4-aminopyrimidine derivatives and their adenosine a2a receptor antagonists, pharmaceutical compositi

专利摘要:
Derivatives of 4-aminopyrimidine and their adenosine A2a receptor antagonists. New 4-amino-pyrimidine derivatives as potent adenosine A2a receptor antagonists of formula (I): The invention also provides a method for the preparation of such compounds, pharmaceutical compositions comprising an effective amount of these compounds and the use of such compounds in the production of a drug for the treatment of pathological changes that can be improved by adenosine A2a receptor antagonism.
公开号:BR112012024870B1
申请号:R112012024870-7
申请日:2011-03-29
公开日:2020-11-17
发明作者:Juan Alberto Camacho Gomez；Julio Cesar Castro-Palomino Laria
申请人:Palobiofarma, S.L；
IPC主号:

专利说明:

Field of invention
[001] The present invention relates to new pyrimidine derivatives conveniently substituted as antagonists of the Aza adenosine receptor. Other objectives of the present invention are to provide a method for the preparation of such compounds, pharmaceutical compositions comprising an effective amount of these compounds, the use of the compounds in the production of a medicament for the treatment of pathological conditions or diseases that can be improved through of adenosine Aza receptor antagonism. Background of the invention
[002] The effects of adenosine are mediated through at least four specific cell membrane receptors, hitherto identified and classified as Ai, AZA, AZB and A3 receptors, belonging to the G protein-coupled receptor family. Ai and A3 receptors they regulate the levels of cellular cAMP through its coupling with Gi proteins, which inhibit adenylate cyclase. In contrast, AZA and AZB receptors couple Gs proteins that activate adenylate cyclase and increase cAMP intracellular levels. Through these receptors adenosine regulates a wide range of physiological functions.
[003] Several preclinical studies demonstrate the usefulness of adenosine Aza receptor antagonists to treat neurodegenerative diseases, mainly Parkinson's, Huntington's or Alzheimer's diseases (Trends in Neurosci. 2006, 29 (11), 647-654, Expert Pinion Ther. Patents, 2007, 17, 979-991; Exp.Neurol 2003, 184 (1), 285-284; Prog Brain Res., 2010, 183, 183-208; J. Alzheimer Dis. 2010, Suppl 1, 117 -126; J. Neurosci 2009; 29 (47), 14741-14751; Neuroscience, 2010, 166 (2), 590-603; J. Pharmacol Exp. Ther. 2009, 330 (1), 294-303; Frontiers Biosci 2008, 13, 2614 -2632).
[004] Despite the welcome utility of A2A receptor antagonists to treat neurodegenerative diseases, such compounds have been considered for complementary symptomatic indications. These are based on evidence that A2A receptor activation can contribute to the pathophysiology of a range of neuropsychiatric disorders and dysfunctions such as depression, excessive daytime sleepiness, restless legs syndrome, hyperactivity and attention deficit disorder, and cognitive fatigue ( Neurology, 2003, 61 (11 Suppl 6), S82-S87; Behav Pharmacol 2009, 20 (2), 134-145; CNS Drugs Discov. 2007, 2 (1), 1-21).
[005] Some authors suggest the application of A2 antagonists for the treatment of diabetes (WO1999035147; WO2001002400).
[006] Other studies suggest the involvement of A2a adenosine receptors in wound healing or atrial fibrillation (Am J Path, 2007, 6, 1774-1778; Arthritis & Rheumatism, 2006, 54 (8), 2,632-2,642).
[007] For this reason, there is growing interest in finding new, potent and selective A2a adenosine antagonists. Some of the potent A2A adenosine antagonists found in the past by pharmaceutical companies have advanced in clinical trials showing positive results and demonstrating the potential of this class of compounds for the treatment of neurodegenerative diseases such as Parkinson's, Huntington's or Alzheimer's, but also in other diseases related to CNS, such as depression, restlessness syndrome, sleep disorders and anxiety (Clin. Neuropharmacol. 2010, 33, 55- 60; Neurosci. 2010, 30 (48), 16284-16292; Parkinsonisn Relat. Disord. 2010, 16 (6), 423-426; Expert Opinion Ther. Patents, 2010, 20 (8), 987-1005; Current Opinion in Drug Discovery & Development, 2010, 13 (4), 466-480 and references therein; Mov. Disorders, 2010, 25 (2), S305).
The present invention relates to new 4-aminopyrimidine derivatives as potent adenosine A2a receptor antagonists. There are reports in the literature showing that the 4-aminopyrimidines of the Formula:
in which R1 and R3 can be heteroaryl groups and R2 can be a hydrogen atom or a substituted alkyl chain, are potent adenosine A2a receptor antagonists (for example, WO 2005058883 A1; W02008116185).
However, it has surprisingly been found that by introducing an electron receptor substituent at position 5 of the pyrimidine ring the potency of the compounds as adenosine A2a antagonists can be considerably increased compared to unsubstituted parent derivatives, such as illustrated by the following examples:

Detailed description of the invention
[0010] The present invention relates to new pyrimidine derivatives of Formula (I):

