WO2016070241A1 - Composés de triazine, compositions et synthèse - Google Patents

Composés de triazine, compositions et synthèse Download PDF

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WO2016070241A1
WO2016070241A1 PCT/AU2015/050685 AU2015050685W WO2016070241A1 WO 2016070241 A1 WO2016070241 A1 WO 2016070241A1 AU 2015050685 W AU2015050685 W AU 2015050685W WO 2016070241 A1 WO2016070241 A1 WO 2016070241A1
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formula
alkyl
compound
group
trityl
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PCT/AU2015/050685
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English (en)
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Graeme Irvine Stevenson
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Ctxt Pty Ltd
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention generally relates to triazine compounds, methods for preparing triazine compounds and compositions comprising triazine compounds.
  • the present invention also relates to triazine compounds and their use as intermediates in methods for preparing target triazine compounds, which enables access to suitable triazine based anti-cancer agents.
  • Cancer is a major disease that is a leading cause of death worldwide.
  • a major aspect of the treatment of cancer is chemotherapy using anti-cancer agents.
  • chemotherapy using anti-cancer agents.
  • the treatment of cancer using chemotherapy is rarely straightforward and there is a general need to develop new and improved anti-cancer agents which act by different mechanisms and pathways.
  • a process for preparing a triazine compound of Formula 1, or a pharmaceutically acceptable salt thereof comprising the steps of: a) providing a trityl protected triazine compound of Formula 2, or a pharmaceutically acceptable salt thereof, and removing the trityl group T to form a triazine compound of Formula 1, or a pharmaceutically acceptable salt thereof:
  • each V is independently selected from the group consisting of -C ! _ 4 alkyl, -NH-, -NCd ⁇ alkyl)-, -0-, -S- and, in either orientation, -NH-C ⁇ alkyl-, -N(C 1 alkyl)-C 1 _ 4 alkyl-, -S-C ⁇ alkyl- and -O-Q ⁇ alkyl-;
  • T is an optionally substituted trityl group
  • Y is absent or selected from the group consisting of -Ci_4alkyl-,
  • R is 0-2 substituents, wherein each substituent is independently selected from the group consisting of -C 3- ecycloalkyl, -OH, -0-d_ 4 alkyl, -N(R 4 ) 2 , -C 1 _ 4 alkylN(R 4 ) 2 , -0-d-4alkyl-N(R 4 ) 2 , -d- 6 cycloalkyl-N(R 4 ) 2 , -O-phenyl, -O-benzyl, -N0 2 , halo, and -CF 3 ;
  • each R 4 is independently selected from the group consisting of H, OH, -C ! _ 4 alkyl, -C(0)Od_ 4 alkyl, -d_ 4 alkyl-OR 7 , and -C(0)R 5 , provided that if one R 4 is OH then the other R 4 cannot be OH; or -N(R 4 ) 2 forms a pyrrolidinyl, piperidinyl, piperazinyl, or morpholino group optionally substituted with d- 4alkyl;
  • K is CH and J is NH; or K is N and J is CH 2 ;
  • R is selected from the group consisting of H, Ci_ 4 alkyl, aryl, and alkylaryl; and R 9 is selected from H and d ⁇ alkyl.
  • the removal of the trityl group T comprises contacting the compound of Formula 2 with an acid or ion exchange resin.
  • the trityl group T may be substituted with 1-3 substituents independently selected from the group consisting of halo, -Ci_ 4 alkyl, and -0-Ci_ 4 alkyl.
  • the trityl group T may be selected from the group consisting of unsubstituted trityl, 2-chlorotrityl-, 4-methoxytrityl, 4,4'-dimethoxytrityl, and 4,4',4"-trimethoxytrityl, and 4-methyltrityl-.
  • the trityl group T may be selected from a trityl protecting group or a trityl resin.
  • the trityl group T is a trityl protecting group selected from unsubstituted trityl- and 2-chlorotrityl-.
  • the trityl protected triazine compound of Formula 2 is prepared by reac
  • T, Y, R, K, J, R 3 J , and R 9 are as described above according to the first aspect.
  • X and L are each independent functional groups capable of reacting together to form a linker V; wherein each V is independently selected from the group consisting of -d_ 4 alkyl, -NH-, -NCd ⁇ alkyl)-, -0-, -S- and, in either orientation, -N(Ci alkyl)-Ci_ 4 alkyl-, and -O-Ci ⁇ alkyl-.
  • the trityl protected triazine compound of Formula 2 is prepared by reacting a compound of Formula 4 with a compound of Formula A:
  • X and L are each independent functional groups capable of reacting together to form a linker V; wherein each V is independently selected from the group consisting of -C ! _ 4 alkyl, -NH-, -NCd ⁇ alkyl)-, -0-, -S- and, in either orientation, -N(Ci alkyl)-Ci_ 4 alkyl-,
  • X may be a functional group comprising a nucleophile and L may be a functional group comprising a suitable leaving group, and wherein the reaction of X and L forms the linker V.
  • X is selected from the group consisting of -NH 2 , -NH(d_ 4 alkyl), -OH, -C ⁇ alkyl-NI ⁇ , -C 1 _ 4 alkyl-NH(C 1 ⁇ alkyl), and
  • L is a halogen selected from the group consisting of chlorine, bromine and iodine.
  • a triazine compound of Formula 1, or a pharmaceutically acceptable salt thereof prepared by the process according to the first aspect or any embodiments thereof.
  • a pharmaceutical composition comprising the triazine compound of Formula 1 of the second aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a method of treating cancer comprising administering to a subject an effective amount of the pharmaceutical composition of the third aspect.
  • a process for preparing a trityl protected triazine compound of Formula 2 by reacting a compound of Formula 3 with a compound of Formula B or by reacting a compound of Formula 4 with a compound of Formula A:
  • X and L are each independent functional groups capable of reacting together to form a linker V; wherein each V is independently selected from the group consisting of -d_ 4 alkyl, -NH-, -NCd ⁇ alkyl)-, -0-, -S- and, in either orientation, -NH-C ⁇ alkyl-, -N(C 1 alkyl)-C 1 _ 4 alkyl-, -S-C ⁇ alkyl- and -O-C ⁇ alkyl-.
