GB2400101A - Compounds capable of binding to the active site of protein kinases - Google Patents

Compounds capable of binding to the active site of protein kinases Download PDF

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Publication number
GB2400101A
GB2400101A GB0307214A GB0307214A GB2400101A GB 2400101 A GB2400101 A GB 2400101A GB 0307214 A GB0307214 A GB 0307214A GB 0307214 A GB0307214 A GB 0307214A GB 2400101 A GB2400101 A GB 2400101A
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library
compound
formula
compounds
libraries
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GB0307214D0 (en
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John Harris
Nicola Church
Andrew Proud
Marcel Kling
Benjamin D Vickery
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Biofocus Discovery Ltd
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Biofocus Discovery Ltd
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Priority to PCT/GB2004/001399 priority patent/WO2004085409A2/en
Publication of GB2400101A publication Critical patent/GB2400101A/en
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/18—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • 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
    • 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
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    • 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
    • C07D403/04—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 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
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • 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

Abstract

The present invention relates to compounds capable of binding to the active site of protein kinase enzymes. The invention further relates to libraries of compounds and a family of libraries of compounds for use in screening programmes against protein kinases as well as the individual compounds for use in hit to lead and lead optimisation projects, and similar stages in the drug discovery process. The invention also provides methods for making compounds and libraries. Compounds disclosed are based on a pyrazine, pyridine or fused pyrazine-imidazole core chemical structure or scaffold. The compounds may be useful in the treatment of cancer, tumours, metastases, inflammation or diabetes.

Description

À ace À . * . À À . . .. . . . À . . . ..
À . . . _ À . À.
24001 01
COMPOUND LIBRARIES
The present invention relates to compounds capable of binding to the active site of protein kinase enzymes. In particular, a family of libraries of compounds is provided for use in screening programmes against protein kineses as well as the individual compounds for use in hit to lead and lead optimization projects, and similar stages in the drug discovery process.
The invention also provides methods for making compounds and libraries.
As part of the process of discovering drugs or agrochemicals it is customary to screen libraries of compounds against biological targets to discover 'hits' which are then further developed into 'leads' and subsequently drugs or agrochemicals, by using the techniques of medicinal chemistry. Accordingly the success or not of the drug or agrochemical discovery project is critically dependent on the quality of the hit and this in turn is dictated by the quality of the screening library.
Technological advances have enabled screening on a very large scale, and the screening of hundreds and thousands of compounds at the start of a discovery program is routine. This does, however, entail a significant cost.
The hits obtained from such screening efforts are not all of the best quality, and often take a large amount of subsequent time and effort in order to get a good lead. It has been estimated that only about 25% of projects actually get to the lead optimization stage, and part of the reason for this is the intractability of hits from high throughput screening.
Screening libraries are commonly collections of compounds from several sources. As a result they typically contain compounds synthesized as part of previous projects in the history of a company. With regard to drug discovery, these collections will be drug-like but are likely to be limited in scope and will be directed to certain areas of a project. It has been the common practice of many pharmaceutical companies in recent times to augment the collections by purchasing either single compounds from À @ À e e, À c e À À À a. ee - 2 vendors, or by contracting the synthesis of combinatorial libraries of compounds. The singly purchased compounds may have been selected to fill in areas of compound space poorly represented in the compound collections. Combinatorial libraries are typically synthesised around well- performing chemistries with some design based on producing 'diversity' in compound space.
A complementary approach, and one that is increasingly preferred, is to screen focused libraries against the target of choice. Focused libraries are becoming of increasing importance in their ability to generate hits capable of rapid expansion in many areas including kineses. Such libraries are slightly more expensive to prepare but have attributes of reliability, reproducibility and provide a considerably higher hit rate: typically 10-100 fold and above compared with random screening. They are, however, very difficult to design and their efficiency relates directly to the amount of effort that has gone into the design. Using these focused libraries it is usually possible to get a number of hits in the low micromolar and below range. As there is a defined set of compounds, the potential exists to observe indications of SAR in a chemical series, and to progress the chemistry efficiently.
Protein kineses constitute approximately 2% of the human genome and are fundamental to many intracellular signalling processes. They form the largest known family of enzymes and act on specific proteins within cells.
Through the phosphorylation of specific sites, protein kineses are responsible for the activation or deactivation of various signaling transduction pathways. Abnormalities in the phosphorylation mechanism are a major factor in many disease states including cancer, diabetes and inflammation.
In a bid to control these disease states, protein kineses have been the focus of attention and the subject of much research for many years.
However, since the development of the first inhibitors back in the early e ce. À e
À À e À À À À À - 3 1980's, there remains a shortage of clinically approved protein kinase inhibitors, with only a limited number of therapeutic agents currently in use. The discovery of safe and selective kinase inhibitors therefore remains highly desirable and is still widely sought after.
The family of focused libraries provided herein is designed to interact with a range of kinase targets. Each library is a defined set of compounds which will enhance the probability of finding a small molecule which will interact with one or more types of protein kineses. Protein crystallography has allowed for the preparation of three-dimensional structures detailing the individual protein sequence alignments of the catalytic domains of many different protein kineses. These can be used to not only identify commonalities in the general structure of protein kineses, but also to ascertain sequences which are unique to the individual kineses.
Advantagously, the invention provides a family of 'focused' libraries of compounds which will provide clear leads for ligands which bind to the active site of protein kinase enzymes. Remarkably, focused libraries according to this invention can provide hit rates of typically 1-13% for the requisite predicted protein kineses. The libraries are defined in detail below and are referred to herein as SFKO9, SFK10, SFKll, SFK14 and SFK20 wherein SFK represents "soft focus _inase library" and the suffixed numbers identify individual libraries.
In the context of the present invention, 'library' means a group of compounds which are structurally related by virtue of a core chemical structure (or 'scaffold'), but which differ from each other by virtue of permutation of specific substituent groups attached to the scaffold. The core chemical structures are referred to as, for example, PS40, PS81 and PS172 (the scaffolds of SFKO9 having general formulae I, II and III respectively) wherein PS represents "pharmascape" and the suffixed numbers identify individual scaffolds. À À
À c * À . c À À - 4 Generally speaking such a library will consist of or comprise a number of compounds, e.g. as many as about 100, about 1000, about 2000, about 3000 or indeed about 10000 compounds. The word 'about' is interpreted to mean plus or minus 20%, more preferably plus or minus 10%, most preferably plus or minus 5% The number of compounds should be sufficient to provide an adequate diversity of related compounds without being so large to be unduly complex or expensive to produce.
The word 'comprises' is interpreted to mean 'includes among other things' and is not interpreted to mean Consists of only'.
In the context of the present invention the terms 'permitted substituents' and analogous terms are used to refer to defined chemical groups that may be attached to a 'scaffold' to provide permutations of the chemical structure of related compounds.
Where the chemical formulae of permitted substituents are shown in this description and claims, the substituent may appear in the compounds as shown (i.e. simply covalently bonded to the scaffold) or may be a derivative of the shown chemical formula of the substituent by virtue of the use of a reactive group to couple the substituent to the scaffold.
Polymerisation of permitted substituents (e.g. diamerisation) is intended to be within the scope of the invention.
It will be appreciated that the total number of permutations created by the permitted substituents may be a very large number, far greater in magnitude than the actual number of compounds in the library. In other words, the number of possible compounds for any'virtual' library may well greatly exceed the number of synthesised compounds making up an embodiment of the 'real' library. The invention is intended to encompass libraries having all, and a number which is less than all, of the permitted substitutions represented by compounds therein.
À À . . a a À À a À a À ÀÀ a À Àa À. c tea À Àa À À À a aea À. a À a - 5 It will be appreciated that some specific combinations of permitted substituents may be more or less difficult to synthesise and/or use in a focused library of the invention. This does not detract from the generality of applicability of the invention as described herein. Real libraries have been synthesised from a selected group of permutations/combinations of permitted substituents, taking into consideration factors affecting the intended purpose of the library and its cost and complexity of synthesis.
Thus, in a first aspect the invention provides a family of libraries of compounds for high throughput investigation of a predetermined kinase enzyme wherein the family includes the libraries SFKO9, SFK10, SFK11, SFK14 and SFK20. In use, the family of libraries is checked for the library or libraries most likely to include a hit which interacts with the predetermined kinase and these libraries are sued for high throughput investigation.
In a second aspect the invention provides a method for making a family of libraries according to a first aspect of the invention, which method is according to the schemes defined herein.
In a third aspect the invention provides a library comprising or consisting of a set of structurally related compounds having a core chemical structure (scaffold) of a general formula selected from the group consisting of: i) Formula I and/or formula II and/or formula III of library SFKO9; ii) Formula I and/or formula II and/or formula III of library SFK10; iii) Formula I and/or formula II and/or formula III of library SFK11; iv) Formula I and/or formula II of library SFK14; and v) Formula I of library SFK20.
Preferably an embodiment of the library comprises or consists of a structurally related set of compounds, said library being selected form the group of libraries which consists of: i) library SFKO9; e À - 6 ii) library SFK10; iii) library SFKll; iv) library SFK14; and v) library SFK20.
Preferably, an embodiment of a library according to the invention comprises compounds having a core chemical structure and permitted substituents thereon, and said library has all or substantially all of the permitted substitutions represented by compounds therein.
Preferably, an embodiment of a library according to the invention comprises compounds having a core chemical structure and permitted substituents thereon, and said library has about 100, about 1000, about 2000, about 3000 or about 10000 compounds represented therein.
In a fourth aspect the invention provides a method for making a compound library according to an aspect of the invention, which method is according to any of the schemes for making a core chemical structure (scaffold) of a library selected form the group of libraries which consists of: i) library SFKO9; ii) library SFK10; iii) library SFKll; iv) library SFK14; and v) library SFK20.
Most of the compounds defined by the permitted substitutions on the scaffolds are also novel per se and the invention is intended to encompass each individual novel compound. Any known compound having a structural formula identical to any one of the compounds covered by the formulae of scaffolds and permitted substitutions described herein is hereby explicitly disclaimed per se.
e À .e e e C C À C À À À C À C C C C C À ce ace e À c cue À C À C À e À À Thus, in a fifth aspect the invention provides a compound having a core chemical structure (scaffold) of SFKO9 which is selected from: i) PS40 IN, excluding the following compounds Ph N>NvOtBu j>N9OtBu OtBu OtBu N N JOHN: H Jo Oi -[N;- AHIN H'N '1 '; OMe N:,N >,N,NN>N F - OMe H; : N PbJ(NN>N:NH ii) PS81 c.
À À À . . À . . c À - 8 iR Art. for
iii) PS172 Art, Preferably an embodiment of a compound according to this aspect of the invention is selected from the compounds represented within the library SFKO9.
In a seventh aspect the invention provides a compound having a core chemical structure (scaffold) of SFK10 which is: Preferably an embodiment of a compound according to this aspect of the invention is selected from the compounds represented within the library SFK10.
In an eighth aspect the invention provides a compound having a core chemical structure (scaffold) of SFK11 which is: À À À À À À À . À À . c . c À . À À - 9 - N:N N:N;
N
SFK11 Core Scaffold Preferably an embodiment of a compound according to this aspect of the invention is selected from the compounds represented within the library SFK1 1.
In a ninth aspect the invention provides a compound having a core chemical structure (scaffold) of SFK14 which is selected from: i) PS173 N:NH2
R N R
excluding: À À e À . À À _.
e c - 10 B2N N OH N OM. Ph H2N 1 OH
M N
NH2 NH2 NH2 N2NiN ON'I OH OH lit ONH2Ni OMe NH2 Ph Nit 83 llM2 O No OBU-t one NH2;: OM. Nor M43 NH 2 Mentioned In literature and Ph Nor OH NH2 ad; or ii) PS174 C C 8 8 C 8 C 8 8 8 À 8 4 8 88 À 8 C C 8 88 1 C C 8 C N:NH2 RN,1N'R
R
Preferably an embodiment of a compound according to this aspect of the invention is selected from the compounds represented within the library SFK14.
In a ninth aspect the invention provides a compound having a core chemical structure (scaffold) of SFK20 which is: mu.
Preferably an embodiment of a compound according to this aspect of the invention is selected from the compounds represented within the library SFK20.
In a further aspect the invention provides a method of making a compound according to an embodiment of the invention which method is according to any of the schemes defined herein for making compounds of a library selected form the group of libraries which consists of: i) library SFKO9; ii) library SFK10; iii) library SFKll; iv) library SFK14; and v) library SFK20.
A. ..e es. :e À .e - 12 In a further aspect the invention provides an assay comprising a family of libraries, a library, or one or more compounds according to the invention.
In a further aspect the invention provides use of an assay according to an embodiment of the invention for identifying a compound which has therapeutic affect.
In a further aspect the invention provides a pharmaceutical composition which comprises a compound according to the invention or a compound identified in an assay according to an embodiment of the invention.
In a further aspect the invention provides a compound having a core chemical structure (scaffold) of a library selected form the group of libraries which consists of: i) library SFKO9; ii) library SFK10; iii) library SFKll; iv) library SFK14; and v) library SFK20 or a compound according to an embodiment of the invention for use in therapy.
In a further aspect the invention provides use of a compound having a core chemical structure (scaffold) of a library selected form the group of libraries which consists of: i) library SFKO9; ii) library SFK10; iii) library SFKll; iv) library SFK14; and v) library SFK20 or a compound according to an embodiment of the invention in the manufacture of a medicament for treatment or prophylaxis of a condition characterized by abnormal kinase activity.
I.... ae.:.e Àe - 13 In a further aspect the invention provides use of a compound having a core chemical structure (scaffold) of a library selected form the group of libraries which consists of: i) library SFKO9; ii) library SFK10; iii) library SFKll; iv) library SFK14; and v) library SFK20 or a compound according to an embodiment of the invention in the manufacture of a medicament for treatment or prophylaxis of a condition selected from cancer, a tumour, metastases, inflammation or diabetes.
The invention will now be described in detail with reference to specific examples of compounds and methods for their production. The libraries SFKO9, SFK10, SFKll, SFK14 and SFK20 and compounds within these libraries will be described in turn.
Within this specification embodiments have been described in a way which 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.
Àe ad. act. e.. - 14
LIBRARY SFKO9 SFKO9 is designed to have a broad focus on the tyrosine and serine/threonine kineses that recognise typical mono-and bicyclic heterocyclic ligands for the ATP binding site. The central design of the library is based on novel applications of the 3-amino-5-carba-pyridine, 2amino-5-carba-pyrazine and 2-amino-5-thia-pyrazine scaffolds.
Each scaffold was docked into the ATP-binding region of a variety of kineses including Zap-70, CDK-2, CDK-4, p38 MAP kinase and FGF-r.
PS40 exhibits the characteristic double H-bonding system seen between ATP and the enzyme backbone in all the ATP sites examined and particularly favourable docking modes were observed for the tyrosine kineses. PS81 exhibits a single H-bond between Alarm of Zap-70 and the pyridine ring-N can form an additional H-bond to the backbone distinct from the more usual "amidine" H-bond, especially in the tyrosine kineses that were examined.
The invention provides a compound library comprising or consisting of a set of structurally related compounds of the general formula (I), (II) and (III) IR1 IR4 IR1 óN::N'R2 R6ó:, R7-S::N; (I) (II) (III) Wherein Rl, and R4 is hydrogen; R2 is alkyl having from 1 to 20 carbon atoms which may linear or branched and may contain one or more heteroatoms, cycloalkyl having from 3 to 20 carbon atoms which may bear one or more substituent groups at any available ring position and may e e À ee. Àe e e contain one or more heteroatoms, aryl having a cyclic aromatic structure containing between 3 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, hetero aryl having a cyclic aromatic structure containing between 1 and 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms or heteroaralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms; R3 and R6 is alkenyl having from 1 to 20 carbon atoms, aryl having a cyclic aromatic structure containing between 2 and 20 carbon atoms which may bear one or more substituent groups at any available ring position or hetero aryl having a cyclic aromatic structure containing between 1 and 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms; R5 is aryl having a cyclic aromatic structure containing between 2 and 20 carbon atoms which may bear one or more substituent groups at any available ring position or aralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms; R7 is aryl having a cyclic aromatic structure containing between 2 and 20 carbon atoms which may bear one or more substituent groups at any available ring position. R1 and R2 may also be joined to form the same ring system.
::: ::e es. ::e À ..
À À À À - 16 Scheme for synthesising compounds of formula (I) (PS40) 1 BOX 11 IR1 1 BOX 2 | R1 N Br NHR1 Rz 'óN::N R3B(OH)2: R2 Br N MeOH Br Pd(oAC)2' PPh3 R3 (A) 160 C, kW (B) DMF, 80OC (0 2,5-Dibromopyrazine (A) can be aminated with the amines described in Box 1. The resultant compounds (B) can then be reacted with the boronic acids described in Box 2 to yield the final compounds with formula (I).
À:: À . . À À . : À . . - . . À - 17 - m, D z I o ( o \ b I o D r I a., Q-ó (3 I 0 I I I I Q I I _ 8 &0- Zó'O)0 -0 o I.. 0 on \ O. o
O I A O O Z O
O O Z 5 O 04 \_4 I I I" O o O z o < I- Zm_ O O o - 0 I to it/ Z: LIZ
_
A Ió(O $ it\ Z" Zi3Z ZI I \ C A A ' I Z z ZZ I I _ zk z
I
Z\JZ I Z 1, \ AZ = o Z I Z I " 0- Z (: : I I e:: ::e c:. :. a. ce: :. e. .. ee.: - 18 General Procedures: Typical example of compound of formula (B), as described in the general reaction scheme; [2-(5'-bromo-2,3,5, 6-tetrabydro-[1,2']bipyrazinyl-4-yl)- ethyl]-dimethyl-amine (1).
N'\/N: N - <NJ (1) Dimethylaminoethylpiperazine (5mmol), 2,5dibromopyrazine (5mmol) and Hunig's base (5mmol) in methanol (2ml) was heated to 160 C for 10 min. The reaction was taken up in DCM. The solution was washed with water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The resultant solid was washed with hexane/DCM (9/1) to afford the desired product (1.07g, 65%). 1H (270MHz, CDCI3) 2.42(6H, s, N(CH3)2), 2.58-2.63(8H, m, 4xCH2), 3.56-3.60(4H, t, 5Hz, 2xCH3), 7.85(1H, s, Ar), 8.12(1H, s, Ar); HPLC: Rib 1.09 (98.70%); m/z (ES): 314 (100%, M+H), 271 (95%, M-N(CH3)2).
Typical example of compound of formula (B), as described in the general reaction scheme; 5'-bmo4-pyndin4-yl-3,4,5,6-tetrabydro-2H-[1, 27bipyrazinyl (2).
N
NNJ
Br N (2) À:: ::. c:- :e À. amp: :. e- Àe ape: - 19 - Yield 3.39, 33%; OH (270MHz, CDCI3) 3.49-3.54 (2H, m), 3.73-3.77 (2H, m), 6.69-6.72 (2H, m), 7.91-7.92 (lH, d, 1.4), 8.17-8.18 (lH, d, 1.4); HPLC 87%; m/z (ES) 321 [M+H]+.
Typical example of compound of formula (B), as described in the general reaction scheme; (5-bromo-pyrazin-2-yl)-furan-2-ylmethyl-amine (3). Now
Br N (a) Yield 7.359, 99%; OH (270MHz, CDCI3) 4.52-4.54 (2H, d, 5.6), 4. 91-4.95 (lH, br.s), 6.25-6.27 (lH, m), 6.32-6.34 (lH, m), 7.36-7.38 (lH, m), 7.72-7.73 (lH, d, 1.4), 8.11-8.12 (lH, d, 1.4); HPLC 99%; m/z (ES) 256 [M+H]+.
Typical example of compound of formula (B), as described in the general reaction scheme; (5-Bromo-pyrazin-2-ylJ-(2-pyridin-4-yl-ethyl)-amine (4).
H
óN:,N:N (4) Yield 6.49, 93%; OH (270MHz, CDCI3) 2.91-2.96 (2H, t, 6.8), 3. 62-3.70 (2H, m), 7.14-7.16 (2H, m), 7.64-7.65 (lH, d, 1.2), 8.10-8.11 (lH, d, 1.2), 8.52-8.55 (2H, m); HPLC 82%; m/z (ES) 279 [M+H]+.
:-: :. ce- ::. ce Àe À À - - 20 General procedure for the synthesis of compounds of formula (I).
The Suzuki reactions were carried out in stem tubes using a 96 position STEM shaker. To a solution of the required intermediates (B) in DMF (0.3mmol, 0.5ml) was added a solution of boronic acid (Box 2) in DMF (0.36mmol, 0.6ml) and 1.5M Na2CO3(aq.) solution (0.75mmol, 0.5ml).
The reaction vessels were then placed in a nitrogen filled glovebox for 30min. Two solutions of palladium acetate (95mg) and triphenylphosphine (335mg) in 1,4-dioxane (15ml) were freshly prepared and placed in a sonication bath for 2min. The palladium catalyst (0.3ml) was added to each reaction vessel inside the glovebox. The vessels were screw capped and then heated at 80 C with agitation for 16h. The reaction mixtures were filtered and purified by preparative reverse phase HPLC.
Typical example of compound of formula (I), as described in the general reaction scheme; [5-(3, 4-dimethoxy-phenyl)-pyrazin-2-yl]-(Z- pyridin-2yl-ethyl)-amine (5). (
MeO (a) Yield 51.9mg, 51%; OH (250MHz, CDCl3) 1.25(1H, br.s), 3.45-3.50 (2H, m), 3.92-4.02 (8H, m) 6.90-6.93 (1H, m), 7.29-7.33 (1H, m), 7.43-7.44 (1H, m), 7.60-7.66 (1H, m), 7.77-7.80 (1H, m), 8.15-8.22 (2H, m), 8.68.69 (1H, m); HPLC 100%; m/z (ES) 337 [M+H]+.
Typical example of compound of formula (I), as described in the general reaction scheme; 4-methyl-N-4-[5-(3-trifluoromethoxy-phenyl)-pyrazin- 2 -ylamino]- phenyl} -benzenesulfonamid e (6).
À::e e.:. À....: . e a ee. .. a - 21 F3C ó) 'ó (6) 1 Yield 73.5mg, 50%; H (250MHz, CDCl3) 2.39(3H, s) 6.82-6.89 (2H, m), 7.06-7.09 (2H, m) 7.10-7.25 (lH, m), 7.38-7.51 (3H, m), 7.63-7.66 (2H, m), 7.79-7.83 (2H, m), 8.23-8.24 (lH,d, 1.4), 8.54-8.55 (lH, d, 1.4); HPLC 100%; m/z (ES) 501 [M+H]+.
