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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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  • A61P3/00—Drugs for disorders of the metabolism
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• • A—HUMAN NECESSITIES
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  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
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  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
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  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the invention relates to certain pyrazine and pyridine compounds that act as inhibitors of the MAP kinase interacting kinases MNK2a, MNK2b and MNKl .
• the invention further relates to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the preparation of a medicament for the prophylaxis and treatment of type 2 diabetes, obesity and in- flammatory conditions, as well as methods of treatment of these disorders.
• Insulin One of the major hormones that influences metabolism is insulin, which is synthesized in the beta cells of the islets of Langerhans of the pancreas. Insulin primarily regulates the direction of metabolism, shifting many processes toward the storage of substrates and away from their degradation (for reviews, see e.g. Shepherd, P. R. et al. ( 1998) Biochem. J. 333: 471-490; Alessi, D. R. & Downes, C. P. (1998) Biochim. Biophys. Acta 1436: 151- 164). Insulin is be- lieved to to be involved in the transport of glucose and amino acids as well as key minerals such as potassium, magnesium, and phosphate from the blood into cells.
• Insulin is also believed to regulate a variety of enzymatic reactions within the cells, which involve the synthesis of large molecules from smaller building block units.
• a deficiency in the action of insulin can cause severe impairment in (i) the storage of glucose in the form of glycogen and the oxidation of glucose for energy; (ii) the synthesis and storage of fat from fatty acids and their precursors and the completion of fatty-acid oxidation; and (iii) the synthesis of proteins from amino acids.
• Type I diabetes insulin-dependent diabetes mellitus (IDDM; formerly referred to as juvenile onset diabetes), for which administration of insulin is required. In this type, insulin is not secreted by the pancreas and hence must be administered.
• Type II diabetes i.e. non-insulin- dependent diabetes mellitus (NIDDM)
• NIDDM non-insulin- dependent diabetes mellitus
• Type II diabetes is characterized clinically by hypergly- cemia and insulin resistance and is commonly associated with obesity.
• Type II diabetes is a heterogeneous group of disorders in which hyperglycemia typi- cally results from both an impaired insulin secretory response to glucose and decreased insulin effectiveness in stimulating glucose uptake by skeletal muscle and in restraining hepatic glucose production (insulin resistance) .
• Glucose homeostasis depends upon a balance between glucose production by the liver and glucose utilization by insulin-dependent tissues, such as fat and muscle, and insulin-independent tissues, such as brain and kidney.
• insulin-dependent tissues such as fat and muscle
• insulin-independent tissues such as brain and kidney.
• type II diabetes the entry of glucose into fat and muscle is reduced and glucose pro- duction in the liver is increased, due to insulin resistance in the tissues.
• the receptor tyrosine kinases are a class of cell-surface receptors.
• the ligands for RTKs include peptide /protein hormones including nerve growth factor (NGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and insulin. Binding of a ligand to an RTK is believed to stimulate the receptor's intrinsic protein-tyrosine kinase activity, which subsequently can stimulate a signal-transduction cascade leading to changes in cellular physiology and patterns of gene expression.
• RTK signaling pathways have a wide spectrum of functions including regulation of cell proliferation and differentia- tion, promotion of cell survival, and modulation of cellular metabolism.
• Ras is a GTP-binding switch protein that acts in a manner similar to a key signaling molecule in pathways triggered by activation of RTKs.
• Ras-linked RTKs in mammalian cells appear to utilize a highly conserved sig- nal-transduction pathway in which activated Ras induces a kinase cascade that culminates in the activation of MAP kinase (mitogen-activated protein kinase).
• MAP kinase mitogen-activated protein kinase
• This serine /threonine kinase which can translocate into the nucleus, phosphorylates many different proteins including transcription factors that regulate expression of what are considered to be important cell-cycle and dif- ferentiation-specific proteins.
• the murine MNKl and MNK2 gene products (“MAP kinase interacting kinase” or “MAP kinase signal-integrating kinase” 1 and 2) are single-domain serine/threonine kinases that share 72% sequence identity (Waskiewicz A.J. et al. ( 1997) EMBO J. 16: 1909- 1920; GenBank Accession Nos. Yl 1091 and Yl 1092). Human MNKl has also been described (Fukunaga, R. et al. (1999) EMBO J. 16: 1921- 1933; GenBank Accession No. AB000409). All these three proteins were identified, in part, by their ability to bind tightly to MAP kinases.
• MNKl and 2 bind the extracellular signal- regulated kinases ERKl and ERK2, and MNKl also binds the stress-activated kinase, p38.
• the eukaryotic initiation factor 4E (eIF4E) has been identified as one of the physiological substrates of MNKl and MNK2 (Scheper, G. C. et al. (2001) MoI. Cell. Biol. 21 : 743-754).
• elFs such as eIF4E
• growth- promoting e.g. cyclin D
• metastasis-related mRNAs e.g. vascular endothelial growth factor
• the human mnk2 gene has been identified and characterized through a yeast two-hybrid screen in which the MNK2 protein interacted with the ligand- binding domain of the estrogen receptor (ER ⁇ ) (Slentz-Kesler, K. et al. (2000) Genomics 69: 63-71). It was shown that the human mnk2 gene has two C- terminal splice variants, designated mnk2a (the nucleotide and amino acid se- quences of mnk2a and MNK2a, respectively, are designated SEQ ID NOS: 1 and 2, respectively; GenBank Accession No.
• mnk2b the nucleotide and amino acid sequences of mnk2b and MNK2b, respectively, are designated SEQ ID NOS: 3 and 4, respectively; GenBank Accession No. AF237776).
• the two isoforms have been shown to be identical over the first 385 amino acids of the coding sequence and differ only in the final exon which encodes an additional 80 residues for mnk2a and 29 residues for mnk2b. It was further shown that the MNK2 interaction was selective for estrogen receptor (ER) as opposed to ERI and that the interaction was specific to MNK2b as opposed to MNK2a or MNKl .
• ER estrogen receptor
• WO02/ 103361 discloses that MNK2 is involved in the insulin-signaling pathway and features a method for identifying a modulator of glucose uptake.
• MNK kinases particularly MNK2 (MNK2a and MNK2b), are involved in the regulation of body-weight and thermogenesis, and thus may be associated with metabolic diseases such as obesity, as well as related disorders such as eating disorder, cachexia, diabetes mellitus, hypertension, coronary heart disease, hypercholesterolemia, dyslipidemia, osteoarthritis, gallstones, and sleep apnea, and disorders related to ROS defence, such as diabetes mellitus, neurodegenerative disorders, and cancer, e.g. cancers of the reproductive organs.
• metabolic diseases such as obesity
• related disorders such as eating disorder, cachexia, diabetes mellitus, hypertension, coronary heart disease, hypercholesterolemia, dyslipidemia, osteoarthritis, gallstones, and sleep apnea
• ROS defence such as diabetes mellitus, neurodegenerative disorders, and cancer, e.g. cancers of the reproductive organs.
• the MNK kinases are believed to be promising targets for anti-inflammatory therapy.
• hnRNP Al heterogeneous nuclear ribonucleoprotein Al , is shown to be another substrate for MNKl .
• hnRNP Al is involved in the synthesis of TNF ⁇ .
• the MNKl protein has also been shown by Worch et al. (Oncogene (2004);
• AML acute myeloid leukaemia
• This invention relates generally to certain pyrazine and pyridine compounds that can act as inhibitors of the MAP kinase interacting kinases MNK2a, MNK2b and MNKl (e.g., MNK2a and MNK2b) and related pharmaceutical compositions and methods.
