TRIAZINE COMPOUNDS, COMPOSITIONS AND SYNTHESIS

FIELD

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.

BACKGROUND

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. However, 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 new class of anti-cancer agents is provided in the international PCT application no. PCT/AU2011/001376 (international PCT publication no. WO2012054978). However, it was found that the process produced material which comprised various problematic impurities. There is a need to provide new methods for producing such anti-cancer agents with improved efficiency, ease of monitoring, and/or improved purity profiles. SUMMARY

In a first aspect, there is provided 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:

Formula 2 Formula 1 wherein

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-,

and -C3_ ₆ cycloalkyl-;

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;

selected from -d^alkyl and phenyl; and

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, Ci_ ₄ alkyl, aryl, and alkylaryl; and R ⁹ is selected from H and d^alkyl. In one embodiment, 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. In another embodiment, the trityl group T is a trityl protecting group selected from unsubstituted trityl- and 2-chlorotrityl-.

In an embodiment, the trityl protected triazine compound of Formula 2 is prepared by reac

Formula 2

wherein T, Y, R, K, J, R 3 ^J , and R 9 , are as described above according to the first aspect; and

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-.

In another embodiment, the trityl protected triazine compound of Formula 2 is prepared by reacting a compound of Formula 4 with a compound of Formula A:

Formula 4

Formula 2 wherein T, Y, R, K, J, R 3 , and R 9 , are as described above according to the first aspect; and

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-, In the above embodiments, 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. In an embodiment, 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 In another embodiment, L is a halogen selected from the group consisting of chlorine, bromine and iodine.

In a second aspect, there is provided 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.

In a third aspect, there is provided 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. In a fourth aspect, there is provided a method of treating cancer comprising administering to a subject an effective amount of the pharmaceutical composition of the third aspect.

In a fifth aspect, there is provided 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:

Formula 3

Formula 2

; or

Formula 4

Formula 2 wherein

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

and -C ₃ _ ₆ cycloalkyl-; 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, -C _! _ ₄ alkyl, -C(0)Od_4alkyl, -d_4alkyl-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 mo holino group optionally substituted with d- 4alkyl;

R ⁵ is selected from -Ci^alkyl and phenyl; and

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 ; and

R is selected from the group consisting of H, Ci_4alkyl, aryl, and alkylaryl; and R ⁹ is selected from H and

In a sixth aspect, there is provided a trityl protected triazine compound of Formula 2 prepared by the process according to the fifth aspect.

In a seventh aspect, there is provided a trityl protected triazine compound selected from a compound of Formula 2 and Formula 4:

Formula 2 Formula 4 wherein

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-,

and -C3_ ₆ cycloalkyl-;

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; and

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 ; and

R is selected from the group consisting of H, Ci_4alkyl, aryl, and alkylaryl; and R ⁹ is selected from H and

In an embodiment, the compound of Formula 2 is a compound of Formula 2(b)(i):

Formula 2(b)(i) In an eighth aspect, there is provided a composition comprising a compound of Formula 1, or a pharmaceutically acceptable salt thereof:

Formula 1 wherein

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-,

and -C3_ ₆ cycloalkyl-;

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; and

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 ; and

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.

In an embodiment, 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.

In an embodiment, 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.

In another embodiment, a compound of Formula 1(b) is:

In a ninth aspect, there is provided a pharmaceutical composition comprising the composition according to the eighth aspect or any embodiment thereof, and a pharmaceutically acceptable excipient. In a tenth aspect, there is provided 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.

In an eleventh aspect, there is provided use of a composition according to the ninth aspect or any embodiment thereof for treating cancer. In an embodiment, the use of the composition comprises the manufacture of a medicament for treating cancer.

BRIEF DESCRIPTION OF THE FIGURES

Embodiments of the present invention will now be further described and illustrated, by way of example only, with reference to the accompanying drawings in which: 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; and

Figure 4 shows LCMS with UV (254nm) for Example 5 and peak table showing retention time.

DETAILED DESCRIPTION

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.

GENERAL TERMS Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter. Thus, as used herein, the singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. For example, reference to "a" includes a single as well as two or more; reference to "an" includes a single as well as two or more; reference to "the" includes a single as well as two or more and so forth.

Those skilled in the art will appreciate that the disclosure herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features.