Scheme for synthesising compounds of formula (II) - (IIa and IIb - PS81) R4 1 Box4 | IR4 Br:óNH2 R5B(OH)2 B:rNR R6B(OH)2 R6ó<NR5 50 % cu(OAc)2, N Pd(OAc)2, PPh3 N 4A MS, pyr, aq. Na2CO (C) air, DCM (D) DMF, 80 C (la) : NaBH(OAc)3:1 R4 IR4 Br:<N R5 R6B(OH) 2 R6N:'R5 Pd(OAc)2, PPh3 ' I N aq. Na2CO3 (E) DMF 80 C (lib) 3-Amino-5-bromopyridine (C) can be subjected to a copper mediated N- arylation with the boronic acids described in Box 3, and the resultant compounds (D) then reacted with the boronic acids described in Box 4 to yield final compounds of formula (IIa). Alternatively, compounds with the general structure (E) can be synthesised through a reductive amination with the aldehydes described in Box 5. Functionalisation at C5 with the À À À À À À . À À . . À . c . . À . 22 boronic acids described in Box 4 yields final compounds with the general formula (IIb).
::: ::e cee. ::e se À .e c À c À c c - 23 o 0 an=O O 0= :30 0 I:3 0 I it_ O - Z O I 0 t 3 0- > 0 :':C', t5_S
LIZ
0-ii. 8N O j D OD R - 0- 0 Z: O O i He O /
I- I O I
, A <> _ I =- 1" À l 1 C À À c.e e À a'.
C À - 24
General Procedures: Typical example of compound of formula (D), as described in the general reaction scheme; (5-bromo-pyridin-3-yl)-(3-nitrophenyl)-amine (7).
Br:ó'N:ó'NO2 (7) 3-Amino-5-bromopyridine (3.119, 18mmol), 3-nitrophenylboronic acid (6.289, 36mmol), copper(II) acetate (1.639, 9mmol), 4A molecular sieves (39) and pyridine (2.9 ml, 36mmol) in DCM (50ml) was stirred vigorously in an open top vessel for 18h. The reaction was filtered and the residue was washed with methanol. SiO2 (109) was added to the solution and concentrated in vacua to dryness. The resultant solid was chromatographed (SiO2, 20%-50% EtOAc in hexane) to afford the desired product (1.619, 30%) as a bright yellow solid. 1H (270MHz, CDCl3) 6.08(1H, br.s, NH), 7.39-7.40(1H, m, r), 7.45-7.60(1H, m, Ar), 7.62(1H, s, Ar), 7.83-7.89(2H, m, Ar), 8.34-8.37 (2H, m, Ar); HPLC: Re 2.06 (77.89%); m/z (ES): 294(100%, M+).
Typical example of compound of formula (D), as described in the general reaction scheme; (5-bromo-pyridin-3-yl)-phenyl-amine (8).
H
Br'ó:,N'0 (8) Yield 860mg, 35%; H (250MHz, CDC13) 5.87 (1H, br.s), 7.07-7. 53 (6H, m), 8.16-8.24 (2H, m); HPLC 92%; m/z (ES) 249 [M+H]+.
:e Àe.:; .e - 25 Typical example of compound of formula (D), as described in the general reaction scheme; (5-bromo-pyridin-3-yl)-(4-methoxy-phenyl)amine (9). Br N (9)
Yield 1.279, 38%; AH (250MHz, COCK) 3.82 (3H, s) 5.61 (lH, br.s), 6.896.92 (2H, d, 8.9) 7.07-7.11 (2H, d, 8.9), 7.27-7.29 (lH, m) 8.06-8.11 (2H, m); HPLC 100%; m/z (ES) 279 [M+H]+.
Typical example of compound of formula (D), as described in the general reaction scheme; (5-bromo-pyridin-3-yl)-(4-chloro-phenyl)-amine (0).
H
Br:<N - , Yield 760mg, 30%; OH (250MHz, CDCl3) 6.11 (lH, br.s), 7.02-7.06 (2H, d, 8.8) 7.27-7.31 (2H, d, 8.8), 7.48-7.50 (lH, m) 8.18-8.24 (2H, m); HPLC 90%; m/z (ES) 283 [M+H]+.
General procedure for the synthesis of compounds of formula (IIa).
The Suzuki reactions were carried out in stem tubes using a 96 position STEM shaker. To a solution of the required intermediates (D) in DMF (0.3mmol, 0.5ml) was added a solution of boronic acid (Box 4) in DMF (0.36mmol, 0.6ml) and 1.5M NazCO3(aq.) solution (0.75mmol, 0.5ml).
The reaction vessels were then placed in a nitrogen filled glovebox for c e e - # e # e e e e e es À. C e e - 26 30min. Two solutions of palladium acetate (95mg) and triphenylphosphine (335mg) in 1,4-dioxane (15ml) were freshly prepared and placed in a sonication bath for 2min. The palladium catalyst (0.3ml) was added to each reaction vessel inside the glovebox. The vessels were screw capped and then heated at 80 C with agitation for 16h. The reaction mixtures were filtered and purified by preparative reverse phase HPLC.
Typical example of compound of formula (IIa), as described in the general reaction scheme; [5-(4-methanesulphoylphenyl) pyridin-3-yl]-phenylamine (11). lo
O ON (11)
Yield 17mg, 17%; AH (250MHz, CDCl3) 3.86 (3H, s), 6.23-6.43 (6H, m)7.63-7.71 (3H, m), 7.95-7.96 (2H, m), 8.33-8.34 (2H, m); HPLC 100%; m/z (ES) 325 [M+H]+.
Typical example of compound of formula (IIa), as described in the general reaction scheme; phenyl-(5-quinolin-3-yl-pyridin-3-yl)amine (12). =3óN (12)
À À. À À
À e. ce. ace À e ae. e. - 27
Yield 34.2mg, 38%; OH (250MHz, CDCI3) 7.16-7.24 (3H, m), 7.38-7.44 (2H, m) 7.71-7.77 (lH, m), 7.7.86-7.93 (lH, m), 7.99-8.04 (2H, m), 8.24-8.27 (lH, m),8.44-8.45 (1H, m), 8.53-8.56 (2H, m), 9.23-9.24 (1H, m); HPLC 98%; m/z (ES) 298 [M+H]+.
Typical example of compound of formula (E), as described in the general reaction scheme; (5-bromo-pyridin-3-ylJ-(4-chloro-benzyl)-amine (13).
Br HCI 3-Amino-5-bromopyridine (2.049, 13mmol), 4-chlorobenzaldehyde (1.839, 13mmol) and sodium triacetoxyborohydride (3.869, 18.2mmol) in DCM (40ml) was stirred at room temperature for 16h. The reaction was taken up in DCM. The solution was washed with water and brine. The organic layer was dried over MgSO4 and concentrated in vacua. The resultant solid was recrystallized from hexane/DCM to afford the desired product (3.149, 81%) as an off-white solid. 1H (270MHz, CDCI3) 4.24-4.68(3H, m, NH, CH2), 6.98-7.00(1H, m, Ar), 7.25-7.36(4H, m, Ar), 7.95-8.02(2H, m, Ar); HPLC: Rt 1.94 (98.70%); m/z (ES): 297(100%, M+).
Typical example of compound of formula (E), as described in the general reaction scheme; (5-bromo-pyridin-3-yl)-furan-3-ylmethyl-amine (14).
Br Hippo | À À À À c ÀÀ . . À À ce ret À À cee À À À C e. À - 28 Yield 2.169, 66%; AH (250MHz, CDCI3) 4.12-4.16 (3H, m), 6.39-6.40 (lH, m) 7.04-7.06 (lH, m), 7.42-7.43 (2H, m) 7.95-8.01 (2H, m); HPLC 98%; m/z (ES) 253 [M+H]+.
Typical example of compound of formula (E), as described in the general reaction scheme; (5-bromo-pyridin-3-y/)-(3,4-difluoro-benzyl}-amine (5)s Br NO SN'' (15) Yield 2.429, 62%; AH (250MHz, CDCI3) 4.30-4.44 (3H, m), 6. 97-7.20 (4H, m) 7.95-8.01 (2H, m); HPLC 95%; m/z (ES) 299 [M+H]+.
Typical example of compound of formula (E), as described in the general reaction scheme; (5-bromo-pyridin-3-yl)-(3,4-dichloro-benzyl)-amine (16).
| Br N C Yield 2.399, 55%; AH (250MHz, CDCI3) 4.30-4.42 (3H, m), 6.97-6. 98 (lH, m), 7.13-7.20 (lH, m), 7.39-7.47 (2H, m), 7.92-8.01 (2H, m); HPLC 75%; m/z (ES) 331 [M+H]+. À
À À c e À - 29 General procedure for the synthesis of compounds of the formula (IIb) The Suzuki reactions were carried out in stem tubes using a 96 position STEM shaker To a solution of the required intermediates (E) in DMF (0.3mmol, 0.5ml) was added a solution of boronic acid (Box 4) in DMF (0.36mmol, 0.6ml) and 1.5M Na2CO3(aq.) solution (0.75mmol, 0.5ml).
The reaction vessels were then placed in a nitrogen filled glovebox for 30min. Two solutions of palladium acetate (95mg) and triphenylphosphine (335mg) in 1,4-dioxane (15ml) were freshly prepared and placed in a sonication bath for 2min. The palladium catalyst (0.3ml) was added to each reaction vessel inside the glovebox. The vessels were screw capped and then heated at 80 C with agitation for 16h. The reaction mixtures were filtered and purified by preparative reverse phase HPLC.
Typical example of compound of formula (IIb), as described in the general reaction scheme; (5'-methoxy-[3,3']bipyridinyl-5-yl)-napAthalen-2ylmethyl-amine (17). OMe N, NO
Yield 72.4mg, 71%; AH (250MHz, CDCl3) 3.83(3H, s), 4.66 (2H, s), 7.247.26 (1H, m) 7.40-7.53 (4H, m), 7.79-7.89 (4H, m), 8.11-8.12 (1H, m), 8.34-8.42 (3H, m); HPLC 100%; m/z (ES) 342 [M+H]+.
Typical example of compound of formula (IIb), as described in the general reaction scheme; naphthalen-2-ylmethyl-(5-pyrimidin-5-yl-pyridin-3-yl)amine (18).
ce À c À c c À e À À C À C À À Àe Àec c c c cce À c a À À e. c e c N,NJ3 N (18) Yield 66.2mg, 70%; H (250MHz, CDCI3) 4.72 (2H, s), 7.13-7.15 (lH, m) 7.62-7.68 (lH, m), 7.78-7.90 (2H, m), 8.20-8.22 (2H, m), 8.30-8.31 (2H, m) ,8.89 (2H, s), 9.08-9.09 (lH, m), 9.25 (lH, s); HPLC 100%; m/z (ES) 314 [M+H]+.
Scheme for synthesising compounds of formula (III) (PS172) 1 1 3 1 BOX7 1 IR1 óNqBr R S 'óN'Br NHR1R2,óN:N Br N IPA, DIPEA S t-BuOH, DIPEA S (F) 80 C, o/n R7 (G) 120 C, 48h R7 (IID 3,6-Dibromopyrazine (F) can undergo thio-etherification with the thiols described in Box 6 to yield compounds with the general structure (G) and then reacted with the amines described in Box 7 to yield final compounds of formula (III).
À . . . À À À À À . . À À . . . . . e.
À À . À. se À - 31 =- Aid A I zz HI z PI I It Z\JZI \} -Zip 'I ZZ Z z I _ ': A -
ZZ
= ' . it' . À gig t.W
W
À À.. e À À a À . . . .
.. À a ce...DTD: À a e Àe - 32 Typical example of compound of formula (G), as described in the general reaction scheme; N-[4-f 5-bromopyrazin-2-ylsulfanyl)-phenyl] -acetamide (19) MeOCHN - 'N:Br (1 9) To a solution of 2,5-dibromopyrazine (PS40), (3.099, 13mmol) in 2- propanol (6ml) heated at 80 C, was added a solution of 4- acetylamidothiophenol (2.179, 13mmol) and Hunig's base (2.26ml, 13mmol) in 2-propanol (6ml) dropwise over 6 hours. The reaction mixture was stirred at 80 C overnight. The reaction was followed by HPLC and MS.
The reaction was concentrated in vacuo and the mixture was dissolved in dichloromethane and washed with water (twice) and brine and dried with magnesium sulphate. The resultant mixture chromatographed (SiO2, 2% MeOH in hexane) to afford the desired product (4.09, 95%) as a light brown solid. AH (270MHz,CD3OD) 8.47-8.46 (1H, d, 11.47, Ar), 7.92- 7.91(1H, d, 11.47, Ar), 7.69-7.68(2H, d, 12.2, Ar), 7.56-7.55(2H, d, 32.2, Ar), 2.14(1H, s, CH3), HPLC: R 2.42 (97.13%); m/z (ES): 324(100%, M+).
Typical example of compound of formula (G), as described in the general reaction scheme; 2-bromo-5-phenylsulfanyl-pyrazine (20). N^S^ (20)
À Àeve Àe c ce À À À À À À À C À c. c.e e À act À À e e ee À À - 33 Yield 2.219, 69%; AH (270MHz, CD3OD) 7.58-7.61 (3H, m) , 7.62-7.63 (2H, m), 7.93-7.94 (1H, d, 1.5), 8.48-8.49 (1H, d, 1.5); HPLC 100%; m/z (ES) 267 [M+H]+.
Typical example of compound of formula (G), as described in the general reaction scheme; Z-bromo-5-(3-chloro-phenylsulfanyl)-pyrazine (21).
NEWS - ,Cl (21) Yield 2.079, 86%; AH (270MHz, CD3OD) 7.43-7.52 (3H, m), 7. 62-7.64 (1H, m), 8.12-8.13 (1H, d, 1.5), 8.51-8.52 (1H, d, 1.5); HPLC 96%; m/z (ES) 301 [M+H]+.
Typical example of compound of formula (G), as described in the general reaction scheme; 4-(5-bromo-pyrazin-2-ylsulfanyl)-phenol (22).
Br/óN; 3\OH (22) Yield 1.949, 57%; AH (270MHz, CD3OD) 6.87-6.91 (2H, d, 8.8), 7.42- 7.45 (2H, d, 8.8), 7.79-7.80 (1H, d, 1.5), 8.46-8.47 (1H, d, 1.5); HPLC 93%; m/z (ES) 283 [M+H]+.
General procedure for the synthesis of compounds of the formula (III).
The reactions were performed in 1.5ml Radleys tubes attached to a heater and shaker. To a solution of intermediate (I) in nBuOH (0.3mmol, 0.3ml) . . . À . . À À À . . À À - 34 was added a solution of the amine (Box 7) in nBuOH (0. 33mmol, 0.2ml) and Hunig's base (0.33mmol, 0.1mL). The reactions were agitated and heated at 120 C for 48h. The reaction mixtures were filtered and purified by preparative HPLC.
Typical example of compound of formula (III), as described in the general reaction scheme; 5'-(3-chloro-4-fluoro-phenylsulfanyl)-4-pyridin-2-yl3,4, 5, 6-tetrabydro-ZH-[1,2 ']bipyrazinyl (Z3).
NSCI
ó, (23) Yield 63mg, 52%; AH (250MHz, CDCI3) 3.68-3.80 (OH, m), 6.66-6.71 (2H, m), 7.03-7.10 (1H, m), 7.23-7.29 (1H, m), 7.40-7.44 (1H, m), 7.49-7. 57 (1H, m), 8.12-8.24 (3H, m); HPLC 100%; m/z (ES) 402 [M+H]+.
Typical example of compound of formula (III), as described in the general reaction scheme; 5'-(4-methoxy- phenylsulfanyl)-4- pyridin-2-yl-3,4, 5, 6tetrabydro-2H-[1, 2']bipyrazinyl (24).
ON N ó>OMe ó,I::NJ À À . À À . À À À À c À À À e
C
À . À À . e. . . À À - 35 Yield 41.4mgl 36%; OH (250MHzl CDC13) 3.69 (8Hl 5)1 3.80 (3Hl s)l 6 65- 6.70 (2Hl my 6.85-6.91 (2Hl m)l 7.41-7.55 (3Hl my 7.97-7.98 (1Hl d 1.5)/ 8.06-8.07 (1Hl dl 1.5)1 8.20-8.23 (1Hl m); HPLC 100%; m/z (ES) 380 [M+H]+ Purification Conditions All compounds have a minimum purity level > 80% as measured by LCMS at 254 nm.
The columns used for the preparative HPLC purification of the various scaffolds are outlined in Table 1:
Table 1
l Scaffold Column PS40 (Formula I) Phenomenex Luna 10,um phenyl-hexyl column (21.2 x 150mm) and Waters SymmetryPrep_ C18 7 Am column (19 x 150mm).
PS81 (Formula II) Phenomenex Luna 10,um phenyl-hexyl column (21.2 x 150mm).
PS172 (Formula III) Waters XterraO Prep MS C18 5 Elm column (19 x 100mm).
The gradient used for PS40 (Formula I) was 95% water (0.2% TFA) / 5% ACN for 1 min to 5% water (0.2 % TFA) / 95% ACN over 8.0 min then held at 5% water (0.2 % TFA) / 95% ACN for 2.0 min. The solvent mixture was then returned to the initial conditions over 0.5 min. The gradient used for PS81 (Formula II) was 95% water (0.2% TFA/10% methanol) / 5% ACN (10% methanol) for 1 min to 5% water (0.2 % TFA/10% methanol) / 95% ACN (10% methanol) over 8.0 min then held at 5% water (0.2 % TFA/10% methanol) / 95% ACN (10% methanol) for 2.0 min. The solvent mixture was then returned to the initial conditions over 0.5 min. À À . * . À À À À À À À c. . . . . À . . e. .e À À - 36 The gradient used for PS172 (Formula III) was 99% water (lOmmol NH3HCO3) / 1% ACN for 1 min to 9% water (lOmmol NH3HCO3) / 91% ACN over 8.0 min then held at 9% water (lOmmol NH3HC03) / 91% ACN for 2.0 min. The solvent mixture was then returned to the initial conditions over 0.5 min. A flow rate of 25 ml/min was used except for PS172 (Formula III) where the main flow was 23.5ml/min and a makeup pump (using ACN only) was used at 1.5ml/min.
The conditions used for the analytical HPLC analysis following preparative HPLC purification are outlined in Table 2:
Table 2
= . . . __ Conditions Detection 1 _. . Column: Phenomenex Luna 5 Am C18 UV detection at 254 nm (diode (2) 30 x 4.6 mm. array range 210-280nm).
Gradient: 95% water (0.2% formic Electrospray ionization: acid) / 5% ACN (0.2% formic acid) for 0.5 min then 95% water (0.2% formic Cone voltage: 25 V. acid) / 5% ACN (0. 2% formic acid) to Cone temperature: 20 C.
2% water (0.2 % formic acid) / 98% Source temperature 120 C.
ACN (0.2% formic acid) over 2.8 min. RF lens voltage: 0.0 V. Held at 2% water (0.2 % formic acid) / Ion energy: 0.5 eV.
98% ACN (0.2% formic acid) for 0.3 Multiplier: 650 V. min. The solvent mixture is then returned to the initial conditions over 0.1 min and the system allowed to re equilibrate for 0.2 min. Flow rate: 2.0 ml/mint Temperature: 30 C.
l Injection volume: 5 Am partial loop. _ À À.. À À À À À a À À C À À À À ece À À À À C. e. À À C - 37 LIBRARY SFK10 SFK10 is designed to have primary focus on CDK-4, a key member of the cyclin-dependent kinase family (Hanks' C-M- G-C Group I kineses) with a broader secondary focus on CDK-2 and other members of the family. The central design of the library is based on a novel application of the imidazo[l,2-a]pyrazine scaffold.
A homology model of CDK-4 was developed based on the published crystal structures of CDK-6 and CDK-2 and guided by an existing homology model of CDK-4. Good docking was observed for the imidazo[1,2-a]pyrazine scaffold when this was substituted with 3-amino and 5-amino functions, with a characteristic double H-bond being formed between the backbone Val96 of the ATP site of CDK-4 and the 5, ring-6-diaza "amidine" system.
The invention provides a compound library comprising or consisting of a set of structurally related compounds of the general formula (I), (II) and (III) N - N Not No N - N: Nat 70 'No 50 R34 50 Wherein R1 is alkyl having from 1 to 20 carbon atoms which may linear or branched and may contain one or more heteroatoms, cycloalkyl having from 3 to 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aryl having a cyclic aromatic structure containing between 3 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, hetero aryl having a cyclic aromatic structure containing between 1 and 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aralkyl having from 1-20 carbon atoms which may bear c. . c.: ace: À . À . À . À q À q À . q À À À À. He.e À a - 38 one or more substituent groups at any available ring position and may contain one or more heteroatoms or heteroaralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms; R2 is alkyl having from 1 to 20 carbon atoms which may linear or branched and may contain one or more heteroatoms, alkenyl having from 1 to 20 carbon atoms, aryl having a cyclic aromatic structure containing between 2 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, cycloalkyl having from 3 to 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aryl having a cyclic aromatic structure containing between 3 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, hetero aryl having a cyclic aromatic structure containing between 1 and 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms or heteroaralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms and R3 is aryl having a cyclic aromatic structure containing between 3 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, hetero aryl having a cyclic aromatic structure containing between 1 and 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aralkyl having from 1- 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms or heteroaralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms. ÀÀ
r e r,. '.. ..e À À - 39 Scheme for synthesising compounds of formula (I) NH2 Pyridine NHTs NaH N NTs + TsCI,'> ' AN Br N Br DMF Br N (A) (B) | TEA, H2O N 2 imethylphenol N - 1 C N N; A: O _- B JN: O J - :N__: H K3PO4, Cul Now Pyridine Br (I) R1 IPA (D) R1 THE (C) NH2 Compounds of type (C) can be acylated by reaction with the acid chloride derivatives generated from the acids described in the acids box.
