WO2005085252A1 - Imidazo ‘1,2-a’ pyrazine compounds which interact with protein kinases - Google Patents
Imidazo ‘1,2-a’ pyrazine compounds which interact with protein kinases Download PDFInfo
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- WO2005085252A1 WO2005085252A1 PCT/GB2005/000842 GB2005000842W WO2005085252A1 WO 2005085252 A1 WO2005085252 A1 WO 2005085252A1 GB 2005000842 W GB2005000842 W GB 2005000842W WO 2005085252 A1 WO2005085252 A1 WO 2005085252A1
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- optionally substituted
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- 0 CC1CCN(*)CC1 Chemical compound CC1CCN(*)CC1 0.000 description 2
- KDISMIMTGUMORD-UHFFFAOYSA-N CC(N1CCCCC1)=O Chemical compound CC(N1CCCCC1)=O KDISMIMTGUMORD-UHFFFAOYSA-N 0.000 description 1
- UZOFELREXGAFOI-UHFFFAOYSA-N CC1CCNCC1 Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 1
- XNMRXDWXYSBGSN-UHFFFAOYSA-N CCCNc(cc1)ncc1C#N Chemical compound CCCNc(cc1)ncc1C#N XNMRXDWXYSBGSN-UHFFFAOYSA-N 0.000 description 1
- ATZHGRNFEFVDDJ-UHFFFAOYSA-N CCCc(cc1)ccc1C(O)=O Chemical compound CCCc(cc1)ccc1C(O)=O ATZHGRNFEFVDDJ-UHFFFAOYSA-N 0.000 description 1
- RXFJHVNBEFFCJX-UHFFFAOYSA-N CCCc(cc1)ccc1C(OC)=O Chemical compound CCCc(cc1)ccc1C(OC)=O RXFJHVNBEFFCJX-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to a novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds in the inhibition of protein kinases, in particular serine/threonine kinases, more particularly mitogen activated protein kinase, more particularly the c-Jun NH2-teminal kinases (JNKs).
- the invention also relates to the compounds for use in medicine and particularly in the prevention and/or treatment of a wide variety of diseases including inflammatory disorders, cancer, angiogenesis, diabetes, metabolic disease and neurological disorders.
- JNK is known to be a c-Jun NH2-terminal kinase.
- c-Jun N terminal kinases are intracellular stress activated signaling molecules.
- the JNK family of serine- threonine kinases are derived from three distinct genes, jnkl, jnk2 and jnk3.
- JNK belong to the family of stress-activated protein kinases that also include p38 protein kinase.
- JNKs are regulated by a wide variety of cellular stresses, growth factors and pro-inflammatory cytokines (TNF ⁇ , IL-l ⁇ ), and have been implicated in the regulation of diverse biological processes such as immune response and apoptosis.
- Down-stream substrates of JNKs include the transcription factors c-jun (crucial for API transcriptional activity), ATF-2, Elkl, p53 and the cell death domain protein (DENN) [Proc. Natl. Acad. Sci. USA,95, 2586-91 (1998)]. These factors regulate the expression of a variety of genes including inflammatory cytokines, MMPs, integrins and regulators of apoptosis, therefore are commonly associated with a number of human diseases. The potential of JNK inhibitors has therefore attracted considerable interest and evidence suggests that JNKs inhibitors would be useful in the treatment of inflammatory, vascular, neurodegenerative, metabolic, immunological and oncological human diseases [Nature Review Drug Discovery, 2, 554-565 (2003]. For example, JNK inhibitors may be useful in the treatment of neurological disorders such as stroke, ischaemia, head injury, Alzheimer's disease, Parkinson's disease, epilepsy, spinal cord injury, head trauma, learning, memory and attention disorders, anxiety and panic disorders.
- neurological disorders such as stroke, is
- JNK inhibitors may also be useful in the treatment of inflammatory and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis, transplant rejection, septic shock and bronchitis.
- inflammatory and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis, transplant rejection, septic shock and bronchitis.
- JNK inhibitors may also be useful in the treatment of cardiovascular diseases, including stroke, atherosclerosis, myocardial reperfusion injury, myocardial infarction and cardiac failure.
- JNK inhibitors may also be useful in the treatment of metabolic diseases such as diabetes, insulin resistance, obesity and metabolic syndrome.
- JNK antagonists may also be useful in the oncology area, in particular for the treatment of solid tumours (including breast, colorectal and pancreatic cancer), small cell lung cancer, ovarian cancer and prostate cancer.
- Inhibitors of JNK activity have also been associated with opthalmic conditions including retinopathies and also macular degeneration.
- JNK inhibitors may be useful in the treatment of a variety of diseases the development of non-peptide JNK inhibitors with good activity, selectivity and pharmacokinetic profiles is needed to fully exploit the clinical potential of this target.
- the present invention provides a class of compounds which interact selectively with the JNK kinase.
- a library designed to aid in the identification of kinase inhibitors comprising 6- aryl-imidazo[l,2-a]pyrazine-8-yl-amine analogues, has been disclosed (IBC conference 7 March 2002 - John Harris).
- WO 02/060492 describes some compounds based on either a 2-amino-6-carba-disubstituted pyrazine scaffold or a 2-amino-6-carba-disubstituted pyridine scaffold, as JAK inhibitors for the treatment of immune disorders.
- WO03/089434 describes certain imidazo[l,2- a]pyrazine-8-yl-amines as modulators of protein kinase.
- the present invention relates to a selected class of compounds which interact selectively with the JNK kinase.
- the above referenced prior art does not disclose the selected class of compounds of the present invention, nor compounds which interact selectively with the JNK kinase.
- the invention provides a compound of formula I: x
- X is -NHR6, -NR6R7 or -OR6;
- R6 and R7 which may be the same or different are hydrogen, - heteroaryl-C ⁇ - 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O- CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, hydroxy, C ⁇ - 5 -hydroxyalkyl, halogen, halo C ⁇ - 6 -alkyl, heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, C ⁇ - 6 -alkylamino, di-C ⁇ - 6 -alkylamino, carboxy, CO 2 Me, SONH 2 , and NO 2 , or heteroaryloxy-C ⁇ .
- 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O- CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, hydroxy, Ci.
- heteroarylamino-Ci-e-alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, hydroxy, C ⁇ - 6 - hydroxyalkyl, halogen, halo C ⁇ - 6 -alkyl , heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, C ⁇ - 6 -alkylamino, di-C ⁇ - 6 -alkylamino, carboxy, CO 2 Me, SONH 2 and NO 2 , or aryl-C ⁇ - 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methyl
- O-CF 3 amino-methyl, amino, C ⁇ - 6 -aminoalkyl, hydroxy, C ⁇ - 6 -hydroxyalkyl, halogen, halo C ⁇ - 6 -alkyl, heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, C ⁇ - 6 -alkylamino, di-C ⁇ - 6 -alkylamino, carboxy, CO 2 Me, SONH 2 and NO 2 , or aryloxy-C ⁇ - 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, hydroxy, C ⁇ - 6 -hydroxyalkyl, halogen, halo C ⁇ - 6 -alkyl, heterocycl
- 6 -alkylamino carboxy, CO 2 Me, SONH 2 and NO 2 , or aryl optionally independently substituted with one or more of C ⁇ - 6 - alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino- methyl, amino, C ⁇ - 6 -aminoalkyl, hydroxy, C ⁇ - 6 -hydroxyalkyl, halogen, halo C ⁇ .
- z is -NC(O)-, -C(O)N-, -NS(O) 2 -, S(O) 2 N-, -NC(O)N-, -NC(O)O- or -OC(O)N-, preferably wherein the third substituent on each N atom is H;
- n 0 or 1
- R3 is: - heteroaryl-C ⁇ . 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O- CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, dimethylamino, C ⁇ - 6 - alkylamino, di-C ⁇ - 6 -alkylamino, hydroxy, C ⁇ - 6 -hydroxyalkyl, C ⁇ - 6 -alkenyl, halogen and halo C ⁇ - 6 -alkyl, C ⁇ - 6 -carboxyalkyl, C ⁇ - 6 -carboxyalkenyl, CONR4R5, CO 2 H, NHCOR4, NHS(O) 2 R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, d-e-alkyl, C
- CF 3 amino-methyl, amino, C ⁇ . 6 -aminoalkyl, dimethylamino, C ⁇ _ 6 - alkylamino, di-C ⁇ - 6 -alkylamino, hydroxy, C ⁇ - 6 -hydroxyaIkyl, C ⁇ - 6 -alkenyl, halogen and halo C ⁇ - 6 -alkyl, C ⁇ - 6 -carboxyalkyl, C ⁇ .
- R4 and R5 may be the same or different and are selected from hydrogen, C ⁇ _ 6 -alkyl, C ⁇ - 6 -alkoxy, aryl, heteroaryl and C ⁇ - 6 -hydroxyalkyl; or heteroaryl optionally independently substituted with one or more of Ci- 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, dimethylamino, C ⁇ - 6 -alkylamino, di-C ⁇ - 6 -alkylamino, hydroxy, C ⁇ - 6 -hydroxyalkyl, C ⁇ - 6 -alkenyl, halogen and halo Ci-e-alkyl, C ⁇ _ 6 -carboxyalkyl, C ⁇ _ 6 -carboxyalkyl, C ⁇ _ 6 -carboxyalkyl, C ⁇ _ 6 -carboxyalkyl,
- 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, Ci-e-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, dimethylamino, C ⁇ - 6 -alkylamino, di-C ⁇ - 6 -alkylamino, hydroxy, C ⁇ - 6 -hydroxyalkyl, C ⁇ - 6 -alkenyl, halogen and halo Ci-e-alkyl, C ⁇ - 6 -carboxyalkyl, C ⁇ - 6 -carboxyalkenyl, CONR4R5, CO 2 H,
- R4 and R5 may be the same or different and are selected from hydrogen, C ⁇ - 6 -alkyl, C ⁇ . 6 -alkoxy, aryl, heteroaryl, C ⁇ _ 6 -hydroxyalkyl; or aryloxy-C ⁇ - 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ _ 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, dimethylamino, Ci- 6 -alkylamino, di-Ci- 6 -alkylamino, hydroxy, C ⁇ - 6 -hydroxyalkyl, C ⁇ - 6 -alkenyl, halogen and halo Ci-e-alkyl, Ci.
- R4 and R5 may be the same or different and are selected from hydrogen, Ci-e-alkyl, C ⁇ _ e-alkoxy, aryl, heteroaryl, C ⁇ - 6 -hydroxyalkyl; or aryl optionally independently substituted with one or more of C ⁇ - 6 - alkoxy, Ci-e-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino- methyl, amino, C ⁇ - 6 -aminoalkyl, dimethylamino, C ⁇ - 6 -alkylamino, di-C ⁇ - 6 - alkylamino, hydroxy, C ⁇ - 6 -hydroxyalkyl, C ⁇ - 6 -alkenyl, halogen and halo Ci-e-
- C ⁇ - 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ _ 6 -alkenyl, aryl, heteroaryl, CONR4R5, CO 2 H, NHCOR4, NHS(O) 2 R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, C ⁇ . 6 -alkyl, C ⁇ - 6 - alkoxy, aryl, heteroaryl and C ⁇ - 6 -hydroxyalkyl; or
- C 3 . 8 -cycloalkyl optionally independently substituted with one or more of Ci-e-alkoxy, C ⁇ - 6 -alkenyl, aryl, heteroaryl, CONR4R5, CO 2 H, NHCOR4, NHS(O) 2 R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, C ⁇ . 6 -alkyl, C ⁇ - 6 - alkoxy, aryl, heteroaryl and C ⁇ .
- R6 and R7 are not both hydrogen.
- R4 and R5 are not both hydrogen.
- R 5 and R 4 are not both hydrogen.
