Field of the Invention

[0001] This invention relates to an improved process of making substituted pyrimidines and synthetic intermediates thereof. In particular, the invention relates to an improved process to prepare N-(2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamides. More specifically, this invention relates to an improved process of making N-(2-ammophenyl)-4-((4-pyridin-3- yl)pyrimidin-2-ylamino)methyl)benzamide that requires fewer steps, is efficient, can be used on an industrial scale, and results in a final product that is suitable for pharmaceutical use.

Description of Related Art

[0002] Histone deacetylases (HDACs) constitute a family of enzymes that deacetylate histones and other cellular proteins. They are major regulators of transcription and are also important in other cellular processes. HDAC inhibition is a validated approach in cancer therapy, as evidenced by encouraging clinical data from various HDAC inhibitors. Moreover, preclinical proof-of-concept studies are emerging from animal models for non-oncologic diseases, including inflammatory and neurodegenerative diseases.

[0003] N-(2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamides (for example, WO 03/024448, WO 2004/069823, WO 2005/092899, US 6,897,220) are known to be useful as inhibitors of histone deacetylases and possess valuable pharmacological properties. MGCD0103 (MethylGene Inc.), one such compound in clinical trials, has been shown to be useful in the treatment of cell proliferative diseases such as Hodgkin Lymphoma, non-Hodgkin Lymphoma, leukemia and solid tumors (e.g., Bonfils et al., Clin Cancer Res. 2008 Jun l;14(l l):3441-9; Garcia-Manero, Blood. 2008 Aug 15;112(4):981-9; Sui et al, J Clin Oncol. 2008 Apr 20;26(12): 1940-7; and Fournel et al, Mol Cancer Ther. 2008 Apr;7(4):759-68).

[0004] Previously disclosed methods for preparing HDAC inhibitors based on substiuted pyrimidines such as N-(2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamides and related compounds (for example, US 6,897,220, WO 2004/069823, and Zhou et al, J Med Chem. 2008 Jul 24;51(14):4072-5) involve five major steps, each one requiring the purification of synthetic intermediates. Further, such methods utilized the benzotriazole-l-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate reagent (BOP reagent) at the last stage of the reaction sequence as the coupling reagent. This reagent is rather expensive and generates N,N,N',N',N",N"-hexamethylphosphinetriamine as a by-product, which is toxic, may be present as an impurity in the final product, and is difficult to remove. In addition to these shortcomings, the first and the last steps of the linear sequence are performed in DMF as a solvent, which is a Class 2 solvent and is not ideal for the last step of the synthesis of a compound intended for a treatment of a human disease.

[0005] An additional drawback to such previously disclosed methods is that they are satisfactory only for laboratory scale yields and as such are not useful for industrial scale synthesis.

[0006] There is, therefore, a need for an improved process to prepare HDAC inhibitors based on substituted pyrimidines such as N-(2-aminophenyl)-4-((pyrimidin-2- ylamino)methyl)benzamides that requires fewer steps, is more efficient than previously disclosed methods, can be used on an industrial scale, and results in a final product that is suitable for pharmaceutical use.

SUMMARY OF THE INVENTION

[0007] The present invention provides an improved process for preparing HDAC inhibitors based on substiuted pyrimindines of Formula (I):

wherein

[0008] Cy is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted and each of which is optionally fused to one or two aryl or heteroaryl rings, or to one or two saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings is also optionally substituted, for example, by 1-4 substituents independently selected form the group consisting of H, halo, cyano, nitro, Q-Csalkyl, Ci-C ₃ alkoxy, Ci-Qalkylamino-, C _\ - C ₃ dialkylamino-, Ci-C ₃ alkylthio-, CF ₃ , CHF ₂ , CH ₂ F, OH, NH ₂ , -NHAc, -NH(CO)0-C ₁ -C ₃ alkyl, -CONH ₂ , -CO-NH-Ci-C ₃ alkyl, -CON(C ₁ -C ₃ alkyl) ₂ , -NH(CO)NH-C ₁ -C ₃ alkyl, -NH(CO)N(Ci- C ₃ alkyl) _2>

cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said cycloalkyl, aryl, heteroary and heterocyclyl are themselves optionally substituted, for example by 1-4 substituents independently selected from the group consisting of H, halo, cyano, nitro, Ci-C ₃ -alkyl, Q-C ₃ - alkoxy, C ₁ -C ₃ -alkylamino-, Q-C dialkylamino-, Ci-C ₃ -alkylthio-, CF ₃ , CHF ₂ , CH ₂ F, OH, NH ₂ , NHAc, NH(CO)0-Ci-C ₃ -alkyl, NH(CO)NH- Ci-C ₃ -alkyl. NH(CO)N(Cj-C ₃ -alkyl) ₂

cycloalkyl, aryl, heteroaryl and heteorcyclyl;

1 9 1 9 9 9

[0009] X is selected from the group consisting of a covalent bond, M -L -M , and L -M -L ; wherein

[0010] L ² , at each occurrence, is independently selected from the group consisting of a chemical bond, Co _-4 hydrocarbyl, C _0-4 hydrocarbyl-(NH)-Co- ₄ hydrocarbyl, C0-4 hydrocarbyl-S- C0-4 hydrocarbyl, and Co_ ₄ hydrocarbyl-(0)-Co- ₄ hydrocarbyl;

[0011] M ¹ , at each occurrence, is independently selected from the group consisting of a chemical bond, -0-, -N(R ⁷ )-, -S-, -S(O)-, -S0 ₂ -, -S0 ₂ N(R ⁷ )-, -N(R ⁷ )-S0 ₂ -, -C(O)-, -C(0)-NH-, -NH-C(O)-, -NH-C(0)-0- and -0-C(0)-NH-;

[0012] wherein R ⁷ is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl, and heteroaryl; and

9 1

[0013] M is selected from the group consisting of M , heteroarylene, and heterocyclyl ene, either of which rings optionally is substituted;

[0014] Ar is arylene or heteroarylene, each of which is optionally substituted; and

[0015] Ay is a 5 to 6 membered aryl, or heteroaryl substituted with a substituent selected from the group consisting of amino, hydroxy, and -NH-PG, wherein PG is an amine protecting to the point of attachment of Ay to

[0016] and Ay is further optionally substituted.

[0017] In certain embodiments, Ay is a 5 to 6 membered aryl substituted with a substituent selected from the group consisting of amino, hydroxy, and -NH-PG, wherein PG is an amine protecting group, which substituent is at a position ortho to the point of attacliment of Ay to

[0018] and Ay is further optionally substituted.

[0019] In certain embodiments, Ay is a 5 to 6 membered aryl substituted with a substituent selected from the group consisting of amino, hydroxy, and -NH-PG, wherein PG is an amine protecting group, which substituent is at a position ortho to the point of attachment of Ay to

[0020] and Ay is further optionally substituted with a halo (for example F), phenyl, optionally substituted phenyl or thienyl.

[0021] In certain embodiments of the present invention, PG is selected from the group consisting of tert-butoxycarbonyl (Boc), F-Moc, benzyloxycarbonyl (Cbz), -COCF ₃ , -CH ₂ Ph and -C(0)Me.

[0022] In certain embodiments, Ay is

[0023] In certain embodiments, A

[0024] wherein PG is a protecting group, selected from the group consisting of tert- butoxycarbonyl (Boc), F-Moc, benzyloxycarbonyl (Cbz), -COCF ₃ , -CH ₂ Ph, -C(0)Me,

-C(0)CF ₃ .

[0025] In certain embodiments, the present invention provides an improved process for preparing N-(2-aminophen -4-((pyrimidin-2-ylamino)methyl)benzamides of Formula (la):

[0026] The present invention further provides improved processes for preparing intermediates used in the process for preparing compounds of Formula (I).

[0027] In certain embodiments, the present invention further provides improved processes for preparing intermediates used in the process for preparing N-(2-aminophenyl)-4-((pyrimidin- 2-ylamino)methyl)benzamides of Formula (la).

[0028] In a first aspect, the present invention provides a process for preparing compounds of Formula (I) as defined abov

[0029] comprising (a) reacting an enaminoketone of Formula (III),

1 1 9

[0030] wherein R and R are independently a C _1-4 alkyl (including, for example R = R = Me), or R and R , together with the N to which they are attached form a ring structure selected from the group consisting of piperidine, pyrrolidine and morpholine,

[0031] with a compound of Formula (V),

! ^H N..x. A. rt 0(C C ₄ alkyl)

H (V) [0032] under conditions that yield a compound of Formula (VI);

[0033] (b) converting the ester of Formula (VI) to an acid of Formula (VII), (VII)

[0034] ; and (c) reacting the acid of Formula (VII) so prepared with a substituted aniline of Fomiula (A)

wherein

R ¹⁰ is selected from the group consisting of amino, hydroxy, and -NH-PG, wherein PG is an amine protecting group; and

R ¹¹ is an optional substituent, for example H, halo (for example F), phenyl, optionally substituted phenyl or thienyl,

[0035] to yield the compound of Formula (I).

[0036] Conversion of the ester of Formula (VI) to the acid of Formula (VII) results in a separable acid of Formula (VII), which is used in the subsequent reaction step. In certain embodiments, separating the acid of Formula (VII) so prepared comprises collecting the acid by filtration.

[0037] In certain embodiments of the first aspect, the compound of Formula (V) is not previously purified from the reaction mixture in which it was prepared.

[0038] In certain embodiments of the first aspect, the ester of Formula (VI) is not purified from the reaction mixture in which it was prepared prior to converting it to the acid of Formula (VII).

[0039] In certain embodiments of the first aspect, the compound of Formula (V) is not previously purified from the reaction mixture in which it was prepared and the ester of Formula (VI) is not purified from the reaction mixture in which it was prepared prior to converting it to the acid of Formula (VII).

[0040] In certain embodiments of the first aspect, the compound of Formula (V) is previously purified from the reaction mixture in which it was prepared.

[0041] In certain embodiments of the first aspect, the ester of Formula (VI) is purified from the reaction mixture in which it was prepared prior to converting it to the acid of Formula (VII).

[0042] In certain embodiments of the first aspect, the compound of Formula (V) is not previously purified from the reaction mixture in which it was prepared and the ester of Formula (VI) is purified from the reaction mixture in which it was prepared prior to converting it to the acid of Formula (VII). In certain embodiments of the first aspect, the compound of Formula (V) is previously purified from the reaction mixture in which it was prepared and the ester of Formula (VI) is purified from the reaction mixture in which it was prepared prior to converting it to the acid of Formula (VII).

[0043] In certain embodiments of the first aspect, the process optionally further comprises purifying the compounds of Formula (I) so prepared. Examples of purification include recrystallization or titruration of the compounds of Formula (I) so prepared. In certain embodiments, the purifying comprises recrystallization.

[0044] In certain embodiments of the first aspect, the present invention provides a process for preparing an N-(2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la) as defined above

[0045] comprising (a) reacting an enaminoketone of Formula (III),

II [0046] wherein R and R are independently a d^alkyl (including, for example R = R = Me), or R and R , together with the N to which they are attached form a ring structure selected from the group consisting of piperidine, pyrrolidine and morpholine,

[0047] with an alkyl-4-(guanidinomethyl)benzoate of Formula (Va),

[0048] under conditions that yield a 4-((pyrimidin-2-ylamino)methyl)benzoic acid alkyl ester of Formula (Via);

[0049] (b) converting the 4-((pyrimidin-2-ylamino)methyl)benzoic acid alkyl

Formula (Via) to a 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila),

[0050] and (c) reacting the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila) so prepared with 1,2-diaminobenzene to yield the compound of Formula (la).

[0051] Conversion of the ester of Formula (Via) to the acid of Formula (Vila) results in a separable acid of Formula (Vila), which is used in the subsequent reaction step. In certain embodiments, separating the acid of Fomiula (Vila) so prepared comprises collecting the acid by filtration.

[0052] In certain embodiments of the first aspect, the compound of Formula (Va) is not previously purified from the reaction mixture in which it was prepared.

[0053] In certain embodiments of the first aspect, the 4-((pyrimidin-2- ylamino)methyl)benzoic acid alkyl ester of Formula (Via) is not purified prior to converting it to the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila).

[0054] In certain embodiments of the first aspect, the compound of Formula (Va) is not previously purified from the reaction mixture in which it was prepared and the 4-((pyrimidin-2- ylamino)methyl)benzoic acid alkyl ester of Formula (Via) is not purified from the reaction mixture in which it was prepared prior to converting it to the 4-((pyrimidin-2-yl- amino)methyl)benzoic acid of Formula (Vila).

[0055] In certain embodiments of the first aspect, the compound of Formula (Va) is previously purified from the reaction mixture in which it was prepared.

[0056] In certain embodiments of the first aspect, the 4-((pyrimidin-2- ylamino)methyl)benzoic acid alkyl ester of Formula (Via) is purified from the reaction mixture in which it was prepared prior to converting it to the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila).

[0057] In certain embodiments of the first aspect, the compound of Formula (Va) is not previously purified from the reaction mixture in which it was prepared and the 4-((pyrimidin-2- ylamino)methyl)benzoic acid alkyl ester of Formula (Via) is purified from the reaction mixture in which it was prepared prior to converting it to the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila).

[0058] In certain embodiments of the first aspect, the compound of Formula (Va) is previously purified from the reaction mixture in which it was prepared and the 4-((pyrimidin-2- ylamino)methyl)benzoic acid alkyl ester of Formula (Via) is purified from the reaction mixture in which it was prepared prior to converting it to the 4-((pyrimidin-2-yl-amiiio)niethyl)benzoic acid of Formula (Vila).

[0059] In certain embodiments of the first aspect, the process optionally further comprises purifying the N-(2-aminophenyl)-4-((pyrimidin-2-ylamiiio)methyl)benzamide of Formula (la) so prepared. Examples of purification include crystallization or titruration of the N-(2- aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la) so prepared. In certain embodiments, the purifying comprises crystallization.

[0060] In a second aspect, the present invention provides a process for preparing a compound of Formula (I)

[0061] comprising (a) reacting an enaminoketone of Formula (III),

I II

1 ^' 2 1 2

[0062] wherein R and R are independently a C _1-4 alkyl ( including, for example R = R = Me), or R ¹ and R ² , together with the N to which they are attached form a ring structure selected from the group consisting of piperidine, pyrrolidine and morpholine,

[0063] with a compound of Formula (V) which has been purified from the reaction mixture in which it was prepared,

[0064] under conditions that yield an ester of Formula (VI);

[0065] (b) converting the ester of Formula (VI) to an acid of Formula (VII),

[0066] without purification of the ester of Formula (VI) prior to converting it to the acid of Formula (VII); and (d) reacting the acid of Formula (VII) so prepared with a substituted aniline of Formula (A)

wherein

R ¹⁰ is selected from the group consisting of amino, hydroxy, and -NH-PG, wherein PG is an amine protecting group; and

R ¹¹ is an optional substituent, for example H, halo (for example F), phenyl or t ienyl. [0067] Conversion of the ester of Formula (VI) to the acid of Formula (VII) results in a separable acid of Formula (VII), which is used in the subsequent reaction step. In certain embodiments, separating the acid of Formula (VII) so prepared comprises collecting the acid by filtration.

