 2-furyl, 3-furyl; thienyl, 2-thienyl, 3-thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl , Thiadiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridazinyl, and pyrazinyl, further substituted, wherein the residues are unsubstituted or independently substituted, substituted or trisubstituted with R8) ego, R8 is 1) F, Cl, Br or J, 2)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with halogen, -OH or methoxy moieties; or _{3) -O- (C 1 -C 4} ) - alkyl (wherein alkyl is optionally substituted mono-, di- or tri-halogen or a methoxy residue is optionally substituted independently from each other), and Provided that when R ⁰ is aryl or heterocyclyl as described, R 8 is at least one halogen or —O— (C ₁ -C ₈ ) -alkyl moiety, Q is —C (O) —, —C (O) —O-methylene, — (C ₁ -C ₄ ) -alkylene or — (C ₀ -C ₂ ) -alkylene-C (O) —NR ¹⁰ -ego, R ¹ is a hydrogen atom or — (C ₁ -C ₂ ) -alkyl, R ¹ -NV is a group piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, 1,2,3-triazine, 1,2,4-triazine, 1,3,5- Triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine 4-7 membered cyclic group selected from ketopiperazine, oxazole, isoxazole, isoxazolidine, 2-isoxazolin, morpholine, thiazole, isothiazole, thiadiazole or thiomorpholine Wherein the cyclic groups are unsubstituted or are independently mono-, di-, or tri-substituted with R 14, R 14 is fluoro, chlorine,-(C ₁ -C ₄ ) -alkyl or -NH ₂ , V is azaindolyl (1H-pyrrolopyridyl), azetidine, azepine, aziridine, azirin, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4 Diazepine, diazirine, 1,3-dioxolane, dioxazole, furan, imidazole, isoquinoline, isothiazole, isothiazolidine, isothiazoline, isoxazole, 2-isoxazolin, isoxa Zolidine, ketopiperazine, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, 1,2-oxathiolane, piperidine, pyran, pyrazine, Pyrazole, pyridazine, piperazine, pyridine, pyridone, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, quinazoline, quinoline, tetrazine, tetrazole, thiadiazine, 1,2-thiazine, 1 , 3-thiazine, 1,4-thiazine, 1,3-thiazole, thiethane, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,2,4-triazine Hetero yarns selected from the group containing compounds derived from 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole Is an cyclyl moiety, wherein the heterocyclyl moiety is unsubstituted or independently of each other mono-, di- or tri-substituted with R 14, G is a direct bond,-(CH ₂ ) _m -or-(CH ₂ ) _m -NR ^10- , m is an integer 0, 1, 2, 3 or 4, M 1) hydrogen atom, 2) heterocyclyl, where heterocyclyl is 1,4-diazepane, ketomorpholine, thiophene, pyridazone, piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, pyrido Nyl, imidazole, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2, 4-triazole, tetrazine, tetrazole, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine, ketopiperazine, oxazole, isoxazole, isoxazolidine , 2-isoxazolin, morpholine, thiazole, isothiazole, tetrahydropyran, 1,4,5,6-tetrahydropyridazinyl, thiadiazole or thiomorpholine Moiety wherein heterocyclyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 14), 3)-(C ₁ -C ₆ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 14; or 4) (C ₃ -C ₆ ) -cycloalkyl, R3, R4 and R22 are the same as or different from each other independently, 1) hydrogen atom, 2) halogen, 3)-(C ₁ -C ₄ ) -alkyl wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, _{4) - (C 1 -C 3} ) - alkyl, perfluoroalkyl, 5) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 13, 6)-(C ₀ -C ₄ ) -alkylene-O-R 19, where R 19 is a) a hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another Mono-, di-, or tri-substituted); c) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13; d) -CF ₃ or e) -CHF ₂ ], 7) -CN, 8) -NR ¹⁰ -SO ₂ -R ¹⁰ , 9) -SO _s -R ¹¹ (where s is 1 or 2), 10) -SO _t -N (R ¹¹ ) -R ¹² , where t is 1 or 2, 11)-(C ₀ -C ₄ ) -alkylene-C (O) —R ¹¹ , 12)-(C ₀ -C ₄ ) -alkylene-C (O) —OR ¹¹ , 13)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹² , 14)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹² , 15)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O)-(C ₁ -C ₄ ) -alkyl, 16) -C (O) -O-C (R15, R16) -O-C (O) -R17, 17)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O) -O- (C ₁ -C ₆ ) -alkyl, 18) -C (O) -O-C (R15, R16) -O-C (O) -O-R17, 19)-(C ₀ -C ₃ ) -alkylene- (C ₃ -C ₆ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 20)-(C ₀ -C ₄ ) -alkylene- (C ₃ -C ₆ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 21)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl, 22)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl, 23)-(C ₀ -C ₃ ) -alkylene-O-CH _2- (C ₁ -C ₃ ) -perfluoroalkylene-CH ₂ -OH, 24) -SO _w -N (R ¹¹ ) -R ¹³ , wherein w is 1 or 2, 25)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹³ , 26)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹³ or 27)

Is a residue from where Me is methyl R11 and R12 are the same or different independently from each other, 1) hydrogen atom, 2)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 3)-(C ₀ -C ₆ ) -alkyl- (C ₃ -C ₆ ) -cycloalkyl, 4) -OR ¹⁷ or 5)-(C ₀ -C ₆ ) -alkyl- (C ₄ -C ₁₅ ) -heterocyclyl, wherein alkyl and heterocyclyl are unsubstituted independently or mono-, di- or tri-substituted with R 13, wherein Heterocyclyl is a group azetidine, cyclopropyl, cyclobutyl, 4,5-dihydro-oxazole, imidazolidine, morpholine, (1,4) -oxazepan, oxazolidine, piperidine, Piperazine, pyrrolidine, tetrahydrothiophene, thiazolidine or thiomorpholine); R11 and R12 together with the nitrogen atom bonded to them group azetidine, cyclopropyl, cyclobutyl, 4,5-dihydro-oxazole, imidazolidine, morpholine, (1,4) -oxazepan, 1 To form a heterocyclic ring selected from 4-oxazepine, oxazolidine, piperidine, piperazine, pyrrolidine, tetrahydrothiophene, thiazolidine or thiomorpholine, R4 and R22 of formula (I) and formula (Ia) may together with the carbon atoms bonded to them form a phenyl moiety, R13 is fluorine, -CN, = O, -OH, -CF ₃ , -C (O) -OR ¹⁰ , -C (O) -N (R ¹⁰ ) -R ²⁰ , -N (R ¹⁰ ) -R ²⁰ ,-(C ₃ -C ₆ ) -cycloalkyl,-(C ₀ -C ₃ ) -alkylene-OR ¹⁰ , -Si- (CH ₃ ) ₃ , -SR ¹⁰ , -SO ₂ -R ¹⁰ ,-( C ₁ -C ₃ ) -perfluoroalkyl or

Residue from where Me is methyl and R ¹⁰ and R ²⁰ are independently of each other hydrogen,-(C ₁ -C ₄ ) -alkyl or-(C ₁ -C ₃ ) -perfluoroalkyl, R ¹⁵ and R ¹⁶ are independently of each other hydrogen or-(C ₁ -C ₄ ) -alkyl, or together form a ring selected from the group cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein each ring is unsubstituted Or substituted one to three times with R ¹⁰ , R17 is-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl-OH,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₆ ) -alkyl,- (C ₃ -C ₈ ) -cycloalkyl,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₈ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,-(C _1- C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted 1, 2 or 3 times with -OH; A compound of Formula I and Ia, which is -O- (C ₁ -C ₄ ) -alkyl or R ¹⁰ . The method according to any one of claims 1 to 6, R ⁰ is 1) phenyl, wherein phenyl is unsubstituted or independently of one another mono- or di-substituted by R8, 2) pyridyl, wherein pyridyl is unsubstituted or independently of one another mono- or di-substituted by R8; or 3) heterocyclyl selected from the group thienyl, thiadiazolyl, isoxazolyl and thiazolyl, where heterocyclyl is substituted with a residue selected from the group thienyl, 2-thienyl and 3-thienyl, wherein the residue is Unsubstituted or independently of each other mono- or di-substituted by R8), R8 is F, Cl, Br, -O-CH ₃ or -O-CF ₃ , Q is -C (O)-, -C (O) -O-methylene, -CH ₂ -C (O) -NH-, methylene or ethylene, R ¹ is a hydrogen atom, R ¹ -NV may form a 4-8 membered cyclic group selected from the groups azetidine, pyrrolidine, piperidine and piperazine, R14 is fluorine, chlorine, methyl, ethyl or -NH ₂ , V is azaindolyl (1H-pyrrolopyridyl), azetidine, 1,4-diazepane, isoxazole, isoquinoline, piperazine, piperidine, pyrazine, pyridazine, pyrimidine, pyrrolidine, quina Heterocyclyl selected from the group containing compounds derived from sleepy, quinoline or tetrahydropyran, wherein the heterocyclyl moieties are unsubstituted or independently substituted or substituted with R14, G is a direct bond,-(CH ₂ ) _m -or-(CH ₂ ) _m -NR ^10- , m is an integer 0, 1 or 2, M is a hydrogen atom, (C ₂ -C ₄ ) -alkyl, isopropyl, azepanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, ketomorpholinyl, morpholinyl, [1,4 ] Oxazepanyl, piperidinyl, piperidonyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidyl, pyrrolidinyl, 1,4,5,6-tetrahydropyridazinyl or tetrahydropyra Nil, wherein the residues are unsubstituted or independently substituted or substituted with R 14, R3, R4 and R22 are the same as or different from each other independently, 1) hydrogen atom, 2) fluorine, chlorine, bromine, iodine, 3)-(C ₁ -C ₄ ) -alkyl wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, _{4) - (C 1 -C 3} ) - alkyl, perfluoroalkyl, 5) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R 13, 6)-(C ₀ -C ₂ ) -alkylene-O-R 19, wherein R 19 is a) a hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another Mono-, di-, or tri-substituted); c) phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13; d) -CF ₃ or e) -CHF ₂ ], 7) -NO ₂ , 8) -NR ¹⁰ -SO ₂ -R ¹⁰ , 9) -SO _s -R ¹¹ (where s is 1 or 2), 10) -SO _t -N (R ¹¹ ) -R ¹² , where t is 1 or 2, 11)-(C ₀ -C ₄ ) -alkylene-C (O) —R ¹¹ , 12)-(C ₀ -C ₄ ) -alkylene-C (O) —OR ¹¹ , 13)-(C ₀ -C ₄ ) -alkylene-C (O) —N (R ¹¹ ) —R ¹² , 14)-(C ₀ -C ₄ ) -alkylene-N (R ¹¹ ) -R ¹² , 15)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O)-(C ₁ -C ₄ ) -alkyl, 16) -C (O) -O-C (R15, R16) -O-C (O) -R17, 17)-(C ₀ -C ₂ ) alkylene-C (O) -O- (C ₂ -C ₄ ) -alkylene-OC (O) -O- (C ₁ -C ₆ ) -alkyl, 18) -C (O) -O-C (R15, R16) -O-C (O) -O-R17, 19)-(C ₀ -C ₃ ) -alkylene-phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 20) pyridinyl, wherein pyridinyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R13, 21) thiazolyl, wherein thiazolyl is unsubstituted or independently of one another mono-, di- or tri-substituted by R13, 22)-(C ₀ -C ₄ ) -alkylene- (C ₃ -C ₆ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 23)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl, 24)-(C ₀ -C ₃ ) -alkylene-O-CH ₂ -CF ₂ -CF ₂ -CH ₂ -O- (C ₀ -C ₃ ) -alkyl, 25)-(C ₀ -C ₃ ) -alkylene-O-CH _2- (C ₁ -C ₃ ) -perfluoroalkylene-CH ₂ -OH or 26)

Is a residue from where Me is methyl R11 and R12 are the same or different independently from each other, 1) hydrogen atom, 2)-(C ₁ -C ₄ ) -alkyl, wherein alkyl is unsubstituted or independently of one another mono-, di- or tri-substituted with R 13, 3)-(C ₀ -C ₆ ) -alkyl-phenyl, 4) -OR ¹⁷ or 5)-(C ₀ -C ₆ ) -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are unsubstituted independently or mono-, di- or tri-substituted with R 13, wherein the heterocyclyl is a group azetidine, Imidazolidine, morpholine, (1,4) -oxazepan or piperidine); R11 and R12 together with the nitrogen atom bonded to them group azetidine, imidazolidine, morpholine, (1,4) -oxazepan, 1,4-oxazepine, piperazine, piperidine, pyrrolidine Or form a ring selected from thiomorpholine, R 13 is fluorine, chlorine, -CN, = O, -OH, -CF ₃ , -C (O) -OR ¹⁰ , -C (O) -N (R ¹⁰ ) -R ²⁰ , -N (R ¹⁰ )- R ²⁰ ,-(C ₃ -C ₆ ) -cycloalkyl,-(C ₀ -C ₃ ) -alkylene-OR ¹⁰ , -Si- (CH ₃ ) ₃ , -SR ¹⁰ , -SO ₂ -R ¹⁰ , - (C ₁ -C ₄₎ - _{alkyl, - (C 1 -C 3)} - perfluoroalkyl or

Residue from where Me is methyl and R ¹⁰ and R ²⁰ are independently of each other hydrogen,-(C ₁ -C ₄ ) -alkyl or-(C ₁ -C ₃ ) -perfluoroalkyl, R ¹⁵ and R ¹⁶ are independently of each other hydrogen or — (C ₁ -C ₄ ) -alkyl, or together form a ring selected from the group cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein each ring is Unsubstituted or substituted one to three times with R ¹⁰ , R17 is-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl-OH,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₆ ) -alkyl,- (C ₃ -C ₈ ) -cycloalkyl,-(C ₁ -C ₆ ) -alkyl-O- (C ₁ -C ₈ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl,-(C _1- C ₆ ) -alkyl- (C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted 1, 2 or 3 times with -OH; A compound of Formula I and Ia, which is -O- (C ₁ -C ₄ ) -alkyl or R ¹⁰ . The method of claim 1, 1- [5- (5-Chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1 H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide, 1- (3-methoxy-benzyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide, 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amides, 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidine-4- Yl) -amide, 1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4- (perhydro-1,4-oxazepin-4-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropyl Piperidin-4-yl) -amide, 1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -5- (perhydro-1,4-oxazepin-4-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropyl Piperidin-4-yl) -amide, 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (perhydro-1,4-oxazepine-4-carbonyl) -1H-pyrrole-2 Carboxylic acid (1-isopropylpiperidin-4-yl) -amide, 3- [1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -2,4 -Dimethyl-1H-pyrrol-3-yl] -propionic acid, 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid benzyl