- R7 is hydrogen and preferably R6 is heteroaryl-Ci- 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino-methyl, amino, Ci-6-aminoalkyl, hydroxy, Ci- 6 -hydroxyalkyl, halogen, halo C ⁇ - 6 -alkyl, heterocyclyl which is optionally substituted, CN, dimethylamino, C ⁇ - 6 - alkylamino, di-C ⁇ - 6 -alkylamino, carboxy, CO 2 Me, SONH 2 , heterocyclyl which is optionally substituted and heterocyclyl-Cl-6-alkyl which is optionally substituted.
- R6 is pyridyl-alkyl which is optionally substituted, more preferably pyridin-3-ylmethyl or pyridine-3-ylethyl, and preferably R7 is hydrogen.
- R6 and R7 which may be the same or different are selected from the following:
- R3 is aryl or heteroaryl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, hydroxy, C ⁇ - 6 - hydroxyalkyl, C ⁇ _ 6 -alkenyl, halogen and halo C ⁇ - 6 -alkyl, C ⁇ - 6 -carboxyalkyl, C ⁇ - 6 - carboxyalkenyl, CONR4R5, CO 2 H, NHCOR4, NHS(O) 2 R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different are either hydrogen, C ⁇ - 6 -alkyl, C ⁇ . 6 -alkoxy, aryl, heteroaryl, Ci- 6 -hydroxyalkyl;
- R3 is phenyl, furan, phenylmethanol; hydroxymethyl-phenyl, optionally being 4- hydroxymethyl-phenyl or 3-hydroxymethyl-phenyl; or aminomethyl-phenyl optionally being 4-aminomethyl-phenyl.
- the present invention provides a pharmaceutical formulation comprising a compound of formula I and a pharmaceutically acceptable diluent or carrier.
- the invention provides a process for the preparation of a compound of formula I as mentioned above.
- the invention provides a method for the prophylaxis or treatment of a JNK receptor-related disorder, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I.
- the present invention provides a method for modulating JNK receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I or a pharmaceutical formulation comprising a compound of formula I.
- the present invention provides a compound of formula I for use in therapy, especially for use in the prophylaxis or treatment of a JNK receptor- related disorder.
- the present invention provides the use of a compound of formula I for the manufacture of a medicament for use in the prophylaxis or treatment of a JNK receptor-related disorder.
- X is:
- the invention provides a compound of formula II:
- R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, heteroarylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, or heteroarylalkynyl which is optionally substituted, alkyl, cycloalkyl; and
- n 0 or 1;
- R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, C ⁇ -C 6 alkyl which is optionally substituted, C 2 -C 6 alkenyl which is optionally substituted, C 2 -C 6 alkynyl which is optionally substituted or C 3 -C 8 cycloalkyl which is optionally substituted; and
- R3 is aryl which is optionally substituted or heteroaryl which is optionally substituted;
- Rl and R2 are not both hydrogen.
- R 5 and R 4 are not both hydrogen.
- Rl is in the 3 or 4 position.
- R2 is hydrogen, alkyl which is optionally substituted, alkoxy which is optionally substituted, aryloxy which is optionally substituted, halogen, hydroxy, CN, CO 2 H, NR 5 R 4 , CO 2 R 5 , CONR 5 R 4 , NR 5 (CO)R 4 , or S(O) p R 5 ; wherein R 5 and R 4 may be the same or different and are selected from hydrogen, alkyl which is optionally substituted, aryl which is optionally substituted, heteroarylalkyl which is optionally substituted and arylalkyl which is optionally substituted.
- R2 is hydrogen
- Rl is hydroxy or NR 5 R 4 where R 5 is hydrogen and R 4 is alkyl which is optionally substituted, aryl which is optionally substituted, heteroarylalkyl which is optionally substituted or arylalkyl which is optionally substituted.
- R3 is aryl which is optionally substituted or heteroaryl which is optionally substituted.
- Z is -NC(O)-, -C(O)N-, -NS(O) 2 -, -S(O) 2 N-, -NC(O)N-, - NC(O)O- or -OC(O)N- and R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, C ⁇ -C 6 alkyl which is optionally substituted, C 2 -C 6 alkenyl which is optionally substituted, C 2 -C 6 alkynyl which is optionally substituted or C 3 -C 8 cycloalkyl which is optionally substituted.
- R2 is hydrogen;
- Rl is hydroxy or NR 5 R 4 where R 5 is an hydrogen and R 4 is alkyl which is optionally substituted, aryl which is optionally substituted, heteroarylalkyl which is optionally substituted or arylalkyl which is optionally substituted; and
- R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, C ⁇ -C 6 alkyl which is optionally substituted, C 2 -C 6 alkenyl which is optionally substituted, C 2 -C 6 alkynyl which is optionally substituted or C 3 -C 8 cycloalkyl which is optionally substituted.
- R3 is selected from 4- hydroxymethyl-phenyl, 4-aminomethyl-phenyl and 3-hydroxymethyl-phenyl and perferably, Z is 0.
- M is 2, R2 is H and Rl is 4-hydroxy.
- the present invention provides a pharmaceutical formulation comprising a compound of formula II and a pharmaceutically acceptable diluent or carrier.
- the invention provides a process for the preparation of a compound of formula II as mentioned above.
- the invention provides a method for the prophylaxis or treatment of a JNK receptor-related disorder, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula II as mentioned above.
- the present invention provides a method for modulating JNK receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula II or a pharmaceutical formulation comprising a compound of formula II.
- the present invention provides a compound of formula II for use in therapy, especially for use in the prophylaxis or treatment of a JNK receptor-related disorder.
- the present invention provides the use of a compound of formula II for the manufacture of a medicament for use in the prophylaxis or treatment of a JNK receptor-related disorder.
- the compounds of formula I or II may be agonists, partial agonists or antagonists for the JNK receptor.
- JNK receptor-related disorders are inflammatory and autoimmune disorders, such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis, transplant rejection, sceptic shock and bronchitis; cancer, in particular solid tumours, (including breast, colorectal and pancreatic cancer) small cell lung cancer, ovarian cancer and prostate cancer; vardiovascular diseases, including stroke, atherosclerosis, myocardial reperfusion injury, myocardial infarction and cardiac failure; angiogenesis; neurological disorders, such as stroke, ischaemia, head injury, Alzheimer's disease, Parkinson's disease, epilepsy, spinal cord injury, head trauma and also learning, memory and attention disorders, anxiety and panic disorders; opthalmic conditions including retinopathies and also macular degeneration and metabolic diseases such as diabetes, insulin resistance, obesity and metabolic syndrome.
- inflammatory and autoimmune disorders such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoria
- the compounds of the invention may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers.
- optical isomers e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers.
- the separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns.
- the invention relates to methods of making compounds of any of the formulae herein comprising reacting any one or more of the compounds of the formulae delineated herein, including any processes delineated herein.
- the compounds of the invention above may be prepared by, or in analogy with, conventional methods.
- a pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Examples of addition salt forming acids are mentioned above.
- the necessary starting materials for preparing the compounds of the invention are either known or may be prepared in analogy with the preparation of known compounds.
- alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms (“C ⁇ _ 6 - alkyl”).
- alkyl examples include methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
- C ⁇ - 6 -alkyl For parts of the range "C ⁇ - 6 -alkyl" all subgroups thereof are contemplated such as C ⁇ - 5 -alkyl, C ⁇ -alkyl, C ⁇ - 3 -alkyl, C ⁇ - 2 -alkyl, C 2 . 6 -alkyl, C 2 . 5 -alkyl, C 2 . 4 -alkyl, C 2 . 3 -alkyl, C 3 . 6 -alkyl, C 4 . 5 -alkyl, etc.
- "Halo ⁇ C ⁇ - 6 -alkyl” means a C ⁇ - 6 -alkyl group substituted with one or more halogen atoms.
- aryI-C ⁇ - 6 -alkyl means a C ⁇ - 6 -alkyl group substituted with one or more aryl groups.
- cycloalkyl denotes a cyclic alkyl group having a ring size from 3 to 8 carbon atoms.
- examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, and cyclooctyl.
- C 3 _ 8 - cycloalkyl all subgroups thereof are contemplated such as C 3 . 7 -cycloalkyl, C 3 . 6 -cycloalkyl, C 3 .
- alkoxy denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms.
- examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy.
- C ⁇ - 6 -alkoxy all subgroups thereof are contemplated such as C ⁇ - 5 -alkoxy, C ⁇ - 4 -alkoxy, C ⁇ - 3 -alkoxy, C ⁇ - 2 -alkoxy, C 2 .
- alkenyl means a straight chain or branched alkenyl radical of 2 to 6 carbon atoms and containing one or more carbon-carbon double bonds and includes but is not limited to ethylene, ⁇ -propyl-1-ene, ⁇ -propyl-2-ene, isopropylene, etc.
- alkynyl means a straight chain or branched alkynyl radical of 2 to 6 carbon atoms and containing one or more carbon-carbon triple bonds and includes but is not limited to ethynyl, 2-methylethynyl etc.
- aryl refers to a 3- 10 membered hydrocarbon ring system having at least one aromatic ring or being fused to one or more saturated or unsaturated rings including, but not limited to phenyl, pentalenyl, indenyl, indanyl, isoindolinyl, chromanyl, naphthyl, fluorenyl, anthryl, phenanthryl and pyrenyl.
- the aryl rings may optionally be substituted with C ⁇ - 6 -alkyl. Examples of substituted aryl groups are benzyl and 2-methylphenyl.
- aryloxy refers to an aryl group bonded to an oxygen atom.
- heteroaryl refers to a 3-10 membered hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S.
- heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, indolyl, pyrazolyl, pyridazinyl, quinolinyl, benzofuranyl, dihydrobenzofuranyl, benzodioxolyl, benzodioxinyl, benzothiazolyl, benzothiadiazolyl, and benzotriazolyl groups.
- heterocyclyl means a 3-10 membered ring system containing one or more heteroatoms selected from N, O or S and includes heteroaryl.
- the heterocyclyl system can contain one ring or may be fused to one or more saturated or unsaturated rings; the heterocyclyl can be fully saturated, partially saturated or unsaturated and includes but is not limited to heteroaryl and heterocarbocyclyl.
- carbocyclyl or heterocyclyl groups include but are not limited to cyclohexyl, phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isoxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxa
- halogen shall mean fluorine, chlorine, bromine or iodine.
- substituted shall mean that one atom or group of atoms in a molecule is replaced by another atom or group and where optional substituents are referred to, but are not specified, suitable substituents include alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkoxy, aryloxy, halogen, hydroxy, NO 2 , CN, C ⁇ - 6 -alkyl-CN, aryl, acetyl, 1, 2, 4-oxadiazoiylmethyl, CHO, NR 3 R 4 , CO 2 R 3 , CONR 3 R 4 , NR 3 (CO) R 4 , S(O) p R 3 ; wherein R 3 and R 4 may be the same or different and are selected from hydrogen, alkyl which is optionally substituted, hydroxyalkyl which is optionally substituted, alkoxy which is optionally substituted, aryl which is optionally substituted,
- leaving group refers to a group to be displaced from a molecule during a nucleophilic displacement reaction.
- leaving groups are bromide, chloride and methanesulfonate, especially bromide and methanesulfonate.
- “Pharmaceutically acceptable” means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
- Treatment includes prophylaxis of the named disorder or condition, or amelioration or elimination of the disorder once it has been established.
- “An effective amount” refers to an amount of a compound that confers a therapeutic effect on the treated subject.
- the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
- prodrug forms means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug.
- pharmacologically acceptable derivative such as an ester or an amide
- ACN means acetonitrile
- DEA diethylamine
- DEPT distortion enhancement polarisation transfer
- DMSO means dimethyl sulfoxide
- ELS electron light scattering
- HPLC means high performance liquid chromatography
- Rt means retention time
- TFA trifluoroacetic acid
- THF means tetrahydrofuran
- TLC means thin layer chromatography
- the compounds of the formula (I) may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof.
- pharmacologically acceptable addition salts mentioned above are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds are able to form.
- Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid.
- Exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like.
- organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, tolu
- Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and amino acids, such as, e.g. arginine and lysine.
- the term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates and the like.
- compositions suitable for administration typically comprise at least one compound of the invention and at least one pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
- the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
- compositions are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients.
- excipients are water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like.
- Such formulations may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like.
- the formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc.
- the formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections.
- Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.
- a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
- routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
- Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
- the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
- compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
- suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
- the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, 'chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
- isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition.
- Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum mono stearate and gelatin.
- Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a compound according to an embodiment of the invention) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
- the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
- a binder such as microcrystalline cellulose, gum tragacanth or gelatin
- an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
- a lubricant such as magnesium stearate or Sterotes
- a glidant such as colloidal silicon dioxide
- the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
- a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
- Systemic administration can also be by transmucosal or transdermal means.
- penetrants appropriate to the barrier to be permeated are used in the formulation.
- penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
- Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
- the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
- the compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
- suppositories e.g., with conventional suppository bases such as cocoa butter and other glycerides
- retention enemas for rectal delivery.
- the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
- a controlled release formulation including implants and microencapsulated delivery systems.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
- the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
- Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art.
- Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
- Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
- the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
- Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
- the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
- the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
- the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
- the therapeutically effective dose can be estimated initially from cell culture assays.
- a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
- IC50 i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms
- levels in plasma may be measured, for example, by high performance liquid chromatography.
- the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
- the dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy.
- the daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
- the present invention provides a class of compounds which interact selectively with the JNK receptor and not significantly with other members of the gene family.
- Table 5 the selectivity of a selection of compounds against a selection of kinases is presented.
- the active ingredient 1 is mixed with ingredients 2, 3, 4 and 5 for about 10 minutes.
- the magnesium stearate is then added, and the resultant mixture is mixed for about 5 minutes and compressed into tablet form with or without film-coating.
- 6,8-Dibromo-imidazo[l,2-a]pyrazine (A) can be aminated with amines.
- the resultant compounds (B) are then Boc protected (C) and can then be reacted with the boronic acids and de-protected to yield the final compounds of formula (D) or be reacted with an amide in presence of copper iodide then de- protected to yield the final compounds of formula (E).
- a suspension of copper(I)iodide (100 mg, 0.53 mmol), (6-Bromo-imidazo[l,2- a]pyrazin-8-yl)-pyridin-3-ylmethyl-amine (430mg, 1.06 mol), benzamide (150mg, 1.35 mmol) and potassium carbonate (300 mg, 2.17 mmol) was prepared in dry toluene (50 mL) and the mixture purged with nitrogen for 15 minutes. ⁇ /V'-dimethylethylenediamine (0.4 mL) was then added and the reaction stirred at room temperature for 15 minutes then heated to reflux for 16 hours.
- 6,8-Dibromo-imidazo[l,2-a]pyrazine (A) can be aminated with amines.
- the resultant compounds (B) can then be reacted with the boronic acids to yield the final compounds of formula (C) or be reacted with an amide in presence of cupper iodide to yield the final compounds of formula (D).
- a suspension of copper(I)iodide (100 mg, 0.53 mmol), 4-(6-Bromo- imidazo[l,2-a]pyrazin-8-ylamino)-cyclohexanol (330 mg, 1.06 mol), thiophene-2-acetamide (190 mg, 1.35 mmol) and potassium carbonate (300 mg, 2.17 mmol) was prepared in dry toluene (50 mL) and the mixture purged with nitrogen for 15 minutes. ⁇ rVV'-dirnethylethylenediamine (0.4 mL) was then added and the reaction stirred at room temperature for 15 minutes then heated to reflux for 16 hours.
- a JNK screening assay was performed in a 384-well and 96-well flashplate format. The kinetics of the reaction were determined under the following conditions: 0.2 ⁇ Ci; 33 P-ATP; 1.5 ⁇ M ATP; 2mU JNKl ⁇ l; 2 ⁇ M c-jun (1-79) peptide substrate incubated for 30 minutes at room temperature.
- a standard ATP concentration of 0.1 x Km (Km previously defined as 15 ⁇ M) was employed.
- Km for JNKl ⁇ l was derived as 4 ⁇ M (4.7 and 4.0 ⁇ M independent observations).
- the kinetics of the reaction were determined under the following conditions 0.2 ⁇ Ci 33 P-ATP; 1.5 ⁇ M ATP; 2mU JNKl ⁇ l; 2 ⁇ M c-jun (1-79) peptide substrate incubated for 30 minutes at room temperature.
Abstract
The present invention relates to a novel compounds of formula I, to pharmaceutical compounds, to processes for their preparation, as well as to the use of the compounds in the inhibition of protein kinases, in particular serine/threonine kinases, more particularly mitogen activated protein kinase, more particularly the c-Jun NH2-teminal kinases (JNKs). The invention also relates to the compounds for use in medicine and particularly n the prevention and/or treatment of a wide variety of diseases including inflammatory disorders, cancer, angiogenesis, diabetes, metabolic disease and neurological disorders.
Description
IMIDAZO λ l , 2-A ! PYRAZINE COMPOUNDS WHICH INTERACT WITH PROTEIN KINASES
TECHNICAL FIELD
The present invention relates to a novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds in the inhibition of protein kinases, in particular serine/threonine kinases, more particularly mitogen activated protein kinase, more particularly the c-Jun NH2-teminal kinases (JNKs). The invention also relates to the compounds for use in medicine and particularly in the prevention and/or treatment of a wide variety of diseases including inflammatory disorders, cancer, angiogenesis, diabetes, metabolic disease and neurological disorders.
BACKGROUND OF THE INVENTION
JNK is known to be a c-Jun NH2-terminal kinase. c-Jun N terminal kinases are intracellular stress activated signaling molecules. The JNK family of serine- threonine kinases are derived from three distinct genes, jnkl, jnk2 and jnk3. JNK belong to the family of stress-activated protein kinases that also include p38 protein kinase. JNKs are regulated by a wide variety of cellular stresses, growth factors and pro-inflammatory cytokines (TNFα , IL-lβ), and have been implicated in the regulation of diverse biological processes such as immune response and apoptosis. Down-stream substrates of JNKs include the transcription factors c-jun (crucial for API transcriptional activity), ATF-2, Elkl, p53 and the cell death domain protein (DENN) [Proc. Natl. Acad. Sci. USA,95, 2586-91 (1998)]. These factors regulate the expression of a variety of genes including inflammatory cytokines, MMPs, integrins and regulators of apoptosis, therefore are commonly associated with a number of human diseases. The potential of JNK inhibitors has therefore attracted considerable interest and evidence suggests that JNKs inhibitors would be useful in the treatment of inflammatory, vascular, neurodegenerative, metabolic, immunological and oncological human diseases [Nature Review Drug Discovery, 2, 554-565 (2003].
For example, JNK inhibitors may be useful in the treatment of neurological disorders such as stroke, ischaemia, head injury, Alzheimer's disease, Parkinson's disease, epilepsy, spinal cord injury, head trauma, learning, memory and attention disorders, anxiety and panic disorders.
JNK inhibitors may also be useful in the treatment of inflammatory and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis, transplant rejection, septic shock and bronchitis.
JNK inhibitors may also be useful in the treatment of cardiovascular diseases, including stroke, atherosclerosis, myocardial reperfusion injury, myocardial infarction and cardiac failure.
JNK inhibitors may also be useful in the treatment of metabolic diseases such as diabetes, insulin resistance, obesity and metabolic syndrome.
JNK antagonists may also be useful in the oncology area, in particular for the treatment of solid tumours (including breast, colorectal and pancreatic cancer), small cell lung cancer, ovarian cancer and prostate cancer.
Inhibitors of JNK activity have also been associated with opthalmic conditions including retinopathies and also macular degeneration.
However, despite indications that JNK inhibitors may be useful in the treatment of a variety of diseases the development of non-peptide JNK inhibitors with good activity, selectivity and pharmacokinetic profiles is needed to fully exploit the clinical potential of this target.
Remarkably, the present invention provides a class of compounds which interact selectively with the JNK kinase.
A library designed to aid in the identification of kinase inhibitors, comprising 6- aryl-imidazo[l,2-a]pyrazine-8-yl-amine analogues, has been disclosed (IBC
conference 7 March 2002 - John Harris). WO 02/060492 describes some compounds based on either a 2-amino-6-carba-disubstituted pyrazine scaffold or a 2-amino-6-carba-disubstituted pyridine scaffold, as JAK inhibitors for the treatment of immune disorders. WO03/089434 describes certain imidazo[l,2- a]pyrazine-8-yl-amines as modulators of protein kinase. The present invention relates to a selected class of compounds which interact selectively with the JNK kinase. The above referenced prior art does not disclose the selected class of compounds of the present invention, nor compounds which interact selectively with the JNK kinase.