[0068] In certain embodiments of the second aspect, the process optionally further comprises purifying the compounds of Formula (I) so prepared. Examples of purification include recrystallization or titruration of the compounds of Formula (I) so prepared. In certain embodiments, the purification comprises recrystallization.

[0069] In certain embodiments of the second aspect, the present invention provides a process for preparing an N-(2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la)

[0070] comprising (a) reacting an enaminoketone of Formula (III),

[0071] wherein R ¹ and R ² are independently a C _1-4 alkyl ( including, for example R ¹ = R ² = Me), or R ¹ and R ² , together with the N to which they are attached form a ring structure selected from the group consisting of piperidine, pyrrolidine and morpholine,

[0072] with an alkyl-4-(guanidinomethyl)benzoate of Formula (Va) which has been purified from the reaction mixture in which it was repared,

[0073] under conditions that yield a 4-((pyrimidin-2-ylamino)methyl)benzoic acid alkyl ester of Formula (Via); 0(C _r C ₄ -alkyl)

O (Via)

[0074] (b) converting the 4-((pyrimidin-2-ylamino)methyl)benzoic acid alkyl ester of Formula (Via) to a 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila),

(Vila)

[0075] without purification of the 4-((pyrimidin-2-ylamino)methyl)benzoic acid alkyl ester of Formula (Via) prior to converting it to the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila); and (c) reacting the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila) so prepared with 1,2-diaminobenzene.

[0076] Conversion of the ester of Formula (Via) to the acid of Formula (Vila) results in a separable acid of Formula (Vila), which is used in the subsequent reaction step. In certain embodiments, separating the acid of Formula (Vila) so prepared comprises collecting the acid by filtration.

[0077] In the second aspect, the process optionally further comprises purifying the N-(2- aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la) so prepared. Examples of purification include recrystallization or titruration of the N-(2-aminophenyl)-4- ((pyrimidin-2-ylamino)methyl)benzamide of Formula (la) so prepared. In certain embodiments, the purification comprises recrystallization.

[0078] In a third aspect, the present invention provides a process for preparing an acid of Formula (VII),

[0079] wherein Cy is as defined in the first aspect above,

[0080] the process comprising reacting an enaminoketone of Formula (III),

I II

[0081] wherein R ¹ and R ² are independently a C _1-4 alkyl (including, for example R ¹ = R ² = Me), or R ¹ and R ² , together with the N to which they are attached form a ring structure selected from the group consisting of piperidine, pyrrolidine and morpholine,

[0082] with a compound of Formula V)

[0083] which has not been purified from the reaction mixture in which it was prepared, under conditions that yield an ester of Formula (VI);

[0084] and converting the ester of Formula (VI) to an acid of Formula (VII).

[0085] Conversion of the ester of Formula (VI) to the acid of Formula (VII) results in a separable acid of Formula (VII). Thus, in certain embodiments of the third aspect, the process optionally further comprises separating the acid of Formula (VII) so prepared from the reaction mixture. In certain embodiments, separating the acid of Formula (VII) so prepared comprises collecting the acid by filtration.

[0086] In certain embodiments of the third aspect, the ester of Formula (VI) is not purified prior to converting it to the acid (VII).

[0087] In certain embodiments of the third aspect, the ester of Formula (VI) is purified prior to converting it to the acid of Formula (VII). Examples of purification include recrystallization or titruration. In certain embodiments, the purifying comprises recrystallization.

[0088] In the third aspect of the present invention, the invention optionally provides a "one- pot" process for preparing an acid of Formula (VII), the process comprising (a) reacting a compound of Formula (IV) x

H ₂ N Ar 0(C _r C ₄ -alkyl) (iv) [0089] with a guanidinylating agent under conditions that yield an ester of Formula (V); (b) reacting the ester of Formula (V) so prepared with an enaminoketone (III), to form an ester of Formula (VI); and (c) converting the ester of Formula (VI) to the acid of Formula (VII); without purification of the ester of Formula (V) from the reaction mixture to prepare it prior to reaction with the enaminoketone of Formula (III), and without purification of the ester of Formula (VI) prior to converting it to the acid of Formula (VII).

[0090] Conversion of the ester of Formula (VI) to the acid of Formula (VII) results in a separable acid of Formula (VII). Thus, in certain embodiments of the third aspect, the process optionally further comprises separating the acid of Formula (VII) so prepared from the reaction mixture. In certain embodiments, separating the acid of Formula (VII) so prepared comprises collecting the acid by filtration.

[0091] In certain embodiments of the third aspect, the present invention provides a process for preparing a 4-((pyrimidin- -yl-amino)methyl)benzoic acid of Formula (Vila),

[0092] wherein Cy is as defined in the first aspect above,

[0093] the process comprising reacting an enaminoketone of Formula (III),

I II

1 9 1

[0094] wherein R and R are independently a C _1-4 alkyl ( including, for example R = R = Me), or R ¹ and R ² , together with the N to which they are attached form a ring structure selected from the group consisting of piperidine, pyrrolidine and morpholine,

[0095] with methyl-4-(guanidinomethyl)benzoate of Formula (Va)

[0096] which has not been purified from the reaction mixture in which it was prepared, under conditions that yield a 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (Via);

[0097] and converting the 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (Via) to a 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Fomiula (Vila).

[0098] In certain embodiments of the third aspect, the 4-((pyrimidin-2- ylamino)methyl)benzoic acid methyl ester of Fomiula (Via) is not purified prior to converting it to the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid (Vila).

[0099] In certain embodiments of the third aspect, the 4-((pyrimidin-2- ylamino)methyl)benzoic acid methyl ester of Formula (Via) is purified prior to converting it to the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid (Vila). Examples of purification include recrystallization or titruration. In certain embodiments, the purifying comprises recrystallization.

[0100] In certain embodiments of the the third aspect of the present invention, the invention optionally provides a "one-pot" process for preparing a 4-((pyrimidin-2-yl- amino)methyl)benzoic acid of Formula (Vila), the process comprising (a) reacting a methyl 4- (aminomethyl)benzoate hydrochloride of Formula (IVa) (IVa)

[0101] with a guanidinylating agent under conditions that yield a 4- (guanidinomethyl)benzoate of Formula (Va); (b) reacting the 4-(guanidinomethyl)benzoate of Fomiula (Va) so prepared with an enaminoketone (Ilia), to form a 4-((pyrimidin-2- ylamino)methyl)benzoic acid methyl ester of Formula (Via); and (c) converting the 4- ((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (Via) to the 4-((pyrimidin- 2-yl-amino)methyl)benzoic acid of Formula (Vila); without purification of the 4- (guanidinomethyl)benzoate of Formula (Va) from the reaction mixture to prepare it prior to reaction with the enaminoketone of Formula (III), and without purification of the 4-((pyrimidin- 2-ylamino)methyl)benzoic acid methyl ester of Formula (Via) prior to converting it to the 4- ((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila).

[0102] Conversion of the ester of Formula (Via) to the acid of Formula (Vila) results in a separable acid of Formula (Vila). Thus, in certain embodiments of the third aspect, the process optionally further comprises separating the acid of Formula (Vila) so prepared from the reaction mixture. In certain embodiments, separating the acid of Formula (Vila) so prepared comprises collecting the acid by filtration.

[0103] In a fourth aspect, the present invention provides a process for preparing an acid of Formula (VII),

[0104] wherein Cy is as defined in the first aspect,

[0105] comprising (a) reacting an enaminoketone of Formula (III),

1 1

[0106] wherein R and R are independently a Ci _-4 alkyl (including, for example R = R =

1 9

Me), or R and R , together with the N to which they are attached form a ring structure selected from the group consisting of piperidine, pyrrolidine and morpholine,

[0107] with a compound of Formula V)

[0108] which has been purified from the reaction mixture in which it was prepared, under conditions that yield an ester of Formula (VI);

and (b) converting the ester of Formula (VI) to an acid of Formula (VII). [0110] In certain embodiments of the fourth aspect, the ester of Formula (VI) is not purified prior to converting it to the acid (VII).

[0111] In certain embodiments of the fourth aspect, the ester of Formula (VI) is purified prior to converting it to the acid (VII). Examples of purification include recrystallization or titruration. In certain embodiments, the purifying comprises recrystallization.

[0112] Conversion of the ester of Formula (VI) to the acid of Formula (VII) results in a separable acid of Formula (VII). Thus, in certain embodiments of the fourth aspect, the process optionally further comprises separating the acid of Formula (VII) so prepared from the reaction mixture. In certain embodiments, separating the acid of Formula (VII) so prepared comprises collecting the acid by filtration.

[0113] In certain embodiments of the fourth aspect, the present invention provides a process for preparing a 4-((pyrimidin- -yl-amino)methyl)benzoic acid of Formula (Vila),

[0114] wherein Cy is as defined in the first aspect,

[0115] comprising (a) reacting an enaminoketone of Formula (III),

[0116] wherein R ¹ and R ² are independently a C ₁ . ₄ alkyl (including, for example R ¹ = R ² =

Me), or R and R , together with the N to which they are attached form a ring structure selected from the group consisting of piperidine, pyrrolidine and morpholine,

[0117] with methyl-4-(guanidinomethyl)benzoate of Formula (Va)

[0118] which has been purified from the reaction mixture in which it was prepared, under conditions that yield a 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula

(Via);

[0119] and (b) converting the 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (Via) to a 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila).

[0120] In certain embodiments of the fourth aspect, the 4-((pyrimidin-2- ylamino)methyl)benzoic acid methyl ester of Formula (Via) is not purified prior to converting it to the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid (Vila).

[0121] In certain embodiments of the third aspect, the 4-((pyrimidin-2- ylamino)methyl)benzoic acid methyl ester of Formula (Via) is purified prior to converting it to the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid (Vila). Examples of purification include crystallization or titruration. In certain embodiments, the purifying comprises crystallization.

[0122] Conversion of the ester of Formula (Via) to the acid of Formula (Vila) results in a separable acid of Formula (Vila). Thus, in certain embodiments of the fourth aspect, the process optionally further comprises separating the acid of Formula (Vila) so prepared from the reaction mixture. In certain embodiments, separating the acid of Formula (Vila) so prepared comprises collecting the acid by filtration.

[0123] In a fifth aspect, the invention provides a process for preparing an enaminoketone of Formula (III),

I II

[0124] comprising reacting a methylketone of Formula (II)

I I

[0125] wherein Cy is as defined in the first aspect above, with a compound of Formula

R ²

1 2 1 2

wherein R and R are independently a C _1-4 alkyl, or R and R , together with the N to which they are attached form a ring structure selected from the group consisting of piperidine, pyrrolidine and morpholine, and R ³ and R ⁴ are independently a C _1-4 alkyl.

[0126] In certain embodiments of the fifth aspect, R ¹ , R ² , R ³ and R ⁴ are not all Me.

[0127] In a sixth aspect, the present invention provides a process for preparing an ester of

Formula (VI)

[0128] wherein Cy is as defined in the first aspect above,

[0129] the process comprising reacting an enaminoketone of Formula (III),

I II

[0130] wherein R ¹ and R ² are independently a C _1-4 alkyl (including, for example R ¹ = R ² = Me), or R ¹ and R ² , together with the N to which they are attached form a ring structure selected from the group consisting of piperidine, pyrrolidine and morpholine,

[0131] with a compound of Formula V)

[0132] which has not been purified from the reaction mixture in which it was prepared, under conditions that yield an ester of Formula (VI);

[0133] In the sixth aspect of the present invention, the invention optionally provides a "one- pot" process for preparing an ester of Foraiula (VI), the process comprising (a) reacting a compound of Formula (IV) with a guanidinylating agent under conditions that yield a compound of Fomiula (V); (b) reacting the compound of Foraiula (V) so prepared with an enaminoketone (III), to form an ester of Formula (VI); without purification of the compound of Formula (V) from the reaction mixture to prepare it prior to reaction with the enaminoketone of Formula (III).

[0134] In certain embodiments of the sixth aspect, the present invention provides a process for preparing a 4-((pyrimidi -2-ylamino)methyl)benzoic acid methyl ester of Formula (Via),

[0135] wherein Cy is as defined in the first aspect above,

[0136] the process comprising reacting an enaminoketone of Formula (III),

[0137] wherein R ¹ and R ² are independently a C _1-4 alkyl (including, for example R ¹ = R ² = Me), or R ¹ and R ² , together with the N to which they are attached form a ring structure selected from the group consisting of piperidine, pyrrolidine and morpholine,

[0138] with methyl-4-(guanidinomethyl)benzoate of Formula (Va)

[0139] which has not been purified from the reaction mixture in which it was prepared, under conditions that yield a 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (Via). [0140] In certain embodiments of the sixth aspect, the 4-((pyrimidin-2- ylamino)methyl)benzoic acid methyl ester of Formula (Via) is not purified from the reaction used to prepare it.

[0141] In certain embodiments of the the sixth aspect of the present invention, the invention optionally provides a "one-pot" process for preparing a 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (Via), the process comprising (a) reacting a methyl 4- (aminomethyl)benzoate hydrochloride of Formula (IVa) with a guanidinylating agent under conditions that yield a 4-(guanidinomethyl)benzoate of Formula (Va); (b) reacting the 4- (guanidinomethyl)benzoate of Formula (Va) so prepared with an enaminoketone (III), to form a 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (Via); without purification of the 4-(guanidinomethyl)benzoate of Formula (Va) from the reaction mixture to prepare it prior to reaction with the enaminoketone of Formula (III).

[0142] In certain embodiments of the sixth aspect, the 4-((pyrimidin-2- ylamino)methyl)benzoic acid methyl ester of Formula (Via) is not purified from the reaction used to prepare it.

[0143] In certain embodiments of the sixth aspect, the 4-((pyrimidin-2- ylamino)methyl)benzoic acid methyl ester of Formula (Via) is purified from the reaction used to prepare it. Examples of purification include recrystallization or trituration. In certain embodiments, the purifying comprises trituration.

[0144] In a seventh aspect, the invention provides a composition comprising a compound prepared according to any of the first or second aspects (including all embodiments thereof) and a pharmaceutically acceptable carrier. In certain embodiments, the composition is a medicament for treating a disease responsive to inhibition of a histone deacetylase. In certain embodiments, the disease responsive to inhibition of a histone deacetylase is a cell proliferative disease, such as, for example, cancer.

[0145] In a eighth aspect, the invention provides the use of a compound prepared according to the first or second aspect (including all embodiments thereof) in the manufacture of a medicament for treating a disease responsive to inhibition of a histone deacetylase. In certain embodiments, the disease responsive to inhibition of a histone deacetylase is a cell proliferative disease, such as, for example, cancer. [0146] The first aspect optionally comprises reacting the acid of Formula (VII) prepared according to the third aspect with a substituted aniline of Formula (A)

wherein

R is selected from the group consisting of amino, hydroxy, and -NH-PG, wherein PG is an amine protecting group; and

Pv ¹¹ is an optional substituent, for example H, halo (for example F), phenyl, optionally substituted phenyl or thienyl. The process also optionally comprises purifying the compound of Formula (I) so prepared. For example, purification methods include recrystallization and/or titruation of the compound of Formula (I). In certain embodiments, said purifying comprises recrystallization.