  • T is an optionally substituted trityl group
  • Y is absent or selected from the group consisting of
  • R is 0-2 substituents, wherein each substituent is independently selected from the group consisting of -C3_ ecycloalkyl, -OH, -0-d- 4 alkyl, -N(R 4 ) 2 , -C 1 - 4 alkylN(R 4 ) 2 , -0-C 1 ⁇ alkyl-N(R 4 ) 2 , -C 3 - 6 cycloalkyl-N(R 4 )2, -O-phenyl, -O-benzyl, -NO2, halogen, and -CF 3 ;
  • each R 4 is independently selected from the group consisting of H,
  • R 5 is selected from -Ci ⁇ alkyl and phenyl
  • R 7 is selected from -H and -Ci_4alkyl
  • K is CH and J is NH; or K is N and J is CH 2 ;
  • R is selected from the group consisting of H, Ci_4alkyl, aryl, and alkylaryl; and R 9 is selected from H and
  • a trityl protected triazine compound of Formula 2 prepared by the process according to the fifth aspect.
  • a trityl protected triazine compound selected from a compound of Formula 2 and Formula 4:
  • L is a functional group capable of reacting to form a linker V; each V is independently selected from the group consisting of -C ! _ 4 alkyl, -NH-, -NCd ⁇ alkyl)-, -0-, -S- and, in either orientation, -N(Ci alkyl)-Ci- 4 alkyl-,
  • T is an optionally substituted trityl group
  • Y is absent or selected from the group consisting of -Ci_4alkyl-,
  • R is 0-2 substituents, wherein each substituent is independently selected from the group consisting of -C3_ ecycloalkyl, -OH, -0-d_ 4 alkyl, -N(R 4 ) 2 , -C 1 _ 4 alkylN(R 4 ) 2 , -C 3 - 6 cycloalkyl-N(R 4 )2, -O-phenyl, -O-benzyl, -NO2, halogen, and -CF 3 ;
  • each R 4 is independently selected from the group consisting of - H, -OH, -C ⁇ alkyl, -C(0)OC M alkyl, -C 1 _ 4 alkyl-OR 7 , and -C(0)R 5 , provided that if one R 4 is OH then the other R 4 cannot be OH; or -N(R 4 )2 forms a pyrrolidinyl, piperidinyl, piperazinyl, or morpholino group optionally substituted with
  • R 5 is selec and phenyl
  • R 7 is selected from -H and -Ci_4alkyl
  • K is CH and J is NH; or K is N and J is CH 2 ;
  • R is selected from the group consisting of H, Ci_4alkyl, aryl, and alkylaryl; and R 9 is selected from H and
  • the compound of Formula 2 is a compound of Formula 2(b)(i):
  • composition comprising a compound of Formula 1, or a pharmaceutically acceptable salt thereof:
  • each V is independently selected from the group consisting of -Ci- 4 alkyl, -NH-, -0-, -S- and, in either orientation, -N(Ci alkyl)-Ci_ 4 alkyl-,
  • Y is absent or selected from the group consisting of -Ci_4alkyl-,
  • R is 0-2 substituents, wherein each substituent is independently selected from the group consisting of -C3_ ecycloalkyl, -OH, -0-d- 4 alkyl, -N(R 4 ) 2 , -C 1 - 4 alkylN(R 4 ) 2 , -0-C 1 ⁇ alkyl-N(R 4 ) 2 , -C 3 - 6 cycloalkyl-N(R 4 )2, -O-phenyl, -O-benzyl, -NO2, halogen, and -CF 3 ;
  • each R 4 is independently selected from the group consisting of H, OH, -d_4alkyl, -C(0)Od_4alkyl, -C ⁇ alkyl-OR 7 , and -C(0)R 5 , provided that if one R 4 is OH then the other R 4 cannot be OH; or -N(R 4 )2 forms a pyrrolidinyl, piperidinyl, piperazinyl, or morpholino group optionally substituted with Ci_ 4alkyl;
  • R 5 is selected from and phenyl
  • R 7 is selected from -H and -Ci_4alkyl
  • K is CH and J is NH; or K is N and J is CH 2 ;
  • R is selected from the group consisting of H, Ci_4alkyl, aryl, and alkylaryl; R 9 is selected from H and and wherein the compound of Formula 1, or the pharmaceutically acceptable salt thereof, is greater than about 80% by weight of the total composition.
  • the composition comprises the compound of Formula 1, or the pharmaceutically acceptable salt thereof, in greater than about 90%, greater than about 95%, or greater than about 97%, by weight of the total composition.
  • the com ound of Formula 1 is a compound of Formula 1(a) or 1(b):
  • Formula 1(a) Formula 1(b) wherein each R, V, Y and R3, may be independently selected from any of the embodiments described herein for these features.
  • a compound of Formula 1(b) is:
  • a pharmaceutical composition comprising the composition according to the eighth aspect or any embodiment thereof, and a pharmaceutically acceptable excipient.
  • a method of treating cancer comprising administering to a subject an effective amount of the pharmaceutical composition according to the ninth aspect or any embodiment thereof.
  • compositions according to the ninth aspect or any embodiment thereof for treating cancer comprising the manufacture of a medicament for treating cancer.
  • Figure 1 shows an LCMS with UV (214nm) for Example 4 and peak table showing retention time
  • Figure 2 shows an LCMS with UV (254nm) for Example 4 and peak table showing retention time
  • Figure 3 shows LCMS with UV (214nm) for Example 5 and peak table showing retention time
  • Figure 4 shows LCMS with UV (254nm) for Example 5 and peak table showing retention time.
  • the present invention is described in the following various non-limiting embodiments, which relate to investigations undertaken to identify novel and advantageous processes for preparing triazine compounds suitable for use as anticancer agents. Intermediate triazine compounds and processes for preparing those intermediate compounds were also identified.
  • an “aromatic” group means a cyclic group having 4m+2 ⁇ electrons, where m is an integer equal to or greater than 1.
  • aromatic is used interchangeably with “aryl” to refer to an aromatic group, regardless of the valency of aromatic group.
  • Aryl whether used alone, or in compound words such as arylalkyl, aryloxy or arylthio, represents: (i) an optionally substituted mono- or polycyclic aromatic carbocyclic moiety, e.g., of about 6 to about 30 carbon atoms, such as phenyl, naphthyl or fluorenyl; or, (ii) an optionally substituted partially saturated polycyclic carbocyclic aromatic ring system in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure such as a tetrahydronaphthyl, indenyl ,indanyl or fluorene ring.
  • Carbocyclic and “carbocyclyl” represent a ring system wherein the ring atoms are all carbon atoms, e.g., of about 3 to about 30 carbon atoms, and which may be aromatic, non-aromatic, saturated, or unsaturated, and may be substituted and/or carry fused rings. Examples of such groups include benzene, cyclopentyl, cyclohexyl, or fully or partially hydrogenated phenyl, naphthyl and fluorenyl.