• MNK2a, MNK2b and MNKl e.g., MNK2a and MNK2b
• this invention relates to a compound of the general formula (I) :
• X is N or CH; Y and Z are each selected from N or CH; when Y and/or Z is CH, the hydrogen of the CH moiety can be replaced by any one of R 2 , R 3 , or R 4 ;
• A is a bond, -NH- or -N-Ci-e alkyl
• R 1 is H or NH 2 ;
• Ar is benzofuranyl, indolyl, hydroxyphenyl, thienyl, benzothiophenyl, pyrrolyl, aminocarbonylphenyl, or azaindolyl, each of which is unsubstituted or substituted with from 1 -2 substituents independently selected from hydroxy, halogen, -CN, -NO 2 , Ci-6 alkyl, Ci-6 alkoxy, acyl, Ci-6 alkylsulphonyl, -C(O)NH 2 , -NH-C(O)-R 7 , and arylsulphonyl;
• R 2 and R 3 are each, independently, located at a position ortho or meta with respect to A; and are each, independently, H, halogen, hydroxy, Ci -6 alkyl, hydroxy-Ci-6 alkyl, carboxy-Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxy-Ci-6 alkoxy, di- Ci-6 alkylamino-Ci-6 alkoxy, or di-Ci-6 alkylaminocarbonyl-Ci-6 alkoxy;
• R 4 is located at a position para or meta with respect to A and is -C(O)NR5R6 or -S(O) 2 NR5R6;
• R 5 is H, Ci-6 alkyl, or aryl-Ci-6 alkyl;
• R 6 is H, Ci-6 alkyl, halo-Ci-6 alkyl, di-Ci-6 alkylamino-Ci-6 alkyl, mono-Ci-6 alkylamino-Ci-6 alkyl, amino-Ci-6 alkyl, hydroxy-Ci-6 alkylamino-Ci-6 alkyl, di(hydroxy-Ci-6 alkyl)amino-Ci-6 alkyl, hydroxy-Ci-6 alkyl, dihydroxy-C3-6 alkyl, cycloalkyl, heterocyclyl, heterocyclyl-Ci-6 alkyl, or heteroaryl-Ci-6 alkyl, wherein the heterocyclyl or heteroaryl is unsubstituted or substituted with from 1-2 substituents independently selected from Ci-6 alkyl, Ci-6 alkyl-OC(O)- or aryl-Ci-6 alkyl, said Ci-6 alkyl-OC(O)- being attached to a ring N atom; or
• R 5 and R 6 together with the nitrogen to which they are attached form a 4 to 7 membered heterocyclyl, wherein the 4 to 7 membered heterocyclyl optionally includes a second heteroatom ring member selected from N, S and O (in these embodiments, two of the ring members of the heterocyclyl are het- eroatoms: one of the two heteroatoms is the nitrogen atom connecting R 5 and R 6 , and the other is either N, S or O), and wherein the 4 to 7 membered het- erocyclyl is optionally substituted with from 1-2 substituents independently selected from Ci-6 alkyl, hydroxy-Ci-6 alkyl, Ci-2-alkoxy-C2-4-alkyl, di-Ci-6 al- kylamino, mono-Ci-6 alkylamino, amino, di-Ci-6 alkylamino-Ci-6 alkyl, mono-Ci-6 alkylamino-Ci-6 alkyl, amino-Ci-6 alkyl
• R 7 is H or Ci-6 alkyl; with the provisos that: when R 1 is NH2, then A is a bond; and when A is -NH- or -N-Ci-e-alkyl then R 1 is H.
• the invention relates to a compound of the general formula (II): or a pharmaceutically acceptable salt, hydrates, geometrical isomers, race- mates, tautomers, optical isomers, N-oxides and prodrug forms thereof, wherein: X is N or CH (or X can be a carbon atom substituted with any substituent described herein); A is a bond, -NH-; R 1 is H or NH 2 ;
• Ar is benzofuranyl, indolyl, hydroxyphenyl, thienyl, benzothiophenyl, pyrrolyl, each of which is unsubstituted or substituted with from 1-2 substituents independently selected from hydroxy, halogen, Ci-6 alkyl, Ci-6 alkoxy, acyl, Ci-6 alkylsulphonyl, and arylsulphonyl;
• R 2 and R 3 are each, independently, located at a position ortho or meta with respect to A; and are each, independently, H, halogen, Ci-6 alkyl, hy- droxy-Ci-6 alkyl, carboxy-Ci-6 alkyl, or Ci-6 alkoxy;
• R 4 is located at a position para or meta with respect to A and is -C(O)NR5R6 or -S(O) 2 NR5R6;
• R 5 is H, Ci-6 alkyl, or aryl-Ci-6 alkyl
• R 6 is H, Ci-6 alkyl, halo-Ci-6 alkyl, di-Ci-6 alkylamino-Ci-6 alkyl, mono-Ci-6 alkylamino-Ci-6 alkyl, amino-Ci-6 alkyl, hydroxy-Ci-6 alkylamino-Ci-6 alkyl, di(hydroxy-Ci-6 alkyl)amino-Ci-6 alkyl, hydroxy-Ci-6 alkyl, dihydroxy-C3-6 alkyl, cycloalkyl, heterocyclyl, heterocyclyl-Ci-6 alkyl, or heteroaryl-Ci-6 alkyl, wherein the heterocyclyl or heteroaryl is unsubstituted or substituted with from 1-2 substituents independently selected from Ci-6 alkyl, Ci-6 alkyl-OC(O)- or aryl-Ci-6 alkyl, said Ci-6 alkyl-OC(O)- being attached to a ring N atom; or
• R 5 and R 6 together with the nitrogen to which they are attached form a 4 to 7 membered heterocyclyl, wherein the 4 to 7 membered heterocyclyl optionally includes a second heteroatom ring member selected from N, S and O (in these embodiments, two of the ring members of the heterocyclyl are het- eroatoms: one of the two heteroatoms is the nitrogen atom connecting R 5 and R 6 , and the other is either N or O), and wherein the 4 to 7 membered heterocy- clyl is optionally substituted with from 1-2 substituents independently selected from Ci-6 alkyl, hydroxy-Ci-6 alkyl, di-Ci-6 alkylamino, mono-Ci-6 al- kylamino, amino, di-Ci-6 alkylamino-Ci-6 alkyl, mono-Ci-6 alkylamino- Ci -6 al- kyl, amino-Ci-6 alkyl, C3-7 cycloalkyl, Ci-6 alkyl
• this invention relates to inhibiting the MAP kinase interacting kinases MNK2a, MNK2b and MNKl (e.g., MNK2a and/or MNK2b) with the compounds described herein.
• the methods can include, e.g., contacting one or more of the MAP kinase interacting kinases MNK2a, MNK2b or MNKl in a sample with a compound having any of the formulae described herein.
• the methods can include administering a compound having any of the formulae described herein to a subject (e.g., a subject in need thereof, e.g., a mammal; e.g., a human; e.g., a human having, identified as having, at risk of having, or identified as being at risk of having one or more of the diseases or disorders described herein) .
• a subject e.g., a subject in need thereof, e.g., a mammal; e.g., a human; e.g., a human having, identified as having, at risk of having, or identified as being at risk of having one or more of the diseases or disorders described herein.
• the compounds of the above formula can exhibit an MNK2 inhibiting activity corresponding to an IC50 of from about 1 nanomolar (nM) to about 3 micromolar ( ⁇ M), or a lower concentration as tested in an con- ventional MNK2a in vitro HTRF assay as will be described below.
• the compounds of the above formula can exhibit an MNK2 inhibiting activity corresponding to an IC50 of from about 1 nM to about 3 ⁇ M (e.g., from about 1 nM to about 2 ⁇ M, from about 1 nM to about 1 ⁇ M, from about 1 nM to about 500 nM, from about 1 nM to about 100 nM, from about 1 nM to about 25 nM, from about 1 nM to about 10 nM).
• an IC50 of from about 1 nM to about 3 ⁇ M (e.g., from about 1 nM to about 2 ⁇ M, from about 1 nM to about 1 ⁇ M, from about 1 nM to about 500 nM, from about 1 nM to about 100 nM, from about 1 nM to about 25 nM, from about 1 nM to about 10 nM).
• the compounds described herein can be used, e.g., for the treatment or prevention of type 2 diabetes; and/or as anti-inflammatory agents, and/or in treatment of disorders related to energy homeostasis, the regulation of body-weight and ther- mogenesis, and metabolic diseases and related disorders, and disorders related to ROS defence, neurodegenerative disorders, and cancer.
• this invention relates to a method for the treatment or pro- phylaxis (e.g., treatment) of a disease, disorder, or condition related to unde- sired activity of MNKl and/or MNK2 kinases (e.g., obesity, eating disorder, cachexia, diabetes mellitus, hypertension, coronary heart disease, hypercholesterolemia, dyslipidemia, hyperlipidemia, hyperglycemia, osteoarthritis, gallstones, sleep apnea, neurodegenerative disorders, cancer, inflammatory condi- tions and type 2 diabetes).
• a disease, disorder, or condition related to unde- sired activity of MNKl and/or MNK2 kinases e.g., obesity, eating disorder, cachexia, diabetes mellitus, hypertension, coronary heart disease, hypercholesterolemia, dyslipidemia, hyperlipidemia, hyperglycemia, osteoarthritis, gallstones, sleep apnea, neurodegenerative disorders, cancer, inflammatory condi- tions and
• the method includes administering to a subject (e.g., a subject in need thereof, e.g., a mammal; e.g., a human; e.g., a human having, identified as having, at risk of having, or identified as being at risk of having one or more of the diseases or disorders described herein) an effective amount of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof.
• a subject e.g., a subject in need thereof, e.g., a mammal; e.g., a human; e.g., a human having, identified as having, at risk of having, or identified as being at risk of having one or more of the diseases or disorders described herein.