Each example of the present disclosure described herein is to be applied mutatis mutandis to each and every other example unless specifically stated otherwise. The present disclosure is not to be limited in scope by the specific examples described herein, which are intended for the purpose of exemplification only. Functionally- equivalent products, compositions and methods are clearly within the scope of the disclosure as described herein.

The term "and/or", e.g., "A and/or B" shall be understood to mean either "A and B" or "A or B" and shall be taken to provide explicit support for both meanings or for either meaning.

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. SPECIFIC TERMS

As will be understood, an "aromatic" group means a cyclic group having 4m+2 π electrons, where m is an integer equal to or greater than 1. As used herein, "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.

The terms "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); or (iii) an optionally substituted fully or partially saturated polycyclic fused ring system that has one or more bridges (examples include quinuclidinyl and dihydro-l,4-epoxynaphthyl). A heteroaromatic group is an aromatic group or ring containing one or more heteroatoms, such as N, O, S, Se, Si or P. As used herein, "heteroaromatic" is used interchangeably with "heteroaryl", and 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 π 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.

The term "optionally 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. The term "optionally substituted" 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, cycloalkanoate, aryloate, heterocyclyloate, heteroaryloate, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, heteroarylcarbonylamino, nitro, alkylthio, cycloalkylthio, arylthio, heterocyclylthio, heteroarylthio, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclysulfonyl, heteroarylsulfonyl, hydroxyl, halo, haloalkyl, haloaryl, haloheterocyclyl, haloheteroaryl, haloalkoxy, haloalkylsulfonyl, silylalkyl, alkenylsilylalkyl, and alkynylsilylalkyl. In an embodiment, optionally substituted may be 1-3 substituents selected from halo, hydroxyl, It will be appreciated that other groups not specifically described may also be used.

The term "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. Examples of haloalkoxy include, without limitation, -OCHF ₂ , -OCF ₃ , -0CH ₂ CC1 ₃ , -OCH ₂ CF ₃ and -OCH2CH2CF ₃ . Examples of haloalkylsulfonyl 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. Thus 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. As understood by a person skilled in the art, 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" whether used alone, or in compound words such as alkynyloxy, 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. The term 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. The term "cycloalkenyloxy" represents the same groups linked through an oxygen atom such as cyclopentenyloxy and cyclohexenyloxy. The term "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. The term "cycloalkenyloxy" represents the same groups linked through an oxygen atom such as cyclopentenyloxy and cyclohexenyloxy. The term "cycloalkenylthio" represents the same groups linked through a sulfur atom such as cyclopentenylthio and cyclohexenylthio. "Formyl" represents a -CHO moiety. "Alkanoyl" represents a -C(=0)-alkyl group in which the alkyl group is as defined supra. In a particular embodiment, an alkanoyl ranges in size from about C2-C2 ₀ - One example is acyl.

"Aroyl" represents a -C(=0)-aryl group in which the aryl group is as defined supra. In a particular embodiment, an aroyl ranges in size from about C7-C2 ₀ - Examples include benzoyl and 1-naphthoyl and 2-naphthoyl.

"Heterocycloyl" represents a -C(=0)-heterocyclyl group in which the heterocylic group is as defined supra. In a particular embodiment, an heterocycloyl ranges in size from about C/t-C2o- "Heteroaroyl" represents a -C(=0)-heteroaryl group in which the heteroaryl group is as defined supra. In a particular embodiment, a heteroaroyl ranges in size from about C2 ₀ - An example is pyridylcarbonyl.

"Carbonyl" represents a -C(=0)- moiety.

"Carboxyl" represents a -C(=0)-OH moiety. "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(¾-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.

"Aminocarbonyl" represents a carboxylic acid amide group -C(=0)NHR or -C(=0)NR2 which is linked to the rest of the molecule through a carbon atom. "Alkylaminocarbonyl" represents a -C(=0)NHR or— C(=0)NR2 group in which R is an alkyl group as defined supra.

"Arylaminocarbonyl" represents a -C(=0)NHR or -C(=0)NR2 group in which R is an aryl group as defined supra. "Heterocyclylaminocarbonyl" represents a -C(=0)NHR or -C(=0)NR2 group in which R is a heterocyclic group as defined supra. In certain embodiments, NR2 is a heterocyclic ring, which is optionally substituted.

