PYRAZINE COMPOUNDS, THEIR USE AND METHODS OF PREPARATION

• US 20100210627A1
• Filed: 08/15/2007
• Published: 08/19/2010
• Est. Priority Date: 08/16/2006
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Prokopowicz, Anthony S. III, Morwick, Tina Marie, Mao, Wang
• Granted Patent: US 8,318,723 B2
• Time in Patent Office: Days
• US Class Current: 514/217.50
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/08 : Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 241/20 : Nitrogen atoms nitro radicals C07D241/16
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond

Abstract

The invention provides compounds according to formula (I)

their use and methods for preparation wherein A, X, Y, R1, R2 and R3 are defined herein. The compounds of the invention inhibit specific serine/threonine kinases involved in inflammatory processes and aberrant cell proliferation, and are thus useful for treating associated diseases and pathological conditions such as Pim kinase-mediated diseases and pathological conditions involving inflammation, including Chron'"'"'s disease, inflammatory bowel disease, rheumatoid arthritis, and chronic inflammatory disease, or aberrant cell proliferation including various cancers.

Claims

1. A compound of formula (I)

wherein:

X is C or N

Y is C or N

R1 is Hydrogen, C1-C3 alkyl,

R2 is Hydrogen, C1-C5 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, each optionally independently substituted with 1-3 R4, wherein R4 is selected from C1-C5 alkyl, C1-C5 alkoxy, carboxamido, acyl, benzyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, hydroxyl and amino optionally mono or disubstituted with C1-C4 alkyl;

wherein each R4 is optionally independently substituted with 1-3 substituents selected from C1-C5 alkyl, C1-C5 alkoxy, acyl, benzyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, hydroxyl and amino optionally mono or disubstituted with C1-C4 alkyl or;

wherein R1 and R2 together with the nitrogen atom to which they are attached form a C3-C8 ring containing 1-3 heteroatoms and which is optionally substituted by 1-3 R5, wherein R5 is selected from C1-C5 alkyl, C1-C5 alkoxy, carboxamido, acyl, benzyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, hydroxyl, and amino optionally mono or disubstituted with C1-C4 alkyl;

wherein each R5 is optionally independently substituted by with substituents selected from hydroxyl, C1-C5 alkoxy, or amino optionally mono or disubstituted with C1-C4 alkyl;

R3 is

or a pharmaceutically acceptable salts thereof.

2. A compound according to formula (I) of claim 1 wherein:

X is C or N

Y is C or N

R1 is Hydrogen, C1-C3 alkyl

R2 is C1-C5 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, each optionally independently substituted with 1-3 R4, wherein R4 is selected from C1-C5 alkyl, C1-C5 alkoxy, carboxamido, benzyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, hydroxyl and amino optionally mono or disubstituted with C1-C4 alkyl;

wherein each R4 is optionally independently substituted with 1-3 substituents selected from C1-C5 alkyl, C1-C5 alkoxy, acyl, benzyl, hydroxyl and amino optionally mono or disubstituted with C1-C4 alkyl

or;

wherein R1 and R2 together with the nitrogen atom to which they are attached form a C3-C8 ring containing 1-3 heteroatoms and which is optionally substituted by 1-3 R5, wherein R5 is selected from C1-C5 alkyl, C1-C5 alkoxy, carboxamido, acyl, benzyl, hydroxyl and amino optionally mono or disubstituted with C1-C4 alkyl;

wherein each R5 is optionally independently substituted with substituents selected from hydroxyl, C1-C5 alkoxy, or amino optionally mono or disubstituted with C1-C4 alkyl

R3 is

or a pharmaceutically acceptable salt thereof.