[0147] In certain embodiments of the first aspect, the process optionally comprises reacting the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila) prepared according to the third aspect with a 1,2-diaminobenzene. The process also optionally comprises purifying the N- (2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la) so prepared. For example, purification methods include recrystallization and/or titruation of the N-(2- aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la). In certain embodiments, said purifying comprises recrystallization.

[0148] In certain embodiments of the first aspect, the invention comprises a process for preparing a compound of Formula (I) comprising (a) guanidinylating a compound of Formula (IV) to prepare a compound of Formula (V); (b) reacting the compound of Formula (V) so prepared with an enaminoketone of Formula (III) to yield an ester of Formula (VI); (c) converting the ester of Formula (VI) to an acid of Formula (VII); and (d) reacting the acid of Formula (VII) with a substituted aniline of Formula (A)

wherein R is selected from the group consisting of amino, hydroxy, and -NH-PG, wherein PG is an amine protecting group; and R ¹¹ is an optional substituent, for example H, halo (for example F), phenyl, optionally substituted phenyl or thienyl, wherein steps (a) to (c) are performed in a "one- pot" process.

[0149] In certain embodiments of the first aspect, the invention comprises a process for preparing an N-(2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamides of Formula (la) comprising (a) guanidinylating a 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (IVa) to prepare methyl-4-(guanidinomethyl)benzoate of Formula (Va); (b) reacting the methyl-4-(guanidinomethyl)benzoate of Formula (Va) so prepared with an enaminoketone of Formula (III) to yield a 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (Via); (c) converting the 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (Via) to a 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila); and (d) reacting the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila) with a 1,2-diaminobenzene, wherein steps (a) to (c) are performed in a "one-pot" process.

[0150] In certain embodiments of the second aspect, the invention comprises a process for preparing a compound of Formula (I) comprising (a) guanidinylating a compound of Formula (IV) to prepare a compound of Formula (V); (b) purifiying the compound of Formula (V) so prepared; (c) reacting the purified compound of Formula (V) with an enaminoketone of Formula (III), to form an ester of Formula (VI); (d) converting the ester of Formula (VI) to an acid of Formula (VII); (e) separating the acid of Formula (VII) so prepared; and (f) reacting the acid of Formula VII) so prepared with a substituted aniline of Formula (A)

wherein

R is selected from the group consisting of amino, hydroxy, and -NH-PG, wherein PG is an amine protecting group; and R ¹¹ is an optional substituent, for example H, halo (for example F), phenyl, optionally substituted phenyl or thienyl, wherein steps steps (c) to (d) are performed in a "one-pot" process. [0151] In certain embodiments of the second aspect, the invention comprises a process for preparing an N-(2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la) comprising (a) guanidinylating a 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (IVa) to prepare methyl-4-(guanidinomethyl)benzoate of Fomiula (Va); (b) purifiying the methyl-4-(guanidinometliyl)benzoate of Formula (Va) so prepared; (c) reacting the purified methyl-4-(guanidinomethyl)benzoate of Formula (Va) with an enaminoketone of Formula (III), to form a 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (Via); (d) converting the 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (Via) to a 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila); (e) separating the 4- ((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila) so prepared; and (f) reacting the 4-((pyrimidi -2-yl-amino)methyl)benzoic acid of Formula (Vila) with a 1,2- diaminobenzene,wherein steps (c) to (d) are performed in a "one-pot" process.

[0152] The first and second aspects of the invention optionally include or further comprise salt formation of the compounds so prepared.

[0153] In certain embodiments of the fifth aspect of the invention, the methylketone of Formula (II) is reacted with an N,N-dialkylfom amide-dialkyl acetal, for example an N,N- dimethylfomiamide-dialkyl acetal. Optionally, the enaminoketone of Fomiula (III) so formed is purified prior to use in a subsequent reaction, such as, for example, by trituration with an organic solvent. The organic solvent can be selected (without limitation) from the group consisting of Et ₂ 0, MTBE, EtOAc, THF, hexane, heptane, toluene, and like, or a mixture of two or more thereof.

[0154] In certain embodiments of the fifth aspect of the invention, the enaminoketone of Fomiula (III) is made by a process comprising reacting a methylketone of Formula (II) with a DMF acetal of the formula (R ¹ )(R ² )NCH(OR ³ )(OR ⁴ ), wherein R ¹ and R ² are independently a Ci. ₄ alkyl, or R ¹ and R ² , together with the N to which they are attached form a ring structure selected from the group consisting of piperidine, pyrrolidine and morpholine, and R ³ and R ⁴ are independently a Ci _-4 alkyl or benzyl, (for example, R ³ and R ⁴ are independently selected from the group consisting of Me, Et, Pr, iso-V , Bu, tert-Bu and benzyl), in the presence of a secondary amine (such as, but not limited to Et ₂ NH, Bu ₂ NH, morpholine, piperidine, pyrrolidine or DBU) or a tertiary amine (such as, but not limited to, Et ₃ N, DIPEA, N-methyl morpholine, N- methylpiperidine, DMAP or NN-dimethylaiiiline) and the like. In certain embodiments of the fifth aspect, R ¹ , R ² , R ³ and R ⁴ are not all Me.

[0155] In certain embodiments of all aspects of the invention, the enaminoketone of Formula (III) is optionally prepared by reacting a methylketone of Formula (II) with approximately 1.0- 6.0 equivalents, including, for example, 1.2 to 4.0 equivalents and 1.5-2.0 equivalents of DMF acetals of the formula Me ₂ NCH(OR)2, where R is selected from the group consisting of Me, Et, Pr, iso-Fr, Bu, tert-Bn, benzyl and the like, in the presence of 0.5-1.5 equivalents of a tertiary amine, such as, but not limited to, Et ₃ N, DIPEA, N-methyl morpholine, N-methylpiperidine, DMAP, NN-dimefhylaniline and the like, in the temperature range of 90-140°C, including, for example 110-120°C. The reaction may optionally proceed in a high boiling aprotic solvent such as pyridine, 1 ,2-dimethoxy ethane (DME), DMSO, diphenyl ether or the like.

[0156] In certain embodiments of all aspects of the invention, the enaminoketone of Formula (III) is optionally prepared by reacting a methylketone of Formula (II) with 1.5-2.0 equivalents of Me ₂ NCH(OMe) ₂ or Me ₂ NCH(OEt) ₂ in the presence of 0.5-1.5 equivalents of a tertiary amine, such as but not limited to Et ₃ N, DIPEA, N-methyl morpholine, N-methylpiperidine, DMAP, NN- dimethylaniline or the like, in the temperature range of 90-140°C, including, for example, 110- 120°C. The reaction may optionally proceed in a high boiling aprotic solvent such as pyridine, 1 ,2-dimethoxy ethane (DME), DMSO, diphenyl ether or the like.

[0157] In certain embodiments of all aspects of the invention, an enaminoketone of Formula (III) is optionally prepared by reacting a methylketone of Formula (II) with 1.5-2.0 equivalents of Me ₂ NCH(OMe) ₂ or Me ₂ NCH(OEt) ₂ in the presence of 0.5-1.5 equivalents of Et ₃ N, including, for example, equimolar quantities of Et ₃ N, in the temperature range of 90-140°C, including, for example, 110-120°C. The reaction may optionally proceed in a high boiling aprotic solvent such as pyridine, 1 ,2-dimethoxy ethane (DME), DMSO, diphenyl ether or the like.

[0158] In certain embodiments of all aspects of the invention, the enaminoketone of Formula (III) is optionally purified prior to use in a subsequent reaction. For example, the enaminoketone of Formula (III) can be purified by trituration with an organic solvent, including, without limitation, an organic solvent is selected from the group consisting of Et ₂ 0, MTBE, EtOAc, THF, hexane, heptane, toluene, and like, or a mixture of two or more thereof.

[0159] The methyl 4-(aminomethyl)benzoate hydrochloride of Formula (IV) can (but need not) be a commercially available compound. [0160] In certain embodiments of the present invention, an acid of Formula (VII) is prepared using a "one-pot," three-stage procedure comprising (a) guanidinylating a compound of Formula (IV) to form a compound of Formula (V); (b) reacting the compound of Formula (V) with an enaminoketone of Formula (III) under basic conditions to produce an ester of Formula (VI); and (c) hydrolyzing the ester of Formula (VI) to produce the acid of Formula (VII).

[0161] In certain embodiments of the present invention, a 4-((pyrimidin-2-yl- amino)methyl)benzoic acid of Formula (Vila) is prepared using a "one-pot," three-stage procedure comprising (a) guanidinylating a methyl 4-(aminomethyl)benzoate hydrochloride of Formula (IVa) to form 4-(guanidinomethyl)benzoate of Formula (Va); (b) reacting the 4- (guanidinomethyl)benzoate of Formula (Va) with an enaminoketone of Formula (III) under basic conditions to produce a 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (Via); and (c) hydrolyzing the 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Formula (Via) to produce the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila).

[0162] In certain mbodiments of any of the first, second, third or fourth aspects, preparation of a compound of Formula (V) comprises reactin a compound of Formula (IV),

x HCI (IV)

[0163] wherein R ⁵ is a C _1-4 alkyl, for example methyl, with lH-pyrazole-l-carboximidamide hydrochloride or lH-l,2,4-triazole-l-carboximidamide hydrochloride (under basic conditions), or 5-methylisothiourea sulfate or cyanamide (under acidic conditions), in a solvent such as MeOH, EtOH, PrOH, wo-PrOH, THF, DME or the like (or a mixture of these solvents), at a temperature of 60-110°C, including, for example, 70 to 90 °C and 75-85 °C. A small amount of base (approximately 0.05 - 0.2 eq) (after neutralizing the HC1 associated with the reaction partners) facilitates the reaction. In certain embodiments, the compound of Formula (V) is prepared by reacting a compound of Formula (IV), such as, for example a methyl 4- (aminomethyl)benzoate hydrochloride of Formula (IVa), with lH-pyrazole-l-carboximidamide as the guanidinylating reagent in refluxing EtOH in the presence of DIPEA (approximately 0.08- 0.15 equivalents). [0164] In certain embodiments of any of the first, second, third or fourth aspects, preparation of methyl-4-(guanidinomethyl)benzoate of Formula (Va) comprises reacting a methyl 4- (aminomethyl)benzoate hydrochloride of Formula (IVa), IVa)

[0165] with lH-pyrazole-l-carboximidamide hydrochloride or lH-l,2,4-triazole-l- carboximidamide hydrochloride (under basic conditions), or -methylisothiourea sulfate or cyanamide (under acidic conditions), in a solvent such as MeOH, EtOH, PrOH, wo-PrOH, THF, DME or the like (or a mixture of these solvents), at a temperature of 60-110°C, including, for example, 70 to 90 °C and 75-85 °C. A small amount of base (approximately 0.05 - 0.2 eq) (after neutralizing the HCI associated with the reaction partners) facilitates the reaction. In certain embodiments, the methyl-4-(guanidinomethyl)benzoate of Formula (Va) is prepared by reacting methyl 4-(aminomethyl)benzoate hydrochloride of Formula (IVa), with lH-pyrazole-1- carboximidamide as the guanidinylating reagent in refluxing EtOH in the presence of DIPEA (approximately 0.08-0.15 equivalents).

[0166] In the third aspect, reaction of the compound of Formula (V) so prepared with an enaminoketone of Formula (III) (pyrimidine ring formation) optionally comprises (a) adding the enaminoketone of Formula (III), such as, for example, in solid form, to the compound of Formula (V) reaction mixture; (b) diluting the reaction mixture 1.5 to 4-fold with a solvent such as, but not limited to, MeOH, EtOH, PrOH, zso-PrOH, THF or DME (or a mixture of these solvents); (c) adding a solution of Li, Na, K methylates or ethylates in quantities of 1.5-4.5 equivalents; and (d) heating the reaction at approximately 60-110°C, including, for example, 75- 90 °C, for approximately 12-24 hours. Step (b) optionally comprises approximately a two-fold dilution of the reaction mixture with ethanol. Step (c) optionally comprises adding NaOMe in MeOH (approximately 3.0 equivalents). Step (d) optionally comprises heating the reaction at reflux conditions for approximately 18 hours. Step (b) optionally comprises approximately a two-fold dilution of the reaction mixture with ethanol, step (c) comprises adding NaOMe in MeOH (approximately 3.0 equivalents), and step (d) comprises heating the reaction at reflux conditions for approximately 18 hours. Alternatively, steps (a) and (b) optionally comprise dissolving or suspending the enaminoketone of Formula (III) before addition to the reaction mixture in an amount of a solvent such as MeOH, EtOH, PrOH, z ^' soPrOH, THF or DME (or a mixture of these solvents) to obtain approximately a 1.5- to 3-fold dilution of the reaction mixture.

[0167] In certain embodiments of the third aspect, reaction of the 4- (guanidinomethyl)benzoate of Formula (Va) so prepared with an enaminoketone of Formula (III) (pyrimidine ring formation) optionally comprises (a) adding the enaminoketone of Formula (III), such as, for example, in solid form, to the methyl-4-(guanidinomethyl)benzoate of Formula (Va) reaction mixture; (b) diluting the reaction mixture 1.5 to 4-fold with a solvent such as, but not limited to, MeOH, EtOH, PrOH, wo-PrOH, THF or DME (or a mixture of these solvents); (c) adding a solution of Li, Na, K methylates or ethylates in quantities of 1.5-4.5 equivalents; and (d) heating the reaction at approximately 60-110°C, including, for example, 75-90°C, for approximately 12-24 hours. Step (b) optionally comprises approximately a two-fold dilution of the reaction mixture with ethanol. Step (c) optionally comprises adding NaOMe in MeOH (approximately 3.0 equivalents). Step (d) optionally comprises heating the reaction at reflux conditions for approximately 18 hours. Step (b) optionally comprises approximately a two-fold dilution of the reaction mixture with ethanol, step (c) comprises adding NaOMe in MeOH (approximately 3.0 equivalents), and step (d) comprises heating the reaction at reflux conditions for approximately 18 hours. Alternatively, steps (a) and (b) optionally comprise dissolving or suspending the enaminoketone of Formula (III) before addition to the reaction mixture in an amount of a solvent such as MeOH, EtOH, PrOH, wo-PrOH, THF or DME (or a mixture of these solvents) to obtain approximately a 1.5- to 3 -fold dilution of the reaction mixture.