"Heteroarylaminocarbonyl" represents a -C(=0)NHR or -C(=0)NR2 group in which R is a heteroaryl group as defined supra. In certain embodiments, NR2 is a heteroaryl ring, which is optionally substituted.

"Cyano" represents a -CN moiety.

"Hydroxyl" represents a -OH 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.

"Alkanoate" represents an -OC(=0)-R group in which R is an alkyl group as defined supra.

"Aryloate" represents a -OC(=0)-R group in which R is an aryl group as defined supra. "Heterocyclyloate" represents an -OC(=0)-R group in which R is a heterocyclic group as defined supra.

"Heteroaryloate" represents an -OC(=0)-R group in which R is a heteroaryl group as defined supra. "Ester" represents an -C(=0)-OR group in which R is a alkyl group as defined supra. "Amino" represents an -N¾ 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. In certain embodiments, 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. In certain embodiments, NR2 is a heteroaryl ring, which is optionally substituted.

"Carbonylamino" represents a carboxylic acid amide group -NHC(=0)R that is linked to the rest of the molecule through a nitrogen atom.

"Alkylcarbonylamino" represents a -NHC(=0)R group in which R is an alkyl group as defined supra.

"Arylcarbonylamino" represents an -NHC(=0)R group in which R is an aryl group as defined supra. "Heterocyclylcarbonylamino" represents an -NHC(=0)R group in which R is a heterocyclic group as defined supra.

"Heteroarylcarbonylamino" represents an -NHC(=0)R group in which R is a heteroaryl group as defined supra. "Nitro" represents a -N(¾ 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(¾-aryl group in which the aryl group is as defined supra.

"Heterocyclylsulfonyl" represents an -S(¾-heterocyclyl group in which the heterocyclic group is as defined supra.

"Heteoarylsulfonyl" presents an -S(¾-heteroaryl group in which the heteroaryl group is as defined supra.

"Aldehyde" represents a -C(=0)H group.

"Alkanal" represents an alkyl-(C=0)H group in which the alkyl group is as defined supra.

The compounds described herein may include salts, solvates, hydrates, isomers, tautomers, racemates, stereoisomers, enantiomers or diastereoisomers of those compounds. For example, 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. In one embodiment, the pharmaceutically acceptable salt is a hydrochloride salt.

It will also be recognised that 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. The term "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. By "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.

The terms "reacting", "react" and "reaction" as used herein are intended to encompass 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.

The term "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.

The term "functional group" or "functional groups" as used herein is intended to encompass groups which can undergo chemical reactions. Organic reactions are facilitated and controlled by the functional groups of the reactants. The atoms of functional groups are linked to each other and to the rest of the molecule by covalent bonds.

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. Sulfur nucleophiles, hydrogen sulfide and its salts, thiols (RSH), thiolate anions (RS-), anions of thiolcarboxylic acids (RC(O)-S-), and anions of dithiocarbonates (RO-C(S)-S-) and dithiocarbamates (R ₂ N-C(S)-S-). Sulfur is very nucleophilic because of its large size, which makes it readily polarizable, and its lone pairs of electrons are readily accessible. Nitrogen nucleophiles include ammonia, azide, amines, and nitrites.

The term "remove", "removing" or "removal" includes cleavage or breaking of a bond. For example, removing the T-group of a compound of Formula 2 may comprise breaking the N-T bond.

TRIAZINE COMPOUNDS

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 ):

Formula 1 wherein R, V, Y, K, J, R 3 ^J , and R 9 , are described further below and may be selected from any of the embodiments as described herein for these features.

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. In another embodiment, 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

-C3_ ₆ cycloalkyl-. In one embodiment, 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, or morpholino group optionally substituted with Ci-4alkyl; R ⁵ is selected from -Ci_4alkyl and phenyl; R ⁷ is selected from -H and In one embodiment, R is 1-2 substituents. In another embodiment, R is 1 substituent. In another embodiment, R is 1 substituent and -0-Ci_4alkyl. In another embodiment, R is -O-CH ₃ .

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.

In an embodiment, K is CH and J is NH; or K is N and J is C¾. In another embodiment, the compound of Formula 1 is a compound selected from a compound of Formula 1(a) or a compound of Formula 1(b):

Formula 1(a) Formula 1(b) In the above Formula 1(a) and 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.