3. A compound according to formula (I) of claim 1 wherein:

X is C

Y is C or N

R1 is Hydrogen, C1-C3 alkyl

R2 is C1-C5 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, each optionally independently substituted with 1-3 R4, wherein R4 is selected from C1-C5 alkyl, C1-C5 alkoxy, carboxamido, benzyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, hydroxyl and amino optionally mono or disubstituted with C1-C4 alkyl;

wherein each R4 is optionally independently substituted with 1-3 substituents selected from C1-C5 alkyl, C1-C5 alkoxy, benzyl, hydroxyl and amino optionally mono or disubstituted with C1-C4 alkyl

or;

wherein R1 and R2 together with the nitrogen atom to which they are attached form a C3-C8 ring containing 1-3 heteroatoms and which is optionally substituted by 1-3 R5, wherein R5 is selected from C1-C5 alkyl, C1-C5 alkoxy, carboxamido, benzyl, hydroxyl and amino optionally mono or disubstituted with C1-C4 alkyl;

wherein each R5 is optionally independently substituted with substituents selected from hydroxyl, C1-C5 alkoxy, or amino optionally mono or disubstituted with C1-C4 alkyl

R3 is

or a pharmaceutically acceptable salts thereof.

4. A compound according to formula (I) of claim 1 wherein:

X is C

Y is C or N

R1 is Hydrogen, C1-C3 alkyl R2 is C1-C5 alkyl, C3-C8 cycloalkyl, each optionally independently substituted with 1-3 R4, wherein R4 is selected from carboxamido, C3-C8 heterocycloalkyl, hydroxyl and amino optionally mono or disubstituted with C1-C4 alkyl;

or;

wherein R1 and R2 together with the nitrogen atom to which they are attached form a C3-C8 ring containing 1-3 heteroatoms and which is optionally substituted by 1-3 R5, wherein R5 is selected from C1-C3 alkyl, benzyl and amino optionally mono or disubstituted with C1-C4 alkyl;

wherein each R5 is optionally independently substituted with amino optionally mono or disubstituted with C1-C4 alkyl

R3 is

5. A method of treating PIM mediated diseases and pathological conditions said method comprised of the step of administering to a patient in need thereof a therapeutic amount of a compound according to claim 1 of a pharmaceutically acceptable salt thereof

6. The method of claim 5 wherein said PIM mediated disease or condition is selected from the group consisting of inflammation osteoarthritis, Guillain-Barre syndrome, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer disease, acute and chronic pain, atherosclerosis, reperfusion injury, bone resorption diseases, congestive heart failure, myocardial infarction, thermal injury, multiple organ injury secondary to trauma, acute purulent meningitis, necrotizing enterocolitis, and syndromes associated with hemodialysis, leukopheresis, and granulocyte transfusion.

7. The method of claim 5 wherein the PIM mediated disease or condition is inflammation.

8. The method of claim 5 wherein the PIM mediated disease or pathological condition is cancer.

9. The method of claim 8 wherein the cancer is selected from the list consisting of prostate, chronic lymphocytic leukemia and non-Hodgkin'"'"'s lymphoma and multiple myeloma.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1.

11. A process for preparing a compound according to claim 1 wherein said process is comprised of the steps of

combining a 2,6-dichloropyrazine or 2,6-dichloropyridine (II) with an amine in a suitable solvent to form a product (IV);

b) treating product (IV) with a reagent (V) and additional reagents required for Suzuki coupling to provide product (I)

c) modifying R₁ or R₂, such as by protection/deprotection.

wherein (X═

C, Y═

N, C).

15. Use of a composition according to claim 1 for the treatment of a PIM mediated disease or condition in a mammal having or at risk of having the infection