ester, 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid methyl ester, 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid, 1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid benzyl ester, 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid benzyl ester, 1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide, 1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2-carboxylic acid methyl ester, 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid methyl ester, 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4- (1-isopropylpiperidin-4-ylcarbamoyl) -1H-pyrrole-2- Carboxylic acid, 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5- (3-methoxy-azetidine-1-carbonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide, 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1H-pyrrole-2,5-dicarboxylic acid 2-[(1-isopropylpiperidine-4- Yl) -amide] 5-[(2-methoxyethyl) -amide], 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -1H-pyrrole-2,5-dicarboxylic acid 2-[(1-isopropylpiperidine-4- Il) -amide] 5-[(2-methoxyethyl) -methylamide], 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -5-phenyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amides, 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-4- (perhydro-1,4-oxazepine-4-sulfonyl) -1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -amide, 4-Bromo-1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpy) Ferridin-4-yl) -amide, 4-Bromo-1-[(5-chloropyridin-2-ylcarbamoyl) -methyl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpiperidin-4-yl) -Amide or 1- [5- (5-chlorothiophen-2-yl) -isoxazol-3-ylmethyl] -4-formyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropylpy Compound of formula (I) and (Ia) which is ferridin-4-yl) -amide. A compound according to any one of claims 1 to 8 comprising condensing a compound of formula 2 with a compound of formula HR ^{8 ′, wherein} the compound of formula 3 is optionally converted to a compound of formulas I and Ia. Process for the preparation of compounds of formulas (I) and (Ia)

In Chemical Formulas 2 and 3 above, R ⁸ residue of the functional ^group, is first defined according to any one of claim 8, wherein -N (R ¹⁾ a donor -VGM however, R ^{8 'are} also present in -N (R ¹⁾ -VGM May be present in the form of a group which is subsequently modified into a final functional group, residue R ⁸⁷ means a group that is subsequently modified with group -QR ⁰ or group -QR ⁰ , and group -C (O) -R ⁸⁶ may be a carboxylic acid or a derivative thereof, and groups R ^1a and R ^1b of Formulas 2 and 3 correspond to R3 and R4 of Formulas I and Ia as defined in any one of claims 1 to 8. And their functional groups may also be in protected or precursor group form. A compound of formula (I) or (la) according to any one of claims 1 to 8, all stereoisomeric forms thereof, mixtures thereof in any proportion and / or physiologically acceptable salts thereof and pharmaceutically acceptable carriers Pharmaceutical formulations comprising. A compound of formula (I) and (Ia) according to any one of claims 1 to 18 for the preparation of a medicament for inhibiting factor Xa and / or factor Vlla or affecting blood coagulation or fibrinolysis, all stereoisomers thereof Use of forms, mixtures thereof and / or physiologically acceptable salts thereof in any ratio. 12. Acute vascular obstruction (PTCA), transient ischemic attack, stroke, intermittent claudication according to claim 11, associated with aberrant thrombus formation, acute myocardial infarction, cardiovascular abnormalities, unstable angina, thromboembolism, thromboembolism treatment or percutaneous transvascular angioplasty , Coronary or peripheral artery bypass surgery, stenosis, restenosis after cardiac or venous angioplasty, maintenance of vascular access for long-term hemodialysis patients, pathological thrombus formation in the veins of the lower abdomen, knee or hip surgery, pulmonary thromboembolism Or disseminated intravascular coagulation, decreased inflammatory response, fibrinolysis, or heart disease, myocardial infarction, angina, vascular restenosis, such as PTCA, which occurs in the vascular system during septic shock, viral infection, or cancer disease. Restenosis after angioplasty, adult respiratory distress syndrome, multi-organ dysfunction and disseminated intravascular coagulation disease Use for thrombosis such as cardiac vein and proximal venous thrombosis.