[0168] In the third aspect, conversion of the ester of Formula (VI) to an acid of Formula (VII) optionally comprises (a) adding to the reaction mixture approximately 1.5 - 2.0 equivalents of an aqueous solution of LiOH, NaOH or KOH, to result in a 2 to 5-fold dilution of the reaction mixture; (b) heating the reaction mixture at 80-120°C for 12-24 hours, for example at reflux conditions for approximately 18 hours; (c) cooling the reaction mixture to room temperature; (d) acidifying the reaction mixture; and (e) collecting the acid of Formula (VII). Step (d) optionally comprises acidification of the reaction mixture with an aqueous solution of an acid such as, but not limited to, HCOOH, AcOH, HC1, HBr, H ₂ S0 ₄ , ¾P0 ₄ or the like. Optionally, the acid of Formula (VII) is collected by filtration. Step (a) optionally comprises adding approximately 1.6 equivalents of aqueous NaOH to the reaction mixture to obtain approximately a 3.5-fold dilution of the reaction mixture. Step (b) optionally comprises heating the reaction mixture at reflux conditions for approximately 18 hours. Step (d) optionally comprises acidification of the reaction mixture to a pH of approximately 4-7, for example 5.8. Step (e) optionally comprises adding an organic solvent such as, but not limited to, MeOH, EtOH, wo-PrOH, THF, acetone or the like to the acidic reaction mixture and collecting the acid of Formula (VII). Step (e) optionally comprises adding an organic solvent such as, but not limited to, MeOH, EtOH, iso- PrOH, THF, acetone or the like to the acidic reaction mixture, wherein the volume of the organic solvent added is approximately 0.5 to 1 times the volume of the acidified suspension, and collecting the acid of Formula (VII).

[0169] In certain embodiments of the third aspect, conversion of the 4-((pyrimidin-2- ylamino)methyl)benzoic acid methyl ester of Formula (Via) to a 4-((pyrimidin-2-yl- amino)methyl)benzoic acid of Formula (Vila) optionally comprises (a) adding to the reaction mixture approximately 1.5 - 2.0 equivalents of an aqueous solution of LiOH, NaOH or KOH, to result in a 2 to 5-fold dilution of the reaction mixture; (b) heating the reaction mixture at 80- 120°C for 12-24 hours, for example at reflux conditions for approximately 18 hours; (c) cooling the reaction mixture to room temperature; (d) acidifying the reaction mixture; and (e) collecting the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila). Step (d) optionally comprises acidification of the reaction mixture with an aqueous solution of an acid such as, but not limited to, HCOOH, AcOH, HC1, HBr, H ₂ S0 ₄ , H ₃ P0 ₄ or the like. Optionally, the 4- ((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila) is collected by filtration. Step (a) optionally comprises adding approximately 1.6 equivalents of aqueous NaOH to the reaction mixture to obtain approximately a 3.5-fold dilution of the reaction mixture. Step (b) optionally comprises heating the reaction mixture at reflux conditions for approximately 18 hours. Step (d) optionally comprises acidification of the reaction mixture to a pH of approximately 4-7, for example 5.8. Step (e) optionally comprises adding an organic solvent such as, but not limited to, MeOH, EtOH, z ^' so-PrOH, THF, acetone or the like to the acidic reaction mixture and collecting the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila). Step (e) optionally comprises adding an organic solvent such as, but not limited to, MeOH, EtOH, iso-ΥτΟΆ, THF, acetone or the like to the acidic reaction mixture, wherein the volume of the organic solvent added is approximately 0.5 to 1 times the volume of the acidified suspension, and collecting the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila).

[0170] In certain embodiments of the first or second aspects, reaction of the acid of Formula (VII) with a 1,2-diaminobenzene optionally comprises an amide coupling reaction of the acid of Formula (VII) with 6-12 equivalents (e.g., 8-9 equivalents) of 1 ,2-diaminobenezene in the presence of 1-3 equivalents (e.g., 1.8-2.0 equivalents) of a coupling reagent such as, but not limited to, HOBt, EDC, HATU, HBTU, BOP, DCC, DIC, CIP, PyBOP, HNTU, AOP, PPAA, PFTU, or the like (or a mixture of two or more thereof), such as, for example, a mixture of HOBt and EDC, in the presence of 2-6 equivalents, (e.g., 4.5-5.0 equivalents) of a tertiary amine such as, but not limited to, Et ₃ N, DIPEA, N-methylmorpholine, N-methylpiperidine, DMAP, N,N- dimethylaniline, N,iV-diethylaniline, DBU, DABCO, or the like, in particular Et ₃ N. The reaction optionally occurs in a solvent such as, but not limited to, MeCN, DMF, NMP, DMA, or THF. The reaction can also occur in DMSO.

[0171] In certain embodiments of the first or second aspects, reaction of the 4-((pyrimidin-2- yl-amino)methyl)benzoic acid of Formula (Vila) with a 1,2-diaminobenzene optionally comprises an amide coupling reaction of the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila) with 6-12 equivalents (e.g., 8-9 equivalents) of 1,2-diaminobenezene in the presence of 1-3 equivalents (e.g., 1.8-2.0 equivalents) of a coupling reagent such as, but not limited to, HOBt, EDC, HATU, HBTU, BOP, DCC, DIC, CIP, PyBOP, HNTU, AOP, PPAA, PFTU, or the like (or a mixture of two or more thereof), such as, for example, a mixture of HOBt and EDC, in the presence of 2-6 equivalents, (e.g., 4.5-5.0 equivalents) of a tertiary amine such as, but not limited to, Et ₃ N, DIPEA, N-methylmorpholine, N-methylpiperidine, DMAP, N,N- dimethylaniline, N,N-diethylaniline, DBU, DABCO, or the like, in particular Et ₃ N. The reaction optionally occurs in a solvent such as, but not limited to, MeCN, DMF, NMP, DMA, or THF. The reaction can also occur in DMSO.

[0172] In certain embodiments of the first and second aspects, prior to reacting the acid of Formula (VII) with a 1,2-diaminobenzene, the acid of Formula (VII) is optionally converted into an activated species such as, but not limited to, an acyl halide, a mixed anhydride, a IH~ imidazol-l-yl or a lH-benzo[d][l,2,3]triazol-l-yl derivative, or the like, Activation can occur, for example, in a solvent such as, but not limited to, THF, MeCN, DME, DMA or DMSO (or a mixture of such solvents) at a temperature ranging from -20° to 80°C. [0173] In certain embodiments of the first and second aspects, prior to reacting the 4- ((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila) with a 1 ,2-diaminobenzene, the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila) is optionally converted into an activated species such as, but not limited to, an acyl halide, a mixed anhydride, a lH-imidazol-1- yl or a lH-benzo[d][l,2,3]triazol-l-yl derivative, or the like. Activation can occur, for example, in a solvent such as, but not limited to, THF, MeCN, DME, DMA or DMSO (or a mixture of such solvents) at a temperature ranging from -20° to 80°C.

[0174] In certain embodiments of the first and second aspects, reacting the acid of Formula (VII) with a 1,2-diaminobenzene optionally comprises an amide coupling reaction of the acid of Formula (VII) with 7-10 equivalents of 1,2-diaminobenzene, in the presence of 1.0-2.5 equivalents of a mixture of HOBT and EDC, and 2.0-4.5 equivalents of Et ₃ N, at a temperature of 18-25°C, in MeCN or DMSO.

[0175] In certain embodiments of the first and second aspects, reacting the 4-((pyrimidin-2- yl-amino)methyl)benzoic acid of Formula (Vila) with a 1,2-diaminobenzene optionally comprises an amide coupling reaction of the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila) with 7-10 equivalents of 1,2-diaminobenzene, in the presence of 1.0-2.5 equivalents of a mixture of HOBT and EDC, and 2.0-4.5 equivalents of Et ₃ N, at a temperature of 18-25°C, in MeCN or DMSO.

[0176] In certain embodiments of the first and second aspects of the invention the 1,2- aminobenzene is a mono-protected 1,2-diaminobenzene of Formula (VIII) and the process optionally comprises a reaction of the acid of Formula (VII) (or an activated species thereof) with a mono-protected 1,2-diaminobenzene of Formula (VIII) (for example 1 - 2.5 equivalents):

VI II

[0177] to form a protected species of Formula IX:

In certain embodiments of the first and second aspects of the invention optionally a reaction of the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila) (or an activated species thereof) with a mono-protected 1,2-diaminobenzene of Formula (VIII) (for example 1 - 2.5 equivalents):

VI II

[0179] to form a protected species of Formula IXa:

[0180] Protecting groups (PG) of the mono-protected 1,2-diaminobenzene of Formula (VIII) include, but are not limited to, tert-butoxycarbonyl (Boc), F-Moc, benzyloxycarbonyl (Cbz), -COCF ₃ , -CH ₂ Ph, -C(0)Me, -C(0)CF ₃ or another protecting group used to protect primary amino groups ("Protective Groups in Organic Synthesis" T. W. Greene, Wiley, NY). For example, protecting groups include, but are not limited to, Boc. Such embodiments of the first and second aspects further comprise a step of deprotection to produce the desired N-(2- aminophenyl)benzamide of Formula (I).

[0181] In certain embodiments of the first and second aspects, when the compound of Formula (I) is purified by recrystallization, the recrystallization optionally comprises (a) dissolving the compound of Formula (I) so prepared in minimal quanitities of a high boiling point solvent, such as, but not limited to, DMA, DMF, N-methylpyrrolidone, DMSO, sulfolan or the like, such as, for example DMSO, at 30-100°C, including, for example, 30-60°C; (b) filtering the solution of step (a); (c) adding to the filtrate 2-6 volumes of an anti-solvent, such as, but not limited to, MeOH, EtOH, iso-PrOH, THF, MeCN or the like, in particular EtOH or iso-PrOH; (d) solubilizing the suspension formed in step (c), for example by heating to reflux (or at 50- 90°C) and stirring, or by heating at a temperature below the boiling points of the binary solvent systems (a person skilled in the art will understand that more than two-component solvent systems may be used for the purpose); (d) slowly cooling the solution to a temperature of approximately -10 to 25°C; and (e) collecting the precipitate so formed. Precipitated compound of Formula (I) can be optionally collected by suction filtration, air dried and kept in vacuum at a temperature of approximately 25-50°C for approximately 16-72 hours. [0182] In certain embodiments of the first and second aspects, when the N-(2-aminophenyl)- 4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la) is purified by recrystallization, the recrystallization optionally comprises (a) dissolving the N-(2-aminophenyl)-4-((pyrimidin-2- ylamino)methyl)benzamide of Formula (la) so prepared in minimal quanitities of a high boiling point solvent, such as, but not limited to, DMA, DMF, N-methylpyrrolidone, DMSO, sulfolan or the like, such as, for example DMSO, at 30-100°C, including, for example, 30-60°C; (b) filtering the solution of step (a); (c) adding to the filtrate 2-6 volumes of an anti-solvent, such as, but not limited to, MeOH, EtOH, iso-PrOH, THF, MeCN or the like, in particular EtOH or iso-PrOH; (d) solubilizing the suspension formed in step (c), for example by heating to reflux (or at 50- 90°C) and stirring, or by heating at a temperature below the boiling points of the binary solvent systems (a person skilled in the art will understand that more than two-component solvent systems may be used for the purpose); (d) slowly cooling the solution to a temperature of approximately -10 to 25°C; and (e) collecting the precipitate so formed. Precipitated compound of Formula (la) can be optionally collected by suction filtration, air dried and kept in vacuum at a temperature of approximately 25-50°C for approximately 16-72 hours.

[0183] In certain embodiments of the first and second aspects, when the compound of Formula (I) is purified by recrystallization, the recrystallization optionally comprises (a) suspending the compound of Formula (I) so prepared in an approximately 1 :2 to 1 :6 mixture of a solvent such as, but not limited to, DMA, DMF, N-methylpyrrolidone, DMSO, sulfolan and like, for example DMSO, and an anti-solvent such as, but not limited to, MeOH, EtOH, iso-PrOH, THF, MeCN and the like, particularly EtOH or iso-PrOH; (b) heating the suspension at approximately 60-120°C to ensure maximal dissolution of the solids; (c) filtering the hot solution; (d) re-heating the filtrates (optionally including precipitated products) to reflux (or at 50-90°C) to ensure complete dissolution of the solids; (e) slowly cooling the solutions to a temperature of approximately -10 to 25°C; and (f) collecting the precipitate so formed. Precipitated compound of Formula (I) so formed is optionally collected by suction filtration, air dried and kept in vacuum at a temperature of approximately 25-50°C for approximately 16-72 hours.

[0184] In certain embodiments of the first and second aspects, when the N-(2-aminophenyl)- 4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la) is purified by recrystallization, the recrystallization optionally comprises (a) suspending the N-(2-aminophenyl)-4-((pyrimidin-2- ylamino)methyl)benzamide of Formula (la) so prepared in an approximately 1 :2 to 1 :6 mixture of a solvent such as, but not limited to, DMA, DMF, N-methylpyrrolidone, DMSO, sulfolan and like, for example DMSO, and an anti-solvent such as, but not limited to, MeOH, EtOH, iso- PrOH, THF, MeCN and the like, particularly EtOH or iso-PrOH; (b) heating the suspension at approximately 60-120°C to ensure maximal dissolution of the solids; (c) filtering the hot solution; (d) re-heating the filtrates (optionally including precipitated products) to reflux (or at 50-90°C) to ensure complete dissolution of the solids; (e) slowly cooling the solutions to a temperature of approximately -10 to 25°C; and (f) collecting the precipitate so formed. Precipitated compound of Formula (la) so formed is optionally collected by suction filtration, air dried and kept in vacuum at a temperature of approximately 25-50°C for approximately 16-72 hours.

[0185] In certain embodiments of the first and second aspects the processes optionally comprises formation of pharmaceutically acceptable salts of the compound of Formula (I) by treatment of solutions or suspensions of the compound of Formula (I) with suitable acids such as HC1, HBr, HI, H ₂ S0 ₄ , H ₃ P0 ₄ , HN0 ₃ , methane sulfonic, ethane sulfonic, benzene sulfonic, p- toluene sulfonic, benzoic, lactic, succininc, salicylic, malic, citric, fumaric, maleic, glycolic, etc.; in solvents such as water, MeOH, EtOH, IP A, acetone, MTBA, 1,2-dimethoxyethane, 1,2- diethoxyethane, dioxane, THF, MeCN, EtOAc or mixtures of these solvents.

[0186] In certain embodiments of the first and second aspects the processes optionally comprise formation of pharmaceutically acceptable salts of the N-(2-aminophenyl)-4- ((pyrimidin-2-ylamino)methyl)benzamide of Formula (la) by treatment of solutions or suspensions of the N-(2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la) with suitable acids such as HC1, HBr, HI, H ₂ S0 ₄ , H ₃ P0 ₄ , HN0 ₃ , methane sulfonic, ethane sulfonic, benzene sulfonic, p-toluene sulfonic, benzoic, lactic, succininc, salicylic, malic, citric, fumaric, glycolic, etc.; in solvents such as water, MeOH, EtOH, IP A, acetone, MTBA, 1,2- dimethoxyethane, 1,2-diethoxyethane, dioxane, THF or mixtures of these solvents.