• this invention relates to a method for the treatment or prophylaxis (e.g., treatment) of type 2 diabetes, which includes administering to a subject (e.g., a subject in need of such treatment as described herein) an effec- tive amount of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof.
• this invention relates to a method for the treatment or prophylaxis (e.g., treatment) of an inflammatory condition, which includes admin- istering to a subject (e.g., a subject in need of such treatment as described herein) an effective amount of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof.
• this invention relates to a method for the treatment or pro- phylaxis (e.g., treatment) of cancer, which includes administering to a subject (e.g., a subject in need of such treatment as described herein) an effective amount of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof.
• this invention relates to a method for the treatment or prophylaxis (e.g., treatment) of obesity, which includes administering to a subject (e.g., a subject in need of such treatment as described herein) an effective amount of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof.
• this invention relates to a method for reducing body weight in a subject, which includes administering to a subject (e.g., a subject in need of such treatment as described herein) an effective amount of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof.
• the subject can be a subject in need thereof (e.g., a subject identified as being in need of such treatment as described herein). Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
• the subject can be a mammal. In certain embodiments, the subject is a human.
• this invention relates to the use of a compound of formula I (e.g., as a medicament) or in the manufacture of a medicament containing a compound of formula I for the treatment or prophylaxis (e.g., treatment) of a disease, disorder, or condition related to undesired activity of MNKl and/or MNK2 kinases as described herein.
• a compound of formula I e.g., as a medicament
• prophylaxis e.g., treatment
• the invention relates to a compound (including a pharmaceutically acceptable salt thereof) of any of the formulae delineated herein (e.g., a compound having formula (I), (II), (III), (IV), (V) or (VI) (or subgenera thereof), including the specific compounds described herein); or a composition or for- mulation (e.g., a pharmaceutical composition or formulation) comprising a compound (including a pharmaceutically acceptable salt thereof) of any of the formulae delineated herein (e.g., a compound having formula (I), (II), (III), (IV), (V) or (VI) (or subgenera thereof), including the specific compounds described herein).
• a composition or for- mulation e.g., a pharmaceutical composition or formulation
• a compound (including a pharmaceutically acceptable salt thereof) of any of the formulae delineated herein e.g., a compound having formula (I), (II), (III), (IV), (V) or (VI) (or subgen
• composition or formulation can further include a pharmaceutically acceptable adjuvant, carrier or diluent. Any such compound can be used in the methods described herein.
• the compound of formula I can be a pyrazine derivative of formula III.
• Y, Z, A, Ar, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 can be defined anywhere herein. It is provided that when R 1 is NH2, then A is a bond; and when A is -NH- or - N-Ci-6-alkyl then Ri is H.
• the compound of formula I can be pyridine derivative of formula IV.
• Y, Z, A, Ar, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 can be defined anywhere herein. It is provided that when R 1 is NH2, then A is a bond; and when A is -NH- or - N-Ci- 6 -alkyl then R 1 is H.
• This invention relates generally to certain pyrazine and pyridine compounds that can act as inhibitors of the MAP kinase interacting kinases MNK2a, MNK2b and MNKl (e.g., MNK2a and MNK2b) and related pharmaceutical compositions and methods.
• MNK2a, MNK2b and MNKl e.g., MNK2a and MNK2b
• certain pyrazine derivatives inhibit the MAP kinase interacting kinases MNK2a and MNK2b. It has surprisingly also been found that, when substituting the pyrazine ring for a pyridine ring, activity was retained for the compounds tested. The present inventors therefore believe the corresponding pyridine derivatives also to exhibit similar activity.
• the compounds of the present invention are generally represented by the general formula I above.
• the compounds of the invention have surprisingly been found by the present inventors also to have MNKl activity. Based on the compounds tested, the MNKl and MNK2 (tested as MNK2a) activities of the compounds of the invention are believed to be of a similar magnitude, such as generally within an activity ratio of MNKl :MNK2 of 1 : 20 to 20: 1.
• the MNKs (encompassing MNKl and MNK2) are believed to be promising targets for anti-inflammatory therapy. While not wishing to be bound by theory, since the present compounds have been found to be highly active in inhibiting MNK2, and also MNKl , as described above, the present compounds are believed to be useful in anti-inflammatory therapy.
• the present compounds are also believed to be useful in anti-cancer therapy, such as in the treatment of AML.
• the invention relates to pyrazine derivatives represented by the general formula (III) below
• the invention relates to pyrazine derivatives represented by the general formula (V] below
• the invention relates to pyridine derivatives represented by the general formula (VI) below
• MNK2 MAP kinase interacting kinases
• MNK2 related disorder disorder or condition associated with the activity of MNK2
• disorder related to undesired activity of MNK2 have been used interchangeably herein to denote any disorder or symptom wherein the MNK2 is involved in the process or presentation of the disorder or the symptom.
• the MNK2 related disorders thus e.g. include, but are not limited to, type 2 diabetes and inflammatory conditions.
• MNKl related disorder disorder or condition associated with the activity of MNKl
• disorder related to undesired activity of MNKl have been used interchangeably herein to denote any disorder or symptom wherein the MNKl is involved in the process or presentation of the disorder or the symptom.
• the MNKl related disorders thus e.g. include, but are not limited to, inflammatory conditions and type 2 diabetes.
• Ci-6-alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms.
• Ci-5-alkyl Ci -4 - alkyl
• Ci -3 -alkyl Ci -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.
• lower 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.
• Halo-Ci-6-alkyl means a Ci-6-alkyl group substituted by one or more halogen atoms. Derived expressions such as "Ci-6 alkoxy" and "Ci- ⁇ alkylamino" are to be construed accordingly where an oxy group, thio group or an amino group, respectively, is bridging the Ci-6 alkyl group to the node at which that substituent is substituted.
• Ci-6-alkoxy For parts of the range "Ci-6-alkoxy" all subgroups thereof are contemplated such as C1-5- alkoxy, Ci-4-alkoxy, Ci-3-alkoxy, Ci-2-alkoxy, C2-6-alkoxy, C2-5-alkoxy, C2-4- alkoxy, C2-3-alkoxy, C3-6-alkoxy, C4-5-alkoxy, etc.
• Examples of said "Ci-6 alkoxy” include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec- butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy. Subgroups of "Ci-6 alkylamino" are to be construed accordingly.
• cycloalkyl denotes a cyclic alkyl group having a ring size from 3 to 7 carbon atoms, optionally additionally substituted by C1-3 alkyl.
• C3-7-cycloalkyl all subgroups thereof are contemplated such as C3-6-cycloalkyl, C3-5-cycloalkyl, C3-4- cycloalkyl, C4-7-cycloalkyl, etc.
• Examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and cycloheptyl.
• acyl is used to specify an optional substituent on Ar which may be straight, branched, cyclic or aromatic, denotes a hydrocarbon having from 1 to 6 carbon atoms and a carbonyl group.
• Ci-6-acyl all subgroups thereof are contemplated such as Ci-5-acyl, Ci-4-acyl, Ci-3-acyl, C1-2- acyl, C2-e-acyl, C2-5-acyl, C2-4-acyl, C2-3-acyl, C3-e-acyl, C4-5-acyl, etc.
• acyl groups include formyl, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, benzoyl, and preferably benzoyl.
• Ci - ⁇ alkylsulphonyl which may be straight, branched, or cyclic, denotes a hydrocarbon having from 1 to 6 carbon atoms with a sulphonyl group.
• Ci-6 alkylsulphonyl all subgroups thereof are contemplated such as C1-5 alkylsulphonyl, C1-4 alkylsulphonyl, C1-3 alkylsulphonyl, C1-2 alkylsulphonyl, C2-6 alkylsulphonyl, C2-5 alkylsulphonyl, C2-4 alkylsulphonyl, C2-3 alkylsulphonyl, C3-6 alkylsulphonyl, C4-5 alkylsulphonyl, etc.
• alkylsulphonyl groups include methylsulphonyl, ethylsulphonyl, propylsulphonyl, n-butylsulphonyl, sec-butylsulphonyl, tert-butylsulphonyl, pentylsulphonyl and hexylsulphonyl.
• halogen shall mean fluorine, chlorine, bromine or iodine.
• aryl refers to a hydrocarbon ring system selected from phenyl, pentalenyl, indenyl, dihydroindenyl, naphthyl, and fluorenyl, or dehydrogenated derivatives thereof.
• the aryl rings may optionally be substituted by Ci-6-alkyl.
• substituted aryl groups are benzyl and 2-methylphenyl.
• Derived expressions such as “aryloxy” and “aryl carbonyl” should be construed accordingly where an oxy group or a carbonyl group, respectively, is bridging the aryl group to the node at which that substituent is substituted.