Compounds of formula (I) are generated from intermediates (D), by reaction with the amines described in the amine sets - amine set A, amine set B and amine set C. The permitted substituents at positions R1 and R2 are shown in acids [R1], amine set A [R2], amine set B [R2] and acid set C [R2]. The allowed combinations are; compounds of type (D), which are generated from acid set 1, are crossed with amines set A [R2] and amine set C [R2] with the exception of lipophilic acids and lipophilic amines. Compounds of type (D), which are generated from acid set 3, are crossed with amine set A, amine set B and amine set C with the exception of lipophilic acids and lipophilic amines. No N
Amine Set A [R2] I I A> Amine Set B [R2] R2'N A; O Amine Set C [R2] H hi (l) H R1 a I. c I t e st tse I e,'s c le - 40 r - - - - I I I I I Z, O I I I O O Z I Q Y Q 0 I O I Z I _ a I u <> __ e r, I" ,,
I Z O _ _ _ C I
S Z = -= O Q O z, a l O z (: f 6_ u' Z Z Z Z _ o _ O z 1l.- Q O I t f -z fz Q <f t s I U} O U I O O I I z m I I. I O. I I, I L---_________I I o f o I go z I I _ _ _ _ _ _ _ _ _ _ _ _ I I I I _ _ I I I, 8 o o (o o>Q 0 O:Q 0 I I Q 0 8 f' f Z Z : o 0 o I 1l f,, _ o 0 I 0 0 À 0 5 Z G 0 = Z 5 0 _ - - 1 : o f I 'iz zZ: 11 Z I 4 c-< f. . f E o_o I f. I I I I ZI:0 Q O f o z: I c 0; o:: I O O, '' L': 2 - , r_,, : Z r t Z' (< I À I Z e ÀÀ. e À e À À e ÀÀ À À À . .. À À À À À À À À Àa. .. À - 41 General Procedures: Synthesis of compound (A), as described in general reaction scheme; N(5-bromo-pyrazine-2-yl)-4-methyl-benzenesulfonamide. Br:
To a stirred solution of 5-bromo-pyrazin-2-ylamine (60 9, 0.34 mol) in pyridine (600 ml) was added tosyl chloride (73.2 9, 0.38 mol). The reaction was stirred at room temperature for 18h then concentrated in vacua. The residue was triturated (dichloromethane: methanol, 1: 1) to give compound (A) (87.6 9, 79%). OH (270 MHz, CDCI3) 2.49 (s, 3H), 7.54 (d, 8.1, 2H), 8.01 (d, 8.3, 2H), 8.32 (d, 1.5, 1H), 8.57 (d, 1.5, 1H); HPLC 97%.
Synthesis of compound (B), as described in general reaction scheme; N(5-bromo-pyrazin-2-yl)-N-cyanomethyl-4-methyl-benzenesutonamide. '"i;
Compound (A) (60 9, 0.19 mol) was added in portions to a suspension of sodium hydride (60% in mineral oil, 8.7 9, 0.22 mol), in DMF (500 ml) over a period of 30 minutes. The mixture was stirred at room temperature for 30 minutes before the addition of bromoacetonitrile (15 ml, 0.23 mol) over a further 30 minutes. The reaction was heated at 60 C for three hours then stirred for 18h at room temperature. After this time the e ece À e À À e e À À e À À e Àe e e e e À he se À ace À À e ee À. À À e - 42 reaction was concentrated in vacuo and the residue was purified by trituration with methanol to give compound (B) (49 9, 68%). OH (270 MHz, CDCl3) 2.41 (s, 3H), 4.68 (s, 2H), 7.42 (d, 8.1, 2H), 7.71 (d, 8.1, 2H), 8.41 (d, 1.2, 1H), 8.92 (d, 1.2, 1H); HPLC 95%.
Synthesis of compound (C), as described in general reaction scheme; 6bromo-imidazo[1, 2-a]pyrazin-3-ylmine.
Br: - N: NH2 A solution of compound (B) (49 9, 0.13) in a mixture of trifluoroacetic acid (360 ml) and water (40 ml) was heated at 40 C for 1 hour. Toluene (2 x 250 ml) was then added and the mixture concentrated in vacua. The residue was treated with an aqueous solution of sodium acetate (40 9, 150 ml) and stirred for lh at 0 C. The product was collected by filtration and washed with cold water to give compound (C) (25 9, 85%). OH (270 MHz, CDCl3) 6. 03 (br s, 2H), 7.27 (s, 1H), 8.52 (d, 1.2), 8.72 (d, 1.2, 1H); Typical example of compound of formula (D), as described in general reaction scheme; cyclopropanecarboxylic acid (6-bromo-imidazo[1,2a]pyrazin-3-yl)-amide (I). N: N
B kN O (1) H b À c À e À À À - 43 To a suspension of 6-bromo-imidazo[1,2a]pyrazin-3-ylmine (C) (2.0 9, 9.4 mmol) in THF (50 ml) was added pyridine (1.5 ml, 18.6 mmol) followed by cyclopropane carbonyl chloride (1.1 9, 10.3 mmol). The reaction was heated at 50 C for 3h then the solvent was removed in vacua. A mixture of ethyl acetate (75 ml) and a saturated solution of NaHCO3 (75 ml) were added to the residue, which resulted in precipitation of a solid. The solid was collected by filtration and washed with water then ethyl acetate to give the desired product as a light brown solid (1.9 9, 72%). OH (250 MHz, DMSO) 0.89 (m, 4H), 1.9 (m, 1H), 2.49 (m, 1H), 7.85 (s, 1H), 8.56 (d, 1.2 1H), 8.84 (d, 1.2, 1H), 10.8 (s, 1H); m/z Typical example of compound of formula (D), as described in general reaction scheme; N-(6-bromo-imidazo[1,2-a]pyrazin-3-yl)-2-methyl benzeamide (2). err B J'N Hi (2)
W
To a solution of o-tolylacetic acid (18.02 9, 120 mmol) in CH2CI2 (200 ml) was added oxalyl chloride (32 ml, 360 mmol) followed by DMF (3 drops).
The reaction was stirred at room temperature for 3h then concentrated in vacuo. The residue was dissolved in THF (50 ml) then added to a suspension of compound (C) in THF (150 ml) and pyridine (9.7 ml, 120 mmol) . The mixture was heated at 50 C for 30 mins. After this time the reaction was concentrated in vacuo and a mixture of ethyl acetate (250 ml) and a saturated solution of NaHCO3 (250 ml) was added. This resulted in the formation of a solid, which was collected by filtration to give the À À e À e À C À e ce ee - 44 desired compound as a brown solid (16.4 9, 79%). OH (250 MHz, DMSO) 2.3 (s, 3H), 3.86 (s, 2H), 7.12-7.16 (m, 3H), 7.27-7.30 (m, 1H), 7.87 (s, 1H), 8.76 (d, 1.2, 1H), 8.87 (d, 1.2 1H); m/z (APCI) 345 (M+); HPLC 100%.
General Procedure for the synthesis of compounds of formula (I) The reactions were carried out in stem tubes with a 96 well stem shaker.
Each tube was charged with a compound of formula (D) (0.3 mmol), followed by the addition of propan-2-ol (0.75 ml), a solution of the amine in propan-2-ol (0.6 mmol, 0.25 ml), a solution of 2,6-dimethylphenol in propan-2-ol (0.24 mmol, 0.25ml), potassium phosphate (0.6 mmol), and copper iodide (0.06 mmol). The reaction vessels were flushed with nitrogen then heated at 80 C for 22h. After this time the reactions were filtered then purified by preparative HPLC.
Typical example of compound of formula (I); N-[6-(2-dimethylaminoethylamino)-imidazo [1,2-a]pyrazin-3-yl]isobutyramide (3).
O N N-
N ee
À e À À e e À. bee À À ee.
À a À À e e. À. À - 45 Yield 41.3 mg, 47%; m/z (ES) 291 (M+1)+; HPLC 100%.
Typical example of compound of formula (I); Z-cyclopropyl-N-[6-(3,5dimethoxy-benzyl amino)-imidazo[1,2-a]pyrazin-3-yl]-acetamide (4).
HN^O 0-
IN (4) 1
Yield 30.9 mg, 27%; m/z (ES) 382 (M+1)+; HPLC 100%.
À e Àe À À ce.c.a ee. À
c. Àe À - 46 Scheme for synthesising compounds of formula (II) and (III) | NH2 O -C_N Sc(OTf)3 N OWN H H MeOH HE (E) l TFA, H2O R2 2 bD hylphenoi NAN R1 C N N
H - B EN TO - EN
HN K3PO4, Cul Nit Pyridine Br (II) R1 IPA (G) H \R1 THF NH2 Pd(OAC)2, PPh3 Na2CO3, DMF B(OH)2-R2 1 R3JNtWo (111) R1 Compounds of type (F) can be acylated by reaction with acid chloride derivatives generated from the acids described in the acids Box.
Compounds of formula (II) are generated from intermediates (G) by reaction with amines described in the amine sets - amine set A, amine set B and amine set C. The permitted substituents at positions R1 and R2 are shown in acids [R1], amine set A [R2], amine set B [R2] and amine set C [R2]. The allowed combinations are; compounds of type (G), which are generated from acid set 1, are crossed with amines set B [R2] with the exception of lipophilic acids and lipophilic amines. Compounds of type (G) , which are generated from acid set 2, are crossed with amine set C with the exception of lipophilic acids and lipophilic amines. Compounds of type (G), which are e a Àe À À À À a a À Àa ecea ala a sea Àe Àa a - 47 generated from acid set 3, are crossed with amine set C with the exception of lipophilic acids and lipophilic amines.
| Amine Set A [R2] I NO-N/> Amine Set B [R2] R2N1'N O Amine Set C [R2] H NO I R1 en- #. ; e: * * À ts.e * I o I O,,, Z I I I I O I I I I 0: I I as' O I I z _ I I I IS I N O V In I I Z (} O z v In _ I C I I O O I I I I I E I o J I Z Z. *a o I o i o\3 (: d I I
O I I O - IN I
I I I O I O I I I I I I O V O _
I zz ? ll I I v I Z I Z I I I I a O À I, V 1 IO {> I 0 0 >\ I (> :2 O O ____________. ___
-
r - - - _ _ I I I I I I s Z u A A A 0{/, O N I ': zl I. OI I D I O ' - I I I I' I. L _ _ _ _ _ _ _ _.
) a Z. l I z z Z 1l 1 O-\ I. II C O Z I I I <_ E _ z v 2, Às
I FF I I I I
( Z I Z _\Z I O I O O z I I Q I I I I (3 I () -& 0 1 I_ _ _.
C
I Z< < 1 C O, = z z Z I s t I: - - - C t3 o O z4: À, - I Es Z-I I O Z i 0 I I _ o. I o. - : a z z >: I s d _ I I 1 I. _ e r À e e e e 8 8 1 e e e 8 8 ' he eveÀ 8 tt, e 8e e À F eC r e e 8 e - 49 Compounds of type (F) can be acylated by reaction with acid chloride derivatives generated from the acids described in Box 1. Compounds of formula (III) are generated from intermediates (G) by reaction with the boronic acid reagents described in Box 2.
| BOX 2 | Jives- ::: ::e À:e:e À me: Àe a. À e.e I: - 50 -'' ICY' to b
_ IN CON
o A I m N - i)
IN N
zig m m À:: :.: À :: :: . . À À À À À Àe À ee. Àe: - 51 Synthesis of compound (F) as described in the general reaction scheme; 6-bromo-2-methyl-imidazo[1,2-a]pyrazin-3-ylamine.
To a solution of 5-bromo-pyrazin-2-ylamine (34.6 9, 0.202 mol) in methanol was added acetaldehyde (27.9 ml, 0.5 mol) followed by Sc(OTf)3 (5 9, 10.1 mmol). The mixture was stirred at room temperature for lh before the addition of tert-octyl isocyanide (40 ml, 0.224 mol). The reaction was stirred at room temperature for 16h then the solvent was removed in vacua. The residue was partitioned between a saturated solution of NaHCO3 (500 ml) and ethyl acetate (750 ml). The organic phase was separated, dried (MgSO4) then concentrated to give the crude product (E). OH (270 MHz, CDCl3) 1.10 (m, 17H), 2.47 (s, 3H), 8.20 (d, 1.2, 1H), 8.64 (d, 1.2, 1H); m/z (APCI) 339 [M+].
Compound (E) was dissolved in dichloromethane (100 ml) and TEA (100 ml) was added and the mixture was stirred for oh. After this time the reaction was adjusted to pH 11 with an aqueous solution of 5M NaOH, which resulted in the precipitation of a solid. The solid was collected by filtration and washed with ethyl acetate to give the desired product (F) (37 9, 81%). OH (250 MHz, DMSO) 2.31 (s, 3H), 5.71 (br s, 2H), 8.27 (d, 1.1, 1H), 8.41 (d, 11.1, 1H); m/z (APCI) 227 [M+]; HPLC 96%.
Typical example of compound of formula (G), as described in general reaction scheme; N-(6-bromo-2-methyl-imidazo[1,2-a]pyrazine-3-yl)isobutyramide (5).
::: ::. À:e:e À ce: Àe ce À -e ee. : - 52 J'N Nil (5) To a suspension of compound (F) (1.14 9, 5 mmol) in THF (50 ml) was added pyridine (0.82 ml, 10 mmol) followed by iso-buturyl chloride (0.8 ml, 7.5 mmol). The reaction was heated at 50 C for 4h. The reaction was concentrated in vacuo and the residue was purified by column chromatography (EtOAc MeOH, 95: 5) to give the desired product as a brown solid (0.67 9, 45%). OH (250 MHz, DMSO) 0.97 (d, 6.1, 3H), 2.05-2.17 (m, 1H), 2.30 (s, 3H), 8.29 (d, 1.3, 1H), 8.77 (d, 1.3, 1H), 10.08 (s, 1H); m/z (APCI) 297 (M+); HPLC 99%.
Typical example of compound of formula (G), as described in general reaction scheme; N-(6-bromo-2-methyl-imidazo[1,2-a]pyrazin-3-yl)-2(tetrabydro-pyran-4-yl)-acetamide (6).
N N
Brat O (6) Ha_ C To a solution of tetrahydropyran-4-ylacetic acid (5 9, 35 mmol) in DCM (70 ml) was added oxalyl chloride (4.6 ml, 52.5 mmol) dropwise followed by DMF (2 drops) and the mixture was stirred at room temperature for 3h.
After this time the reaction was concentrated in vacua and the residue was dissolved in THF (25 ml) then added to a suspension of compound (F) (5.67 9, 25 mmol) in THF (50 ml) and pyridine (4 ml, 50 mmol). The reaction was heated at 50 C for 4h then concentrated in vacua. A mixture e e À a À e # e e e e - 53 of a saturated aqueous solution of NaHCO3 (150 ml) followed by ethyl acetate (150 ml) was added to the residue, which resulted in the formation of a solid. The solid was collected by filtration, which was washed with ethyl acetate to give the desired product as an off white solid (4.81 9, 55%). OH (250 MHz, DMSO) 1.30-1.36 (m, 2H), 1.60-1.66 (m, 2H), 1.97- 2.03 (m, 1H), 2.29 (s, 3H), 2.39 (d, 7.5, 2H), 3.26-3.31 (m, 2H), 3.81- 3.87 (m, 2H), 8.32 (d, 1.2 1H), 8.77 (d, 1.2, 1H), 10.11 (s, 1H); m/z Typical example of compound of formula (G), as described in general reaction scheme; isoxazole-5-carboxylic acid (6-bromo-2-methylimidazo[1,2-a]pyrazin-3-yl)-amide (7). BrN
7: (.1 To a suspension of compound (F) (3.0 9, 13.2 mmol) in THE (75 ml) and pyridine (2.1 ml, 26.4 mmol) was added isoxazole-5-carbonyl chloride (2.2 9, 16.5 mmol) and the reaction was heated at 50 C for 2h. After this time the reaction was concentrated in vacuo and a mixture of a saturated aqueous solution of NaHCO3 (100 ml) followed by ethyl acetate (100 ml) was added to the residue, which resulted in the formation of a solid. Thesolid was collected by filtration and washed with ethyl acetate to give the desired product as a brown solid (3.5 9, 83%). OH (250 MHz, DMSO) 2.35 (s, 1H), 7.31 (d, 1.9, 1H), 8.73 (d, 1.3, 1H), 8.83 (d, 1.3, 1H), 8.86 (d, 1.9, 1H), 11.13 (s, 1H); m/z (APCI) 322 (M+); HPLC 99%.
:: :e sue:e A: À. e. À e.e ace: - 54 Typical example of compound of formula (G), as described in general reaction scheme; N-(6-bromo-2-methyl-imidazo[1,2-a]pyrazin-3-yl)-3chloro-4-floro-benzemide (8).
Jan - N Not i/ (8) Cl F To a suspension of compound (F) (3.0 g, 13.2 mmol) in THE (75 ml) and pyridine (2.1 ml, 26.4 mmol) was added 3-chloro-4fluorobenzyl chloride (3.2 9, 16.5 mmol) and the reaction was heated at 50 C for 2h. After this time the reaction was concentrated in vacuo and a mixture of a saturated aqueous solution of NaHCO3 (100 ml) followed by ethyl acetate (100 ml) was added to the residue, which resulted in the formation of a solid. The solid was collected by filtration and washed with ethyl acetate to give the desired product as a brown solid (3.8 9, 75%). OH (250 MHz, DMSO) 2.35 (s, 1H), 7.63 (t, 8.9, 1H), 8.03-8.10 (m, 1H), 8.28-8.32 (m, 1H), 8.65 (d, 11.1, 1H), 8.81 (d, 1.1, 1H), 10.84 (s, 1H); m/z (APCI) 383 (M+); HPLC 98%.
Typical example of compound of formula (G), as described in general reaction scheme; thiophene-2-carboxylic acid (6-bromo-2-methylimidazo[1,2-a]pyrazin-3-yl)-amide (9).
::: ::e e:. :e À e.: Àe e. Àe eee: - 55 Br4: HE (9) To a suspension of compound (F) (4.5 9, 20. 0 mmol) in DCM (200 ml) and pyridine (3.2 ml, 40 mmol) was added 2- thiophene carbonylchloride (2.15 ml, 20 mmol) and the reaction was heated at 50 C for 2h. After this time the reaction was concentrated in vacua and a mixture of a saturated aqueous solution of NaHCO3 (150 ml) followed by ethyl acetate (150 ml) was added to the residue, which resulted in the formation of a solid. The solid was collected by filtration and washed with ethyl acetate to give the desired product as a brown solid (3.0 9, 45%). OH (250 MHz, DMSO) 2.35 (s, 1H), 7.28 (dd, J 3.9, 4.9, 1H), 7.94 (d, 4.9, 1H), 8.06 (d, 3.0, 1H), 8.58 (d, 1.2, 1H), 8.82 (d, 1.2, 1H), 10.63 (s, 1H); m/z (APCI) 337 (M); HPLC 94%.
Typical example of compound of formula (G), as described in general reaction scheme; N-(6-bromo-2-methyl-imidazo[1,2-a]pyrazine-3-yl) benzemide (10).
NO N Bra HN3O (1 O)
To a suspension of compound (F) (3.0 9, 13.2 mmol) in THE (75 ml) and pyridine (2.1 ml, 26.4 mmol) was added benzoyl chloride (2.1 ml, 16.5 mmol) and the reaction was heated at 50 C for 2h. After this time the ::: ::e eye:e À À be: À. .e Àe.e: - 56 reaction was concentrated in vacua and a mixture of a saturated aqueous solution of NaHCO3 (100 ml) followed by ethyl acetate (100 ml) was added to the residue, which resulted in the formation of a solid. The solid was collected by filtration and washed with ethyl acetate to give the desired product as a brown solid (3.7 9, 84%). OH (250 MHz, DMSO) 2.36 (s, 1H), 7.53-7.68 (m, 3H), 8.04-8.08 (m, 2H), 8.57 (d, 1.3, 1H), 8.82 (d, 1.3, 1H), 10.63 (s, 1H); m/z (APCI) 331 (M+); HPLC 91%.
General procedure for the synthesis of compounds of formula (II).
* R2'N --0 (II) The reactions were carried out in stem tubes with a 96 well stem shaker.
Each tube was charged with a compound of formula (G) (0.3 mmol), followed by the addition of propan-2-ol (0.75 ml), a solution of the amine in propan-2-ol (0.6 mmol, 0.25 ml), a solution of 2,6-dimethylphenol in propan-2-ol (0. 24 m mol. 0. 25 m l), potassium phosphate (0. 6 m mol), and copper iodide (0.06 mmol). The reaction vessels were flushed with nitrogen then heated at 80 C for 22h. After this time the reactions were filtered then purified by preparative HPLC.
Typical example of compound of formula (II); cyclobutanecarboxylic acid [6-(3-methyoxy-propylamino)-2-methyl-imidazo[1, 2-a]pyrazin-3-yl] amide (11).
:::: *:. :. A: À. e. À Àe À. : - 57 oNg to Nit (11) Yield 43.6 mg, 46%; m/z (ES) 318 (M+ 1)+; HPLC 100%.
Typical example of compound of formula (II); N-[2-methyl-6-(2-thiophen2-yl-ethylamino)-imidazo[1, 2-a]pyrazin-3-yl]-acetamide (12).
1 (12) 1 Yield 30.2 mg, 32%; m/z (ES) 316 (M+1)+; HPLC 100%.
General procedure for the synthesis of compounds of formula (III) I, The reactions were carried out in stem tubes with a 96 well stem shaker.
To a solution of a compound of formula (G) in DMF (0.3mmol, 0.5ml) was added a solution of boronic acid in DMF (0.36mmol, 0.6ml) and 1.5M e e I ce It.. - 58
Na2CO3(aq.) solution (0.75mmol, 0.5ml). The reaction vessels were then placed in a nitrogen filled glovebox for 30min. Two solutions of palladium acetate (95mg) and triphenylphosphine (335mg) in 1,4-dioxane (15ml) were freshly prepared and placed in a sonication bath for 2min. The palladium catalyst (0.3ml) was added to each reaction vessel inside the glovebox. The vessels were screw capped and then heated at 80 C with agitation for 16h. The reaction mixtures were filtered and purified by preparative HPLC.
Typical example of compound of formula type (III); N-[6-(3-acety/aminophenyl)-2-methyl-imidazo[1,2-a]pyrazin-3-yl]-benzemide ( 3).
OW % - N H \
HN
(13) hi o Yield 97.0 mg, 83%; OH (250 MHz, DMSO) 2.04 (s, 1H), 2.37 (s, 3H), 7.36 (t, J 8.0, lH), 7.56-7.72 (m, 5H), 8.09-8.12 (m, 2H), 8.22-8.23 (m, 1H), 8.58 (d, 1.4, 1H), 9.06 (d, 1.4, 1H), 10.07 (s, 1H), 10.62 (s, 1H); m/z (ES) 386 (M+1)+; HPLC 98%.
Typical example of compound of formula type (III); N-[2-methyl-6-(4morpholin-4-yl-phenyl)-imidazo[1,2-a]pyrazin-3-yl]-benzemide ( 4).