[0187] In certain embodiments of the fourth aspect, the process of preparing an acid of Formula (VII) optionally comprises (a) providing an intermediate compound of Formula (V); (b) reacting the compound of Formula (V) with an enaminoketone of Fomiula (III) under basic conditions; and (c) collecting the acid of Formula (VII) so formed. The process for providing the compound of Formula (V) optionally comprises reacting a compound of Formula (IV) with 1H- pyrazole-l-carboximidamide hydrochloride or lH-l,2,4-triazole-l-carboximidamide hydrochloride under basic conditions, or S-methylisothiourea sulfate [G. Wagner et. al., Pharmazie 1973, 28, 293-296] or cyanamide (under acidic conditions) in a solvent such as water, MeOH, EtOH, wo-PrOH, THF, DME (or a mixture of such solvents) or the like in the presence of an organic base. Organic bases include, but are not limited to, Et ₃ N, DIPEA, N-methyl morpholine, N-methylpiperidine, DMAP, NN-dimethylaniline and the like (for example, 0.2-1.2 equivalents of organic base after neutralization of the HCl associated with the hydrochlorides used). The reaction can be carried out at a temperature of approximately 60-110°C. The process for providing the compound of Formula (V) optionally comprises reacting a compound of Formula (IV) with lN-pyrazole-l-carboximidamide hydrochloride, for example in refluxing EtOH and, for example, in the presence of DIPEA (0.5-1.0 equivalents after neutralization of the HCl associated with the hydrochloride used).

[0188] In certain embodiments of the fourth aspect, the process of preparing a 4-((pyrimidin- 2-yl-amino)methyl)benzoic acid of Formula (Vila) optionally comprises (a) providing an intermediate methyl 4-(guanidinomethyl)benzoate of Formula (Va); (b) reacting the methyl 4- (guanidinomethyl)benzoate of Formula (Va) with an enaminoketone of Formula (III) under basic conditions; and (c) collecting the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila) so formed. The process for providing the 4-(guanidinomethyl)benzoate of Formula (Va) optionally comprises reacting a methyl 4-(aminomethyl)benzoate hydrochloride of Formula (IVa) with lH-pyrazole-l-carboximidamide hydrochloride or lN-l,2,4-triazole-l- carboximidamide hydrochloride under basic conditions, or 5-methylisothiourea sulfate [G. Wagner et. al., Pharmazie 1973, 28, 293-296] or cyanamide (under acidic conditions) in a solvent such as water, MeOH, EtOH, wo-PrOH, THF, DME (or a mixture of such solvents) or the like in the presence of an organic base. Organic bases include, but are not limited to, Et ₃ N, DIPEA, N-methyl morpholine, N-methylpiperidine, DMAP, NN-dimethylaniline and the like (for example, 0.2-1.2 equivalents of organic base after neutralization of the HCl associated with the hydrochlorides used). The reaction can be carried out at a temperature of approximately 60- 110°C. The process for providing the 4-(guanidinomethyl)benzoate of Formula (Va) optionally comprises reacting a methyl 4-(aminomethyl)benzoate hydrochloride of Formula (IVa) with 1H- pyrazole-l-carboximidamide hydrochloride, for example in refluxing EtOH and, for example, in the presence of DIPEA (0.5-1.0 equivalents after neutralization of the HCl associated with the hydrochloride used). Commercially available methyl 4-(aminomethyl)benzoate hydrochloride of Formula (IVa) can be used.

[0189] In certain embodiments of the fourth aspect, the process of preparing an acid of Formula (VII) optionally comprises reacting a compound of Formula (V) with an enaminoketone of Formula (III) in a "one-pot," two stage process:

(a) First stage - the pyrimidine ring formation - is the reaction of an enaminoketone of Formula (III) with a compound of Formula (V) (1.0-1.5 eq.) in a solvent such as, but not limited to, MeOH, EtOH, PrOH, wo-PrOH, THF, or DME (or a mixture of two or more thereof) followed by the addition of a solution of Li, Na or K methylates or ethylates in quantities of 1.5-4.5 equivalents and heating at 40-110°C for 12-72 hours. In certain embodiments, the conditions are: NaOMe in MeOH (4.0 equivalents) and running the reaction at reflux conditions for 48 hours.

(b) Second stage - ester hydrolysis - is an addition to the reaction mixture of 1.5-5.0 equivalents of an aqueous solution of LiOH, NaOH or KOH accompanied by a 2- to 5- fold dilution of the reaction mixture with a solvent such as, but not limited to, MeOH, EtOH, PrOH, zso-PrOH, THF or DME (or a mixture two or more thereof), heating the reaction mixture at 40-120°C for 12-24 hours, followed by cooling to the room temperature, evaporating of the organics from the reaction mixture, diluting the alkaline aqueous solution with more water, washing the alkaline diluted solution with a solvent such as, but not limited to, EtOAc, toluene, MTBE, Me-THF or the like, followed by a final acidification with an aqueous acid solution such as, but not limited to, HCOOH, AcOH, HC1, HBr, H ₂ S0 ₄ , H ₃ P0 ₄ or the like. Acidification of the reaction mixture (pH 4-7) leads to formation of precipitates (acids VII), which may be collected by, for example, suction filtration.

[0190] In certain embodiments of the fourth aspect, the process of preparing a 4-((pyrimidin- 2-yl-amino)methyl)benzoic acid of Formula (Vila) optionally comprises reacting a methyl 4- (guanidinomethyl)benzoate of Formula (Va) with an enaminoketone of Formula (III) in a "one- pot," two stage process:

(a) First stage - the pyrimidine ring formation - is the reaction of an enaminoketone of Formula (III) with a guanidine of Formula (Va) (1.0-1.5 eq.) in a solvent such as, but not limited to, MeOH, EtOH, PrOH, ώο-PrOH, THF, or DME (or a mixture of two or more thereof) followed by the addition of a solution of Li, Na or K methylates or ethylates in quantities of 1.5-4.5 equivalents and heating at 40-110°C for 12-72 hours. In certain embodiments, the conditions are: NaOMe in MeOH (4.0 equivalents) and running the reaction at reflux conditions for 48 hours,

(b) Second stage - ester hydrolysis - is an addition to the reaction mixture of 1.5-5.0 equivalents of an aqueous solution of LiOH, NaOH or KOH accompanied by a 2- to 5- fold dilution of the reaction mixture with a solvent such as, but not limited to, MeOH, EtOH, PrOH, wo-PrOH, THF or DME (or a mixture two or more thereof), heating the reaction mixture at 40-120°C for 12-24 hours, followed by cooling to the room temperature, evaporating of the organics from the reaction mixture, diluting the alkaline aqueous solution with more water, washing the alkaline diluted solution with a solvent such as, but not limited to, EtOAc, toluene, MTBE, Me-THF or the like, followed by a final acidification with an aqueous acid solution such as, but not limited to, HCOOH, AcOH, HC1, HBr, H ₂ S0 ₄ , H ₃ P0 ₄ or the like. Acidification of the reaction mixture (pH 4-7) leads to formation of precipitates (acids Vila), which may be collected by, for example, suction filtration.

[0191] In certain embodiments of the various aspect of the present invention, Cy is optionally substituted aryl or optionally substituted heteroaryl, for example optionally substituted heteroaryl. The heteroaryl can be (but is not limited to) pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which is optionally substituted. In certain embodiments the heteroaryl is optionally substituted pyridinyl.

[0192] In certain embodiments of any aspect of the present invention, Cy is selected from the group consisting of

[0 93] In certa n em o ments any aspect o t e present nvention, Cy s se ected from

group consisting of r ^v and rf .

[0194] In certain embodiments of any aspect of the present invention, Cy is

[0195] In certain embodiments of any aspect of the present invention, the compound of

Formula (I) is an N-(2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula

(la).

[0196] In certain embodiments of any aspect of the present invention, the compound of Fomiula (V) is methyl-4-(guanidinomethyl)benzoate of Fomiula (Va).

[0197] In certain embodiments of any aspect of the present invention, the compound of Formula (VI) is a 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Fomiula (Via).

[0198] In certain embodiments of any aspect of the present invention, the compound of Fomiula (VII) is a 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila).

[0199] In certain embodiments of the invention, X is not a covalent bond.

[0200] In certain embodiments of the invention, X is -C¾-.

[0201] In certain embodiments of the invention, Ar is p-phenyleiie.

[0202] In the present invention, a disease responsive to inhibition of a histone deacetylase can be a cell proliferative disease such as, but not limited to, cancer. Alternatively, diseases responsive to inhibition of a histone deacetylase by the compounds of the invention include those selected from the group consisting of Hodgkin Lymphoma, non-Hodgkin Lymphoma, leukemia and solid tumors.

[0203] The foregoing merely summarizes the above aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below. The patent and scientific literature referred to herein establishes knowledge that is available to those with skill in the art. Each issued patent, patent application, and other publication cited herein are hereby incorporated by reference in their entirety. In the case of inconsistencies, the teachings of the present disclosure will prevail.

DETAILED DESCRIPTION OF THE INVENTION

[0204] Previously described processes to prepare N-(2-aminophenyl)-4-((pyrimidin-2- ylamino)methyl)benzamides of Formula (la) and synthetic intermediates thereof are shown generally in Scheme 1 :

Scheme 1

[0205] The present invention provides an improved process of making N-(2-aminophenyl)-4- ((pyrimidin-2-ylamino)methyl)benzamides of Formula (la) and synthetic intermediates thereof. In particular, the invention provides an improved process to prepare N-(2-aminophenyl)-4- ((pyrimidin-2-ylamino)methyl)benzamides of Formula (la) that requires fewer steps, is efficient, can be used on an industrial scale, and results in a final product that is suitable for pharmaceutical use. The compounds prepared according to the present invention are suitable for methods for treating cell proliferative diseases and conditions or other diseases responsive to treatment with iV-(2-aminophenyl)-4-((pyrimidin-2-ylamiiio)methyl)benzamide compounds of Formula (la).

[0206] The process according to the present invention is generally described in Scheme 2: Scheme 2

R = Me, Et, Pr, Bu , iso-Pr, tert-Bu , etc.

wherein the steps of preparing a compound of Formula (Vila) from a compound of Formula (IVa) are performed in a "one-pot" process, i.e., no isolation steps are performed during the process to prepare a compound of Formula (Vila). For clarity, the compound of Formula III is prepared in a separate reaction, purified and then used in the process of preparing a compound of Formula (Vila) from a compound of Formula (IVa). [0207] The present invention further provides improved processes for preparing intermediates used in the process for preparing N-(2-aminophenyl)-4-((pyrimidin-2- ylamino)methyl)benzamides of Formula (la). Such processes are generally described in Scheme 2 and Scheme 3 :

Scheme 3

[0208] Scheme 3 generally describes a process to prepare a compound of Formula (Vila) according to the present invention, wherein compound of Formula (Va) is purified from a reaction used to prepare it prior to reaction with a compound of Formula (III), and wherein the process of preparing a compound of Foraiula (Vila) from the reaction of a compound of Foraiula (Va) and a compound of Formula (III) does not include the step of purifying an intermediate compound of Formula (Via) (compare Scheme 1) prior to conversion to the compound of Formula (Vila), i.e., the process of preparing a compound of Formula (Vila) from the reaction of compound of Formula (Va) and a compound of Formula (III) is a "one-pot" two-stage procedure leading to the compound of Formula (Vila).

[0209] The invention is further related to conversion of free bases of compounds of Formula (I) into pharmaceutically acceptable salts X thereof (scheme 4). Suitable acids to form such salts include, without limitation, inorganic acids such as HCl, HBr, HI, H ₂ S0 , H ₃ P0 ₄ and HN0 ₃ , or organic acids such as methane sulfonic, ethane sulfonic, benzene sulfonic, p-toluene sulfonic, benzoic, lactic, succinic, salicylic, malic, citric, fumaric, maleic, glycolic etc, in solvents such as water, MeOH, EtOH, IP A, acetone, MTBA, 1 ,2-dimethoxyethane, 1,2-diethoxyethane, dioxane, THF, MeCN, EtOAc or mixtures of these solvents.

Scheme 4

[0210] In certain embodiments, salts X are made by reacting Compounds of Formula (I) (free bases) with an acid of formula HB in a solvent. Such reaction is typically conducted in two steps, though it is within the scope of this invention to simply combine both the free base and the acid in the solvent at the same time.

[0211] In certain embodiments, the free base I is dissolved or suspended in an appropriate amount of a solvent at an appropriate temperature (typically between -10 and +20°C, alternatively between 0 and +10°C). In the second step an appropriate acid (or a solution/suspension thereof) is added to the solution (or suspension) of the free base I. It is within the skill of one of ordinary skill in the art to determine suitable amounts of acid to be used.

[0212] In certain embodiments, the salts X precipitate from the reaction mixture and are collected by a suction filtration, rinsed with an appropriate solvent and dried. Alternatively, if the salt does not precipitate form the reaction mixture (or does not sufficiently precipitate) then the solvent is partially or completely evaporated to yield the salts X.

[0213] In certain embodiments, the isolated salts are repurified, either by a re-crystalization from an appropriate solvent or by a trituration with an appropriate solvent. The isolated salts may exist as solvates or hydrates.

[0214] For purposes of the present invention, the following definitions will be used (unless expressly stated otherwise).

[0215] Reference to "a compound of the formula (I), formula (II), etc.," (or equivalently, "a compound according to the first aspect", or "a compound of the present invention", and the like), herein is understood to include reference to N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers, enantiomers and tautomers thereof and unless otherwise indicated.

[0216] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an "alkyl" moiety generally refers to a monovalent radical (e.g. CH ₃ -CH ₂ -), in certain circumstances a bivalent linking moiety can be "alkyl," in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH ₂ - CH ₂ -), which is equivalent to the term "alkylene." (Similarly, in circumstances in which a divalent moiety is required and is stated as being "aryl," those skilled in the art will understand that the term "aryl" refers to the corresponding divalent moiety, arylene). All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S). On occasion a moiety may be defined, for example, as (A) _a -B-, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B- and when a is 1 the moiety is A-B-. Also, a number of moietes disclosed here may exist in multiple tautomeric forms, all of which are intended to be encompassed by any given tautomeric structure.

[0217] For simplicity, reference to a "C _n -C _m " heterocyclyl or "C _n -C _m " heteroaryl means a heterocyclyl or heteroaryl having from "n" to "m" annular atoms, where "n" and "m" are integers. Thus, for example, a C ₅ -C6-heterocyclyl is a 5- or 6- membered ring having at least one heteroatom, and includes pyrrolidinyl (C ₅ ) and piperidinyl (C ₆ ); C ₆ -hetoaryl includes, for example, pyridyl and pyrimidyl.

[0218] The term "hydrocarbyl" refers to a straight, branched, or cyclic alkyl, alkenyl, or alkynyl, each as defined herein. A "Co" hydrocarbyl is used to refer to a covalent bond. Thus, "Co-C ₃ -hydrocarbyl" includes a covalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl, propynyl, and cyclopropyl.