  • Heterocyclyl or “heterocyclic” whether used alone, or in compound words such as heterocyclyloxy represents: (i) an optionally substituted cycloalkyl or cycloalkenyl group, e.g., of about 3 to about 30 ring members, which may contain one or more heteroatoms such as nitrogen, oxygen, or sulfur (examples include pyrrolidinyl, morpholino, thiomorpholino, or fully or partially hydrogenated thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, oxazinyl, thiazinyl, pyridyl and azepinyl); (ii) an optionally substituted partially saturated polycyclic ring system in which an aryl (or heteroaryl) ring and a heterocyclic group are fused together to form a cyclic structure (examples include chromanyl, dihydrobenzofuryl and indolinyl);
  • a heteroaromatic group is an aromatic group or ring containing one or more heteroatoms, such as N, O, S, Se, Si or P.
  • heteroaryl is used interchangeably with “heteroaryl”
  • a heteroaryl group refers to monovalent aromatic groups, bivalent aromatic groups and higher multi valency aromatic groups containing one or more heteroatoms.
  • Heteroaryl whether used alone, or in compound words such as heteroaryloxy represents: (i) an optionally substituted mono- or poly cyclic aromatic organic moiety, e.g., of about 5 to about 30 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen, sulfur or silicon; the heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized ⁇ electrons to provide aromatic character, provided that the rings do not contain adjacent oxygen and/or sulfur atoms.
  • Typical 6-membered heteroaryl groups are pyrazinyl, pyridazinyl, pyrazolyl, pyridyl and pyrimidinyl.
  • All regioisomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. Typical 5-membered heteroaryl rings are furyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrrolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, triazolyl, and silole. All regioisomers are contemplated, e.g., 2-thienyl and 3-thienyl.
  • Bicyclic groups typically are benzo-fused ring systems derived from the heteroaryl groups named above, e.g., benzofuryl, benzimidazolyl, benzthiazolyl, indolyl, indolizinyl, isoquinolyl, quinazolinyl, quinolyl and benzothienyl; or, (ii) an optionally substituted partially saturated polycyclic heteroaryl ring system in which a heteroaryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure such as a tetrahydroquinolyl or pyrindinyl ring.
  • fused means that a group is either fused by another ring system or unfused, and "fused” refers to one or more rings that share at least two common ring atoms with one or more other rings. Fusing may be provided by one or more carbocyclic, heterocyclic, aryl or heteroaryl rings, as defined herein, or be provided by substituents of rings being joined together to form a further ring system.
  • the fused ring may be a 5, 6 or 7 membered ring of between 5 and 10 ring atoms in size.
  • the fused ring may be fused to one or more other rings, and may for example contain 1 to 4 rings.
  • substitution means that a functional group is either substituted or unsubstituted, at any available position. Substitution can be with one or more functional groups selected from, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, formyl, alkanoyl, cycloalkanoyl, aroyl, heteroaroyl, carboxyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, heteroaryloxycarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, heteroarylaminocarbonyl, cyano, alkoxy, cycloalkoxy, aryloxy, heterocyclyloxy, heteroaryloxy, alkanoate,
  • halo or "halogen” whether employed alone or in compound words such as haloalkyl, haloalkoxy or haloalkylsulfonyl, represents fluorine, chlorine, bromine or iodine. Further, when used in compound words such as haloalkyl, haloalkoxy or haloalkylsulfonyl, the alkyl may be partially halogenated or fully substituted with halogen atoms which may be independently the same or different. Examples of haloalkyl include, without limitation, -CH2CH2F, -CF2CF 3 and -CH2CHFCI.
  • haloalkoxy examples include, without limitation, -OCHF 2 , -OCF 3 , -0CH 2 CC1 3 , -OCH 2 CF 3 and -OCH2CH2CF 3 .
  • haloalkylsulfonyl examples include, without limitation, -SO2CF 3 , - SO2CCI3, -SO2CH2CF3 and -SO2CF2CF3.
  • Alkyl whether used alone, or in compound words such as alkoxy, alkylthio, alkylamino, dialkylamino or haloalkyl, represents straight or branched chain hydrocarbons ranging in size from one to about 20 carbon atoms, or more.
  • alkyl moieties include, unless explicitly limited to smaller groups, moieties ranging in size, for example, from one to about 6 carbon atoms or greater, such as, methyl, ethyl, n- propyl, iso-propyl and/or butyl, pentyl, hexyl, and higher isomers, including, e.g., those straight or branched chain hydrocarbons ranging in size from about 6 to about 20 carbon atoms, or greater.
  • the term "Ci_ 4 alkyl” means a straight or branched chain with 1, 2, 3 or 4 carbon atoms or a range comprising any of two of those integers.
  • Alkenyl whether used alone, or in compound words such as alkenyloxy or haloalkenyl, represents straight or branched chain hydrocarbons containing at least one carbon-carbon double bond, including, unless explicitly limited to smaller groups, moieties ranging in size from two to about 6 carbon atoms or greater, such as, methylene, ethylene, 1-propenyl, 2-propenyl, and/or butenyl, pentenyl, hexenyl, and higher isomers, including, e.g., those straight or branched chain hydrocarbons ranging in size, for example, from about 6 to about 20 carbon atoms, or greater.
  • Alkynyl represents straight or branched chain hydrocarbons containing at least one carbon-carbon triple bond, including, unless explicitly limited to smaller groups, moieties ranging in size from, e.g., two to about 6 carbon atoms or greater, such as, ethynyl, 1-propynyl, 2- propynyl, and/or butynyl, pentynyl, hexynyl, and higher isomers, including, e.g., those straight or branched chain hydrocarbons ranging in size from, e.g., about 6 to about 20 carbon atoms, or greater.
  • Cycloalkyl represents a mono- or polycarbocyclic ring system of varying sizes, e.g., from about 3 to about 20 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • the term cycloalkyloxy represents the same groups linked through an oxygen atom such as cyclopentyloxy and cyclohexyloxy.
  • cycloalkylthio represents the same groups linked through a sulfur atom such as cyclopentylthio and cyclohexylthio.
  • Cycloalkenyl represents a non-aromatic mono- or polycarbocyclic ring system, e.g., of about 3 to about 20 carbon atoms containing at least one carbon-carbon double bond, e.g., cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • cycloalkenyloxy represents the same groups linked through an oxygen atom such as cyclopentenyloxy and cyclohexenyloxy.
  • cycloalkenylthio represents the same groups linked through a sulfur atom such as cyclopentenylthio and cyclohexenylthio.