DISCLOSURE OF THE INVENTION
Formula I
In a first aspect the invention provides a compound of formula I: x
wherein, X is -NHR6, -NR6R7 or -OR6;
R6 and R7 which may be the same or different are hydrogen, - heteroaryl-Cι-6-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O- CF3, amino-methyl, amino, Cι-6-aminoalkyl, hydroxy, Cι-5-hydroxyalkyl, halogen, halo Cι-6-alkyl, heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, Cι-6-alkylamino, di-Cι-6-alkylamino, carboxy, CO2Me, SONH2, and NO2, or heteroaryloxy-Cι.6-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O- CF3, amino-methyl, amino, Cι-6-aminoalkyl, hydroxy, Ci.6-hydroxyalkyl,
halogen, halo Ci-β-al yl, heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, Cι-6-alkylamino, di-Ci-g-alkylamino, carboxy, CO2Me, SONH2 and NO2, or heteroaryl optionally independently substituted with one or more of Ci- e-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino-methyl, amino, Cι-6-aminoalkyl, hydroxy, Cι-6-hydroxyalkyl, halogen, halo Cι-6-alkyl, heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, Cι-6-alkylamino, di-Cι-6-alkylamino, carboxy, CO2Me,
SONH2 and NO2, or heteroarylamino-Ci-e-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino-methyl, amino, Cι-6-aminoalkyl, hydroxy, Cι-6- hydroxyalkyl, halogen, halo Cι-6-alkyl , heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, Cι-6-alkylamino, di-Cι-6-alkylamino, carboxy, CO2Me, SONH2 and NO2, or aryl-Cι-6-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, . O-CF3, amino-methyl, amino, Cι-6-aminoalkyl, hydroxy, Cι-6-hydroxyalkyl, halogen, halo Cι-6-alkyl, heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, Cι-6-alkylamino, di-Cι-6-alkylamino, carboxy, CO2Me, SONH2 and NO2, or aryloxy-Cι-6-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino-methyl, amino, Cι-6-aminoalkyl, hydroxy, Cι-6-hydroxyalkyl, halogen, halo Cι-6-alkyl, heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, Cι-6-alkylamino, di-Cι.6-alkylamino, carboxy, CO2Me, SONH2 and NO2, or aryl optionally independently substituted with one or more of Cι-6- alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino- methyl, amino, Cι-6-aminoalkyl, hydroxy, Cι-6-hydroxyalkyl, halogen,
halo Cι.6-alkyl, heterocyclyl which is optionally substituted, heterocyclyl- Cl-6-alkyl which is optionally substituted, CN, dimethylamino, d-6- alkylamino, di-Cι-6-alkylamino, carboxy, C02Me, SONH2 and NO2, or Ci-e-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, aryl, heteroaryl, cycloalkyl, CONMe2, CO2Me, CO2tBu, N(COCH2OEt)2, NHCOMe, amino, dimethylamino, Cι-6-alkylamino, di-Ci- 6-alkylamino and heterocyclyl which is optionally substituted, or C3-8-cycloalkyl, optionally independently substituted with one or more of Cι-6-alkoxy which is optionally substituted, aryl which is optionally substituted, heteroaryl which is optionally substituted, alkyl which is optionally substituted, alkoxy which is optionally substituted, aryloxy which is optionally substituted, halogen, hydroxy, CN, CO2H, NRΞR4, CO2R5, CONR5R4, NR5(CO)R4, S(O)pR5, wherein R5 and R4 can be the same or different and are selected from hydrogen, alkyl which is optionally substituted, aryl which is optionally substituted, heteroarylalkyl which is optionally substituted, heteroaryl. which is optionally substituted, alkyl and arylalkyl which is optionally substituted, and p = 1 or 2; or C3-8 cycloalkyl-Cι-6-alkyl, optionally independently substituted with one or more of Cι.6-alkoxy, aryl, heteroaryl, or heterocyclyl optionally independently substituted with one or more of COMe, SO2Me;
z is -NC(O)-, -C(O)N-, -NS(O)2-, S(O)2N-, -NC(O)N-, -NC(O)O- or -OC(O)N-, preferably wherein the third substituent on each N atom is H;
n is 0 or 1
R3 is: - heteroaryl-Cι.6-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O- CF3, amino-methyl, amino, Cι-6-aminoalkyl, dimethylamino, Cι-6- alkylamino, di-Cι-6-alkylamino, hydroxy, Cι-6-hydroxyalkyl, Cχ-6-alkenyl, halogen and halo Cι-6-alkyl, Cι-6-carboxyalkyl, Cι-6-carboxyalkenyl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where
R4 and R5 may be the same or different and are selected from hydrogen, d-e-alkyl, Cι-6-alkoxy, aryl, heteroaryl and Cι-6-hydroxyalkyl; or heteroaryloxy-Cι-6-alkyl optionally independently substituted with one or more of Cι.6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-
CF3, amino-methyl, amino, Cι.6-aminoalkyl, dimethylamino, Cι_6- alkylamino, di-Cι-6-alkylamino, hydroxy, Cχ-6-hydroxyaIkyl, Cι-6-alkenyl, halogen and halo Cι-6-alkyl, Cι-6-carboxyalkyl, Cι.6-carboxyalkenyl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι_6-alkyl, Cι-6-alkoxy, aryl, heteroaryl and Cι-6-hydroxyalkyl; or heteroaryl optionally independently substituted with one or more of Ci- 6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino-methyl, amino, Cι-6-aminoalkyl, dimethylamino, Cι-6-alkylamino, di-Cι-6-alkylamino, hydroxy, Cι-6-hydroxyalkyl, Cι-6-alkenyl, halogen and halo Ci-e-alkyl, Cι_6-carboxyalkyl, Cι-6-carboxyalkenyl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6-alkyl, Cι_ 6-alkoxy, aryl, heteroaryl and Cι-6-hydroxyalkyl; or aryl-Cι.6-alkyl optionally independently substituted with one or more of Cχ-6-alkoxy, Ci-e-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino-methyl, amino, Cι-6-aminoalkyl, dimethylamino, Cι-6-alkylamino, di-Cι-6-alkylamino, hydroxy, Cι-6-hydroxyalkyl, Cι-6-alkenyl, halogen and halo Ci-e-alkyl, Cι-6-carboxyalkyl, Cι-6-carboxyalkenyl, CONR4R5, CO2H,
NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6-alkyl, C±. 6-alkoxy, aryl, heteroaryl, Cι_6-hydroxyalkyl; or aryloxy-Cι-6-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, Cι_6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino-methyl, amino, Cι-6-aminoalkyl, dimethylamino, Ci-6-alkylamino, di-Ci-6-alkylamino, hydroxy, Cι-6-hydroxyalkyl, Cι-6-alkenyl, halogen and halo Ci-e-alkyl, Ci.6-carboxyalkyl, Cι-6-carboxyalkenyl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may
be the same or different and are selected from hydrogen, Ci-e-alkyl, Cι_ e-alkoxy, aryl, heteroaryl, Cι-6-hydroxyalkyl; or aryl optionally independently substituted with one or more of Cι-6- alkoxy, Ci-e-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino- methyl, amino, Cι-6-aminoalkyl, dimethylamino, Cι-6-alkylamino, di-Cι-6- alkylamino, hydroxy, Cι-6-hydroxyalkyl, Cι-6-alkenyl, halogen and halo Ci-e-alkyl, Cι-6-carboxyalkyl, Cι-6-carboxyalkenyl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6-alkyl, Ci- 6-alkoxy, aryl, heteroaryl, Ci-e-hydroxyalkyl; or
Cι-6-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, Cι_6-alkenyl, aryl, heteroaryl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι.6-alkyl, Cι-6- alkoxy, aryl, heteroaryl and Cι-6-hydroxyalkyl; or
C3.8-cycloalkyl optionally independently substituted with one or more of Ci-e-alkoxy, Cι-6-alkenyl, aryl, heteroaryl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι.6-alkyl, Cι-6- alkoxy, aryl, heteroaryl and Cι.6-hydroxyalkyl; or arylalkenyl optionally independently substituted preferably with one or more of Cι-6-alkoxy, Cι-6-alkenyl, aryl, heteroaryl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6-alkyl, Ci- 6-alkoxy, aryl, heteroaryl and Cι-6-hydroxyalkyl; or heteroarylalkenyl optionally independently substituted preferably with one or more of Cι_6-alkoxy, Cι-6-alkenyl, aryl, heteroaryl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6- alkyl, Cι.6-alkoxy, aryl, heteroaryl and Ci-6-hydroxyalkyl; or arylalkynyl optionally independently substituted preferably with one or more of Cι-6-alkoxy, Cι-6-alkenyl, aryl, heteroaryl, CONR4R5, " CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6-alkyl, C%. 5-alkoxy, aryl, heteroaryl and Ci-6-hydroxyalkyl; or
heteroarylalkynyl optionally independently substituted preferably with one or more of Ci-e-alkoxy, Cι_6-alkenyl, aryl, heteroaryl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6- alkyl, Cι-6-alkoxy, aryl, heteroaryl and Ci-6-hydroxyalkyl;
or a pharmaceutically acceptable salt, hydrate, solvate, geometrical isomer, tautomer, optical isomer, or prodrug form thereof.
Preferably, R6 and R7 are not both hydrogen. Preferably R4 and R5 are not both hydrogen. Preferably, R5 and R4 are not both hydrogen.
In a preferred embodiment, R7 is hydrogen and preferably R6 is heteroaryl-Ci- 6-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino-methyl, amino, Ci-6-aminoalkyl, hydroxy, Ci-6-hydroxyalkyl, halogen, halo Cι-6-alkyl, heterocyclyl which is optionally substituted, CN, dimethylamino, Cι-6- alkylamino, di-Cι-6-alkylamino, carboxy, CO2Me, SONH2, heterocyclyl which is optionally substituted and heterocyclyl-Cl-6-alkyl which is optionally substituted.
More preferably R6 is pyridyl-alkyl which is optionally substituted, more preferably pyridin-3-ylmethyl or pyridine-3-ylethyl, and preferably R7 is hydrogen.
In a preferred embodiment, R6 and R7 which may be the same or different are selected from the following:
lylmethyl
More preferably R3 is phenyl, furan, phenylmethanol; hydroxymethyl-phenyl, optionally being 4- hydroxymethyl-phenyl or 3-hydroxymethyl-phenyl; or aminomethyl-phenyl optionally being 4-aminomethyl-phenyl.
Preferred compounds of formula I are given in the Examples.
Any known compound having a structural formula identical to any one of the compounds covered by formula (I) is hereby explicitly disclaimed per se.
In a second aspect the present invention provides a pharmaceutical formulation comprising a compound of formula I and a pharmaceutically acceptable diluent or carrier.
In a third aspect the invention provides a process for the preparation of a compound of formula I as mentioned above.
In a fourth aspect the invention provides a method for the prophylaxis or treatment of a JNK receptor-related disorder, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I.
In a fifth aspect the present invention provides a method for modulating JNK receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I or a pharmaceutical formulation comprising a compound of formula I.
In a sixth aspect the present invention provides a compound of formula I for use in therapy, especially for use in the prophylaxis or treatment of a JNK receptor- related disorder.
In another aspect the present invention provides the use of a compound of formula I for the manufacture of a medicament for use in the prophylaxis or treatment of a JNK receptor-related disorder.
Formula II In a preferred embodiment, X is:
Thus, in a particularly preferred embodiment, the invention provides a compound of formula II:
wherein, m=0, 1,2,3;
Rl and R2, which may be the same or different, can be hydrogen, alkyl which is optionally substituted, alkoxy which is optionally substituted, aryloxy which is optionally substituted, halogen, hydroxy, CN, CO2H, NR5R4, CO2RΞ, CONR5R4, NR5(CO)R4, S(O)pR5, wherein R5 and R4 can be the same or different and are selected from hydrogen, alkyl which is optionally substituted, aryl which is
optionally substituted, heteroaryl which is optionally substituted, heteroarylalkyl which is optionally substituted, alkyl and arylalkyl which is optionally substituted, and p = 1 or 2;
R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, heteroarylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, or heteroarylalkynyl which is optionally substituted, alkyl, cycloalkyl; and
n=0 or 1; and
when n=l, Z is -NC(O)-, -C(O)N-, -NS(O)2-, -S(O)2N-, -NC(O)N-, -NC(O)O- or -OC(O)N- and R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, Cι-C6 alkyl which is optionally substituted, C2-C6 alkenyl which is optionally substituted, C2-C6 alkynyl which is optionally substituted or C3-C8 cycloalkyl which is optionally substituted; and
when n=0, R3 is aryl which is optionally substituted or heteroaryl which is optionally substituted;
or a pharmaceutically acceptable salt, hydrate, solvate, geometrical isomer, tautomer, optical isomer, or prodrug form thereof.
Preferably, Rl and R2 are not both hydrogen. Preferably, R5 and R4 are not both hydrogen.
Preferably, Rl is in the 3 or 4 position.
Preferred substituents include alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkoxy, aryloxy, halogen, hydroxy, NO2, CN, Cι-6 hydroxyalkyl, hydroxymethyl, d-6-aminoalkyl, aminomethyl, NR5R4, CO2R5, CONR5R4, NR5(CO) R4, S(O)pR5;
wherein R5 and R4 which may be the same or different are selected from hydrogen, alkyl which is optionally substituted, hydroxyalkyl which is optionally substituted, alkoxy which is optionally substituted, aryl which is optionally substituted, heteroaryl which is optionally substituted, heteroarylalkyl which is optionally substituted and arylalkyl which is optionally substituted; wherein p=l or 2.
Preferably m=2.
Preferably, R2 is hydrogen, alkyl which is optionally substituted, alkoxy which is optionally substituted, aryloxy which is optionally substituted, halogen, hydroxy, CN, CO2H, NR5R4, CO2R5, CONR5R4, NR5(CO)R4, or S(O)pR5; wherein R5 and R4 may be the same or different and are selected from hydrogen, alkyl which is optionally substituted, aryl which is optionally substituted, heteroarylalkyl which is optionally substituted and arylalkyl which is optionally substituted.
More preferably, R2 is hydrogen.
Preferably, Rl is hydroxy or NR5R4 where R5 is hydrogen and R4 is alkyl which is optionally substituted, aryl which is optionally substituted, heteroarylalkyl which is optionally substituted or arylalkyl which is optionally substituted.
Preferably, when n=0, R3 is aryl which is optionally substituted or heteroaryl which is optionally substituted.
Preferably, when n=l, Z is -NC(O)-, -C(O)N-, -NS(O)2-, -S(O)2N-, -NC(O)N-, - NC(O)O- or -OC(O)N- and R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, Cι-C6 alkyl which is optionally substituted, C2-C6 alkenyl which is optionally substituted, C2-C6 alkynyl which is optionally substituted or C3-C8 cycloalkyl which is optionally substituted.