À À : ; : . - : - 59 O^NH
N
I N (14)
Yield 90.3 mg, 72%; OH (250 MHz, DMSO) 2.35 (s, 3H), 3.14-3.17 (m, 4H), 3.71-3.75 (m, 4H), 7.60 (d, 8.9, 2H), 8.11 (d, 8.4, 2H), 8.56 (d, 1.4, lH), 9.02 (d, 1.4, lH), 10.57 (s, 1H); m/z (ES) 414 (M+1)+; HPLC 100%.
Purification Conditions All compounds have a minimum purity level 2 80% as measured by LCMS at 254 nm.
The columns used for the preparative HPLC purification of the various scaffolds are outlined in Table 1:
Table 1 A.
Scaffold Column Formula (I) and (II) Varian Ansys MetaChem Polaris C18 Loom 21.2 x 150mm Formula (III) Phenomenex Luna 10pm phenyl-hexyl 21.20 x 150mm.
The gradient used for compounds of formulas (I) and (II) was 95% water (lOmmol NH3HCO3) 5% THF/MeOH (3:1) for 1 min to 5% water (lOmmol NH3HCO3) / 95% THF/MeOH (3:1) over 8.0 min then held at 5% water (lOmmol NH3HCO3) / 95% THF/MeOH (3:1) for 2.0 min. The solvent mixture was then returned to the initial conditions over 0.5 min. À . :: : : À- . : : : e. Àe - 60 The gradient used for compounds of formula (III) was 95% water (0.2% TFA/10% methanol) 5% acetonitrile (10% methanol) for 1 min to 5% water (0.2% TFA/10% methanol) / 95% acetonitrile (10% methanol) over 8.0 min then held at 5% water (0.2% TFA/10% methanol) / 95% acetonitrile (10% methanol) for 2.0 min. The solvent mixture was then returned to the initial conditions over 0.5 min. A flow rate of 25 ml/min is used for both methods.
The conditions used for the analytical HPLC analysis following preparative HPLC purification are outlined in Table 2:
Table 2
-
Conditions Detection . .. ... ,.
Column: Waters Xterra( Prep MS C18 5pm UV detection at 254 rim 4.6 x 100mm. (diode array range 210 280nm).
Gradient: 95% water (10 mM NH3HCO3) / 5% ACN for 0.5 min then 95% water (10 mM Electrospray NH3HCO3) / 5% ACN to 2% water (10 mM ionization: NH3HCO3) / 98% ACN over 3.5 min. Held at 2% water (10 mM NH3HCO3) / 98% ACN for Cone voltage: 30 V. 0.5 min. The solvent mixture is then returned Cone temperature: 20 to the initial conditions over 0.1 min and the C.
system allowed to re-equilibrate for 0.2 min. Source temperature 150 C.
Flow rate: 2.0 ml/mint RF lens voltage: 0.0 V. Temperature: 30 C. Ion energy: 0.5 eV.
Injection volume: 5,um partial loon. Multiplier: 650 V. À tee À - 61 LIBRARY SFK11 SFK11 is designed to have primary focus on the FGF receptor1 kinase, a member of a small group of kineses (Harks' Group XV kineses) which are fairly typical of the receptor tyrosine kinase family, and a key anti- angiogenesis target. The library has a broader secondary focus on other members of the tyrosine kinase family. The central design of the library is based on a novel application of the imidazo[1,2-a]pyrazine scaffold. Good docking was observed for the imidazo[1,2a]pyrazine scaffold when this was substituted with 3-amino and 5-amino functions, with a characteristic double H-bond being formed between the backbone Ala564 of the ATP site of FGF receptor-1 and the 5, ring-6-diaza "amidine" system.
The invention provides a compound library comprising or consisting of a set of structurally related compounds of the general formula (I), (II) and (III) NON o NO N NON 1 /R1 11 1,R1 1,R1 Nl - 0 INN 0 H2N - 0 H R2 H R2 H R2 (I) (11) (III) Wherein Rat is alkyl having from 1 to 20 carbon atoms which may linear or branched and may contain one or more heteroatoms, cycloalkyl having from 3 to 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aryl having a cyclic aromatic structure containing between 3 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, hetero aryl having a cyclic aromatic structure containing between 1 and 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aralkyl having from 1-20 carbon atoms which may bear À À * . : À À À À . . e À .: À À :: À ' À - 62 one or more substituent groups at any available ring position and may contain one or more heteroatoms or heteroaralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms; R2 is alkyl having from 1 to 20 carbon atoms which may be linear or branched and may contain one or more heteroatoms, alkenyl having from 1 to 20 carbon atoms, aryl having a cyclic aromatic structure containing between 2 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, cycloalkyl having from 3 to 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aryl having a cyclic aromatic structure containing between 3 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, hetero aryl having a cyclic aromatic structure containing between 1 and 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms or heteroaralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms; and wherein R3 is alkyl having from 1 to 20 carbon atoms which may linear or branched and may contain one or more heteroatoms or cycloalkyl having from 3 to 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms.
Scheme for synthesising compounds of formula (I) (PS109) A general scheme for introducing substituents to produce compounds of SFK11 PS109, is as follows: : . : cÀ - c c - 63 N R CHO N N 1 TEA NN 1:N Br: Br: Brt Sc(OT03 IN N (A) >(>NC (B) A /\ (C) BOX 3 | R2 Cl, Jew - NR1 3 2 R3 Jam - NtR N Cul, phenol, NH,N H R2 K3PO4 H R2 2-Amino-5-bromopyrazine (A) can be converted to the substituted 3- amino-6-bromoimidazo[l,2-a]pyrazines (B) using the aldehydes described in Box 1 and then deprotected to give primary amines (C). The resultant amines can be acylated with acid chlorides prepared from the acids described in Box 2 to give amides (D). The final compounds (I) can be prepared by reacting 6-bromoimidazo[1,2-a]pyrazines (D) with the amines described in Box 3.
The permitted substituents at positions R1, R2 and R3 are shown in Boxes 1, 2 and 3 respectively, in the following schematic diagram.
Box 3 \ ': / Box 1 * Scatter N_ * Diagram H \Box2 À À: ece: À . * . a À b O f Q ';: i,,, . l ' . <-8 {8 X b 57L 8 (: r 0 ( >\ 8 \/ \-38 < -b-8 8{: 9 6 O 86 t3-'8 a, < 2.8 1 (:it) \% /TV 2: /8 2 _ >-8 2 2 : ,/I, a 0\ -8 (-" ''1) C.'\\ ii 1 y 0 -z38) 2) # \ it - Or- Q b:, / \ T 2 2 8 ok\ /; 2' (, 0 =- < ;> 0 8 - 8 I-\ ? A-- 8 b8 (< ) >2 8 2 FOX ó5 (3 .8 - i Q 8 2 :/\-' </ 8 <: <8 (> 0 Nl\:,)} y: e.e ee' .e;. a. ee - 65 General Procedures Typical example of compound of formula (B), as described in general reaction scheme; (6-bromo-2-ethylimidazo[1, 2-a]pyrazin-3-yl) -(1,1, 3, 3- tetramethylbutyl)-amine (1).
Br:N I (1) To a cooled solution (0 C) of 2-amino-5-bromopyrazine (A) (34. 6 9, 200 mmol) and scandium trifluoromethanesulfonate (4.92 9, 10 mmol) in methanol (480 mL) was added propionaldehyde (145 mL, 2 mol). After allowing to warm to room temperature for 30 minutes, the solution was recooled to 0 C and 1,1,3,3-tetramethylbutyl isocyanide (38.6 mL, 220 mmol) was added to the solution. After stirring for 16 hours at room temperature, the reaction mixture was acidified to pH 1 using hydrochloric acid (1M). The methanol was removed in vacuo and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was separated, dried and concentrated to yield a brown oil, which was purified by column chromatography (25% ethyl acetate/hexane) to yield the desired imidazo[1,2-a]pyrazine (1) as a pale yellow oil (29.7 9, 42%). HPLC 98%; 1H NMR (250 MHz, CDCl3) 8.68 (d, = 0.7 Hz, 1H), 8.22 (d, = 0.7 Hz, 1H), 2.89 (brs, 1H), 2.81 (q, = 7.5 Hz, 2H), 1.69 (s, 2H), 1.38 (t, = 7.5 Hz, 3H), 1.19 (s, 6H), 1.12 (s, 9H); Typical example of compound of formula (B), as described in general reaction scheme; [6-bromo-2-(4-diethylaminophenyl)-imidazo[1,2- a]pyrazin-3-yl]-(1, 1, 3, 3-tetramethylbutyl) -amine (2).
À À a*. .: :: . .; À: :e À . À - 66 ,:3N H'N><>< (2) Yield 2.48 9, 58%; HPLC 99%; H NMR (250 MHz, CDCl3) 8.69 (d, = 1.2 Hz, 1H), 8.23 (d, = 1.2 Hz, 1H), 7.72 (d, = 8.9 Hz, 2H), 6.72 (d, = 8.9 Hz, 2H), 3.37 (q, = 7.0 Hz, 4H), (q, = 7.0 Hz, 4H), 1.61 (s, 2H), 1.20 (t, = 7.0 Hz, 6H), 1.06 (s, 9H), 1.01 (s, 6H); 13C NMR (62.9 MHz, CDCl3) 147.8,145.0, 141.1, 136.3, 129.4, 124.4, 122.3, 120.3, 116.6, 111.3, 61.4, 57.0, 44.6, 31.8, 31.7, 29.1, 12.6; MS (APCI) 474/472 [M+H]+ Typical example of compound of formula (B), as described in general reaction sche me; (6-bromo-2-phenethylimidazo[1, 2-a]pyrazin-3-yl)- (1, 1,3,3-tetramethylbutyl)-amine (3). BrJN
H'NX>< (3) Yield 29.79, 33%; HPLC 91%; 1H NMR (250 MHz, CDCl3) 8.70 (d, = 1.2 Hz, 1H), 8.15 (d, = 1.2 Hz, 1H), 7.23 (m, 3H), 7.10 (m, 2H), 3.09 (m, 4H), 1.54 (s, 2H), 1.09 (s, 6H), 1.05 (s, 9H); 13C NMR (62.9 MHz, CDCl3) 145.4, 141.4, 141.2, 136.5, 128.5, 128.4, 126.3, 126.1, 122.4, 116.8, 60.1, 56.6, 35.5, 31.8, 31.5, 30.4, 29.2; MS (APCI) 431/429 [M+H]+.
: :: the:. .e. ,..e À À 4 - 67 Typical example of compound of formula (B), as described in general reaction scheme; N-{4-[6-bromo-3-(1,1,3,3-tetramethylbutylamino)imidazo[1,2-a]pyrazin-2-yl]-phenyl3-acetamide (4).
Br:N MONO H'N><>< (4) Yield 43.09, 47%; HPLC 98%; 1H NMR (250 MHz, DMSO) 10.04 (s, lH), 8.75 (d, = 1.2 Hz, lH), 8.64 (d, = 1.2 Hz, lH), 8.05 (d, = 8.7 Hz, 2H), 7.64 (d, = 8.7 Hz, 2H), 4.60 (s, lH), 2.05 (s, 3H), 1.60 (s, 2H), 0.97 (s, OH), 0.90 (s, 6H); 13C NMR (62.9 MHz, DMSO) 168.3, 142.2, 141.5, 139.2, 135.7, 128.7, 128.5, 125.8, 121.6, 118.3, 117.3, 60.8, 55.5, 31.5, 31.3, 28.7, 24.0; MS (APCI) 460/458 [M+H]+.
Typical example of compound of formula (C), as described in general reaction scheme; 6-bromo-2-(3-trifluoromethylphenyl)-imidazo[1,2a]pyrazin-3-ylamine (5).
Br;N F3 NH2 (5) Imidazo[1,2-a]pyrazine (4.82 9, 12 mmol) was dissolved in a solution of trifluoroacetic acid (12 mL) and dichloromethane (12 mL). After stirring at room temperature for 1 hour the reaction was judged by HPLC analysis to r a.. , ..
À * - 68 have reached completion. The dark solution was concentrated and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was separated, dried and concentrated to yield the desired amine (5) as an orange solid (11.19, 92%). HPLC 96%; 1H NMR (250 MHz, DMSO) 8.68 (d, = 1.2 Hz, 1H), 8.63 (d, = 1.2 Hz, 1H), 8.29 (m, 2H), 7.69 (m, 1H), 7.66 (m, 1H), 6.18 (s, 2H); MS (APCI) 359/357 [M+H]+ Typical example of compound of formula (C), as described in general reaction sche me; 2-benzyl-6-bromoimidazo[1,2-a]pyrazin-3- ylamine (6). N:N Brunt (6)
Yield 1.129, 90%; HPLC 90%; 1H NMR (250 MHz, DMSO) 8.47 (s, 1H), 8.32 (s, 1H), 7.26 (m, 5H), 5.86 (s, 2H), 4.07 (s, 2H); 13C NMR (62.9 MHz, DMSO) 139.8, 139.7, 132.7, 132.3, 130.2, 128.6, 128.1, 125.9, 121.4, 114.1, 32.3; MS (APCI) 305/303 [M+H]+.
Typical example of compound of formula (C), as described in general reaction scheme; 6-bromo-2-furan-3-ylimidazo[1,2-a]pyrazin-3-ylamine (7).
|BrJN: l NH2 À À me: e. e: À À . . me: ale. :. . - 69
Yield 13.29, 91%; HPLC 92%; 1H NMR (250 MHz, DMSO) 8.56 (d, = 1.2 Hz, 1H), 8.49 (d, = 1.2 Hz, 1H), 8.28 (s, 1H), 7.78 (s, 1H), 7.01 (s, 1H), 5.95 (s, 2H); 13C NMR (62.9 MHz, DMSO) 142.3, 138.9, 138.5, 131.7, 127.6, 123.1, 120.1, 118.1, 113.0, 107.6; MS (APCI) 281/279 [M+H]+ Typical example of compound of formula (C), as described in general reaction scheme; 6-bromo-2-(4-dimethylaminophenyl)imidazo[1,2- a]pyrazin-3-ylamine (8).
|Br:NN I NH2 (8) Yield 16.5 9, 90%; HPLC 80%; 1H NMR (250 MHz, DMSO) 8.53 (d, = 1.2 Hz, 1H), 8.48 (d, = 1.2 Hz, 1H), 7.83 (d, = 8.9 Hz, 2H), 6.78 (d, = 8.9 Hz, 2H), 5.85 (s, 2H), 2.93 (s, 6H); 13C NMR (62.9 MHz, DMSO) 149.6, 139.5, 133.0, 128.3, 127.5, 121.5, 121.3, 114.0, 112.1, 39.9; MS Typical example of compound of formula (D), as described in general reaction scheme; N-(Z-benzyl-6-bromoimidazo[1,2-a]pyrazin-3-yl)-2cyclohexylacetamide (9). BrJN3 (9) 0
À..e.e.:. - 70
To a solution of cyclohexylacetic acid (57 mg, 0.4 mmol) in THE (0.5 mL) was added oxalyl chloride (70 AL, 0.8 mmol). After stirring for 2 hours, 2- benzyl-6-bromoimidazo[1,2-a]pyrazin-3-ylamine (6) (9lmg, 0.3mmol) and a solution of diisopropylethylamine (0.14 mL, 0.8 mmol) in THE was added to the reaction mixture which was heated to 60 C for 16 hours.
The resultant suspension was diluted with dimethylsulfoxide (1 mL), filtered and purified by reverse-phase preparative HPLC to yield the desired product (9) (9.4mg, 7%). HPLC 100%; 1H NOR (250 MHz, DMSO) 10.18 (s, 1H), 8.80 (d, J = 1.2 Hz, 1H), 8.33 (d, J = 1.2 Hz, 1H), 7.21 (m, 5H), 4.01 (s, 2H), 2.32 (d, = 6.9 Hz, 2H), 1.71 (m, 6H), 1.29-0.90 (m, 5H); MS (ES) 429/427 [M+H]+.
Typical example of compound of formula (D), as described in general reaction scheme; furoic acid [6-bromo-2-(3-phenoxyphenyl)imidazo[1,2a]pyrazin-3-yl]-amide (10). N:N_: N:O (1 O)
Yield 89.8 mg, 63%; HPLC 100%; 1H NOR (250 MHz, DMSO) 10.77 (s, 1H), 8.98 (d, J = 1.3 Hz, 1H), 8.77 (d, J = 1.3 Hz, 1H), 8.02 (dd, J = 0. 7, 1.7 Hz, 1H), 7.73 (dt, = 1.2, 8.1 Hz, 1H), 7.55 (dd, = 1.6, 2.4 Hz, 1H), 7.50 (t, = 7.9 Hz, 1H), 7.32 (m, 3H), 7.04 (m, 4H), 6.76 (dd, = 1.7, 3.5 Hz, 1H); MS (ES) 477/475 [M+H]+.
À À 'c: A: c: : : À - 71 Typical example of compound of formula (D), as described in general reaction scheme; N-[6-bromo-2-(3,4-difluorophenyl)imidazo[1,2- a]pyrazin-3-yl]-4-methoxy benzemide (11). 4,N.F He
(11) '5 OMe Yield 23.4 mg, 17%; HPLC 100%; tH NOR (250 MHz, DMSO) 10.74 (s, 1H), 9.01 (d, = 1.3 Hz, 1H), 8.77 (d, = 1.3 Hz, 1H), 8.06 (d, = 8.9 Hz, 2H), 7.95 (m, 1H), 7.81 (m, 1H), 7.56 (m, 1H), 7.13 (d, = 8.9 Hz, 2H), 3.86 (s, 3H); MS (ES) 461/459 [M+H]+.
Typical example of compound of formula (D), as described in general reaction scheme; cyclopropanecarboxylic acid [6-bromo-2-(4dimethylaminophenyl)imidazo [1,2-a]pyrazin-3-yl]-amide (12).
h] q) as- Yield 3.7 mg, 3%; HPLC 100%; 1H NMR (250 MHz, DMSO) 10.59 (s, 1H), 8.84 (d, = 1.3 Hz, 1H), 8.26 (d, = 1.3 Hz, 1H), 7.83 (d, = 9.0 Hz, 2H), 6.82 (d, = 9.0 Hz, 2H), 2.96 (s, 6H), 1.96 (m, 1H), 0.93 (m, 4H); MS (ES) 402/400 [M+H]+.
::: :e À. ::e he t. eecee .e À - 72 Typical example of compound of formula (I), as described in general reaction scheme; cyclopentanecarboxylic acid [2-cyclohexyl-6-(2pyrrolidin-l-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-amide (13).
AN,,N: (13) To a'Stem' reaction tube was added sequentially cyclopentanecarboxylic acid (6-bromo-2-cyclohexylimidazo[1,2-a]pyrazin-3yl)-amide (91.2 mg, 0.23 mmol), potassium phosphate (0.13 9, 0.6 mmol), a solution of 2,6- dimethylphenol (0.29 mg, 0.24 mmol) in isopropanol (0.25 mL), a solution of N-(2-aminoethyl)pyrrolidine (69 mg, 0.6 mmol) in isopropanol (0.25 mL), isopropanol (0.25 mL) and copper (I) iodide (11 mg, 0.06 mmol).
The reaction tubes were flushed with nitrogen, sealed and heated at 80 C for 16 hours. After allowing to cool, the reaction mixture was diluted with DMSO (1 mL), filtered and purified by reverse-phase preparative HPLC to yield the desired product (13) as a dark solid (41.2 mg, 42%). HPLC 100%; MS (ES) 425 [M+H]+.
Typical example of compound of formula (I), as described in general reaction scheme; N-[2-(4-diethylaminophenyl)-6-(2-pycrolidin-1-ylethylamino)-imidazo[1,2-apyrazin-3-yl]-2-phenylpropionamide (14).
À: À a.: act: :. c. a.. À : À . :.
ce À - - 73 N No Yield 38.5 mg, 32%; HPLC 100%; MS (ES) 526 [M+H]+.
Typical example of compound of formula (I), as described in general reaction scheme; 4-methoxycyclohexanecarboxylic acid [6-(4dimethylaminobutylamino)-2-phenethylimidazo[1, 2-a]pyrazin-3-yl]-amide (75) N:N Me2N H: H OMe Yield 16.8 mg, 36%; HPLC 100%; MS (ES) 421 [M+H]+.
Typical example of compound of formula (I), as described in general reaction scheme; 4-dimethylamino-N-[6-(3-dimethylaminopropylamino)-2phenylimidazo [1,2-a]pyrazin-3-yl]-butyramide (16).
cecce.e.. :.e cent' ecea. - 74
Me2N-H to (16) NMe2 Yield 18.0 mg, 17%; HPLC 100%; MS (ES) 424 [M+H]+.
Scheme for synthesising compounds of formula (II) (PS109) A general scheme for introducing substituents to produce compounds of SFKll PS109, is as follows: |BOX4 | O ,NH2 R,CHO Jo, --R1 J(NH2 Brat SC(OTf)3 r CUI. K2CO3 (A) NC (B) dimethylethylenediamine J:NN-R] Strong Acid N R2 CI H (F) (E) \ |BOX5 | J(N:N O H Nor H R2 (11) 2-Amino-5-bromopyrazine (A) can be converted to the substituted 3- amino-6-bromoimidazo[1,2-a]pyrazines (B) using the aldehydes described in Box 4. The intermediates (B) can then be reacted with acetamide to give amides (E). These can be deprotected to give primary amines (F).
À:: ::e e... ::. .e À.
e ee À - 75 The resultant amines can be acylated with the acid chlorides prepared from the acids described in Box 5 to give the amides (II).
The permitted substituents at positions R1 and R2 are shown in Boxes 4 and 5 respectively, in the following schematic diagram.