12. A compound chosen from:

Cpd # Structure name 1 (E)-3-{3-[6-(4-Amino-cyclohexylamino)-pyrazin-2- yl]-phenyl}-acrylic acid 2 (E)-3-{3-[6-(4-Amino-cyclohexylamino)-pyrazin-2- yl]-phenyl}-acrylic acid 3 (E)-3-{3-[6-(4-Hydroxy-cyclohexylamino)-pyrazin- 2-yl]-phenyl}-acrylic acid 4 (E)-3-(3-{6-[(Piperidin-4-ylmethyl)-amino]-pyrazin- 2-yl}-phenyl)-acrylic acid 5 (E)-3-{3-[6-(4-Amino-butylamino)-pyrazin-2-yl]- phenyl}-acrylic acid 6 (E)-3-{3-[6-(3-Amino-propylamino)-pyrazin-2-yl]- phenyl}-acrylic acid 7 (E)-3-{3-[6-(3-Amino-2,2-dimethyl-propylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 8 (E)-3-{3-[6-(3-Dimethylamino-propylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 9 (E)-3-{3-[6-(2-Dimethylamino-ethylamino)-pyrazin- 2-yl]-phenyl}-acrylic acid 10 (E)-3-(3-{6-[Methyl-(3-methylamino-propyl)- amino]-pyrazin-2-yl}-phenyl)-acrylic acid 11 (E)-3-{3-[6-(3-Ethylamino-propylamino)-pyrazin-2- yl]-phenyl}-acrylic acid 12 (E)-3-{3-[6-(2-Amino-ethylamino)-pyrazin-2-yl]- phenyl}-acrylic acid 13 (E)-3-(3-{6-[Methyl-(2-methylamino-ethyl)-amino]- pyrazin-2-yl}-phenyl)-acrylic acid 14 (E)-3-(3-{6-[(3-Dimethylamino-propyl)-methyl- amino]-pyrazin-2-yl}-phenyl)-acrylic acid 15 (E)-3-{3-[6-(Carbamoylmethyl-amino)-pyrazin-2- yl]-phenyl}-acrylic acid 16 (E)-3-{3-[6-(2-Carbamoyl-ethylamino)-pyrazin-2- yl]-phenyl}-acrylic acid;

MS, electrospray 17 (E)-3-{3-[6-(2-Hydroxy-ethylamino)-pyrazin-2-yl]- phenyl}-acrylic acid 18 E)-3-{3-[6-(3-Hydroxy-propylamino)-pyrazin-2-yl]- phenyl}-acrylic acid 19 (E)-3-{3-[6-(3-Methoxy-propylamino)-pyrazin-2-yl]- phenyl}-acrylic acid 20 (E)-3-{3-[6-(2-Methoxy-ethylamino)-pyrazin-2-yl]- phenyl}-acrylic acid 21 (E)-3-{3-[6-(2-Acetylamino-ethylamino)-pyrazin-2- yl]-phenyl}-acrylic acid 22 (E)-3-{3-[6-(4-Aminomethyl-piperidin-1-yl)-pyrazin- 2-yl]-phenyl}-acrylic acid 23 (E)-3-{3-[6-(4-Methyl-[1,4]diazepan-1-yl)-pyrazin- 2-yl]-phenyl}-acrylic acid 24 (E)-3-{3-[6-(4-Dimethylamino-piperidin-1-yl)- pyrazin-2-yl]-phenyl}-acrylic acid 25 Preparation of 14 (E)-3-{3-[6-(4-Amino-piperidin- 1-yl)-pyrazin-2-yl]-phenyl}-acrylic acid 26 (E)-3-[3-(4-Methyl-3,4,5,6-tetrahydro-2H- [1,2′

]bipyrazinyl-6′

-yl)-phenyl]-acrylic acid 27 (E)-3-[3-(6-[1,4]Diazepan-1-yl-pyrazin-2-yl)- phenyl]-acrylic acid 28 (E)-3-[3-(3,4,5,6-Tetrahydro-2H-[1,2′