More preferably R2 is hydrogen; Rl is hydroxy or NR5R4 where R5 is an hydrogen and R4 is alkyl which is optionally substituted, aryl which is optionally substituted, heteroarylalkyl which is optionally substituted or arylalkyl which is optionally substituted; and
when n=0, R3 is aryl which is optionally substituted or heteroaryl which is optionally substituted, or when n=l, Z is -NC(O)-, -C(O)N-, -NS(O)2-, - S(O)2N-, -NC(O)N-, -NC(O)O- or -OC(O)N- R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, Cι-C6 alkyl which is optionally substituted, C2-C6 alkenyl which is optionally substituted, C2-C6 alkynyl which is optionally substituted or C3-C8 cycloalkyl which is optionally substituted.
In one preferred embodiment of formula (II), R3 is selected from 4- hydroxymethyl-phenyl, 4-aminomethyl-phenyl and 3-hydroxymethyl-phenyl and perferably, Z is 0. Preferably, in this embodiment M is 2, R2 is H and Rl is 4-hydroxy.
Preferred compounds of formula II are given in the Examples.
Any known compound having a structural formula identical to any one of the compounds covered by formula (II) is hereby explicitly disclaimed per se.
In a further aspect the present invention provides a pharmaceutical formulation comprising a compound of formula II and a pharmaceutically acceptable diluent or carrier.
In a further aspect the invention provides a process for the preparation of a compound of formula II as mentioned above.
In a further aspect the invention provides a method for the prophylaxis or treatment of a JNK receptor-related disorder, which comprises administering
to a subject in need of such treatment an effective amount of a compound of formula II as mentioned above.
In a further aspect the present invention provides a method for modulating JNK receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula II or a pharmaceutical formulation comprising a compound of formula II.
In a further aspect the present invention provides a compound of formula II for use in therapy, especially for use in the prophylaxis or treatment of a JNK receptor-related disorder.
In a further aspect the present invention provides the use of a compound of formula II for the manufacture of a medicament for use in the prophylaxis or treatment of a JNK receptor-related disorder.
The compounds of formula I or II may be agonists, partial agonists or antagonists for the JNK receptor.
Examples of putative JNK receptor-related disorders are inflammatory and autoimmune disorders, such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis, transplant rejection, sceptic shock and bronchitis; cancer, in particular solid tumours, (including breast, colorectal and pancreatic cancer) small cell lung cancer, ovarian cancer and prostate cancer; vardiovascular diseases, including stroke, atherosclerosis, myocardial reperfusion injury, myocardial infarction and cardiac failure; angiogenesis; neurological disorders, such as stroke, ischaemia, head injury, Alzheimer's disease, Parkinson's disease, epilepsy, spinal cord injury, head trauma and also learning, memory and attention disorders, anxiety and panic disorders; opthalmic conditions including retinopathies and also macular degeneration and metabolic diseases such as diabetes, insulin resistance, obesity and metabolic syndrome.
The compounds of the invention may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g.
as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers. The separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns.
All diastereomeric forms possible (pure enantiomers, tautomers, racemic mixtures and unequal mixtures of two or more enantiomers) are within the scope of the invention. Such compounds can also occur as cis- or trans-, E- or Z- double bond isomer forms. All isomeric forms and mixtures thereof are contemplated.
In a further aspect the invention relates to methods of making compounds of any of the formulae herein comprising reacting any one or more of the compounds of the formulae delineated herein, including any processes delineated herein. The compounds of the invention above may be prepared by, or in analogy with, conventional methods.
The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. A pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Examples of addition salt forming acids are mentioned above.
The necessary starting materials for preparing the compounds of the invention are either known or may be prepared in analogy with the preparation of known compounds.
Definitions
The following definitions shall apply throughout the specification and the appended claims.
Preferably, unless otherwise stated or indicated, the term "alkyl" denotes a straight or branched alkyl group having from 1 to 6 carbon atoms ("Cι_6- alkyl"). Examples of said lower alkyl include methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl. For parts of the range "Cι-6-alkyl" all subgroups thereof are contemplated such as Cι-5-alkyl, C^-alkyl, Cι-3-alkyl, Cι-2-alkyl, C2.6-alkyl, C2. 5-alkyl, C2.4-alkyl, C2.3-alkyl, C3.6-alkyl, C4.5-alkyl, etc. "Halo~Cι-6-alkyl" means a Cι-6-alkyl group substituted with one or more halogen atoms. Likewise, "aryI-Cι-6-alkyl" means a Cι-6-alkyl group substituted with one or more aryl groups.
Preferably, unless otherwise stated or indicated, the term "cycloalkyl" denotes a cyclic alkyl group having a ring size from 3 to 8 carbon atoms. Examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, and cyclooctyl. For parts of the range "C3_8- cycloalkyl" all subgroups thereof are contemplated such as C3.7-cycloalkyl, C3. 6-cycloalkyl, C3.5-cycloalkyl, C3-4-cycloalkyl, C4.8-cycloalkyl, C4.7-cycloalkyl, C4.6- cycloalkyl, C4.5-cycloalkyl, C5.7-cycloalkyl, C6-7-cycloalkyl, etc.
Preferably, unless otherwise stated or indicated, the term "alkoxy" denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms. Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy. For parts of the range "Cι-6-alkoxy" all subgroups thereof are contemplated such as Cι-5-alkoxy, Cι-4-alkoxy, Cι-3-alkoxy, Cι-2-alkoxy, C2. 6-alkoxy, C2.5-alkoxy, C2.4-alkoxy, C2.3-alkoxy, C3.6-alkoxy, C4.5-alkoxy, etc.
Preferably, unless otherwise stated or indicated, the term "alkenyl" means a straight chain or branched alkenyl radical of 2 to 6 carbon atoms and containing one or more carbon-carbon double bonds and includes but is not limited to ethylene, π-propyl-1-ene, π-propyl-2-ene, isopropylene, etc.
Preferably, unless otherwise stated or indicated, the term "alkynyl" means a straight chain or branched alkynyl radical of 2 to 6 carbon atoms and
containing one or more carbon-carbon triple bonds and includes but is not limited to ethynyl, 2-methylethynyl etc.
Preferably, unless otherwise stated or indicated, the term "aryl" refers to a 3- 10 membered hydrocarbon ring system having at least one aromatic ring or being fused to one or more saturated or unsaturated rings including, but not limited to phenyl, pentalenyl, indenyl, indanyl, isoindolinyl, chromanyl, naphthyl, fluorenyl, anthryl, phenanthryl and pyrenyl. The aryl rings may optionally be substituted with Cι-6-alkyl. Examples of substituted aryl groups are benzyl and 2-methylphenyl. Likewise, aryloxy refers to an aryl group bonded to an oxygen atom.
Preferably, unless otherwise stated or indicated, the term "heteroaryl" refers to a 3-10 membered hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S. Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, indolyl, pyrazolyl, pyridazinyl, quinolinyl, benzofuranyl, dihydrobenzofuranyl, benzodioxolyl, benzodioxinyl, benzothiazolyl, benzothiadiazolyl, and benzotriazolyl groups.
Preferably, "heterocyclyl" means a 3-10 membered ring system containing one or more heteroatoms selected from N, O or S and includes heteroaryl. The heterocyclyl system can contain one ring or may be fused to one or more saturated or unsaturated rings; the heterocyclyl can be fully saturated, partially saturated or unsaturated and includes but is not limited to heteroaryl and heterocarbocyclyl. Examples of carbocyclyl or heterocyclyl groups include but are not limited to cyclohexyl, phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isoxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazine, phthalazine, piperazine, piperidine, pteridine, purine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine,
pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline, quinoline, quinoxaline, quinazoline, quinolizine, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, triazole, and trithiane.
Unless otherwise stated or indicated, the term "halogen" shall mean fluorine, chlorine, bromine or iodine.
Preferably, unless otherwise stated or indicated, the term "substituted" shall mean that one atom or group of atoms in a molecule is replaced by another atom or group and where optional substituents are referred to, but are not specified, suitable substituents include alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkoxy, aryloxy, halogen, hydroxy, NO2, CN, Cι-6-alkyl-CN, aryl, acetyl, 1, 2, 4-oxadiazoiylmethyl, CHO, NR3R4, CO2R3, CONR3R4, NR3(CO) R4, S(O)pR3; wherein R3 and R4 may be the same or different and are selected from hydrogen, alkyl which is optionally substituted, hydroxyalkyl which is optionally substituted, alkoxy which is optionally substituted, aryl which is optionally substituted, heteroaryl which is optionally substituted, heteroarylalkyl which is optionally substituted and arylalkyl which is optionally substituted; wherein p=l or 2.
The term "leaving group" refers to a group to be displaced from a molecule during a nucleophilic displacement reaction. Examples of leaving groups are bromide, chloride and methanesulfonate, especially bromide and methanesulfonate.
"Pharmaceutically acceptable" means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
"Treatment" as used herein includes prophylaxis of the named disorder or condition, or amelioration or elimination of the disorder once it has been established.
"An effective amount" refers to an amount of a compound that confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
The term "prodrug forms" means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug. Reference is made to Goodman and Gilman 's, The Pharmacological basis of Therapeutics, 8th ed., Mc-Graw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p. 13-15.
The following abbreviations have been used:
ACN means acetonitrile,
DEA means diethylamine, DEPT means distortion enhancement polarisation transfer,
DMSO means dimethyl sulfoxide,
ELS means electron light scattering,
HPLC means high performance liquid chromatography,
Rt means retention time, TFA means trifluoroacetic acid,
THF means tetrahydrofuran,
TLC means thin layer chromatography.
Clinical Use The compounds of the formula (I) may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof. The pharmacologically acceptable addition salts mentioned above are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds are able to form. Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid. Exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid,
toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like. Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and amino acids, such as, e.g. arginine and lysine. The term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates and the like.
For clinical use, compounds of the invention can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise at least one compound of the invention and at least one pharmaceutically acceptable carrier. As used herein the language "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients. Examples of excipients are water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. Such formulations may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like.
The formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc. The
formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections. Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.
A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as
lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, 'chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum mono stearate and gelatin.
Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a compound according to an embodiment of the invention) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as
colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
Systemic administration can also be by transmucosal or transdermal means.
For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art.
It is especially advantageous to formulate oral or parenteral compositions in
dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.
The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
The dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy. The daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
Within this specification embodiments have been described in a way that enables a clear and concise specification to be written, but it will be appreciated that embodiments may be variously combined or separated without parting from the invention.
The invention will now be further illustrated by the following non-limiting Examples.
EXAMPLES
Preferred compounds of formula I are shown in Table 1. Table 1
The activity of exemplary compounds of formula I is presented in Table 2, wherein "+" indicates active compounds and "++" indicates more active compounds. In Table 2, "++" represents an IC50<lμM, "+" represents lμM<IC50 <10μM and "nd" represents "not determined".
Table 2
Preferred compounds of formula II are shown in Table 3.
Table 3
The inhibitory activity on JNK of exemplary compounds of formula II is presented in Table 4, wherein "+" indicates active compounds and "++" indicates very active compounds. In Table 2, "++" represents an IC50<200nM, "+" represents 200nM<IC50 <lμM and "nd" represents "not determined".
Table 4
Remarkably, the present invention provides a class of compounds which interact selectively with the JNK receptor and not significantly with other members of the gene family. As evidence of this, in Table 5 the selectivity of a selection of compounds against a selection of kinases is presented.
Table 5
Experimental methods All reagents were commercial grade and were used as received without further purification, unless otherwise specified. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified.
Preparation Of A Pharmaceutical Composition
EXAMPLE 1: Preparation of tablets Ingredients mg/tablet
1. Active compound of formula (I) or (II) 10.0
2. Cellulose, microcrystalline 57.0 3. Calcium hydrogen phosphate 15.0
4. Sodium starch glycolate 5.0
5. Silicon dioxide, colloidal 0.25
6. Magnesium stearate 0.75
The active ingredient 1 is mixed with ingredients 2, 3, 4 and 5 for about 10 minutes. The magnesium stearate is then added, and the resultant mixture is mixed for about 5 minutes and compressed into tablet form with or without film-coating.
