WO2015006875A1 - Procédé de préparation de pyrimidines substituées - Google Patents

Procédé de préparation de pyrimidines substituées Download PDF

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Publication number
WO2015006875A1
WO2015006875A1 PCT/CA2014/050684 CA2014050684W WO2015006875A1 WO 2015006875 A1 WO2015006875 A1 WO 2015006875A1 CA 2014050684 W CA2014050684 W CA 2014050684W WO 2015006875 A1 WO2015006875 A1 WO 2015006875A1
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WIPO (PCT)
Prior art keywords
formula
group
hydrocarbyl
compound
acid
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PCT/CA2014/050684
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English (en)
Inventor
Stephane Raeppel
Zhihong Zhou
Frederic Gaudette
David Llewellyn
Arkadii Vaisburg
David Delorme
Franck Raeppel
Marie-Claude Granger
Simon Roy
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Methylgene Inc.
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Publication of WO2015006875A1 publication Critical patent/WO2015006875A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton

Definitions

  • This invention relates to an improved process of making substituted pyrimidines and synthetic intermediates thereof.
  • the invention relates to an improved process to prepare N-(2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamides.
  • 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.
  • Histone deacetylases 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.
  • N-(2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamides are known to be useful as inhibitors of histone deacetylases and possess valuable pharmacological properties.
  • MGCD0103 MetalGene 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.
  • the present invention provides an improved process for preparing HDAC inhibitors based on substiuted pyrimindines of Formula (I):
  • 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
  • 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
  • X is selected from the group consisting of a covalent bond, M -L -M , and L -M -L ;
  • 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;
  • 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-;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl, and heteroaryl;
  • M is selected from the group consisting of M , heteroarylene, and heterocyclyl ene, either of which rings optionally is substituted;
  • Ar is arylene or heteroarylene, each of which is optionally substituted
  • 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
  • Ay is further optionally substituted.
  • 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
  • Ay is further optionally substituted.
  • 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
  • Ay is further optionally substituted with a halo (for example F), phenyl, optionally substituted phenyl or thienyl.
  • a halo for example F
  • phenyl optionally substituted phenyl or thienyl.
  • PG is selected from the group consisting of tert-butoxycarbonyl (Boc), F-Moc, benzyloxycarbonyl (Cbz), -COCF 3 , -CH 2 Ph and -C(0)Me.
  • Ay is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • 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,
  • the present invention provides an improved process for preparing N-(2-aminophen -4-((pyrimidin-2-ylamino)methyl)benzamides of Formula (la):
  • the present invention further provides improved processes for preparing intermediates used in the process for preparing compounds of Formula (I).
  • 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).
  • the present invention provides a process for preparing compounds of Formula (I) as defined abov
  • R 10 is selected from the group consisting of amino, hydroxy, and -NH-PG, wherein PG is an amine protecting group;
  • R 11 is an optional substituent, for example H, halo (for example F), phenyl, optionally substituted phenyl or thienyl,
  • separating the acid of Formula (VII) so prepared comprises collecting the acid by filtration.
  • the compound of Formula (V) is not previously purified from the reaction mixture in which it was prepared.
  • 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).
  • 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).
  • the compound of Formula (V) is previously purified from the reaction mixture in which it was prepared.
  • 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).
  • 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).
  • the process optionally further comprises purifying the compounds of Formula (I) so prepared.
  • purification include recrystallization or titruration of the compounds of Formula (I) so prepared.
  • the purifying comprises recrystallization.
  • the present invention provides a process for preparing an N-(2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la) as defined above
  • 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.
  • separating the acid of Fomiula (Vila) so prepared comprises collecting the acid by filtration.
  • the compound of Formula (Va) is not previously purified from the reaction mixture in which it was prepared.
  • 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).
  • 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).
  • the compound of Formula (Va) is previously purified from the reaction mixture in which it was prepared.
  • 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).
  • 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).
  • 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).
  • the process optionally further comprises purifying the N-(2-aminophenyl)-4-((pyrimidin-2-ylamiiio)methyl)benzamide of Formula (la) so prepared.
  • purification include crystallization or titruration of the N-(2- aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la) so prepared.
  • the purifying comprises crystallization.
  • the present invention provides a process for preparing a compound of Formula (I)
  • R 10 is selected from the group consisting of amino, hydroxy, and -NH-PG, wherein PG is an amine protecting group;
  • R 11 is an optional substituent, for example H, halo (for example F), phenyl or t ienyl.
  • 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.
  • separating the acid of Formula (VII) so prepared comprises collecting the acid by filtration.
  • the process optionally further comprises purifying the compounds of Formula (I) so prepared.
  • purification include recrystallization or titruration of the compounds of Formula (I) so prepared.
  • the purification comprises recrystallization.
  • the present invention provides a process for preparing an N-(2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la)
  • 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.
  • separating the acid of Formula (Vila) so prepared comprises collecting the acid by filtration.
  • the process optionally further comprises purifying the N-(2- aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la) so prepared.
  • purification include recrystallization or titruration of the N-(2-aminophenyl)-4- ((pyrimidin-2-ylamino)methyl)benzamide of Formula (la) so prepared.
