HK1135694B - Imino-imidazo-pyridine derivatives having antithrombotic activity - Google Patents

Description

Imino-imidazo-pyridine derivatives with antithrombotic activity

the present invention relates to novel compounds of formula I having antithrombotic activity, in particular inhibiting protease-activated receptor 1(PAR1), processes for their preparation and their use as medicaments.

Protease-activated receptor 1(PAR1) is a thrombin receptor belonging to the class of G protein-coupled receptors (GPCRs). The gene for PAR1 is located on chromosome 5q13, consists of two exons and covers a region of approximately 27 kb. PAR1 is expressed in endothelial cells, smooth muscle cells, fibroblasts, neurons and human platelets, among others. In platelets, PAR1 is an important signaling receptor involved in initiating platelet aggregation. Activation of PARs is performed by proteolytic cleavage of a portion of the N-terminus of PARs, thereby exposing a new N-terminal sequence, which then activates the receptor (Pharmacol Rev 54: 203-217, 2002).

Blood coagulation is a process of controlling blood flow that is critical to the survival of mammals. The process of coagulation and subsequent clot dissolution after wound healing begins after vascular injury, which can be divided into four phases:

1. and (3) a vasoconstriction stage: by this stage, blood loss from the damaged area is reduced.

2. The next stage is thrombin activated platelets. The platelets aggregate at the site of the vessel wall injury and form a quiescent, loose platelet clot. Fibrinogen is primarily responsible for stimulating platelet aggregation. Platelets also bind to exposed collagen of the damaged vessel wall.

3. Initially quiescent, loose aggregates of platelets are cross-linked by fibrin. A thrombus is a white thrombus if it contains only platelets and fibrin; if red blood cells are also present, they are red thrombi.

4. After the wound has healed, the thrombus is dissolved by the action of plasmin.

Two alternative pathways (the intrinsic and extrinsic pathways) lead to the formation of fibrin clots. These pathways are initiated by different mechanisms, but at a later stage, they converge to produce a common coagulation cascade pathway extension. The formation of red thrombi or clots at the base of the vessel wall abnormalities without wounds is the result of intrinsic pathways. Fibrin clot formation in response to tissue damage or injury is the result of the extrinsic pathway. Both pathways contain relatively large amounts of proteins, which are called coagulation factors.

The intrinsic pathway requires coagulation factors VIII, IX, X, XI and XII as well as prekallikrein, high molecular weight kininogen, calcium ions and platelet-derived phospholipids. Each of these proteins leads to the activation of factor X. The intrinsic pathway is initiated when kallikrein, high molecular weight kininogen factors XI and XII bind to negatively charged surfaces. This time is called the contact period. Exposure to vessel wall collagen is the primary stimulus for the contact period. The result of the processes during the contact phase is the conversion of prekallikrein to kallikrein, which in turn activates factor XII. Factor XIIa further hydrolyzes prekallikrein to kallikrein, leading to activation. With increased activation of factor XII, activation of factor XI occurs, which results in the release of bradykinin, a vasodilator. Thus, the initial stage of vasoconstriction ends. Bradykinin is caused by high molecular weight kininogen. In Ca²⁺In the presence of ions, factor XIa activates factor IX. Factor IX is a zymogen comprising a vitamin K-dependent c-carboxyglutamic acid (GLA) group. In Ca²⁺Upon binding of the ion to these GLA groups, serine protease activity becomes apparent. Many of the serine proteases of the blood coagulation cascade (factors II, VII, IX and X) contain this retinoid K-dependent GLA group. Factor IXa cleaves factor X and results in factor Xa activation. The essential condition for the formation of factor IXa is the presence of Ca on the surface of activated platelets²⁺The ions and the factors VIIIa, Ixa and X form a kinase complex. One of the responses of activated platelets is to present phosphatidylserine and phosphatidylinositol along the surface. Exposure of these phospholipids only makes the formation of kinase complexes possible. In this process, factor VIII functions as a receptor for factors IXa and X. Factor VIII is therefore a cofactor in the coagulation cascade. Activation of factor VIII with the formation of factor VIIIa (the actual receptor) requires only very small amounts of thrombin. With increasing thrombin concentration, factor VIIIa is finally further cleaved and inactivated by thrombin. For factor VIII, this dual activity of thrombin leads to self-limitation of kinase complex formation and thus to arrest blood clotting.

PAR1 and PAR4 play a key role in thrombin activation of human platelets; activation of these receptors in platelets leads to morphological changes, ADP release and platelet aggregation (Nature 413: 26-27, 2001).

PAR1 inhibitors are described, for example, in european patent applications EP1391451 or EP1391452, U.S. patent applications US6,063,847 and US 2004/0152736 and international application WO 03/089428.

The compounds of formula I of the present invention are suitable for prophylactic or therapeutic use in humans suffering from diseases with thrombotic, embolic, hypercoagulative or fibrotic changes. Examples of such diseases are thrombosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, myocardial infarction, hypertension, inflammatory diseases, rheumatism, asthma, glomerulonephritis or osteoporosis. The compounds of formula I of the present invention are useful for secondary prevention and are suitable for both acute and long-term therapy.

Accordingly, the present invention relates to compounds of formula I

And/or all stereoisomeric or tautomeric forms of the compounds of the formula I and/or mixtures of these forms in any ratio, and/or physiologically tolerable salts of the compounds of the formula I, where

R1, R2, R3 and R4 are identical or different and are each independently of the others

1)-(C₁-C₆) -alkyl, wherein alkyl is unsubstituted or substituted by- (C)₆-C₁₄) -aryl, - (C)₃-C₆) -cycloalkyl, Het, halogen, -NH₂OH or methoxy are, independently of one another, mono-, di-or tri-substituted,

2)-O-(C₁-C₈) -alkyl, wherein alkyl is unsubstituted or substituted by- (C)₆-C₁₄) -aryl, - (C)₃-C₆) -cycloalkyl, Het, halogen, -NH₂-OH or methoxy are mono-, di-or tri-substituted independently of each other, wherein- (C)₆-C₁₄) -aryl and Het are unsubstituted or additionally mono-, di-or tri-substituted by R15,

3)-(C₀-C₄) alkylene-C (O) -R11, wherein R11 is

3)1) a hydrogen atom, and (b) a hydrogen atom,

3)2)-(C₁-C₆) -an alkyl group,

3)3)-(C₀-C₄) -alkylene- (C)₆-C₁₄) -an aryl group,

3)4)-(C₀-C₄) alkylene-Het or

3)5)-(C₀-C₄) -alkylene- (C)₃-C₆) -a cycloalkyl group,

4)-(C₀-C₄) alkylene-C (O) -O-R11, wherein R11 is as defined above,

5)-(C₀-C₄) alkylene-N (R12) -R13, wherein R12 and R13 are identical or different and are each independently of the other

5)1) a hydrogen atom, and (b) a hydrogen atom,

5)2)-(C₁-C₆) -an alkyl group,

5)3)-(C₁-C₃) -a fluoroalkyl group,

5)4)-(C₀-C₄) -alkylene- (C)₆-C₁₄) -an aryl group,

5)5)-(C₀-C₄) alkylene-Het or

5)6)-(C₀-C₄) -alkylene- (C)₃-C₆) -a cycloalkyl group,

6)-(C₀-C₄) alkylene-C (O) -N (R12) -R13, wherein R12 and R13 are identical or different and are each independently of the other as defined aboveIn the meaning of,

7)-(C₀-C₄) alkylene-N (R12) -C (O) -R13, wherein R12 and R13 are identical or different and are each, independently of one another, as defined above,

8)-(C₁-C₃) -a fluoroalkyl group,

9)-O-(C₁-C₃) -a fluoroalkyl group,

10)-SO₂-CH₃，

11)-SO₂-CF₃，

12)-NO₂，

13)-CN，

14)-OH，

15)＝O，

16) a hydrogen atom or

17) The halogen(s) are selected from the group consisting of,

r10 and R15 are identical or different and are each independently of the other

1) A hydrogen atom, and a nitrogen atom,

2)-(C₁-C₄) -an alkyl group,

3)-O-(C₁-C₄) -an alkyl group,

4)-(C₁-C₃) -a fluoroalkyl group,

5)-O-(C₁-C₃) -a fluoroalkyl group,

6)-(C₀-C₄) alkylene-N (R16) (R17) wherein R16 and R17 are each independently of the other a hydrogen atom or- (C)₁-C₆) -an alkyl group,

7)-(C₀-C₄) -alkylene- (C)₆-C₁₄) -an aryl group,

8)-(C₀-C₄) -alkylene- (C)₃-C₆) -a cycloalkyl group,

9)-(C₀-C₄) -an alkylene-Het group having at least one of the formulae,

10)-OH，

11)＝O，

12)-NO₂，

13)-CN，

14) the halogen(s) are selected from the group consisting of,

15)-SO₂-(C₁-C₄) -alkyl or

16)-SO₂-(C₁-C₃) -a fluoroalkyl group,

r5, R6, R7, R8 and R9 are identical or different and are each independently of the other

1) A hydrogen atom, and a nitrogen atom,

2)-(C₀-C₄) -alkylene- (C)₆-C₁₄) -aryl, wherein aryl is unsubstituted or substituted by- (C)₁-C₄) Alkyl, - (C)₆-C₁₄) Aryl, Het, - (C)₃-C₆) -cycloalkyl, halogen, -NH₂OH or methoxy are, independently of one another, mono-, di-or tri-substituted,

3)-(C₀-C₄) -alkylene- (C)₃-C₆) -a cycloalkyl group,

4)-(C₀-C₄) -alkylene-Het wherein Het is unsubstituted or substituted by- (C)₁-C₄) Alkyl, - (C)₆-C₁₄) Aryl, Het, - (C)₃-C₆) -cycloalkyl, -C (O) -O-R16, -C (O) -N (R16) (R17), halogen, -NH₂-OH or methoxy, independently of one another, are mono-, di-or tri-substituted, wherein R16 and R17 are as defined above,

5)-SF₅，

6)-(C₁-C₆) -alkyl, wherein alkyl is unsubstituted or substituted by halogen, -NH₂-OH or methoxy independently of one another-, di-or tri-substituted,

7)-O-(C₁-C₈) -alkyl, wherein alkyl is unsubstituted or substituted by- (C)₆-C₁₄) -aryl, - (C)₃-C₆) -cycloalkyl, Het, halogen, -NH₂OH or methoxy are, independently of one another, mono-, di-or tri-substituted,

8)-(C₀-C₄) alkylene-C (O) -R11, wherein R11 is as defined above,

9)-(C₀-C₄) alkylene-C (O) -O-R11, wherein R11 is as defined above,

10)-(C₀-C₄) alkylene-N (R12) -R13, wherein R12 and R13 are identical or different and are each, independently of the others, as defined above,

11)-(C₀-C₄) alkylene-C (O) -N (R12) -R13, wherein R12 and R13 are identical or different and are each, independently of the others, as defined above,

12)-(C₀-C₄) alkylene-N (R12) -C (O) -R13, wherein R12 and R13 are identical or different and are each, independently of one another, as defined above,

13)-(C₁-C₃) -a fluoroalkyl group,

14)-O-(C₁-C₃) -a fluoroalkyl group,

15)-SO₂-CH₃，

16)-SO₂-CF₃，

17)-NO₂，

18)-CN，

19) -OH or

20) Halogen, or

R5 and R6, R6 and R7, R7 and R8, or R8 and R9 form, together with the ring atoms to which they are bonded, a four-to eight-membered heterocyclic ring which forms a bicyclic ring system together with the benzene ring to which the heterocyclic ring is fused,wherein the heterocyclic moiety is unsubstituted or substituted by- (C)₁-C₄) Alkyl, - (C)₆-C₁₄) -aryl, - (C)₃-C₆) -cycloalkyl, halogen, -NH₂-OH or methoxy are, independently of one another, mono-, di-or tri-substituted.

2) The invention further relates to compounds of the formula I and/or all stereoisomeric or tautomeric forms of the compounds of the formula I and/or mixtures of these forms in any ratio, and/or physiologically tolerable salts of the compounds of the formula I

R1, R2, R3 and R4 are identical or different and are each independently of the others

1)-(C₁-C₆) -alkyl, wherein alkyl is unsubstituted or substituted by- (C)₃-C₆) -cycloalkyl, halogen, -NH₂-OH, methoxy, - (C)₆-C₁₄) Aryl or Het are mono-, di-or tri-substituted independently of one another,

wherein aryl is selected from phenyl, naphthyl, anthracenyl and fluorenyl and wherein aryl is unsubstituted or mono-, di-or tri-substituted by R15,

wherein Het is selected from acridinyl, azaA group, an azetidinyl group, an aziridinyl group, a benzimidazolyl group, a benzofuranyl group, a benzothienyl group, a benzothiophenyl group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzisoxazolyl group, a benzisothiazolyl group, a carbazolyl group, a 4 aH-carbazolyl group, a carbolinyl group, a quinazolinyl group, a quinolyl group, a 4H-quinolyl group, a quinoxalinyl group, a quinuclidinyl group, a chromanyl group, a chromenyl group, a cinnolinyl group, a decahydroquinolyl group, a dibenzofuranyl group, a dibenzothienyl group, a dihydrofuro [2, 3-b ]]Tetrahydrofuranyl (dihydrofuran [2, 3-b ]]tetrahydrofuran), dihydrofuranyl, dioxolyl, dioxanyl, 2H, 6H-1, 5, 2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, dihydrofuranyl, dioxanyl, 2H-thienyl, and mixtures thereof,Isobenzofuranyl, isochromanyl, isoindolyl, isoindolinyl, isoindolyl, isothiazolyl, isothiazolidinyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxathiolanyl (oxolanyl), pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, oxathianthrenyl (phenoxathiinyl), phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl (pyroazolidinyl), pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, and pyrazolidinyl, Pyridothiazolyl, pyridothienyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1, 2, 5-thiadiazinyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thianthrenyl, thiazolidinyl, thiazolinyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl, thienopyrrolyl, thienopyridyl, thienothiazolyl, thienothienyl, thiomorpholinyl, triazinyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 5-triazolyl, 1, 3, 4-triazolyl and xanthenyl and wherein Het is unsubstituted or otherwise mono-or mono-represented by R15, A di-or tri-substitution of the amino group,

2)-O-(C₁-C₆) -alkyl, wherein alkyl is unsubstituted or substituted by- (C)₆-C₁₄) -aryl, - (C)₃-C₆) -cycloalkyl, Het, halogen, -NH₂OH or methoxy, independently of one another, are mono-, di-or tri-substituted, wherein Het and aryl are as defined above,

3)-(C₀-C₄) alkylene-C (O) -R11, wherein R11 is

3)1) a hydrogen atom, and (b) a hydrogen atom,

3)2)-(C₁-C₆) -an alkyl group,

3)3)-(C₀-C₄) -alkylene- (C)₆-C₁₄) -aryl, wherein aryl is as defined above,

3)4)-(C₀-C₄) -alkylene-Het wherein Het is as defined above, or

3)5)-(C₀-C₄) -alkylene- (C)₃-C₆) -a cycloalkyl group,

4)-(C₀-C₄) alkylene-C (O) -O-R11, wherein R11 is as defined above,

5)-(C₀-C₄) alkylene-N (R12) -R13, wherein R12 and R13 are identical or different and are each independently of the other