Preparation Of Compounds Of Formula (I)
General Scheme for synthesising compounds of formula (I)
6,8-Dibromo-imidazo[l,2-a]pyrazine (A) can be aminated with amines. The resultant compounds (B) are then Boc protected (C) and can then be reacted with the boronic acids and de-protected to yield the final compounds of formula (D) or be reacted with an amide in presence of copper iodide then de- protected to yield the final compounds of formula (E).
General Procedures: 6,8-Dibromo-imidazo[l,2-a]pyrazine A mixture of 2-Amino-3,5-dibromopyrazine (72.0 g, 285 mmol) in ethanol (1.1 L) was stirred at room temperature and treated with bromoacetaldehyde diethylacetal (97 mL, 640 mmol), water (72 mL) and concentrated hydrobromic acid (72 mL). The reaction was heated at reflux for five hours, then cooled slowly to room temperature over 16 hours. The resulting white precipitate was then filtered, resuspended in dichloromethane (2 L) and basified with aqueous sodium carbonate solution. After vigorous mixing, the organic phase was separated, dried over MgSO4 and concentrated in vacuo, to
give a pale yellow solid. Purification of the crude solid was achieved by suspending it in diisopropyl ether (500 mL) and stirring vigorously for one hour. The resulting suspension was filtered to give the title compound (A) as a pale yellow solid (74.5 g, 95 %). MPt: 168-170 °C
Typical example of compound of formula (B) General procedure for amine displacement
To a solution of 6,8-dibromoimidazo[1 ,2-a]pyrazine (10mmol) in 2-propanol (10ml) was added the amine (15mmol, 1.5eq.) and Λ/,A/-diisopropylethylamine (15mmol, 1.5eq.). The reaction was heated at 80°C for 18h. The mixture was concentrated in vacuo. The residue was partitioned between water and dichloromethane, the organic phase was separated, washed with water, brine, dried (MgSθ4) and concentrated in vacuo to give the desired product which was then purified by flash chromatography (ethyl acetate:hexane).
Example (6-Bromo-imidazo[lf2-a]pyrazin-8-yl)-cyclopropylmethyl amine
Following the above method for amine displacement, 1.39g of the title compound was obtained in 62% yield. δH(270MHz, CDCI3) 0.28-0.34 (2H, m, CH2), 0.54-0.62 (2H, m, CH2), 1.06- 1.20 (1H, m, 10-H), 3.41-3.46 (2H, m, 9-H), 6.24 (1H, br, NH), 7.43 (1H, d, J 1.2, 2-H), 7.47 (1H, d, J 1.2, 3-H ), 7.55 (1H, s, 4-H).
Typical example of compound of formula (C) General procedure for Boc protection
To a solution of the amine (6mmol) and 4-dimethylaminopyridine (0.6mmol, O.leq.) in tetrahydrofuran (6ml) was added di-tert-butyl carbonate (7.2mmol, 1.2eq.). The reaction was heated at 50°C for 18h. The mixture was concentrated in vacuo. The residue was partitioned between water and dichloromethane, the organic phase was separated, washed with 10% citric acid, saturated sodium bicarbonate, water, brine, dried (MgSO4) and concentrated in vacuo to give the Boc protected amine. The crude mixture was purified by flash chromatography (ethyl acetate :hexane).
Example
(6-Bromo-imidazo[lr2-a]pyrazin-8-yl)-cyclo propylmethyl carbamic acid tert butyl ester
Following the general method for Boc protection, 1.53g of the title compound was obtained in 80% yield. δH (270MHz, CDCI3) 0.17-0.20 (2H, m, CH2), 0.36-0.43 (2H, m, CH2), 1.20- 1.27 (1H, m, 10-H), 1.40 (9H, s, 3xCH3), 3.83-3.85 (2H, d, 7.1, 9-H), 7.64 (1H, d, J 1.0, 2-H), 7.77 (1H, d, J 1.2, 3-H), 8.13 (1H, s, 4-H).
Typical example of compound of formula (D)
General procedure for boronic acid coupling and Boc de-protection
To a solution of (6-Bromo-imidazo[l,2-a]pyrazin-8-yl)-cyclo propylmethyl carbamic acid tert butyl ester (0.2mmol) in dimethylformamide (0.5ml) was added a solution of boronic acid (0.24mmol, 1.2eq.) in dimethylformamide (0.6ml) and IM aqueous sodium bicarbonate solution (0.5ml). The reaction vessel was flushed with nitrogen. A stock solution of palladium acetate (63mg) and triphenylphosphine (223mg) in 1,4 dioxane (15ml) was prepared and (0.3mi), (0.005mmol, 0.025eq. of Pd), (0.005mmol, 0.025eq. of Pd) was added to the reaction vessel under nitrogen. The vessel was then sealed and heated at 80°C with agitation for 16h. The reaction mixture was filtered and concentrated in vacuo. The residue was suspended in dichloromethane (0.2ml) and trifluoro acetic acid (0.8ml) and agitated for lh. The mixture was concentrated in vacuo. The residue was dissolved in dimethylformamide (1.5ml), filtered and purified by prep-HPLC to give the desired compound.
Typical example of compound of formula (E)
N-{8-[(Pyridin-3-ylmethyl)-amino]-imidazo[l,2-a]pyrazin-6-yl}- benzamide.
A suspension of copper(I)iodide (100 mg, 0.53 mmol), (6-Bromo-imidazo[l,2- a]pyrazin-8-yl)-pyridin-3-ylmethyl-amine (430mg, 1.06 mol), benzamide (150mg, 1.35 mmol) and potassium carbonate (300 mg, 2.17 mmol) was prepared in dry toluene (50 mL) and the mixture purged with nitrogen for 15 minutes. Λ^/V'-dimethylethylenediamine (0.4 mL) was then added and the reaction stirred at room temperature for 15 minutes then heated to reflux for 16 hours. The resulting suspension was cooled to room temperature and
filtered through a short silica pad with dichloromethane (100 mL) and ethylacetate (100 mL). Combined filtrates were concentrated in vacuo, then suspended in dichloromethane (0.2ml) and trifluoroacetic acid (0.8ml), agitated for 1 hour, then concentrated in vacuo. The crude material was recrystallised from toluene to give the title compound as a white solid (190 mg, 52 %). MPt: 170-173 °C. LCMS (AP+): 345 [100 %, (M+H)+j\
Preparation Of Compounds Of Formula (II)
General Scheme for synthesising compounds of formula (II)
6,8-Dibromo-imidazo[l,2-a]pyrazine (A) can be aminated with amines. The resultant compounds (B) can then be reacted with the boronic acids to yield the final compounds of formula (C) or be reacted with an amide in presence of cupper iodide to yield the final compounds of formula (D).
General Procedures: 6,8-Dibromo-imidazo[l,2-a]pyrazine
A mixture of 2-Amino-3,5-dibromopyrazine (72.0 g, 285 mmol) in ethanol (1.1 L) was stirred at room temperature and treated with bromoacetaldehyde diethylacetal (97 mL, 640 mmol), water (72 mL) and concentrated hydrobromic acid (72 mL). The reaction was heated at reflux for five hours, then cooled slowly to room temperature over 16 hours. The resulting white
precipitate was then filtered, resuspended in dichloromethane (2 L) and basified with aqueous sodium carbonate solution. After vigorous mixing, the organic phase was separated, dried over MgSO4 and concentrated in vacuo, to give a pale yellow solid. Purification of the crude solid was achieved by suspending it in diisopropyl ether (500 mL) and stirring vigorously for one hour. The resulting suspension was filtered to give the title compound as a pale yellow solid (74.5 g, 95 %). MPt: 168-170 °C
Typical example of compound of formula (B) General procedure for amine displacement
A mixture of 6,8-dibromo-imidazo[l,2-a]pyrazine (1.0 g, 3.6 mmol) and amine (4.0 mmol) was prepared in a microwave reaction tube with magnetic stirrer. To this was added ethyldiisopropylamine (0.63 mL, 4.0 mmol) and ethanol (2.5 mL). The reaction tube was sealed and placed in a microwave reactor and heated at 160 °C for 20 minutes, with stirring. The reaction was then cooled and dichloromethane (15 mL) and water (10 mL) were added. The product was extracted with dichloromethane (2 x 10 mL) and the combined organics then washed with brine (10 mL) and dried over MgSO4. Purification of the crude was achieved by flash column chromatography (0 to 10 % methanol in dichloromethane).
Example 4-(6-Bromo-imidazo[l/2-a]pyrazin-8-ylamino)-cyclohexanol
Following the General procedure for amine displacement reactions, 6,8- dibromo-imidazo[l,2-a]pyrazine (1.0 g, 3.6 mmol) and trans-4- aminocyclohexanol hydrochloride (4.0 mmol, 602 mg) were coupled to give the title compound as an off-white solid (839 mg, 2.7 mmol, 76 %). MPt: 141-144 °C
Typical example of compound of formula (C) General procedure for boronic acid coupling
A mixture of bromo-imidazo[l,2-a]pyrazine (B) (0.3 mmol) and boronic acid
(0.36 mmol) was prepared in a microwave reaction tube with magnetic stirrer.
To this was added sodium carbonate (95 mg, 0.9 mmol), triphenylphosphine (24 mg, 0.09 mmol) and palladium acetate (7 mg, 0.03 mmol) followed by
dimethoxyethane (1.5 mL) and water (0.5 mL). The reaction tube was flushed with nitrogen, then sealed and placed in a microwave reactor and heated at 150 °C for 45 minutes, with stirring. The reaction was then cooled and ethylacetate (15 mL) and water (10 mL) were added. The dark mixture was filtered free of palladium residues and the organics extracted into ethylacetate (2 x 10 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. Purification of the crude material was achieved by preparative HPLC or by silica chromatography using a Biotage system eluting with a gradient of 0 % methanol in dichloromethane to 25 % methanol in dichloromethane, over 36 x 20 mL fractions.
Example
3-[8-(4-Hydroxy-cyclohexylamino)-imidazo[lr2-a]pyrazin-6-γl]-N- methyl-benzamide Following the General procedure for boronic acid coupling, 4-(6-Bromo- imidazo[l,2-a]pyrazin-8-ylamino)-cyclohexanol (93 mg, 0.3 mmol) and 3-(/V- methylaminocarbonyl)phenylboronic acid (65 mg, 0.36 mmol) were coupled to give the title compound as an off-white solid (45 mg, 0.12 mmol, 41 %).LCMS (ES+): 366 [100 %, (M+H)+]. XH NMR (400 MHz, 6-DMSO): δ/ppm 8.54 (q, IH, J=4.3 Hz), 8.47 (s, IH), 8.44 (s+fs, IH), 8.15 (d, IH, J=8.1 Hz), 7.93 (d, IH, J = 1.0 Hz), 7.82 (d, IH, J=7.8 Hz), 7.58 (t, IH, J=7.8 Hz), 7.55 (d, IH, 0.8 Hz), 7.26 (d, IH, J=7.8 Hz), 4.62 (d, IH, J=4.3 Hz), 4.11-4.21 (m, IH), 3.44-3.55 (m, IH), 2.86 (d, 3H, J=4.5 Hz), 1.89-2.08 (m, 4H), 1.32-1.60 (4H, m).
Typical example of compound of formula (D)
N-[8-(4-Hydroxy-cyclohexylamino)-imidazo[lr2-a]pyrazin-6-yl]-2- thiophen-2-yl-acetamide.