]bipyrazinyl- 6′

-yl)-phenyl]-acrylic acid 29 (E)-3-{3-[6-(4-Benzyl-[1,4]diazepan-1-yl)-pyrazin- 2-yl]-phenyl}-acrylic acid 30 (E)-3-{3-[6-(3-Dimethylamino-pyrrolidin-1-yl)- pyrazin-2-yl]-phenyl}-acrylic acid 31 (E)-3-{3-[6-(4-Acetyl-[1,4]diazepan-1-yl)-pyrazin-2- yl]-phenyl}-acrylic acid 32 (E)-3-{3-[6-(4-Hydroxy-piperidin-1-yl)-pyrazin-2- yl]-phenyl}-acrylic acid 33 (E)-3-{3-[6-(4-Hydroxymethyl-piperidin-1-yl)- pyrazin-2-yl]-phenyl}-acrylic acid 34 (E)-3-[3-(6-Morpholin-4-yl-pyrazin-2-yl)-phenyl]- acrylic acid 35 (E)-3-[3-(6-Azepan-1-yl-pyrazin-2-yl)-phenyl]- acrylic acid 36 (E)-3-{3-[6-(4-Methyl-[1,4]diazepan- 1-yl)-pyridin-2- yl]-phenyl}-acrylic acid 37 (E)-3-{5-[6-(4-Methyl-[1,4]diazepan-1-yl)-pyrazin- 2-yl]-pyridin-3-yl}-acrylic acid 38 3-{3-[6-(4-Methyl-[1,4]diazepam-1-yl)-pyrazin-2- yl]-phenyl}-propionic acid 39 (E)-3-{3-[6-(4-Methyl-[1,4]diazepan-1-yl)-pyrazin- 2-yl]-phenyl}-acrylic acid methyl ester 40 (E)-3-{3-[6-(4-Methyl-[1,4]diazepan-1-yl)-pyrazin- 2-yl]-phenyl}-acrylamide 41 (E)-3-{3-[6-(4-Methyl-[1,4]diazepan-1-yl)-pyrazin- 2-yl]-phenyl}-prop-2-en-1-ol 42 (E)-3-{3-[6-(4-Methyl-[1,4]diazepan-1-yl)-pyrazin- 2-yl]-phenyl}-acrylonitrile 43 1-Methyl-4-(6-{3-[(E)-2-(1H-tetrazol-5-yl)-vinyl]- phenyl}-pyrazin-2-yl)-[1,4]diazepane 44 N-((E)-3-{3-[6-(4-Methyl-perhydro-1,4-diazepin-1- yl)-pyrazin-2-yl]-phenyl}-acryloyl)- methanesulfonamide 45 (E)-N-(2-Hydroxy-ethyl)-3-{3-[6-(4-methyl- perhydro-1,4-diazepin-1-yl)-pyrazin-2-yl]-phenyl}- acrylamide 46 (E)-3-{3-[6-(4-Amino-cyclohexylamino)-pyridin-2- yl]-phenyl}-acrylic acid 47 (E)-3-[3-(4-Aminomethyl-3,4,5,6-tetrahydro-2H- [1,2′

]bipyridinyl-6′

-yl)-phenyl]-acrylic acid 48 (E)-3-(3-{6-[Methyl-(3-methylamino-propyl)- amino]-pyridin-2-yl}-phenyl)-acrylic acid 49 (E)-3-(3-{6-[Methyl-(2-methylamino-ethyl)-amino]- pyridin-2-yl}-phenyl)-acrylic acid 50 (E)-3-[3-(4-Dimethylamino-3,4,5,6-tetrahydro-2H- [1,2′

]bipyridinyl-6′

-yl)-phenyl]-acrylic acid 51 (E)-3-{3-[6-(2-Amino-ethylamino)-pyridin-2-yl]- phenyl}-acrylic acid 52 (E)-3-{3-[6-(3-Dimethylamino-propylamino)- pyridin-2-yl]-phenyl}-acrylic acid 53 (E)-3-{3-[6-(4-Amino-butylamino)-pyridin-2-yl]- phenyl}-acrylic acid 54 (E)-3-{3-[6-(4-Methyl-piperazin-1-yl)-pyridin-2-yl]- phenyl}-acrylic acid 55 (E)-3-{3-[6-(4-Amino-cyclohexylamino)-pyridin-2- yl]-phenyl}-acrylic acid 56 (E)-3-[3-(6-[1,4]Diazepan-1-yl-pyridin-2-yl)- phenyl]-acrylic acid 57 (E)-3-{3-[6-(3-Dimethylamino-propylamino)- pyridin-2-yl]-phenyl}-acrylic acid 58 (E)-3-{3-[6-(Carbamoylmethyl-amino)-pyridin-2-yl]- phenyl}-acrylic acid 59 (E)-3-{3-[6-(3-Amino-2,2-dimethyl-propylamino)- pyridin-2-yl]-phenyl}-acrylic acid 60 (E)-3-{3-[6-(3-Amino-propylamino)-pyridin-2-yl]- phenyl}-acrylic acid 61 (E)-3-(3-{6-[(Piperidin-4-ylmethyl)-amino]-pyridin- 2-yl}-phenyl)-acrylic acid 62 (E)-3-{3-[6-(4-Hydroxy-cyclohexylamino)-pyridin- 2-yl]-phenyl}-acrylic acid 63 (E)-3-[3-(6-Morpholin-4-yl-pyridin-2-yl)-phenyl]- acrylic acid 64 (E)-3-{3-[6-(4-Hydroxy-cyclohexylamino)-pyridin- 2-yl]-phenyl}-acrylic acid 65 (E)-3-{3-[6-(2-Methoxy-ethylamino)-pyridin-2-yl]- phenyl}-acrylic acid 66 (E)-3-[3-(4-Hydroxymethyl-3,4,5,6-tetrahydro-2H- [1,2′