• Examples of and aryloxy group are phenoxy, and naphthoxy, and an example of an aryl carbonyl is benzoyl.
• heteroaryl refers to a hydrocarbon ring system selected from the group consisting of furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, azaindolyl, quinazolinyl, indolyl, isoindolyl, 1 ,3-dihydro-isoindolyl, pyrazolyl, pyridazinyl, pyrazinyl, quinolinyl, quinoxalinyl, thiadiazolyl, indazolyl, chromanyl, purinyl, benzofuranyl, 2,3- dihydrobenzofuranyl, benzodioxolyl, benzodioxinyl, 2,3-dihydro- l ,4- benzodioxinyl,
• heteroaryloxy and “heteroaryl carbonyl” should be construed accordingly where an oxy group or a carbonyl group, respectively, is bridging the heteroaryl group to the node at which that substituent is substituted.
• exemplary heteroaryl carbonyl groups include furoyl and isonicotinoyl.
• heterocyclyl refers to a hydrocarbon ring system, containing 4 to 8 ring members that have at least one heteroatom (e.g., S, N, or O) as part of the ring. It includes saturated, partially unsaturated and unsaturated nonaromatic heterocycles. Suitable heterocyclic groups include azetidinyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, piperidyl, azepinyl, piperazinyl, diazepanyl, perhydrodiazepinyl, morpholinyl, thiomorpholinyl, pyranyl, and dioxanyl groups.
• such an exemplary spiro radical is 2,7- diazaspiro[4.5]dec-2-yl.
• Coupled agent refers to a substance capable of catalyzing a coupling reaction, such as amidation, or esterification.
• Examples of coupling agents include, but are not limited to, carbonyldiimidazole, dicyclohexylcarbodimide, pyridine, 4-dimethylaminopyridine, and triphenylphosphine.
• Another example of a coupling agent is l-[3- (dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride, which is used in the presence of hydroxybenzotriazole and a base such as triethylamine.
• reducing agent refers to a substance capable of reducing another substance and it itself is oxidized.
• reducing agents include, but are not limited to, hydrogen, sodium, potassium, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyboro hydride, lithium aluminiumhydride, and diisobutylaluminium hydride.
• “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.
• mammal includes organisms, which include mice, rats, cows, sheep, pigs, rabbits, goats, and horses, monkeys, dogs, cats, and preferably humans.
• An effective amount refers to an amount of a compound that confers a therapeutic effect (e.g., treats, controls, ameliorates, prevents, delays the onset of, or reduces the risk of developing a disease, disorder, or condition or symp- toms thereof) 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
• halo-Ci-6-alkyl means a Ci-6-alkyl group that is substituted by one or more halogen atoms.
• halo-Ci-6-alkyl group such as a halo-Ci-3 alkyl group
• the preferred meaning of halo is fluoro
• X is as defined above for the respective formula
• Y, Z, Ar, Ri, R2, R 3 , R4, R 5 and R 6 are as defined for formula (I);
• A is a bond or -NH-, provided that when R 1 is NH2, then A is a bond; and when A is -NH- then R i is H.
• X is as defined above for the respective formula; Y and Z are as defined for formula (I); A is a bond or -NH-,
• Ar is benzofuranyl, indolyl, hydroxyphenyl, thienyl, benzothiophenyl, pyrrolyl, aminocarbonylphenyl, or azaindolyl, each of which is unsubstituted or substituted with from 1 -2 substituents independently selected from hydroxy, halogen, -CN, -NO2, Ci-6 alkyl, Ci-6 alkoxy, acyl, Ci-6 alkylsulphonyl, -C(O)NH 2 , and arylsulphonyl;
• R i , and R 4 are as defined for formula (I);
• R 2 and R 3 are each, independently, located at a position ortho or meta with respect to A and are each, independently, H, halogen, hydroxy, C1-3 alkyl, Ci-3 alkoxy, C1-3 alkoxy-Ci-3 alkoxy, di-Ci-6 alkylamino-Ci-6 alkoxy, or di-Ci-6 alkylaminocarbonyl-Ci-6 alkoxy;
• R 5 is H, Ci -3 alkyl, or aryl-Ci -3 alkyl
• R 6 is H, Ci-3 alkyl, halo-Ci-3 alkyl, di-Ci-4 alkylamino-Ci-6 alkyl, mono-Ci-4 alkylamino-Ci-6 alkyl, amino-Ci-6 alkyl, hydroxy-Ci-3 alkylamino-Ci-5 alkyl, di(hydroxy-Ci-3 alkyl) amino-C 1-5 alkyl, hydroxy-Ci-5 alkyl, dihydroxypro- pyl, cycloalkyl, heterocyclyl, heterocyclyl-Ci-4 alkyl, or heteroaryl-Ci-3 alkyl, wherein the heterocyclyl or heteroaryl is unsubstituted or substituted with from 1-2 substituents, preferably one, independently selected from C1-3 alkyl, Ci -5 alkyl-OC(O)-, or aryl-Ci -3 alkyl, said Ci -5 alkyl-OC(O)- being attached to a ring N atom, more
• R 5 and R 6 together with the nitrogen to which they are attached form a 4 to 7 membered heterocyclyl, wherein the 4 to 7 membered heterocy- clyl, optionally includes a second heteroatom selected from N and O (in these embodiments, two of the ring members of the heterocyclyl are heteroatoms: one of the two heteroatoms is the nitrogen atom connecting R5 and R6, and the other is either N or O), and wherein the 4 to 7 membered heterocyclyl is unsubstituted or substituted with from 1-2 substituents, preferably one, inde- pendently selected from C1-3 alkyl, hydroxy-Ci-3 alkyl, Ci-2-alkoxy-C2-4-alkyl, di-Ci-3 alkylamino, mono-Ci-3 alkylamino, amino, di-Ci-3 alkylamino-Ci-4 alkyl, mono-Ci-3 alkylamino-Ci-4 alkyl, amino-Ci-4 alkyl, C
• one of Y and Z is N. In another preferred group of compounds, both Y and Z are CH.
• both R 2 and R 3 are other than H, then both R 2 and R 3 are not in a position ortho of A.
• both R 2 and R 3 when both R 2 and R 3 are other than H, then both R 2 and R 3 are not located in a position that is ortho with respect to A.
• R 2 and R 3 can each be, independently, halogen, hydroxy, Ci-6 alkyl, or Ci-6 alkoxy, C 1-3 alkoxy-Ci-3 alkoxy, di-Ci-6 alkylamino-Ci-6 alkoxy, or di-Ci-6 al- kylaminocarbonyl-Ci-6 alkoxy; and both of R 2 and R 3 can each be located in a position that is meta with respect to A.
• R 4 is located at a position that is para with respect to A.
• R 2 is located at a position that is ortho with respect to A
• R 3 is located at a position that is meta with respect to A
• R 4 is located at a position that is para or meta with respect to A
• Ar is a heteraryl
• R 4 is most preferably located para with respect to A; i.e. the sub- stituents R 2 , R 3 and R 4 of the above formulae I, III and IV are located in a posi- tion ortho, meta and para, respectively, of A, as shown below
• Y and Z can be defined as CH or N.
• substituents R 2 and R 3 in the compounds of the present invention include H, halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, C 1-6 alkoxy-Ci-6 alkoxy, di-Ci-6 alkylamino-Ci-6 alkoxy, or di-Ci-6 al- kylaminocarbonyl-Ci-6 alkoxy, and more preferably H, fluoro, chloro, hydroxy, methyl, methoxy, 2-ethoxyethoxy, 2-(dimethylamino)ethoxy, and dimethylami- nocarbonylmethoxy.
• R 4 is -C(O)NR 5 R 6 .
• R 5 are H, methyl, ethyl and benzyl.