  • the purification comprises recrystallization.
  • the present invention provides a process for preparing an acid of Formula (VII),
  • the process optionally further comprises separating the acid of Formula (VII) so prepared from the reaction mixture.
  • separating the acid of Formula (VII) so prepared comprises collecting the acid by filtration.
  • the ester of Formula (VI) is not purified prior to converting it to the acid (VII).
  • the ester of Formula (VI) is purified prior to converting it to the acid of Formula (VII).
  • purification include recrystallization or titruration.
  • the purifying comprises recrystallization.
  • 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
  • the process optionally further comprises separating the acid of Formula (VII) so prepared from the reaction mixture.
  • separating the acid of Formula (VII) so prepared comprises collecting the acid by filtration.
  • the present invention provides a process for preparing a 4-((pyrimidin- -yl-amino)methyl)benzoic acid of Formula (Vila),
  • 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).
  • 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).
  • purification include recrystallization or titruration.
  • the purifying comprises recrystallization.
  • 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)
  • the process optionally further comprises separating the acid of Formula (Vila) so prepared from the reaction mixture.
  • separating the acid of Formula (Vila) so prepared comprises collecting the acid by filtration.
  • the present invention provides a process for preparing an acid of Formula (VII),
  • the ester of Formula (VI) is not purified prior to converting it to the acid (VII).
  • the ester of Formula (VI) is purified prior to converting it to the acid (VII).
  • purification include recrystallization or titruration.
  • the purifying comprises recrystallization.
  • the process optionally further comprises separating the acid of Formula (VII) so prepared from the reaction mixture.
  • separating the acid of Formula (VII) so prepared comprises collecting the acid by filtration.
  • the present invention provides a process for preparing a 4-((pyrimidin- -yl-amino)methyl)benzoic acid of Formula (Vila),
  • 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).
  • 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).
  • purification include crystallization or titruration.
  • the purifying comprises crystallization.
  • the process optionally further comprises separating the acid of Formula (Vila) so prepared from the reaction mixture.
  • separating the acid of Formula (Vila) so prepared comprises collecting the acid by filtration.
  • the invention provides a process for preparing an enaminoketone of Formula (III),
  • 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.
  • R 1 , R 2 , R 3 and R 4 are not all Me.
  • the present invention provides a process for preparing an ester of
  • 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).
  • the present invention provides a process for preparing a 4-((pyrimidi -2-ylamino)methyl)benzoic acid methyl ester of Formula (Via),
  • 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).
  • the 4-((pyrimidin-2- ylamino)methyl)benzoic acid methyl ester of Formula (Via) is not purified from the reaction used to prepare it.
  • the 4-((pyrimidin-2- ylamino)methyl)benzoic acid methyl ester of Formula (Via) is purified from the reaction used to prepare it.
  • purification include recrystallization or trituration.
  • the purifying comprises trituration.
  • 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.
  • the composition is a medicament for treating a disease responsive to inhibition of a histone deacetylase.
  • the disease responsive to inhibition of a histone deacetylase is a cell proliferative disease, such as, for example, cancer.
  • 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.
  • the disease responsive to inhibition of a histone deacetylase is a cell proliferative disease, such as, for example, cancer.
  • the first aspect optionally comprises reacting the acid of Formula (VII) prepared according to the third aspect with a substituted aniline of Formula (A)
  • R is selected from the group consisting of amino, hydroxy, and -NH-PG, wherein PG is an amine protecting group;
  • 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.
  • purification methods include recrystallization and/or titruation of the compound of Formula (I).
  • said purifying comprises recrystallization.
  • 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.
  • purification methods include recrystallization and/or titruation of the N-(2- aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula (la).
  • said purifying comprises recrystallization.
  • 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)
  • 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.
  • 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)
  • 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)
  • 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.
  • 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)
  • the first and second aspects of the invention optionally include or further comprise salt formation of the compounds so prepared.
  • the methylketone of Formula (II) is reacted with an N,N-dialkylfom amide-dialkyl acetal, for example an N,N- dimethylfomiamide-dialkyl acetal.
  • an N,N-dialkylfom amide-dialkyl acetal for example an N,N- dimethylfomiamide-dialkyl acetal.
  • 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.
  • 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.
  • 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.
  • R 1 , R 2 , R 3 and R 4 are not all Me.
  • 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 e
  • 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.
  • 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.
  • the enaminoketone of Formula (III) is optionally purified prior to use in a subsequent reaction.
  • 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.
  • 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).
  • 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).
  • preparation of a compound of Formula (V) comprises reactin a compound of Formula (IV),
  • 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 solvent such as MeOH, EtOH, PrOH, wo-PrOH, THF, DME or the like (or a mixture of these solvents
  • 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).
  • a compound of Formula (IV) such as, for example a methyl 4- (aminomethyl)benzoate hydrochloride of Formula (IVa)
  • DIPEA approximately 0.08- 0.15 equivalents
  • preparation of methyl-4-(guanidinomethyl)benzoate of Formula (Va) comprises reacting a methyl 4- (aminomethyl)benzoate hydrochloride of Formula (IVa), IVa)
  • 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).
  • reaction of the compound of Formula (V) so prepared with an enaminoketone of Formula (III) 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.