]bipyridinyl-6′

-yl)-phenyl]-acrylic acid 67 (E)-3-{5-[6-(4-Aminomethyl-piperidin-1-yl)-pyrazin- 2-yl]-pyridin-3-yl}-acrylic acid 68 (E)-3-[5-(6-[1,4]Diazepan-1-yl-pyrazin-2-yl)- pyridin-3-yl]-acrylic acid 69 (E)-3-{5-[6-(4-Amino-butylamino)-pyrazin-2-yl]- pyridin-3-yl}-acrylic acid 70 (E)-3-{5-[6-(3-Amino-2,2-dimethyl-propylamino)- pyrazin-2-yl]-pyridin-3-yl}-acrylic acid 71 (E)-3-{5-[6-(4-Amino-cyclohexylamino)-pyrazin-2- yl]-pyridin-3-yl}-acrylic acid 72 (E)-3-{5-[6-(3-Amino-propylamino)-pyrazin-2-yl]- pyridin-3-yl}-acrylic acid 73 (E)-3-(5-{6-[(Piperidin-4-ylmethyl)-amino]-pyrazin- 2-yl}-pyridin-3-yl)-acrylic acid 74 (E)-3-{5-[6-(Carbamoylmethyl-amino)-pyrazin-2- yl]-pyridin-3-yl}-acrylic acid 75 (E)-3-[6-(4-Amino-cyclohexylamino)- [2,3′

]bipyridinyl-5′

-yl]-acrylic acid 76 (E)-3-[6-(4-Amino-butylamino)-[2,3′

]bipyridinyl-5′

- yl]-acrylic acid 77 (E)-3-[6-(4-Methyl-[1,4]diazepan-1-yl)- [2,3′

]bipyridinyl-5′

-yl]-acrylic acid 78 (E)-3-(4-Aminomethyl-3,4,5,6-tetrahydro-2H- [1,2′

;

6′

,3″

]terpyridin-5″

-yl)-acrylic acid 79 (E)-3-[6-(Carbamoylmethyl-amino)- [2,3′

]bipyridinyl-5′

-yl]-acrylic acid 80 3-{3-[6-(4-Amino-cyclohexylamino)-pyrazin-2-yl]- phenyl}-propionic acid 81 3-{3-[6-(4-Amino-cyclohexylamino)-pyrazin-2-yl]- phenyl}-propionic acid 82 3-(3-{6-[(Piperidin-4-ylmethyl)-amino]-pyrazin-2- yl}-phenyl)-propionic acid 83 3-{3-[6-(4-Dimethylamino-piperidin-1-yl)-pyrazin-2- yl]-phenyl}-propionic acid 84 (E)-3-{3-[6-(4-Carbamoyl-piperidin-1-yl)-pyrazin-2- yl]-phenyl}-acrylic acid 85 (E)-3-{3-[6-(4-Methoxy-piperidin-1-yl)-pyrazin-2- yl]-phenyl}-acrylic acid 86 (E)-3-(3-{6-[(1-Methyl-piperidin-4-ylmethyl)- amino]-pyrazin-2-yl}-phenyl)-acrylic acid 87 (E)-3-{3-[6-(Piperidin-4-ylamino)-pyrazin-2-yl]- phenyl}-acrylic acid 88 (E)-3-{3-[6-(1-Methyl-piperidin-4-ylamino)-pyrazin- 2-yl]-phenyl}-acrylic acid 89 (E)-3-{3-[6-(1-Benzyl-piperidin-4-ylamino)-pyrazin- 2-yl]-phenyl}-acrylic acid 90 (E)-3-{3-[6-(1-Acetyl-piperidin-4-ylamino)-pyrazin- 2-yl]-phenyl}-acrylic acid 91 (E)-3-{3-[6-(4-Acetylamino-cyclohexylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 92 N-(6-{3-[(E)-2-(1H-Tetrazol-5-yl)-vinyl]-phenyl}- pyrazin-2-yl)-cyclohexane-1,4-diamine 93 4-(6-{3-[(E)-2-(1H-tetrazol-5-yl)-vinyl]-phenyl}- pyrazin-2-yl)-[1,4]diazepane 94 N,N,N′