JO / SFK11 H N_ Scatter HI * \ Diagram Box 5 À at: I: À À e..: a4^ . :: . ^ . À - 76 8 4"-> r''--8 - ? : 8:: Hi 8 - <3; :: i: b >. 8 IP a of tPi 8 95:0 -A 2 P 'b 2 ' i -8 '\P J | O (> ii if; / I P I, d? / ? flu (3<-8 t3\ 8 W ma ( W \ (0\: P ' P:,wT 2 Z I ? ó1:} ( 0 _ 0 (3 0 if, 8 2 I_ 2 2) 2 Z r c< 2 Z- I ? - Q t}- I_ 0 W' ? >40 ó 'N0 9 TO 1 a)3048 (2 S C a hi '\m Imp 3 <_\Woj fg 2 8; (3u -a- 8 I So of\,; ;) I-? Q *bee:: :::e c: . : : - 77 General Procedures Typical example of compound of formula (E), as described in general reaction scheme; N-[2-benzyl-3-(1,1,3,3tetramethylbutylamino)imidazo[1,2-a]pyrazin-6-yl]-acetamide (17). J(NN
H H'N)<>< (17) (2-Benzyl-6-bromoimidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3tetramethylbutyl)amine (20.0 9, 48 mmol), acetamide (4.23 9, 72 mmol), copper (I) iodide (1.38 9, 7.2 mmol), N,N'-dimethylethylenediamine (0.77 mL, 7.2 mmol), copper bronze (0.10 9, 1.6 mmol) and potassium carbonate (13.2 9, 96 mmol) were weighed into a 250 mL round-bottom flask. After the flask was evacuated and flushed with nitrogen (x 3), toluene (54 mL) was added and the reaction mixture heated (100 C) for 24 hours. After LCMS analysis showed that all the starting material had been consumed, the reaction mixture was diluted with ethyl acetate and filtered through a short plug of silica. The filtrate was concentrated and the residue purified by column chromatography to yield the desired amide (17) as a yellow solid (8.89 9, 47%). HPLC 98%; tH NOR (250 MHz, DMSO) 10. 52 (s, 1H), 9.17 (s, 1H), 8.62 (s, 1H), 7.20 (m, 5H), 4.46 (s, 1H), 4.09 (s, 2H), 2.09 (s, 3H), 1.63 (s, 2H), 1.08 (s, 6H), 1.03 (s, 9H); Typical example of compound of formula (E), as described in general reaction scheme; N-[2-(4-diethylaminophenyl)-3-(1,1,3,3- tetramethylbutylamino)-imidazo[1, 2-a]pyrazin-6-yl]-acetamide (18).
: j 7. e. - 78..DTD: | J(NJNN H H'NX>< (18) Yield 5.0 9, 41%; HPLC 95%; 1H NMR (250 MHz, CDCl3) 9.20 (d, = 1.2 Hz, 1H), 8.75 (s, 1H), 8.66 (d, = 1.2 Hz, 1H), 7.82 (d, = 8.9 Hz, 2H), 6.73 (d, = 8.9 Hz, 2H), 3.41 (q, = 7.1 Hz, 4H), 3.19 (s, 1H), 2.23 (s, 3H), 1.66 (s, 2H), 1.20 (t, = 7.1 Hz, 6H), 1.09 (s, 9H), 1.06 (s, 6H); MS Typical example of compound of formula (F), as described in general reaction scheme; N-(3-amino-2-benzylimidazo[1,2-a]pyrazin-6-yl) acetamide (19).
J(NJN3 H NH2 (19) The protected amine (17) (5.0 9, 12.7 mmol) was weighed into a 100 mL round-bottom flask and was dissolved in 4M HCl/dioxane (30 mL). After stirring at room temperature for 16 hours, the solution was analysed by LCMS and determined to have reached completion. The reaction mixture was concentrated and the crude residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was separated, dried and concentrated to give the desired amine (19) as a dark yellow solid (2.1 9, 59%). HPLC 99%; 1H NMR (250 MHz, DMSO) À À .: e. : À . . . e: À : : À ee - 79 10.31 (51 1H)/ 8.69 (sl 1H)/ 8.49 (sl 1H)/ 7.25 (ml 5H)l 5.45 (51 2H)l 4. 04 (sl 2H)l 2.08 (sl 3H); MS (APCI) 282 [M+H]+.
Typical example of compound of formula (F)l as described in general reaction scheme; N-[2-(4-acetylaminophenyl)-3-aminoimidazo[1,2a]pyrazin-6-yl]-acetamide (20).
( N:, N:N H NH2 O (20) Yield 1.37 9l 82%; HPLC 93%; 1H NMR (250 MHzl DMSO) 10.06 (sl 1H) 8.83 (dl = 1.2 Hzl 1H)l 8.62 (dl = 1.2 Hzl 1H)l 7.92 (dl = 8.7 Hzl 2H)l 7 64 (dl = 8.7 Hzl 2H)l 5.57 (51 2H)l 2.10 (51 3H)l 2.05 (51 3H); MS Typical example of compound of formula (II)l as described in general reaction scheme; N-[6-acetamido-2-(2,3-dibydrobenzo[1,4]dioxin-6-yl)imidazo[1,2-a]pyrazin-3-yl]-2-(2, 3-dimethoxyphenyl)-acetamide (21).
J(N i t ' : To a 'Stem' reaction tube containing 2l3dimethoxyphenylacetic acid (58.9 ma/ 0.3 mmol) in THF (0.5 mL) was added oxalyl chloride (25 pLl 0.3 ::: ::e I::r eeee À À . - 80 mmol) and a drop of DMF. The reaction mixture was flushed with nitrogen, capped and shaken for 2 hours. Solid N-[3-amino-2-(2,3dihydrobenzo[1,4]dioxin-6-yl)-imidazo[1,2-a]pyrazin-6-yl]-acetamide (65 mg, 0.2 mmol) and a solution of diisopropylethylamine (70 AL, 0.4 mmol) in THE (0.5 mL) was added to the acid chloride solution and the reaction again flushed with nitrogen and capped. After heating to 60 C for 16 hours, the reaction mixture was allowed to cool, diluted with DMSO (Amy), filtered and purified by reverse-phase preparative HPLC to yield the desired amide (21) as a pale yellow solid (18.2 mg, 18%); HPLC 100%; 1H NMR (250 MHz, DMSO) 10.62 (s, 1H), 10.46 (s, 1H), 8.90 (d, = 1.4 Hz, 1H), 8.72 (d, = 1.4 Hz, 1H), 7.48 (m, 1H), 6.98 (m, 5H), 4.28 (s, 4H), 3.82 (s, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 2.11 (s, 3H); MS (ES) 504 [M+H]+.
Typical example of compound of formula (II), as described in general reaction scheme; N-[6-acety/amino-2-(3-trifluoromethylpheny/)- imidazo[1, 2-a]pyrazin-3-yl]-2-ethylbutyramide (22). CF3 art/'
Yield 2.3 mg, 3%; HPLC 100%; 1H NMR (250 MHz, DMSO) 10.74 (s, 1H), 10.71 (s, 1H), 8.99 (d, = 1.4 Hz, 1H), 8.73 (d, = 1.4 Hz, 1H), 8.23 (m, 2H), 7.76 (m, 2H), 2.12 (s, 3H), 2.03 (m, 1H), 0.96 (m, 4H), 0.88 (m, 6H); MS (ES) 434 [M+H]+.
À e: Àe.: * e. e e e À e e * *e ee - 81 Typical example of compound offormula (II), as described in general reaction scheme; N-(6-acetylamino-2-benzylimidazo[1,2-a]pyrazin-3-yl)- 2-phenoxyacetamide (23).
Yield 38.2 mg, 46%; HPLC 100%; 1H NMR (250 MHz, DMSO) 10.60 (s, lH), 10. 39 (s, lH), 8.81 (d, = 1.4 Hz, lH), 8.73 (d, = 1.4 Hz, lH), 7.21 (m, 5H), 4.88 (s, 2H), 3.98 (s, lH), 3.96 (s, lH), 2.11 (s, 3H); MS (ES) 416 [M+H]+.
Typical example of compound of formula (II), as described in general reaction scheme; benzo[b]thiophene-3-carboxylic acid (6-acetylamino-2phenethylimidazo [1,2-a]pyrazin-3-yl)-amide (24).
NW
Yield 21.4 mg, 23%; HPLC 100%; 1H NMR (250 MHz, DMSO) 10.60 (s, 1H), 10.42 (s, lH), 8.81 (d, = 1.4 Hz, lH), 8.80 (d, = 1.4 Hz, lH), 7.97 (m, 2H), 7.67 (s, lH), 7.38 (m, 2H), 7.19 (m, 5H), 4.09 (s, 2H), 2. 34 (s, 4H), 2.12 (s, 3H); MS (ES) 470 [M+H]+.
:e À A:. I À - 82 Typical example of compound of formula (II), as described in general reaction scheme; N-[6-acetylamino-2-(3phenoxyphenyl)-imidazo[1, 2- a]pyrazin-3-yl]-2-(2-methoxyphenyl)-acetamide (25).
,... . Yield 36.6 mg, 36%; HPLC 100%; 1H NMR (250 MHz, DMSO) 10.65 (s, 1H), 10.40 (s, 1H), 8.93 (d, = 1.4 Hz, 1H), 8.85 (d, = 1.4 Hz, 1H), 7.76-6.87 (m, 13H), 3.83 (s, 3H), 3.70 (s, 2H), 2.12 (s, 3H); MS (ES) 508 [M+H]+ Scheme for synthesising compounds of formula (III) (PS109) A general scheme for introducing substituents to produce compounds of SFK11 PS109, is as follows: it.. a.. I. - 83 E3 N:NH2 R1CHO xb,NR1 F3CNH2 Br Sc(OTf)3,N Cul, K2CO3, (A) ><yNC (8) H /\ /\ dimethylethylenediamine C N IN Strong Acid [3 (G) \ N:- R1 NaOH, H2O O N - N N F. C N:N O H R2 H R2 (111) (J) 2-Amino-5-bromopyrazine (A) can be converted to the substituted 3- amino-6-bromoimidazo[1,2-a]pyrazines (B) using the aldehydes described in Box 6. The intermediates (B) can be reacted with trifluoroacetamide to give amides (G) and then deprotected to give primary amines (H). The resultant amines can be acylated with acid chlorides prepared from the acids described in Box 7 to give amides (a) and deprotected to give the primary amines (III).
The permitted substituents at positions Rob and R2 are shown in Boxes 1 and 2 respectively, in the following schematic diagram.
NON /Box6 H. N;N- SFK11 N_ Scatter HI * \ Diagram Box 7 .: e B': c-e *e:.
. . - 84 i' _ an 8 t}8 b 8 =: ' o o (it) 8 8 - 8 8 u Z/3-h}I b óoruN aft -\ 1 (: :8 o/ COP 1 8 '! ?3 8 U 8 / ,. )y p,.y to / 38 &-\-; I (-3% / Q: Liz 8- o-8 8" you A G got mu., Z I 8 9 \\ z, 8- it> 8-<) / of "8 {}9 o,: Z-I so 1 8.:' <Y (2 S 8 8 8 53 - . . (348 6 ; )\u -,, (--8; :8 /\i <-> im ul a: À at: À.: :. e. cee. .: a. À. :. À -
General Procedures Typical example of compound of formula (G), as described in general reaction scheme; 2,2,2-trifluoro-N-[2-furan-3-yl-3-(1, 1, 3, 3- tetramethylbutylamino)imidazo [1,2-a]pyrazin-6-yl]-acetamide (26).
F3C N ' 1 (26) 1 (2-(3-Furyl)-6-bromoimidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3tetramethylbutyl)amine (11.7 9, 30 mmol), trifluoroacetamide (5.0 9, 45 mmol), copper (I) iodide (0.86 9, 4.5 mmol), N,N'- dimethylethylenediamine (0.5 mL, 4.7 mmol), copper bronze (0.065 9, 1.0 mmol) and potassium carbonate (8.3 9, 60 mmol) were weighed into a mL round-bottom flask. After the flask was evacuated and flushed with nitrogen (x 3), toluene (35 mL) was added and the reaction mixture heated (100 C) for 24 hours. After LCMS analysis showed that all the starting material had been consumed, the reaction mixture was diluted with ethyl acetate and filtered through a short plug of silica. The filtrate was concentrated and the residue purified by column chromatography to yield the desired amide (26) as a yellow solid (9.0 9, 71%). HPLC 93%; 1H NMR (250 MHz, DMSO) 12.16 (s, 1H), 9.09 (s, 1H), 8.85 (s, 1H), 8.31 (s, 1H), 7.76 (s, 1H), 7.09 (s, 1H), 4.65 (s, 1H), 1.67 (s, 2H), 1.04 (s, 6H), 1.03 (s, 9H); MS (APCI) 424 [M+H]+.
Typical example of compound of formula (G), as described in general reaction scheme; N-[2-benzo[1,3]dioxol-5-yl-3-(1,1,3,3tetramethylbutylamino)imidazo[1,2-a]pyrazin-6-yl]-2,2, 2 trifluoroacetamide (27).
À: A: A. : :- Àe a...: À :e À À - . - 86 n.,,: Yield 2.85 9, 15%; HPLC 95%; 1H NOR (250 MHz, CDCl3) 9.20 (s, 1H), 8.73 (s, 1H), 8.55 (s, 1H), 7.43 (s, 1H), 7.39 (d, = 8.0 Hz, 1H), 6.92 (d, }= 8.0 Hz, 1H), 6.04 (s, 2H), 3.20 (s, 1H), 1.64 (s, 2H), 1.08 (s, 9H), Typical example of compound of formula (H), as described in general reaction scheme; N-[3-amino-2-(4-diethylaminophenyl)-imidazo[1,2- a]pyrazin-6-yl]-2,2,2 -trifluoroacetamide (28).
l F3C INTO AN | H NH2 (28) N-[2-(4-Diethylaminophenyl)-3-(1,1,3,3-tetramethylbutylamino)imidazo[1,2-a]pyrazin-6-yl]-2,2,2-trifluoroacetamide (2.5 9, 5.0 mmol) was weighed into a 100 mL round-bottom flask and was dissolved in 4M HCl/dioxane (20 mL). After stirring at room temperature for 16 hours, the solution was analysed by LCMS and determined to have reached completion. The reaction mixture was concentrated and the crude residue was partitioned between ethyl acetate and saturated sodium bicarbonate.
The organic phase was separated, dried and concentrated to give the desired amine (28) as a dark yellow solid (1.3 g, 67%). HPLC 100%; 1H À À À: À-: À À À À . . e. Àe.e.: :: À.
À . À . - 87 NMR (250 MHzl CDCl3) 8.81 (sl 1H)/ 8.68 (sl 1H)/ 7.78 (dl = 8 4 Hz 2H)l 6 77 (dl = 8.4 Hzl 2H)l 3.77 (sl 2H)l 3.42 (q/ = 7.0 Hzl 4H)l 1.21 (tl = 7.0 Hzl 6H); MS (APCI) 393 [M+H]+.
Typical example of compound of formula (H)l as described in general reaction scheme; N-[3-amino-2-(3,4-difluorophenyl)-imidazo[1,2a]pyrazin-6-yl]-2, 2,2-trifluoroacetamide (29).
Tl...- (29) Yield 1.6 9l 97%; HPLC 89%; 1H NMR (250 MHzl DMSO) 11 98 (sl 1H) 8.82 (sl 1H)l 8.74 (sl 1H)l 7.92 (ml 1H)l 7.81 (ml 1H)l 7.49 (ml 1H)l 5. 95 Typical example of compound of formula (III)l as described in general reaction scheme; N-(6-amino-2-ethylimidazo[1,2-a]pyrazin-3-yl)-2-(4isopropylphenoxy)-acetamide (30).
(30) O To a 'Stem' reaction tube containing (4-isopropylphenoxy)acetic acid (58.3 ma/ 0.3 mmol) in THF (0.5 mL) was added oxalyl chloride (25 pLl 0.3 mmol) and a drop of DMF. The reaction mixture was flushed with À: . I: ace: :. e. ce. If: :e .. .. . - 88 nitrogen, capped and shaken for 2 hours. Solid N-(3-amino-2-ethylimidazo[1,2-a]pyrazin-6-yl)-2,2,2-trifluoroacetamide (55 mg, 0.2 mmol) and a solution of diisopropylethylamine (70 pL, 0.4 mmol) in THE (0.5 mL) was added to the acid chloride solution and the reaction again flushed with nitrogen and capped. After heating to 60 oc for 16 hours, the tubes were uncapped and a solution of sodium hydroxide (40 mg, 1 mmol) in H2O (0.5 mL) added to the reaction mixture which was heated for a further 4 hours.
The tubes were allowed cool and the contents diluted with DMSO (0.5 mL), filtered and purified by reverse-phase preparative HPLC to yield the desired amide (30) as a pale yellow solid (30.4 mg, 43%). HPLC 100%; MS (ES) 356 [M+H]+.
Typical example of compound of formula (III), as described in general reaction sche me; N-(6-amino-2-phenethylimidazo[1, 2-a]pyrazin-3-yl)-2(4-fluorophenyl)-acetamide (3).
| ,4, r-)) I
NO
(31) IF Yield 28.4 mg, 36%; HPLC 100%; MS (ES) 390 [M+H]+.
Typical example of compound of formula (III), as described in general reaction scheme; N-[6-amino-2-(2,3-dibydrobenzo[1,4]dioxin-6-yl)imidazo[1,2-a]pyrazin-3-yl]-2-(3,5-dimethoxyphenyl)-acetamide (32).
À À À . Àe.:: e as: a:: À. À - 89 : I,? (32) OMe
Yield 28.0 mg, 30%; HPLC 95%; MS (ES) 462 [M+H]+.
Typical example of compound of formula (III), as described in general reaction scheme; N-[6-amino-2-(3-phenoxyphenyl)-imidazo[1,2a]pyrazin-3-yl]-3-(2-methoxyphenyl)- propionamide (33). H,N
(33) Income Yield 27.0 mg, 28%; HPLC 100%; MS (ES) 480 [M+H]+.
Purification Conditions All compounds have a minimum purity level 80% as measured by LCMS at 254 nm.
The columns used for the preparative HPLC purification of the various scaffolds are outlined in Table 1: À À c: Ale: e:: À en. . :. :-.
- go -
Table 1
_ _. . _ Scaffold Column I All compounds Varian Polaris 1Olm C18-A 150 x 21.2mm The gradient used for the preparative HPLC purification of all compounds was 95% water (lOmmol NH3HC03) 5% Acetonitrile for 1 min to 5% water (lOmmol NH3HCO3) / 95% Acetonitrile over 8.0 min then held at 5% water (lOmmol NH3HCO3) / 95% Acetonitrile for 2.0 min. The solvent mixture was then returned to the initial conditions over 0.5 min. A flow rate of 25 ml/min was used.
The conditions used for the analytical HPLC analysis following preparative HPLC purification are outlined in Table 2:
Table 2
-
Conditions Detection . . _ _ Column: Waters Xterra Prep MS C18 51lm UV detection at 254 rim 4.6 x 100mm. (diode array range 210 280nm).
Gradient: 95% water (10 mM NH3HCO3) / 5% ACN for 0.5 min then 95% water (10 mM Electrospray NH3HC03) / 5% ACN to 2% water (10 mM ionization: NH3HCO3) / 98% ACN over 3.5 min. Held at 2% water (10 mM NH3HCO3) / 98% ACN for Cone voltage: 30 V. 0.5 min. The solvent mixture is then returned Cone temperature: 20 to the initial conditions over 0.1 min and the C.
system allowed to re-equilibrate for 0.2 min. Source temperature 150 C.
Flow rate: 2.0 ml/mint RF lens voltage: 0.0 V. Temperature: 30 C. Ion energy: 0.5 eV.
Injection volume: 5 1lm partial loop. Multiplier: 650 V. À À it: ce.: À:: it. À :e À . À . - 91 LIBRARY SFK14 SFK14 is designed to have a broad focus on the tyrosine and serine/threonine kineses that recognise typical mono-and bicyclic heterocyclic ligands for the ATP binding site. The central scaffold is based on a novel application of the 3-aminopyrazine scaffold bearing substitutents at the 2 and 6 positions. Each scaffold has been docked into the ATP-binding region of a variety of kineses including Zap-70, CDK2, p38 MAP kinase, FGFrl, PKA, Hck and Erk2 and all have shown they are capable of mimicking the characteristic double H- bonding system seen between ATP and the enzyme backbone in protein kinase ATP sites.
The invention provides a compound library comprising or consisting of structurally related compounds of general formula (I) and (II): KN'^<NH2 KNKNH2 (I) (II) R3 Wherein Ar is aryl having a cyclic aromatic structure containing between 3 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, hetero aryl having a cyclic aromatic structure containing between 1 and 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms or heteroaralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and contains one or more heteroatoms; R1 is alkenyl having from 1 to 20 carbon atoms, aryl having a cyclic aromatic structure containing between 2 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, aryl having a cyclic À. ce ac* : *:. ':e tee e:: . - 92 aromatic structure containing between 3 and 20 carbon atoms which may bear one or more substituent groups at any available ring position or hetero aryl having a cyclic aromatic structure containing between 1 and 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms; R2 is hydrogen; R3 is alkyl having from 1 to 20 carbon atoms which may be linear or branched and may contain one or more heteroatoms, cycloalkyl having from 3 to 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aryl having a cyclic aromatic structure containing between 3 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, hetero aryl having a cyclic aromatic structure containing between 1 and 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms or heteroaralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms; and R4 is alkenyl having from 1 to 20 carbon atoms, aryl having a cyclic aromatic structure containing between 2 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, aryl having a cyclic aromatic structure containing between 3 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, hetero aryl having a cyclic aromatic structure containing between 1 and 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms or heteroaralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms. R2 and R3 may also be joined to form the same ring system.
: : .e em: :e - 93 Scheme for synthesising compounds of formula (I) (PS173) A general scheme for introducing substituents to produce compounds of SFK14 PS173 is as follows: E1 | BOX 21 :N>NH2 ArB(OH)2 'óN - NH2 R1 B(OH)2,óN;:NH2 Br Br Br N Ar R1 NAr (A) (B) (I) 2-Amino-3,5-dibromopyrazine (A) can be reacted with the boronic acids described in Box 1. The resultant compound (B) can be then be reacted with the boronic acids described in Box 2.
The permitted substituents at position Ar and R1 are shown in Boxes 1 and 2 respectively, in the following schematic diagram.
Box 2 N - 'NH2 SFK14 \*óN1* Scatter Diagram Box 1 : : t: - 94 I C z N ,dó5 HIT b z m O I oN N <_ O It) z Con O I O IN \ o b N _-' - Ph_ of' À À ace a À e e e ee eve ece.
À e e e ee see ee e e e - 95 General Procedures Typical example of compound of formula (B), as described in general reaction scheme; 5-bromo3-(3,4-dimethoxyphenyl)pyrazine-2-amine (1) NNH2 Br N, To a mixture of 3amino-2, 6-dibromopyrazine (18 mmol, req.) and boronic acid (21.6 mmol, 1. 2 eq.) in 40 ml degassed DMF was added a 30 ml 1.5 M degassed solution of sodium carbonate (45 mmol, 2.5 eq.). The mixture was then degassed for a further 5 mins by bubbling N2 through.