  • a solvent such as, but not limited to, MeOH, EtOH, PrOH, zso-PrOH, THF or DME (or a mixture of these solvents
  • a solvent such as, but not limited to, MeOH, EtOH, Pr
  • 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.
  • 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.
  • 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.
  • reaction of the 4- (guanidinomethyl)benzoate of Formula (Va) so prepared with an enaminoketone of Formula (III) 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.
  • a solvent such as, but not limited to, MeOH, EtOH, PrOH, wo-PrOH, THF or DME (or a mixture of these solvents
  • 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.
  • 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.
  • 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.
  • 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 , 3 ⁇ 4P0 4 or the like.
  • 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).
  • 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.
  • an acid such as, but not limited to, HCOOH, AcOH, HC1, HBr, H 2 S0 4 , H 3 P0 4 or the like.
  • 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- ⁇ , 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).
  • 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
  • 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.,
  • the acid of Formula (VII) 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.
  • 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.
  • the 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila) 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.
  • 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.
  • 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.
  • 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):
  • 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):
  • 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).
  • 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).
  • 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
  • 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.
  • 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
  • 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
  • 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-he
  • a solvent such as, but not limited to, DMA, DMF, N-methylpyrrolidone, DMSO, sulfolan and like, for example DMSO
  • an anti-solvent such as, but not limited
  • 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.
  • suitable acids such as HC1, HBr, HI, H 2 S0 4 , H 3 P0 4 , HN0 3 , methane
  • 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-diethoxye
  • 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.
  • 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).
  • 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.
  • 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).
  • 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).
  • 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.
  • 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:
  • 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.
  • the conditions are: NaOMe in MeOH (4.0 equivalents) and running the reaction at reflux conditions for 48 hours.
  • 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
  • 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:
  • 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, ⁇ -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.
  • the conditions are: NaOMe in MeOH (4.0 equivalents) and running the reaction at reflux conditions for 48 hours,
  • 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 (
  • 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.
  • the heteroaryl is optionally substituted pyridinyl.
  • Cy is selected from the group consisting of
  • Formula (I) is an N-(2-aminophenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide of Formula
  • the compound of Fomiula (V) is methyl-4-(guanidinomethyl)benzoate of Fomiula (Va).
  • the compound of Formula (VI) is a 4-((pyrimidin-2-ylamino)methyl)benzoic acid methyl ester of Fomiula (Via).
  • the compound of Fomiula (VII) is a 4-((pyrimidin-2-yl-amino)methyl)benzoic acid of Formula (Vila).
  • X is not a covalent bond.
  • X is -C3 ⁇ 4-.
  • Ar is p-phenyleiie.
  • a disease responsive to inhibition of a histone deacetylase can be a cell proliferative disease such as, but not limited to, cancer.
  • 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.
  • 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.
  • 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).
  • R Me, Et, Pr, Bu , iso-Pr, tert-Bu , etc.
  • 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).
  • 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).
  • 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 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).
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • references 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.
  • 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.”
  • 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.”
  • 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).
  • 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.
  • 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.
  • 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.
  • “Co-C 3 -hydrocarbyl” includes a covalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl, propynyl, and cyclopropyl.
  • 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]
  • 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.
  • 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.
  • 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.
  • alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
  • 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.
  • alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
  • alkylene alkenylene
  • alkynylene alkynylene
  • alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.
  • alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene.
  • alkynylene groups include, without limitation, ethynylene, propynylene, and butynyl ene.
  • 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.
  • 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.
  • carrier as employed herein is intended to mean a cycloalkyl or aryl moiety.
  • carrier also includes a cycloalkenyl moiety having at least one carbon- carbon double bond.
  • 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.
  • the cycloalkyl group is fused to an aryl, heteroaryl or heterocyclic group.
  • 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.
  • 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 -.
  • 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.
  • the aryl group is a C 6 -Ci 0 aryl group, for example a C 6 aryl group.
  • aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
  • 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.
  • the aralkyl group is (C 1 -C 6 )alk(C6-C 1 o)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
  • arylalkyl this term, and terms related thereto, is intended to indicate the order of groups in a compound as “aryl - alkyl”.