  • Cycloalkynyl represents a non-aromatic mono- or polycarbocyclic ring system, e.g., of about 3 to about 20 carbon atoms containing at least one carbon-carbon double bond, e.g., cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • cycloalkenyloxy represents the same groups linked through an oxygen atom such as cyclopentenyloxy and cyclohexenyloxy.
  • cycloalkenylthio represents the same groups linked through a sulfur atom such as cyclopentenylthio and cyclohexenylthio.
  • "Formyl” represents a -CHO moiety.
  • an aroyl ranges in size from about C7-C2 0 - Examples include benzoyl and 1-naphthoyl and 2-naphthoyl.
  • an heterocycloyl ranges in size from about C/t-C2o-
  • a heteroaroyl ranges in size from about C2 0 -
  • An example is pyridylcarbonyl.
  • Oxycarbonyl represents a carboxylic acid ester group -CO2 which is linked to the rest of the molecule through a carbon atom.
  • Alkoxycarbonyl represents an -CC alkyl group in which the alkyl group is as defined supra. In a particular embodiment, an alkoxycarbonyl ranges in size from about C2-C2 0 - Examples include methoxycarbonyl and ethoxycarbonyl.
  • Aryloxycarbonyl represents an -C(3 ⁇ 4-aryl group in which the aryl group is as defined supra. Examples include phenoxycarbonyl and naphthoxycarbonyl.
  • Heterocyclyloxycarbonyl represents a -CC ⁇ -heterocyclyl group in which the heterocyclic group is as defined supra.
  • Heteroaryloxycarbonyl represents a -CO-heteroaryl group in which the heteroaryl group is as defined supra.
  • NR2 is a heterocyclic ring, which is optionally substituted.
  • NR2 is a heteroaryl ring, which is optionally substituted.
  • Cyano represents a -CN moiety.
  • Alkoxy represents an -O-alkyl group in which the alkyl group is as defined supra. Examples include methoxy, ethoxy, n-propoxy, iso-propoxy, and the different butoxy, pentoxy, hexyloxy and higher isomers.
  • Aryloxy represents an -O-aryl group in which the aryl group is as defined supra. Examples include, without limitation, phenoxy and naphthoxy.
  • Alkenyloxy represents an -O-alkenyl group in which the alkenyl group is as defined supra.
  • An example is allyloxy.
  • Heterocyclyloxy represents an -O-heterocyclyl group in which the heterocyclic group is as defined supra.
  • Heteroaryloxy represents an -O-heteroaryl group in which the heteroaryl group is as defined supra.
  • An example is pyridyloxy.
  • Amino represents an -N3 ⁇ 4 moiety.
  • Alkylamino represents an -NHR or -NR2 group in which R is an alkyl group as defined supra. Examples include, without limitation, methylamino, ethylamino, n- propylamino, isopropylamino, and the different butylamino, pentylamino, hexylamino and higher isomers.
  • Arylamino represents an -NHR or -NR2 group in which R is an aryl group as defined supra.
  • An example is phenylamino.
  • Heterocyclylamino represents an -NHR or -NR2 group in which R is a heterocyclic group as defined supra.
  • NR2 is a heterocyclic ring, which is optionally substituted.
  • Heteroarylamino represents a -NHR or ⁇ NR 2 group in which R is a heteroaryl group as defined supra.
  • NR2 is a heteroaryl ring, which is optionally substituted.
  • Neitro represents a -N(3 ⁇ 4 moiety.
  • Alkylthio represents an -S-alkyl group in which the alkyl group is as defined supra. Examples include, without limitation, methylthio, ethylthio, n-propylthio, iso propylthio, and the different butylthio, pentylthio, hexylthio and higher isomers.
  • Arylthio represents an -S-aryl group in which the aryl group is as defined supra. Examples include phenylthio and naphthylthio.
  • Heterocyclylthio represents an -S-heterocyclyl group in which the heterocyclic group is as defined supra.
  • Heteroarylthio represents an -S-heteroaryl group in which the heteroaryl group is as defined supra.
  • Sulfonyl represents an -SO2 group that is linked to the rest of the molecule through a sulfur atom.
  • Alkylsulfonyl represents an -SC ⁇ -aikyl group in which the alkyl group is as defined supra.
  • Arylsulfonyl represents an -S(3 ⁇ 4-aryl group in which the aryl group is as defined supra.
  • Heterocyclylsulfonyl represents an -S(3 ⁇ 4-heterocyclyl group in which the heterocyclic group is as defined supra.
  • Heteoarylsulfonyl presents an -S(3 ⁇ 4-heteroaryl group in which the heteroaryl group is as defined supra.
  • the compounds described herein may include salts, solvates, hydrates, isomers, tautomers, racemates, stereoisomers, enantiomers or diastereoisomers of those compounds.
  • salts of the compound of Formula 1 and compound of Formula l(b)(i) are preferably pharmaceutically acceptable salts, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation compounds described herein and of pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable acids or pharmaceutically acceptable base salts.
  • Salts of pharmaceutically acceptable acids include salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • Pharmaceutically acceptable base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium; alkylammonium(such as salts formed from triethylamine) and alkoxyammonium (such as those formed with ethanolamine).
  • Base salts also include salts formed from ethylenediamine, choline; and amino acids (such as arginine, lysine or histidine).
  • General information on types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is as described in general texts such as "Handbook of Pharmaceutical Salts" P.H.Stahl, C.G.Wermuth, 1 st edition, 2002, Wiley- VCH.
  • the pharmaceutically acceptable salt is a hydrochloride salt.
  • the compounds of the present invention may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form.
  • the invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
  • Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.
  • Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • Hydroxyl groups may be esterified with groups including lower alkyl carboxylic acids, such as acetic acid and 2,2-dimethylpropionic acid, sulfonated with groups including alkyl sulfonic acids, such as methyl sulfonic acid or glycosylated to form glucuronide derivatives.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • reacting means a chemical reaction which is a process that leads to the transformation of one set of chemical substances to another.
  • Reactions may include the formation and/or breakage of one or more chemical bonds between atoms.
  • Reacting may require contacting the reagents in a suitable solvent and may also require the addition of other agents to facilitate the reaction, such as the addition of base, acid and/or a catalyst.
  • the reactions may require more than one step to complete conversion of the starting materials to the desired products or they may require other conditions, such as cooling or heating. As would be understood in the art heating may be conventional heating or microwave - assisted heating.
  • contacting as used herein are intended to encompass components coming into physical contact. Where the components may be dissolved in solvents, washed, neutralised, acidified or basified prior to contact.