• R 6 is selected from di-Ci-3 alkylamino-Ci-3 alkyl, mono-Ci-3 alkylamino-Ci-3 alkyl, amino-Ci-3 alkyl, heterocyclyl and het- erocyclyl-Ci-3 alkyl, wherein the heterocyclyl is 4-, 5- or 6-membered containing 1 or 2 heteroatoms selected from O and N, preferably 5 membered and preferably containing one heteroatom atom being an N atom; wherein the heterocyclyl is unsubstituted or substituted with from 1-2 substituents, prefera- bly one, independently selected from C1-3 alkyl, C1-5 alkyl-OC(O)-, or aryl-Ci-3 alkyl, and preferably C1-3 alkyl, said C1-5 alkyl-OC(O)- being attached to a ring N atom of the heterocyclyl; or R 5 and R 6 together with the nitrogen to which they are attached form
• R 6 examples include hydrogen, methyl, isopropyl, cyclopentyl, trifluorore- thyl, hydroxyethyl, hydroxypentyl, dihydroxypropyl, dimethylaminoethyl, di- ethylaminoethyl, dimethylaminopropyl , 3 - dimethylamino- 2 , 2 - dimethylpropyl , hydroxypropylaminoethyl, [bis(2-hydroxyethyl)amino]propyl, morpholinylethyl, morpholinylpropyl, azetidinyl, pyrrolidinyl, pyrrolidinylethyl, furylmethyl, pyridinylmethyl, piperidinyl, piperidinylmethyl, tetrahydrofuranylmethyl, imi- dazolylethyl, pyrazolidinyl, wherein any heterocyclyl or heteroaryl is substituted
• R 6 include hydrogen, methyl, isopropyl, cyclopentyl, 2,2,2-trifluororethyl, 2-hydroxyethyl, l-hydroxymetyl-2-metylpropyl, 2,3- dihydroxypropyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, 3- dimethylaminopropyl, 3-dimethylamino-2,2-dimethylpropyl, 2-(2- hydroxypropylamino)ethyl, 3-[bis(2-hydroxyethyl)amino]propyl, 2-(4- morpholinyl)ethyl, 3-(4-morpholinyl)propyl, iV-metyl-pyrrolidin-3-yl, 2- (pyrrolidin- 1-yl) ethyl, piperidin-3-yl,N-( ⁇ -butyloxycarbonyl-piperidin)-3- ylmethyl, 2-furylmethyl,
• R 6 is N- metyl-pyrrolidin-3-yl, 2-(pyrrolidin- 1 -yl)ethyl, N-( ⁇ -butyloxycarbonyl-piperidin)- 3-ylmethyl, pyridin-2-ylmethyl, or l-benzylpiperidin-4-yl.
• Examples of the 4 to 7-membered heterocyclyl formed by R 5 and R 6 together with the nitrogen to which they are attached include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tiomorpholinyl, piperazinyl, and perhydrodiazepinyl which may be unsubstituted or substituted in one or two positions, preferably one, independently with Ci -6 alkyl, hydroxy-Ci-6 alkyl, di-Ci-6 alkylamino, mono-Ci-6 alkylamino, amino, di-Ci-6 alkylamino-Ci-6 alkyl, mono-Ci-6 al- kylamino-Ci-6 alkyl, amino-Ci-6 alkyl, C3-7 cycloalkyl, heteroaryl-carbonyl and Ci -6 alkyl-OC(O)NH-, preferably with Ci -3 alkyl, hydroxy-Ci-3 alkyl, Ci- 2 -alk
• 4 to 7-membered heterocyclyl formed by R 5 and R 6 together with the nitrogen to which they are attached include 3- aminoazetidin- 1-yl, 3-aminopyrrolidin- l-yl, 3,5-dimethylpiperazin- l-yl, 3- methylpiperazin- 1-yl, 4-isopropylpiperazin- l-yl, 4-ethylpiperazin- l-yl, 4-(2- methoxyethoxy)piperazin- 1 -yl, 4-(2-hydroxyethyl)piperazin- 1 -yl, 2-(pyrrolidin- 1 -ylmethyl)pyrrolidin- 1 -yl, 3-(t-butyloxycarbonylamino)-azetidin- 1 -yl, mor- pholin-4-yl, piperidin- 1-yl, 2-[(dimethylamino)methyl]piperidin- l-yl, 4-(2- furoyl
• X is as defined above for the respective formula
• Y, Z, A, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined for formula (I);
• Ar is benzofuranyl, indolyl, hydroxyphenyl, thienyl, benzothiophenyl, pyrrolyl, aminocarbonylphenyl, or azaindolyl, wherein benzofuranyl, indolyl, thienyl, benzothiophenyl, pyrrolyl, and azaindolyl is unsubstituted or substituted with from 1-2 substituents independently selected from hydroxy, halogen, -CN, -NO2, Ci-6 alkyl, Ci-6 alkoxy, acyl, Ci-6 alkylsulphonyl, -C(O)NH 2 , and arylsulphonyl.
• Especially preferred compounds of formulae I, III, and IV above are those in which Ar is hydroxyphenyl, methoxyhydroxyphenyl, fluorohydroxyphenyl, (benzoyl)hydroxyphenyl, benzofuranyl, aminocarbonylphenyl or indolyl, more preferably benzofuranyl or indolyl, and most preferably indolyl.
• the benzofuranyl or indolyl is preferably 2-benzofuranyl and 2- or 5-indolyl, more preferably 2-benzofuranyl and 2-indolyl.
• Especially preferred compounds of formulae II, V, and VI above are those in which Ar is hydroxyphenyl, benzofuranyl, aminocarbonylphenyl or indolyl, more preferably benzofuranyl or indolyl, and most preferably indolyl.
• the benzofuranyl or indolyl is preferably 2-benzofuranyl and 2- or 5-indolyl, more preferably 2-benzofuranyl and 2-indolyl.
• Ar is unsubsti- tuted or substituted with hydroxy, halogen, -CN, -NO2, C1-3 alkyl, C1-2 alkoxy, benzoyl, C1-3 alkylsulphonyl, -C(O)NlHh, and phenylsulphonyl; preferably with hydroxy, halogen, cyano, C1-3 alkyl, C1-2 alkoxy, methylsulphonyl, isopropyl- sulphonyl and -C(O)NIHh, and more preferably with hydroxy, fluoro, chloro, cyano, methyl, methoxy and -C(O)NlHh.
• X is as defined above for the respective formula; one of Y and Z is N, i.e. giving a pyridine ring; A is -NH-; and Ar, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined for formula (I);
• 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, sulphuric 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, benzenesulphonic acid, toluenesul- phonic acid, methanesulphonic 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, benzenesulphonic acid, to
• Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, al- kylamines, benzathine, and amino acids, such as, e.g. arginine and lysine.
• the term addition salt as used herein also comprises solvates which the com- pounds and salts thereof are able to form, such as, for example, hydrates, al- coholates and the like.
• the compounds described herein can be used in the treatment or prophylaxis of any disorder or condition associated with the activity of MNKl , MNK2a and/or MNK2b, such as metabolic diseases, e.g. obesity, as well as related disorders such as eating disorder, cachexia, diabetes mellitus, hypertension, coronary heart disease, hypercholesterolemia, dyslipidemia, hyperlipidemia, hyperglycemia, osteoarthritis, gallstones, and sleep apnea, and disorders related to ROS defence, such as diabetes mellitus, neurodegenerative disorders, and cancer, e.g. cancers of the reproductive organs, leukaemia, e.g. acute myeloid leukaemia (AML), and inflammatory conditions.
• metabolic diseases e.g. obesity
• related disorders such as eating disorder, cachexia, diabetes mellitus, hypertension, coronary heart disease, hypercholesterolemia, dyslipidemia, hyperlipidemia, hyperglycemia, osteoarthritis, gallstones, and sleep a
• the compound may also be used in the treatment or prophylaxis of disorders relating to the insulin-signaling pathway.
• disorders are type 2 diabetes.
• the compound is used in the treatment or prophylaxis of type 2 diabetes, cancer, in- flammatory conditions, and obesity, and more preferably type 2 diabetes, inflammatory conditions, and obesity.
• Another aspect of the present invention is a method for the treatment or prophylaxis of any of the above conditions or disorders, and especially type 2 dia- betes, said method comprising administering to a subject (e.g., mammal, hu- man, or animal) in need of such treatment an effective amount of a compound as described above.
• a subject e.g., mammal, hu- man, or animal
• a further aspect of the invention relates to a method for the treatment or pro- phylaxis disorders related to the insulin-signaling pathway, said method comprising administering to a subject (e.g., mammal, human, or animal) in need of such treatment an effective amount of a compound as described above.
• a subject e.g., mammal, human, or animal
• Another aspect of the invention relates to a method for the treatment or pro- phylaxis of anti-inflammatory conditions, said method comprising administering to a subject (e.g., mammal, human, or animal) in need of such treatment an effective amount of a compound as described above
• Inflammatory conditions can include arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, burns, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HIV, pulmonary edema, kidney stones, minor
• a further aspect of the present invention relates to a method for the treatment or prophylaxis of cancer, said method comprising administering to a subject (e.g., mammal, human, or animal) in need of such treatment an effective amount of a compound as described above.
• a subject e.g., mammal, human, or animal
• “Cancer” refers to cellular- proliferative disease states, including but not limited to: Cardiac: sarcoma (an- giosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancrea
• the invention also features a method for reducing body-weight (e.g., treating body-weight disorders).
• the method includes administering to a subject in need thereof an effective amount of a compound of the formula (I) .