  • alkyl-aryl is intended to indicate the order of the groups in a compound as “alkyl-aryl”.
  • heterocyclyl is 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.
  • the heterocyclic group is non-aromatic, in which case the group is also known as a heterocycloalkyl.
  • the heterocyclic group is a bridged heterocyclic group (for example, a bicyclic moiety with a methylene, ethylene or propylene bridge).
  • 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.
  • heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino.
  • the heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl group.
  • 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.
  • the heterocyclic group is a heteroaryl group.
  • 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.
  • 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.
  • a heteroaryl group may be pyrimidinyl, pyridinyl, benzimidazolyl, thienyl, benzothiazolyl, benzofuranyl and indolinyl.
  • 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.
  • 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.
  • arylene is 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.
  • a heteroalicyclic group refers specifically to a non-aromatic heterocyclyl radical.
  • a heteroalicyclic may contain unsaturation, but is not aromatic.
  • 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.
  • 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.
  • a heteroalicyclylalkyl group refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is non-aromatic.
  • 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-
  • halohydrocarbyl as employed herein is a hydrocarbyl moiety, in which from one to all hydrogens have been replaced with an independently selected halo.
  • 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.
  • substituents which are themselves not further substituted (unless expressly stated otherwise) are:
  • 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 alkylcycl
  • 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
  • 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
  • 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 )
  • 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.
  • substituted phenyls include 2-flurophenyl, 3,4- dichlorophenyl, 3-chloro-4-fluoiO-phenyl, 2-fluoro-3-propylphenyl.
  • substituted n-octyls include 2,4-dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included within this definition are methylenes (-C3 ⁇ 4-) substituted with oxygen to form carbonyl -CO-.
  • 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.
  • 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.
  • 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.
  • 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.
  • a cycloalkyl when 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.
  • 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.
  • 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.
  • the two alkyl groups may combine together to form an alkylene chain, for example a C
  • 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.
  • 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.
  • substituents on aryl groups include, but are not limited to, haloalkyl and those groups recited as examples of alkyl substituents.
  • substituents on aryl groups include, but are not limited to, haloalkyl and those groups recited as examples of alkyl substituents.
  • the two alkyl groups may combine together to form an alkylene chain, for example a C 1-3 alkylene chain.
  • 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.
  • the two alkyl groups may combine together to form an alkylene chain, for example a C 1-3 alkylene chain.
  • a heterocyclic group can be optionally substituted on carbon, nitrogen and/or sulfur at one or more positions.
  • substituents on carbon include those groups recited as examples of alkyl substituents.
  • substituents on nitrogen include, but are not limited to alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl.
  • 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.
  • Substituents on ring groups include halogen, alkoxy and alkyl.
  • Substituents on alkyl groups include halogen and hydroxy.
  • halogen refers to chlorine, bromine, fluorine, or iodine.
  • acyl refers to an alkylcarbonyl or arylcarbonyl substituent.
  • acylamino refers to an amide group attached at the nitrogen atom (i.e., R-CO-NH-).
  • 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.
  • sulfonamido refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom.
  • 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.
  • ureido refers to a substituted or unsubstituted urea moiety.
  • radical means a chemical moiety comprising one or more unpaired electrons.
  • substituents on cyclic moieties 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.
  • an optionally substituted phenyl includes, but is not limited to, the following:
  • 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.
  • saturated or unsaturated three- to eight-membered carbocyclic rings include phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • 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.
  • 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.
  • salt(s) denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
  • 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.
  • the compounds of the present invention which contain a basic moiety 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,
  • the compounds of the present invention which contain an acidic moiety 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.
  • 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
  • salts are intended to mean salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects.
  • 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.
  • 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.
  • 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.
  • 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”.
  • nitrogen protecting group is intended to mean a group capable of selectively masking the reactivity of a nitrogen (N) group.
  • 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.
  • These protecting groups may be removed at a convenient stage using methods known from the art.
  • 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.
  • 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.
  • purification examples 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.
  • purified compound refers to a desired compound which has gone through a purification process.
  • 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.
  • one-pot process refers to a process in which there is no separation or purification of an intermediate compound.
  • 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).
  • MTBE 290 mL, drum grade
  • hexane 290 mL, HPLC grade
  • 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).
  • 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.
  • 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.