-Trimethyl-N′

-(6-{3-[(E)-2-(1H-tetrazol-5-yl)- vinyl]-phenyl}-pyrazin-2-yl)-propane-1,3-diamine 95 N¹-(6-{3-[(E)-2-(1H-Tetrazol-5-yl)-vinyl]-phenyl}- pyrazin-2-yl)-propane-1,3-diamine 96 1-Methyl-4-(6-{3-[(E)-2-(1H-tetrazol-5-yl)-vinyl]- phenyl}-pyridin-2-yl)-perhydro-1,4-diazepine 97 N-(6-{3-[(E)-2-(1H-Tetrazol-5-yl)-vinyl]-phenyl}- pyridin-2-yl)-cyclohexane-1,4-diamine 98 Piperidin-4-ylmethyl-(6-{3-[(E)-2-(1H-tetrazol-5-yl)- vinyl]-phenyl}-pyridin-2-yl)-amine

or the pharmaceutically acceptable salts thereof.

13. A compound of claim 12 chosen from

Cpd # Structure name 1 (E)-3-{3-[6-(4-Amino-cyclohexylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 2 (E)-3-{3-[6-(4-Amino-cyclohexylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 3 (E)-3-{3-[6-(4-Hydroxy-cyclohexylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 4 (E)-3-(3-{6-[(Piperidin-4-ylmethyl)-amino]- pyrazin-2-yl}-phenyl)-acrylic acid 5 (E)-3-{3-[6-(4-Amino-butylamino)-pyrazin- 2-yl]-phenyl}-acrylic acid 6 (E)-3-{3-[6-(3-Amino-propylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 7 (E)-3-{3-[6-(3-Amino-2,2-dimethyl- propylamino)-pyrazin-2-yl]-phenyl}-acrylic acid 8 (E)-3-{3-[6-(3-Dimethylamino- propylamino)-pyrazin-2-yl]-phenyl}-acrylic acid 9 (E)-3-{3-[6-(2-Dimethylamino-ethylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 10 (E)-3-(3-{6-[Methyl-(3-methylamino- propyl)-amino]-pyrazin-2-yl}-phenyl)- acrylic acid 11 (E)-3-{3-[6-(3-Ethylamino-propylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 12 (E)-3-{3-[6-(2-Amino-ethylamino)-pyrazin- 2-yl]-phenyl}-acrylic acid 13 (E)-3-(3-{6-[Methyl-(2-methylamino-ethyl)- amino]-pyrazin-2-yl}-phenyl)-acrylic acid 14 (E)-3-(3-{6-[(3-Dimethylamino-propyl)- methyl-amino]-pyrazin-2-yl}-phenyl)- acrylic acid 15 (E)-3-{3-[6-(Carbamoylmethyl-amino)- pyrazin-2-yl]-phenyl}-acrylic acid 16 (E)-3-{3-[6-(2-Carbamoyl-ethylamino)- pyrazin-2-yl]-phenyl}-acrylic acid; MS, electrospray 17 (E)-3-{3-[6-(2-Hydroxy-ethylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 18 E)-3-{3-[6-(3-Hydroxy-propylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 19 (E)-3-{3-[6-(3-Methoxy-propylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 20 (E)-3-{3-[6-(2-Methoxy-ethylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 21 (E)-3-{3-[6-(2-Acetylamino-ethylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 22 (E)-3-{3-[6-(4-Aminomethyl-piperidin-1-yl)- pyrazin-2-yl]-phenyl}-acrylic acid 23 (E)-3-{3-[6-(4-Methyl-[1,4]diazepan-1-yl)- pyrazin-2-yl]-phenyl}-acrylic acid 24 (E)-3-{3-[6-(4-Dimethylamino-piperidin-1- yl)-pyrazin-2-yl]-phenyl}-acrylic acid 25 Preparation of 14 (E)-3-{3-[6-(4-Amino- piperidin-1-yl)-pyrazin-2-yl]-phenyl}-acrylic acid 26 (E)-3-[3-(4-Methyl-3,4,5,6-tetrahydro-2H- [1,2′