5)1) a hydrogen atom, and (b) a hydrogen atom,

5)2)-(C₁-C₆) -an alkyl group,

5)3)-(C₁-C₃) -a fluoroalkyl group,

5)4)-(C₀-C₄) -alkylene- (C)₆-C₁₄) -aryl, wherein aryl is as defined above,

5)5)-(C₀-C₄) -alkylene-Het wherein Het is as defined above, or

5)6)-(C₀-C₄) -alkylene- (C)₃-C₆) -a cycloalkyl group,

6)-(C₀-C₄) alkylene-C (O) -N (R12) -R13, wherein R12 and R13 are identical or different and are each, independently of the others, as defined above,

7)-(C₀-C₄) alkylene-N (R12) -C (O) -R13, wherein R12 and R13 are identical or different and are each, independently of one another, as defined above,

8)-(C₁-C₃) -a fluoroalkyl group,

9)-O-(C₁-C₃) -a fluoroalkyl group,

10)-SO₂-CH₃，

11)-SO₂-CF₃，

12)-NO₂，

13)-CN，

14)-OH，

15)＝O，

16) a hydrogen atom or

17) The halogen(s) are selected from the group consisting of,

r10 and R15 are identical or different and are each independently of the other

1) A hydrogen atom, and a nitrogen atom,

2)-(C₁-C₄) -an alkyl group,

3)-O-(C₁-C₄) -an alkyl group,

4)-(C₁-C₃) -a fluoroalkyl group,

5)-O-(C₁-C₃) -a fluoroalkyl group,

6)-(C₀-C₄) alkylene-N (R16) (R17) wherein R16 and R17 are each independently of the other a hydrogen atom or- (C)₁-C₆) -an alkyl group,

7)-(C₀-C₄) -alkylene- (C)₆-C₁₄) -aryl, wherein aryl is as defined above,

8)-(C₀-C₄) -alkylene- (C)₃-C₆) -a cycloalkyl group,

9)-(C₀-C₄) -alkylene-Het, wherein Het is as defined above,

10)-OH，

11)＝O，

12)-NO₂，

13)-CN，

14) the halogen(s) are selected from the group consisting of,

15)-SO₂-(C₁-C₄) -alkyl or

16)-SO₂-(C₁-C₃) -a fluoroalkyl group,

r5, R6, R7, R8 and R9 are identical or different and are each independently of the other

1) A hydrogen atom, and a nitrogen atom,

2)-(C₀-C₄) -alkylene- (C)₆-C₁₄) -aryl, wherein aryl is unsubstituted or substituted by- (C)₁-C₄) Alkyl, - (C)₆-C₁₄) Aryl, Het, - (C)₃-C₆) -cycloalkyl, halogen, -NH₂OH or methoxy, independently of one another, are mono-, di-or tri-substituted, where aryl and Het are as defined above,

3)-(C₀-C₄) -alkylene- (C)₃-C₆) -a cycloalkyl group,

4)-(C₀-C₄) -alkylene-Het wherein Het is unsubstituted or substituted by- (C)₁-C₄) Alkyl, - (C)₆-C₁₄) Aryl, Het, - (C)₃-C₆) -cycloalkyl, -C (O) -O-R16, -C (O) -N (R16) (R17), halogen, -NH₂OH or methoxy, wherein R16 and R17 are as defined above, wherein aryl and Het are as defined above,

5)-SF₅，

6)-(C₁-C₆) -alkyl, wherein alkyl is unsubstituted or substituted by halogen, -NH₂OH or methoxy are, independently of one another, mono-, di-or tri-substituted,

7)-O-(C₁-C₈) -alkyl, wherein alkyl is unsubstituted or substituted by- (C)₆-C₁₄) -aryl, - (C)₃-C₆) -cycloalkyl, Het, halogen, -NH₂OH or methoxy, independently of one another, are mono-, di-or tri-substituted, where aryl and Het are as defined above,

8)-(C₀-C₄) alkylene-C (O) -R11, wherein R11 is as defined above,

9)-(C₀-C₄) alkylene-C (O) -O-R11, wherein R11 is as defined above,

10)-(C₀-C₄) alkylene-N (R12) -R13, wherein R12 and R13 are identical or different and are each, independently of the others, as defined above,

11)-(C₀-C₄) alkylene-C (O) -N (R12) -R13, wherein R12 and R13 are identical or different and are each, independently of the others, as defined above,

12)-(C₀-C₄) alkylene-N (R12) -C (O) -R13, wherein R12 and R13 are identical or different and are each, independently of one another, as defined above,

13)-(C₁-C₃) -a fluoroalkyl group,

14)-O-(C₁-C₃) -a fluoroalkyl group,

15)-SO₂-CH₃，

16)-SO₂-CF₃，

17)-NO₂，

18)-CN，

19) -OH or

20) Halogen, or

R5 and R6, R6 and R7, R7 and R8 or R8 and R9 form, together with the ring atoms to which they are bonded, a four-to eight-membered heterocyclic ring selected from benzimidazole, benzisothiazole, benzisoxazole, benzo [1, 3 ] benzo, together with the benzene ring to which the heterocyclic ring is fused]Dioxole, benzofuran, benzothiazole, benzisoxazole, benzothiophene, benzo [2 ]1，3]Oxathiolanes (oxathioles), benzoxazoles, benzothiazoles, benzotriazoles, quinazolines, quinazolinones, quinolines, 4H-quinolizines, quinoxalines, chromans, chromenes, cinnolines, 2, 3-dihydrobenzo [1, 4] s]Dioxins, 2, 3-dihydrobenzofuranyl, 1, 3-dihydro-isobenzofuran, 3, 4-dihydro-2H-benzo [1, 4]]Oxazines, 2, 3-dihydrobenzoxazoles, 2, 3-dihydrobenzothiazoles, 1, 3-dihydrobenzo [ c ]]Thiophene, 2, 3-dihydro-benzo [ b ]]Thiophene, indazole, indole, indoline, isobenzofuran, isoquinoline, isochroman, isoindole, isoindoline, 7-oxabicyclo [4.2.0]Octa-1, 3, 5-triene, phthalazine, 2, 3, 4, 5-tetrahydro-1H-benzo [ b]Aza derivatives6, 7, 8, 9-tetrahydro-5-oxa-9-azabenzocycloheptatriene (benzocycloheptalene), 3, 4, 5, 6-tetrahydro-2H-benzo [ b][1，4]A bicyclic system of oxazoline (oxazoline), tetrahydroquinoline, 1, 2, 3, 4-tetrahydroquinoxaline or tetrahydroisoquinoline, wherein the heterocyclic moiety is unsubstituted or substituted by- (C)₁-C₄) Alkyl, - (C)₆-C₁₄) -aryl, - (C)₃-C₆) -cycloalkyl, halogen, -NH₂-OH or methoxy are, independently of one another, mono-, di-or tri-substituted.

3) The invention further relates to compounds of the formula I and/or all stereoisomeric or tautomeric forms of the compounds of the formula I and/or mixtures of these forms in any ratio, and/or physiologically tolerable salts of the compounds of the formula I

R1, R2, R3 and R4 are identical or different and are each independently of the others

1) A hydrogen atom, and a nitrogen atom,

2)-(C₁-C₄) -an alkyl group,

3)-O-(C₁-C₄) -an alkyl group,

4)-(C₀-C₄) alkylene-C (O) -N (R12) -R13, wherein R12 and R13 are the same or different and are each independently of the other a hydrogen atomOr- (C)₁-C₄) -an alkyl group,

5)-(C₁-C₃) -a fluoroalkyl group,

6)-(C₀-C₄) alkylene-C (O) -O- (C)₁-C₄) -alkyl or

7)＝O，

8) The halogen(s) are selected from the group consisting of,

r10 is 1) a hydrogen atom,

2)-(C₁-C₄) -an alkyl group,

3)-(C₀-C₄) -alkylene- (C)₃-C₆) -cycloalkyl or

4)-(C₀-C₄) -an alkylene-phenyl group,

r5, R6, R7, R8 and R9 are identical or different and are each independently of the other

1) A hydrogen atom, and a nitrogen atom,

2)-(C₁-C₃) -a fluoroalkyl group,

3) the halogen(s) are selected from the group consisting of,

4)-O-(C₁-C₄) -an alkyl group,

5)-OH，

6)-(C₁-C₄) -an alkyl group,

7)-SF₅，

8)-(C₀-C₄) alkylene-NH-C (O) - (C)₁-C₃) -a fluoroalkyl group,

9)-(C₀-C₄) alkylene-N (R12) -R13, wherein R12 and R13 are the same or different and are each independently of the other a hydrogen atom or- (C)₁-C₄) -alkyl, or

10)-(C₀-C₄) -alkylene-Het wherein Het is selected from morpholinyl or pyrrolidinyl and is unsubstitutedOr is- (C)₁-C₄) -alkyl, ═ O or-NH₂Mono-or di-substituted independently of each other, or

R5 and R6, R6 and R7, R7 and R8 or R8 and R9 form, together with the ring atoms to which they are bonded, a four-to eight-membered heterocyclic ring selected from 2, 3-dihydro-benzo [1, 4] benzo together with the phenyl ring to which said heterocyclic ring is fused]Dioxins, benzo [1, 3 ]]Dioxoles, 3, 4-dihydro-2H-benzo [1, 4]]Oxazines, 2, 3, 4, 5-tetrahydro-1H-benzo [ b ]]Aza derivativesA bicyclic system of tetrahydroquinoline, tetrahydroisoquinoline, 1, 2, 3, 4-tetrahydroquinoxaline or 6, 7, 8, 9-tetrahydro-5-oxa-9-azabenzocycloheptatriene wherein the heterocyclic moiety is unsubstituted or substituted with- (C)₁-C₄) -alkyl or halogen mono-or di-substituted.

The invention further relates to compounds of formula I selected from:

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt,

2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) -1- (3-pentafluorothiophenyl) ethanone in the form of the trifluoroacetate salt,

2- (1-cyclopropyl-3-iminoimidazo [1, 5-a ] pyridin-2-yl) -1- (3, 5-di-tert-butyl-4-hydroxyphenyl) ethanone in the form of the trifluoroacetate salt,

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-1-phenylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt,

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-8-methylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt,

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-8-methylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the hydrobromide salt,

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-7-trifluoromethylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt,

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-7-trifluoromethylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the hydrobromide salt,

methyl 2- [2- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2-oxoethyl ] -3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylate in the form of the trifluoroacetate salt,

2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methyl ester in the form of the trifluoroacetate salt,

1- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt,

1- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2- (3-imino-8-methylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt,

1- (3-dimethylamino-5-pentafluorothiophenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt,

2- [2- (8-tert-butyl-4-methyl-3, 4-dihydro-2H-benzo [1, 4] oxazin-6-yl) -2-oxoethyl ] -7-ethoxy-3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamide in the form of the trifluoroacetate salt,

2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -7-chloro-3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamide in the form of the trifluoroacetate salt,

2, 2, 2-trifluoro-N- {3- [2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) acetyl ] -5-pentafluorothiophenyl } acetamide in the form of the trifluoroacetate salt,

1- (3-bromo-4-methoxy-5-trifluoromethylphenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) -ethanone in the form of the trifluoroacetate salt,

2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) -1- (4-methoxy-3-morpholin-4-yl-5-trifluoromethylphenyl) ethanone in the form of the trifluoroacetate salt,

6-ethoxy-3-imino-2- [2- (3-methylamino-5-pentafluorothiophenyl) -2-oxoethyl ] -2, 3-dihydro-1H-imidazo [1, 5-a ] pyridin-5-one in the form of the trifluoroacetate salt,

2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -6-ethoxy-3-imino-2, 3-dihydro-1H-imidazo [1, 5-a ] pyridin-5-one in the form of the trifluoroacetate salt,

2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -7-ethoxy-3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamide in the form of the trifluoroacetate salt or ethyl 2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -3-imino-5-methoxy-2, 3-dihydroimidazo [1, 5-a ] pyridine-7-carboxylate in the form of the trifluoroacetate salt.

Term "(C)₁-C₄) -alkyl "or" (C)₁-C₆) Alkyl is understood to mean a hydrocarbon radical whose carbon chain is linear or branched and which comprises from 1 to 4 carbon atoms or from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, 2, 3-dimethylbutyl or neohexyl.

The term "- (C)₀-C₄) Alkylene is understood to mean a hydrocarbon radical whose carbon chain is linear or branched and which contains from 1 to 4 carbon atoms, such as methylene, ethylene, 1-methylmethylene, propylene, 1-methylethylene, butylene, 1-propylmethylene, 1-ethyl-1-methylmethylene, 1, 2-dimethylethylene, 1-dimethylmethylene, 1-ethylethylene, 1-methylpropylene, 2-methylpropylene. "-C₀Alkylene group "Is a covalent bond.

The term "-O- (C)₁-C₈) Alkyl is understood to mean alkoxy whose carbon chain is straight or branched and which contains from 1 to 8 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy.

Term "(C)₃-C₆) -cycloalkyl "is understood to mean a group such as a compound derived from a 3-to 6-membered monocyclic ring, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane.

The term "- (C)₆-C₁₄) Aryl is understood to mean an aromatic carbon radical having from 6 to 14 carbon atoms in the ring. - (C)₆-C₁₄) Aryl is, for example, phenyl, naphthyl (e.g. 1-naphthyl, 2-naphthyl), anthracenyl or fluorenyl. Naphthyl and especially phenyl are preferred aryl groups.

The term "Het" is understood to mean ring systems having from 4 to 15 carbon atoms which are present in the form of mono-, di-or tricyclic systems bonded to one another and which, depending on the ring size, each contain one, two, three or four identical or different heteroatoms selected from oxygen, nitrogen or sulfur. Examples of such ring systems are acridinyl, azaA group, an azetidinyl group, an aziridinyl group, a benzimidazolyl group, a benzofuranyl group, a benzothienyl group, a benzothiophenyl group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzisoxazolyl group, a benzisothiazolyl group, a carbazolyl group, a 4 aH-carbazolyl group, a carbolinyl group, a quinazolinyl group, a quinolyl group, a 4H-quinolyl group, a quinoxalinyl group, a quinuclidinyl group, a chromanyl group, a chromenyl group, a cinnolinyl group, a decahydroquinolyl group, a dibenzofuranyl group, a dibenzothienyl group, a dihydrofuro [2, 3-b ]]Tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H, 6H-1, 5, 2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, indolyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl,Isoquinolyl, isochromanyl, isoindolyl, isoindolinyl, octahydroisoquinolinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, epixothiolanyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, thioxanthyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothienyl, Pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1, 2, 5-thiadiazinyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thianthrenyl, thiazolidinyl, thiazolinyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl, thienopyrrolyl, thienopyridyl, thienothiazolyl, thienothienyl, thiomorpholinyl, triazinyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 5-triazolyl, 1, 3, 4-triazolyl, or xanthenyl.