An example of a compound of Formula 1(b), which can be prepared by the process is:

An example of a compound of Formula 1(b) as a hydrochloride salt, which can be prepared by the process is:

PROCESS FOR PREPARING TRIAZINE COMPOUNDS OF FORMULA 1

Scheme 1 below provides an example of a multi-step process for preparing a compound of Formula 1 :

Scheme 1: Synthetic scheme for production of compounds of Formula 1, which may be prepared using one or more of the reaction steps.

It will be appreciated that various embodiments of the process as described herein may comprise or consist of any one or more of the steps of Scheme 1.

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. For example, 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.

In the first aspect as described above, there is provided 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

Formula 2 Formula 1 wherein

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-,

and -C3_ ₆ cycloalkyl-;

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,

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;

R ⁵ is selected from -d^alkyl and phenyl; and

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

It will be appreciated that each of V, T, Y, R, K, J, R 3 and R 9 , as described above, may be independently selected from any one of the embodiments for these features as described herein, or combination of features thereof. In one embodiment, 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. It will be appreciated that the contacting of the compound of Formula 2 with the ion exchange resin, for example, 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. In one embodiment, the solvent is a dioxane, methanol and water mixture. In another embodiment, the solvent is dioxane.

The process may include further steps to work up the reaction and isolate the compounds described herein. For example, 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. In one embodiment, 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. Examples of 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) Removal of the T group may produce or isolate the free base (for example -NHMe or - N¾) 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.

In one embodiment, 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.

Trityl Group T

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:

Trityl group

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.

The process described herein utilises or forms tritylamines. Tritylamines (N- tritylamines) may also be known as triphenylmethylamines and may be of the formula Tr-NR2. For example, of the Formula:

N-Tritylamine

The use of a liable halide, for example chloride, may be used in the process to introduce the trityl group. For example, trityl chloride is a alkyl halide that is used to introduce the trityl group.

In one embodiment, T is an unsubstituted trityl group. In another embodiment, the trityl group is a substituted trityl group. In a further embodiment, 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. In one embodiment, 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-. In a further embodiment, the trityl group is selected from unsubstituted trityl- and 2- chlorotrityl-.

In one embodiment, T is selected from an optionally substituted trityl protecting group or an optionally substituted trityl resin.

In one embodiment, T is a trityl protecting group. In another embodiment, the trityl protecting group is an unsubstituted trityl- group. In another embodiment, 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:

t

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- chlorotrityl resin, hydrasube 2-chlorotrityl resin, L-threnonil-ol 2-chlorotrityl resin. In an embodiment, 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. In one embodiment the solid support is a polymer. Suitable trityl resins are loaded on to polystyrene.

In an embodiment, 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.

In an embodiment, 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.

In an embodiment, 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).

In one embodiment, 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. In another embodiment, the trityl resin is 2-chlorotrityl chloride resin.

In one embodiment, the trityl resin is cross-linked with divinylbenzene (DVB). The DVB polystyrene may selected from 1 % DVB polystyrene and 2% DVB polystyrene. In an embodiment, the trityl resin is cross-linked with 2% DVB polystyrene.

PROCESSES FOR PREPARING TRIAZINE COMPOUNDS OF FORMULA 2 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.

In another aspect, a process can be provided for preparing a triazine compound of Formula 2 comprising the step of:

a) reacting a compound of Formula 3 with a compound of Formula B to form a compound of Formula 2:

Formula 3

Formula 2

;or b) reacting a compound selected from Formula 4 with a compound of Formula A to form a compound of Formula 2:

Formula 4

Formula 2 wherein V, T, Y, R, R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁹ , K, and J are as described herein. It will be appreciated that these variables may be selected from any one of the embodiments described herein.

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.

In one embodiment, the reaction of the nucleophile of X and the leaving group of L forms the linker V. In one embodiment, 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. In one embodiment, the nucleophilic substitution is S _N 2 nucleophilic substitution. In another embodiment, the nucleophilic substitution is S^Ar nucleophilic aromatic substitution.