To the latter mixture, a yellow suspension of triphenylphosphine (2.7 mmol, 0.15 eq.) and palladium acetate (0.9 mmol, 0.05 eq.) in degassed dioxane (18 ml) was added under a nitrogen atmosphere. After the addition was complete, the reaction mixture was heated overnight at 80 C with stirring. The reaction mixture was diluted with ethyl acetate (50 ml) and the solid was filtered. The filtrate was washed with water and brine and the organic solution was then filtered through a short pad of silica and washed with ethyl acetate. The filtrate was evaporated to dryness under reduced pressure and the crude organic residue was triturated with diethyl ether to give the required compound as a yellow solid (1.729, 30%) . 1H NMR (CDCl3): OH 7.87 (s, 1H, PyzH), 7.07-7.03 (m, 2H, ArH), 6.91 (d, ]=8 Hz, 1H, ArH), 6.26 (brs, exe., 2H, NH2), 3.65 (s, 6H, 2xCH3); MS (APCI) m/z: 310&312 isotopes, (100%, [M+H]+), 351&353 isotopes (20%, [M+ CH3CN]+), 232 (24%, [M+H-Br]+); HPLC 96%.
Typical example of compound of formula (B), as described in general reaction scheme; 4-(3-amino-6-bromopyrazin-2yl)phenol (2).
À e Àe À À À À À C À À À À À À - 96 BrJ:N < Yield (4.22 9, 87%); 1H NMR (DMSO): H 9.83 (brs, exe., lH, OH), 7.98 (s, lH, PyzH), 7.52 (d, ]=9Hz, 2H, ArH), 6.84 (d, ]=9Hz, 2H, ArH), 6.33 (brs, exe., 2H, NH2); MS (APCI) m/z: 264&266 isotopes (100%,[M-H]-); HPLC 98%.
Typical example of compound of formula (B), as described in general reaction sche me; 4-(3-amino-6-bromopyrazin-2-yl)benzamide (3). NNH2 Br N,
(3) NH2 Yield (2.5 g, 48%); 1H NMR (DMSO): H 8.10 (brs, exe., 2H, CONH2), 7.98 (d, ]=8.5 Hz, 2H, ArH), 7.73 (d, J=8.5Hz, 2H, ArH), 7.46 (s, 1H, PyzH), 6.54 (brs, exe., 2H, NH2); MS (APCI) m/z: 293&295 isotopes,(100%, [M + H]+), 334&336 isotopes (35%, [M+ CH3CN]+), 215 (35%, [M +H-Br]+); HPLC 96%.
Typical example of compound of formula (B), as described in general reaction scheme; S-bromo-3-[4-(dimethylamino) phenyl]pyrazine-2-amine (4).
e À ee.
À À À .À À À À e À a e e À C e e. Àe À À - 97 N - ,,NH2 'MN Yield (3.58 9, 68%); 1H NMR (DMSO): H 7.92 (s, 1H, PyzH), 7.56 (d, ]=9 Hz, 2H, Ar), 6.78 (d, ] =9Hz, 2H, Ar), 6.28 (brs, exe., 2H, NH2), 2.96(s, 6H, CH3x2); MS (APCI) m/z: 293&295 isotopes,(100%, [M+H]+), 334&336 isotopes (15%, [M+ CH3CN]+), 215 (16%, [M+H-Br]+); HPLC 99%.
Typical example of compound of formula (B), as described in general reaction scheme; 5-bromo-3-dibenzo[b, d]furan-4-ylpyrazin-2-amine (5). NH2 g: Br (5)
Yield (3 9, 49%); 1H NMR (DMSO): H 8.25 (dd, ]=7.5 Hz & 1.5 Hz, 1H, ArH), 8.21-8.18 (m, sH, ArH), 8.19 (s, 1H, ArH), 7.71 (d, ]=8Hz, 1H, ArH), 7.617.36 (m, 5H, ArH), 6.51 (brs, exe., 2H, NH2); MS (APCI) m/z: 340&342 isotopes,(100%, [M+H]+), 381 & 383 isotopes (47%, [M+ CH3CN]+), 262 (31%, [M+H-Br]+); HPLC (94%).
General procedure for the synthesis of compounds of formula (I).
To a solution of compound of formula (B) in degassed DMF (0.3mmol, 1 eq., 0.5ml) was added a solution of boronic acid in DMF (0.36mmol, 1.2 eq., 0. 6ml) and 1.5M Na2CO3 (degassed aq.) solution (0.75mmol, 2.5 eq., 0.5 ml). A solution of palladium (II) acetate (0.015 mmol, 0.05 eq., 168mg) and triphenylphosphine (0.045 mmol, 0.15 eq., 588mg) in À c À c À c À . . À À e. À. . À - 98 degassed 1,4-dioxane (15ml) was freshly prepared and placed in a sonication bath for 2min. The palladium catalyst (0.3ml, yellow suspension) was then added to the reaction vessel under a nitrogen atmosphere and the contents were heated at 80 C with agitation for 16h.
The reaction mixtures were filtered and purified by preparative reverse phase HPLC.
Typical example of compound of formula (I), as described in general reaction scheme; 3-(4-morpholin-4-ylphenyl)-5-pyridin-4-ylpyrazin-2 amine (6).
:ó X:N 1 (6) TO 1 Yield 50.6mg, 51%; 1H NOR (DMSO): OH 8.63 (s, lH, PyzH), 8.57(dd, ]=5Hz &1.5 Hz, 2H, ArH), 7.94(d, ]=5Hz, 2H, ArH), 7.70 (d, ]=9Hz, 2H, ArH) , 7.06 (d, ]=9Hz, 2H, ArH), 6.57 (brs, exe., 2H, NH2), 3.77-3.73 (m, 4H, 2xCH2); MS (ES) m/z: 334,(100%, [M+H]+); HPLC 100%.
Typical example of compound of formula (I), as described in general reaction scheme; 4-[3-amino-6-(6-methoxypyridin-3-yl)pyrazine-2 yl]phenol (7).
IN - <NH2
NN (7)
À . À:: À . . À .: À À e À À .e Àe À _ 99 _ Yield 47mg, 53%; 1H NMR (DMSO): H 9.75 (s, exe., 1H, OH), 8.74(d, J=1.5Hz, 1H, PyH), 8.44 (s, 1H, PyzH), 8. 24(dd, ]=8.5Hz&1.5Hz, 1H, PyH), 7.63 (d, ]=8.5Hz, 2H, ArH), 6.87 (d, J=8. 5Hz, 3H, 2xArH+lxPyH), 6.20 (brs, exe., 2H, NH2), 3.87 (s, 3H, CH3); MS (ES) m/z: 295 (100%, [M+H]+); HPLC 100%.
Typical example of compound of formula (I), as described in general reaction scheme; 4-[3-amino-6-(2,4-dimethoxy-pyrimidin-5-yl)-Pyrazin2-yl]-N-(2-hydroxy-ethyl)-benzamide (8). () O
Yield 54.5mg, 46%; 1H NMR (DMSO): H 8.77 (s, 1H, ArH), 8.55(t, exe., ]=5.5Hz, 1H, NH), 8.44 (s, 1H, ArH), 7.97 (d, J=8.5Hz, 2H, ArH), 7.86 (d, ]=8.5 Hz, 2H, ArH), 6.47 (brs, exe., 2H, NH2), 4.76 (t, exe., ]=5.5Hz, 1H, OH), 4.01 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.51 (q, ]=5.5HZ, 2H, CH2), 3.37-3.31 (m, 2H, CH2); MS (ES) m/z: 397,(100%, [M+H]+); HPLC 100%.
Typical example of compound of formula (I), as described in general reaction scheme; 3-[4-(dimethylaminophenyl]-5-(2-furyl) pyrazin-2-amine (9). N<NH2
:'I'''C 1 À À À À À À À 8 À À À À 8 8 8 8 À. À 8 - 100 Yield 31.3mg, 37%; 1H NMR (DMSO): OH 8.20 (s, lH, PyzH), 7.71(dd, ]=2Hz&1Hz, lH, FurH), 7.61 (d, J=9Hz, 2H, ArH), 6.82 (d, J=9Hz, 2H, ArH), 6.80-6.78 (m, lH, ArH), 6.56 (dd, ]=3Hz&2Hz, lH, FurH), 6.22 (brs, exe., 2H, NH2), 2.96 (s, 6H, CH3x2); MS (ES) m/z: 281(100%, [M+H]+); HPLC 100%.
Scheme for synthesising compounds of formula (II) (PS174) A general scheme for introducing substituents to produce compounds of SFK 14 PS174 is as follows: [3 R3 óN:(NH2 HNR2 'óNq'NH2 R4g(0H) 'óNq'NH2 Br N Br N R4 N-JN,R3 (A) (C) R2 R2 The C3 bromine of 2-amino-3,5 dibromopyrazine (A) can be selectively displaced with the primary and secondary amines or anilines described in Box 3. The resultant compounds (C) can then be reacted with the boronic acids described in Box 4 to form the desired targets (II).
The permitted substituents at position R2, R3 and R4 are shown in Boxes 3 and 4 respectively, of the following diagrams.
SFK 14 Box 4 N: NH2 \ 'ó PS174 Scatter Diagram \ N N- 1 \ \ Box 3 À le e a ' ; , . e - 101 0N AZI ZI N AZI ZI I \/ :- I (it)
Z Z - \ \
ELI 0 m - 0 HI to C' O ohm O \=/ O O o: -0 3 OWN 04 N Oóm K1 N I I (3 m zAz /3 m A f 3 m 0 I IN IN,., / m I I zag m 0 N
ZNON
IN O _ _
=3 m IN 0 ?3 3 m
O N
I o 3 0 0 z3 3:3 63Z :: ::' cue::' i t'. - 102
General procedures Typical example of compound of formula (C), as described in general reaction scheme; 5-bromo-N3-(2-methoxyethyl)pyrazine2,3-diamine (10).
B WIIN'1NO (1 O) A mixture of 2-amino-3, 5-dibromopyrazine (6 mmol, Len.), primary amine (6.6 mmol, 1.1 eq.) and DIPEA (6.6 mmol, 1.1 eq.) in ethanol (lml) was placed in the CEM Discover and heated at 180 C (70W) for 25min.
The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate. The organic solution was washed with water and brine then decolorised by refluxing the solution with charcoal for 1 hour. The unwanted solid was filtered off and the solvent removed under reduced pressure. The crude organic residue was triturated with hexane to give the desired product as a yellow solid (0.899, 69%); 1H NMR (CDCl3): OH 7. 42 (s, 1H, PyzH), 4.98 (brs, exe., 1H, NH), 4.47 (brs, exe., 2H, NH2), 3.61 (m, 4H, CH2), 3.38 (s, 3H, CH3); MS (APCI) m/z: 247 & 249 isotopes, (83%, [M+H]+), 215&217 isotopes, (100%, [M- OCH3+H]+), 288 & 290 isotopes, (7%, [M+CH3CN]+); HPLC 99%.
Typical example of compound of formula (C), as described in general reaction scheme; N3-benzyl-5-bromopyrazine-2, 3-diamine (11).
(, i:: À À . À À À . À . À . À À À À À À . . À À À À À À . À À . À e. .e À À - 103 Yield (1.33 9, 80%); lH NMR (CDCl3): H 7.29 -7.46 (m, 5H, ArH), 7.43 (s, lH, PyzH), 4.69 (brs, exe., lH, NH), 4.56 (d, ]=6 Hz, 2H, CH2), 4.31 (brs, exe., 2H, NH2); MS (APCI) m/z: 279&281 isotopes, (100%, [M+H]+) HPLC 94%.
Typical example of compound of formula (C), as described in general reaction scheme; 5-bromo-3-(4-methylpiperazin-1-ylJpyrazine-2-amine (12) NNH2 XBr N N- <,N: (12) Yield (0.759, 46%); lH NMR (CDCl3): H 7.66 (s, lH, PyzH), 4.59 (brs, exe., 2H, NH2), 3.16 (brs, 4H, CH2), 2.49 (brs, 4H, CH2), 2.28 (s, 3H,CH3); MS (APCI) m/z: 272&274 isotopes, (100%, [M+H]+); HPLC 99%.
Typical example of compound of formula (C), as described in general reaction scheme; N3-(4-methoxy-2-methylphenyl)pyrazine-2,3-diamine (13).
NNH2 o- (13) A mixture of 2-amino-3, 5-dibromopyrazine (4 mmol, leq.), aniline (4. 4 mmol, 1.1 eq.) and K2CO3 (4.4 mmol, 1.1 eq.) in DMF (lml) was placed in the Smith Creator and heated at 170 C for 30 minutes. The highly viscous À À. À ÀÀÀÀ. À À À À À À À À .e a a À.
À À . À À À . À À À - 104 black solid was diluted with ethyl acetate filtered through a short pad of silica. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate and washed with water then brine. The ethyl acetate was removed under reduced pressure and the crude red oil was purified by column chromatography (50% hexane: ethyl acetate) to give the product as a green solid (0.289, 15%); 1H NMR (CDCl3): OH 7.65 (s, 1H, PyzH), 7.22-7.19 (m, 1H, ArH), 6.79-6.71 (m, 2H, ArH), 6.07 (brs, 1H, NH), 4.37 (brs, 2H, NH2), 3.81 (s, 3H, OCH3), 2.15 (s, 3H, CH3); MS (APCI) m/z: 309 & 311 isotopes, (100%, [M+H]+); HPLC 92%.
General procedure for the synthesis of compounds of formula (II).
To a solution of compound of formula (C) in degassed DMF (0.3mmol, 1 eq., 0.5ml) was added a solution of boronic acid in DMF (0.36mmol, 1.2 eq., 0. 6ml) and 1.5M Na2CO3 (degassed aq.) solution (0.75mmol, 2.5 eq., 0.5ml). A solution of palladium (II) acetate (0.015 mmol, 0.05 eq., 168mg) and triphenylphosphine (0.045 mmol, 0.15 eq., 588mg) in degassed 1, 4-dioxane (15ml) was freshly prepared and placed in a sonication bath for 2min. The palladium catalyst (0.3ml, yellow suspension) was then added to the reaction vessel under a nitrogen atmosphere and the contents were heated at 80 C with agitation for 16h.
The reaction mixtures were filtered and purified by preparative reverse phase HPLC: Typical example of compound of formula (II), as described in general reaction scheme; {3-[5-amino-6-(benzylamino)pyrazine-2yl]phenyl}methanol (14).
tee c À C À À À ce ase ee. e - 105 NNH2
NNH (14)
Yield 10.4mg, 11%; 1H NMR (DMSO): H 8.52 (s, lH, PyzH), 7.91 (brs, lH, ArH), 7.83 (d, ]=7.5Hz, lH, ArH), 7.69 (brs, lH, ArH), 7.63 (d, ]=7.5Hz, lH, ArH), 7.47 (t, ]=7.5Hz, lH, ArH), 6.29 (brs, exe., 2H, NH2), 5.26-5.24 (m, exe., 2H, NH+OH), 4.57-4.52 (m, 4H, CH2x2); MS (ES) m/z: 308 (100%, [M+H]+); HPLC 100%.
Typical example of compound of formula (II), as described in general reaction scheme; 3-[5-amino-6-(l H-indol-5-ylamino)pyrazin-2-yl]phenol (5) . NH2 N4NHm
Yield 33.6mg, 35%; 1H NMR (DMSO): H 10.95 (brs, exe., lH, indolNH), 9.37 (brs, exe., lH, OH), 8.06 (brs, 2H, NH+ ArH), 7.82 (s, lH, ArH), 7.42-7.12 (m, 6H, ArH), 6.65 (d, ]=8Hz, lH, Ha-indol), 6.38 (brs, 3H, NH2+ H,8-indol); MS (ES) m/z: 318 (100%, [M+H]+); HPLC 100%.
Typical example of compound of formula (II), as described in general reaction scheme; N3-(Z-furylmethyl)-5-(5-isopropyl-2- methoxyphenyl) pyrazine -Z. 3-d famine (16).
À À À À À À . À À À À 1 ce À- À À ace À . À . À .< À À À - 106 1NXNH2 1 (16) Yield 47.4mg/ 46%; 1H NMR (DMSO): H 7.85 (s, 1H, PyzH)/ 7.70 (d ]=2.5Hz, 1H, ArH), 7.56 (dd, J=2Hz&1Hz, 1H, Fur-H), 7.07 (dd, ]=8.5Hz&2.5Hz, 1H, ArH), 6.94(d, ]=8.5Hz, 1H, ArH), 6.66 (t, exe., ]=5Hz, 1H, NH), 6.38 (dd, ]=3Hz&2Hz, 1H, Fur-H), 6.30-6.28 (m, 1H, Fur H), 6.08 (brs, exe., 2H, NH2), 4.57 (d, J=5Hz, 2H, CH2), 3.77 (s, 3H, OCH3), 2.90-2.79 (m, 1H, CH), 1.19 (s, 3H, CH3), 1.17 (s, 3H, CH3); MS (ES) m/z: 339 (100%, [M+H]+); HPLC 100%.
Typical example of compound of formula (II), as described in general reaction scheme; 5-(3-aminophenyl)-3-(4-methylpiperazin--yl)pyrazin2-amine (17).
X
Yield 56.1mg, 66%; 1H NMR (DMSO): H 8.02 (s, 1H, PyzH), 7.12-7.11 (m, 1H, ArH), 7.04-6.98 (m, 1H, ArH), 6.49-6.45 (m, 1H, ArH), 5.95 (brs, exe., 2H, NH2), 5.07 (brs, exe., 2H, NH2), 3.12-2.98(m, 4H, 2xCH2), 2.52- 2.47 (m, 4H, 2xCH2), 2.22 (s, 3H, CH3); MS (ES) m/z: 285 (100%, [M+H]+); HPLC 100%.
À a.
À e À À À e À Àe ae- À ace À . À . À e. À . . - 107 Purification Conditions All compounds have a minimum purity level 2 80% as measured by LCMS at 254 nm.
The columns used for the preparative HPLC purification of the various scaffolds are outlined in Table 1:
Table 1
j. _. . ., . ._.
Scaffold Column _. , All compounds Waters Xterra Prep MS C18 51lm 19 x 100mm it, . _. __ _.
The gradient used for the preparative HPLC purification of all compounds was 95% water (lOmmol NH3HCO3) 5% acetonitrile for 1 min to 5% water (lOmmol NH3HCO3) / 95% acetonitrile over 8.0 min then held at 5% water (lOmmol NH3HCO3) / 95% acetonitrile for 2.0 min. The solvent mixture was then returned to the initial conditions over 0.5 min. A flow rate of 25 ml/min was used.
The conditions used for the analytical HPLC analysis following preparative HPLC purification are outlined in Table 2:
Table 2
Conditions Detection _. _.. . _ Column: Waters Xterra Prep MS C18 51lm UVdetection at 254 nm 4.6 x 100mm. (diode array range 210 280nm).
Gradient: 95% water (10 mM NH3HCO3) / 5% ACN for 0.5 min then 95% water (10 mM Electrospray NH3HCO3) / 5% ACN to 2% water (10 mM ionisation: NH3HCO3) / 98% ACN over 3.5 min. Held at 2% water (10 mM NH3HCO3) / 98% ACN for Cone voltage: 30 V. 0.5 min. The solvent mixture is then returned Cone temperature: 20 to the initial conditions over 0.1 min and the C.
system allowed to re-equilibrate for 0.2 min. Source temperature 150 C.
Flow rate: 2.0 ml/mint RF lens voltage: 0.0 V. Temperature: 30 C. Ion energy: 0.5 eV.
Iniection volume: 5 m _artial loop. Multiplier: 650 V. À À À À À . À À À À À À e À À e ÀÀa ee. À À cee À À e À À ace À. À À - 108 LIBRARY SFK20 SFK20 is designed to have a broad focus on tyrosine and serine/threonine kineses that recognise typical bicyclic heterocyclic ligands for the ATP binding site. The central design of the library is based on novel applications of the imidazopyrazine-2-one scaffold which has been docked into the ATP-binding region of a variety of kineses including CDK2, FGFrl, PKA, Hck and Erk2. The library has been designed to mimic the characteristic double H- bonding system seen between ATP and the protein kinase backbone by utilising the embedded amide motif. Two major docking modes are observed: In mode 1, the amide donor-acceptor pair provides the key backbone interactions (for example, H-bonds to Phe82 and Glum in CDK2): In mode 2, a pyrazine nitrogen acts as acceptor and the amide NH as donor, with a third H-bond possible to the amide CO.
The invention provides a compound library comprising or consisting of a set of structurally related compounds of the general formula (I).
Wherein R1 is alkyl having from 1 to 20 carbon atoms which may linear or branched and may contain one or more heteroatoms, cycloalkyl having from 3 to 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aryl having a cyclic aromatic structure containing between 3 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, hetero aryl having a cyclic aromatic structure containing between 1 and 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may À. ... . . e e e À e À À À e e e À ce es. e e ee e e e e. e. e e - 109 contain one or more heteroatoms or heteroaralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms; and R2 is alkenyl having from 1 to 20 carbon atoms, aryl having a cyclic aromatic structure containing between 2 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, aryl having a cyclic aromatic structure containing between 3 and 20 carbon atoms which may bear one or more substituent groups at any available ring position, hetero aryl having a cyclic aromatic structure containing between and 20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms, aralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms or heteroaralkyl having from 1-20 carbon atoms which may bear one or more substituent groups at any available ring position and may contain one or more heteroatoms.
Scheme for synthesising compounds of formula (I) | BOX1 | KN' - NH2 NH2R1 N,,NH2 R2B(OH)2 NKNH2 Br;NlBr P' BrJ:N NH R2:l lo,R1 (A) (B) (C) CDI, Dioxane ó XN)=0 (' R1 2-Amino-3, 5-dibromopyrazine (A) can be aminated with the amines described in Box 1. The resultant compounds (B) can then be reacted with À À . À e À À À À À . À À À ti0 the boronic acids described in Box 2. Cyclisation of the intermediates (C) yields the desired targets (I).
À . À À À À . À À . c. e'. À .e . À À À it! o 1 IZ Z. '; _ At \ U Z 1 " I I \ \ZN 0/ 0ó N In \ \ _ a Q I Q o O Or 0 < ó 2 t3G __ opt 43 I I o 30 0 I o ^ Z_ O O O I 0 I o G I 3 G o >3 3 \$ ' O z o o; > tG _.