R5 and R6, R6 and R7, R7 and R8 or R8 and R9 form, together with the ring atoms to which they are bonded, a four-to eight-membered heterocyclic ring which, together with the benzene ring to which it is fused, forms a bicyclic system consisting of two ring systems bonded to one another, of which one ring is phenyl and the other ring forms a partially saturated or aromatic ring system which, depending on the ring size, contains one, two or three identical or different heteroatoms from the group consisting of oxygen, nitrogen or sulfur. Examples of such ring systems are e.g. benzimidazole, benzisothiazole, benzisoxazole, benzo [1, 3 ] benzo]Dioxoles, benzofuranyl, benzothiazoles, benzisoxazoles, benzothiophenes, benzo [1, 3 ]]Oxathiolanes, benzoxazoles, benzothiazoles, benzotriazoles, quinazolinesQuinazolinones, quinolines, 4H-quinolizines, quinoxalines, chromans, chromenes, cinnolines, 2, 3-dihydrobenzo [1, 4] s]Dioxins, 2, 3-dihydrobenzofuranyl, 1, 3-dihydroisobenzofuran, 3, 4-dihydro-2H-benzo [1, 4]]Oxazines, 2, 3-dihydrobenzoxazoles, 2, 3-dihydrobenzothiazoles, 1, 3-dihydrobenzo [ c ]]Thiophene, 2, 3-dihydrobenzo [ b ]]Thiophene, indazole, indole, indoline, isobenzofuran, isoquinoline, isochroman, isoindole, isoindoline, 7-oxabicyclo [4.2.0]Octa-1, 3, 5-triene, phthalazine, 2, 3, 4, 5-tetrahydro-1H-benzo [ b]Aza derivatives6, 7, 8, 9-tetrahydro-5-oxa-9-azabenzocycloheptatriene, 3, 4, 5, 6-tetrahydro-2H-benzo [ b][1，4]A group such as oxazoline, tetrahydroquinoline, 1, 2, 3, 4-tetrahydroquinoxaline or tetrahydroisoquinoline.

The term "- (C)₁-C₃) Fluoroalkyl is understood to mean an alkyl radical which is partially or completely fluorinated and which is derived, for example, from the following groups:

-CF₃、-CHF₂、-CH₂F、-CHF-CF₃、-CHF-CHF₂、-CHF-CH₂F、-CH₂-CF₃、-CH₂-CHF₂、-CH₂-CH₂F、-CF₂-CF₃、-CF₂-CHF₂、-CF₂-CH₂F、-CH₂-CHF-CF₃、-CH₂-CHF-CHF₂、-CH₂-CHF-CH₂F、-CH₂-CH₂-CF₃、-CH₂-CH₂-CHF₂、-CH₂-CH₂-CH₂F、-CH₂-CF₂-CF₃、-CH₂-CF₂-CHF₂、-CH₂-CF₂-CH₂F、-CHF-CHF-CF₃、-CHF-CHF-CHF₂、-CHF-CHF-CH₂F、-CHF-CH₂-CF₃、-CHF-CH₂-CHF₂、-CHF-CH₂-CH₂F、-CHF-CF₂-CF₃、-CHF-CF₂-CHF₂、-CHF-CF₂-CH₂F、-CF₂-CHF-CF₃、-CF₂-CHF-CHF₂、-CF₂-CHF-CH₂F、-CF₂-CH₂-CF₃、-CF₂-CH₂-CHF₂、-CF₂-CH₂-CH₂F、-CF₂-CF₂-CF₃、-CF₂-CF₂-CHF₂or-CF₂-CF₂-CH₂F。

The term "halogen" is understood to mean fluorine, chlorine, bromine or iodine; fluorine, chlorine or bromine, in particular fluorine or chlorine, are preferred.

The term "═ O" is understood to mean groups such as carbonyl (-c (O)) or nitroso (-N ═ O).

Functional groups of the intermediates used, for example amino or carboxyl groups in the compounds of the formula I, can be masked in this context with suitable protecting groups. Suitable protecting groups for amino functions are, for example, tert-butoxycarbonyl, benzyloxycarbonyl or phthaloyl and trityl or tosyl protecting groups. Suitable protecting groups for the carboxyl group are, for example, alkyl, aryl or arylalkyl esters. Protecting Groups can be introduced and removed using well known techniques or those described herein (see Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis (1999), 3 rd edition, Wiley-Interscience). The term protecting group also includes suitable polymer-bound protecting groups.

The compounds of the invention may be prepared by well known methods or by methods described herein.

The invention also includes possible tautomeric forms of the structures shown, for example, formulae III/IIIt or I/It (when R1 in formula I is, for example, OH):

the invention further relates to a process for the preparation of a compound of the formula I and/or of a stereoisomeric form of a compound of the formula I and/or of a physiologically tolerable salt of a compound of the formula I, which comprises

a) Reacting a compound of formula II with a compound of formula III in the presence of a base and a solvent to obtain a compound of formula I,

the compound of the formula II is

Wherein the groups R5, R6, R7, R8 and R9 are as defined for formula I, Y is chloro, bromo, mesylate or tosylate,

the compound of the formula III is

Or

b) Reacting a compound of formula VII with a compound Z-CN wherein Z is tosylate or bromine in the presence of a base to give a compound of formula I,

the compound of the formula VII is

Wherein the radicals R1 to R10 are as defined for formula I, or

c) The compounds of the formula I prepared according to process a) or b) are isolated in free form or are released from physiologically tolerable salts or, in the presence of acidic or basic groups, are converted into physiologically tolerable salts or

d) The compounds of the formula I prepared in enantiomeric or diastereomeric form as a result of their chemical structure, or suitable precursors of the compounds of the formula I, prepared according to process a) or b), are separated into the pure enantiomers or diastereomers by salt formation with an enantiomerically pure acid or base, chromatography on a chiral stationary phase or derivatization with an enantiomerically pure chiral compound, for example an amino acid, separation of the diastereomers thus obtained, and cleavage of the chiral auxiliary groups.

The invention further relates to a process for the preparation of compounds of formula I according to scheme 1.

The flow chart is as follows:

here, the starting materials II and III, where III is optionally present in salt form, are reacted at RT or at slightly elevated temperatures of from 40 ℃ to 60 ℃ advantageously in the presence of a base, preferably Hunig's base, in a solvent, preferably Dimethylformamide (DMF), to give the compounds of the formula I. The groups R1 to R10 are as defined in formula I, Y is a good leaving group such as chloro, bromo, mesylate or tosylate, preferably bromo or mesylate.

The compounds of formula II are commercially available or may be obtained according to methods known in the literature. The following describes the obtaining of the pentafluorothio derivatives of formula II.

The compounds of the formula III can be prepared according to scheme 2 (see also DE 2211796).

The flow chart is as follows:

here, the compound of formula IV, optionally in the form of its salt (HA), is cyclized with a cyanide source V, preferably in the presence of a base, to give the desired imidazopyridines. Suitable acids HA are preferably HBr, HCl, trifluoroacetic acid (TFA) and sulfuric acid. Z is a good leaving group, preferably tosylate or bromine.

Compounds of the type of formula IV are commercially available or may be obtained according to scheme 3 a.

Flow chart 3 a:

here, pyridines of type VI are reacted in the presence of the nitrogen nucleophile "N" and optionally subsequently to convert-NH₂Conversion to pyridylmethylamine IV with unmasking of the group. Suitable nitrogen nucleophiles here are ammonia (which directly produces compounds of the type IV without further unmasking), azides such as sodium azide (which subsequently has to be reduced to build up the amino function, for which reason triphenylphosphine (bioorg. med. chem. lett.2925, 2002) or noble metal catalysts such as palladium or platinum are suitable in the presence of hydrogen (j.med. chem.5005, 2002)), phthalimides (which subsequently have to be treated with hydrazine to unmask the amino function (j.med. chem.1315, 2004)) or urotropin (which for unmasking the amino function has to be treated with acid, preferably hydrochloric acid (Synthesis 2145, 2003)). The groups R1 to R4, R10 and Y are as defined above, where Y here may also be-OH, which is activated in situ to a good leaving group and subsequently substituted with one of the above-mentioned nitrogen nucleophiles (chem. pharm. Bull.1493, 1989; bioorg. Med. chem. Lett.2463, 2004).

Another method for obtaining amines of type IV is shown in scheme 3 b.

Flow chart 3 b:

starting from 2-cyanopyridines of type VIa, the nitrile functions are reduced with a reducing agent such as hydrogen in the presence of a metal catalyst such as palladium or raney nickel to give amines of type IV. The substituent R10 can be introduced in this way if the nitrile function is reacted before reduction with an organometallic reagent, such as a Grignard reagent or an organolithium compound. The imine intermediate thus obtained can be reduced to the amine IV with sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride. The groups R1 to R4 and R10 are as defined above. Met is-Li or-MgBr.

Alternatively, compounds of formula (I) may be prepared as shown in scheme 4.

The flow chart is as follows:

here, the compound of formula VII (optionally in the form of its salt (HA)) is cyclized with a cyanide source V (preferably cyanogen bromide) in the presence of a base (preferably Hunig's base) in a solvent such as water, methanol, ethanol, acetic acid, acetonitrile, toluene or a suitable mixture of these solvents (preferably in toluene) to give the desired imidazopyridines.

The compound of formula VII is obtained according to scheme 5 by reacting an amine of formula III with an acetophenone derivative of formula II. The reaction is preferably carried out in a solvent such as DMF, Tetrahydrofuran (THF) or acetonitrile, preferably in THF. Suitable bases are Hunig's base, lithium hexamethyldisilazane (lithium hexamethyldisilazane) or potassium carbonate, preferably lithium hexamethyldisilazane. The groups herein are as defined above.

The flow chart is as follows:

alternatively, compounds of formula VII may be obtained according to scheme 6 by reacting an amine of formula IX with a pyridyl derivative of the type of formula VIII. The reaction is carried out in a solvent such as DMF, THF, acetonitrile or ethanol, preferably in THF. Suitable bases are Hunig's base, lithium hexamethyldisilazane or potassium carbonate, preferably lithium hexamethyldisilazane. The groups herein are as defined above.

The flow chart is as follows:

if one of the radicals R5, R6, R7, R8 or R9 is pentafluorothio (-SF)₅) These compounds of formula IIa (Y ═ Br) type can then be prepared as shown in scheme 7.

The flow chart is as follows:

here, the acetophenone derivatives of the formula Xa can be reacted, for example, with Br₂N-bromosuccinimide (NBS) or phenyltrimethyl tribromide (phenyltrimethyl tribromide), preferably in glacial acetic acid, methanol or methanol/THF mixture, to give the compound of formula IIa, or the corresponding ketal of acetophenone derivative X, i.e. the compound of formula XIa, is brominated with, for example, the above brominating reagent, preferably phenyltrimethyl tribromide. Subsequently, to obtain the compound of formula IIa, the ketal is cleaved in the presence of an acid, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, preferably sulfuric acid.

The ketals of the formulae XI, XIa and XI' can be obtained starting from the ketones of the formula X by ketalization reactions known to the person skilled in the art. Preferably, the reaction to obtain the compound of formula XI is carried out with methyl orthoformate in methanol in the presence of DL-10-camphorsulfonic acid (scheme 8).

The flow chart is as follows:

the groups R5 to R9 herein are as defined above. The radical W is- (C)₁-C₄) -an alkyl group. The radical W' is ethylene, propylene or butylene, or together with the radical-O-C-O-forms a 1, 3-dioxo ring of 5, 6 or 7 ring members. Ketals of this type are obtained by reaction with alkylene glycols such as ethylene glycol in the presence of an acid such as sulfuric acid or p-toluenesulfonic acid and/or a dehydrating agent. In the simplest case, the reaction is carried out in toluene in the presence of catalytic amounts of p-toluenesulfonic acid in a water separator.

Compounds of formula Xa more complexly substituted, wherein R5, R6, R7, R8 or R9 are pentafluorothio and further wherein R5, R6, R7, R8 or R9 are not hydrogen, can be obtained starting from commercially available pentafluorothio derivatives. Derivatives which are not commercially available can be obtained by methods analogous to known methods of preparation (Tetrahedron 56(2000) 3399; Organic Letters 4(17) (2002) 3013; WO 2005/047240). For 1- (3-dimethylamino-5-pentafluorothiophenyl) ethanone, which has not been described before, the synthetic route is shown in scheme 9.

The flow chart is as follows:

starting from commercially available 3- (pentafluorothio) benzoic acid XIVa, it is first nitrated and subsequently reduced to the amine with palladium on charcoal in the presence of hydrogen, using reactions known to the person skilled in the art. The 3-amino-5-pentafluorosulfanylbenzoic acid obtained is then dimethylated at the amine nitrogen under Eschweiler-Clark conditions, the carboxylic acid is converted into the acid chloride with thionyl chloride and subsequently reacted with O, N-dimethylhydroxylamine. The 3-dimethylamino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide XIIa thus obtained is converted with methylmagnesium bromide into the corresponding pentafluorothio derivative of the formula Xa.

The compounds of the formula I prepared according to schemes 1 or 4, which are present in enantiomeric form due to their chemical structure, or suitable precursors of the compounds of the formula I, can be separated into the pure enantiomers by salt formation with enantiomerically pure acids or bases, chromatography on chiral stationary phases or derivatization with enantiomerically pure chiral compounds, such as amino acids, separation of the diastereomers thus obtained and removal of the chiral auxiliary groups (method c), or the compounds of the formula I prepared according to schemes 1 or 4 can be separated off in free form or, in the presence of acidic or basic groups, can be converted into physiologically tolerable salts (method d).

The acidic or basic products of the compounds of formula I may be present in the form of their salts or in free form. Preference is given to pharmaceutically tolerable salts, for example alkali metal or alkaline earth metal salts or hydrochlorides, sulfates, hemisulfates, methanesulfonates, p-toluenesulfonate, all possible phosphates and also salts of amino acids, of trona or carboxylic acids, such as lactates, citrates, tartrates, acetates, adipates, fumarates, gluconates, glutamates, maleates or pamoate.

Physiologically tolerable salts are prepared in a manner known per se from the compounds of the formula I, including the stereoisomeric forms thereof, which are capable of salt formation, in accordance with process step c). If the compounds of the formula I contain acidic functional groups, stable alkali metal, alkaline earth metal or optionally substituted ammonium salts can be formed with basic reagents such as hydroxides, carbonates, hydrogen carbonates, alkoxides and ammonia or organic bases, for example trimethylamine or triethylamine, ethanolamine, diethanolamine or triethanolamine, aminotributol or even basic amino acids, for example lysine, ornithine or arginine. The basic groups of the compounds of formula I form acid addition salts with acids. Inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hemisulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, cyclohexylsulfamic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, acetic acid, oxalic acid, tartaric acid, succinic acid, glycerophosphoric acid, lactic acid, malic acid, adipic acid, citric acid, fumaric acid, maleic acid, gluconic acid, glucuronic acid, palmitic acid or trifluoroacetic acid are suitable.