In one embodiment, 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. In another embodiment, X is -Ci_ ₄ alkyl-NH ₂ . In yet a further embodiment, X is -CH ₂ -NH ₂ . In one embodiment, L is a halogen selected from the group consisting of chlorine, bromine and iodine. In another embodiment, L is chlorine. In one embodiment, X is -Ci_4alkyl-NH2 and L is a halogen selected from the group consisting of chlorine, bromine and iodine. In another embodiment, X is -CH2-NH2 and L is chlorine.

The reaction of X and L may take place in suitable solvents. In one embodiment, 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. In one embodiment, the solvent is DMF.

In a further embodiment, the reaction of X and L may include additional reagents, such as a catalyst, base, or acid. Suitable 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). In one embodiment, the additional reagents are selected from the group potassium carbonate (K2CO ₃ ), cesium carbonate (CS2CO ₃ ), potassium acetate (KOAc), sodium bicarbonate (NaHC(¾). In one embodiment, potassium carbonate is added to the reaction.

In one embodiment, for the reaction of X and L, the solvent is DMF in the presence of potassium carbonate (K2CO ₃ ).

The reaction of X and L may be carried out at room temperature or it may be heated.

PROCESS FOR PREPARING COMPOUNDS OF FORMULA 3 OR FORMULA 4 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:

Formula 5

Formula 3

For example, the process of preparing a compound of Formula 2 may involve steps of Scheme 2:

ormu a Scheme 2: Synthesis of intermediate compound of Formula 2 via intermediate compound of Formula 3.

Alternatively, a compound of Formula 3 may be provided or purchased.

In one embodiment, a compound of Formula 3 is selected from a compound of Formula 3(a) and a compound of Formula 3(b):

Formula 3(a) _and Formula 3(b)

In one embodiment, the compound of Formula 3(b) is:

In another embodiment, the process further comprises preparing a compound of Formula 4 by reacting a compound of Formula 5 with a compound of Formula B:

ormu a Y— N-T

Formula 4 For example, the process of preparing a compound of Formula 2 may involve steps of Scheme 3:

Formula 4 Formula 2

Scheme 3: Synthesis of intermediate compound of Formula 2 via intermediate compound of Formula 4. For the process of preparing compounds of Formula 3 or compounds of Formula 4 the 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. In one embodiment, 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.

In one embodiment, a compound of Formula 5 is selected from a compound of Formula 5(a) and a compound of Formula 5(b):

Formula 5(a) Formula 5(b)

; and

In one embodiment, the compound of Formula 5 is a compound of Formula 5(b)(i):

Formula 5(b)(i)

In another embodiment, a compound of Formula 4 may be prepared by reacting a compound of Formula 7 with a compound of Formula E:

Formula 7 Formula 4 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. Alternatively, a compound of Formula B may be provided or purchased. In one embodiment, X of a compound of Formula E comprises a leaving group. In one embodiment, X ¹ is chlorine..

REPRESENTATIVE PROCESSES

In one embodiment, 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):

Formula 3(b)(i) Formula 2(b)(i)

wherein T is as defined herein.

In another embodiment, 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):

Formula 4(b)(i) Formula l(b)(i) wherein T is as defined herein.

The process may optionally include preparing a compound of Formula 4(b)(i). In an embodiment, 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):

Formula 4(b)(i) wherein T is as defined herein.

INTERMEDIATES Surprisingly, 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.

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.

Surprisingly, in at least some embodiments 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. In some embodiments, 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. In addition, 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. Surprisingly, 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. Furthermore, 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. In addition, in at least some embodiments the intermediates have improved NMR properties, compared to previous synthetic methods allowing for better characterisation of reaction intermediates and allowing monitoring of reaction steps.

The compounds of Formula 2 and/or Formula 4 may be intermediates in the process of preparing compounds of Formula 1. In one embodiment, a compound of Formula 2 is selected from a compound of Formula 2(a) and a compound of Formula 2(b):

Formula 2(a) Formula 2(b)

and

In another embodiment, the compound of Formula 2 is a compound of Formula 2(b)(i):

Formula 2(b)(i)

wherein T is as defined herein.

In one embodiment, a compound of Formula 4 is selected from a compound of Formula 4(a) and a compound of Formula 4(b):

^L

Formula 4(a) . Formula 4(b)

In one embodiment, the compound of Formula 4 is a compound of Formula 4(b)(i):

Formula 4(b)(i) wherein T is as defined herein.