]bipyrazinyl-6′

-yl)-phenyl]-acrylic acid 27 (E)-3-[3-(6-[1,4]Diazepan-1-yl-pyrazin-2- yl)-phenyl]-acrylic acid 28 (E)-3-[3-(3,4,5,6-Tetrahydro-2H- [1,2′

]bipyrazinyl-6′

-yl)-phenyl]-acrylic acid 29 (E)-3-{3-[6-(4-Benzyl-[1,4]diazepan-1-yl)- pyrazin-2-yl]-phenyl}-acrylic acid 30 (E)-3-{3-[6-(3-Dimethylamino-pyrrolidin-1- yl)-pyrazin-2-yl]-phenyl}-acrylic acid 31 (E)-3-{3-[6-(4-Acetyl-[1,4]diazepan-1-yl)- pyrazin-2-yl]-phenyl}-acrylic acid 32 (E)-3-{3-[6-(4-Hydroxy-piperidin-1-yl)- pyrazin-2-yl]-phenyl}-acrylic acid 33 (E)-3-{3-[6-(4-Hydroxymethyl-piperidin-1- yl)-pyrazin-2-yl]-phenyl}-acrylic acid 34 (E)-3-[3-(6-Morpholin-4-yl-pyrazin-2-yl)- phenyl]-acrylic acid 35 (E)-3-[3-(6-Azepan-1-yl-pyrazin-2-yl)- phenyl]-acrylic acid 36 (E)-3-{3-[6-(4-Methyl-[1,4]diazepan-1-yl)- pyridin-2-yl]-phenyl}-acrylic acid 37 (E)-3-{5-[6-(4-Methyl-[1,4]diazepan-1-yl)- pyrazin-2-yl]-pyridin-3-yl}-acrylic acid 38 3-{3-[6-(4-Methyl-[1,4]diazepam-1-yl)- pyrazin-2-yl]-phenyl}-propionic acid 39 (E)-3-{3-[6-(4-Methyl-[1,4]diazepan-1-yl)- pyrazin-2-yl]-phenyl}-acrylic acid methyl ester 40 (E)-3-{3-[6-(4-Methyl-[1,4]diazepan-1-yl)- pyrazin-2-yl]-phenyl}-acrylamide 41 (E)-3-{3-[6-(4-Methyl-[1,4]diazepan-1-yl)- pyrazin-2-yl]-phenyl}-prop-2-en-1-ol 42 (E)-3-{3-[6-(4-Methyl-[1,4]diazepan-1-yl)- pyrazin-2-yl]-phenyl}-acrylonitrile 43 1-Methyl-4-(6-{3-[(E)-2-(1H-tetrazol-5-yl)- vinyl]-phenyl}-pyrazin-2-yl)-[1,4]diazepane 44 N-((E)-3-{3-[6-(4-Methyl-perhydro-1,4- diazepin-1-yl)-pyrazin-2-yl]-phenyl}- acryloyl)-methanesulfonamide 45 (E)-N-(2-Hydroxy-ethyl)-3-{3-[6-(4-methyl- perhydro-1,4-diazepin-1-yl)-pyrazin-2-yl]- phenyl}-acrylamide

or the pharmaceutically acceptable salts thereof.