[0219] The term "aliphatic" is intended to mean both saturated and unsaturated, straight chain or branched aliphatic hydrocarbons. As will be appreciated by one of ordinary skill in the art, "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl or alkynyl moieties. [0220] The term "alkyl" is intended to mean a straight chain or branched aliphatic group having from 1 to 12 carbon atoms, for example 1-8 carbon atoms, and alternatively 1-6 carbon atoms. Other examples of alkyl groups have from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms and alternatively 2-6 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. A "Co" alkyl (as in "C ₀ -C ₃ alkyl") is a covalent bond.

[0221] The term "alkenyl" is intended to mean an unsaturated straight chain or branched aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, and alternatively 2-6 carbon atoms. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0222] The term "alkynyl" is intended to mean an unsaturated straight chain or branched aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, and alternatively 2-6 carbon atoms. Examples of alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0223] The terms "alkylene," "alkenylene," or "alkynylene" as used herein are intended to mean an alkyl, alkenyl, or alkynyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Examples of alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Examples of alkynylene groups include, without limitation, ethynylene, propynylene, and butynyl ene.

[0224] The term "azolyl" as employed herein is intended to mean a five-membered saturated or unsaturated heterocyclic group containing two or more hetero-atoms, as ring atoms, selected from the group consisting of nitrogen, sulfur and oxygen, wherein at least one of the hetero- atoms is a nitrogen atom. Examples of azolyl groups include, but are not limited to, optionally substituted imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl.

[0225] The term "carbocycle" as employed herein is intended to mean a cycloalkyl or aryl moiety. The term "carbocycle" also includes a cycloalkenyl moiety having at least one carbon- carbon double bond.

[0226] The term "cycloalkyl" is intended to mean a saturated, partially unsaturated or unsaturated mono-, bi-, tri- or poly-cyclic hydrocarbon group having about 3 to 15 carbons, alternatively having 3 to 12 carbons, alternatively 3 to 8 carbons, alternatively 3 to 6 carbons, and alternatively 5 or 6 carbons. In certain embodiments, the cycloalkyl group is fused to an aryl, heteroaryl or heterocyclic group. Examples of cycloalkyl groups include, without limitation, cyclopenten-2-enone, cyclopenten-2-enol, cyclohex-2-enone, cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, etc.

[0227] The term "heteroalkyl" is intended to mean a saturated or unsaturated, straight chain or branched aliphatic group, wherein one or more carbon atoms in the group are independently replaced by a moiety selected from the group consisting of O, S, N, N-alkyl, -S(O)-, -S(0) ₂ -, -S(0) ₂ NH-, or -NHS(0) ₂ -.

[0228] The term "aryl" is intended to mean a mono-, bi-, tri- or polycyclic aromatic moiety, for example a C ₆ -C ₁₄ aromatic moiety, for example comprising one to three aromatic rings. Alternatively, the aryl group is a C ₆ -Ci ₀ aryl group, for example a C ₆ aryl group. Examples of aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.

[0229] The terms "aralkyl" or "arylalkyl" are intended to mean a group comprising an aryl group covalently linked to an alkyl group. If an aralkyl group is described as "optionally substituted", it is intended that either or both of the aryl and alkyl moieties may independently be optionally substituted or unsubstituted. For example, the aralkyl group is (C ₁ -C ₆ )alk(C6-C ₁ o)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. For simplicity, when written as "arylalkyl" this term, and terms related thereto, is intended to indicate the order of groups in a compound as "aryl - alkyl". Similarly, "alkyl-aryl" is intended to indicate the order of the groups in a compound as "alkyl-aryl".

[0230] The terms "heterocyclyl", "heterocyclic" or "heterocycle" are intended to mean a group which is a mono-, bi-, or polycyclic structure having from about 3 to about 14 atoms, wherein one or more atoms are independently selected from the group consisting of N, O, and S. The ring structure may be saturated, unsaturated or partially unsaturated. In certain embodiments, the heterocyclic group is non-aromatic, in which case the group is also known as a heterocycloalkyl. In certain embodiments, the heterocyclic group is a bridged heterocyclic group (for example, a bicyclic moiety with a methylene, ethylene or propylene bridge). In a bicyclic or polycyclic structure, one or more rings may be aromatic; for example one ring of a bicyclic heterocycle or one or two rings of a tricyclic heterocycle may be aromatic, as in indan and 9,10- dihydro anthracene. Examples of heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino. In certain embodiments, the heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl group. Examples of such fused heterocycles include, without limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically excluded from the scope of this term are compounds where an annular O or S atom is adjacent to another O or S atom.

[0231] In certain embodiments, the heterocyclic group is a heteroaryl group. As used herein, the term "heteroaryl" is intended to mean a mono-, bi-, tri- or polycyclic group having 5 to 18 ring atoms, including 5 to 14 ring atoms (e.g., 5, 6, 9, or 10 ring atoms) and, for example, having 6, 10, or 14 pi electrons shared in a cyclic array; and having, in addition to carbon atoms, between one or more heteroatoms selected from the group consisting of N, O, and S. The term "heteroaryl" is also intended to encompass the N-oxide derivative (or N-oxide derivatives, if the heteroaryl group contains more than one nitrogen such that more than one N-oxide derivative may be formed) of a nitrogen-containing heteroaryl group. For example, a heteroaryl group may be pyrimidinyl, pyridinyl, benzimidazolyl, thienyl, benzothiazolyl, benzofuranyl and indolinyl. Examples of heteroaryl groups include, without limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, benzo[b]thienyl, naphtha[2,3-b]thianthrenyl, zanthenyl, quinolyl, benzothiazolyl, benzimidazolyl, beta-carbolinyl and perimidinyl. Illustrative examples of N-oxide derivatives of heteroaryl groups include, but are not limited to, pyridyl N-oxide, pyrazinyl N-opxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, triazinyl N-oxide, isoquinolyl N-oxide and quinolyl N-oxide.

[0232] The terms "arylene," "heteroarylene," or "heterocyclylene" are intended to mean an aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.

[0233] A heteroalicyclic group refers specifically to a non-aromatic heterocyclyl radical. A heteroalicyclic may contain unsaturation, but is not aromatic.

[0234] A heterocyclylalkyl group refers to a residue in which a heterocyclyl is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical. Examples include (4- methylpiperazin-l-yl) methyl, (morpholin-4-yl) methyl, (pyridine-4-yl) methyl,2- (oxazolin-2-yl) ethyl,4- (4-methylpiperazin-l-yl)-2-butenyl, and the like. If a heterocyclylalkyl is described as "optionally substituted" it is meant that both the heterocyclyl and the corresponding alkylene, alkylidene, or alkylidyne radical portion of a heterocyclylalkyl group may be optionally substituted. A "lower heterocyclylalkyl" refers to a heterocyclylalkyl where the "alkyl" portion of the group has one to six carbons.

[0235] A heteroalicyclylalkyl group refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is non-aromatic.

[0236] Examples of heterocyclyls and heteroaryls include, but are not limited to, azepinyl, azetidinyl, acridinyl, azocinyl, benzidolyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzofuryl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzothienyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolmyl, benzoxazolyl, benzoxadiazolyl, benzopyranyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, coumarinyl, decahydroquinolinyl, dibenzofuryl, 1,3-dioxolane, 2H,6H- 1,5,2- dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), furanyl, furopyridinyl (such as fuor[2,3-c]pyridinyl, furo[3,2- b]pyridinyl or furo[2,3-b]pyridinyl), furyl, furazanyl, hexahydrodiazepinyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H- indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolinyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxetanyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, plienazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyiTolopyridyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydro-l,l-dioxothienyl, tetrahydro furanyl, tetrahydro furyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrazolyl, thiazolidinyl, 6H- 1,2,5-thiadiazinyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholuiyl sulfone, thianthrenyl, thiazolyl, thienyl, tliienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, triazinylazepinyl, triazolyl (e.g., 1,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,5-triazolyl, 1 ,3,4- triazolyl), and xanthenyl.

[0237] A "halohydrocarbyl" as employed herein is a hydrocarbyl moiety, in which from one to all hydrogens have been replaced with an independently selected halo.

[0238] As employed herein, and unless stated otherwise, when a moiety (e.g., alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, etc.) is described as "optionally substituted" it is meant that the group optionally has from one to four, such from one to tliree or one or two, independently selected non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular -CH- substituted with oxo is -C(O)-) nitro, halohydrocarbyl, hydrocarbyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido grotips. Examples of substituents, which are themselves not further substituted (unless expressly stated otherwise) are:

(a) halo, hydroxy, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino,

(b) Ci-C ₅ alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, Ci-Cgalkyl, Q-Cgalkenyl, Q-Cgalkoxy, Ci-Cgalkyamino, Ci-Cgalkoxycarbonyl, aryloxycarbonyl, C ₂ -Cgacyl, -C(O)-N(R ³⁰ )-alkyl-cycloalkyl, -C(O)-N(R ³⁰ )-alkyl-heterocyclyl, -C(0)-N(R ³⁰ )- alkyl-aryl, -C(O)-N(R ³⁰ )-alkyl-heteroaryl, -C(0)-cycloalkyl, -C(0)-heterocyclyl, -C(0)-aryl, -C(0)-heteroaryl, C ₂ -Cgacylamino, Ci-Cgalkylthio, arylalkylthio, arylthio, Q-Cgalkylsulfmyl, arylalkylsulfmyl, arylsulfmyl, Ci-Cgalkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, Co-C6N-alkyl carbamoyl, C ₂ -C ₁₅ N V- dialkylcarbamoyl, C ₃ -C ₇ cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C ₃ -C7heterocycle, C ₅ - Ci5heteroaryl or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above; and

(c) -(CR ^J "R ^JJ )s-NR ^JU R ^{J 1} , wherein s is from 0 (in which case the nitrogen is directly bonded to the moiety that is substituted) to 6, R ³² and R ³³ are each independently hydrogen, halo, hydroxyl or Q-Qalkyl, and R and R are each independently hydrogen, cyano, oxo, hydroxyl, Q-Cgalkyl, Ci-Cgheteroalkyl, Cj-Cgalkenyl, carboxamido, CrQalkyl-carboxamido, carboxamido-Q-Qalkyl, amidino, C ₂ - Qhydroxyalkyl, CrQalkylaryl, aryl-Ci-C ₃ alkyl, Ci-C3alkylheteroaryl, heteroaryl-Ci-C ₃ alkyl, Q-Qalkylheterocyclyl, heterocyclyl-Ci-C ₃ alkyl C _\ - C ₃ alkylcycloalkyl, cycloalkyl-Ci-C ₃ alkyl, C2-C ₈ alkoxy, C ₂ -C8alkoxy-C ₁ -C ₄ alkyl, Ci-Csalkoxycarbonyl, . aryloxycarbonyl, aryl-Ci-Csalkoxycarbonyl, heteroaryloxycarbonyl, heteroaryl-Ci-Csalkoxycarbonyl, Ci-Cgacyl, Co-C ₈ alkyl- carbonyl, aryl-Co-C ₈ alkyl-carbonyl, heteroaryl-Co-C ₈ alkyl-carbonyl, cycloalkyl- Co-Cgalkyl-carbonyl, heterocyclyl-Co-C ₈ alkyl-carbonyl, Co-Csalkyl-NH-carbonyl, aryl-Co-Csalkyl-NH-carbonyl, heteroaryl-Co-C ₈ alkyl-NH-carbonyl, cycloalkyl-Co- Cgalkyl-NH-carbonyl, heterocylclyl-Co-C ₈ alkyl-NH-carbonyl, cycloalkyl-S(0) ₂ -, heterocyclyl-S(0) ₂ -, aryl-S(0) ₂ -, heteroaryl-S(0) ₂ -, Co-C ₈ alkyl-0-carbonyl, aryl- Co-Csalkyl-O-carbonyl, heteroaryl-Co-C ₈ alkyl-0-carbonyl, cycloalkyl-Co-Cgalkyl- O-carbonyl, heterocyclyl-Co-C ₈ alkyl-0-carbonyl, Q-Cgalkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, Q- Csalkyl-NH-sulfonyl, arylalkyl-NH-sulfonyl, aryl-NH-sulfonyl, heteroarylalkyl- NH-sulfonyl, heteroaryl-NH-sulfonyl aroyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-Q-Csalkyl-, cycloalkyl-Ci-C ₃ alkyl-, heterocyclyl-CrQalkyl-, heteroaryl-Q-Qalkyl-, or a protecting group, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above; or R ³⁰ and R ³¹ taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents selected from the group consisting of (a) above, a protecting group, and (X -Y -), wherein said heterocyclyl may also be bridged (forming a bicyclic moiety with a methylene, ethylene or propylene bridge); wherein

X is selected from the group consisting of H, Q-Cgalkyl, C ₂ -Cgalkenyl-, C ₂ - Qalkynyl-, -C ₀ -C ₃ alkyl-C ₂ -C ₈ alkenyl-C ₀ -C ₃ alkyl, C ₀ -C ₃ alkyl-C ₂ -C ₈ alkynyl- C ₀ -C ₃ alkyl, C ₀ -C ₃ alkyl-O-C ₀ -C ₃ alkyl-, HO-C ₀ -C ₃ alkyl-, C ₀ -C ₄ alkyl-N(R ³⁰ )- C ₀ -C ₃ alkyl-, N(R ³⁰ )(R ³¹ )-C ₀ -C ₃ alkyl-, N(R ³⁰ )(R ³¹ )-C ₀ -C ₃ alkenyl-, N(R ³⁰ )(R ³¹ )-C ₀ -C ₃ alkynyl-, (N(R ³⁰ )(R ³¹ )) ₂ -C=N-, C ₀ -C ₃ alkyl-S(0)o _-2 -C ₀ - C ₃ alkyl-, CF ₃ -Co-C alkyl-, Ci-Csheteroalkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-CrQalkyl-, cycloalkyl-Ci-C ₃ alkyl-, heterocyclyl-Ci-C ₃ alkyl-, heteroaryl-Ci-C ₃ alkyl-, N(R ³⁰ )(R ³¹ )-heterocyclyl-Ci-C ₃ alkyl-, wherein the aryl, cycloalkyl, heteroaryl and heterocycyl are optionally substituted with from 1 to 3 substituents from (a); and

Y ³¹ is selected from the group consisting of a direct bond, -0-, -N(R ³⁰ )-, -C(O)-, -O-C(O)-, -C(0)-0-, -N(R ³⁰ )-C(O)-, -C(0)-N(R ³⁰ )-, -N(R ³⁰ )-C(S)-, -C(S)- N(R ³⁰ )-, -N(R ³⁰ )-C(O)-N(R ³¹ )-, -N(R ³⁰ )-C(NR ³⁰ )-N(R ³¹ )-, -N(R ³⁰ )-C(NR ³¹ )-, -C(NR ³¹ )-N(R ³⁰ )-, -N(R ³⁰ )-C(S)-N(R ³¹ )-, -N(R ³⁰ )-C(O)-O-, -0-C(0)-N(R ³¹ )-, -N(R ³⁰ )-C(S)-O, -0-C(S)-N(R ³¹ )-, -S(O) _0-2 -, -S0 ₂ N(R ³¹ )-, -N(R ³¹ )-S0 ₂ - and

-N(R ³⁰ )-SO ₂ N(R ³¹ )-

[0239] A moiety that is substituted is one in which one or more (e.g., one to four, one to three, or and one or two), hydrogens have been independently replaced with another chemical substituent. As a non- limiting example, substituted phenyls include 2-flurophenyl, 3,4- dichlorophenyl, 3-chloro-4-fluoiO-phenyl, 2-fluoro-3-propylphenyl. As another non-limiting example, substituted n-octyls include 2,4-dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included within this definition are methylenes (-C¾-) substituted with oxygen to form carbonyl -CO-.