Compounds of Formula 2 and compounds of Formula 4 may be obtained as a solid. In an embodiment, the compounds are crystalline or powdered solids. For example, the compounds may be obtained on work up as individual crystals. In one embodiment, a compound of Formula 2(b)(i) is obtained as a solid. In another embodiment, 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. TARGET TRIAZINE COMPOUNDS AND COMPOSITIONS THEREOF

In another aspect, there is provided a 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.

In other embodiments, 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. For example, 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%.

It will be appreciated that each V, Y, R, R , K, and J can be independently selected from any one of the embodiments as described herein.

In another embodiment, 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%.

It will be appreciated that various methods can be used to determine the purity of the compounds, or composition thereof. For example, liquid chromatography (LC), mass spectrometry methods (MS), and UV detection may be used, or combination thereof.

In an embodiment, the compound of Formula 1 is a compound of Formula 1(a):

Formula 1(a)

In another embodiment, the compound of Formula 1 is a compound of Formula 1(b):

Formula 1(b)

In a further embodiment, 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. In one embodiment, there is provided a process for preparing a compound of Formula 1 or pharmaceutically acceptable salt thereof, with greater than about 80% purity. In other embodiments, 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.

The purity of compound of the present invention may also be analysed using techniques

1 13

known in the art such as H-NMR, C-NMR, derivatisation experiments, mass spectrometry, liquid chromatography, UV detection, microanalysis, chemiluminescence nitrogen detection, or any combination thereof. It will be appreciated by persons skilled in the art that the one or more of the above techniques can be used to determine purity of a compound described herein.

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each claim of this application.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

In order that the nature of the present invention may be more clearly understood preferred forms thereof will now be described by reference to the following non-limiting Examples. EXAMPLES

5

Scheme 4: Synthesis of target compound and HC1 salt Example 1 - Compound 1

Preparation of l-(N-Trityl-aminomethyl)-4-(aminomethyl)benzene

Compound 1

The mixture of 1 ,4-bis(aminomethyl)benzene (compound A) (30.0g, 0.22mol) and trityl chloride (43. Og, 0.15mol) in dioxane (300mL) was stirred at room temperature for overnight. TLC showed most of compound A was consumed. The reaction mixture was poured into water (400 mL), adjusted the pH=8-9 with 2N NaOH solution. Extracted with DCM (300 mL x3) and combined the organic layers. The organic phase was washed with brine, dried over anhydrous Na2S0 ₄ , filtered and concentrated under reduce pressure. The residue was purified by silica column (DCM:MeOH=100:0 to 50: 1) to give compound 1 as a yellow oil (30.00g, 36%). TLC: Rf=0.43 silica gel MeOH/DCM=l/10 v/v. H NMR (400 MHz, CDC1 ₃ ) δ 7.60-7.58 (m, 6H), 7.40-7.29 (m, 10H), 7.24-7.21 (m 3H), 3.88 (s, 2H), 3.37 (s, 2H).

Example 2: Compound 2

Preparation of l-[4-chloro-6-(4-N-trityl-aminomethyl)-benzylamino-{l,3,5}- triazin-2-yl-amino]-imidazolidine-2,4-dione

Compound b Compound 2

To the mixture of Compound 1 (10.00 g, 27 mmol) in DMF (70 mL) was added l-(4,6- dichloro-[l,3,5]-triazin-2-yl-amino)-imidazolidine-2,4-dione (compound b) (7.0g, 26.6mol), K2CO ₃ (5.50 g, 40 mmol). The reaction was stirred at room temperature for 4h. TLC showed all of the l-(4,6-dichloro-[13,5]-triazin-2-yl-amino)-imidazolidine- 2,4-dione was consumed. The reaction mixture was poured into water (1L) and extracted with EtOAc (100 mL x3). Combined the organic layer and washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by silica column (DCM:MeOH=100:l to 40: 1) to give compound 2 as a white solid (8.00 g, 50%). TLC: Rf=0.48 silica gel Pet ether;EtOAc=l : l v/v. ^J H NMR (400 MHz, MeOD) δ 7.57 - 7.47 (m, 6H), 7.29-7.15 (m, 13H), 4.51 (d, / = 9.6 Hz, 1H), 4.42 (s, 1H), 4.16 (d, / = 20.8 Hz, 1H), 3.86 (s, 1H), 3.25 (s, 2H).