  • Functional groups can include alkenyl, alkynyl, aryl such as phenyl, alkylaryl such as benzyl, haloalkyl, hydroxyl, carbonyl, aldehydes, alkanoate, carboxyl, esters, ethers such as alkoxy, ketals, amines such as amino and alkylamino, amides such as alkylcarbonylamino, imines, and imides. It will be appreciated that these functional groups can be defined as described above or herein for these terms. As would be understood in the art a moiety is a part of a molecule that may include either whole functional groups or parts of functional groups as substructures.
  • a “leaving group” is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage.
  • Leaving groups can be anions or neutral molecules.
  • Anionic leaving groups are halides such as C1-, Br-, and I-, and sulfonate esters, such as tosylate (TsO-).
  • Neutral molecule leaving groups are water (H2O) and ammonia (NH 3 ).
  • a "nucleophile” is a chemical species that donates an electron pair to an electrophile to form a chemical bond in relation to a reaction. All molecules or ions with a free pair of electrons or at least one pi bond can act as nucleophiles.
  • Carbon nucleophiles are alkyl metal halides found in the Grignard reaction, Blaise reaction, Reformatsky reaction, and Barbier reaction, organolithium reagents, and anions of a terminal alkyne.
  • Enols are also carbon nucleophiles. The formation of an enol is catalyzed by acid or base. Enols are ambident nucleophiles, but, in general, nucleophilic at the alpha carbon atom.
  • Enols are commonly used in condensation reactions, including the Claisen condensation and the aldol condensation reactions.
  • Oxygen nucleophiles are water (H2O), hydroxide anion, alcohols, alkoxide anions, hydrogen peroxide, and carboxylate anions.
  • Nitrogen nucleophiles include ammonia, azide, amines, and nitrites.
  • removing includes cleavage or breaking of a bond.
  • removing the T-group of a compound of Formula 2 may comprise breaking the N-T bond.
  • a new class of trisubstituted triazine compounds show promise as anti-cancer agents with anticancer activity in the nanomolar range.
  • the present inventors have identified novel triazine compounds that can be used as intermediates in preparing target triazine compounds.
  • the novel triazine compounds at least in some embodiments, can also provide advantages for facilitating improved purity of target triazine compounds.
  • Target triazine compounds of particular interest as anticancer agents are compounds of Formula 1 , or a pharmaceutically acceptable salt thereof, which in some embodiments may provide a compound with a free amine substituent (-NH 2 ):
  • Each V may be independently selected from the group consisting of -Ci_4alkyl-, -NH-, - N(Ci-4alkyl)-, -0-, -S- and, in either orientation, -NH-C ⁇ alkyl-, -N(C 1 _ 4 alkyl)-C 1 _ 4alkyl-, In one embodiment, when V is selected from the group consisting of -S-Ci_4alkyl- and -O- the heteroatom of V is directly bonded to the central triazine ring of a compound of Formula 1.
  • V is selected from the group consisting of -NH-C 1 _ 4 alkyl-, -N(C 1 _ 4 alkyl)-C 1 ⁇ alkyl-, -S-C ⁇ alkyl- and -O-C ⁇ alkyl-.
  • Each linker V may be the same or different. In one embodiment, each linker V is the same. In an embodiment, V is -NH-Ci_4alkyl-. In another embodiment, V is -NH-CH2-.
  • Y may be absent or selected from the group consisting of and
  • Y is -Ci_4alkyl-. In a further embodiment, Y CH 2 -.
  • R may be 0-2 substituents, wherein each substituent is independently selected from the group consisting of -Ci_4alkyl, -C3_ ecycloalkyl, -OH, -0-d_ 4 alkyl, -N(R 4 ) 2 , -C 1 _ 4 alkylN(R 4 ) 2 , -C 3- 6 cycloalkyl-N(R 4 )2, -O-phenyl, -O-benzyl, -NO2, halogen, and -CF 3 ; each R 4 is independently selected from the group consisting of H, OH, -Ci- 4 alkyl, -C(0)OC M alkyl, -Ci- 4 alkyl-OR 7 , and -C(0)R 5 , provided that if one R 4 is OH then the other R 4 cannot be OH; or -N(R 4 )2 forms a pyrrolidinyl, piperidinyl, piperazinyl,
  • R 9 may be selected from H and Ci_4alkyl. In one embodiment, R 9 is hydrogen or methyl. In a particular embodiment, R 9 is hydrogen.
  • K is CH and J is NH; or K is N and J is C3 ⁇ 4.
  • the compound of Formula 1 is a compound selected from a compound of Formula 1(a) or a compound of Formula 1(b):
  • R may be selected from the group consisting of H, aryl, and alkylaryl. In another embodiment, R is selected from the group consisting of H, -Ci_4alkyl. In another embodiment R is H.
  • Scheme 1 Synthetic scheme for production of compounds of Formula 1, which may be prepared using one or more of the reaction steps.
  • the trityl intermediate triazine compounds of Formula 2 can be advantageously used in preparing target triazine compounds of Formula 1 by removal of the trityl group.
  • one surprising advantage provided by the compounds of Formula 2 is that the trityl group can be removed to form compounds of Formula 1 without introducing significant or problematic impurities.
  • each V is independently selected from the group consisting of -C ! _ 4 alkyl, -NH-, -NCd ⁇ alkyl)-, -0-, -S- and, in either orientation, -NH-C ⁇ alkyl-, -N(C 1 alkyl)-C 1 _ 4 alkyl-, -S-C ⁇ alkyl- and -O-Q ⁇ alkyl-;
  • T is an optionally substituted trityl group
  • Y is absent or selected from the group consisting of -Ci_4alkyl-,
  • R is 0-2 substituents, wherein each substituent is independently selected from the group consisting of -C 3- ecycloalkyl, -OH, -0-d_ 4 alkyl, -N(R 4 ) 2 , -C 1 _ 4 alkylN(R 4 ) 2 , -C 3 - 6 cycloalkyl-N(R 4 )2, -O-phenyl, -O-benzyl, -NO2, halogen, and -CF 3 ;
  • each R 4 is independently selected from the group consisting of H,
  • R 5 is selected from -d ⁇ alkyl and phenyl
  • R 7 is selected from -H and -d_ 4 alkyl
  • K is CH and J is NH; or K is N and J is CH 2 ;
  • R is selected from the group consisting of H, d_ 4 alkyl, aryl, and alkylaryl; and R 9 is selected from H and
  • the process for preparing a target trisubstituted triazine compound of Formula 1, or a pharmaceutically acceptable salt thereof comprises removal of the T group by contacting the compound of Formula 2 with an ion exchange resin or acid.