I O. O i o Q z o h3o 2 Q Q \ -G 5 Z O O O OI = Q z o o) - 3 8 <3 G z Z O. G o G t33m Z3 c À e. r a, . . À À C À . . . À À - À À - 112 General procedures Typical example of compound of formula (B), as described in the general reaction scheme; N3-[(1 R)-] - phenylethyl]-5-bromo-2, 3-pyrazine diamine (I) X'óN NH2 Br N NH (1) 4/ A mixture of 2-amino-3, 5-dibromopyrazine (60 mmol, Len.), (S)-(-)- (alpha)-methylbenzylamine (66 mmol, 1.1 eq.) and DIPEA (66 mmol, 1.1 eq.) in ethanol (15ml) was placed in the CEM Discover and heated and stirred at 180 C for 90 mins. The contents of the tubes were then transferred to a round-bottomed flask and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and brine and then filtered through a pad of silica using ethyl acetate as the eluant. The solvent was evaporated under reduced pressure and the crude residue was slurried in hexane. The solidified product was filtered, washed with hexane and dried to give the product as a brown solid (6.829, 77%); 1HNMR (250MHz, DMSO06): dppm, 7.64-7.30 (m, 4H, ArH), 7.23-7.19 (m, 1H, ArH), 7.18 (s, 1H, PyraH), 6.84 (d, 1H, 7.50 Hz, NH), 6.29 (brs, 2H, NH2), 5.13-5.01 (m, 1H, CH), 1.4 (d, 3H, 7.50Hz, CH3); MS (AP+, [M+H]+) m/z: 293 & 295 (M+1), 334 & 336 (M+CH3CN); HPLC 95%.
Typical example of compound of formula (B), as described in the general reaction scheme; N3-cyclohexyl-5-bromo-2, 3-pyrazine diamine (Z). À À a
À À - . - 113 N:NH2 Br N NH (2)b Yield (59, 77%); 1HNMR (250MHz, DMSOd6): dppm, 7.11 (s, 1H, PyraH), 6.23 (brs, 1H, NH), 6.17 (brs, 2H, NH2), 3.71-3.66 (m, 1H, NCH), 1.97- 1.88 (m, 2H, CH2), 1.73-1.56 (m, 2H, CH2), 1.37-1.28 (m, 1H, CH), 1.23- 1.11 (m, 5H, CH2x2 & CH); MS (AP+, [M+H]+) m/z: 271 & 273 (M+1), 312 & 314 (M+CH3CN); HPLC 100%.
Typical example of compound of formula (B), as described in the general reaction scheme; N3-(3-pyridylmethyl)-5-bromo-2, 3-pyrazine diamine (3).
N - <NH2 BrNNH (3) Yield (8.609, 73%);1HNMR (250MHz, DMSOd6): dppm, 8.51 (d, 1H, 5Hz, PyrH), 7.74 (t, 1H, 7.50Hz, PyrH), 7.31 (d, 1H, 7.50Hz, PyrH) , 7.26 (t, 1H, 5Hz, NH), 7.19 (s, 1H, PyraH), 7.18-7.15 (m, 1H, PyrH), 6.27 (s, 2H, NH2), 4.58 (d, 2H, 5Hz, CH2); MS (AP+, [M+H]+) m/z: 280 & 282 (M+1); HPLC 99%. r. À
Àe I t e., e ''' a À ., - 114 Typical example of compound of formula (B), as described in the general reaction scheme; N3-cyclopropylmethyl-5-bromo-2, 3-pyrazine diamine (4).
BrJ:NlNH (4) v Yield (119, 84%); 1HNMR (250MHz, DMSOd6): dppm, 6.91 (s, lH, PyraH), 6.40 (t, lH, 5Hz, NH), 5.98 (s, 2H, NH2), 2.88 (t, 2H, 5Hz, CH2), 0.81- 0.74 (m, lH, CH), 029-0.25 (m, 2H, CH2), 0.22-0.17 (m, 2H, CH2); MS (E5+, [M+H]+) m/z: 243 & 245 (M+1), 284 & 286 (M+ CH3CN); HPLC 98%.
Typical example of compound of formula (B), as described in the general reaction scheme; N3-(3-methoxyphenyl)-5-bromo-2, 3-pyrazine diamine (5) N - NH2 Br^N NH A mixture of 2-amino-3, 5-dibromopyrazine (4 mmol, leq.), 4methoxyaniline (4.4 mmol, 1.1 eq.) and K2CO3 (4.4 mmol, 1.1 eq.) in DMF (lml) was placed in the Smith Creator and heated with stirring for 30 mins at 160 C. The contents of the tubes (highly viscous black semi-solid) were dissolved in ethyl acetate and combined. The mixture was then filtered À À À À À À À À À . . À À À À À À À - 115 through a short pad of silica and the filtrate was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water and brine. The ethyl acetate was removed under reduced pressure and the crude organic residue was further purified by a silica column chromatography using ethyl acetate/ hexane (1:3 and then 1:1).
After the evaporation of the fractions that contained the product, the residue was crystallized by triturating in hexane/ 20% DCM. The solid was filtered, washed with hexane/ 20% DCM and dried to give the title product as a brown solid (4.379, 19% ); 1HNMR (250MHz, CDCI3) oppm: 8.52 (s,lH, NH), 7.58 (d, 2H, 9Hz, ArH), 7.36 (s, 1H, PyraH), 6.90 (d, 2H, 9Hz, ArH), 6.56 (s, 2H, NH2), 3.69(s, 3H,CH3); MS (ES+, [M+H]+) m/z: 295 &297 (M+1); HPLC 89 %.
General procedure for the synthesis of compounds of formula (C) The Suzuki reactions were carried out in STEM tubes using a 96 position heater shaker unit.
To a solution of the required intermediates (B) in degassed DMF (0.3mmol, 1 eq., 0.5ml) was added a solution of boronic acid (Box 2) in DMF (0.36mmol, 1.2 eq., 0.6ml) and 1.5M Na2CO3 (degassed aq.) solution (0.75mmol, 2.5 eq., 0.5ml). A solution of palladium (II) acetate (0.015 mmol, 0.05 eq., 168mg) and triphenylphosphine (0.045 mmol, 0.15 eq., 588mg) in degassed 1,4-dioxane (15ml) was freshly prepared and placed in a sonication bath for 2min. The palladium catalyst (0.3ml, yellow suspension) was then added to the reaction vessel under a nitrogen atmosphere and the contents were heated at 80 C with agitation for 16h.
The reaction mixtures were filtered and purified by preparative reverse phase HPLC.
Typical example of compound of formula (C), as described in the general reaction scheme; N3-(4-pyridylmethyl)-5-(3-thienyl)-2, 3-pyrazine diamine (6).
À a e.e À , À À À À À À Àe. es - 116 Yield (4.5 mg, 5%); 1HNMR (250MHz, DMSOd6): bppm, 8.32 (d, 2H, 5Hz, PyrH), 7.50 (s, 1H, PyraH), 7.44 (s, 1H, ThiopH), 7.35-7.30 (m, 2H, ThiopH), 7.26 (d, 2H, 5Hz, PyrH), 6.82 (t, 1H, 5Hz, NH), 5.98 (brs, 2H, NH2), 4.47 (d, 2H, 5Hz, CH2); MS (ES+, [M+H]+) m/z: 284 (M+1); HPLC 99.60%.
Typical example of compound of formula (C), as described in the general reaction scheme; N3-(lH-S-indolyl-5-(3-biphenyl)-Z, 3-pyrazine diamine (7) . N1NH
Yield (3.1 mg, 3%); 1HNMR (250MHz, DMSOd6): bppm, 11.20 (brs, 1H, IndH), 8.42 (d, 1H, 9Hz, IndH), 8.30 (s, 1H, IndH), 8.20 (s, 1H, PyraH), 8.05 (d, 1H, 5Hz, ArH), 7.81-7.42 (m, 11H, ArH/IndH), 6.66 (s, 2H, NH2), 6.53 (brs, 1H, NH); MS (ES+, [M+H]+) m/z: 378 (M+1); HPLC 81%. À *
. e.
À À À Àe. ee * - 117 Typical example of compound of formula (C), as described in the general reaction scheme;2-[5-amino-6-(cyclohexylamine)-2pyrazinyl]-3 furaldebyde (8).
H4O N - <NH2 (8) Yield (4.8 mg, 5.50%);1HNMR (250MHz, DMSO66): dppm, 10.3 (s, 1H, CHO), 7.75 (s, 1H, PyraH), 7.67 (d, 1H, 2.5Hz, FurH), 6.78 (d, 1H, J 2.5Hz, FurH), 6.72 (s, 2H, NH2), 6.35 (d, 1H, 5Hz, NH), 3.67-3.55 (m, 1H, NCH), 2.06-1.89 (m, 2H, CH2), 1.77-1.61 (m, 3H, CH2), 1.47-1.15 (m, 5H, CH2x2 & CH); MS (ES+, [M+H]+) m/z: 287 (M+1); HPLC 100%.
Typical example of compound of formula (C), as described in the general reaction scheme; N3-(3-methoxypropyl)-5-(4-morpholinophenyl)-2, 3pyrazine diamine (9). NNH2 1 Cf '^
oJ (g' o Yield (4.4 mg, 4.27%); 1HNMR (250MHz, DMSO06): dppm, 7.74 (d, 2H, 7.5Hz, ArH), 7.62 (s, 1H, PyraH), 6.95 (d, 2H, 7.5Hz, ArH), 6.17 (t, 1H, 5Hz, NH), 5.93 (s, 2H, NH2), 3.71-3.75 (m, 4H, CH2), 3.47-3.38 (m, 4H, À c À ret es À - 118 NCH2)l 3.29 (s, 3H/ OCH3)l 3.12-3.08 (ml 4H/ CH2)l 1. 85-1.77 (m, 2H CH2); MS (ES+l [M+H]+) m/z: 344 (M+1); HPLC 100%.
General procedure for the synthesis of compounds of formula (I) To a solution of the required intermediates (C) (71.2 mgl 0.196 mmol) in anhydrous 1l4-dioxane (lml) was added a solution of 1l1'carbonyidiimidazole (2.5eq.) in anhydrous 1l4-dioxane (0.5ml). The reactions were heated at 65 c, overnight after which they were transferred into a 48 well plate and purified by preparative reverse phase HPLC.
Typical example of compound of formula (I), as described in the general reaction scheme; 1-[3-hydroxy-2, 2-dimethylpropyl)-6-(3, 4, 5trimethoxyphenyl)-2, 3-dibydro-lH-imidazo[4, 5-b]pyrazin-2-one (10).
N H
1 1 ' (1 o) Yield (2 mgl 2.6%); IHNMR (250MHzl DMSOd6): bppm/ 12 10 (sl 1Hl NH)l 8.55 (sl 1Hl PyraH)l 7.34 (sl ZHl ArH)l 4.72 (brsl 1Hl OH)l 3.85 (sl 6H, OMex2), 3.74 (s, 2H, CH2O), 3.68 (s, 3H, OMe), 3.23 (s, 2H, NCH2), 0.91 (s, 6H, CH3x2); MS (ES+, [M+H]+) m/z: 389 (M+1); HPLC 100%.
* Typical example of compound of formula (I), as described in the general reaction scheme; 6-(1, 3-benzodioxol-5-yl)-1-[(1R)--phenylethyl])-2,3dibydro-1H-imidazo [4, 5-b]pyrazin-2-one (11).
À Àe e À À À À . . À À À ^ À À - 119 0""'4 1 Wo (11) Yield (4.4 mg, 3%); 1HNMR (250MHz, DMSOd6): hppm, 8.17 (s, 1H, PyraH), 7.30-7.22 (m, 4H, ArH), 7.13-7.01(m, 3H, ArH), 6.77 (d, 1H, 7.5Hz, ArH), 5.87 (s, 2H, OCH2), 5.47 (q, 1H, 7.5Hz, CH), 1.74 (d, 3H, CH3); MS (ES+, [M+H]+) m/z: 361 (M+1), 402 (M++ CH3CN); HPLC 100%.
Typical example of compound of formula (I), as described in the general reaction scheme; 3-[2-oxo-3-(4-pyridylmethyl)-2, 3-dibydro-l H- imidazo[4, 5-b]pyrazin-5-yl]benz-amide (12).
H2N Jó N'XN:= (12) N Yield (5.6 mg, 26.70%); 1HNMR (250MHz, DMSOd6): bppm, 8.85 (s, 1H, PyraH), 8.52 (d, 2H, 5Hz, PyrH), 8.44 (s, 1H, ArH), 8.08 (brs, 2H, NH2), 7.86 (d, 1H, 7.5Hz, ArH), 7.55-7.46 (m, 2H, ArH), 7.35 (d, 2H, 5Hz, PyrH), 5.11 (s, 2H, CH2); MS (ES+, [M+H]+) m/z: 347 (M+1); HPLC 100%.
Typical example of compound of formula (I), as described in the general reaction scheme; 1-[2-(dimethylamino)ethyl]-6-(3, 4, 5trimethoxyphenyl)-2, 3-dibydro-1H-imidazo [4, 5-b]pyrazin-2-one (73).
À eve À e À * À À À À * À À À - 120 of (13) / Yield (4.6 mg, 11.57%); 1HNMR (250MHz, DMSOd6): bppm, 12.10 (brs, 1H, NH), 8.55 (s, lH, PyraH), 7.31 (s, 2H, ArH), 3.97 (t, 2H, 7.5Hz, CH2), 3.84 (s, 6H, 2 x OCH3) 3.68 (s, 3H, OCH3), 2.60 ((t, 2H, 7.5Hz, CH2), 2.19 (s, 6H, N(CH3)2); MS (ES+, [M+H]+) m/z: 374 (M+1); HPLC 100%.
Purification Conditions All compounds have a minimum purity level 2 80% as measured by LCMS at 254 nm.
The columns used for the preparative HPLC purification of the various scaffolds are outlined in Table 1:
Table 1
Scaffold Column
_
| All compounds Varian Polaris lOIlm C18-A 150 x 21.2mm The gradient used for the preparative HPLC purification of all compounds was 95% water (lOmmol NH3HCO3) 5% acetonitrile for 1 min to 5% water (lOmmol NH3HCO3) / 95% acetonitrile over 8.0 min then held at 5% water (iOmmol NH3HCO3) / 95% acetonitrile for 2.0 min. The solvent mixture was then returned to the initial conditions over 0.5 min. A flow rate of 25 ml/min was used.
c À À c À . . . c c.
À c c À À * a c À C C C C À C C À À C À C tea À c - 121 The conditions used for the analytical HPLC analysis following preparative HPLC purification are outlined in Table 2:
Table 2
Conditions | Detection Column: Waters XterraO Prep MS C18 Sum UV detection at 254 rim 4.6 x 100mm. (diode array range 210 280nm).
Gradient: 95% water (10 me NH3HCO3) / 5% ACN for 0.5 min then 95% water (10 mM Electrospray NH3HCO3) / 5% ACN to 2% water (10 mM ionization: NH3HCO3) / 98% ACN over 3.5 min. Held at 2% water (10 mM NH3HCO3) / 98% ACN for Cone voltage: 30 V. 0.5 min. The solvent mixture is then returned Cone temperature: 20 to the initial conditions over 0.1 min and the C.
system allowed to re-equilibrate for 0.2 min. Source temperature 150 C.
Flow rate: 2.0 ml/mint RF lens voltage: 0.0 V. Temperature: 30 C. Ion energy: 0.5 eV.
Injection volume: 5 urn Partial IOOD. MultiDlier: 650 V. 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 of the invention. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents.

Claims (24)

À À À. e À À À À À À À À À - 122 CLAIMS
1. A family of libraries of compounds for high throughput investigation of a predetermined kinase enzyme wherein the family includes the libraries SFKO9, SFK10, SFK11, SFK14 and SFK20.
2. A method for making a family of libraries according to claim 1, which method is according to the schemes defined herein.
3. A library comprising or consisting of a set of structurally related compounds having a core chemical structure (scaffold) of a general formula selected from the group consisting of: i) Formula I and/or formula II and/or formula III of library SFKO9; ii) Formula I and/or formula II and/or formula III of library SFK10; iii) Formula I and/or formula II and/or formula III of library SFKll; iv) Formula I and/or formula II of library SFK14; and v) Formula I of library SFK20.
4. A library according to claim 3 which comprises or consists of a structurally related set of compounds, said library being selected form the group of libraries which consists of: i) library SFKO9; ii) library SFK10; iii) library SFK11; iv) library SFK14; and v) library SFK20.
5. A library according to claim 3 or 4 which comprises compounds having a core chemical structure and permitted substituents thereon, and said library has all or substantially all of the permitted substitutions represented by compounds therein.
À e cc.
À À À . À À À À À . . À À À - 123
6. A library according to any one of claims 3 to 5 which comprises compounds having a core chemical structure and permitted substituents thereon, and said library has about 100, about 1000, about 2000, about 3000 or about 10000 compounds represented therein.
7. A method for making a compound library according to any one of claims 3 to 6, which method is according to any of the schemes for making a core chemical structure (scaffold) of a library selected form the group of libraries which consists of: i) library SFKO9; ii) library SFK10; iii) library SFKll; iv) library SFK14; and v) library SFK20.
8. A compound having a core chemical structure (scaffold) of SFKO9 which is selected from: i)PS40 IN - <NOR, excluding the following compounds: À À À C À 8 8 8 8 À À , 8 À À À À À À À 81 À , - 124 óN:NHMe Pb N OtEt Ph N OoBu Ph N OtEtu Otto N N N N >ON H of oJ[: IN > ON EN H2N '1 Jut;4OMe IN N: INNING FiOMe H:; N: No iN Phi N: ii) PS81
R Art. for
iii) PSt72 À . À À À À À À À . À . . e. . . . À . À À À À -
IR
IN - <NR,
9. A compound according to claim 8 which is selected from the compounds represented within the library SFKO9.
10. A compound having a core chemical structure (scaffold) of SFK10 which is:
N
11. A compound according to claim 10 which is selected from the compounds represented within the library SFK10.
12. A compound having a core chemical structure (scaffold) of SFK11 which is:
N - N
NIXON;
N
SFK11 Core Scaffold
13. A compound according to claim 12 which is selected from the compounds represented within the library SFKll. À
À 8 ' À À À 8 8 À À À À À À 8 À'.
À À À À À À À - 126
14. A compound having a core chemical structure (scaffold) of SFK14 which is selected from: i) PS173 NNH2 excluding: H2N N P owe Ph H2N 1 OH Me N:ó NH2 NH2 NH2 oMe H2N ON OH H2N H240H M. N_Nit OH ó1 OMe [ó NH2 Phi ='OMe O N - OH NH2 :3NH2 NH2 NH2 Of - t ó0 \5 m0R MeNH 2 Menboned In literature and À À À . À À . . . À À À . À À À À- .. À À 127 Ph
POOH NH2 or
ii) PS174
15. A compound according to claim 14 which is selected from the compounds represented within the library SFK14.
16. A compound having a core chemical structure (scaffold) of SFK20 which is: lo -
17. A compound according to claim 16 which is selected from the compounds represented within the library SFK20.
18. A method of making a compound according to any one of claims 8 to 17, which method is according to any of the schemes defined herein for making compounds of a library selected form the group of libraries which consists of: i: À t À À À ' e e 7 t t - 128 i) library SFKO9; ii) library SFK10; iii) library SFKll; iv) library SFK14; and v) library SFK20.
19. An assay comprising a family of libraries according to claim 1, a library according to any one of claims 3 to 6, or one or more compounds according to any of claims 8 to 17.
20. Use of an assay according to claim 19 for identifying a compound which has therapeutic affect or importation of a compound identified using an assay according to claim 19.
21. A pharmaceutical composition which comprises a compound having a core chemical structure (scaffold) of a library selected from the group of libraries which consists of: i) library SFKO9; ii) library SFK10; iii) library SFKll; iv) library SFK14; and v) library SFK20; or a compound according to any one of claims 8 to 17; or a compound identified in an assay according to claim 19.
22. A compound having a core chemical structure (scaffold) of a library selected from the group of libraries which consists of: i) library SFKO9; ii) library SFK10; iii) library SFKll; iv) library SFK14; and v) library SFK20 r t e'se t C À C t et t t e e tre e e r c ee sea e ee.
e tt e e c see At e c - 129 or a compound according to any one of claims 8 to 17 for use in therapy.
23. Use of a compound having a core chemical structure (scaffold) of a library selected from the group of libraries which consists of: i) library SFKO9; ii) library SFK10; iii) library SFKll; iv) library SFK14; and v) library SFK20 or a compound according to any one of claims 8 to 17 in the manufacture of a medicament for treatment or prophylaxis of a condition characterized by abnormal kinase activity.
24. Use of a compound having a core chemical structure (scaffold) of a library selected form the group of libraries which consists of: i) library SFKO9; ii) library SFK10; iii) library SFKll; iv) library SFK14; and v) library SFK20 or a compound according to any one of claims 8 to 17 in the manufacture of a medicament for treatment or prophylaxis of a condition selected from cancer, a tumour, metastases, inflammation or diabetes.