In process step d), if the compounds of the formula I are present in the selected synthesis in the form of diastereomers or enantiomeric mixtures or are formed in the form of diastereomers or enantiomeric mixtures, they are separated into the pure stereoisomers by chromatographic treatment on optionally chiral support materials, or, if the racemic compounds of the formula I are capable of salt formation, the diastereomeric salts formed can also be crystallized fractionally using optically active bases or acids as auxiliary agents. Suitable chiral stationary phases for the thin-layer or column chromatographic separation of enantiomers are, for example, modified silica gel supports ("Pirkle phase") and high molecular weight carbohydrates such as triacetyl cellulose. For analytical purposes, suitable derivatizations known to the person skilled in the art can be used, as can gas chromatography on chiral stationary phases. For the separation of enantiomers of racemic carboxylic acids, diastereomeric salts of different solubilities are formed with optically active, usually commercially available bases such as (-) -nicotine, (+) -and (-) -phenylethylamine, quinine base, L-lysine or L-and D-arginine, the less soluble components are separated off in solid form, the more soluble components are precipitated from the mother liquor, and the pure enantiomers are obtained from the diastereomeric salts thus obtained. In essentially the same way, racemic compounds of formula I containing a basic group such as amino can be converted into the pure enantiomers with optically active acids such as (+) -camphor-10-sulfonic acid, D-and L-tartaric acid, D-and L-lactic acid and (+) and (-) -mandelic acid. Chiral compounds comprising an alcohol or amine function can also be converted into the corresponding esters or amides with the enantiomerically pure amino acids suitably activated or optionally N-protected, or conversely chiral carboxylic acids can be converted into amides with carboxy-protected enantiomerically pure amino acids or into the corresponding chiral esters with enantiomerically pure hydroxycarboxylic acids such as lactic acid. The chirality of the amino acid or alcohol groups introduced in stereoisomerically pure form can then be used for the separation of isomers by separation of the now present diastereomers by crystallization or chromatography using a suitable stationary phase, followed by removal of the accompanying chiral moiety by a suitable method.

Furthermore, it may lead to the case that some compounds of the invention utilize diastereomerically or enantiomerically pure starting products for the preparation of the framework structure. The end product can therefore also be purified by other methods or simplified methods. These starting products are prepared beforehand in enantiomerically or diastereomerically pure form according to methods known from the literature. This may particularly mean the use of enantioselective methods in the synthesis of the framework structures, or the separation of enantiomers (or diastereomers) at an early synthesis stage, not just at the end product stage. Also, simplification of the separation can be achieved by performing it in two or more stages.

The invention also relates to medicaments comprising an effective amount of at least one compound of the formula I and/or a physiologically tolerable salt of the compound of the formula I and/or optionally a stereoisomeric form of the compound of the formula I, together with pharmaceutically suitable and physiologically tolerable bases, additives and/or other active ingredients and excipients.

Due to their pharmacological profile, the compounds of the invention are suitable, for example, for the prophylaxis, secondary prophylaxis and therapy of all such diseases which can be treated by inhibition of the protease-activated receptor 1(PAR 1). Thus, the compounds of the invention are suitable for prophylactic and therapeutic use in humans. They are suitable both for acute and for long-term treatment. The compounds of formula I are useful in patients suffering from health disorders or diseases associated with thrombosis, embolism, hypercoagulability or fibrotic changes.

These include myocardial infarction, angina and all other forms of acute coronary syndrome, stroke, peripheral vascular disorders, deep vein thrombosis, pulmonary embolism, embolism or thrombotic events resulting from cardiac arrhythmias, cardiovascular events such as revascularization, angioplasty and similar interventions such as restenosis following stent implantation and bypass surgery. Furthermore, the compounds of formula I can also be used for all interventions leading to contact of blood with foreign surfaces, such as for dialysis patients and patients with indwelling catheters. The compounds of formula I may be used to reduce the risk of thrombosis following surgical interventions such as knee and hip surgery.

The compounds of formula I are suitable for use in the treatment of patients with disseminated intravascular coagulation, sepsis and other intravascular events with inflammation. Furthermore, the compounds of the formula I are suitable for the prophylaxis and treatment of patients suffering from atherosclerosis, diabetes and metabolic syndrome and their sequelae. Disorders of the hemostatic system (e.g., fibrin deposition) are implicated in the mechanisms leading to tumor growth and tumor metastasis, and in inflammatory and degenerative joint disorders such as rheumatoid arthritis and arthropathies. The compounds of formula I are suitable for retarding or preventing such processes.

Other indications for which compounds of formula I are useful are fibrotic changes of the lung such as chronic obstructive pulmonary disease, Adult Respiratory Distress Syndrome (ARDS) and fibrotic changes of the eye such as fibrin deposition after eye surgery. The compounds of formula I are also suitable for the prevention and/or treatment of scarring.

The medicament of the present invention may be administered orally, inhaled, rectally or transdermally or by subcutaneous, intra-articular, intraperitoneal or intravenous injection. Oral administration is preferred. The stent may be coated with a compound of formula I or other surface that contacts blood in vivo.

The invention also relates to a process for the preparation of a medicament, which comprises bringing at least one compound of the formula I into a suitable administration form with a pharmaceutically suitable and physiologically tolerable matrix and optionally further suitable active ingredients, additives or excipients.

Suitable solid or galenical forms are, for example, granules, powders, coated tablets, capsules or microcapsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and preparations with prolonged release of the active ingredient, in the preparation of which conventional excipients such as bases, disintegrants, binders, coatings, expanding agents, glidants or lubricants, flavors, sweeteners and solubilizers are used. Common excipients which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycols and solvents such as sterile water and mono-or poly-hydroxy alcohols such as glycerol.

Preferably, the pharmaceutical preparations are prepared and administered in the form of dosage units, wherein each unit contains as active ingredient a dose of a compound of the invention of the formula I. In the case of solid dosage units such as tablets, capsules, coated tablets or suppositories, the dose may be up to about 1000mg, but preferably from about 50 to 300mg, and in the case of injections in the form of ampoules, up to about 300mg, but preferably from about 10 to 100 mg.

For the treatment of adult patients weighing about 70kg, a daily dose of about 2mg to 1000mg, preferably about 50mg to 500mg, of active ingredient is suitable, depending on the efficacy of the compound of formula I. However, in some cases, higher or lower daily doses may also be used. The daily dose can be administered either by single administration of each dosage unit or of a number of smaller dosage units, or by multiple administration of subdivided doses at regular intervals.

The compounds of formula I can be administered either as monotherapy or in combination or together with all antithrombotic agents (anticoagulants and platelet aggregation inhibitors), thrombolytic agents (plasminogen activators of any type), other profibrinolytic (pro fibrinolytic) actives, hypotensive agents, blood glucose regulators, lipid lowering agents and antiarrhythmics.

Examples

Usually by chromatography-mass spectrometry (LCUV/ESI-MS coupling) and¹H-NMRThe final product was characterized. By giving the relevant retention time in ion flow (LCMS-rt) and the corresponding M + H in the relevant mass spectrum⁺Signals describe the compounds. If no M + H can be obtained under the conditions⁺Quality signal, then given as an alternative¹H-NMR data. The abbreviations used are explained or correspond to the usual specifications. If not stated otherwise, chromatography is carried out on silica gel using ethyl acetate/heptane or DCM/methanol mixtures as eluents.

Solvent evaporation is usually carried out on a rotary evaporator at 35 ℃ to 45 ℃ under reduced pressure, which is described by "liberation of solvent", "concentration" or "removal of solvent".

If not mentioned otherwise, the LCUV/MS analysis is carried out under the following conditions:

column: YMC J' shere ODS H8020X 2.1mm, Waters GmbH, Helfmann-Park 10, 65760 Eschborn, Germany; the filler is 4 mu m in diameter,

eluent: ACN: H₂O + 0.05% TFA (flow rate 1ml/min)

Gradient: 4: 96(0min) → 95: 5(2min) → 95: 5(2.4min) → 4: 96(2.45min)

Ionization: ESI⁺

In contrast, the LCUV/MS analysis, herein labeled "method B", was performed under the following conditions:

column: YMC J' sphere 33X 2; filler 4. mu.M

Eluent: ACN + 0.05% TFA: H₂O + 0.05% TFA (flow rate 1ml/min)

Gradient: 5: 95(0min) → 95: 5(2.5min) → 95: 5(3.0min)

Ionization: ESI⁺

Preparative HPLC using Reverse Phase (RP) silica gel was performed by the following method:

method A, which is a standard method if nothing else is mentioned herein

Column: merck (Darmstadt, Germany)RP18 25×250mm，10μm

Solvent: ACN: H₂O + 0.05% TFA (flow rate 25ml/min)

Gradient: 10: 90(0min) → 90: 10(40min)

Method B

Column: merckRP18 25×250mm，10μm

Solvent: ACN: H₂O + 0.05% TFA (flow rate 25ml/min)

Gradient: 0: 100(0min) → 0: 100(5min) → 20: 80(20min)

The reaction is carried out in a standard reaction apparatus such as a single-or multi-neck flask, which is suitably filled with 5ml to 2000ml if not otherwise described, and equipped with a septum, stopper, condenser, stirrer or other equipment as required. All reactions were carried out with argon as protective gas and with stirring with a magnetic stirrer, if not mentioned otherwise.

Abbreviations used:

abs

ACN acetonitrile

Boc butoxycarbonyl group

DCM dichloromethane

DIPEA N, N-diisopropylethylamine (Hunig's base)

DMF dimethyl formamide

DMSO dimethyl sulfoxide

Retention time of LCMS-Rt compounds in ion flux

LCUV/MS liquid chromatography-ultraviolet spectrum/mass spectrum

MeOH methanol

RT Room temperature (20 ℃ to 25 ℃ C.)

TFA trifluoroacetic acid

THF tetrahydrofuran

Example 1

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt

1a)1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- [ (pyridin-2-ylmethyl) amino ] ethanone hydrobromide

First, 2- (aminomethyl) pyridine (100mg) was introduced into anhydrous THF (12ml), which was treated with a lithium hexamethyldisilazane solution (1.01ml, 1M THF solution) under argon at RT with stirring. After 30 minutes, 2-bromo-1- (3, 5-di-tert-butyl-4-hydroxyphenyl) ethanone (0.5eq., 151mg, dissolved in 1.5ml anhydrous THF) was added dropwise. To complete the reaction, the remaining amount of bromide (151mg) was added and, after 2 hours, the precipitate formed was filtered off with suction and dried. 98mg of the title compound obtained were contaminated with a small amount of THF, but did not interfere with further reaction.

LCMS-Rt：1.21min [M+H⁺]：355.1

1b) 1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- [ (pyridin-2-ylmethyl) amino ] ethanone hydrobromide (95mg) was dissolved in water. After addition of saturated sodium bicarbonate solution, the mixture was extracted with ethyl acetate (three times). The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. 67mg of free base were obtained.

It was taken up in toluene (5ml) and treated with cyanogen bromide (22mg, dissolved in 1.5ml of toluene) with stirring. After 1.5 h, the solvent was concentrated and the residue was purified by preparative HPLC. The product containing fractions were combined, acetonitrile removed and freeze dried. 40mg of the desired compound are obtained.

LCMS-Rt：1.30min [M+H⁺]：380.1

Alternatively, 1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) ethanone can be prepared as the trifluoroacetate salt as follows:

1c) imidazo [1, 5-a ] pyridin-3-ylamines in the form of trifluoroacetates

2-Aminomethylpyridine (1g) was dissolved in abs. toluene (5ml) and treated with cyanogen bromide (1g) dissolved in abs. toluene (5ml) with stirring. After stirring for 4 hours at RT, the mixture was allowed to stand over the weekend. The solvent was then decanted from the resulting precipitate and the residue was washed with acetonitrile. Subsequently, about 300mg of 1.7g of the precipitate was purified by preparative HPLC (method B). The product containing fractions were combined, acetonitrile released and freeze dried. 74mg of the desired compound are obtained.

LCMS-Rt：0.34min [M+H⁺]：134.1

1d)1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt

Imidazo [1, 5-a ] pyridin-3-ylamine trifluoroacetate (10mg) was dissolved in abs. DMF (1.5ml) and treated with Hunig's base (7. mu.l) under stirring at RT. 2-bromo-1- (3, 5-di-tert-butyl-4-hydroxyphenyl) ethanone (14mg, dissolved in 0.5ml DMF) was then added dropwise. After stirring for 4 hours at RT, the mixture was allowed to stand overnight, then treated with saturated saline solution and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. Residual DMF was removed under high vacuum. The crude product obtained was purified by preparative HPLC. The product containing fractions were combined, acetonitrile released and freeze dried. 9mg of the desired compound are obtained.

LCMS-Rt：1.33min [M+H⁺]：380.2

Example 2

2- (3-Iminoimidazo [1, 5-a ] pyridin-2-yl) -1- (3-pentafluorothiophenyl) ethanones as trifluoroacetate salts

2a) 2-bromo-1- (3-pentafluorothiophenyl) ethanone

First, 3-pentafluorothioacetophenone (400mg) was introduced into glacial acetic acid (10ml) and bromine (91. mu.l, dissolved in 1ml of glacial acetic acid) was slowly added dropwise. After stirring for 4 hours at RT, the mixture was allowed to stand overnight before releasing the solvent. The residue was taken up twice with toluene and allowed to dry. The crude product obtained was purified by preparative HPLC. The product containing fractions were combined, acetonitrile released and freeze dried. 252mg of the desired compound are obtained.

LCMS-Rt：1.69min [M+H⁺]：324.9

2b) 2- (3-Iminoimidazo [1, 5-a ] pyridin-2-yl) -1- (3-pentafluorothiophenyl) -ethanones as trifluoroacetates

Imidazo [1, 5-a ] pyridin-3-ylamine in the form of the trifluoroacetate salt (20mg, example 1c) was reacted as in example 1d) with 2-bromo-1- (3-pentafluorosulfanyl-phenyl) ethanone (26mg) in the presence of Hunig's base. THF was used as the solvent instead of DMF. 25mg of the desired compound are obtained.

LCMS-Rt：1.13min [M+H⁺]：378.0

Example 3

2- (1-cyclopropyl-3-iminoimidazo [1, 5-a ] pyridin-2-yl) -1- (3, 5-di-tert-butyl-4-hydroxy-phenyl) ethanone in the form of the trifluoroacetate salt

3a)2- [ (cyclopropylpyridin-2-ylmethyl) amino ] -1- (3, 5-di-tert-butyl-4-hydroxy-phenyl) ethanone

C-cyclopropyl-C-pyridin-2-ylmethylamine (200mg) was almost completely dissolved in abs. After addition of a lithium hexamethyldisilazane solution (1.8ml, 1M in THF) for 30 minutes, 2-bromo-1- (3, 5-di-tert-butyl-4-hydroxyphenyl) ethanone (296mg, dissolved in 3ml abs. After stirring for 2 hours, water was added and the aqueous phase was extracted three times with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. The crude product obtained was purified by preparative HPLC. The product-containing fractions were combined, acetonitrile was liberated, made basic with saturated potassium carbonate solution and extracted three times with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. 13mg of the desired compound are obtained.

LCMS-Rt：1.33min [M+H⁺]：395.1

3b) 2- (1-cyclopropyl-3-iminoimidazo [1, 5-a ] pyridin-2-yl) -1- (3, 5-di-tert-butyl-4-hydroxyphenyl) ethanone in the form of the trifluoroacetate salt

2- [ (cyclopropylpyridin-2-ylmethyl) amino ] -1- (3, 5-di-tert-butyl-4-hydroxyphenyl) ethanone (13mg) was cyclised with cyanogen bromide (4mg) in toluene as described in example 1 b). 4mg of the desired compound are obtained.

LCMS-Rt：1.42min [M+H⁺]：420.2

Example 4

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-1-phenylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt

4a) 1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- [ (phenylpyridin-2-ylmethyl) amino ] -ethanone in the form of the trifluoroacetate salt

Phenyl (2-pyridyl) methylamine hydrochloride (150mg) was dissolved in a small amount of water, made basic with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. 113mg of free base are obtained. 55mg of this was dissolved in THF (4ml) and 2-bromo-1- (3, 5-di-tert-butyl-4-hydroxyphenyl) ethanone (96mg, dissolved in 2ml THF) was added dropwise with stirring. After stirring for 4 hours at RT, the mixture was left overnight and the precipitate formed was filtered off. The mother liquor was concentrated and purified by preparative chromatography. The product containing fractions were combined, acetonitrile released and freeze dried. 12mg of the desired compound are obtained.