  • the contacting of the compound of Formula 2 with the ion exchange resin may be achieved by providing the compound in solution with a solvent and the ion exchange resin for a predetermined time, optionally with any one or more of stirring, agitation and heating.
  • the solvent may be an aqueous solvent, for example comprising or consisting of water and/or a lower alcohol.
  • Suitable aqueous solvents for removal of the T group may include dioxane, methanol, water and mixtures thereof.
  • the solvent is a dioxane, methanol and water mixture.
  • the solvent is dioxane.
  • the process may include further steps to work up the reaction and isolate the compounds described herein.
  • the process may also include one or more of the steps selected from extraction, isolation and purification, or a mixture of two or more steps.
  • the compounds described herein may be precipitated from solution, extracted, purified by column chromatography, recrystallisation, freeze dried or a mixture of two or more of the steps described.
  • Removal of the T group includes cleavage of the trityl protecting group or trityl resin to form the target compound of Formula 1.
  • suitable reagents for removing trityl protecting groups are: a) contact with an ion exchange resin, such as amberlyst 15 resin, or b) under acidic conditions c) tetrazole in triflurorethanol (TFE)
  • TFE triflurorethanol
  • Removal of the T group may produce or isolate the free base (for example -NHMe or - N3 ⁇ 4) or a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt of a compound of Formula 1 may be produced by contacting the free base with an acid.
  • the T group is removed under acidic conditions. In one embodiment the acidic conditions are mild acidic conditions. In one embodiment, the compound of Formula 2 is contacted with acid in organic solvent. In another embodiment, the compound of Formula 2 is contacted with acid in an aqueous solvent. In one embodiment, the compound of Formula 2 is contacted with 4M HC1 in dioxane. In another embodiment, the compound of Formula 2 is contacted with aqueous HC1. In another embodiment, the trityl group T is removed by contact with a protic acid or an ion exchange resin. The ion exchange resin can be selected from amberlyst 15 resin.
  • T is an optionally substituted trityl group.
  • the trityl group may also be known as triphenylmethyl, or triphenyl methyl group and is often abbreviated as Tr, Trt or -CPI1 3 .
  • a trityl group is a hydrocarbon with the formula (CeHs ⁇ C-. For example:
  • the trityl group is more commonly used for protecting hydroxyl groups (-OH).
  • the present inventors have surprising found that the trityl groups provide advantages in the synthesis of target anti-mitotic agents as amine (or amino) protecting groups.
  • Tritylamines N- tritylamines
  • triphenylmethylamines may also be known as triphenylmethylamines and may be of the formula Tr-NR2.
  • Tr-NR2 the formula:
  • a liable halide for example chloride
  • trityl chloride is a alkyl halide that is used to introduce the trityl group.
  • T is an unsubstituted trityl group.
  • the trityl group is a substituted trityl group.
  • the substituted trityl group has 1-3 substituents, each independently selected from the group consisting of halo, -Ci_ 4 alkyl, It will be appreciated that a substituted trityl group having 1-3 substituents may have 1-2 substituents, 2-3 substituents, 1 substituent, 2 substituents or 3 substituents. In one embodiment, when the trityl group has more than one substituent the substituents are on separate phenyl rings of the trityl group.
  • T is a trityl group is selected from the group consisting of unsubstituted trityl, 2-chlorotrityl-, 4- methoxytrityl, 4,4'-dimethoxytrityl, and 4,4',4"-trimethoxytrityl-, and 4-methyltrityl-.
  • the trityl group is selected from unsubstituted trityl- and 2- chlorotrityl-.
  • T is selected from an optionally substituted trityl protecting group or an optionally substituted trityl resin.
  • T is a trityl protecting group.
  • the trityl protecting group is an unsubstituted trityl- group.
  • T is an optionally substituted trityl resin.
  • Trityl resins are versatile resins for solid phase synthesis. Solid-phase synthesis can also be considered as a type of protecting group chemistry with the functional group attached to a resin directly or indirectly via an intervening linker. For trityl resins, the trityl group acts as a linker to the solid support. For example:
  • R H, CH 3 , OCH3, CI
  • Suitable trityl resins include trityl chloride resin, 2-chlorotrityl chloride resin, 4- methoxytrityl chloride resin, 4,4'-dimethoxytrityl chloride resin, and 4,4',4"- trimethoxytrityl chloride resin, 4-methyltrityl chloride resin, 4-aminobutan-l-ol 2- chlorotrityl resin, 4-aminomethylbenzoyl 2-chlorotrityl resin, 4-aminopropan-l-ol 2- chlorotrityl resin, bromoacetic acid 2-chlorotrityl resin, cyanoacetic acid 2-chlorotrityl resin, 4-cyanobenzoic acid 2-chlorotrityl resin, glycinol 2-chlorotrityl resin, propiolic acid 2-chlorotrityl resin, ethyleneglygol 2-chlorotrityl resin, N-Fmoc-hydroxylamine 2- chloro
  • the trityl resin is 2-chlorotrityl resin.
  • the resin may be regenerated before use (e.g. if hydrolysis on storage) using thionyl chloride, and may be discarded after use.
  • the solid support is a polymer. Suitable trityl resins are loaded on to polystyrene.
  • the substitution of resin varies from about 0.3 to about 2.0 mmol/g resin. In other embodiments, the substitution of trityl resin is about 0.3-1.0 mmol/g resin, about 0.3-1.2 mmol/g resin, about 0.4-1.0 mmol/g resin, or about 0.8 -1.6 mmol/g resin.
  • the bead size of trityl resin varies from about 100-400 mesh. In a further embodiment, the bead size of trityl resin is about 100-200 mesh or about 200- 400 mesh.
  • the swelling volume of the trityl resin in DCM is about 2-5 ml/g
  • Compatible solvents for solid phase synthesis would be known to the person skilled in the art and it would be understood to include solvents that swells the solid support resin. Suitable solvents include tetrahydrofuran (THF), dichloromethane (DCM), dimethyl formamide (DMF), dimethoxy ethane (DME), N-methyl-2-pyrrolidone (NMP), and dimethylacetamide (DMA).
  • the trityl resin is selected from the group consisting of trityl chloride resin, 2-chlorotrityl chloride resin, 4-methoxytrityl chloride resin, 4,4'- dimethoxytrityl chloride resin, and 4,4',4"-trimethoxytrityl chloride resin, and 4- methyltrityl chloride resin.