14. A compound according to claim 13 chosen from:

Cpd # Structure name 1 (E)-3-{3-[6-(4-Amino-cyclohexylamino)-pyrazin-2- yl]-phenyl}-acrylic acid 2 (E)-3-{3-[6-(4-Amino-cyclohexylamino)-pyrazin-2- yl]-phenyl}-acrylic acid 3 (E)-3-{3-[6-(4-Hydroxy-cyclohexylamino)-pyrazin- 2-yl]-phenyl}-acrylic acid 4 (E)-3-(3-{6-[(Piperidin-4-ylmethyl)-amino]-pyrazin- 2-yl}-phenyl)-acrylic acid 5 (E)-3-{3-[6-(4-Amino-butylamino)-pyrazin-2-yl]- phenyl}-acrylic acid 6 (E)-3-{3-[6-(3-Amino-propylamino)-pyrazin-2-yl]- phenyl}-acrylic acid 7 (E)-3-{3-[6-(3-Amino-2,2-dimethyl-propylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 8 (E)-3-{3-[6-(3-Dimethylamino-propylamino)- pyrazin-2-yl]-phenyl}-acrylic acid 9 (E)-3-{3-[6-(2-Dimethylamino-ethylamino)-pyrazin- 2-yl]-phenyl}-acrylic acid 10 (E)-3-(3-{6-[Methyl-(3-methylamino-propyl)- amino]-pyrazin-2-yl}-phenyl)-acrylic acid 11 (E)-3-{3-[6-(3-Ethylamino-propylamino)-pyrazin-2- yl]-phenyl}-acrylic acid 12 (E)-3-{3-[6-(2-Amino-ethylamino)-pyrazin-2-yl]- phenyl}-acrylic acid 13 (E)-3-(3-{6-[Methyl-(2-methylamino-ethyl)-amino]- pyrazin-2-yl}-phenyl)-acrylic acid 15 (E)-3-{3-[6-(Carbamoylmethyl-amino)-pyrazin-2- yl]-phenyl}-acrylic acid 16 (E)-3-{3-[6-(2-Carbamoyl-ethylamino)-pyrazin-2- yl]-phenyl}-acrylic acid;

MS, electrospray 22 (E)-3-{3-[6-(4-Aminomethyl-piperidin-1-yl)-pyrazin- 2-yl]-phenyl}-acrylic acid 23 (E)-3-{3-[6-(4-Methyl-[1,4]diazepan-1-yl)-pyrazin- 2-yl]-phenyl}-acrylic acid 24 (E)-3-{3-[6-(4-Dimethylamino-piperidin-1-yl)- pyrazin-2-yl]-phenyl}-acrylic acid 25 Preparation of 14 (E)-3-{3-[6-(4-Amino-piperidin- 1-yl)-pyrazin-2-yl]-phenyl}-acrylic acid 26 (E)-3-[3-(4-Methyl-3,4,5,6-tetrahydro-2H- [1,2′

]bipyrazinyl-6′

-yl)-phenyl]-acrylic acid 27 (E)-3-[3-(6-[1,4]Diazepan-1-yl-pyrazin-2-yl)- phenyl]-acrylic acid 28 (E)-3-[3-(3,4,5,6-Tetrahydro-2H-[1,2′

]bipyrazinyl- 6′

-yl)-phenyl]-acrylic acid 29 (E)-3-{3-[6-(4-Benzyl-[1,4]diazepan-1-yl)-pyrazin- 2-yl]-phenyl}-acrylic acid 30 (E)-3-{3-[6-(3-Dimethylamino-pyrrolidin-1-yl)- pyrazin-2-yl]-phenyl}-acrylic acid 36 (E)-3-{3-[6-(4-Methyl-[1,4]diazepan-1-yl)-pyridin-2- yl]-phenyl}-acrylic acid 43 1-Methyl-4-(6-{3-[(E)-2-(1H-tetrazol-5-yl)-vinyl]- phenyl}-pyrazin-2-yl)-[1,4]diazepane

or a pharmaceutically acceptable salt thereof.