[0011] in which:
[0012] - R1 represents a five-membered heteroaryl ring, optionally substituted by one or more substituents selected from the group consisting of halogen, lower alkyl, cycloalkyl, lower alkoxy or cyano.
[0013] - R2 independently represents:
[0014] a) a hydrogen atom.
[0015] b) an alkyl or cycloalkyl group, which is optionally substituted by one or more halogen atoms or by one or more cycloalkyl, hydroxyl or alkoxy groups
[0016] - R3 represents independently:
[0017] a) a halogen atom
[0018] b) a cyan group
[0019] c) a trifluoromethyl group
[0020] d) a cyclopropyl or cyclobutyl group
[0021] e) a five-membered heteroaryl group optionally substituted by one or more halogen atoms or by one or more groups such as alkyl, cycloalkyl, alkoxy, monoamino or dialkylamino.
[0022] - R4 represents independently:
[0023] a) a five-membered heteroaryl group optionally substituted by one or more halogen atoms or by one or more groups such as alkyl, cycloalkyl, alkoxy, monoamino or dialkylamino, alkoxyalkyl
[0024] b) a group N (R5) (R6) in which R5 and R6 represent independently:
[0025] • A hydrogen atom.
[0026] • A linear or branched alkyl or cycloalkyl group, optionally substituted by one or more halogen atoms or by one or more groups such as cycloalkyl, alkoxy, monoamino or dialkylamino.
[0027] - R5 and R6 form, together with the nitrogen atom to which they are attached, a saturated heterocyclic group of 4 to 6 members in which another heteroatom can be inserted, which is optionally substituted by one or more halogen atoms
[0028] c) a group -OR7or -SR7, in which R7 represents independently:
[0029] - an alkyl or cycloalkyl group, linear or branched, optionally substituted by one or more halogen atoms or by one or more groups such as cycloalkyl, alkoxy, monoamino or dialkylamino.
[0030] - a phenyl ring optionally substituted by one or more halogen atoms.
[0031] Other aspects of the present invention are: (a) the pharmaceutically acceptable salts of such compounds, (b) the pharmaceutical compositions comprising an effective amount of said compounds, (c) the use of such compounds in the production of a medicament for the treatment of diseases which can be improved by antagonism of an adenosine receptor, (d) procedures for the treatment of diseases which can be improved by antagonism of an adenosine receptor comprising such procedures for administering these compounds of the present invention to a patient who requires such treatment, and (e) the combination of such compounds with other drugs used for the treatment of disease conditions which can be improved by antagonism of an adenosine receptor.
[0032] As used herein, the term lower alkyl includes radicals, linear or branched, optionally substituted, having from 1 to 8, preferably from 1 to 6, and more preferably from 1 to 4 carbon atoms.
[0033] Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and tert-butyl, n-pentyl, 1-methyl-butyl, 2-methyl-butyl, isopentyl, 1 -ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl , 2,3-dimethyl-butyl, 2-methylpentyl, 3-methylpentyl, and isohexyl radicals.
[0034] As used herein, the term lower alkoxy encompasses the optionally substituted linear or branched oxygen-containing radicals, each having alkyl portions of 1 to 8, preferably 1 to 6, and more preferably 1 to 4 atoms of carbon.
Preferred alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy, t-butoxy, trifluoromethoxy, difluoromethoxy, hydroxyethoxy, 2-hydroxyethoxy or 2-hydroxypropoxy.
[0036] As used herein, the term lower alkylthio encompasses optionally substituted straight or branched thio-containing radicals, each having alkyl portions of 1 to 8, preferably 1 to 6, and more preferably 1 to 4 atoms of carbon.
Preferred alkylthio radicals include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, sec-butylthio, t-butylthio, trifluoromethylthio, difluoromethylthio, hydroxymethylthio, 2-hydroxyethylthio or 2-hydroxypropylthio.
[0038] As used herein, the term cyclic group encompasses, unless otherwise specified, heterocyclic and carbocyclic radicals. Cyclic radicals can contain one or more rings. Carbocyclic radicals can be aromatic or alicyclic, for example, cycloalkyl radicals. Heterocyclic radicals also include heteroaryl radicals.
[0039] As used herein, the term aromatic group typically includes a 5- to 14-membered aromatic ring system, such as a 5 or 6-membered ring that may contain one or more heteroatoms selected from O, S and N. there are no heteroatoms present, the radical is called an aryl radical, when at least one heteroatom is present, it is called a heteroaryl radical. The aromatic radical can be monocyclic or polycyclic, such as phenyl or naphthyl. When a medium or aromatic radical carries two or more substituents, the substituents can be the same or others.
[0040] As used herein, the term five-membered heteroaryl ring typically encompasses a 5-membered ring system comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N.
[0041] Examples include the radicals furyl, oxadiazolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, triazolyl, imidazolidinyl and pyrazolyl. Preferred radicals are optionally substituted pyrazolyl, triazolyl, thiazolyl, and furyl.
[0042] When a heteroaryl radical carries two or more substituents, the substituents can be the same or others.
[0043] As used herein, some of the atoms, radicals, fractions, chains or cycles present in the general structures of the invention are "optionally substituted". This means that these atoms, radicals, fractions, chains or cycles can be either substituted or unsubstituted in any position by one or more, for example, 1, 2, 3 or 4, substituents, through which the hydrogen atoms bond atoms, radicals, fractions, chains or cycles are replaced by chemically acceptable atoms, radicals, units, chains or cycles. When two or more substituents are present, each substituent may be the same or another.
[0044] As used herein, the term halogen atom encompasses fluorine, chlorine, bromine or iodine atoms, typically a fluorine, chlorine or bromine atom, more preferably a chlorine or fluorine atom. The term halo, when used as a prefix, has the same meaning.
[0045] As used herein, the term pharmaceutically acceptable salt encompasses salts with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids, for example, hydrochloric, sulfuric, phosphoric, diphosphoric, hydro-hydrobromic, hydro-hydro and nitric, as well as organic acids, for example, citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic. Pharmaceutically acceptable bases include alkali metals (for example, sodium or potassium) and organic bases and alkaline earth metal hydroxides (for example, calcium or magnesium), for example, alkylamines, arylalkyl amines and heterocyclic amines.
[0046] Other preferred salts according to the invention are quaternary ammonium compounds, in which an equivalent of an anion (X-) is associated with the positive charge of the N atom. The X- can be an anion of several acids minerals such as, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate, or an anion of an organic acid, such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate , trifluoroacetate, methanesulfonate and p-toluenesulfonate. X- is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably, the X- will be chloride, bromide, trifluoroacetate or methanesulfonate.
[0047] According to an embodiment of the present invention, in the compounds of Formula (I), R1 independently represents optionally substituted pyrazole, triazole, thiazole or thiophene rings.
[0048] According to a preferred embodiment of the present invention, in the compounds of Formula (I), R1 independently represents an optionally substituted pyrazole, triazole, or thiazole, and R2 represents a hydrogen atom
[0049] According to the most preferred embodiment of the present invention, in the compounds of Formula (I), R1 independently represents the optionally substituted pyrazole, triazole, or thiazole rings, R2 represents a hydrogen atom and R3 represents a bromine atom, a cyano group or a trifluoromethyl group.
[0050] According to the most preferred embodiment of the present invention, in the compounds of Formula (I), R1 and R4 independently represent optionally substituted pyrazole, triazole, thiazole or thiophene rings, R2 represents a hydrogen atom and R3 represents a bromine atom, a cyano group or a trifluoromethyl group.
[0051] According to an even more preferred embodiment of the present invention, in the compounds of Formula (I), R1 and R4 represent a pyrazole ring optionally substituted by one or more substituents, the group R2 represents a hydrogen atom and the group R3 represents a bromine atom, a cyano group or a trifluoromethyl group.
[0052] According to another preferred embodiment of the present invention, in the compounds of Formula (I), R1 represents optionally substituted pyrazole, thiazole or triazole rings, R2 represents a hydrogen atom, R3 represents a bromine atom and R4 represents independently a group - N (R5) (R6), in which R5 represents a hydrogen atom and R6 represents an alkyl group optionally substituted by fluorine, amino, dialkylamino and alkoxy atoms.
[0053] According to another preferred embodiment of the present invention, in the compounds of Formula (I), R1 represents an optionally substituted pyrazole ring, R2 represents a hydrogen atom, R3 represents a bromine atom and R4 represents independently the isopropyl, cyclopropyl and cyclobutyl rings optionally substituted by fluorine atoms.
[0054] According to another preferred embodiment of the present invention, in the compounds of Formula (I), R1 represents an optionally substituted pyrazole ring, R2 represents a hydrogen atom, R3 represents a bromine atom and R4 represents independently optionally substituted oxygen or sulfur atoms.
[0055] The particular individual compounds of the present invention include: 5-bromo-6-isopropyl-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-2,6-di- (1 H -pyrazol-1-yl) pyrimidine-4-amine 5-bromo-6-cyclopropyl-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-6- (4-methyl-1 H -pyrazol-1-i) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-2- (1 H-pyrazol-1-i) -6- (pi rrol idi n-1 -yl) pyrimidine-4-amine 5-bromo-N4-cyclopentyl-2- (1H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-6- (piperidin-1-i I ) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-6-morpholino-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-6- (4-methylpiperazin-1-ii) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-N4-cyclopropyl-2- (1 H-pyrazol-1-yl) pyrimidine- 4,6-diamine 6- (azetidin-1-yl) - 5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-N4-cyclobutyl-2- (1 H- pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-6- (2-methyl-pyrrolidin-1-i) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5 -bromo-6 - ((R) -2-methyl-pyrrolidin-1-i I ) -2- (1 H-pyrazol-1-i) pyrimidine-4-amine 5-bromo-N4, N4-dimethyl-2- (1H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-N4, N4-diethyl-2- (1H-pyrazol-1-yl) pyrimidine-4,6-diamine {(R) -1- [6-amino-5-bromo-2- (1 H- pyrazol-1-yl) pyrimidine-4-yl] -pyrrolidin-2-ylmethanol 1 - [6-amino-5-bromo-2- (1 H-pyrazol-1-yl) pyramid-4-yl ] azetidi n-3-ol {(S) -1 - [6-amino-5-bromo-2- (1 H-pyrazol-1-i I) pi midi na-4-yl] -pi idol n-2-ylmethanol 1 - [6-amino-5-bromo-2- (1 H-pyrazol-1-yl) pyramid-4-yl] -pyrol i di n-3-ol 5- bromo-6 - ((S) -3-fluoropyrrolidin-1-yl) -2- (1H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-6 - [(R) -2- (methoxymethyl) -pyrrolidin-1-yl] -2- (1 H-pyrazol-1 - yl) pyrimidine-4-amine 5-bromo-6 - [(S) -3- (dimethylamino) -pyrrolidin-1-yl] -2 - (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-6- (2,5-dimethylpyrrolidin-1-i) -2- (1 H-pyrazol-1-yl) pyrimidine -4-amine 5-bromo-6- (3,3-difluoroazetidin-1-i) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-N4-methyl- 2- (1 H-pyrazol-1-yl) pyrimid ina-4,6-diamine 5-bromo-N4-ethyl-2- (1H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-N4- (prop-2-ynyl) -2- ( 1H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-N4- (2-morpholinoethyl) -2- (1H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-N4 -isopropyl-2- (1H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-N4- (cyclopropylmethyl) -2- (1H-pyrazol-1-yl) pyrimidine-4,6-diamine 5 -bromo-N4-propyl-2- (1 H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4,6-diamine 5 -chloro-2,6-di- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-iodo-2,6-di (1 H-pyrazol-1-yl) pyrimidine-4-amine 4- amino-2,6-di- (1 H-pyrazol-1-yl) pyrimidine-5-carbonitrile 4-amino-6-N-cyclopentylamino-2- (1H-pyrazol-1-yl) pyrimidine-5-carbonitrile 5 -bromo-N-methyl-2,6-di- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-N-ethyl-2,6-di (1 H-pyrazol-1-yl ) pyrimidine-4-amine N-benzyl-5-bromo-2,6-di (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-N- (prop-2-ynyl) -2, 6-di (1H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-N- (2-morpholinoethyl) -2,6-di (1H-pyrazol-1-yl) pir imidine-4-amine 5-bromo-N- [2- (piperidin-1-i) ethyl] -2,6-di (1 H-pyrazol-1-i) pyridine-4-amine 5-bromo-N-cyclobutyl-2,6-di (1H-pyrazol-1-yl) pyrimidine-4-amine N- (2-aminoethyl) - 5-bromo-2,6-di (1H-pyrazol-1 -yl) pyrimidine-4-amine N4-tert-butyl-5-bromo-2- (1H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-2- (4-methyl-1 H- pyrazol-1-yl) -6- (1 H-pyrazol-1-yl) pyrimidine-4-amine 6- (azetidin-1-yl) -5-bromo-2- (4-methyl-1 H-pyrazole- 1-yl) pyrimidine-4-amine 5-bromo-N4-cyclopentyl-2- (4-methyl-1H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-N4-cyclopropyl-2- ( 4-methyl-1H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-N4-cyclobutyl-2- (4-methyl-1 H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-2- (4-methyl-1H-pyrazol-1-yl) -6- (2-methyl-pyrrolidin-1-yl) pyrimidine-4-amine 5-bromo-2- (4-methyl-1H -pyrazol-1-yl) -6 - ((R) -2-methyl-pyrrolidin-1-yl) pyrimidine-4-amine 5-bromo-N-cyclopropyl-2- (4-chloro-1H-pyrazol-1 -yl) pyrimidine-4,6-diamine 6- (azetidin-1-yl) -5-bromo-2- (4-chloro-1H-pyrazol-1-yl) pyrimidin-4-amine 5-bromo-2, 6 -di- (4-methyl-1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-2,6-di- (4-chloro-1H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-2,6-di- (3-methyl-1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-2,6-di- (3-trifluoromethyl-1 H-pyrazol-1 -yl) pyri midi na-4-amine 5-bromo-2,6-di- [5- (ethoxycarbonyl) -3-methyl-1 H-pyrazol-1-yl] pyrimidin-4-amine 5-bromo-6 - (3,5-dimethyl-1 H-pyrazol-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-6- (1H-imidazol-1-yl) -2- (1H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-6- (4-chloro-1 H-pyrazol-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-2- (1 H-pyrazol-1-yl) -6- (2H-1,2,3-triazol-2-yl) pyrimidine-4-amine 5-bromo-2- (1 H-pyrazol-1-yl) -6- (1 H-1,2,4-triazol-1-yl) pyrimidine-4-amine 5-bromo-6-isopropoxy-2- (1 H-pyrazol- 1-yl) pyrimidine-4-amine 5-bromo-2- (4-chloro-1H-pyrazol-1-yl) -6- (1H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-2 - (4-chloro-1 H-pyrazol-1-yl) -6- (4-methyl-1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-2- (3,5-dimethyl- 1 H-pyrazol-1-yl) -6- (1 H-pyrazol-1-i) pi midi na-4-ami na 5-bromo-N4-cyclopentyl-2- (3,5-dimethyl-1H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-2- (3,5-dimethyl-1 H-pyrazole -1 -i I) -6- (pyrrole idi n-1 -i I) pyridine-4-amine 5-bromo-N4-isopropyl-2- (3,5-dimethyl-1H-pyrazole-1 -yl) pyrimidine-4,6-diamine 5-bromo-2,6-bis (3,5-dimethyl-1 H-pyrazol-1-yl) pyrimidine-4-amine 5- (1-methyl-1 H- pi razol-4-i) -2,6-di (1 H-pyrazol-1-yl) pyrimidine-4-amine 2,6-di (1 H-pyrazol-1-i) -5- (1 H-pyrazol-4-yl) pyrimidine-4-amine 2,6-di (1 H-pyrazol-1-yl) -5- (thiophen-2-yl) pyrimidine-4-amine 5-cyclopropyl I-2 , 6-di (1 H-pyrazol-1-yl) pyrimidine-4-amine 2,6-di (1 H-pyrazol-1-yl) -5- (thiazol-2-yl) pyrimidine-4-amine 2 , 6-di (1 H-pyrazol-1-yl) -5- (oxazol-2-yl) pyrimidine-4-amine 5- (trifluoromethyl) -2,6-di (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-Bromo-2,6-di (thiazol-2-yl) pyrimidine-4-amine 5-Bromo-2- (1 H-pyrazol-1-yl) -6- (thiazol-2- il) pyrimidine-4-amine 5-Bromo-6- (1 H-pyrazol-1-yl) -2- (thiazol-2-yl) pyrimidine-4-amine 5-bromo-N4- [1 - (dimethylamino) propan-2-yl] -2- (1 H-pyrazol-1 -i I) pi mri id- 4,6-diamine 5-bromo-N4- (1-methoxypropane-2-yl) -2- (1 H-pyrazol-1 -i I) pi mri midi na-4 , 6-diamine 5-bromo-6- (1 H-pyrazol-1-i) -2- (2 H-1,2,3-triazol-2-yl) pyrimidine-4-amine 5-bromo-6 -ethoxy-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine
[0056] The compounds of the present invention can be prepared by one of the processes described below. Synthetic routes are described by specific examples, which are by no means limited to the scope of the present invention.
[0057] Derivatives where the substituent R3 is a bromine or chlorine atom can be prepared by the sequence of reactions represented in scheme 1.
[0058] The methylthio group of the commercially available Formula (II) derivative (Aldrich) was oxidized using 1.2 equivalents of meta-chloroperbenzoic acid at room temperature in dichloromethane (DCM) as a solvent resulting in the Formula (III) sulfoxide, which precipitates directly from the reaction.
[0059] Position 5 of the pyrimidine derivative of Formula (III) was brominated using N-bromosuccinimide in dimethylformamide (DMF) at room temperature to obtain the derivative of Formula (IV). The analogous reaction using N-chlorosuccinimide leads to chlorinated derivatives at position 5 of the pyrimidine ring is also the subject of the present invention. Layout 1

[0060] Reagents and conditions: (a) m-chloroperbenzoic acid (1.2 eq), DCM, room temperature; (b) N-bromosuccinimide (1.2 eq), DMF, room temperature; (c) pyrazole (1.3 eq), cesium carbonate, DMF, room temperature; (d) 3-methylpyrazole (3 eq), cesium carbonate, DMF, 85 ° C; (e) pyrrolidine (3 eq), THF, 60 ° C, (f) sodium methoxide, methanol, room temperature.
[0061] The halogenated sulfoxides of Formula (IV) react with different commercially available five-membered heterocycle derivatives (eg pyrazoles or triazoles), at room temperature, using dimethylformamide (DMF) as a solvent, in the presence of such a base like cesium carbonate. For example, if the compound of Formula (IV) reacts with pyrazole under these conditions it will provide the derivative of Formula (V).
[0062] The chlorine atom at position 6 of the pyrimidine derivative of Formula (V) can also be replaced by derivatives of five-membered heterocycles (eg pyrazoles or triazoles) using DMF as a solvent and the presence of such a base such as cesium carbonate at 85 ° C. For example, the reaction of derivative (V) with pyrazole under these conditions provides the compound of Formula (VI), which is an example of the type of compounds claimed by the present invention.
[0063] In addition, the pyrimidine derivatives of Formula (V) can also be reacted with the commercially available primary or secondary amines, alcohols and thiols, at room temperature to obtain the compound of Formula (I) claimed by the present invention. For example, the reaction of derivative (V) with sodium methoxide or pyrrolidine, under these conditions, leads to the formation of the compound of Formula (VII) or (VIII), which are specific examples of the compounds of Formula (I) claimed in the present invention.
[0064] To synthesize the pyrimidine derivatives in which the R3 substituent of position 5 of the pyrimidine defined above corresponds to a cyano group or heteroaryl groups, the procedures described in scheme 2 can be used.