  • the trityl resin is 2-chlorotrityl chloride resin.
  • the trityl resin is cross-linked with divinylbenzene (DVB).
  • the DVB polystyrene may selected from 1 % DVB polystyrene and 2% DVB polystyrene.
  • the trityl resin is cross-linked with 2% DVB polystyrene.
  • the preparation of a target trisubstituted triazine compound of Formula 1, or a pharmaceutically acceptable salt thereof, may further comprise a process for preparing a compound of Formula 2.
  • a process for preparing a triazine compound of Formula 2 comprising the step of:
  • X and L are each functional groups that are capable of reacting together to form a linker V. It will be appreciated that X may be a functional group comprising a nucleophile and L may be a functional group comprising a suitable leaving group, and wherein the reaction of X and L forms the linker V.
  • the reaction of the nucleophile of X and the leaving group of L forms the linker V.
  • the reaction is a nucleophilic substitution reaction.
  • the reaction may be a S N I nucleophilic substitution, an S N 2 nucleophilic substitution or a S N Ar nucleophilic aromatic substitution.
  • the nucleophilic substitution is S N 2 nucleophilic substitution.
  • the nucleophilic substitution is S ⁇ Ar nucleophilic aromatic substitution.
  • X is selected from the group consisting of -NH 2 , NH(Ci_ 4 alkyl)- , -OH, -Ci-4alkyl-NH(Ci-4alkyl), and -Ci- 4 alkyl-OH.
  • X is -Ci_ 4 alkyl-NH 2 .
  • X is -CH 2 -NH 2 .
  • L is a halogen selected from the group consisting of chlorine, bromine and iodine.
  • L is chlorine.
  • X is -Ci_4alkyl-NH2 and L is a halogen selected from the group consisting of chlorine, bromine and iodine.
  • X is -CH2-NH2 and L is chlorine.
  • suitable solvents are polar aprotic solvents selected from the group consisting of tetrahydrofuran (THF), ethyl acetate (EtOAc), acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), or a mixture thereof.
  • THF tetrahydrofuran
  • EtOAc ethyl acetate
  • acetone dimethylformamide
  • MeCN acetonitrile
  • DMSO dimethyl sulfoxide
  • the solvent is DMF.
  • the reaction of X and L may include additional reagents, such as a catalyst, base, or acid.
  • additional reagents are selected from the group consisting of potassium carbonate (K2CO 3 ), cesium carbonate (CS2CO 3 ), potassium acetate, sodium bicarbonate, N,N-Diisopropylethylamine (DIPEA).
  • the additional reagents are selected from the group potassium carbonate (K2CO 3 ), cesium carbonate (CS2CO 3 ), potassium acetate (KOAc), sodium bicarbonate (NaHC(3 ⁇ 4).
  • potassium carbonate is added to the reaction.
  • the solvent is DMF in the presence of potassium carbonate (K2CO 3 ).
  • reaction of X and L may be carried out at room temperature or it may be heated.
  • a triazine compound of Formula 3 or Formula 4 may be prepared from a compound of Formula 5.
  • the process may further comprise preparing a compound of Formula 3 by reacting a compound of Formula 5 with a compound of Formula A:
  • a compound of Formula 3 may be provided or purchased.
  • a compound of Formula 3 is selected from a compound of Formula 3(a) and a compound of Formula 3(b):
  • the compound of Formula 3(b) is:
  • the process further comprises preparing a compound of Formula 4 by reacting a compound of Formula 5 with a compound of Formula B:
  • Scheme 3 Synthesis of intermediate compound of Formula 2 via intermediate compound of Formula 4.
  • variables X, L, V, T, Y, R, R 3 , R 4 , R 5 , R 7 , R 9 , K, and J can be provided for any embodiments as described herein for these features.
  • the reaction of X and L may take place in suitable solvents as described above and may include additional reagents, such as a catalyst, base, or acid as described herein. It will be appreciated that these conditions may be selected from any one of the embodiments described herein.
  • the compound of Formula 5 is optionally prepared from a compound of Formula 6.
  • a compound of Formula 5 may be prepared by reacting a compound of Formula 6 with a compound of Formula C:
  • Formula 6 Formula 5 wherein L, V, Y, K, J, R and T, may be selected from any of the embodiments described herein for these features. Alternatively, a compound of Formula 5 may be provided or purchased.
  • a compound of Formula 5 is selected from a compound of Formula 5(a) and a compound of Formula 5(b):
  • the compound of Formula 5 is a compound of Formula 5(b)(i):
  • a compound of Formula 4 may be prepared by reacting a compound of Formula 7 with a compound of Formula E:
  • Formula 7 wherein L, V, Y, K, J, R 3 J , R 9 and T, may be selected from any of the embodiments described herein for these features.
  • X 1 is a functional group of the trityl protecting group or trityl resin which is capable of reacting with the free amine of the compound of Formula 7 to form the compound of Formula 4.
  • a compound of Formula B may be prepared by reacting a compound of Formula D with a compound of Formula E:
  • Formula D Formula B wherein X, Y, R 9 and T are as defined herein; and wherein X 1 is a functional group of the trityl protecting group or trityl resin which is capable of reacting with the free amine of the compound of Formula D to form the compound of Formula B.
  • a compound of Formula B may be provided or purchased.
  • X of a compound of Formula E comprises a leaving group.
  • X 1 is chlorine..
  • the process comprises reacting l-[4-chloro-6-(4- methoxybenzyl)amino- ⁇ l,3,5 ⁇ -triazin-2-yl-amino]-imidazolidine-2,4-dione of Formula 3(b)(i) with a compound of Formula B(i) to form a compound of Formula 2(b)(i):
  • T is as defined herein.
  • the process comprises reacting a compound of Formula 4(b)(i) with 4-methoxybenzylamine, of Formula A(i), to form a compound of Formula 2(b)(i):
  • the process may optionally include preparing a compound of Formula 4(b)(i).
  • the compound of Formula 4(b)(i) is prepared by reacting l-(4,6-dichloro- [l,3,5]-triazin-2-yl-amino)-imidazolidine-2,4-dione, of Formula 5(b)(i), with a compound of Formula B(i):
  • the processes at least in some embodiments described herein can provide improved efficiency, improved ease of accessing target triazine compounds, improve the ability to monitor reaction processes and/or provide target compounds with improved purity.
  • the present inventors identified in previous processes for preparing triazine compounds that significant impurities were present and were problematic to remove.
  • the intermediates and processes described herein reduce the amount of impurities and can provide compositions with high purity of the target triazine compounds, at least in some embodiments.