Example 3: Compound 3

Preparation of l-[4-(4-N-Trityl-aminomethyl-benzylamino)-6-(4- methoxybenzylamino)-{l,3,5}-triazin-2-yl-amino]-imidazolidin e-2,4-dione

To the mixture of Compound 2 (7.00g, 11.5 mmol) in DMF (70 mL) was added 4- methoxybenzylamine (1.90 g, 13.8 mmol), K2CO ₃ (2.40 g, 17.3 mmol). The reaction was stirred at 70°C for 6 h. TLC showed all the Compound 2 was consumed completely. The reaction mixture was poured into water (700 mL) and stirred for 10 min. Extracted with EtOAc (150 mL x3), combined the organic layers and washed with water and brine. The organic extracts were dried over anhydrous Na2SC>4, filtered and concentrated to remove 80% of EtOAc. Filtered the solid, dried under reduce pressure to give Compound 3 as a white solid (6.05 g, 75%). TLC: Rf=0.39 silica gel DCM;MeOH=20:l v/v. ^J H NMR (400 MHz, d6-DMSO)5 11.04 (s, 1H), 9.08 - 8.67 (m, 1H), 7.53 - 7.09 (m, 23H), 6.90 - 6.68 (m, 2H), 4.45 - 3.90 (m, 6H), 3.65 (s, 3H), 3.17 - 2.96 (m, 3H).

Example 4: Compound 4

Preparation of l-[4-(4-aminomethyl-benzylamino)-6-(4-methoxybenzylamino)- {l,3,5}-triazin-2-yl-amino]-imidazolidine-2,4-dione

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). A solution of Compound 3 (500 mg, 0.71 mmol) in Dioxane/MeOH/H ₂ 0 (40/60/20 mL) was added to the washed resin (15. Og) and the mixture was stirred at 50°C overnight. Filtered the resin and removed the filtrate. The resin was washed with 2N N¾ in MeOH until no desired peak can be detected. Concentrated under reduce pressure and the residue was purified by silica column (DCM:MeOH:NH3.H ₂ O=30: 1 :0.1 to 10: 1 :0.1) to give a white solid (200mg). The white solid was washed with Et ₂ 0 (20 mL). Filtered and dried to give Compound 4 as a white solid (130 mg, 39%). TLC: Rf=0.28 silica gel DCM;MeOH=10: l v/v. LC- MS:[M+l] ⁺ =464.2. Purity (HPLC): 97.7% at 254nm and 96.8% at 214 nm. ^J H NMR (400 MHz, MeOD) δ 7.28-7.24 (m, 6H), 6.86-6.82 (m 2H), 4.51-4.37 (m, 4H), 4.13 - 3.82(m, 4H), 3.77 (s, 3H). LC/MS with UV at 214 and 254, indicate >96% and 97%, respectively, with a strong signal to noise ratio (see Figures 1 and 2). Example 5: Compound 5

Preparation of l-[4-(4-aminomethyl-benzylamino)-6-(4-methoxybenzylamino)- {l,3,5}-triazin-2-yl-amino]-imidazolidine-2,4-dione, HQ salt.

Compound 5

The reaction mixture of Compound 3 (1.00 g, 1.42 mmol) in 4M HQ/Dioxane (15 mL) was stirred at 70°C overnight. TLC showed that most Compound 3 was consumed. Filtered the solid and washed with EtOAc (10 mL). The solid was dissolved in water (20 mL) and extracted with EtOAc (15 mL*3). The aqueous phase was freeze dried to give the desired product, Compound 5, (500mg, 71%) as white solid. TLC: Rf=0.28 silica gel DCM;MeOH=10:l v/v. LC-MS:[M+l] ⁺ =464.2. Purity (HPLC): 97.1% at 254 nm and at 214 nm. ^J H NMR (400 MHz, MeOD) δ 7.48-7.21 (m, 6H), 6.92-6.89(m H), 4.68-4.58 (m, 4H), 4.13 - 3.94(m, 4H), 3.79 (s, 3H). LC/MS with UV at 254 and14, both indicate >97 with a strong signal to noise ratio (see Figures 3 and 4).