[0065] Reagents and conditions: (g) copper (I) cyanide (1.1 eq), pyridine, microwave (MW), 20 min at 250 ° C; (h) thiazolyl-2-tributyltanane, cesium carbonate, palladium catalyst, dioxane, water, microwave, 20 min. at 150 ° C.
[0066] The introduction of the cyan group is performed using the method described by A.P. Ijzerman et al. Biorganic & Medical Chemistry 2008. For example, the reaction of bromine derivatives of Formula (VII) with copper (I) cyanide under microwave conditions for 20 minutes at 250 ° C gave the compound of Formula (IX) containing a cyano group at position 5 of the pyrimidine ring.
[0067] On the other hand, the bromine derivative of Formula (VI) reacts with commercial heteroaryl boronic acids in a conventional Suzuki coupling reaction or with commercially available tributylstannane heteroaryl derivatives in a conventional Stille reaction to result in derivatives where the position five of the pyrimidine ring is replaced by a heterocyclic ring. For example, the reaction of the compound of Formula (VII) with thiazole 2-tributylstannyl mediated by catalysis of palladium produces the compound of Formula (X), which is a specific example of the compounds claimed in the present invention.
[0068] The compounds in which the amino group at position 4 of the pyrimidine ring is replaced by an R2 alkyl group, as defined above, can be obtained using the synthetic route described in scheme 3. Scheme 3

[0069] Reagents and conditions: (i) NaNO2 (10 eq), AcOH, room temperature; Q) thionyl chloride (2 eq), DMF / DCM, 40 ° C, 2h; (k) R2-NH2 (3 eq), THF, room temperature, 24h.
[0070] The Formula (VI) derivative reacts with sodium nitrite in acetic acid at room temperature for the respective Formula (XI) pyrimidinone. The reaction of this derivative with thionyl chloride in a DMF / DCM solution (1/2: v / v) at 40 ° C leads to the formation of the 4-chloro-pyrimidine derivative with Formula (XII). The compound (XII) then reacts with commercially available amines in very good yields, resulting in the desired N-pyrimidine-4-amines of the general Formula (XIII), which are the subject of the present invention.
[0071] If the residues R1 and R4, defined in the General Formula (I), are the same, the derivatives can also be synthesized following the procedure described in scheme 4. Scheme 4

[0072] Reagents and conditions: (L) N-bromosuccinimide (1.2 eq), DMF, room temperature, (m) 4-methyl-pyrazole (4 eq), cesium carbonate, DMF, 85 ° C.
[0073] The bromination of the commercially available compound of Formula (XIV) is carried out with N-bromo-succinimide in DMF resulting in the compound of Formula (XV). The reaction of the compound (XIV) with different commercial pyrazoles, in the presence of cesium carbonate in DMF, at 85 ° C leads to the formation of the pyrimidine derivatives replaced by the identical pyrazole derivatives in positions 2 and 6, such as the compound of Formula (XVI), which is a specific example of the compounds of Formula (I) claimed by the present invention.
[0074] Similarly, if residue R4, as defined in General Formula (I), is an alkyl or cycloalkyl group, derivatives can also be synthesized following the procedure described in scheme 5. Scheme 5

[0075] Reagents and conditions: (L) N-bromosuccinimide (1.2 eq), DMF, room temperature, (m) pyrazole (4 eq), cesium carbonate, DMF, 85 ° C.
[0076] The bromination of the commercially available compound of Formula (XVII) is carried out with N-bromo-succinimide in DMF resulting in the compound of Formula (XVIII). The reaction of the compound (XVIII) with different commercial pyrazoles, in the presence of cesium carbonate in DMF at 85 ° C leads to the formation of derivatives, such as the compound of Formula (XIX), which is a specific example of the compounds of Formula ( I) claimed by the present invention.
[0077] When the substituents at positions 2 and 6 of the pyrimidine ring are heterocyclic rings that cannot be introduced by nucleophilic substitution, the corresponding derivatives can be synthesized as described in scheme 6.
[0078] The commercially available derivative (XVI) reacts with commercially available pinacol esters of heteroaryl boronic acids in a conventional Suzuki coupling reaction or with commercially available tributyltanane heteroaryl derivatives in a conventional Stille reaction to result in a mixture of all substitutions possible that can be separated by a chromatography column. For example, the reaction of the compound of Formula (XVI) with thiazole 2-tributylstanil mediated by palladium catalysis yields the compounds of Formula (XX), (XXI) and (XXII). These intermediates can be brominated and replaced by various pyraz derivatives resulting in the compounds of Formula (XXIII), (XIV) and (XV), which represent specific examples of the compounds of Formula (I) claimed by the present invention. Layout 6

[0079] Reagents and conditions: (h) (h) thiazolyl-2-tributyltanane, cesium fluoride, palladium catalyst, dioxane, 24 h at 80 ° C; (L) N-bromosuccinimide (1.2 eq), DMF, room temperature, (m) pyrazole (4 eq), cesium carbonate, DMF, 85 ° C. Pharmacological activity Binding assay with competition radioactive subtype of the A2a adenosine receptor
[0080] Recombinant human adenosine receptor membranes were purchased from Receptor Biology, Inc. (USA).
[0081] Competition assays were performed by incubating membranes from hAi receptors transfected into CHO cells, [3H] -DPCPX as a radioligand, the buffer (20 mM HEPES (pH = 7.4), 10 MgCl2 mM, 100 mM NaCI, 2 units / mL adenosine deaminase), and the unlabeled ligand in a total volume of 0.2 mL for 60 minutes at 25 ° C. R-PIA was used to determine non-specific binding. Filter with GF / 52 Schleicher & Schuell filters (pre-soaked with 0.5% polyethyleneimine) in a Brandel cell collector. The unbound radioligand was removed with (3 x 250 pl) 20 mM HEPES (pH = 7.4), 100 mM NaCl and MgCl210 mM.
[0082] Competition tests were performed by incubating membranes of transfected hA2a receptors for HeLa cells, [3H] -ZM241385 as radioligand, buffer (50 mM Tris-HCI (pH = 7.4), 10 mM MgCI2, 1 mM EDTA, 2 units / ml adenosine deaminase), and the unlabeled ligand in a total volume of 0.2 ml for 30 minutes at 25 ° C. The NECA was used to determine the non-specific binding. Filtration with GF / 52 Schleicher & Schuell filters (pre-soaked with 0.5% polyethyleneimine) in a Brandel cell collector. The unbound radioligand was removed with 3 x 250 pl frozen, 50 mM Tris-HCI (pH = 7.4), 10 mM MgCI and 1 mM EDTA.
[0083] The concentration and response curves of the binding competition were performed by testing 6 different concentrations (range between 10 nm and 100 pM). The inhibition constant (Ki) for each compound was calculated using the Cheng-Prusoff equation: Ki = Clso / (1 + [L] / KD)
[0084] In which Cho is the concentration of the compound that displaces the binding of the radioligand by 50%, [L] is the concentration of free radioligand and KD is the dissociation constant of each radioligand. IC50 values were obtained by adjusting the data using non-linear regression, using the Prism 2.1 software (GraphPad, San Diego, CA). Measurement of cyclic adenosine monophosphate production.
[0085] These assays were performed on the adenosine recipients transfected using a cAMP enzyme immunoassay kit (Amersham Biosciences). CHO-A2A cells were seeded (10,000 cells / well) in 96-well culture plates and incubated at 37 ° C in an atmosphere with 5% CO2 in the Dulbecco nutrient mixture F-12 (DMEM F-12) modified by Eagle, containing 10% fetal bovine serum (FCS) and 1% L-Glutamine. The cells were washed 3 times with 200 µl of test medium (DMEM-F12 and HEPES at 25 mM pH = 7.4) and pre-incubated with test medium containing 30 mM rolipram and the test compounds at 37 ° C for 15 min. The 1 µM NECA was incubated for 15 min at 37 ° C (total incubation time 30 min.). The reaction was stopped with buffer, the lysis buffer fed in the kit and the enzyme immunoassay was performed for the detection of intracellular cAMP at 450 nm in an Ultra Evolution Detector (Tecan). The data were adjusted by non-linear regression using GraphPad Prism v2.01 (GraphPad Software).
[0086] Table 1 shows the inhibition constants against the A2a adenosine receptor obtained in the binding assay and in the second messenger cAMP production assay for some examples:


[0087] From Table 1 it can be seen that the compounds of Formula (I) are potent antagonists of the A2a adenosine receptor.
[0088] The derivatives of the present invention are useful in the treatment or prevention of diseases known to be susceptible to improvement through treatment with an adenosine receptor antagonist, in particular those susceptible to improvement through treatment with the antagonist of the adenosine. adenosine receptor. Such diseases are, for example, ischemia, supraventricular arrhythmias, atrial fibrillation, acute renal failure, asthma, myocardial reperfusion injury, diseases due to fluid retention, allergic reactions, including, but not limited to rhinitis, urticaria, scleroderma, arthritis , other autoimmune diseases, inflammatory bowel diseases, diabetes mellitus, obesity, Parkinson's disease, Huntington's disease, dystonia, such as agitated leg syndrome, dyskinesias such as those caused by prolonged use of neuroleptic or dopamine drugs or sleep disorders , congestive heart failure, hypertension, intradialitic hypotension, dementia, and anxiety disorders.
[0089] In this way, the derivatives of the present invention and their pharmaceutically acceptable salts, and pharmaceutical compositions comprising such a compound and / or its salts, can be used in a method of treating disorders of the human body which comprises administration to an individual that such treatment requires an effective amount of the pyrimidine derivative of the invention or a pharmaceutically acceptable salt thereof.
[0090] The present invention also provides pharmaceutical compositions comprising, as an active ingredient at least one pyrimidine derivative of Formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient can comprise from 0.001% to 99% by weight, preferably from 0.01% to 90% by weight of the composition depending on the nature of the formulation and whether an additional dilution must be made before application. Preferably, the compositions are marketed in a form suitable for oral, topical, nasal, rectal, percutaneous or injectable administration.
[0091] Pharmaceutically acceptable excipients which are mixed with the active compound, or salts of such compound, to form the compositions of the present invention are well known per se and the excipients actually used depend inter alia on the intended method of administering the compositions.
[0092] The compositions of this invention are preferably adapted for administration and per se injectable. In this case, compositions for oral administration can take the form of tablets, retard tablets, sublingual tablets, capsules, aerosols for inhalation, solutions for inhalation, inhalation of dry powder, or liquid preparations such as mixtures, elixirs, syrups or suspensions. , all containing the compound of the present invention; such preparations can be made by methods well known in the art.
[0093] Diluents that can be used in the preparation of the compositions include liquid and solid diluents that are compatible with the active ingredient, together, if desired, with coloring or flavoring agents. The tablets or capsules can conveniently contain between 2 and 500 mg of active ingredient or the equivalent amount of a salt thereof.
[0094] The liquid composition adapted for oral use can be in the form of solutions or suspensions. The solutions can be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form syrup. The suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavoring agent.
[0095] Compositions for parenteral injection can be prepared from soluble salts, which may or may not be lyophilized and can be dissolved in a pyrogen-free aqueous medium or other suitable parenteral injection fluid.
[0096] Effective doses are usually in the proportion of 2 to 2000 mg of active ingredient per day. The daily dosage can be administered in one or more treatments, preferably from 1 to 4 treatments per day.
[0097] The synthesis of the compounds of the invention is illustrated by the following examples (1 to 99), including the preparation of intermediates, which in no way limit the scope of the invention.
[0098] Reagents in general, starting materials and solvents were purchased from commercial suppliers and used as received. Concentration refers to evaporation under vacuum using a Büchi rotary evaporator. The reaction products were purified, when necessary, by silica gel flash chromatography (40 to 63 pm) with the indicated solvent system. The spectroscopic data were recorded on a Varian Gemini 200 spectrometer, Varian Gemini 300 spectrometer, Varian Inova 400 spectrometer and Brucker DPX-250 spectrometer. The melting points were recorded on a Buchi 535 device. HPLC-MS were performed on a Gilson instrument equipped with a Gilson 321 pump piston, a Gilson 864 vacuum degasser, a Gilson 215 liquid handler, a Gilson injection module 189, a Gilson ValveMate 7000, a 1/1000 divider, a Gilson 307 make up pump activator, a detector with a Gilson 170 diode array, and aQa Thermoquest Finnigan detector. Semi-preparative purifications were performed using a Symmetry C18 reverse phase column (100 Δ, 5 nm, 19 x 100 mm, purchased from WATERS), and water / ammonium formate (0.1%, pH = 3) and acetonitrile / ammonium formate (0.1%, pH = 3) as a mobile phase. Intermediate 1: 6-chloro-2- (methylsulfinyl) pyrimidine-4-amine:
[0099] A solution of 15.3 g (68.6 mmol) of m-chloroperbenzoic acid (77%) (Aldrich) dissolved in 200 ml of DCM was added over 30 minutes to a stirred solution of 10.0 g (57 , 2 mmol) of 6-chloro-2- (methylthio) -pyrimidine-4-amine in 300 ml of dichloromethane. The reaction mixture was stirred at room temperature for 4 hours. The white precipitate formed was filtered, washed several times with DCM and then, after drying, resulted in 10.4 g (94.9%) of intermediate 1.
[00100] 1H-NMR (300 MHz, DMSO-d6): δ = 3.28 (s, 3H), 6.64 (s, 1H), 8.11 (s, 2H). Intermediate 2: 5-bromo-6-chloro-2- (methylsulfinyl) pyrimidine-4-amine:
[00101] 11.2 g (62.6 mmol) of N-bromo-succinimide was added slowly to a cooled suspension of 10 g (52.2 mmol) of 6-chloro-2 - (methylsulfinyl) pyrimidine-4-amine in 130 ml_ of DMF. After 50 minutes of stirring at room temperature, the precipitate was filtered, washed with cold DMF, several times with cold water and dried in vacuo. 11.4 g (81%) of a white solid were obtained.
[00102] 1H-NMR (300 MHz, DMSO-d6): δ = 2.78 (s, 3H), 8.17 (d, 2H). Intermediate 3: 5-bromo-2,6-dichloropyrimidine-4-amine:
[00103] 2 g (12.2 mmol) of 4-amino-2,6-dichloropyrimidine were dissolved in 10 ml of DMF. To this solution, 2.6 g (14.6 mmol) of N-bromo-succinimide were added. The reaction mixture was stirred at room temperature overnight. The solution was poured into 200 ml of cold water. The formed precipitate was filtered and washed with water. The product obtained was 2.7 g (91.9%) as a white powder.
[00104] 1H-NMR (300 MHz, DMSO-d6): δ = 8.16 (d, 2H). Intermediate 4: 2,5,6-trichloropyrimidine-4-amine:
[00105] 1 g (6.1 mmol) of 4-amino-2,6-dichloropyrimidine was dissolved in 5 ml of DMF. To this solution was added 0.98 g (7.32 mmol) of N-chlorosuccinimide. The solution was poured into 100 ml of cold water. The formed precipitate was filtered, washed with water and dried to produce 1.4 g (80%) of a white solid.
[00106] 1H-NMR (300 MHz, DMSO-d6): δ = 8.24 (d, 2H). Intermediate 5: 5-bromo-6-chloro-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine:
[00107] 1 g (3.7 mmol) of 5-bromo-6-chloro-2- (methylsulfinyl) pyrimidine-4-amine (intermediate 2) was suspended in 10 ml of DMF. To this suspension 0.33 g (4.8 mmol) of pyrazole and 0.8 g of cesium carbonate were added. The reaction mixture was immediately turned light yellow and left stirring at room temperature for about 1 to 2 hours. After almost complete conversion to the corresponding mono-substituted derivative as indicated by TLC, the solution was poured into 100 ml of cold water. The formed precipitate was filtered, washed with water and dried to give 0.66 g (65%) of the desired product.
[00108] 1H-NMR (300 MHz, DMSO-d6): δ = 6.56 (dd, 1H), 7.81 (d, 1H), 8.44 (d, 1H), 8.15 (d, 2H).
[00109] The following intermediates were synthesized using the procedure described for intermediate 5 from the corresponding pyrazole derivatives. Intermediate 6: 5-bromo-6-chloro-2- (4-methyl-1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00110] 1H-NMR (300 MHz, DMSO-dβ): δ = 2.08 (s, 3H), 7.63 (s, 1H), 8.21 (s, 1H), 8.17 (d, 2H). Intermediate 7: 5-bromo-6-chloro-2- (4-chloro-1 H-pyrazol-1-II) pyrimidine-4-amine.
[00111] 1H-NMR (300 MHz, DMSO-d6): δ = 7.94 (s, 1H), 8.57 (s, 1H), 8.13 (d, 2H). Intermediate 8: 5-bromo-2,6-di (1 H-pyrazol-1-yl) pyrimidine-4 (3H) -one.
[00112] 1.84 g (6 mmol) of 5-bromo-2,6-di- (1H-pyrazol-1-yl) pyrimidine-4-amine (example 1) were dissolved in 20 ml of acetic acid. To this solution was added a solution of 4.16 g (18.4 mmol) of NaNO2 in 8 ml of water in four batches over a period of five hours. The mixture was stirred at room temperature for 30 hours. The solvent was removed in vacuo and the crude residue was washed with water to obtain 1.22 g (65.8%) of pure intermediate 8.
[00113] 1H-NMR (300 MHz, DMSO-d6): δ = 6.50 (m, 2H), 7.73 (d, 1H), 7.75 (d, 1H), 8.30 (d, 1H), 8.53 (d, 1H). Intermediate 9: 5-bromo-4-chloro-2,6-di (1 H-pyrazol-1-yl) -pyrimidine.
[00114] A solution of 1 g (3.26 mmol) of 5-bromo-2,6-di (1 H-pyrazol-1-yl) pyrimidine-4 (3H) -one (intermediate 8) in 10 mL of DMF and 40 mL of DCM, dripped, a solution of 0.71 mL (9.8 mmol) of thionyl chloride in 10 mL of DCM. The reaction mixture was refluxed for two hours, to the point that no starting material was observed by TLC. The solution was extracted twice with 10 ml of saturated NaHCO3 solution and brine. The organic layer was separated, dried with MgSO4 and concentrated to give 0.65 g (61.5%) of the 4-chloropyrimidine derivative.
[00115] 1H-NMR (300 MHz, DMSO-d6): δ = 6.68 (dd, 1H), 6.73 (dd, 1H), 7.95 (d, 1H), 8.02 (d, 1H), 8.76 (d, 1H), 8.80 (d, 1H). Intermediate 10: 2,6-dichloro-5-iodo-pyrimidine-4-amine:
[00116] 1 g (6.1 mmol) of 4-amino-2,6-dichloropyrimidine was dissolved in 5 ml of DMF. To this solution was added 0.76 g (7.32 mmol) of N-iodo-succinimide. The solution was stirred for 18 h at room temperature and then poured into 100 ml of cold water. The formed precipitate was filtered, washed with water and dried to give 1.2 g (76%) of a pale yellow solid.
[00117] 1H-NMR (300 MHz, DMSO-d6): δ = 8.11 (d, 2H). Intermediate 11: 2,5,6-trichloropyrimidine-4-amine.
[00118] 1H-NMR (300 MHz, DMSO-d6): δ = 8.14 (d, 2H). Intermediate 12: 5-bromo-6-chloro-2- (3,5-dimethyl-1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00119] 1H-NMR (300 MHz, DMSO-d6): δ = 2.59 (s, 3H), 2.65 (s, 3H), 6.4 (s, 1H), 8.18 (d, 2H). Intermediate 13: 5-bromo-6-chloro-2- (2H-1,2,3-triazol-2-yl) pyrimidine-4-amine.
[00120] 1H-NMR (300 MHz, DMSO-d6): δ = 7.81 (d, 1H), 8.44 (d, 1H), 8.15 (d, 2H). Examples Derivatives of intermediate 5 (R1 = PIRAZOL) Example 1: 5-bromo-2,6-di- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00121] 0.11 g (1.64 mmol) of 1H-pyrazole and 0.18 g (0.55 mmol) of cesium carbonate were added to a solution of 0.15 g (0.55 mmol) of 5 -bromo-6-chloro-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine (Intermediate 5) in 3 ml of DMF. The mixture was stirred at 85 ° C for 24 hours. The DMF solvent was concentrated under reduced pressure. The crude residue was washed with water and dried resulting in 0.13 g (77%) of example 1.