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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006036883A3 (en) * 2004-09-24 2006-06-22 Janssen Pharmaceutica Nv Imidazo{4,5-b}pyrazinone inhibitors of protein kinases
WO2006067466A2 (en) * 2004-12-22 2006-06-29 The Wellcome Trust Limited Pyrazines and pyridines and derivatives thereof as therapeutic compounds
WO2008016669A3 (en) * 2006-08-02 2008-12-11 Cytokinetics Inc Certain chemical entities, compositions and methods
WO2009095399A3 (en) * 2008-02-01 2009-10-01 Akinion Pharmaceuticals Ab Pyrazine derivatives and their use as protein kinase inhbitors
JP2010506934A (en) * 2006-10-19 2010-03-04 シグナル ファーマシューティカルズ，エルエルシー Heteroaryl compounds, compositions thereof, and their use as protein kinase inhibitors
US7851484B2 (en) 2007-03-30 2010-12-14 Cytokinetics, Inc. Certain chemical entities, compositions, and methods
AU2005322338B2 (en) * 2004-12-27 2011-06-09 Alcon, Inc. Aminopyrazine analogs for treating glaucoma and other rho kinase-mediated diseases
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US8227603B2 (en) 2006-08-01 2012-07-24 Cytokinetics, Inc. Modulating skeletal muscle
CN101522681B (en) * 2006-08-02 2012-10-03 赛特凯恩蒂克公司 Certain chemical entities, compositions and methods
US8299248B2 (en) 2006-08-02 2012-10-30 Cytokinetics, Incorporated Certain 1H-imidazo[4,5-b]pyrazin-2(3H)-ones and 1H-imidazo[4,5-b]pyrazin-2-ols and methods for their use
JP2013526609A (en) * 2010-05-24 2013-06-24 ユニヴァーシティー オブ ロチェスター Bicyclic heteroaryl kinase inhibitors and methods of use
US8546404B2 (en) 2005-12-13 2013-10-01 Merck Sharp & Dohme Compounds that are ERK inhibitors
US8716483B2 (en) 2008-02-21 2014-05-06 Merck Sharp & Dohme Corp. Compounds that are ERK inhibitors
US10272082B2 (en) 2011-07-13 2019-04-30 Cytokinetics, Inc. Combination ALS therapy
US10485800B2 (en) 2012-11-30 2019-11-26 The University Of Rochester Mixed lineage kinase inhibitors for HIV/AIDS therapies

Families Citing this family (85)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002953255A0 (en) * 2002-12-11 2003-01-02 Cytopia Research Pty Ltd Protein kinase inhibitors
JP2007516196A (en) * 2003-07-02 2007-06-21 ガラパゴス エヌブイ Pyrazine and pyralidine derivatives as Rho kinase inhibitors
WO2005033105A2 (en) * 2003-09-30 2005-04-14 Amgen Inc. Vanilloid receptor ligands and their use in treatments
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DK1689715T3 (en) 2003-12-03 2011-05-23 Ym Biosciences Australia Pty tubulin inhibitors
WO2005058876A1 (en) * 2003-12-16 2005-06-30 Gpc Biotech Ag Pyrazine derivatives as effective compounds against infectious diseases
AU2005209257A1 (en) * 2004-01-23 2005-08-11 Amgen Inc. Vanilloid receptor ligands and their use in treatments
WO2005121126A1 (en) * 2004-04-13 2005-12-22 Icagen, Inc. Polycyclic pyrazines as potassium ion channel modulators
US20090131445A1 (en) * 2004-10-14 2009-05-21 Compass Pharmaceuticals Llc Furazano '3, 4-B! Pyrazines and Their Use as Anti-Tumor Agents
WO2007076360A1 (en) 2005-12-22 2007-07-05 Alcon Research, Ltd. (indazol-5-yl)-pyrazines and (1,3-dihydro-indol-2-one)- pyrazines for treating rho kinase-mediated diseases and conditions
GB0500226D0 (en) * 2005-01-07 2005-02-16 Biofocus Discovery Ltd Compounds which bind to the active site of protein kinase enzymes
US7799778B1 (en) 2005-01-12 2010-09-21 Alcon, Inc. 5-substituted 2-aminopyridine analogs for treating allergic and inflammatory diseases
US7713975B1 (en) 2005-01-12 2010-05-11 Alcon, Inc. 3,6-substituted imidazol[1,2-b]pyridazine analogs for treating allergic and inflammatory diseases
US7867999B1 (en) 2005-12-22 2011-01-11 Alcon Research, Ltd. Hydroxyamino- and amino-substituted pyridine analogs for treating rho kinase-mediated diseases and conditions
AR064420A1 (en) 2006-12-21 2009-04-01 Alcon Mfg Ltd OPHTHALMIC PHARMACEUTICAL COMPOSITIONS THAT INCLUDE AN EFFECTIVE AMOUNT OF ANALOGS OF 6-AMINOIMIDAZO [1,2B] PIRIDAZINAS, USEFUL FOR THE TREATMENT OF GLAUCOMA AND / OR CONTROL THE NORMAL OR ELEVATED INTRAOCULAR PRESSURE (IOP).
US8263585B2 (en) 2007-05-04 2012-09-11 Novartis Ag Organic compounds
EA019509B1 (en) 2007-11-16 2014-04-30 Райджел Фармасьютикалз, Инк. Carboxamide, sulfonamide and amine compounds for metabolic disorders
EP2231666B1 (en) 2007-12-12 2015-07-29 Rigel Pharmaceuticals, Inc. Carboxamide, sulfonamide and amine compounds for metabolic disorders
US8268834B2 (en) 2008-03-19 2012-09-18 Novartis Ag Pyrazine derivatives that inhibit phosphatidylinositol 3-kinase enzyme
BRPI0911681B8 (en) 2008-04-23 2021-05-25 Rigel Pharmaceuticals Inc compound, pharmaceutical composition, and, method of activating the 5'-amp activated protein kinase pathway in a cell in vitro
US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
HUE035029T2 (en) 2008-05-21 2018-03-28 Ariad Pharma Inc Phosphorous derivatives as kinase inhibitors
US8110578B2 (en) 2008-10-27 2012-02-07 Signal Pharmaceuticals, Llc Pyrazino[2,3-b]pyrazine mTOR kinase inhibitors for oncology indications and diseases associated with the mTOR/PI3K/Akt pathway
RU2011123647A (en) 2008-11-10 2012-12-20 Вертекс Фармасьютикалз Инкорпорейтед COMPOUNDS USEFUL AS ATR KINASE INHIBITORS
CN106496210B (en) 2008-12-19 2020-06-09 沃泰克斯药物股份有限公司 Compounds useful as inhibitors of ATR kinase
NZ599549A (en) 2009-10-26 2013-11-29 Signal Pharm Llc Methods of synthesis and purification of heteroaryl compounds
EP2343294A1 (en) 2009-11-30 2011-07-13 Bayer Schering Pharma AG Substituted triazolopyridines
WO2011143419A1 (en) 2010-05-12 2011-11-17 Vertex Pharmaceuticals Incorporated Pyrazines useful as inhibitors of atr kinase
AU2011253025A1 (en) 2010-05-12 2012-11-29 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
EP2568984A1 (en) 2010-05-12 2013-03-20 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
EP2569286B1 (en) 2010-05-12 2014-08-20 Vertex Pharmaceuticals Inc. Compounds useful as inhibitors of atr kinase
WO2011143425A2 (en) 2010-05-12 2011-11-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
WO2011143422A1 (en) 2010-05-12 2011-11-17 Vertex Pharmaceuticals Incorporated 2 -aminopyridine derivatives useful as inhibitors of atr kinase
US8623869B2 (en) 2010-06-23 2014-01-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US20130165426A1 (en) * 2010-07-06 2013-06-27 Université de Montréal Imidazopyridine, imidazopyrimidine and imidazopyrazine derivatives as melanocortin-4 receptor modulators
WO2012100342A1 (en) 2011-01-27 2012-08-02 Université de Montréal Pyrazolopyridine and pyrazolopyrimidine derivatives as melanocortin-4 receptor modulators
KR20140027974A (en) 2011-04-05 2014-03-07 버텍스 파마슈티칼스 인코포레이티드 Aminopyrazine compounds useful as inhibitors of tra kinase
CN103501612B (en) 2011-05-04 2017-03-29 阿里亚德医药股份有限公司 The compound that cell is bred in cancer caused by suppression EGF-R ELISA
US9096602B2 (en) 2011-06-22 2015-08-04 Vertex Pharmaceuticals Incorporated Substituted pyrrolo[2,3-B]pyrazines as ATR kinase inhibitors
US8822469B2 (en) 2011-06-22 2014-09-02 Vertex Pharmaceuticals Incorporated Pyrrolo[2,3-B]pyrazines useful as inhibitors of ATR kinase
WO2012178125A1 (en) 2011-06-22 2012-12-27 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
EP2751088B1 (en) 2011-09-30 2016-04-13 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
RU2677292C2 (en) 2011-09-30 2019-01-16 Вертекс Фармасьютикалз Инкорпорейтед Processes for making compounds useful as inhibitors of atr kinase
US8853217B2 (en) 2011-09-30 2014-10-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
MX2014003796A (en) 2011-09-30 2015-01-16 Vertex Pharma Compounds useful as inhibitors of atr kinase.
CA2850491C (en) 2011-09-30 2020-10-27 Vertex Pharmaceuticals Incorporated Treating pancreatic cancer and non-small cell lung cancer with atr inhibiors
EP2768500B1 (en) 2011-10-19 2019-08-21 Signal Pharmaceuticals, LLC Treatment of cancer with tor kinase inhibitors
EP2776422A1 (en) 2011-11-09 2014-09-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
WO2013071093A1 (en) 2011-11-09 2013-05-16 Vertex Pharmaceuticals Incorporated Pyrazine compounds useful as inhibitors of atr kinase
WO2013071088A1 (en) 2011-11-09 2013-05-16 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
US8841449B2 (en) 2011-11-09 2014-09-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
EP2776429A1 (en) 2011-11-09 2014-09-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
CA2857155C (en) 2011-12-02 2021-09-21 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1h)-one, a solid form thereof and methods of their use
EA028462B1 (en) 2012-02-24 2017-11-30 СИГНАЛ ФАРМАСЬЮТИКАЛЗ, ЭлЭлСи Methods for treating advanced non-small cell lung cancer using tor kinase inhibitor combination therapy
WO2013152298A1 (en) 2012-04-05 2013-10-10 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase and combination therapies thereof
AU2013204563B2 (en) 2012-05-05 2016-05-19 Takeda Pharmaceutical Company Limited Compounds for inhibiting cell proliferation in EGFR-driven cancers
DK2904406T3 (en) 2012-10-04 2018-06-18 Vertex Pharma METHOD OF DETERMINING THE ATR INHIBITION, INCREASED DNA DAMAGE
WO2014062604A1 (en) 2012-10-16 2014-04-24 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
AU2013203714B2 (en) 2012-10-18 2015-12-03 Signal Pharmaceuticals, Llc Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity
NZ731337A (en) 2012-12-07 2019-02-22 Vertex Pharma Compounds useful as inhibitors of atr kinase
AR094494A1 (en) 2013-01-16 2015-08-05 Signal Pharm Llc REPLACED PIRROLOPIRIMIDINS, THEIR COMPOSITIONS, AND THEIR TREATMENT METHODS
JP2016512815A (en) 2013-03-15 2016-05-09 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ Condensed pyrazolopyrimidine derivatives useful as inhibitors of ATR kinase
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
SG10201708111YA (en) 2013-04-17 2017-11-29 Signal Pharm Llc Combination therapy comprising a dihydropyrazino-pyrazine compound and an androgen receptor antagonist for treating prostate cancer
NZ629332A (en) 2013-04-17 2017-05-26 Signal Pharm Llc Treatment of cancer with dihydropyrazino-pyrazines
EP2986319A1 (en) 2013-04-17 2016-02-24 Signal Pharmaceuticals, LLC Combination therapy comprising a tor kinase inhibitor and n-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide for treating cancer
CA2909625C (en) 2013-04-17 2021-06-01 Signal Pharmaceuticals, Llc Combination therapy comprising a tor kinase inhibitor and a 5-substituted quinazolinone compound for treating cancer
WO2014172426A1 (en) 2013-04-17 2014-10-23 Signal Pharmaceuticals, Llc Treatment of cancer with dihydropyrazino-pyrazines
NZ631082A (en) 2013-04-17 2017-06-30 Signal Pharm Llc Methods for treating cancer using tor kinase inhibitor combination therapy
US9359364B2 (en) 2013-04-17 2016-06-07 Signal Pharmaceuticals, Llc Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b] pyrazin-2(1H)-one
CA2912627C (en) 2013-05-29 2022-03-15 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one, a solid form thereof and methods of their use
EP2818471A1 (en) * 2013-06-27 2014-12-31 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Nitrogen bicyclic compounds as inhibitors for Scyl1 and Grk5
PL3077397T3 (en) 2013-12-06 2020-04-30 Vertex Pharmaceuticals Inc. 2-amino-6-fluoro-n-[5-fluoro-pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, its preparation, different solid forms and radiolabelled derivatives thereof
JP2017514806A (en) 2014-04-16 2017-06-08 シグナル ファーマシューティカルズ，エルエルシー Methods of treating cancer using TOR kinase inhibitor combination therapy
WO2015160882A1 (en) 2014-04-16 2015-10-22 Signal Pharmaceuticals, Llc SOLID FORMS COMPRISING 7-(6-(2-HYDROXYPROPAN-2YL) PYRIDIN-3-YL)-1-(TRANS)-4-METHOXYCYCLOHEXYL)-3, 4-DIHYDROPYRAZINO[2,3-b] PYRAZIN-2(1H)-ONE, AND A COFORMER, COMPOSITIONS AND METHODS OF USE THEREOF
NZ714742A (en) 2014-04-16 2017-04-28 Signal Pharm Llc Solid forms of 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one, compositions thereof and methods of their use
WO2015160880A1 (en) 2014-04-16 2015-10-22 Signal Pharmaceuticals, Llc SOLID FORMS COMPRISING 1-ETHYL-7-(2-METHYL-6-(1H-1,2,4-TRIAZOL-3-YL) PYRIDIN-3-YL)-3,4-DIHYDROPYRAZINO(2,3-b)PYRAZIN-2(1H)-ONE, AND A COFORMER, COMPOSITIONS AND METHODS OF USE THEREOF
SI3152212T1 (en) 2014-06-05 2020-06-30 Vertex Pharmaceuticals Inc. Radiolabelled derivatives of a 2-amino-6-fluoro-n-(5-fluoro-pyridin-3-yl)- pyrazolo(1,5-a)pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, the preparation of said compound and different solid forms thereof
RS59054B1 (en) 2014-06-17 2019-08-30 Vertex Pharma Method for treating cancer using a combination of chk1 and atr inhibitors
NZ629796A (en) 2014-07-14 2015-12-24 Signal Pharm Llc Amorphous form of 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7h-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-n-methylbenzamide, compositions thereof and methods of their use
JP2017520603A (en) 2014-07-14 2017-07-27 シグナル ファーマシューティカルズ，エルエルシー Method for treating cancer using substituted pyrrolopyrimidine compound and composition thereof
AU2016331955B2 (en) 2015-09-30 2022-07-21 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of DNA damaging agents and ATR inhibitors
KR20210019607A (en) 2016-06-07 2021-02-22 자코바이오 파마슈티칼스 컴퍼니 리미티드 Novel heterocyclic derivatives useful as shp2 inhibitors
CA3057582C (en) 2017-03-23 2024-01-09 Jacobio Pharmaceuticals Co., Ltd. Novel heterocyclic derivatives useful as shp2 inhibitors
BR112019027402A2 (en) 2017-06-22 2020-07-07 Celgene Corporation treatment of hepatocellular carcinoma characterized by infection with the hepatitis b virus

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0254259A2 (en) * 1986-07-21 1988-01-27 Otsuka Pharmaceutical Factory, Inc. p-Aminophenol derivatives
WO1990014338A1 (en) * 1989-05-20 1990-11-29 Fisons Plc Anti-inflammatory 4-aminophenol derivatives
WO2000023444A1 (en) * 1998-10-21 2000-04-27 Abbott Laboratories 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds
WO2000055139A2 (en) * 1999-03-12 2000-09-21 Boehringer Ingelheim Pharmaceuticals, Inc. Heterocyclic urea and related compounds useful as anti-inflammatory agents
WO2001023887A1 (en) * 1999-09-29 2001-04-05 Lion Bioscience Ag 2-aminopyridine derivatives and combinatorial libraries thereof
WO2002024681A2 (en) * 2000-09-20 2002-03-28 Ortho-Mcneil Pharmaceutical, Inc. Pyrazine derivatives as modulators of tyrosine kinases
WO2003051366A2 (en) * 2001-12-13 2003-06-26 Abbott Laboratories 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer
WO2003068223A1 (en) * 2002-02-11 2003-08-21 Bayer Corporation Aryl ureas with raf kinase and angiogenesis inhibiting activity
WO2004002963A1 (en) * 2002-06-28 2004-01-08 Nippon Shinyaku Co., Ltd. Amide derivative

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3929700B2 (en) * 1998-01-28 2007-06-13 塩野義製薬株式会社 New tricyclic compounds
PL355639A1 (en) * 1999-09-10 2004-05-04 Merck & Co, Inc. Tyrosine kinase inhibitors
UA76977C2 (en) * 2001-03-02 2006-10-16 Icos Corp Aryl- and heteroaryl substituted chk1 inhibitors and their use as radiosensitizers and chemosensitizers
GB0119472D0 (en) * 2001-08-09 2001-10-03 Astrazeneca Ab Compounds
US20040167182A1 (en) * 2002-06-25 2004-08-26 Becker Daniel P. Hydroxamic acid and amide compounds and their use as protease inhibitors

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0254259A2 (en) * 1986-07-21 1988-01-27 Otsuka Pharmaceutical Factory, Inc. p-Aminophenol derivatives
WO1990014338A1 (en) * 1989-05-20 1990-11-29 Fisons Plc Anti-inflammatory 4-aminophenol derivatives
WO2000023444A1 (en) * 1998-10-21 2000-04-27 Abbott Laboratories 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds
WO2000055139A2 (en) * 1999-03-12 2000-09-21 Boehringer Ingelheim Pharmaceuticals, Inc. Heterocyclic urea and related compounds useful as anti-inflammatory agents
WO2001023887A1 (en) * 1999-09-29 2001-04-05 Lion Bioscience Ag 2-aminopyridine derivatives and combinatorial libraries thereof
WO2002024681A2 (en) * 2000-09-20 2002-03-28 Ortho-Mcneil Pharmaceutical, Inc. Pyrazine derivatives as modulators of tyrosine kinases
WO2003051366A2 (en) * 2001-12-13 2003-06-26 Abbott Laboratories 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer
WO2003068223A1 (en) * 2002-02-11 2003-08-21 Bayer Corporation Aryl ureas with raf kinase and angiogenesis inhibiting activity
WO2004002963A1 (en) * 2002-06-28 2004-01-08 Nippon Shinyaku Co., Ltd. Amide derivative

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7608622B2 (en) 2004-09-24 2009-10-27 Janssen Pharmaceutica Nv Imidazo[4,5-b]pyrazinone inhibitors of protein kinases
WO2006036883A3 (en) * 2004-09-24 2006-06-22 Janssen Pharmaceutica Nv Imidazo{4,5-b}pyrazinone inhibitors of protein kinases
WO2006067466A2 (en) * 2004-12-22 2006-06-29 The Wellcome Trust Limited Pyrazines and pyridines and derivatives thereof as therapeutic compounds
WO2006067466A3 (en) * 2004-12-22 2007-07-05 Wellcome Trust Ltd Pyrazines and pyridines and derivatives thereof as therapeutic compounds
US7737152B2 (en) 2004-12-22 2010-06-15 The Wellcome Trust Limited 6-carboaryl-oxy-pyrazin-2-yl-carboaryl-amines and compositions comprising said compounds
AU2005322338B2 (en) * 2004-12-27 2011-06-09 Alcon, Inc. Aminopyrazine analogs for treating glaucoma and other rho kinase-mediated diseases
US8546404B2 (en) 2005-12-13 2013-10-01 Merck Sharp & Dohme Compounds that are ERK inhibitors
US8227603B2 (en) 2006-08-01 2012-07-24 Cytokinetics, Inc. Modulating skeletal muscle
CN101522681B (en) * 2006-08-02 2012-10-03 赛特凯恩蒂克公司 Certain chemical entities, compositions and methods
US8293761B2 (en) 2006-08-02 2012-10-23 Cytokinetics, Inc. Certain chemical entities, compositions and methods
US10766899B2 (en) 2006-08-02 2020-09-08 Cytokinetics, Incorporated Methods for preparing substituted imidazo[4,5-b]pyrazines
US7956056B2 (en) 2006-08-02 2011-06-07 Cytokinetics, Inc. Certain 1H-imidazo[4,5-B]pyrazin-2(3H)-ones and 1H-imidazo[4,5-B]pyrazin-2-ols, compositions thereof, and methods for their use
EP2995619A1 (en) * 2006-08-02 2016-03-16 Cytokinetics, Inc. Certain chemical entities, compositions and methods comprising imidazopyrimidines
KR101410453B1 (en) 2006-08-02 2014-06-27 싸이토키네틱스, 인코포레이티드 Certain chemical entities, compositions and methods
US8716291B2 (en) 2006-08-02 2014-05-06 Cytokinetics, Inc. Certain 1H-imidazo[4,5-b]pyrazin-2(3H)-ones and 1H-imidazo[4,5-b]pyrazin-2-ols and methods for their use
WO2008016669A3 (en) * 2006-08-02 2008-12-11 Cytokinetics Inc Certain chemical entities, compositions and methods
US7598248B2 (en) 2006-08-02 2009-10-06 Cytokinetics, Inc. Certain 1H-imidazo[4,5-b]pyrazin-2(3H)-ones and 1H-imidazo[4,5-b]pyrazin-2-ols, compositions thereof, and methods for their use
US8299248B2 (en) 2006-08-02 2012-10-30 Cytokinetics, Incorporated Certain 1H-imidazo[4,5-b]pyrazin-2(3H)-ones and 1H-imidazo[4,5-b]pyrazin-2-ols and methods for their use
CN102993204A (en) * 2006-08-02 2013-03-27 赛特凯恩蒂克公司 Certain chemical entities, compositions and methods
EP2583970A1 (en) * 2006-08-02 2013-04-24 Cytokinetics, Inc. Certain chemical entities, compositions and methods comprising imidazopyrimidines
EA017925B1 (en) * 2006-08-02 2013-04-30 Цитокинетикс, Инкорпорэйтед 1H-IMIDAZO[4,5-b]PYRAZIN DERIVATIVES
JP2010506934A (en) * 2006-10-19 2010-03-04 シグナル ファーマシューティカルズ，エルエルシー Heteroaryl compounds, compositions thereof, and their use as protein kinase inhibitors
US7851484B2 (en) 2007-03-30 2010-12-14 Cytokinetics, Inc. Certain chemical entities, compositions, and methods
EP2671876A3 (en) * 2008-02-01 2014-02-05 Akinion Pharmaceuticals AB Pyrazine derivatives and their use as protein kinase inhbitors
CN101970418B (en) * 2008-02-01 2013-07-03 阿基宁医药品公司 Pyrazine derivative and its uses as protein kinase inhibitor
US8436171B2 (en) 2008-02-01 2013-05-07 Akinion Pharmaceuticals Ab Amino substituted pyrazines as inhibitors or protein kinases
JP2014148522A (en) * 2008-02-01 2014-08-21 Akinion Pharmaceuticals Ab Novel compounds, and use and preparation thereof
WO2009095399A3 (en) * 2008-02-01 2009-10-01 Akinion Pharmaceuticals Ab Pyrazine derivatives and their use as protein kinase inhbitors
JP2011510948A (en) * 2008-02-01 2011-04-07 アチニオン・ファーマスーティカルズ・アクチエボラーグ Novel compounds, their use and production
US8716483B2 (en) 2008-02-21 2014-05-06 Merck Sharp & Dohme Corp. Compounds that are ERK inhibitors
JP2012509903A (en) * 2008-11-25 2012-04-26 ユニバーシティー オブ ロチェスター MLK inhibitors and methods of use
JP2013526609A (en) * 2010-05-24 2013-06-24 ユニヴァーシティー オブ ロチェスター Bicyclic heteroaryl kinase inhibitors and methods of use
US10272082B2 (en) 2011-07-13 2019-04-30 Cytokinetics, Inc. Combination ALS therapy
US10485800B2 (en) 2012-11-30 2019-11-26 The University Of Rochester Mixed lineage kinase inhibitors for HIV/AIDS therapies

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