A suspension of copper(I)iodide (100 mg, 0.53 mmol), 4-(6-Bromo- imidazo[l,2-a]pyrazin-8-ylamino)-cyclohexanol (330 mg, 1.06 mol), thiophene-2-acetamide (190 mg, 1.35 mmol) and potassium carbonate (300 mg, 2.17 mmol) was prepared in dry toluene (50 mL) and the mixture purged with nitrogen for 15 minutes. ΛrVV'-dirnethylethylenediamine (0.4 mL) was then added and the reaction stirred at room temperature for 15 minutes then heated to reflux for 16 hours. The resulting suspension was cooled to room
temperature and filtered through a short silica pad with dichloromethane (100 mL) and ethylacetate (100 mL). Combined filtrates were concentrated in vacuo and the crude material was then purified by flash column chromatography (100 % ethylacetate) to give the title compound as a viscous orange oil (149 mg, 0.40 mmol, 38 %).LCMS (AP+): 372 [100 %, (M+H)*]1!! NMR (400 MHz, d6-DMSO): δ/ppm 8.48 (s, IH), 7.57 (s, IH), 7.45 (d, IH, 3=1.0 Hz), 7.43 (d, IH, J=1.0 Hz), 7.30 (dd, IH, 3=4.0, 2.5 Hz), 7.04 (s, IH), 7.02-7.04 (m, IH), 5.88 (d, IH, 3=8.1 Hz), 3.95 (s, 2H), 3.86-3.94 (m, IH), 3.66-3.73 (m, IH), 2.00-2.17 (m, 4H), 1.84 (br. s, IH), 1.29-1.50 (m, 4H).
Biological Methods For Formula (I) And (II) Experimental methods
A JNK screening assay was performed in a 384-well and 96-well flashplate format. The kinetics of the reaction were determined under the following conditions: 0.2μCi; 33P-ATP; 1.5μM ATP; 2mU JNKlαl; 2μM c-jun (1-79) peptide substrate incubated for 30 minutes at room temperature.
A standard ATP concentration of 0.1 x Km (Km previously defined as 15μM) was employed. For example the Km for JNKlαl was derived as 4μM (4.7 and 4.0μM independent observations). The kinetics of the reaction were determined under the following conditions 0.2μCi 33P-ATP; 1.5μM ATP; 2mU JNKlαl; 2μM c-jun (1-79) peptide substrate incubated for 30 minutes at room temperature.
The assay, as described, was then validated using both staurosporine and 3NK inhibitor II as standard inhibitors.
It will be appreciated by those skilled in the art that the foregoing description is exemplary and explanatory in nature, and is intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognise apparent modifications and variations that may be made without departing from the spirit as scope of the invention as defined in the appended claims.
Claims
1. A compound of formula I: x
wherein, X is -NHR6, -NR6R7 or -OR6;
R6 and R7 which may be the same or different are hydrogen, heteroaryl-Cι-6-alkyI optionally independently substituted with one or more of Cι-6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O- CF3, amino-methyl, amino, Cι-6-aminoalkyl, hydroxy, Cι-6-hydroxyalkyl, halogen, halo Cι-6-alkyl, heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, Cι-6-alkylamino, di-Cι-6-alkylamino, carboxy, CO2Me, SONH2, and NO2, or heteroaryloxy-Cι-6-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O- CF3, amino-methyl, amino, Cι-6-aminoalkyl, hydroxy, Ci-6-hydroxyalkyl, halogen, halo Cι-6-alkyl, heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, Cι_6-alkylamino, di-Cι-6-alkylamino, carboxy, CO2Me, SONH2 and NO2, or heteroaryl optionally independently substituted with one or more of Cι-6- alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino- methyl, amino, Cι-6-aminoalkyl, hydroxy, Cι-6-hydroxyalkyl, halogen, halo Ci-e-alkyl, heterocyclyl which is optionally substituted, heterocyclyl- Cl-6-alkyl which is optionally substituted, CN, dimethylamino, Cι-6- alkylamino, di-Cι-6-alkylamino, carboxy, CO2Me, SONH2 and NO2, or heteroarylamino-Cι-6-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino-methyl, amino, Cι.6-aminoalkyl, hydroxy, Ci-e- hydroxyalkyl, halogen, halo Cι-6-alkyl , heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, Cι-6-alkylamino, di-Cι_6-alkylamino, carboxy, CO2Me, SONH2 and NO2, or aryl-Cι-6-alkyl optionally independently substituted with one or more of Ci-e-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3 amino-methyl, amino, Cι-6-aminoalkyl, hydroxy, Ci-e-hydroxyalkyl, halogen, halo Cι-6-alkyl, heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, Cι-6-alkylamino, di-Cι-6-alkylamino, carboxy, CO2Me, SONH2 and NO2, or aryloxy-Cι-6-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino-methyl, amino, Cι-6-aminoalkyl, hydroxy, Cι-6- hydroxyalkyl, halogen, halo Cι-6-alkyl, heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, Cι_6-alkylamino, di-Cι-6-alkylamino, carboxy, CO2Me, SONH2 and NO2, or aryl optionally independently substituted with one or more of Cι-6- alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino- methyl, amino, Cι-6-aminoalkyl, hydroxy, Ci-6-hydroxyalkyl, halogen, halo Cι-6-alkyl, heterocyclyl which is optionally substituted, heterocyclyl- Cl-6-alkyl which is optionally substituted, CN, dimethylamino, Cι-6- alkylamino, di-Cι-6-alkylamino, carboxy, CO2Me, SONH2 and NO2, or Cι_6-alkyl optionally independently substituted with one or more of Ci-e-alkoxy, aryl, heteroaryl, cycloalkyl, CONMe2, CO2Me, CO2tBu, N(COCH2OEt)2, NHCOMe, amino, dimethylamino, Cι_6-alkylamino, di-Ci- 6-alkylamino and heterocyclyl which is optionally substituted, or C3.8-cycloalkyl, optionally independently substituted with one or more of Cι-6-alkoxy which is optionally substituted, aryl which is optionally substituted, heteroaryl which is optionally substituted, alkyl which is optionally substituted, alkoxy which is optionally substituted, aryloxy which is optionally substituted, halogen, hydroxy, CN, CO2H, NR5R4, CO2R5, CONR5R4, NR5(CO)R4, S(O)pR5, wherein R5 and R4 can be the same or different and are selected from hydrogen, alkyl which is optionally substituted, aryl which is optionally substituted, heteroaryl which is optionally substituted, heteroarylalkyl which is optionally substituted, alkyl and arylalkyl which is optionally substituted, and p = 1 or 2; or C3.8 cycloalkyl-Cι-6-aIkyl, optionally independently substituted with one or more of Ci-e-alkoxy, aryl, heteroaryl, or heterocyclyl optionally independently substituted with one or more of COMe, SO2Me;
z is -NC(O)-, -C(O)N-, -NS(O)2-, S(O)2N-, -NC(O)N-, -NC(O)O- or -OC(O)N-;
n is 0 or 1
R3 is: heteroaryl-Cι-6-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O- CF3, amino-methyl, amino, Cι-6-aminoalkyl, dimethylamino, Cι_6- alkylamino, di-Cι-6-alkylamino, hydroxy, Ci-e-hydroxyalkyl, Cι-6-alkenyl, halogen and halo Cι-6-alkyl, Cι-6-carboxyalkyl, Cι-6-carboxyalkenyl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6-alkyl, Cι-6-alkoxy, aryl, heteroaryl and Cι-5-hydroxyalkyl; or heteroaryloxy-Cι-6-alkyl optionally independently substituted with one or more of Cι_6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O- CF3, amino-methyl, amino, Cι-6-aminoalkyl, dimethylamino, Cι-6- alkylamino, di-Cι-6-alkylamino, hydroxy, Ci-e-hydroxyalkyl, Cι-6-alkenyl, halogen and halo Cι-6-alkyl, Cι-6-carboxyalkyl, Cι-6-carboxyalkenyl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6-alkyl, Cι_6-alkoxy, aryl, heteroaryl and Cι-6-hydroxyalkyl; or heteroaryl optionally independently substituted with one or more of Cι_6- alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino- methyl, amino, Cι-6-aminoalkyl, dimethylamino, Cι-6-alkylamino, di-Cι_6- alkylamino, hydroxy, Ci-6-hydroxyalkyl, Cι_6-alkenyl, halogen and halo Ci-e-alkyl, Cι-6-carboxyalkyl, Ci-6-carboxyalkenyl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6-alkyl, Ci- e-alkoxy, aryl, heteroaryl and Ci-6-hydroxyalkyl; or aryl-Cι-6-alkyl optionally independently substituted with one or more of Ci-e-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino-methyl, amino, Cι-6-aminoalkyl, dimethylamino, Cι-6-alkylamino, di-Cι-6-alkylamino, hydroxy, Ci-6-hydroxyalkyl, Cι-6-alkenyl, halogen and halo Ci-e-alkyl, Cι-6-carboxyalkyl, Cι.6-carboxyalkenyl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6-alkyl, Ci- 6-alkoxy, aryl, heteroaryl, Cι-6-hydroxyalkyl; or aryloxy-Cι-6-alkyl optionally independently substituted with one or more of Cι-6-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino-methyl, amino, Cι-6-aminoalkyl, dimethylamino, Cι-6-alkylamino, di-Cι-6-aIkylamino, hydroxy, Cι-6-hydroxyalkyl, Cι-6-alkenyl, halogen and halo Ci-e-alkyl, Cι-6-carboxyalkyl, Cι-6-carboxyalkenyl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6-alkyl, Ci- 6-alkoxy, aryl, heteroaryl, Cι-6-hydroxyalkyl; or aryl optionally independently substituted with one or more of Cι-6- alkoxy, Cι_6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino- methyl, amino, Cι-6-aminoalkyl, dimethylamino, Cι-6-alkylamino, di-Cι-6- alkylamino, hydroxy, Ci-6-hydroxyalkyl, Cι_6-alkenyl, halogen and halo Ci-e-alkyl, Cι-6-carboxyalkyl, Cι-6-carboxyalkenyl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6-alkyl, Ci- 5-alkoxy, aryl, heteroaryl, Ci-6-hydroxyalkyl; or Ci-e-alkyl optionally independently substituted with one or more of Ci-e-alkoxy, Cι_6-alkenyl, aryl, heteroaryl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6-alkyl, Cι-6- alkoxy, aryl, heteroaryl and Cι-6-hydroxyalkyl; or C3.8-cycloalkyl optionally independently substituted with one or more of Ci-e-alkoxy, Cι-6-alkenyl, aryl, heteroaryl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, Cι-6-alkyl, Cι-6- alkoxy, aryl, heteroaryl and Cι-5-hydroxyalkyl; arylalkenyl which is optionally substituted; or heteroarylalkenyl which is optionally substituted; or arylalkynyl which is optionally substituted; or heteroarylalkynyl which is optionally substituted; or a pharmaceutically acceptable salt, hydrate, solvate, geometrical isomer, tautomer, optical isomer, or prodrug form thereof.
2. A compound according to claim 1 wherein substituents are selected from alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkoxy, aryloxy, halogen, hydroxy, NO2, CN, Cι-6 hydroxyalkyl, hydroxy methyl, Cι-6-aminoalkyl, aminomethyl, NR5R4, CO2R5, CONR5R4, NR5(CO) R4, S(O)pR5; wherein R5 and R4 which may be the same or different are selected from hydrogen, alkyl which is optionally substituted, hydroxyalkyl which is optionally substituted, alkoxy which is optionally substituted, aryl which is optionally substituted, heteroaryl which is optionally substituted, heteroarylalkyl which is optionally substituted and arylalkyl which is optionally substituted; wherein p=l or 2.
3. A compound according to claim 1 or 2 wherein R7 is hydrogen and R6 is heteroaryl-Cι-6-alkyl optionally independently substituted with one or more of Ci-e-alkoxy, Cι-6-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino- methyl, amino, Cι-6-aminoalkyl, hydroxy, Cι-6-hydroxyalkyl, halogen, halo Cι-6- alkyl, heterocyclyl which is optionally substituted, CN, dimethylamino, Cι-6- alkylamino, di-Cι-6-alkylamino, carboxy, CO2Me, SONH2, heterocyclyl which is optionally substituted and heterocyclyl-Cl-6-alkyl which is optionally substituted.
4. A compound according to any one of the preceding claims wherein R6 is pyridyl-alkyl which is optionally substituted and R7 is hydrogen.