[00122] 1H-NMR (300 MHz, DMSO-d6): δ = 6.57 (dd, 1H), 6.60 (dd, 1H), 7.52 (s, 1H), 7.81 (d, 1H), 7.87 (d, 1H), 8.41 (s, 1H), 8.51 (d, 1H), 8.60 (d, 1H).
[00123] The title compound can also be synthesized from intermediate 3, using the procedure described for example 68 and pyrazole instead of 4-methyl-pyrazole.
[00124] Examples 2 to 33 were synthesized using the procedure described for example 1, starting from intermediate 5 and the corresponding pyrazole derivatives or amines: Example 2: 5-bromo-6- (4-methyl-1 H-pyrazol-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00125] 1H-NMR (300 MHz, DMSO-d6): δ = 2.12 (s, 3H), 6.57 (dd, 1H), 7.53 (s, 1H), 7.70 (s, 1H), 7.81 (d, 1H), 8.32 (s, 1H), 8.43 (d, 2H), 8.52 (d, 1H). Example 3: 5-bromo-2- (1 H-pyrazol-1-yl) -6- (pyrrolidin-1-yl) pyrimidine-4-amine.
[00126] 1H-NMR (300 MHz, DMSO-d6): δ = 1.85 (m, 4H), 3.73 (t, 4H), 6.47 (dd, 1H), 6.85 (s, 2H), 7.69 (d, 1H), 8.45 (d, 1H). Example 4: 5-bromo-N4-cyclopentyl-2- (1 H-pyrazol-1-yl) pyrimidine-4, 6-diamine.
[00127] 1H-NMR (300 MHz, DMSO-dθ): δ = 1.55 (m, 4H), 1.70 (m, 2H), 1.96 (m, 2H), 4.40 (m, 1H), 6.26 (d, 1H), 6.48 (dd, 1H), 6.75 (s, 2H), 7.71 (d, 1H), 8.46 (d, 1H). Example 5: 5-bromo-6- (piperidin-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00128] 1 H-NMR (300 MHz, DMSO-de): δ = 1.61 (m, 6H), 3.44 (m, 4H), 6.49 (dd, 1H), 7.07 (s , 2H), 7.72 (d, 1H), 8.45 (d, 1H). Example 6: 5-bromo-6-morpholino-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00129] 1H-NMR (300 MHz, DMSO-dθ): δ = 3.48 (t, 4H), 3.71 (t, 4H), 6.50 (dd, 1H), 7.19 (s, 2H), 7.74 (d, 1H), 8.48 (d, 1H). Example 7: 5-bromo-6- (4-methylpiperazin-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00130] 1 H-NMR (300 MHz, DMSO-dθ): δ = 2.21 (s, 3H), 2.43 (t, 4H), 3.49 (t, 4H), 6.50 (dd , 1H), 7.12 (s, 2H), 7.73 (d, 1H), 8.46 (d, 1H). Example 8: 5-bromo-N4-cyclopropyl-2- (1 H-pyrazol-1-yl) pyrimidine-4, 6-diamine.
[00131] 1 H-NMR (300 MHz, DMSO-dθ): δ = 0.61 (m, 2H), 0.71 (m, 2H), 2.90 (m, 1H), 6.48 (dd , 1H), 6.73 (d, 1H), 6.76 (s, 2H), 7.71 (d, 1H), 8.50 (d, 1H). Example 9: 6- (azetidin-1-yl) -5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00132] 1 H-NMR (300 MHz, DMSO-dθ): δ = 2.23 (q, 2H), 4.29 (t, 4H), 6.46 (dd, 1H), 6.87 (s , 2H), 7.70 (d, 1H), 8.42 (d, 1H). Example 10: 5-bromo-N4-cyclobutyl-2- (1 H-pyrazol-1-yl) pyrimidine-4, 6-diamine.
[00133] 1 H-NMR (300 MHz, CDCh): δ = 1.64 (m, 2H), 2.13 (m, 2H), 2.23 (m, 2H), 4.60 (m, 1H ), 6.48 (dd, 1H), 6.72 (d, 1H), 6.76 (s, 2H), 7.70 (d, 1H), 8.46 (d, 1H). Example 11: 5-bromo-6- (2-methyl-pyrrolidin-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00134] 1 H-NMR (300 MHz, DMSO-de): δ = 1.21 (d, 3H), 1.55 (m, 1H), 1.75 (m, 1H), 1.94 (m , 1H), 2.08 (m, 1H), 3.62 (m, 1H), 3.94 (m, 1H), 4.52 (m, 1H), 6.48 (dd, 1H), 6 , 88 (s, 2H), 7.71 (d, 1H), 8.42 (d, 1H). Example 12: 5-bromo-6 - ((R) -2-methyl-pyrrolidin-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00135] 1H-NMR (300 MHz, DMSO-de): δ = 1.21 (d, 3H), 1.55 (m, 1H), 1.77 (m, 1H), 1.93 (m, 1H), 2.09 (m, 1H), 3.62 (m, 1H), 3.92 (m, 1H), 4.52 (m, 1H), 6.48 (dd, 1H), 6, 88 (s, 2H), 7.71 (d, 1H), 8.42 (d, 1H). Example 13: 5-bromo-N4, N4-dimethyl-2- (1 H-pyrazol-1-yl) pyrimidine-4, 6-diamine.
[00136] 1H-NMR (300 MHz, DMSO-de): δ = 3.09 (s, 6H), 6.49 (dd, 1H), 7.00 (s, 2H), 7.72 (d, 1H), 8.47 (d, 1H). Example 14: 5-bromo-N4, N4-diethyl-2- (1 H-pyrazol-1-yl) pyrimidine-4, 6-diamine.
[00137] 1H-NMR (300 MHz, DMSO-de): δ = 1.19 (t, 6H), 3.55 (c, 4H), 6.49 (dd, 1H), 6.96 (s, 2H), 7.72 (d, 1H), 8.41 (d, 1H). Example 15: ((R) -1- (6-amino-5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4-yl) -pyrrolidin-2-yl) methanol.
[00138] 1H-NMR (300 MHz, DMSO-de): δ = 1.76 (m, 1H), 1.96 (m, 4H), 3.64 (m, 2H), 3.91 (m, 1H), 4.51 (m, 1H), 4.81 (t, 1H), 6.49 (dd, 1H), 6.90 (s, 2H), 7.71 (d, 1H), 8, 45 (d, 1H). Example 16: 1- (6-amino-5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4-yl) azetidin-3-ol.
[00139] 1H-NMR (300 MHz, DMSO-de): δ = 4.00 (m, 2H), 4.48 (m, 3H), 5.66 (d, 1H), 6.47 (dd, 1H), 6.90 (s, 2H), 7.70 (d, 1H), 8.43 (d, 1H). Example 17: ((S) -1- (6-amino-5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4-yl) -pyrrolidin-2-yl) methanol.
[00140] 1H-NMR (300 MHz, DMSO-de): δ = 1.87 (m, 5H), 3.62 (m, 2H), 3.91 (m, 1H), 4.52 (m, 1H), 4.83 (m, 1H), 6.49 (dd, 1H), 6.90 (s, 2H), 7.72 (d, 1H), 8.46 (d, 1H). Example 18: 1- (6-amino-5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4-yl) -pyrrolidin-3-ol.
[00141] 1H-NMR (300 MHz, DMSO-de): δ = 1.83 (m, 1H), 1.90 (m, 1H), 3.58 (m, 1H), 3.74 (m, 1H), 3.88 (m, 2H), 4.32 (m, 1H), 4.96 (d, 1H), 6.47 (dd, 1H), 6.85 (s, 2H), 7, 70 (d, 1H), 8.44 (d, 1H). Example 19: 5-bromo-6 - ((S) -3-fluoropyrrolidin-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00142] 1H-NMR (300 MHz, DMSO-dβ): δ = 2.04 (m, 1H), 2.17 (m, 1H), 3.90 (m, 3H), 4.08 (m, 1H), 5.40 (d, 1H), 6.48 (dd, 1H), 6.96 (s, 2H), 7.71 (d, 1H), 8.47 (d, 1H). Example 20: 5-bromo-6 - ((R) -2- (methoxymethyl) pyrrolidin-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00143] 1H-NMR (300 MHz, DMSO-de): δ = 1.77 (m, 2H), 1.95 (m, 2H), 3.24 (s, 3H), 3.30 (m, 1H), 3.54 (m, 1H), 3.61 (m, 1H), 3.98 (m, 1H), 4.67 (m, 1H), 6.47 (dd, 1H), 6, 90 (s, 2H), 7.69 (d, 1H), 8.39 (d, 1H). Example 21: 5-bromo-6 - ((S) -3- (dimethylamino) -pyrrolidin-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00144] 1H-NMR (300 MHz, DMSO-de): δ = 1.68 (m, 1H), 2.04 (m, 1H), 2.17 (m, 6H), 2.63 (m, 1H), 3.55 (t, 1H), 3.80 (m, 3H), 6.45 (dd, 1H), 6.86 (s, 2H), 7.68 (d, 1H), 8, 43 (d, 1H). Example 22: 5-bromo-6- (2,5-dimethylpyrrolidin-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00145] 1H-NMR (300 MHz, DMSO-de): δ = 1.34 (d, 6H), 1.72 (m, 2H), 2.00 (m, 2H), 4.65 (m, 2H), 6.48 (dd, 1H), 6.85 (s, 2H), 7.71 (d, 1H), 8.39 (d, 1H). Example 23: 5-bromo-6- (3,3-difluoroazetidin-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00146] 1H-NMR (300 MHz, DMSO-de): δ = 4.67 (t, 4H), 6.50 (dd, 1H), 7.15 (s, 2H), 7.73 (d, 1H), 8.48 (d, 1H). Example 24: 5-bromo-N4-methyl-2- (1 H-pyrazol-1-yl) pyrimidine-4, 6-diamine.
[00147] 1H-NMR (300 MHz, DMSO-de): δ = 2.91 (d, 3H), 6.47 (dd, 1H), 6.70 (s, 2H), 6.75 (m, 1H), 7.70 (d, 1H), 8.49 (d, 1H). Example 25: 5-bromo-N4-ethyl-2- (1 H-pyrazol-1-yl) pyrimidine-4,6-diamine.
[00148] 1 H-NMR (300 MHz, DMSO-dθ): δ = 1.15 (t, 3H), 3.45 (m, 2H), 6.47 (dd, 1H), 6.71 (s , 2H), 6.75 (t, 1H), 7.70 (d, 1H), 8.46 (d, 1H). Example 26: 5-bromo-N4- (prop-2-ynyl) -2- (1 H-pyrazol-1-yl) pyrimidine-4, 6-diamine.
[00149] 1 H-NMR (300 MHz, DMSO-dθ): δ = 3.04 (t, 1H), 4.18 (d, 2H), 6.50 (dd, 1H), 6.87 (s , 2H), 7.16 (t, 1H), 7.72 (d, 1H), 8.52 (d, 1H). Example 27: 5-bromo-N4- (2-morpholinoethyl) -2- (1 H-pyrazol-1-yl) pyrimidine-4,6-diamine.
[00150] 1 H-NMR (300 MHz, DMSO-dθ): δ = 2.44 (t, 4H), 2.52 (t, 2H), 3.52 (t, 2H), 3.56 (t , 4H), 6.48 (dd, 1H), 6.61 (t, 1H), 6.76 (s, 2H), 7.70 (d, 1H), 8.45 (d, 1H). Example 28: 5-bromo-N4-isopropyl-2- (1 H-pyrazol-1-yl) pyrimidine-4,6-diamine.
[00151] 1 H-NMR (300 MHz, DMSO-dθ): δ = 1.21 (d, 6H), 4.35 (m, 1H), 6.19 (d, 1H), 6.47 (dd , 1H), 6.74 (s, 2H), 7.70 (d, 1H), 8.45 (d, 1H). Example 29: 5-bromo-N4- (cyclopropylmethyl) -2- (1H-pyrazol-1-II) pyrimidine-4,6-diamine.
[00152] 1 H-NMR (300 MHz, DMSO-dθ): δ = 0.30 (m, 2H), 0.41 (m, 2H), 1.13 (m, 1H), 3.29 (t , 2H), 6.48 (dd, 1H), 6.73 (s, 2H), 6.81 (t, 1H), 7.71 (d, 1H), 8.45 (d, 1H). Example 30: 5-bromo-N4-propyl-2- (1 H-pyrazol-1-yl) pyrimidine-4, 6-diamine.
[00153] 1 H-NMR (300 MHz, DMSO-dθ): δ = 0.88 (t, 3H), 1.58 (m, 2H), 3.38 (m, 2H), 6.48 (dd , 1H), 6.73 (m, 3H), 7.70 (d, 1H), 8.44 (d, 1H). Example 31: 5-bromo-N4-propyl-2- (1 H-pyrazol-1-yl) pyrimidine-4,6-diamine.
[00154] 1 H-NMR (300 MHz, DMSO-dθ): δ = 0.88 (t, 3H), 1.58 (m, 2H), 3.38 (m, 2H), 6.48 (dd , 1H), 6.73 (m, 3H), 7.70 (d, 1H), 8.44 (d, 1H). Example 32: (R) -N4-sec-butyl-5-bromo-2- (1H-pyrazol-1-II) pyrimidine-4,6-diamine.
[00155] 1H-NMR (300 MHz, DMSO-de): δ = 0.87 (t, 3H), 1.18 (d, 3H), 1.53 (m, 1H), 1.60 (m, 1H), 4.18 (m, 1H), 6.13 (d, 1H), 6.47 (dd, 1H), 6.74 (s, 2H), 7.71 (d, 1H), 8, 45 (d, 1H). Example 33: (S) -N4-sec-butyl-5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4, 6-diamine
[00156] 1H-NMR (300 MHz, DMSO-de): δ = 0.87 (t, 3H), 1.18 (d, 3H), 1.53 (m, 1H), 1.60 (m, 1H), 4.18 (m, 1H), 6.14 (d, 1H), 6.48 (dd, 1H), 6.74 (s, 2H), 7.71 (d, 1H), 8, 45 (d, 1H). Derivatives of intermediate 1 (R1 = pyrazole, R4 = -S-R7) Example 34: 5-bromo-6- (phenylthio) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00157] 74 pl (0.73 mmol) of thiophenol and 0.178 g (0.55 mmol) of CS2CO3 were added to a solution of 0.1 g (0.36 mmol) of 5-bromo-6-chloro-2 - (1 H-pyrazol-1-yl) pyrimidine-4-amine (intermediate 5) in 4 ml of THF. The mixture was allowed to react under microwave conditions for 15 min. at 100 ° C. Then the reaction mixture was poured into 10 ml of cold water. The white precipitate formed was filtered, washed several times with cold water and dried.
[00158] 1H-NMR (300 MHz, DMSO-de): δ = 6.40 (dd, 1H), 7.39 (t, 1H), 7.54 (m, 4H), 7.62 (m, 2H), 7.68 (m, 2H). Example 35: 5-bromo-6- (methylthio) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00159] 0.05 g (0.73 mmol) of sodium methanethiolate was added to a solution of 0.1 g (0.36 mmol) of 5-bromo-6-chloro-2- (1 H-pyrazole- 1-yl) pyrimidine-4-amine (intermediate 5) in 4 ml of THF. The mixture was stirred for 1 hour at room temperature. Then, it was poured into 10 mL of cold water. The precipitate formed was filtered, washed several times with cold water and dried.
[00160] 1H-NMR (300 MHz, DMSO-dβ): δ = 2.56 (s, 3H), 6.54 (dd, 1H), 7.47 (s, 2H), 7.78 (d, 1H), 8.57 (d, 1H).
[00161] Examples 36 to 38 were synthesized using the procedure described for example 35 from intermediate 5, using the sodium salts of the corresponding thiolates: Example 36: 5-bromo-6- (ethylthio) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00162] 1H-NMR (300 MHz, DMSO-de): δ = 1.34 (t, 3H), 3.19 (q, 2H), 6.55 (dd, 1H), 7.46 (s, 2H), 7.79 (d, 1H), 8.52 (d, 1H). Example 37: 5-bromo-6- (propylthio) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00163] 1H-NMR (300 MHz, DMSO-de): δ = 1.01 (t, 3H), 1.71 (m, 2H), 3.18 (t, 2H), 6.56 (dd, 1H), 7.47 (s, 2H), 7.79 (d, 1H), 8.51 (d, 1H). Example 38: 5-bromo-6- (isopropylthio) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00164] 1H-NMR (300 MHz, DMSO-dβ): δ = 1.40 (d, 6H), 4.04 (m, 1H), 6.55 (dd, 1H), 7.46 (s, 2H), 7.79 (d, 1H), 8.51 (d, 1H). Derivatives of intermediate 1 (R1 = pyrazole, R4 = -O-R7) Example 39: 5-bromo-6-phenoxy-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00165] 0.07 g (0.73 mmol) of phenol and 0.1 g (0.73 mmol) of K2CO3 were added to a solution of 0.1 g (0.36 mmol) of 5-bromo-6 -chloro-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine (intermediate 5) in 4 ml of THF. The mixture was allowed to react under microwave conditions for 30 min. at 100 ° C. Then the reaction mixture was placed in 10 ml of cold water. The white precipitate formed was filtered, washed several times with cold water and dried.
[00166] 1H-NMR (300 MHz, DMSO-dβ): δ = 6.45 (dd, 1H), 7.26 (m, 4H), 7.46 (m, 3H), 7.70 (d, 1H), 8.06 (d, 1H).
[00167] Examples 40 to 42 were synthesized using the procedure described for example 39 of intermediate 5, using the corresponding aryl or hetero-aryl-phenol: Example 40: 5-bromo-2- (1 H-pyrazol-1-yl) -6- (pyridine-2-ylxi) pyrimidine-4-amine.
[00168] 1H-NMR (300 MHz, DMSO-de): δ = 6.39 (dd, 1H), 6.55 (m, 2H), 7.58 (t, 1H), 7.69 (d, 1H), 7.80 (m, 1H), 8.03 (s, 2H), 8.47 (d, 1H). Example 41: 5-bromo-2- (1 H-pyrazol-1-II) -6- (pyridine-3-ylxi) pyrimidine-4-amine.