LCMS-Rt：1.40min [M+H⁺]：431.3

4b) 1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-1-phenylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- [ (phenylpyridin-2-ylmethyl) amino ] ethanone trifluoroacetate (12mg) was reacted in analogy to example 1b) in toluene. 3mg of the desired compound are obtained.

LCMS-Rt：1.50min [M+H⁺]：456.2

Example 5

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-8-methylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate or hydrobromide salt

5a) 8-methylimidazo [1, 5-a ] pyridin-3-ylamine in the form of the trifluoroacetate salt

2-aminomethyl-3-methylpyridine (500mg) was dissolved in abs toluene (15ml) and cyanogen bromide (455mg, dissolved in 5ml toluene) was added dropwise with stirring. After 1 hour, the precipitate is filtered off with suction and the mother liquor is discarded. The precipitate and viscous flask residue were purified by preparative HPLC. The product containing fractions were combined, acetonitrile released and freeze dried. 191mg of the desired compound were isolated as the trifluoroacetate salt. LCMS-Rt: 0.68min [ M + H ]⁺]：148.1

5b) 1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-8-methylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the hydrobromide salt or

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-8-methylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt

8-methylimidazo [1, 5-a ] pyridin-3-ylamine (30mg, as trifluoroacetate) was dissolved in abs. THF (5ml), treated with Hunig's base (19. mu.l) and 2-bromo-1- (3, 5-di-tert-butyl-4-hydroxyphenyl) ethanone (38mg, dissolved in 1.5ml abs. THF) was slowly added dropwise. After stirring for 2h at RT, the mixture was allowed to stand overnight and then warmed to 60 ℃ to complete the reaction, a small amount of bromide (4mg) was added again. The precipitate formed is filtered off with suction and dried. 8.5mg of the title compound are obtained as the hydrobromide salt.

LCMS-Rt：1.30min [M+H⁺]：394.2

To obtain the trifluoroacetate salt, the mother liquor is concentrated and purified by preparative HPLC. The product containing fractions were combined, acetonitrile released and freeze dried. 23mg of the desired compound are obtained in the form of the trifluoroacetate salt.

LCMS-Rt：1.30min [M+H⁺]：394.2

Examples 6a and 6b

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-7-trifluoromethylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate (6a) or the hydrobromide (6b)

6a) 7-trifluoromethylimidazo [1, 5-a ] pyridin-3-ylamine

C- (4-Trifluoromethylpyridin-2-yl) methylamine hydrochloride (600mg) was dissolved in water, treated with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. 300mg of free base are obtained. This was dissolved in abs toluene (15ml) and cyanogen bromide (191mg, dissolved in 5ml toluene) was slowly added dropwise. After 24 hours, the precipitate formed is filtered off with suction, dried and purified by preparative HPLC. The product containing fractions were combined, acetonitrile released and freeze dried. 168mg of the desired compound was obtained as the trifluoroacetate salt.

LCMS-Rt：0.76min [M+H⁺]：202.1

6b)1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-7-trifluoromethylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate and hydrobromide salt

7-Trifluoromethylimidazo [1, 5-a ] pyridin-3-ylamine (25mg) was reacted as in example 5 b). 11.6mg of the hydrobromide salt were obtained, after chromatography 9mg of the trifluoroacetic acid derivative were obtained.

TFA salt: LCMS-Rt: 1.38min [ M + H⁺]：448.2

HBr salt: LCMS-Rt: 1.38min [ M + H⁺]：448.2

Example 7

2- [2- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2-oxoethyl ] -3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methyl ester in the form of the trifluoroacetate salt

7a) 6-Aminomethylnicotinic acid trifluoroacetic acid salt

6-Cyanonicotinic acid (1g) in the form of the trifluoroacetate salt was dissolved in methanol (300ml), treated with Raney nickel (0.224g) and hydrogenated in a shaker autoclave at 80 ℃ under 10 bar of hydrogen pressure for 20 hours. Subsequently, the mixture was filtered, the residue was washed with a water/methanol mixture and the filtrate was concentrated. The residue was taken up in ACN/water and freeze-dried. 500mg of product was obtained, which was pure enough for the next step. LCMS-Rt: 0.14min [ M + H⁺]：153.1

7b) 6-aminomethyl nicotinic acid methyl ester in the form of the trifluoroacetate salt

6-Aminomethylnicotinic acid trifluoroacetate (500mg) was dissolved in methanol (45 ml). After addition of concentrated sulfuric acid (10 drops), the solution was refluxed for 24 hours. After cooling, the solvent was removed, the residue was dissolved in water and purified by preparative HPLC. The product containing fractions were combined, ACN released and lyophilized. 395mg of the desired compound was obtained as the trifluoroacetate salt.

LCMS-Rt：0.27min [M+H⁺]：167.1

7c) 3-Aminoimidazo [1, 5-a ] pyridine-6-carboxylic acid methyl ester

Methyl 6-aminomethylnicotinate trifluoroacetate (390mg) was dissolved in toluene (35ml) and treated with Hunig's base (230. mu.l). Then, cyanogen bromide (0.35ml of a 5M solution in acetonitrile) was slowly added dropwise. After stirring for 3 hours at RT, the solvent was removed and the residue was taken up with water and saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. The product containing fractions were combined, acetonitrile released and freeze dried. The residue was then taken up in a small amount of water, treated with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 110mg of the desired compound are obtained. LCMS-Rt: 0.67min [ M + H ]⁺]：192.1

7d) 2- [2- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2-oxoethyl ] -3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methyl ester in the form of the trifluoroacetate salt

Methyl 3-aminoimidazo [1, 5-a ] pyridine-6-carboxylate (26mg) was dissolved in abs. dmf (2.5ml), and 2-bromo-1- (3, 5-di-tert-butyl-4-hydroxyphenyl) ethanone (45mg, dissolved in 1.5ml abs. dmf) was slowly added dropwise. After stirring for 5 hours, the reaction mixture was allowed to stand overnight, then additional bromide (10mg, dissolved in 0.5ml abs. dmf) was added to complete the reaction. After stirring for a further 2 hours, the solvent was removed and the residue was purified by preparative HPLC. The product containing fractions were combined, acetonitrile released and freeze dried. 50mg of the desired compound are obtained in the form of the trifluoroacetate salt.

LCMS-Rt：1.30min [M+H⁺]：438.3

Example 8

2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methyl ester in the form of trifluoroacetate salt

Methyl 3-aminoimidazo [1, 5-a ] pyridine-6-carboxylate (20mg) was dissolved in abs, DMF (1ml) and 2-bromo-1- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) ethanone (45mg, dissolved in 1ml abs, DMF; prepared according to WO 2004/078721) was slowly added dropwise. After stirring for 4 hours at RT, the mixture was warmed to 40 ℃ for an additional 1 hour. The reaction mixture was allowed to stand over the weekend and then the solvent was removed under high vacuum. The residue was purified by preparative HPLC. The product containing fractions were combined, acetonitrile released and freeze dried. 40mg of the desired compound were obtained as the trifluoroacetate salt.

LCMS-Rt：1.27min [M+H⁺]：481.2

Example 9

1- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt

Reacting the imidazo [1, 5-a ] in the form of trifluoroacetate salt]Pyridin-3-ylamine (16mg, example 1c) was dissolved in abs. DMF (1ml), treated with Hunig's base (31. mu.l) and 2-bromo-1- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) ethanone (45mg, dissolved in 1ml abs. DMF; prepared according to WO 2004/078721) was slowly added dropwise. After stirring for 2 hours at RT, the mixture was allowed to stand overnight and then removed under high vacuumAnd (4) removing the solvent. The residue was purified by preparative HPLC. The product containing fractions were combined, acetonitrile released and freeze dried. 12mg of the desired compound were obtained as the trifluoroacetate salt. LCMS-Rt: 1.28min [ M + H⁺]：423.3

Example 10

1- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2- (3-imino-8-methylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt

8-methylimidazo [1, 5-a ] pyridin-3-ylamine (30mg, example 5a) in the form of the trifluoroacetate salt was dissolved in abs, DMF (2ml), treated with Hunig's base (19. mu.l) and 2-bromo-1- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) ethanone (43mg, dissolved in 1ml abs, DMF; prepared according to WO 2004/078721) was slowly added dropwise. After 4.5 hours, additional bromide (4mg in 0.1ml DMF) was added to complete the reaction. After stirring for a further 3 hours, the mixture was allowed to stand overnight and then the solvent was removed under high vacuum. The residue was purified by preparative HPLC. The product containing fractions were combined, acetonitrile released and freeze dried. 26mg of the desired compound were obtained as the trifluoroacetate salt.

LCMS-Rt：1.33min [M+H⁺]：437.1

Example 11

1- (3-dimethylamino-5-pentafluorothiophenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt

11a) 3-amino-5-pentafluorosulfanylbenzoic acid

3-Pentafluorosulfobenzoic acid (3.0g) was dissolved in fuming nitric acid (20ml) and stirred at RT with exclusion of water. Concentrated sulfuric acid (1.5ml) was then added and the mixture was stirred at 75 ℃. After stirring at 75 ℃ for 6 hours, it was allowed to stand overnight, then additional sulfuric acid (1.5ml) was added and the mixture was heated at 75 ℃ for 8 hours. After allowing to stand overnight, ice water was added and stirred for 2 hours. Crystallization started and was complete overnight in the refrigerator. The precipitate is then filtered off with suction and dried under high vacuum. 2.7g of 3-pentafluorothio-5-nitrobenzoic acid are obtained. After extraction three times with dichloromethane, drying of the combined dichloromethane phases over magnesium sulfate and concentration of the solvent, 530mg can be obtained further from the mother liquor.

Subsequently, 2.7g was dissolved in methanol (70ml), Raney nickel (about 500mg) was added, and the mixture was hydrogenated under a hydrogen atmosphere (hydrogen balloon). After 2 hours, the catalyst is filtered off and the filter residue is washed thoroughly with methanol. The filtrate was concentrated and dried under high vacuum. 2.3g of crude product are obtained, which is reacted directly in the next step. LCMS-Rt: 1.21min [ M + H⁺]：264.0

11b) 3-dimethylamino-5-pentafluoro-thiobenzoic acid

To each of two microwave vials was added 3-amino-5-pentafluorosulfanylbenzoic acid (800mg), formic acid (12ml) and 37% strength formalin solution (8 ml). Both containers were then heated at 110 ℃ for 30 minutes. After cooling, the solutions were combined and added to ice water. After extraction three times with ethyl acetate, the combined organic phases were dried over magnesium sulfate, filtered and concentrated. 1.76g of the title compound are obtained, which are reacted directly in the next step.

LCMS-Rt：1.48min [M+H⁺]：292.0

11c) 3-dimethylamino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide

3-dimethylamino-5-pentafluorosulfanylbenzoic acid (1.0g) was dissolved in dichloromethane (60 ml). Thionyl chloride (5ml) was added with stirring and the mixture stirred at RT for 2 h. To complete the reaction, it was then heated at reflux for 3 hours. After cooling, the solvent was removed, the residue was dissolved in dichloromethane (50ml), treated with N, O-dimethylhydroxylamine hydrochloride and Hunig's base (1ml) was added. After stirring for 1 hour, the solvent was removed, and the residue was taken up in ethyl acetate and washed 5 times with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. 980mg of the title compound are obtained, which are reacted directly in the next step.

LCMS-Rt：1.53min [M+H⁺]：335.0

11d)1- (3-dimethylamino-5-pentafluorothiophenyl) ethanone

3-dimethylamino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide (980mg) was dissolved in abs. THF (50ml), and methyl magnesium bromide solution (2.1 ml; 3M in ether) was added dropwise at 0 ℃ with stirring. After complete addition, the ice bath was removed and the mixture was stirred at RT for 1 hour. To complete the reaction, an additional amount of methylmagnesium bromide solution (0.3ml) was added and the mixture was stirred for an additional 2 hours. After storage overnight in the refrigerator, the reaction mixture was treated with 1N hydrochloric acid with cooling. After addition of water and ethyl acetate, extraction was performed twice more with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (n-heptane/ethyl acetate 100/0 to 50/50 in 30 min). The product-containing fractions are combined, the solvent is removed and the residue is dried under high vacuum. 650mg of the title compound are obtained.

LCMS-Rt：1.69min [M+H⁺]：290.0

11e) [3- (1, 1-Dimethoxyethyl) -5-Pentafluorosulphenyl ] dimethylamine

1- (3-dimethylamino-5-pentafluorothiophenyl) ethanone (650mg) was dissolved in methanol (50ml) and treated with trimethyl orthoformate (715mg) and DL-10-camphorsulfonic acid (10mg) with stirring. After stirring for 3 hours, a further amount of orthoester (200mg) was added, and the mixture was stirred for 2 hours and then allowed to stand overnight. The solvent is then removed and the residue is dried under high vacuum. 730mg of crude product are obtained, which are reacted directly in the next step.

¹H-NMR(400MHz，DMSO-d₆)[ppm]：7.01(1H)；6.79(1H)；6.93(1H)；3.10(6H)；2.98(6H)；1.47(3H)

11f) [3- (2-bromo-1, 1-dimethoxyethyl) -5-pentafluorothiophenyl ] dimethylamine and [3- (2-bromo-1, 1-dimethoxyethyl) -5-pentafluorothiophenyl ] methylamine

[3- (1, 1-Dimethoxyethyl) -5-pentafluorothiophenyl ] dimethylamine (730mg) was dissolved in a mixture of methanol (15ml) and THF (15 ml). To this was added phenyltrimethyl tribromide (818mg) with stirring. After 3 hours, some more phenyltrimethyl tribromide (205mg) was added to complete the reaction, and the mixture was stirred at 60 ℃ for 2 hours. After standing overnight, sodium thiosulfate solution, water and ethyl acetate were added. The aqueous phase was further extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (n-heptane/ethyl acetate 100/0 to 50/50 in 30 min). The product-containing fractions are combined, the solvent is removed and the residue is dried under high vacuum.

490mg of dimethylamino and 144mg of monomethylamino are obtained. Dimethylamine derivatives:

¹H-NMR(500MHz，DMSO-d₆)[ppm]：7.14(1H)；7.00(1H)；6.95(1H)；3.85(2H)；3.14(6H)；2.99(6H)

monomethylamine derivatives:

¹H-NMR(500MHz，DMSO-d₆)[ppm]：7.02(1H)；6.91(1H)；6.84(1H)；6.34(1H)；3.80(2H)；3.14(6H)；2.71(3H)

11g) 2-bromo-1- (3-dimethylamino-5-pentafluorothiophenyl) ethanone

[3- (2-bromo-1, 1-dimethoxyethyl) -5-pentafluorothiophenyl ] dimethylamine (230mg) was suspended in water (2.3ml), and then concentrated sulfuric acid (2.3ml) was added dropwise with cooling. After stirring for 2h at RT, the mixture was diluted with water (20ml) and extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in acetonitrile/water, frozen and freeze-dried overnight. 170mg of the desired compound are obtained.