• body weight disorders refers to the disorders caused by an imbalance between energy intake and energy expenditure, resulting in abnor- mal body (e.g., excessive) weights. Such body weight disorders include obesity.
• the methods delineated herein can also include the step of identifying that the subject is in need of treatment of a MNKl or MNK2-related disorder, such as type 2 diabetes.
• a further aspect of the present invention is a method for modulating MNK 1 or MNK2 activity (e.g., antagonizing the MNK2), comprising administering to a subject (e.g., mammal, human, or animal) in need thereof an effective amount of a compound as described above or a composition comprising a compound as described above.
• a subject e.g., mammal, human, or animal
• Another aspect of the present invention is the use of a compound as described above in the manufacture of a medicament for use in the treatment or prophylaxis of any disorder or condition associated with the activity of MNKl , MNK2a and /or MNK2b, such as the conditions specified above, including metabolic diseases, e.g. obesity, as well as related disorders such as eating disorder, cachexia, diabetes mellitus, hypertension, coronary heart disease, hypercholesterolemia, dyslipidemia, hyperlipidemia, hyperglycemia, osteoarthritis, gallstones, and sleep apnea, and disorders related to ROS defence, such as diabe- tes mellitus, neurodegenerative disorders, and cancer, e.g. cancers of the reproductive organs, leukaemia, e.g. acute myeloid leukaemia (AML), and in- flammatory conditions, and especially type 2 diabetes, cancer, inflammatory conditions, and obesity.
• metabolic diseases e.g. obesity
• related disorders such as eating disorder, cachexia,
• another aspect of the present invention is a pharmaceutical for- mulation containing a compound as described above as an active ingredient, in combination with a pharmaceutically acceptable diluent or carrier.
• the pharmaceutical formulation may be used in the treatment or prophylaxis of any of the above conditions, wherein the active ingredient is a compound as described above.
• the amount of active compounds is between 0. 1-95% by weight of the preparation, preferably between 0.2-20% by weight in preparations for parenteral use and preferably between 1 and 50% by weight in preparations for oral administration.
• the compounds of the invention are formulated into pharma- ceutical formulations for oral, rectal, parenteral or other mode of administration.
• Pharmaceutical formulations 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.
• the invention relates to methods of making compounds of any of the formulae herein comprising reacting any one or more of the com- pounds of the formulae delineated herein, including any processes delineated herein.
• the compounds of the formula (I) 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 compounds of formula (I) 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, as mentioned above.
• optical isomers e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers, as mentioned above.
• 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 chemicals used in the synthetic routes delineated herein may include, for example, solvents, reagents, catalysts, and protecting group and deprotecting group reagents.
• the methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds.
• various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
• Synthetic chemistry transformations and protecting group methodologies protecting group methodologies (protection and deprotec- tion) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers ( 1989); T.W. Greene and P.G.M.
• 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 invention will now be further illustrated by the following non-limiting Ex- amples of the inventive compounds and the methods for their preparation.
• the compounds of the Examples exhibit an MNK2 inhibiting activity corresponding to an IC50 of from 0.6 ⁇ M to about 1 nM, as tested for MNK2a activity according to the in vitro MNK2a HTRF assay, which will be described in detail further below.
• DCM dichloromethane
• DMF dimethylformamide
• HPLC means high performance liquid chromatography
• R.T. (rt.) means room temperature
• TFA means trifluoroacetic acid
• THF means tetrahydrofuran
• NBS means N-bromosuccinimide
• HOBT means 1-hydroxybenzotriazole hydrate
• EDC means l-(3-dimethylaminopyopyl)-3-ethylcarbodiimide hydrochloride
• TEA triethylamine
• TBTU O-benzotriazol- l-yl-N,N,N',N'-tetra-methyluronium tetra- fluoroborate
• ACN means acetonitrile
• Microwave reactions were performed with a Personal Chemistry Smith Creator or Synthesizer using 0.5-2 mL or 2-5 mL Smith Process Vials fitted with aluminum caps and septa.
• Analytical HPLC was performed on an Agilent 1 100 system equipped with System A: ACE 3 (C8, 50 x 3.0 mm) or System B: YMC ODS-AQ, (33 x 3.0 mm) using the eluent system: water/0. 1%TFA and CH3CN, 1 mL/min, with a gradient time of 3 min.
• Preparative HPLC was performed on a Gilson system equipped with System A: ACE 5 C8 column (50 x 20 mm) gradient time 5 min, system B: YMC ODS-AQ ( 150 x 30 mm) gradient time 8.5 min, system C: YMC ODS-AQ (50x20 mm) gradient time 5 min, or system D: ACE 5 C8 column ( 15O x 30 mm) gradient time 8.5 min using the eluent system: water/0.1%TFA and CH3CN unless oth- erwise indicated.
• NBS (100 g, 561.8 mmol) was added in small portions to a stirred solution of 2-aminopyrazine (25 g, 263 mmol) in dichloromethane (600 ml) over a period of 1 hour.
• the reaction was stirred at r.t. for Ih and washed with water.
• the organic phase was dried (MgS ⁇ 4) and evaporated.
• the crude product was filtered through a plug of silica using 2.5% MeOH in dichloromethane as the elu- ent.
• Method A The amide (1 eq), PdCl 2 (dppf) (0.05 eq), KOAc (4 eq) and Bispina- colatoborane (1.5 eq) were dissolved in 2 mL dry DMF and the mixture was heated at 8O 0 C for 1 hrs. Then the reaction was cooled to room temperature and water (0.5 mL), NaHCO 3 (6 eq), PdCl 2 (dppf) (0.05 eq) and 4-(2-amino-5- bromopyrazin-3-yl)phenol (Intermediate 3) (1.2 eq) were added and the resulting mixture was heated at 100 0 C overnight. The crude reaction was filtered, concentrated and purified using preparative HPLC system D.
• Method B The amide (1 eq), PdCl 2 (dppf) (0.05 eq), KOAc (4 eq) and Bispina- colatoborane (1.5 eq) were dissolved in 2 mL dry DMF and the mixture was heated at 8O 0 C for 1 hrs. Then the reaction was cooled to room temperature and water (0.5 mL), NaHCO 3 (6 eq), PdCl 2 (dppf) (0.05 eq) and 4-(6- chloropyrazin-2-yl)phenol (Intermediate 2) (1.2 eq) were added and the resulting mixture was heated at 100 0 C overnight. The crude reaction was filtered, concentrated and purified using preparative HPLC system D.
• Method D The sulphonamide (1 eq), PdCl 2 (dppf) (0.05 eq), KOAc (4 eq) and Bispinacolatoborane (1.5 eq) were dissolved in 2 mL dry DMF and the mixture was heated at 8O 0 C for 1 hrs. Then the reaction was cooled to room temperature and water (0.5 mL), NaHCO 3 (6 eq), PdCl 2 (dppf) (0.05 eq) and 4-(6- chloropyrazin-2-yl)phenol (Intermediate 2) (1.2 eq) were added and the resulting mixture was heated at 100 0 C overnight. The crude reaction was filtered, concentrated and purified using preparative HPLC system D.
• the amides /sulphonamides in Methods A-D were made by conventional amide coupling between phenylcarboxylic acids /phenylsulphonyl chlorides and aliphatic amines.
• Method E The boronic acid (1.3 eq), Pd(tetrakis) (0.05 eq), NaHCO 3 (3 eq) were mixed with 3-bromo-5-[4-(morpholin-4-ylcarbonyl)phenyl]pyrazin-2-amine (Intermediate 8) (1 eq) in 1 mL DME and 0.5 mL H 2 O and then heated at 120 0 C for 900 s in microwave. The crude reaction was filtrated and concentrated and then purified using preparative HPLC system A,C or D.
• Method F The boronic acid (1.3 eq), Pd(tetrakis) (0.05 eq), NaHCO 3 (3 eq) were mixed with 3-chloro-5-[4-(morpholin-4-ylcarbonyl)phenyl]pyrazine (1 eq) in 1 mL DME and 0.5 mL H 2 O and then heated at 120 0 C for 900 s in microwave. The crude reaction was filtrated and concentrated and then purified using preparative HPLC system A,C or D.
• the central pyrazine scaffold in Methods E-F were made by a Suzuki coupling between 3-amino-2, 6-dibromopyrazine/2, 6-dicholorpyrazine and [4- (Morpholine-4-carbonyl)phenyl] boronic acid.
• Method G The boronic acid (1.3 eq), Pd(tetrakis) (0.05 eq), NaHCO 3 (3 eq) were mixed with 5-bromo-3-[lH-indol-2-yl]pyrazin-2-amine (1 eq) in 1 niL DME and 0.5 niL H2O and then heated at 120 0 C for 900 s in microwave. The crude reaction was filtrated and concentrated and then purified using preparative HPLC system A, C or D.