[00169] 1H-NMR (300 MHz, DMSO-dθ): δ = 6.46 (dd, 1H), 7.33 (s, 2H), 7.52 (d, 1H), 7.71 (s, 1H), 7.77 (d, 1H), 8.07 (d, 1H), 8.51 (d, 1H), 8.56 (d, 1H). Example 42: 6- (5-chloropyridine-3-ylxi) -5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00170] 1H-NMR (300 MHz, DMSO-dθ): δ = 6.48 (dd, 1H), 6.37 (s, 2H), 7.73 (s, 1H), 8.11 (m, 2H), 8.58 (m, 2H). Example 43: 5-bromo-6-methoxy-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00171] 3 mL (1.5 mmol) of a solution (0.5 M) of sodium methanolate in methanol was added to a solution of 0.1 g (0.36 mmol) of 5-bromo-6-chloro -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine (intermediate 5) in 4 ml of THF. The mixture was stirred for 1 hour at room temperature. Then, the solvent was removed under reduced pressure, the residue was washed several times with cold water, filtered and dried.
[00172] 1H-NMR (300 MHz, DMSO-dθ): δ = 3.99 (s, 3H), 6.54 (dd, 1H), 7.31 (s, 2H), 7.77 (d, 1H), 8.53 (d, 1H).
[00173] The following example was synthesized using the procedure described for example 43 of intermediate 5 using a solution of sodium 2,2,2-trifluoroethanolate in 2,2,2-trifluoroethanol: Example 44: 6- (2,2,2-trifluoroethoxy) -5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00174] 1H-NMR (300 MHz, DMSO-d6): δ = 5.17 (m, 2H), 6.56 (dd, 1H), 7.33 (s, 2H), 7.79 (d, 1H), 8.64 (d, 1H). Example 45: 5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4,6-diamine.
[00175] A solution of 0.10 g (0.37 mmol) of 5-bromo-6-chloro-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine (intermediate 5) and 0.05 g (0.77 mmol) of sodium azide in dioxane (10 ml) was stirred at 80 ° C for 6 h. The solvent was then evaporated, and the residue was dissolved in methanol, Pd on charcoal (10 mg) was added and hydrogenated for 30 min. The solvent was again evaporated and the residue crystallized from ethanol.
[00176] 1 H-NMR (300 MHz, DMSO-d6): δ = 6.46 (d, 1H), 6.70 (s, 2H), 6.74 (s, 2H), 7.69 (d , 1H), 8.48 (d, 1H). Example 46: 5-chloro-2,6-di- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00177] 1 g (5.04 mmol) of 2,5,6-trichloropyrimidine-4-amine (intermediate 4) was allowed to react with 2.1 g (30.2 mmol) of 1H-pyrazole and 2 g (6 , 05 mmol) of CS2CO3 in 5 ml of DMF at 85 ° C for 24 hours. The DMF was removed in vacuo. The crude residue was washed several times with water and then dried.
[00178] 1 H-NMR (300 MHz, DMSO-d6): δ = 6.57 (dd, 1H), 6.62 (dd, 1H), 7.70 (s, 1H), 7.81 (d , 1H), 7.90 (d, 1H), 8.36 (s, 1H), 8.59 (d, 1H), 8.63 (d, 1H). Example 47: 5-iodo-2,6-di (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00179] The compound was synthesized using the procedure described for example 32, using intermediate 10 as a starting material.
[00180] 1 H-NMR (300 MHz, DMSO-dθ): δ = 6.56 (dd, 1H), 6.60 (dd, 1H), 7.55 (s, 2H), 7.79 (d , 1H), 7.87 (d, 1H), 8.74 (d, 1H), 8.75 (d, 1H). Example 48: 4-amino-2,6-di- (1 H-pyrazol-1-yl) pyrimidine-5-carbonitrile.
[00181] A mixture of 0.2 g (0.65 mmol) of 5-bromo-2,6-di (1H-pyrazol-1-yl) pyrimidine-4-amine and 0.06 g (0.72 mmol ) of copper (I) in 3 ml of pyridine cyanide was irradiated with microwave at 250 ° C for 20 min. After the almost complete conversion of the corresponding carbonitrile, as indicated by the TLC, ethyl acetate was added and filtered through celite. The solution was extracted twice with 10 ml of saturated NaHCOa solution and brine. The organic layer was separated, dried with MgSO4 and concentrated resulting in 0.065 g (39.6%) of the desired product.
[00182] 1H-NMR (300 MHz, DMSO-d6): δ = 6.58 (dd, 1H), 6.63 (dd, 1H), 7.72 (s, 1H), 7.81 (d, 1H), 7.89 (d, 1H), 8.39 (s, 1H), 8.55 (d, 1H), 8.61 (d, 1H). Example 49: 4-amino-6-N-cyclopentylamino-2- (1 H-pyrazol-1-yl) pyrimidine-5-carbonitrile.
[00183] The compound was synthesized using the procedure described for example 34 and 5-bromo-N4-cyclopentyl-2- (1 H-pyrazol-1-yl) pyrimidine-4,6-diamine (example 4) as a product of departure.
[00184] 1H-NMR (300 MHz, DMSO-dβ): δ = 1.55 (m, 4H), 1.70 (m, 2H), 1.96 (m, 2H), 4.41 (m, 1H), 6.25 (d, 1H), 6.48 (dd, 1H), 6.74 (s, 2H), 7.73 (d, 1H), 8.48 (d, 1H). Example 50: 5-bromo-N-methyl-2,6-di- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00185] 0.124 g (1.84 mmol) of methylamine hydrochloride and 0.45 g (1.38 mmol) Cβ2C03 were added to a solution of 0.1 g (0.31 mmol) of 5-bromo-4- chloro-2,6-di- (1 H-pyrazol-1-yl) pyrimidine (intermediate 9) in 3 ml of THF. The reaction mixture was stirred at room temperature in a reaction tube for 48 hours. THF was removed in vacuo and the crude product was washed with water and dried.
[00186] 1H-NMR (300 MHz, DMSO-de): δ = 2.89 (d, 3H), 6.58 (dd, 1H), 6.60 (dd, 1H), 7.83 (d, 1H), 7.87 (d, 1H), 7.95 (m, 1H), 8.46 (d, 1H), 8.65 (d, 1H).
[00187] Examples 51 to 57 were synthesized using the procedure described for example 50 from 5-bromo-4-chloro-2,6-di- (1 H-pyrazol-1-yl) pyrimidine and corresponding amine ( intermediate 9) as a starting product. Example 51: 5-bromo-N-ethyl-2,6-di- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00188] 1 H-NMR (300 MHz, DMSO-dθ): δ = 1.22 (t, 3H), 3.60 (m, 2H), 6.58 (dd, 1H), 6.60 (dd , 1H), 7.83 (d, 1H), 7.87 (d, 1H), 7.95 (t, 1H), 8.46 (d, 1H), 8.65 (d, 1H). Example 52: N-benzyl-5-bromo-2,6-di- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00189] 1 H-NMR (300 MHz, DMSO-dθ): δ = 4.75 (d, 2H), 6.53 (dd, 1H), 6.57 (dd, 1H), 7.30 (m , 3H), 7.44 (d, 2H), 7.79 (d, 1H), 7.82 (d, 1H), 8.43 (d, 1H), 8.51 (t, 1H), 8 , 55 (d, 1H). Example 53: 5-bromo-N- (prop-2-ynyl) -2,6-di (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00190] 1 H-NMR (300 MHz, DMSO-dθ): δ = 3.14 (t, 1H), 4.32 (m, 2H), 6.59 (dd, 1H), 6.61 (dd , 1H), 7.85 (d, 1H), 7.89 (d, 1H), 8.30 (t, 1H), 8.48 (d, 1H), 8.71 (d, 1H). Example 54: 5-bromo-N- (2-morpholinoethyl) -2,6-di (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00191] 1 H-NMR (300 MHz, DMSO-de): δ = 2.45 (t, 4H), 2.58 (t, 2H), 3.57 (t, 2H), 3.59 (t , 4H), 6.58 (dd, 1H), 6.60 (dd, 1H), 7.68 (t, 1H), 7.83 (d, 1H), 7.87 (d, 1H), 8 , 48 (d, 1H), 8.65 (d, 1H). Example 55: 5-bromo-N- [2- (piperidine-1-i) ethyl] -2,6-di- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00192] 1 H-NMR (300 MHz, DMSO-de): δ = 1.37 (m, 2H), 1.48 (m, 4H), 2.44 (m, 4H), 2.58 (t , 2H), 3.60 (m, 2H), 6.58 (dd, 1H), 6.60 (dd, 1H), 7.66 (t, 1H), 7.83 (d, 1H), 7 , 87 (d, 1H), 8.48 (d, 1H), 8.65 (d, 1H). Example 56: 5-bromo-N-cyclobutyl-2,6-di- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00193] 1 H-NMR (300 MHz, CDCh): δ = 1.86 (m, 2H), 2.04 (m, 2H), 2.54 (m, 2H), 4.75 (m, 1H ), 6.22 (d, 1H), 6.46 (dd, 1H), 6.48 (dd, 1H), 7.81 (d, 1H), 7.82 (d, 1H), 8.42 (d, 1H), 8.53 (d, 1H). Example 57: N- (2-aminoethyl) -5-bromo-2,6-di (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00194] 1H-NMR (300 MHz, DMSO-de): δ = 1.22 (t, 3H), 3.60 (m, 2H), 6.58 (dd, 1H), 6.60 (dd, 1H), 7.83 (d, 1H), 7.87 (d, 1H), 7.95 (t, 1H), 8.46 (d, 1H), 8.65 (d, 1H). Example 58: N4-tert-butyl-5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4, 6-diamine.
[00195] 1H-NMR (300 MHz, DMSO-de): δ = 1.46 (s, 9H), 5.43 (s, 1H), 6.48 (dd, 1H), 6.76 (s, 2H), 7.71 (d, 1H), 8.37 (d, 1H). Derived from intermediate 6 (R1 = 4-methyl-pyrazole)
[00196] Examples 59 to 65 were synthesized using the procedure described for example 1 of intermediate 6 and the corresponding amines or pyrazole derivatives: Example 59: 5-bromo-2- (4-methyl-1 H-pyrazol-1-yl) -6- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00197] 1H-NMR (300 MHz, DMSO-dβ): δ = 2.09 (s, 3H), 6.60 (dd, 1H), 7.50 (s, 1H), 7.63 (s, 1H), 7.87 (d, 1H), 8.36 (s, 1H), 8.38 (s, 1H), 8.60 (d, 1H). Example 60: 6- (azetidin-1-yl) -5-bromo-2- (4-methyl-1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00198] 1H-NMR (300 MHz, DMSO-dβ): δ = 2.06 (s, 3H), 2.23 (m, 2H), 4.28 (t, 4H), 6.81 (s, 2H), 7.51 (s, 1H), 8.19 (s, 1H). Example 61: 5-bromo-N4-cyclopentyl-2- (4-methyl-1H-pyrazol-1-yl) pyrimidine-4,6-diamine.
[00199] 1H-NMR (300 MHz, DMSO-de): δ = 1.55 (m, 4H), 1.70 (m, 2H), 1.96 (m, 2H), 2.08 (s, 3H), 4.40 (m, 1H), 6.19 (d, 1H), 6.69 (s, 2H), 7.52 (s, 1H), 8.23 (s, 1H). Example 62: 5-bromo-N4-cyclopropyl-2- (4-methyl-1H-pyrazol-1-yl) pyrimidine-4,6-diamine.
[00200] 1H-NMR (300 MHz, DMSO-dβ): δ = 0.62 (m, 2H), 0.72 (m, 2H), 2.08 (s, 3H), 2.91 (m, 1H), 6.18 (d, 1H), 6.68 (s, 2H), 7.51 (s, 1H), 8.22 (s, 1H). Example 63: 5-bromo-N4-cyclobutyl-2- (4-methyl-1H-pyrazol-1-II) pyrimidine-4,6-diamine.
[00201] 1H-NMR (300 MHz, DMSO-dβ): δ = 1.63 (m, 2H), 1.85 (m, 2H), 2.08 (m, 2H), 2.10 (s, 3H), 4.59 (m, 1H), 6.18 (d, 1H), 6.69 (s, 2H), 7.53 (s, 1H), 8.23 (s, 1H). Example 64: 5-bromo-2- (4-methyl-1 H-pyrazol-1-II) -6- (2-methyl-pyrrolidin-1-yl) pyrimidine-4-amine.
[00202] 1H-NMR (300 MHz, DMSO-de): δ = 1.20 (d, 3H), 1.56 (m, 1H), 1.75 (m, 1H), 1.94 (m, 1H), 2.07 (m, 1H), 2.09 (s, 3H), 3.62 (m, 1H), 3.94 (m, 1H), 4.52 (m, 1H), 6, 80 (s, 2H), 7.52 (s, 1H), 8.20 (s, 1H). Example 65: 5-bromo-2- (4-methyl-1 H-pyrazol-1-i) -6 - ((R) -2-methyl I-pyrrolidin-1-yl) pyrimidine-4-amine.
[00203] 1H-NMR (300 MHz, DMSO-dβ): δ = 1.21 (d, 3H), 1.57 (m, 1H), 1.77 (m, 1H), 1.93 (m, 1H), 2.08 (m, 1H), 2.12 (s, 3H), 3.63 (m, 1H), 3.93 (m, 1H), 4.52 (m, 1H), 6, 80 (s, 2H), 7.52 (s, 1H), 8.20 (s, 1H). Derived from intermediate 7 (R1 = 4-chloro-1H-pyrazole)
[00204] Examples 66 and 67 were synthesized using the procedure described for example 1 of intermediate 7 and the corresponding amines or pyrazole derivatives: Example 66: 5-bromo-N-cyclopropyl-2- (4-chloro-1 H-pyrazol-1-yl) pyrimidine-4,6-diamine.
[00205] 1H-NMR (300 MHz, DMSO-dβ): δ = 0.60 (m, 2H), 0.70 (m, 2H), 2.88 (m, 1H), 6.71 (d, 1H), 6.80 (s, 2H), 7.73 (s, 1H), 8.35 (s, 1H). Example 67: 6- (azetidin-1-yl) -5-bromo-2- (4-chloro-1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00206] 1H-NMR (300 MHz, DMSO-dβ): δ = 2.12 (q, 2H), 4.28 (t, 4H), 6.77 (s, 2H), 7.72 (s, 1H), 8.35 (s, 1H). Derivatives of the same substituent at positions 2 and 6 of the pyrimidine ring: Example 68: 5-bromo-2,6-di- (4-methyl-1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00207] 0.2 ml (2.47 mmol) of 4-methyl-1H-pyrazole and 0.4 g (1.24 mmol) of cesium carbonate were added to a solution of 0.15 g (0.62 mmol) of 5-bromo-2,6-dichloropyrimidin-4-amine (intermediate 3) in 3 ml of DMF. The mixture was heated to 85 ° C for 24 h. The DMF was concentrated in vacuo. The residue was washed with water and dried resulting in 0.16 g (78.7%) of a white solid.
[00208] 1 H-NMR (300 MHz, DMSO-d6): δ = 2.07 (s, 3H), 2.10 (s, 3H), 7.69 (s, 1H), 7.72 (s , 1H), 8.31 (s, 1H), 8.39 (s, 1H), 8.16 (d, 2H).
[00209] The following derivatives were synthesized by the method used for example 68 using the corresponding pyrazole derivative: Example 69: 5-bromo-2,6-di- (4-chloro-1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00210] 1 H-NMR (300 MHz, DMSO-d6): δ = 7.71 (s, 1H), 7.74 (s, 1H), 8.36 (s, 1H), 8.41 (d , 1H), 8.16 (d, 2H). Example 70: 5-bromo-2,6-di- (3-methyl-1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00211] 1 H-NMR (300 MHz, DMSO-d6): δ = 2.08 (t, 3H), 2.11 (t, 3H), 6.54 (d, 1H), 6.60 (d , 1H), 7.62 (d, 1H), 7.68 (d, 1H), 7.40 (d, 2H). Example 71: 5-bromo-2,6-di- (3-trifluoromethyl-1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00212] 1 H-NMR (300 MHz, DMSO-d6): δ = 6.49 (d, 1H), 6.56 (d, 1H), 7.60 (d, 1H), 7.65 (d , 1H), 7.35 (d, 2H). Example 72: 5-bromo-2,6-di- [5- (ethoxycarbonyl) -3-methyl-1 H-pyrazol-1-yl] pyrimidin-4-amine.