  • the intermediates and processes described herein provide greater than 80% purity of the target triazine compounds.
  • the intermediate compounds and processes described herein also facilitate the monitoring of reaction steps as well as isolation, characterisation and purification of the intermediates and target triazine compounds of Formula 1.
  • the intermediate compounds in the processes can precipitate or crystallise as solids from reaction mixtures, or purification processes thereafter, which improves handling and isolation of the intermediates.
  • the intermediate compounds also provide an advantageous UV chromophore, which enables monitoring of reactions and provides an ability to identify completion of a reaction step.
  • the intermediates have improved NMR properties allowing for better characterisation of reaction intermediates, which further improves monitoring of reactions.
  • One aspect provides, a compound selected from the group consisting of Formula 2 and Formula 4:
  • Formula 2 Formula 4 wherein L, V, T. Y, R, R 3 , R 4 , R 5 , R 7 , R 9 , K, and J, are as herein described and can be independently selected from any one of the embodiments as described herein.
  • Previous methods produced intermediate compounds as residues which are difficult to isolate and purify.
  • the present inventors found that using a trityl protecting group could produce compounds of Formula 2 and Formula 4 as solids, resulting in improved handling. In addition, it was also easier to isolate and purify the reaction intermediates.
  • the present inventors found that in at least some embodiments the intermediate compounds Formula 2 and Formula 4 have an advantageous UV chromophore, for example a high signal to noise ratio and an increase in absorption, which enables monitoring of reactions and also means that it is simpler to identify completion of a reaction step.
  • the intermediates have improved NMR properties, compared to previous synthetic methods allowing for better characterisation of reaction intermediates and allowing monitoring of reaction steps.
  • a compound of Formula 2 is selected from a compound of Formula 2(a) and a compound of Formula 2(b):
  • the compound of Formula 2 is a compound of Formula 2(b)(i):
  • T is as defined herein.
  • a compound of Formula 4 is selected from a compound of Formula 4(a) and a compound of Formula 4(b):
  • the compound of Formula 4 is a compound of Formula 4(b)(i):
  • Compounds of Formula 2 and compounds of Formula 4 may be obtained as a solid.
  • the compounds are crystalline or powdered solids.
  • the compounds may be obtained on work up as individual crystals.
  • a compound of Formula 2(b)(i) is obtained as a solid.
  • a compound of Formula 4(b)(i) is obtained as a solid.
  • the intermediate compound of Formula 2 and/or compound of Formula 4 can be obtained in good purity.
  • composition comprising a compound of Formula 1, or a pharmaceutically acceptable salt thereof:
  • Formula 1 wherein the compound of Formula 1, or pharmaceutically acceptable salt thereof, is provided in the composition in an amount greater than about 80% by weight of the total composition.
  • the composition comprises a compound of Formula 1 or pharmaceutically acceptable salt thereof, in an amount greater than about 90%, greater than about 95%, or greater than about 97%, by weight of the total composition.
  • the compound of Formula 1 may be provided in a composition in an amount of at least (in % by weight of the total composition) 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%.
  • V, Y, R, R , K, and J can be independently selected from any one of the embodiments as described herein.
  • the composition comprises less than about 20% of impurities (wt% of total composition).
  • the impurities may be in the composition in an amount (wt% of total composition) of less than about 15%, 10%, 5%, 4%, 3%, 2%, or 1%.
  • LC liquid chromatography
  • MS mass spectrometry methods
  • UV detection may be used, or combination thereof.
  • the compound of Formula 1 is a compound of Formula 1(a):
  • the compound of Formula 1 is a compound of Formula 1(b):
  • the compound of Formula 1(b) is a compound of Formula l(b)(i):
  • Formula l(b)(i) There is also provided a process for preparing a compound of Formula 1 or pharmaceutically acceptable salt thereof, containing less than about 20%, by weight, of impurities.
  • the impurities may be in an amount (wt%) less than about 15%, 10%, 5%, 4%, 3%, 2%, or 1%, by weight.
  • a process for preparing a compound of Formula 1 or pharmaceutically acceptable salt thereof with greater than about 80% purity.
  • the process for preparing a compound of Formula 1 provides compound of Formula 1 or pharmaceutically acceptable salt thereof, with greater than about 90% purity, greater than about 95% purity, greater than about 96%, or greater than about 97% purity.
  • Amberlyst 15 Resin (15.00 g) was washed with pure water (150 mL), 2N HQ (150 mL), water (150 mL), then 2N NH 3 in MeOH (150 mL), then washed with water (150 mL), 2N HQ (150 mL), and then water (150 mL).

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Abstract

La présente invention concerne généralement des composés de triazine, des procédés de préparation de composés de triazine et des compositions comprenant des composés de triazine. La présente invention concerne également des composés de triazine et leur utilisation en tant qu'intermédiaires dans des procédés de préparation de composés de triazine cible, permettant l'accès à des agents anticancéreux à base de triazine.
PCT/AU2015/050685 2014-11-03 2015-10-30 Composés de triazine, compositions et synthèse WO2016070241A1 (fr)

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US10246466B2 (en) 2014-01-24 2019-04-02 Tp Therapeutics, Inc. Diaryl macrocycles as modulators of protein kinases
US10316044B2 (en) 2015-07-02 2019-06-11 Tp Therapeutics, Inc. Chiral diaryl macrocycles as modulators of protein kinases

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WO2004026844A1 (fr) * 2002-09-23 2004-04-01 Reddy Us Therapeutics, Inc. Methodes et compositions a base de nouveaux composes de triazine
WO2012054978A1 (fr) * 2010-10-27 2012-05-03 Ludwig Institute For Cancer Research Limited Nouveaux agents anticancéreux

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WO2004026844A1 (fr) * 2002-09-23 2004-04-01 Reddy Us Therapeutics, Inc. Methodes et compositions a base de nouveaux composes de triazine
WO2012054978A1 (fr) * 2010-10-27 2012-05-03 Ludwig Institute For Cancer Research Limited Nouveaux agents anticancéreux

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10246466B2 (en) 2014-01-24 2019-04-02 Tp Therapeutics, Inc. Diaryl macrocycles as modulators of protein kinases
US10618912B2 (en) 2014-01-24 2020-04-14 Turning Point Therapeutics, Inc. Diaryl macrocycles as modulators of protein kinases
US10316044B2 (en) 2015-07-02 2019-06-11 Tp Therapeutics, Inc. Chiral diaryl macrocycles as modulators of protein kinases

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