• Method H The boronic acid (1.3 eq), Pd(tetrakis) (0.05 eq), NaHCO 3 (3 eq) were mixed with 2-(6-chloropyrazin-2-yl)-lH-indole (1 eq) in 1 rnL DME and 0.5 niL H2O and then heated at 120 0 C for 900 s in microwave. The crude reaction was filtrated and concentrated and then purified using preparative HPLC system A, C or D.
• Method J The boronic acid (1.3 eq), Pd(tetrakis) (0.05 eq), NaHCO 3 (3 eq) were mixed with 3-(l-benzofuran-2-yl)-5-bromopyrazin-2-amine (prepared in Ex- ample 54) (1 eq) in 1 mL DME and 0.5 mL H 2 O and then heated at 120 0 C for 900 s in microwave. The crude reaction was filtrated and concentrated and then purified using preparative HPLC system A, C or D.
• Method K The amide (1 eq), PdCl 2 (dppf) (0.05 eq), KOAc (4.5 eq) and bis(neopentyl glycolato)diboron (1.5 eq) were dissolved in 2 mL dry DME and the mixture was heated at 125 0 C for 1200 s in microwave. Then the reaction was cooled to room temperature and water (0.5 mL), NaHCO 3 (2 eq), Pd(tetrakis) (0.05 eq) and 2-(6-chloropyrazin-2-yl)- lH-indole (0.95 eq) were added and the resulting mixture was heated at 12O 0 C for 700 s in microwave. The crude reaction was filtered and concentrated and then purified using preparative HPLC system A, C or D.
• Method L The amide (1 eq), PdCl 2 (dppf) (0.05 eq), KOAc (4.5 eq) and bis(neopentyl glycolato)diboron (1.5 eq) were dissolved in 2 mL dry DME and the mixture was heated at 125 0 C for 1200 s in microwave. Then the reaction was cooled to room temperature and water (0.5 mL), NaHCO 3 (2 eq), Pd(tetrakis) (0.05 eq) and 5-bromo-3-[lH-indol-2-yl]pyrazin-2-amine (0.95 eq) were added and the resulting mixture is heated at 12O 0 C for 700 s in microwave. The crude reaction was filtered and concentrated and then purified using preparative HPLC system A, C or D.
• Method M The amide (1 eq), PdCl 2 (dppf) (0.05 eq), KOAc (4.5 eq) and bis(neopentyl glycolato)diboron (1.5 eq) were dissolved in 2 rnL dry DME and the mixture was heated at 125 0 C for 1200 s in microwave. Then the reaction was cooled to room temperature and water (0.5 mL), NaHCC"3 (2 eq), Pd(tetrakis) (0.05 eq) and 3-(l-benzofuran-2-yl)-5-bromopyrazin-2-amine (0.95 eq) were added and the resulting mixture was heated at 12O 0 C for 700 s in microwave. The crude reaction was filtered and concentrated and then purified using preparative HPLC system A, C or D.
• the central pyrazine scaffolds in Methods G-M were made via a general Suzuki coupling between benzofuran-2-boronic acid/ l-Boc-indole-2-boronic acid and 3-amino-2, 6-dibromopyrazine/2, 6-dichloropyrazine.
• the amides in Methods K-M were made by conventional amide coupling between phenylcarboxylic acids and aliphatic amines.
• Method N 4-[5-amino-6-(l-benzofuran-2-yl)pyrazin-2-yl]benzoic acid (1 eq), the amine (1.5 eq), HOBT (1.3 eq), EDC (1.3 eq) and TEA (1.3 eq) were dissolved in 3 mL THF and stirred at room temperature overnight. The solution was concentrated and then purified using preparative HPLC system A, C or D.
• Method O 4-[6-(lH-indol-2-yl)pyrazin-2-yl]benzoic acid (1 eq), the amine (1.5 eq), HOBT (1.3 eq), EDC (1.3 eq) and TEA (1.3 eq) were dissolved in 3 mL THF and stirred at room temperature overnight. The solution was concentrated and then purified using preparative HPLC system A, C or D.
• the central pyrazine scaffolds in Methods N and O were made via two general Suzuki couplings, the first between benzofuran-2-boronic acid/ 1-Boc-indole- 2-boronic acid and 3-amino-2, 6-dibromopyrazine/2, 6-dichloropyrazine, and the second between the corresponding intermediate from the first and 4- carboxyphenylboronic acid.
• Any starting materials used in the Examples, the preparation of which has not been described herein, are commercially available and/ or can be prepared by the skilled person merely using standard synthesis procedures and pathways known in the field of preparatory organic chemistry.
• Example 13 4-[6-(4-hvdroxyphenyl)pyrazin-2-yl1-2-methyl-N-(2-pyrrolidin-l- ylethyljbenzenesulphonamide
• N,N,N'-Trimethyl-l ,3-propanediamine (1 1.2 mg, 0.095 mmol) was treated according to Method O to give the product as a yellow gum in an amount of 1.3 mg (yield 5%).
• Amine N-(3-aminopropyl)morpholine (9.5 mg). Purified by reversed phase preparative HPLC using XTerra Prep MS Cl 8 5 ⁇ m 19 x 50mm, flow 25 ml/min, 50 mM pH IO NH4HCO3 / ACN, fractions collected based on UV- signal (254 nm). Yield: 2.3 mg (16%). Yellow solid. HPLC 100% (system A. 10- 97% MeCN over 3 minutes. MS (electronspray) M+H+ m/z 434.4.
• Amine l-(3-dimethylaminopropyl)-piperazine (1 1.3 mg). Purified by reversed phase preparative HPLC using XTerra Prep MS C 18 5 ⁇ m 19 x 50 mm, flow 25 ml/min, 50 mM pH IO NH4HCO3 / ACN, fractions collected based on UV- signal (254 nm). Yield: 6.2 mg (41%). Yellow solid. HPLC 100% (system A. 10- 97% MeCN over 3 minutes. MS (electronspray) M+H+ m/z 461.4.
• NBS (45 g, 253 mmol) was added in portions to a suspention of 2- aminopyrazine (25 g, 263 mmol) in dichloromethane (500 ml) over a period of 2h. The mixture was filtered and evaporated. The residue was suspended in dichloromethane (60 ml) and stirred for 10 minutes before hexane (60 ml) was added. The mixture was stirred vigorously for 15 minutes and filtrated. The yellow powder was washed with CH2CI2/ hexane 1 : 1 (3x). The solid was dis- solved in diethylether and washed with water (3x), dried (mgso4) and evaporated, yield: 15.0 g (33%). Light yellow solid.
• a stock solution of the 4-(6-chloropyrazin-2-yl)phenol was made by dissolving 210 mg in 14 ml DME and 1 ml was added to each vial (15 mg, 0.073 mmol).
• a stock solution was made by dissolving 260 mg NaHCC"3 in 6.76 ml H2O and 0.5 ml (0.24 mmol) was added to each vial, followed by the requisite boronic acid (0.1 mmol) and tetrakis(triphenylphosphine)palladium (3 mg, 0.0026 mmol)
• the mixtures were heated 130 0 C for 600 s, evaporated and dissolved in MeOH water (9: 1) (1.5 ml), filtered and purified as described below.
• Step z A mixture of 3,5-dibromo pyridine (250 mg, 1.05 mmol 300 mg) iV-Boc- indol-2-yl boronic acid (300 mg, 1.15 mmol), palladium tetrakis(triphenylphosphine) (6 mg), sodium bicarbonate (1 13 mg, 3.6 mmol) in DME (3.5 ml) and water (1 ml) was heated in a microwave reactor at 120 0 C for 900 s to effect the Suzuki coupling. The material was further heated in the microwave to 150 0 C for 300 s, and subsequently to 180 0 C for a further 300 s to effect the removal of the BOC-group.
• Step U A mixture of 2-(5-bromopyridin-3-yl)- l//-indole trifluoroacetate (100 mg, 0.26 mmol), 4-carboxy-phenylboronic acid (47 mg, 0.28 mmol), NaHCC"3 (84 mg, 1 mmol) and palladium tetrakis(triphenylphosphine) (6 mg. 0.005 mmol) in DME (3.5 mL) and water (1 mL) were heated to 120 0 C in the micro- wave for 600 s. The reaction mixture was diluted with methanol and filtered through celite to remove insoluble salt before concentrating in vacuo. The material was used without further purification and thus exisited as Na+ salt.