[00213] 1 H-NMR (300 MHz, DMSO-dθ): δ = 1.25 (m, 6H), 4.24 (m, 4H), 2.02 (s, 3H), 2.08 (s , 3H), 6.49 (d, 1H), 6.54 (d, 1H), 7.38 (d, 2H).
[00214] The following example was synthesized using the procedure described for example 1 of intermediate 5, using the pyrazole derivatives or the corresponding amines: Example 73: 5-bromo-6- (3,5-dimethyl-1 H-pyrazol-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00215] 1H-NMR (300 MHz, DMSO-de): δ = 2.11 (s, 6H), 6.04 (s, 1H), 6.58 (dd, 1H), 7.54 (s, 1H), 7.82 (d, 1H), 8.42 (s, 1H), 8.53 (d, 1H). Example 74: 5-bromo-6- (1 H-imidazol-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00216] 1H-NMR (300 MHz, DMSO-dθ): δ = 6.57 (dd, 1H), 7.40 (d, 1H), 7.52 (s, 1H), 7.81 (d, 1H), 7.85 (d, 1H), 8.41 (s, 1H), 8.31 (s, 1H), 8.51 (d, 1H). Example 75: 5-bromo-6- (4-chloro-1 H-pyrazol-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00217] 1H-NMR (300 MHz, DMSO-dθ): δ = 6.57 (dd, 1H), 7.51 (s, 1H), 7.65 (s, 1H), 7.81 (d, 1H), 8.26 (s, 1H), 8.41 (s, 1H), 8.52 (d, 1H). Example 76: 5-bromo-2- (1 H-pyrazol-1-yl) -6- (2H-1,2,3-triazol-2-yl) pyrimidine-4-amine.
[00218] 1H-NMR (300 MHz, DMSO-dθ): δ = 6.58 (dd, 1H), 7.55 (s, 1H), 7.96 (d, 2H), 7.81 (d, 1H), 8.41 (s, 1H), 8.54 (d, 1H). Example 77: 5-bromo-2- (1 H-pyrazol-1-yl) -6- (1 H-1,2,4-triazol-1-yl) pyrimidine-4-amine.
[00219] 1H-NMR (300 MHz, DMSO-dθ): δ = 6.58 (dd, 1H), 7.55 (s, 1H), 7.81 (d, 1H), 8.41 (s, 1H), 8.46 (s, 1H), 8.54 (d, 1H), 8.66 (s, 1H). Example 78: 5-bromo-6-isopropoxy-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00220] 1H-NMR (300 MHz, DMSO-dθ): δ = 1.32 (d, 6H), 5.36 (m, 1H), 6.52 (dd, 1H), 7.31 (s, 2H), 7.74 (d, 1H), 8.52 (d, 1H). Example 79: 5-bromo-2- (4-chloro-1 H-pyrazol-1-yl) -6- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00221] 1H-NMR (300 MHz, DMSO-dθ): δ = 6.61 (dd, 1H), 7.50 (s, 1H), 7.58 (s, 1H), 7.89 (d, 1H), 8.26 (s, 1H), 8.38 (s, 1H), 8.62 (d, 1H). Example 80: 5-bromo-2- (4-chloro-1 H-pyrazol-1-yl) -6- (4-methyl-1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00222] 1H-NMR (300 MHz, DMSO-de): δ = 2.06 (s, 3H), 7.36 (s, 2H), 7.59 (s, 1H), 7.66 (s, 1H), 8.27 (s, 1H), 8.34 (s, 1H). Example 81: 5-bromo-2- (3,5-dimethyl-1 H-pyrazol-1-yl) -6- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00223] 1H-NMR (300 MHz, DMSO-de): δ = 2.08 (s, 6H), 6.01 (s, 1H), 6.60 (dd, 1H), 7.52 (s, 1H), 7.88 (d, 1H), 8.40 (s, 1H), 8.61 (d, 1H). Example 82: 5-bromo-N4-cyclopentyl-2- (3,5-dimethyl-1 H-pyrazol-1-yl) pyrimidine-4,6-diamine.
[00224] 1H-NMR (300 MHz, DMSO-dβ): δ = 1.55 (m, 4H), 1.70 (m, 2H), 1.96 (m, 2H), 2.06 (s, 6H), 4.40 (m, 1H), 6.01 (s, 1H), 6.25 (d, 1H), 6.73 (s, 2H). Example 83: 5-bromo-2- (3,5-dimethyl-1 H-pyrazol-1-yl) -6- (pyrrolidin-1-yl) pyrimidine-4-amine.
[00225] 1H-NMR (300 MHz, DMSO-dβ): δ = 1.86 (m, 4H), 2.06 (s, 6H), 3.73 (t, 4H), 6.02 (s, 1H), 6.83 (s, 2H). Example 84: 5-bromo-N4-isopropyl-2- (3,5-dimethyl-1 H-pyrazol-1-yl) pyrimidine-4,6-diamine.
[00226] 1H-NMR (300 MHz, DMSO-dβ): δ = 1.16 (d, 6H), 2.08 (s, 6H), 4.23 (m, 1H), 6.00 (s, 1H), 6.12 (d, 1H), 6.72 (s, 2H).
[00227] The following derivative was synthesized by the method used for example 68 using 3,5-dimethyl-1H-pyrazole as starting material: Example 85: 5-bromo-2,6-bis (3,5-dimethyl-1H-pyrazol-1-yl) pyrimidine-4-amine.
[00228] 1H-NMR (300 MHz, DMSO-dβ): δ = 2.06 (s, 6H), 2.11 (s, 6H), 6.02 (s, 1H), 6.05 (s, 1H), 7.49 (s, 1H), 8.39 (s, 1H). Derivatives containing a heterocyclic ring at position 5 (R3) of the pyrimidine ring: Example 86: 5- (1-methyl-1 H-pyrazol-4-yl) -2,6-di (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00229] A mixture of 0.1 g (0.33 mmol) of 5-bromo-2,6-di- (1H-pyrazol-1-yl) pyrimidine-4-amine (example 1), 0.10 g (0.49 mmol) of 1-methyl-pyrazol-4 pinacol-boronic acid, 0.23 (0.72 mmol) ester of cesium carbonate and 5 mg (6.5 umol) of [1, T-bis ( diphenylphosphino) ferrocene] dichloropaladium complex dichloromethane (II) in 3 ml of dioxane and 0.5 ml of water was irradiated with microwave at 140 ° C for 30 min. After cooling to room temperature, ethyl acetate was added and filtered through celite. The solution was extracted twice with 10 ml of saturated NaHCOa solution and brine. The organic layer was separated, dried with MgSO4 and concentrated. The residue was purified by column chromatography with silica gel and methylene chloride and methanol as the eluent, resulting in 45.5 mg (45.3%) of the desired product.
[00230] 1 H-NMR (300 MHz, DMSO-d6): δ = 4.05 (s, 3H), 6.56 (dd, 1H), 6.59 (dd, 1H), 7.25 (s , 1H), 7.45 (s, 1H), 7.52 (s, 1H), 7.80 (d, 1H), 7.86 (d, 1H), 8.40 (s, 1H), 8 , 51 (d, 1H), 8.59 (d, 1H).
[00231] The following derivative was synthesized by the method used for example 86 using the corresponding boronic acid pinacol ester: Example 87: 2,6-di- (1 H-pyrazol-1-yl) -5- (1 H-pyrazol-4-yl) pyrimidine-4-amine.
[00232] 1 H-NMR (300 MHz, DMSO-dθ): δ = 6.56 (dd, 1H), 6.60 (dd, 1H), 7.28 (d, 1H), 7.48 (s , 1H), 7.52 (s, 1H), 7.80 (d, 1H), 7.86 (d, 1H), 8.40 (s, 1H), 8.51 (d, 1H), 8 , 60 (d, 1H), 13.55 (d, 1H). Example 88: 2,6-di- (1 H-pyrazol-1-yl) -5- (thiophen-2-yl) pyrimidine-4-amine.
[00233] 1 H-NMR (300 MHz, DMSO-d6): δ = 6.57 (dd, 1H), 6.60 (dd, 1H), 6.58 (dd, 1H), 7.02 (d , 1H), 7.18 (d, 1H), 7.53 (s, 1H), 7.80 (d, 1H), 7.86 (d, 1H), 8.41 (s, 1H), 8 , 51 (d, 1H), 8.60 (d, 1H). Example 89: 5-cyclopropyl-2,6-di (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00234] 1 H-NMR (300 MHz, DMSO-de): δ = 0.41 (m, 2H), 0.65 (m, 2H), 1.61 (m, 1H), 6.57 (dd , 1H), 6.61 (dd, 1H), 7.54 (s, 1H), 7.81 (d, 1H), 7.88 (d, 1H), 8.42 (s, 1H), 8 , 51 (d, 1H), 8.60 (d, 1H). Example 90: 2,6-di- (1 H-pyrazol-1-yl) -5- (thiazol-2-yl) pyrimidine-4-amine.
[00235] The reaction was carried out according to the method described by Morgan in Chem. Eur. J. 2010, 16, 4279-4283.
[00236] A mixture of 8.9 mg (13.1 umol) of the Pd-PEPPSI-IPr catalyst, 0.1 g (0.33 mmol) of 5-bromo-2,6-di (1 H-pyrazole- 1 - il) pyrimidine-4-amine (example 1), 0.1 g (0.65 mmol) of cesium fluoride and activated, crushed 4Â molecular sieves (33 mg) in a glass flask was purged with argon and was 1 ml of dioxane is added. Then 0.15 (0.39 mmol) of 2-tri-butyl-stanylthiazole was added and the reaction mixture was stirred at 80 ° C for 24 h. The mixture was filtered through celite / CsF. The solvent was removed in vacuo. The residue was purified by column chromatography with silica gel and methylene chloride and methanol as the eluent, resulting in 47.9 mg (47.2%) of the desired product.
[00237] 1H-NMR (300 MHz, DMSO-dβ): δ = 6.57 (dd, 1H), 6.58 (dd, 1H), 7.34 (d, 1H), 7.52 (s, 1H), 7.81 (d, 1H), 7.86 (d, 1H), 7.92 (d, 1H), 8.41 (s, 1H), 8.51 (d, 1H), 8, 60 (d, 1H).
[00238] The following derivative was synthesized by the method used for example 90 using 2-tributilstaniloxazole: Example 91: 5- (oxazol-2-yl) -2,6-di (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00239] 1H-NMR (300 MHz, DMSO-de): δ = 6.57 (dd, 1H), 6.56 (dd, 1H), 7.28 (d, 1H), 7.51 (s, 1H), 7.81 (d, 1H), 7.85 (d, 1H), 7.90 (d, 1H), 8.40 (s, 1H), 8.50 (d, 1H), 8, 58 (d, 1H). Example 92: 5- (tri-fluoromethyl) -2,6-di (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00240] The reaction was carried out according to the method described by Buchwald in Science 2010, 328, 1679-1681.
[00241] A solution of 11.3 mg (20 umol) of Pd (dba) 2 and 15.8 mg (29.4 umol) of 2- (Dicyclohexylphosphmo) 3,6-dimethoxy-2,, 4 'was added , 6, -triisopropyl-1,1'-biphenyl in 3 ml of dioxane to a mixture of 0.1 g (0.33 mmol) of 5-bromo-2,6-di (1 H-pyrazol-1 -yl) pyrimidine-4-amine (example 1), 0.04 g (0.65 mmol) of potassium fluoride. Then 0.093 g (0.65 mmol) of trimethyl (trifluoromethyl) silane were added and the reaction mixture was stirred at 140 ° C for 20 h. The mixture was filtered through celite and concentrated in vacuo. The residue was purified by column chromatography with silica gel and methylene chloride and methanol as the eluent, resulting in 41.6 mg (43.1%) of the desired product.
[00242] 1 H-NMR (300 MHz, DMSO-d6): δ = 6.55 (dd, 1H), 6.58 (dd, 1H), 7.51 (s, 1H), 7.80 (d , 1H), 7.86 (d, 1H), 8.40 (s, 1H), 8.50 (d, 1H), 8.58 (d, 1H). Derivatives containing a heterocyclic ring linked by a carbon-carbon bond to positions 2 or 6 of the pyrimidine ring:
[00243] Intermediates 14 to 16 were synthesized using the procedure described for example 90 from 2,6-dichloropyrimidin-4-amine and 2- (tributylstannyl) thiazole in a conventional Stille reaction. The three intermediate products formed were separated by column chromatography with silica gel and cyclohexane and ethyl acetate as eluent: Intermediate 14: 2-Chloro-6- (thiazol-2-yl) pyrimidine-4-amine.
[00244] 1 H-NMR (300 MHz, DMSO-d6): δ = 6.80 (s, 1H), 7.50 (s, 2H), 7.64 (d, 1H), 8.09 (d , 1H). Intermediate 15: 6-chloro-2- (thiazol-2-yl) pyrimidine-4-amine.
[00245] 1 H-NMR (300 MHz, DMSO-dθ): δ = 6.78 (s, 1H), 7.49 (s, 2H), 7.56 (d, 1H), 8.04 (d , 1H). Intermediate 16: 2,6-Di- (thiazol-2-yl) pyrimidine-4-amine.
[00246] 1 H-NMR (300 MHz, DMSO-dθ): δ = 6.84 (s, 1H), 7.51 (s, 2H), 7.57 (d, 1H), 7.65 (d , 1H), 8.06 (d, 1H), 8.11 (d, 1H).
[00247] The following intermediates were synthesized using the procedure described for intermediate 3 from the corresponding thiazolliprimidine-4-amine and N-bromosuccinimide as a starting product: Intermediate 17: 5-bromo-2-chloro-6- (thiazol-2-yl) pyrimidine-4-amine.
[00248] 1H-NMR (300 MHz, DMSO-dβ): δ = 7.41 (d, 1H), 8.01 (d, 1H), 8.16 (s, 2H). Intermediate 18: 5-bromo-6-chloro-2- (thiazol-2-yl) pyrimidine-4-amine.
[00249] 1H-NMR (300 MHz, DMSO-de): δ = 7.35 (d, 1H), 7.96 (d, 1H), 8.17 (s, 2H). Example 93: 5-Bromo-2,6-di (thiazol-2-yl) pyrimidine-4-amine.
[00250] The compound was synthesized following the procedure described for the synthesis of intermediate 3, using intermediate 16 as a starting product:
[00251] 1H-NMR (300 MHz, DMSO-dβ): δ = 7.35 (d, 1H), 7.41 (d, 1H), 7.96 (d, 1H), 8.01 (d, 1H), 8.18 (s, 2H).
[00252] Examples 94 and 95 were synthesized using the procedure described for example 1, from intermediates 17 and 18 and corresponding pyrazole: Example 94: 5-Bromo-2- (1 H-pyrazol-1-yl) -6- (thiazol-2-yl) pyrimidine-4-amine.
[00253] 1H-NMR (300 MHz, DMSO-dβ): δ = 6.57 (dd, 1H), 7.40 (d, 1H), 7.53 (s, 1H), 7.81 (d, 1H), 8.00 (d, 1H), 8.40 (s, 1H), 8.42 (d, 1H). Example 95: 5-Bromo-6- (1 H-pyrazol-1-yl) -2- (thiazol-2-yl) pyrimidine-4-amine.
[00254] 1H-NMR (300 MHz, DMSO-dβ): δ = 6.60 (dd, 1H), 7.36 (d, 1H), 7.51 (s, 1H), 7.87 (d, 1H), 7.97 (d, 1H), 8.42 (s, 1H), 8.60 (d, 1H). Example 96: 5-bromo-N4- [1 - (dimethylamino) propan-2-yl] -2- (1 H-pyrazol-1-yl) pyrimidine-4,6-diamine.
[00255] 1H-NMR (300 MHz, DMSO-dβ): δ = 1.18 (d, 3H), 2.15 (s, 6H), 2.20 (m, 1H), 2.43 (m, 1H), 4.27 (m, 1H), 6.18 (d, 1H), 6.46 (dd, 1H), 6.77 (s, 2H), 7.68 (d, 1H), 8, 42 (d, 1H). Example 97: 5-bromo-N4- (1-methoxypropane-2-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4,6-diamine.
[00256] 1H-NMR (300 MHz, DMSO-dθ): δ = 1.15 (d, 3H), 3.32 (s, 3H), 3.40 (d, 2H), 4.43 (m, 1H), 6.15 (d, 1H), 6.46 (dd, 1H), 6.77 (s, 2H), 7.68 (d, 1H), 8.42 (d, 1H). Example 98: 5-bromo-6- (1 H-pyrazol-1-yl) -2- (2H-1,2,3-triazol-2-yl) pyrimidine-4-amine.
[00257] 1H-NMR (300 MHz, DMSO-dβ): δ = 6.57 (dd, 1H), 6.60 (dd, 1H), 7.52 (s, 1H), 7.81 (d, 1H), 7.87 (d, 1H), 8.41 (s, 1H), 8.51 (d, 1H), 8.60 (d, 1H). Example 99: 5-bromo-6-ethoxy-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine.
[00258] 1H-NMR (300 MHz, DMSO-dβ): δ = 1.29 (d, 6H), 5.29 (m, 2H), 6.54 (dd, 1H), 7.31 (s, 2H), 7.77 (d, 1H), 8.54 (d, 1H).