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Abstract

Cette invention concerne un procédé amélioré de production de composés de formule (I) et de leurs intermédiaires synthétiques. En particulier, l'invention concerne un procédé amélioré de préparation de N-(2-aminophényl)-4- ((pyrimidin-2-ylamino)méthyl)benzamides qui nécessite peu d'étapes, est efficace, peut être utilisé à l'échelle industrielle, et donne lieu à un produit final qui est approprié à une utilisation pharmaceutique.
PCT/CA2014/050684 2013-07-18 2014-07-18 Procédé de préparation de pyrimidines substituées WO2015006875A1 (fr)

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WO2018213329A1 (fr) 2017-05-15 2018-11-22 Blueprint Medicines Corporation Associations d'inhibiteurs de ret et d'inhibiteurs de mtorc1, et utilisations de celles-ci pour le traitement de cancers liés à une activité ret aberrante
US10183928B2 (en) 2016-03-17 2019-01-22 Blueprint Medicines Corporation Inhibitors of RET
US10202365B2 (en) 2015-02-06 2019-02-12 Blueprint Medicines Corporation 2-(pyridin-3-yl)-pyrimidine derivatives as RET inhibitors
US10227329B2 (en) 2016-07-22 2019-03-12 Blueprint Medicines Corporation Compounds useful for treating disorders related to RET
US10584114B2 (en) 2015-11-02 2020-03-10 Blueprint Medicines Corporation Inhibitors of RET
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11273160B2 (en) 2018-04-03 2022-03-15 Blueprint Medicines Corporation RET inhibitor for use in treating cancer having a RET alteration
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11919904B2 (en) 2019-03-29 2024-03-05 Incyte Corporation Sulfonylamide compounds as CDK2 inhibitors
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors

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US10202365B2 (en) 2015-02-06 2019-02-12 Blueprint Medicines Corporation 2-(pyridin-3-yl)-pyrimidine derivatives as RET inhibitors
US10774070B2 (en) 2015-02-06 2020-09-15 Blueprint Medicines Corporation 2-(pyridin-3-yl)-pyrimidine derivatives as RET inhibitors
US10584114B2 (en) 2015-11-02 2020-03-10 Blueprint Medicines Corporation Inhibitors of RET
US11279688B2 (en) 2015-11-02 2022-03-22 Blueprint Medicines Corporation Inhibitors of RET
US10183928B2 (en) 2016-03-17 2019-01-22 Blueprint Medicines Corporation Inhibitors of RET
US10227329B2 (en) 2016-07-22 2019-03-12 Blueprint Medicines Corporation Compounds useful for treating disorders related to RET
WO2018213329A1 (fr) 2017-05-15 2018-11-22 Blueprint Medicines Corporation Associations d'inhibiteurs de ret et d'inhibiteurs de mtorc1, et utilisations de celles-ci pour le traitement de cancers liés à une activité ret aberrante
US11963958B2 (en) 2018-04-03 2024-04-23 Rigel Pharmaceuticals, Inc. RET inhibitor for use in treating cancer having a RET alteration
US11273160B2 (en) 2018-04-03 2022-03-15 Blueprint Medicines Corporation RET inhibitor for use in treating cancer having a RET alteration
US11872192B2 (en) 2018-04-03 2024-01-16 Blueprint Medicines Corporation RET inhibitor for use in treating cancer having a RET alteration
US11866432B2 (en) 2018-10-11 2024-01-09 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11919904B2 (en) 2019-03-29 2024-03-05 Incyte Corporation Sulfonylamide compounds as CDK2 inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors

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