[0240] When there are two optional substituents bonded to adjacent atoms of a ring structure, such as for example a phenyl, thiophenyl, or pyridinyl, the substituents, together with the atoms to which they are bonded, optionally form a 5- or 6- membered cycloalkyl or heterocycle having 1, 2, or 3 annular heteroatoms.

[0241] A group, such as a hydrocarbyl, heteroalkyl, heterocyclic and/or aryl group can be unsubstituted. Or a group, such as a hydrocarbyl, heteroalkyl, heterocyclic and/or aryl group can be substituted with from 1 to 4 (e.g., one to three, or one or two) independently selected substituents.

[0242] Examples of substituents on alkyl groups include, but are not limited to, hydroxyl, halogen (e.g., a single halogen substituent or multiple halo substituents; in the latter case, groups such as -CF ₃ or an alkyl group bearing Cl ₃ ), oxo, cyano, nitro, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, -OR ^a , -SR ^a , -S(=0)R ^e , -S(=0) ₂ R ^e , -P(=0) ₂ R ^e , -S(=0) ₂ OR ^e , -P(=0) ₂ OR ^e , -NR ^b R°, -NR ^b S(=0) ₂ R ^e , -NR ^b P(=0) ₂ R ^e , -S(=0) ₂ NR ^b R ^c , -P(=0) ₂ NR ^b R ^c , -C(=0)OR ^e , -C(=0)R ^a , -C(=0)NR ^b R°, -OC(=0)R ^a , -OC(=0)NR ^b R°, -NR ^b C(=0)OR ^e , -NR ^d C(=0)NR ^b R°, -NR ^d S(=0) ₂ NR ^b R ^c , -NR ^d P(=0) ₂ NR ^b R ^c , -NR ^b C(=0)R ^a or -NR ^b P(=0) ₂ R ^e , wherein R ^a is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R ^b , R° and R ^d are independently hydrogen, alkyl, cycloalkyl, heterocycle or aryl, or said R ^b and R° together with the N to which they are bonded optionally form a heterocycle; and R ^e is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. In the aforementioned exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can themselves be optionally substituted.

[0243] Examples of substituents on alkenyl and alkynyl groups include, but are not limited to, alkyl or substituted alkyl, as well as those groups recited as examples of alkyl substituents.

[0244] Examples of substituents on cycloalkyl groups include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups recited above as examples of alkyl substituents. Other examples of substituents include, but are not limited to, spiro-attached or fused cyclic substituents, for example spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted. Alternatively, when a cycloalkyl is substituted by two C _1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, for example a C _1-3 alkylene chain. Cycloalkyl groups having this crosslinked structure include bicyclo[2.2.2]octanyl and norbornanyl.

[0245] Examples of substituents on cycloalkenyl groups include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups recited as examples of alkyl substituents. Other examples of substituents include, but are not limited to, spiro-attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro- attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted. Alternatively, when a cycloalkenyl is substituted by two C _1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, for example a C _1-3 alkylene chain.

[0246] Examples of substituents on aryl groups include, but are not limited to, nitro, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, cyano, alkyl or substituted alkyl, as well as those groups recited above as examples of alkyl substituents. Other examples of substituents include, but are not limited to, fused cyclic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalky, cylcoalkenyl, heterocycle and aryl substituents can themselves be optionally substituted. Still other examples of substituents on aryl groups (phenyl, as a non-limiting example) include, but are not limited to, haloalkyl and those groups recited as examples of alkyl substituents. Alternatively, when an aryl group is substituted by two C _1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, for example a C _1-3 alkylene chain.

[0247] Examples of substituents on heterocyclic groups include, but are not limited to, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, nitro, oxo (i.e., =0), cyano, alkyl, substituted alkyl, as well as those groups recited as examples of alkyl substituents. Other examples of substituents on heterocyclic groups include, but are not limited to, spiro- attached or fused cylic substituents at any available point or points of attachement, for example spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloakenyl, fused heterocycle and fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted. Alternatively, when a heterocyclic is substituted by two C _1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, for example a C _1-3 alkylene chain.

[0248] A heterocyclic group can be optionally substituted on carbon, nitrogen and/or sulfur at one or more positions. Examples of substituents on carbon include those groups recited as examples of alkyl substituents. Examples of substituents on nitrogen include, but are not limited to alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl. Examples of substituents on sulfur include, but are not limited to, oxo and Ci _-6 alkyl. Nitrogen and sulfur heteroatoms may independently be optionally oxidized and nitrogen heteroatoms may independently be optionally quaternized.

[0249] Substituents on ring groups, such as aryl, heteroaryl, cycloalkyl and heterocyclyl, (when present) include halogen, alkoxy and alkyl.

[0250] Substituents on alkyl groups (when present) include halogen and hydroxy.

[0251] The term "halogen" or "halo" as employed herein refers to chlorine, bromine, fluorine, or iodine. As herein employed, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent. The term "acylamino" refers to an amide group attached at the nitrogen atom (i.e., R-CO-NH-). The term "carbamoyl" refers to an amide group attached at the carbonyl carbon atom (i.e., NH ₂ -CO-). The nitrogen atom of an acylamino or carbamoyl substituent is additionally optionally substituted. The term "sulfonamido" refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom. The term "amino" is meant to include NH ₂ , alkylamino, di-alkyl-amino (wherein each alkyl moiety may be the same or different), arylamino, and cyclic amino groups. The term "ureido" as employed herein refers to a substituted or unsubstituted urea moiety.

[0252] The term "radical" as used herein means a chemical moiety comprising one or more unpaired electrons.

[0253] Where optional substituents of a moiety are chosen from "one or more" groups it is to be understood that the moiety optionally has, unless otherwise stated, from one up to the maximum number of substitutable hydrogens on the moiety replaced with a substituent independently chosen from among the specified groups.

[0254] In addition, substituents on cyclic moieties (i.e., cycloalkyl, heterocyclyl, aryl, heteroaryl) include 5- to 6-membered mono- and 9- to 14-membered bi-cyclic moieties fused to the parent cyclic moiety to form a bi- or tri-cyclic fused ring system. Substituents on cyclic moieties also include 5- to 6-membered mono- and 9- to 14-membered bi-cyclic moieties attached to the parent cyclic moiety by a covalent bond to form a bi- or tri-cyclic bi-ring system. For example, an optionally substituted phenyl includes, but is not limited to, the following:

[0255] A saturated or unsaturated three- to eight-membered carbocyclic ring includes, for example, a four- to seven-membered and a five- or six-membered, saturated or unsaturated carbocyclic ring. Examples of saturated or unsaturated three- to eight-membered carbocyclic rings include phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0256] A saturated or unsaturated three- to eight-membered heterocyclic ring contains at least one heteroatom selected from oxygen, nitrogen, and sulfur atoms. So, for example, the saturated or unsaturated three- to eight-membered heterocyclic ring can contain one or two Iieteroatoms with the remaining ring- constituting atoms being carbon atoms. The saturated or unsaturated three- to eight-membered heterocyclic ring can also be a saturated or unsaturated four- to seven-membered heterocyclic ring or a saturated or unsaturated five- or six-membered heterocyclic ring. Examples of saturated or unsaturated three- to eight-membered heterocyclic groups include thienyl, pyridyl, 1,2,3-triazolyl, imidazolyl, isoxazolyl, pyrazolyl, piperazinyl, piperazino, piperidyl, piperidino, morpholinyl, morpholino, homopiperazinyl, homopiperazino, thiomorpholinyl, thiomorpholino, tetrahydropyrrolyl, and azepanyl.

[0257] The compounds of the present invention form salts which are also within the scope of this invention. Reference to a compound of the invention, for example a compound of Formula (I), herein is understood to include reference to salts thereof, unless otherwise indicated.

[0258] The term "salt(s)", as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound of Formula (I) contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety such as but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic (exhibiting minimal or no undesired toxicological effects), physiologically acceptable) salts are one example, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of the compounds of the invention may be formed, for example, by reacting a compound of the present invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salts precipitates or in an aqueous medium followed by lyophilization.

[0259] The compounds of the present invention which contain a basic moiety, such as but not limited to an amine or a pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfanotes (e.g., 2- hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2- naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3 -phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0260] The compounds of the present invention which contain an acidic moiety, such as but not limited to a carboxylic acid, may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glycamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen- containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibuty and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

[0261] As used herein, the term "pharmaceutically acceptable salts" is intended to mean salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects.

[0262] Another aspect of the invention provides compositions including a compound, N- oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug of a compound according to the present invention as described herein, or a racemic mixture, diastereomer, enantiomer or tautomer thereof. For example, in certain embodiments of the invention, a composition comprises a compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug of a compound according to the present invention as described herein present in at least about 30% enantiomeric or diastereomeric excess. In certain embodiments of the invention, the compound, N-oxide, hydrates, solvate, pharmaceutically acceptable salt, complex or prodrug is present in at least about 50%, at least about 80%, or even at least about 90% enantiomeric or diastereomeric excess. In certain embodiments of the invention, the compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug is present in at least about 95%, at least about 98%, or at least about 99% enantiomeric or diastereomeric excess. In certain embodiments of the invention, a compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug is present as a substantially racemic mixture.

[0263] The terms "protect", "protected", and "protecting" are intended to refer to a process in which a functional group in a chemical compound is selectively masked by a non-reactive functional group in order to allow a selective reaction(s) to occur elsewhere on said chemical compound. Such non-reactive functional groups are herein termed "protecting groups". For example, the term "nitrogen protecting group", is intended to mean a group capable of selectively masking the reactivity of a nitrogen (N) group. The term "suitable protecting group" is intended to mean a protecting group useful in the preparation of the compounds of the present invention. Such groups are generally able to be selectively introduced and removed using mild reaction conditions that do not interfere with other portions of the subject compounds. Protecting groups that are suitable for use in the processes and methods of the present invention are well known, such as but not limited to, Bn- (or -CH ₂ Ph), -CHPh ₂ , alloc (or CH ₂ =CH-CH ₂ -0-C(0)-), BOC-, -Cbz (or Z-), -F-moc, -C(0)-CF ₃ , N-Phthalimide,l-Adoc-, TBDMS-, TBDPS-, TMS-, TIPS-, IPDMS-, -SiR ₃ , SEM-, t-Bu-, Tr-, THP- and Allyk These protecting groups may be removed at a convenient stage using methods known from the art. The chemical properties of such protecting groups, methods for their introduction and their removal art known in the art and can be found for example in T. Greene and P. Wuls, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999), herein incorporated by reference in its entirety. The terms "deprotect", "deprotected", and "deprotecting" are intended to refer to the process of removing a protecting group from a compound.

[0264] The term "anti-solvent" refers to a fluid that is added to a solution, which comprises at least one solvent and at least one solute, to cause the solubility of the solute in the solvent to decrease. An anti-solvent can be especially useful to decrease the solubility of the solute to such a point that at least some of the solute precipitates from the solution.

[0265] The term "purification" refers to a process in which the purity of a desired compound is increased. It also refers to a process in which the percentage of a desired compound in a mixture is increased as a result of such process. Purification may be performed in a single reaction vessel, or in a multitude of reaction vessels. Examples of purification include: dissolving and filtering off impurities away from a mixture comprising both the desired compound and impurities; dissolving preferentially with a solvent the desired compound from a mixture comprising both the desired compound and impurities to generate a solution, followed by filtering of the solution, and isolating the desired compound by evaporation of the solvent or crystallization of the desired compound; re-crystallization of the desired compound; and the use of chromatography of the mixture comprising impurities and the desired compound. The phrase "purified compound" refers to a desired compound which has gone through a purification process.

[0266] The phrase "one-pot process" refers to a process, or a part of a process, in which a compound is subjected to successive chemical reactions in just one reactor vessel. The phrase "one-pot process" refers to a process in which there is no separation or purification of an intermediate compound.

[0267] The foregoing merely summarizes various aspects and embodiments of the invention and is not intended to be limiting in nature. Particular embodiments of these aspects are described more fully below.

Synthetic Schemes and Experimental Procedures

[0268] The processes of the invention can be performed according to the reaction schemes for the examples illustrated below utilizing methods known to one of ordinary skill in the art. These schemes serve to exemplify some procedures of the invention. One skilled in the art will recognize that other general synthetic procedures may be used. In certain embodiments, the processes of the invention can use components that are commercially available. Any kind of substitutions can be made to the starting components according to procedures that are well known to those skilled in the art to obtain the compounds prepared according to the present invention.

Example 1

(E)-3 -(Dimethylamino)- 1 -(pyridin-3-yl)prop-2-en- 1 -one (1)

1

[0269] 3 -Acetyl-pyridine (30.0 g, 247.6 mmol) and DMF dimethyl acetal (65.8 mL, 495.2 mmol) were mixed together and then heated to reflux for 4h. The reaction mixture was evaporated to dryness and then 50 mL diethyl ether was added to give brown suspension. The solid material was collected by filtration to provide the title compound 36.97 g (85% yield) as an orange crystalline product. ^! H NMR (400 MHz, CDC1 ₃ ) δ (ppm): 9.08 (d, J = 2.2 Hz, 1H), 8.66 (dd, J = 4.9, 1.4 Hz, 1H), 8.26-8.23 (m, 1H), 7.85 (d, J = 12.1 Hz, 1H), 7.40 (dd, J = 7.8, 4.9 Hz, 1H), 5.68 (d, J = 12.1 Hz, 1H), 3.20 (s, 3H), 2.97 (s, 3H). MS (m/z): 177.1 (M+H).

Example 2

(E)-3 -(Dimethylamino)- 1 -(pyridin-3 -yl)prop-2-en- 1 -one (1)

1

[0270] A 3L, three-neck round bottom flask equipped with a thermometer, nitrogen inlet and a mechanical stirrer was charged with 3-acetylpyridine (454 mL, 4.13 mol), N,N- dimethylformamide diethyl acetal (1061 mL, 6,20 mol) and Et ₃ N (99.5%, 575 ml, 4.13 mol). The resultant mixture was stirred vigorously and then heated to reflux (110°C) for 18 hours to afford a dark homogenous solution. The reaction mixture was then cooled to 50°C, quickly transferred to a 3L one-neck round-bottom flask and evaporated under reduced pressure to afford a brownish solid, which was then immediately re-suspended in a mixture of MTBE (290 mL, drum grade) and hexane (290 mL, HPLC grade). The suspension was gently stirred at room temperature for 4 hours, then the solid material was collected by filtration, washed with a 1 :1 mixture of MTBE/hexane (2 x 500 mL), followed by 500 mL hexane and dried, to afford title compound (700g, 96% yield). 9.07 (d, J=1.2 Hz, 1H), 8.66 (dd, 3=4 , 1.4 Hz, 1H), 8.22 (d, J=7.9 Hz, 1H), 7.77 (d, J=12.2 Hz, 1H), 7.46 (dd, J=7.7, 4.9 Hz, 1H), 5.87 (d, J=12.2 Hz, 1H), 3.17 (s, 3H), 2.94 (s, 3H).