A compound according to claim 1 or 2 wherein R6 and R7 which may be the same or different are selected from the following:
lylmethyl 
uO NMe-
A compound according to any one of the preceding claims wherein R3 is aryl or heteroaryl optionally independently substituted with one or more of Ci-e- alkoxy, Ci-e-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF3, amino-methyl, amino, Cι-6-aminoalkyl, hydroxy, Cj-6-hydroxyalkyl, Cι-6-alkenyl, halogen and halo Ci-e-alkyl, Cι-6-carboxyalkyl, Cι-6-carboxyalkenyl, CONR4R5, CO2H, NHCOR4, NHS(O)2R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different are either hydrogen, Cι-6-alkyl, Cι-6-alkoxy, aryl, heteroaryl, Cι-6- hydroxyalkyl.
A compound according to any one of the preceding claims wherein R3 is phenyl; furan; phenylmethanol; hydroxymethyl-phenyl, optionally being 4- hydroxymethyl-phenyl or 3-hydroxymethyl-phenyl; or aminomethyl-phenyl optionally being 4-aminomethyl-phenyl.
8. A compound of formula (I) selected from:
9. A compound of the Formula (II): 
wherein, m=0, 1,2,3;
Rl and R2 which may be the same or different can be hydrogen, alkyl which is optionally substituted, alkoxy which is optionally substituted, aryloxy which is optionally substituted, halogen, hydroxy, CN, CO2H, NR5R4, CO2R5, CONR5R4, NR5(CO)R4, S(O)pR5; wherein R5 and R4 can be the same or different and are selected from hydrogen, alkyl which is optionally substituted, aryl which is optionally substituted, heteroaryl which is optionally substituted, heteroarylalkyl which is optionally substituted, alkyl and arylalkyl which is optionally substituted, and p = 1 or 2;
R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, heteroarylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, or heteroarylalkynyl which is optionally substituted, alkyl, cycloalkyl;
n=0 or 1;
when n = l, Z is -NC(O)-, -C(O)N-, -NS(O)2-, -S(O)2N-, -NC(O)N-, -NC(O)O- or -OC(O)N- and R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, Cι-C6 alkyl which is optionally substituted, C2-C6 alkenyl which is optionally substituted, C2-C6 alkynyl which is optionally substituted, C3-C8 cycloalkyl which is optionally substituted; when n=0 R3 is aryl which is optionally substituted or heteroaryl which is optionally substituted; or a pharmaceutically acceptable salt, hydrate, solvate, geometrical isomer, tautomer, optical isomer, or prodrug form thereof,
10. A compound according to claim 9 wherein Rl is in the 3 or 4 position.
11. A compound according to claim 9 or 10 wherein the substituents are selected from alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkoxy, aryloxy, halogen, hydroxy, NO2, CN, Cι-6 hydroxyalkyl, hydroxymethyl, Cι-6-aminoalkyl, aminomethyl, NR5R4, CO2R5, CONR5R4, NR5(CO) R4, S(O)pR5; wherein R5 and R4 which may be the same or different are selected from hydrogen, alkyl which is optionally substituted, hydroxyalkyl which is optionally substituted, alkoxy which is optionally substituted, aryl which is optionally substituted, heteroaryl which is optionally substituted, heteroarylalkyl which is optionally substituted and arylalkyl which is optionally substituted; wherein p=l or 2.
12. A compound according to any one of claims 9 to 11 wherein m=2.
13. A compound according to any one of claims 9 to 12 wherein R2 is hydrogen, alkyl which is optionally substituted, alkoxy which is optionally substituted, aryloxy which is optionally substituted, halogen, hydroxy, CN, CO2H, NR5R4, CO2R5, CONR5R4, NR5(CO)R4, or S(O)pR5; wherein R5 and R4 may be the same or different and are selected from hydrogen, alkyl which is optionally substituted, aryl which is optionally substituted, heteroarylalkyl which is optionally substituted and arylalkyl which is optionally substituted.
14. A compound according to any one of claims 9 to 13 wherein R2 is hydrogen.
15. A compound according to any one of claims 9 to 14 wherein Rl is hydroxy or NR5R4 where R5 is hydrogen and R4 is alkyl which is optionally substituted, aryl which is optionally substituted, heteroarylalkyl which is optionally substituted or arylalkyl which is optionally substituted.
16. A compound according to any one of claims 9 to 15 wherein n=0 and R3 is aryl which is optionally substituted or heteroaryl which is optionally substituted.
17. A compound according to any one of claims 9 to 15 wherein n=l; Z is -NC(O)- , -C(O)N-, -NS(O)2-, -S(O)2N-, -NC(O)N-, -NC(O)O- or -OC(O)N-; and R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, Cι-C6 alkyl which is optionally substituted, C2-C6 alkenyl which is optionally substituted, C2-C6 alkynyl which is optionally substituted or C3-C8 cycloalkyl which is optionally substituted.
18. A compound according to any one of claims 9 to 17 wherein R3 is selected from 4-hydroxymethyl-phenyl, 4-aminomethyl-phenyl and 3-hydroxymethyl- phenyl and Z is 0. Preferably, in this embodiment M is 2, R2 is H and Rl is 4- hydroxy.
19. A compound of formula (II) selected from:
4-[6-(3-Amino-phenyI)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexanol
{3-[8-(4-Hydroxy-cyclohexylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-phenyl}- morpholin-4-yl-methanone
3-[8-(4-Hydroxy-cyclohexylamino)-imidazo[1,2-a]pyrazin-6-yl]-N-phenyl- benzamide
N-[6-(3-Chloro-4-fluoro-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-N'-pyridin-4- ylmethyl-cyclohexane-1,4-diamine 3-[8-(4-Hydroxy-cyclohexylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-benzoic acid
4-[8-(4-Hydroxy-cyclohexylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-phenol
3-[8-(4-Hydroxy-cyclohexylamino)-imidazo[1,2-a]pyrazin-6-yl]-N-(2-hydroxy- ethyl)-benzamide
4-[6-(3-Hydroxymethyl-phenyl)-imidazo[1 ,2-a]pyrazin-8-ylarnino]- cyclohexanol
3-[8-(4-Hydroxy-cyclohexylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-N,N-dimethyl- benzamide
3-[8-(4-Hydroxy-cyclohexylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-N-methyl- benzamide
4-(6-Benzofuran-2-yl-imidazo[1 ,2-a]pyrazin-8-ylamino)-cyclohexanol
4-[6-(4-Aminomethyl-phenyl)-imidazo[1 ,2-a]pyrazin-8-ylamino]-cyclohexanol
4-[8-(4-Hydroxy-cyclohexylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-benzoic acid
4-(6-Furan-3-yl-imidazo[1,2-a]pyrazin-8-ylamino)-cyclohexanol
[6-(3-Chloro-4-fluoro-phenyl)-imidazo[1 ,2-a]pyrazin-8-yl]-cyclohexyl-amine
N-[6-(3-Chloro-4-fluoro-phenyl)-imidazo[1 ,2-a]pyrazin-8-yl]-cyclohexane-1 ,4- diamine
4-[6-(2-Methoxy-phenyl)-imidazo[1 ,2-a]pyrazin-8-ylamino]-cyclohexanol 4-[6-(4-Dimethylamino-phenyl)-imidazo[1 ,2-a]pyrazin-8-ylamino]- cyclohexanol
3-[8-(1-Methylcarbamoyl-ethylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-benzamide
N-[8-(4-Hydroxy-cyclohexylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-2-thiophen-2- yl-acetamide
3-[8-(4-Hydroxy-cyclohexylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-phenol
4-[6-(3-Dimethylamino-phenyl)-imidazo[1 ,2-a]pyrazin-8-ylamino]- cyclohexanol
4-(6-Pyridin-3-yl-imidazo[1 ,2-a]pyrazin-8-ylamino)-cyclohexanol
4-(6-Pyridin-4-yi-imidazo[1 ,2-a]pyrazin-8-ylamino)-cyclohexanol
N-[8-(4-Hydroxy-cyclohexylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-benzamide
3-[8-(4-Hydroxy-cyclohexylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-benzamide
4-[6-(4-Hydroxymethyl-phenyl)-imidazo[1 ,2-a]pyrazin-8-ylamino]- cyclohexanol
N-{3-[8-(4-Hydroxy-cyclohexylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-phenyl}- acetamide
4-[6-(3-Chloro-4-fluoro-phenyl)-imidazo[1 ,2-a]pyrazin-8-ylamino]- cyclohexanol
4-[6-(4-Hydroxymethyl-phenyl)-imidazo[1 , 2-a]pyrazin-8-ylamino]- cyclohexanol 4-[6-(4-Aminomethyl-phenyl)-imidazo[1 , 2-a]pyrazin-8-ylamino]-cyclohexanol
4-[6-(3-Hydroxymethy!-phenyl)-imidazo[1, 2a]pyrazin-8-ylamino]- cyclohexanol
20. A pharmaceutical formulation comprising a compound according to any preceding claim and a pharmaceutically acceptable diluent or carrier.
21. A process for the preparation of a compound according to any one of claims 1 to 19, which comprises at least one of the steps of: a) reaction of a first intermediate compound with a second intermediate compound; and b) obtaining a compound according to any one of claims 1 to 19.
22. A method according to claim 21 which comprises all of steps a) to b).
23. A method for the prophylaxis or treatment of a 3NK receptor-related disorder, which comprises administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutical formulation according to claim 20.
24. The method according to claim 23, wherein the disorder is selected from inflammatory and autoimmune disorders, such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis, transplant rejection, septic shock and bronchitis; cancer, in particular solid tumours (including breast, colorectal and pancreatic cancer), small cell lung cancer, ovarian cancer and prostate cancer; cardiovascular diseases, such as stroke, atherosclerosis, myocardial reperfusion injury, myocardial infarction and cardiac failure; angiogenesis; neurological disorders, such as stroke, ischaemia, head injury, Alzheimer's disease, Parkinson's disease, epilepsy, spinal cord injury, head trauma and also learning, memory and attention disorders, anxiety and panic disorders; an opthalmic condition selected from retinopathies and macular degeneration; and metabolic diseases such as diabetes, insulin resistance, obesity and metabolic syndrome.
25. A method for modulating 3NK receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutical formulation according to claim 20.
26. A compound according to any one of claims 1 to 19 for use in therapy.
27. Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for use in the prophylaxis or treatment of a JNK receptor- related disorder.
28. The use according to claim 27, wherein the disorder is selected from inflammatory and autoimmune disorders, such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis, transplant rejection, septic shock and bronchitis; cancer, in particular solid tumours (including breast, colorectal and pancreatic cancer), small cell lung cancer, ovarian cancer and prostate cancer; cardiovascular diseases, such as stroke, atherosclerosis, myocardial reperfusion injury, myocardial infarction and cardiac failure; angiogenesis; neurological disorders, such as stroke, ischaemia, head injury, Alzheimer's disease, Parkinson's disease, epilepsy, spinal cord injury, head trauma and also learning, memory and attention disorders, anxiety and panic disorders; an opthalmic condition selected from retinopathies and macular degeneration; metabolic diseases such as diabetes, insulin resistance, obesity and metabolic syndrome.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0404889A GB0404889D0 (en) | 2004-03-04 | 2004-03-04 | Compounds which interact with protein kinases |
| GB0404889.8 | 2004-03-04 | ||
| GB0426259A GB0426259D0 (en) | 2004-11-30 | 2004-11-30 | Compounds which interact with protein kinases |
| GB0426259.8 | 2004-11-30 |
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| Publication Number | Publication Date |
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| WO2005085252A1 true WO2005085252A1 (en) | 2005-09-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB2005/000842 WO2005085252A1 (en) | 2004-03-04 | 2005-03-04 | Imidazo ‘1,2-a’ pyrazine compounds which interact with protein kinases |
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| WO (1) | WO2005085252A1 (en) |
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