权利要求:
Claims (8)
[0001]
1. Compound, characterized by the fact that it is selected from: 5-bromo-2,6-di- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-6- (4-methyl-1 H-pyrazol-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-2- (1 H-pyrazol-1-i) -6- (pi rrol idi n-1 -i I) pi midi na-4-amine 5-bromo-N4-cyclopentyl-2- (1 H-pyrazol-1-i I) pi midi na-4,6-diamine 5-bromo -6- (piperidin-1-i I) -2- (1 H-pyrazol-1-i) pyrimidine-4-amine 5-bromo-6-morpholino-2- (1 H-pyrazole- 1-yl) pyrimidine-4-amine 5-bromo-6- (4-methylpiperazin-1-i) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-N4-cyclopropyl -2- (1 H-pyrazol-1-i) pi midi na-4,6-diamine 6- (azetidin-1-yl) -5-bromo-2- (1 H-pyrazol-1-i ) pyridine i-na-4-amine 5-bromo-N4-cyclobutyl-2- (1 H-pyrazol-1-i) pyridine-4,6-diamine 5-bromo-6- (2 -methyl-pyrrolidin-1-i) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-6 - ((R) -2-methyl-pyrrolidin-1-i) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 1- [6-amino-5-bromo-2- (1 H-pyrazol-1-yl) pyrimidi na-4-yl] azetidin-3-ol 1- [6-amino-5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4-yl] -pyrrolidin-3-ol 5-bromo- 6 - ((S) -3-fluoropyrrolidin-1-i) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-6 - [(S) -3- (dimethylamino) -pyrrolidin-1-yl] -2- (1H-pyrazol-1-yl) pyrimidine-4-amine 5-bronno-6- (2,5-dimethylpyrrolidin-1-i) -2- (1 H-pyrazole -1 - yl) pyrimidine-4-amine 5-bromo-6- (3,3-difluoroazetidin-1-i) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo- N4-isopropyl-2- (1 H-pyrazol-1-i) pyrimidine-4,6-diamine 5-bromo-N4-propyl-2- (1 H-pyrazol-1-yl) pyrimidine- 4,6-diamine 5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-chloro-2,6-di- (1 H-pyrazol-1-yl) pyrimidine- 4-amine 4-amino-2,6-di- (1 H-pyrazol-1-yl) pyrimidine-5-carbonitrile 4-amino-6-N-cyclopentylamino-2- (1 H-pyrazol-1-i ) pi midi na-5-carbonitrile N4-tert-butyl-5-bromo-2- (1 H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-2- (4-methyl-1 H-pyrazol-1-yl) -6- (1 H-pyrazol-1-yl) pyrimidine-4-amine 6- (azetidin-1-yl) -5-bromo-2- (4-methyl- 1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-N4-cyclopentyl-2- (4-methyl-1 H-pyrazol-1-i I) pi midi na- 4,6-diamine 5 -bromo-N4-cyclopropyl-2- (4-methyl-1 H-pyrazol-1-i) pi midi na- 4,6-diamine 5-bromo-N4-cyclobutyl-2- (4-methyl-1 H-pyrazol-1-i) pi ri midi na- 4,6-diamine 5-bromo-2- (4-methyl-1 H-pyrazol-1-i) -6- (2-methyl-pi idol n-1 - yl) pyrimidine-4-amine 5-bromo-2- (4-methyl-1H-pyrazol-1-yl) -6 - ((R) -2-methyl-pyrrolidin-1-i ) pyrimidine-4-amine 5-bromo-N-cyclopropyl-2- (4-chloro-1 H-pyrazol-1-i) pyridine-4,6-diamine 6- ( azetidin-1-yl) -5-bromo-2- (4-chloro-1 H-pyrazol-1-i I) pi midi n- 4-amine 5-bromo-2,6-di- (4-methyl -1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-2,6-di- (4-chloro-1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-2, 6-di- (3-methyl-1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-6- (3,5-dimethyl-1 H-pyrazol-1-i) -2- ( 1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-6- (1 H-imidazol-1-i) -2- (1 H-pyrazol-1-i I) pi midi na- 4- 5-bromo-6- (4-chloro-1 H- amine pyrazol-1-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-2- (1 H-pyrazol-1-yl) -6- (2H-1,2, 3-triazol-2-yl) pyrimidine-4-amine 5-bromo-2- (1 H-pyrazol-1-yl) -6- (1 H-1,2,4-triazol-1-yl) pyrimidine- 4-amine 5-bromo-6-isopropoxy-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-2- (4-chloro-1 H-pyrazol-1-yl) -6 - (1 H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-2- (4-chloro-1 H-pyrazol-1-yl) -6- (4-methyl-1 H-pyrazol-1 - yl) pyrimidine-4-amine 5-bromo-2- (3,5-dimethyl-1 H-pyrazol-1-i) -6- (1 H-pyrazol-1 - yl) pyrimidine-4-amine 5 -bromo-N4-cyclopentyl-2- (3,5-dimethyl-1 H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-2- (3,5-dimethyl-1 H-pyrazole- 1 -i I) -6- (pyrrole idi n-1 - yl) pyrimidine-4-amine 5-bromo-N4-isopropyl-2- (3,5-dimethyl-1 H-pyrazol-1-yl) pyrimidine -4,6-diamine 5-bromo-2,6-bis (3,5-dimethyl-1 H-pyrazol-1-i) pyrimidine-4-amine 5-Bromo-2,6-di - (thiazol-2-yl) pyrimidine-4-amine 5-Bromo-2- (1 H-pyrazol-1-yl) -6- (thiazol-2-yl) pyrimidine-4-amine 5-Bromo-6- (1 H-pyrazol-1-yl) -2- (thiazol-2-yl) pyrimidine-4-am 5-bromo-N4- [1- (dimethylamino) propan-2-yl] -2- (1 H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-N4- (1-methoxypropane- 2-yl) -2- (1 H-pyrazol-1-yl) pyrimidine-4,6-diamine 5-bromo-6- (1 H-pyrazol-1-yl) -2- (2H-1,2, 3-triazol-2-yl) pyrimidine-4-amine 5-bromo-6-ethoxy-2- (1 H-pyrazol-1-yl) pyrimidine-4-amine
[0002]
2. A compound according to claim 1, characterized by the fact that it is for use in the treatment of a disease or pathological condition susceptible to improvement through antagonism of the adenosine A2a receptor.
[0003]
3. Compound according to claim 1, characterized by the fact that it is for use in the treatment of a pathological condition or disease in which the pathological condition or disease is ischemia, supraventricular arrhythmias, atrial fibrillation, acute renal failure, reperfusion injury of the myocardium, diseases due to fluid retention, allergic reactions including but not limited to urticaria rhinitis, scleroderma, arthritis, other autoimmune diseases, inflammatory bowel disease, diabetes mellitus, obesity, Parkinson's disease, Huntington's disease, dystonia such such as restless legs syndrome, dyskinesias such as those caused by prolonged use of neuroleptic drugs or dopamine or sleep disturbances, congestive heart failure, hypertension, intradialytic hypotension, dementia, anxiety disorders, and glaucoma.
[0004]
4. Compound according to claim 3, characterized by the fact that it is for use in the treatment of a pathological condition or disease in which the pathological conditions or diseases are arrhythmias, atrial fibrillation, Parkinson's disease, Huntington's disease, Alzheimer's, dystonias such as restless legs syndrome, dyskinesias such as those caused by prolonged use of neuroleptic drugs or dopamine or sleep disorders, dementia, anxiety disorders, and diabetes mellitus.
[0005]
5. Pharmaceutical composition, characterized in that it comprises a compound, as defined in claim 1, mixed with a pharmaceutically acceptable diluent or carrier.
[0006]
6. Combination product, characterized by the fact that it comprises a compound, as defined in claim 1, and another compound for the treatment of diseases such as ischemia, supraventricular arrhythmias, atrial fibrillation, acute renal failure, myocardial reperfusion injury, diseases due to fluid retention, allergic reactions including but not limited to rhinitis, urticaria, scleroderma, arthritis, other autoimmune diseases, inflammatory bowel disease, diabetes mellitus, obesity, Parkinson's disease, Huntington's disease, Alzheimer's disease, dystonias such as restless legs syndrome, dyskinesias such as those caused by prolonged use of neuroleptics or dopamine or sleep disturbances, congestive heart failure, hypertension, intradialytic hypotension, dementia, anxiety disorders, and diabetes mellitus, for simultaneous, separate use or sequential.
[0007]
7. Combination product, characterized by the fact that it comprises a compound, as defined in claim 1, with levodopa, dopamine agonists, MAO-B inhibitors, acetylcholine esterase inhibitors or any drug used to treat Parkinson's, Huntington's disease and Alzheimer's.
[0008]
8. Combination product, characterized by the fact that it comprises a compound, as defined in claim 1, with insulin, metformin, LPG agonists, sulfonyl ureas, DPP-IV inhibitors or any drug used to treat Diabetes.

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法律状态:
2016-10-18| B25G| Requested change of headquarter approved|Owner name: PALOBIOFARMA, S.L. (ES) |

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2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-07-02| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-07-30| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-04-22| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

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2020-07-28| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-11-17| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 29/03/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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ES201030489|2010-03-31|

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ES201030489A|ES2365960B1|2010-03-31|2010-03-31|NEW ANTAGONISTS OF ADENOSINE RECEPTORS.|

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PCT/IB2011/000664|WO2011121418A1|2010-03-31|2011-03-29|4 - aminopyrimidine derivatives and their as as adenosine a2a receptor antagonists|

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