LCMS-Rt：1.80min [M+H⁺]：367.9；369.9

11h) 1- (3-dimethylamino-5-pentafluorothiophenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the trifluoroacetate salt

Reacting the imidazo [1, 5-a ] in the form of trifluoroacetate salt]Pyridin-3-ylamine (20mg, example 1c) was dissolved in abs. THF (5ml) and 2-bromo-1- (3-dimethylamino-5-pentafluorothiophenyl) ethanone (29mg) and Hunig's base (14. mu.l) were added. After stirring for 6 hours at RT and standing overnight, water was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. The product containing fractions were combined, acetonitrile released and freeze dried. 18mg of the desired compound are obtained as the trifluoroacetate salt. LCMS-Rt: 1.21min [ M + H⁺]：421.0

Example 12

2- [2- (8-tert-butyl-4-methyl-3, 4-dihydro-2H-benzo [1, 4] oxazin-6-yl) -2-oxoethyl ] -7-ethoxy-3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamide in the form of the trifluoroacetate salt

12a) 4-chloro-6, N-dimethylnicotinamide

4-hydroxy-6-methylnicotinic acid (5g) was dissolved in abs. DCM (30ml) and treated with 10 drops of DMF. To the mixture was carefully added oxalyl chloride (15ml) dropwise. After stirring for another 4 hours and standing overnight, the solvent was removed and the mixture was connected to a high vacuum for further drying. The obtained 4-chloro-6-methylnicotinoyl chloride (8g) was dissolved in abs. dcm (160 ml). After cooling to 0 ℃ a 40% strength methanolic solution of methylamine (66ml) was added dropwise over the course of 15 minutes. After removing the cooling, the mixture was stirred at RT for a further 2 hours. After addition of water (150ml), it was extracted with DCM (three times). The combined organic phases were dried over sodium sulfate, filtered and concentrated. 4.4g of the desired compound are obtained.

LCMS-Rt：0.34min [M+H⁺]：185.1

12b) 4-ethoxy-6, N-dimethylnicotinamide

4-chloro-6, N-dimethylnicotinamide (2.4g) was dissolved in abs. ethanol (40ml) with stirring and treated with sodium ethoxide (1.8 g). After stirring at RT for 4 hours, the mixture was allowed to stand overnight. After addition of water, it was extracted 3 times with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 2.2g of the desired compound are obtained.

LCMS-Rt：0.32min [M+H⁺]：195.1

12c) 4-ethoxy-6, N-dimethyl-1-oxynicotinamide

4-ethoxy-6, N-dimethylnicotinamide (2.2g) was dissolved in chloroform (160ml) and treated with m-chloroperbenzoic acid (2.7g) in portions under ice cooling and stirring. After removing the ice bath, the mixture was stirred for 4 hours and allowed to stand overnight. After addition of a 5% strength sodium carbonate solution, it is extracted three times with chloroform. The combined organic phases were dried over sodium sulfate, filtered and concentrated to yield 979mg of crude product. It was purified by chromatography on silica gel (gradient elution with DCM/MeOH). The product containing fractions were combined and allowed to dry. 717mg of the sought product are obtained.

The aqueous phase was freeze dried overnight and the residue was stirred with DCM. After filtration, it was allowed to dry. The residue was an additional 720mg of the desired product.

LCMS-Rt：0.52min [M+H⁺]：211.1

12d) 4-ethoxy-6-hydroxymethyl-N-methylnicotinamide in the form of trifluoroacetate salt

4-ethoxy-6, N-dimethyl-1-oxynicotinamide (720mg) was dissolved with stirring in abs. DCM (45ml) and treated with trifluoroacetic anhydride (4.8 ml). After stirring at RT, the mixture was allowed to stand overnight and then 75% of the solvent was removed. The residue was treated with saturated sodium chloride solution and adjusted to pH 9 with potassium carbonate. After extraction with DCM (three times), it was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC. The product containing fractions were combined, acetonitrile released and freeze dried. 696mg of the desired compound are obtained.

LCMS-Rt：0.25min [M+H⁺]：211.1

12e) Methanesulfonic acid 4-ethoxy-5-methylcarbamoylpyridin-2-ylmethyl ester

4-ethoxy-6-hydroxymethyl-N-methylnicotinamide (696mg, as trifluoroacetate salt) was taken up with a small amount of DCM, treated with saturated saline solution and adjusted to pH 9 with solid potassium carbonate. After extraction with DCM (three times), the combined organic phases were dried over sodium sulfate, filtered and concentrated. 445mg of TFA-free compound were obtained. This was dissolved in anhydrous CM (30ml) and treated successively with methanesulfonic anhydride (1.3g, dissolved in 5ml abs. dcm) and triethylamine (1.44 ml). After 2 hours, water and saturated saline solution were added. After extraction with DCM (3 times), the combined organic phases were dried over sodium sulfate, filtered and concentrated. To remove triethylamine to the greatest possible extent, the residue was extracted again in the presence of 10% strength citric acid. 485mg of the desired compound are obtained.

LCMS-Rt：0.72min [M+H⁺]：289.0

12f) 6-aminomethyl-4-ethoxy-N-methylnicotinamide

4-ethoxy-5-methylcarbamoylpyridin-2-ylmethyl mesylate (436mg) dissolved in abs. MeOH (7ml) was added dropwise over the course of 10 minutes to a solution of methanolic ammonia (7.1 ml; 7N) in a microwave vial, with stirring, at RT. After standing overnight, the solvent was removed and the residue was purified by preparative HPLC. The product containing fractions were combined, acetonitrile released and freeze dried. The product was treated with saturated sodium chloride solution and made basic with potassium carbonate. After extraction with dichloromethane, the combined organic phases are dried over sodium sulfate, filtered and concentrated. 71mg of the title compound are obtained.

LCMS-Rt：0.27min [M+H⁺]：210.1

12g) 3-amino-7-ethoxyimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamides in the form of trifluoroacetate salts

First, 6-aminomethyl-4-ethoxy-N-methylnicotinamide (68mg) was dissolved in abs. Then, at RTThis mixture was treated by dropwise adding cyanogen bromide (48mg) dissolved in abs. After stirring for 4 hours at RT, the solvent was removed under reduced pressure, the residue was stirred with dichloromethane and the insolubles were filtered off. The filtrate was dried and subsequently purified by preparative HPLC. The filter residue is extracted again with dichloromethane and the residue obtained after filtration is likewise purified by preparative HPLC. The product containing fractions were combined and acetonitrile was removed under reduced pressure. After lyophilization, 15mg of the title compound were obtained in addition to 21mg of the starting material. LCMS-Rt: 0.69min [ M + H ]⁺]：235.0

12h) 2-bromo-1- (8-tert-butyl-4-methyl-3, 4-dihydro-2H-benzo [1, 4] oxazin-6-yl) ethanone

1- (8-tert-butyl-4-methyl-3, 4-dihydro-2H-benzo [1, 4)]Oxazin-6-yl) ethanone (250mg, available from Chembiotek, india) was warmed to 50 ℃ to 55 ℃ in a mixture of acetic acid (4ml) and toluene (8 ml). Bromine (200mg, dissolved in acetic acid) was carefully added dropwise at this temperature. After 2.5 hours, the heating was removed and the mixture was treated with ice-water at RT and extracted three times with toluene. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified on silica gel to give 65mg of the desired compound, slightly contaminated, in addition to an additional 43mg of product, and 37mg of starting material. LCMS-Rt: 1.81min [ M + H⁺]：326.0；328.0

12i) 2- [2- (8-tert-butyl-4-methyl-3, 4-dihydro-2H-benzo [1, 4] oxazin-6-yl) -2-oxoethyl ] -7-ethoxy-3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamide in the form of the trifluoroacetate salt

Under stirring, under argon, 3-amino-7-ethoxyimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamide in the form of the trifluoroacetate salt (12mg) was treated with Hunig's base (6.3. mu.l) in abs. DMF (3 ml). Subsequently, 2-bromo-1- (8-tert-butyl-4-methyl-3, 4-hydro-2H-benzo [1, 4] oxazin-6-yl) ethanone (12.5mg) dissolved in abs. After stirring for 2.5 hours at RT, the mixture was warmed at 40 ℃ for 30 minutes and then allowed to stand overnight. The solvent was then removed under high vacuum and the residue was purified by preparative HPLC. The product containing fractions were combined and acetonitrile was removed under reduced pressure. After lyophilization, 10mg of the title compound was obtained.

LCMS-Rt：1.24min [M+H⁺]：480.2

Example 13

2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -7-chloro-3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamide in the form of the trifluoroacetate salt

13a) 3-amino-7-chloroimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamides in the form of trifluoroacetate salts

3-amino-7-chloroimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamide was synthesized analogously to example 12a-g), omitting step 12 b). 9mg of the title compound are obtained.

LCMS-Rt：0.32min [M+H⁺]：225.0

13b) 2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -7-chloro-3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamide in the form of the trifluoroacetate salt

In analogy to the procedure described in example 12, 3-amino-7-chloroimidazo [1, 5-a ] is reacted]Pyridine-6-carboxylic acid methylamide (9mg, as TFA salt) was coupled with 2-bromo-1- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) ethanone (10mg, prepared according to WO 2004/078721) in the presence of Hunig's base. 4mg of the title compound are obtained. LCMS-Rt: 1.24min [ M + H⁺]：514.2

Example 14

2, 2, 2-trifluoro-N- {3- [2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) acetyl ] -5-pentafluorothiophenyl } acetamide in the form of the trifluoroacetate salt

14a) 3-amino-N-methoxy-N-methyl-5-pentafluorosulfanyl benzamide

3-amino-5-pentafluorosulfanylbenzoic acid (200mg, example 11a) was dissolved in dichloromethane (12 ml). Then, under stirring, the following were added successively: n, O-dimethylhydroxylamine x HCl (148mg), 1-propanephosphoric anhydride (242mg) and triethylamine (292. mu.l). The clear solution was stirred at RT for 4 hours and allowed to stand over the weekend. For work-up, the reaction mixture is concentrated, the residue is taken up in ethyl acetate and extracted twice with potassium hydrogen sulfate solution. After the ethyl acetate phase was subsequently extracted twice with sodium carbonate solution, it was dried over magnesium sulfate, filtered and concentrated. The crude product obtained was purified by preparative chromatography. The product-containing fractions were combined, freed from acetonitrile, made basic with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 77mg of the desired compound are obtained.

LCMS-Rt：1.30min [M+H⁺]：307.0

14b) N-methoxy-N-methyl-5-pentafluorothio-3- (2, 2, 2-trifluoroacetylamino) -benzamide

3-amino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide (77mg) was dissolved in dichloromethane (3ml), and triethylamine (42. mu.l) was added with stirring and with removal of water, followed by trifluoroacetic anhydride (45. mu.l). After stirring for 3 hours at RT and standing overnight, water and saturated sodium bicarbonate solution were added, the phases were separated, the dichloromethane phase was washed three more times with water, dried over magnesium sulfate, filtered and concentrated. The resulting product (86mg) was used in the next stage without further purification.

LCMS-Rt：1.53min [M+H⁺]：403.0

14c) N- (3-acetyl-5-pentafluorothiophenyl) -2, 2, 2-trifluoroacetamide

N-methoxy-N-methyl-5-pentafluorosulfanyl-3- (2, 2, 2-trifluoroacetylamino) benzamide (20mg) was dissolved in anhydrous THF (2ml) and stirred at RT for 30 min with a lithium hexamethyldisilazane solution (45. mu.l, 1M in THF). Then, methyl magnesium bromide solution (17. mu.l, 3M in ether) was added dropwise at 0 ℃ with stirring. After stirring for 1 hour at RT, 1N hydrochloric acid was added dropwise with cooling, followed by addition of water and ethyl acetate. The organic phase was separated and the aqueous phase was extracted twice more with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. 17mg of crude product are obtained. After further N-methoxy-N-methyl-5-pentafluorothio-3- (2, 2, 2-trifluoroacetylamino) benzamide (60mg) was reacted in the manner described (resulting crude product: 60mg), the crude products were combined and purified by preparative chromatography. The product-containing fractions were combined, freed from acetonitrile, made basic with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 37mg of the desired compound are obtained.

LCMS-Rt：1.61min [M+H⁺]：358.0

14d) N- [3- (2-Bromoacetyl) -5-pentafluorothiophenyl ] -2, 2, 2-trifluoroacetamide

First, N- (3-acetyl-5-pentafluorothiophenyl) -2, 2, 2-trifluoroacetamide (20mg) was dissolved in glacial acetic acid (1ml) and bromine (9mg) dissolved in glacial acetic acid (90. mu.l) was slowly added dropwise. After stirring for 30 minutes at RT, the mixture was warmed at 60 ℃ for 1 hour. After cooling to RT, the glacial acetic acid was diluted with a large amount of water and extracted three times with ethyl acetate. The combined extracts were washed with sodium bicarbonate solution until acid free, dried over magnesium sulfate, filtered and concentrated. The resulting crude product (24mg) was used in the next stage without further purification.

¹H-NMR(400MHz，CDCl₃)[ppm]：8.45[1H]，8.35[1H]，8.25[1H]，4.45[s，2H]

14e) 2, 2, 2-trifluoro-N- {3- [2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) acetyl ] -5-pentafluorothiophenyl } acetamide in the form of the trifluoroacetate salt

Imidazo [1, 5-a ] pyridin-3-ylamine trifluoroacetate (20mg, example 1c) was dissolved in anhydrous THF (4ml) and N- [3- (2-bromoacetyl) -5-pentafluorothiophenyl ] -2, 2, 2-trifluoroacetamide (26mg) was added with stirring. After the addition of DIPEA (10 μ l), the mixture was stirred at RT for 1 hour and left to stand overnight. Thereafter, the reaction mixture was treated with water, extracted three times with ethyl acetate, and the combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. The oily residue was purified by preparative chromatography. The product containing fractions were combined, acetonitrile released and freeze dried. 7mg of the desired compound are obtained.

LCMS-Rt：1.22min [M+H⁺]：489.0

Example 15

1- (3-bromo-4-methoxy-5-trifluoromethylphenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) -ethanone in the form of the trifluoroacetate salt

15a) 2-bromo-1- (3-bromo-4-methoxy-5-trifluoromethylphenyl) ethanone

At RT, a mixture of water (0.4ml) and concentrated sulphuric acid (0.4ml) was added first followed by 4-methoxy-3-trifluoromethylacetophenone (100 mg). Subsequently, potassium bromate (77mg) was added in portions with stirring. After stirring for 4 hours, the reaction mixture was left overnight at deep cold. Then treated with water and ethyl acetate and the aqueous phase extracted three times with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. The crude product was prepurified on silica gel (n-heptane/ethyl acetate gradient elution) followed by final purification by preparative chromatography. The product containing fractions were combined, acetonitrile released and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 12mg of the desired compound are obtained.

LCMS-Rt：1.74min[M+H⁺]：374.8(50％)，376.9(100％)，378.8(45％)15b)1- (3-bromo-4-methoxy-5-trifluoromethylphenyl) -2- (3-iminoimidazo [1, 5-a) in the form of the trifluoroacetate salt]Pyridin-2-yl) ethanones

First, imidazo [1, 5-a ] pyridin-3-ylamine trifluoroacetate (8mg, example 1c) was introduced into anhydrous DMF (0.5ml) together with Hunig's base (5.5. mu.l) at RT. 2-bromo-1- (3-bromo-4-methoxy-5-trifluoromethylphenyl) ethanone (12mg, dissolved in 0.5ml anhydrous DMF) was added dropwise with stirring. After stirring for 3.5 h at RT, the solvent was removed and the residue was purified by preparative chromatography. The product containing fractions were combined, acetonitrile released and freeze dried. 4mg of the desired compound are obtained.