Example 3

(E)-3 -(Dimethylamino)- 1 -(pyridin-4-yl)prop-2-en- 1 -one (2)

2

[0271] A solution of 4-acetylpyridine (4.20 g, 34.7 mmol) in N,N-dimethylformamide dimethyl acetal (24 mL, 180.7 mmol) was heated at 120°C in a pressure reaction vessel for 1.5 h. The heating was stopped and the mixture was allowed to cool down to room temperature. The solvent was evaporated under reduced pressure and the residue was triturated with diethyl ether, to afford the title compound as a yellow solid (4.41 g, 72% yield). 1H NM (400 MHz, DMSO- d ₆ ) δ (ppm): 8.67 (d, J = 6.1 Hz, 2H), 7.81-7.75 (m, 3H), 5.83 (d, J = 12.1 Hz, 1H), 3.17 (s, 3H), 2.94 (s, 3H). ). MS (m/z): 177.1 (M+H).

Example 4

-((4-(Pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzoic

[0272] A 3L, three-neck round bottom flask equipped with a thermometer, nitrogen inlet and a mechanical stirrer was charged with 4-(aminomethyl)benzoate hydrochloride (IVa) (125.0 g, 0.62 mol) andlH-pyrazole-l-carboximidamide hydrochloride (100 g, 0.68 mol). A solution of DIPEA (237 mL, 1.36 mol) in EtOH (200 mL) was added to the flask. The reaction mixture was heated at 45°C for 2 hours. Solid (E)-3-(dimethylamino)-l-(pyridin-3-yl)prop-2-en-l -one (1, 1 10 g, 0.62 mol) and EtOH (200 mL) were added to the reaction mixture, which was then heated to reflux for 0.5 hours and treated with 25% w/w NaOMe in MeOH (425 mL, 1.86 mol) (slow addition). The resultant mixture turned into orange viscous slurry and was heated to reflux for 18 hours. To this mixture, at reflux, 2N NaOH (500 mL) and water (500 mL) were added. The mixture gradually turned into a clear amber solution and was heated to reflux for an additional 18 hours, cooled to room temperature and acidified with 4N HCl (ca 740 mL) to pH 5.8, to form a suspension. To the suspension acetone (2 L) was added. The suspension was stirred for an additional 2 hours at room temperature, the solid was collected by suction filtration and washed with acetone (3 x 100 mL). The product was dried at 30°C in vacuum to afford the title compound (152 g, 80% yield). 12.84 (bs, 1H), 9.22 (bs, 1H), 8.68 (bs, 1H), 8.40 (d, J=5.0 Hz, 2H), 8.00 (t, J=6.2 Hz, 1H), 7.89 (d, J=8.2 Hz, 2H), 7.50 (m, 3H), 7.27 (d, J=5.1 Hz, 1H), 4.65 (d, J=5.3 Hz, 2H). Example 5

N-(2-Aminophenyl)-4-(( -(pyridin-3-yl)pyrimidin-2-ylaimno)methyl)benzamide (4)

[0273] A 5L, three-neck round bottom flask equipped with a thermometer, nitrogen inlet and a mechanical stirrer was charged with 4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzoic acid (3, 154 g, 0.5 mol), acetonitrile (2.5 L) and Et ₃ N (336 mL, 2.41 mol). To this suspension was added a solution of 1,2-phenylenediamine (228 g, 2.1 mol) in acetonitrile (1 L) at room temperature. To the reaction mixture was added HOBT (122 g, 0.9 mol) and EDC x HC1 (193 g, 1.0 mol). The resultant suspension was stirred at room temperature for 24-72 hours. The progress of the reaction was monitored by NMR or HPLC for the disappearance of the acid 3. The precipitate was collected by suction filtration and washed with acetonitrile (4 x 250 mL), water (4 x 250 mL), and MTBE (2 x 200 mL), to afford a material which was triturated with MeOH at reflux for 18 hours. The resultant slurry was filtered at 50°C and washed with MeOH (2 x 50 mL) to produce after drying the title compound 4 (132-150g, 66-75% yield). 1H NMR (400 MHz, OMSO-de) δ (ppm): 9.60 (s, 1H), 9.25 (s, 1H), 8.69 (d, J=3.7 Hz, 1H), 8.42 (d, J=5.2 Hz, 2H), 8.02 (t, J=6.2 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.52 (m, 3H), 7.27 (d, J=5.1 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.96 (t, J=7.5 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.59 (t, J=7.5 Hz, 1H), 4.88 (s, 2H), 4.66 (d, J=5.6 Hz, 2H).

Example 6

N-(2-Aminophenyl)-4-(( -(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide (4)

[0274] A 2L, three-neck round bottom flask equipped with a thermometer, nitrogen inlet, a mechanical stirrer and a dropping funnel was charged with 4-((4-(pyridin-3-yl)pyrimidin-2- ylamino)methyl)benzoic acid (3, 40 g, 0.131 mol), 1,2-phenylenediamine (59.3 g, 0.548 mol), 1- hydroxybenzotriazole hydrate (HOBT) (21.7 g, 0.156 mol) and DMSO (240 mL) at room temperature. To this stirred mixture Et ₃ N (43.7 mL, 0.313 mol) was added. The reaction mixture was stirred for 10 min then was charged with a suspension of l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC x HC1) (30.04 g, 0.156 mol)) in DMSO (240 mL) at the same temperature. The addition occurred in three equal portions over 30 min.

[0275] The reaction mixture was then stirred for 20 hours (the progress of the reaction was monitored by NMR or HPLC for the disappearance of the acid 3). Upon completion of the reaction 30% IP A in water (800 mL) was added to the reaction mixture in three portions over 30 min. After complete addition the reaction mixture turned into a suspension which was cooled to 0-5°C over 45 min and then stirred at the same temperature for another hour. The solid material was collected by a suction filtration, washed with 30% IP A (400 mL) and air-dried to afford crude title compound 4 (43.04 g, 83% yield).

Example 7

Recrystallization of N-(2-aminophenyl)-4-((4-(pyridin-3 -yl)pyrimidin-2- ylamino)methyl)benzamide (4)

[0276] A 2 L 3 -neck round bottom flask equipped with a mechanical stirrer, a condenser and a thermometer was charged with a material similar to the one derived in the Example 6 (43.42 g) and ethanol (868 mL). The mixture was heated to reflux. Then DMSO (276 mL) was slowly added (under reflux conditions, at about 90°C) to keep the solid in solution. The mixture was cooled to around 80°C then filtered through a Bucher funnel (hot filtration). The filtrate was collected, heated to reflux until the precipitated solids went back into the solution. The heating was stopped and the mixture was allowed to slowly cool down to room temperature overnight. The solid was collected by filtration, washed with a mixture of 25% DMSO/75% EtOH (200 mL) then with pure ethanol (2 x 200 mL). The solid was dried in a vacuum oven at 40°C overnight to afford pure product 4 (34.02 g, 78% recovery) as a light beige solid.

Example 8

Recrystallization of N-(2-aminophenyl)-4-((4-(pyridin-3 -yl)pyrimidin-2-

[0277] A 2L, three-neck round bottom flask equipped with a thermometer, nitrogen inlet and a mechanical stirrer was charged with material derived in the Example 6 (42.04 g) followed by DMSO (126 mL) at room temperature. The suspension was heated to 45°C over 20 min to allow for the dissolution of the solid. The solution was stirred for an additional 15 min then cooled to 25-30°C, stirred for another 15 min at the same conditions and suction filtered. The filter was rinsed with DMSO (42 mL), the filtrate and washings were combined and transferred into another 2L, three-neck round bottom flask equipped with a thermometer, nitrogen inlet, a mechanical stirrer, a reflux condenser and an addition funnel. With a moderate Stirling the flask was charged with IPA (672 mL) over a period of 1 hour in 5 equal portions. After complete addition of IPA, the contents of the flask were heated to 70-75°C over 45 min and stirred at the same temperature for an additional 30 min, then cooled to room temperature over 4 hours. A precipitate formed which was collected by suction filtration, washed with IPA (168 mL) and vacuum dried at 50°C, to afford title compound 4 (37.5-39.0 g, 72.5-75.4% yield).

[0278] Typical characteristics for such a meterial are 1H NMR (400 MHz, DMSO-<¾) δ (ppm): 9.60 (s, 1H), 9.24 (s, 1H), 8.68 (d, J=4.0 Hz, 1H), 8.41 (d, J=5.2 Hz, 2H), 8.02 (t, J=6.4 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.52 (m, 3H), 7.26 (d, J=4.8 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.96 (td, J=7.6 Hz, 1H), 6.77 (dd, J=7.8, 1.0 Hz, 1H), 6.58 (td, J=7.4, 1.0 Hz, 1H), 4.88 (s, 2H), 4.65 (d, J=6.0 Hz, 2H). MS (m/z): 397.2 (M+H).

Example 9

Methyl 4-(guanidinometh l)benzoate dihydrate (Va)

[0279] A 2L, three-neck round bottom flask equipped with a thermometer, nitrogen inlet and a mechanical stirrer was charged with 4-(aminomethyl)benzoate hydrochloride (IVa) (50.0 g, 248 mmol), lH-pyrazole-l-carboximidamide hydrochloride (43.6 g, 298 mmol), EtOH (250 mL) and DIPEA (130 mL, 744 mmol). The reaction mixture was heated to reflux for 3 hours and cooled to room temperature. The solvent was evaporated under reduced pressure and a saturated aqueous solution of NaHC0 ₃ (250 mL) was added to the residue followed by water (1 L). A precipitate formed which was collected by suction filtration, washed with water and vacuum dried to afford title compound Va (58.5 g, quantitative yield, supposedly a di-hydrate). 1H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.94 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 3.84 (s, 3H). MS (m/z): 208.1 (M+H).

Example 10

4-((4-(Pyridin-3 -yl)pyrimidin-2-ylamino)methyl)benzoic acid (3)

[0280] A 2 L three-neck-round bottomed flask equipped with a mechanical stirrer was charged with (E)-3-(dimethylamino)-l-(pyridin-3-yl)prop-2-en-l-one (1) (15.26, 86.60 mmol) and methyl 4-(guanidinomethyl)benzoate di-hydrate (Va) (23.17 g, 95.26 mmol) in MeOH (262 mL). The mixture was stirred and heated to reflux for 10 minutes to get a solution. Sodium methoxide (18.71 g, 346.39 mmol) in MeOH (262 mL, 25% w/w solution) was added. The reaction mixture was heated to reflux and stirred for 48 hours (the disappearance of 1 was followed by MS or TLC). Sodium hydroxide (2.5M in water, 157 mL, 392.50 mmol) and MeOH (157 mL) were added and the reaction mixture was stirred and heated to reflux for 23 hours, cooled to room temperature and the MeOH was evaporated under reduced pressure. Water (700 mL) was added to the remaining aqueous alkaline solution which was washed with ethyl acetate (3 x 350 mL), acidified to pH = 5-6 with 2N HC1 to precipitate the product. The precipitate was collected by suction filtration, washed with water and vacuum dried to afford title compound 3 as a white solid (29.77 g, quantitative yield). 1H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.20 (s, 1H), 8.66 (d, J = 3.5 Hz, 1H), 8.39 (d, J = 5.1 Hz, 2H), 7.96 (t, J = 6.3 Hz, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.50 (m, 1H), 7.40 (d, J = 6.4 Hz, 2H), 7.23 (d, J = 5.1 Hz, 1H), 4.61 (d, J = 5.3 Hz, 2H). MS (m/z): 307.2 (M+H). Example 11

N-(2-Aminoplienyl)-4-((4-(^yridin-3-yl)pyrimidm

5

[0281] A 250 ml three-neck round bottom flask equipped with a mechanical stirrer, thermometer and nitrogen inlet was charged with 10.0 g of N-(2-aminophenyl)-4-[(4-pyridin-3- yl-pyrimidin-2-ylamino)-methyl]-benzamide (4) and EtOH (150 ml). The temperature was adjusted to 0-5 °C and hydrobromic acid (48% w/w, 6.2 ml, 2.2 eq.) was added while keeping the temperature below 10 °C. The reaction mixture was stirred at 0-5 °C for 3 hours, the precipitate formed was collected by filtration and rinsed with EtOH (2x 20 ml) and heptanes (2x20 ml). The filter cake was re-suspended in heptanes (10 ml) and the mixture was stirred for 1 hour at 20-25 °C. Filtration of the suspension afforded a solid material that was rinsed with heptanes (2x20 ml), dried in a high vacuum oven at 20-25 °C for 24 hours at which time the temperature was increased to 40-45 °C. The heating continued until constant weight was reached. Yields: 8.45- 9.86 g (60-70 %).

Example 12

N-(2-Aminophenyl)-4-((4-( yridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide

diliydrobromide (5)

5

[0282] A suspension iV-(2-aminophenyl)-4-[(4-pyridin-3-yl-pyrimidin-2-ylamino)-m ethyl]- benzamide (4) (10. Og) in deionized water (100 mL) in a 250 mL three-neck round bottom flask equipped with a mechanical stirrer, thermometer and nitrogen inlet was cooled to 0-5 °C. HCl (31%w/w) (6.4 mL) was added over a period of 1 minute under vigorous agitation to dissolve the solids. The solution was quickly filtered, the pH was adjusted to 7 - 9 using NaOH (2.5N) (31.2 mL) while maintaining agitation for 30 min at 0-5 °C. A precipitate was formed which was collected by filtration, rinsed with deionized water (60 mL) in three portions and ethanol (40 mL) in two portions. The filter cake was air-dried followed by drying in a vacuum oven at 20-25 °C for 10 minutes then re-suspended in ethanol (150 mL). The temperature of the suspension was adjusted to 0-5 °C. Hydrobromic acid (48%w/w) (6.2 mL) was added to the suspension over 1 minute maintaining the temperature at 0-5 °C. The suspension was stirred at the same temperature with moderate agitation for an additional 3 hours then filtered. The filter cake was rinsed with ethanol (40 mL) in two portions and then heptane (40 mL) in two portions. The solids were re-suspended in heptane (100 mL) with moderate agitation for 1 hour at 20-25 °C, collected again by filtration and rinsed with heptane (40 mL) in two portions. The material was then dried in a high vacuum oven at 20-25 °C for 24 hours at which time the temperature was increased to 40-45 °C. The heating continued until constant weight was reached. Yields: 6.34- 10.7 g (45-76 %).

[0283] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.