• the title compound was synthesised using general procedure 3 starting from crude sodium 4-[5-(lH-Indol-2-yl)pyridin-3-yl] benzoate (Intermediate 10) (10 mg 0.03 mmol), 1-methylpiperazine (10 ⁇ l), HOBt (6 mg, 0.044 mmol), EDC (8.6 mg, 0.44 mmol) and triethylamine (14 ⁇ l, 0.1 mmol) in 0.5 ml THF. The crude material was purified using preparative HPLC to give a yellow gum (4.4 mg, 29%).
• the title compound was synthesised using general procedure 1 starting from 4-(6-chloropyrazin-2-yl)phenol (300 mg, 1.45 mmol), 4-amino 2-methoxy benzoic acid (267 mg, 1.60 mmol), Pd 2 (dba) 3 (30 mg, 0.0363 mmol), Xantphos (40 mg, 0.0725 mmol), Na ⁇ BuO (200 mg, 2.03 mmol) and dioxane (20 ml). Crude material subsequently used without further purification.
• the title compound was synthesised using general procedure 1 starting from 4-(6-chloropyrazin-2-yl)phenol (300 mg, 1.45 mmol), 4-amino 2-methoxy 5- chloro benzoic acid (322 mg, 1.60 mmol), Pd 2 (dba) 3 (30 mg, 0.0363 mmol), Xantphos (40 mg, 0.0725 mmol), Na ⁇ BuO (200 mg, 2.03 mmol) and dioxane (20 ml). Crude material subsequently used without further purification.
• the title compound was synthesised using general procedure 1 starting from 4-(6-chloropyrazin-2-yl)phenol (300 mg, 1.45 mmol), 4-amino 3-methoxy benzoic acid (267 mg, 1.60 mmol), Pd 2 (dba) 3 (30 mg, 0.0363 mmol), Xantphos (40 mg, 0.0725 mmol), Na ⁇ BuO (200 mg, 2.03 mmol) and dioxane (20 ml). Crude material subsequently used without further purification.
• the title compound was synthesised using general procedure 1 starting from 4-(6-chloropyrazin-2-yl)phenol (300 mg, 1.45 mmol), 4-amino 3-chloro benzoic acid (274 mg, 1.60 mmol), Pd 2 (dba) 3 (30 mg, 0.0363 mmol), Xantphos (40 mg, 0.0725 mmol), Na ⁇ BuO (200 mg, 2.03 mmol) and dioxane (20 ml). Crude material subsequently used without further purification.
• the title compound was synthesised using general procedure 1 starting from 4-(6-chloropyrazin-2-yl)phenol (300 mg, 1.45 mmol), 3-amino benzoic acid (220 mg, 1.60 mmol), Pd 2 (dba) 3 (30 mg, 0.0363 mmol), Xantphos (40 mg, 0.0725 mmol), Na ⁇ BuO (200 mg, 2.03 mmol) and dioxane (20 ml). Crude material subsequently used without further purification.
• the title compound was synthesised using general procedure 1 starting from 4-(6-chloropyrazin-2-yl)phenol ( 100 mg, 0.84 mmol), 3-amino 4-chloro benzoic acid ( 171 mg, 1 mmol), Pd 2 (dba) 3 ( 10 mg), Xantphos ( 15 mg), Na ⁇ BuO (200 mg, 2.03 mmol) and dioxane ( 10 ml). Crude material subsequently used without further purification.
• the title compound was synthesised using general procedure 1 starting from 4-(6-chloropyrazin-2-yl)phenol ( 100 mg, 0.84 mmol), 3-amino 4-methoxy benzoic acid ( 168mg, 1 mmol), Pd 2 (dba) 3 ( 10 mg), Xantphos ( 15 mg), Na ⁇ BuO (200 mg, 2.03 mmol) and dioxane ( 10 ml). Crude material subsequently used without further purification.
• the title compound was synthesised using general procedure 1 starting from 4-(6-chloropyrazin-2-yl)phenol ( 100 mg, 0.84 mmol), 3-amino 4-methyl benzoic acid ( 151 mg, 1 mmol), Pd 2 (dba) 3 (10 mg), Xantphos ( 15 mg), Na ⁇ BuO (200 mg, 2.03 mmol) and dioxane ( 10 ml). Crude material subsequently used without further purification.
• the requisite benzoic acids ( 1 eq.) were treated with triethyl amine (3.0 eq.) and O-(benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium tetrafluorob orate (TBTU) ( 1.2 eq.), dissolved in DMF (around 5 ml/mmol of starting material) and treated with the requisite amines ( 1.25 eq.). The mixtures were allowed to stand at room temp overnight. Additional equivalents of the reagents were added to incomplete reactions and the mixtures heated at 60 0 C overnight to drive conversions to completion. The products were subsequently purified using preperative HPLC (high throughput).
• the title compound was prepared using general procedure 2, starting from 4- ⁇ [6-(4-hydroxyphenyl)pyrazin-2-yl]amino ⁇ -2-methoxybenzoic acid (Intermediate 12) (20 mg, 0.059 mmol), N,N-dimethylpropane-l ,3-diamine (10 ⁇ l), triethyl- amine (25 ⁇ l, 0.177 mmol) and TBTU (23 mg, 0.071 mmol). The crude material was purified using preparative HPLC to give an off-white solid, (10.5 mg).
• the title comopound was prepard using general procedure 2, starting from 5- chloro-4- ⁇ [6-(4-hydroxyphenyl)pyrazin-2-yl]amino ⁇ -2-methoxybenzoic acid (In- termediate 13) (20 mg, 0.54 mmol), 2-pyrrolidin- l-ylethanamine (10 ⁇ l), triethylamine (22 ⁇ l, 0.16 mmol) and TBTU (23 mg, 0.071 mmol). The crude material was purified using preparative HPLC to give an off-white solid, (3.8 mg).
• the title comopound was prepard using general procedure 2, starting from 5- chloro-4- ⁇ [6-(4-hydroxyphenyl)pyrazin-2-yl]amino ⁇ -2-methoxybenzoic acid (In- termediate 13) (20 mg, 0.54 mmol), 3-morpholin-4-ylpropan- 1 -amine (15 mg), triethylamine (22 ⁇ l, 0.16 mmol) and TBTU (21 mg, 0.065 mmol). The crude material was purified using preparative HPLC to give a white solid (10.7 mg).
• the aqueous phase was extracted with ethyl acetate (2 x 25 ml) and the combined organic phases dried (MgS ⁇ 4) and filtered. The solution was concentrated in vacuo and the crude (44 mg, 90%+ pure) used without further purification.
• the title compound was synthesised using general procedure 3 starting from 4- ⁇ [6-( lH-indol-2-yl)pyrazin-2-yl]amino ⁇ -3-methoxybenzoic acid, (Intermediate 22) (10 mg 0.03 mmol), N, l-dimethylpyrrolidin-3-amine (10 ⁇ l), HOBt (6 mg, 0.044 mmol), EDC (8.6 mg, 0.44 mmol) and triethylamine (14 ⁇ l, 0.1 mmol) in 0.5 ml THF. The crude material was purified using preparative HPLC to give a yellow gum (6.6 mg, 41%).
• the title compound was synthesised using general procedure 3 starting from 4- ⁇ [6-( lH-indol-2-yl)pyrazin-2-yl]amino ⁇ -3-methoxybenzoic acid, (Intermediate 22) (10 mg 0.03 mmol), morpholine (10 ⁇ l), HOBt (6 mg, 0.044 mmol), EDC (8.6 mg, 0.44 mmol) and triethylamine (14 ⁇ l, 0.1 mmol) in 0.5 ml THF. The crude material was purified using preparative HPLC to give a yellow gum (4.0 mg, 27%).
• the title compound was synthesised using general procedure 3 starting from 4- ⁇ [6-( lH-indol-2-yl)pyrazin-2-yl]amino ⁇ -3-methoxybenzoic acid, (Intermediate 22) (10 mg 0.03 mmol), N,N-diethylethane-l ,2-diamine (10 ⁇ l), HOBt (6 mg, 0.044 mmol), EDC (8.6 mg, 0.44 mmol) and triethylamine (14 ⁇ l, 0.1 mmol) in 0.5 ml THF. The crude material was purified using preparative HPLC to give a yellow gum (7.6 mg, 48%).
• the title compound was synthesised using general procedure 3 starting from 4- ⁇ [6-( lH-indol-2-yl)pyrazin-2-yl]amino ⁇ -3-methoxybenzoic acid, (Intermediate 22) (10 mg 0.03 mmol), iV,iV-dimethylpropane-l ,3-diamine (10 ⁇ l), HOBt (6 mg, 0.044 mmol), EDC (8.6 mg, 0.44 mmol) and triethylamine (14 ⁇ l, 0.1 mmol) in 0.5 ml THF. The crude material was purified using preparative HPLC to give a yellow gum (6.7 mg, 43%).

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