LCMS-Rt：1.21min [M+H⁺]：428.0；430.0

Example 16

2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) -1- (4-methoxy-3-morpholin-4-yl-5-trifluoromethylphenyl) ethanone in the form of the trifluoroacetate salt

16a)1- (3-bromo-4-hydroxy-5-trifluoromethylphenyl) ethanone

4-hydroxy-3- (trifluoromethyl) acetophenone (4g) was first added to acetonitrile (150ml) and N-bromosuccinimide (4.5g, dissolved in 100ml acetonitrile) was added dropwise at-10 ℃. After complete addition, the cooling bath was removed and the mixture was stirred for 5 hours. After standing overnight, the solvent volume was reduced to a quarter and the residue was treated with n-heptane/water. After separation of the organic phase, it is washed once with 5% strength sodium thiosulfate solution and once with water. The precipitate formed in the course of the reaction (6.9g) was filtered off with suction and was reacted directly in the next stage.

¹H-NMR(500MHz，DMSO-d₆)[ppm]：11.3[br，1H]，8.37[1H]，8.06[1H]，2.57[s，3H]

16b) 1-bromo-5- (1, 1-dimethoxyethyl) -2-methoxy-3-trifluoromethylbenzene

1- (3-bromo-4-hydroxy-5-trifluoromethylphenyl) ethanone (6.8g) was dissolved in anhydrous methanol (50ml) and treated successively with DL-10-camphorsulfonic acid (111mg) and trimethyl orthoformate (8 ml). After stirring at RT for 2 hours DMF (75ml) and potassium carbonate (5.0g) were added followed by methyl iodide (3 ml). After stirring for 6 hours, the batch was allowed to stand overnight and treated with a 1: 1 n-heptane/water mixture. After separation of the organic phase, it is extracted once more with n-heptane, and the combined heptane phases are dried over magnesium sulfate, filtered and concentrated. 7g of the desired product are obtained.

¹H-NMR(500MHz，DMSO-d₆)[ppm]：7.92[1H]，7.64[1H]，3.90[s，3H]，3.09[s，6H]，1.50[s，3H]

16c)4- [5- (1, 1-Dimethoxyethyl) -2-methoxy-3-trifluoromethylphenyl ] morpholine

1-bromo-5- (1, 1-dimethoxyethyl) -2-methoxy-3-trifluoromethylbenzene (2g) was added first and argon gas was introduced thereinto with stirring for 0.5 hour. Subsequently, the mixture was treated with Pd (II) acetate (13mg), BINAP (54mg) and sodium t-butyrate (784mg), followed by morpholine (0.6 ml). The resulting mixture was stirred under argon at 85 ℃ for 8 hours, allowed to stand overnight at RT, then stirred at 85 ℃ for a further 8 hours and allowed to stand overnight. The solvent was then removed and the residue was purified on silica gel (n-heptane-ethyl acetate gradient elution). 468mg of the desired product are obtained.

¹H-NMR(500MHz，DMSO-d₆)[ppm]：7.26[1H]，7.23[1H]，3.88[s，3H]，3.78[m，4H]，3.10[s，6H]，3.06[m，4H]，1.47[s，3H]

16d) 2-bromo-1- (4-methoxy-3-morpholin-4-yl-5-trifluoromethylphenyl) ethanone

4- [5- (1, 1-Dimethoxyethyl) -2-methoxy-3-trifluoromethylphenyl ] morpholine (460mg) was first added to anhydrous THF (4ml) and methanol (1.6ml), and phenyltrimethylammonium bromide (530mg) was added under stirring at 7 ℃. The cooling bath was then removed and the mixture was stirred for 8 hours. After standing overnight, treatment was carried out with a 5% strength sodium thiosulfate solution (0.8ml) and water (4 ml). The aqueous phase was extracted three times with ethyl acetate, and the combined ethyl acetate extracts were dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in acetonitrile (15ml) and treated with a mixture of acetonitrile (5ml) (90 parts), water (10) and TFA (0.05) followed by TFA (0.5 ml). The mixture was stirred at RT for about 4 hours. The solvent was then removed and the residue was treated with water, neutralized with saturated sodium bicarbonate solution, extracted three times with ethyl acetate, and the combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified on silica gel (n-heptane-ethyl acetate gradient elution). After combining the product containing fractions, the mixture was allowed to dry. 200mg of the desired compound are obtained.

LCMS-Rt：1.67min [M+H⁺]：382.0；384.0

16e) 2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) -1- (4-methoxy-3-morpholin-4-yl-5-trifluoromethylphenyl) ethanone in the form of the trifluoroacetate salt

Imidazo [1, 5-a ] pyridin-3-ylamine trifluoroacetate (30mg, example 1c) was dissolved in anhydrous DMF (4ml) with stirring and DIPEA (20. mu.l) was added. After slowly dropwise addition of 2-bromo-1- (4-methoxy-3-morpholin-4-yl-5-trifluoromethylphenyl) ethanone (51mg, dissolved in 1ml dmf) over the course of 15 min, the mixture was stirred at RT for 3.5 h. After standing overnight, the solvent was removed and the residue was purified by preparative chromatography. The product containing fractions were combined, acetonitrile released and freeze dried. 35mg of the desired compound are obtained.

LCMS-Rt：1.17min [M+H⁺]：435.1

Example 17

6-ethoxy-3-imino-2- [2- (3-methylamino-5-pentafluorothiophenyl) -2-oxoethyl ] -2, 3-dihydro-1H-imidazo [1, 5-a ] pyridin-5-one as trifluoroacetate salt

17a) 3-ethoxy-2-fluoro-6-methylpyridine

2-fluoro-3-hydroxy-6-methylpyridine (500mg) was first added to anhydrous DMF (20ml) and potassium carbonate (1g) was added. Thereafter, iodoethane (0.6ml) was added dropwise with stirring and the mixture was stirred for 1 hour. Subsequently, water and ethyl acetate were added to the reaction mixture. After separation of the organic phase, the mixture was extracted three more times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. The resulting crude product (477mg) was directly reacted in the next step.

¹H-NMR(500MHz，DMSO-d₆)[ppm]：7.52[dd，1H]，7.10[d，IH]，4.10[q，2H]，2.32[s，3H]，1.33[t，3H]

17b) 6-bromomethyl-3-ethoxy-2-fluoropyridine

First, 3-ethoxy-2-fluoro-6-methylpyridine (400mg) was introduced into carbon tetrachloride (30ml), and after N-bromosuccinimide (505mg) and 2, 2' -azobis (2-methylpropanenitrile) (85mg) were added, the reaction mixture was heated under reflux for 7 hours. After standing overnight at RT, treated with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (n-heptane-ethyl acetate gradient elution). After combining the product containing fractions, it was allowed to dry. 393mg of the desired compound are obtained.

LCMS-Rt：1.40min [M+H⁺]：233.9；235.9

17c) C- (5-ethoxy-6-fluoropyridin-2-yl) methylamine as trifluoroacetate salt

6-bromomethyl-3-ethoxy-2-fluoropyridine (390mg) was dissolved in chloroform (50ml) and treated with hexamethylenetetramine (234mg) with stirring. After stirring at 50 ℃ for 1 hour, the solvent was removed and the residue was taken up in anhydrous ethanol (35 ml). After addition of concentrated hydrochloric acid (1ml), the mixture was stirred at 50 ℃ for 3 hours and allowed to stand at RT overnight. After removal of the solvent, the residue was taken up in water and freeze-dried. A portion of the crude product was purified by preparative chromatography. The product containing fractions were combined, acetonitrile released and freeze dried. 134mg of the desired compound are obtained.

LCMS-Rt：0.48min[M+H⁺]：171.1

17d) 3-amino-6-ethoxy-1H-imidazo [1, 5-a ] pyridin-5-one as trifluoroacetate salt

C- (5-ethoxy-6-fluoropyridin-2-yl) methylamine trifluoroacetate salt (134mg) was taken up in a small amount of water, treated with 1.5ml of saturated sodium chloride solution, made basic with potassium carbonate (47mg) and the aqueous phase extracted three times with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in anhydrous toluene (8ml) and dissolved with stirring. The mixture was then worked up by dropwise addition of cyanogen bromide solution (0.18ml, 5M in acetonitrile). After 1.5 hours, the solvent was removed and the residue was purified by preparative chromatography. The product containing fractions were combined, acetonitrile released and freeze dried. The freeze-drying with water was repeated three times in the presence of TFA (0.05%). Thereafter, 55mg of the desired compound was obtained.

LCMS-Rt：0.31min [M+H⁺]：194.1

17e) 2-bromo-1- (3-methylamino-5-pentafluorothiophenyl) ethanone

[3- (2-bromo-1, 1-dimethoxyethyl) -5-pentafluorothiophenyl ] methylamine (400mg, prepared as described in example 11f) was suspended in water (4ml) and concentrated sulfuric acid (4ml) was added dropwise with stirring and cooling. After stirring at RT for 4 hours, the batch was poured onto ice water and carefully adjusted to pH 8 with saturated sodium bicarbonate solution. It was then extracted three times with ethyl acetate, and the combined extracts were dried over magnesium sulfate, filtered and concentrated. 312mg of crude product are obtained. 100mg of the total was purified by preparative chromatography. The product-containing fractions were combined, freed from acetonitrile, made basic with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 59mg of the desired compound are obtained.

LCMS-Rt：1.67min [M+H⁺]：353.9；355.9

17f) 6-ethoxy-3-imino-2- [2- (3-methylamino-5-pentafluorothiophenyl) -2-oxoethyl ] -2, 3-dihydro-1H-imidazo [1, 5-a ] pyridin-5-one

3-amino-6-ethoxy-1H-imidazo [1, 5-a ] pyridin-5-one trifluoroacetate salt (25mg) was dissolved in a small amount of water and made basic with saturated sodium bicarbonate solution. The aqueous phase was extracted three times with ethyl acetate, and the combined extracts were dried over sodium sulfate, filtered and concentrated. 14mg of the free base was obtained, which was dissolved in DMF (2.5 ml). To this solution was added dropwise, with stirring, 2-bromo-1- (3-methylamino-5-pentafluorothiophenyl) ethanone (26mg, dissolved in 0.5ml DMF) over the course of 5 minutes. The mixture was stirred at RT for 3 hours and allowed to stand overnight. The solvent was then removed and the crude product was purified by preparative chromatography. The product containing fractions were combined, acetonitrile released and freeze dried. 17mg of the desired compound are obtained.

LCMS-Rt：1.18min [M+H⁺]：467.0

Example 18

2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -6-ethoxy-3-imino-2, 3-dihydro-1H-imidazo [1, 5-a ] pyridin-5-one in the form of the trifluoroacetate salt

In analogy to example 17) 3-amino-6-ethoxy-1H-imidazo [1, 5-a ] pyridin-5-one trifluoroacetate (25mg, example 17) was reacted with 2-bromo-1- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenylethanone (30mg, example 10). 19mg of the title compound are obtained.

LCMS-Rt：1.27min [M+H⁺]：483.2

Example 19

2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -7-ethoxy-3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamide in the form of the trifluoroacetate salt

19a) N- (4-ethoxy-5-methylcarbamoylpyridin-2-ylmethyl) -N' - (fluoren-9-ylmethyl-oxycarbonyl) thiourea

500mg (2.39mmol) of 6-aminomethyl-4-ethoxy-N-methylnicotinamide (example 12f) are dissolved in 25ml of dioxane and treated with 672.4mg (2.39mmol) of fluoren-9-ylmethoxycarbonyl isothiocyanate at RT. After 1 hour, the solvent was removed from the mixture and the residue was taken up in DCM. It was washed three times with aqueous LiCl and once with water. Over MgSO₄After drying, the mixture was concentrated and the crude product thus obtained (875mg) was reacted further without further purification. LCMS-Rt: 1.31min [ M + H⁺]：491.2

19b) (7-ethoxy-6-methylcarbamoyl-2H-imidazo [1, 5-a ] pyridin-3-ylidene) carbamic acid 9H-fluoren-9-ylmethyl ester

875mg of N- (4-ethoxy-5-methylcarbamoylpyridin-2-ylmethyl) -N' - (fluoren-9-ylmethoxycarbonyl) thiourea (example 19a, crude product) were dissolved in 25ml of dioxane and treated with 837mg (1.96mmol) of mercury (II) trifluoroacetate at RT. After 10 min, the mixture was concentrated and the residue was taken up in DCM. The organic phase is washed three times with 4% strength LiCl solution, once with water and once with MgSO₄Dried and concentrated on a rotary evaporator. The crude product thus obtained (590mg) was further reacted without further purification.

LCMS-Rt：1.25min [M+H⁺]：457.2

19c) 2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -7-ethoxy-3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamide in the form of the trifluoroacetate salt

590mg of (7-ethoxy-6-methylcarbamoyl-2H-imidazo [1, 5-a ] pyridin-3-ylidene) carbamic acid 9H-fluoren-9-ylmethyl ester (19b, crude) are dissolved in 25ml of dimethylacetamide and treated with 573mg (1.55mmol) of 2-bromo-1- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) ethanone (prepared according to WO 2004/078721). The solution was stirred at 70 ℃ for 3 hours. After standing overnight at RT, it was stirred for a further 2 hours at 95 ℃. The solvent was then separated off and the crude product was purified twice on preparative HPLC, after which 63.5mg of the title compound could be isolated.

LCMS-Rt (method B): 1.52min [ M + H⁺]：524.2

Example 20

2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -3-imino-5-methoxy-2, 3-dihydroimidazo [1, 5-a ] pyridine-7-carboxylic acid ethyl ester in the form of trifluoroacetate salt

20a) 2-hydroxy-6-methylisonicotinic acid ethyl ester

20.0g (130.6mmol) 2-hydroxy-6-methylisonicotinic acid are dissolved in 200ml ethanol and concentrated H is added in 20ml₂SO₄And (6) processing. After the reaction mixture was refluxed for 2 hours, the solvent was removed therefrom. The residue was taken up in NaHCO₃The solution was taken up and extracted three times with DCM. The combined organic phases were washed with Na₂SO₄Drying and concentration isolated 20.1g of the title compound.

LCMS-Rt：0.82min [M+H⁺]：182.2

20b) 2-methoxy-6-methylisonicotinic acid ethyl ester

20.0g (111.4mmol) of ethyl 2-hydroxy-6-methylisonicotinate (20a) are suspended in 330ml of toluene. After adding 36.54g (132.5mmol) Ag₂CO₃And 23.5g (165.6mmol) of methyl iodide, the mixture is heated to 100 ℃ with KPG stirring. After 4 hours, the reaction mixture was cooled to RT and filtered through celite. The filtrate was washed twice with water and Na₂SO₄Drying and concentration isolated 16.9g of the title compound as a yellowish oil.

LCMS-Rt：1.49min [M+H⁺]：196.2

20c) 2-bromomethyl-6-methoxyisonicotinic acid ethyl ester

16.9g (86.6mmol) of ethyl 2-methoxy-6-methylisonicotinate (19b) are dissolved in carbon tetrachloride and heated to reflux after addition of 16.18g (90.9mmol) of N-bromosuccinimide and 0.28g (1.73mmol) of AIBN. After refluxing for 3 hours and standing overnight at RT, 7.7g (43.3mmol) of N-bromosuccinimide were further added and the mixture was refluxed for 3 hours. After cooling to RT, it was diluted with DCM and saturated NaHCO₃The solution was washed twice, once with water, over MgSO₄Dried and concentrated on a rotary evaporator. The residue was purified on preparative HPLC. The product fractions were freed of acetonitrile under reduced pressure and the aqueous solution was extracted with DCM. The organic phase was washed with MgSO₄Dried and concentrated on a rotary evaporator, 10.95g of the title compound are isolated.

LCMS-Rt：1.65min [M+H⁺]：274.1

20d) 2-aminomethyl-6-methoxyisonicotinic acid ethyl ester

6.72g (47.9mmol) of hexamethylenetetramine (urotropin) are initially introduced into 250ml of chloroform, and a solution of 10.95g (39.95mmol) of ethyl 2-bromomethyl-6-methoxyisonicotinate (20c) in chloroform is added dropwise at 0 ℃. The mixture was stirred at RT for 4.5 hours, after which 3.36g (24.0mmol) of hexamethylenetetramine (urotropin) were added. After standing at RT for a further 60 hours, the solvent was distilled off under reduced pressure and the residue was dissolved in 500ml of ethanol. 50ml of concentrated HCl were added and the mixture was stirred at RT for 2 hours. After addition of a further 30ml of concentrated HCl and stirring overnight at RT, the solvent is removed under reduced pressure. The residue was taken up in DCM and washed with K₂CO₃Care was taken to handle until no more gassing was observed. Subsequently, it is saturated with K₂CO₃The solution is washed twice, and the solution is washed,the organic phase was washed with MgSO₄Dried and concentrated. The crude product thus obtained (7.60g) was further reacted without further purification. LCMS-Rt: 0.74min [ M + H⁺]：211.2

20e) N- (4-ethoxycarbonyl-6-methoxypyridin-2-ylmethyl) -N' - (fluoren-9-ylmethoxycarbonyl) thiourea

6.67g (31.7mmol) ethyl 2-aminomethyl-6-methoxyisonicotinite (20d) are dissolved in 175ml toluene and treated at RT with 8.93g (281.3mmol) fluoren-9-ylmethoxycarbonyl isothiocyanate. After 15 minutes, the precipitate obtained is filtered off and dried at 50 ℃ and 4.6g of the title compound are isolated. The filtrate was concentrated, the residue was taken up in DCM and washed three times with water. The organic phase was washed with MgSO₄Dried and concentrated. The crude product thus obtained is chromatographed on silica gel (heptane/ethyl acetate 90: 10 → 75: 25), 8.1g of the title compound being able to be isolated in turn.

LCMS-Rt：2.21min [M+H⁺]：492.0

20f) 3-imino-5-methoxy-2, 3-dihydroimidazo [1, 5-a ] pyridine-7-carboxylic acid ethyl ester

1.17g (2.38mmol) N- (4-ethoxycarbonyl-6-methoxypyridin-2-ylmethyl) -N' - (fluoren-9-ylmethoxycarbonyl) thiourea (20e) were treated with 491mg (2.38mmol) of DCC in 25ml toluene and refluxed for 6 hours. After standing overnight at RT, the solvent is removed from the mixture and the residue is chromatographed on silica gel (heptane/ethyl acetate 75: 25 → ethyl acetate/methanol 90: 10) to give 88mg of the title compound. LCMS-Rt: 0.81min [ M + H [ ]⁺]：236.2

20g) 2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -3-imino-5-methoxy-2, 3-dihydroimidazo [1, 5-a ] pyridine-7-carboxylic acid ethyl ester in the form of trifluoroacetate salt

88mg (0.37mmol) of ethyl 3-imino-5-methoxy-2, 3-dihydroimidazo [1, 5-a ] pyridine-7-carboxylate (20f) are dissolved in 4ml of dimethylacetamide and treated with a solution of 138.5mg (0.37mmol) of 2-bromo-1- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) ethanone (prepared according to WO 2004/078721) in 2ml of dimethylacetamide. After 24 h at RT, the mixture is freed of the solvent under reduced pressure and the residue is purified by preparative HPLC to isolate 61mg of the title compound.

LCMS-Rt (method B): 1.66min [ M + H⁺]：525.3

Pharmacological examples

PAR1 assay: PAR 1-mediated inhibition of platelet aggregation

Pharmacological testing of the substances was performed in 96-well format plates, with TRAP (thrombin-receptor activating peptide) -induced platelet aggregation. For this purpose, blood from healthy volunteers was sampled into 20ml syringes which had been previously filled with 2ml of 3.13% strength sodium citrate solution. After centrifugation at 150 Xg for 20-minutes, Platelet Rich Plasma (PRP) was separated and treated with 1. mu.l of PGE1 solution (500. mu.g/ml ethanol solution)/ml PRP. After 5min incubation at RT, it was centrifuged at 120 × g for 15 min to remove leukocytes. PRP without leukocytes was transferred in 5 ml/portion batches to 15ml PP tubes and centrifuged at 360 × g for 15 min to pellet platelets. Subsequently, the plasma was decanted and the platelet pellet from 5ml PRP was resuspended in 1ml Tyrode (120mM NaCl, 2.6mM KCl, 12mM NaHCO₃，0.39mM NaH₂PO₄ x H₂O, 10mM HEPES, 0.35% BSA, 5.5mM glucose, pH 7.4) and adjusted to 3X 10 with Tyrode⁵Platelet count per microliter (μ l). 13ml of these cells were then addedThe suspension was diluted with 866. mu.l 10mM CaCl₂Solution treatment, pipetting it into a 96-well plate in an amount of 120. mu.l per well, into the wells of which 96-well plate 15. mu.l of the test substance has been previously added. After incubation at RT for 30 min in the dark, 15. mu.l of TRAP solution (70-100. mu.M) were added as agonist, shaken for 20min at 37 ℃ in SpectraMax 340 and the kinetics recorded at 650 nm. The area under the curve for the negative control (Tyrode/DMSO) and the positive control (15 μ Ι agonist/DMSO) was calculated and the difference was defined as the 100% value. Test substances were pipetted as serial dilutions and assayed in duplicate, and AUC for each substance concentration was also determined, and% AUC inhibition compared to control was calculated. From this% inhibition, IC50 was calculated by non-linear regression analysis according to the 4-parameter equation.

The results are given in table 2.

Table 2:

compounds of the examples	Inhibition of platelet aggregation IC50[μM]	Compounds of the examples	Inhibition of platelet aggregation IC50[μM]
				2	13	12	0.02
3	0.85	18	9.5
				6b	0.73	19	0.9
8	0.51	20	0.07

Claims (11)

1. A compound of formula I

And/or all stereoisomeric or tautomeric forms of the compounds of the formula I and/or mixtures of these forms in any ratio, and/or physiologically tolerable salts of the compounds of the formula I, where R1, R2, R3 and R4 are identical or different and are each independently of the other

1) A hydrogen atom, and a nitrogen atom,

2)-(C₁-C₄) -an alkyl group,

3)-O-(C₁-C₄) -an alkyl group,

4) -C (O) -N (R12) -R13, wherein R12 and R13 are the same or different and are independent of each other

Is a hydrogen atom or- (C)₁-C₄) -an alkyl group,

5)-(C₁-C₃) -a fluoroalkyl group,

6)-C(O)-O-(C₁-C₄) -alkyl or

7)＝O，

8) F, Cl or Br, and (c) in the presence of a catalyst,

r10 is 1) a hydrogen atom,

2)-(C₁-C₄) -an alkyl group,

3)-(C₃-C₆) -cycloalkyl or

4) A phenyl group,

r5, R6, R7, R8 and R9 are identical or different and are each independently of the other

1) A hydrogen atom, and a nitrogen atom,

2)-(C₁-C₃) -a fluoroalkyl group,

3) f, Cl or Br, and (c) in the presence of a catalyst,

4)-O-(C₁-C₄) -an alkyl group,

5)-OH，

6)-(C₁-C₄) -an alkyl group,

7)-SF₅，

8) -N (R12) -R13, wherein R12 and R13 are the same or different and are each independently a hydrogen atom or- (C)₁-C₄) -alkyl, or

9) -Het, wherein Het is selected from morpholinyl or pyrrolidinyl and is unsubstituted or substituted by — (C)₁-C₄) Alkyl is mono-or di-substituted independently of each other, or

R6 and R7 or R7 and R8 form, together with the ring atoms to which they are bonded, a heterocyclic ring selected from 2, 3-dihydro-benzo [1, 4] benzo together with the phenyl ring to which said heterocyclic ring is fused]Dioxins, benzo [1, 3 ]]Dioxoles, 3, 4-dihydro-2H-benzo [1, 4]]Oxazines, 2, 3, 4, 5-tetrahydro-1H-benzo [ b ]]Aza derivativesA bicyclic system of tetrahydroquinoline, tetrahydroisoquinoline, 1, 2, 3, 4-tetrahydroquinoxaline or 6, 7, 8, 9-tetrahydro-5-oxa-9-azabenzocycloheptatriene wherein the heterocyclic moiety is unsubstituted or substituted with- (C)₁-C₄) -alkyl mono-or di-substituted.

2. The compound of claim 1, which is a compound

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) ethanone,

2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) -1- (3-pentafluorothiophenyl) ethanone,

2- (1-cyclopropyl-3-iminoimidazo [1, 5-a ] pyridin-2-yl) -1- (3, 5-di-tert-butyl-4-hydroxyphenyl) ethanone,

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-1-phenylimidazo [1, 5-a ] pyridin-2-yl) ethanone,

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-8-methylimidazo [1, 5-a ] pyridin-2-yl) ethanone,

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-8-methylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the hydrobromide salt,

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-7-trifluoromethylimidazo [1, 5-a ] pyridin-2-yl) ethanone,

1- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2- (3-imino-7-trifluoromethylimidazo [1, 5-a ] pyridin-2-yl) ethanone in the form of the hydrobromide salt,

2- [2- (3, 5-di-tert-butyl-4-hydroxyphenyl) -2-oxoethyl ] -3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methyl ester,

2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methyl ester,

1- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) ethanone,

1- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2- (3-imino-8-methylimidazo [1, 5-a ] pyridin-2-yl) ethanone,

1- (3-dimethylamino-5-pentafluorothiophenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) ethanone,

2- [2- (8-tert-butyl-4-methyl-3, 4-dihydro-2H-benzo [1, 4]]Oxazin-6-yl) -2-oxoethyl]-7-ethoxy-3-imino-2, 3-dihydroimidazo [1, 5-a]Pyridine-6-carboxylic acid methyl amide,

2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -7-chloro-3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamide,

1- (3-bromo-4-methoxy-5-trifluoromethylphenyl) -2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) -ethanone in the form of the trifluoroacetate salt,

2- (3-iminoimidazo [1, 5-a ] pyridin-2-yl) -1- (4-methoxy-3-morpholin-4-yl-5-trifluoromethylphenyl) ethanone in the form of the trifluoroacetate salt,

6-ethoxy-3-imino-2- [2- (3-methylamino-5-pentafluorothiophenyl) -2-oxoethyl ] -2, 3-dihydro-1H-imidazo [1, 5-a ] pyridin-5-one in the form of the trifluoroacetate salt,

2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -6-ethoxy-3-imino-2, 3-dihydro-1H-imidazo [1, 5-a ] pyridin-5-one in the form of the trifluoroacetate salt,

2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -7-ethoxy-3-imino-2, 3-dihydroimidazo [1, 5-a ] pyridine-6-carboxylic acid methylamide in the form of the trifluoroacetate salt or ethyl 2- [2- (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2-oxoethyl ] -3-imino-5-methoxy-2, 3-dihydroimidazo [1, 5-a ] pyridine-7-carboxylate in the form of the trifluoroacetate salt.

3. A medicament comprising an effective amount of at least one compound of the formula I as claimed in any of claims 1 to 2 and pharmaceutically suitable and physiologically tolerable bases, additives and/or further active ingredients.

4. A medicament according to claim 3, which comprises an effective amount of at least one compound of the formula I as claimed in any of claims 1 to 2 and also excipients and/or further active ingredients.

5. The use of a compound of the formula I as claimed in any of claims 1 to 2 for the preparation of medicaments for the prophylaxis, secondary prophylaxis and therapy of all diseases which are accompanied by thrombosis, embolism, hypercoagulability or fibrotic changes.

6. Use as claimed in claim 5, which comprises myocardial infarction, angina and other forms of acute coronary syndrome, stroke, peripheral vascular disorders, deep vein thrombosis, pulmonary embolism, embolism or thrombotic events resulting from cardiac arrhythmias, cardiovascular events, or thrombosis that reduces the risk of surgical intervention or dry prognosis leading to blood contact with foreign surfaces, or disseminated intravascular coagulation, sepsis and other intravascular events with inflammation, atherosclerosis, diabetes and metabolic syndrome and their sequelae, tumor growth and metastasis, inflammatory and degenerative joint disorders, disorders of the haemostatic system, fibrotic changes of the lung, adult respiratory distress syndrome or fibrin deposition in the eye following eye surgery, or prevention and/or treatment of scarring.

7. The use as claimed in claim 5, which comprises revascularization and angioplasty and restenosis after dry surgery, reducing the risk of thrombosis after knee and hip surgery, reducing the risk of thrombosis in dry prognosis leading to blood contact with foreign surfaces in dialysis patients and patients with indwelling catheters, rheumatoid arthritis and joint diseases, fibrin deposition, chronic obstructive pulmonary disease.

8. The use as claimed in claim 5, which includes restenosis following stent implantation and bypass surgery.

9. A process for the preparation of a compound of formula I as claimed in any of claims 1 to 2, which comprises

a) Reacting a compound of formula II with a compound of formula III in the presence of a base and a solvent to obtain a compound of formula I,

the compound of the formula II is

Wherein the groups R5, R6, R7, R8 and R9 are as defined for formula I, Y is chloro, bromo, mesylate or tosylate,

the compound of the formula III is

Or

b) Reacting a compound of formula VII with a compound Z-CN wherein Z is tosylate or bromine in the presence of a base to give a compound of formula I,

the compound of the formula VII is

Wherein the radicals R1 to R10 are as defined for formula I, or

c) The compounds of the formula I prepared according to process a) or b) are isolated in free form or are released from physiologically tolerable salts or, in the presence of acidic or basic groups, are converted into physiologically tolerable salts or

d) The compounds of the formula I prepared in enantiomeric or diastereomeric form as a result of their chemical structure, or suitable precursors of the compounds of the formula I, prepared according to process a) or b), are separated into the pure enantiomers or diastereomers by salt formation with an enantiomerically pure acid or base, chromatography on a chiral stationary phase or derivatization with an enantiomerically pure chiral compound, separation of the diastereomers thus obtained, and cleavage of the chiral auxiliary group.

10. The method of claim 9, wherein the chiral compound is an amino acid.

11. A process for the preparation of a compound of formula VII as claimed in claim 9 wherein a compound of formula VIII is reacted with a compound of formula IX in the presence of a base and a solvent to give a compound of formula I:

wherein the groups R1, R2, R3, R4 and R10 are as defined for formula I, Y is chloro, bromo, mesylate or tosylate,

the compound of formula IX is: