EA046117B1 - HETEROCONDENSED PYRIDONE COMPOUNDS AND THEIR APPLICATION AS IDH INHIBITORS - Google Patents

Description

This invention relates to certain substituted heterofused pyridone analogs that modulate isocitrate dehydrogenase (IDH) activity. The compounds of the present invention are therefore useful in the treatment of diseases caused by mutated IDH1 and/or mutated IDH2 enzyme and/or wild-type IDH1 enzyme. The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for treating diseases using pharmaceutical compositions containing these compounds.

State of the art

Isocitrate dehydrogenases (IDHs) are a family of metal-dependent oxidoreductases involved in cellular metabolism. These enzymes catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, producing carbon dioxide and NADH or NADPH in the process.

Three different species of this family have been identified: IDH1 and IDH2, which are structurally related homodimers and use NADP' as an electron acceptor, and IDH3, which is a heterotrimeric complex and uses NAD' as an electron acceptor instead.

IDH1 is localized in the cytoplasm and peroxisomes and represents the main source of NADPH production for cells, while IDH2 is localized in mitochondria as an integral part of the tricarboxylic acid cycle (TCA cycle). The human IDH1 gene encodes a 414 amino acid protein, the amino acid sequence of which can be found under UniProtKB accession number 075874. The human IDH2 gene encodes a 452 amino acid protein, the amino acid sequence of which can be found under UniProtKB accession number P48735.

Somatic heterozygous mutations in isocitrate dehydrogenase 1 (IDH1) have been identified in approximately 80% of stage II-III gliomas, and in secondary glioblastomas (see Balss, J. Acta Neuropathol, 2008, 116, 597-602, Watanabe, T., Am. J. Pathol, 2009, 174, 1149-1153, Yan, H. N. Engl. J. Med. 2009, 360, 765-773). IDH1 mutations have also been found in 50% of chondrosarcomas (see Amary MF, J. Pathol 2011, 224, 334-43), in 15%-20% of intrahepatic cholangiocarcinoma (see Borger DR, Oncol. 2012, 17, 72-9 ) and less frequently (<5%) in other solid tumors (eg, glioblastomas, colorectal cancer, esophageal cancer, bladder cancer, melanoma, prostate carcinoma, breast adenocarcinoma (see Cerami E, Cancer Discov. 2012, 2, 401 -4).

IDH1 and IDH2 mutations have also been observed in a variety of hematopoietic neoplasms, most commonly in 10-15% of acute myeloid leukemia (AML) (see, for example, Mardis ER, NEngl J. Med. 2009, 361, 1058-66, Gross S, J Exp. Med. 2010, 207, 339-44, Marcucci G, J. Clin. Oncol. 2010, 28, 2348-55) and 20% of angio-immunoblastic T-cell lymphoma (see Cairns RA, Blood 2012, 119 , 1901-3).

Interestingly, the same mutations in IDH1 or IDH2 have been identified in the majority of spindle cell enchondromas and hemangiomas in patients with Ollier disease and Maffucci syndrome, non-hereditary skeletal diseases (see Amary et al., Nature Genetics, 2011, 1261-1265; and Pansuriya TS, Nat. Genet. 2011, 43, 1256-61).

All mutations were found in heterozygosity in a mutually exclusive manner and in specific tissues. These mutations are in the catalytic domain of the enzyme responsible for coordinating 2-oxoglutarate and include mainly Arg 132 (R132) in IDH1 and Arg 140 (R140) or Arg 172 (R172) in IDH2, which can mutate to different amino acids. Other mutations have been identified in IDH1, although at very low frequencies (eg, Arg 100 and Gly 97; Dang L, Nature, 2009, 462, 739-44). In all cases, these mutation points of Arg to Cys, His, Lys, Leu, or Ser abolish magnesium binding and prevent the conversion of isocitrate to alpha-ketoglutarate. Instead, the mutated enzymes acquire a neomorphic activity that converts alpha-ketoglutarate to R(-)-2hydroxyglutarate (R-2-hG) (see P.S. Ward et al., Cancer Cell, 2010, 17, 225). In general, the production of 2-HG is enantiospecific, resulting in the formation of the D-enantiomer (also known as the R-enantiomer or R-2-HG). R(-)-2-hydroxyglutarate has been shown to act as an oncometabolite, mainly through the inhibition of certain DNA and histone demethylases. The consequence at the cellular level is epigenetic reprogramming leading to a different transcriptional activation that causes dedifferentiation and tumor formation.

Overexpression of IDH1 has been shown to restrain less differentiated tumor cell states, promote growth, accelerate tumor progression, and reduce susceptibility to RTK-targeted therapies in glioblastoma (GBM) and other solid and systemic tumor models. At the molecular level, reduction of IDH1 activity causes decreased production of α-ketoglutarate (α-KG) and NADPH, depletion of reduced glutathione, increased levels of reactive oxygen species (ROS), and improved histone methylation and expression of differentiation markers. Pharmacological inhibition of IDH1 with small molecules reduces GBM tumor burden and improves survival of PDX mice. These data also suggest that the cancer-associated increase in IDH1 expression represents an actionable (drug-responsive)

- 1 046117 agents) cancer-promoting mechanism and provides the rationale for evaluating wild-type IDH1 inhibitors as anticancer agents (see Calvert et al., 2017, Cell Reports 19, 1858-1873).

Therefore, inhibition of IDH enzyme activity is a potential therapeutic option for the treatment of tumors and other diseases associated with IDH.

Accordingly, there is an urgent medical need for therapeutic agents active against diseases caused by and/or associated with mutated IDH enzymes and/or redundant IDH dt functions, and some attempts are being made to develop inhibitors, in particular small molecule inhibitors of their alpha-hydroxyl neomorphic activity.

Certain pyridopyridin-7-one derivatives having biological activity as kinase inhibitors are disclosed in WO 2005/047284 on behalf of Hoffmann La Roche.

Other pyridopyrimidin-7-one compounds useful as kinase inhibitors are disclosed in WO 2007044813, on behalf of Exelixis Inc., and in WO 2008/034008 on behalf of Deciphera Pharmaceuticals Lcc.

The inventors have discovered that the compounds of formula (I) described below are inhibitors of mutated IDH1 enzymes and/or mutated IDH2 enzymes and/or wild type IDH1 and are thus useful for the treatment of diseases caused by high levels of 2-HG, or caused by superfunctions of IDH dt.

Accordingly, the first object of the present invention is a substituted heterofused pyridone derivative of formula (I)

R3 R4

R6b (I) where

X represents nitrogen or -CH-;

R1a represents hydrogen or linear or branched (C1-C ₆ )alkyl;

R1b is (C1- _C6 )alkyl, or together with the atom to which they are bonded, R1a and R1b can form ( _C3 - _C6 )cycloalkyl;

A represents (C ₃ -C ₆ )cycloalkyl, aryl selected from phenyl and naphthyl, pyridinyl, adamantyl, 2-oxoquinoline-3-is, III-benzimidazol-2-yl, 1,2,4-oxadiazol-5- yl or 4-oxo-3,4-dihydroquinazolin-2-yl;

each R6a is hydrogen; hydroxymethyl; halogen; methylsulfonyl; optionally substituted heteroaryl selected from the group consisting of thienyl, 1-methyl-pyrazolyl and pyridyl; heterocyclyl selected from the group consisting of morpholinyl, piperazinyl and tetrahydropyridinyl, optionally substituted with ethyl, benzyloxycarbonyl, acryloyl, t-butoxycarbonyl or cyclopropylcarbonyl; -OR7, -СООМе, -CONR7R8; -CH(R14)NR7R8; 2-fluoropyridin-4-yl; phenyl-2carbonitrile; tert-butyl 3,6-diidropyridin-1(2H)-carboxylate or 2-trifluoromethylpyridin-4-yl;

Where

R14 represents hydrogen or straight or branched (C1- _C6 )alkyl, optionally substituted with ( _C3 - _C6 )cycloalkyl;

R8 represents hydrogen;

R7 selected from: hydrogen; linear or branched (C1-C ₆ )alkyl; (C ₃ -C ₆ )cycloalkyl, optionally substituted with two halogen atoms; phenyl; heterocyclyl selected from the group consisting of piperidinyl, pyrrolyl, pyrrolidinyl and tetrahydropyranyl, optionally substituted with (C1- _C6 )alkyl, acryloyl, isopropyl, isobutyryl, t-butoxycarbonyl and benzyloxycarbonyl; or, together with the nitrogen atom to which they are bonded, R7 and R8 form a 5-7 membered heterocyclyl group, optionally containing one additional heteroatom selected from O and NR9, optionally substituted with halogen or C1- _C3 alkyl; or, together with the nitrogen atom to which they are bonded, R7 and R8 form 4-piperazine-1-carboxylic acid phenyl ester;

Where:

R9 is hydrogen, straight or branched (C1- _C6 )alkyl, -COOR10 or -COR11; Where

R10 represents linear or branched (C1-C ₆ )alkyl;

R11 is linear or branched (C1- _C6 )alkyl, optionally substituted with halogen or OH, or ( _C2 - _C6 )alkenyl;

R6b is hydrogen or halogen;

R2 represents linear or branched (C1-C ₆ )alkyl, optionally substituted with halogen; hydroxyl; benzyl, optionally substituted with hydroxyl, one or two fluorine atoms or methyl; cyclopropyl; cyclobutylmethyl; cyclohexylmethyl; 2-methoxyethyl; 4-fluoro-2(trifluoromethyl)benzyl; 2,2-dimethyl-3-propanoic acid; 2,2-dimethyl-3-propanamide; A2,2-trimethyl

- 2 046117

3-propanamide; VU2,2-tetramethyl-3-propanamide; 2,2-dimethyl.s-\-(3-methyl.lpheni.l) propanamide; N-(2hydroxyethyl)-2,2-dimethyl-3-propanamide; N(2-hydroxypropyl)-2,2-dimethyl-3-propanamide; N-[3-(1hydroxyethyl)phenyl]-2,2-dimethyl-3-propanamide; 2,2-dimethyl-3-propanenitrile and 4-ethynyl-2-fluorobenzyl;

R3 is hydrogen, cyano, NR13R13a, OR12, linear (C1- _C6 )alkyl or (2,4dimethoxybenzyl)amino;

Where

R12 represents linear (C1- _C6 )alkyl;

each R13, R13a is independently selected from hydrogen or linear (C1- _C6 )alkyl;

R4 represents hydrogen or linear (C ₁ -C ₆ )alkyl;

R5 is hydrogen, fluorine or -OR12 or a pharmaceutically acceptable salt thereof.

Preferred compounds of formula (I) are those where

X represents nitrogen;

R5 represents hydrogen or fluorine.

More preferred compounds of formula (I) are those where

A is aryl;

R2 represents linear or branched (C ₁ -C ₆ )alkyl.

Most preferred compounds of formula (I) are those where

R6a is -CH(R14)NR7R8;

where R7 and R8 form a 6-membered heterocyclyl group containing one additional heteroatom NR9.

Preferred specific compounds of formula (I) or pharmaceutically acceptable salts thereof are those listed below:

methyl 4-{(1S)-1 -[(8-benzyl-7-oxopyrido[2,3 -<1]pyrimidin-2yl)amino]ethyl} benzoate (compound 1);

methyl 4-{(lS)-l -[(8-ethyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino]ethyl}benzoate (compound 2);

methyl 4-[(18)-1-{[8-(methoxymethyl)-7-oxopyrido[2,3-b]pyrimidin-2yl]amino}ethyl]benzoate (compound 3);

methyl 4-{(lS)-l - [(8-methyl-7-oxopyrido[2,3 -d] pyrimide in-2-yl)amino]ethyl } benzoate (compound 4);

methyl 4-[(18)-1-{[8-(2-methylpropyl)-7-oxopyrido[2,3-b]pyrimidin-2yl]amino}ethyl]benzoate (compound 5);

methyl 4-[(18)-1-{[8-(4-fluorobenzyl)-7-oxopyrido[2,3^]pyrimidin-2yl]amino}ethyl]benzoate (compound 6);

methyl 4-[(18)-1-{[8-(3,5-difluorobenzyl)-7-oxopyrido[2,3-b]pyrimidin-2yl]amino}ethyl]benzoate (compound 7);

methyl 4-[(18)-1-({8-[4-fluoro-2-(trifluoromethyl)benzyl]-7-oxopyrido[2,3b]pyrimidin-2-yl}amino)ethyl]benzoate (compound 8 );

methyl 4-[(18)-1-{[7-oxo-8-(propan-2-yl)-pyrido[2,3-b]pyrimidin-2yl]amino}ethyl]benzoate (compound 9);

methyl 4-[(lS)-l-({8-[(3-methyloxetan-3-yl)methyl]-7-oxopyrido[2,3-d]pyrimidin2-yl}amino)ethyl]benzoate (compound 10 );

methyl 4-[(18)-1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3^]pyrimidin-2yl]amino}ethyl]benzoate (compound 11);

2-{[(lS)-l-cyclohexylethyl]amino}-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one (com.

12);

-ethyl-2- {[(1S)-1 -(4-methoxifenyl)ethyl] amino } pyrid o[2,3 ^]pyrimidin-7(8H)-one

- 3 046117 (connection 13);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino}-8-ethylpyrido[2,3-c1]pyrimidin-7(8H)-one (compound 14);

2-{[(lS)-l -(4-chlorophenyl)ethyl] amino } -8-(pentan-3-yl)pyride o[2,3 -d]pyrimidin7(8H)-one (compound 15);

8-benzyl-2-{[(1S)-1 -(4-chlorophenyl)ethyl] amino } pyrid o[2,3 -d]pyrimidin-7(8H)-one (compound 16);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino}-8-(2-fluoroethyl)pyrido[2,3^]pyrimidin7(8H)-one (compound 17);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino)-8-(2,2,2-trifluoroethyl)pyrido[2,3d]πyrimidin-7(8H)-one (compound 18) ;

2-{[(18)-1-(4-chlorophenyl)ethyl]amino}-8-(2-methylpropyl)pyrido[2,3-0]pyrimidin7(8H)-one (compound 19);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino)-8-(cyclopropylmethyl)pyrido[2,3d]πpyrimidin-7(8H)-one (compound 20);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino)-8-(4-methoxybenzyl)pyrido[2,3d]πpyrimidin-7(8H)-one (compound 21);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino}-8-(2-fluorobenzyl)pyrido[2,3^]pyrimidin7(8H)-one (compound 22);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino)-8-(3,4-difluorobenzyl)pyrido[2,3d]πpyrimidin-7(8H)-one (compound 23);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino)-8-[3-(trifluoromethyl)benzyl]pyrido[2,3d]πpyrimidin-7(8H)-one (compound 24);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino)-8-(2,4-difluorobenzyl)pyrido[2,3d]πpyrimidin-7(8H)-one (compound 25);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino)-8-[4-(trifluoromethoxy)benzyl]pyrido[2,3d]πyrimidin-7(8H)-one (compound 26);

4- {[2-{[(1S)-1 -(4-chlorophenyl)ethyl] amino } -7-oxopyride o[2,3 -d]pyrimidin-8(7H)yl]methyl (benzonitrile (com. 27);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino}-8-(4-fluorobenzyl)pyrido[2,3^]pyrimidin7(8H)-one (compound 28);

2-{[(lS)-l -(4-chlorophenyl)ethyl] amino )-8-(3,5-difluorobenzyl)pyride o[2,3 d]nnpHMHflHH-7(8H)-OH (compound 29) ;

2-{[(18)-1-(4-chlorophenyl)ethyl]amino)-8-(3-methoxybenzyl)pyrido[2,3d]πpyrimidin-7(8H)-one (compound 30);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino)-8-(2,6-difluorobenzyl)pyrido[2,3d]nHpHMHflHH-7(8H)-OH (compound 31);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino)-4-methyl-8-(2-methylpropyl)pyrido[2,3d]πpyrimidin-7(8H)-one (compound 32) ;

8-(2,2-dimethylpropyl)-2-{[(18)-1-(4-methoxyphenyl)ethyl]amino)pyrido[2,3- 4 046117

0]pyrimidin-7(8H)-one (compound 33);

2-{ [(1 S)-l-(4-bromophenyl)ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3<1]pyrimidin-7(8H)-one (compound 34 );

2-{[(1S)-1 -(4-bromophenyl)ethyl]amino}-8-(3-hydroxy-2,2dimethylpropyl)pyrido[2,3-c1]pyrimidin-7(8H)-one (com. 35);

8-(2,2-dimethylpropyl)-2-{[(18)-1-(naphthalene-2-yl)ethyl]amino}pyrido[2,3<1]pyrimidin-7(8H)-one (com. 36);

methyl 2,2-dimethyl-3 -[2- {[(1S)-1 -(naphthalene-2-yl)ethyl]amino} -7-oxopyr ido[2,3 <1]pyrimidin-8(7H)- yl]propanoate (compound 37);

8-(3-hydroxy-2,2-dimethylpropyl)-2-{[(1S)-1 -(naphthalene-2yl)ethyl]amino}pyrido[2,3-c1]pyrimidin-7(8H)-one ( connection 38);

8-(2,2-dimethylpropyl)-2-{[(1R)-1-phenylethyl]amino}pyrid o[2,3 -<1]pyrimidin7(8H)-one (compound 39);

8-(2,2-dimethylpropyl)-2-{[(18)-1-phenylethyl]amino}pyrido[2,3-(1]pyrimidin7(8H)-one (compound 40);

8-(2,2-dimethylpropyl)-2-[(2-phenylpropan-2-yl)amino]pyrido[2,3-(1]pyrimidin7(8H)-one (compound 41);

8-(2,2-dimethylpropyl)-2-[(1-phenylcyclopropyl)amino]pyrido[2,3-(1]pyrimidin7(8H)-one (compound 42);

8-(2,2-dimethylpropyl)-2-[(1-phenylcyclobutyl)amino]pyrido[2,3-(1]pyrimidin7(8H)-one (compound 43);

8-(2,2-dimethylpropyl)-2-{ [ 1 -(tricyclo[3.3.1.1 ³⁷ ]dec-1 - yl)ethyl] amino} pyrido[2,3 <1]pyrimidin-7(8H)-one (connection 44);

8-[(3 -methyloxetan-3 -yl)methyl]-2-{[(1S)-1 -(naphthalene-2-yl)ethyl]amino} pyrido[2,3 <1]pyrimidin-7(8H) -on (comm. 45);

8-(2-hydroxy-2-methylpropyl)-2-{[(1S)-1-phenylethyl]amino}pyrid o[2,3 <1]pyrimidin-7(8H)-one (compound 46);

8-(2,2-dimethylpropyl)-6-fluoro-2-((8)-1-phenylethylamino)-8H-pyrido[2,3<1]pyrimidin-7-one (compound 47);

Methyl 4-[(18)-1-{[8-(2-hydroxy-2-methylpropyl)-7-oxo-7,8-dihydropyrido[2,3 <1]pyrimidin-2-yl]amino}ethyl] benzoate (compound 48);

8-(2,2-dimethylpropyl)-2-{[(18)-1-(4-phenoxyphenyl)ethyl]amino}pyrido[2,3<1]pyrimidin-7(8H)-one (compound 49) ;

2-{[(1S)-1 -(6-chloro-2-oxoquinolin-3-yl)ethyl] amino} -8-(2,2dimethylpropyl)pyrido[2,3-c1]pyrimidin-7(8H)- he (comm. 50);

8-benzyl-2-{[(1S)-1 -(5-chloro-1 H-benzimidazol-2-yl)ethyl] amino } pyrid o[2,3 <1]pyrimidin-7(8H)-one (comm. 51);

8-benzyl-2-({(18)-1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5yl]ethyl}amino)pyrido[2,3-c1]pyrimidine-7(8H )-on (comm. 52);

2-({(18)-1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}amino)-8-(2,2-5 046117 dimethylpropyl)pyrido[2 ,3-с!]pyrimidin-7(8Н)-one (compound 53);

8-(2,2-dimethylpropyl)-2-{[(1S)-1 -(4-oxo-3,4-dihydroquinazolin-2yl)ethyl]amino}pyrido[2,3-c!]pyrimidine-7( 8H)-on (compound 54);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(3hydroxy-2,2-dimethylpropyl)pyrido[2,3 -с!]pyrimidin-7(8Н)-one (compound 55);

4-(4-{(8)-1-[8-(3-Hydroxy-2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3d]pyrimidin-2-ylamino]ethyl} benzyl )piperazine-1-carboxylic acid tert-butyl ester (compound 56);

2-{(S)-1-[4-(3,3-difluoropiperidin-1-ylmethyl)phenyl]ethylamino}-8-(2,2dimethylpropyl)-6-fluoro-8H-pyrido[2,3-th] pyrimidin-7-one (compound 57);

2-{(S)-1-[4-(3,3-difluoropiperidin-1-ylmethyl)phenyl]ethylamino}-8-(2,2dimethylpropyl)-6-methoxy-8H-pyrido[2,3-th] pyrimidin-7-one (compound 58);

4-(4-{(8)-1-[8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3-pyrimidin-2ylamino]ethyl}benzyl)piperazine-1 -carboxylic acid tert-butyl ester (compound 59);

2-{[(18)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2dimethylpropyl)-5 -methylpyrido[2,3 - d] pyrimidin-7(8H)-one (compound 60);

8-(butan-2-yl)-2- {[(1S)-1 - {4-[(3,3-difluoropiperidin-1 yl)methyl]phenyl}ethyl]amino}pyrido[2,3ch1]pyrimidin- 7(8H)-one (compound 61);

8-[(2 8)-butan-2-yl]-2-{[(lS)-l-{4-[(3,3-difluoropiperidin-1yl)methyl]phenyl}ethyl]amino}pyrido[2 ,3^]pyrimidin-7(8H)-one (compound 62);

ethyl 2-[2-{[(lS)-l-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino} -7oxopyrido[2,3^]pyrimidin-8(7H )-yl]propanoate (compound 63);

2-[2-{[(lS)-l-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino} -7oxopyrido[2,3^]pyrimidin-8(7H) -yl]propanenitrile (compound 64);

2-{[(18)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[(28)-3methylbutan-2-yl]pyrido[2 ,3^]pyrimidin-7(8H)-one (compound 65);

8-[(1S)-1-cyclohexylethyl]-2-{[(1S)-1 - {4-[(3,3-difluoropiperidin-1 yl)methyl]phenyl}ethyl]amino}-pyrido[2,3 ^]pyrimidin-7(8H)-one (compound 66);

2-{[(lS)-l - {4-[(4,4-difluoropiper idin-1 -yl)methyl]-3-fluorophenyl}ethyl] amino} -8[(28)-3-methylbutan-2- yl]pyrido[2,3^]pyrimidin-7(8H)-one (compound 67);

2-({(1S)-1 - [3-fluoro-4-(morpholin-4-ylmethyl)phenyl]ethyl} amino)-8-[(2 S)-3 methylbutan-2-yl]pyrido[2, 3^]pyrimidin-7(8H)-one (compound 68);

2-{[(18)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[(28)-3,3dimethylbutan-2-yl]pyrido [2,3^]pyrimidin-7(8H)-one (compound 69);

8-(2,2-dimethylpropyl)-2-{[(18)-1-phenylpropyl]amino}pyrido[2,3-0]pyrimidin7(8H)-one (compound 70);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino}-8-(3-hydroxybenzyl)pyrido[2,3d]πpyrimidin-7(8H)-one (compound 71);

2-{[(18)-1-(4-chlorophenyl)ethyl]amino}-8-(4-hydroxybenzyl)pyrido[2,3d]πpyrimidin-7(8H)-one (compound 72);

- 6 046117

4-[(lS)-l-{[8-(2,6-difluorobenzyl)-7-oxopyrido[2,3-c1]pyrimidin-2yl]amino}ethyl]benzoic acid (compound 73);

4-[(18)-1-{[8-(2-fluorobenzyl)-7-oxopyrido[2,3-c1]pyrimidin-2yl]amino}ethyl]benzoic acid (compound 74);

4-[(18)-1-{[8-(2,6-difluorobenzyl)-7-oxopyrido[2,3-c1]pyrimidin-2yl]amino}ethyl]-M-(4,4-difluorocyclohexyl)benzamide (conn. 75);

4-[(18)-1-{[8-(2,6-difluorobenzyl)-7-oxopyrido[2,3-c1]pyrimidin-2yl]amino}ethyl]-M-(1-methylpiperidin-4-yl )benzamide (compound 76);

8-(2,6-difluorobenzyl)-2-{[(18)-1-{4-[(4,4-difluoropiperidin-1yl)carbonyl]phenyl}ethyl]amino}pyrido[2,3-(1] pyrimidin-7(8H)-one (compound 77);

4-[(18)-1-{[8-(2,6-difluorobenzyl)-7-oxopyrido[2,3-c1]pyrimidin-2yl]amino}ethyl]-M-(tetrahydro-2H-pyran-4 -yl)benzamide (compound 78);

K-(4,4-difluorocyclohexyl)-4-[( 1S)-1 - {[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3 <1]pyrimidin-2-yl]amino}ethyl ]benzamide (compound 79);

K-cyclopentyl-4-[(18)-1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3-(1]pyrimidin 2-yl]amino}ethyl]benzamide (com. 80),

K-cyclohexyl-4-[(18)-1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3-(1]pyrimidin2-yl]amino}ethyl]benzamide (compound 81) ;

2-chloro-M-(4,4-difluorocyclohexyl)-4-(1-{[8-(2,2-dimethylpropyl)-7oxopyrido[2,3-(1]pyrimidin-2-yl]amino}ethyl) benzamide (compound 82);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)carbonyl]phenyl}ethyl]amino}-8-(2,2dimethylpropyl)pyrido[2,3-c1]pyrimidine -7(8H)-one (compound 83);

K-(4,4-difluorocyclohexyl)-4-(1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3<1]pyrimidin-2-yl]amino}ethyl)-2- fluorobenzamide (compound 84);

N-(3,3-difluorocyclobutyl)-4-[(1 S)-1 - {[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3 <1]pyrimidin-2-yl]amino} ethyl]benzamide (compound 85);

4-[(18)-1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3-c1]pyrimidin-2yl]amino}ethyl]benzamide (compound 86);

8-(2,2-dimethylpropyl)-2-{[(1S)-1 - { 4-[(4-hydroxypiperid in-1 yl)carbonyl]phenyl}ethyl]amino}pyrido[2,3-c1] pyrimidin-7(8Н)-one (compound 87);

2-lor-N-(4,4-difluorocyclohexyl)-4-[(1S)-1 - {[8-(2,2-d immethylpropyl)-7-oxo-7,8dihydropyrido[2,3-( 1]pyrimidin-2-yl]amino}ethyl]benzamide (compound 88);

K-(4,4-difluorocyclohexyl)-4-[(18)-1-{[8-(2,2-dimethylpropyl)-7-oxo-7,8dihydropyrido[2,3-(1]pyrimidin-2- yl]amino}ethyl]-2-fluorobenzamide (compound 89);

8-(2,2-dimethylpropyl)-2-( {(lS)-l-[3 -fluoro-4(hydroxymethyl)phenyl]ethyl } amino)pyrido[2,3 -d]pyrimidine-7(8H)- he (conn. 90);

2-({(18)-1-[4-(hydroxymethyl)phenyl]ethyl}amino)-8-(2-methylpropyl)pyrido[2,3d]pyrimidin-7(8H)-one (compound 91);

8-(2,6-difluorobenzyl)-2-({(18)-1-[4-(hydroxymethyl)phenyl]ethyl}amino)pyrido[2,3d]pyrimidin-7(8H)-one (compound 92 );

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2-({(lS)-l - [4-(hydroxymethyl)phenyl]ethyl } amino)-8-(2-hydroxy-2methylpropyl)pyrido[2,3-c!]pyrimidin-7(8H)-one ( connection 93);

2-{[(lS)-l - { 4-[(4,4-difluoropiper idin-1 -yl)methyl]-3-fluorophenyl (ethyl] amino } -8 (2,2-dimethylpropyl)pyrido[2 ,3-(1]pyrimidin-7(8H)-one (compound 94);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2methylpropyl)pyrido[2,3-(1]pyrimidin- 7(8H)-one (compound 95);

8-benzyl-2-[(1-{4-[(4,4-difluoropiperidin-1yl)methyl]phenyl}ethyl)amino]pyrido[2,3-(1]pyrimidin-7(8H)-one (compound 96);

2-[(1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl)amino]-8-(2fluorobenzyl)pyrido[2,3-c1]pyrimidin-7(8H)- he (conn. 97);

8-(2,6-difluorobenzyl)-2-[(1-{4-[(4,4-difluoropiperidin-1yl)methyl]phenyl}ethyl)amino]pyrido[2,3-(1]pyrimidin-7( 8H)-on (compound 98);

8-(2,6-difluorobenzyl)-2-{[(18)-1-{4-[(4,4-difluoropiperidin-1yl)methyl]phenyl}ethyl]amino}pyrido[2,3-d]pyrimidine -7(8H)-one (compound .99);

2-[(1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl)amino]-8-(2fluoroethyl)pyrido[2,3^]pyrimidin-7(8H)-one (connection 100);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8propylpyrido[2,3^]pyrimidin-7(8H)-one ( connection 101);

2-({(18)-1-[4-(azepan-1-ylmethyl)phenyl]ethyl}amino)-8-propylpyrido[2,3d]pyrimidin-7(8H)-one (compound 102);

2-{[(lS)-l - { 4-[(4-acetylpiperazin-1-yl)methyl] phenyl }ethyl]amino } -8propylpyrido[2,3-0]pyrimidin-7(8Н)-one (compound . 103);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2methylpropyl)pyrido[2,3^]pyrimidin-7( 8H)-on (compound 104);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2dimethylpropyl)pyrido[2,3^]pyrimidin- 7(8H)-one (compound 105);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2,2trifluoroethyl)pyrido[2,3^] pyrimidin-7(8H)-one (compound 106);

8-[2,3-difluoro-2-(fluoromethyl)propyl]-2-{[(18)-1-{4-[(4,4-difluoropiperidin-1yl)methyl]phenyl}ethyl]amino}pyrido[ 2,3 -d] pyrimidin-7(8H)-one (compound 107);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[3,3,3trifluoro-2-(trifluoromethyl)propyl] pyrido[2,3^]pyrimidin-7(8Н)-one (compound 108);

8-(cyclobutylmethyl)-2- {[(1S)-1 - {4-[(4,4-difluoropiperidin-1 yl)methyl] phenyl } ethyl] amino } pyrido[2,3 -d] pyrimidine-7( 8H)-on (compound 109);

8-(2,2-dimethylpropyl)-2-({ (1S)-1 -[4-(morpholin-4ylmethyl)phenyl]ethyl}amino)pyrido[2,3^]pyrimidin-7(8H)-one ( connection 110);

8-(2,2-dimethylpropyl)-2-({ (1S)-1 -[4-(pyrrolidin-1 ylmethyl)phenyl]ethyl}amino)pyrido[2,3^]pyrimidin-7(8H)-one (connection 111);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2methylbenzyl)pyrido[2,3^]pyrimidin-7( 8H)-on (compound 112);

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8-(cyclohexylmethyl)-2-{ [(1S)-1 - {4-[(4,4-difluoropiperidin-1 yl)methyl]phenyl}ethyl]amino}pyrido[2,3-c1]pyrimidin-7( 8H)-on (compound 113);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2methoxyethyl)pyrido[2,3-c!]pyrimidin- 7(8H)-one (compound 114);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[4-fluoro-2(trifluoromethyl)benzyl]pyrido[2 ,3-<1]pyrimidin-7(8H)-one (compound 115);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(3,3,3trifluoro-2,2-dimethylpropyl)pyrido [2,3-(1]pyrimidin-7(8Н)-one (compound 116);

2-{[(18)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2dimethylpropyl)pyrido[2,3-c1]pyrimidine -7(8H)-one (compound 117);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-4-methyl-8-(2methylpropyl)pyrido[2,3-c1 ]pyrimidin-7(8Н)-one (compound 118);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2hydroxy-2-methylpropyl)pyrido[2,3-( 1]pyrimidin-7(8H)-one (compound 119);

2-{[(18)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[2(hydroxymethyl)-2-methylpentyl]pyrido[2, 3-<1]pyrimidin-7(8H)-one (compound 120);

2,2-dimethyl-3 -[2-{[(1S)-1 -(naphthalene-2-yl)ethyl]amino)-7-oxopyr ido[2,3 <1]pyrimidin-8(7H)-yl ]propanoic acid (compound 121);

2,2-dimethyl-3 -[2-{[(1S)-1 -(naphthalene-2-yl)ethyl]amino}-7-oxopyr ido[2,3 <1]pyrimidin-8(7H)-yl ]propanamide (compound 122);

18G,2,2-trimethyl-3-[7-oxo-2-{[(18)-1-phenylethyl]amino}pyrido[2,3-(1]pyrimidin8(7H)-yl]propanamide (compound 123 );

N, 18G,2,2-tetramethyl-3-[7-oxo-2-{[(1S)-1-phenylethyl]amino}pyrido[2,3 <1]pyrimidin-8(7H)-yl]propanamide ( connection 124);

2,2-dimethyl-M-(3-methylphenyl)-3-[7-oxo-2-{[(18)-1-phenylethyl]amino}pyrido[2,3c!]pyrimidin-8(7H)-yl ]propanamide (compound 125);

PM-(2-hydroxyethyl)-2,2-dimethyl-3 - [7-oxo-2-{[(1S)-1 phenylethyl]amino}pyrido[2,3-(1]pyrimidin-8(7H)- yl]propanamide (compound 126);

N-(3 -hydroxypropyl)-2,2-dimethyl-3 - [7-oxo-2-{[(1S)-1phenylethyl]amino}pyrido[2,3-(1]pyrimidin-8(7H)-yl ]propanamide (compound 127);

N-[3-(1-hydroxyethyl)phenyl]-2,2-dimethyl-3-[7-oxo-2-{[(1S)-1phenylethyl]amino}pyrido[2,3-(1]pyrimidine-8 (7H)-yl]propanamide (compound 128);

2,2-dimethyl-3 -[2-{[(1S)-1 -(naphthalene-2-yl)ethyl]amino}-7-oxopyr ido[2,3 <1]pyrimidin-8(7H)-yl ]propanenitrile (compound 129);

8-(2,2-dimethylpropyl)-2-( {(lS)-l-[4-(l -methyl-1 H-pyrazol-4yl)phenyl]ethyl}amino)pyrido[2,3-<1] pyrimidin-7(8H)-one (compound 130);

8-(2,2-dimethylpropyl)-2-({(18)-1-[4-(pyridin-4-yl)phenyl]ethyl}amino)pyrido[2,3<1]pyrimidin-7(8H) -on (comm. 131);

8-(2,2-dimethylpropyl)-2-({(18)-1-[4-(2-fluoropyridin-4yl)phenyl]ethyl}amino)pyrido[2,3-<1]pyrimidine-7(8H )-on (connection 132)

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8-(2,2-dimethylpropyl)-2-( { (1S)-1 -[4-(thiophen-3-yl)phenyl]ethyl } amino)pyrido[2,3 0]pyrimidin-7(8H)- he (conn. 133);

4'-[(18)-1-{[8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyr ido[2,3-c!]pyrimidin-2yl]amino}ethyl]biphenyl- 2-carbonitrile (compound 134);

8-(3 -hydroxy-2,2-dimethylpropyl)-2-({ (lS)-l-[4-(l -methyl-1 H-pyrazol-4yl)phenyl]ethyl}amino)pyrido[2,3 -c1]pyrimidin-7(8H)-one (compound 135);

8-(3-hydroxy-2,2-dimethylpropyl)-2-({ (1S)-1 -[4-(thiophen-3 yl)phenyl]ethyl}amino)pyrido[2,3-(1]pyrimidin- 7(8H)-one (compound 136);

8-(2,2-dimethylpropyl)-2-({ (1S)-1 -[4(methylsulfonyl)phenyl]ethyl}amino)pyrido[2,3-(1]pyrimidin-7(8H)-one (compound . 137);

8-(2,2-dimethylpropyl)-2-({ (1S)-1 -[4-(piperazin-1 ylmethyl)phenyl]ethyl}amino)pyrido[2,3-(1]pyrimidine-7(8H) -one dihydrochloride (compound 138);

2-{[(lS)-l - { 4-[(4-ac yloylpiperazin-1 -yl)methyl] phenyl }ethyl] amino } -8-(2,2dimethylpropyl)pyrido[2,3-c1]pyrimidin- 7(8H)-one (compound 139);

2-{[(lS)-l - { 4-[(4-ac yloylpiperazin-1 -yl)methyl] phenyl }ethyl] amino } -8-(3 hydroxy-2,2-dimethylpropyl)pyrido[2,3 -(1]pyrimidin-7(8Н)-one (compound 140);

2-{[(lS)-l - { 4- [(4-ac yloylpiperazin-1 -yl)methyl] -3 -fluorophenyl }ethyl]amino } -8(2,2-dimethylpropyl)pyrido[2,3- c1]pyrimidin-7(8H)-one (compound 141);

2-{[(lS)-l - { 4-[(4-ac yloylpiperazin-1 -yl)carbonyl] phenyl }ethyl] amino } -8-(2,2dimethylpropyl)pyrido[2,3-(1]pyrimidine -7(8H)-one (compound 142);

2-({(lS)-l-[4-( { 4-[(2E)-but-2-enoyl] piperazin-1 -yl } methyl)phenyl]ethyl } amino)-8(2,2-dimethylpropyl )pyrido[2,3-с1]pyrimidin-7(8Н)-one (compound 143);

8-(2,2-dimethylpropyl)-2- {[(1S)-1 -(4- {[4-(2-methylacryloyl)piperazin-1 yl] methyl } phenyl)ethyl]amino } pyrido[2,3 -d]pyrimidin-7(8H)-one (compound 144);

8-(2,2-dimethylpropyl)-2-[(8)-1-(4-hydroxyphenyl)ethylamino]-8H-pyrido[2,3d]πpyrimidin-7-one (compound 145);

4-(4-{(8)-1-[8-((8)-1,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3d]πpyrimidin-2-ylamino]ethyl benzyl ester (compound 146);

2-{[(18)-1-{4-[(3,3-difluoroazetidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2dimethylpropyl)pyrido[2,3-th]pyrimidine -7(8H)-one (compound 147);

2-{[(18)-1-{4-[(3,3-difluoropyrrolidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2dimethylpropyl)pyrido[2,3-th]pyrimidine -7(8H)-one (compound 148);

8-[(2R)-butan-2-yl]-2-{[(lS)-l - { 4-[(3,3-difluoro-piperidin-1yl)methyl]phenyl}ethyl]amino} pyrido[2 ,3 -d] pyrimidin-7(8H)-one (compound 149);

2-{[(lS)-l-(4-{ [(2R,6 S)-2,6-dimethylmorpholin-4-yl]methyl } -3 fluorophenyl)ethyl]amino}-8-[(28)- 3-methylbutan-2-yl]pyrido[2,3^]pyrimidin-7(8H)-one (compound 150);

2-{[(lS)-l-(4-{ [(2R,6 S)-2,6-dimethylmorpholin-4-yl]methyl } -2fluorophenyl)ethyl]amino}-8-(2,2-dimethylpropyl )pyrido[2,3^]pyrimidin-7(8H)-one (com.

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151);

2-{[(lS)-l - { 4-[(4,4-difluoropiper idin-1 -yl)methyl]-2-fluorophenyl }ethyl] amino } -8(2,2-dimethylpropyl)pyrido[2, 3-(1]pyrimidin-7(8H)-one (compound 152);

8-(2,2-dimethylpropyl)-2-({ (1S)-1 -[2-fluoro-4-(morpholin-4ylmethyl)phenyl]ethyl } amino)pyrido[2,3 -d]pyrimidine-7( 8H)-on (compound 153);

4-(4-{(8)-1-[8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin-2ylamino]ethyl}phenoxy)piperidine- 1-carboxylic acid tert-butyl ester (compound 154);

8-((S)-1,2-d imethylpropyl)-2- { (S)-1 - [4-(piperidin-4-yloxy)phenyl]ethylamino } -8Hpyrido[2,3-th]pyrimidin-7 -on (comm. 155);

2- { (S)-1 -[4-(1 - Acryloylpiperidin-4-yloxy)phenyl]ethylamino} -8-(2,2dimethylpropyl)-8H-pyrido[2,3-th]pyrimidin-7-one (connection 156);

8-(2,2-dimethylpropyl)-2- {[(1S)-1 -(4- {[4-(2-methylpropanoyl)piperazin-1 yl] methyl } phenyl)ethyl]amino } pyrido[2,3 -d]pyrimidin-7(8H)-one (compound 157);

2-{[(lS)-l-(4-{ [4-(cyclopropylcarbonyl)piperazin-1 yl]methyl}phenyl)ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3^] pyrimidin-7(8H)-one (compound 158);

2- { (S)-1 -[4-(1 - Acryloylpiperidin-4-yloxy)phenyl]ethylamino} -8-((S)-1,2dimethylpropyl)-8H-pyrido[2,3^]pyrimidine-7 -on (comm. 159);

8-((8)-1,2-dimethylpropyl)-2-{(8)-1-[4-(1-isobutyrylpiperidin-4yloxy)phenyl]ethylamino}-8H-pyrido[2,3^]pyrimidin-7 -on (comm. 160);

2- { (S)-1 -[4-(4-Acryloylpiperazin-1 -ylmethyl)phenyl]ethylamino} -8-((S)-1,2dimethylpropyl)-8H-pyrido[2,3^]pyrimidin-7 -on (comm. 161);

8-((8)-1,2-dimethylpropyl)-2-((8)-1-{4-[4-(2-methylacryloyl)piperazin-1 ylmethyl]phenyl}ethylamino)-8H-pyrido[2, 3^]pyrimidin-7-one (compound 162);

2-{[(18)-1-(4-bromophenyl)ethyl]amino}-8-[(28)-3-methylbutan-2-yl]pyrido[2,3d]pyrimidin-7(8H)-one ( connection 163);

2-{[(lS)-l-(4-{ [(2R,6 S)-2,6-dimethylmorpholin-4-yl]methyl } phenyl)ethyl] amino } -8[(2S)-1,1 ,1-trifluoropropan-2-yl]pyrido[2,3^]pyrimidin-7(8H)-one (compound 164);

4'-[(18)-1-({8-[(28)-3-methylbutan-2-yl]-7-oxo-7,8-dihydropyrido[2,3d]πpirimidin-2-yl}amino) ethyl]biphenyl-2-carbonitrile (compound 165);

2-({(lS)-l - [4-(2-fluoropyridin-4-yl)phenyl]ethyl} amino)-8-[(2 S)-3-methylbutan-2yl]pyrido[2,3^] pyrimidin-7(8H)-one (compound 166);

tert-butyl 4-{4-[(18)-1-({8-[(28)-3-methylbutan-2-yl]-7-oxo-7,8dihydropyrido[2,3-b]pyrimidin-2 -yl}amino)ethyl]phenyl}-3,6-dihydropyridine1(2H)carboxylate (compound 167);

2-({(lS)-l-[4-(l-acryloyl-1,2,3,6-tetrahydropyride in-4-yl)phenyl]ethyl} amino)-8[(2 S)-3 - methylbutan-2-yl] pyrido[2,3 -d] pyrimidin-7(8H)-one (compound 168);

2-{[(lS)-l - { 4-[(4-ac yloylpiperazin-1 -yl)methyl] phenyl }ethyl] amino } -8-[(2S)-1,1,1 trifluoropropan-2-yl ]pyrido[2,3-0]pyrimidin-7(8Н)-one (compound 169);

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2-{[(18)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(propan-2yl)pyrido[2,3-b]pyrimidine -7(8H)-one (compound 170);

8-[(18)-1-cyclopropylethyl]-2-{[(18)-1-(4-{[(2K,68)-2,6-dimethylmorpholin-4yl]methyl}-3-fluorophenyl)ethyl] amino}pyrido[2,3-b]pyrimidin-7(8H)-one (compound 171);

2-{[(lS)-l -(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl] amino } -8-[(2 S)-3 methylbutan-2-yl]pyrido [2,3-b]pyrimidin-7(8H)-one (compound 172);

8-[(2S)-3-methylbutan-2-yl]-2-( { (1S)-1 - [4-(morpholin-4yl)phenyl]ethyl}amino)pyrido[2,3-b]pyrimidine -7(8H)-one (compound 173);

benzyl 4-{4-[(18)-1-({8-[(28)-3-methylbutan-2-yl]-7-oxo-7,8-dihydropyrido[2,3d]pyrimidin-2-yl } amino)ethyl] phenyl } piperazine-1-carboxylate (compound 174);

2-({(lS)-l - [4-(4-acryloylpiperazin-1 -yl)phenyl]ethyl} amino)-8-[(2 S)-3 -methylbutan2-yl]pyrido[2,3-b ]pyrimidin-7(8Н)-one (compound 175);

8-[(2 S)-3 -methylbutan-2-yl]-2-( { (1S)-1 - [4-(piperazin-1 yl)phenyl]ethyl}amino)pyrido[2,3-b] pyrimidin-7(8H)-one (compound 176);

2-({(lS)-l - [4-(4-ethylpiperazin-1 -yl)phenyl]ethyl } amino)-8-[(2 S)-3 -methylbutan-2yl]pyrido[2,3-b ]pyrimidin-7(8Н)-one (compound 177);

benzyl 4-{2-fluoro-4-[(18)-1-({8-[(28)-3-methylbutan-2-yl]-7-oxo-7,8dihydropyrido[2,3-b]pyrimidine -2-yl}amino)ethyl]phenyl (piperazine-1-carboxylate (compound 178);

2-({(18)-1-[4-(4-acryloylpiperazin-1-yl)-3-fluorophenyl]ethyl(amino)-8-[(28)-3methylbutan-2-yl]pyrido[2,3 -b]pyrimidin-7(8H)-one (compound 179);

8-[(2 S)-3 -methylbutan-2-yl]-2-( { (1S)-1 - [6-(piperazin-1 -yl)pyrid in-3 yl]ethyl(amino)pyrido[2 ,3-b]pyrimidin-7(8H)-one (compound 180);

2-({(lS)-l - [6-(4-acryloylpiperazin-1 -yl)pyrid in-3 -yl]ethyl (amino)-8-[(2 S)-3 methylbutan-2-yl]pyrido [2,3-b]pyrimidin-7(8H)-one (compound 181);

2-{[(lS)-l - { 4-[(4-ac yloylpiperazin-1 -yl)methyl]phenyl (ethyl] amino (-8-(2azidoethyl)pyrido[2,3-b]pyrimidin-7( 8H)-on (compound 182);

2-{[(lS)-l - { 4- [(4-ac yloylpiperazin-1 -yl)methyl] -3 -fluorophenyl (ethyl] amino (-8 (propan-2-yl) pyrido[2,3- b]pyrimidin-7(8H)-one (compound 183);

2-{[(lS)-l - { 4- [(4-ac yloylpiperazin-1 -yl)methyl] phenyl (ethyl] amino (-8-(propan-2yl) pyrido[2,3-b]pyrimidin- 7(8H)-one (compound 184);

tert-butyl 4-(4-{(18)-1-[(8-ethyl-7-oxo-7,8-dihydropyrido[2,3-b]pyrimidin-2yl)amino]ethyl(benzyl)piperazine-1 -carboxylate (compound 185);

2-{[(lS)-l - { 4-[(4-ac yloylpiperazin-1 -yl)methyl] phenyl (ethyl] amino } -8ethylpyrido[2,3-b]pyrimidin-7(8H)-one ( connection 186);

2-{[(18)-1-{4-[1-(4-acryloylpiperazin-1-yl)propyl]phenyl(ethyl]amino]-8(propan-2-yl)pyrido[2,3^]pyrimidine -7(8H)-one (compound 187);

8-[(2S)-3-methylbutan-2-yl]-2-{[(1S)-1 - { 4-[(4-methyl-3-oxopiperazin-1yl)methyl]phenyl (ethyl]amino (pyrido[2,3 -d]pyrimidin-7(8H)-one (compound 188);

tert-butyl 4-(4-{(18)-1-[(8-ethyl-7-oxo-7,8-dihydropyrido[2,3-b]pyrimidin-2- 12 046117 yl)amino]ethyl)benzoyl )piperazine-1-carboxylate (compound 189);

2-{[(lS)-l - { 4-[(4-ac yloylpiperazin-1 -yl)carbonyl] phenyl )ethyl] amino } -8ethylpyrido[2,3-(1]pyrimidin-7(8H)-one (connection 190);

2-{[(18)-1-{4-[(4-acryloylpiperazin-1-yl)carbonyl]-3-fluorophenyl)ethyl]amino}-8[(2 S)-3 -methylbutan-2-yl] pyrido[2,3 -d]pyrimidin-7(8Н)-one (compound 191);

N-(1-acryloylpiperidin-4-yl)-2-fluoro-4-[(1S)-1 - {[7-oxo-8-(propan-2-yl)-7,8dihydropyrido[2,3^] pyrimidin-2-yl]amino) ethyl]benzamide (compound 192);

tert-butyl 6-[(18)-1-({8-[(28)-3-methylbutan-2-yl]-7-oxo-7,8-dihydropyrido[2,3b]pyrimidin-2-yl} amino)ethyl]-3',6'-dihydro-3,4'-b1pyridine-G(2'H)-carboxylate (compound 193);

2-{[(1S)-1 -(1'-acryloyl-1',2',3',6'-tetrahydro-3,4'-bipyridin-6-yl)ethyl]amino)-8[(2 S)-3-methylbutan-2-yl]pyrido[2,3-d]pyrimidin-7(8H)-one (compound 194);

2-({(18)-1-[G-(cyclopropylcarbonyl)-G,2',3',6'-tetrahydro-3,4'-bipyridin-6yl]ethyl}amino)-8-[(28) -3-methylbutan-2-yl]pyrido[2,3^]pyrimidin-7(8H)-one (compound 195);

8-[(2S)-3-methylbutan-2-yl]-2-( { (1S)-1 - [2'-(trifluoromethyl)-3,4' -bipyridin-6yl]ethyl)amino)pyrido [2,3^]pyrimidin-7(8H)-one (compound 196);

2-{[(18)-1-(2'-fluoro-3,4'-bipyridin-6-yl)ethyl]amino)-8-[(28)-3-methylbutan-2yl]pyrido[2,3 -b]pyrimidin-7(8H)-one (compound 197);

2-{[(lS)-l - { 4-[(4-ac yloylpiperazin-1 -yl)methyl] phenyl )ethyl] amino } -8-[(2 S)-1 fluoropropan-2-yl]pyrido[ 2,3^]pyrimidin-7(8H)-one (compound 198);

2-{[(lS)-l - { 4-[(4-ac yloylpiperazin-1 -yl)methyl] phenyl )ethyl] amino } -8-[(2 S)-1 hydroxypropan-2-yl]pyrido[ 2,3-b]pyrimidin-7(8H)-one (compound 199);

tert-butyl 4-{4-[(18)-1-{[4-cyano-8-(2,2-dimethylpropyl)-7-oxo-7,8dihydropyrido[2,3-b]pyrimidin-2-yl ]amino}ethyl]benzyl (piperazine-1-carboxylate (com. 200);

2-{[(lS)-l - { 4-[(4-ac yloylpiperazin-1 -yl)methyl] phenyl )ethyl] amino )-8-(2,2dimethylpropyl)-4-ethoxypyrido[2,3-b ]pyrimidin-7(8Н)-one (compound 201);

2-{[(lS)-l - {4-[(4-ac yloylpiperazin-1 -yl)methyl] phenyl }ethyl] amino )-8-(2,2dimethylpropyl)-4-(methylamino)pyrido[2, 3-b]pyrimidin-7(8H)-one (compound 202);

2-{[(lS)-l - { 4-[(4-ac yloylpiperazin-1 -yl)methyl] phenyl)ethyl] amino) -4(dimethylamino)-8-(propan-2-yl)pyrido[2 ,3-b]pyrimidin-7(8H)-one (compound 203);

2-{[(lS)-l - { 4- [(4-ac yloylpiperazin-1 -yl)methyl] phenyl)ethyl] amino) -7-oxo-8(propan-2-yl)-7,8- dihydropyrido[2,3-d]pyrimidine-4-carbonitrile (compound 204);

2-{[(lS)-l - { 4-[(4-ac yloylpiperazin-1 -yl)methyl] phenyl)ethyl] amino) -4-[(2,4dimethoxybenzyl)amino]-8-(propane-2 -yl)pyrido[2,3-0]pyrimidin-7(8H)-one (compound 205);

2-{[(lS)-l - { 4-[(4-ac yloylpiperazin-1 -yl)methyl] phenyl)ethyl] amino) -4-amino-8(propan-2-yl)pyrido[2,3 ^]pyrimidin-7(8H)-one (compound 206);

2-{[(lS)-l-(4-{ [(2К)-4-acryloyl-2-methylpiperazin-1-yl]methyl) phenyl)ethyl]amino) 8-ethylpyrido[2,3^]pyrimidin- 7(8H)-one (compound 207);

2-{[(lS)-l-(4-{ [(ZY)-4-acryloyl-3-methylpiperazin-1-yl]methyl) phenyl)ethyl] amino) - 13 046117

8-ethylpyrido[2,3-b]pyrimidin-7(8Н)-one (compound 208);

2- {[(1S)-1 -(4- { [(2K)-4-acryloyl-2-(propan-2-yl)piperazin-1 yl]methyl}phenyl)ethyl]amino}-8-ethylpyrido[ 2,3-d]pyrimidin-7(8H)-one (compound 209);

2-{[(lS)-l-(4-{ [(2 8)-4-acryloyl-2-methylpiperazin-1 -yl] methyl} phenyl )ethyl] amino} 8-ethylpyrido[2,3-b] pyrimidin-7(8Н)-one (compound 210);

2-{[(lS)-l-(4-{[(3 8)-4-acryloyl-3 -methylpiperazin-1 -yl] methyl } phenyl )ethyl] amino } 8-ethylpyrido[2,3^]pyrimidine -7(8H)-one (compound 211);

2-{[(1S)-1 -(4-{[(2 8)-4-acryloyl-2-(propan-2-yl)piperazin-1 yl]methyl}phenyl)ethyl]amino}-8-ethylpyrido [2,3-d]pyrimidin-7(8H)-one (compound 212);

2-{[(lS)-l - { 6-[(4-ac yloylpiperazin-1 -yl)methyl] pyridin-3 -yl }ethyl] amino } -8(propan-2-yl)pyrido[2,3 -b]pyrimidin-7(8H)-one (compound 213);

2-{[(18)-1-{4-[1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8ethylpyrido[2,3-b]pyrimidin-7(8H)-one (connection 214);

2-{[(18)-1-{4-[1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8methylpyrido[2,3-b]pyrimidin-7(8H)-one (connection 215);

2-{[(18)-1-{4-[1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(2,6difluorobenzyl)pyrido[2,3-b]pyrimidine -7(8H)-one (compound 216);

2-{[(18)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-(4-ethynyl2-fluorobenzyl)pyrido[2,3-b]pyrimidine -7(8H)-one (compound 217);

2-{[(18)-1-{4-[1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8cyclopropylpyrido[2,3^]pyrimidin-7(8H)-one ( connection 218);

2-{[(lS)-l-{4-[l -(4-ac yloylpiperazin-1 -yl)-2cyclopropylethyl]phenyl}ethyl]amino}-8-ethylpyrido[2,3-b]pyrimidin-7( 8H)-on (compound 219);

2-{[(lS)-l-{4-[l -(4-ac yloylpiperazin-1 -yl)-2cyclopropylethyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3 -b]pyrimidine -7(8H)-one (compound 220);

2-{[(lS)-l-(4-{l - [4-(2-methylacryloyl)piperazin-1 -yl] propyl } phenyl )ethyl] amino } 8-(propan-2-yl)pyrido[2 ,3-b]pyrimidin-7(8H)-one (compound 221);

2-({(lS)-l-[4-(l - { 4-[(2E)-but-2-enoyl]piperazin-1 -yl } propyl)phenyl]ethyl } amino)8-(propan-2 -yl)pyrido[2,3-b]pyrimidin-7(8H)-one (compound 222);

2-{[(lS)-l-(4-{ [(3 R)-1 -acryloylpyrrolidin-3-yl] oxy } phenyl )ethyl] amino } -8ethylpyrido[2,3-b]pyrimidin-7(8H )-on (comm. 223);

2-{[(lS)-l-(4-{[(3S)-l -acryloylpyrrolidin-3 -yl] oxy } phenyl )ethyl] amino } -8ethylpyrido[2,3-b]pyrimidin-7(8H) -on (connection 224);

phenyl 4-[(18)-1-{4-[(18)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3b]pyrimidin-2- yl]amino}ethyl]phenyl}propyl]piperazine-1-carboxylate (compound 225);

phenyl 4-[(1К)-1-{4-[(18)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3d]pyrimidin-2- yl]amino}ethyl]phenyl}propyl]piperazine-1-carboxylate (compound 226);

2-{[(18)-1-{4-[(18)-1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-14 046117 (propan-2-yl)pyrido [2,3-<1]pyrimidin-7(8H)-one (compound 227);

2-{[(18)-1-{4-[(1К)-1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8(propan-2-yl)pyrido[2, 3-<1]pyrimidin-7(8H)-one (compound 228);

2-{[(1К)-1-{4-[(1К)-1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8(propan-2-yl)pyrido[2, 3-<1]pyrimidin-7(8H)-one (compound 229);

2-{[(lS)-l-{4-[(lS)-l -(4-ac yloylpiperazin-1 -yl)-2cyclopropylethyl] phenyl }ethyl] amino } -8-(propan-2-yl)pyride o[2,3 -d]pyrimidin-7(8H)-one (compound 230);

2-{[(lS)-l-{4-[(lR)-l -(4-ac yloylpiperazin-1 -yl)-2cyclopropylethyl] phenyl }ethyl] amino } -8-(propan-2-yl)pyride o[2,3 -d]pyrimidin-7(8H)-one (compound 231);

4-{4-[(S)-1 -(1-Ethyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7ylamino)ethyl]benzyl}piperazine-1-carboxylic acid tert-butyl ester (connection 232);

4-(l-{4-[(S)-l-(l -Ethyl-2-oxo-1,2-dihydro-[1, 6]naphthyride in-7ylamino)ethyl]phenyl}propyl)piperazine-1- carboxylic acid tert-butyl ester (compound 233);

4-((S)-l -{4-[(S)-1 -(1 -Ethyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7ylamino)ethyl]phenyl}propyl)piperazine -1-carboxylic acid phenyl ester (compound 234);

7-{(S)-1 - [4-(3,3-difluoro-piperidin-1-ylmethyl)phenyl]ethylamino} -1 -(2,2dimethylpropyl)-1H-[1,6]naphthyridin-2-one (connection 235);

7- { (S)-1 -[4-(4-Acr yloylpiperazin-1 -ylmethyl)phenyl]ethylamino } -1 -ethyl-1H[1,6]naphthyridin-2-one (compound 236);

7-((S)-1 - { 4- [ 1 -(4-Acr yloylpiperazin-1 -yl)propyl]phenyl } -ethylamino)-1 -ethyl-1H[1,6]naphthyridin-2-one (comp. 237);

7-((S)-l-{4-[(S)-l -(4-Acr yloylpiperazin-1 -yl)propyl]phenyl}ethylamino)-1-ethyl1H-[1,6]naphthyridin-2-one (conn. 238);

7-{[(lS)-l-{4-[(lS)-l -(4-ac yloylpiperazin-1 -yl)propyl]phenyl }ethyl] amino } -1 (propan-2-yl)-1, 6-naphthyridin-2(1H)-one (compound 239);

2-{[(lS)-l-{4-[l -(4-propanoylpiperazin-1 -yl) propyl] phenyl }ethyl]amino } -8(propan-2-yl)pyrido[2,3-th] pyrimidin-7(8H)-one (compound 240);

2-{[(lS)-l-(4-{(lS)-l-[4-(3-chloropropanoyl)piperazin-1 -yl]-2cyclopropylethyl } phenyl )ethyl] amino } -8-(propan-2 -yl)pyrid o[2,3 -d]pyrimidin-7(8H)-one (compound 242);

2-{[(lS)-l-(4-{(lR)-l-[4-(3 -hydroxypropanoyl)piperazin-1 yl] propyl } phenyl )ethyl] amino } -8-(propan-2-yl )pyrido[2,3 -d]pyrimide in-7(8H)-one (compound 243);

2-[(1 - { 4-[ 1 -(4-ac yloylpiperazin-1 -yl)-2cyclopropylethyl]phenyl}cyclopropyl)amino]-8-(propan-2-yl)pyrido[2,3-th]pyrimidine7 (8H)-on (compound 244);

- 15 046117

2-[(l -{4-[(lR)-l -(4-ac yloylpiperazin-1 -yl)-2cyclopropylethyl]phenyl}cyclopropyl)amino]-8-(propan-2-yl)pyrido[2,3 -с!]pyrimidine7(8Н)-one (compound 245);

2-[(1 - {4-[( 1S)-1 -(4-ac yloylpiperazin-1 -yl)-2cyclopropylethyl]phenyl}cyclopropyl)amino]-8-(propan-2-yl)pyrido[2,3 -(1]pyrimidin7(8H)-one (compound 246);

2-[(1-{4-[1-(4-acryloylpiperazin-1-yl)propyl]phenyl}cyclopropyl)amino]-8(propan-2-yl)pyrido[2,3-(1]pyrimidin-7 (8H)-on (compound 247);

2-[(1 - { 4-[( 1R)-1 -(4-ac yloylpiperazin-1 -yl)propyl] phenyl } cyclopropyl)amino]-8(propan-2-yl)pyrido[2,3-( 1]pyrimidin-7(8H)-one (compound 248);

2-[(1 - { 4-[( 1S)-1 -(4-ac yloylpiperazin-1 -yl)propyl] phenyl } cyclopropyl)amino] -8(propan-2-yl)pyrido[2,3-( 1]pyrimidin-7(8H)-one (compound 249);

2-{[(lS)-l - { 4- [(2E)-pent-2-en-3 -yl] phenyl }ethyl] amino } -8-(propan-2-yl)pyride o[2,3 <1]pyrimidin-7(8H)-one (compound 250); And

7-{[(lS)-l-{4-[(lS)-l -(4-ac yloylpiperazin-1 -yl)-2cyclopropylethyl] phenyl }ethyl] amino } -1 -(propan-2-yl)- 1,6-naphthyride in-2(1H)-one (com.

251).

If a stereogenic center or other form of asymmetric center is present in a compound of the present invention, all forms of such optical isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Compounds containing a stereogenic center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well known techniques and the individual enantiomer may be used. In cases where the compounds have unsaturated carbon-carbon double bonds, both cis (Z) and trans (E) isomers are within the scope of this invention.

In cases where compounds can exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is considered to be included in this invention, regardless of whether it exists in equilibrium or predominantly in one form.

Pharmaceutically acceptable salts of the compounds of formula (I) include salts with inorganic or organic acids, for example, nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, fumaric, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, isethionic and salicylic acids.

Pharmaceutically acceptable salts of the compounds of formula (I) also include salts with inorganic or organic bases, for example alkali or alkaline earth metals, especially hydroxides, carbonates or bicarbonates of sodium, potassium, calcium, ammonium or magnesium, acyclic or cyclic amines.

The term (C1- _C6 )alkyl refers to an aliphatic (C1-C6) hydrocarbon chain containing only carbon-carbon single bonds, which can be straight or branched. Typical examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, n-hexyl and the like.

The term (C ₃ -C ₆ )cycloalkyl means, unless otherwise specified, a 3-6 membered all-carbon monocyclic ring that may contain one or more double bonds, but does not have a fully conjugated π-electron system.

Examples of (C ₃ -C ₆ )cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexanyl, cyclohexenyl and cyclohexadienyl. The (C ₃ -C ₆ ) cycloalkyl ring may optionally be further fused or bonded to aromatic and non-aromatic carbocyclic or heterocyclic rings.

The term heterocyclyl refers to a 3-7 membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include, for example, pyranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, thiazolinyl, thiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyridinyl, 1,3-dioxolanyl, piperidinyl, piperazine silt, morpholinil and the like. The heterocyclyl ring may optionally be further fused or bonded to aromatic and non-aromatic carbocyclic or heterocyclic rings.

The term (C ₂ -C ₆ )alkenyl refers to an aliphatic straight or branched (C ₂ -C ₆ ) hydrocarbon chain containing at least one carbon-carbon double bond. Typical examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1- or 2-butenyl, and the like.

- 16 046117

The term (C2- _C6 )alkynyl refers to an aliphatic straight or branched ( _C2 - _C6 ) hydrocarbon chain containing at least one carbon-carbon triple bond. Typical examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1- or 2-butynyl, and the like.

By the term (C ₁ -C ₆ )alkoxy is meant any of the above-defined (C ₁ -C ₆ )alkyl linked to the remainder of the molecule through an oxygen atom (-O-).

The term aryl refers to a mono-, bi- or polycarbocyclic hydrocarbon with 1-4 ring systems, optionally further fused or linked together by single bonds, where at least one of the carbocyclic rings is aromatic, where the term aromatic refers to a fully conjugated π system -electronic communications. Non-limiting examples of such aryl groups include phenyl, α- or β-naphthyl, α- or βtetrahydronaphthalenyl, biphenyl and indanyl.

The term heteroaryl refers to aromatic heterocyclic rings, typically 5-7 membered heterocycles with 1-3 heteroatoms selected from N, O or S; the heteroaryl ring may optionally be further fused or bonded to aromatic and non-aromatic carbocyclic and heterocyclic rings. Non-limiting examples of such heteroaryl groups include, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiophenyl, thiadiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, indazolyl, cinnoline silt, benzo [1,3]dioxolyl, benzo[1,4]dioxynyl, benzothiazolyl, benzothiophenyl, benzofuranyl, isoindolinyl, benzoimidazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl , 2,3-dihydroindolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl, benzopyranyl, 2,3-dihydrobenzoxazinyl, 2,3-dihydroquinoxalinyl and the like.

The term halogen refers to fluorine, chlorine, bromine or iodine.

The term polyfluorinated (C1-C6)alkyl or polyfluorinated (C1-C6)alkoxy means any of the above-defined (C1-C6)alkyl or (C1-C6)alkoxy groups which are substituted by more than one fluorine atom, such as, for example, trifluoromethyl , trifluoroethyl, 1,1,1,3,3,3hexafluoropropyl, trifluoromethoxy and the like.

By the term hydroxy(C ₁ -C ₆ )alkyl is meant any of the above-defined (C ₁ -C ₆ )alkyl groups bearing a hydroxyl group, such as, for example, hydroxymethyl, 2hydroxyethyl, 3-hydroxypropyl and the like.

From all of the above, it will be clear to one skilled in the art that any group whose name is a compound name, such as, for example, arylamino, should be understood as traditionally interpreted by the parts from which it is derived, for example, an amino group that is substituted with aryl, where aryl is as defined above .

Likewise, any of the terms such as, for example, (C1- _C6 )alkylthio, (C1- _C6 )alkylamino, di(C1- _C6 )alkylamino, (C1- _C6 )alkoxycarbonyl, (C1- _C6 )alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, (C ₃ -C ₇ )cycloalkyloxycarbonyl and the like, include groups where the groups are (C1-C ₆ )alkyl, (C1-C ₆ )alkoxy, aryl, (C ₃ -C ₇ )cycloalkyl and such as defined above.

The present invention also relates to methods for preparing a compound of general formula (I) as defined above using the reaction routes and synthetic schemes described below, using methods available in the art and readily available starting materials. The preparation of certain embodiments of the present invention is described in the following examples, but those skilled in the art will understand that the described preparations can be easily adapted to prepare other embodiments of the present invention. For example, the synthesis of non-exemplified compounds of the invention can be accomplished by those skilled in the art with obvious modifications, for example, by appropriate protection of interfering groups, by suitable substitution of reagents with others known in the art, or by standard modification of reaction conditions. Alternatively, other reactions mentioned herein or known in the art will be found useful for preparing other compounds of the invention.

The compounds of the present invention can be prepared from readily available starting materials using the following general methods and techniques. Unless otherwise indicated, the starting materials are known compounds or can be prepared from known compounds according to generally known techniques. It should be understood that where typical or preferred process conditions are described (ie, temperature, reaction time, reactant molar ratios, solvents, pressures), other process conditions may also be used unless otherwise noted. Optimal reaction conditions may vary depending on the specific reagents or solvent used, but such conditions can be determined by one of ordinary skill in the art using conventional optimization techniques.

The compound of general formula (I), as defined above, can be prepared according to the general synthetic methods described in Scheme 1, starting with the intermediate compound of formula (II). Scheme 1

Therefore, the method of the present invention includes the following steps: Step 1a) reacting the compound of formula (II)

where G represents chlorine, MeS(O) ₂ - or MeS(O)-;

R2, R3, R4 and R5 are as defined above;

with a compound of formula (III)

where A, R1a, R1b, R6a and R6b are as defined above;

to obtain a compound of general formula (I). to obtain a compound of general formula (I), wherein A, R1a, R1b, R2, R3, R4, R5, R6a and R6b are as defined above.

The compound of formula (II) can be prepared according to synthetic scheme 2 or scheme 4 shown below:

a compound of formula (II), where G is MeS(O) ₂ - or MeS(O)-, can be prepared according to scheme 2

Scheme 2

Step 2a) replacement of chlorine intermediate of formula (IV)

where R3 represents hydrogen or linear (C ₁ -C ₆ )alkyl, with an intermediate amine of formula (V)

IR2-NH, (V) where R2 is as defined above to give a compound of formula (IV);

Step 2b) reaction of the compound of formula (VI)

where R2 and R3 are as defined above, with a reducing agent to obtain a compound of formula (VII);

Step 2c) reacting the resulting compound of formula (VII)

- 18 046117

where R2 and R3 are as defined above, with a suitable oxidizing reagent to obtain a compound of formula (VIII);

Step 2d) reacting the resulting compound of formula (VIII)

where R2 and R3 are as defined above, with a compound of formula (IX)

R5 ¹ (IX) where Y is a suitable leaving group for the Wittig or Horner-Wadsworth-Emmons reaction (or HVE reaction), such as triphenylphosphorane or diethylphosphonate and

R5 is hydrogen or fluorine to give a compound of formula (X);

Step 2e) Cyclization of intermediate of formula (X)

where R2, R3, R4 and R5 are as defined above, under basic conditions, to give an intermediate of formula (XI);

Step 2f) mixing the resulting intermediate of formula (XI):

R3 R4

N ^R5 jl 'З^ 14 14 О

R2 (XI) where R2, R3, R4 and R5 are as defined above, with an oxidizing reagent to produce a compound of formula (II) wherein G is MeS(O) ₂ - or MeS(O) - and R2, R3, R4 and R5 are as defined above;

The compound of formula (II) where G is chlorine and X is nitrogen or -CH- can be prepared according to Scheme 4 below:

Scheme 4

Step 4a) reaction of the compound of formula (XVIII)

wherein R3 is hydrogen or optionally substituted linear or branched (C1- _C6 )alkyl and Hal is preferably bromine or iodine, with an intermediate of formula (V)

R2-NH ₂ (V) where R2 is as defined above to give a compound of formula (XIX);

- 19 046117

Step 4b) mixing the resulting intermediate of formula (XIX)

where R2, R3 and Hal are as defined above, with the reagent of formula (XVIIb)

wherein R4 is hydrogen or optionally substituted linear or branched (C1- _C6 ) alkyl, R5 and T are hydrogen, to give a compound of formula (Xb);

Step 4c) cyclization of intermediate of formula (Xb):

where R2, R3, R4, R5 and T are as defined above, with the addition of acetic anhydride, to obtain an intermediate of formula (II), where G is chlorine, R4 is hydrogen or optionally substituted linear or branched (C1-C6 ) alkyl, R5 is hydrogen and R2 and R3 are as defined above;

Step 4d) chlorine substitution of intermediate compound of formula (IVa)

wherein X is N, or -CH, with an amine intermediate of formula (V) R2-NH ₂ (V) wherein R2 is as defined above to give a compound of formula (VIa); Step 4e) reaction of the compound of formula (VIa)

where X represents N or -CH, and R2 is as defined above, with a reducing agent, to obtain compound (VIIa);

Step 4f) reacting the resulting compound of formula (VIIa)

where X is N or -CH, and R2 is as defined above with a suitable oxidizing reagent;

Step 4g) reacting the resulting compound of formula (VIIIa)

where R2 is as defined above, with a compound of formula (IXa) o 6 R5 । (IXa) wherein R5 is hydrogen or OR12 wherein R12 is optionally substituted straight or branched (C1- _C6 )alkyl to give a compound of formula (II) wherein G is chlorine and X is nitrogen or -CH -, R2 is as defined above, R3 and R4 are hydrogen, and R5 is hydrogen, or OR12, where R12 is optionally substituted straight or branched (C1 -C ₆ )alkyl.

According to step 1a, the replacement of a leaving group such as methyl sulfone, methyl sulfoxide or a chlorine intermediate of formula (II) with an intermediate of formula (III) is carried out using an organic base such as DIPEA, CsF as a reaction accelerator, in a suitable solvent such as ACN , DMSO, and at a temperature of 60-120°C with normal heating

- 20 046117 or microwave irradiation, for 1-24 hours;

alternatively, and more specifically, if G is chlorine, the reaction can be carried out under conditions well known to one skilled in the art. For example, the halide can be replaced by a Buchwald-Hartwin amination reaction with a suitable palladium source such as PEPPSI precatalyst and a base such as Cs ₂ CO 3 in a solvent such as toluene or ACN at a temperature of 60-110°C with conventional heating or microwave irradiation, and for a period of 1-24 hours.

According to step 2a, the replacement of the chlorine of a compound of formula (IV) with an amine of formula R2-NH2 (V) can be carried out neat or in the presence of a suitable base such as Na ₂ CO3, K ₂ CO _3; Cs ₂ CO3, TEA, DIPEA and the like, in a suitable solvent such as DMF, DMA, ACN, DMSO and the like, at a temperature from room temperature to reflux.

According to step 2b of the method for reducing the ester of formula (VI), the preparation of the compound of formula (VII) can be carried out in various ways, and the experimental conditions are well known in the art. A reducing agent such as lithium hydride and the like may be used in a suitable solvent such as THF at 0° C. to room temperature for 2 to about 24 hours. Preferably, the reaction is successfully carried out with lithium aluminum hydride in THF at room temperature.

According to process step 2c, the oxidation of the intermediate of formula (VII) to the aldehyde of formula (VIII) can be carried out in the presence of manganese(II) dioxide, pyridinium chlorochromate, iodoxybenzoic acid (IBX), tetrapropylammonium perruthenate (PTPA), 4methylmorpholine N-oxide or sodium hypochloride. TEMPO/Bu ₄ NHSO ₄ , in a solvent such as DCM, ACN, THF, EtOAc, acetone or chloroform, at room temperature.

According to step 2d of the method, the aldehyde of formula (VIII) is reacted with a phosphorane of formula (IX) under Wittig reaction conditions, for example in the presence of a base such as TEA, LiHMDS, KHMDS, NaH, KOtBu and the like, in a suitable solvent such as THF, Et2O and the like, at a temperature of -20° C. to room temperature, or alternatively, the aldehyde of formula (VIII) is reacted with a phosphonate of formula (IX) under Horner-Wadsworth-Emmons reaction (or CVE reaction) conditions, such as the presence of a base such such as LiOH, NaOH, TEA, NaH and the like, in a suitable solvent such as THF at room temperature.

According to method step 2e, the cyclization of an intermediate of formula (X) to give a compound of formula (XI) can be carried out in the presence of a base such as TEA, DBU, DABCO and the like, in a suitable solvent such as DMF, DMA, DIPEA and the like, at temperature to approximately boiling temperature under reflux for 1-24 hours.

According to step 2f, the oxidation of the methylthio group of the intermediate compound of formula (XI) to obtain a compound of formula (II), where G is MeS(O) ₂ -or MeS(O), can be carried out in the presence of an oxidizing agent well known to specialists in the art, such as, for example, oxon or m-chloroperbenzoic acid and the like, in a suitable solvent such as DCM or at room temperature for 1-4 hours.

According to step 4a, the replacement of the chlorine of the compound of formula (XVIII) with an amine of formula (V) can be carried out as described above in step 2a.

In step 4b, the intermediate of formula (XIX) is reacted with acrylic or crotonic acid of formula (XVIIb) in a Heck-type reaction, in the presence of a catalyst such as dichlorobis(benzonitrile)palladium(II) and tri-o-tolylphosphine, and in the presence of a base such as TEA in a suitable solvent such as THF, DMF, DMA and the like. The reaction mixture is heated to approximately 100°C for a period of time equal to approximately overnight or less, which is necessary for the reaction to complete under classical thermal conditions or in a microwave apparatus.

According to method step 4c, the cyclization of the intermediate of formula (Xb) can be carried out in the presence of acetic anhydride and the like, in a suitable solvent such as THF, DMF, DMA and the like, at approximately reflux for a period of 1-24 hours. obtaining a compound of formula (II) as defined above.

According to process step 4d, replacing the chlorine of a compound of formula (IVa) with an amine of formula (V) to produce a compound of formula (VIa) can be carried out as described in step 2a above.

According to process step 4e, the reduction of the ester of formula (VIa) to obtain a compound of formula (VIIa) can be carried out as described above in step 2b

According to process step 4f, the oxidation of the intermediate of formula (VIIa) to the aldehyde of formula (VIIIa) can be carried out as described above in step 2b.

In step 4g, the compound of formula (VIIIa) is cyclized under the conditions described in step 3a to obtain a compound of formula (II) wherein G is chlorine and X is nitrogen or CH-.

The first compound of general formula (I) can be successfully converted into the second compound

- 21 046117 of formula (I) by treatment according to well-known synthesis conditions.

Examples of suitable transformations are described below: transformation 1) transformation of a compound of formula (I)

where R6a represents a group of the formula -COOR7, R7 represents an optionally substituted linear or branched (C1-C6) alkyl, into a compound of formula (I), where R6a represents a group of the formula -CH2OH, by reaction with a suitable reducing reagent;

transformation 2) transformation of a compound of formula (I)

where R6a represents a group of formula -CH ₂ OH, into a compound of formula (I), where R6a represents a group -CH(R14)NR7R8, where R14 represents hydrogen, first by converting the -CH ₂ OH group to the corresponding aldehyde-CHO, then reacting the resulting derivative with a compound of the formula R7R8NH (XX), where

R6 and R7 are as defined above, under reductive amination conditions, in the presence of suitable reducing agents;

transformation 3) transformation of a compound of formula (I)

wherein R6a is a group of the formula -COOR7, wherein R7 is an optionally substituted linear or branched (C1-C6) alkyl, to a compound of formula (I), wherein R6a is a group of the formula -COOH under acidic or basic conditions; transformation 4) transformation of a compound of formula (I)

wherein R6a is a group of formula -COOH, into a compound of formula (I), wherein R6a is a group of formula -CONR7R8, wherein R7 and R8 are as defined above, by reacting with a compound of formula R7R8NH (XX), in the presence of suitable amide coupling agents ;

transformation 5) transformation of a compound of formula (I)

R6a

R6a

(I) (I) wherein A is aryl or heteroaryl, and R6a is chlorine, bromine or iodo, into a compound of formula (I), wherein R6a is an optionally substituted group selected from (C1- _C6 )alkyl, ( C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, (C ₃ -C ₇ )cycloalkyl, heterocyclyl, aryl, heteroaryl, by reaction with a reagent of formula R6aQ (XXI), where R6a is as defined above, and Q represents a group selected from boronic acid, boronic ester and -Sn[(C ₁ -C ₆ )αalkyl] ₃ under Pd-catalyzed cross-coupling conditions;

transformation 6) transformation of a compound of formula (I)

R9-N0y-0T0 --Η- θ 0dLS (I) (I) where R6a represents a linker group M of the formula -CH(R14)NR7R8 or -CONR7R8 or NR7R8, where R14 represents hydrogen or an optionally substituted linear or branched (C ₁ -C ₆ )alkyl, R7 and R8, together with the nitrogen atom to which they are bonded, can form a 5-7 membered heterocyclyl group, optionally containing one additional group, such as N-R9, where R9 is a suitable protecting group, into the compound formula (I) wherein A is as defined above and R9 is hydrogen, under alkaline or acid hydrogenation conditions;

transformation 7) transformation of a compound of formula (I) /—У ° Λ Λ

H-ν M+- A Jx ---An ^m t ^a A (I) ® where R6a represents a linker group M of the formula -CH(R14)NR7R8, or -CONR7R8 or NR7R8, where R14 represents hydrogen or an optionally substituted linear or branched (C ₁ -C ₆ )alkyl, R7 and R8 together with the nitrogen atom to which they are linked may form a 5-7 membered heterocyclyl group, optionally containing one additional group such as N-R9, where R9 represents hydrogen, into a compound of formula (I) where A is as defined

- 22 046117 above, and R9 is -COR11, where R11 is an optionally substituted linear or branched (C ₁ -C ₆ )alkyl, (C1-C6) alkenyl or (C1-C6) alkynyl, by reaction with a reagent of the formula R11COW ( XXII), where R11 is as defined above and W represents OH or Cl;

transformation 8) transformation of a compound of formula (I)

where R2 represents a group of the formula L-COOalkyl, where L represents an optionally substituted group selected from linear or branched (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl-(C1C ₆ )alkyl, aryl-( C1- _C6 )alkyl and heterocyclyl-(C1- _C6 )alkyl, into a compound of formula (I), wherein R2 represents a group of formula L-COOH, wherein L is as defined above; in acidic or alkaline conditions;

transformation 9) transformation of a compound of formula (I)

wherein R2 is a group of the formula L-COOH, where L is as defined above, into a compound of formula (I), where R2 is a group of the formula L-CONR7R8, where L, R7 and R8 are as defined above, by reacting with the compound formula R7R8NH (XX), in the presence of amide coupling agents;

transformation 10) transformation of a compound of formula (I)

where R2 represents a group of the formula L-CONH2 where L is as defined above, into a compound of formula (I), where R2 represents a group of the formula L-CN, where L is as defined above, by reaction with a dehydrogenating agent;

transformation 11) transformation of a compound of formula (I)

wherein A is aryl or heteroaryl, and R6a is chlorine, bromine or iodo, into a compound of formula (I), wherein R6a is a methylsulfonyl group, under cross-coupling reaction conditions;

transformation 12) transformation of a compound of formula (I)

where L represents a group selected from aryl(C1-C ₆ )alkyl, and heterocyclyl-(C1-C ₆ )alkyl, in the compound of formula (I), where L is as defined above under strong Lewis acid conditions;

transformation 13) transformation of a compound of formula (I)

where R6a represents a phenolic group, into a compound of formula (I), where R6a represents an OR7 group, where R7 is as defined above, by reacting with a reagent of formula R7-X (XXIII), where R7 is as defined above and X is is hydroxy, bromine, iodine, -OMs or -OTs;

transformation 14) transformation of a compound of formula (I)

where A is as defined above and R6a is a group -OR7, where R7 is a heterocyclyl group, and P1 is a suitable protecting group, into a compound of formula (I), where A is as defined above and R7 is heterocyclyl, according to a technique well known in the art (see, for example, Green, Theodora W. and Wuts, Peter G.M. Protective Groups in Organic Synthesis, Third Edition) such as, for example, under alkaline or acid hydrogenation conditions;

transformation 15) transformation of a compound of formula (I)

- 23 046117

where A is as defined above, and R6a is a -OR7 group, where R7 is a heterocyclyl group, into a compound of formula (I), where A and R11 are as defined above, by reacting with a reagent of formula R11 COW (XXII), Where

R11 is as defined above, and W represents OH or Cl;

conversion 16) conversion of a compound of formula (I) (I) ^{L Br} ® where L represents a group selected from aryl(C ₁ -C ₆ )alkyl and heterocyclyl-(C ₁ -C ₆ )alkyl, into a compound of formula (I) , where L is as defined above under Sonogashira reaction conditions.

According to conversion method 1, the ester of formula (I) can be reacted in various ways and under various experimental conditions known in the art with a reducing agent to produce the corresponding alcohol compound of formula (I). For example, with lithium aluminum hydride or the like, in a suitable solvent such as THF, at a temperature of from 0° C. to room temperature, from 2 to about 24 hours. Preferably, the reaction is successfully carried out with lithium aluminum hydride in THF at room temperature.

According to the conversion method 2, first the oxidation of the intermediate compound of formula (I) can be carried out in the presence of manganese(II) dioxide, pyridinium chlorochromate, o-iodoxybenzoic acid (IBX), tetrapropylammonium perruthenate (PTPA), 4-methylmorpholine N-oxide (NMO), sodium hypochlorite/TEMPO/Bu ₄ NHSO ₄ in a solvent such as methylene chloride, ACN, THF, EtOAc, acetone or chloroform at room temperature to give the aldehyde of formula (I). The aldehyde intermediate is then further reacted under reductive amination conditions with the reagent of formula (XX) in the presence of a reducing agent such as NaBH4, NACNBH3, NaBH(OAc)3 and the like, in a solvent such as MeOH, EtOH, 2,2,2-trifluoroethanol and the like, at a temperature of from rt to 40°C, and for from 1 to about 12 hours. This reduction reaction may optionally be carried out in the presence of a suitable catalyst such as AcOH, TPA and the like.

According to transformation 3, the reaction is carried out under aqueous alkaline conditions such as aqueous LiOH, NaOH or KOH, or under acidic conditions such as AcOH, TFA or HCl, in an organic solvent such as a lower alcohol, THF, DMF, DCM or 1. 4-dioxane or mixtures thereof, at room temperature to about 80°C and for about 1 to about 12 hours.

According to transformation 4, the amidation of the compound of formula (I) is carried out in the presence of a suitable primary or secondary amine of formula (XX), under alkaline conditions, preferably with DIPEA or TEA, in a suitable solvent such as DCM, DMF, THF, 1,4- dioxane or DMA, in the presence of a suitable condensing agent, for example dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3benzotriazine (DHBT), O-benzotriazolyltetramethylisouronium tetrafluoroborate (TBTU), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) or 2-(1Hbenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (GBTU), at a temperature of about -10°C to reflux, and for a suitable period of time, for example from about 30 minutes to about 96 hours. This reaction is optionally carried out in the presence of a suitable catalyst, such as DMAP, or in the presence of an additional coupling reagent, such as Nhydroxybenzotriazole (GOBT); or alternatively, the conversion can also be carried out, for example, by the mixed anhydride method, using an alkyl chloroformate such as ethyl, isopropyl, benzyl chloroformate, in the presence of a tertiary amine such as TEA, DIPEA or pyridine, in a suitable solvent such as, for example, toluene, DCM, THF, DMF and the like, at ct; or alternatively, the carboxylic acid is converted first to the corresponding acyl chloride by reaction with an activating agent such as thionyl chloride, oxalyl chloride, cyanuric chloride or I-χλορ-Ν,^2-trimethylpropenylamine (Hosez's reagent), neat or in a suitable solvent such as toluene or DCM , optionally in the presence of a catalytic amount of DMF, at a temperature of from about -10° C. to reflux, and for a suitable time, for example from about 30 minutes to about 4 hours. Said acid chloride is then reacted with a suitable primary or secondary amine of formula ( XX), in a suitable solvent such as DCM, chloroform, THF, diethyl ether, 1,4-dioxane, ACN, toluene or DMF and the like, at a temperature of about -10° C. to reflux, and for a suitable time time, for example from about 30 minutes to about 96 hours, in the presence of a suitable base such as TEA, DIPEA or pyridine.

- 24 046117

According to transformation 5, the reaction of a compound of formula (I) with a compound of general formula (XXI) is carried out under standard Suzuki coupling conditions using a Pd-based catalyst such as Pd(dppf)Cl ₂ , PdCl2(PPh3)2 and Pd(PPh3) ₄ , with a suitable base such as Na2CO3, Cs2CO3, K3PO ₄ , in a suitable solvent such as 1,4-dioxane, 1,4-dioxane/water, THF, DMF, toluene and the like, at a temperature from room temperature to 130°C , under classical thermal conditions, or in a microwave apparatus, for a period of time from 1 to 48 hours.

According to transformation 6, deprotection of a compound of formula (I) is carried out under acidic conditions, such as, for example, TPA, HCl and the like, in a solvent such as DCM, 1,4-dioxane, or with a catalytic amount of CuCl in a suitable solvent such as MeOH, EtOH, or EtOH/water mixture, at rt to reflux, and for 1 to about 12 hours.

According to transformation 7, the conversion of a compound of formula (I) where an amine group is present into the corresponding carboxamide derivative is carried out by reacting with a compound of formula (XXII). One skilled in the art will appreciate that the reaction can be carried out in a variety of ways and under a variety of reaction conditions that are widely known in the art for the production of carboxamides (see, for example, Scott, C.J. et al. J. Med. Chem. 2005, 48 , 1344-1358; Amino Acids, Peptides and Proteins in Organic Chemistry: Building Blocks, Catalysis and Coupling Chemistry, Volume 3; Andrew B. Hughes, Ayman El-Faham, Fernando Albericio). As an example, if an acid chloride is used, the reaction is carried out in a suitable solvent, such as, for example, DCM, THF, 1,4-dioxane, ACN, or DMF or the like, at a temperature of about -10° C. to reflux , and for a suitable time, for example, from about 30 minutes to about 96 hours. The reaction is carried out in the presence of a suitable proton acceptor, such as triethylamine, N,Ndiisopropylethylamine or pyridine; or if a carboxylic acid is involved, the reaction is carried out in the presence of a coupling agent such as, for example, 2-(N-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 1,3dicyclohexylcarbodiimide, 1, 3-diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N-cyclohexylcarbodiimide-N'-propylmethylpolystyrene or N-cyclohexylcarbodiimide-Nmethylpolystyrene, in a suitable solvent such as, for example, dichloromethane, tetrahydrofuran, 1,4dioxane, acetonitrile, N , N-dimethylformamide, at a temperature of from about -10° C. to reflux, and for a time from about 30 minutes to about 48 hours. This reaction is optionally carried out in the presence of a suitable catalyst, for example, 4-dimethylaminopyridine, or in the presence an additional coupling agent such as N-hydroxybenzotriazole.

According to transformation 8, the reaction is carried out as described for transformation 3.

According to transformation 9, the reaction is carried out as described for transformation 4.

According to conversion 10, the conversion of the amide of formula (I) to the corresponding nitrile by reaction with a dehydrogenating agent such as trifluoroacetic anhydride used as a solvent at room temperature to reflux temperature for 1 to 4 hours.

According to transformation 11, the conversion of a compound of formula (I) to the corresponding methylsulfonyl compound of formula (I) is carried out using any of the cross-coupling reactions suitable for the formation of C-S bonds (Org. Lett, 2002, 4, pp 4423-4425). These reactions involve coupling with sodium methanesulfinate in the presence of CuI in a suitable solvent such as DMSO and the like at a temperature of 90°C to 130°C for 6-24 hours.

According to conversion method 12, the conversion of a compound of formula (I) to the corresponding hydroxy derivative of formula (I) is carried out by reaction with a Lewis acid such as BBr ₃ , AlCl ₃ or the like in a suitable solvent such as DCM at 0° C. for 1- 4 hours

According to method conversion 13, the reaction of a compound of formula (I) with a reagent of formula (XXIII) wherein X is bromine, iodine, -OMs or -OTs, can be carried out in the presence of a suitable base such as Na ₂ CO ₃ , K ₂ CO _{3 ;} Cs ₂ CO ₃ , NaH, KH and the like, in a suitable solvent such as DMF, DMA, ACN, acetone, THF and the like, at a temperature of 0° C. to reflux. If an intermediate of formula (XXIII) where X is hydroxy is used, the reaction is advantageously carried out under Mitsunobu alkylation conditions in the presence of a suitable reagent such as, for example, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate (DBAD) , 1,1'-(azodicarbonyl)dipiperidine (ADDP), and a phosphine reagent such as, for example, trimethylphosphine, tri-tert-butylphosphine, triphenylphosphine and the like, in a suitable solvent such as THF, DMF, DCM, toluene, benzene and the like, at temperatures from 0°C to 65°C.

According to transformation 14, the reaction is carried out as described for transformation 6.

According to transformation 15, the reaction is carried out as described for transformation 7.

From the foregoing, it will be clear to one skilled in the art that any compound of formula (I) bearing a functional group that can be further converted to another functional group by methods well known in the art, resulting in other compounds of formula

- 25 046117 (I), is included in the scope of the present invention.

When preparing compounds of general formula (I) according to any of the above process variations, optional functional groups in the starting materials, reagents and intermediates that may cause undesired side reactions must be carefully protected according to conventional methods (see, for example, Green, Theodora W. and Wuts, Peter G. M. - Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons Inc., New York (NY), 1999). Also, the transformation of the latter into free compounds without the protection removed can be carried out according to known methods.

Compounds of each general formula can be further converted into other compounds of the same general formula according to methods well known in the literature, as described in the experimental section.

In any embodiment of the process for preparing the compounds of formula (I), the starting materials and any other reagents are known or readily prepared by known methods.

The compounds of formula (III) can be prepared as described in WO 2014141104 A1 and WO 2017/019429.

Compounds of formula (IV), (V), (VIIIa), (IX), (IXa), (IXb), (XII), (XIII), (XIV), (XVIIa), (XVIIb) and (XVIII), either commercially available or can be prepared by known methods.

The final compounds can be isolated and purified using conventional techniques, for example, chromatography and/or crystallization and salt formation.

The compounds of general formula (I), as defined above, can be converted into pharmaceutically acceptable salts. The compounds of general formula (I) as defined above, or pharmaceutically acceptable salts thereof, can then be formulated with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition.

The synthesis of the compound of general formula (I), according to the synthetic methods described above, can be carried out stepwise, with each intermediate product being isolated and purified, if necessary, by standard purification methods, such as, for example, column chromatography, before carrying out the subsequent reaction. Alternatively, two or more steps of the synthesis sequence can be performed using a so-called one-pot procedure known in the art, whereby only the compound resulting from two or more steps is isolated and purified.

In cases where a compound of general formula (I) contains one or more asymmetric centers, the compound can be separated into individual stereoisomers using techniques known to those skilled in the art. Such techniques include standard chromatographic techniques, including chiral stationary phase chromatography, or crystallization. General methods for separating compounds containing one or more asymmetric centers are described, for example, in Jacques, Jean; Collet, Andre; Wilen, Samuel H., Enantiomers, Racemates, and Resolutions, John Wiley & Sons Inc., New York (NY), 1981.

The present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament with anticancer activity.

Furthermore, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament with anticancer activity, wherein the anticancer activity is caused by and/or associated with elevated levels of 2-hydroxyglutarate, mutated IDH enzymes or overfunctions IDH dt.

In the most preferred embodiment of the present invention, the cancer is selected from the group consisting of: carcinomas; hematopoietic tumors of the lymphoid cell line; hematopoietic tumors of the myeloid cell line; tumors of mesenchymal origin; tumors of the central and peripheral nervous system; melanoma; seminomas; teratocarcinomas; osteosarcomas; pigment xeroderma; keratoxanthomas; thyroid cancer; Kaposi's sarcoma; chondrosarcomas and cholangiocarcinomas.

The present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, for use in a method of treating a mammal in need thereof in combination with a chemotherapy regimen.

In one embodiment, the chemotherapy regimen includes at least one cytostatic or cytotoxic agent.

Cytostatic or cytotoxic agents include, but are not limited to, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g., COX-2 inhibitors), matrix metalloprotease inhibitors, telomerase inhibitors, tyrosine kinases, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents (eg, angiogenesis inhibitors), farnesyltransferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, other cdk inhibitors, tubulin-binding agents,

- 26 046117 topoisomerase I inhibitors, topoisomerase II inhibitors, aromatase inhibitors, kinesin inhibitors, therapeutic monoclonal antibodies, mTOR inhibitors, histone deacetylase inhibitors, hypoxic response inhibitors, PD-1 antagonists or an antigen-binding fragment thereof that specifically binds to PD-1 or PD-1 L1.

When formulated as a fixed dose, such combination products use the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within the approved dosage range.

The compounds of formula (I) can be used sequentially with known anticancer agents if the combination formulation is not suitable.

The compounds of formula (I) of the present invention suitable for administration to a mammal, eg a human, can be administered by conventional routes and the dosage level depends on the age, weight and condition of the patient and the route of administration.

For example, a suitable dose taken for oral administration of a compound of formula (I) may range from about 10 to about 1000 mg per dose 1 to 5 times daily. The compounds of the invention can be administered in various dosage forms, for example, orally, in the form of tablets, capsules, sugar-coated or film-coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, for example, intramuscularly or by intravenous and/or intrathecal and/or intraspinal injection or infusion.

Pharmaceutical compositions containing the compounds of the present invention are usually prepared by conventional methods and administered in a suitable pharmaceutical form.

For example, solid oral forms may contain, together with the active compound, diluents such as lactose, dextrose, sucrose, sucrose, cellulose, corn starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; binding agents, for example starches, gum acacia, methylcellulose gelatin, carboxymethylcellulose or polyvinylpyrrolidone; disintegrants, such as starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; dyes; sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfates; and generally non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. These pharmaceutical compositions can be produced in a known manner, for example by mixing, granulating, tableting, sugar coating or film coating.

Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions.

By way of example, syrups may contain, as a carrier, sucrose or sucrose with glycerol and/or mannitol and sorbitol.

Suspensions and emulsions may contain, as examples of carriers, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

Suspensions or solutions for intramuscular injection may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, sterile water, olive oil, ethyl oleate, glycols, for example propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.

Solutions for intravenous injection or infusion may contain, as a carrier, sterile water or, preferably, they may be in the form of sterile, aqueous, isotonic, saline solutions or may contain propylene glycol as a carrier.

The suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, for example cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

The present invention also provides a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, and at least one pharmaceutically acceptable excipient, carrier or diluent.

The present invention also provides a pharmaceutical composition of a compound of formula (I), further containing one or more chemotherapeutic agents. Chemotherapeutic agents include, but are not limited to, cytostatic or cytotoxic agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (eg, COX-2 inhibitors), matrix metalloprotease inhibitors, telomerase, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents (eg, angiogenesis inhibitors), farnesyltransferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, other cdk inhibitors, tubulin-binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, aromatase inhibitors, kinesin inhibitors, therapeutic monoclonal antibodies, mTOR inhibitors, histone deacetylase inhibitors,

- 27 046117 hypoxic response inhibitors, PD-1 antagonists or an antigen-binding fragment thereof that specifically binds to PD-1 or PD-L1.

The invention further provides an in vitro method of inhibiting the activity of a mutated IDH protein which comprises contacting said protein with an effective amount of a compound of formula (I) as defined above.

Additionally, the invention provides a kit containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, and one or more chemotherapeutic agents, in the form of a combination preparation for simultaneous, separate or sequential use in anticancer therapy.

experimental part

The short forms and abbreviations used herein have the following meaning:

G gram mg milligram ml milliliter µl microliter mm millimolar mmol millimoles µM micromolar MHz Megahertz h watch) Hz Hertz mm millimeters min minutes MKM micron M molar ABS bovine serum albumin dtt dithiothreitol NADPH Nicotinamide adenine By Hold Time dinucleotide phosphate 2-HG 2-Hydroxyglutaric acid KOtBu /7?rs/77-potassium butoxide CT room temperature TEA triethylamine DMAR 4-dimethylaminopyridine DME 1,2-dimethoxyethane TFC Trifluoroacetic acid _{Na2SO4 ​} Sodium sulfate AcOH Acetic acid PEER Electrospray ionization Na ₂ CO ₃ Sodium carbonate to ₂ from ₃ potassium carbonate _{Cs2CO3 ​} Cesium carbonate K ₃ RO ₄ potassium phosphate LiOH lithium hydroxide NaOH sodium hydroxide CON potassium hydroxide /?-TsOH p-toluenesulfonic acid EtOAc ethyl acetate LiHMD lithium bis(trimethylsilyl)amide S NMP X-methyl-2-pyrrolidone NaH sodium hydride DMA N,N-dimethyl acetamide KH potassium hydride DMF N,N-dimethylformamide DXM dichloromethane DIPEA N, X-diisopropyl-M-ethylamine hex hexane THF tetrahydrofuran DMSO Dimethyl sulfoxide MeOH methanol ACN acetonitrile EtOH ethanol Bn benzyl -OMs mesylate -OTs tosylate GOBT N-hydroxybenzotriazole DCC 1,3-Dicyclohexylcarbo diimide NMR Nuclear magnetic resonance M.C. Mass spectroscopy m/z mass to charge ratio LC Liquid chromatography

MgCI ₂ Magnesium Chloride

EDC1 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

TBTU tetrafluoroborate N, I, N, N-tetramethyl-O-(benzotriazol-1 -yl)uronium

RP-HPLC Reverse phase high performance liquid chromatography

Biochemical analysis

In Vitro Assays for IDH2 Inhibitors (R132H or R132C) and IDH2 ^K72K

The activity of the mutated IDH enzyme to convert alpha-ketoglutarate to 2hydroxyglutaric acid is measured using a NADPH depletion assay. In the assay, the remaining cofactor is measured at the end of the reaction with the addition of catalytic excess diaphorase and resase

- 28 046117 rin, to create a fluorescent signal proportional to the amount of NADPH remaining. The enzyme IDH1 DT, as well as mutated isoforms of the enzymes IDH1 ^I132H , IDH1 ^w32S and IDH2 ^E172K , are commercially available proteins (see, for example, Sino Biological, Abcam, Active Motif or Creative BioMart).

The IDH1 homodimer enzyme ^I132H is diluted to 8 nM in 10 μl of analytical buffer (150 mM NaCl, 50 mM Tris-HCl pH 7.6, 10 mM MgCl ₂ , 0.001% Triton X-100, 4 mM p-mercaptoethanol); add 0.2 μl of test compound, previously serially diluted 1 to 3, >10 experimental points from 1 mM in DMSO, and the mixture is incubated for 15 min at room temperature. The reaction is started by adding 10 μl of substrate mixture (12 μM NADPH, 3.4 mM alpha-ketoglutarate in assay buffer) and the mixture is incubated for 60 min at room temperature. The reaction is completed by adding 5 μl of detection buffer (100 μg/ml diaphorase, 30 μM resasurin, in assay buffer IX) and incubated for 15 min before reading on a ViewLux plate reader at Ex544/Esh590.

Compounds were assayed for activity against IDH1 ^m32C using the same assay as above with the following modifications: final concentrations of IDH1 ^m32C and alpha-ketoglutarate in the assay buffer were 2 nM and 0.14 mM, respectively.

Compounds were assayed for activity against IDH2 ^1<G21k using the same assay as above with the following modifications: final concentrations of IDH2 ^I72K and alpha-ketoglutarate in the assay buffer were 16 NM and 0.55 mM, respectively.

Enzyme assay for wild type (WT) IDH1

The activity of IDH1DT to convert isocitric acid to alpha-ketoglutarate is measured using a NADPH production assay. In the assay, the forming cofactor is measured continuously with the addition of catalytic excess diaphorase and resasurin to generate a fluorescent signal proportional to the amount of NADPH formed.

The compounds are pre-incubated with the enzyme, then the reaction is started by adding NADP+, isocitrate, diaphorase and the appropriate substrate, resazurin. Diaphorase reduces resazurin to the highly fluorescent resorufin with concomitant oxidation of NADPH to NADP. More specifically, 0.2 μl of the test compound, previously serially diluted 1 to 3, 10 experimental points from 1 mM in DMSO, is added to 0.016 NM IDH1DT enzyme in 10 μl of assay buffer (150 mM NaCl, 50 mM Tris-HCl pH 7, 6, 10 mM MgCl2, 0.001% Triton X-100, 4 mM βmercaptoethanol); the mixture is incubated for 15 minutes at room temperature. The reaction is started by adding 10 μl of substrate mixture (400 μM NADP+, 40 μM isocitrate, 5 μg/ml diaphorase and 7 μM resazurin in assay buffer), the mixture is incubated at room temperature, and the reaction is read on a ViewLux plate reader at Ex544/Em590 continuously.

Biochemical activity

The biochemical activity against the IDH1 ^I132N , IDH1 ^sh32S and IDH2 ^Sh72K mutants of standard compounds, which was determined in the above-described analyses, is presented in table. 1 as IC ₅₀ values (μM), and the biochemical activity against the wild-type IDH1 enzyme, determined according to the above-described assays, is presented in table. 2 as IC ₅₀ values (µM).

Table 1

No. Connection IDH1 ^K132N 1S50(µM) IDH1 ^K132S 1S50(µM) IDG2 ^Ya172K 1S50(µM) 1 1.829 0.622 5 1.128 0.45 6 3.335 1.336 6,645 7 2,963 1.41 8 2.436 1.385 9 1.53 0.604 10 3.852 1.923 AND 0.362 0.181 6.1 12 3.481 1.775 5.02 14 1,742 0.85 5,733 16 1.003 0.46 2,696 17 4,907 1,893 18 4.07 1.551 19 0.41 0.203 6.68 20 0.74 0.332 5.02 21 2,491 0.586

- 29 046117

22 0.451 0.195 2,986 23 2,088 0.891 3,494 24 3.527 1.722 2.96 25 1,943 0.524 26 2,361 1.257 2,204 27 1,071 0.336 2,595 28 1.476 0.59 2,514 thirty 1,343 0.406 2,523 31 0.323 0.147 2.2 32 3,769 1.151 33 0.461 0.19 34 0.219 0.135 3.35 35 0.211 0,>106 5,053 36 0.178 0,>105 6,543 37 1.481 0.805 4,847 38 0.137 0.067 7.51 40 0.16 0.071 41 2,464 1,408 42 1,383 0.951 43 1.642 1.047 44 1.09 0.811 45 0.554 0.206 47 1.811 0.597 49 0.118 0.067 4.355 50 0.068 0.038 2,509 52 1.758 0.786 53 0.941 0.529 55 0.137 0.065 57 0.543 0.208 60 0.341 0.139 61 0.071 0.038 5,023 62 0.082 0.044 5.7 63 0.29 0.123

- 30 046117

64 0.21 0.133 65 0.02 0.011 66 0.161 0.094 4.537 67 0.037 0.015 7.36 68 0.078 0.029 69 0.036 0.022 70 0.478 0.177 71 2,479 0.964 4.833 72 2,589 1.236 75 0.407 0.431 76 2.38 3.635 77 0.207 0.209 78 0.896 1.381 79 0.529 0.357 80 0.444 0.282 81 0.288 0.172 82 0.146 0.134 83 0.347 0.196 4,261 84 0.19 0.15 85 1,767 1.462 88 0.138 0.097 89 0.112 0.075 90 0.697 0.391 92 0.713 0.715 94 0.071 0.03 5,568 95 0.425 0.162 5.156 96 0.801 0.42 5.02 97 0.524 0.323 5.03 98 0.366 0.217 5,344 99 0.201 0.132 3.626 100 3,064 1,595 101 0.575 0.271 2,667 102 4.325 2,803

- 31 046117

103 1,593 0.634 104 0.276 0.121 5.132 105 0.105 0.055 4,727 106 1.227 0.667 2.91 107 0.722 0.459 108 0.459 0.307 109 0.334 0.218 5.681 BY 0.238 0.104 111 4,038 1.423 112 0.19 0.178 113 0.367 0.282 5,508 114 2,371 1,913 115 0.672 0.825 116 0.176 0.101 5.02 117 0.055 0.029 5,509 118 1,296 0.923 119 2.232 1.164 120 0.221 0.108 121 3,904 1.635 122 0.717 0.386 129 0.197 0.098 6.68 130 0.18 0.093 5.03 131 0.284 0.17 132 0.194 0.124 6,114 133 0.218 0.141 5,051 134 0.152 0.061 6.115 135 0.4 0.202 136 0.122 0.054 137 3,468 1,299 138 2,258 0.777 139 0.042 0.021 0.264 140 0.249 0.115 3.226 141 0.038 0.031 0.213

- 32 046117

142 0.176 0.214 0.552 143 0.236 0.066 144 0.078 0.025 145 3,561 1.322 146 0.059 0.016 1.417 147 0.473 0.173 148 0.187 0.109 5.828 149 0.085 0.048 3.326 150 0.02 0.008 151 0.095 0.02 152 0.158 0.065 5.617 153 0.226 0.041 154 0.199 0.079 5,383 155 0.455 0.147 156 0.139 0.091 0.476 157 0.162 0.051 158 0.126 0.04 159 0.077 0.037 0.51 160 0.068 0.031 161 0.022 0.013 0.299 162 0.084 0.03 163 0.163 0.087 6.6 164 0.759 0.406 165 0.157 0.085 5,663 166 0.179 0.093 7,569 167 0.03 0.023 2,562 168 0.029 0.016 0.137 169 0.193 0.179 0.414 170 0.167 0.09 3.111 171 0.169 0.055 172 0.179 0.056 3,586 173 0.575 0.144 174 0.042 0.032

- 33 046117

175 0.065 0.066 0.442 176 3.51 1,909 177 0.978 0.401 178 0.046 0.03 5.02 179 0.123 0.063 2.355 180 999 3,541 181 0.175 0.351 0.878 182 0.103 0.061 183 0.052 0.039 184 0.126 0.227 0.201 185 2,373 1.271 186 0.392 0.811 0.431 187 0.002 0.002 0.018 188 0.33 0.12 189 3,769 0.811 190 1.938 3,598 0.679 191 0.07 0.116 0.902 192 0.227 0.252 0.645 193 0.126 0.089 194 0.338 0.2 1,791 195 0.593 0.184 196 0.955 0.141 197 2,343 0.405 198 0.132 0.401 0.248 199 1.403 1.529 0.717 201 0.42 0.173 202 0.666 0.104 206 0.013 0.015 0.098 207 0.624 208 0.213 209 0.046 210 0.183 211 0.525

- 34 046117

212 0.061 214 0.004 0.002 0.015 215 0.004 216 0.001 217 0.015 218 0.013 219 0.001 0.001 0.006 220 0.001 0.001 0.015 221 0.068 222 0.147 223 1.673 224 1,697 227 0.007 0.005 0.049 228 0.002 0.002 0.025 229 0.083 0.044 0.386 230 0.001 0.001 0.011 231 0.001 0.001 0.014 232 0.330 235 0.128 0.048 5.11 236 0.105 237 0.004 0.004 0.027 238 0.004 0.004 0.025 239 0.002 0.002 0.020 240 0.068 241 0.272 0.196 0.146 242 0.010 243 0.020 244 0.002 0.003 0.021 245 0.002 0.002 0.020 246 0.002 0.001 0.019 247 0.005 0.004 0.035 248 0.004 0.002 0.030 249 0.005 0.003 0.033 251 0.002

- 35 046117

Cellular assay for IDH m inhibitors

Colonies of HT-1080 (commercially available) and 87-MG-^H,ri ^R132H cells (obtained similarly to the method described in J. Mol. Neurosci 2013, 50, 165-71) are maintained in E-MEM 10% FBS and incubated at 37°C in a humidified atmosphere of 5% CO ₂ . Stably transfected U87-MG cell colonies were also supplemented with 500 μg/ml G418.

Cells are seeded into 96-well black flat-bottom plates at a density of 500 cells/well in 100 μl of complete medium. After 24 h, the medium is replaced with 200 μl of fresh medium, and compounds (dissolved in DMSO) are introduced into the cells using a D300E digital pipette (Tecan).

After 72 hours of incubation, 100 µl from each well is collected and used for 2HG(-)-2-hydroxyglutarate quantification).

- 36 046117

Levels of 2-HG in cell culture medium were determined by LC-MS/MS. Cell supernatants (100 μl/well) were treated with 1 M aqueous trichloroacetic acid containing 130 μM internal standard 2-HG-d3 (20 μl/well) in a 96-well plate. The plates are sealed, shaken moderately for 60 minutes, centrifuged at 4000 rpm for 15 minutes, placed in a cooled autopipettor, being careful not to shake them, and aliquots of the top of the samples are injected directly into the chromatography system. Calibration standards are prepared by tenfold dilution of aqueous 2-HG stock solutions with cell culture blank and denatured in the same manner as described above for the samples. Samples and standards were analyzed for 2-HG by reverse phase chromatography on a C18 column, eluting with aqueous 0.15% formic acid, and quickly washed with 90% methanol at the end of the run. 2-HG is determined by negative ion electrospray ionization using the internal standard method on a triple quadrupole mass spectrometer, monitoring the MRM transitions 147>129 (2-HG) and 150>132(2-HG-d3).

2-HG inhibition was calculated by comparing treated and control data using Assay Explore (Symyx) where the IC50 was determined using a sigmoidal fitting algorithm.

In table 3 and 4 present the IC ₅₀ values (μM) of typical compounds for inhibiting the formation of 2HG in two colonies of cells and 87MG_^3T1 R132H and HT-1080 (IDGA^X determined according to the above analysis.

- 37 046117

141 0.024 150 0.127 151 0.321 156 0.289 159 0.081 170 0.637 175 0.021 219 0.0004 220 0.0005 227 0.0004 228 0.0006 229 0.013 230 0.0004 237 0.0010

Table 4

No. Connection HT1080 2-HGIC50 (µM) 49 0.307 62 0.169 65 0.082 66 0.353 67 0.067 68 0.315 89 0.505 94 0.203 105 0.116 110 0.590 116 0.311 117 0.155 139 0.022 140 0.108 142 0.075 143 0.517 170 0.442 183 0.021 184 0.028 187 <0.001 191 0.040 206 0.0101 209 0.0302 212 0.0531 214 0.0021 215 0.0023 216 0.0011 217 0.0082 218 0.0021 219 0.0004 220 0.0003 221 0.1424 222 0.1680

- 38 046117

224 1.0668 227 0.0014 228 0.0008 229 0.0200 230 0.0004 231 0.0003 237 0.0004 238 0.0009 239 0.0009 241 0.0647 242 0.0045 243 0.038 244 0.0016 245 0.0010 246 0.0021 247 0.0030 248 0.0031 249 0.0029 251 0.0023

Typical compounds of the invention when tested in colonies of cells having mutated forms of IDH1, as shown in table. 3 and 4 showed dose-dependent inhibition of cellular 2-HG formation with potency lower than 5 µM. As expected, the compounds showed any effect on cell proliferation even at the highest dose (10 μM).

Preparation of compounds of formula (i)

For reference to any specific compound of formula (I) of the invention, optionally in the form of a pharmaceutically acceptable salt, see the experimental section and the claims. Referring to the following examples, the compounds of the present invention were synthesized using the methods described herein or other methods that are well known in the art.

To better illustrate the present invention, without limiting it, the following examples are given.

The symbols and conventions used herein in the methods, diagrams, and examples correspond to those used in contemporary scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry.

Compound names are IUPAC names created using ACD Name (from Advanced Chemistry Development, Inc.).

Unless otherwise stated, all materials, including anhydrous solvent such as DMF, THF, DCM, were obtained from commercial suppliers of the best quality and used without further purification. All reactions involving air- or moisture-sensitive compounds were carried out under nitrogen or argon atmosphere.

General purification and analysis methods

Flash chromatography is carried out on silica gel (Merck grade 9395, 60A).

The HPLC equipment consists of a Waters Alliance™ HT 2795 system equipped with a Waters 996 PDA detector and a Waters Model ZQ 2000 single quadrupole mass spectrometer equipped with an electrospray ion source (ESI). Instrumental control, data collection and data processing are carried out by Empower 2 and MassLynx 4.1 programs.

HPLC was carried out at 25°C with a flow rate of 1.2 ml/min using a YMC-triart C ₁₈ column (4.6x50 mM, 3 μm). Mobile phase B is 5 mM ammonium acetate buffer pH=5.2 with acetonitrile (95:5), and mobile phase C is H ₂ O/acetonitrile (5:95); the gradient is from 10 to 90% C in 5 min, then changes to 100% C in 0.1 min. The injection volume is 10 µl. The mass spectrometer operates in positive and negative ionization modes, the capillary voltage is set to 3.5 kV (ER ⁺ ) and 2.8 kV (ER ^- ); the voltage on the cone is 14 V (ER ⁺ ) and 28 V (ER ^- ); source temperature is 120°C; set a full scan, mass mileage from 100 to 800 a.m.u.

The preparative HPLC equipment consists of a Shimadzu HPLC system equipped with an SCL-8A system controller, two LC-8A pumps, an SPD6A UV spectrophotometric detector, and a Rheodyne manual injection system. Data acquisition (similar signal) and data processing about

- 39 046117 run using the Empower 2 program. Purification is carried out at 25°C with a flow rate of 15 ml/min using a Waters X-Terra MS RP18 column (150x30 mM, 10 μM). Mobile phase A is 0.1% TFA in water/acetonitrile (95:5) or alternatively, mobile phase A is 0.05% NH ₃ in water/acetonitrile (95:5) and mobile phase B is H ₂ O/acetonitrile (5:95); the gradient is from 10 to 90% B in 15 min, then changes to 100% B in 0.1 min. Injection volume max 500 µl.

The Ή-NMR spectrum was recorded at a constant temperature of 28°C on a Varian INOVA 400 spectrometer operating at 400.5 MHz and equipped with a 5 mM ¹ H{ ¹⁵ N- ³¹ P} z-axis indirect PFG detector probe, and on a Varian INOVA 500 spectrometer , operating at 499.7 MHz and equipped with a 5 mM 1H{ ¹³ N- ¹⁵ P} triple resonant indirect detector probe. Chemical shifts are calculated relative to the residual solvent signals (DMSO-dg: 2.50 ppm for ¹ H). The data is recorded as follows: chemical shift (5), multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, ws=broad singlet, dd=doublet of doublets, ddd=doublet of doublets of doublets, m=multiplet), interaction constants (J, Hz) and number of protons.

As described previously (M. Colombo, F. R. Sirtori, V. Rizzo, Rapid Commun Mass Spectrom 2004, 18(4), 511-517), a high-resolution ESI(+) mass spectrum (HRMS) was obtained on a Q-Tof mass spectrometer Ultima (Waters, Manchester, UK) directly coupled to an Agilent 1100 micro-HPLC system (Palo Alto, US).

Receipt 1.

Step 1: 4-(2,2-dimethylpropylamino)-2-methylsulfanylpyrimidine-5-carboxylic acid ethyl ester [(VI), I2=2,2-dimethylpropyl, R3=H] step 2a

4-Chloro-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester (2.0 g, 8.59 mmol) was dissolved in THF (20.0 ml), triethylamine (1.8 ml, 12.89 mmol) was added ) and neopentylamine (1.1 ml, 9.45 mmol) and stir for 1 hour at reflux. The precipitated salts are filtered and the solvent is evaporated under reduced pressure. The resulting oil is dissolved in Et ₂ O, washed with sodium water and then dried over Na ₂ SO ₄ . The salts are filtered and the solvent is evaporated in vacuo to give the product (1.50 g, 62% yield), which is transferred without further purification.

1H NMR (500 MHz, DMSO^) δ=8.55 (s, 1H), 8.39 (t, J=5.9 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H ), 3.38 (d, J=6.1 Hz, 2H), 2.47 (s, 3 N), 1.30 (t, J=7.1 Hz, 3 N), 0.93 (s , 9 N). LCMS: m/z 284 [M+H]+ @ w.u. 7.86 min. MSVR (IER) calc. for C13H21N3O2S [M+H]+ 284.1427 found 284.1429.

According to the same method, but using 1-amino-2-methylpropan-2-ol, the following compounds are obtained:

4-(2-hydroxy-2-methylpropylamino)-2-methylsulfanylpyrimidine-5-carboxylic acid ethyl ester [(VI), K2=2-hydroxy-2-methylpropylamino, R3=H]

The title compound is obtained as a colorless oil (64% yield);

1H NMR (500 MHz, DMSO^) δ=8.55 (s, 1H), 8.48 (t, J=5.3 Hz, 1H), 4.76 (s, 1H), 4.28 (q , J=7.0 Hz, 2H), 3.45 (d, J=5.5 Hz, 2H), 2.47 (s, 3H), 1.30 (t, J=7.1 Hz, 3H ), 1.13 (s, 6H). LCMS: m/z 286 [M+H]+ @ w.u. 5.64 min. MSVR (IER) calc. for C ₁₂ H ₁₉ N ₃ O ₃ S [M+H]+ 286.1220 found 286.1225;

Ethyl 4-{[(2S)-3-methylbutan-2-yl]amino}-2-(methylsulfanyl)pyrimidin-5-carboxylate [(VI), R2=(2S)-3-methylbutan-2-yl, R3 =H]

The title compound is obtained as a colorless oil (71% yield);

1H NMR (500 MHz, DMSO^ ₆ ) δ=8.55 (s, 1H), 8.20 (d, J=8.39 Hz, 1H), 4.28 (dq, J=1.14, 7 .09 Hz, 2H), 4.18 (dkvd>5.11,6.76, 8.30 Hz, 1H), 2.47 (s, 3H), 1.79-1.92 (m, 1H) , 1.30 (t, J=7.09 Hz, 3H), 1.14 (d, J=6.71 Hz, 3H), 0.91 (d, J=6.86 Hz, 3H), 0 .89 (d, J=6.71 Hz, 3H). LCMS: m/z 284 [M+H]+ @ w.u. 7.89 min. MSVR (IER) calc. for C^H^OzS [M+H]+ 284.1427 found 284.1430;

Ethyl 4-{[(2S)-3,3-dimethylbutan-2-yl]amino}-2-(methylsulfanyl)pyrimidin-5-carboxylate [(VI), R2=(2S)-3-methylbutan-2-yl , R3=H]

- 40 046117

Chiral

N NH

The title compound is obtained as a light yellow oil (56% yield);

1H NMR (500 MHz, DMSO-06) δ=8.55 (s, 1H), 8.32 (d, J=9.00 Hz, 1H), 4.23-4.34 (m, 2H), 4.19 (kvd, J=6.77, 9.13 Hz, 1H), 2.47 (s, 3H), 1.30 (t, J=7.09 Hz, 3H), 1.11 (d , J=6.86 Hz, 3H), 0.92 (s, 9H). LCMS: m/z 298 [M+H]+ @ w.u. 8.14 min. MSVR (IER) calc. for C ₁₄ H ₂₄ N ₃ O ₂ S [M+H]+ 298.1584 found 298.1583.

Ethyl 2-(methylsulfanyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]amino}pyrimidine-5-carboxylate

[(VI), I2=DO)-3-methylbutan-2-yl, R3=H]

O Chiral

S Ν ΝΗ

The title compound is obtained as a light yellow oil (56% yield).

1H NMR (500 MHz, DMSOHO δ=8.66 (s, 1H), 8.35 (d, J=9.00 Hz, 1H), 5.17-5.36 (m, J=7.27, 8.75 Hz, 1H), 4.31 (kv, J=7.02 Hz, 2H), 1.41 (d, J=7.02 Hz, 3H), 1.31 (t, J=7, 09 Hz, 3H) LCMS: m/z 310 [M+H]+ @ v.a. 7.22 min HRMS (ESI) calculated for C _n H ₁₅ F ₃ N ₃ O ₂ S [M+H ]+ 310.0832 found 310.0832.

6-chloro-4-(2,2-dimethylpropylamino)nicotinic acid ethyl ester [(VIa), R2=2,2dimethylpropyl, X=CH]

1H NMR (DMSO-06) δ=8.53 (s, 1H), 8.25 (t, J=5.6 Hz, 1H), 6.92 (s, 1H), 4.31 (sq, J =7.2 Hz, 2H), 3.09 (d, J=5.6 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 0.95 (s, 9H). LCMS: m/z 271 [M+H]+ @ w.u. 7.55 min.

MSVR (IER) calc. for С1зН ₂ оСШ ₂ 0 ₂ [M+H]+ 271.1208 found 271.1208.

6-chloro-4-ethylaminonicotinic acid ethyl ester [(VIa), I2=ethyl, X=CH]

The title compound is obtained as a light yellow oil (80% yield).

1H NMR (DMSO-06) δ 8.52 (s, 1H), 8.05 (t, J=5.2 Hz, 1H), 6.80 (s, 1H), 4.29 (q, J= 7.2 Hz, 2H), 3.253.32 (m, 2H), 1.31 (t, J=7.1 Hz, 3H), 1.17 (t, J=7.2 Hz, 3H). LCMS: m/z 229 [M+H]+ @ w.u. 6.27 min.

MSVR (IER) calc. for C ₁₀ H ₁₄ ClN ₂ O ₂ [M+H]+ 229.0739 found 229.0745.

6-chloro-4-isopropylaminonicotinic acid ethyl ester [(VIa), I2=propan-2-yl, X=CH]

1H NMR (DMSO-06) δ=8.53 (s, 1H), 7.98 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 4.29 (sq, J =7.1 Hz, 2H), 3.803.93 (m, 1H), 1.31 (t, J=7.1 Hz, 3H), 1.19 (d, J=6.4 Hz, 6H). LCMS: m/z 243 [M+H]+ @ w.u. 6.72 min.

MSVR (IER) calc. for CnH ₁₆ ClN ₂ O ₂ [M+H]+ 243.0895 found 243.0901.

Preparation 2. [4-(2,2-Dimethylpropylamino)-2-methylsulfanylpyrimidin-5-yl]methanol [(VII), I2=2,2-dimethylpropyl, R3=H]

Stage 2b.

LiAlH ₄ (11.1 ml, 10.58 mmol, 4% in THF) was added to a solution of 4-(2,2dimethylpropylamino)-2-methylsulfanylpyrimidine-5-carboxylic acid ethyl ester (1.5 g, 5.29 mmol) in THF (15 ml) at ~5°C for more than 15 minutes. After stirring for 1 hour, add ice water (0.40 ml) and 15% aqueous NaOH (0.40 ml), then add more ice water (1.2 ml). After 30 minutes

- 41 046117 the quenched reaction mixture is filtered and the filter cake is washed with AcOEt. The combined organic washes are dried over Na ₂ SO ₄ and filtered. The solvent was evaporated in vacuo to give the product (1.25 g, 98% yield) which was used without further purification.

1H NMR (500 MHz, DMSO-06) δ=7.80 (s, 1H), 6.61 (t, J=6.0 Hz, 1H), 5.27 (t, J=5.3 Hz, 1H), 4.36 (d, J=5.0 Hz, 2H), 3.28 (d, J=6.3 Hz, 2H), 2.40 (s, 3H), 0.89 (s , 9 N). LCMS: m/z 242 [M+H] ⁺ @ w.u. 5.64 min. MSVR (IER) calc. for C11H19N3OS [M+H] ⁺ 242.1322 found 242.1319.

The following compound is prepared in essentially the same manner:

1-(5-Hydroxymethyl-2-methylsulfanylpyrimidin-4-ylamino)-2-methylpropan-2-ol [(VII), R2=methylpropan-2-ol, R3=H]

The title compound is obtained as a white solid (77% yield);

1H NMR (500 MHz, DMSO-06) δ=7.81 (s, 1H), 6.61 (t, J=5.7 Hz, 1H), 5.27 (t, J=5.2 Hz, 1H), 4.66 (s, 1H), 4.36 (d, J=5.2 Hz, 2H), 3.36 (d, J=5.8 Hz, 2H), 2.40 (s, 3H), 1.11 (s, 6H). LCMS: m/z 244 [M+H] ⁺ @ w.u. 3.83 min. MSVR (IER) calc. for C10H17N3O2S [M+H] ⁺ 244.1114 found 244.1111;

[4-{[(2S)-3-Methylbutan-2-yl]amino}-2-(methylsulfanyl)pyrimidin-5-yl]methanol [(VII), R2=(2S)3-methylbutan-2-yl, R3=H]

The title compound is obtained as a colorless oil (65% yield);

1H NMR (500 MHz, DMSO-06) δ=7.79 (s, 1H), 6.37 (d, J=8.08 Hz, 1H), 5.21 (t, J=5.49 Hz, 1H), 4.33 (d, J=5.49 Hz, 2H), 4.00-4.11 (m, 1H), 2.40 (s, 3H), 1.82 (kvd, J=6 .71, 13.27 Hz, 1H), 1.10 (d, J=6.71 Hz, 3H), 0.88 (d, J=6.71 Hz, 3H), 0.87 (d, J =6.86 Hz, 3H). LCMS: m/z 242 [M+H] ⁺ @ w.u. 5.63 min. MSVR (IER) calc. for C11H20N3OS [M+H] ⁺ 242.1322 found 242.1320;

[4- {[(2S)-3,3-Dimethylbutan-2-yl]αmino} -2-(methylsulfanyl)pyrimidin-5 -yl]methanol [(VII), R2=(2S)3,3-dimethylbutan- 2-yl, R3=H]

The title compound is obtained as a colorless oil (65% yield);

1H NMR (500 MHz, DMSO-06) δ=7.79 (s, 1H), 6.28 (d, J=9.00 Hz, 1H), 5.35 (t, J=5.26 Hz, 1H), 4.32-4.42 (m, 2H), 4.16 (kvd, J=6.84, 9.07 Hz, 1H), 2.40 (s, 3H), 1.08 (d , J=6.71 Hz, 3H), 0.90 (s, 9H). LCMS: m/z 256 [M+H] ⁺ @ w.u. 6.0 min. MSVR (IER) calc. for C ₁₂ H ₂₂ N ₃ OS [M+H] ⁺ 256.1478 found 256.1475;

[2-(methylsulfanyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]amino}pyrimidin-5-yl]methanol [(VII), R2=(2S)-1,1 ,1-trifluoropropan-2-yl, R3=H]

The title compound is obtained as a colorless oil (60% yield). LCMS: m/z 268 [M+H]+ @ w.u. 5.45 min. (6-chloro-4-ethylaminopyridin-3-yl)methanol [(VIIa), R2=ethyl, X=CH]

1H NMR (DMSO-06) δ=7.77 (s, 1H), 6.49 (s, 1H), 6.11 (t, J=5.1 Hz, 1H), 5.18 (t, J =5.4 Hz, 1H), 4.37 (d, J=5.3 Hz, 2H), 3.17 (kvd, J=7.1, 5.7 Hz, 2H), 1.15 (t , J=7.2 Hz, 3H). LCMS: m/z 187 [M+H] ⁺ @ w.u. 4.06 min.

MSVR (IER) calc. for C ₈ H ₁₂ N ₂ OCl [M+H] ⁺ 187.0633, 187.0638 was found.

(6-Chloro-4-isopropylaminopyridin-3-yl)methanol [(VIIa), 112=propan-2-yl, X=CH]

1H NMR (DMSOA) δ=7.76 (s, 1H), 6.53 (s, 1H), 5.81 (d, J=7.8 Hz, 1H), 5.24 (t, J=5 .4 Hz, 1H), 4.38 (d, J=5.2 Hz, 2H), 3.65-3.77 (m, 1H), 1.16 (d, J=6.4 Hz, 6H ). LCMS: m/z 201 [M+H] ⁺ @ w.u. 2.74 min.

MSVR (IER) calc. for C ₉ H ₁₄ ClN ₂ O [M+H] ⁺ 201.0789 found 201.0787.

- 42 046117

[6-Chloro-4-(2,2-dimethylpropylamino)pyridin-3-yl]methanol [(VIIa), k2=2,2-dimethylpropylpropyl, X=CH]

1H NMR (DMSO-de) δ=7.73 (s, 1H), 6.62 (s, 1H), 6.08 (t, J=5.9 Hz, 1H), 5.40 (t, J =5.3 Hz, 1H), 4.45 (d, J=5.2 Hz, 2H), 2.98 (d, J=5.9 Hz, 2H), 0.93 (s, 9H). LCMS: m/z 229 [M+H]+ @ w.u. 5.59 min.

MSVR (IER) calc. for C ₁₁ H ₁₈ ClN ₂ O [M+H]+ 229.1102 found 229.1105.

Receipt 3.

4-(2,2-Dimethylpropylamino)-2-methylsulfanylpyrimidine-5-carbaldehyde [(VIII), I2=2,2-dimethylpropyl, R3=H]

Stage 2c.

[4-(2,2-Dimethylpropylamino)-2-methylsulfanylpyrimidin-5-yl]methanol (1.25 g, 5.17 mmol) was dissolved in DCM (30 ml), MnO ₂ (3.15 g, 36 .19 mmol). The resulting suspension is stirred overnight. Solids are removed by filtration through a pad of celite, which is washed with additional DCM. The solvent was evaporated in vacuo to give the product (1.17 g, 95% yield).

1H NMR (500 MHz, DMSO-06) δ=9.77 (s, 1H), 8.78 (t, J=5.6 Hz, 1H), 8.54 (s, 1H), 3.40 ( d, J=6.3 Hz, 2H), 2.50 (s, 3H), 0.92 (s, 9H). LCMS: m/z 240 [M+H]+ @ w.u. 6.74 min.

MSVR (IER) calc. for C _n H ₁₇ N ₃ OS [M+H]+ 240.1165 found 240.1166.

According to the same method, the following compounds are obtained:

4-(2-Hydroxy-2-methylpropylamino)-2-methylsulfanylpyrimidine-5-carbaldehyde [(VIII), R2=2Hydroxy-2-methylpropyl, R3=H]

The title compound was obtained in quantitative yield;

1H NMR (500 MHz, DMSO-de) δ=9.76 (s, 1H), 8.84 (t, J=5.3 Hz, 1H), 8.54 (s, 1H), 4.79 ( s, 1H), 3.47 (d, J=5.6 Hz, 2H), 1.13 (s, 6H). LCMS: m/z 242 [M+H]+ @ w.u. 4.53 min.

MSVR (IER) calc. for C10H15N3O2S [M+H]+ 242.0958 found 242.0957;

4-{[(2S)-3-Methylbutan-2-yl]amino}-2-(methylsulfanyl)pyrimidin-5-carbaldehyde[(VIII), E2=DO)-3-methylbutan-2-yl, R3=H ]

The title compound is obtained as a colorless oil (90% yield);

1H NMR (500 MHz, DMSO-de) δ=9.75 (s, 1H), 8.57 (d, J=8.69 Hz, 1H), 8.54 (s, 1H), 4.15- 4.26 (m, 1H), 2.50 (s, 3H), 1.79-1.93 (m, 1H), 1.15 (d, J=6.71 Hz, 3H), 0.91 (d, J=6.86 Hz, 3H), 0.89 (d, J=6.86 Hz, 3H). LCMS: m/z 240 [M+H]+ @ w.u. 6.77 min. MSVR (IER) calc. for C _n H ₁₈ N ₃ OS [M+H]+ 240.1165 found 240.1168;

4-{[(2S)-3,3-Dimethylbutan-2-yl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde [(VIII), R2=(2S)-3,3-dimethylbutane-2- silt, R3=H]

The title compound is obtained as a colorless oil (92% yield);

1H NMR (500 MHz, DMSO-de) δ=9.76 (s, 1H), 8.70 (d, J=9.00 Hz, 1H), 8.54 (s, 1H), 4.21 ( kvd, J=6.77, 9.28 Hz, 1H), 2.50 (s, 3H), 1.13 (d, J=6.86 Hz, 3H), 0.92 (s, 9H). LCMS: m/z 254 [M+H]+ @ w.u. 7.07 min. MSVR (IER) calc. for C12H20N3OS [M+H]+ 254.1322 found 254.1324;

2-(Methylsulfanyl)-4- {[(2S)-1,1,1-trifluoropropan-2-yl] amino } pyrimidine-5-carbaldehyde [(VIII), R2=(2S)-1,1,1 - trifluoropropan-2 -yl, R3=H]

- 43 046117

The title compound is obtained as a colorless oil (90% yield).

1H NMR (500 MHz, DMSO-dg) δ=9.82 (s, 1H), 8.69 (s, 1H), 8.66 (d, J=9.15 Hz, 1H), 5.19- 5.39 (m, 1H), 2.53 (s, 3H), 1.43 (d, J=7.02 Hz, 3H). LCMS: m/z 266 [M+H]+ @ w.u. 6.13 min. MSVR (IER) calc. for C9H11F3N3OS [M+H]+ 266.0570 found 266.0572.

2-(Methylsulfanyl)-4-(propan-2-ylamino)pyrimidine-5-carbaldehyde [(Viii), I2=propan-2-yl, R3=H]

The title compound is obtained as a colorless oil (92% yield).

1H NMR (500 MHz, D\1CO)-s16) δ=9.74 (s, 1H), 8.53 (s, 1H), 8.45 (d, J=7.32 Hz, 1H), 4 .28-4.44 (m, 1H), 2.50 (s, 3H), 1.24 (d, J=6.56 Hz, 6H). LCMS: m/z 212 [M+H]+ @ w.u. 5.9 min. MSVR (IER) calc. for C ₉ H _i4 N ₃ OS [M+H]+ 212.0852 found 212.0856.

2-(Methylsulfanyl)-4-{[(2S)-1-(tetrahydro-2H-pyran-2-yloxy)propan-2-yl]amino}pyrimidin-5carbaldehyde [(VIII), I2=(^)-1 -(tetrahydro-2H-pyran-2-yloxy, R3=H]

The title compound is obtained as a colorless oil (89% yield).

1H NMR (500 MHz, D\1CO)-s16) δ=9.75 (s, 1H), 8.53 (s, 1H), (d, J=7.78 Hz, 1H), 8.55 ( s, 1H), 4.65 (dd, J=2.9, 4.27 Hz, 1H), 4.45-4.56 (m, 1H), 2.50 (s, 3H), 3.69 -3.77 (m, 2H), 3.39-3.50 (m, 2H), 2.49 (s, 3H), 1.401.73 (m, 6H), 1.25 (d, J=6 .56 Hz, 6H). LCMS: m/z 312 [M+H]+ @ w.u. 10.47 min. MSVR (IER) calc. for C14H22N3O3S [M+H]+ 312.1377 found 312.1375.

2-Chloro-4-(propan-2-ylamino)pyrimidine-5-carbaldehyde [(Viiia), I2=propan-2-yl, R3=H]

LCMS: m/z 200 [M+H]+ @ w.u. 4.87 min. 6-chloro-4-ethylaminopyridine-3-carbaldehyde [(Viiia), I2=propan-2-yl, X=CH]

1H NMR (DMSO-dg) δ=9.86 (d, J=0.6 Hz, 1H), 8.56 (t, J=4.7 Hz, 1H), 8.44 (s, 1H), 6.85 (s, 1H), 3.34 (s, 2H), 1.17 (t, J=7.2 Hz, 3H). LCMS: m/z 185 [M+H]+ @ w.u. 4.89 min.

MSVR (IER) calc. for C ₈ H ₁₀ ClN ₂ O [M+H]+ 185.0476 Found 185.0481.

6-Chloro-4-isopropylaminopyridine-3-carbaldehyde [(Viiia), I2=propan-2-yl, X=CH] ci

1H NMR (DMSO-dg) δ=9.85 (d, J=0.5 Hz, 1H), 8.40-8.49 (m, 2H), 6.90 (s, 1H), 3.90 (dt, J=7.9, 6.5 Hz, 1H), 1.20 (d, J=6.4 Hz, 6H). LCMS: m/z 199 [M+H]+ @ w.u. 7.84 min. MSVR (IER) calc. for C ₉ H ₁₂ ClN ₂ O [M+H]+ 199.0633 found 199.0632.

6-Chloro-4-(2,2-dimethylpropylamino)pyridine-3-carbaldehyde [(Viiia), I2=2,2-dimethylpropyl, X=CH]

1H NMR (DMSO-dg) δ=9.88 (s, 1H), 8.76 (t, J=5.6 Hz, 1H), 8.45 (s, 1H), 7.00 (s, 1H ), 3.14 (d, J=6.1 Hz, 2H), 0.94 (s, 9H). LCMS: m/z 279 [M+H]+ @ w.u. 6.46 min. MSVR (IER) calc. for C _n H ₁₆ ClN ₂ O [M+H]+ 227.0946 Found 227.0949.

Receipt 4.

Methyl ester (E) -3-[4 -(2-hydroxy-2-methylpropylamino)-2-methylsulphanylpyrimidin-5 yl]acrylic acid [(X), I2=2-hydroxy-2-methylpropyl, R3=R4= R5=H] stage 2d

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4-(2-Hydroxy-2-methylpropylamino)-2-methylsulfanylpyrimidine-5-carbaldehyde (500.0 mg, 2.07 mmol) was dissolved in THF (7 ml), methyl (triphenylphosphoranilidene) acetate (831.3 mg) was added , 2.49 mmol). The resulting suspension is stirred at reflux for 1 hour. The reaction mixture is cooled to room temperature, then diluted with AcOEt and washed with water, then with saturated sodium chloride solution. The organic phases are separated and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (50-70% AcOEt/hexane) of the title product (498.7 mg, 81% yield).

1H NMR (500 MHz, DMSO^ ₆ ) δ=8.37 (s, 1H), 7.79 (d, J=16.0 Hz, 1H), 7.49-7.45 (m, 1H), 6.52 (d, J=15.7 Hz, 1H), 4.62 (s, 1H), 3.72 (s, 3H), 3.44 (d, J=6.1 Hz, 2H), 2.44 (s, 3H), 1.13-1.01 (m, 6H).

LCMS: m/z 298 [M+H]+ @ w.u. 5.06 min.

MSVR (IER) calc. for C13H19N3O3S [M+H]+ 298.1220 found 298.1217.

Receiving 5.

8-(2-Hydroxy-2-methylpropyl)-2-methylsulfanyl-8H-pyrido[2,3^]pyrimidin-7-one [(XI), R2=2Г hydroxy-2-methylpropyl, R3=R4=R5= H]

Stage 2e.

Methyl ester (E)-3-[4-(2-hydroxy-2-methylpropylamino)-2-methylsulfanylpyrimidin-5yl]acrylic acid (495.0 mg, 1.66 mmol) was dissolved in DIPEA (7.0 ml) there add DBU (0.25 ml, 1.66 mmol) and stir at reflux overnight. The reaction mixture is cooled to room temperature, then diluted with DCM, and washed with water, then with saturated NH ₄ Cl. The organic phases are separated and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (1-10% MeOH/DCM) of the title product (350.7 mg, 79% yield).

1H NMR (500 MHz, DMSO) δ=8.88 (s, 1H), 7.94 (d, J=9.5 Hz, 1H), 6.65 (d, J=9.5 Hz, 1H) , 4.53 (s, 1H), 4.44 (s, 2H), 2.60 (s, 3H), 1.10 (s, 6H). LCMS: m/z 266 [M+H]+ @ w.u. 4.50 min. MSVR (IER) calc. for C ₁₂ H ₁₅ N ₃ O ₂ S [M+H]+ 266.0958 found 266.0965;

8-[^)-Butan-2-yl]-2-(methylsulfanyl)pyrido[2,3^]pyrimidin-7(8H)-one [(XI), I2=^)-butan-2yl, R3=R4 =R5=H]

1H NMR (500 MHz, DMSO-de) δ=8.86 (s, 1H), 7.90 (d, J=9.46 Hz, 1H), 6.59 (brs, 1H), 5.39 ( ws, 1H), 2.59 (s, 3H), 2.23 (ws, 1H), 1.90 (ws, 1H), 1.52 (ws, 3H), 0.73 (t, J=7 ,47 Hz, 3H).

Receipt 6.

8-(2,2-Dimethylpropyl)-6-fluoro-2-methylsulfanyl-8H-pyrido[2,3^]pyrimidin-7-one [(XI), R2=2,2dimethylpropyl, R3=R4=H, R5 =F]

Stage 3 a.

Lithium hydroxide monohydrate (26.1 mg, 0.62 mmol) is added to a solution of ethyl (diethoxyphosphoryl)(fluoro)acetate (0.10 ml, 0.50 mmol) and 4-(2,2-dimethylpropylamino)-2-methylsulfanylpyrimidine -5carbaldehyde (100.0 mg, 0.41 mmol) in THF (5.0 ml). The solution is stirred overnight at room temperature, under these conditions spontaneous cyclization of the acrylic ester intermediate to the title compound occurs.

The reaction mixture is diluted with DCM and washed with water, then with saturated sodium chloride solution. The organic phases are separated and dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (10-30% AcOEt/hexane) to give the product (50.2 mg, 43% yield).

1H NMR (500 MHz, DUSO-cH,) δ=8.88 (s, 1H), 7.92 (d, J=9.0 Hz, 1H), 4.33 (shs, 2H), 2.61 (s, 3H), 0.93 (s, 9H). LCMS: m/z 282 [M+H]+ @ w.u. 6.59 min. MSVR (IER) calc. for C ₁₃ H ₁₆ FN ₃ OS [M+H]+ 282.1071

- 45 046117 found 282.1069.

Receipt 7.

8-(2,2-Dimethylpropyl)-6-methoxy-2-methylsulfanyl-8H-pyrido|2,3^|pyrimidin-7-one

K_2=2,2-dimelylpropyl, R3=R4=H, R5=OMe]

Stage 3 a.

[(XI),

4-(2,2-Dimethylpropylamino)-2-methylsulfanylpyrimidine-5-carbaldehyde (120.0 g, 0.50 mmol) and ethyl methoxyacetate (0.062 ml, 0.62 mmol) were stirred in toluene (4.0 ml) at 0 °C under nitrogen. Potassium tertbutoxide (61.4 mg, 0.55 mmol) was added gradually. The mixture is stirred to room temperature and then to 65°C for 48 hours. The reaction mixture is concentrated in vacuo and triturated with AcOEt to remove the remaining starting aldehyde. The remaining solid was then purified by silica gel column chromatography (30-90% AcOEt/hexane) to give the title product (38.8 mg, 24% yield).

1H NMR (500 MHz, DMSO-s1 ₆ ) δ=8.80 (s, 1H), 7.27 (s, 1H), 4.33 (bs, 2H), 3.84 (s, 3H), 2 .58 (s, 3H), 0.90 (s, 9H). LCMS: m/z 294 [M+H]+ @ w.u. 6.24 min. MSVR (IER) calc. for C ₁₄ H ₁₉ N ₃ O ₂ S [M+H]+ 294.1271 found 294.1273.

Receiving 8.

8-[DO)-3-Methylbutan-2-yl]-2-(methylsulfanyl)pyrido[2,3Y]pyrimidin-7(8H)-one [(XI), R2=(2S)-3methylbutan-2-yl , R3=R4=R5=H|

Stage 3 a.

LiHMDS (4 ml of 1 M solution in THF, 4 mmol) was added to THF (15 ml) at -78°C and treated with EtOAc (0.5 ml, 4.64 mmol). The solution was stirred at -78°C for 10 min, then solid 4-{[(2S)-3-methylbutan-2-yl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde (280 mg, 1. 16 mmol) in one portion, and the solution was stirred at -78°C for 10 minutes, then removed from the cooling bath, heated to RT for 3 hours. The reaction mixture was cooled in an ice bath and quenched with saturated NH ₄ Cl solution and extracted with EtOAc ( 2x1 ml), dried over Na ₂ SO ₄ , filtered and concentrated. Purification by column chromatography using Hex/EtOAc 8:2 gave a whitish solid of the title compound (250 mg, 80% yield).

1H NMR (500 MHz, DMSOU6) δ=8.87 (s, 1H), 7.91 (d, J=9.30 Hz, 1H), 6.45-6.72 (m, 1H), 4, 86-5.45 (m, 1H), 2.58 (s, 3H), 1.37-1.65 (m, 3H), 1.03 (shs, 3H), 0.59 (d, J= 13.42 Hz, 3H). LCMS: m/z 264 [M+H]+ @ w.u. 6.26 min. MSVR (IER) calc. for C ₁₃ H ₁₈ N ₃ OS [M+H]+ 264.1165 found 264.1174

According to the same method, the following compounds are obtained:

8-[(2S)-3,3-Dimethylbutan-2-yl]-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one

I2=^)-3,3-dimethylbutan-2-yl, R3=R4=R5=H]

[(XI),

Chiral 'O'

LCMS: m/z 278 [M+H]+ @ w.u. 7.02 min; 2-(methylsulfanyl)-8-[DO)-1,1,1-trifluoropropan-2yl]pyrido[2,3Y]pyrimidin-7(8H)-one [(XI), K2=^)-1,1, 1-trifluoropropan-2-yl, R3=R4=R5=H]

Chiral

Oh, F'F

1H NMR (500 MHz, DMSOU6) δ=8.95 (s, 1H), 8.92 (s, 1H), 8.00 (d, J=9.46 Hz, 1H), 7.98 (d, J=9.61 Hz, 1H), 6.73 (d, J=9.46 Hz, 1H), 6.61 (d, J=9.46 Hz, 1H), 6.32-6.46 ( m, 1H), 6.05-6.19 (m, 1H), 2.59 (s, 3H), 2.58 (s, 3H), 1.88 (d, J=7.32 Hz, 3H ), 1.75 (d, J=7.02 Hz, 3H). LCMS: m/z 290 [M+H]+ @ w.u. 5.91 min. MSVR (IER) calc. for C11H11F3N3OS [M+H]+ 290.0570 found 290.0569.

2-(Methylsulfanyl)-8-(propan-2-yl)pyrido[2,3Y]pyrimidin-7(8H)-one [(XI), I2=propan-2-yl,

R3=R4=R5=H|

- 46 046117

1H NMR (500 MHz, DMSO-de) δ=8.86 (s, 1H), 7.88 (d, J=9.46 Hz, 1H), 6.57 (d, J=9.46 Hz, 1H), 5.68 (brs, 1H), 2.60 (s, 3H), 1.54 (d, J=7.02 Hz, 6H). LCMS: m/z 236 [M+H]+ @ w.u. 9.10 min. MSVR (IER) calc. for C11H14N3OS [M+H]+ 236.0852 found 236.0861.

2-(methylsulfanyl)-8-[(2S)-1-(tetrahydro-2H-pyran-2-yloxy)propan-2-yl]pyrido[2,3d]pyrimidin-7(8H)-one [(XI) , K.2=(^)-1-(tetrahydro-2H-pyran-2-yloxy)propan-2-yl, R3=R4=R5=H]

1H NMR (500 MHz, DMSO-dJ δ=8.87 (s, 1H), 7.90 (d, J=9.46 Hz, 1H), 6.59 (bs, 1H), 5.40-6 .04 (m, 1H), 4.60 (s, 1H), 4.00 (m, 2H), 3.73 (m, 2H), 3.41 (shs, 2H), 2.59 (s, 3H), 1.07-1.73 (m, 9H). LCMS: m/z 336 [M+H]+ @ v.a. 9.82 min HRMS (ESI) calculated for C ₁₆ H ₂₂ N ₃ O ₃ S [M+H]+ 336.1377 found 336.1372.

4-Chloro-8-(2,2-dimethylpropyl)-2-(methylsulfanyl)pyrido[2,3^]pyrimidin-7(8Н)-one [(XI), R2=2,2dimethylpropyl, R3=Cl, R4 =R5=H]

1H NMR (500 MHz, DPSO-sb,) δ=7.99 (d, J=9.76 Hz, 1H), 6.72 (d, J=9.76 Hz, 1H), 4.30 (shs , 2H), 2.62 (s, 3H), 0.91 (s, 9H). LCMS: m/z 298 [M+H]+ @ w.u. 7.13 min. MSVR (IER) calc. for C ₁₃ H ₁₇ ClN ₃ OS [M+H]+ 298.0776 Found 298.0783.

7-Chloro-1-ethyl-1H-[1,6]naphthyridin-2-one [(II), G=Cl, X=CH, I2=Ethyl, R3=R4=R5=H]

1H NMR (DMSO-06) δ=8.74 (s, 1H), 8.02 (d, J=9.6 Hz, 1H), 7.69 (s, 1H), 6.71 (d, J =9.6 Hz, 1H), 4.21 (kv, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H). LCMS: m/z 209 [M+H]+ @ w.u. 4.28 min.

MSVR (IER) calc. for C ₁₀ H ₁₀ ClN ₂ O [M+H]+ 209.0476 Found 209.0485.

7-Chloro-1-isopropyl-1H-[1,6]naphthyridin-2-one [(II), G=Cl, X=CH, I2=propan-2-yl, R3=R4=R5=H]

1H NMR (DMSOHO δ=8.71 (s, 1H), 7.96 (d, J=9.5 Hz, 1H), 7.79 (brs, 1H), 6.63 (d, J=9, 5 Hz, 1H), 5.14 (shs, 1H), 1.50 (d, J=6.9 Hz, 6H).LCMS: m/z 223 [M+H]+ @ v.u. 7, 11 min.

MSVR (IER) calc. for C11H12C1N2O [M+H]+ 223.0633 found 223.0633.

7-Chloro-1-(2,2-dimethylpropyl)-1H-[1,6]naphthyridin-2-one [(II), G=Cl, X=CH, I2=ethyl, R3=R4=R5=H ]

1H NMR (DMSO9 δ:= 8.71 (s, 1H), 8.01 (d, J=9.5 Hz, 1H), 7.84 (s, 1H), 6.72 (d, J=9 .5 Hz, 1H), 4.18 (shs, 2H), 0.91 (s, 9H).LCMS: m/z 251 [M+H]+ @ v.u. 5.79 min.

MSVR (IER) calc. for C ₁₃ H ₁₆ ClN ₂ O [M+H]+ 251.0946 Found 251.0949.

Receipt 9.

2-Chloro-8-(propan-2-yl)pyrido[2,3^]pyrimidin-7(8H)-one [(XI), K.2=(^)-3-methylbutan-2-yl,

R3=R4=R5=H]

Stage 4g.

LiHMDS (8 ml of 1 M solution in THF, 18 mmol) is added to THF (20 ml) at -78°C and treated

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EtOAc (1.6 ml, 18.1 mmol). The solution was stirred at -78°C for 10 min, then a solution of 2-chloro-4-(propan-2-ylamino)pyrimidin-5-carbaldehyde (0.9 g, 4.5 mmol) was added in THF (10 ml) dropwise and the solution was stirred at -78°C for 10 minutes, then removed from the cooling bath and heated to RT for 3 hours. The reaction mixture was cooled in an ice bath and quenched with saturated NH4Cl solution and extracted with EtOAc (2x1 ml), dried over Na ₂ SO ₄ , filter and concentrate. Purification by column chromatography using Hex/EtOAc 8:2 gave a whitish solid of the title compound (100 mg, 10% yield).

LCMS: m/z 224 [M+H] ⁺ @ w.u. 4.26 min.

Getting 10.

2-(Methylsulfanyl)-7-oxo-8-(2,2-dimethylpropyl)-7,8-dihydropyrido[2,3Apyrimidine-4-carbonitrile [(XI), R2=2,2-dimethylpropyl, R3=CN, R4=R5=H] transformation A

4-Chloro-8-(2,2-dimethylpropyl)-2-methylsulfanyl-8H-pyrido[2,3Apyrimidin-7-one (60 mg, 0.2 mmol) was dissolved in DMSO (4.5 ml), add triethylamine (300 μl) and NAOH (18 mg, 0.2 mmol) and stir for 1 hour at 50°C. Then add water, 10 ml and extract with AcOEt twice. The organic phases are washed with saturated sodium chloride solution and then dried over Na ₂ SO ₄ . The salts are filtered and the solvent is evaporated in vacuo. The crude product was purified by SiO ₂ column chromatography using hexane/AcOEt 8/2 to give the product (12 mg, 20% yield).

¹ H NMR (500 MHz, DMSO^) δ=7.94 (d, J=9.61 Hz, 1H), 6.83 (d, J=9.61 Hz, 1H), 4.28 (shs, 2H), 2.63 (s, 3H), 0.91 (s, 3H). LCMS: m/z 289 [M+H] ⁺ @ w.u. 7.09 min. MSVR (IER) calc. milking C ₁₄ H ₁₇ N ₄ OS [M+H] ⁺ 289.1118 found 289.1122.

Receipt 11.

4-Amino-2-(methylsulfanyl)-8-(propan-2-yl)pyrido[2,3Apyrimidin-7(8H)-one [(XI), R2=propan2-yl, R3=NH ₂ , R4=R5 =H] transformation B

4-Chloro-8-iso11ro11yl-2-methylsulfanyl-811-11irido[2.3-c1]11irimidin-7-one (50 mg, 0.15 mmol) in 30% NH ₄ OH is heated to 60°C for 3 hours. The product precipitates and is filtered with quantitative yield. No other cleaning is carried out.

LCMS: m/z 251 [M+H]+ @ w.u. 9.33 min. MSVR (IER) calc. milking C _n H ₁₅ N ₄ OS [M+H]+251.0961 found 251.0961.

Receiving 12.

4-(Methylamino)-2-(methylsulfanyl)-8-(2,2-dimethylpropyl)pyrido[2,3Apyrimidin-7(8H)-one [(XI), I2=2,2-demitpropyl, R3=N( H)Me, R4=R5=H] transformation C

4-Chloro-8-(2,2-dimethylpropyl)-2-methylsulfanyl-8H-pyrido[2,3Apyrimidin-7-one (40 mg, 0.13 mmol) was dissolved in THF (4 ml) and methylamine 1 was added thereto. 0 M in EtOH (100 µl) and stir for 12 h at room temperature. Then add 10 ml water and extract with AcOEt twice. The organic phases are washed with saturated sodium chloride solution and then dried over Na ₂ SO ₄ . The salts are filtered and the solvent is evaporated in vacuo. The crude product was purified by SiO ₂ column chromatography using DCM/MeOH 98/2 to give the product (33 mg, 85% yield).

1H NMR (500 MHz, DMSO^) δ=8.11 (q, J=4.02 Hz, 1H), 8.01 (d, J=9.61 Hz, 1H), 6.39 (d, J =9.61 Hz, 1H), 4.27 (shs, 2H), 2.93 (d, J=4.42 Hz, 3H), 2.52 (s, 3H), 0.89 (s, 9H ). LCMS: m/z 293 [M+H] ⁺ @ w.u. 6.63 min. MSVR (IER) calc. giving C ₁₄ H ₂₁ N ₄ OS [M+H] ⁺ 293.1431 found 293.1436.

Receipt 13.

4-Ethoxy-2-(methylsulfanyl)-8-(propan-2-yl)pyrido[2,3Apyrimidin-7(8H)-one [(XI), R2=2,2dimethylpropyl, R3=OEt, R4=R5= H] transformation D

- 48 046117

4-Chloro-8-(2,2-dimethylpropyl)-2-methylsulfanyl-8H-pyrido[2.3H]pyrimidin-7-one (50 mg, 0.17 mmol) dissolved in EtOH (4 ml) in the presence of K2CO3 (46 mg, 0.34 mmol) and stir for 12 hours at room temperature. Then add 10 ml water and extract with AcOEt twice. The organic phases are washed with saturated sodium chloride solution and then dried over Na ₂ SO ₄ . The salts are filtered and the solvent is evaporated in vacuo. The crude product was purified by SiO ₂ column chromatography using DCM/MeOH 98/2 to give the product (40 mg, 76% yield).

¹ H NMR (500 MHz, DMSO-dg) δ=7.86 (d, J=9.61 Hz, 1H), 6.51 (d, J=9.61 Hz, 1H), 4.50 (kv , J=7.07 Hz, 2H), 4.29 (shs, 2H), 2.59 (s, 3H), 1.38 (t, J=7.09 Hz, 3H), 0.90 (s , 9H). LCMS: m/z 308 [M+H]+ @ w.u. 7.09 min. MSVR (IER) calc. for C1 ₅ H ₂₂ N ₃ O ₂ S [M+H] ⁺ 308.1427 found 308.1428.

Receipt 14.

8-[(2S)-1 -Fluoropropan-2-yl]-2-(methylsulfanyl)pyrido[2,3 -d]pyrimidin-7(8H)-one [(XI), R2=(2 S)-1fluoropropane -2-yl, R3=R4=R5=H] transformation F

To a solution of 8-[(2S)-1-hydroxypropan-2-yl]-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.40 mmol) in MeCN (1.5 ml) add triethylamine (509 μl, 3.66 mmol) and perfluoro-1-butanesulfonyl fluoride (214.4 μl, 1.194 mmol), then NEt ₃ (HF) ₃ (198 μl, 1.213 mmol) and the resulting mixture is stirred at room temperature for 12 hours. The reaction mixture is diluted with water (6 ml) and extracted with DCM (3x6 ml). The combined organic fractions are washed with saturated sodium chloride solution (6 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness to obtain the crude product. Flash column chromatography (diethyl ether) gave 86.7 mg (86%) of the desired product.

^1H NMR (500 MHz, DMSO-dg) δ=8.90 (s, 1H), 7.94 (d, J=9.46 Hz, 1H), 6.61 (d, J=9.46 Hz , 1H), 5.85 (shs, 1H), 5.11 (td, J=8.00, 48.00 Hz, 1H), 4.84 (ddd, J=5.60, 8.70, 46 .20 Hz, 1H), 2.59 (s, 3H), 1.49 (d, J=6.86 Hz, 3H). LCMS: m/z 254 [M+H] ⁺ @ w.u. 8.06 min. MSVR (IER) calc. for C ₁₃ H ₁₇ FN ₃ OS [M+H] ⁺ 254.0758 found 254.0762.

Receiving 15.

8-Benzyl-2-(methylsulfanyl)pyrido[2,3^]pyrimidin-7(8H)-one [(XI), K2=benzyl, R3=R4=R5=H] stage 3 a'

A mixture of 2-(methylsulfanyl)pyrido[2,3^]pyrimidin-7(8H)-one (100 mg, 0.52 mmol), cesium carbonate (337 mg, 1.04 mmol) and benzyl bromide (133 mg, 0. 78 mmol) in anhydrous DMF (2 ml) are purged with nitrogen and heated in a sealed tube at 90°C for 1 hour. The reaction mixture is cooled to room temperature and diluted with water. The product is precipitated, filtered and washed with water. 8-Benzyl-2-(methylsulfanyl)pyrido[2,3^]pyrimidin-7(8H)-one was obtained as a yellow solid (117 mg, 80% yield).

1H NMR (500 MHz, DMSO-dg) δ=8.91 (s, 1H), 8.00 (d, J=9.46 Hz, 1H), 7.17-7.35 (m, 5H), 6.71 (d, J=9.46 Hz, 1H), 5.50 (s, 2H), 2.50 (s, 3H). LCMS: m/z 284 [M+H] ⁺ v.a. 5.92 min. MSVR (IER) calc. for C ₁₅ H ₁₄ N ₃ OS [M+H] ⁺ 284.0852 found 284.0865.

According to the same method, but using a suitable alkylating reagent, the following compounds are prepared:

8-Ethyl-2-(methylsulfanyl)pyrido[2,3^]pyrimidin-7(8H)-one [(XI), K2=ethyl, R3=R4=R5=H]:

The title compound is obtained as a yellow oil (65% yield).

1H NMR (401 MHz, DMSO-е ₆ ) δ 8.88 (s, 1H), 7.93 (d, J=9.40 Hz, 1H), 6.62 (d, J=9.52 Hz, 1H), 4.32 (kv, J=7.04 Hz, 2H), 2.60 (s, 3H), 1.22 (t, J=7.02 Hz, 3H). LCMS: m/z 222 [M+H] ⁺ v.a. 4.95 min. MSVR (IER) calc. for C ₁₀ H ₁₂ N ₃ OS [M+H] ⁺ 222.0696 Found 222.07;

2-(Methylsulfanyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XI), K2=isopropyl,

R3=R4=R5=H]:

The title compound is obtained as a light yellow foam (70% yield).

1H NMR (401 MHz, DMSO-06) δ 8.85 (s, 1H), 7.87 (d, J=9.52 Hz, 1H), 6.57 (d, J=9.40 Hz, 1H ), 5.69 (td, J=6.93, 13.73 Hz, 1H), 2.60 (s, 3H), 1.54 (d, J=6.96 Hz, 6H). LCMS: m/z 236 [M+H] ⁺ v.a. 5.53 min. MSVR

- 49 046117 (IER) calc. for C11H14N3OS [M+H]+ 236.0852 found 236.0861.

8-(4-Bromo-2-fluorobenzyl)-2-(methylsulfanyl)pyrido[2,3^]pyrimidin-7(8H)-one [(XI), K2=4-bromo2-fluorobenzyl, R3=R4=R5 =H]:

The title compound is obtained as a whitish foam (75% yield).

1H NMR (500 MHz, DMSO-06) δ=8.93 (s, 1H), 8.02 (d, J=9.46 Hz, 1H), 7.57 (dd, J=1.83, 9 .91 Hz, 1H), 7.29 (dd, J=1.68, 8.39 Hz, 1H), 6.96 (t, J=8.24 Hz, 1H), 6.71 (d, J =9.61 Hz, 1H), 5.48 (s, 2H), 2.44 (s, 3H). LCMS: m/z 379 [M+H] ⁺ v.a. 6.71 min. MSVR (IER) calc. for C ₁₅ H ₁₂ BrFN ₃ OS [M+H] ⁺ 379.9863 found 379.9872.

Getting 16.

4-Methyl-2-(methylsulfanyl)pyrido[2,3^]pyrimidin-7(8H)-one [(XI), R2=H, R3=Me, R4=R5=H]

Step 3a: To a mixture of 4-chloro-6-methyl-2-(methylthio)pyrimidine (1 g, 5.7 mmol) in 5 ml acetonitrile add 2 ml of a 28% ammonium hydroxide solution in water. The reaction mixture is heated to 120°C for 72 hours. Once complete, the mixture is cooled to rt and diluted with water to obtain a precipitate. The solid was filtered and dried in vacuo to give 6-methyl-2-(methylsulfanyl)pyrimidin-4-amine (0.76 g, 86% yield).

1H NMR (401 MHz, DMSO-06) δ=6.75 (brs, 2H), 5.96 (d, J=0.46 Hz, 1H), 2.36-2.38 (m, 3H), 2.13(s, 3H)

Stage 3b:

To a solution of 6-methyl-2-(methylsulfanyl)pyrimidin-4-amine (1.1 g, 7.06 mmol) in 7 ml of methanol add iodine monochloride (1.5 g, 9.24 mmol) in small portions at 0° WITH. The reaction mixture is then stirred overnight. After evaporation of the solvent, the residue was triturated with acetone and the product 5-iodo-6-methyl-2-(methylsulfanyl)pyrimidin-4-amine was collected by filtration (1.32 g, 66% yield).

LCMS: m/z 282 [M+H] ⁺ v.a. 5.65 min.

Stage 3c:

To a solution of 5-iodo-6-methyl-2-(methylsulfanyl)pyrimidin-4-amine (1.49 g, 4.9 mmol) in DMA (10 ml) add ethyl acrylate (1.06 ml, 9.8 mmol) , Pd(OAc) ₂ (0.22 g, 0.98 mmol), (+) BINAP (0.61 g, 0.98 mmol) and TEA (2 ml, 14.7 mmol). The reaction mixture is then heated to 100°C and reacted overnight. After the solvent was evaporated, the residue was diluted with water, and the aqueous layer was extracted with ethyl acetate. The solvent was evaporated in vacuo to give the desired intermediate ethyl (2E)-3-[4-amino-6-methyl-2-(methylsulfanyl)pyrimidin-5-yl]prop-2-enoate (0.5 g, 21% yield ).

LCMS: m/z 254 [M+H] ⁺ v.a. 6.53 min.

Stage 3d:

To a solution of ethyl (2E)-3-[4-amino-6-methyl-2-(methylsulfanyl)pyrimidin-5-yl]prop-2-enoate (0.5 g, 1.9 mmol) in DIPEA (2 ml ) add 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, 1 ml) at reflux for 15 hours. After evaporation of the volatile compounds, the residue is triturated with acetone to obtain the desired product 4- methyl-2-(methylsulfanyl)pyrido[2,3^]pyrimidin-7(8H)-one (0.14 g, 35% yield). 1H NMR (401 MHz, DMSO-06) δ=12.30 (brs, 1H), 8.05 (d, J=9.76 Hz, 1H), 6.47 (d, J=9.76 Hz, 1H), 2.61 (s, 3H), 2.54 (s, 3H). LCMS: m/z 208 [M+H] ⁺ @ w.u. 3.84 min. MSVR (IER) calc. for C ₁₃ H ₂₁ N ₃ O ₂ S [M+H] ⁺ 208.0539 found 208.0545.

Receipt 17.

8-Benzyl-2-(methylsulfonyl)pyrido[2,3^]pyrimidin-7(8H)-one [(II), G=Me-S(O) ₂ -,_R2=benzyl, R3=R4=R5= H]

Stage 2f.

8-Benzyl-2-(methylsulfanyl)pyrido[2.3M]pyrimidin-7(8H)-one (110 mg, 0.388 mmol) was dissolved in 5 ml DCM. m-CPBA (251 mg, 1.55 mmol) was added to the stirred solution. The reaction mixture is stirred for 2 hours at room temperature. LCMS indicates completion of the reaction. The sample is diluted with 10 ml DCM and washed twice with saturated NaHCO ₃ then with saturated sodium chloride solution. The organic phase is separated and dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The solvent was evaporated to give 8-benzyl-2-(methylsulfonyl)pyrido[2,3^]pyrimidin7(8H)-one (105 mg, 86% yield) as a yellow solid.

1H NMR (401 MHz, DMSOA) δ=9.32 (s, 1H), 8.17 (d, J=9.64 Hz, 1H), 7.36-7.42 (m, 2H), 7, 19-7.34 (m, 3H), 6.99 (d, J=9.52 Hz, 1H), 5.52 (s, 2H), 3.39 (s, 3H) 8.91 (s, 1H), 8.00 (d, J=9.46 Hz, 1H), 7.17-7.35 (m, 5H),

- 50 046117

6.71 (d, J=9.46 Hz, 1H), 5.50 (s, 2H). LCMS: m/z 316 [M+H]+ v.a. 4.80 min. MSVR (IER) calc. for C ₁₅ H ₁₄ N ₃ O ₃ S [M+H]+ 316.0751 found 316.0760.

According to the same method, the following compounds are obtained:

8-(2-Hydroxy-2-methylpropyl)-2-methanesulfonyl-8H-pyrido[2,3^]pyrimidin-7-one [(II), G=MeS(O) ₂ -,_R2=2-hydroxy- 2-methylpropyl, R3=R4=R5=H]

¹ H NMR (500 MHz, DMSOA) δ=9.29 (s, 1H), 8.12 (d, J=9.6 Hz, 1H), 6.94 (d, J=9.5 Hz, 1H ), 4.50 (s, 1H), 4.44 (s, 2H), 3.47 (s, 3H), 1.12 (s, 6H). LCMS: m/z 320 [M+H]+ @ w.u. 3.35 min MSVR (IER) calc. for C ₁₂ H ₁₅ N ₃ O ₄ S [M+H]+ 320.0675 found 320.0677;

8-(3-Hydroxy-2,2-dimethylpropyl)-2-methanesulfonyl-8H-pyrido[2,3^]pyrimidin-7-one G=Me-S(O)2-, I2=3-hydroxy-2 ,2-dimethylpropyl, R3=R4=R5=H]

[(II),

1H NMR (500 MHz, DMSOA) δ=9.29 (s, 1H), 8.12 (d, J=9.6 Hz, 1H), 6.94 (d, J=9.5 Hz, 1H) , 4.57 (t, J=5.8 Hz, 1H), 4.35 (shs, 2H), 3.47 (s, 3H), 3.20 (d, J=5.8 Hz, 2H) , 0.83 (s, 6

H) LCMS: m/z 312 [M+H]+ @ w.u. 3.76 min. MSVR (IER) calc. for C ₁₃ H ₁₇ N ₃ O ₄ S [M+H]+ 312.1013 found 312.1016;

8-(2,2-Dimethylpropyl)-6-fluoro-2-methanesulfonyl-8H-pyrido[2,3^]pyrimidin-7-one [(II), G=MeS(O) ₂ -, K2=2, 2-dimethylpropyl, R3=R4=H, R5=F]

1H NMR (500 MHz, DMSO-0 ₆ ) δ=9.29 (s, 1H), 8.11 (d, J=8.7 Hz, 1H), 4.34 (brs, 2H), 3.47 (s, 3H), 0.94 (s, 9H). LCMS: m/z 314 [M+H]+ @ w.u. 5.21 min. MSVR (IER) calc. for C ₁₃ H ₁₆ N ₃ O ₃ FS [M+H]+ 314.0969 found 314.0967;

8-(2,2-Dimethylpropyl)-2-methanesulfonyl-6-methoxy-8H-pyrido[2,3^]pyrimidin-7-one [(II), G=MeS(O) ₂ -, K2=2, 2-dimethylpropyl, R3=R4=H, R5=OMe]

1H NMR (500 MHz, DMSOA) δ=9.17 (s, 1H), 7.45 (s, 1H), 4.35 (brs, 2H), 3.92 (s, 3H), 3.43 ( s, 3H), 1.16 (s, 0H), 0.92 (s, 9H). LCMS: m/z 326 [M+H]+ @ w.u. 4.91 min. MSVR (IER) calc. for C ₁₄ H ₁₉ N ₃ O ₄ S [M+H]+ 326.1169 found 326.1164;

8-[(2S)-3-Methylbutan-2-yl]-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one [(II), G=MeS(O) ₂ - , K2=(28)-3-methylbutan-2-yl, R3=R4=R5=H]

Purification by column chromatography using Hex/EtOAc 8:2 gave an off-white solid of the title compound (250 mg, 95% yield).

1H NMR (500 MHz, DMSO- _c16 ) δ=9.29 (s, 1H), 8.10 (d, J=9.46 Hz, 1H), 6.71-7.06 (m, 1H) , 4.83-5.43 (m, 1H), 3.45 (s, 3H), 1.41-1.68 (m, 3H), 1.05 (d, J=6.56 Hz, 3H ), 0.59 (shs, 3H). LCMS: m/z 296 [M+H]+ @ w.u. 4.92 min. MSVR (IER) calc. for C ₁₃ H ₁₈ N ₃ O ₃ S [M+H]+296.1064 found 296.1065;

8-[(2S)-3,3-Dimethylbutan-2-yl]-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one [(II), G=MeS(O) ₂ -, K2=(28)-3,3-dimethylbutan-2-yl, R3=R4=R5=H]

Purification by column chromatography using Hex/EtOAc 8:2 gave an off-white solid of the title compound (50 mg, 95% yield). LCMS: m/z 310 [M+H]+ @ w.u. 5.07 min.

- 51 046117

2-(Methylsulfonyl)-8-(propan-2-yl)pyrido[2,3^]pyrimidin-7(8Н)-one [(II), G=Me-S(O) ₂ -,

K2=propan-2-yl, R3=R4=R5=H]

Purification by column chromatography using Hex/EtOAc 8:2 gave an off-white solid of the title compound (479 mg, 69% yield).

1H NMR (500 MHz, DMSO-06) δ=9.27 (s, 1H), 8.07 (d, J=9.46 Hz, 1H), 6.88 (d, J=9.46 Hz, 1H), 5.65 (spt, J=6.80 Hz, 1H), 3.46 (s, 3H), 1.56 (d, J=7.02 Hz, 6H). LCMS: m/z 268 [M+H]+ @ w.u. 4.48 min. MSVR (IER) calc. for C _n H1 ₃ N ₃ O ₃ S [M+H]+ 268.0751 found 268.0746;.

8-[(2S)-1-Fluoropropan-2-yl]-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one [(II), G=MeS(O)2- , K2=^)-1-fluoropropan-2-yl, R3=R4=R5=H]

Ή NMR (500 MHz, DMSOS6) δ=9.31 (s, 1H), 8.13 (d, J=9.61 Hz, 1H), 6.92 (d, J=9.61 Hz, 1H) , 5.81 (shs, 1H), 5.12 (td, J=8.50, 47.90 Hz, 1H), 4.87 (ddd, J=5.80, 9.30, 46.20 Hz , 1H), 3.47 (s, 3H), 1.52 (d, J=7.02 Hz, 3H). LCMS: m/z 286 [M+H]+ @ w.u. 3.74 min. MSVR (IER) calc. for C ₁₁ H ₁₃ FN ₃ O ₃ S [M+H]+ 286.0656 Found 286.0654;

8-[(2S)-1-Hydroxypropan-2-yl]-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one [(II), G=MeS(O)2- , R2 (^H-hydroxyiroian-3-yl, R3=R4=R5=H]

Chiral

U λ Λ

SNNO ¹¹ I

Ο Λ A

1H NMR (500 MHz, DMSOS6) δ=9.27 (s, 1H), 8.08 (d, J=9.46 Hz, 1H), 6.88 (d, J=9.46 Hz, 1H) , 5.54 (shs, 1H), 4.83 (t, J=5.95 Hz, 1H), 4.02-4.23 (m, 1H), 3.70-3.87 (m, 1H ), 3.45 (s, 3H), 1.47 (d, J=6.86 Hz, 3H). LCMS: m/z 284 [M+n] ⁺ @ w.u. 3.74 min. MSVR (IER) calc. for C _n H ₁₄ N ₃ O ₄ S [M+H]+ 284.07, 284.0702 was found.

8-(4-Bromo-2-fluorobenzyl)-2-(methylsulfonyl)pyrido[2,3^]pyrimidin-7(8H)-one [(II), G=Me-S(O)2-, K2= 4-bromo-2-fluorobenzyl, R3 =R4=R5 =H]

Purification by column chromatography using Hex/EtOAc 7:3 gave a whitish solid of the title compound (90% yield).

°' '°

JUL

1H NMR (500 MHz, DMSO^) δ=9.34 (s, 1H), 8.19 (d, J=9.61 Hz, 1H), 7.57 (dd, J=1.83, 9, 91 Hz, 1H), 7.29 (dd, J=1.75, 8.31 Hz, 1H), 7.12 (t, J=8.31 Hz, 1H), 6.99 (d, J= 9.61 Hz, 1H), 5.51 (s, 2H), 3.37 (s, 3H). LCMS: m/z 411 [M+H]+ @ w.u. 5.52 min. MSVR (IER) calc. for C ₁₅ H ₁₂ BrFN ₃ O ₃ S [M+H]+ 411.9762 found 411.9763.

Receiving 18.

2-Chloro-8-(2,2-dimethylpropyl)-5-methyl-8H-pyrido[2,3^]pyrimidin-7-one [(II),G=Cl, R2=2,2dimethylpropyl, R3=H , R4=Me, R5=H]

Stages 4a, 4b and 4c.

Stage 4a:

5-Bromo-2,4-dichloropyrimidine (1.0 g, 4.38 mmol) was dissolved in THF (20.0 ml), triethylamine (0.94 ml, 6.57 mmol) and neopentylamine (0.45 ml, 5.25 mmol) and stir for 2 hours at room temperature. The precipitated salts are filtered and the solvent is evaporated under reduced pressure. The resulting oil is dissolved in Et ₂ O, washed with saturated sodium chloride solution, and then dried over Na ₂ SO ₄ . The salts are filtered and the solvent is evaporated in vacuo to give the product (1.13 g, 70% yield) which is carried over without further purification.

- 52 046117

Ή NMR (500 MHz, DMSO-06) δ=8.24 (s, 1H), 7.46 (t, J=6.25 Hz, 1H), 3.26 (d, J=6.41 Hz, 2H), 0.88 (s, 9H). LCMS: m/z 278 [M+H]+ @ w.u. 6.98 min. MSVR (IER) calc. for C ₉ H ₁₄ BrClN ₃ O [M+H] ⁺ 278.0054 found 278.0058;

Stage 4b:

A 3-neck round bottom flask is charged with (5-bromo-2-chloropyrimidin-4-yl)-(2,2dimethylpropyl)amine (200.0 mg, 0.72 mmol), crotonic acid (154.4 mg, 1.79 mmol), DIPEA (0.50 ml, 2.94 mmol) and THF (2.5 ml). The mixture was degassed using 3 vacuum/argon cycles, then tri-o-tolylphosphine (4.4 mg, 0.014 mmol) and dichlorobis(benzonitrile)palladium(II) (5.5 mg, 0.014 mmol) were added. The mixture is again degassed using 3 vacuum/argon cycles, then heated to 75°C and stirred under argon for 20 hours;

Stage 4c:

Acetic anhydride (0.17 mL, 1.79 mmol) was then added and the mixture was further stirred at 75° C. for 2 hours. The reaction was quenched with water and the mixture was cooled to room temperature. The reaction mixture is diluted with Et ₂ O and washed with water, then with saturated sodium chloride solution. The organic phases are separated and dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (10-30% AcOEt/hexane) to give the title product (90.8 mg, 48% yield). 1H NMR (500 MHz, DMSO^ ₆ ) δ=9.04 (s, 1H), 6.66 (kV, J=1.2 Hz, 1H), 4.20 (s, 2H), 2.47 ( d, J=1.2 Hz, Zn), 0.90 (s, 9 N). LCMS: m/z 266 [M+H] ⁺ @ w.u. 6.50 min. MSVR (IER) calc. for C ₁₃ H ₁₆ N ₃ OCl [M+H] ⁺ 266.1055, 266.1065 was found.

Receipt 19.

Preparation of 4-[4-(^)-1-aminoethyl)phenoxy]piperidine-1carboxylic acid benzyl ester hydrochloride [(III), A=phenyl, R1a=H, R1b=Me, R6a=O-R7, R6b=H, R7=4-piperidine-1-carboxylic acid benzyl ester]

(III)

Stage 1:

4-Fluoroacetophenone (0.691 g, 5.0 mmol) is dissolved in DMF (10.0 ml), cesium carbonate (3.26 g, 10.0 mmol) and 1-(tert-butoxycarbonyl)-4-hydroxypiperidine ( 2.01 g, 10.0 mmol) and stirred for 2 days at 100°C. The cesium carbonate is filtered off and the solution is diluted with ether and washed with water (3x10 ml) and then dried over Na ₂ SO ₄ . The crude product was purified by silica gel column chromatography (10-70% AcOEt/hexane) to give 4-(4acetylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (547.5 mg, 34% yield).

1H NMR (500 MHz, DMSO-dg) δ=7.86-7.95 (m, 2H), 7.02-7.12 (m, 2H), 4.71 (tt, J=8.1, 3.8 Hz, 1H), 3.613.71 (m, 2H), 3.19 (shs, 2H), 1.87-1.98 (m, 2H), 1.46-1.60 (m, 2H ), 1.40 (s, 9H). LCMS: m/z 342 [M+Na] ⁺ @ v.u. 6.68 min. MSVR (IER) calc. for C ₁₈ H ₂₅ NNaO ₄ [M+Na] ⁺ 342.1676 Found 342.1677.

Stage 2:

To a solution of 4-(4-acetylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (250.0 mg) in dioxane (4.0 ml) add HCl (4M in dioxane, 1.0 ml). The mixture was stirred overnight at room temperature and then concentrated to dryness to give a white solid, which was dried in vacuo to give 1-[4-(piperidin-4-yloxy)phenyl]ethanone hydrochloride compound as a white solid (220. 0 mg).

1H NMR (500 MHz, DMSO-de) δ=8.63 (brs, 2H), 7.86-8.01 (m, 2H), 7.04-7.17 (m, 2H), 4.80 (tt, J=7.6, 3.6 Hz, 1H), 3.21-3.28 (m, 2H), 3.09 (ddd, J=12.7, 8.8, 3.5 Hz , 2H), 2.52 (s, 3H), 2.12 (ddkv, J=10.2, 7.1, 3.5 Hz, 2H), 1.76-1.90 (m, 2H). LCMS: m/z 220 [M+H] ⁺ @ w.u. 3.32 min.

MSVR (IER) calc. for C ₁₃ H ₁₈ ClNO ₂ [M+H] ⁺ 220.1332, 220.1338 was found.

Stage 3:

1-[4-(Piperidin-4-yloxy)phenyl]ethanone (215.0 mg, 0.841 mmol) was dissolved in DCM (5.0 ml), TEA (0.35 ml, 2.522 mmol) and benzyl chloroformate ( 0.27 ml, 1.009 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture is washed with water, then with saturated sodium chloride solution. The organic phases are separated and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (10-70% AcOEt/hexane) to give 4-(4-acetylphenoxy)piperidine-1-carboxylic acid benzyl ester (210.1 mg, 70% yield).

1H NMR (500 MHz, DMSO-dg) δ=7.86-7.95 (m, 2H), 7.27-7.42 (m, 5H), 7.03-7.12 (m, 2H) , 5.08 (s, 2H), 4.69-4.79 (m, 1H), 3.65-3.83 (m, 2H), 3.20-3.41 (m, 2H), 2 .51 (shs, 3H), 1.96 (ddd, J=9.4, 6.1, 2.8 Hz, 2H), 1.50

- 53 046117

1.65 (m, 2H). LCMS: m/z 376 [M+Na]+ @ v.u. 6.66 min.

MSVR (IER) calc. for C ₂ 1H ₂ 3NaNO ₄ [M +Na]+ 376.1519 found 376.1526.

Stage 4:

A mixture of tetraethoxytitanium (0.237 ml, 1.132 mmol), ^)-2-methylpropane-2-sulfinamide (68.2 mg, 0.566 mmol) and 4-(4-acetylphenoxy)piperidine-1-carboxylic acid benzyl ester (200.0 mg , 0.566 mmol) in THF (15.0 ml) was heated to 80°C overnight and then cooled to room temperature. NaBH ₄ (107.0 mg, 2.829 mmol) was added to this mixture at 0°C. The mixture is then slowly warmed to room temperature over about 5 hours. MeOH (3 ml) is added to quench excess NaBH ₄ and then water is added. The resulting mixture is filtered to remove solids and the aqueous phase is extracted twice with EtOAc, dried over Na ₂ SO ₄ and concentrated. The crude product is purified by silica gel column chromatography (0-10% MeOH/DCM) to give 4-{4-[(S)-1-((S)-2methylpropan-2-sulfinylamino)ethyl]phenoxy}piperidine-benzyl ester 1-carboxylic acid (185.6 mg, 72% yield), ¹ H NMR (500 MHz, DMSO^) δ=7.30-7.42 (m, 5H), 7.28 (d, J=8, 5 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H), 5.49 (d, J=6.7 Hz, 1H), 5.08 (s, 2H), 4.55 (tt, J=7.8, 3.9 Hz, 1H), 4.30 (quin, J=6.8 Hz, 1H), 3.61-3.84 (m, 2H), 3.223.32 ( m, 2H), 1.91 (ddd, J=9.5, 6.2, 2.9 Hz, 2H), 1.46-1.61 (m, 2H), 1.36 (d, J= 6.9 Hz, 3H), 1.10 (s, 9H). LCMS: m/z 459 [M+H]+ @ w.u. 6.93 min. MSVR (IER) calc. for C ₂₅ H ₃₄ N ₂ O ₄ S [M+H]+ 459.2312 found 459.2305

Stage 5:

Add HCl (2 ml, 8.0 mmol, 4M in 1,4-dioxane). The mixture is stirred at room temperature overnight. To this mixture is added 6 ml of ethyl ether and the resulting precipitate is collected by filtration, washed with ethyl ether (2x10 ml) and then dried to the title product (quantitative yield).

1H NMR (500 MHz, DMSO-d6) δ=8.18 (brs, 3H), 7.39 (d, J=8.8 Hz, 2H), 7.28-7.45 (m, 5H), 7.03 (d, J=8.8 Hz, 2H), 5.08 (s, 2H), 4.61 (tt, J=7.8, 3.7 Hz, 1H), 4.34 (spt , J=6.1 Hz, 1H), 1.74-1.98 (m, 2H), 1.54 (dtd, J=12.8, 8.6, 3.9 Hz, 2H), 1, 46 (d, J=6.9 Hz, 3H). LCMS: m/z 377 [M+Na]+ @ w.u. 5.36 min.

MSVR (IER) calc. for C ₂ 1H ₂₇ ClNaN ₂ O3 [M +Na]+ 377.1835 found 377.1835

Getting 20.

Preparation of benzyl 4-{4-[O)-1-aminoethyl]-2-fluorophenyl}piperazine-1-carboxylate hydrochloride [(III), A=phenyl, R1a=H, R1b=Me, R6a=NR7R8, R6b=H , R7=4-piperazine-1-carboxylic acid benzyl ester]

Stage 1.

A mixture of tetraethoxytitanium (0.456 ml, 2 mmol), ^)-2-methylpropane-2-sulfinamide (131 mg, 1 mmol), and benzyl 4-(4-acetyl-2-fluorophenyl)piperazine-1-carboxylate (356.0 mg, 1 mmol) in THF (15.0 ml) was heated to 80°C overnight and then cooled to room temperature. NaBH4 (185.0 mg, 4 mmol) was added to this mixture at 0°C. The mixture is then slowly warmed to room temperature over about 5 hours. MeOH (3 ml) is added to the quenched NaBH4 residue and then water is added. The resulting mixture is filtered to remove solids and the aqueous phase is extracted twice with EtOAc, dried over Na2SO4 and concentrated. The crude product is purified by silica gel column chromatography (0-10% MeOH\DCM) to give benzyl 4-{4-[O)-1-{[^)-tert-butylsulfinyl]amino}ethyl]-2-fluorophenyl}piperazine -1-carboxylate (256 mg, 55% yield), 1H NMR (500 MHz, DMSO-d6) δ=7.29-7.42 (m, 5H), 7.20 (dd, J=1.83, 13.88 Hz, 1H), 7.11 (dd, J=1.75, 8.31 Hz, 1H), 6.99 (t, J=8.69 Hz, 1H), 5.61 (d, J=7.47 Hz, 1H), 5.10 (s, 2H), 4.31 (quin, J=6.83 Hz, 1H), 3.55 (shs, 4H), 2.96 (t, J=4.58 Hz, 4H), 1.35 (d, J=6.71 Hz, 3H), 1.10 (s, 9H). LCMS: m/z 462 [M+H]+ @ w.u. 6.85 min. MSVR (IER) calc. for C ₂₄ H ₃₃ FN ₃ O ₃ S [M+H]+462.2221 found 462.2232.

Stage 2:

To a solution of benzyl 4-{4-[O)-1-{[^)-tert-butylsulfinyl]amino}ethyl]-2-fluorophenyl}piperazine-1carboxylate (250 mg) in MeOH (5 ml) add HCl (2 ml , 8.0 mmol, 4M in 1,4-dioxane). The mixture is stirred at room temperature overnight. To this mixture is added 6 ml of ethyl ether and the resulting precipitate is collected by filtration, washed with ethyl ether (2x10 ml) and then dried to the title product (quantitative yield).

1H NMR (500 MHz, DMSO-d6) δ=8.29 (brs, 3H), 7.28-7.43 (m, 6H), 7.23 (dd, J=1.98, 8.39 Hz , 1H), 7.09 (t, J=8.85 Hz, 1H), 5.11 (s, 2H), 4.36 (quin, J=5.91 Hz, 1H), 3.56 (shs , 4H), 2.89-3.07 (m, J=4.58 Hz, 4H), 1.46 (d, J=6.71 Hz, 3H). LCMS: m/z 341 [M(-NH ₃ )+H]+ @ w.a. 5.4 min.

MSVR (IER) calc. for C20H25FN3O2 [M(AN3)+H]+ 341.1160 found 341.1164.

According to the same method, the following compounds are obtained:

Preparation of benzyl 4-{4-[O)-1-aminoethyl]-2-fluorophenyl}piperazine-1-carboxylate hydrochloride [(III),

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A=phenyl, R1a=H, R1b=Me, R6a=NR7R8, R6b=H, R7 benzyl ester of 4-piperazine-1-carboxylic acid]

1H NMR (500 MHz, DMSO-b6) δ=8.19 (brs, 3H), 7.36-7.42 (m, 4H), 7.34 (d, J=8.69 Hz, 3H), 7.00 (d, J=8.85 Hz, 2H), 5.10 (s, 2H), 4.30 (spt, J=6.30 Hz, 1H), 3.54 (shs, 4H), 3.15 (d, J=4.88 Hz, 4H), 1.46 (d, J=6.71 Hz, 3H). LCMS: m/z 340 [M+H]+ @ w.u. 5.06 min. MSVR (IER) calc. for C ₂₀ H ₂₆ N ₃ O ₂ [M+H] ⁺ 340.2020 found 340.2018.

Receiving 21.

tert-Butyl 4-{1-[4-( 1 -aminocyclopropyl)phenyl]-2-cyclopropylethyl} piperazine-1-carboxylate

[(III), A=phenyl, R1a uCL=cyclopropyl, R6a=4-CH(R14)NR7R8, R6b=H, R7-R8=4-piperazine-1-carboxylic acid benzyl ester, R14=cyclopropylmethyl]

Stage 1.

To a solution of 1-(4-bromophenyl)cyclopropanamine (1.0 g, 4.71 mmol) in ACN (6.5 ml) at 0°C, slowly add trifluoroacetic anhydride (0.72 ml, 5.26 mmol, 1. 1 eq.) in the presence of TEA (1.31 ml, 9.42 mmol, 2 eq.). The mixture is stirred at the same temperature for 15 minutes. The cooling bath is then removed and the mixture is heated at rt for 1 hour. A mixture of water (10 ml) and brine (5 ml) is added and the suspension is stirred for 15 minutes. The precipitate is vacuum filtered and the solid is washed with n-hexane and oven dried under vacuum to give N-[1-(4bromophenyl)cyclopropyl]-2,2,2-trifluoroacetamide as a white solid (1.4 g, 96% ).

1H NMR (500 MHz, DMSO-b6) δ=10.22 (s, 1H), 7.47-7.56 (m, 2H), 7.08-7.17 (m, 2H), 1.20 -1.31 (m, 4H).

Stage 2.

n-Butyllithium 1.6 M in hexane (5.67 ml, 9.07 mmol, 2 eq.) is added dropwise to a solution of N-[1-(4bromophenyl)cyclopropyl]-2,2,2-trifluoroacetamide (1, 4 g, 4.54 mmol) in dry THF (45 ml) at -78°C and then stirred for a further 40 minutes under argon. A-methoxy-Amethylcyclopropaneacetamide (0.845 g, 5.90 mmol, 1.3 eq.) dissolved in THF (1 ml) was added to the solution. The mixture was stirred at -78°C for 45 minutes, saturated aqueous ammonium chloride (50 ml) was added and the mixture was heated to rt. The layers are separated and the organic phase is washed with saturated sodium chloride solution and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The solid was dissolved in a small amount of DCM and then hexane (25 ml) was added dropwise with vigorous stirring to obtain a white solid. The solid was collected by filtration, washed with a small amount of hexane and dried in vacuo to give N-{1-[4(cyclopropylacetyl)phenyl]cyclopropyl}-2,2,2-trifluoroacetamide (0.915 g, 65%).

1H NMR (500 MHz, DMSO-D,) δ=10.27 (s, 1H), 7.89 (d, J=8.69 Hz, 2H), 7.24 (d, J=8.54 Hz , 2H), 2.90 (d, J=6.71 Hz, 2H), 1.29-1.41 (m, 3H), 0.96-1.09 (m, 1H), 0.44- 0.53 (m, 2H), 0.11-0.17 (m, 2H).

Step 3 Titanium(IV) isopropoxide (2.14 mL, 7.2 mmol, 5 eq.) is added to a solution of N-{1-[4(cyclopropylacetyl)phenyl]cyclopropyl}-2,2,2-trifluoroacetamide (0. 45 g, 1.44 mmol) and tert-butyl piperazine-1-carboxylate (0.644 g, 3.45 mmol, 2.4 eq.) in THF (8 ml) and stirred at 60°C overnight. The mixture was cooled to room temperature and MeOH (3 mL) was added, then sodium cyanoborohydride (0.18 g, 2.88 mmol, 2 eq.) was added portionwise. The mixture was stirred at room temperature for 8 hours, then water (15 ml) and MeOH (4 ml) were added and the mixture was stirred at rt overnight. The mixture is filtered to remove solids and the solids are washed with MeOH and water. Most of the volatiles are removed and the residue is extracted with EtOAc (2x). The combined organic extracts are dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product is purified by column chromatography, eluting with a 300/300/0 to 300/300/100 DCM/hexane/EtOAc gradient to give tert-butyl 4-[2-cyclopropyl-1-(4-{1-[(trifluoroacetyl) amino]cyclopropyl}phenyl)ethyl]piperazine 1-carboxylate as a white foam (0.46 g, 66%).

1H NMR (500 MHz, DMSO-b6) δ=10.15 (s, 1H), 7.19 (d, J=8.39 Hz, 2H), 7.08 (d, J=8.39 Hz, 2H), 3.42 (dd, J=5.72, 9.07 Hz, 1H), 3.16-3.31 (m, 4H), 2.22 (shs, 4H), 1.69-1 .81 (m, 1H), 1.50-1.60 (m, 1H), 1.34 (s, 9H),

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1.21-1.29 (m, 4H), 0.25-0.44 (m, 3H), -0.11-0.03 (m, 2H).

Stage 4.

Aqueous KOH (2M, 8 mL) was added to a solution of tert-butyl 4-[2-cyclopropyl-1-(4-{1[(trifluoroacetyl)amino]cyclopropyl}phenyl)ethyl]piperazine-1-carboxylate (0.46 g ) in EtOH (15 ml) and the resulting mixture was stirred at room temperature for 48 hours. Volatile substances were removed under reduced pressure, and saturated. aqueous NaHCO ₃ and partition with DCM. The combined organic extracts are dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give tert-butyl 4-{1-[4-(1-aminocyclopropyl)phenyl]-2-cyclopropylethyl}piperazine-1carboxylate as light yellow viscous oil (0.358 g, 97%).

1H NMR (500 MHz, DMSO-de) δ=7.23 (d, J=8.24 Hz, 2H), 7.13 (d, J=8.24 Hz, 2H), 3.42 (dd, J=5.49, 9.00 Hz, 1H), 3.25 (d, J=4.27 Hz, 4H), 2.22 (shs, 5H), 1.73-1.83 (m, 1H ), 1.55 (s, 1H), 1.33 (s, 9H), 0.85-0.97 (m, 4H), 0.34-0.45 (m, 1H), 0.25- 0.32 (m, 2H), -0.02 (d, J=18.76 Hz, 2H).

Example 1.

Methyl 4-{(^)-1-[(8-benzyl-7-oxopyrido[2,3^]pyrimidin-2-yl)amino]ethyl}benzoate [(I), X=N, I2=benzyl, A =phenyl, R1a=H, R1b=Me, R6a=-COOMe, R6b=H, R3=R4=R5=H] stage 1a, conn. 1

To a solution of the compound 8-benzyl-2-(methylsulfonyl)pyrido[2,3^|pyrimidin-7(8H)-one (100 mg, 0.32 mmol) in ANH (2 ml) add ^)-methyl 4-( 1-Aminoethyl)benzoate (86 mg, 0.48 mmol). The reaction mixture is heated to 90°C for 2 hours. The reaction mixture is diluted with EtOAc (4 ml) and washed with water (5 ml) and saturated sodium chloride solution (5 ml). The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel column chromatography (DCM/EtOAc 8/2) to give the title compound as a light yellow foam (100 mg, 76% yield).

1H NMR (401 MHz, DMSO-de) δ=8.63 (s, 1H), 8.50 (d, J=7.20 Hz, 1H), 7.79 (d, J=8.18 Hz, 2H), 7.75 (d, J=9.52 Hz, 1H), 7.41 (d, J=8.06 Hz, 2H), 7.08-7.19 (m, 3H), 7, 04 (d, J=5.61 Hz, 2H), 6.28 (d, J=9.52 Hz, 1H), 5.44 (d, J=14.04 Hz, 1H), 5.11 ( d, J=14.40 Hz, 1H), 5.07 (quin, J=7.00 Hz, 1H), 3.83 (s, 3H), 1.44 (d, J=6.96 Hz, 3H). LCMS: m/z 415 [M+H]+ v.a. 6.21 min.

MSVR (IER) calc. for C ₂₄ H ₂₃ N ₄ O ₃ [M+H]+ 415.1765 found 415.177. According to the same method, the following compounds are obtained:

Methyl 4-{(^)-1-[(8-ethyl-7-oxopyrido[2,3^]pyrimidin-2-yl)amino]ethyl}benzoate [(I), X=N,

I2=ethyl, A=phenyl, R1a=H, R1b=Me, R6a=-COOMe, R6b=H, R3=R4=R5=H] conn. 2

1H NMR (401 MHz, DMSO-de) δ=8.59 (s, 1H), 8.49 (d, J=6.6 Hz, 1H), 7.85-7.94 (m, 2H), 7.67 (d, J=9.3 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 6.21 (d, J=9.2 Hz, 1H), 5, 08 (quin, J=6.9 Hz, 1H), 4.15 (dkv, J=12.7, 6.6 Hz, 1H), 3.90-4.06 (m, 1H), 3.82 (s, 3H), 1.49 (d, J=7.2 Hz, 3H), 0.87 (t, J=6.8 Hz, 3H). LCMS: m/z 353 [M+H]+ v.a. 5.61 min. MSVR (IER) calc. for C ₁₉ H ₂₁ N ₄ O ₃ [M+H]+ 353.1608 found 353.1602;

Methyl 4-[(k)-1-{[8-(methoxymethyl)-7-oxopyrido[2,3^|pyrimidin-2-yl|amino(ethyl|benzoate [(I), X=N, I2=methoxymethyl , A=phenyl, R1a=H, R1b=Me, R6a=-COOMe, R6b=H, R3=R4=R5=H] connection 3

Chiral

ABOUT

1H NMR (401 MHz, DMSO-de) δ=8.61 (s, 1H), 8.57 (d, J=7.63 Hz, 1H), 7.91 (d, J=8.24 Hz, 2H), 7.73 (d, J=9.30 Hz, 1H), 7.55 (d, J=8.24 Hz, 2H), 6.23 (d, J=9.46 Hz, 1H) , 5.50 (d, J=9.00 Hz, 1H), 5.36 (d, J=9.15 Hz, 1H), 5.14 (quin, J=7.09 Hz, 1H), 3 .82 (s, 3H), 3.11 (s, 3H), 1.49 (d, J=7.02 Hz, 3H).

LCMS: m/z 369 [M+H]+ v.a. 5.24 min. MSVR (IER) calc. for C ₁₉ H ₂₁ N ₄ O ₄ [M+H]+ 369.1558 found 369.1567;

Methyl 4-{(^)-1-[(8-methyl-7-oxopyrido[2.3h!]pyrimidin-2-yl)amino]ethyl}benzoate [(I), X=N, I2=methyl, A =Phenyl, R1a=H, R1b=Me, R6a=-COOMe, R6b=H, R3=R4=R5=H] conn. 4

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1H NMR(401 MHz, DMSO-de) 5=8.96(bhs, 1H), 8.05 (g,J=8.54 Hz, 1H), 7.91 (d, J=7.93 Hz, 2H), 7.58 (d, J=7.02 Hz, 2H), 6.68 (d, J=8.54 Hz, 1H), 5.25-5.46 (m, 1H), 3, 92 (shs, 3H), 3.82 (s, 3H), 1.50 (d, J=7.02 Hz, 3H). LCMS: m/z 339 [M+H]+ v.a. 5.67 min. MSVR (IER) calc. for C ₁₈ H ₁₉ N ₄ O ₃ [M+H] ⁺ 339.1452 found 339.1443;

Methyl 4-[(H)-1-['[8-(2-methylpropyl)-7-oxopyrido[2,3H]pyrimidin-2-yl]amino}ethyl]benzoate [(I),

X=N, K2=2-methylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=-COOMe, R6b=H, R3=R4=R5=H] conn. 5

1H NMR (401 MHz, DMSO-f;) δ=8.60 (s, 1H), 8.47 (d, J=6.47 Hz, 1H), 7.91 (d, J=8.30 Hz , 2H), 7.69 (d, J=9.15 Hz, 1H), 7.51 (d, J=8.18 Hz, 2H), 6.22 (d, J=9.15 Hz, 1H ), 5.07 (quin, J=6.87 Hz, 1H), 3.92 (dd, J=7.81, 12.08 Hz, 1H), 3.82 (s, 3H), 3.77 (dd, J=7.60, 12.00 Hz, 1H), 1.88 (tt, J=6.74, 13.64 Hz, 1H), 1.49 (d, J=7.08 Hz, 3H), 0.72 (d, J=6.71 Hz, 3H), 0.57 (d, J=6.47 Hz, 3H). LCMS: m/z 381 [M+H] ⁺ v.a. 6.2 min. MSVR (IER) calc. for C ₂₁ H ₂₅ N ₄ O ₃ [M+H] ⁺ 381.1921 found 381.1915;

Methyl 4-[A)-1-{[8-(4-fluorobenzyl)-7-oxopyrido[2,3Upyrimidin-2-yl]amino}ethyl]benzoate [(I), X=N, R2=4-fluorobenzyl , A=phenyl, R1a=H, R1b=Me, R6a=-COOMe, R6b=H, R3=R4=R5=H] conn. 6

1H NMR (500 MHz, DMSO-06) δ=8.60 (s, 1H), 8.47 (d, J=6.47 Hz, 1H), 7.91 (d, J=8.30 Hz, 2H), 7.69 (d, J=9.15 Hz, 1H), 7.51 (d, J=8.18 Hz, 2H), 6.22 (d, J=9.15 Hz, 1H) , 5.07 (quin, J=6.87 Hz, 1H), 3.92 (dd, J=7.81, 12.08 Hz, 1H), 3.82 (s, 3H), 3.77 ( dd, J=7.60, 12.00 Hz, 1H), 1.88 (tt, J=6.74, 13.64 Hz, 1H), 1.49 (d, J=7.08 Hz, 3H ), 0.72 (d, J=6.71 Hz, 3H), 0.57 (d, J=6.47 Hz, 3H). LCMS: m/z 433 [M+H] ⁺ v.a. 6.29 min. MSVR (IER) calc. for C24H22FN4O3 [M+H] ⁺ 433.1671 found 433.1685;

Methyl 4-[A)-1-{[8-(3,5-difluorobenzyl)-7-oxopyrido[2,3^]pyrimidin-2-yl]amino}ethyl]benzoate [(I), X=N, K2=3,5-difluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=-COOMe, R6b=H, R3=R4=r5=H] conn. 7

G

1H NMR (500 MHz, DMSO-f;) δ=8.60 (s, 1H), 8.47 (d, J=6.47 Hz, 1H), 7.91 (d, J=8.30 Hz , 2H), 7.69 (d, J=9.15 Hz, 1H), 7.51 (d, J=8.18 Hz, 2H), 6.22 (d, J=9.15 Hz, 1H ), 5.07 (quin, J=6.87 Hz, 1H), 3.92 (dd, J=7.81, 12.08 Hz, 1H), 3.82 (s, 3H), 3.77 (dd, J=7.60, 12.00 Hz, 1H), 1.88 (tt, J=6.74, 13.64 Hz, 1H), 1.49 (d, J=7.08 Hz, 3H), 0.72 (d, J=6.71 Hz, 3H), 0.57 (d, J=6.47 Hz, 3H). LCMS: m/z 451 [M+H] ⁺ v.a. 6.36 min. MSVR (IER) calc. for C ₂₄ H ₂₁ F ₂ N ₄ O ₃ [M+H] ⁺ 451.1576 Found 451.1584;

Methyl 4-[(H)-1-(['8-[4-fluoro-2-(trifluoromethyl)benzyl]-7-oxopyrido[2,3H]pyrimidin-2-yl}amino)ethyl]benzoate [( I), X=N, K2=4-fluoro-2-(trifluoromethyl)benzyl, A=phenyl, R1a=H, R1b=Me, R6a=COOMe, R6b=H, R3=R4=R5=H] conn. 8

1H NMR (500 MHz, DMSOA δ=8.70 (s, 1H), 8.55 (d, J=6.71 Hz, 1H), 7.85 (d, J=9.30 Hz, 1H), 7.57 (dd, J=2.44, 9.15 Hz, 1H), 7.52 (d, J=8.24 Hz, 2H), 7.11 (d, J=8.39 Hz, 2H ), 7.05 (dt, J=2.29, 8.39 Hz, 1H), 6.24-6.35 (m, 2H), 5.49 (d, J=16.01 Hz, 1H) , 5.30 (d, J=15.71 Hz, 1H), 4.80 (quin, J=7.02 Hz, 1H), 3.81 (s, 3H), 1.31-1.47 ( m, 3H) LCMS: m/z 501 [M+H] ⁺ v.a. 6.65 min HRMS (ESI) calculated for C ₂₅ H ₂₁ F ₄ N ₄ O ₃ [M+H] ⁺ 501 ,1545 found 501,1541;

Methyl 4-[(P)-1-['[7-oxo-8-(propan-2-yl)pyrido[2.3P]pyrimidin-2-yl]amino}ethyl]benzoate [(I), X= N, R2=H3-nр, A=phenyl, R1a=H, R1b=Me, R6a=-COOMe, R6b=H, R3=R4=R5=H] conn. 9

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1H NMR (500 MHz, DMSO-de) δ=8.50-8.63 (m, 1H), 8.22-8.49 (m, 1H), 7.90 (d, J=8.39 Hz , 2H), 7.62 (d, J=8.85 Hz, 1H), 7.52 (d, J=8.08 Hz, 2H), 6.16 (d, J=8.85 Hz, 1H ), 5.39-5.79 (m, 1H), 5.00-5.33 (m, 1H), 3.81 (s, 3H), 1.49 (d, J=6.86 Hz, 3H), 0.97-1.39 (m, 6H). LCMS: m/z 367 [M+H]+ v.a. 5.98 min. MSVR (IER) calc. for C ₂₀ H ₂₃ N ₄ O ₃ [M+H] ⁺ 367.1765 found 367.1757;

Methyl 4-[(1S)-1-({8-[(3-methyloxetan-3-yl)methyl]-7-oxopyrido[2,3-d]pyrimidin-2-yl}amino)ethyl]benzoate [( I), X=N, K2=7-oxo-8-(3-methyloxetan-3-yl), A=phenyl, R1a=H, R1b=Me, R6a=-COOMe,

R6b=H, R3=R4=R5=H] conn. 10

LCMS: m/z 409 [M+H] ⁺ v.a. 5.2 min. MSVR (IER) calc. for C ₂₂ H ₂₅ N ₄ O ₄ [M+H] ⁺ 409.1871 found 409.1873;

Methyl 4-[(1S)-1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]benzoate [(I), X= N, K2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=-COOMe, R6b=H, R3=R4=R5=H] conn. eleven

1H NMR (500 MHz, DMSO-06) δ=8.59 (s, 1H), 8.47 (d, J=7.32 Hz, 1H), 7.91 (d, J=8.08 Hz, 2H), 7.68 (d, J=9.15 Hz, 1H), 7.49-7.56 (m, 2H), 6.23 (d, J=9.30 Hz, 1H), 5, 12 (t, J=6.79 Hz, 1H), 4.01-4.25 (m, 1H), 3.93 (d, J=12.51 Hz, 1H), 3.82 (s, 3H ), 1.48 (d, J=7.02 Hz, 3H), 0.42-1.00 (m, 9H). LCMS: m/z 395 [M+H] ⁺ v.a. 6.44 min. MSVR (IER) calc. for C ₂₂ H ₂₇ N ₄ O ₃ [m+H] ⁺ 395.2078 found 395.2077;

2-{[(1S)-1-Cyclohexylethyl]amino}-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one [(I), X=N, K2=ethyl,

A=cyclohexyl, R1a=H, R1b=Me, R6a=R6b=H, R3=R4=R5=H] connection 12

1H NMR (401 MHz, DMSO-d;) δ=8.54 (s, 1H), 7.61-7.75 (m, 2H), 6.21 (d, J=9.28 Hz, 1H) , 4.12-4.35 (m, 2H), 3.85-3.95 (m, 1H), 1.48-1.79 (m, 6H), 0.90-1.25 (m, 11H). LCMS: m/z 301 [M+H] ⁺ v.a. 6.94 min. MSVR (IER) calc. for C ₁₇ H ₂₅ N ₄ O [M+H] ⁺ 301.2023 found 301.2029;

8-Ethyl-2-{[(1S)-1-(4-methoxyphenyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one K2=Ethyl, A=phenyl, R1a=H , R1b=Me, R6a=4-methoxy, R6b=H, R3=R4=R5=H] conn. 13

[(I), X=N,

1H NMR (401 MHz, DMSO-06) δ=8.56 (s, 1H), 8.33 (d, J=7.45 Hz, 1H), 7.67 (d, J=9.28 Hz, 1H), 7.267.38 (m, 2H), 6.79-6.92 (m, 2H), 6.21 (d, J=9.40 Hz, 1H), 5.01 (quin, J=7 .42 Hz, 1H), 4.15-4.34 (m, 1H), 4.024.15 (m, 1H), 3.70 (s, 3H), 1.46 (d, J=6.96 Hz , 3H), 1.02 (t, J=6.71 Hz, 3H). LCMS: m/z 325 [M+H] ⁺ v.a. 5.73 min. MSVR (IER) calc. for C ₁₈ H ₂₁ N ₄ O ₂ [M+H] ⁺ 325.1659 found 325.1663;

2-{[(1S)-1-(4-Chlorophenyl)ethyl]amino}-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one [(I), X=N, K2=Ethyl , A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 14

Chiral

Cl

1H NMR (401 MHz, DMSO-06) δ=8.58 (s, 1H), 8.43 (d, J=7.32 Hz, 1H), 7.67 (d, J=9.40 Hz, 1H), 7.397.45 (m, 2H), 7.33-7.38 (m, 2H), 6.22 (d, J=9.52 Hz, 1H), 4.87-5.14 (m , 2H), 4.14-4.26 (m, 1H), 3.99-4.07 (m, 1H), 1.47 (d, J=7.08 Hz, 3H), 0.94 ( t, J=6.77 Hz, 3H). LCMS: m/z 329 [M+H] ⁺ v.a. 6.24 min. MSVR (IER) calc. for C17H18CIN4O [M+H] ⁺ 329.1164 found 329.1167;

2-{[(1 S)-1-(4-Chlorophenyl)ethyl]amino}-8-(pentan-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) , X=N, R2=pentan-3-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 15

- 58 046117

1H NMR (401 MHz, DMSO-de) δ=8.89 (s, 1H), 8.09 (d, J=8.67 Hz, 1H), 8.01 (d, J=8.67 Hz, 1H), 7.337.48 (m, 4H), 6.63 (d, J=8.54 Hz, 1H), 5.11-5.47 (m, 2H), 1.57-1.78 (m , 4H), 1.43-1.51 (m, 3H), 0.77-0.96 (m, 6H). LCMS: m/z 371 [M+H]+ v.a. 7.78 min. MSVR (IER) calc. for C ₂₀ H ₂₄ ClN ₄ O [M+H] ⁺ 371.1633 found 371.1642;

8-Benzyl-2-{[(^)-1-(4-chlorophenyl)ethyl]amino}pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N,

K2=benzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 16

1H NMR (500 MHz, DMSO) δ=8.62 (s, 1H), 8.47 (d, J=7.63 Hz, 1H), 7.75 (d, J=9.30 Hz, 1H) , 7.267.30 (m, 2H), 7.22-7.26 (m, 2H), 7.15-7.20 (m, 3H), 7.08 (d, J=6.10 Hz, 2H ), 6.28 (d, J=9.46 Hz, 1H), 5.46 (d, J=14.18 Hz, 1H), 5.17 (d, J=14.03 Hz, 1H), 4.99-5.07 (m, 1H), 1.41 (d, J=7.02 Hz, 3H). LCMS: m/z 391 [M+H] ⁺ v.a. 6.86 min. MSVR (IER) calc. for C ₂₂ H ₂₀ ClN ₄ O [M+H] ⁺ 391.132 found 391.1324;

2-{[(1 S)-1-(4-Chlorophenyl)ethyl]amino}-8-(2-fluoroethyl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I), X =N, K2=2-fluoroethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 17

Chiral ci

F

1H NMR (500 MHz, DMSO) δ=8.61 (s, 1H), 8.52 (d, J=6.86 Hz, 1H), 7.72 (d, J=9.30 Hz, 1H) , 7.387.43 (m, 2H), 7.33-7.38 (m, 2H), 6.24 (d, J=9.30 Hz, 1H), 4.96-5.04 (m, 1H ), 4.26-4.75 (m 4H), 1.45 (d, J=7.02 Hz, 3H). LCMS: m/z 347 [M+n] ⁺ v.a. 6.03 min. MSVR (IER) calc. for C ₁₇ H ₁₇ ClFN ₄ O [m+H] ⁺ 347.107 found 347.1069;

2-{[(^)-1-(4-Chlorophenyl)ethyl]amino}-8-(2,2,2-trifluoroethyl)pyrido[2,3^]pyrimidin-7(8H)-one [(I) , X=N, K2=2,2,2-trifluoroethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 18

1H NMR (500 MHz, DMSO-06) δ=8.65 (s, 1H), 8.63 (m, 1H), 7.79 (d, J=9.46 Hz, 1H), 7.38- 7.42 (m, 2H), 7.33-7.38 (m, 2H), 6.29 (d, J=9.46 Hz, 1H), 5.14-5.24 (m, 1H) , 4.99-5.07 (m, 1H), 4.74-4.87 (m, 1H), 1.41-1.52 (m, 3H). LCMS: m/z 383 [M+H] ⁺ v.a. 6.61 min. MSVR (IER) calc. for C ₁₇ H ₁₅ ClF ₃ N ₄ O [M+H] ⁺ 383.0881 found 383.0893;

2-{[(^)-1-(4-Chlorophenyl)ethyl]amino}-8-(2-methylpropyl)pyrido[2,3^]pyrimidin-7(8H)-one [(I),

X=N, K2=2-methylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 19

1H NMR (500 MHz, DMSO) δ=8.59 (s, 1H), 8.41 (d, J=7.45 Hz, 1H), 7.69 (d, J=9.28 Hz, 1H) , 7.277.46 (m, 4H), 6.23 (d, J=9.28 Hz, 1H), 5.01 (quin, J=6.87 Hz, 1H), 3.95 (dd, J= 7.51, 12.14 Hz, 1H), 3.68-3.89 (m, 1H), 1.92 (df, J=6.60 Hz, 1H), 1.46 (d, J=7 .08 Hz, 3H), 0.75 (d, J=6.59 Hz, 3H), 0.62 (d, J=6.59 Hz, 3H). LCMS: m/z 357 [M+H] ⁺ v.a. 6.86 min. MSVR (IER) calc. for C ₁₉ H ₂₂ ClN ₄ O [M+H] ⁺ 357.1477 found 357.148;

2-{[(^)-1-(4-Chlorophenyl)ethyl]amino}-8-(cyclopropylmethyl)pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, K2 =cyclopropylmethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 20

- Chiral

1H NMR (500 MHz, DMSO) δ=8.60 (s, 1H), 8.46 (d, J=6.86 Hz, 1H), 7.70 (d, J=9.30 Hz, 1H) , 7.187.44 (m, 4H), 6.24 (d, J=9.15 Hz, 1H), 4.82-5.06 (m, 1H), 4.04 (dd, J=6.86 , 12.66 Hz, 1H), 3.76-3.89 (m, 1H),

- 59 046117

1.46 (d, J=7.02 Hz, 3H), 0.89-1.03 (m, 1H), 0.24-0.35 (m, 4H). LCMS: m/z 355 [M+H]+ v.a. 6.67 min. MSVR (IER) calc. for CAClNi) [M+H] ⁺ 355.132 found 357.1424;

2-{[(^)-1-(4-Chlorophenyl)ethyl]amino}-8-(4-methoxybenzyl)pyrido[2,3^]pyrimidin-7(8H)-one [(I),

X=N, R2=4-methoxybenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 21

¹ H NMR (500 MHz, DMSO-06) δ=8.62 (s, 1H), 8.48 (d, J=7.47 Hz, 1H), 7.72 (d, J=9.30 Hz , 1H), 7.267.35 (m, 4H), 7.01 (d, J=8.39 Hz, 2H), 6.67 (d, J=8.54 Hz, 2H), 6.26 (d , J=9.30 Hz, 1H), 5.37 (d, J=13.88 Hz, 1H), 5.05-5.14 (m, 2H), 3.68 (s, 3H), 1 .45 (d, J=7.02 Hz, 3H). LCMS: m/z 421 [M+H] ⁺ v.a. 6.75 min. MSVR (IER) calc. for C^ClN^ [M+H] ⁺ 421.1426 Found 357.1442;

2-{[(^)-1-(4-Chlorophenyl)ethyl]amino}-8-(2-fluorobenzyl)pyrido[2,3^]pyrimidin-7(8H)-one

X=N, R2=2-fluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 22

[(I),

1H NMR (500 MHz, DMSO-06) δ=8.64 (s, 1H), 8.13-8.52 (m, 1H), 7.80 (d, J=9.30 Hz, 1H), 7.24-7.41 (m,

2H), 7.11-7.24 (m, 4H), 6.90-7.09 (m, 1H), 6.52-6.84 (m, 1H), 6.31 (d, J= 9.30 Hz, 1H), 5.49 (d, J=15.10 Hz, 1H), 5.20-5.32 (m, 1H), 4.82-4.95 (m, 1H), 1.32-1.49 (m, 3H). LCMS: m/z 409 [M+H] ⁺ v.a. 6.9 min. MSVR (IER) calc. for C22H19CIFN4O [M+H] ⁺ 409.1226 Found 409.123;

2-{[(^)-1-(4-chlorophenyl)ethyl]amino}-8-(3,4-difluorobenzyl)pyrido[2,3^]pyrimidin-7(8H)-one [(I),

X=N, R2=3,4-difluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 23

1H NMR (500 MHz, DMSO-06) δ=8.56-8.70 (m, 1H), 8.52 (d, J=7.47 Hz, 1H), 7.76 (d, J=9 ,30 Hz, 1H),

7.32-7.44 (m, 1H), 7.13-7.30 (m, 4H), 6.97-7.08 (m, 1H), 6.71-6.87 (m, J =5.03 Hz, 1H), 6.28 (d, J=9.30 Hz, 1H), 5.34-5.50 (m, 1H), 4.88-5.28 (m, 2H) , 1.38-1.51 (m, 3H). LCMS: m/z 427 [M+H] ⁺ v.a. 6.9 min. MSVR (IER) calc. for C22H18OT2N4O [M+H] ⁺ 427.1132 found 427.1137;

2-{[(^)-1-(4-chlorophenyl)ethyl]amino}-8-[3-(trifluoromethyl)benzyl]pyrido[2,3^]pyrimidin-7(8H)one [(I), X =N, R2=3-(trifluoromethyl)benzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 24

1H NMR (500 MHz, DMSO-06) δ=8.56-8.72 (m, 1H), 8.31-8.53 (m, 1H), 7.70-7.80 (m, 1H) , 7.51-7.66 (m, 2H), 7.39 (t, J=7.63 Hz, 1H), 7.21-7.28 (m, 3H), 7.17 (d, J =8.39 Hz, 2H), 6.30 (d, J=9.30 Hz, 1H), 5.58 (d, J=14.49 Hz, 1H), 5.22 (d, J=14 .95 Hz, 1H), 4.89-5.05 (m, 1H), 1.32-1.49 (m, 3H). LCMS: m/z 459 [M+H] ⁺ v.a. 7.34 min. MSVR (IER) calc. for C ₂₂ H ₁₉ ClF ₃ N ₄ O [M+H] ⁺ 459.1194 found 459.1192;

2-{[(^)-1-(4-chlorophenyl)ethyl]amino}-8-(2,4-difluorobenzyl)pyrido[2,3^]pyrimidin-7(8H)-one [(I), X =N, R2=2,4-difluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 25

1H NMR (500 MHz, DMSO-06) δ=8.57-8.73 (m, 1H), 8.49 (d, J=7.63 Hz, 1H), 7.79 (d, J=9 .30 Hz, 1H), 7.31-7.42 (m, 1H), 7.13-7.28 (m, 4H), 6.53-7.00 (m, 2H), 6.30 ( d, J=9.46 Hz, 1H), 5.42 (d, J=14.64 Hz, 1H), 5.20 (d, J=14.95 Hz, 1H), 4.80-4, 99 (m, 1H), 1.33-1.47 (m, 3H). LCMS: m/z 427 [M+H] ⁺ v.a. 6.97 min. MSVR (IER) calc. for C22I I^ClFAjO) [M+H] ⁺ 427.1132 found 427.1136;

2-{[(1 S)-1 -(4-Chlorophenyl)ethyl] amino }-8-[4-(trifluoromethoxy)benzyl] pyrido [2,3^]pyrimidin7(8H)-one [(I), X =N, R2=4-(trifluoromethoxy)benzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=I] conn. 26

- 60 046117

1H NMR (500 MHz, DMSO-de) δ=8.57-8.68 (m, 1H), 8.27-8.54 (m, 1H), 7.64-7.80 (m, 1H) , 7.33-7.48 (m, 1H), 7.30 (d, J=8.39 Hz, 2H), 7.21-7.25 (m, 2H), 7.08-7.19 (m, 3H), 6.28 (d, J=9.30 Hz, 1H), 5.40-5.55 (m, 1H), 4.99-5.28 (m, 2H), 1, 38-1.49 (m, 3H). LCMS: m/z 475 [M+H]+ v.a. 7.46 min. MSVR (IER) calc. for C ₂₂ H ₁₉ ClF ₃ N ₄ O ₂ [M+H] ⁺ 475.1143 found 475.114;

4-{[2-{[(^)-1-(4-Chlorophenyl)ethyl]amino}-7-oxopyrido[2,3^]pyrimidin-8(7H)-yl]methyl}benzonitrile [(I), X=N, K2=4-cyanobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 27

1H NMR (500 MHz, DMSO-th) δ=8.65 (s, 1H), 8.51 (d, J=7.32 Hz, 1H), 7.79 (d, J=9.46 Hz, 1H), 7.62 (d, J=8.08 Hz, 2H), 7.17-7.25 (m, 2H), 7.14 (d, J=7.63 Hz, 4H), 6, 29 (d, J=9.30 Hz, 1H), 5.54 (d, J=15.10 Hz, 1H), 5.20 (d, J=15.10 Hz, 1H), 4.92 ( quin, J=7.28 Hz, 1H), 1.38 (d, J=7.02 Hz, 3H).

LCMS: m/z 416 [M+H] ⁺ v.a. 6.4 min. MSVR (IER) calc. for C ₂₃ Hi ₉ ClN ₄ O [M+H] ⁺ 416.1273 found 416.129;

2-{[(^)-1-(4-Chlorophenyl)ethyl]amino}-8-(4-fluorobenzyl)pyrido[2,3^]pyrimidin-7(8H)-one [(I),

X=N, R2=4-fluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 28

1H NMR (500 MHz, DMSO-d;) δ=8.63 (s, 1H), 8.50 (d, J=7.47 Hz, 1H), 7.75 (d, J=9.30 Hz , 1H), 7.287.33 (m, 2H), 7.22-7.28 (m, 2H), 7.08 (dd, J=5.80, 7.93 Hz, 2H), 6.95 ( t, J=8.85 Hz, 2H), 6.27 (d, J=9.30 Hz, 1H), 5.42 (d, J=14.34 Hz, 1H), 5.12 (d, J=14.18 Hz, 1H), 5.04 (quin, J=6.98 Hz, 1H), 1.43 (d, J=6.86 Hz, 3H). LCMS: m/z 409 [M+H] ⁺ v.a. 6.4 min. MSVR (IER) calc. for C ₂₂ H ₁₉ ClFN ₄ O [M+H] ⁺ 409.1226 Found

409.1228;

2-{[(^)-1-(4-Chlorophenyl)ethyl]amino}-8-(3,5-difluorobenzyl)pyrido[2,3^]pyrimidin-7(8H)-one [(I),

X=N, R2=3,5-difluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 29

1H NMR (500 MHz, DMSO-d;) δ=8.65 (s, 1H), 8.53 (d, J=7.78 Hz, 1H), 7.78 (d, J=9.30 Hz , 1H), 7.25 (d,

J=8.24 Hz, 2H), 7.17 (d, J=8.39 Hz, 2H), 7.05 (tt, J=2.30, 9.50 Hz, 1H), 6.69 ( d, J=6.71 Hz, 2H), 6.29 (dD=9.46 Hz, 1H), 5.50 (d, J=14.79 Hz, 1H), 5.16 (d, J= 15.10 Hz, 1H), 4.98 (quin, J=7.10 Hz, 1H), 1.39 (d, J=7.02 Hz, 3H). LCMS: m/z 427 [M+H] ⁺ v.a. 6.99 min. MSVR (IER) calc. for C ₂₂ H ₁₈ ClF ₂ N ₄ O [M+H] ⁺ 427.1132 found 427.1139;

2-{[(^)-1-(4-Chlorophenyl)ethyl]amino}-8-(3-methoxybenzyl)pyrido[2,3^]pyrimidin-7(8H)-one [(I),

X=N, K2=3-methoxybenzyl A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. thirty

1H NMR (500 MHz, DMSO-d;) δ=8.56-8.69 (m, 1H), 8.47 (d, J=7.78 Hz, 1H), 7.76 (d, J= 9.46 Hz, 1H), 7.24-7.30 (m, 2H), 7.20 (d, J=8.24 Hz, 2H), 7.10 (t, J=7.85 Hz, 1H), 6.79 (dd, J=2.13, 7.93 Hz, 1H), 6.70 (shs, 1H), 6.61 (d, J=7.47 Hz, 1H), 6, 29 (d, J=9.30 Hz, 1H), 5.45 (d, J=14.34, 1H), 5.16 (d, J=14.49 Hz, 1H), 4.965.07 (m , 1H), 3.64-3.73 (m, 3H), 1.37-1.49 (m, 3H). LCMS: m/z 421 [M+H] ⁺ v.a. 6.79 min. MSVR (IER) calc. for C ₂₃ H ₂₂ ClN ₄ O ₂ [M+H] ⁺ 421.1426 Found 421.1436;

2-{[(^)-1-(4-Chlorophenyl)ethyl]amino}-8-(2,6-difluorobenzyl)pyrido[2,3^]pyrimidin-7(8H)-one [(I), X =N, R2==2,6-difluorobenzyl A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 31

- 61 046117

Ή NMR (500 MHz, DMSOb) δ=8.60 (s, 1H), 8.09-8.47 (m, J=8.08 Hz, 1H), 7.74 (d, J=9.30 Hz, 1H), 7.26-7.43 (m, 3H), 7.21 (d, J=8.24 Hz, 2H), 6.87-7.05 (m, 2H), 6.24 (d, J=9.30 Hz, 1H), 5.56 (d, J=14.95 Hz, 1H), 5.30 (d, J=14.95 Hz, 1H), 4.98-5 .05 (m, 1H), 1.32-1.48 (m, 3H). LCMS: m/z 427 [M+H]+ v.a. 6.84 min. MSVR (IER) calc. for C ₂₂ H ₁₈ ClF ₂ N ₄ O [M+H] ⁺ 427.1132 found 427.1135;

2-{[(18)-1-(4-Chlorophenyl)ethyl]amino}-4-methyl-8-(2-methylpropyl)pyrido[2,3-0]pyrimidin-7(8H)one [(I) , X=N, R2=2-methylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=Me, R4=R5=H] conn. 32

1H NMR (500 MHz, DMSO-de) δ=8.36 (d, J=7.02 Hz, 1H), 7.87 (d, J=9.61 Hz, 1H), 7.28-7, 43 (m, 4H), 6.20 (d, J=9.61 Hz, 1H), 4.98 (d, J=10.83 Hz, 1H), 3.96 (dd, J=7.40 , 11.97 Hz, 1H), 3.79-3.87 (m, J=11.74 Hz, 1H), 1.79-1.97 (m, 1H), 1.43 (d, J= 7.02 Hz, 3H), 1.23 (s, 3H), 0.73 (d, J=6.86 Hz, 3H), 0.60 (d, J=6.71 Hz, 3H). LCMS: m/z 371 [M+H] ⁺ v.a. 7.11 min. MSVR (IER) calc. for C ₂₀ H ₂₄ ClN ₄ O [M+H] ⁺ 371.1633 found

371.1633;

8-(2,2-Dimethylpropyl)-2-['[('H)-'1-(4-methoxyphenyl)ethyl]amino}pyrido[2,3U]pyrimidin-7(8H)-one [(I) , X=N, R2=2,2-dimethylπpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-MeO, R6b=H, R3=R4=R5=H] conn. 33

1H NMR (500 MHz, DMSO-de) δ=8.52-8.57 (m, 1H), 8.32 (d, J=7.63 Hz, 1H), 7.67 (d, J=9 .15 Hz, 1H), 7.29 (d, J=8.54 Hz, 2H), 6.86 (d, J=8.54 Hz, 2H), 6.22 (d, J=9.30 Hz, 1H), 5.01-5.36 (dkv, J=7.6, 6.90, Hz, 1H), 3.87-4.44 (m, 2H), 3.70 (s, 3H ), 1.44 (d, J=7.02 Hz, 3H), 0.58-1.02 (m, 9H).

LCMS: m/z 367 [M+n] ⁺ v.a. 6.6 min. MSVR (IER) calc. for C ₂₁ H ₂₇ N ₄ O ₂ [M+H] ⁺ 367.2129 found 367.2132;

2-{[(^)-1-(4-Bromophenyl)ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2.3H]pyrimidin-7(8H)-one [(I), X= N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Br, R6b=H, R3=R4=R5=H] conn. 34

1H NMR (500 MHz, DMSO-dg) δ=8.58 (s, 1H), 8.40 (d, J=7.47 Hz, 1H), 7.68 (d, J=9.30 Hz, 1H), 7.50 (d, J=8.40 Hz, 2H), 7.34 (d, J=8.39 Hz, 2H), 6.23 (d, J=9.30 Hz, 1H) , 5.04 (quin, J=6.90 Hz, 1H), 3.96-4.25 (m, 2H), 1.45 (d, J=7.02 Hz, 3H), 0.75 ( shs, 9N). LCMS: m/z 415 [M+H] ⁺ v.a. 7.21 min. MSVR (IER) calc. for C ₂₀ H ₂₄ BrN ₄ O [M+H] ⁺ 415.1128 found 415.1135;

2-{[(^)-1-(4-Bromophenyl)ethyl]amino}-8-(3-hydroxy-2,2-dimethylpropyl)pyrido[2.3H]pyrimidin7(8H)-one [(I), X=N, R2=3-hydroxy-2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Br, R6b=H, R3=R4=R5=H] conn. 35

1H NMR (500 MHz, DMSO-de) δ=8.52-8.67 (m, 1H), 8.47 (d, J=7.63 Hz, 1H), 7.72 (d, J=9 .30 Hz, 1H), 7.46-7.53 (m, 2H), 7.37 (d, J=8.24 Hz, 2H), 6.26 (d, J=9.15 Hz, 1H ), 4.94-5.35 (m, J=6.94, 6.94 Hz, 1H), 4.60 (shs, 1H), 4.01-4.28 (m, 2H), 3, 06 (shs, 2H), 1.45 (d, J=7.02 Hz, 3H), 0.62 (shs, 6H). LCMS: m/z 431 [M+H] ⁺ v.a. 6.25 min. MSVR (IER) calc. for C ₂₀ H ₂₄ BrN ₄ O ₂ [M+H] ⁺ 431.1077 found 431.1085;

8-(2,2-Dimethylpropyl)-2-{[(^)-1-(naphthalene-2-yl)ethyl]amino}pyrido[2.3H]pyrimidin-7(8H)-one [(I), X=N, R2=2,2-dimethylpropyl, A=2-naphthalene^ R1a=H, R1b=Me, R6a=R6b=H, R3=R4=R5=H] conn. 36

- 62 046117

Ή NMR (500 MHz, DMSO-dg) δ=8.59 (s, 1H), 8.49 (d, J=7.47 Hz, 1H), 7.76-7.92 (m, 4H), 7.66 (d, J=9.30

Hz, 1H), 7.58 (dd, J=1.45, 8.46 Hz, 1H), 7.41-7.48 (m, 2H), 6.20 (d, J=9.30 Hz , 1H), 5.25 (quin, J=7.32 Hz, 1H), 3.90-4.36 (m, 2H), 1.56 (d, J=7.02 Hz, 3H), 0 .50-1.04 (m, 9H). LCMS: m/z 387 [M+H]+ v.a. 7.27 min. MSVR (IER) calc. for C ₂₄ H ₂₇ N ₄ O [M+H]+ 387.218 found 387.2178;

Methyl 2,2-dimethyl-3-[2-{[(^)-1-(naphthalene-2-yl)ethyl]amino}-7-oxopyrido[2,3Upyrimidine

8(7H)-yl]propanoate [(I), X=N, K2=methyl-2,2-dimethyl-3-propanoate, A=2-naphthalenyl, R1a=H, R1b=Me,

R6a=R6b=H, R3=R4=R5=H] conn. 37

1H NMR (500 MHz, DMSO-dg) δ=8.60 (s, 1H), 8.55 (d, J=7.47 Hz, 1H), 7.80-7.92 (m, 4H), 7.68 (d, J=9.30 Hz, 1H), 7.58 (dd, J=1.45, 8.46 Hz, 1H), 7.38-7.50 (m, 2H), 6 ,18 (d, J=9.30 Hz, 1H), 5.12-5.32 (m, J=7.17 Hz, 1H), 4.21-4.28 (m, 2H), 3, 42 (s, 3H), 1.56 (d, J=7.02 Hz, 3H), 1.07-1.11 (m, 3H), 0.83 (s, 3H). LCMS: m/z 431 [M+H]+ v.a. 6.63 min. MSVR (IER) calc. for C ₂₅ H ₂₇ N ₄ O ₃ [M+H]+ 431.2078 found 431.2076;

8-(3-Hydroxy-2,2-dimethylpropyl)-2-{[(>)-'1-(naphthalene-2-yl)ethyl]amino}pyrido[2,3D]pyrimidin-7(8H)-one [(I), X=N, R2=3-hydroxy-2,2-dimethylpropyl, A=2-naphthalenyl, R1a=H, R1b=Me, R6a=R6b=H, R3=R4=R5=H] conn. . 38

1H NMR (500 MHz, DMSO-0 ₆ ) δ=8.61 (s, 1H), 8.55 (d, J=7.32 Hz, 1H), 7.79-7.92 (m, 4H) , 7.71 (d, J=9.30 Hz, 1H), 7.60 (d, J=8.54 Hz, 1H), 7.37-7.52 (m, 2H), 6.23 ( d, J=9.30 Hz, 1H), 5.08-5.47 (m, J=7.32, 7.32 Hz, 1H), 4.50-4.69 (m, 1H), 3 .96-4.40 (m, 2H), 3.00-3.16 (m, 2H), 1.56 (s, 3H), 0.80-0.86 (m, 3H), 0.68 -0.74 (m, 3H). LCMS: m/z 403 [M+H]+ v.a. 6.34 min. MSVR (IER) calc. for C ₂₄ H ₂₇ N ₄ O ₂ [M+H]+ 403.2129 found

403.214;

8-(2,2-Dimethylpropyl)-2-{[('1G)-'1-phenylethyl]amino}pyrido[2,3D]pyrimidin-7(8H)-one [(I), X=N,

R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=R6b=H, R3=R4=R5=H] conn. 39

1H NMR (500 MHz, DMSOU) δ=8.50-8.60 (m, 1H), 8.05-8.43 (m, 1H), 7.67 (d, J=9.30 Hz, 1H ), 7.36-7.42 (m, 2H), 7.26-7.33 (m, 2H), 7.15-7.22 (m, 1H), 6.22 (d, J=9 ,30 Hz, 1H), 5.01-5.30 (m, 1H), 3.79-4.33 (m, 2H), 1.46 (d, J=7.02 Hz, 3H), 0 .66-0.99 (m, 9H). LCMS: m/z 337 [M+H]+ v.a. 6.73 min. MSVR (IER) calc. for C ₂₀ H ₂₅ N ₄ O [M+H]+ 337.2023 found 337.2025;

8-(2,2-Dimethylpropyl)-2-{[(>)-'1-phenylethyl]amino}pyrido[2,3D]pyrimidin-7(8H)-one [(I), X=N,

R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=R6b=H, R3=R4=R5=H] conn. 40

Chiral

ABOUT

1H NMR (500 MHz, DMSOU) δ=8.57 (s, 1H), 8.39 (d, J=7.63 Hz, 1H), 7.67 (d, J=9.15 Hz, 1H) , 7.38 (d,

J=7.63 Hz, 2H), 7.30 (t, J=7.55 Hz, 2H), 7.16-7.21 (m, 1H), 6.22 (d, J=9.30 Hz, 1H), 5.08 (t, J=7.09 Hz, 1H), 3.98-4.28 (m, 2H), 1.46 (d, J=7.02 Hz, 3H), 0.77 (shs, 9N). LCMS: m/z 337 [M+H]+ v.a. 6.73 min. MSVR (IER) calc. for C20H25N4O [M+H]+ 337.2023 found 337.2024;

8-(2,2-Dimethylpropyl)-2-[(2-phenylpropan-2-yl)amino]pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N,

R2=2,2-dimethylpropyl, A=phenyl, R1a=R1b=Me, R6a=R6b=H, R3=R4=R5=H] conn. 41

1H NMR (500 MHz, DMSOU) δ=8.57 (brs, 1H), 8.15 (brs, 1H), 7.64 (d, J=8.85 Hz, 1H), 7.38 (d, J=6.71 Hz, 2H), 7.25 (t, J=7.63 Hz, 2H), 7.11-7.16 (m, 1H), 6.20 (d, J=9.30 Hz, 1H), 3.73 (shs, 2H), 1.71 (s, 6H), 0.54

- 63 046117 (shs., 9N). LCMS: m/z 351 [M+H]+ v.a. 7.02 min. MSVR (IER) calc. for C ₂₁ H ₂₇ N4O [M+H]+ 351.218 found 351.2176;

8-(2,2-Dimethylpropyl)-2-1(1-phenylcyclopropyl)amino|pyrido[2,3Upyrimidin-7('8Н)-one [(I),

X=N, I2=2,2-dimethylpropyl, A=phenyl, R1a-R1b=cyclopropyl, R6a=R6b=H, R3=R4=R5=H] conn. 42

1H NMR (500 MHz, DMSOA) δ=8.64 (s, 1H), 8.60 (s, 1H), 7.68-7.72 (m, 1H), 7.22 (d, J=7 ,32 Hz, 2H), 7.16-7.19 (m, 2H), 7.06-7.13 (m, 1H), 6.25 (d, J=9.30 Hz, 1H), 3 .87-4.29 (m, 2H), 1.23-1.38 (m, 2H), 0.90-0.95 (m, 2H), 0.61 (s, 9H). LCMS: m/z 349 [M+H]+ v.a. 6.71 min. MSVR (IER) calc. for C ₂₁ H ₂₅ N ₄ O [M+H]+

349.2023 found 349.2021;

8-(2,2-Dimethylpropyl)-2-[(1-phenylcyclobutyl)amino]pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N,

I2=2,2-dimethylpropyl, A=phenyl, R1a-P1b=cyclobutyl, R6a=R6b=H, R3=R4=R5=H] conn. 43

1H NMR (500 MHz, DMSOA) δ=8.69 (s, 1H), 8.58 (s, 1H), 7.65 (d, J=9.00 Hz, 1H), 7.45-7, 52 (m, 2H),

7.29 (t, J=8.01 Hz, 2H), 7.10-7.18 (m, 1H), 6.20 (d, J=9.30 Hz, 1H), 3.88 (shs , 2H), 1.90-2.13 (m, 4H), 0.9-0.94 (m, 2H), 0.57 (s, 9H). LCMS: m/z 363 [M+H]+ v.a. 7.16 min. MSVR (IER) calc. for C ₂₂ H ₂₇ N ₄ O [M+H]+

363.218 found 363.2187;

8-(2,2-Dimethylpropyl)-2-{[1-(tricyclo[3,3,1,1 ³ ' ⁷ ]dec-1-yl)ethyl]amino}pyrido[2,3^]pyrimidine7(8H )-one [(I), X=N, I2=2,2-dimethylpropyl, A=adamantanyl, R1a=H, R1b=Me, R6a=R6b=H, R3=R4=R5=H] conn. 44

1H NMR (500 MHz, DMSO- _s16 ) δ 8.53 (s, 1H), 7.57-7.72 (m, 1H), 7.17-7.56 (m, 1H), 6.07 -6.29 (m, 1H), 4.20 (shs, 2H), 3.84-4.05 (m, 1H), 1.94 (shs, 3H), 1.39-1.71 (m , 12n), 1.05 (d, J=6.86 Hz, 3n), 0.86-0.96 (m, 9n). LCMS: m/z 395 [M+H]+ v.a. 8.81 min. MSVR (IER) calc. for C ₂₄ H ₃₄ N ₄ O [M+H]+ 395.2806 Found

395.2813;

8-[(3-Methyloxetan-3-yl)methyl]-2-{[(^)-1-(naphthalene-2-yl)ethyl]amino}pyrido[2,3^]pyrimidin7(8H)-one [ (I), X=N, I2=(3-methyloxetan-3-yl)methyl, A=2-naphthalenyl, R1a=H, R1b=Me, R6a=R6b=H, R3=R4=R5=H] conn. . 45

1H NMR (500 MHz, DMSOA) δ=8.65 (s, 1H), 8.60 (d, J=7.02 Hz, 1H), 7.78-7.91 (m, 3H), 7, 74 (d, J=9.30 Hz, 1H), 7.54 (d, J=8.39 Hz, 1H), 7.39-7.52 (m, 3H), 6.23 (d, J =9.30 Hz, 1H), 4.99-5.46 (m, J=6.63, Hz, 1H), 4.66-4.69 (m, 1H), 4.56 (d, J =5.80 Hz, 1H), 4.38 (d, J=6.10 Hz, 1H), 4.35 (d, J=5.80 Hz, 1H), 4.19-4.25 (m , 1H), 4.03-4.12 (m, 1H), 1.49-1.62 (m, 3H), 1.20-1.43 (m, 3H). LCMS: m/z 401 [M+H]+ v.a. 6.0 min. MSVR (IER) calc. for C ₂₄ H ₂₅ N ₄ O ₂ [M+H]+ 401.1972 found 401.1973;

8-(2-Hydroxy-2-methylpropyl)-2-(^)-1-phenylethylamino)-8H-pyrido[2,3^]pyrimidin-7-one [(I),

X=N, I2=2-hydroxy-2-methylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=R6b=H, R3=R4=R5=H] conn. 46

1H NMR (500 MHz, DMSOA) δ=8.63 (s, 1H), 8.51 (d, J=7.8 Hz, 1H), 7.74 (d, J=9.3 Hz, 1H) , 7.41-7.37 (m, 2H), 7.30 (t, J=7.6 Hz, 2H), 7.23-7.14 (m, 1H), 6.28 (d, J =9.3 Hz, 1H), 5.05 (quin, J=7.2 Hz, 1H), 4.58 (s, 1H), 4.29 (d, J=13.3 Hz, 1H), 4.17 (d, J=13.3 Hz, 1H), 1.46 (d, J=7.3 Hz, 3H), 1.04 (s, 3H), 0.86 (shs, 3H). LCMS: m/z 339 [M+H]+ @ w.u. 5.45 min. MSVR (IER) calc. for C ₁₉ H ₂₂ N ₄ O ₂ [M+H]+ 339.1816 Found 339.1812;

8-(2,2-Dimethylpropyl)-6-fluoro-2-(^)-1-phenylethylamino)-8H-pyrido[2,3^]pyrimidin-7-one [(I),

X=N, I2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=R6b=H, R3=R4=H, R5=F] conn. 47

- 64 046117

1H NMR (500 MHz, DMSO) δ=8.58 (s, 1H), 8.39 (d, J=7.3 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H) , 7.38 (d, J=7.5 Hz, 2H), 7.30 (t, J=7.5 Hz, 2H), 7.24-7.13 (m, 1H), 5.06 ( quin, J=6.9 Hz, 1H), 5.31-4.95 (m, 1H), 4.334.02 (m, 2H), 1.46 (d, J=7.0 Hz, 3H), 0.78 (shs, 9 N). LCMS: m/z 355 [M+H]+ @ w.u. 7.10 min. MSVR (IER) calc. for C20H23FN4O [M+H]+ 355.1929 found 355.1926;

4-{^)-1-[8-(2-Hydroxy-2-methylpropyl)-7-oxo-7,8-dihydropyrido[2,3D]pyrimidin-2-ylamino]ethyl}benzoic acid methyl ester [(I ), X=N, R2=2-Hydroxy-2-methylpropyl, A=Phenyl, R1a=H, R1b=Me, R6a=-COOMe, R6b=H, R3=R4=R5=H] conn. 48

1H NMR (500 MHz, DMSOU) δ=8.64 (s, 1H), 8.57 (d, J=7.2 Hz, 1H), 7.95-7.86 (m, 2H), 7, 74 (d, J=9.2 Hz, 1H), 7.54 (d, J=7.9 Hz, 2H), 6.28 (d, J=9.3 Hz, 1H), 5.11 ( quin, J=6.9 Hz, 1H), 4.55 (s, 1H), 4.25 (d, J=13.1 Hz, 1H), 4.11 (d, J=13.1 Hz, 1H), 3.82 (s, 3H), 1.48 (d, J=7.0 Hz, 3H), 1.01 (s, 3H), 0.83 (shs, 3H). LCMS: m/z 397 [M+H]+ @ w.u. 5.32 min. MSVR (IER) calc. for C ₂₁ H ₂₄ N ₄ O ₄ [M+H]+ 397.1871 found 397.1868;

8-(2,2-Dimethylpropyl)-2-{[(^)-1-(4-phenoxyphenyl)ethyl]amino}pyrido[2,3D]pyrimidin-7(8H)-one [(I), X= N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-phenoxy, R6b=H, R3=R4=R5=H] conn. 49

1H NMR (500 MHz, DMSO) δ=8.58 (s, 1H), 8.38 (d, J=7.47 Hz, 1H), 7.68 (d, J=9.30 Hz, 1H) , 7.337.41 (m, 4H), 7.10 (t, J=7.32 Hz, 1H), 6.95 (t, J=7.78 Hz, 4H), 6.24 (d, J= 9.30 Hz, 1H), 5.91 (m, 1H), 4.00-4.10 (m, 2H), 1.47 (d, J=7.02 Hz, 3H), 0.90- 0.94 (m, 6H), 0.74-0.81 (m, 3H). LCMS: m/z 429 [M+H]+ v.a. 7.66 min. MSVR (IER) calc. for C ₂₆ H ₂₉ N ₄ O ₂ [M+H]+ 429.2285 found 429.2289.

Example 2.

Preparation of 2-{[(^)-1-(6-chloro-2-oxoquinolin-3-yl)ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3d]pyrimidin-7(8H) -one [(I), X=N, K2=2,2-dimethylpropyl, A=2-oxoquinolin-3-yl, R1a=H, R1b=Me, R6a=6-chloro, R6b=H, R3=R4 =R5=H] stage 1a conn. 50

To a solution of the compound 8-(2,2-dimethylpropyl)-2-(methylsulfonyl)pyrido[2,3D]pyrimidin-7(8H)one (50 mg, 0.17 mmol) in ACN (1 ml) and DIPEA (123 µl, 0.68 mM) add 3-[(1S)-1aminoethyl]-6-chloroquinolin-2(III)-one hydrochloride (prepared as described in WO 2016171755) (65 mg, 0.255 mmol). The reaction mixture is heated to 90°C for 4 hours. The reaction mixture is diluted with EtOAc (4 ml) and washed with water (5 ml) and saturated sodium chloride solution (5 ml). The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel column chromatography (DCM/EtOAc/EtOH 7/2/1) to give the title compound as an off-white solid (44 mg, 60% yield).

1H NMR (500 MHz, DMSO) δ=12.05 (s, 1H), 8.61 (s, 1H), 8.35 (d, J=7.17 Hz, 1H), 7.61-7, 75 (m, 3H), 7.46 (dd, J=8.77, 2.21, Hz, 1H), 7.30 (d, J=8.85 Hz, 1H), 6.23 (d, J=9.30 Hz, 1H), 5.26 (quin, J=6.94 Hz, 1H), 3.82-4.42 (m, 2H), 1.43 (d, J=6.86 Hz, 3H), 0.52-1.02 (m, 9H). LCMS: m/z 438 [M+H]+ v.a. 5.88 min. MSVR (IER) calc. for C ₂₃ H ₂₅ ClN ₅ O ₂ [M+H]+ 438.1692 found 438.1692.

According to the same method, the following compounds are obtained:

8-Benzyl-2-{[(^)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]amino}pyrido[2,3D]pyrimidin-7(8H)-one [(I), X=N, R2=benzyl, A=1H-benzimidazol-2-yl, R1a=H, R1b=Me, R6a=5-chloro, R6b=H, R3=R4=R5=H] conn. 51

1H NMR (500 MHz, DMSOU) δ=12.09-12.60 (m, 1H), 8.59-8.74 (m, 1H), 8.40 (d, J=7.32 Hz, 1H ), 7.78 (d, J=9.46 Hz, 1H), 7.58 (s, 1H), 7.54 (d, J=8.54 Hz, 1H), 7.12-7.18 (m, 1H), 7.09 (d, J=7.32 Hz, 2H), 6.86-7.05

- 65 046117 (m, 3H), 6.31 (d, J=9.30 Hz, 1H), 5.28-5.51 (m, 2H), 5.08-5.16 (m, 1H) , 1.55-1.65 (m, 3H). LCMS: m/z 431 [M+H]+ v.a. 5.57 min. MSVR (IER) calc. for C23H20CIN6O [M+H] ⁺ 431.1382 found 431.139;

2-({(^)-1-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}amino)-8-(2,2-dimethylpropyl)pyrido[2,3d ]pyrimidin-7(8H)-one [(I), X=N, R2=2,2-dimethylpropyl,

A=1,2,4-oxadiazol-5-yl, R1a=H, R1b=Me, R6a=3-(4-chlorophenyl), R6b=H, R3=R4=R5=H] conn. 52

Chiral

Ici—/1/// ^- _ν Α- _ν Α ₀ '^' ν- ^{0 1} H NMR (500 MHz, DMSOA) δ=8.51-8.71 (m, 2H), 7.93-8 .01 (m, 2H), 7.74 (d, J=9.46 Hz, 1H), 7.63 (d, J=8.54 Hz, 2H), 6.30 (d, J=9, 30 Hz, 1H), 5.31-5.59 (m, J=7.17 Hz, 1H), 3.85-4.35 (m, 3H), 1.69 (d, J=7.17 Hz, 3H), 1.59 (m, 9H). LCMS: m/z 439 [M+H] ⁺ v.a. 7.23 min. MSVR (IER) calc. for C ₂₂ H ₂₄ ClN ₆ O ₂ [M+H] ⁺

439.1644 found 439.164;

8-Benzyl-2-({(^)-1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}amino)pyrido[2,3^]pyrimidine7(8H) -one [(I), X=N, R2=benzyl, A=1,2,4-oxadiazol-5-yl, R1a=H, R1b=Me, R6a=3-(4-chlorophenyl), R6b=H ,

R3=R4=R5=H] conn. 53

1H NMR (500 MHz, DMSOA) δ=8.72 (s, 1H), 8.69 (d, J=6.84 Hz, 1H), 7.91 (d, J=8.54 Hz, 2H) , 7.81 (d,

J=9.28 Hz, 1H), 7.61 (d, J=8.54 Hz, 2H), 6.96-7.17 (m, 5H), 6.35 (d, J=9.15 Hz, 1H), 5.39 (quin, J=7.00 Hz, 1H), 5.36 (d, J=13.79 Hz, 1H), 5.15 (d, J=14.28 Hz, 1H), 1.63 (d, J=7.08 Hz, 3H). LCMS: m/z 459 [M+H] ⁺ v.a.

6.97 min. MSVR (IER) calc. for C ₂₄ H ₂₀ ClN ₆ O ₂ [M+H]+459.1331 found 459.1336;

8-(2,2-Dimethylpropyl)-2-{[(^)-1-(4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]amino}pyrido[2,3^]pi rimidin-7 (8H)-one [(I), X=N, R2=2,2-dimethylpropyl, A=4-oxo-3,4-dihydroquinazolin-2-yl, R1a=H,

R1b=Me, R6a=R6b=H, R3=R4=R5=H] conn. 54

1H NMR (500 MHz, DMSO-dg) δ=12.37 (brs, 1H), 8.64 (s, 1H), 8.00-8.12 (m, 2H), 7.64-7.79 (m, 2H), 7.56 (d, J=8.24 Hz, 1H), 7.42-7.53 (m, 2H), 6.25 (d, J=9.30 Hz, 1H) , 4.91 (t, J=6.79 Hz, 1H), 3.90-4.07 (m, 1H), 1.56 (d, J=7.02 Hz, 3H), 0.70 ( shs, 9N). LCMS: m/z 405 [M+H] ⁺ v.a. 5.17 min. MSVR (IER) calc. for C ₂₂ H ₂₅ N ₆ O ₂ [M+H] ⁺ 405.2034 found 405.2041.

Example 3.

Step 8: 2-{^)-1-[4-(4,4-difluoropiperidin-1-ylmethyl)phenyl]ethylamino}-8-(3-hydroxy-2,2dimethylpropyl)-8H-pyrido[2,3D] pyrimidin-7-one [(I), X=N, R2=3-hydroxy-2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=4,4-difluoropiperidin-1-yl, R3=R4=R5=H] stage 1a, conn. 55

^)-1-[4-(4,4-difluoropiperidin-1-ylmethyl)phenyl]ethylamine (prepared as described in WO2017019429) 13.5 mg, 0.053 mmol) was dissolved in DMSO (0.5 ml). To this solution, 8-(3-hydroxy-2,2-dimethylpropyl)-2-methanesulfonyl-8H-pyrido[2,3D]pyrimidin-7one (15 mg, 0.048 mmol), CsF (8.0 mg, 0.053 mmol) and DIPEA (0.01 ml, 0.058 mmol). The reaction mixture is then heated at 75°C for 4 hours and then warmed to room temperature. The reaction mixture is slowly poured over cold water/saturated sodium chloride solution. The precipitated solids are filtered, washed with water and dried in vacuum. The resulting dried solid (16.1 mg, 69% yield) was taken up without further purification.

1H NMR (500 MHz, DMSO-dg) δ=8.60 (s, 1H), 8.43 (d, J=7.5 Hz, 1H), 7.72 (d, J=9.3 Hz, 1H), 7.36 (d, J=7.6 Hz, 2H), 7.23 (d, J=7.8 Hz, 2H), 6.25 (d, J=9.2 Hz, 1H) , 5.11 (quin, J=6.7 Hz, 1H), 4.56 (shs, 1H), 4.353.88 (m, 2H), 3.48 (s, 2H), 3.04 (shs, 2H), 2.43 (shs, 4H), 1.91 (t, J=13.3 Hz, 4H), 1.46 (d, J=7.0 Hz, 3H), 1.040.31 (m, 6H). LCMS: m/z 486 [M+H] ⁺ @ w.u. 6.22 min. MSVR (IER) calc. for C ₂₆ H ₃₄ F ₂ N ₅ O ₂ [M+H] ⁺ 486.2675 found 486.2670.

According to the same method, the following compounds are obtained:

- 66 046117 tert-Butyl ether 4-(4-{^)-1-[8-(3-hydroxy-2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin- 2-ylamino]ethyl}benzyl)piperazine-1-carboxylic acid [(I), X=N, R2=3-hydroxy2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=tert-butyl ester of 4-piperazine-1-carboxylic acid, R3=R4=R5=H] comp. 56

1H NMR (500 MHz, DMSOA) δ=8.60 (s, 1H), 8.43 (d, J=7.3 Hz, 1H), 7.72 (d, J=9.3 Hz, 1H) , 7.35 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 6.25 (d, J=9.3 Hz, 1H), 5 .11 (quin, J=7.2 Hz, 1H), 4.57 (shs, 1H), 4.373.89 (m, 2H), 3.41 (s, 2H), 3.27 (shs, 4H) , 3.04 (shs, 2H), 2.26 (shs, 4H), 1.46 (d, J=6.9 Hz, 3H), 1.37 (s, 9H), 0.70 (shs, 6H). LCMS: m/z 551 [M+H]+ @ w.u. 6.42 min. MSVR (IER) calc. for C ₃₀ H ₄₃ N ₆ O ₄ [M+H]+ 551.3341 found 551.3344;

2-{^)-1-[4-(3,3-Difluoropiperidin-1-ylmethyl)phenyl]ethylamino}-8-(2,2-dimethylpropyl)-6-fluoro8H-pyrido[2,3^]pyrimidin- 7-one [(I), X=N, I2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=F, R7-R8=3,3-difluoropiperidine- 1-yl, R3=R4=H, R5= F] conn. 57

1H NMR (500 MHz, DMSOA) δ=8.58 (s, 1H), 8.37 (d, J=7.2 Hz, 1H), 7.69 (d, J=9.3 Hz, 1H) , 7.33 (d, J=8.1 Hz, 2H), 7.26-7.11 (m, 2H), 5.04 (quin, J=7.0 Hz, 1H), 4.39- 3.88 (m, 2H), 3.59-3.44 (m, 2H), 2.60-2.52 (m, 2H), 2.36 (shs, 2H), 1.83 (kvd, J=7.0, 13.5 Hz, 2H), 1.62 (quin, J=5.9 Hz, 2H), 1.46 (d, J=7.0 Hz, 3H), 0.72 ( shs, 9N). LCMS: m/z 488 [M+H]+ @ w.u. 7.55 min. MSVR (IER) calc. for C ₂₆ H ₃₃ F ₃ N ₅ O [M+H]+ 488.2632 found 488.2637;

2-{^)-1-[4-(3,3-Difluoropiperidin-1-ylmethyl)phenyl]ethylamino}-8-(2,2-dimethylpropyl)-6-methoxy8H-pyrido[2,3^]pyrimidin- 7-one [(I), X=N, I2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=3,3-difluoropiperidine- 1-yl, R3=R4=H, R5=OMe] conn. 58

1H NMR (500 MHz, DMSOA) δ=8.50 (brs, 1H), 8.01 (brs, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.20 (d, J=8.1 Hz, 2H), 7.07 (s, 1H), 5.01 (shs, 1H), 4.38-3.95 (m, 2H), 3.73 (s, 3H), 3.50 (d, J=2.0 Hz, 2H), 2.57-2.43 (m, 4H), 1.90-1.76 (m, 2H), 1.67-1.57 ( m, 2H), 1.44 (d, J=7.0 Hz, 3H), 0.70 (shs, 9H).

LCMS: m/z 500 [M+H]+ @ w.u. 7.21 min. MSVR (IER) calc. for C ₂₇ H ₃₆ F ₂ N ₅ O ₂ [M+H]+ 500.2832 found 500.2827;

tert-Butyl ether 4-(4-{^)-1-[8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin-2-ylamino]ethyl }-benzyl)piperazine-1-carboxylic acid [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H , R7-R8=tert-butyl ester of 4-piperazine-1carboxylic acid, R3=R4=R5=H] comp. 59

1H NMR (500 MHz, DMSOA) δ=8.57 (s, 1H), 8.36 (d, J=7.5 Hz, 1H), 7.67 (d, J=9.3 Hz, 1H) , 7.32 (d, J=7.9 Hz, 2H), 7.22 (d, J=7.9 Hz, 2H), 6.22 (d, J=9.3 Hz, 1H), 5 .06 (quin, J=7.0 Hz, 1H), 4.34-3.89 (m, 2H), 3.42 (s, 2H), 3.27 (shs, 4H), 2.26 ( ws, 4H), 1.45 (d, J=7.0 Hz, 3H), 1.37 (s, 9H), 0.73 (ws, 9H). LCMS: m/z 535 [M+H]+ @ w.u. 7.43 min. MSVR (IER) calc. for C ₃₀ H ₄₃ N ₆ O ₃ [M+H]+ 535.3391 found 535.3387;

2-{^)-1-[4-(3,3-Difluoropiperidin-1-ylmethyl)phenyl]ethylamino}-8-(2,2-dimethylpropyl)-5-methyl8H-pyrido[2,3^]pyrimidin- 7-one [(I), X=N, I2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=3,3-difluoropiperidine- 1-yl, R3=R5=H, R4= Me] conn. 60

1H NMR (500 MHz, DMSO-de) δ=8.64 (s, 1H), 8.32 (d, J=7.3 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H), 7.21 (d, J=8.1 Hz, 2H), 6.09 (s, 1H), 5.05 (quin, J=7.0 Hz, 1H), 4.27-3, 86 (m, 4H), 3.56-3.44 (m, 2H), 2.61-2.52 (m, 2H), 2.32 (s, 3H), 1.84 (tt, J= 6.9, 13.6 Hz, 2H), 1.61 (quin, J=5.9 Hz, 2H), 1.46 (d, J=7.2 Hz, 3H), 1.01-0, 47 (m, 9H).

- 67 046117

LCMS: m/z 484 [M+H] ⁺ @ w.u. 7.48 min. MSVR (IER) calc. for C ₂₇ H ₃₆ F ₂ N ₅ O [M+H] ⁺ 484.2883 found 484.2874;

8-(Butan-2-yl)-2-{[(^)-G{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}pyrido[2,3d]pyrimidin- 7(8n)-one [(I), X=N, K2=-butan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7- R8=3,3-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 61

1H NMR (500 MHz, DMSO-de) δ=8.56 (brs, 1H), 8.08-8.43 (m, 1H), 7.58-7.73 (m, 1H), 7.30 (shs, 2H), 7.16-7.25 (m, 2H), 6.17 (shs, 1H), 4.83-5.46 (m, 2H), 3.44-3.55 (m , 2H), 2.53-2.61 (m, 2H), 2.30-2.41 (m, 2H), 1.74-1.93 (m, J=6.79, 13.46, 13.46 Hz, 2H), 1.56-1.71 (m, 2H), 1.38-1.56 (m, 8H), 0.30-1.21 (m, 3H). LCMS: m/z 456 [M+H]+ @ w.u. 7.04 min. MSVR (IER) calc. for C ₂₅ H ₃₂ F ₂ N ₅ O [M+H] ⁺ 456.257 found 456.2567;

8-[(2S)-Butan-2-yl]-2-{[(1S)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}pyrido[2 ,3^]pyrimidin-7(8H)-one [(l), X=N, R2=-(2S)-6ymaH-2-un, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=3,3-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 62

1H NMR (500 MHz, DMSOA) δ=8.56 (brs, 1H), 8.08-8.43 (m, 1H), 7.58-7.73 (m, 1H), 7.30 (brs , 2H), 7.16-7.25 (m, 2H), 6.17 (shs, 1H), 4.83-5.46 (m, 2H), 3.44-3.55 (m, 2H ), 2.53-2.61 (m, 2H), 2.30-2.41 (m, 2H), 1.74-1.93 (m, J=6.79, 13.46, 13, 46 Hz, 2H), 1.56-1.71 (m, 2H), 1.38-1.56 (m, 8H), 0.30-1.21 (m, 3H). LCMS: m/z 456 [M+H] ⁺ @ w.u. 7.03 min. MSVR (IER) calc. for C ₂₅ H ₃₂ F ₂ N ₅ O [M+H] ⁺ 456.257 found 456.2574;

Ethyl 2-[2-{[(^)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-7-oxopyrido[2,3d]pyrimidin-8( 7H)-yl]propanoate [(I), X=N, K2=ethyl-2-propanoate, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=3.3 -difluoropiperidin-1-yl, R3=R4=R5=H] conn. 63

1H NMR (500 MHz, DMSOA) δ=8.59-8.65 (m, 1H), 8.45-8.57 (m, 1H), 7.73 (d, J=9.30 Hz, 1H ), 7.36 (dd, J=3.36, 7.93 Hz, 2H), 7.16-7.26 (m, 2H), 6.24 (d, J=13.95 Hz, 1H) , 5.66-5.90 (m, 1H), 4.89-5.13 (m, 1H), 3.964.06 (m, 2H), 3.46-3.56 (m, 4H), 2 .32-2.39 (m, 2H), 1.77-1.92 (m, 2H), 1.61 (shs, 2H), 1.38-1.54 (m, 3H), 1.17 (d, J=7.17 Hz, 3H), 1.03 (t, J=7.09 Hz, 3H). LCMS: m/z 500 [M+H] ⁺ @ w.a. 6.6 min. MSVR (IER) calc. for C ₂₆ H ₃₂ F ₂ N ₅ O ₄ [M+H] ⁺ 500.2468 found 500.2463;

2-[2-{[(^)-1-{4-[(3,3-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-7-oxopyrido[2,3d]pyrimidin-8(7H )-yl]propanenitrile [(I), X=N, K2=2-propanenitrile, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=3,3-difluoropiperidine- 1-yl, R3=R4=R5=H] conn. 64

1H NMR (500 MHz, DMSOA) δ=8.60-8.73 (m, 2H), 7.72-7.80 (m, 1H), 7.42 (d, J=7.93 Hz, 1H ), 7.36 (d, J=7.93 Hz, 1H), 7.17-7.28 (m, 2H), 6.23-6.53 (m, 2H), 5.08-5, 34 (m, 1H), 3.44-3.55 (m, 2H), 2.53-2.58 (m, 2H), 2.31-2.38 (m, 2H), 1.77- 1.88 (m, 2H), 1.56-1.63 (m, 2H), 1.46-1.51 (m, 6H). LCMS: m/z 453 [M+H] ⁺ @ w.u. 6.24 min. MSVR (IER) calc. for C ₂₄ H ₂₇ F ₂ N ₆ O [M+n] ⁺ 453.2209 found 453.2198;

2-{[(1S)-1-{4-[(3,3-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[(2S)-3-methylbutan-2yl]pyrido[2 ,3^]pyrimidin-7(8H)-one [(I), X=N, K2=-^)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4 -CH ₂ NR7R8, R6b=H, R7-R8=3,3-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 65

1H NMR (500 MHz, DMSO-d;) δ=8.54-8.59 (m, 1H), 8.33-8.40 (m, 1H), 7.62-7.66 (d, J =10.8 Hz, 1H), 7.19-7.38 (m, 4H), 6.09-6.23 (m, 1H), 4.97-5.09 (m, 1H), 4, 76-4.86 (m, 1H), 3.50 (shs, 2H), 2.53-2.61 (m, 2H), 2.32-2.39 (m, 2H), 2.02- 2.10 (m, 1H), 1.78-1.89 (m, 2H), 1.57-1.65 (m, 2H), 1.44-1.53 (m, 3H), 0. 99-1.10 (m, 3H), 0.61-0.77 (m, 3H), 0.06-0.1 (d, J=6.1 Hz, 3H). LCMS: m/z 470 [M+H] ⁺ @ w.u. 7.22 min. MSVR (IER) calc. for C26H34F2N5O [M+H] ⁺ 470.2726 Found 470.2721;

8-[(1S)-1 -Cyclohexylethyl] -2-{[(1S)-1 -{4-[(3,3-difluoropiperidin-1 -yl)methyl]phenyl}ethyl] amino}pyrido[2,3 ^]pyrimidin-7(8H)-one [(I), X=N, K2=-(^)-1-cyclohexylethyl, A=phenyl, R1a=H, R1b=Me,

- 68 046117

R6a=4-CH2NR7R8, R6b=H, R7-R8=3,3-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 66

1H NMR (500 MHz, DMSO-dg) δ=8.53-8.59 (m, 1H), 8.35-8.40 (m, 1H), 7.62-7.66 (m, 1H) , 7.19-7.38 (m,

4H), 6.08-6.23 (m, 1H), 5.10-5.21 (m, 1H), 4.79-4.97 (m, 1H), 3.47-3.54 ( m, 4H), 2.53-2.61 (m, 2H), 2.32-2.39 (m, 2H), 1.74-2.06 (m, 4H), 1.43-1, 66 (m, 5H), 0.66-1.44 (m, 9H), 0.42-0.52 (m, 1H). LCMS: m/z 510 [M+H]+ @ w.u. 7.90 min. MSVR (IER) calc. for C ₂₉ H ₃₈ F ₂ N ₅ O [M+H]+ 510.3039 found 510.3040;

2-{[(1S)-1-{4-[(4,4-Difluoropiperidin-1-yl)methyl]-3-fluorophenyl}ethyl]amino}-8-[(2S)-3-methylbutane

2-yl]pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=-(2S)-3-methylbutan-2-yl, A=phenyl, R1a=H , R1b=Me, R6a=4-CH ₂ NR7R8, R6b=F, R7-R8=4,4-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 67

^1H NMR (500 MHz, DMSO-d) δ=8.53-8.61 (m, 1H), 8.34-8.42 (m, 1H), 7.62-7.68 (m, 1H ), 7.32 (dd, J=7.63 Hz, 1H), 7.06-7.24 (m, 2H), 6.10-6.24 (m, 1H), 4.95-5, 05 (m, 1H), 4.75-4.85 (m, 1H), 3.54 (shs, 2H), 2.43-2.48 (m, 4H), 1.85-1.97 ( m, 5H), 1.44-1.51 (m, 3H), 1.0-1.08 (m, 3H), 0.59-0.76 (m, 3H), 0.06-0, 1 (d, J=6.71 Hz, 3H). LCMS: m/z 488 [M+H]+ v.a. 7.16 min. MSVR (IER) calc. for C ₂₆ N ₃₃ F ₃ N ₅ O [M+H]+ 488.2632 found

488.2639;

2-({(1S)-1-[3-Fluoro-4-(morpholin-4-ylmethyl)phenyl]ethyl}amino)-8-[(2S)-3-methylbutan-2-yl]pyri to[2 ,3^]pyrimidin-7(8H)-one [(I), X=N, K2=-^)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8 , R6b=F, R7-R8=morpholin-4-yl, R3=R4=R5=H] conn. 68

1H NMR (500 MHz, DMSO-dg) δ=8.54-8.61 (m, 1H), 8.33-8.42 (m, 1H), 7.62-7.67 (m, 1H) , 7.31 (dd, J=7.63 Hz, 1H), 7.05-7.21 (m, 2H), 6.10-6.25 (m, 1H), 4.94-5.05 (m, 1H), 4.75-4.86 (m, 1H), 3.52 (shs, 4H), 3.44 (shs, 2H), 2.33 (shs, 4H), 1.92- 1.97 (m, 1H), 1.43-1.51 (m, 3H), 1.0-1.08 (m, 3H), 0.54-0.76 (m, 3H), 0. 05-0.1 (d, J=6.71 Hz, 3H). LCMS: m/z 454 [M+H]+ v.a. 6.07 min. MSVR (IER) calc. for C ₂₅ H ₃₃ N ₅ O ₂ [M+H]+ 454.2613 found 454.2612;

2-{[(1S)-1-{4-[(3,3-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[(2S)-3,3-dimethylbutan-2yl]pyrido [2,3^]pyrimidin-7(8H)-one [(I), X=N, K2=-^)-3,3-dimethylbutan-2-yl, A=phenyl,

R1a=H,

R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=3,3-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 69

1H NMR (500 MHz, DMSO-de) δ=8.54 (s, 1H), 8.38 (d, J=6.56 Hz, 1H), 7.61 (d, J=9.15 Hz, 1H), 7.30 (d,

J=7.93 Hz, 2H), 7.21 (d, J=7.93 Hz, 2H), 6.10 (d, J=9.30 Hz, 1H), 5.41 (kv, J= 7.02 Hz, 1H), 4.90 (quin, J=6.86 Hz, 1H), 3.45-3.56 (m, 2H), 2.53-2.61 (m, 2H), 2.33-2.40 (m, 2H), 1.78-1.90 (m, 2H), 1.57-1.65 (m, 2H), 1.48 (d, J=6.86 Hz, 3H), 1.15-1.22 (m, 3H), 0.98 (s, 9H). LCMS: m/z 484 [M+H]+ @ w.u. 7.64 min. MSVR (IER) calc. for C27H36F2N5O [M+H]+ 484.2883 found 484.2876;

8-(2,2-Dimethylpropyl)-2-{[(^)-1-phenylpropyl]amino}pyrido[2,3^]pyrimidin-7(8H)-one [(I),

X=N, K2=-2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=ethyl, R6a=R6b=H, R3=R4=R5=H] conn. 70\Chiral

1H NMR (500 MHz, DMSO-de) δ=8.56 (s, 1H), 8.37 (d, J=7.93 Hz, 1H), 7.67 (d, J=9.30 Hz, 1H), 7.38 (d, J=7.17 Hz, 2H), 7.30 (t, J=7.55 Hz, 2H), 7.14-7.25 (m, 1H), 6, 22 (d, J=9.30 Hz, 1H), 4.76-5.09 (m, 1H), 3.964.32 (m, 2H), 1.65-1.93 (m, 2H), 0 .85-0.98 (m, 3H), 0.80 (shs, 9H). LCMS: m/z 351 [M+H]+ v.a. 7.16 min. MSVR (IER) calc. for C ₂₁ H ₂₇ N ₄ O [M+H]+ 351.2180 found 351.2180.

8-(2,2-Dimethylpropyl)-2-[^)-1-(4-hydroxyphenyl)ethylamino]-8H-pyrido[2,3^]pyrimidin-7-one [(I), X=N, I2 =-2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=OH, R6b=H, R3=R4=R5=H] conn. 145 but

- 69 046117

Ή NMR (500 MHz, DMSO-sH) δ=9.21 (s, 1H), 8.55 (s, 1H), 8.25 (d, J=7.5 Hz, 1H), 7.67 ( d, J=9.2 Hz, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.2 Hz, 2H), 6.22 (d, J=9.2 Hz, 1H), 4.88-5.26 (m, 1H), 4.05-4.30 (m, 2H), 1.42 (d, J=7.0 Hz, 3H ), 0.82 (shs, 9N). LCMS: m/z 353 [M+H]+ @ w.u. 5.78 min

MSVR (IER) calc. for C ₂₀ H ₂₅ N ₄ O ₂ [M+H]+ 353.1972 found 353.1976

Benzyl ester 4-(4-{^)-1-[8-(^)-1,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin-2-ylamino]ethyl} phenoxy)piperidine-1-carboxylic acid [(I), X=N, R2=-(S)-1,2 dimethylpropyl), A=phenyl, R1a=H, R1b=Me, R6a=-O-R7, R6b =H, R7=benzyl ester of 4-piperidine-1carboxylic acid, R3=R4=R5=H] comp. 146

1H NMR (500 MHz, DMSO-dg) δ=8.50-8.62 (m, 1H), 8.23-8.37 (m, 1H), 7.64 (d, J=9.3 Hz , 1H), 7.15-7.42 (m, 7H), 6.90 (d, J=8.5 Hz, 2H), 6.04-6.29 (m, 1H), 4.77- 5.33 (m, 4H), 4.51 (spt, J=4.0 Hz, 1H), 3.68 (shs, 2H), 3.26 (shs, 2H), 1.40-2.11 (m, 8H), 0.13-1.19 (m, 9H). LCMS: m/z 570 [M+H]+ @ w.u. 7.59 min

MSVR (IER) calc. for C ₃₃ H ₄₀ N ₅ O ₄ [M+H]+ 570.3075 found 570.3100

2-{[(1S)-1-{4-[(3,3-Difluoroazetidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyri to[2,3^ ]pyrimidin-7(8H)-one [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8= -(3,3-difluoroazetidin-1-yl, R3=R4=R5=H] compound 147

1H NMR (500 MHz, DMSO-dg) δ=8.57 (s, 1H), 8.36 (d, J=7.47 Hz, 1H), 7.67 (d, J=9.30 Hz, 1H), 7.33 (d,

J=7.93 Hz, 2H), 7.22 (d, J=7.93 Hz, 2H), 6.22 (d, J=9.30 Hz, 1H), 5.07 (quin, J= 7.17 Hz, 1H), 3.93-4.32 (m, 2H), 3.65 (s, 2H), 3.54 (t, J=12.43 Hz, 4H), 1.45 ( d, J=7.02 Hz, 3H), 0.76 (shs, 9H). LCMS: m/z 442 [M+H]+ @ w.u. 6.77 min. MSVR (IER) calc. for C24H30N5O [M+H]+ 442.2413 found 442.2423.

2-{[(^)-1-{4-[(3,3-Difluoropyrrolidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyri to[2,3^ ]pyrimidin-7(8H)-one [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8= -(3,3-difluoropyrrolidin-1-yl, R3=R4=R5=H] compound 148

1H NMR (500 MHz, DMSO-0 ₆ ) δ=8.58 (s, 1H), 8.36 (d, J=7.32 Hz, 1H), 7.67 (d, J=9.30 Hz , 1H), 7.33 (d, J=8.08 Hz, 2H), 7.23 (d, J=7.78 Hz, 2H), 6.22 (d, J=9.15 Hz, 1H ), 5.06 (quin, J=7.21 Hz, 1H), 3.87-4.34 (m, 2H), 3.55 (s, 2H), 2.72-2.88 (m, 2H), 2.64 (d, J=6.41 Hz, 2H), 2.13-2.29 (m, 2H), 1.46 (d, J=7.02 Hz, 3H), 0, 73 (shs, 9N).

LCMS: m/z 456 [M+H]+ @ w.u. 7.13 min. MSVR (IER) calc. for C ₂₅ H ₃₂ N ₅ O [M+H]+ 456.257 found 456.2582.

8-[(2R)-Butan-2-yl]-2-{[(1S)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}pyrido[2 ,3^]pyrimidin-7(8H)-one [(I), X=N, R2=-(2R)-butan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=-(3,3-difluoropiperidin-1-yl, R3=R4=R5=H] compound 149

1H NMR (500 MHz, DMSO-0 ₆ ) δ=8.58 (s, 1H), 8.36 (d, J=7.32 Hz, 1H), 7.67 (d, J=9.30 Hz , 1H), 7.33 (d, J=8.08 Hz, 2H), 7.23 (d, J=7.78 Hz, 2H), 6.22 (d, J=9.15 Hz, 1H ), 5.06 (quin, J=7.21 Hz, 1H), 3.87-4.34 (m, 2H), 3.55 (s, 2H), 2.72-2.88 (m, 2H), 2.64 (d, J=6.41 Hz, 2H), 2.13-2.29 (m, 2H), 1.46 (d, J=7.02 Hz, 3H), 0, 73 (shs, 9N).

LCMS: m/z 456 [M+H]+ @ w.u. 7.02 min. MSVR (IER) calc. for C ₂₅ H ₃₂ F ₂ N ₅ O [M+H]+ 456.257 found 456.2568.

2-{[(1S)-1-(4-{[(2R,gS)-2,g-dimethylmorpholin-4-yl]methyl}-3-fluorophenyl)ethyl]amino}-8-[(2S)- 3methylbutan-2-yl]pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=-(2S)-3-methylbutan-2-yl, A=phenyl, R1a =H, R1b=Me, R6a=4-CH ₂ NR ₇ R ₈ , R6b=F, R7-R8=(2R,gS)-2,g-dimethylmorpholin-4-yl, R3=R4=R5=H] conn. 150

Chiral

1H NMR (500 MHz, DMSO^6) δ= 8.60 (s, 1H), 8.36 (d, J=7.47 Hz, 1H), 7.65 (d, J=9.60 Hz, 1H), 7.30 (t,

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J=7.47 Hz, 1H), 7.05-7.21 (m, 2H), 6.22 (d, J=9.60 Hz, 1H), 4.95-5.03 (m, 1H ), 4.76-4.85 (m, 1H), 3.46-3.54 (m, 2H), 3.43 (s, 2H), 2.59-2.67 (m, 4H), 1.59-1.68 (m, 1H), 1.48 (m, 3H), 0.95-1.08 (m, 9H), 0.73 (d, J=6.25 Hz, 3H) , 0.08 (d, J=6.25 Hz, 3H). LCMS: m/z 482 [M+H]+ @ w.u. 6.77 min. MSVR (IER) calc. for C ₂₇ H ₃₇ FN ₅ O ₂ [M+H]+ 482.2926 Found 482.2931.

2-{[(1S)-1-(4-{[(2R,gS)-2,g-Dimethylmorpholin-4-yl]methyl}-2-fluorophenyl)ethyl]amino}-8-(2,2- dimethylpropyl)pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H,

R1b=Me, R6a=4-CH ₂ NR7R8, R6b=F, R7-R8=(2R,6S)-2,6-dimethylmoppholin-4-yl, R3=R4=R5=H] conn. 151

^1H NMR (500 MHz, DMSO-dg) δ= 8.59 (s, 1H), 8.44 (d, J=7.32 Hz, 1H), 7.68 (d, J=9.30 Hz , 1H), 7.33 (t,

J=8.01 Hz, 1H), 7.08 (d, J=11.13 Hz, 1H), 7.04 (d, J=7.78 Hz, 1H), 6.23 (d, J= 9.30 Hz, 1H), 5.33 (quin, J=6.98

Hz, 1H), 3.86-4.35 (m, 2H), 3.47-3.63 (m, 2H), 3.37-3.45 (m, 2H), 2.57-2, 71 (m, 2H), 1.54-1.71 (m, 2H), 1.45 (d, J=7.02 Hz, 3H), 0.99 (d, J=6.25 Hz, 6H ), 0.70 (shs, 9N). LCMS: m/z 482 [M+H]+ @ w.u. 7.08 min. MSVR (IER) calc. for C ₂₇ H ₃₇ FN ₅ O ₂ [M+H]+ 482.2926 Found 482.2931.

2-{[(1 S)-1 - {4-[(4,4-Difluoropiperidin-1 -yl)methyl]-2-fluorophenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[ 2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=2-F, R7-R8=4,4-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 152

Chiral

1H NMR (500 MHz, DMSO-dg) δ= 8.59 (s, 1H), 8.45 (d, J=7.47 Hz, 1H), 7.68 (d, J=9.30 Hz, 1H), 7.35 (t, J=7.85 Hz, 1H), 7.11 (d, J=11.44 Hz, 1H), 7.06 (dd, J=0.92, 7.93 Hz, 1H), 6.24 (d, J=9.30 Hz, 1H), 5.35 (quin, J=7.05 Hz, 1H), 3.92-4.34 (m, 2H), 3.50 (d, J=2.14 Hz, 2H), 2.44 (shs, 4H), 1.82-2.02 (m, 4H), 1.45 (d, J=7.02 Hz , 3H), 0.71 (shs, 9H). LCMS: m/z 488 [M+H]+ @ w.u. 7.43 min. MSVR (IER) calc. for C ₂₆ H ₃₃ F ₃ N ₅ O [M+H]+ 488.2632 found 488.2637.

8-(2,2-Dimethylpropyl)-2-(['('^)-'1-[2-fluoro-4-(morpholin-4-ylmethyl)phenyl]ethyl}amino)pyrido[2,3d]- pyrimidin-7(8H)-one [(I), X=N, E2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=2-F , R7-R8=morpholin-4-yl, R3=R4=R5=H] conn. 153

1H NMR (500 MHz, DMSO-dg) δ= 8.59 (s, 1H), 8.45 (d, J=7.63 Hz, 1H), 7.68 (d, J=9.30 Hz, 1H), 7.34 (t, J=7.93 Hz, 1H), 7.09 (d, J=11.29 Hz, 1H), 7.06 (dd, J=1.07, 7.93 Hz, 1H), 6.23 (d, J=9.30 Hz, 1H), 5.35 (quin, J=7.02 Hz, 1H), 3.86-4.33 (m, 2H), 3.54 (t, J=4.35 Hz, 4H), 3.37-3.45 (m, 2H), 2.31 (shs, 4H), 1.45 (d, J=7.02 Hz , 3H), 0.72 (shs, 9H). LCMS: m/z 454 [M+H]+ @ w.u. 6.33 min. MSVR (IER) calc. for C ₂₅ H ₃₃ FN ₅ O ₂ [M+H]+ 454.2613 found 454.2603.

2-{[(1S)-1-(4-Bromophenyl)ethyl]amino}-8-[(2S)-3-methylbutan-2-yl]pyrido[2,3-d]pyrimidin-7(8H)- he [(I), X=N, R2=-(2S)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=Br, R6b=H, R3=R4=R5 =H] conn. 163

1H NMR (500 MHz, DMSOA) δ=8.60 (s, 1H), 8.34 (d, J=7.44 Hz, 1H), 7.65 (d, J=9.70 Hz, 1H) , 7.49 (d, J=8.41 Hz, 2H), 7.31 (d, J=8.41 Hz, 2H), 6.23 (d, J=9.70 Hz, 1H), 4 .88-4.98 (m, 1H), 4.73-4.85 (m, 1H), 1.661.75 (m, 1H), 1.46 (d, J=7.12 Hz, 3H), 1.10 (d, J=6.71 Hz, 3H), 0.71 (d, J=6.41 Hz, 3H), 0.08 (d, J=6.71 Hz, 3H). LCMS: m/z 415 [M+H]+ @ w.u. 7.14 min. MSVR (IER) calc. for C ₂₀ H ₂₄ BrN ₄ O [M+H]+ 415.1128 found 415.1143.

2-{[(^)-1-(4-{[(2R^)-2,6-Dimethylmorpholin-4-yl]methyl}phenyl)ethyl]amino}-8-[^)-1,1,1trifluoropropane -2-yl]pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=-(2S)-1,1,1-trifluoropropan-2-yl, A= phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=(2R,gS)-2,g-dimethylmorpholin-4-yl,

R3=R4=R5=H] conn. 164

1H NMR (500 MHz, DMSOC) δ=8.63 (m, 2H), 7.72 (d, J=9.46 Hz, 1H), 7.20-7.31 (m, 4H), 6, 18 (d,

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J=9.45 Hz, 1H), 6.01-6.10 (m, 1H), 4.79 (quin, J=6.7 Hz, 1H), 3.48-3.51 (m, 2H ), 3.37-3.45 (m, 2H), 2.57-2.71 (m, 2H), 1.87 (d, J=7.17 Hz, 1H), 1.56-1, 71 (m, 3H), 1.46 (d, J=6.86 Hz, 3H), 0.95-1.05 (m, 6H). LCMS: m/z 490 [M+H]+ @ w.u. 6.35 min. MSVR (IER) calc. for C ₂₅ H ₃₇ F ₃ N ₅ O ₂ [M+H]+ 490.2425 found 490.2415.

2-{[(^)-1-{4-[(3,3-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3d]pyrimidine -7(8H)-one [(I), X=N, P2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR ₇ R ₈ , R6b =, R7-R8=(3,3-difluoropiperidin-1-yl, R3=R4=R5=H] compound 170

¹ H NMR (500 MHz, DMSO-dg) δ= 8.56 (bs, 1H), 8.36 (d, J=6.71 Hz, 1H), 7.62 (d, J=9.15 Hz , 1H), 7.33 (d, J=7.93 Hz, 2H), 7.21 (d, J=7.93 Hz, 2H), 6.15 (d, J=9.15 Hz, 1H ), 5.44-5.56 (shs, 1H), 4.99 (m, 2H), 3.49 (shs, 2H), 2.53-2.61 (m, 2H), 2.31- 2.35 (m, 2H), 1.74-1.93 (m, J=6.79, 13.46, 13.46 Hz, 2H), 1.56-1.71 (m, 2H), 1.38-1.56 (m, 9H). LCMS: m/z 442 [M+H]+ @ w.u. 6.77 min. MSVR (IER) calc. for C ₂₄ H ₃₀ F ₂ N ₅ O [M+H] ⁺ 442.2413 found 442.2418.

8-[(1S)-1-Cyclopropylethyl]-2-{[(1S)-1-(4-{ [(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-3-fluorophenyl )ethyl]amino}pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, P2=(^)-1-cyclopropylethyl, A=phenyl, R1a=H, R1b=Me , R6a=4-CH ₂ NR7R8, R6b =, K7-K8=DO,68)-2,6-dimethylmorpholin-4-yl, R3=R4=R5=h] conn. 171

Chiral

ABOUT

1H NMR (500 MHz, DMSO-dg) δ= 8.53-8.59 (brs, 1H), 8.34-8.41 (brs, 1H), 7.65 (d, J=9.3 Hz , 1H), 7.197.33 (m, 4H), 6.14 (d, J=9.3 Hz, 1H), 4.89-5.00 (shm, 1H), 4.54 (shm, 1H) , 3.52 (shs, 2H), 3.37 (s, 2H), 2.57-2.67 (m, 4H), 1.80 (m, 1H) 1.41-1.61 (m, 6H), 0.97 (m, 6H), 0.25-0.64 (m, 4H). LCMS: m/z 462 [M+H] ⁺ @ w.u. 6.26 min. MSVR (IER) calc. for C ₂₇ H ₃ 6N ₅ O ₂ [M+H] ⁺ 462.2864 found 462.2872.

2-{[(1S)-1 -(6-Chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl] amino }-8-[(2S)-3 -methylbutan-2-yl] pyri to[2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A=2-oxo-quinolin-3-yl, R1a=H,

R1b=Me, R6a=6-chloro, R6b=H, R3=R4=R5=H] stage 1a, conn. 172

1H NMR (500 MHz, DMSO-06) δ=12.04 (s, 1H), 8.63 (s, 1H), 8.27 (d, J=5.95 Hz, 1H), 7.72 ( d, J=1.98 Hz, 1H), 7.66 (d, J=9.00 Hz, 1H), 7.55 (s, 1H), 7.46 (dd, J=2.21, 8 .62 Hz, 1H), 7.31 (d, J=8.85 Hz, 1H), 6.21 (d, J=9.30 Hz, 1H), 4.93-5.08 (m, 1H ), 4.71 (kv, J=6.86 Hz, 1H), 1.84-1.93 (m, 1H), 1.47 (d, J=6.86 Hz, 3H), 1.41 (d, J=6.86 Hz, 3H), 0.98 (d, J=6.71 Hz, 3H), 0.61 (d, J=6.41 Hz, 3H). -0.24 (d, J=6.71 Hz, 3H). LCMS: m/z 438 [M+H] ⁺ v.a. 5.68 min. MSVR (IER) calc. for C ₂₃ H ₂₄ ClN ₅ O ₂ [M+H] ⁺ 438.1692 found 438.1685.

8-[(2S)-3-methylbutan-2-yl]-2-({(1S)-1-[4-(morpholin-4-yl)phenyl]ethyl}amino)pyrido[2,3-d] pyrimidin-7(8H)-one [(I), X=N, P2=^)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-NR7R8, R6b= H, R7-R8=morpholin-4-yl R3=R4=R5=H] stage 1a, conn. 173

1H NMR (500 MHz, DMSOO δ=8.56 (s, 1H), 8.24 (d, J=7.02 Hz, 1H), 7.64 (d, J=9.15 Hz, 1H), 7.23 (d, J=8.69 Hz, 1H), 7.16 (d, J=8.69 Hz, 1H), 6.87 (d, J=8.69 Hz, 2H), 6, 19 (d, J=9.15 Hz, 1H), 4.78-5.15 (shm, 2H), 3.71 (m, 4H), 3.02 (m, 4H), 1.41-1 .52 (m, 4H), 0.98-1.22 (m, 3H), 0.61-0.80 (m, 3H), 0.12-0.17 (m, 3H).LCMS: m /z 422 [M+n] ⁺ v.a. 6.3 min HRMS (ESI) calculated for C ₂₄ H ₃₁ N ₅ O ₂ [M+H] ⁺ 422.2551 found 422.2545.

Benzyl-4-{4-[(1S)-1-({8-[(2S)-3-methylbutan-2-yl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2yl}amino)ethyl]phenyl}piperazine-1-carboxylate [(I), X=N, K2=^)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4 -NR7R8, R6b=H, R7-R8=benzylpiperazine-1-carboxylate, R3=R4=R5=H] stage 1a, conn. 174

1H NMR (500 MHz, DMSO-е ₆ ) δ=8.55 (shs, 1H), 8.24 (d, J=7.32 Hz, 1H), 7.63 (d, J=9.30 Hz , 1H), 7.287.42 (m, 5H), 7.23 (d, J=8.69 Hz, 1H), 7.15 (d, J=8.69 Hz, 1H), 6.89 (d , J=8.69 Hz, 2H), 6.20 (d, J=9.30 Hz, 1H),

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5.09 (s, 2H), 4.77-4.97 (shm, 2H), 3.51 (shs, 4H), 3.04 (shs, 4H), 1.41-1.52 (m, 4H), 1.16-1.21 (shm, 3H), 0.550.75 (m, 3H), 0.13 (d, J=6.56 Hz, 3H). LCMS: m/z 555 [M+H]+ v.a. 7.38 min. MSVR (IER) calc. for C ₃₂ H ₃₉ N ₆ O ₃ [M+H]+ 555.3078 found 555.3092.

8-[(2S)-3-Methylbutan-2-yl]-2-({(1S)-1-[4-(piperazin-1-yl)phenyl]ethyl}amino)pyrido[2,3-d] pyrimidin-7(8H)-one [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-NR7R8, R6b =H, R7-R8=piperazin-1-yl, R3=R4=R5=H] stage 1a, conn. 176

¹ H NMR (500 MHz, DMSO-dg) δ=8.56 (s, 1H), 8.24 (m, 1H), 7.64 (m, 1H), 7.11-7.26 (m, 2H), 6.9 (d, J=8.69 Hz, 2H), 6.19 (m, 1H), 4.78-5.15 (shm, 2H), 3.21 (m, 4H), 3.14 (m, 4H), 1.41-1.52 (m, 4H), 0.98-1.22 (m, 3H), 0.61-0.80 (m, 3H), 0. 12-0.17 (m, 3H). LCMS: m/z 421 [M+H]+ v.a. 4.98 min. MSVR (IER) calc. for C24H33N6O [M+H]+ 421.2711 found 421.2714.

2-({(1S)-1-[4-(4-Ethylpiperazin-1-yl)phenyl]ethyl}amino)-8-[(2S)-3-methylbutan-2-yl]pyrido[2,3d] pyrimidin-7(8H)-one [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-NR7R8, R6b =H, R7-R8=4-ethylpiperazin-1-yl, R3=R4=R5=H] stage 1a, conn. 177

1H NMR (500 MHz, DMSO-06) δ=8.56 (bs, 1H), 8.25 (d, J07,.32 Hz, 1H), 7.63 (d, J=9.30 Hz, 1H ), 7.21 (d, J=8.54 Hz, 1H), 7.13 (d, J=8.54 Hz, 1H), 6.85 (d, J=8.54 Hz, 2H), 6.19 (d, J=9.30 Hz, 1H), 4.75-5.19 (m, 2H), 3.05 (shs, 4H), 2.46 (shs, 4H), 2.34 (kv, J=7.10 Hz, 2H), 1.41-1.52 (m, 4 N), 1.03-1.22 (m, 3H), 1.01 (t, J=7, 17 Hz, 3H), 0.61-0.79 (m, 3H), 0.14 (d, J=6.56 Hz, 3H). LCMS: m/z 449 [M+H]+ v.a. 5.25 min. MSVR (IER) calc. for C ₂₆ H ₃₇ N ₆ O [M+H]+ 449.3024 found 449.3021.

Benzyl 4-{2-fluoro-4-[(1S)-1-({8-[(2S)-3-methylbutan-2-yl]-7-oxo-7,8-dihydropyrido[2,3-d ]pyrimidin-2-yl} amino)ethyl]phenyl}piperazine-1-carboxylate [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b =Me, R6a=4-NR7R8, R6b=F, R7-R8=benzylpiperazine-1-carboxylate, R3=R4=R5=H] stage 1a, conn. 178

1H NMR (500 MHz, DMSO-dg) δ=8.59 (s, 1H), (8.29 (d, J=7.17 Hz, 1H), 7.65 (dd, J=3.97, 9.00 Hz, 1H), 7.27-7.42 (m, 5H), 6.95-7.15 (m, 3H), 6.05-6.30 (m, 1H), 5.09 (s, 2H), 4.92 (m, 1H), 4.79 (m, 1H), 3.53 (shs, 4H), 2.91 (shs, 4H), 1.95 (m, 1n) , 1.41-1.49 (m, 3H), 1.02-1.11 (m, 3H), 0.59-0.77 (m, 3H), 0.09-0.13 (m, 3n) LCMS: m/z 573 [M+H]+ v.a. 7.48 min HRMS (ESI) calculated for C ₃₂ H ₃₈ FN ₆ O ₃ [M+H]+ 573.2984 found 573 ,3004.

8-[(2S)-3-Methylbutan-2-yl]-2-( {(1 S)-1-[6-(piperazin-1 -yl)pyridin-3 -yl]ethyl}amino)pyrido[2 ,3d]pyrimidin-7(8H)-one [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A pyridin-3-yl, R1a=H, R1b=Me, R6a =4NR7R8, R6b=H, R7-R8=piperazin-1-yl, R3=R4=R5=H] stage 1a, conn. 180

1H NMR (500 MHz, DMSO-de) δ 8.57 (s, 1H), 8.25 (m, 1H), 8.11 (brs, 1H), 7.65 (d, J=9.30 Hz , 1H), 7.44 (d, J=8.39 Hz, 1H), 6.74 (d, J=8.39 Hz, 1H), 6.22 (d, J=9.30 Hz, 1H ), 4.91 (m, 1H), 4.80 (m, 1H), 3.33 (m, 4H), 2.76 (m, 4H), 2.07 (m, 1H), 1.43 -1.52 (m, 3H), 0.98-1.08 (m, 3H), 0.55-0.81 (m, 3H), 0.17 (d, J=6.56 Hz, 1H ). LCMS: m/z 422 [M+H]+ v.a. 4.63 min. MSVR (IER) calc. for C ₂₃ H ₃₂ N ₇ O [M+H]+ 422.266 Found 422.267.

tert-Butyl 4-(4-{(^)-1-[(8-ethyl-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin-2-yl)amino]ethyl}benzyl)piperazin- 1-carboxylate [(I), X=N, R2=ethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=tert-butyl ether 4- piperazine-1-carboxylic acid, R3=R4=R5=H] comp. 185

¹ H NMR (500 MHz, DMSO-dg) δ=8.58 (s, 1H), 8.43 (d, J=7.17 Hz, 1H), 7.66 (d, J=9.30 Hz , 1H), 7.47 (d,

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J=8.08 Hz, 1H), 7.42 (d, J=8.08 Hz, 1H), 7.33 (d, J=8.08 Hz, 1H), 7.22 (d, J= 8.08 Hz, 1H), 6.21 (d, J=9.30 Hz, 1H), 5.03 (kv, J=7.1 Hz, 1H), 4.46 (s, 2H), 4 .01-4.21 (m, 2H), 3.58 (s, 2H), 3.38-3.47 (shs, 8H), 1.47 (d, J=7.02 Hz, 3H), 1.38 (s, 9H), 0.89 (m, 3H). LCMS: m/z 493 [M+H]+ @ w.u. 6.37 min. MSVR (IER) calc. for C27H36N6O3 [M+H] ⁺ 493.2922 found 493.2921;

8-[(2S)-3-Methylbutan-2-yl]-2-{[(1S)-1-{4-[(4-methyl-3-oxopiperazin-1-yl)methyl]phenyl}ethyl]amino }pyrido[2,3Upyrimidin-7(8H)-onecarboxylate [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a= 4-CH ₂ NR7R8, R6b=H, R7-R8=-4-methyl-3-oxopiperαzin-1-yl, R3=R4=R5=H] comp.

188

¹ H NMR (500 MHz, DMSO-06) δ=8.56 (s, 1H), 8.37 (d, J=7.32 Hz, 1H), 7.64 (d, J=9.30 Hz , 1H), 7.217.37 (m, 4H), 6.04-6.29 (m, 1H), 4.69-5.09 (m, 2H), 3.46 (s, 2H), 3. 17-3.25 (m, J=4.73 Hz, 2H), 2.91 (shs, 2H), 2.78 (s, 3H), 2.58 (sh quin, J=4.70 Hz, 2H), 1.44-1.54 (m, 4H), 0.99-1.09 (m, 3H), 0.58-0.76 (m, 3H), 0.08 (d, J= 6.56 Hz, 3H). LCMS: m/z 463 [M+H] ⁺ @ w.u. 5.52 min. MSVR (IER) calc. milking C ₂₇ H ₃₅ N ₆ O ₂ [M+H] ⁺ 463.2816 Found 463.2819;

tert-Butyl 4-(4-{(^)-1-[(8-ethyl-7-oxo-7,8-dihydropyrido[2,3Upyrimidin-2-yl)amino]ethyl}benzoyl)piperazine-1-carboxylate [(I), X=N, K2=ethyl, A=phenyl, R1a H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=tert-butyl ether 4-piperazine-1- carboxylic acid, R3=R4=R5=H] conn. 189

1H NMR (500 MHz, DMSO-06) δ=8.59 (s, 1H), 8.49 (d, J=7.17 Hz, 1H), 7.68 (d, J=9.30 Hz, 1H), 7.46 (d, J=8.24 Hz, 2H), 7.35 (d, J=8.24 Hz, 2H), 6.21 (d, J=9.30 Hz, 1H) , 5.05 (quin, J=6.90 Hz, 1H), 3.94-4.35 (m, 2H), 3.37-3.62 (m, 8H), 1.49 (d, J =7.02 Hz, 3H), 1.39 (s, 9H), 0.89 (t, J=6.86 Hz, 3H). LCMS: m/z 507 [M+H] ⁺ @ w.u. 5.78 min. MSVR (IER) calc. for C ₂₇ H ₃₅ N ₆ O ₄ [M+H] ⁺ 507.2715 found 507.2722;

tert-Butyl 4-{4-[(^)-1-{[4-cyano-8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3Upyrimidin-2-yl]amino }ethyl]benzyl}piperazine-1-carboxylate [(I), X=N, K2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H , R7-R8=tert-butyl ester of 4-piperazine-1-carboxylic acid, R3=CN, R4=R5=H] comp. 200

CN

1H NMR (500 MHz, DMSO-06) δ=8.93 (d, J=7.47 Hz, 1H), 7.71 (d, J=9.46 Hz, 1H), 7.32 (d, J=8.08 Hz, 2H), 7.23 (d, J=7.78 Hz, 2H), 6.42 (d, J=9.46 Hz, 1H), 5.05 (kv, J= 7.02 Hz, 1H), 3.96 (dd, J=12.51 Hz, 2H), 3.43 (s, 2H), 3.28 (shs, 4H), 2.20-2.32 ( m, J=4.27 Hz, 4H), 1.46 (d, J=7.02 Hz, 3H), 1.37 (s, 9H), 0.91 (s, 3H), 0.72 ( shs, 6N). LCMS: m/z 560 [M+H] ⁺ @ w.u. 10.34 min. MSVR (IER) calc. for C ₃₁ H41N ₇ O ₃ [M+H] ⁺ 560.3344 found 560.3362;

Phenyl 4-[(^)-1-{4-[(^)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3Upyrimidin-2-yl] amino}ethyl]phenyl}propyl]piperazine-1-carboxylate [(I), X=N, R2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-CHR14NR7R8, R6b= H, R7-R8=4-piperazine-1-carboxylic acid phenyl ester, R14=Ethyl,

R3=R4=R5=H] conn. 225

1H NMR (500 MHz, DMSO-06) δ=8.57 (s, 1H), 8.33 (d, J=7.93 Hz, 1H), 7.63 (d, J=9.3 Hz, 1H), 7.36 (d, J=7.78 Hz, 2H), 7.32 (d, J=7.78 Hz, 2H), 7.17 (d, J=7.78 Hz, 2H) , 7.16 (d, J=7.78 Hz, 1H), 7.01 (d, J=7.78 Hz, 1H), 6.16 (d, J=9.3 Hz, 2H), 5 .48 (shs, 1H), 5.00 (shs, 1H), 3.50 (shs, 4H), 3.36 (m, 1H), 2.30 (shs, 4H), 1.82-1, 92 (m, 1H), 1.63-1.73 (m, 1H), 1.48 (d, J=6.9 Hz, 3H), 0.96 (shs, 6H), 0.67-0 .74 (m, 3H). LCMS: m/z 555 [M+H] ⁺ @ w.u. 8.68 min. MSVR (IER) calc. for C ₃₂ H ₃₉ N ₆ O ₃ [M+H] ⁺ 555.3078 found 555.3085;

Phenyl 4-[(^)-1-{4-[(^)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3Upyrimidin-2-yl] amino}ethyl]phenyl}propyl]piperazine-1-carboxylate [(I), X=N, R2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-CHR ₁₄ NR ₇ R ₈ , R6b=H, R7-R8=4-piperazine-1-carboxylic acid phenyl ester, R14=ethyl, R3=R4=R5=H] comp. 226

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1H NMR (500 MHz, DMSO-06) δ=8.57 (s, 1H), 8.33 (d, J=7.93 Hz, 1H), 7.63 (d, J=9.3 Hz, 1H), 7.36 (d, J=7.78 Hz, 2H), 7.32 (d, J=7.78 Hz, 2H), 7.17 (d, J=7.78 Hz, 2H) , 7.16 (d, J=7.78 Hz, 1H), 7.01 (d, J=7.78 Hz, 1H), 6.16 (d, J=9.3 Hz, 2H), 5 .48 (shs, 1H), 5.00 (shs, 1H), 3.50 (shs, 4H), 3.36 (m, 1H), 2.30 (shs, 4H), 1.82-1, 92 (m, 1H), 1.63-1.73 (m, 1H), 1.48 (d, J=6.9 Hz, 3H), 0.96 (shs, 6H), 0.67-0 .74 (m, 3H). LCMS: m/z 555 [M+H]+ @ w.u. 8.68 min. MSVR (IER) calc. milking C ₃₂ H ₃₉ N ₆ O ₃ [M+H] ⁺ 555.3078 found 555.3085.

2-{[(^)-1-{4-[(2E)-pent-2-en-3-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3^ ]pyrimidin7(8H)-one [(I), X=N, I2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=(2E)-pent-2-ene-3- silt, R6b=H,

R3=R4=R5=H] conn. 250

1H NMR (500 MHz, DMSO-06) δ=8.51-8.60 (m, 1H), 8.36 (d, J=7.17 Hz, 1H), 7.62 (d, J=9 .15 Hz, 1H), 7.25-7.36 (m, 4H), 7.15 (m, 1H), 6.15 (d, J=9.00 Hz, 1H), 5.42-5 .82 (m, 1H), 5.00 (shs, 1H), 2.44 (kv, J=7.32 Hz, 2H), 1.74 (d, J=6.71 Hz, 3H), 1 .24-1.54 (m, 9H), 0.87 (t, J=7.8 Hz, 3H). LCMS: m/z 377 [M+H] ⁺ @ w.u. 13.71 min.

Example 4.

2-{[(^)-1-(4-chlorophenyl)ethyl]amino}-8-(3-hydroxybenzyl)pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N , R2=3-hydroxybenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] transformation 13, conn. 71

To a stirred suspension of 2-{[(^)-1-(4-chlorophenyl)ethyl]amino}-8-(3-methoxybenzyl)pyrido[2,3^]pyrimidin-7(8H)-one (50 mg, 0 ,12 mmol), obtained as described in example 1, in anhydrous dichloromethane (5 ml) is added dropwise, under argon, a 1 M solution of BBr ₃ (1 ml, 1 mmol) in DCM at 0°C. The ice bath is removed and the mixture is stirred at room temperature overnight. The reaction mixture is diluted with DCM and washed with saturated NaHCO ₃ solution, then with water and saturated sodium chloride solution. After drying over Na ₂ SO ₄ , the solvent was removed to give the crude product, which was purified by column chromatography and eluted with DCM/MeOH 95/5 to give the title compound (34 mg, 70% yield).

1H NMR (500 MHz, DMSO-de) δ=9.29 (s, 1H), 8.61 (s, 1H), 8.44 (d, J=7.93 Hz, 1H), 7.76 ( d, J=9.46 Hz, 1H), 7.21-7.30 (m, 3H), 7.00 (t, J=7.70 Hz, 1H), 6.60 (d, J=7 .63 Hz, 1H), 6.51-6.57 (m, 2H), 6.30 (d, J=9.30 Hz, 1H), 5.37 (d, J=14.18 Hz, 1H ), 5.12 (d, J=14.34 Hz, 1H), 4.97-5.07 (m, 1H), 1.38-1.46 (m, 4H).

LCMS: m/z 407 [M+H] ⁺ v.a. 6.05 min. MSVR (IER) calc. giving C ₂₂ H ₂₀ ClN ₄ O ₂ [M+H] ⁺ 407.127 found 407.1276.

According to the same method, the following compounds are obtained:

2-{[(1 S)-1 -(4-Chlorophenyl)ethyl] amino }-8-(4-hydroxybenzyl)pyrido[2,3^] pyrimidin-7 (8H)-one [(I), X= N, R2=4-hydroxybenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-Cl, R6b=H, R3=R4=R5=H] conn. 72

1H NMR (500 MHz, DMSO-de) δ=9.10-9.70 (m, 1H), 8.61 (s, 1H), 8.48 (d, J=7.63 Hz, 1H), 7.72 (d, J=9.30 Hz, 1H), 7.28-7.38 (m, 4H), 6.96 (d, J=8.39 Hz, 2H), 6.55 (d , J=8.24 Hz, 2H), 6.26 (d, J=9.30 Hz, 1H), 5.32 (d, J=13.88 Hz, 1H), 5.11 (quin, J =6.90 Hz, 1H), 5.05 (d, J=14.03 Hz, 1H), 1.45 (d, J=6.86 Hz, 3H). LCMS: m/z 407 [M+H] ⁺ v.a. 5.93 min. MSVR (IER) calc. giving C ₂₂ H ₂₀ ClN ₄ O ₂ [M+H] ⁺ 407.127 found 407.1274;

Example 5.

4-[(^)-1-{[8-(2,6-Difluorobenzyl)-7-oxopyrido[2,3^]pyrimidin-2-yl]amino}ethyl]benzoic acid [(I), X=N , R2=2,6-difluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-COOH, R6b=H, R3=R4=R5=H] transformation 3, conn. 73

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Lithium hydroxide (0.022 g, 0.52 mmol) is added to the solution of methyl 4-[(1S)-1-{[8-(2,6 difluorobenzyl)-7-oxo-7,8-dihydropyrido[2,3^] pyrimidin-2-yl]amino}ethyl]benzoate (0.030 g, 0.07 mmol) in THF:water (1:1, 2 ml) and the reaction mixture was stirred at room temperature for 18 hours. The solvent (THF) was removed at under reduced pressure, and the aqueous residue is diluted with water. The aqueous phase was acidified with hydrochloric acid (1M) until a precipitate formed, the solid was filtered, washed with water and dried in vacuo to give the title compound as a white solid (0.029 g, 99% yield).

¹ H NMR (500 MHz, DMSO-06) δ=12.77 (brs, 1H), 8.61 (s, 1H), 8.47 (d, J=7.93 Hz, 1H), 7.66 -7.93 (m, 3H), 7.39 (d, J=8.08 Hz, 2H), 7.19-7.35 (m, 1H), 6.87-7.05 (m, 2H ), 6.24 (d, J=9.15 Hz, 1H), 5.53 (d, J=15.25 Hz, 1H), 5.28 (d, J=15.25 Hz, 1H), 4.98-5.15 (m, 1H), 1.38-1.53 (m, 3H). LCMS: m/z 437 [M+H]+ v.a. 4.94 min. MSVR (IER) calc. for C23H19F2N4O3 [M+H] ⁺ 437.142, 437.1413 was found.

According to the same method, the following compounds are obtained:

4-[(1 S)-1 - {[8-(2-Fluorobenzyl)-7-oxopyrido[2,3^]pyrimidin-2-yl] amino}ethyl] benzoic acid [(I), X=N, R2=2-fluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-COOH, R6b=H, R3=R4=R5=H] conn. 74

¹ H NMR (500 MHz, DMSO-06) δ=12.77 (brs, 1H), 8.59-8.70 (m, 1H), 8.52 (d, J=7.63 Hz, 1H) , 7.80 (d, J=9.30 Hz, 1H), 7.70 (d, J=8.08 Hz, 2H), 7.26-7.48 (m, 2H), 7.16- 7.24 (m, 2H), 6.85-7.10 (m, 1H), 6.53-6.81 (m, 1H), 6.31 (d>9.30 Hz, 1H), 5 .39-5.53 (m, 1H), 5.22 (d, J=15.40 Hz, 1H), 4.85-5.04 (m, 1H), 1.37-1.47 (m , 3H). LCMS: m/z 419 [M+H] ⁺ v.a. 4.97 min. MSVR (IER) calc. giving C ₂₃ H ₂₀ FN ₄ O ₃ [M+H] ⁺ 419.1514 found 419.1517.

Example 6.

4-[(^)-1-{[8-(2,6-Difluorobenzyl)-7-oxopyrido[2,3^]pyrimidin-2-yl]amino}ethyl]-N-(4,4-difluorocyclohexyl )benzamide [(I), X=N, R2=2,6-difluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CONR7R8,

R6b=H, R7=4,4-difluorocyclohexyl, R8=H, R3=R4=R5=H] transformation 4, conn. 75

A solution of TBTU (12 mg, 0.04 mmol) in DCM (1 ml) was added to a solution of 4-[(1S)-1-{[8-(2,6 difluorobenzyl)-7-oxopyrido[2,3^]pyrimidine -2-yl]amino}ethyl]benzoic acid (10 mg, 0.02 mmol), DIPEA (10 µM, 0.06 mmol) and 4,4-difluorocyclohexylamine hydrochloride (6.8 mg, 0.04 mmol) in DXM (1 ml). The reaction mixture was stirred at room temperature for 12 h, the solvents were removed in vacuo, the residue was partitioned between DCM and water, and the organic layer was dried. The crude product was purified by silica gel column chromatography (eluent: DCM/EtOAc/EtOH: 60/35/5) to obtain the title compound (9.95 g, 90% yield).

¹ H NMR (500 MHz, DMSO-06) δ=8.60 (s, 1H), 8.43 (d, J=8.08 Hz, 1H), 8.14 (d, J=7.63 Hz , 1H), 7.73 (d, J=9.46 Hz, 1H), 7.67 (d, J=8.08 Hz, 1H), 7.36 (d, J=8.24 Hz, 1H ), 7.26 (t, J=6.86 Hz, 1H), 6.94 (t, J=8.16 Hz, 1H), 6.24 (d, J=9.30 Hz, 1H), 5.53 (d, J=14.79 Hz, 1H), 5.31 (d, J=14.95 Hz, 1H), 4.98-5.12 (m, 1H), 3.88-4 .02 (m, 1H), 1.80-2.11 (m, 6H), 1.61 (kV, J=12.15 Hz, 2H), 1.32-1.49 (m, 3H). LCMS: m/z 554 [M+H] ⁺ v.a. 4.85 min. MSVR (IER) calc. giving C ₂₉ H ₂₈ F ₄ N ₅ O ₂ [M+H] ⁺ 554.2174 found 554.2181.

According to the same procedure, but using suitably substituted derivatives, the following compounds are obtained:

4-[(^)-1-{[8-(2,6-Difluorobenzyl)-7-oxopyrido[2,3^]pyrimidin-2-yl]amino}ethyl]-N-(1-methyl piperidin-4 -yl)benzamide [(I), X=N, R2=2,6-difluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CONR7R8,

R6b=H, R7=N-1-methylpiperidin-4-yl, R8=H, R3=R4=R5=H] conn. 76

1H NMR (500 MHz, DMSO-06) δ=8.60 (s, 1H), 8.43 (d, J=7.93 Hz, 1H), 8.07 (d, J=7.78 Hz, 1H), 7.73 (d,

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J=9.30 Hz, 1H), 7.67 (d, J=8.08 Hz, 2H), 7.35 (d, J=8.08 Hz, 2H), 7.22-7.30 ( m, 1H), 6.94 (t, J=8.08 Hz, 2H), 6.24 (d, J=9.30 Hz, 1H), 5.53 (d, J=14.79 Hz, 1H), 5.32 (d, J=14.95 Hz, 1H), 5.05 (quin, J=7.40 Hz, 1H), 3.613.78 (m, 1H), 2.75 (d, J=11.29 Hz, 2H), 2.15 (s, 3H), 1.92 (t, J=10.90 Hz, 2H), 1.72 (d, J=11.59 Hz, 2H) , 1.55 (tkv, J=3.70, 12.10 Hz, 2H), 1.38 (d, J=7.02 Hz, 3H). LCMS: m/z 533 [M+H]+ v.a. 4.82 min. MSVR (IER) calc. for C ₂₉ H ₃₁ F ₂ N6O ₂ [M+H]+ 533.2471 found 533.2473;

8-(2,6-Difluorobenzyl)-2-{[(^)-1-{4-[(4,4-difluoropiperidin-1-yl)carbonyl]phenyl}ethyl]amino}pyrido[2,3^] pyrimidin-7(8H)-one [(I), X=N, I2=2,6-difluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4CONR7R8, R6b=H, R7=4.4 -difluoropiperidin-1-yl, R8=H, R3=R4=R5=H] conn. 77

¹ H NMR (500 MHz, DMSOC6) 5=8.61 (s, 1H), 8.43 (d, J=8.39 Hz, 1H), 7.74 (d, J=9.46 Hz, 1H ), 7.347.39 (m, 2H), 7.31 (d, J=7.93 Hz, 2H), 7.24-7.32 (m, 1H), 6.92-7.01 (m, J=8.08, 8.08 Hz, 2H), 6.25 (d, J=9.30 Hz, 1H), 5.54 (d, J=14.95 Hz, 1H), 5.37 ( d, J=15.25 Hz, 1H), 5.04-5.19 (m, 1H), 3.66 (shs, 2H), 3.40 (shs, 2H), 2.01 (shs, 4H ), 1.39 (d, J=7.02 Hz, 3H). LCMS: m/z 540 [M+H]+ w.a. 6.03 min. MSVR (IER) calc. for C ₂₈ H ₂₆ F ₄ N ₅ O ₂ [M+H]+ 540.2017 found 540.2028;

4-[(^)-1-{[8-(2,6-Difluorobenzyl)-7-oxopyrido[2,3^]pyrimidin-2-yl]amino}ethyl]-N-(tetrahydro2H-pyran-4- yl)benzamide [(I), X=N, I2=2,6-difluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CONR7R8, R6b=H, R7=tetrahydro-2H-pyran- 4-yl, R8=H, R3=R4=R5=H] conn. 78

1H NMR (500 MHz, DMSOU) 5=8.61 (s, 1H), 8.44 (d, J=7.93 Hz, 1H), 8.14 (d, J=7.47 Hz, 1H) , 7.73 (d, J=9.30 Hz, 1H), 7.68 (d, J=8.24 Hz, 2H), 7.36 (d, J=8.24 Hz, 2H), 7 ,22-7.30 (m, 1H), 6.94 (t, J=8.20 Hz, 2H), 6.24 (d, J=9.15 Hz, 1H), 5.53 (d, J=14.95 Hz, 1H), 5.32 (d, J=15.10 Hz, 1H), 4.99-5.09 (m, 1H), 3.92-4.03 (m, 1H ), 3.87 (d, J=10.07 Hz, 2H), 3.37 (t, J=11.60 Hz, 2H), 1.73 (tdd, J=2.02, 3.91, 12.64 Hz, 2H), 1.49-1.61 (m, 2H), 1.39 (d, J=6.86 Hz, 3H). LCMS: m/z 520 [M+H]+ v.a. 5.2 min. MSVR (IER) calc. for C ₂₈ H ₂₈ F ₂ N ₅ O ₃ [M+H]+ 520.2155 found 520.2153;

X-(4,4-Difluorocyclohexyl)-4-[(>)-'1-['[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3D]pyrimidin-2yl]amino}ethyl]benzamide [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CONR7R8, R6b=H, R7=4,4-difluorocyclohexyl, R8=H, R3 =R4=R5=H] conn. 79

¹ H NMR (500 MHz, DMSO-dg) 5=8.48-8.62 (m, 1H), 8.44 (d, J=7.32 Hz, 1H), 8.18 (d, J= 7.78 Hz, 1H), 7.79 (d, J=8.08 Hz, 2H), 7.68 (d, J=9.30 Hz, 1H), 7.45 (d, J=8, 08 Hz, 2H), 6.23 (d, J=9.30 Hz, 1H), 5.11 (quin, J=7.02 Hz, 1H), 3.91-4.07 (m, 3H) , 1.81-2.07 (m, 6H), 1.55-1.67 (m, 2H), 1.47 (d, J=7.17 Hz, 3H), 0.67-0.98 (m, 9H). LCMS: m/z 498 [M+H]+ v.a. 6.27 min. MSVR (IER) calc. for C ₂₇ H ₃₄ F ₂ N ₅ O ₂ [M+H]+ 498.2675 found 498.269;

X-Cyclopentyl-4-[(>)-'1-['[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3D]pyrimidin-2-yl]amino}ethyl]benzamide [(I) , X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CONR7R8, R6b=H, R7=-cyclopentyl, R8=H, R3=R4=R5= H] conn. 80

¹ H NMR (500 MHz, DMSO-dg) 5=8.49-8.66 (m, 1H), 8.43 (d, J=7.47 Hz, 1H), 8.15 (d, J= 7.17 Hz, 1H), 7.71-7.83 (m, 2H), 7.67 (d, J=9.30 Hz, 1H), 7.44 (d, J=8.08 Hz, 2H), 6.23 (d, J=9.30 Hz, 1H), 5.12 (t, J=6.79 Hz, 1H), 3.84-4.35 (m, 3H), 1, 80-1.90 (m, 2H), 1.60-1.71 (m, 2H), 1.42-1.57 (m, 7H), 0.62-1.00 (m, 9H). LCMS: m/z 498 [M+H]+ v.a. 6.21 min. MSVR (IER) calc. for CJ134X502 [M+H]+ 448.2707 found 448.2706;

X-Cyclohexyl-4-[(>)-'1-['[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3D]pyrimidin-2-yl]amino}ethyl]benzamide [(I) , X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CONR7R8, R6b=H, R7=cyclohexyl, R8=H, R3=R4=R5=H ] conn. 81

- 77 046117

1H NMR (500 MHz, DMSOU) δ=8.48-8.63 (m, 1H), 8.12-8.46 (m, 1H), 8.07 (d, J=8.08 Hz, 1H ), 7.71-7.83 (m, 2H), 7.59-7.70 (m, 1H), 7.44 (d, J=8.08 Hz, 2H), 6.23 (d, J=9.30 Hz, 1H), 4.83-5.33 (m, 1H), 3.90-4.35 (m, 2H), 3.73 (d, J=3.51 Hz, 1H ), 1.78 (shs, 2H), 1.71 (shs, 2H), 1.54-1.65 (m, J=11.74 Hz, 1H), 1.47 (d, J=7, 02 Hz, 3H), 1.21-1.35 (m, 4H), 1.04-1.16 (m, 1H), 0.60-0.99 (m, 9H). LCMS: m/z 462 [M+H]+ v.a. 6.51 min. MSVR (IER) calc. for C27H36N5O2 [M+H] ⁺ 462.2864 found 462.2861;

2-Chloro-X-(4,4-difluorocyclohexyl)-4-(1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3^]pyrimidine

2-yl]amino}ethyl)benzamide [(I), X=N, K2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CONR7R8, R6b=Cl, R7=-4 ,4-difluorocyclohexyl, R8=H, R3=R4=R5=H] conn. 82

1H NMR (500 MHz, DMSOU) δ=8.50-8.64 (m, 1H), 8.46 (d, J=7.32 Hz, 1H), 8.14-8.37 (m, 1H ), 7.59-7.72 (m, 1H), 7.50 (d, J=8.54 Hz, 1H), 7.22-7.41 (m, 2H), 6.25 (d, J=9.15 Hz, 1H), 4.97-5.30 (m, 1H), 3.74-4.33 (m,

3H), 1.78-2.09 (m, 6H), 1.50-1.62 (m, 2H), 1.46 (d, J=7.17 Hz, 3H), 0.72-0 .99 (m, 9H).

LCMS: m/z 532 [M+H] ⁺ v.a. 6.47 min. MSVR (IER) calc. milking C ₂₇ H ₃₃ ClN ₅ O ₂ [M+H] ⁺ 532.2286 Found 532.2276;

2-{[(^)-1-{4-[(4,4-Difluoropiperidin-1-yl)carbonyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3^ ]pyrimidin-7(8H)-one [(I), X=N, I2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CONR7R8, R6b=H, R7=4, 4-difluoropiperidin-1-yl, R8=H, R3=R4=R5=H] conn. 83

1H NMR (500 MHz, DMSOU) δ=8.56 (s, 1H), 8.24 (bs, 1H), 7.66 (d, J=9.15 Hz, 1H), 7.43-7, 48 (m, 2H), 7.33-7.41 (m, 2H), 6.23 (d, J=9.46 Hz, 1H), 5.17 (shs, 1H), 3.90-4 .28 (m, 2H), 3.55 (shs, 4n), 1.88-2.10 (m, 4n), 1.51 (d, J=7.02 Hz, 3H), 0.78 ( shs, 9N). LCMS: m/z 484 [M+H] ⁺ v.a. 6.18 min. MSVR (IER) calc. giving C ₂₆ H ₃₂ ClF ₂ N ₅ O ₂ [M+H] ⁺ 484.2519 found 484.2524;

Na(4,4-Difluorocyclohexyl)-4-(1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3^]pyrimidin-2yl]amino}ethyl)-2-fluorobenzamide [(I ), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CONR7R8, R6b=F, R7=4,4-difluorocyclohexyl, R8=H, R3=R4= R5=H] conn. 84

1H NMR (500 MHz, DMSO-06) δ=8.48-8.64 (m, 1H), 8.44 (d, J=7.32 Hz, 1H), 8.19 (d, J=7 .63 Hz, 2H), 7.69 (d, J=9.30 Hz, 1H), 7.05-7.35 (m, 2H), 6.25 (d, J=9.30 Hz, 1H ), 4.94-5.29 (m, J=7.17, 7.17 Hz, 1H), 3.814.30 (m, 3H), 1.77-2.08 (m, 6H), 1, 57 (d, J=10.07 Hz, 2H), 1.46 (d, J=7.02 Hz, 3H), 0.62-0.99 (m, 9H). LCMS: m/z 516 [M+H] ⁺ v.a. 6.47 min. MSVR (IER) calc. giving C ₂₇ H ₃₃ F ₃ N ₅ O ₂ [M+H] ⁺ 516.2581 found 516.2584;

N-(3,3-Difluorocyclobutyl)-4-[(1S)-1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3^]pyrimidin-2yl]amino}ethyl]benzamide [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CONR7R8, R6b=H, R7=3,3-difluorocyclobutyl, R8=H, R3 =R4=R5=H] conn. 85

1H NMR (500 MHz, DMSO-06) δ=8.71 (d, J=6.71 Hz, 1H), 8.47-8.63 (m, 1H), 8.44 (d, J=7 .32 Hz, 1H), 7.80 (d, J=7.78 Hz, 2H), 7.68 (d, J=9.30 Hz, 1H), 7.26-7.57 (m, 2H ), 6.23 (d, J=9.30 Hz, 1H), 5.03-5.31 (m, 1H), 3.88-4.31 (m, 3H), 2.85-3, 02 (m, 3H), 2.70-2.80 (m, 1H), 1.47 (d, J=7.02 Hz, 3H), 0.54-1.02 (m, 9H). LCMS: m/z 470 [M+H] ⁺ v.a. 6.05 min. MSVR (IER) calc. giving C ₂₅ H ₂₉ F ₂ N ₅ O ₂ [M+H] ⁺ 470.2362 found 470.2355;

4-[(^)-1-{[8-(2,2-Dimethylpropyl)-7-oxopyrido[2,3^]pyrimidin-2-yl]amino}ethyl]benzamide [(I), X=N, I2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CONH2, R6b=H, R3=R4=R5=H] conn. 86

- 78 046117

1H NMR (500 MHz, DMSOA) δ=8.58 (s, 1H), 8.43 (d, J=7.17 Hz, 1H), 7.87 (brs, 1H), 7.81 (d, J=7.93 Hz, 2H), 7.68 (d, J=9.15 Hz, 1H), 7.44 (d, J=8.08 Hz, 2H), 7.27 (s, 1H) , 6.23 (d, J=9.30 Hz, 1H), 4.97-5.38 (m, J=7.09, 7.09 Hz, 1H), 3.81-4.34 (m , 2H), 1.47 (d, J=7.02 Hz, 3H), 0.49-1.04 (m, 9H).

LCMS: m/z 380 [M+H] ⁺ v.a. 5.03 min. MSVR (IER) calc. giving C ₂₁ H ₂₆ N ₅ O ₂ [M+H] ⁺ 380.2081 found 380.2093;

8-(2,2-Dimethylpropyl)-2-{ [(1S)-1 -{4-[(4-hydroxypiperidin-1 -yl)carbonyl]phenyl}ethyl] amino } pyrido[2,3^]pyrimidin- 7(8H)-one [(I), X=N, C2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CONR7R8, R6b=H, R7=4-hydroxypiperidine-1 -silt, R8=H, R3=R4=R5=H] conn. 87

Ή NMR (500 MHz, DMSO-06) δ=8.59 (s, 1H), 8.42 (d, J=7.17 Hz, 1H), 7.68 (d, J=9.30 Hz, 1H), 7.42 (d, J=8.08 Hz, 2H), 7.31 (d, J=7.93 Hz, 2H), 6.23 (d, J=9.30 Hz, 1H) , 5.08 (quin, J=6.86 Hz, 1H), 4.78 (d, J=3.81 Hz, 1H), 3.91-4.25 (m, 2H), 3.71 ( dkv, J=3.28, 7.85 Hz, 1H), 3.42-3.49 (m, 2H), 3.04-3.22 (m, 2H), 1.61-1.79 ( m, 2H), 1.48 (d, J=7.02 Hz, 3H), 1.21-1.39 (m, 2H), 0.71 (shs, 9H). LCMS: m/z 464 [M+H]+ v.a. 5.1 min. MSVR (IER) calc. for C26H34N5O3 [M+H] ⁺ 464.2656 Found 464.2658;

2-Chloro-N-(4,4-difluorocyclohexyl)-4-[(^)-1-{[8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3^] pyrimidin-2-yl]amino}ethyl]benzamide [(I), X=N, C2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CONR7R8, R6b=Cl, R7=4,4-difluorocyclohexyl, R8=H, R3=R4=R5=H] conn. 88

1H NMR (500 MHz, DMSO-06) δ=8.59 (s, 1H), 8.46 (d, J=7.63 Hz, 1H), 8.36 (d, J=7.32 Hz, 1H), 7.68 (d, J=9.30 Hz, 1H), 7.51 (s, 1H), 7.27-7.43 (m, 2H), 6.25 (d, J=9 .15 Hz, 1H), 5.09 (quin, J=6.79 Hz, 1H), 3.97-4.29 (m, 2H), 3.84-3.97 (m, 1H), 1 .88-2.11 (m, 4H), 1.85 (d, J=12.66 Hz, 2H), 1.50-1.65 (m, 2H), 1.46 (d, J=7 .02 Hz, 3H), 0.84 (shs, 9H). LCMS: m/z 532 [M+H] ⁺ v.a. 6.58 min. MSVR (IER) calc. for C ₂₇ H ₃₃ ClF ₂ N ₅ O ₃ [M+H] ⁺ 532.2286 Found 532.2289;

N(4,4-Difluorocyclohexyl)-4-[(^)-1-{[8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3d]pyrimidin-2-yl] amino}ethyl]-2-fluorobenzamide [(I), X=N, C2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CONR7R8, R6b=F, R7=4 ,4-difluorocyclohexyl, R8=H, R3=R4=R5=H] conn. 89

1H NMR (500 MHz, DMSO-06) δ=8.48-8.64 (m, 1H), 8.44 (d, J=7.63 Hz, 1H), 8.19 (d, J=7 .78 Hz, 1H), 7.69 (d, J=9.30 Hz, 1H), 7.41-7.54 (m, 1H), 7.07-7.34 (m, 2H), 6 .25 (d, J=9.30 Hz, 1H), 4.99-5.30 (m, J=6.48, 6.48 Hz, 1H), 3.84-4.31 (m, 3H ), 1.78-2.07 (m, 6H), 1.52-1.64 (m, J=10.37 Hz, 2H), 1.46 (d, J=7.02 Hz, 3H) , 0.62-0.98 (m, 9H). LCMS: m/z 516 [M+H] ⁺ v.a. 6.48 min. MSVR (IER) calc. giving C ₂₇ H ₃₃ F ₃ N ₅ O ₃ [M+H] ⁺ 516.2581 found 516.2580.

Example 7.

8-(2,2-Dimethylpropyl)-2-( {(1S)-1-[3-fluoro-4-(hydroxymethyl)phenyl]ethyl } amino)pyrido[2,3 ^]pyrimidine-7(8H)- he [(I), X=N, C2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ OR7, R6b=F,

R7=H, R3=R4=R5=H] transformation 1, conn. 90

Methyl 4-[(^)-1-{[8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin-2-yl]amino}ethyl]-2 -fluorobenzoate (100 mg, 0.24 mmol) is dissolved in 5 ml of dry THF under argon at 0°C, and LiAlH4 (1.0 ml of 1M solution) is added. The reaction is completed in 30 minutes, a few drops of aqueous NaHCO3 are added to obtain a colloidal precipitate. The suspension is diluted with EtOAc and distilled to collect the organic fraction. The combined organic layers are dried, filtered and evaporated to give the desired product 8-(2,2-dimethylpropyl)-2-({(^)-1-[3-fluoro-4-(hydroxymethyl)phen

- 79 046117 nid]ethid}amino)11irido[2,3-c1]pyrimidin-7(811)-one in the form of a yellow fluorescent oil.

1H NMR (500 MHz, DMSO-06) δ=8.58 (s, 1H), 8.38 (d, J=7.32 Hz, 1H), 7.68 (d, J=9.46 Hz, 1H), 7.327.42 (m, 1H), 7.19 (d, J=7.78 Hz, 1H), 7.13 (d, J=11.29 Hz, 1H), 6.23 (d, J=9.15 Hz, 1H), 5.17 (t, J=5.72 Hz, 1H), 5.07 (quin, J=7.32 Hz, 1H), 4.47 (d, J= 5.64 Hz, 2H), 3.91-4.32 (m, 2H), 1.45 (d, J=7.02 Hz, 3H), 0.77 (shs, 9H). LCMS: m/z 385 [M+H]+ v.a. 5.63 min. MSVR (IER) calc. for C ₂₁ N ₂₆ FN ₄ O ₂ [M+H] ⁺ 385.2035 found 385.2043.

Working similarly, but using suitably substituted starting materials, the following compounds are obtained:

2-({(18)-1-[4-(hydroxymethyl)phenyl]ethyl}amino)-8-(2-methylpropyl)pyrido[2,3-4]pyrimidin7(8H)-one [(I), X =N, R2=2-methylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ OR7, R6b=H, R7=H, R3=R4=R5=H] conn. 91

1H NMR (500 MHz, DMSO-06) δ=8.57 (s, 1H), 8.51 (d, J=7.78 Hz, 1H), 7.68 (d, J=9.30 Hz, 1H), 7.32 (d, J=8.08 Hz, 2H), 7.23 (d, J=8.08 Hz, 2H), 6.21 (d, J=9.15 Hz, 1H) , 5.10 (t, J=5.64 Hz, 1H), 4.92-5.05 (m, 1H), 4.43 (d, J=5.80 Hz, 2H), 3.93- 4.00 (m, 1H), 3.84-3.90 (m, 1H), 1.89-1.97 (m, 1H), 1.46 (d, J=7.02 Hz, 3H) , 0.78 (d, J=6.71 Hz, 3H), 0.69 (d, J=6.56 Hz, 3H). LCMS: m/z 353 [M+H] ⁺ v.a. 5.29 min. MSVR (IER) calc. for C ₂₀ N ₂₅ N ₄ O ₂ [M+H] ⁺ 353.1972 found 353.197;

8-(2,6-Difluorobenzyl)-2-({(^)-1-[4-(hydroxymethyl)phenyl]ethyl}amino)pyrido[2,3Apyrimidin7(8H)-one [(I), X=N , R2=2,6-difluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH2OR7, R6b=H, R7=H, R3=R4=R5=H] conn. 92

1H NMR (500 MHz, DMSO-06) δ=8.58 (s, 1H), 8.34 (d, J=8.54 Hz, 1H), 7.73 (d, J=9.46 Hz, 1H), 7.277.37 (m, 1H), 7.24 (d, J=7.93 Hz, 2H), 7.14 (d, J=7.93 Hz, 2H), 6.98 (t, J=8.24 Hz, 2H), 6.24 (d, J=9.30 Hz, 1H), 5.55 (d, J=15.10 Hz, 1H), 5.37 (d, J= 14.79 Hz, 1H), 5.08 (t, J=5.64 Hz, 1H), 5.02 (quin, J=7.50 Hz, 1H), 4.39 (d, J=5, 64 Hz, 2H), 1.36 (d, J=7.17 Hz, 3H). LCMS: m/z 423 [M+H] ⁺ v.a. 5.25 min. MSVR (IER) calc. for C ₂₃ N ₂₁ F ₂ N ₄ O ₂ [M+H] ⁺ 423.1627 found 423.162;

2-({(^)-1-[4-(Hydroxymethyl)phenyl]ethyl}amino)-8-(2-hydroxy-2-methylpropyl)pyrido[2,3Apyrimidin-7(8H)-one [(I) , X=N, R2=2-hydroxy-2-methylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ OR7, R6b=F, R7=H, R3=R4=R5=H ]conn. 93

1H NMR (500 MHz, DMSO-06) δ=8.62 (s, 1H), 8.48 (d, J=7.8 Hz, 1H), 7.73 (d, J=9.3 Hz, 1H), 7.34 (d, J=7.9 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 6.27 (d, J=9.3 Hz, 1H) , 5.09 (t, J=5.7 Hz, 1H), 5.05 (quin, J=7.2 Hz, 1H), 4.63 (s, 1H), 4.43 (d, J= 5.8 Hz, 2H), 4.38-4.18 (m, 2H), 1.45 (d, J=6.9 Hz, 3H), 1.09-0.90 (m, 6H). LCMS: m/z 369 [M+H] ⁺ v.a. 4.47 min. MSVR (IER) calc. for C ₂₀ N ₂₅ N ₄ O ₃ [M+H] ⁺ 369.1921 found 369.1921.

Example 8.

2-{[(^)-1-{4-[(4,4-Difluoropiperidin-1-yl)methyl]-3-fluorophenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2, 3Apyrimidin-7(8H)-one [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=F, R7 -R8=4,4-difluoropiperidin-1-yl, R3=R4=R5=H] transformation 2, conn. 94

Step 1: Preparation of 4-[(^)-1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3Apyrimidin-2yl]amino}ethyl]-2-fluorobenzaldehyde

8-(2,2-dimethylpropyl)-2-({(^)-1-[3-fluoro-4-(hydroxymethyl)phenyl]ethyl}amino)pyrido[2,3Apyrimidin-7(8H)-one (75 mg, 0.2 mmol) was dissolved in DCM (10 ml) in the presence of manganese dioxide (347 mg, 4.0 mmol) and stirred at room temperature for 18 hours. The solution was filtered through a pad of celite and washed with DCM. The filtrate is concentrated to obtain the corresponding aldehyde, which is used in the next step without further purification.

Stage 2:

Preparation of the title compound 4-[(18)-1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3

- 80 046117 c1]11irimidin-2-yl]amino}ethyl]-2-fluoroenzaldehyde (30 mg, 0.08 mmol) is reacted with 4,4-difluoropiperidine hydrochloride (25 mg, 0.16 mmol) in the presence of sodium triacetoxyborohydride (102 mg, 0.48 mmol) in THF for 4 hours. After completion of the reaction, the mixture is treated with NaHCO ₃ and AcOEt. The organic phase is evaporated in vacuo and the crude product is purified by column chromatography on (DCM/EtOAc/EtOH: 7/2/1) to give the title compound.

¹ H NMR (500 MHz, DMSO-06) δ=8.59 (s, 1H), 8.38 (d, J=7.17 Hz, 1H), 7.68 (d, J=9.30 Hz , 1H), 7.287.38 (m, 1H), 7.06-7.24 (m, 2H), 6.24 (d, J=9.15 Hz, 1H), 4.87-5.40 ( m, J=7.02, 7.02 Hz, 1H), 3.76-4.40 (m, 2H), 3.55 (s, 2H), 2.47 (shs, 4H), 1.80 -1.97 (m, 4H), 1.46 (d, J=7.02 Hz, 3H), 0.50-1.02 (m, 9H). LCMS: m/z 488 [M+H]+ v.a. 7.15 min. MSVR (PER) calc. for C ₂₆ N ₃₃ F ₃ N ₅ O [M+H] ⁺ 488.2632 found 488.2636.

According to the same method, but using other amines, the following compounds are obtained: 2-{[(^)-1-{4-[(4,4-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8 -(2-methylpropyl)pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=2-methylpropyl, A=phenyl, R1a=H, R1b=Me, R6a= 4CH2NR7R8, R6b=H, R7-R8=4,4-difluoropiperidin-1-yl, R3=R4=R5=H] comp. 95

¹ H NMR (500 MHz, DMSO-06) δ=8.58 (s, 1H), 8.40 (d, J=7.02 Hz, 1H), 7.69 (d, J=9.30 Hz , 1H), 7.307.34 (m, 2H), 7.23 (d, J=7.93 Hz, 2H), 6.21 (d, J=9.30 Hz, 1H), 4.99-5 .03 (m, 1H), 3.81-4.06 (m, 2H), 3.47 (s, 2H), 2.43 (shs, 4H), 1.84-2.00 (m, 5H ), 1.46 (d, J=7.02 Hz, 3H), 0.72 (d, J=6.56 Hz, 3H), 0.60 (d, J=6.56 Hz, 3H). LCMS: m/z 456 [M+H] ⁺ v.a. 6.9 min. MSVR (PER) calc. for C ₂₅ N ₃₂ F ₂ N ₅ O [M+H] ⁺ 456.257 found 456.257;

8-Benzyl-2-[(1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl)amino]pyrido[2,3-4]pyrimidin7(8H)-one [(I ), X=N, R2=benzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=4,4difluoropiperidin-1-yl, R3=R4= R5=H] conn. 96

¹ H NMR (500 MHz, DMSO-06) δ=8.61 (s, 1H), 8.42 (d, J=8.08 Hz, 1H), 7.74 (d, J=9.30 Hz , 1H), 6.987.38 (m, 9H), 6.28 (d, J=9.30 Hz, 1H), 5.44 (d, J=14.18 Hz, 1H), 5.20 (d , J=14.18 Hz, 1H), 4.94-5.12 (m, 1H), 3.46 (s, 2H), 2.39-2.46 (m, 4H), 1.83- 1.98 (m, 4H), 1.34-1.49 (m, 3H). LCMS: m/z 490 [M+H] ⁺ v.a. 7.87 min. MSVR (PER) calc. for C28N30F2N5O [M+H] ⁺ 490.2413 found 490.2403;

2-[(1-{4-[(4,4-Difluoropiperidin-1-yl)methyl]phenyl}ethyl)amino]-8-(2-fluorobenzyl)pyrido[2,3d]pyrimidin-7(8H)- he [(I), X=N, K2=2-fluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=4,4-difluoropiperidine- 1-yl, R3=R4=R5=H] conn. 97

^1H NMR (500 MHz, DMSO-do) δ=8.58-8.67 (m, 1H), 8.07-8.47 (m, 1H), 7.79 (d, J=9.46 Hz, 1H), 7.19-7.36 (m, 2H), 7.15 (d, J=7.93 Hz, 2H), 7.07 (d, J=7.93 Hz, 2H), 6.96 (t, J=7.17 Hz, 1H), 6.54-6.82 (m, 1H), 6.31 (dD=9.46 Hz, 1H), 5.44-5.55 (m, 1H), 5.24-5.36 (m, 1H), 4.73-5.12 (m, 1H), 3.41-3.48 (m, 2H), 2.42 (shs , 6H), 1.83-1.99 (m, 4H), 1.32-1.44 (m, 3H). LCMS: m/z 508 [M+H] ⁺ v.a. 8.2 min. MSVR (IER) calc. for C ₂₈ N ₂₉ F ₃ N ₅ O [M+H] ⁺ 508.2319 found 508.2307;

8-(2,6-Difluorobenzyl)-2-[(1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl)amino]pyrido[2,3d]pyrimidine-7(8H )-one [(I), X=N, K2=2,6-difluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR ₇ R ₈ , R6b=H, R7-R8 =4,4-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 98

1H NMR (500 MHz, DMSO-06) δ=8.59 (s, 1H), 8.34 (d, J=8.39 Hz, 1H), 7.73 (d, J=9.30 Hz, 1H), 7.287.38 (m, 1H), 7.21-7.28 (m, 2H), 7.13 (d, J=7.93 Hz, 2H), 6.97 (t, J=8 .24 Hz, 2H), 6.24 (d, J=9.46 Hz, 1H), 5.55 (d, J=14.95 Hz, 1H), 5.35 (d, J=14.95 Hz, 1H), 4.99-5.13 (m, 1H), 3.43 (s, 2H), 2.42 (shs, 4H), 1.86-1.97 (m, 4H), 1 .31-1.50 (m, 3H). LCMS: m/z 526 [M+H] ⁺ v.a. 8.03 min. MSVR (IER) calc. for C ₂₈ N ₂₈ F ₄ N ₅ O [M+H] ⁺ 526.2225 found 526.2216;

8-(2,6-Difluorobenzyl)-2-{[(^)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}pyrido[2,3^] pyrimidin-7(8H)-one [(I), X=N, R2=2,6-difluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=4 ,4-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 99

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1H NMR (500 MHz, DMSO) δ=8.59 (s, 1H), 8.34 (d, J=8.39 Hz, 1H), 7.73 (d, J=9.30 Hz, 1H) , 7.287.42 (m, 1H), 7.25 (d, J=7.93 Hz, 2H), 7.09-7.21 (m, 2H), 6.91-7.06 (m, 2H ), 6.24 (d, J=9.30 Hz, 1H), 5.55 (d, J=15.10 Hz, 1H), 5.35 (d, J=15.25 Hz, 1H), 4.99-5.28 (m, 1H), 3.43 (s, 1H), 3.34 (shs, 1H), 2.42 (shs, 4H), 1.861.97 (m, 4H), 1 .34-1.49 (m, 3H). LCMS: m/z 526 [M+H] ⁺ v.a. 8.05 min. MSVR (IER) calc. for C ₂₈ N ₂₈ F ₄ N ₅ O [M+H] ⁺ 526.2225 found 526.2215;

2-[(1-{4-[(4,4-Difluoropiperidin-1-yl)methyl]phenyl}ethyl)amino]-8-(2-fluoroethyl)pyrido[2,3^]pyrimidin-7(8H) -one [(I), X=N, R2=2-fluoroethyl, A=phenyl, R1a H, R1b=Me, R6a=4-CH2NR7R8, R6b=H, R7R8=4,4-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 100

1H NMR (500 MHz, DMSOA) δ=8.53-8.64 (m, 1H), 8.48 (d, J=7.17 Hz, 1H), 7.69-7.73 (m, 1H ), 7.33 (d, J=7.93 Hz, 2H), 7.23 (d, J=8.08 Hz, 2H), 6.15-6.31 (m, 1H), 4.93 -5.28 (m, 1H), 4.14-4.52 (m, 4H), 3.47 (s, 2H), 2.43 (shs, 4H), 1.80-1.97 (m , 4H), 1.46 (d, J=7.17 Hz, Zn). LCMS: m/z 446 [M+H] ⁺ v.a. 5.76 min. MSVR (IER) calc. for C28N27N5O [M+H] ⁺ 446.2162 found 446.2162.

2-{[(18)-1-{4-[(4,4-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-propylpyrido[2,3-p]pyrimidin-7(8H) -one [(i), X=N, R2=propyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=4,4difluoropiperidin-1-yl , R3=R4=R5=H]conn. 101

1H NMR (500 MHz, DMSO-de) δ=8.53-8.64 (m, 1H), 8.48 (d, J=7.17 Hz, 1H), 7.69-7.73 (m , 1H), 7.33 (d, J=7.93 Hz, 2H), 7.23 (d, J=8.08 Hz, 2H), 6.15-6.31 (m, 1H), 4 .93-5.28 (m, 1H), 3.88-4.10 (m, 2H), 3.47 (shs, 2H), 2.43 (shs, 4H), 1.80-1.97 (m, 4H), 1.46 (d, J=7.17 Hz, 3H), 1.31-1.40 (m, 2H), 0.78 (t, J=7.32 Hz, 3H) . LCMS: m/z 442 [M+H]+ v.a. 6.58 min. MSVR (IER) calc. for C ₂₄ N ₃₀ F ₂ N ₅ O [M+H] ⁺ 442.2413 found 442.2411;

2-({(18)-1-[4-(Azepan-1-ylmethyl)phenyl]ethyl}amino)-8-propylpyrido[2,3^]pyrimidin-7(8H)-one [(I), X =N, R2=propyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR ₇ R ₈ , R6b=H, K7-K8=azepan-1-yl, R3=R4=R5= H] conn. 102

1H NMR (500 MHz, DMSOA) δ=8.57 (s, 1H), 8.41 (d, J=7.32 Hz, 1H), 7.67 (d, J=9.30 Hz, 1H) , 7.31 (d, J=7.63 Hz, 2H), 7.23 (d, J=7.78 Hz, 2H), 6.20 (d, J=9.15 Hz, 1H), 4 .95-5.32 (m, 1H), 3.85-4.21 (m, 2H), 3.513.58 (m, 2H), 2.54 (shs, 4H), 1.53 (shs, 8H ), 1.46 (d, J=7.02 Hz, 3H), 1.17-1.42 (m, 2H), 0.79 (t, J=7.40 Hz, 3H). LCMS: m/z 420 [M+H] ⁺ v.a. 4.95 min. MSVR (IER) calc. for C ₂₅ N ₃₄ N ₅ O [M+H] ⁺ 420.2758 found 420.2763;

2-{[(18)-1-{4-[(4-Acetylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-propylpyrido[2,3-p]pyrimidin-7(8H)-one [(I), X=N, R2=propyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=4acetylpiperazin-1-yl, R3=R4 =R5=H] conn. 103

1H NMR (500 MHz, DMSOA) δ=8.58 (s, 1H), 8.42 (d, J=7.32 Hz, 1H), 7.67 (d, J=9.30 Hz, 1H) , 7.32 (d, J=8.08 Hz, 2H), 7.22 (d, J=7.93 Hz, 2H), 6.20 (d, J=9.30 Hz, 1H), 4 .97-5.26 (m, 1H), 3.85-4.12 (m, 2H), 3.433.46 (m, 6H), 2.17-2.33 (m, 4H), 1.95 (s, 3H), 1.46 (d, J=7.17 Hz, 3H), 1.22-1.40 (m, 2H), 0.78 (t, J=7.40 Hz, 3H) . LCMS: m/z 449 [M+H] ⁺ v.a. 4.97 min. MSVR (IER) calc. for C ₂₅ N ₃₃ N ₆ O ₂ [M+H] ⁺ 449.266 Found 449.2663;

2-{[(18)-1-{4-[(4,4-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2-ethylpropyl)pyrido[2,3d]pyrimidin-7 (8H)-one [(I), X=N, K2=2-propyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=4, 4-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 104

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1H NMR (500 MHz, DMSO-dg) δ=8.51-8.63 (m, 1H), 8.41 (d, J=7.32 Hz, 1H), 7.69 (d, J=9 .15 Hz, 1H), 7.32 (d, J=7.93 Hz, 2H), 7.23 (d, J=8.08 Hz, 2H), 6.14-6.29 (m, 1H ), 4.97-5.30 (m, 1H), 3.97 (dd, J=7.40, 12.12 Hz, 1H), 3.83 (dd, J=7.70, 12.28 Hz, 1H), 3.48 (s, 2H), 2.43 (shs, 4H), 1.83-1.96 (m, 5H), 1.46 (d, J=7.02 Hz, 3H ), 0.73 (d, J=6.71 Hz, 3H), 0.60 (d, J=6.56 Hz, 3H). LCMS: m/z 456 [M+H]+ v.a. 6.89 min. MSVR (IER) calc. for C ₂₅ N ₃₂ F ₂ N ₅ O [M+H] ⁺ 456.257 found 456.2564;

2-['[(L)-1-*'4-[(4,4-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3R ]pyrimidin-7(8H)-one [(I), X=N, K2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8= 4,4-difluoropiperidin-1-yl, R3=R4=R5=H] comp. 105

1H NMR (500 MHz, DMSO-dg) δ=8.57 (s, 1H), 8.36 (d, J=7.17 Hz, 1H), 7.67 (d, J=9.00 Hz, 1H), 7.317.35 (m, 2H), 7.23 (d, J=8.24 Hz, 2H), 6.22 (d, J=9.15 Hz, 1H), 5.04-5, 11 (m, 1H), 3.96-4.26 (m, 2H), 3.48 (s, 2H), 2.44 (d, J=4.12 Hz, 4H), 1.84- 1.99 (m, 4H), 1.45 (d, J=7.02 Hz, 3H), 0.68-0.94 (m, 9H). LCMS: m/z 470 [M+H] ⁺ v.a. 7.23 min. MSVR (IER) calc. for C ₂₆ N ₃₄ F ₂ N ₅ O [M+H] ⁺ 470.2726 Found 470.2723;

2-{[(^)-1-{4-[(4,4-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2,2-trifluoroethyl)pyrido[2,3R ]pyrimidin-7(8H)-one [(I), X=N, K2=2,2,2-trifluoroethyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7- R8=4,4-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 106

1H NMR (500 MHz, DMSO-dg) δ=8.61-8.68 (m, 1H), 8.29-8.60 (m, 1H), 7.63-7.84 (m, 1H) , 7.33 (d, J=7.78 Hz, 2H), 7.23 (d, J=8.24 Hz, 2H), 6.28 (d, J=9.30 Hz, 1H), 4 .98-5.11 (m, 2H), 4.64-4.88 (m, 1H), 3.48 (s, 2H), 2.43 (shs, 4H), 1.79-1.97 (m, 4H), 1.46 (d, J=7.02 Hz, 3H). LCMS: m/z 482 [M+H] ⁺ v.a. 6.64 min. MSVR (IER) calc. for C ₂₃ H ₂₅ F ₅ N ₅ O [M+H] ⁺ 482.1974 found 482.1974;

8-[2,3-difluoro-2-(fluoromethyl)propyl]-2-{[(^)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino} pyrido[2,3D]pyrimidin-7(8H)-one [(I), X=N, K2=2,3-difluoro-2-(fluoromethyl)propyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=4,4-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 107

1H NMR (500 MHz, DMSO-dg) δ 8.55-8.66 (m, 1H), 8.49 (d, J=8.08 Hz, 1H), 7.74 (d, J=9, 30 Hz, 1H), 7.37 (d, J=7.78 Hz, 2H), 7.24 (d, J=7.93 Hz, 2H), 6.16-6.34 (m, 1H) , 5.18-5.21 (m, 1H), 4.35-4.66 (m, 6H), 3.47 (s, 2H), 2.44 (shs, 4H), 1.84-1 .99 (m, 4H), 1.42-1.53 (m, 3H). LCMS: m/z 510 [M+H] ⁺ v.a. 6.42 min. MSVR (IER) calc. for C25H29F5N5O [M+H] ⁺ 510.2287 found 510.228;

2-{[(^)-1-{4-[(4,4-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[3,3,3-trifluoro-2-(trifluoromethyl) propyl]pyrido[2,3R]pyrimidin-7(8H)-one [(I), X=N, K2=3,3,3-trifluoro-2-(trifluoromethyl)propyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=4,4-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 108

1H NMR (500 MHz, DMSO-dg) δ=8.65 (s, 1H), 8.55 (d, J=7.93 Hz, 1H), 7.76 (d, J=9.46 Hz, 1H), 7.26

7.31 (m, 2H), 7.20-7.26 (m, 2H), 6.27 (d, J=9.30 Hz, 1H), 5.04-5.15 (m, 1H) , 4.66-4.80 (m, 1H), 4.52 (dd, J=6.41, 13.88 Hz, 1H), 4.09-4.29 (m, J=8.08 Hz , 1H), 3.47 (s, 2H), 2.43 (shs, 4H), 1.85-1.98 (m, 4H), 1.44-1.53 (m, 3H). LCMS: m/z 564 [M+H] ⁺ v.a. 7.23 min. MSVR (IER) calc. for C ₂₅ H ₂₆ F ₈ N ₅ O [M+H] ⁺ 564.2004 found

564.1195;

8-(Cyclobutylmethyl)-2-{[(^)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}pyrido|2,3-c1|pyrimidin-7 (811)-one [(I), X=N, K2=cyclobutylmethyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=4,4-difluoropiperidine-1- silt, R3=R4=R5=H] conn. 109

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1H NMR (500 MHz, DMSO-de) δ=8.57 (s, 1H), 8.42 (d, J=7.32 Hz, 1H), 7.66 (d, J=9.30 Hz, 1H), 7.33 (d, J=7.93 Hz, 2H), 7.25 (d, J=7.93 Hz, 2H), 6.20 (d, J=9.30 Hz, 1H) , 4.99-5.32 (m, 1H), 4.17 (dd, J=7.24, 12.43 Hz, 1H), 4.06 (dd, J=7.70, 12.43 Hz , 1H), 3.48 (s, 2H), 2.43 (shs, 4H), 2.10-2.22 (m, 2H), 2.01-2.09 (m, 1H), 1, 91 (t, J=13.96 Hz, 4H), 1.66-1.76 (m, 4H), 1.47 (d, J=7.02 Hz, 3H). LCMS: m/z 468 [M+H]+ v.a. 6.96 min. MSVR (IER) calc. for C26H32F2N5O [M+H] ⁺ 468.257 found 468.2566;

8-(2,2-Dimethylpropyl)-2-({(^)-1-[4-(morpholin-4-ylmethyl)phenyl]ethyl}amino)pyrido[2,3^]pyrimidin-7(8H)- he [(I), X=N, I2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=morpholine-4- silt, R3=R4=R5=H] conn. 110

1H NMR (500 MHz, DMSO^) δ=8.57 (s, 1H), 8.36 (d, J=7.47 Hz, 1H), 7.67 (d, J=9.15 Hz, 1H ), 7.32 (d, J=7.93 Hz, 2H), 7.22 (d, J=7.93 Hz, 2H), 6.22 (d, J=9.30 Hz, 1H), 4.91-5.31 (m, J=6.90 Hz, 1H), 3.89-4.30 (m, 2H), 3.53 (t, J=4.42 Hz, 4H), 3 .39 (s, 2H), 2.30 (shs, 4H), 1.45 (d, J=7.02 Hz, 3H), 0.47-0.99 (m, 9H). LCMS: m/z 436 [M+H] ⁺ v.a. 5.8 min. MSVR (IER) calc. for C ₂₅ H ₃₄ N ₅ O ₂ [M+H] ⁺ 436.2707 found 436.2716;

8-(2,2-Dimethylpropyl)-2-( {(1S)-1 -[4-(pyrrolidin-1 -ylmethyl)phenyl]ethyl}amino)pyrido[2,3^]pyrimidin-7(8H)- he [(I), X=N, I2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=-pyrrolidine-1 -silt, R3=R4=R5=H] conn. 111

1H NMR (500 MHz, DMSO^) δ=8.47-8.66 (m, 1H), 7.99-8.44 (m, 1H), 7.67 (d, J=9.15 Hz, 1H), 7.31 (d, J=8.08 Hz, 2H), 7.22 (d, J=7.63 Hz, 2H), 6.22 (d, J=9.15 Hz, 1H) , 4.95-5.35 (m, J=7.17, 7.17 Hz, 1H), 3.83-4.30 (m, 2H), 3.51 (shs, 2H), 2.32 -2.43 (m, 4H), 1.66 (shs, 4H), 1.45 (d, J=7.02 Hz, 3H), 0.56-1.00 (m, 9H). LCMS: m/z 420 [M+H] ⁺ v.a. 5.29 min. MSVR (IER) calc. for C ₂₅ H ₃₄ N ₅ O [M+H] ⁺ 420.2758 found 420.2761.

2-{[(1 S)-1 -{4-[(4,4-Difluoropiperidin-1 -yl)methyl]phenyl}ethyl] amino }-8-(2-methylbenzyl)pyrido[2,3^]pyrimidine -7(8H)-one [(I), X=N, I2=2-methylbenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=4,4- difluoropiperidin-1-yl, R3=R4=R5=H] conn. 112

1H NMR (500 MHz, DMSO^) δ=8.63 (s, 1H), 8.35 (d, J=8.08 Hz, 1H), 7.80 (d, J=9.30 Hz, 1H ) 8.47-7.23 (dd, J=7.78, 7.23, Hz, 1H), 7.11 (dd, J=7.17 Hz, 1H), 7.0.3 (d, J=8.24 Hz, 2H), 7.0 (d, J=8.24 Hz, 2H), 6.92 (dd, J=7.47 Hz, 1H), 6.37 (d, J= 7.78 Hz, 1H), 6.32 (d, J=9.30 Hz, 1H), 5.40 (d, J=15.25 Hz, 1H), 5.19 (d, J=15, 25 Hz, 1H), 4.82 (m, J=7.32 Hz, 1H), 3.46 (shs, 2H), 2.43 (s, 3H), 2.38-2.42 (m, 4H), 1.87-1.96 (m, 4H), 1.33 (d, J=6.86 Hz, 3H). LCMS: m/z 504 [M+H] ⁺ v.a. 6.97 min. MSVR (IER) calc. for C ₂₉ H ₃₂ F ₂ N ₅ O [M+H] ⁺ 504.257 found 504.2578;

8-(cyclohexylmethyl)-2-{[(^)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}pyrido[2,3^]pyrimidin-7( 8H)-one [(I), X=N, R2=cyclohexylmethyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, K7-R8=4,4-difluoropiperidin-1-yl , R3=R4=R5=H] conn. 113

1H NMR (500 MHz, DMSO^) δ=8.58 (s, 1H), 8.41 (d, J=7.63 Hz, 1H), 7.68 (d, J=9.46 Hz, 1H ), 7.33 (d, J=8.08 Hz, 2H), 7.24 (d, J=7.93 Hz, 2H), 6.20 (d, J=9.30 Hz, 1H), 5.08 (quin, J=7.17 Hz, 1H), 4.02 (dd, J=7.40, 12.28 Hz, 1H), 3.87 (dd, J=7.63, 12, 35 Hz, 1H), 33.47 (s, 2H), 2.41-2.47 (m, 4H), 1.84-1.96 (m, 4H), 1.58-1.70 (m , 3H), 1.48-1.55 (m, 2H), 1.46 (d, J=7.02 Hz, 3H), 0.89-1.43 m 6H). LCMS: m/z 496 [M+H] ⁺ v.a. 7.52 min. MSVR (IER) calc. for C ₂₈ H ₃₆ F ₂ N ₅ O [M+H] ⁺ 496.2883 found 496.2885;

2-{[(1 S)-1 -{4-[(4,4-Difluoropiperidin-1 -yl)methyl]phenyl}ethyl] amino }-8-(2-methoxyethyl)pyrido[2,3d]pyrimidin- 7(8H)-one [(I), X=N, R2=2-methoxyethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=4 ,4-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 114

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1H NMR (500 MHz, DMSO-06) δ=8.51-8.61 (m, 1H), 8.18-8.48 (m, 1H), 7.68 (d, J=9.30 Hz , 1H), 7.34 (d, J=7.63 Hz, 2H), 7.23 (d, J=7.93 Hz, 2H), 6.21 (d, J=9.30 Hz, 1H ), 4.93-5.30 (m, 1H), 4.28 (t, J=6.25 Hz, 2H), 3.45-3.51 (m, 2H), 3.25-3, 30 (m, 2H), 3.15 (s, 3H), 2.43 (shs, 4H), 1.81-1.96 (m, 4H), 1.46 (d, J=7.02 Hz , 3H). LCMS: m/z 458 [M+H] ⁺ v.a. 5.79 min. MSVR (IER) calc. giving C ₂₄ H ₃₀ F ₂ N ₅ O ₂ [M+H] ⁺ 458.2362 found 458.2368;

2-{[(^)-1-{4-[(4,4-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[4-fluoro-2-(trifluoromethyl)benzyl]pyrido[ 2,3^]pyrimidin-7(8H)-one [(I), X=N, P2=4-fluoro-2-(trifluoromethyl)benzyl, A=phenyl, R1a=H, R1b=Me, R6a=4 -CH ₂ NR7R8, R6b=H, R7-R8=4,4-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 115

1H NMR (500 MHz, DMSO^) δ=8.66 (s, 1H), 8.44 (d, J=7.93 Hz, 1H), 7.85 (d, J=9.30 Hz, 1H ), 7.72 (dd, J=2.44, 9.00 Hz, 1H), 7.17-7.25 (m, 1H), 6.93 (s, 4H), 6.55 (dd, J=4.96, 8.31 Hz, 1H), 6.33 (d, J=9.30 Hz, 1H), 5.57 (d, J=16.17 Hz, 1H), 5.45 ( d, J=16.17 Hz, 1H), 4.79 (quin, J=7.44 Hz, 1H), 3.38 (m, 2H), 2.29-2.45 (m, 4H), 1.82-1.97 (m, 4H), 1.26-1.44 (m, 3H). LCMS: m/z 576 [M+H]+ v.a. 7.37 min. MSVR (IER) calc. giving C ₂₉ H ₂₈ F ₆ N ₅ O [M+H] ⁺ 576.2193 found 576.21938;

2-{[(^)-1-{4-[(4,4-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(3,3,3-trifluoro-2,2-dimethylpropyl )pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, P2=3,3,3-trifluoro-2,2-dimethylpropyl, A=phenyl, R1a=H, R1b =Me, R6a=4-CH2NR7R8, R6b=H, R7-R8=4,4-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 116

1H NMR (500 MHz, DMSO-06) δ=8.55-8.64 (m, 1H), 8.48 (d, J=7.78 Hz, 1H), 7.73 (d, J=9 .30 Hz, 1H), 7.31 (d, J=7.93 Hz, 2H), 7.23 (d, J=8.08 Hz, 2H), 6.26 (d, J=9.30 Hz, 1H), 5.02-5.29 (m, 1H), 4.31-4.55 (m, 2H), 3.48 (s, 2H), 2.43 (shs, 4H), 1 .85-1.97 (m, 4H), 1.46 (d, J=7.02 Hz, 3H), 0.79-1.17 (m, 6H). LCMS: m/z 524 [M+H] ⁺ v.a. 7.34 min. MSVR (IER) calc. giving C ₂₆ H ₃₁ F ₅ N ₅ O [M+H] ⁺ 524.2444 found 524.2455;

2-{[(^)-1-{4-[(3,3-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3^] pyrimidin-7(8H)-one [(I), X=N, P2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=3 ,3-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 117

1H NMR (500 MHz, DMSO-06) δ=8.58 (s, 1H), 8.36 (d, J=7.32 Hz, 1H), 7.67 (d, J=9.46 Hz, 1H), 7.33 (d, J=8.08 Hz, 2H), 7.22 (d, J=7.93 Hz, 2H), 6.22 (d, J=9.30 Hz, 1H) , 5.06 (quin, J=7.13 Hz, 1H), 3.93-4.23 (m, 2H), 3.46-3.55 (m, 2H), 2.56 (d, J =11.74 Hz, 1H), 2.52 (m, 1H), 2.36 (shs, 2H), 1.84 (spt, J=6.80 Hz, 2H), 1.61 (quin, J =5.83 Hz, 2H), 1.46 (d, J=7.02 Hz, 3H), 0.71 (shs, 9H). LCMS: m/z 470 [M+H] ⁺ v.a. 7.31 min. MSVR (IER) calc. for C26H34F2N5O [M+H] ⁺ 470.2726 Found 470.272;

2-{[(^)-1-{4-[(4,4-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-4-methyl-8-(2-ethylpropyl)pyrido[2,3 ^]pyrimidin-7(8H)-one [(I), X=N, R2=2-methylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=4 ,4-difluoropiperidin-1-yl, R3=Me, R4=R5=H] conn. 118

1H NMR (500 MHz, DMSO-06) δ=8.33 (d, J=7.47 Hz, 1H), 7.86 (d, J=9.61 Hz, 1H), 7.31 (d, J=7.93 Hz, 2H), 7.22 (d, J=7.93 Hz, 2H), 6.18 (d, J=9.46 Hz, 1H), 4.69-5.40 ( m, 1H), 3.94-4.01 (m, 1H), 3.79-3.88 (m, 1H), 3.47 (s, 2H), 2.53 (s, 3H), 2 .43 (shs, 4H), 1.83-1.97 (m, J=13.88, 13.88 Hz, 1H), 1.44 (d, J=7.17 Hz, 3H), 0, 72 (d, J=6.71 Hz, 3H), 0.60 (d, J=6.56 Hz, 3H). LCMS: m/z 576 [M+H] ⁺ v.a. 7.01 min. MSVR (IER) calc. giving C26H34F2N5O [M+H] ⁺ 470.2726 Found 470.2723;

2-{^)-1-[4-(4,4-Difluoropiperidin-1-ylmethyl)phenyl]ethylamino}-8-(2-hydroxy-2-methylpropyl)8H-pyrido[2,3^]pyrimidin-7 -one [(I), X=N, P2=2-hydroxy-2-methylpropyl, A=phenyl, R1a=H, R1b=Me,

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R6a=4-CH2NR7R8, R6b=H, R7-R8=4,4-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 119

1H NMR (500 MHz, DMSO-dg) δ=8.63 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 7.74 (d, J=9.3 Hz, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.23 (d, J=7.9 Hz, 2H), 6.28 (d, J=9.3 Hz, 1H) , 5.04 (quin, J=7.0 Hz, 1H), 4.63-3.73 (m, 3H), 3.48 (s, 2H), 2.44 (d, J=5.3 Hz, 4H), 1.98-1.79 (m, 4H), 1.46 (d, J=7.0 Hz, 3H), 1.26-0.80 (m, 6H). LCMS: m/z 472 [M+H]+ v.a. 6.86 min. MSVR (IER) calc. for C ₂₅ H ₃₂ F ₂ N ₅ O ₂ [M+H] ⁺ 472.2519 found 472.2520;

2-{[(^)-1-{4-[(4,4-Difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[2-(hydroxymethyl)-2methylpentyl]pyrido[2,3 ^]pyrimidin-7(8H)-one [(I), X=N, R2=2-hydroxy-2-methylpentyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b =H, R7-R8=4,4-difluoropiperidin-1-yl, R3=R4=R5=H] conn. 120

1H NMR (500 MHz, DMSO-06) δ=8.61 (d, J=3.97 Hz, 1H), 8.43 (d, J=7.17 Hz, 1H), 7.73 (d, J=9.15 Hz, 1H), 7.35 (d, J=7.93 Hz, 2H), 7.11-7.28 (m, 2H), 6.26 (d, J=9.30 Hz, 1H), 5.05-5.38 (m, 1H), 4.15-4.48 (m, 3H), 3.48 (s, 2H), 2.86-3.22 (m, 2H), 2.44 (shs, 4H), 1.92 (t, J=13.80 Hz, 4H), 1.47 (dd, J=2.82, 6.94 Hz, 3H), 1.121, 46 (m, 4H), 0.82-0.89 (m, 3H), 0.65-0.74 (m, 3H). LCMS: m/z 514 [M+H] ⁺ v.a. 6.99 min. MSVR (IER) calc. for C28H38F2N5O2 [M+H] ⁺ 514.2988 found 514.2994.

Example 9.

2,2-Dimethyl-3-[2-{[(^)-1-(naphthalene-2-yl)ethyl]amino}-7-oxopyrido[2,3^]pyrimidin-8(7H)yl]propanoic acid [(I), X=N, R2=2,2-dimethyl-3-propanoic acid, A=naphthalene-2-yl, R1a=H, R1b=Me, R6a=R6b=H, R3=R4=R5= H] transformation 8, conn. 121

Lithium hydroxide (0.022 g, 0.52 mmol) is added to the solution of methyl 2,2-dimethyl-3-|2-{|(N)-1(naphthalene-2-yl)ethyl]amino}-7-oxopyrido[2 ,3^]pyrimidin-8(7H)-yl]propanoate (0.030 g, 0.07 mmol) in THF:water (1:1, 2 ml) and the reaction mixture was stirred at room temperature for 18 hours. Solvent (THF ) is removed under reduced pressure and the aqueous residue is diluted with water. The aqueous phase is acidified with hydrochloric acid (1M) to precipitate, the solid is filtered, washed with water and dried in vacuo to give the title compound as a white solid (0.029 g, >99%).

1H NMR (500 MHz, DMSO-06) δ=12.08 (brs, 1H), 8.57 (s, 1H), 8.50 (d, J=7.47 Hz, 1H), 7.81- 7.94 (m, 4H), 7.66 (d, J=9.30 Hz, 1H), 7.59 (dd, J=1.22, 8.54 Hz, 1H), 7.37-7 .51 (m, 2H), 6.17 (d, J=9.30 Hz, 1H), 5.195.35 (m, J=7.02 Hz, 1H), 4.38 (d, J=12, 96 Hz, 1H), 4.27 (d, J=12.81 Hz, 1H), 1.55 (d, J=7.02 Hz, 3H), 1.02 (s, 3H), 0.91 (s, 3H). LCMS: m/z 417 [M+H] ⁺ v.a. 4.74 min. MSVR (IER) calc. for C ₂₄ H ₂₅ N ₄ O ₃ [M+H] ⁺ 417.1921 found 417.1924.

Example 10.

2,2-Dimethyl-3-[2-{[(^)-1-(naphthalene-2-yl)ethyl]amino}-7-oxopyrido[2,3^]pyrimidin-8(7H)yl]propanamide [ (I), X=N, R2=2,2-dimethyl-3-propanamide, A=naphthalene-2-yl, R1a=H, R1b=Me, R6a=R6b=H, R8 11, R3=R4=R5 =H] transformation 9, conn. 122

To a solution of TBTU (32 mg, 0.1 mmol) in DCM (2 ml) add 2,2-dimethyl-3-[2-{[(^)-1-(naphthalene2-yl)ethyl]amino}-7- oxopyrido[2,3^]pyrimidin-8(7H)-yl]propanoic acid (20 mg, 0.05 mmol), DIPEA (10 μl, 0.06 mmol) and ammonium hydrate 30% (1 ml). The reaction mixture was stirred at room temperature for 16 hours, the solvents were removed in vacuo, the residue was partitioned between DCM and water, and the organic layer was dried. The crude residue was purified by silica gel column chromatography (eluent: DCM/EtOAc/EtOH: 60/30/10) to give the title compound (18 g, 90% yield).

1H NMR (500 MHz, DMSO-06) δ=8.56 (s, 1H), 8.49 (d, J=7.78 Hz, 1H), 7.97 (s, 1H), 7.79- 7.90 (m, 3H), 7.55-7.69 (m, 2H), 7.40-7.51 (m, 2H), 7.13 (shs, 1H), 6.91 (shs, 1H), 6.19 (d, J=9.30 Hz, 1H), 5.33 (t,>7.24 Hz,

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1H), 4.44 (d, J=13.12 Hz, 1H), 4.28 (d, J=12.81 Hz, 1H), 1.55 (d, J=6.86 Hz, 3H) , 1.00 (s, 3H), 0.97 (s, 3H). LCMS: m/z 416 [M+H]+ v.a. 5.42 min. MSVR (IER) calc. for C ₂₄ H ₂₆ N ₅ O ₂ [M+H]+ 416.2081 found 416.2088.

According to the same procedure, but using suitably substituted derivatives, the following compounds are obtained:

^2,2-trimethyl-3-[7-oxo-2-{[(^)-1-phenylethyl]amino}pyrido[2,3D]pyrimidin-8(7H)-yl]propanamide [(I), X =N, R2=N, 2,2-trimethyl-3-propanamide, A=phenyl, R1a=H, R1b=Me, R6a=R6b=H, R8=H, R3=R4=R5=H] conn. 123

Ή NMR (500 MHz, DMSO-dg) δ=8.49-8.61 (m, 1H), 8.34 (d, J=8.08 Hz, 1H), 7.68-7.98 (m , 1H), 7.66 (d, J=9.30 Hz, 1H), 7.23-7.47 (m, 4H), 7.12-7.22 (m, 1H), 6.20 ( d, J=9.30 Hz, 1H), 5.22 (quin, J=6.98 Hz, 1H), 4.17-4.37 (m, 2H), 2.48 (s, 3H), 1.44 (d, J=6.86 Hz, 3H), 0.88-1.11 (m, 6H). LCMS: m/z 380 [M+H]+ w.a. 5.03 min. MSVR (IER) calc. for C ₂₁ H ₂₆ N ₅ O ₂ [M+H]+ 380.2081 found 380.2086;

HH2,2-Tetramethyl-3-[7-oxo-2-{[(^)-1-phenylethyl]amino}pyrido[2,3D]pyrimidin-8(7H)-yl]propanamide [(I), X= N, R2=N, ^2,2-tetramethyl-3-propanamide, A=phenyl, R1a=H, R1b=Me, R6a=R6b=H, R8=H, R3=R4=R5=H] conn. 124

1H NMR (500 MHz, DMSO-dg) δ=8.52-8.63 (m, 1H), 8.42 (d, J=7.78 Hz, 1H), 7.69 (d, J=9 .46 Hz, 1H), 7.38 (d, J=7.63 Hz, 2H), 7.25-7.32 (m, 2H), 7.12-7.22 (m, 1H), 6 .21 (d, J=9.30 Hz, 1H), 5.07 (s, 1H), 4.42 (d, J=5.49 Hz, 2H), 2.79-3.12 (m, 6H), 1.46 (d, J=7.02 Hz, 3H), 0.90-1.17 (m, 6H).

LCMS: m/z 394 [M+H]+ v.a. 5.49 min. MSVR (IER) calc. for C ₂₂ H ₂₈ N ₅ O ₂ [M+H]+ 394.2238 found 394.2246;

2,2-Dimethyl<N-(3-methylphenyl)-3-[7-oxo-2-{[(^)-1-phenylethyl]amino}pyrido[2,3D]pyrimidin8(7H)-yl]propanamide [ (I), X=N, R2=2,2-dimethyl-N-(3-methylphenyl)propanamide, A=phenyl, R1a=H, R1b=Me, R6a=R6b=H, R8=H, R3=R4 =R5=H] conn. 125

1H NMR (500 MHz, DMSO-dg) δ=9.04 (s, 1H), 8.54 (s, 1H), 8.28 (d, J=7.78 Hz, 1H), 7.68 ( d, J=9.30 Hz, 1H), 7.28-7.42 (m, 4H), 7.23 (t, J=7.55 Hz, 2H), 7.07-7.19 (m , 2H), 6.84 (d, J=7.47 Hz, 1H), 6.22 (d, J=9.30 Hz, 1H), 4.97-5.19 (m, J=7, 24, 7.24 Hz, 1H), 4.13-4.50 (m, 2H), 2.25 (s, 3H), 1.24 (d, J=4.27 Hz, 3H), 1, 02-1.19 (m, 6N). LCMS: m/z 456 [M+H]+ v.a. 6.61 min. MSVR (IER) calc. for C ₂₇ H ₃₀ N ₅ O ₂ [M+H]+ 456.2394 found 456.2396;

Na(2-Hydroxyethyl)-2,2-dimethyl-3-[7-oxo-2-{[(^)-1-phenylethyl]amino}pyrido[2,3D]pyrimidin8(7H)-yl]propanamide [( I), X=N, R2=N-(2-hydroxyethyl)-2,2-dimethyl-3-propanamide, A=phenyl, R1a=H, R1b=Me, R6a=R6b=H, R8=H, R3 =R4=R5=H] conn. 126

1H NMR (500 MHz, DMSO-de) δ=8.55 (s, 1H), 8.37 (d, J=7.63 Hz, 1H), 7.66 (d, J=9.30 Hz, 1H), 7.43 (d, J=7.47 Hz, 1H), 7.35-7.42 (m, 1H), 7.25-7.34 (m, 3H), 7.10-7 .22 (m, 1H), 6.20 (d, J=9.30 Hz, 1H), 5.13-5.29 (m, 1H), 4.57 (t, J=5.57 Hz, 1H), 4.22-4.38 (m, 2H), 2.97-3.18 (m, 4H), 1.41-1.52 (m, 3H), 1.01-1.06 ( m, 3H), 0.930.98 (m, 3H). LCMS: m/z 410 [M+H]+ w.a. 4.78 min. MSVR (IER) calc. for C ₂₂ H ₂₈ N ₅ O ₃ [M+H]+ 410.2187 found 410.2186;

X-(3-Hydroxypropyl)-2,2-dimethyl-3-[7-oxo-2-['[('^)-'1-phenylethyl]amino}pyrido[2,3^]pyrimidine-8(7H )-yl]propanamide [(I), X=N, R2 \-(2-hydroxyethyl)-2,2-dimethyl-3-propanamide, A=phenyl, R1a=H, R1b=Me, R6a=R6b=H , R8=H, R3=R4=R5=H] conn. 127

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1H NMR (500 MHz, DMSO-06) δ=8.54 (s, 1H), 8.36 (d, J=7.78 Hz, 1H), 7.66 (d, J=9.30 Hz, 1H), 7.44 (d, J=7.63 Hz, 2H), 7.39 (t, J=5.49 Hz, 1H), 7.28 (t, J=7.63 Hz, 2H) , 7.18 (kv, J=6.96 Hz, 1H), 6.20 (d, J=9.30 Hz, 1H), 5.14-5.36 (m, J=4.42, 7 ,17, 7.17 Hz, 1H), 4.19-4.50 (m, 3H), 3.36 (m, 2H), 2.97-3.16 (m, 2H), 1.38- 1.60 (m, 5n), 0.94-1.10 (m, 6n). LCMS: m/z 424 [M+H] ⁺ v.a. 4.85 min. MSVR (IER) calc. giving C ₂₃ H ₃₀ N ₅ O ₃ [M+H] ⁺ 424.2343 found 424.2349;

Ν-[3-(1-Γ hydroxyethyl)phenyl]-2,2-dimethyl-3-[7-oxo-2-{ [(1S)-1-phenylethyl]amino} pyrido[2,3^]pyrimidine- 8(7H)yl]propanamide [(I), X=N, R2=N-[3-(1-hydroxyethyl)phenyl]-2,2-dimethyl-3-propanamide, A=phenyl, R1a=H, R1b =Me, R6a=R6b=H, R8=H, R3=R4=R5=H] conn. 128

¹ H NMR (500 MHz, DMSO-06) δ=9.07-9.26 (m, 1H), 8.47-8.59 (m, 1H), 8.29 (d, J=7.63 Hz, 1H), 7.69 (d, J=9.30 Hz, 1H), 7.42-7.62 (m, 2H), 7.37 (d, J=7.63 Hz, 2H), 7.06-7.33 (m, 5H), 7.00 (d, J=7.63 Hz, 1H), 6.136.26 (m, 1H), 4.93-5.27 (m, 1H) , 4.54-4.74 (m, 1H), 4.34-4.49 (m, 2H), 1.26-1.33 (m, 6H), 1.16 (shs, 3H), 1 .07 (shs, 3N). LCMS: m/z 486 [M+H] ⁺ v.a. 5.71 min. MSVR (IER) calc. giving C ₂₈ H ₃₂ N ₅ O ₃ [M+H] ⁺ 486.25 found 486.2493.

Example 11.

2,2-Dimethyl-3-[2-{[(^)-1-(naphdain-2-yl)ethyl]amino}-7-oxopyrido[2,3^]pyrimidin-8(7H)yl]propanenitrile [ (I), X=N, I2=2,2-dimethyl-3-propanenitrile, A=phenyl, R1a=H, R1b=Me, R6a=R6b=H, R8=H, R3=R4=R5=H] transformation 10, conn. 129

Solution of 2,2-dimethyl-3-[2-{[(1S)-1-(naphthalene-2-yl)ethyl]amino}-7-oxopyrido[2,3^]pyrimidin8(7H)-yl]propanamide (10 mg, 0.02 mmol) in 1 ml trifluoroacetic anhydride is heated at 100°C for 1 hour. The reaction is completed, the solvent is removed in vacuo and the crude product is purified by silica gel column chromatography (eluent: DCM/EtOAc/EtOH : 60/35/5) to obtain the title compound (7.5 g, 90% yield).

1H NMR (500 MHz, DMSO-06) δ=8.23-8.70 (m, 2H), 7.81-7.94 (m, 4H), 7.73 (d, J=9.30 Hz , 1H), 7.59 (d, J=8.39 Hz, 1H), 7.34-7.53 (m, 2H), 6.25 (d, J=9.30 Hz, 1H), 5 ,18-5.51 (m, J=7.05, Hz, 1H), 4.20-4.57 (m, 2H), 1.56 (d, J=7.02 Hz, 3H), 1 .04-1.49 (m, 6H). LCMS: m/z 398 [M+H] ⁺ v.a. 6.37 min. MSVR (IER) calc. giving C ₂₄ H ₂₄ N ₅ O [M+H] ⁺ 398.1976 Found 398.1985.

Example 12.

8-(2,2-Dimethylpropyl)-2-({(^)-1-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]ethyl}amino)pyrido[2,3d]pyrimidin- 7(8H)-one [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=1-methyl-1Hpyrazol-4-yl, R6b=H , R8=H, R3=R4=R5=H] transformation 5, conn. 130

In a 5 ml microwave test tube, a solution of 2-{[(^)-1-(4-bromophenyl)ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3^]pyrimidin-7(8H)-one (30 mg, 0.07 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole (29 mg, 0.24 mmol) , Cs ₂ CO ₃ (46 mg, 0.14 mmol) in dioxane (2 ml) was bubbled with N2 for 3 min, then Cl ₂ Pd(dppf)CH ₂ Cl ₂ (5 mg, 0.007 mmol) was added. The capped tube is heated to 100°C for 4 hours. After cooling, the reaction mixture is diluted with EtOAc (10 ml) and washed with water (10 ml). After separation, the aqueous phase is extracted with EtOAc (3x10 ml). The combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel column chromatography (DCM/EtOAc 8/2) to give an off-white solid (14.5 mg, 50% yield).

¹ H NMR (500 MHz, DMSO-06) δ=8.57 (s, 1H), 8.07-8.42 (m, 1H), 8.06 (s, 1H), 7.79 (d, J=0.46 Hz, 1H), 7.67 (d, J=9.30 Hz, 1H), 7.44-7.52 (m, 2H), 7.35 (d, J=8.08 Hz, 2H), 6.22 (d, J=9.15 Hz, 1H), 4.95-5.34 (m, J=6.98, Hz, 1H), 3.99-4.29 ( m, 2H), 3.84 (s, 3H), 1.47 (d, J=7.02 Hz, 3H), 0.65-0.98 (m, 9H).

LCMS: m/z 417 [M+H]+ v.a. 6.05 min. MSVR (IER) calc. giving C ₂₄ H ₂₉ N ₆ O [M+H] ⁺ 417.2398 found

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417.24.

According to the same procedure, the following compounds are obtained:

8-(2,2-Dimethylpropyl)-2-({(^)-1-[4-(pyridin-4-yl)phenyl]ethyl}amino)pyrido[2,3^]pyrimidin7(8H)-one [ (I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, Rga=pyridin-4-yl, R6b=H, R8=H, R3=R4=R5= H] conn. 131

1H NMR (500 MHz, DMSO-06) δ=8.51-8.65 (m, 3H), 8.46 (d, J=7.32 Hz, 1H), 7.76 (d, J=8 .08 Hz, 2H), 7.60-7.70 (m, 3H), 7.53 (d, J=8.08 Hz, 2H), 6.23 (d, J=9.30 Hz, 1H ), 4.97-5.42 (m, 1H), 3.88-4.38 (m, 2H), 1.451.55 (m, 3H), 0.52-1.04 (m, 9H). LCMS: m/z 414 [M+H]+ v.a. 6.05 min. MSVR (IER) calc. for C ₂₅ H ₂₈ N ₅ O [M+H]+ 414.2289 found 414.2293;

8-(2,2-Dimethylpropyl)-2-({(^)-1-[4-(2-fluoropyridin-4-yl)phenyl]ethyl}amino)pyrido[2,3^]pyrimidine-7(8H )-one [(I), X=N, P2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=2-fluoropyridin-4-yl, R6b=H, R8=H, R3=R4=R5=H] conn. 132

1H NMR (500 MHz, DMSO-dg) δ=8.50-8.63 (m, 1H), 8.47 (d, J=7.47 Hz, 1H), 8.27 (d, J=5 .34 Hz, 1H), 7.82 (d, J=8.08 Hz, 2H), 7.60-7.71 (m, 2H), 7.54 (d, J=8.08 Hz, 2H ), 7.49 (s, 1H), 6.23 (d, J=9.46 Hz, 1H), 5.035.40 (m, 1H), 3.88-4.32 (m, 2H), 1 .50 (d, J=7.02 Hz, 3H), 0.55-1.01 (m, 9H).

LCMS: m/z 432 [M+H]+ v.a. 6.72 min. MSVR (IER) calc. for C ₂₅ H ₂₇ FN ₅ O [M+H]+ 432.2194 found 432.2197;

8-(2,2-Dimethylpropyl)-2-({(^)-1-[4-(thiophen-3-yl)phenyl]ethyl}amino)pyrido[2,3^]pyrimidin7(8H)-one [ (I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, Rga=thiophen-3-yl, R6b=H, R8=H, R3=R4=R5= H] conn. 133

1H NMR (500 MHz, DMSO-06) δ=8.47-8.66 (m, 1H), 8.41 (d, J=7.17 Hz, 1H), 7.79 (dd, J=1 ,37, 2.90 Hz, 1H), 7.62-7.72 (m, 2H), 7.61 (dd, J=3.05, 5.03 Hz, 1H), 7.51 (dd, J=1.22, 5.03 Hz, 1H), 7.36-7.45 (m, 2H), 7.34 (d, J=8.39 Hz, 1H), 6.23 (dd, J =6.25, 9.15 Hz, 1H), 4.85-5.38 (m, 1H), 3.84-4.33 (m, 2H), 1.49 (d, J=7.02 Hz, 3H), 0.60-0.99 (m, 9H). LCMS: m/z 419 [M+H]+ v.a. 7.39 min. MSVR (IER) calc. for C ₂₄ H ₂₇ N ₄ OS [M+H]+ 419.19 found 419.1909.

4'-[(^)-1-{[8-(2,2-Dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin-2-yl]amino}ethyl]biphenyl-2 -carbonitrile [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=phenyl-2-carbonitrile, R6b=H, R8=H, R3=R4 =R5=H] conn. 134

1H NMR (500 MHz, DMSO) δ=8.60 (s, 1H), 8.47 (d, J=7.47 Hz, 1H), 7.93 (dd, J=0.76, 7.78 Hz, 1H), 7.77 (dt, J=1.30, 7.74 Hz, 1H), 7.68 (d, J=9.30 Hz, 1H), 7.56-7.60 (m , 2H), 7.54 (shs, 4H), 6.23 (d, J=9.30 Hz, 1H), 5.17 (quin, J=6.75 Hz, 1H), 3.93-4 .33 (m, 2H), 1.53 (d, J=7.02 Hz, 3H), 0.44-1.12 (m, 9H). LCMS: m/z 438 [M+H]+ v.a. 7.1 min. MSVR (IER) calc. for C ₂₇ H ₂₈ N ₅ O [M+H]+ 438.2289 found 438.229;

8-(3-Hydroxy-2,2-dimethylpropyl)-2-(['('^)-'1-[4-('1-methyl-'1H-pyrazol-4-yl)phenyl]ethyl}amino )pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, P2=3-hydroxy-2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, Rga =1-methyl-1H-pyrazol-4-yl, R6b=H, R8=H, R3=R4=R5=H] conn. 135

Ή NMR (500 MHz, DMSO-dg) δ=8.51-8.65 (m, 1H), 8.17-8.46 (m, 1H), 8.06 (s, 1H), 7.79 (s, 1H), 7.72 (d, J=9.30 Hz, 1H), 7.43-7.52 (m, 2H), 7.38 (d, J=7.93 Hz, 2H) , 6.25 (d, J=9.30 Hz, 1H), 4.89-5.37 (m, J=7.24, 7.24 Hz, 1H), 4.60 (shs, 1H), 4.13 (shs, 2H), 3.84 (s, 3H), 3.07 (d, J=5.49 Hz, 2H), 1.47 (d, J=7.02 Hz, 3H), 0.45-0.94 (m, 6H). LCMS: m/z 433 [M+H]+ v.a. 5.24 min. MSVR (IER) calc. for C ₂₄ H ₂₉ N ₆ O ₂ [M+H]+ 433.2347 nai

- 89 046117 deno 433.235;

8-(3-Hydroxy-2,2-dimethylpropyl)-2-({('^)-'1-[4-(thiophen-3-yl)phenyl]ethyl}amino)pyrido[2,3^]pyrimidine -7 (8H)-one [(I), X=N, K2=3-hydroxy-2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=thiophen-3-yl, R6b= H, R8=H, R3=R4=R5=H] conn. 136

1H NMR (500 MHz, DMSO-dg) δ=8.53-8.69 (m, 1H), 8.14-8.51 (m, 1H), 7.80 (dd, J=1.14, 2.82 Hz, 1H), 7.72 (d, J=9.30 Hz, 1H), 7.65 (d, J=8.08 Hz, 2H), 7.57-7.62 (m, 1H), 7.49-7.53 (m, 1H), 7.25-7.48 (m, 2H), 6.206.32 (m, 1H), 5.15 (t, J=6.86 Hz , 1H), 4.51-4.71 (m, 1H), 4.05-4.33 (m, 2H), 3.08 (d, J=5.34 Hz, 2H), 1.41- 1.53 (m, 3H), 0.47-0.96 (m, 6H). LCMS: m/z 435 [M+H]+ v.a. 6.52 min. MSVR (IER) calc. for C ₂₄ H ₂₇ N ₆ O ₂ [M+H]+ 435.1849 found 435.1852;

4'-[(1S)-1-({8-[(2S)-3-Methylbutan-2-yl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl} amino but)ethyl]biphenyl-2-carbonitrile [(I), X=N, K2=^)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=phenyl-2- carbonitrile, R6b=H, R8=H, R3=R4=R5=H] conn. 165

Ή NMR (500 MHz, DMSOA) δ=8.60 (s, 1H), 8.47 (d, J=7.47 Hz, 1H), 7.93 (dd, J=0.76, 7.78 Hz, 1H), 7.77 (dt, J=1.30, 7.74 Hz, 1H), 7.68 (d, J=9.30 Hz, 1H), 7.56-7.60 (m , 2H), 7.54 (shs, 4H), 6.23 (d, J=9.30 Hz, 1H), 5.17 (quin, J=6.75 Hz, 1H), 3.93-4 .33 (m, 2H), 1.53 (d, J=7.02 Hz, 3H), 0.44-1.12 (m, 9H). LCMS: m/z 438 [M+H]+ v.a. 6.96 min. MSVR (IER) calc. for C ₂₇ H ₂₈ N ₅ O [M+H]+ 438.2289 found 438.2296.

2-({(1S)-1-[4-(2-Fluoropyridin-4-yl)phenyl]ethyl}amino)-8-[(2S)-3-methylbutan-2-yl]pyrido[2,3- d]pyrimidin-7(8H)-one [(I), X=N, K2=^)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=2fluoropyridin-4- silt, R6b=H, R8=H, R3=R4=R5=H] conn. 166

Ή NMR (500 MHz, DMSO-06) δ=8.55-8.61 (m, 1H), 8.40 (d, J=7.47 Hz, 1H), 8.27 (d, J=5 ,30 Hz, 1H), 7.81 (d, J=8.0 Hz, 2H), 7.62-7.68 (m, 2H), 7.54 (d, J=8.08 Hz, 2H ), 7.42-7.52 (m, 2H), 6.22 (d, J=9.30 Hz, 1H), 4.99-5.07 (m, 1H), 4.87-4, 96 (m, 1H), 4.73-4.80 (m, 1H), 2.57-2.60 (m, 1H), 1.55 (d, J=7.02 Hz, 3H), 1 .0-1.08 (m, 3H), 0.59-0.72 (m, 3H), 0.01 (d, J=6.41 Hz, 3H). LCMS: m/z 432 [M+H]+ v.a. 6.68 min. MSVR (IER) calc. for C25H27FN5O [M+H]+ 432.2194 found 432.2197.

tert-Butyl 4-{4-[(1S)-1-({8-[(2S)-3-methylbutan-2-yl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine -2yl}amino)ethyl]phenyl}-3,6-dihydropyridin-1(2H)-carboxylate [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A=phenyl, R1a =H, R1b=Me, R6a=tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate, R6b=H, R8=H, R3=R4=R5=H]com. 167

Ή NMR (500 MHz, DMSO-06) δ=8.55-8.61 (m, 1H), 8.40 (d, J=7.47 Hz, 1H), 8.27 (d, J=5 ,30 Hz, 1H), 7.81 (d, J=8.0 Hz, 2H), 7.62-7.68 (m, 2H), 7.54 (d, J=8.08 Hz, 2H ), 7.42-7.52 (m, 2H), 6.22 (d, J=9.30 Hz, 1H), 4.99-5.07 (m, 1H), 4.87-4, 96 (m, 1H), 4.73-4.80 (m, 1H), 2.57-2.60 (m, 1H), 1.55 (d, J=7.02 Hz, 3H), 1 .0-1.08 (m, 3H), 0.59-0.72 (m, 3H), 0.01 (d, J=6.41 Hz, 3H). LCMS: m/z 518 [M+H]+ v.a. 7.75 min. MSVR (IER) calc. for SzoNLOz [M+H]+ 518.3126 Found 518.3115.

tert-Butyl 6-[(1S)-1-({8-[(2S)-3-methylbutan-2-yl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2yl} amino)ethyl]-3',6'-dihydro-3,4'-bipyridin-1'(2'H)-carboxylate [(I), X=N, K2=^)-3-methylbutan-2-yl , A=pyridin-2-yl, R1a=H, R1b=Me, R6a=tert-butyl 3,6-dihydropyridin-1(2H)-carboxylate, R6b=H, R8=H, R3=R4=R5=H ] conn. 193

- 90 046117

LCMS: m/z 519 [M+H]+ v.a. 6.82 min. MSVR (IER) calc. for C ₂₉ H ₃₉ M ₆ O3 [M+H] ⁺ 519.3078 found 519.3085.

8-[(2S)-3-Methylbutan-2-yl]-2-({(1S)-1-[2'-(trifluoromethyl)-3,4'-bipyridin-6-yl]ethyl}amino)pyrido [2,3Upyrimidin-7(8H)-one [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A=pyridin-2-yl, R1a=H, R1b=Me, R6a=2-trifluoromethylpyridin-4-yl, R6b=H, R8=H, R3=R4=R5=H] conn. 196

1H NMR (500 MHz, DMSO-de) δ=9.10 (s, 1H), 8.85 (s, 1H), 8.76 (s, 1H), 8.43 (d, J=6.56 Hz, 1H), 8.29 (d, J=8.39 Hz, 1H), 8.09 (m, 1H), 7.96 (d, J=9.30 Hz, 1H), 7.66 ( dd, J=8.85 Hz, 1H), 7.42 (d, J=8.39 Hz, 1H), 6.23 (d, J=9.30 Hz, 1H), 4.70-5, 07 (m, 2H), 1.40-1.59 (m, 4H), 0.93-1.02 (m, 3H), 0.59 (d, J=6.25 Hz, 3H), - 0.01 (d, J=6.25 Hz, 3H). LCMS: m/z 483 [M+H] ⁺ v.a. 6.29 min. MSVR (IER) calc. for C ₂₅ H ₂₆ F ₃ N ₆ O [M+H] ⁺ 483.2115 found 483.213.

2-{[(1S)-1-(2'-Fluoro-3,4'-bipyridin-6-yl)ethyl]amino}-8-[(2S)-3-methylbutan-2-yl]pyrido[2 ,3-d]pyrimidin-7(8H)-one [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A=pyridin-2-yl, R1a=H, R1b= Me, R6a=2fluoropyridin-4-yl, R6b=H, R8=H, R3=R4=R5=H] conn. 197

LCMS: m/z 433 [M+H] ⁺ v.a. 5.77 min. MSVR (IER) calc. for C ₂₄ H ₂₆ FN ₆ O [M+H] ⁺ 433.2147 found 433.215.

Example 13.

8-(2,2-Dimethylpropyl)-2-({(1S)-1-[4-(methylsulfonyl)phenyl]ethyl}amino)pyrido[2,3U pyrimidin-7(8H)-one [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=methylsulfonyl, R6b=H, R8=H, R3=R4=R5=H] transformation 11, conn. 137

In a 5 ml microwave test tube to a solution of 2-{[(^)-1-(4-bromophenyl)ethyl]amino}8-(2,2-dimethylpropyl)pyrido[2,3Upyrimidin-7(8H)-one (30 mg , 0.07 mmol) add sodium methanesulfinate (22 mg, 0.21 mmol), CuI (41 mg, 0.21 mmol) in DMSO (2 ml). The capped tube is heated at 120°C for 6 hours. After cooling, the reaction mixture is diluted with EtOAc (10 ml) and washed with water (10 ml). After separation, the aqueous phase is extracted with EtOAc (3x10 ml). The combined organic phases are dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel column chromatography (DCM/EtOAc 8/2) to give an off-white solid (10 mg, 35% yield).

¹ H NMR (500 MHz, DMSO-06) δ=8.60 (s, 1H), 8.50 (d, J=7.17 Hz, 1H), 7.88 (d, J=8.24 Hz , 2H), 7.68 (d, J=9.30 Hz, 1H), 7.65 (d, J=8.24 Hz, 2H), 6.24 (d, J=9.30 Hz, 1H ), 5.00-5.43 (m, J=7.02, 7.02 Hz, 1H), 3.82-4.32 (m, 2H), 3.16 (s, 3H), 1, 49 (d, J=7.17 Hz, 3H), 0.51-0.98 (m, 9H). LCMS: m/z 415 [M+H] ⁺ v.a. 5.51 min. MSVR (PER) calc. for C21H27N4O3S [M+H] ⁺ 415.1799 found 415.1797.

Example 14.

8-(2,2-dimethylpropyl)-2-[^)-1-(4-piperazin-1-ylmethylphenyl)ethylamino]-8H-pyrido[2,3Upyrimidin-7-one hydrochloride [(I), X=N , P2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=4-piperazin-1-yl, R3=R4=R5=H] transformation 6, conn. 138

To a solution of tert-butyl ether 4-(4-A)-1-[8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3Upyrimidin-2-ylamino]ethyl}benzyl)piperazine -1-carboxylic acid (compound 59) (65.0 mg, 0.122 mmol) in a mixture of dioxane (3.0 ml) and MeOH (1.0 ml) add HCl (4M in dioxane, 0.6 ml). The mixture was stirred overnight at room temperature and then concentrated to dryness to give a white solid, which was dried in vacuo to give the title compound as a white solid (57.0 mg, quantitative).

1H NMR (500 MHz, DMSO) δ=11.72 (brs, 1H), 9.32 (brs, 2H), 8.59 (s, 1H), 8.46 (d, J=7.32 Hz, 1H),

- 91 046117

7.68 (d, J=9.15 Hz, 1H), 7.54 (shs, 2H), 7.47 (d, J=7.63 Hz, 2H), 6.24 (d, J=9 ,30 Hz, 1H), 5.14 (quin, J=6.90 Hz, 1H), 3.93-4.54 (m, 5H), 3.28-3.52 (m, 5H), 1 .47 (d, J=7.17 Hz, 3H), 0.79 (shs, 9H). LCMS (HPLC Method 1): m/z 435 [M+H]+ @ w.a. 5.17 min. MSVR (PER) calc. giving C ₂₅ H ₃₅ N ₄ O ₃ S [M+H] ⁺ 415.1799 found 415.1797.

Example 15.

2-{^)-1-[4-(4-Acryloylpiperazin-1-ylmethyl)phenyl]ethylamino}-8-(2,2-dimethylpropyl)-8H-pyrido[2,3^]pyrimidin-7-one [ (I), X=N, I2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=4-piperazin-1-yl, R11= buhhh, R3=R4=R5=H] transformation 7, conn. 139

To a solution of 8-(2,2-dimethylpropyl)-2-[^]-1-(4-piperazin-1-ylmethyl-phenyl)ethylamino]-8H-pyrido[2,3^]pyrimidin-7-one hydrochloride ( 55.0 mg, 0.12 mmol) and DIPEA (0.04 ml, 0.24 mmol) in DCM (1.0 ml) add acryloyl chloride (0.01 ml, 0.13 mmol) at 0°C. After 30 minutes, the reaction is quenched with water. The mixture is extracted with DCM, dried over Na ₂ SO ₄ , filtered, and concentrated to give a yellow oil. The crude product was purified by silica gel chromatography (1-10% MeOH/DCM) to show the title product as a white foam (37.5 mg, 66% yield).

¹ H NMR (500 MHz, DMSO-06) δ=8.57 (s, 1H), 8.36 (d, J=7.2 Hz, 1H), 7.67 (d, J=9.3 Hz , 1H), 7.33 (d, J=8.1 Hz, 2H), 7.23 (d, J=7.9 Hz, 2H), 6.76 (dd, J=10.4, 16, 7 Hz, 1H), 6.22 (d, J=9.3 Hz, 1H), 6.08 (dd, J=2.4, 16.7 Hz, 1H), 5.65 (dd, J= 2.4, 10.4 Hz, 1H), 5.06 (quin, J=7.2 Hz, 1H), 4.40-3.87 (m, 2H), 3.50 (d, J=17 .5 Hz, 4 N), 3.44 (s, 2H), 2.31 (shs, 4 N), 1.46 (d, J=6.9 Hz, 3H), 1.05-0.53 (m, 9 N).

LCMS: m/z 489 [M+H] ⁺ @ w.u. 5.88 min. MSVR (IER) calc. for C ₂₈ H ₃₇ N ₆ O ₂ [M+H] ⁺ 489.2973 found 489.2966.

According to the same method, the following compounds are obtained:

2-{^)-1-[4-(4-Acryloylpiperazin-1-ylmethyl)phenyl]ethylamino}-8-(3-hydroxy-2,2-dimethylpropyl)-8H-pyrido[2,3^]pyrimidin- 7-one [(I), X=N, K2=3-hydroxy-2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7- R8=4-piperazin-1-yl, R11=vinyl, R3=R4=R5=H] conn. 140

1H NMR (500 MHz, DMSOU) δ=8.60 (s, 1H), 8.43 (d, J=7.5 Hz, 1H), 7.72 (d, J=9.3 Hz, 1H) , 7.36 (d, J=7.9 Hz, 2H), 7.23 (d, J=7.9 Hz, 2H), 6.76 (dd, J=10.5, 16.6 Hz, 1H), 6.26 (d, J=9.2 Hz, 1H), 6.08 (dd, J=2.4, 16.7 Hz, 1H), 5.65 (dd, J=2.4 , 10.4 Hz, 1H), 5.11 (quin, J=6.9 Hz, 1H), 4.56 (shs, 1H), 4.20-4.00 (m, 2H), 3.51 (d, J=14.2 Hz, 4 N), 3.43 (s, 2H), 3.03 (shs, 2H), 2.31 (shs, 4 N), 1.46 (d, J= 7.0 Hz, 3H) 0.93-0.58 (m, 6H). LCMS: m/z 505 [M+H] ⁺ @ w.u. 5.01 min. MSVR (IER) calc. for C ₂₈ H ₃₆ N ₆ O ₃ [M+H] ⁺ 505.2922 found 505.2922;

2-{[(^)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]-3-fluorophenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3^ ]pyrimidin-7(8H)-one [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=F, R7-R8=4-piperazin-1-yl, R11=buhu^ R3=R4=R5=H] conn. 141

1H NMR (500 MHz, DMSO-06) δ=8.59 (s, 1H), 8.38 (d, J=7.47 Hz, 1H), 7.68 (d, J=9.46

Hz, 1H), 7.33 (t, J=7.70 Hz, 1H), 7.08-7.23 (m, 2H), 6.76 (dd, J=10.52, 16.62 Hz , 1H), 6.24 (d, J=9.46 Hz, 1H), 6.07 (dd, J=2.29, 16.62 Hz, 1H), 5.64 (dd, J=2, 29, 10.37 Hz, 1H), 5.06 (quin, J=7.13 Hz, 1H), 3.90-4.33 (m, 2H), 3.43-3.60 (m, 6H ), 2.34 (shs, 4H), 1.46 (d, J=7.02 Hz, 3H), 0.92 (shs, 3H), 0.69 (shs, 6H). LCMS: m/z 507 [M+H] ⁺ @ w.u. 5.98 min. MSVR (IER) calc. for C ₂₈ H ₃₆ N ₆ O ₃ [M+H] ⁺ 507.2879 found 507.2874;

2-{[(^)-1-{4-[(4-Acryloylpiperazin-1-yl)carbonyl]-3-fluorophenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3^ ]pyrimidin-7(8H)-one [(I), X=N, I2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-C(O)NR7R8, R6b= F, R7-R8=4-piperazin-1-yl, R11=vinyl, R3=R4=R5=H] comp. 142

1H NMR (500 MHz, DMSO-06) δ=8.61 (s, 1H), 8.43 (d, J=7.17 Hz, 1H), 7.70 (d, J=9.30 Hz, 1H), 7.347.45 (m, 1H), 7.30 (d, J=6.86 Hz, 2H), 6.63-6.91 (m, 1H), 6.25 (d, J=9 ,30 Hz, 1H), 6.12 (dd, J=2.29, 16.78 Hz, 1H), 5.70 (s, 1H), 5.11 (quin, J=6.67 Hz, 1H ), 3.89-4.32 (m, 2H), 3.39-3.78 (m, 6H), 3.22 (shs, 2H), 1.48 (d, J=7.02 Hz, 3H), 0.93 (shs, 3H), 0.73 (shs, 6H). LCMS: m/z 521 [M+H] ⁺ @ w.u. 5.44 min. MSVR (IER) calc. for C ₂₈ H ₃₄ FN ₆ O ₃ [M+H] ⁺ 521.2671 found 521.2672;

2-({(^)-1-[4-({4-[(2E)-but-2-enoyl]piperazin-1-yl}methyl)phenyl]ethyl}amino)-8-(2,2- dimethylpro

- 92 046117 pyl)pyrido[2,3-c1]pyrimidin-7(811)-one [(I), X=N, R2 2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a =4-C(O)NR7R8, R6b=H, R7-R8=4-piperazin-1-ul, K'1'1=propenyl, R3=R4=R5=H] conn. 143

¹ H NMR (500 MHz, DMSOA) δ=8.57 (s, 1H), 8.36 (d, J=7.32 Hz, 1H), 7.67 (d, J=9.15 Hz, 1H ), 7.33 (d, J=7.93 Hz, 2H), 7.23 (d, J=8.08 Hz, 2H), 6.64 (kvd, J=6.90, 14.90 Hz , 1H), 6.46 (kvd, J=1.50, 14.95 Hz, 1H), 6.22 (d, J=9.30 Hz, 1H), 5.06 (kvd, J=7, 20 Hz, 1H), 3.92-4.37 (m, 2H), 3.44-3.62 (m, 4H), 3.43 (s, 2H), 2.252.33 (m, 4H), 1.82 (dd, J=1.68, 6.8 Hz, 3H), 1.46 (d, J=7.02 Hz, 3H), 0.92 (shs, 3H), 0.73 (shs , 6H). LCMS: m/z 503 [M+H]+ @ w.u. 6.11 min. MSVR (IER) calc. for C ₂₈ H ₃₉ N ₆ O ₂ [M+H]+ 503.3129 found 503.3117;

8-(2,2-Dimethylpropyl)-2-['[O)-'1-(4-['[4-(2-methylacryloyl)piperazin-'1-yl]methyl}phenyl)ethyl]amino}pyrido [2,3^]pyrimidin-7(8H)-one [(I), X=N, I2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-C(O )NR7R8, R6b=H, R7-R8=4-piperazin-1-yl, R11=methylvinyl, R3=R4=R5=H] comp. 144

¹ H NMR (500 MHz, DMSOA) δ=8.57 (s, 1H), 8.36 (d, J=7.32 Hz, 1H), 7.67 (d, J=9.30 Hz, 1H ), 7.33 (d, J=8.08 Hz, 2H), 7.23 (d, J=7.93 Hz, 2H), 6.22 (d, J=9.30 Hz, 1H), 5.15 (quin, J=1.40 Hz, 1H), 5.07 (quin, J=6.83 Hz, 1H), 4.92 (shs, 1H), 3.89-4.33 (m , 2H), 3.44 (shs, 6H), 2.30 (shs, 4H), 1.81 (s, 3H), 1.45 (d, J=7.02 Hz, 3H), 0.92 (shs, 3H), 0.73 (shs, 6H). LCMS: m/z 503 [M+H]+ @ w.u. 6.20 min. MSVR (IER) calc. for C ₂₉ H ₃₉ N ₆ O ₂ [M+H]+ 503.3129 found 503.3122;

8-(2,2-Dimethylpropyl)-2- {[(1S)-1 -(4- {[4-(2-methylpropanoyl)piperazin-1 -yl]methyl} phenyl)ethyl]amino}pyrido[2, 3^]pyrimidin-7(8H)-one [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=O-R7, R6b=H, R7-= 4-piperazin-1-yl, R11=2-isopropyl, R3=R4=R5=H] comp. 157 q _ Chiral ¹ H NMR (500 MHz, DMSO-dg) δ=8.57 (s, 1H), 8.36 (d, J=7.3 Hz, 1H), 7.67 (d, J= 9.2 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.13-7.28 (m, 2H), 6.22 (d, J=9.3 Hz, 1H), 5.06 (quin, J=6.9 Hz, 1H), 3.86-4.34 (m, 2H), 3.43 (s, 2H), 3.43 (shs, 4H), 2.82 (spt, J=6.6 Hz, 1H), 2.32 (shs, 2H), 2.25 (shs, 2H), 1.46 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.7 Hz, 6H), 0.74 (shs, 9H). LCMS: m/z 505 [M+H]+ @ w.u. 6.28 min.

MSVR (IER) calc. for C ₂₉ H ₄₁ N ₆ O ₂ [M+H]+ 505.3286 Found 505.3286;

2-{[(1 S)-1 -(4- {[4-(Cyclopropylcarbonyl)piperazin-1 -yl]methyl} phenyl)ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3 ^]pyrimidin-7(8H)-one [(I), X=N, I2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=O-R7, R6b=H, R7 -= 4-piperazin-4-yl, R11=cyclopropyl, R3=R4=R5=H] comp. 158

О - νΉ ^/ ~'·'·| Chiral

Ο _Ν χ0 ^Λ φ ¹ H NMR (500 MHz, DMSO-dg) δ=8.58 (s, 1H), 8.36 (d, J=7.3 Hz, 1H), 7.67 (d, J =9.3 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.23 (d, J=7.9 Hz, 2H), 6.22 (d, J=9 .3 Hz, 1H), 5.06 (quin, J=7.1 Hz, 1H), 3.89-4.32 (m, 2H), 3.63 (shs, 2H), 3.44 (s , 2H), 3.42 (shs, 2H), 2.35 (shs, 2H), 2.26 (shs, 2H), 1.86-1.99 (m, 1H), 1.46 (d, J=7.0 Hz, 3H), 0.74 (shs, 9H), 0.57-0.74 (m, 4H). LCMS: m/z 503 [M+H]+ @ w.u. 6.07 min

MSVR (IER) calc. for C ₂₉ H ₃₉ N ₆ O ₂ [M+H]+ 503.3129 found 503.3137;

2-{^)-1-[4-(4-Acryloylpiperazin-1-ylmethyl)phenyl]ethylamino}-8-(^)-1,2-dimethylpropyl)-8Hpyrido[2,3^]pyrimidin-7-one [(I), X=N, I2=-^)-1,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=4-piperazine-1 -yl, R11=vinyl, R3=R4=R5=H] conn. 161

^1H NMR (500 MHz, DMSO-dg) δ=8.56 (s, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.20-7.33 (m, 4H) , 6.76 (dd, J=16.6, 10.4 Hz, 1H), 6.10-6.22 (m, 1H), 6.07 (dd, J=16.6, 2.3 Hz , 1H), 5.64 (dd, J=10.4, 2.3 Hz, 1H), 4.78-5.07 (m, 2H), 3.41-3.55 (m, 6H), 2.30 (shs, 4H), 1.36-2.07 (m, 4H), 0.07-1.09 (m, 9H). LCMS: m/z 489 [M+H]+ @ w.u. 5.77 min. MSVR (IER) calc. for C28H36N6O2 [M+H]+ 489.2973 found 489.2973;

8-(^)-1,2-Dimethylpropyl)-2-(^)-1-{4-[4-(2-methylacryloyl)piperazin-1-ylmethyl]phenyl}ethylamino)-8H-pyrido[2,3 ^]pyrimidin-7-one [(I), X=N, I2=-^)-1,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b= H, R7-R8=4-piperazin-1-yl, R11=methylvinyl, R3=R4=R5=H] comp. 162

- 93 046117

1H NMR (500 MHz, DMSO-06) δ=8.56 (s, 1H), 7.20-7.35 (m, 4H), 6.10-6.22 (m, 1H), 4.75 -5.16 (m, 4H), 3.27-3.47 (m, 6H), 2.32 (shs, 4H), 1.80-1.85 (m, 3H), 1.00-1 .55 (m, 4H), 0.07-0.86 (m, 9N). LCMS: m/z 503 [M+H]+ @ w.u. 6.08 min. MSVR (IER) calc. for C29H39N6O2 [M+H] ⁺ 503.3129 found 503.3136;

2-({(1S)-1-[4-(1-Acryloyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]ethyl}amino)-8-[(2S)-3-methylbutan- 2-yl]pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl, R6b=H, R8=H, R3=R4=R5=H] Comp. 168

1H NMR (500 MHz, DMSO-06) δ 8.58 (s, 1H), 8.40 (d, J=7.47 Hz, 1H), 7.63 (d, J=9.3 Hz, 1H ), 7.23-7.42 (m, 4H), 6.88 (dd, J=10.68, 18.30 Hz, 1H), 6.21 (d, J=9.30 Hz, 1H) , 6.04-6.16 (m, 2H), 5.70 (dd, J=2.29, 10.68 Hz, 1H), 4.95-5.10 (m, 1H), 4.74 -4.87 (m, 1H), 4.24 (shs, 1H), 4.14 (shs, 1H), 2.44 (m, 2H), 1.86-1.94 (m, 1H), 1.47 (d, J=6.86 Hz, 3H), 0.99-1.14 (m, 3H), 0.70 (d, J=6.41 Hz, 3H), 0.05 (d , J=6.41 Hz, 3H). LCMS: m/z 472 [M+H] ⁺ v.a. 6.24 min. MSVR (IER) calc. for C ₂₈ H ₃₄ N ₅ O [M+H] ⁺ 472.2707 found 472.2700;

2-{[(1S)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-[(2S)-1,1,1-trifluoropropan2-yl]pyrido [2,3^]pyrimidin-7(8H)-one [(I), X=N, K2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8 , R6b=H, R7-R8=4-piperazin-1-yl, R11=vinyl, R3=R4=R5=H] comp. 169

1H NMR (500 MHz, DMSOU) δ=8.63 (m, 2H), 7.72 (d, J=9.46 Hz, 1H), 7.22-7.35 (m, 4H), 6, 76 (dd, J=10.37, 18.91 Hz, 1H), 6.18 (d, J=9.46 Hz, 1H), 6.01-6.10 (m, 2H), 5.65 (dd, J=2.29, 10.37 Hz, 1H), 4.79 (quin, J=6.71 Hz, 1H), 3.42-3.54 (m, 6H), 2.27- 2.31 (m, 4H), 1.87 (d, J=7.17 Hz, 1H), 1.47 (d, J=6.86 Hz, 3H), 1.36 (d, J=7 ,17 Hz, 3H). LCMS: m/z 515 [M+H] ⁺ @ w.u. 5.71 min. MSVR (IER) calc. for C ₂₆ H ₃₀ F ₃ N ₆ O ₂ [M+H] ⁺ 515.2377 found 515.2363.

2-({(1S)-1-[4-(4-Acryloylpiperazin-1-yl)phenyl]ethyl}amino)-8-[(2S)-3-methylbutan-2-yl]pyrido[2,3^ ]pyrimidin-7(8H)-one [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4NR7R8, R6b= H, R7-R8=4-piperazin-1-yl, R11=vinyl, R3=R4=R5=H] comp. 175

1H NMR (500 MHz, DMSO-06) δ=8.55 (s, 1H), 8.27 (d, J=7.63 Hz, 1H), 7.63 (d, J=9.15 Hz, 1H), 7.24 (d, J=8.69 Hz, 1H), 7.16 (d, J=8.69 Hz, 1H), 6.90 (d, J=8.69 Hz, 2H) , 6.84 (dd, J=10.45, 16.55 Hz, 1H), 6.20 (d, J=9.15 Hz, 1H), 6.12 (dd, J=2.29, 16 .78 Hz, 1H), 5.69 (dd, J=2.30, 10.50 Hz, 1H), 5.11-5.22 (m, 1H), 4.76-4.96 (m, 1H), 3.66 (d, J=18.00 Hz, 4H), 3.06 (shs, 4H), 1.39-1.53 (m, 4H), 0.98-1.21 (m , 3H), 0.60-0.80 (m, 3H), 0.13 (d, J=6.24 Hz, 3H). LCMS: m/z 475 [M+H] ⁺ @ w.u. 5.96 min. MSVR (IER) calc. for C ₂₇ H ₃₅ N ₆ O ₂ [M+H] ⁺ 475.2816 Found 475.2813.

2-({(1S)-1-[4-(4-Acryloylpiperazin-1-yl)-3-fluorophenyl]ethyl}amino)-8-[(2S)-3-methylbutan-2-yl]pyrido[2 ,3^]pyrimidin-7(8H)-one [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4 -NR7R8, R6b=F, R7-R8=4-piperazin-1-yl, R11=vinyl, R3=R4=R5=H] comp. 179

1H NMR (500 MHz, DMSO-06) δ=8.57 (s, 1H), 8.28-8.45 (m, 1H), 7.64-7.68 (m, 1H), 6.92 -7.18 (m, 3H), 6.83 (dd, J=10.45, 16.40 Hz, 1H), 6.10-6.24 (m, 2H), 5.70 (dd, J =2.06, 10.45 Hz, 1H), 4.92 (m, 1H), 4.79 (m, 1H), 3.68 (d, J=16.93 Hz, 4H), 2.92 (shs, 4H), 1.95 (m, 1H), 1.42-1.51 (m, 3H), 0.99-1.16 (m, 3H), 0.11 (d, J=6 .56 Hz, 3H). LCMS: m/z 493 [M+H] ⁺ @ w.u. 6.07 min. MSVR (IER) calc. for C ₂₇ H ₃₄ FN ₆ O ₂ [M+H] ⁺ 493.2722 found 493.2736.

2-({(1S)-1-[6-(4-Acryloylpiperazin-1-yl)pyridin-3-yl]ethyl}amino)-8-[(2S)-3-methylbutan-2-yl]pyrido[ 2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A=pyridin-3-yl, R1a=H,

- 94 046117

R1b=Me, R6a=4-NR7R8, R6b=H, R7-R8=4-nunepa3HH-1-ra, R11=vinyl, R3=R4=R5=H] conn. 181

1H NMR (500 MHz, DMSO-06) δ=8.57 (s, 1H), 8.30 (m, 1H), 8.15 (brs, 1H), 7.65 (d,

J=9.46 Hz, 1H), 7.49 (m, 1H), 6.80-6.87 (m, 2H), 5.70 (dd, J=2.70, 10.3 Hz, 1H ), 4.90 (m, 1H), 4.81 (m, 1H), 3.62 (d, J=19.52 Hz, 4H), 3.44 (shs, 4H), 2.10 (m , 1H), 1.44-1.51 (m, 3H); 0.99-1.07 (m, 3H); 0.55-0.65 (m, 3H), 0.17 (d, J=6.41 Hz, 3H). LCMS: m/z 476 [M+H]+ @ w.u. 5.49 min. MSVR (IER) calc. for C26H34N7O2 [M+H] ⁺ 476.2769 found 476.2777.

2-{[(^)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-(2-azidoethyl)pyrido[2,3d]nipimidin-7(8H )-one [(I), X=N, I2=2-azidoethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH2NR7R8, R6b=H, R7-R8=4-ninepasine-1- silt, R11=vinyl, R3=R4=R5=H] conn. 182

1H NMR (500 MHz, DMSO-06) δ=8.60 (m, 1H), 8.50 (m, 1H), 7.63-7.73 (m, 1H), 7.17-7.37 (m, 2H), 6.75 (dd, J=10.22, 16.78 Hz, 1H), 6.12-6.29 (m, 2H), 6.08 (dd, J=2.36 , 16.70 Hz, 1H), 5.26 (m, 2H), 5.04 (m, 1H), 4.44 (m, 1H), 4.17-4.37 (m, 2H), 3 .34-3.71 (m, 6H), 2.20-2.34 (m, 4H), 1.41-1.49 (m, 3H). LCMS: m/z 488 [M+H] ⁺ @ w.u. 5.12 min. MSVR (IER) calc. for C ₂₅ H ₃ N ₉ O ₂ [M+H] ⁺ 488.22517 found 488.2525.

2-{[(^)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]-3-fluorophenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3Apyrimidin- 7(8H)-one [(I), X=N, I2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=F, R7-R8 =4-ninepasin-1-yl, R11=vinyl, R3=R4=R5=H] conn. 183

¹ H NMR (500 MHz, DMSO-06) δ=8.57 (s, 1H), 8.37 (d, J=6.71 Hz, 1H), 7.63 (d, J=9.30 Hz , 1H), 7.32 (t, J=7.47 Hz, 1H), 7.10-7.24 (m, 2H), 6.75 (dd, J=10.52, 16.62 Hz, 1H), 6.17 (d, J=9.30 Hz, 1H), 6.07 (dd, J=1.83, 16.47 Hz, 1H), 5.64 (dd, J=1.98 , 10.37 Hz, 1H), 5.49 (shm, 1H), 4.99 (quin, J=6.98 Hz, 1H), 3.49 (shs, 6H), 2.31 (shs, 4H ), 1.48 (d, J=6.86 Hz, 9H). LCMS: m/z 479 [M+H] ⁺ @ w.u. 6.74 min. MSVR (IER) calc. for C ₂₆ H ₃₂ FN ₆ O ₂ [M+H] ⁺ 479.2566 Found 479.2577.

2-{[(^)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3d]nipimidin-7 (8H)-one [(I), X=N, I2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8= 4-ninepasin-1-yl, R11=vinyl, R3=R4=R5=H] comp. 184

1H NMR (500 MHz, DMSOA) δ=8.55 (s, 1H), 8.36 (d, J=6.86 Hz, 1H), 7.62 (d, J=9.30 Hz, 1H) , 7.32 (d, J=7.63 Hz, 2H), 7.22 (d, J=7.47 Hz, 2H), 6.76 (dd, J=10.52, 16.62 Hz, 1H), 6.15 (d, J=9.30 Hz, 1H), 6.07 (dd, J=1.98, 16.62 Hz, 1H), 5.64 (dd, J=1.98 , 10.52 Hz, 1H), 5.50 (shs, 1H), 5.0 (m, 1H), 3.50 (shs, 4H), 3.42 (shs, 2H), 2.28 (shs , 4H), 1.44-1.52 (m, 9H). LCMS: m/z 461 [M+H] ⁺ @ w.u. 5.29 min. MSVR (IER) calc. for C ₂₆ H ₃₃ N ₆ O ₂ [M+H] ⁺ 461.266 Found 461.2661.

2-{[(18)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-ethylpyrido[2,3-4]pyrimidin-7(8H)-one [(I), X=N, R2=ethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7-R8=4piperazin-1-yl, R11=vinyl , R3=R4=R5=H] conn. 186

1H NMR (500 MHz, DMSOA) δ=8.58 (s, 1H), 8.43 (d, J=7.02 Hz, 1H), 7.67 (d, J=9.30 Hz, 1H) , 7.35 (d, J=7.78 Hz, 2H), 7.23 (d, J=7.78 Hz, 2H), 6.75 (dd, J=10.52, 16.62 Hz, 1H), 6.20 (d, J=9.30 Hz, 1H), 6.07 (dd, J=2.21, 16.62 Hz, 1H), 5.65 (dd, J=2.21 , 10.52 Hz, 1H), 5.02 (quin, J=7.05 Hz, 1H), 3.49 (m, 6H), 3.42 (s, 2H), 2.29 (shs, 4H ), 1.47 (d, J=7.17 Hz, 3H), 0.90 (t, J=6.86 Hz, 3H). LCMS: m/z 447 [M+H] ⁺ @ w.u. 4.92 min. MSVR (IER) calc. for C25H31N6O2 [M+H] ⁺ 447.2503, 447.2518 was found.

2-{[(^)-1-{4-[1-(4-Acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3Apyrimidin-7 (8H)-one [(I), X=N, I2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4CH(R14)NR7R8, R6b=H, R7-R8= 4-ninepasin-1-yl, R11=vinyl, R3=R4=R5=H, R14=ethyl] comp. 187

- 95 046117

1H NMR (500 MHz, DMSO-06) δ=8.56 (s, 1H), 8.34 (d, J=6.85 Hz, 1H), 7.62 (d, J=9.30 Hz, 1H), 7.30 (d,

J=7.63 Hz, 2H), 7.14 (d, J=7.63 Hz, 2H), 6.69 (dd, J=10.98, 17.54 Hz, 1H), 6.15 ( d, J=9.30 Hz, 1H), 6.01 (dd,

J=1.98, 17.54 Hz, 1H), 5.59 (dd, J=1.98, 10.98 Hz, 1H), 5.44 (shs, 1H), 4.98 (shs, 1H ), 3.40-3.52 (shm, 4H), 3.222-3.26 (m, 1H), 2.28 (shs, 4H), 1.80-1.89 (m, 1H), 1, 61-1.67 (m, 1H), 1.44-1.52 (m, 9H), 0.65-0.72 (m, Zn). LCMS: m/z 489 [M+H]+ @ w.u. 7.09 min. MSVR (IER) calc. milking C ₂₈ H ₃₇ N ₆ O ₂ [M+H] ⁺ 489.2973 found 489.2981

2-{[(18)-1-{4-[(4-Acryloylpiperazin-1-yl)carbonyl]phenyl}ethyl]amino}-8-ethylpyrido[2,3-4]pyrimidin-7(8H)-one [(I), X=N, R2=ethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CONR7R8, R6b=H, R7-R8=4piperazin-1-yl, R11=bhhm, R3 =R4=R5=H] conn. 190

Chiral

1H NMR (500 MHz, DMSO-06) δ=8.59 (s, 1H), 8.50 (d, J=7.17 Hz, 1H), 7.68 (d, J=9.30 Hz, 1H), 7.47 (d, J=8.08 Hz, 2H), 7.37 (d, J=8.08 Hz, 2H), 6.61-6.95 (m, 1H), 6, 22 (d, J=9.30 Hz, 1H), 6.12 (dd, J=2.29, 16.62 Hz, 1H), 5.70 (d, J=10.83 Hz, 1H), 5.05 (kv, J=7.1 Hz, 1H), 3.99-4.27 (m, 2H), 3.57 (shs, 8H), 1.49 (d, J=7.02 Hz , 3H), 0.89 (t, J=6.63 Hz, 3H). LCMS: m/z 461 [M+H] ⁺ @ w.u. 4.58 min. MSVR (IER) calc. for C ₂₅ H ₂₉ N ₆ O ₃ [M+H] ⁺ 461.2296 Found 461.2306

2-{[(1S)-1-{4-[(4-Acryloylpiperazin-1-yl)carbonyl]-3-fluorophenyl}ethyl]amino}-8-[(2S)-3-methylbutan-2-yl] pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-CONR7R8, R6b=F, R7-R8=4-piperazin-1-yl, R11=buhu^ R3=R4=R5=H] conn. 191 _ Chiral

ΆχО F I

1H NMR (500 MHz, DMSO-06) δ=8.60 (s, 1H), 8.41 (d, J=6.25 Hz, 1H), 7.66 (d, J=9.30 Hz, 1H), 7.37 (d, J=7.32 Hz, 1H), 7.18-7.32 (m, 2H), 6.68-6.86 (m, 1H), 6.24 (d , J=9.30 Hz, 1H), 6.11 (dd, J=2.29, 16.62 Hz, 1H), 5.66-5.73 (m, 1H), 5.01 (kv, J=7.1 Hz, 1H), 4.77-4.99 (m, 1H), 3.45-3.69 (m, 6H), 3.18-3.25 (m, 2H), 1 .91 (m, 1H), 1.50 (d, J=6.86 Hz, 3H), 0.76 (d, J=5.80 Hz, 3H), 0.64 (d, J=5, 80 Hz, 3H), 0.12 (d, J=5.80 Hz, 3H). LCMS: m/z 521 [M+H] ⁺ @ w.u. 5.44 min. MSVR (IER) calc. for C ₂₈ H ₃₃ FN ₆ O ₃ [M+H] ⁺ 521.2671 found 521.2684.

N(1-Acryloylpiperidin-4-yl)-2-fluoro-4-[(^)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3d] pyrimidin-2-yl]amino}ethyl]benzamide [(I), X=N, K2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4CONR7R8, R6b=H, R7= H, R8=4-piperidin-1-yl, R11=bhh^, R3=R4=R5=H] conn. 192 _ gA'L-AA Chiral

A/'D.A · A k X

Ν Ν O /St o o

1H NMR (500 MHz, DMSOA) δ 8.57 (s, 1H), 8.42 (d, J=7.32 Hz, 1H), 8.15 (d, J=7.78 Hz, 1H), 7.63 (d, J=9.46 Hz, 1H), 7.49 (t, J=7.40 Hz, 1H), 7.27 (d, J=9.76 Hz, 2H), 6, 81 (dd, J=10.45, 16.70 Hz, 1H), 6.17 (d, J=8.85 Hz, 1H), 6.08 (dd, J=2.36, 16.70 Hz , 1H), 5.66 (dd, J=2.36, 10.45 Hz, 1H), 5.54 (shs, 1H), 5.06 (quin, J=7.00 Hz, 1H), 4 .27 (d, J=12.51 Hz, 1H), 3.92-4.01 (m, 2H), 3.18 (t, J=11.90 Hz, 1H), 2.84 (t, J=11.74 Hz, 1H), 1.82 (shs, 2H), 1.51 (d, J=4.88 Hz, 2H), 1.48 (d, J=7.02 Hz, 3H) , 1.36 (shs, 6n). LCMS: m/z 506 [M+H] ⁺ @ w.u. 9.44 min. MSVR (IER) calc. for C ₂₇ H ₃₂ FN ₆ O ₃ [M+H] ⁺ 506.2515 found 506.2528.

2-{[(1S)-1-(1'-Acryloyl-1',2',3',6'-tetrahydro-3,4'-bipyridin-6-yl)ethyl]amino}-8-[( 2S)-3-methylbutan-2-yl]pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=(2S)-3-methylbutan-2-yl, A =pyridin-2-yl, R1a=H, R1b=Me, R6a=4-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl, R6b=H, R3=R4=R5=H] Connection 194

1H NMR (500 MHz, DMSO-06) δ 8.61 (s, 1H), 8.59 (s, 1H), 8.34 (d, J=6.25 Hz, 1H), 7.62-7 .80 (m, 2H), 7.21 (d, J=8.24 Hz, 1H), 7.46 (d, J=8.24 Hz, 2H), 6.89 (dd, J=10, 37, 16.93 Hz, 1H), 6.09-6.23 (m, 3H), 5.70 (dd, J=2.29, 16.93 Hz, 1H), 4.97 (quin, J =6.90 Hz, 1H), 4.70-4.77 (m, 1H), 4.27 (shm, 1H), 4.15-4.27 (shm, 1H), 3.713.79 (m, 2H), 2.52-2.55 (m, 2H), 1.48-1.60 (m, 4H), 0.97-1.03 (m, 3H), 0.57-0.63 ( m, 3H), 0.01 (d, J=6.71 Hz,

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3H). LCMS: m/z 473 [M+H] ⁺ v.a. 5.28 min. MSVR (IER) calc. for C ₂₇ H ₃₃ N ₆ O ₂ [M+H] ⁺ 473.266 Found 473.2667;

2-({(^)-1-[1'-(Cyclopropylcarbonyl)-1',2',3',6'-tetrahydro-3,4'-bipyridin-6-yl]ethyl}amino)-8[ (2S)-3 -methylbutan-2-yl] pyrido[2,3A] pyrimidin-7(8H)-one [(I),

R2=(2S)-3-MeTun6ymaH-2-un,

A=pyridin-2-yl, R1a=H, R1b=Me, R6a=4-(1-cyclopropylcarbonyl 1,2,3,6-tetrahydropyridin-4-yl, R6b=H, R3=R4=R5=H] Connection 195

LCMS: m/z 487 [M+H]+ v.a. 5.52 min. MSVR (IER) calc. for C ₂₈ H ₃₅ N ₆ O ₂ [M+H] ⁺ 487.2816 Found 487.2813;

2-{[(1S)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-[(2S)-1-fluoropropan-2yl]pyrido[2,3A ]pyrimidin-7(8H)-one [(I), X=N, R2=(2S)-1-fluoropropan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-(4 -acryloylpiperazin-1-yl)methyl, R6b=H, R3=R4=R5=H] Comp. 198

^1H NMR (500 MHz, DMSO^) δ 8.60 (s, 1H), 8.47 (d, J=5.64 Hz, 1H), 7.68 (d, J=9.15 Hz, 1H ), 7.21-7.37 (m, 4H), 6.75 (dd, J=10.29, 16.70 Hz, 1H), 6.20 (d, J=9.15 Hz, 1H) , 6.07 (dd, J=2.21, 16.70 Hz, 1H), 5.64 (dd, J=2.21, 10.29 Hz, 1H), 4.91 (td, J=6 .48, 12.96 Hz, 1H), 4.36 (m, 1H), 3.38-3.60 (m, 8H), 2.30 (shs, 4H), 1.47 (d, J= 7.02 Hz, 3H), 1.05 (dd, J=7.02 Hz, 3H). LCMS: m/z 479 [M+H] ⁺ v.a. 5.94 min. MSVR (IER) calc. for C ₂₆ H ₃₂ FN ₆ O ₂ [M+H] ⁺ 479.2566 Found 479.2572;

2-{[(1S)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-[(2S)-1-hydroxypropan-2yl]pyrido[2,3 -i]pyrimidin-7(8H)-one [(I), X=N, R2=(2S)-1-hydroxypropan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4- (4-acryloylpiperazin-1-yl)methyl, R6b=H, R3=R4=R5=H] Comp. 199

¹ H NMR (500 MHz, DMSO-06) δ 8.56 (s, 1H), 7.63 (d, J=9.00 Hz, 1H), 7.19-7.49 (m, 4H), 6.76 (dd, J=10.52, 16.78 Hz, 1H), 6.04-6.22 (shm, 2H), 5.61-5.77 (shm, 1H), 5.27 ( shs, 1H), 5.01 (m, 1H), 4.68-4.79 (shm, 1H), 4.42-4.52 (shm, 1H), 4.17-4-37 (shm, 2H), 3.39 -3.60 (m, 6H), 2.29 (m, 4H), 1.36-1.51 (m, 6H). LCMS: m/z 477 [M+H] ⁺ v.a. 4.37 min. MSVR (IER) calc. for C ₂₆ H ₃₂ N ₆ O ₃ [M+H] ⁺ 477.2609 found 477.2605;

2-{[(^)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)-4ethoxypyrido[2,3A]pyrimidin- 7(8H)-one [(I), X=N, C2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-(4-acryloylpiperazin-1-yl)methyl, R6b=H, R3=O ethyl, R4=R5=H] Comp. 201

¹ H NMR (500 MHz, DMSO-06) δ 8.19 (d, J=7.63 Hz, 1H), 7.67 (d, J=9.46 Hz, 1H), 7.30-7, 37 (m, 2H), 7.18-7.28 (m, 2H), 6.76 (dd, J=10.29, 16.70 Hz, 1H), 6.05-6.10 (m, 2H), 5.64-5.68 (m, 1H), 4.98-5.23 (m, 1H), 4.28-4.53 (m, 2H), 4.02 (dd, J= 7.17, 15.56 Hz, 2H), 3.46-3.56 (m, 4H), 3.40-3.46 (m, 2H), 2.31 (shs, 4H), 1.421.49 (m, 6H), 1.37 (t, J=7.09 Hz, 3H), 0.73 (shm. 6H). LCMS: m/z 533 [M+H] ⁺ v.a. 10.12 min. MSVR (IER) calc. for C30H41N6O3 [M+H] ⁺ 533.3235 found 533.3249;

2-{[(^)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)-4(methylamino)pyrido[2, 3A]pyrimidin-7(8H)-one [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=4-(4-acryloylpiperazine-1- yl)methyl, R6b=H, R3=N-Methyl, R4=R5=H] Comm. 202

1H NMR (500 MHz, DMSOA6) δ. 7.72-7.89 (m, 1H), 7.53-7.64 (m, 1H), 7.32 (d, J=8.08 Hz, 1H), 7.15-7.29 ( m, 4H), 6.76 (ddd, J=4.27, 10.49, 16.66 Hz, 1H), 6.03-6.18 (m, 1H), 5.99 (d, J= 9.46 Hz, 1H), 5.60-5.71 (m, 1H), 4.88 (dkv, J=7.32, 7.63 Hz, 1H), 4.11 (dd, J=5 ,19 Hz, 2H), 3.51 (shs, 4H), 3.44 (d, J=6.86 Hz, 2H), 2.90 (d, J=4.27 Hz, 3H), 2, 32 (shs, 4H), 1.31 (d, J=7.02 Hz, 3H), 0.90 (shs, 3H), 0.73 (shs, 6H).

LCMS: m/z 518 [M+H] ⁺ v.a. 10.12 min. MSVR (IER) calc. for C ₂₉ H40N ₇ O ₂ [M+H] ⁺ 518.3238 found 518.3239;

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2-{[(^)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-4-(dimethylamino)-8-(propan2-yl)pyrido[2,3 ^]pyrimidin-7(8H)-one [(I), X=N, I2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-(4acryloylpiperazin-1-yl) methyl, R6b=H, R3=N, N-diMethyl, R4=R5=H] Comp. 203

LCMS: m/z 505 [M+H] ⁺ v.a. 6.05 min. MSVR (IER) calc. for C ₂₈ H ₃₈ N ₇ O ₂ [M+H] ⁺ 504.3082 found 504.3095;

2-{[(^)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-7-oxo-8-(propan-2-yl)-7,8dihydropyrido[ 2,3^]pyrimidine-4-carbonitrile [(I), X=N, I2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-(4-acryloylpiperazin-1- yl)methyl, R6b=H, R3=CN, R4=R5=H] Comm. 204

1H NMR (500 MHz, DMSO-06) δ 8.92 (d, J=7.17 Hz, 1H), 7.66 (d, J=9.46 Hz, 1H), 7.32 (d, J =8.08 Hz, 2H), 7.23 (d, J=8.08 Hz, 2H), 6.76 (dd, J=10.45, 16.70 Hz, 1H), 6.35 (d , J=9.46 Hz, 1H), 6.07 (dd, J=2.36, 16.70 Hz, 1H), 5.64 (dd, J=2.36, 10.45 Hz, 1H) , 4.98 (d, J=6.56 Hz, 1H), 3.50 (shs, 4H), 3.43 (s, 2H), 2.28 (shs, 4H), 1.48 (d, J=7.17 Hz, 3H). LCMS: m/z 486 [M+H] ⁺ v.a. 6.18 min. MSVR (IER) calc. for C ₂₇ H ₃₂ N ₇ O ₂ [M+H] ⁺ 486.2612 found 486.2614;

2-{[(18)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-4-[(2,4-dimethoxybenzyl)amino]-8-(propan- 2-yl)pyrido[2,3^]pyrimidin-7(8H)-one R1a=H, R1b=Me, R6a=4-(4-aKpunounnunepa3UH-1-un)Memun, R4=R5=H] Comp. 205

[(I), X=N, I2=propan-2-yl, A=phenyl,

R6b=H, R3 (2,4-dimethoxybenzyl)amino,

LCMS: m/z 626 [M+H] ⁺ v.a. 6.67 min. MSVR (IER) calc. for C35H43N7O4 [M+H] ⁺ 626.345 found 626.3475;

2-{[(^)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-4-amino-8-(propan-2-yl)pyrido[2,3 ^]pyrimidin-7(8H)-one [(I), X=N, I2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-(4acryloylpiperazin-1-yl) methyl, R6b=H, R3=NH2, R4=R5=H] Comp. 206

Ν

Chiral

1H NMR (500 MHz, DMSO-dg) δ 7.82 (d, J=9.15 Hz, 1H), 6.75 (dd, J=10.52, 16.62 Hz, 1H), 6.07 (dd, J=2.21, 16.70 Hz, 1H), 5.91 (shs, 1H), 4.98 (d, J=13.88 Hz, 1H), 3.49 (d, J= 6.56 Hz, 6H), 2.29 (shs, 4H), 1.171.58 (m, 9H). LCMS: m/z 476 [M+H]+ v.a. 4.81 min. MSVR (IER) calc. for C ₂₆ H ₃₄ N ₇ O ₂ [M+H] ⁺ 476.2769 found 476.2777;

2-{[(1S)-1-(4-{[(2R)-4-Acryloyl-2-methylpiperazin-1-yl]methyl}phenyl)ethyl]amino}-8-ethylpyrido[2,3^]pyrimidine -7(8H)-one [(I), X=N, R2=ethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-(2R)-(4-acryloyl-2methylpiperazin-1-yl )methyl, R6b=H, R3=R4=R5=H] Comp. 207

1H NMR (500 MHz, DMSO-06) δ 8.57 (s, 1H), 8.42 (d, J=7.17 Hz, 1H), 7.67 (d, J=9.46 Hz, 1H ), 7.34 (d, J=7.78 Hz, 2H), 7.23 (d, J=7.78 Hz, 2H), 6.63-6.90 (m, 1H), 6.20 (d, J=9.30 Hz, 1H), 6.01-6.14 (m, 1H), 5.575.71 (m, 1H), 5.01 (quin, J=6.30 Hz, 1H) , 1.47 (d, J=7.02 Hz, 3H), 1.03 (dd, J=6.25, 10.68 Hz, 3H), 0.89 (kv, J=6.81 Hz, 3H). LCMS: m/z 461 [M+H] ⁺ v.a. 5.13 min. MSVR (IER) calc. for C ₂₆ H ₃₃ N ₆ O ₂ [M+H] ⁺ 461.266 Found 461.2656;

2-{[(1S)-1-(4-{[(3R)-4-Acryoyl-3-methylpiperazin-1-yl]methyl}phenyl)ethyl]amino}-8-ethylpyrido[2,3^]pyrimidine -7(8H)-one [(I), X=N, R2=ethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-(3R)-(4-acryloyl-2methylpiperazin-1-yl )methyl, R6b=H, R3=R4=R5=H] Comp. 208

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1H NMR (500 MHz, DMSOA) δ 8.57 (s, 1H), 8.42 (d, J=7.17 Hz, 1H), 7.67 (d, J=9.46 Hz, 1H), 7.34 (d, J=7.78 Hz, 2H), 7.23 (d, J=7.78 Hz, 2H), 6.63-6.90 (m, 1H), 6.20 (d , J=9.30 Hz, 1H), 6.01-6.14 (m, 1H), 5.575.71 (m, 1H), 5.01 (quin, J=6.30 Hz, 1H), 1 .47 (d, J=7.02 Hz, 3H), 1.03 (dd, J=6.25, 10.68 Hz, 3H), 0.89 (kv, J=6.81 Hz, 3H) . LCMS: m/z 461 [M+H] ⁺ v.a. 5.61 min. MSVR (IER) calc. for C ₂₆ H ₃₃ N ₆ O ₂ [M+H] ⁺ 461.266 Found 461.2655;

2-{[(1S)-1-(4-{(2R)-4-Acryloyl-2-(propan-2-yl)piperazin-1-yl]methyl}phenyl)ethyl]amino}-8ethylpyrido[2, 3^]pyrimidin-7(8H)-one [(I), X=N, R2=ethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-(2R)-(4acryloyl-2-( propan-2-yl)piperazin-1-yl)methyl, R6b=H, R3=R4=R5=H] Comm. 209

1H NMR (500 MHz, DMSO^) δ 8.57 (s, 1H), 8.42 (d, J=6.86 Hz, 1H), 7.67 (d, J=9.30 Hz, 1H) , 7.34 (d, J=7.78 Hz, 2H), 7.23 (d, J=7.93 Hz, 2H), 6.59-6.85 (m, 1H), 6.20 ( d, J=9.46 Hz, 1H), 6.07 (d, J=16.62 Hz, 1H), 5.65 (dd, J=11.29, 19.37 Hz, 1H), 5, 00 (shs, 1H), 4.14-4.28 (m, 3H), 3.95-4.08 (m, 4H), 3.71-3.80 (m, 2H), 3.083.20 ( m, 1H), 2.87-2.95 (m, 1H), 2.11-2.20 (m, 1H), 1.47 (d, J=7.02 Hz, 3H), 0.74 -1.08 (m, 9H). LCMS: m/z 489 [M+H]+ v.a. 6.25 min. MSVR (IER) calc. for C28H37N6O2 [M+H] ⁺ 489.2973 found 489.298;

2-{[(1S)-1-(4-{[(2S)-4-acryloyl-2-methylpiperazin-1-yl]methyl}phenyl)ethyl]amino}-8-ethylpyrido[2,3^]pyrimidine -7(8H)-one [(I), X=N, R2=Ethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-(2R)-(4-acryloyl-2methylpiperazin-1-yl )methyl, R6b=H, R3=R4=R5=H] Comp. 210

1H NMR (500 MHz, DMSOA) δ 8.58 (s, 1H), 8.42 (d, J=7.47 Hz, 1H), 7.67 (d, J=9.30 Hz, 1H), 7.34 (d, J=7.78 Hz, 2H), 7.23 (d, J=7.93 Hz, 2H), 6.65-6.87 (m, 1H), 6.20 (d , J=9.30 Hz, 1H), 6.09 (d, J=17.23 Hz, 1H), 5.64 (t, J=8.70 Hz, 1H), 5.02 (quin, J =6.83 Hz, 1H), 4.00-4.28 (m, 3H), 3.63-3.92 (m, 5H), 3.08-3.26 (m, 2H), 1, 95-2.04 (m, 1H), 1.47 (d, J=7.02 Hz, 3H), 0.98-1.10 (m, 3H), 0.90 (t, J=6, 33 Hz, 3H). LCMS: m/z 461 [M+H] ⁺ v.a. 5.14 min. MSVR (IER) calc. giving C ₂₆ H ₃₃ N ₆ O ₂ [M+H] ⁺ 461.266 Found 461.2675;

2-{[(1 S)-1 -(4- {[(3 S)-4-Acryloyl-3 -methylpiperazin-1 -yl]methyl}phenyl)ethyl] amino }-8-ethylpyrido[2,3^ ]pyrimidin-7(8H)-one [(I), X=N, K2=ethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-(3R)-(4-acryloyl-2methylpiperazine-1 -yl)methyl, R6b=H, R3=R4=R5=H] Comp. 211

1H NMR (500 MHz, DMSO^) δ 8.58 (s, 1H), 8.42 (d, J=7.17 Hz, 1H), 7.67 (d, J=9.30 Hz, 1H) , 7.35 (d, J=7.93 Hz, 2H), 7.24 (d, J=7.93 Hz, 2H), 6.74 (dd, J=10.60, 16.70 Hz, 1H), 6.21 (d, J=9.30 Hz, 1H), 6.07 (d, J=16.32 Hz, 1H), 5.64 (dd, J=1.37, 10.22 Hz, 1H), 5.02 (quin, J=7.32 Hz, 1H), 4.00-4.29 (m, 5H), 3.35-3.45 (m, 4H), 2.61 (shs, 2H), (1.47 (d, J=7.02 Hz, 3H), 1.17 (kv, J=7.10 Hz, 3H), 0.91 (t, J=6.86 Hz, 3H) LCMS: m/z 461 [M+H] ⁺ v.a. 5.61 min HRMS (ESI) calculating C ₂₆ H ₃₃ N ₆ O ₂ [M+H] ⁺ 461.266 Found 461 ,2672;

2-{[(1S)-1-(4-{[(2S)-4-Acryloyl-2-(propan-2-yl)piperazin-1-yl]methyl}phenyl)ethyl]amino}-8ethylpyrido[2 ,3^]pyrimidin-7(8H)-one [(I), X=N, R2=ethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-(2R)-(4acryloyl-2- (propan-2-yl)piperazin-1-yl)methyl, R6b=H, R3=R4=R5=H] Comp. 212

1H NMR (500 MHz, DMSO^) δ 8.57 (s, 1H), 8.42 (d, J=6.86 Hz, 1H), 7.67 (d, J=9.30 Hz, 1H) , 7.34 (d, J=8.08 Hz, 2H), 7.23 (d, J=7.93 Hz, 2H), 6.72 (dd, J=10.37, 16.62 Hz, 1H), 6.20 (d, J=9.46 Hz, 1H), 6.07 (dd, J=2.21, 16.70 Hz, 1H), 5.56-5.73 (m, 1H ), 5.01 (t, J=6.86 Hz, 1H), 3.66-4.29 (m, 6H), 2.87-3.28 (m, 3H), 2.66 (d, J=15.25 Hz, 1H), 2.17 (d, J=6.56 Hz, 1H), 2.01-2.09 (m, 2H), 1.47 (d, J=7.02 Hz, 3H), 0.78-0.98 (m, 9H). LCMS: m/z 489 [M+H] ⁺ v.a. 6.13 min.

MSVR (IER) calc. for C28H37N6O2 [M+H] ⁺ 489.2973 found 489.2977;

2-{[(^)-1-{6-[(4-Acryloylpiperazin-1-yl)methyl]pyridin-3-yl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3 ^]pyrimidin-7(8H)-one [(I), X=N, R2=ethyl, A=pyridin-3-yl, R1a=H, R1b=Me, R6a=6-(4acryloylpiperazin-1-yl) methyl, R6b=H, R3=R4=R5=H] Comp. 213

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1H NMR (500 MHz, DMSOb) δ 8.57 (s, 1H), 8.51 (bs, 1H), 8.42 (d, J=6.41 Hz, 1H), 7.74 (d, J =8.08 Hz, 1H), 7.63 (d, J=9.30 Hz, 1H), 7.38 (d, J=7.93 Hz, 1H), 6.76 (dd, J=10 ,37, 16.62 Hz, 1H), 6.17 (d, J=9.30 Hz,

1H), 6.08 (dd, J=1.91, 16.85 Hz, 1H), 5.65 (dd, J=1.75, 10.75 Hz, 1H), 5.20-5.58 (m, 1H), 5.04 (shs, 1H), 3.56 (shs, 2H), 3.51 (m, 4H), 2.22-2.44 (m, 4H), 1.51 ( d, J=6.86 Hz, 9H). LCMS: m/z 462 [M+H]+ v.a. 4.57 min. MSVR (IER) calc. giving C ₂₅ H ₃₂ N ₇ O ₂ [M+H] ⁺ 462.2612 found 462.2606;

2-{[(^)-1-{4-[1-(4-Acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-ethylpyrido[2,3^]pyri midin-7(8H) -one [(I), X=N, R2=ethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH(R14)NR7R8, R6b=H, R7-R8=4 piperazine-1- silt, R11=vinyl, R3=R4=R5=H, R14=ethyl] Comp. 214

1H NMR (500 MHz, DMSO^) δ 8.58 (s, 1H), 8.40 (d, J=4.42 Hz, 1H), 7.67 (d, J=9.30 Hz, 1H) , 7.33 (d, J=7.63 Hz, 2H), 7.14 (d, J=7.93 Hz, 2H), 6.69 (dd, J=10.60, 16.55 Hz, 1H), 6.20 (d, J=9.30 Hz, 1H), 6.01 (d, J=16.78 Hz, 1H), 5.60 (d, J=10.52 Hz, 1H) , 4.90-5.38 (m, 1H), 3.90-4.35 (m, 2H), 3.44 (shs, 4H), 3.19-3.28 (m, 1H), 2 .23 (shs, 4H), 1.84 (kvd, J=6.66, 13.27 Hz, 1H), 1.56-1.72 (m, 1H), 1.47 (d, J=7 .02 Hz, 3H), 0.82 (td, J=7.02, 10.37 Hz, 3H), 0.57-0.75 (m, 3H). LCMS: m/z 475 [M+H] ⁺ v.a. 5.4 min. MSVR (IER) calc. giving C ₂₇ H ₃₅ N ₆ O ₂ [M+H] ⁺ 475.2816 Found 475.2824;

2-{[(18)-1-{4-[1-(4-Acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-methylpyrido[2,3a]pyrimidan-7(8H)-one [(I), X=N, R2=methyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH(R14)NR7R8, R6b=H, R7-R8=4-piperazin-1-yl , R11=vinyl, R3=R4=R5=H, R14=ethyl] Comp. 215

1H NMR (500 MHz, DMSO-de) δ 8.57 (s, 1H), 8.39 (d, J=7.63 Hz, 1H), 7.69 (d, J=9.30 Hz, 1H ), 7.37 (d, J=7.63 Hz, 2H), 7.15 (dD=7.93 Hz, 2H), 6.70 (dd, J=10.52, 16.62 Hz, 1H ), 6.18-6.28 (m, 1H), 6.02 (d, J=16.78 Hz, 1H), 5.60 (dd, J=1.98, 10.37 Hz, 1H) , 5.13 (quin, J=6.90 Hz, 1H), 3.47 (d, J=17.54 Hz, 4H), 3.37 (d, J=3.51 Hz, 3H), 3 .20-3.28 (m, 1H), 2.26 (shs, 4H), 1.79-

1.92 (m, 1H), 1.66 (dt, J=7.32, 14.41 Hz, 1H), 1.48 (d, J=6.71 Hz, 3H), 0.55-0 .91 (m, 3H). LCMS: m/z 461 [M+H] ⁺ v.a. 5.12 min. MSVR (IER) calc. for C ₂₆ H ₃₃ N ₆ O ₂ [M+H] ⁺ 461.266 Found 461.265;

2-{[(^)-1-{4-[1-(4-Acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(2,6difluorobenzyl)pyrido[2,3H]pyrimidine-7 (8H)-one [(I), X=N, R2=2,6-difluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH(R14)NR7R8, R6b=H, K7- R8=4-piperazin-1-yl, R11=vinyl, R3=R4=R5=H, R14=ethyl] Comp. 216

1H NMR (500 MHz, DMSO-de) δ 8.59 (s, 1H), 8.32 (d, J=8.39 Hz, 1H), 7.73 (d, J=9.30 Hz, 1H ), 7.27-7.39 (m, 1H), 7.25 (d, J=7.93 Hz, 2H), 7.07 (d, J=6.25 Hz, 2H), 6.96 (t, J=8.08 Hz, 2H), 6.71 (dd, J=10.45, 16.70 Hz, 1H), 6.25 (d, J=9.30 Hz, 1H), 6 .03 (dd, J=2.36, 16.70 Hz, 1H), 5.59-5.65 (m, 1H), 5.55 (dd, J=6.90, 14.9 Hz, 1H ), 5.36 (d, J=14.95 Hz, 1H), 5.10 (quin, J=7.55 Hz, 1H), 3.47 (shs, 4H), 3.18-3.27 (m, 1H), 2.25 (shs, 4H), 1.751.93 (m, J=6.71, 12.66 Hz, 1H), 1.56-1.72 (m, 1H), 1, 36 (d, J=6.86 Hz, 3H), 0.60-0.77 (m, 3H). LCMS: m/z 461 [M+H] ⁺ v.a. 6.17 min. MSVR (IER) calc. giving C ₃₂ H ₃₄ F ₂ N ₆ O ₂ [M+H] ⁺ 573.2784 found 573.2791;

2-{[(^)-1-{4-[1-(4-Acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-cyclopropylpyrido[2.3H]pyrimidin-7(8H)-one [(I), X=N, I2=cyclopropyl, A=phenyl, R1a=H, R1b=Me, R6a=4CH(R14)NR7R8, R6b=H, R7-R8=4-piperαzin-1-yl, R11 =vinyl, R3=R4=R5=H, R14=ethyl] Comp. 218

1H NMR (500 MHz, DMSO-de) δ 8.53 (s, 1H), 8.29 (d, J=7.47 Hz, 1H), 7.63 (d, J=9.30 Hz, 1H ), 7.35 (d, J=6.86 Hz, 2H), 7.15 (d, J=8.08 Hz, 2H), 6.70 (dd, J=10.75, 16.85 Hz , 1H), 6.14 (d, J=9.30 Hz, 1H), 6.02 (d, J=16.47 Hz, 1H), 5.55-5.67 (m, 1H), 5 .08-5.39 (m, 1H), 3.40-3.58 (m, 4H), 3.21-3.29 (m, 1H), 2.57-2.67 (m, 1H) , 2.26 (shs, 4H), 1.59-1.94 (m, 2H), 1.49 (d, J=7.02 Hz, 3H), 1.01-1.06 (m, 1H ), 0.79-0.86 (m, 1H), 0.70 (t, J=7.32 Hz, 3H), 0.61 (shs 1H), 0.32 (shs 1H). LCMS: m/z 487 [M+H] ⁺ v.a. 6.25 min. MSVR (IER) calc. giving C ₂₈ H ₃₅ N ₆ O ₂ [M+H] ⁺ 487.2816 Found 487.2829;

- 100 046117

2-{[(^)-1-{4-[1-(4-Acryloylpiperazin-1-yl)-2-cyclopropylethyl]phenyl}ethyl]amino}-8-ethylpipugo[2,3-d]nupuMuguH-7 (8H)-OH [(I), X=N, I2=ethyl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH(R14)NR7R8, R6b=H, R7-R8 4-hierazine -1-yl, R11 vinyl, R3=R4=R5=H, R14 cyclo·phonylmethyl] Comp. 219

1H NMR (500 MHz, DMSO-de) δ 8.61 (s, 1H), 8.44 (d, J=5.03 Hz, 1H), 7.70 (d, J=9.30 Hz, 1H ), 7.11-7.44 (m, 4H), 6.72 (dd, J=10.83, 16.32 Hz, 1H), 6.23 (d, J=9.30 Hz, 1H) , 6.04 (d, J=16.32 Hz, 1H), 5.62 (d, J=10.37 Hz, 1H), 5.05 (d, J=6.86 Hz, 1H), 3 .95-4.41 (m, 2H), 3.43-3.62 (m, 4H), 2.28 (shs, 4H), 1.55-1.85 (m, 2H), 1.51 (d, J=6.86 Hz, 3H), 0.71-1.04 (m, 3H), 0.18-0.51 (m, 4H), -0.13-0.10 (m, 2H). LCMS: m/z 501 [M+H]+ v.a. 7.27 min. MSVR (IER) calc. for C ₂₉ H ₃₇ N ₆ O ₂ [M+H] ⁺ 501.2973 found 501.2978;

2-{[(^)-1-{4-[1-(4-Acryloylpiperazin-1-yl)-2-cyclopropylethyl]phenyl}ethyl]amino}-8-(propan-2yl)pyrido[2,3^ ]pyrimidin-7(8H)-one [(I), X=N, I2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4CH(R14)NR7R8, R6b=H, R7-R8=4-piperazin-1-yl, R11=vinyl, R3=R4=R5=H, R14=cyclopropylmethyl]

Conn. 220

¹ H NMR (500 MHz, DMSO-06) δ 8.56 (s, 1H), 8.34 (brs, 1H), 7.62 (d, J=9.15 Hz, 1H), 7.27- 7.40 (m, 2H),

7.17 (d, J=7.78 Hz, 2H), 6.68 (dd, J=10.37, 16.47 Hz, 1H), 6.15 (d, J=9.00 Hz, 1H ), 6.01 (d, J=16.47 Hz, 1H), 5.59 (d, J=10.52 Hz, 1H), 4.99 (d, J=5.95 Hz, 1H), 3.40-3.56 (m, 5H), 2.23 (shs, 4H), 1.54-1.84 (m, 2H), 1.221.52 (m, 7H), -0.18-0 .50 (m, 6H), -0.05-0.02 (m, 2H). LCMS: m/z 515 [M+H] ⁺ v.a. 9.75 min. MSVR (IER) calc. for C30H3 ₉ N6O2 [M+H] ⁺ 515.3129 found 515.3143;

2-{[(^)-1-(4-{1-[4-(2-Methylacryloyl)piperazin-1-yl]propyl}phenyl)ethyl]amino}-8-(propan-2yl)pyrido[2, 3^]pyrimidin-7(8H)-one [(I), X=N, I2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4CH(R14)NR7R8, R6b= H, R7-R8=4-piperazin-1-yl, R11=2-methylvinyl, R3=R4=R5=H, R14=ethyl] Comp. 221

¹ H NMR (500 MHz, DMSO-d^ δ 8.56 (s, 1H), 8.12-8.39 (m, 1H), 7.63 (d, J=9.15 Hz, 1H), 7.23-7.42 (m, 2H), 7.09-7.18 (m, 2H), 6.15 (d, J=9.15 Hz, 1H), 5.21-5.56 ( m, 1H), 5.07-5.17 (m, 1H), 4.92-5.04 (m, 1H), 4.744.89 (m, 1H), 3.36-3.48 (m, 4H), 3.18-3.28 (m, 1H), 2.14-2.35 (m, 4H), 1.81-1.91 (m, 1H), 1.71-1.81 ( m, 3H), 1.58-1.69 (m, 1H), 1.21-1.56 (m, 9H), 0.61-0.74 (m, 3H). LCMS: m/z 503 [M+H] ⁺ v.a. 7.49 min MSVR (IER) calculated for C29H39N6O2 [M+H] ⁺ 503.3129 found 503.3141;

2-({(^)-1-[4-(1-{4-[(2E)-but-2-enoyl]piperazin-1-yl}propyl)phenyl]ethyl}amino)-8-(propan- 2yl)pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, I2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4CH( R14)NR7R8, R6b=H, R7-R8=4-piperazin-1-yl, R11=(2E)-propen-2-yl, R3=R4=R5=H, R14=ethyl] Com. 222

¹ H NMR (500 MHz, DMSO-06) δ 8.56 (s, 1H), 8.13-8.38 (m, 1H), 7.62 (d, J=9.15 Hz, 1H), 7.27-7.37 (m,

2H), 7.09-7.18 (m, 2H), 6.51-6.66 (m, 1H), 6.32-6.47 (m, 1H), 6.15 (d, J= 9.15 Hz, 1H), 5.36-5.76 (m, 1H), 4.89

5.32 (m, 1H), 3.38-3.58 (m, 4H), 3.16-3.29 (m, 1H), 2.21 (shs, 4H), 1.81-1, 91 (m, 1H), 1.73-1.80 (m, 3H), 1.601.71 (m, 1H), 1.25-1.57 (m, 9n), 0.62-0.77 ( m, 3H). LCMS: m/z 503 [M+H] ⁺ v.a. 7.45 min. MSVR (IER) calc. for C ₂₉ H ₃₉ N ₆ O ₂ [M+H] ⁺ 503.3129 found 503.3132;

2-{[(^)-1-{4-[(^)-1-(4-Acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyri to[ 2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4CH(R14)NR7R8, R6b=H, R7-R8=4-piperazin-1-yl, R11=vinyl, R3=R4=R5=H, R14=Ethyl] Comp. 227

Chiral O

^1H NMR (500 MHz, DMSO-06) δ 8.48-8.59 (m, 1H), 8.35 (d, J=6.56 Hz, 1H), 7.62 (d, J=9 ,30 Hz, 1H), 7.25-7.38 (m, 2H), 7.13 (d, J=7.78 Hz, 2H), 6.69 (dd, J=10.22, 16, 62 Hz, 1H), 6.15 (d, J=9.30 Hz, 1H), 5.94-6.09

- 101 046117 (m, 1H), 5.59 (d, J=10.22 Hz, 1H), 5.39-5.52 (shs, 1H), 4.95-5.03 (m, 1H) , 3.40-3.57 (m, 4H), 3.17-3.28 (m, 1H), 2.16-2.32 (m, 4H), 1.80-1.91 (m, 1H), 1.58-1.74 (m, 1H), 1.47 (d, J=7.02 Hz, 3H), 1.20-1.43 (m, 6H), 0.62-0 .75 (m, 3H). LCMS: m/z 489 [M+H]+ v.a. 7.12 min. MSVR (IER) calc. giving C ₂₈ H ₃₇ N ₆ O ₂ [M+H] ⁺ 489.2973 found 489.2982;

2-{[(^)-1-{4-[(^)-1-(4-Acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyri to[ 2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4CH(R14)NR7R8, R6b=H, R7-R8=4-piperαzin-1-yl, R11=buhu^ R3=R4=R5=H, R14=ethyl] Comp. 228

¹ H NMR (500 MHz, DMSO-do) δ 8.56 (s, 1H), 8.11-8.38 (m, 1H), 7.62 (d, J=9.30 Hz, 1H), 7.25-7.37 (m, 2H), 7.13 (d, J=7.93 Hz, 2H), 6.69 (dd, J=10.37, 16.47 Hz, 1H), 6 .15 (d, J=9.30 Hz, 1H), 6.01 (dd, J=1.98, 16.47 Hz, 1H), 5.55-5.66 (m, 1H), 5, 39- 5.52 (shs, 1H), 4.87-5.32 (m, 1H), 3.39-3.52 (m, 4H), 3.25 (dd, J=6.25, 7 .93 Hz, 1H), 2.23 (shs, 4H), 1.60-1.91 (m, 2H), 1.47 (d, J=7.02 Hz, 3H), 1.20-1 .43 (m, 6H), 0.62-0.75 (m, 3H). LCMS: m/z 489 [M+H] ⁺ v.a. 7.12 min. MSVR (IER) calc. giving C ₂₈ H ₃₇ N ₆ O ₂ [M+H] ⁺ 489.2973 found 489.2975;

2-{[(lR)-1-{4-[(1R)-1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyri to[ 2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4CH(R14)NR7R8, R6b=H, R7-R8=4-piperαzin-1-yl, R11=buhu^ R3=R4=R5=H, R14=ethyl] Comp. 229

Chiral

O

1H NMR (500 MHz, DMSO^) δ 8.56 (s, 1H), 8.35 (d, J=6.41 Hz, 1H), 7.62 (d, J=9.30 Hz, 1H) , 7.25-7.38 (m, 2H), 7.10-7.19 (m, 2H), 6.69 (dd, J=10.37, 16.62 Hz, 1H), 6.15 (d, J=9.46 Hz, 1H), 5.97-6.08 (m, 1H), 5.59 (d, J=12.51 Hz, 1H), 5.42-5.52 ( shs, 1H), 4.90-5.06 (m, 1H), 3.41-3.56 (m, 4H), 3.20-3.29 (m, 1H), 2.14-2, 34 (m, 4H), 1.80-1.92 (m, 1H), 1.59-1.72 (m, 1H), 1.47 (d, J=7.02 Hz, 3H), 1 .20-1.43 (m, 6H), 0.63-0.75 (m, 6H). LCMS: m/z 489 [M+H] ⁺ v.a. 6.74 min. MSVR (IER) calc. giving C ₂₈ H ₃₇ N ₆ O ₂ [M+H] ⁺ 489.2973 found

489.2978;

2-{[(^)-1-{4-[(^)-1-(4-Acryloylpiperazin-1-yl)-2-cyclopropylethyl]phenyl}ethyl]amino}-8-(propan-2-yl) pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, K2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH( R14)NR7R8, R6b=H, R7-R8=4-piperαzin-1-yl, R11=vinyl, R3=R4=R5=H, R14=pn^opropylmethyl] comp. 230

Chiral

1H NMR (500 MHz, DMSO^) δ 8.56 (s, 1H), 8.35 (d, J=6.86 Hz, 1H), 7.62 (d, J=9.30 Hz, 1H) , 7.28-7.39 (m, 2H), 7.17 (d, J=7.93 Hz, 2H), 6.68 (dd, J=10.52, 16.70 Hz, 1H), 6.15 (d, J=9.30 Hz, 1H), 6.01 (dd, J=2.06, 16.70 Hz, 1H), 5.59 (dd, J=1.98, 10, 68 Hz, 1H), 5.37-5.49 (w, 1H), 4.98 (t, J=6.56 Hz, 1H), 3.38-3.56 (m, 5H), 2, 23 (shs, 4H), 1.54-1.82 (m, 2H), 1.47 (m, 10H), 0.25-0.37 (m, 2H), -0.09-0.02 (m, 2H). LCMS: m/z 515 [M+H] ⁺ v.a. 7.97 min. MSVR (IER) calc. giving C ₃₀ H ₃₉ N ₆ O ₂ [M+H] ⁺ 515.3129 found 515.314;

2-{[(^)-1-{4-[(^)-1-(4-Acryloylpiperazin-1-yl)-2-cyclopropylethyl]phenyl}ethyl]amino}-8-(propan-2-yl) pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, K2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH( R14)NR7R8, R6b=H, R7-R8=4-piperαzin-1-yl, R11=buhu^ R3=R4=R5=H,

R14=cyclopropylmethyl] conn. 231

1H NMR (500 MHz, DMSO-de) δ 8.56 (s, 1H), 8.12-8.37 (m, 1H), 7.62 (d, J=9.30 Hz, 1H), 7 .27-7.40 (m, 2H), 7.11-7.23 (m, 2H), 6.68 (dd, J=10.37, 16.47 Hz, 1H), 6.15 (d , J=9.00 Hz, 1H), 6.00 (d, J=16.47 Hz, 1H),

5.59 (d, J=10.37 Hz, 1H), 5.39-5.51 (m, 1H), 4.93-5.30 (m, 1H), 3.39-3.53 ( m, 5H), 2.23 (shs, 4H), 1.53-1.81 (m, 3H), 0.95-1.50 (m, 9H), 0.24-0.45 (m, 3H), -0.12-0.05 (m, 2H). LCMS: m/z 515 [M+H] ⁺ v.a. 7.65 min. MSVR (IER) calc. for C30H39N6O2 [M+H] ⁺ 515.3129 found 515.3135;

2-{[(^)-1-{4-[1-(4-Propanoylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3^] pyrimidin-7(8H)-one [(I), X=N, R2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4CH(R14)NR7R8, R6b=H, R7 -R8=4-piperαzin-1-yl, R11=3rra, R3=R4=R5=H, R14=ethyl] Comp. 240

- 102 046117

1H NMR (500 MHz, DMSO^ ₆ ) δ 8.56 (s, 1H), 8.35 (bs, 1H), 7.62 (d, J=9.15 Hz, 1H), 7.30 (d , J=7.78 Hz, 2H), 7.13 (d, J=7.78 Hz, 2H), 6.15 (d, J=9.30 Hz, 1H), 5.39-5.72 (m, 1H), 4.99 (b.s., 1H), 3.34 (b.s., 4H), 3.183.26 (m, 1H), 2.11-2.31 (m, 6H), 1.77- 1.93 (m, 1H), 1.65 (dd, J=7.70, 13.50 Hz, 1H), 1.00-1.56 (m, 9H), 0.89 (dt, J= 2.14, 7.40 Hz, 3H), 0.59-0.73 (m, 3H). LCMS: m/z 491 [M+H]+ v.a. 5.64 min. MSVR (IER) calc. for C28H39N6O2 [M+H] ⁺ 491.3129 found 491.313;

1-Acryloyl-4-{4-[(^)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3^]pyrimidin-2-yl]amino }ethyl]phenyl}piperidine-4-carbonitrile [(I), X=N, P2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=piperidine-4-carbonitrile, R6b=H , R11=vinyl, R3=R4=R5=H] Conn. 241

^1H NMR (500 MHz, DMSO-do) δ 8.50-8.58 (m, 1H), 8.19-8.43 (m, 1H), 7.62 (d, J=9.30 Hz , 1H), 7.37-7.53 (m, 4H), 6.83 (dd, J=10.52, 16.62 Hz, 1H), 6.05-6.18 (m, 2H), 5.66-5.73 (m, 1H), 5.39-5.57 (m, 1H), 4.94-5.30 (m, 1H), 4.61 (d, J=12.22 Hz, 1H), 4.24 (d, J=12.20 Hz, 1H), 3.31 (m, 1H), 2.88 (t, J=12.89 Hz, 1H), 2.05- 2.22 (m, 2H), 1.80-2.02 (m, 2H), 1.12-1.62 (m, 9H). LCMS: m/z 471 [M+H] ⁺ v.a. 10.25 min. MSVR (IER) calc. for C ₂₈ H ₃₁ N ₆ O ₂ [M+H] ⁺ 471.2503 found 471.25;

2-{[(1 S)-1 -(4- {(1S)-1-[4-(3 -Chloropropanoyl)piperazin-1 -yl]-2-cyclopropylethyl } phenyl)ethyl]amino}-8-( propan-2-yl)pyrido[2,3^]pyrimidin-7(8H)-one [(I), X=N, R2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH(R14)NR7R8, R6b=H, R7-R8=4-piperazin-1-yl, R11=2-chloroethyl, R3=R4=R5=H, R14=cyclopropylmethyl] Comp. 242

^1H NMR (500 MHz, DMSO-de) 8.56 (s, 1H), 8.35 (d, J=6.86 Hz, 1H), 7.62 (d, J=9.30 Hz, 1H ), 7.28-7.39 (m, 2H), 7.18 (d, J=8.08 Hz, 2H), 6.15 (d, J=9.00 Hz, 1H), 5.40 -5.55 (shs, 1H), 4.91-5.02 (m, 1H), 3.70 (t, J=6.5 Hz, 2H), 3.35-3.45 (m, 5H ), 2.71 (t, J=6.5 Hz, 2H), 2.14-2.33 (m, 4H), 1.69-1.81 (m, 1H), 1.21-1, 57 (m, 10H), 0.24-0.37 (m, 3H), -0.11-0.02 (m, 2H). LCMS: m/z 551 [M+H] ⁺ v.a. 7.8 min. MSVR (IER) calc. for C ₃₀ H ₄₀ ClN ₆ O ₂ [M+H] ⁺ 551.2896 Found 551.2897;

2-{[(^)-1-(4-{(^)-1-[4-(3-Hydroxypropanoyl)piperazin-1-yl]propyl}phenyl)ethyl]amino}-8(propan-2-yl )pyrido2,3^] pyrimidin-7(8H)-one [(I), X=N, R2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-CH(R14 )NR7R8, R6b=H, R7-R8=4-piperazin-1-yl, R11=2-hydroxyethyl, R3=R4=R5=H, R14=ethyl] Comp. 243

¹ H NMR (500 MHz, DMSO-de) 8.56 (s, 1H), 8.12-8.39 (m, 1H), 7.62 (d, J=9.15 Hz, 1H), 7 .28-7.38 (m, 2H), 7.08-7.17 (m, 2H), 6.15 (d, J=9.00 Hz, 1H), 5.39-5.77 (m , 1H), 4.92-5.32 (m, 1H), 3.88-4.01 (m, 2H), 3.173.30 (m, 5H), 2.09-2.32 (m, 6H ), 1.59-1.90 (m, 3H), 1.48 (d, J=6.86 Hz, 3H), 1.03-1.14 (m, 6H), 0.62-0, 75 (m, 3H). LCMS: m/z 507 [M+H] ⁺ v.a. 7.43 min. MSVR (IER) calc. for C ₂₈ H ₃₉ N ₆ O ₃ [M+H] ⁺ 507.3078 found 507.3083;

Example 16.

tert-Butyl 4-(4-{^)-1-[8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin-2-ylamino]ethyl}phenoxy )piperidine-1-carboxylic acid [(I), X=N, R2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=-O-R7, R6b=H, R7=tert -butyl ester of 4-piperidine-1-carboxylic acid, R3=R4=R5=H] transformation 13, comp. 154

8-(2,2-dimetide11po11ide)-2-[H]-1-(4-hydroxy-(])enide)ethidamino]-811-11irido[2,3-с1]11irimidin-7-one (20.0 mg, 0.057 mmol) dissolved in DMF (2.0 ml), cesium carbonate (37.0 mg, 0.113 mmol) and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (19.0 mg, 0.068 mmol) were added. and stir

- 103 046117 heat for 5 hours at 100°C. The cesium carbonate is filtered off and the solution is diluted with AcOEt and washed with water (3x10 ml) and then dried over Na2SO4. The crude product was purified by silica gel column chromatography (AcOEt) to give the title product (11.5 mg, 38% yield). ¹ H NMR (500 MHz, DMSO-06) δ=8.56 (s, 1H), 8.31 (d, J=7.5 Hz, 1H), 7.67 (d, J=9.3 Hz , 1H), 7.28 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 6.22 (d, J=9.3 Hz, 1H ), 5.04 (quin, J=7.1 Hz, 1H), 4.48 (tt, J=7.8, 3.7 Hz, 1H), 3.93-4.31 (m, 2H) , 3.53-3.69 (m, 2H), 3.15 (shs, 2H), 1.78-1.91 (m, 2H), 1.43-1.53 (m, 2H), 1 .43 (d, J=6.9 Hz, 3H), 1.39 (s, 9H), 0.79 (shs, 9H). LCMS: m/z 536 [M+H]+ @ w.u. 7.78 min. MSVR (IER) calc. milking C ₃₀ H ₄₂ N ₅ O ₄ [M+H] ⁺ 536.3232 found 536.3243.

Example 17.

8-A)-1,2-Dimethylpropyl)-2-{^)-1-[4-(piperidin-4-yloxy)phenyl]ethylamino}-8H-pyrido[2,3d]pyrimidin-7-one [( I), X=N, P2=^)-1,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=-O-R7, R6b=H, R7-R8=4-piperazine-1 -il, , R3=R4=R5=H] transformation 14, conn. 155

To a stirred solution of 4-(4-A)-1-[8-(^)-1,2-dimethylpropyl)-7-oxo-7,8dihydropyrido[2,3Upyrimidin-2-ylamino]ethyl}phenoxy benzyl ester )piperidine-1-carboxylic acid (40.0 mg, 0.070 mmol) in absolute ethanol (1.0 ml) is added, under nitrogen, 10% Pd/C (1:1 catalyst/substrate by weight), then cyclohexadiene ( 0.066 ml, 0.702 mmol). The suspension is stirred at 60°C for 1 hour. The catalyst was removed by filtration through a pad of cellite and the filtrate was evaporated to dryness in vacuo to give the title product (22.2 mg, 73% yield).

¹ H NMR (500 MHz, DMSOO δ=8.55 (d, J=14.9 Hz, 1H), 8.27 (d, J=6.9 Hz, 1H), 7.64 (d, J= 9.2 Hz, 1H), 7.12-7.33 (m, 2H), 6.86 (d, J=8.2 Hz, 2H), 6.21 (d, J=9.3 Hz, 1H), 4.18-5.34 (m, 3H), 2.03-3.01 (m, 4H), 1.131.95 (m, 7H), 0.09-1.12 (m, 9H) LCMS: m/z 436 [M+H] ⁺ @ v.u. 5.17 min

MSVR (IER) calc. for C ₂₅ H ₃₄₃ N ₅ O ₂ [M+H] ⁺ 436.2707 found 436.2719.

Example 18.

2-A)-1-[4-(1-Acryloylpiperidin-4-yloxy)phenyl]ethylamino}-8-(2,2-dimethylpropyl)-8Hpyrido[2,3Upyrimidin-7-one [(I), X= N, P2=2,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=O-R7, R6b=H, R7-= 4-piperidin-4-yl, R11=vinyl, R3=R4 =R5=H] transformation 15, conn. 156

To a solution of 8-(^)-1,2-dimethylpropyl)-2-A)-1-[4-(piperidin-4-yloxy)phenyl]ethylamino}-8H-pyrido[2,3Upyrimidin-7-one hydrochloride ( 50.0 mg, 0.11 mmol) and DIPEA (0.04 ml, 0.22 mmol) in CH2O2 (1.0 ml) add acryloyl chloride (8 μl, 0.12 mmol) at 0°C. After 30 minutes, the reaction is quenched with water. The mixture is extracted with DCM, dried over Na ₂ SO ₄ , filtered and concentrated to give a yellow oil. The crude product was purified by silica gel chromatography (1-10% MeOH/DCM) to show the title product as a white foam (32 mg, 60% yield).

1H NMR (500 MHz, DMSO-06) δ=8.56 (s, 1H), 8.32 (d, J=7.6 Hz, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.29 (d, J=8.5 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.81 (dd, J=16.7, 10.4 Hz, 1H), 6.22 (d, J=9.3 Hz, 1H), 6.08 (dd, J=16.6, 2.4 Hz, 1H), 5.66 (dd, J=10 ,4, 2.3 Hz, 1H), 5.04 (quin, J=7.1 Hz, 1H), 4.56 (tt, J=7.6, 3.8 Hz, 1H), 4.02 -4.20 (m, 2H), 3.76-3.90 (m, 2H), 3.28-3.37 (m, 2H), 1.90 (shs, 2H), 1.53 (shs , 2H), 1.44 (d, J=7.0 Hz, 3H), 0.79 (shs, 9H).

LCMS: m/z 490 [M+H] ⁺ @ w.u. 6.31 min. MSVR (IER) calc. for C ₂₈ H ₃₆ N ₅ O ₃ [M+H] ⁺ 490.2813 found 490.2813.

According to the same method, the following compounds are obtained:

2-A)-1-[4-(1-Acryloylpiperidin-4-yloxy)phenyl]ethylamino}-8-(^)-1,2-dimethylpropyl)-8Hpyrido[2,3Upyrimidin-7-one [(I) , X=N, R2=-(S)-1,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=OR7, R6b=H, R7-=4-piperidin-4-yl, R11 =vinyl, R3=R4=R5=H] conn. 159

¹ H NMR (500 MHz, DMSO-de) δ=8.50-8.60 (m, 1H), 7.64 (d, J=9.3 Hz, 1H), 7.15-7.30 ( m, 2H), 6.91 (d, J=8.5 Hz, 2H), 6.81 (dd, J=16.7, 10.4 Hz, 1H), 6.10-6.22 (m , 1H), 6.08 (dd, J=16.8, 2.4 Hz, 1H), 5.66 (dd, J=10.4, 2.4 Hz, 1H), 4.77-5, 20 (m, 2H), 4.56 (tt, J=7.3, 3.6 Hz, 1H), 3.35-3.80 (m, 4H), 1.02-2.11 (m, 8H), 0.100.89 (m, 9H). LCMS: m/z 490 [M+H] ⁺ @ w.u. 6.20 min. MSVR (IER) calc. for C ₂₈ H ₃₆ M ₅ O ₃ [M+H] ⁺ 490.2813 found 490.2813;

8-((S)-1,2-Dimethylpropyl)-2-{^)-1-[4-(1-isobutyrylpiperidin-4-yloxy)phenyl]ethylamino}-8Hpyrido[2,3Upyrimidin-7-one [( I), X=N, R2=-(S)-1,2-dimethylpropyl, A=phenyl, R1a=H, R1b=Me, R6a=OR7, R6b=H, R7-=4-piperidin-4-yl , R11=and-propyl, R3=R4=R5=H] conn. 160

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1H NMR (500 MHz, DMSO^) δ=8.54-8.57 (m, 1H), 7.64 (d, J=9.3 Hz, 1H), 7.19-7.26 (m, 2H), 6.90 (d,

J=8.4 Hz, 2H), 6.11-6.22 (m, 1H), 4.82-5.31 (m, 2H), 4.44-4.63 (m, 1H), 3 ,19-3.72 (m, 4H), 2.87 (dt, J=13.4, 6.7

Hz, 1H), 1.11-2.12 (m, 5H), 0.13-1.07 (m, 12H). LCMS: m/z 506 [M+H]+ @ w.u. 6.60 min

MSVR (IER) calc. for C ₂₉ H ₄₀ N ₅ O ₃ [M+H] ⁺ 506.3126 Found 506.3130.

2-{[(1S)-1-(4-{[(3R)-1-Acryloylpyrrolidin-3-yl]oxy}phenyl)ethyl]amino}-8-ethylpyrido[2,3-d]pyrimidin-7( 8H)-one [(I), X=N, K2=ethyl, A=phenyl, R1a=H, R1b=Me, R6a=O-R7, R6b=H, R7-=pyrrolidin3-yl, R11=vinyl, R3=R4=R5=H] conn. 223

Chiral =

1H NMR (500 MHz, DMSO^) δ 8.57 (s, 1H), 8.14-8.44 (m, 1H), 7.67 (d, J=9.15 Hz, 1H), 7, 32 (d, J=7.78 Hz, 2H), 6.88 (dd, J=3.36, 8.69 Hz, 2H), 6.46-6.68 (m, 1H), 6.21 (d, J=9.15 Hz, 1H), 6.07-6.15 (m, 1H), 5.585.71 (m, 1H), 4.88-5.27 (m, 2H), 4, 03-4.30 (m, 2H), 3.37-3.89 (m, 4H), 1.98-2.22 (m, 2H), 1.45 (d, J=7.02 Hz, 3H), 0.94-1.19 (m, 3H). LCMS: m/z 434 [M+H] ⁺ @ w.u. 5.13 min. MSVR (IER) calc. for C ₂₄ H ₂₇ N ₅ O ₃ [M+H] ⁺ 434.2187 found 434.2191.

2-{[(1S)-1-(4-{[(3R)-1-Acryloylpyrrolidin-3-yl]oxy}phenyl)ethyl]amino}-8-ethylpyrido[2,3-d]pyrimidin-7( 8H)-one [(I), X=N, K2=ethyl, A=phenyl, R1a=H, R1b=Me, R6a=O-R7, R6b=H, R7-=pyrrolidine

3-yl, R11=vinyl, R3=R4=R5=H] conn. 224

1H NMR (500 MHz, DMSO-06) δ 8.56 (s, 1H), 8.38 (d, J=7.17 Hz, 1H), 7.67 (d, J=9.30 Hz, 1H ), 7.32 (dd, J=1.98, 8.69 Hz, 2H), 6.80-6.93 (m, 2H), 6.47-6.66 (m, 1H), 6, 19-6.25 (m, 1H), 6.07-6.17 (m, 1H), 5.59-5.71 (m, 1H), 4.89-5.28 (m, 2H), 4.03-4.33 (m, 2H), 3.45-3.90 (m, 4H), 2.00-2.25 (m, 2H), 1.45 (d, J=7.02 Hz, 3H), 0.871.08 (m, 3H). LCMS: m/z 434 [M+H] ⁺ @ w.u. 5.12 min. MSVR (IER) calc. giving C ₂₄ H ₂₇ N ₅ O ₃ [M+H] ⁺ 434.2187 found 434.2191.

Example 19.

2-{[(^)-1-{4-[(^)-1-(Piperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3

d]pyrimidin-7(8H)-one [(I), X=N, K2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-CHR14NR7R8,

R6b=H, R7-R8=4-piperazin-1-yl, R14=ethyl, R3=R4=R5=H] transformation 6,

To a solution of phenyl 4-[(^)-1-{4-[(^)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3d]pyrimidin- 2-yl]amino}ethyl]phenyl}propyl]piperazine-1-carboxylate (compound 225) (155.0 mg, 0.279 mmol) in a mixture of n-propanol (4.0 ml) add NaOH (1.0 ml, 12.5 mmol). The mixture is stirred for 8 hours at 80 and then concentrated to dryness. The crude product was dissolved in DCM and water, the organic phase was separated and washed with saturated sodium chloride solution, dried (Na ₂ SO ₄ ) and volatiles removed in vacuo to give the title compound as a light yellow oil to give (140.0 mg , quantitative).

LCMS (HPLC Method 1): m/z 435 [M+H] ⁺ @ w.a. 4.12 min. MSVR (IER) calc. giving C ₂₅ H ₃₅ N ₆ O [M+H] ⁺ 435. 5770 found 435.5765.

The following compound is prepared essentially by the method of Example 19.

2-{[(^)-1-{4-[(^)-1-(Piperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3d ]pyrimidin-7(8H)-one [(I), X=N, K2=propan-2-yl, A=phenyl, R1a=H, R1b=Me, R6a=4-CHR14NR7R8, R6b=H, R7- R8=4-piperazin-1-yl, R14=ethyl, R3=R4=R5=H] transformation 6,

LCMS (HPLC Method 1): m/z 435 [M+H] ⁺ @ w.a. 4.12 min. MSVR (IER) calc. giving C ₂₅ H ₃₅ N ₆ O [M+H] ⁺ 435. 5770 found 435.5771.

Example 20

2-{[(^)-1-{4-[(4-Acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-(4-ethynyl-2-fluorobenzyl)pyrido[2,3^] pyrimidin-7(8H)-one [(I), X=N, R2=4-ethynyl-2-fluorobenzyl, A=phenyl, R1a=H, R1b=Me, R6a=O-R7, R6b=H, R6a =4-(4-acryloylpiperazin-1-yl)methyl, R6b=H, R3=R4=R5=H] transformation 16,

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Conn. 217.

Stage 1 transformation 16:

Nitrogen is bubbled through a solution of tert-butyl 4-{4-[(^)-1-{[8-(4-bromo-2-fluorobenzyl)-7-oxo-7,8dihydropyrido[2,3^]pyrimidin-2- yl]amino}ethyl]benzyl}piperazine-1-carboxylate (130 mg, 0.2 mmol) and TEA (195 µl, 1.4 mmol) in DMF (2.8 ml) for 30 min. Bis(triphenylphosphine)palladium(II) dichloride (28 mg, 0.04 mmol, 20% mol) and CuI (8 mg, 0.04 mmol, 20% mol) were added and degassing was continued for a further 5 min. Add trimethylsilylacetylene (166 μL, 1.2 mmol) while degassing for an additional 10 seconds. The reaction mixture is heated to 70°C for 2.5 hours and then the heat is removed. The mixture is diluted with water and extracted with EtOAc and washed with saturated sodium chloride solution, dried (Na ₂ SO ₄ ), filtered, and concentrated to give the crude product, then purified by RP-HPLC, eluting with a 7/3-0/10 H2O/ACH gradient to give 93 mg tert-butyl 4-(4-{(^)-1-[(8-{2-fluoro-4-[(trimethylsilyl)ethynyl]benzyl}-7-oxo-7,8dihydropyrido[2,3L]pyrimidin- 2-yl)amino]ethyl } benzyl)piperazine-1-carboxylate.

¹ H NMR (500 MHz, DMSO-dg) δ 8.63 (s, 1H), 8.46 (d, J=7.78 Hz, 1H), 7.80 (d, J=9.46 Hz, 1H), 7.36 (d, J=10.68 Hz, 1H), 7.06 (d, J=7.93 Hz, 2H), 6.99 (dd, J=0.76, 8.39 Hz, 1H), 6.97 (d, J=7.93 Hz, 2H), 6.54 (t, J=7.93 Hz, 1H), 6.30 (d, J=9.30 Hz, 1H), 5.51 (d, J=15.56 Hz, 1H), 5.25 (d, J=15.56 Hz, 1H), 4.88 (quin, J=7.21 Hz, 1H) , 3.30 (shs, 2H), 3.28 (shs, 4H), 2.18-2.33 (m, 4H), 1.37 (s, 12H), 0.23 (s, 9H). LCMS: m/z 669 [M+H]+ @ w.u. 8.71 min MSVR (IER) calc. for C ₃₇ H ₄₆ FN ₆ O ₃ Si [M+H] ⁺ 669.3379 found 669.3397.

Step 2. tert-Butyl 4-(4-{(^)-1-[(8-{2-fluoro-4-[(trimethylsilyl)ethynyl]benzyl}-7-oxo-7,8dihydropyrido[2,3^ ]pyrimidin-2-yl)amino]ethyl}benzyl)piperazine-1-carboxylate (88 mg, 0.131 mmol) and K2CO3 (18 mg, 0.131 mmol) and MeOH (3 ml) were placed in a flask and stirred at room temperature for 45 min. The mixture is diluted with EtOAc and water. The organic phases are separated and washed with saturated sodium chloride solution and dried (Na ₂ SO ₄ ). The solvent is removed in vacuo to give the desired compound tert-butyl 4-{4-[(^)-1-{[8-(4-ethynyl-2-fluorobenzyl)-7-oxo-7,8-dihydropyrido[2,3 ^]pyrimidin-2-yl]amino}ethyl]benzyl}piperazine-1-carboxylate as a light yellow oil (74 mg, B=95%). 1H NMR (500 MHz, DMSO-dg) δ 8.63 (s, 1H), 8.45 (d, J=7.93 Hz, 1H), 7.80 (d, J=9.46 Hz, 1H ), 7.38 (d, J=10.83 Hz, 1H), 7.07-7.12 (m, 2H), 7.04 (d, J=7.78 Hz, 1H), 6.97 -7.03 (m, 2H), 6.61 (t, J=7.93 Hz, 1H), 6.30 (d, J=9.30 Hz, 1H), 5.48 (d, J= 15.71 Hz, 1H), 5.26 (d, J=15.71 Hz, 1H), 4.90 (quin, J=7.13 Hz, 1H), 4.29 (s, 1H), 3 .28 (shs, 4H), 2.24 (shs, 4H), 1.37 (s, 9H). LCMS: m/z 597 [M+H] ⁺ @ w.u. 7.30 min. MSVR (IER) calc. for C34H38FN6O3 [M+H] ⁺ 597.2984 found 597.3001.

Step 3 conversion 6: tert-butyl 4-{4-[(^)-1-{[8-(4-ethynyl-2-fluorobenzyl)-7-oxo-7,8dihydropyrido[2,3^]pyrimidine-2 -yl]amino}ethyl]benzyl}piperazine-1-carboxylate is dissolved in DCM (5 ml) in a flask and HCl 4M in dioxane (2 ml) is added. The solution is stirred at room temperature for 1 hour. The volatiles are removed in vacuo and the residue is dissolved in DCM and diluted with saturated NaHCO ₃ solution to pH 9. The organic phase is extracted, washed with saturated sodium chloride solution, dried (Na ₂ SO ₄ ) and evaporated in a vacuum. The residue contains the compound 8-(4ethynyl-2-fluorobenzyl)-2-( {(1S)-1 -[4-(piperazin-1 -ylmethyl)phenyl]ethyl } amino)pyrido[2,3^]pyrimidine7(8H) -it is in the form of a light yellow oil (60 mg, B=98%).

Step 4, transformation 7: To a solution of 8-(4-ethynyl-2-fluorobenzyl)-2-({(^)-1-[4-(piperazin-1ylmethyl)phenyl]ethyl}amino)pyrido-[2,3^ ]pyrimidin-7(8H)-one (60.0 mg, 0.12 mmol) in CH ₂ Cl ₂ (1.0 ml) add acryloyl chloride (10 μl, 0.12 mmol) at 0°C. After 30 minutes, the reaction is quenched with water. The mixture is partitioned with DCM and saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered and concentrated to give a yellow oil. The crude product was purified by silica gel chromatography (1-10% MeOH/DCM) to give the title product as an off-white foam (40 mg, 60% yield).

1H NMR (500 MHz, DMSO-dg) δ=8.63 (s, 1H), 8.45 (d, J=7.93 Hz, 1H), 7.80 (d, J=9.46 Hz, 1H), 7.39 (d, J=10.68 Hz, 1H), 7.07-7.15 (m, 2H), 6.99-7.07 (m, 3H), 6.76 (dd , J=10.45, 16.70 Hz, 1H), 6.61 (t, J=7.93 Hz, 1H), 6.30 (d, J=9.30 Hz, 1H), 6.08 (dd, J=2.36, 16.70 Hz, 1H), 5.66 (dd, J=2.40, 10.50 Hz, 1H), 5.49 (d, J=15.56 Hz, 1H), 5.26 (d, J=15.71 Hz, 1H), 4.90 (quin, J=7.02 Hz, 1H), 4.30 (s, 1H), 3.51 (d, J=4.12 Hz, 4H), 3.38 (shs, 2H), 2.29 (shs, 4H), 1.37 (d, J=7.02 Hz, 3H). LCMS: m/z 551 [M+H] ⁺ @ w.u. 5.94 min. MSVR (IER) calc. for C ₃₂ H ₃₂ FN ₆ O ₂ [M+H] ⁺ 551.2526 Found 551.258.

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Example 21.

2-[(1-{4-[1 -(4-Acryloylpiperazin-1 -yl)-2-cyclopropylethyl]phenyl} cyclopropyl)amino]-8-(propan-2-yl)pyrido[2,3^]pyrimidine -7(8H)-one [(I), X=N, K2=propan-2-yl, A=phenyl, R1aH1b=cyclopropyl, R6a=4-CH(R14)NR7R8, R6b=H, R7-R8= 4-piperazin-1-yl, R11=buh^, R3=R4=R5=H, R14=cyclopropylmethyl] comp. 244

Stage a (stage 1a). tert-Butyl 4-{1-[4-(1-aminocyclopropyl)phenyl]-2-cyclopropylethyl}piperazine-1-carboxylate (355 mg, 0.921 mmol, 1.1 eq.) was dissolved in DMSO (11 ml). To this solution, 2-(methylsulfonyl)-8-(propan-2-yl)pyrido[2,3d]pyrimidin-7(8H)-one (223.7 mg, 0.837 mmol), CsF (140 mg, 0.920 mmol) and DIPEA (0.175 ml, 0.1 mmol). The reaction mixture is then heated at 75°C for 4 hours and then warmed to room temperature. The reaction mixture is slowly poured over cold water/saturated sodium chloride solution. The precipitated solids are filtered, washed with water, and dried in vacuo. The resulting dried solid tert-butyl 4-{2-cyclopropyl-1-[4-(1-{[7-oxo-8-(propan-2yl)-7,8-dihydropyrido[2,3^]pyrimidin-2 -yl]amino}cyclopropyl)phenyl]ethyl}piperazine-1-carboxylate (105 mg, 22%) was taken without further purification.

1H NMR (500 MHz, DMSO-de) δ=8.58-8.63 (m, 2H), 7.65 (d, J=9.30 Hz, 1H), 7.00-7.14 (m , 4H), 6.20 (d, J=9.15 Hz, 1H), 5.33 (shs, 1H), 3.38-3.42 (m, 1H), 3.21 (shs, 4H) , 2.04-2.27 (m, 4H), 1.73-1.84 (m, 1H), 0.210.43 (m, 4H), -0.14-0.06 (m, 2H).

Stage b transformation 6.

To a solution of tert-butyl 4-{2-cyclopropyl-1-[4-(1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3d]pyrimidin-2- yl]amino}cyclopropyl)phenyl]ethyl}piperazine-1-carboxylate (100 mg, 0.174 mmol) in a mixture of dioxane (4.0 ml) and MeOH (1.0 ml) add HCl (4M in dioxane, 1 ml). The mixture is stirred for 5 hours at room temperature. The volatiles are removed in vacuo and the residue is dissolved in DCM and diluted with saturated NaHCO ₃ solution to pH 9. The organic phase is extracted and washed with saturated sodium chloride solution, dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue contains the compound 2-[(1-{4-[2-cyclopropyl-1-(piperazin-1-yl)ethyl]phenyl}cyclopropyl)amino]-8(propan-2-yl)pyrido[2,3^] pyrimidin-7(8H)-one as a yellow viscous oil (95 mg, quantitative). LCMS (HPLC Method 1): m/z 435 [M+H]+ @ w.a. 5.17 min.

Stage with transformation 7.

To a solution of 2-[(1-{4-[2-cyclopropyl-1-(piperazin-1-yl)ethyl]phenyl}cyclopropyl)amino]-8-(propan-2-yl)pyrido[2,3^] Pyrimidin-7(8H)-one (95 mg, 0.174 mmol) in DCM (3.5 ml) was added with acryloyl chloride (0.014 ml, 0.174 mmol, 1 eq.) at 0°C. After 10 minutes the reaction is quenched with sat. aqueous NaHCO3 and extracted with DCM, dried over Na ₂ SO ₄ , filtered, and concentrated to give a yellow oil.

The crude product was purified by silica gel chromatography (1-5% EtOH/DCM) to give the title product as a white foam (56 mg, 61% yield).

1H NMR (500 MHz, DMSO-de) δ=8.57-8.64 (m, 2H), 7.65 (d, J=9.30 Hz, 1H), 7.00-7.15 (m , 4H), 6.68 (dd, J=10.45, 16.70 Hz, 1H), 6.20 (d, J=9.15 Hz, 1H), 6.02 (dd, J=2, 29, 16.62 Hz, 1H), 5.59 (dd, J=2.36, 10.45 Hz, 1H), 5.13-5.39 (m, 1H), 3.37-3.54 (m, 5H), 2.20 (shs, 4H), 1.80 (shs, 1H), 1.43-1.69 (m, 1H), 0.95-1.35 (shs, 10 N) , 0.13-0.42 (m, 3H), -0.03 (dd, J=4.96, 15.33 Hz, 2H)

LCMS: m/z 527 [M+H] ⁺ @ w.u. 7.54 min. MSVR (IER) calc. for C ₃₁ H ₃₉ N ₆ O ₂ [M+H] ⁺ 527.3129 found 527.3135.

The following compounds are prepared essentially by the method of Example 21.

2-[(1-{4-[1-(4-.cryloylpiperazin-1-yl)propyl]phenyl}cyclopropyl)amino]-8-(propan-2-yl)pyrido[2,3^]pyrimidin-7 (8H)-one [(I), X=N, K2=propan-2-yl, A=phenyl, R1a-R1b=cyclopropyl, R6a=4CH(R14)NR7R8, R6b=H, R7-R8=4- piperazin-1-yl, R11 vinyl, R3=R4=R5=H, R14=ethyl] comp. 247

LCMS: m/z 501 [M+H] ⁺ @ w.u. 7.23 min. MSVR (IER) calc. for C ₂ 9H ₃₇ N6O ₂ [M+H] ⁺ 501.6351 found 501.6355.

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Example 22.

2-[(1-{4-[(1R)-1 -(4-Acryloylpiperazin-1 -yl)-2-cyclopropylethyl]phenyl } cyclopropyl)amino]-8(propan-2-yl)pyrido[2,3 ^]pyrimidin-7(8H)-one [(I),

R2=propan-2-yl, A=phenyl, R1 aR1b cyclopronyl, R6a=4-CH(R14)NR7R8, R6b=H, R7-R8=4-piperazin-1-yl, R11 vinyl, R3=R4= R5=H, R14 cyclopronylmethyl] comp. 245 isomer 1

and 2-[(1-{4-[(^)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl]phenyl}cyclopropyl)amino]-8(propan-2-yl)pyrido[2, 3^]pyrimidin-7(8H)-one [(I),

R2=propan-2-yl, A=phenyl, R1 aR1b=cyclopropyl, R6a=4-CH(R14)NR7R8, R6b=H, R7-R8 4-11 and 11erazin-1-yl, R11 vinyl, R3=R4=R5 =H, R14 cyclopronylmethyl] conn. 246 isomer 2

2-[(1-{4-[1-(4-Acryloylpiperazin-1-yl)-2-cyclopropylethyl]phenyl}cyclopropyl)amino]-8(propan-2-yl)pyrido[2,3^]pyrimidin- 7(8H)-one (30 mg, 0.057 mmol) was dissolved in MeOH (1 ml) and separated by chiral HPLC using the following conditions: Chiralpak AD-H 5x50 cm column; eluent Hexane/and-prOH 60/40 flow rate 50 ml/min; detection wavelength 334 nM; column temperature 25°C. Isomer 1 was isolated as the first peak to elute (7 mg, 0.013 mmol).

1H NMR (DMSO) δ: 8.60 (s, 1H), 8.59 (s, 1H), 7.65 (d, J=9.30 Hz, 1H), 7.02-7.16 (m , 4H), 6.68 (dd, J=10.45, 16.70 Hz, 1H), 6.20 (d, J=9.00 Hz, 1H), 6.02 (dd, J=2, 29, 16.62 Hz, 1H), 5.59 (dd, J=2.29, 10.52 Hz, 1H), 5.18-5.42 (m, 1H), 3.37-3.53 (m, 5H), 2.20 (shs, 4H), 1.80 (shs, 1H), 1.40-1.61 (m, 1H), 1.20-1.36 (m, 6H), 0.97-1.15 (m, 4H), 0.34 (d, J=4.73 Hz, 1H), 0.17-0.29 (m, 2H), -0.11-0.05 (m, 2H). LCMS: m/z 527 [M+H] ⁺ @ w.u. 7.54 min. MSVR (IER) calc. for C ₃ iH ₃₉ N ₆ O ₂ [M+H] ⁺ 527.3129 found 527.3133.

Isomer 2 was isolated as the second eluting peak (8 mg, 1.52 mmol).

Ή NMR (DMSOU) δ: 8.61 (s, 1H), 8.59 (s, 1H), 7.65 (d, J=9.30 Hz, 1H), 7.00-7.16 (m , 4H), 6.68 (dd, J=10.45, 16.70 Hz, 1H), 6.20 (d, J=9.30 Hz, 1H), 6.02 (dd, J=2, 29, 16.62 Hz, 1H), 5.59 (dd, J=2.21, 10.45 Hz, 1H), 5.20-5.36 (m, 1H), 3.38-3.52 (m, 5H), 2.20 (shs, 4H), 1.74-1.85 (m, 1H), 1.48-1.57 (m, 1H), 1.20-1.36 (m , 6H), 0.97-1.15 (m, 4H), 0.31-0.40 (m, 1H), 0.17-0.28 (m, 3H), -0.16-0, 03 (m, 2N). LCMS: m/z 527 [M+H] ⁺ @ w.u. 7.54 min. MSVR (IER) calc. for C _3i H ₃₉ N ₆ O ₂ [M+H] ⁺ 527.3129 found 527.3129.

The following compounds are prepared essentially by the method of Example 22.

Isomer 1 is isolated as the first peak to elute.

2-[(1-{4-[(^)-1-(4-acryloylpiperazin-1-yl)propyl]phenyl}cyclopropyl)amino]-8-(propan-2yl)pyrido[2,3Upyrimidin-7(8H )-one [(I), X=N, I2=propan-2-yl, A=phenyl, R1a-R1b=cyclopropyl, R6a=4-CH(R14)NR7R8, R6b=H, R7-R8=4- piperazin-1-yl, R11=vinyl, R3=R4=R5=H, R14=ethyl] comp. 248

LCMS: m/z 501 [M+H] ⁺ @ w.u. 7.23 min. MSVR (IER) calc. for C ₂₉ H ₃₇ N ₆ O ₂ [M+H] ⁺ 501.6351, 501.6353 was found.

Isomer 2 is isolated as the second eluting peak

2-[(1-{4-[(^)-1-(4-acryloylpiperazin-1-yl)propyl]phenyl}cyclopropyl)amino]-8-(propan-2yl)pyrido[2,3Upyrimidin-7(8H )-one [(I), X=N, I2=propan-2-yl, A=phenyl, R1a-R1b=cyclopropyl, R6a=4-CH(R14)NR7R8, R6b=H, R7-R8=4- piperazin-1-yl, R11=vinyl, R3=R4=R5=H, R14=ethyl] comp. 249 Chiral

LCMS: m/z 501 [M+H]+ @ w.u. 7.23 min. MSVR (IER) calc. for C ₂₉ H ₃₇ N ₆ O ₂ [M+H] ⁺ 501.6351, 501.6354 was found.

Example 21.

4-{4-[^)-1-(1-ethyl-2-oxo-1,2-dihydro[1,6]naphthyridin-7-ylamino)ethyl]benzyl}piperazine-1-carboxylic acid tert-butyl ester [(I), X=N, I2=ethyl, X=CH, A=phenyl, R1a=H, R1b=Me, R6a=4CH2NR7R8, R6b=H, R7-R8=tert-butyl ether 4-piperazine-1 -carboxylic acid, R3=R4=R5=H] Stage 1a, conn. 232

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To a solution of 4-[4-(^)-1-aminoethyl)benzyl]piperazine-1-carboxylic acid tert-butyl ester (0.30 g, 0.94 mmol), 7-chloro-1-ethyl-1H-[ 1,6]naphthyridin-2-one (0.25 g, 1.17 mmol) and cesium carbonate (0.76 g, 2.35 mmol) in toluene (10 ml) under nitrogen add dichloro[1,3-bis (2,6-di-3-pentylphenyl)imidazol2-ylidene](3-chloropyridyl)palladium(11) (0.08 g, 0.12 mmol) and the mixture was heated at 100°C overnight. After cooling to room temperature, the mixture is filtered through a pad of silica gel and eluted with ethyl acetate. The filtrate is concentrated under reduced pressure and the residue is purified by chromatography on silica gel (0-20%) acetone/EtOAc.

1H NMR (DMSO) δ: 8.30 (s, 1H), 7.66 (d, J=9.3 Hz, 1H), 7.49 (d, J=7.5 Hz, OH), 7, 35 (d, J=8.1 Hz, 2H), 7.22 (d, J=8.1 Hz, 2H), 6.18 (shs, 1H), 6.15 (d, J=9.3 Hz, 1H), 5.00 (shs, 1H), 4.08 (dkv, J=13.9, 6.9 Hz, 1H), 3.85-3.96 (m, 1H), 3.41 (s, 2H), 3.27 (shs, 4H), 2.25 (t, J=4.8 Hz, 4H), 1.45 (d, J=6.9 Hz, 3H), 1.37 (s, 9H), 1.00 (shs, 3H). LCMS: m/z 492 [M+H] ⁺ @ w.u. 6.16 min. MSVR (IER) calc. for C ₂₈ H ₃₈ N ₅ O ₃ [M+H] ⁺ 492.2969 found 492.2974 tert-Butyl ether 4-( 1-{ 4-[(S)-1-(1 -ethyl-2-oxo- 1,2-dihydro[1,6] naphthyridin-7-ylamino)ethyl]phenyl}propyl)piperazine-1-carboxylic acid [(I), X=N, C2=Ethyl, X=CH, A=phenyl, R1a =H, R1b=Me, R6a=4-CHR14NR7R8, R6b=H, R7-R8=4-piperazine-1-carboxylic acid tert-butyl ester, R14=ethyl, R3=R4=R5=H] comp. 233

1H NMR (DMSO-th) δ: 8.31 (s, 1H), 7.66 (d, J=9.3 Hz, 1H), 7.49 (dd, J=6.9, 3.1 Hz , 1H), 7.35 (d, J=8.1 Hz, 2H), 7.14 (d, J=8.1 Hz, 2H), 6.14 (d, J=9.5 Hz, 1H ), 4.96 (shs, 1H), 4.02-4.17 (m, J=13.4, 7.2 Hz, 1H), 3.85 (shs, 1H), 3.11-3, 30 (m, 5H), 2.19 (shs, 4H), 1.75-1.92 (m, 1H), 1.65 (tkv, J=14.6, 7.4 Hz, 1H), 1 .46 (d, J=6.9 Hz, 3H), 1.31 (d, J=3.7 Hz, 9H), 0.94 (shs, 3H), 0.68 (td, J=7, 2, 2.9 Hz, 3H). LCMS: m/z 520 [M+H] ⁺ @ w.u. 6.67 min

MSVR (IER) calc. for C ₃₀ H4 ₂ N ₅ O ₃ [M+H] ⁺ 520.3282 found 520.3284 According to the same method, the following compounds are obtained:

Phenyl ether 4-((S)-1 - { 4-[(S)-1-(1-ethyl-2-oxo-1,2-dihydro[1,6] naphthyridin-7-ylamino)ethyl]phenyl} propyl)piperazine-1-carboxylic acid [(I), X=N, R2=ethyl, X=CH, A=phenyl, R1a=H, R1b=Me, R6a=4-CHR14NR7R8, R6b=H, R7-R8 =4-piperazine-1-carboxylic acid phenyl ester, R14=Ethyl, R3=R4=R5=H] comp. 234

1H NMR (DMSO-de) δ: 8.32 (s, 1H), 7.67 (d, J=9.3 Hz, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.31-7.40 (m, 5H), 7.16-7.22 (m, 3H), 7.01-7.08 (m, 2H), 6.15 (d, J=9.3 Hz, 2H), 5.00 (shs, 1H), 4.12 (dd, J=13.5, 6.9 Hz, 1H), 3.86 (shs, 1H), 3.36-3.59 (m, 3H), 2.25-2.36 (m, 4H), 1.82-1.94 (m, 1H), 1.59-1.76 (m, 1H), 1.48 (d , J=6.9 Hz, 3H), 0.96 (shs, 3H), 0.67-0.73 (m, 3H).

7-{(8)-1-[4-(3,3-Difluoropiperidin-1-ylmethyl)phenyl]ethylamino}-1-(2,2-dimethylpropyl)-1H-[1,6]naphthyridin-2-one [(I), X=N, R2=ethyl, X=CH, A=phenyl, R1i=H, R1b=Me, R6a=4-CH ₂ NR7R8, R6b=H, R7R8=4-(3,3- difluoropiperidin-1-yl), R3=R4=R5=H] conn. 235

1H NMR (DMSO^) δ: 8.28 (s, 1H), 7.66 (d, J=9.5 Hz, 1H), 7.43 (d, J=7.0 Hz, 1H), 7 .34 (d, J=8.1 Hz, 2H), 7.22 (d, J=7.9 Hz, 2H), 6.24 (shs, 9H), 6.16 (d, J=9, 3 Hz, 1H), 4.92-5.00 (m, 1H), 3.50-3.80 (m, 4H), 2.362.58 (m, 4H), 1.77-1.91 (m , 2H), 1.58-1.66 (m, 2H), 1.44 (d, J=6.9 Hz, 3H), 0.78 (shs, 9H). LCMS: m/z 469 [M+H]+ @ w.u. 7.05 min. MSVR (IER) calc. for C ₂₇ H ₃₅ F ₂ N ₄ O [M+H] ⁺ 469.2774 found 469.2765

Example 22.

7-{ (S)- 1-[4-(4-Acryloylpiperazin-1 -ylmethyl)phenyl]ethylamino }-1 -ethyl-1H-[1,6]naphthyridin-2-one [(I), X=N , R2=Ethyl, X=CH, A=phenyl, R1a=H, R1b=Me, R6a=4-CHR14NR7R8, R6b=H, R7-R8=4piperazin-1-yl, R11=buhuh, R14=ethyl, R3 =R4=R5=H] transformation 7, conn. 236

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To a solution of 1-ethyl-7-({(^)-1-[4-(piperazin-1-ylmethyl)phenyl]ethyl}amino)-1,6-naphthyridin-2-one (47.0 mg, 0. 12 mmol) in CH2C12 (1.0 ml) add acryloyl chloride (10 µl, 0.12 mmol) at 0°C. After 30 minutes, the reaction is quenched with water. The mixture is partitioned with DCM and saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered, and concentrated to give a yellow oil. The crude product was purified by silica gel chromatography (1-10% MeOH/DCM) to give the title product as an off-white foam (38 mg, 71% yield).

¹ H NMR (DMSOA) δ: 8.30 (s, 1H), 7.66 (d, J=9.5 Hz, 1H), 7.49 (d, J=7.3 Hz, 1H), 7 .36 (d, J=7.9 Hz, 2H), 7.24 (d, J=7.9 Hz, 2H), 6.66-6.82 (m, 1H), 6.15 (d, J=9.3 Hz, 1H), 6.08 (dd, J=16.7, 2.4 Hz, 1H), 5.65 (dd, J=10.4, 2.4 Hz, 1H), 5.00 (shs, 1H), 4.09 (dkv, J=13.9, 7.0 Hz, 1H), 3.81-3.97 (m, 1H), 3.49 (d, J= 9.2 Hz, 4H), 3.43 (s, 2H), 2.30 (shs, 4H), 1.46 (d, J=6.9 Hz, 3H), 1.00 (shs, 2H) . LCMS: m/z 446 [M+H]+ @ w.u. 4.76 min. MSVR (IER) calc. for C ₂₆ H ₃₂ N ₅ O ₂ [M+H]+446.2551, 446.2555 was found.

According to the same method, the following compounds are obtained: 7-{[(1S)-1-{4-[(1S)-1-(4acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-1-(propan- 2-yl)-1,6-naphthyridin-2(1H)-one [(I), X=N, R2=propan-2-yl, X=CH, A=phenyl, R1a=H, R1b=Me, R6a=4-CHR14NR7R8, R6b=H, R7-R8=4piperazin-1-yl, R11=buhuh, R14=ethyl, R3=R4=R5=H], conn. 237

¹ H NMR (DMSO-06) δ: 8.31 (s, 1H), 7.66 (d, J=9.3 Hz, 1H), 7.46-7.51 (m, 1H), 7. 31-7.41 (m, 2H), 7.127.19 (m, 2H), 6.70 (ddd, J=16.7, 10.4, 1.9 Hz, 1H), 6.07-6, 22 (m, 2H), 6.02 (dt, J=16.7, 2.5 Hz, 1H), 5.56-5.64 (m, 1H), 4.99 (shs, 1H), 4 .04-4.12 (m, 1H), 3.78-3.93 (m, 1H), 3.41-3.55 (m, 4H), 3.21-3.30 (m, 1H) , 2.25 (shs, 4H), 1.58-1.89 (m, 2H), 1.46 (d, J=6.9 Hz, 3H), 0.82-1.06 (m, 3H ), 0.64-0.76 (m, 3H)

LCMS: m/z 474 [M+H] ⁺ @ w.u. 4.65 min. MSVR (IER) calc. for C ₂₈ H ₃₆ N ₅ O ₂ [M+H] ⁺ 474.2864 found 474.2864

7-((S)-1-{4-[(S)-1-(4-Acryloylpiperazin-1-yl)propyl]phenyl}-ethylamino)-1-ethyl-1H-[1,6]naphthyridin-2 -one [(I), X=N, R2=ethyl, X=CH, A=phenyl, R1a=H, R1b=Me, R6a=4-CHR14NR7R8, R6b=H, R7-R8=4piperazin-1-yl , R11=buhuh, R14=Ethyl, R3=R4=R5=H] transformation 7, conn. 238

1H NMR (DMSOA) δ: 8.31 (s, 1H), 7.66 (d, J=9.3 Hz, 1H), 7.44-7.51 (m, 1H), 7.35 (d , J=8.1 Hz, 2H), 7.16 (d, J=8.1 Hz, 2H), 6.70 (dd, J=16.7, 10.4 Hz, 1H), 6.15 (d, J=9.3 Hz, 2H), 6.02 (dd, J=16.6, 2.4 Hz, 1H), 5.60 (dd, J=10.4, 2.2 Hz, 1H), 4.99 (ws, 1H), 4.00-4.16 (m, 1H), 3.86 (ws, 1H), 3.45 (ws, 4H), 3.21-3.29 (m, 1H), 2.24 (shs, 4H), 1.77-1.93 (m, 1H), 1.59-1.73 (m, 1H), 1.46 (d, J=6 .9 Hz, 3H), 0.95 (shs, 3H), 0.64-0.73 (m, 3H)

LCMS: m/z 474 [M+H] ⁺ @ w.u. 4.27 min. MSVR (IER) calc. for C ₂₈ H ₃₆ N ₅ O ₂ [M+H] ⁺ 474.2864 found 474.2861

7-{[(^)-1-{4-[(^)-1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-1-(propan-2-yl)-1, 6naphthyridin-2(1H)-one [(I), X=N, R2=propan-2-yl, X=CH, A=phenyl, R1a=H, R1b=Me, R6a=4CHR14NR7R8, R6b=H, R7 -R8=4-piperazin-1-yl, R11=vinyl, R14=ethyl, R3=R4=R5=H] transformation 7, conn. 239

1H NMR (DMSOA) δ: 8.29 (s, 1H), 7.61 (d, J=9.30 Hz, 1H), 7.43 (d, J=7.02 Hz, 1H), 7. 34 (d, J=8.08 Hz, 2H), 7.17 (d, J=8.08 Hz, 2H), 6.70 (dd, J=10.52, 16.62 Hz, 1H), 6.31 (ws, 1H), 6.10 (d, J=9.15 Hz, 1H), 6.03 (dd, J=2.44, 16.62 Hz, 1H), 5.58-5 .63 (m, 1H), 5.20 (shs, 1H), 4.94 (shs, 1H), 3.41-3.56 (m, 4H), 3.20-3.30 (m, 1H ), 2.25 (d, J=4.27 Hz, 4H), 1.78-1.93 (m, 1H), 1.58-1.73 (m, 1H), 1.09-1, 52 (m, 9H), 0.69 (t, J=7.32 Hz, Zn). LCMS: m/z 488 [M+H] ⁺ @ w.u. 4.27 min. MSVR (IER) calc. for C ₂₈ H ₃₈ N ₅ O ₂ [M+H] ⁺ 488.3020 found 488.3015

7-{[(^)-1-{4-[(^)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl]phenyl}ethyl]amino}-1-(propan-2-yl) -1,6-naphthyridin-2(1H)-one [(I), X=N, R2=propan-2-yl, X=CH, A=phenyl, R1a=H, R1b=Me, R6a=4- CHR14NR7R8, R6b=H, R7-R8=4-piperazin-1-yl, R11=vinyl, R14=cyclopropylmethyl,

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R3=R4=R5=H] transformation 7, conn. 251

Chiral

ABOUT

1H NMR (DMSO-0b) δ: 8.57 (s, 1H), 8.34 (d, J=6.86 Hz, 1H), 7.62 (d, J=9.30 Hz, 1H), 7.28-7.39 (m, 2H), 7.17 (d, J=7.90 Hz, 2H), 6.68 (dd, J=10.50, 16.70 Hz, 1H), 6 .15 (d, J=9.30 Hz, 1H), 6.01 (dd, J=2.06, 16.70 Hz, 1H), 5.59 (dd, J=1.98, 10.68 Hz, 1H), 5.38-5.47 (w, 1H), 4.96 (t, J=6.55 Hz, 1H), 3.38-3.56 (m, 5H), 2.24 (shs, 4H), 1.54-1.83 (m, 2H), 1.47 (m, 10H), 0.27-0.36 (m, 2H), -0.09-0.02 ( m, 2H). LCMS: m/z 514 [M+H]+ @ w.u. 4.85 min. MSVR (IER) calc. for C31H40N5O2 [M+H] ⁺ 514.6736 Found 514.6732.

Claims (23)

1. Compound of formula (I) R3 R4 R6b (I) where X represents nitrogen or -CH-; R1a represents hydrogen or linear or branched (C1-C ₆ )alkyl; R1b is (C1- _C6 )alkyl or, together with the atom to which they are bonded, R1a and R1b can form ( _C3 - _C6 )cycloalkyl; A represents (C ₃ -C ₆ )cycloalkyl, aryl selected from phenyl and naphthyl, pyridinyl, adamantyl, 2-oxoquinolin-3-yl, III-benzimidazol-2-yl, 1,2,4-oxadiazol-5- yl or 4-oxo-3,4-dihydroquinazolin-2-yl; each R6a is hydrogen; hydroxymethyl; halogen; methylsulfonyl; heteroaryl selected from the group consisting of thienyl, 1-methylpyrazolyl, pyridyl and pyridyl substituted with fluorine or trifluoromethyl; heterocyclyl selected from the group consisting of morpholinyl, piperazinyl and tetrahydropyridinyl, optionally substituted with ethyl, benzyloxycarbonyl, acryloyl, t-butoxycarbonyl or cyclopropylcarbonyl; -OR7, -СООМе, -CONR7R8; -CH(R14)NR7R8; 2-fluoropyridin-4-yl; phenyl-2-carbonitrile; tert-butyl-3,6-dihydropyridin-1(2H)-carboxylate or 2trifluoromethylpyridin-4-yl; Where R14 represents hydrogen or straight or branched (C1- _C6 )alkyl, optionally substituted with ( _C3 - _C6 )cycloalkyl; R8 represents hydrogen; R7 is selected from hydrogen; linear or branched (C1-C ₆ )alkyl; (C ₃ -C ₆ )cycloalkyl, optionally substituted with two halogen atoms; phenyl; heterocyclyl selected from the group consisting of piperidinyl, pyrrolyl, pyrrolidinyl and tetrahydropyranyl, optionally substituted with (C1C ₆ )alkyl, acryloyl, isopropyl, isobutyryl, t-butoxycarbonyl and benzyloxycarbonyl; or together with the nitrogen atom to which they are bonded, R7 and R8 form a 5-7 membered heterocyclyl group, optionally containing one additional heteroatom selected from O and NR9, optionally substituted with halogen or C1- _C3 alkyl; or together with the nitrogen atom to which they are bonded, R7 and R8 form 4-piperazine-1-carboxylic acid phenyl ester; Where R9 is hydrogen, straight or branched (C1- _C6 )alkyl, -COOR10 or -COR11; Where R10 represents linear or branched (C1-C ₆ )alkyl; R11 is linear or branched (C1- _C6 )alkyl, optionally substituted with halogen or OH, or ( _C2 - _C6 )alkenyl; R6b is hydrogen or halogen; R2 represents linear or branched (C1-C ₆ )alkyl, optionally substituted with halogen or hydroxyl; benzyl, optionally substituted with hydroxyl, one or two fluorine atoms or methyl; cyclopropyl; cyclobutylmethyl; cyclohexylmethyl; 2-methoxyethyl; 4-fluoro-2(trifluoromethyl)benzyl; 2,2-dimethyl-3-propanoic acid; 2,2-dimethyl-3-propanamide; O2,2-trimethyl3-propanamide; OH2,2-tetramethyl-3-propanamide; 2,2-dimethyl-M-(3-methylphenyl)propanamide; N-(2hydroxyethyl)-2,2-dimethyl-3-propanamide; O(2-hydroxypropyl)-2,2-dimethyl-3-propanamide; N-[3-(1 hydroxyethyl)phenyl]-2,2-dimethyl-3-propanamide; 2,2-dimethyl-3-propanenitrile and 4-ethynyl-2-fluorobenzyl; - 111 046117 R3 is hydrogen, cyano, NR13R13a, OR12, linear (C ₁ -C ₆ )alkyl or (2,4dimethoxybenzyl)amino; Where R12 represents linear (C1- _C6 )alkyl; each R13, R13a is independently selected from hydrogen or linear (C1- _C6 )alkyl; R4 represents hydrogen or linear (C1- _C6 )alkyl; R5 is hydrogen, fluorine or -OR12 or a pharmaceutically acceptable salt thereof. 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X represents nitrogen; R5 represents hydrogen or fluorine. 3. A compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof, where A is aryl; R2 represents linear or branched (C1-C ₆ )alkyl. 4. The compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, where R6a is -CH(R14)NR7R8; where R7 and R8 form a 6-membered heterocyclyl group containing one additional heteroatom NR9. 5. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of methyl 4-{(^)-1-[(8-benzyl-7-oxopyrido[2,3^]pyrimidin-2-yl)amino]ethyl} benzoate (compound 1); methyl 4-{(^)-1-[(8-ethyl-7-oxopyrido[2,3^]pyrimidin-2-yl)amino]ethyl}benzoate (compound 2); methyl 4-[(^)-1-{[8-(methoxymethyl)-7-oxopyrido[2,3-4|pyrimidin-2-yl]amino}ethyl]benzoate (compound 3); methyl 4-{(^)-1-[(8-methyl-7-oxopyrido[2,3^]pyrimidin-2-yl)amino]ethyl}benzoate (compound 4); methyl 4-[(1S)-1-{[8-(2-methylpropyl)-7-oxopyrido[2,3^]pyrimidin-2-yl]amino}ethyl] benzoate (compound 5); methyl 4-[(k)-1-{[8-(4-fluorobenzyl)-7-oxopyrido[2,3^]pyrimidin-2-yl]amino}ethyl]benzoate (compound 6); methyl 4-[(^)-1-{[8-(3,5-difluorobenzyl)-7-oxopyrido[2,3^]pyrimidin-2-yl]amino}ethyl]benzoate (compound 7); methyl 4-[(^)-1-({8-[4-fluoro-2-(trifluoromethyl)benzyl]-7-oxopyrido[2,3^]pyrimidin-2-yl}amino)ethyl]benzoate (com. 8); methyl 4-[(^)-1-{[7-oxo-8-(propan-2-yl)pyrido[2,3^]pyrimidin-2-yl]amino}ethyl]benzoate (compound 9); methyl 4-[(1S)-1-({8-[(3-methyloxetan-3-yl)methyl]-7-oxopyrido[2,3^]pyrimidin-2-yl}amino)ethyl]benzoate (com. 10); methyl 4-[(^)-1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3^]pyrimidin-2-yl]amino}ethyl]benzoate (compound 11); 2-{[(1S)-1 -cyclohexylethyl] amino } -8 -ethylpyrido[2,3 -d]pyrimidin-7 (8H)-one (compound 12); 8-ethyl-2-{[(^)-1-(4-methoxyphenyl)ethyl]amino}pyrido[2,3^]pyrimidin-7(8Н)-one (compound 13); 2-{[(^)-1-(4-chlorophenyl)ethyl]amino}-8-ethylpyrido[2,3^]pyrimidin-7(8H)-one (compound 14); 2-{[(^)-1-(4-chlorophenyl)ethyl]amino}-8-(pentan-3-yl)pyrido[2,3^]pyrimidin-7(8H)-one (compound 15); 8-benzyl-2-{[(^)-1-(4-chlorophenyl)ethyl]amino}pyrido[2,3^]pyrimidin-7(8H)-one (compound 16); 2-{[(^)-1-(4-chlorophenyl)ethyl]amino}-8-(2-fluoroethyl)pyrido[2,3^]pyrimidin-7(8H)-one (compound 17); 2-{[(^)-1-(4-chlorophenyl)ethyl]amino}-8-(2,2,2-trifluoroethyl)pyrido[2,3^]pyrimidin-7(8H)-one (compound 18 ); 2-{[(1S)-1 -(4-chlorophenyl)ethyl]amino}-8-(2-methylpropyl)pyrido[2,3^]pyrimidin-7(8H)-one (compound 19); 2-{[(1S)-1 -(4-chlorophenyl)ethyl]amino}-8-(cyclopropylmethyl)pyrido[2,3^]pyrimidin-7 (8H)-one (compound 20); 2-{[(k)-1-(4-chlorophenyl)ethyl]amino}-8-(4-methoxybenzyl)pyrido[2,3^]pyrimidin-7(8H)-one (compound 21); 2-{[(k)-1-(4-chlorophenyl)ethyl]amino}-8-(2-fluorobenzyl)pyrido[2,3^]pyrimidin-7(8H)-one (compound 22); 2-{[(1S)-1 -(4-chlorophenyl)ethyl]amino } -8-(3,4-difluorobenzyl)pyrido[2,3-d]pyrimidin-7(8H)-one (com. 23); 2-{[(^)-1-(4-chlorophenyl)ethyl]amino}-8-[3-(trifluoromethyl)benzyl]pyrido[2,3^]pyrimidin-7(8H)one (compound 24); 2-{[(1S)-1 -(4-chlorophenyl)ethyl]amino}-8-(2,4-difluorobenzyl)pyrido[2,3^]pyrimidin-7(8H)-one (compound 25); 2-{[(1S)-1 -(4-chlorophenyl)ethyl]amino}-8-[4-(trifluoromethoxy)benzyl]pyrido[2,3^]pyrimidin7(8H)-one (compound 26); 4-{[2-{[(^)-1-(4-chlorophenyl)ethyl]amino}-7-oxopyrido[2,3^]pyrimidin-8(7Н)-yl]methyl}benzonitrile (compound 27) ; 2-{[(1S)-1 -(4-chlorophenyl)ethyl]amino}-8-(4-fluorobenzyl)pyrido[2,3^]pyrimidin-7(8H)-one (compound 28); 2-{[(^)-1-(4-chlorophenyl)ethyl]amino}-8-(3,5-difluorobenzyl)pyrido[2,3^]pyrimidin-7(8H)-one (compound 29); - 112 046117 2-{[(1S)-1 -(4-chlorophenyl)ethyl]amino } -8-(3-methoxybenzyl)pyrido[2,3-d]nupuMuguH-7 (8H)-one (compound 30); 2-{[(1S)-1 -(4-chlorophenyl)ethyl]amino } -8-(2,6-difluorobenzyl)pyrido[2,3-d]nupuMuguH-7(8H)-OHa (compound 31) ; 2-{[(1S)-1 -(4-chlorophenyl)ethyl]amino } -4-methyl-8-(2-methylpropyl)pyrido[2,3-d]nupuMuguH-7 (8H)one (compound 32 ); 8-(2,2-dimethylpropyl)-2-{[(P)-1-(4-methoxyphenyl)ethyl]amino}pyrido[2,3^]pyrimidin-7(8H)-one (compound 33); 2-{[(1S)-1 -(4-bromophenyl)ethyl]amino } -8-(2,2-dimethylpropyl)pyrido[2,3-d]nupuMuguH-7 (8H)-one (compound 34) ; 2-{[(1S)-1 -(4-bromophenyl)ethyl]amino } -8-(3-hydroxy-2,2-dimethylpropyl)pyrido[2,3-d]nupuMuguH7(8H)-one (com. 35); 8-(2,2-dimethylpropyl)-2-{[(P)-1-(naphthalene-2-yl)ethyl]amino}pyrido[2,3^]pyrimidin-7(8H)-one (compound 36 ); methyl 2,2-dimethyl-3-[2-{[( 1S)-1 -(naphthalene-2-yl)ethyl] amino }-7-oxo pyrido [2,3-d]pyrimidin8(7H)-yl] propanoate (compound 37); 8-(3 -hydroxy-2,2-dimethylpropyl)-2-{ [(1S)-1 -(naphthalene-2-yl)ethyl]amino}pyrido[2,3^]pyrimidin-7(8H)-one (connection 38); 8-(2,2-dimethylpropyl)-2-{[(^)-1-phenylethyl]amino}pyrido[2,3^]pyrimidin-7(8Н)-one (compound 39); 8-(2,2-dimethylpropyl)-2-{[(P)-1-phenylethyl]amino}pyrido[2,3^]pyrimidin-7(8H)-one (compound 40); 8-(2,2-dimethylpropyl)-2-[(2-phenylpropan-2-yl)amino]pyrido[2,3^]pyrimidin-7(8H)-one (compound 41); 8-(2,2-dimethylpropyl)-2-[(1-phenylcyclopropyl)amino]pyrido[2,3^|pyrimidin-7 (8Н)-one (compound 42); 8-(2,2-dimethylpropyl)-2-[(1-phenylcyclobutyl)amino]pyrido[2,3^]pyrimidin-7(8H)-one (compound 43); 8-(2,2-dimethylpropyl)-2-{ [ 1 -(tricyclo[3,3,1,1 ^3,7 ]dec-1 -yl)ethyl]amino}pyrido [2.3^|pyrimidine7(8H)- she (comm. 44); 8-[(3-methyloxetan-3-yl)methyl]-2-{ [(1S)-1 -(naphthalene-2-yl)ethyl]amino}pyrido[2,3^]pyrimidin7(8H)-one ( connection 45); 8-(2-hydroxy-2-methylpropyl)-2-{[(P)-1-phenylethyl]amino}pyrido[2,3^]pyrimidin-7(8H)-one (compound 46); 8-(2,2-dimethylpropyl)-6-fluoro-2-(^)-1-phenylethylamino)-8H-pyrido[2,3^]pyrimidin-7-one (compound 47); methyl 4-[(P)-1-{[8-(2-hydroxy-2-methylpropyl)-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin-2yl]amino}ethyl]benzoate (comp. 48); 8-(2,2-dimethylpropyl)-2-{[(P)-1-(4-phenoxyphenyl)ethyl]amino}pyrido[2,3^]pyrimidin-7(8H)-one (compound 49); 2-{[(P)-1-(6-chloro-2-oxoquinolin-3-yl)ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3^]pyrimidin-7(8H) -she (comm. 50); 8-benzyl-2-{ [(1S)-1 -(5-chloro-1H-benzimidazol-2-yl)ethyl]amino}pyrido[2,3^]pyrimidin-7 (8H)-one (compound 51 ); 8-benzyl-2-({(P)-1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}amino)pyrido[2,3^]pyrimidine7(8H) -she (comm. 52); 2-({(P)-1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}amino)-8-(2,2-dimethylpropyl)pyrido[2,3d ]pyrimidin-7(8Н)-one (compound 53); 8-(2,2-dimethylpropyl)-2-{[(P)-1-(4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]amino}pyrido[2,3^]pyrimidin-7( 8Н)-ona (compound 54); 2-{[(P)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(3-hydroxy-2,2-dimethylpropyl)pyrido[2 ,3^]pyrimidin-7(8H)-one (compound 55); 4-(4-{^)-1-[8-(3-hydroxy-2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin-2-ylamino]ethyl}benzyl )piperazine-1-carboxylic acid tert-butyl ether (compound 56); 2-{^)-1-[4-(3,3-difluoropiperidin-1-ylmethyl)phenyl]ethylamino}-8-(2,2-dimethylpropyl)-6-fluoro-8Hpyrido[2,3^]pyrimidin- 7-ona (compound 57); 2-{^)-1-[4-(3,3-difluoropiperidin-1-ylmethyl)phenyl]ethylamino}-8-(2,2-dimethylpropyl)-6-methoxy8H-pyrido[2,3^]pyrimidin- 7-ona (compound 58); 4-(4-{^)-1-[8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin-2-ylamino]ethyl}benzyl)piperazine-1 -carboxylic acid tert-butyl ether (compound 59); 2-{[(P)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)-5methylpyrido[2,3^ ]pyrimidin-7(8Н)-one (compound 60); 8-(butan-2-yl)-2-{[(P)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}pyrido[2,3d]pyrimidine -7(8Н)-ona (compound 61); 8-[^)-butan-2-yl]-2-{[(P)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}pyri - 113 046117 go[2,3-d]nupuMuguH-7(8H)-OHa (compound 62); ethyl 2-[2-{[(^)-1-{4-[(3,3-difluoropipervdin-1-yl)methyl]phenyl}ethyl]amino}-7-oxopyrvdo[2,3d]pyrimidin-8( 7H)-yl]propanoate (compound 63); 2-[2-{[(^)-1-{4-[(3,3-difluoropipervdin-1-yl)methyl]phenyl}ethyl]amino}-7-oxopyrido[2,3d]pyrimidin-8(7H )-yl]propanenitrile (compound 64); 2-{[(^)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[^)-3-methylbutan-2yl|pyrido[2.3d |pyrimidin-7(8Н)-one (compound 65); 8-[(1S)-1 -cyclohexylethyl]-2-{ [(1S)-1 -{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl|amiHo}nupugo[2,3 -d]nupuMuguH-7(8H)-OHa (compound 66); 2-{ [(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluorophenyl}ethyl]amino}-8-[(2S)-3-methylbutan2-yl| pyrido[2.3d|pyrimidin-7(8Н)-one (compound 67); 2-({(1S)-1-[3-fluoro-4-(morpholin-4-ylmethyl)phenyl]ethyl}amino)-8-[(2S)-3-methylbutan-2-yl]pyrido[2. .3d|pyrimidin-7(8Н)-one (compound 68); 2-{[(1S)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[(2S)-3,3-dimethylbutan-2yl]pyrido [2,3-d]pyrimidin-7(8Н)-one (compound 69); 8-(2,2-dimethylpropyl)-2-{[(1S)-1-phenylpropyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (compound 70); 2-{[(1S)-1 -(4-chlorophenyl)ethyl|amino}-8-(3-hydroxybenzyl)pyrido[2,3-pyrimidin-7(8H)-one (compound 71); 2-{[(1S)-1 -(4-chlorophenyl)ethyl|amino}-8-(4-hydroxybenzyl)pyrido[2.3d|pyrimidin-7(8Н)-one (compound 72); 4-[(1S)-1-{[8-(2,6-difluorobenzyl)-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]benzoic acid (compound 73); 4-[(1S)-1-{[8-(2-fluorobenzyl)-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]benzoic acid (compound 74); 4-[(1S)-1-{[8-(2,6-difluorobenzyl)-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]-N-(4,4-difluorocyclohexyl )benzamide (compound 75); 4-[(1S)-1-{[8-(2,6-difluorobenzyl)-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]-N-(1-methylpiperidin-4 -yl)benzamide (compound 76); 8-(2,6-difluorobenzyl)-2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)carbonyl]phenyl}ethyl]amino}pyrido[2.3d|pyrimidin- 7(8H)-ona (compound 77); 4-[(1S)-1-{[8-(2,6-difluorobenzyl)-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]/-(tetrahydro2H-pyran-4- yl)benzamide (compound 78); N(4,4-difluorocyclohexyl)-4-[(^)-1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3d|pyrimidin-2yl|amino}ethyl|benzamide (com. 79); N-cyclopentyl-4-[(1S)-1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino}ethyl|benzamide (compound 80 ), N-cyclohexyl-4-[(1S)-1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino}ethyl|benzamide (compound 81 ); 2-chloro-N(4,4-difluorocyclohexyl)-4-(1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3d|pyrimidin-2yl|amino}ethyl)benzamide (com. 82); 2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)carbonyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2.3d|pyrimidin- 7(8H)-ona (compound 83); N-(4,4-difluorocyclohexyl)-4-(1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)-2- fluorobenzamide (compound 84); N(3,3-difluorocyclobutyl)-4-[(^)-1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3d|pyrimidin-2yl|amino}ethyl|benzamide (com. 85); 4-[(1S)-1-{[8-(2,2-dimethylpropyl)-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]benzamide (compound 86); 8-(2,2-dimethylpropyl)-2-{[(1S)-1-{4-[(4-hydroxypiperidin-1-yl)carbonyl]phenyl}ethyl]amino}pyrido[2,3d|pyrimidin-7 (8H)-she (compound 87); 2-chloro-N(4,4-difluorocyclohexyl)-4-[(^)-1-{[8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3-d] pyrimidin-2-yl]amino}ethyl]benzamide (compound 88); Na(4,4-difluorocyclohexyl)-4-[(^)-1-{[8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3d|pyrimidin-2-yl| amino}ethyl|-2-fluorobenzamide (compound 89); 8-(2,2-dimethylpropyl)-2-({(1S)-1-[3-fluoro-4-(hydroxymethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidine-7(8H) -she (comm. 90); 2-({(1S)-1-[4-(hydroxymethyl)phenyl]ethyl}amino)-8-(2-methylpropyl)pyrido[2,3-d]pyrimidin7(8H)-one (compound 91); 8-(2,6-difluorobenzyl)-2-({(1S)-1-[4-(hydroxymethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin7(8H)-one (compound 92 ); 2-({(1S)-1-[4-(hydroxymethyl)phenyl]ethyl}amino)-8-(2-hydroxy-2-methylpropyl)pyrido[2,3-d]pyri - 114 046117 midin-7(8Н)-one (compound 93); 2-{[(^)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluorophenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2, 3d|pyrimidin-7(8Н)-one (compound 94); 2-{[(^)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2-methylpropyl)pyrigo[2,3-d]nupuMuguH -7(8H)-OHa (compound 95); 8-benzyl-2-[(1-{4-[(4.4-di(|)torpiperidin-1-yl)methyl|(|)enyl}ethyl)amino|pyrido[2.3d|pyrimidin7(8H)-one ( connection 96); 2-[(1-{4-[(4.4-di(|)torpiperidin-1-yl)methyl|(|)enyl;ethyl)amino|-8-(2-(|)torbenzyl)pyrido[2.3d| pyrimidin-7(8Н)-one (compound 97); 8-(2,6-difluorobenzyl)-2-[(1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl)amino]pyrido[2,3d]pyrimidin-7(8H )-she (comm. 98); 8-(2,6-difluorobenzyl)-2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}pyrido[2,3-d ]pyrimidin-7(8Н)-one (compound 99); 2-[(1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl)amino]-8-(2-fluoroethyl)pyrido[2,3-d]pyrimidin-7(8H )-she (comm. 100); 2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-propylpyrido[2,3-d]pyrimidin-7(8H) -she (connection 101); 2-({(1S)-1-[4-(azepan-1-ylmethyl)phenyl]ethyl}amino)-8-propylpyrido[2,3-d]pyrimidin-7(8H)-one (compound 102) ; 2-{[(1S)-1-{4-[(4-acetylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-propylpyrido[2,3-d]pyrimidin-7(8H)-one (connection 103); 2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2-methylpropyl)pyrido[2,3-d]pyrimidine -7(8Н)-ona (compound 104); 2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3-d ]pyrimidin-7(8Н)-one (compound 105); 2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2,2-trifluoroethyl)pyrido[2,3 -d]pyrimidin-7(8H)-one (compound 106); 8-[2,3-difluoro-2-(fluoromethyl)propyl]-2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino} pyrido[2,3-d]pyrimidin-7(8H)-one (compound 107); 2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[3,3,3-trifluoro-2-(trifluoromethyl) propyl]pyrido[2,3-d]pyrimidin-7(8H)-one (compound 108); 8-(cyclobutylmethyl)-2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}pyrido[2,3-d]pyrimidin-7 (8H)-she (compound 109); 8-(2,2-dimethylpropyl)-2-({(1S)-1-[4-(morpholin-4-ylmethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-7(8H) -she (connection 110); 8-(2,2-dimethylpropyl)-2-({(1S)-1-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-7(8H) -she (connection 111); 2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2-methylbenzyl)pyrido[2,3d]pyrimidin-7 (8H)-she (compound 112); 8-(cyclohexylmethyl)-2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}pyrido[2,3-d]pyrimidin-7 (8H)-she (compound 113); 2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2-methoxyethyl)pyrido[2,3d]pyrimidin-7 (8H)-she (compound 114); 2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[4-fluoro-2-(trifluoromethyl)benzyl]pyrido[ 2,3-d]pyrimidin-7(8Н)-one (compound 115); 2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(3,3,3-trifluoro-2,2-dimethylpropyl )pyrido[2,3-d]pyrimidin-7(8Н)-one (compound 116); 2-{[(1S)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3-d ]pyrimidin-7(8Н)-one (compound 117); 2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-4-methyl-8-(2-methylpropyl)pyrido[2,3 -d]pyrimidin-7(8H)-one (compound 118); 2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2-hydroxy-2-methylpropyl)pyrido[2,3 -d]pyrimidin-7(8H)-one (compound 119); 2-{[(1S)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-[2-(hydroxymethyl)-2methylpentyl]pyrido[2,3 -d]pyrimidin-7(8H)-one (compound 120); 2,2-dimethyl-3-[2-{ [(1 S)-1-(naphthalene-2-yl)ethyl]amino } -7-oxopyrido[2,3-d]pyrimidin-8(7H)yl] propanoic acid (compound 121); 2,2-dimethyl-3-[2-{[(1S)-1-(naphthalene-2-yl)ethyl]amino}-7-oxopyrido[2,3-d]pyrimidin-8(7H)yl|propanamide (connection 122); N,2,2-grimethyl-3-[7-oxo-2-{[(1S)-1-phenylethyl]amino}pyrido[2,3-d]pyrimidin-8(7H)-yl]propanamide (com. 123); CC2.2-tetramethyl-3-[7-oxo-2-{ [(1S)-1-phenylethyl]amino}pyrido[2,3-pyrimidine-8(7H) - 115 046117 yl]propanamide (compound 124); 2,2-dimethyl-N-(3-methylphenyl)-3-[7-oxo-2-{[(^)-1-phenylethyl]amino}pyrido[2,3^]pyrimidin8(7H)-yl]propanamide (connection 125); Ch(2-hydroxyethyl)-2,2-dimethyl-3-[7-oxo-2-{[(^)-1-phenylethyl]amino}pyrido[2,3^]pyrimidin8(7H)-yl]propanamide ( connection 126); H(3-hydroxypropyl)-2,2-dimethyl-3-[7-oxo-2-{[(^)-1-phenylethyl]amino}pyrido[2,3^]pyrimidin-8(7H)-yl] propanamide (compound 127); Ch[3-(1-hydroxyethyl)phenyl]-2,2-dimethyl-3-[7-oxo-2-{[(^)-1-phenylethyl]amino}pyrido[2,3d]pyrimidine-8(7H )-yl]propanamide (compound 128); 2,2-dimethyl-3-[2-{[(^)-1-(naphthalene-2-yl)ethyl]amino}-7-oxopyrido[2,3^]pyrimidin-8(7H)yl]propanenitrile ( connection 129); 8-(2,2-dimethylpropyl)-2-({(^)-1-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]ethyl}amino)pyrido[2,3d]pyrimidin- 7(8H)-ona (compound 130); 8-(2,2-dimethylpropyl)-2-({(^)-1-[4-(pyridin-4-yl)phenyl]ethyl}amino)pyrido[2,3^]pyrimidin7(8H)-one ( connection 131); 8-(2,2-dimethylpropyl)-2-({(^)-1-[4-(2-fluoropyridin-4-yl)phenyl]ethyl}amino)pyrido[2,3^]pyrimidin-7(8H )-she (connection 132) 8-(2,2-dimethylpropyl)-2-({(18)-1-[4-(thiophen-3-yl)phenyl]ethyl}amino)pyrido[2,3-4]pyrimidin7(8H)-one (connection 133); 4'-[(^)-1-{[8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin-2-yl]amino}ethyl]biphenyl-2 -carbonitrile (compound 134); 8-(3-hydroxy-2,2-dimethylpropyl)-2-({(^)-1-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]ethyl}amino)pyrido|2, 3-1|pyrimidin-7(8Н)-one (compound 135); 8-(3-hydroxy-2,2-dimethylpropyl)-2-({(^)-1-[4-(thiophen-3-yl)phenyl]ethyl}amino)pyrido[2,3d]pyrimidine-7( 8Н)-ona (compound 136); 8-(2,2-dimethylpropyl)-2-({(18)-1-[4-(methylsulfonyl)phenyl]ethyl}amino)pyrido[2,3-4]pyrimidin7(8H)-one (compound 137 ); 8-(2,2-dimethylpropyl)-2-({(^)-1-[4-(piperazin-1-ylmethyl)phenyl]ethyl}amino)pyrido[2,3^]pyrimidin-7(8H)- it is dihydrochloride (compound 138); 2-{[(^)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3^]pyrimidin- 7(8H)-ona (compound 139); 2-{[(^)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-(3-hydroxy-2,2-dimethylpropyl)pyrido[2,3 ^]pyrimidin-7(8H)-one (compound 140); 2-{[(1S)-1 -{4-[(4-acryloylpiperazin-1 -yl)methyl]-3-fluorophenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3^ ]pyrimidin-7(8Н)-one (compound 141); 2-{[(^)-1-{4-[(4-acryloylpiperazin-1-yl)carbonyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3^]pyrimidin- 7(8H)-ona (compound 142); 2-({(^)-1-[4-({4-[(2E)-but-2-enoyl]piperazin-1-yl}methyl)phenyl]ethyl}amino)-8-(2,2- dimethylpropyl)pyrido[2,3^]pyrimidin-7(8H)-one (compound 143); 8-(2,2-dimethylpropyl)-2-{[(^)-1-(4-{[4-(2-methylacryloyl)piperazin-1-yl]methyl}phenyl)ethyl]amino}pyrido[2, 3^]pyrimidin-7(8H)-one (compound 144); 8-(2,2-dimethylpropyl)-2-[^)-1-(4-hydroxyphenyl)ethylamino]-8H-pyrido[2,3^]pyrimidin-7-one (compound 145); 4-(4-{^)-1-[8-(^)-1,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin-2-ylamino]ethyl}phenoxy) piperidine-1-carboxylic acid benzyl ester (compound 146); 2-{ [(^)-1-{4-[(3,3-diphgorazetidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3d]pyrumidine -7(8Н)-ona (compound 147); 2-{[(1S)-1 -{4-[(3,3-difluoropyrrolidin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2,3^] pyrimidin-7(8H)-one (compound 148); 8-[(2R)-butan-2-yl]-2-{[(1S)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}pyrido[2 ,3^]pyrimidin-7(8H)-one (compound 149); 2-{[(1S)-1-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-3-fluorophenyl)ethyl]amino}-8-[(2S)- 3methylbutan-2-yl]pyrido[2,3^]pyrimidin-7(8H)-one (compound 150); 2-{[(1S)-1-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-2-fluorophenyl)ethyl]amino}-8-(2,2dimethylpropyl) pyrido[2,3^]pyrimidin-7(8Н)-one (compound 151); 2-{[(^)-1-{4-[(4,4-difluoropiperidin-1-yl)methyl]-2-fluorophenyl}ethyl]amino}-8-(2,2-dimethylpropyl)pyrido[2, 3^]pyrimidin-7(8H)-one (compound 152); 8-(2,2-dimethylpropyl)-2-({(^)-1-[2-fluoro-4-(morpholin-4-ylmethyl)phenyl]ethyl}amino)pyrido[2,3d]pyrimidin-7( 8Н)-ona (compound 153); 4-(4-{^)-1-[8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin-2-ylamino]ethyl}phenoxy)piperidine-1 -carboxylic acid tert-butyl ether (compound 154); 8-(^)-1,2-dimethylpropyl)-2-{^)-1-[4-(piperidin-4-yloxy)phenyl]ethylamino}-8H-pyrido[2,3 - 116 046117 d]nupuMuguH-7-OHa (compound 155); 2-{(S)-1-[4-(1-acryloylpiperidin-4-yloxy)phenyl]ethylamino}-8-(2,2-dimethylpropyl)-8H-pyrigo[2,3-d]nupuMuguH-7- OHa (connection 156); 8-(2,2-dimethylpropyl)-2-{ [(^)-1-(4-{[4-(2-methylpropanoyl)piperazin-1-yl]methyl}phenyl)ethyl]amiHo}nupugo[2, 3-d]nupuMuguH-7(8H)-OHa (compound 157); 2-{[(1S)-1-(4-{ [4-(cyclopropylcarbonyl)piperazin-1 -yl|methyl}phenyl)ethyl|amino}-8-(2,2-dimethylpropyl)pyrido[2.3А|pyrimidine -7(8Н)-ona (compound 158); 2-{(S)-1-[4-(1 -a1filoylpiperidin-4-yloxy)phenyl|ethylamino}-8-((b)-1,2-dimethylpropyl)-8H-pyrido[2.3H|pyrimidine-7 -she (comm. 159); 8-((S)-1.2-dimethylpropyl)-2-{(0)-1-[4-( 1 -isobutyrylpiperidin-4-yloxy)phenyl|ethylamino}-8Нpyrido[2.3Н|pyrimidin-7-one (compound . 160); 2-(^)-1-[4-(4-acryloylpiperazin-1-ylmethyl)phenyl|ethylamino}-8-(^)-1,2-dimethylpropyl)-8Hpyrido[2.3H|pyrimidin-7-one (compound . 161); 8-((b)-1.2-dimethylpropyl)-2-((b)-1-{4-[4-(2-methyla1filoyl)piperazin-1-ylmethyl|((enyl}ethylamino)-8H-pyrido[ 2.3А|pyrimidin-7-one (compound 162); 2-{[(1S)-1-(4-bromophenyl)ethyl]amino}-8-[(2S)-3-methylbutan-2-yl]pyrido[2,3-d]pyrimidin-7(8H)one (conn. 163); 2-{[(1S)-1-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}phenyl)ethyl]amino}-8-[(2S)-1,1 ,1-trifluoropropan-2-yl]pyrido[2,3-d]pyrimidin-7(8H)-one (compound 164); 4'-[(1S)-1-({8-[(2S)-3-methylbutan-2-yl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl} amino)ethyl]biphenyl-2-carbonitrile (compound 165); 2-({(1S)-1-[4-(2-fluoropyridin-4-yl)phenyl]ethyl}amino)-8-[(2S)-3-methylbutan-2-yl]pyrido[2,3- d]pyrimidin-7(8H)-one (compound 166); tert-butyl 4-{4-[(1S)-1-({8-[(2S)-3-methylbutan-2-yl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine2 -yl}amino)ethyl| phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (compound 167); 2-({(1S)-1-[4-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]ethyl}amino)-8-[(2S)-3-methylbutan- 2-yl]pyrido[2,3-d]pyrimidin-7(8H)-one (compound 168); 2-{[(1S)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-[(2S)-1,1,1-trifluoropropan2-yl| pyrido [2,3 -d| pyrimidin-7 (8H)-one (compound 169); 2-{[(1S)-1-{4-[(3,3-difluoropiperidin-1-yl)methyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3d]pyrimidine -7(8Н)-ona (compound 170); 8-[(1S)-1-cyclopropylethyl]-2-{[(1S)-1-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-3-fluorophenyl) ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (compound 171); 2-{[(1S)-1 -(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl|amino} -8-[(2S)-3 -methylbutan-2-yl|pyrido [2.3Н|pyrimidin-7(8Н)-one (compound 172); 8-[(2S)-3-methylbutan-2-yl]-2-({(1S)-1-[4-(morpholin-4-yl)phenyl]ethyl}amino)pyrido[2,3-d] pyrimidin-7(8H)-one (compound 173); benzyl 4-{4-[(1S)-1-({8-[(2S)-3-methylbutan-2-yl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2yl }amino)ethyl]phenyl}piperazine-1-carboxylate (compound 174); 2-({(1 S)-1-[4-(4-acryloylpiperazin-1 -yl)phenyl]ethyl}amino)-8-[(2S)-3 -methylbutan-2-yl|pyrido[2.3А| pyrimidin-7(8H)-one (compound 175); 8-[(2S)-3-methylbutan-2-yl]-2-({(1S)-1-[4-(piperazin-1-yl)phenyl]ethyl}amino)pyrido[2,3-d] pyrimidin-7(8H)-one (compound 176); 2-({(1S)-1-[4-(4-ethylpiperazin-1-yl)phenyl]ethyl}amino)-8-[(2S)-3-methylbutan-2-yl]pyrido[2,3d] pyrimidin-7(8Н)-one (compound 177); benzyl 4-{2-fluoro-4-[(1S)-1-({8-[(2S)-3-methylbutan-2-yl]-7-oxo-7,8-dihydropyrido[2,3-d ]pyrimidin-2-yl}amino)ethyl]phenyl}piperazine-1-carboxylate (compound 178); 2-({(^)-1-[4-(4-acryloylpiperazin-1-yl)-3-fluorophenyl]ethyl}amino)-8-[(2S)-3-methylbutan-2-yl]pyrido[2 ,3-d]pyrimidin-7(8Н)-one (compound 179); 8-[(2S)-3-methylbutan-2-yl]-2-({(1S)-1-[6-(piperazin-1-yl)pyridin-3-yl]ethyl}amino)pyrido[2, 3d]pyrimidin-7(8Н)-one (compound 180); 2-({(1S)-1-[6-(4-acryloylpiperazin-1-yl)pyridin-3-yl]ethyl}amino)-8-[(2S)-3-methylbutan-2-yl]pyrido[ 2,3-d]pyrimidin-7(8Н)-one (compound 181); 2-{[(1S)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-(2-azidoethyl)pyrido[2,3d]pyrimidin-7(8H )-ona (comm. 182); 2-{[(1S)-1 -{4-[(4-acryloylpiperazin-1 -yl)methyl| -3-fluorophenyl}ethyl|amino}-8-(propan-2-yl)pyrido[2,3-th|pyrimidin-7(8H)-one (compound 183); 2-{[(1S)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3d]pyrimidin-7 (8H)-ona (compound 184); tert-butyl 4-(4-{(1S)-1-[(8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]ethyl}benzyl)piperazine -1-carboxylate (compound 185); 2-{[(1S)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-ethylpyrido[2,3-d]pyrimi - 117 046117 din-7(8Н)-one (compound 186); 2-{[(^)-1-{4-[1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrigo[2,3-d ]nupuMuguH-7(8H)-OHa (compound 187); 8-[(2S)-3 -methylbutan-2-yl]-2-{[(18)-1-{4-[(4-methyl-3-oxopiperazin-1 -yl)methyl]phenyl}ethyl]amiHo }nupugo[2,3-d]nupuMuguH-7(8H)-OHa (compound 188); tert-butyl 4-(4-{(^)-1-[(8-ethyl-7-oxo-7,8-dihydropyrido[2,3^|pyrimidin-2-yl)amino|ethyl}benzoyl)piperazin- 1-carboxylate (compound 189); 2-{[(^)-1-{4-[(4-acryloylpiperazin-1-yl)carbonyl]phenyl}ethyl]amino}-8-ethylpyrido[2,3^]pyrimidin-7(8H)-one ( connection 190); 2-{[(^)-1-{4-[(4-acryloylpiperazin-1-yl)carbonyl]-3-fluorophenyl}ethyl]amino}-8-[^)-3-methylbutan-2-yl]pyrido [2,3^]pyrimidin-7(8H)-one (compound 191); N(1-acryloylpiperidin-4-yl)-2-fluoro-4-[(^)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3d] nirimidin-2-yl]amino}ethyl]benzamide (compound, 192); tert-butyl 6-[(1S)-1-({8-[(2S)-3-methylbutan-2-yl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2yl} amino)ethyl]-3',6'-dihydro-3,4'-bipyridine-G(2H)-carboxylate (compound 193); 2-{[(^)-1-(G-acryloyl-G,2',3',6'-tetrahydro-3,4'-bipyridin-6-yl)ethyl]amino}-8-[^)- 3-methylbutan-2-yl]pyrido[2,3-d]pyrimidin-7 (8H)-one (compound 194); 2-({(^)-1-(G-(cyclopropylcarbonyl)-G,2',3',6'-tetrahydro-3,4'-bipyridin-6-yl]ethyl}amino)-8[^) -3-methylbutan-2-yl]pyrido[2,3^]pyrimidin-7(8H)-one (compound 195); 8-[(2S)-3-methylbutan-2-yl]-2-({(1S)-1-[2'-(trifluoromethyl)-3,4'-bipyridin-6-yl]ethyl}amino)pyrido [2,3^]pyrimidin-7(8H)-one (compound 196); 2-{[(1S)-1-(2'-fluoro-3,4'-bipyridin-6-yl)ethyl]amino}-8-[(2S)-3-methylbutan-2-yl]pyrido[2 ,3-d]pyrimidin-7(8H)-one (compound 197); 2-{[(^)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-[^)-1-fluoropropan-2yl]pyrido[2,3^ ]pyrimidin-7(8Н)-one (compound 198); 2-{[(^)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-[^)-1-hydroxypropan-2yl]pyrido[2,3^ ]pyrimidin-7(8H)-one (compound 199); tert-butyl 4-{4-[(^)-1-{[4-cyano-8-(2,2-dimethylpropyl)-7-oxo-7,8-dihydropyrido[2,3d]pyrimidin-2-yl ] amino} ethyl] benzyl} piperazine-1-carboxylate (compound 200); 2-{[(^)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)-4ethoxypyrido[2,3^]pyrimidine -7(8Н)-ona (compound 201); 2-{[(^)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-(2,2-dimethylpropyl)-4(methylamino)pyrido[2, 3^]pyrimidin-7(8H)-one (compound 202); 2-{[(^)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-4-(dimethylamino)-8-(propan2-yl)pyrido[2,3 ^]pyrimidin-7(8H)-one (compound 203); 2-{[(^)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-7-oxo-8-(propan-2-yl)-7,8dihydropyrido[ 2,3^]pyrimidine-4-carbonitrile (compound 204); 2-{[(^)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-4-[(2,4-dimethoxybenzyl)amino]-8-(propan- 2-yl)pyrido[2,3^]pyrimidin-7(8H)-one (compound 205); 2-{[(^)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-4-amino-8-(propan-2-yl)pyrido[2,3 ^]pyrimidin-7(8H)-one (compound 206); 2-{[(1S)-1-(4-{[(2R)-4-acryloyl-2-methylpiperazin-1-yl]methyl}phenyl)ethyl]amino}-8-ethylpyrido[2,3^]pyrimidine -7(8Н)-ona (compound 207); 2-{[(1S)-1-(4-{ [(3R)-4-acryloyl-3 -methylpiperazin-1 -yl] methyl}phenyl)ethyl]amino}-8-ethylpyrido[2,3^]pyrimidine -7(8Н)-ona (compound 208); 2-{[(1S)-1-(4-{[(2R)-4-acryloyl-2-(propan-2-yl)piperazin-1-yl]methyl}phenyl)ethyl]amino}-8-ethylpyrido [2,3^]pyrimidin-7(8H)-one (compound 209); 2-{[(1S)-1-(4-{[(2S)-4-acryloyl-2-methylpiperazin-1-yl]methyl}phenyl)ethyl]amino}-8-ethylpyrido[2,3^]pyrimidine -7(8Н)-ona (compound 210); 2-{[(1S)-1-(4-{[(3S)-4-acryloyl-3-methylpiperazin-1-yl]methyl}phenyl)ethyl]amino}-8-ethylpyrido[2,3^]pyrimidine -7(8Н)-ona (compound 2R); 2-{[(1S)-1-(4-{[(2S)-4-acryloyl-2-(propan-2-yl)piperazin-1-yl]methyl}phenyl)ethyl]amino}-8-ethylpyrido [2,3^]pyrimidin-7(8H)-one (compound 212); 2-{[(1S)-1 -{6-[(4-acryloylpiperazin-1 -yl)methyl] pyridin-3 -yl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3 ^]pyrimidin-7(8H)-one (compound 213); 2-{[(^)-1-{4-[1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-ethylpyrido[2,3^]pyrimidin-7(8H)- she (connection 214); 2-{[(^)-1-{4-[1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-methylpyrido[2,3^]pyrimidin-7(8H)- she (connection 215); 2-{[(^)-1-{4-[1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(2,6-difluorobenzyl)pyrido[2,3^] pyrimidin-7(8H)-one (compound 216); 2-{[(^)-1-{4-[(4-acryloylpiperazin-1-yl)methyl]phenyl}ethyl]amino}-8-(4-ethynyl-2-fluorobenzyl)pi - 118 046117 pugo[2,3-d]nupuMuguH-7(8H)-OHa (compound 217); 2-{[(^)-1-{4-[1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-cyclopropylpyrvdo[2,3d]nupuMuguH-7(8H)-OHa (connection 218); 2-{[(^)-1-{4-[1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl]phenyl}ethyl]amino}-8-ethylpyrigo[2,3-d]nupuMuguH-7 (8H)-OHa (compound 219); 2-{[(^)-1-{4-[1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl]phenyl}ethyl]amino}-8-(propan-2yl)pyrido[2.3L|pyrimidine -7(8Н)-ona (compound 220); 2-{ [(^)-1-(4-{1-[4-(2-methylacryloyl)piperazin-1-yl]propyl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[ 2.3L|pyrimidin-7(8H)-one (compound 221); 2-({(^)-1-[4-(1-{4-[(2E)-but-2-enoyl]piperazin-1-yl}propyl)phenyl]ethyl}amino)-8-(propan- 2-yl)pyrido[2.3L|pyrimidin-7(8H)-one (compound 222); 2-{ [(1S)-1-(4-{[(3R)-1-acryloylpyrrolidin-3-yl]oxy}phenyl)ethyl]amino}-8-ethylpyrido[2,3-d]pyrimidin-7( 8Н)-ona (compound 223); 2-{ [(1S)-1-(4-{[(3S)-1-acryloylpyrrolidin-3-yl]oxy}phenyl)ethyl]amino}-8-ethylpyrido[2,3-d]pyrimidin-7( 8Н)-ona (compound 224); phenyl 4-[(^)-1-{4-[(^)-1-{[7-oxo-8-(propan-2-yl)-7.8-dihydropyrido[2.3L|pyrimidin-2-yl|amino }ethyl]phenyl}propyl]piperazine-1-carboxylate (compound 225); phenyl 4-[(1R)-1-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl]amino}ethyl]phenyl}propyl]piperazine-1-carboxylate (compound 226); 2-{ [(1S)-1-{4-[(1S)-1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2.3 L|pyrimidin-7(8H)-one (compound 227); 2-{[(1S)-1-{4-[(1R)-1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2.3 L|pyrimidin-7(8H)-one (compound 228); 2-{[(1R)-1-{4-[(1R)-1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2.3 L|pyrimidin-7(8H)-one (compound 229); 2-{[(1S)-1-{4-[(1S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl]phenyl}ethyl]amino}-8-(propan-2-yl) pyrido[2,3-d]pyrimidin-7(8Н)-one (compound 230); 2-{[(1S)-1-{4-[(1R)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl]phenyl}ethyl]amino}-8-(propan-2-yl) pyrido[2,3-d]pyrimidin-7(8Н)-one (compound 231); 4-{4-[(S)-1-(1-ethyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-ylamino)ethyl]benzyl}piperazine-1-carboxylic acid tert- butyl ether (compound 232); 4-(1-{4-[(S)-1-(1-ethyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-ylamino)ethyl]phenyl}propyl)piperazine-1 -carboxylic acid tert-butyl ether (compound 233); 4-((S)-1-{4-[(S)-1-(1-ethyl-2-oxo-1,2-dihydro[1,6]naphthyridin-7-ylamino)ethyl]phenyl}propyl) piperazine-1-carboxylic acid phenyl ester (compound 234); 7-{(S)-1-[4-(3,3-difluoropiperidin-1-ylmethyl)phenyl]ethylamino}-1-(2,2-dimethylpropyl)-1H-[1,6]naphthyridin-2-one (connection 235); 7-{(S)-1-[4-(4-acryloylpiperazin-1-ylmethyl)phenyl]ethylamino}-1-ethyl-1H-[1,6]naphthyridin-2-one (compound 236); 7-((S)-1-{4-[1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethylamino)-1-ethyl-1H-[1,6]naphthyridin-2one (compound 237) ; 7-((S)-1-(4-[(S)-1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethylamino)-1-ethyl-1H-[1,6]naphthyridin-2- she (conn. 238); 7-{[(1S)-1-{4-[(1S)-1-(4-acryloylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-1-(propan-2-yl)-1, 6naphthyridin-2(1H)-one (compound 239); 2-{[(1S)-1-{4-[1-(4-propanoylpiperazin-1-yl)propyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-th |pyrimidin-7(8Н)-one (compound 240); 2-{[(1S)-1-(4-{(1S)-1-[4-(3-chloropropanoyl)piperazin-1-yl| -2-cyclopropylethyl}phenyl)ethyl|amino}-8-(propane -2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (compound 242); 2-{[(1S)-1-(4-{(1R)-1-[4-(3-hydroxypropanoyl)piperazin-1-yl]propyl}phenyl)ethyl]amino}-8-(propan-2- yl)pyrido[2.3L|pyrimidin-7(8H)-one (compound 243); 2-[(1-{4-[1 -(4-acryloylpiperazin-1 -yl)-2-cyclopropylethyl|phenyl}cyclopropyl)amino| -8-(propan2-yl)pyrido[2.3L|pyrimidin-7(8H)-one (compound 244); 2-[(l-{4-[(1R)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl]phenyl}cyclopropyl)amino]-8(propan-2-yl)pyrido[2.3L| pyrimidin-7(8H)-one (compound 245); 2-[(l-{4-[(1S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl]phenyl}cyclopropyl)amino]-8(propan-2-yl)pyrido[2.3L| pyrimidin-7(8H)-one (compound 246); 2-[(1-{4-[1 -(4-acryloylpiperazin-1 -yl)propyl|phenyl}cyclopropyl)amino| -8-(propan-2-yl)pyrido[2.3L|pyrimidin-7(8H)-one (compound 247); 2-[(1-{4-[(GK)-1-(4-acryloylpiperazin-1-yl)propyl|phenyl}cyclopropyl)amino|-8-(propan-2-yl)pyrido[2.3L|pyrimidin- 7(8H)-ona (compound 248); 2-[(1-{4-[(1S)-1 -(4-acryloylpiperazin-1-yl)propyl]phenyl}cyclopropyl)amino| -8-(propan-2-yl)pi - 119 046117 rido[2,3^]pyrimidin-7(8Н)-one (compound 249); 2-{[(^)-1-{4-[(2E)-pent-2-en-3-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3- 1]pyrimidin7(8H)-one (compound 250) and 7-{[(^)-1-{4-[(^)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl]phenyl}ethyl]amino}-1-(propan-2-yl) -1,6-naphthyridin-2(1H)-one (compound 251). 6. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1, comprising reacting a compound of formula (II) where G represents chlorine, MeS(O) ₂ - or MeS(O)-; R2, R3, R4 and R5 are as defined in paragraph 1; with a compound of formula (III) where A, R1a, R1b, R6a and R6b are as defined in paragraph 1; to obtain a compound of general formula (I). 7. The method according to claim 6, wherein in the compound of formula (II) G represents MeS(O) ₂ - or MeS(O)- and R2, R3, R4 and R5 are as defined in claim 1, and the compound of formula (II) is prepared according to the following steps: Step 2a): replacement of chlorine intermediate of formula (IV) where R3 represents hydrogen or linear (C ₁ -C ₆ )alkyl by reaction with an amine intermediate of formula (V) IR2—NH ₂ (V) where R2 is as defined in paragraph 1, to obtain a compound of formula (U1); Step 2b): Reacting the compound of formula (VI) where R2 and R3 are as defined above, with a reducing agent, to obtain a compound of formula (VII); Step 2c): Reacting the resulting compound of formula (VII): where R2 and R3 are as defined in claim 1, with a suitable oxidizing reagent, to obtain a compound of formula (VIII); Step 2d): reacting the resulting compound of formula (VIII) where R2 and R3 are as defined above, with a compound of formula (IX) - 120 046117 o ^γ 4 R5 ¹ (IX) where Y is a suitable leaving group for the Wittig or Horner-Wadsworth-Emmons reaction (or HVE reaction) selected from triphenylphosphorane and diethylphosphonate, and R5 is hydrogen or fluorine, to give a compound of formula ( X); Step 2e): Cyclization of the intermediate of formula (X) where R2, R3, R4 and R5 are as defined in claim 1, under alkaline conditions, to obtain intermediate compound (XI); Step 2f): mixing the resulting compound of formula (XI) where R2, R3, R4 and R5 are as defined above, with an oxidizing reagent to obtain a compound of formula (II). 8. The method according to claim 6, wherein in the compound of formula (II) G represents chlorine, R4 represents hydrogen or optionally substituted linear or branched (^^Dalkyl, R5 represents hydrogen and R2 and R3 are as defined in claim. 1, and the compound of formula (II) is prepared according to the following steps: Step 4a): reaction of the compound of formula (XVIII): R3 xL. -Hal N er N CI (XVIII) where R3 is hydrogen or optionally substituted linear or branched alkyl, and Hal is preferably bromine or iodine, with an intermediate of formula (V): R2—NH ₂ (V) where R2 is as defined in paragraph 1, to obtain a compound of formula (XIX); Step 4b): mixing the compound of formula (XIX): where R2, R3 and Hal are as defined above, with the reagent of formula (XVIIb) R4 O ABOUT R5 T (XVIIb) where R4 is hydrogen or optionally substituted linear or branched (^-^alkyl, R5 and T are hydrogen, to give a compound of formula (Xb); Step 4c): Cyclization of the compound of formula (Xb) where R2, R3, R4, R5 and T are as defined above by adding acetaldehyde to obtain an intermediate of formula (II). 9. The method according to claim 6, wherein in the compound of formula (II) G represents chlorine, X represents nitrogen or -CH-, R2 is as defined in claim 1, R3 and R4 represent hydrogen and R5 represents - 121 046117 is hydrogen or OR12, where R12 is an optionally substituted linear or branched (C ₁ -C ₆ )alkyl, and the compound of formula (II) is prepared according to the following steps: Step 4d): replacement of chlorine atom in intermediate (IVa) where X represents N or -CH, with an intermediate amine of formula (V) IR2—NH ₂ (V) where R2 is as defined in claim 1, to obtain a compound of formula (VIa); Step 4e): Reaction of the compound of formula (VIa) where X is N or -CH and R2 is as defined above with a reducing agent to give compound (VIIa); Step 4f): reacting the resulting compound of formula (VIIa) where X is N or -CH and R2 is as defined above, with a suitable oxidizing reagent, to obtain a compound of formula (VIIIa); Step 4g): reacting the resulting compound of formula (VIIIa) where R2 is as defined above, with a compound of formula (IXa): where R5 represents hydrogen or OR12, where R12 represents an optionally substituted linear or branched (C-COalkyl.) to obtain a compound of formula (II). 10. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the production of a medicinal product with anticancer activity. 11. Use according to claim 10, wherein the anticancer activity is caused by and/or associated with increased levels of 2-hydroxyglutarate. 12. Use according to claim 10, wherein the anticancer activity is caused by and/or associated with mutated IDH (isocitrate dehydrogenase) enzymes. 13. Use according to claim 10, wherein the anticancer activity is caused by and/or associated with the superfunctions of IDH wt (wild-type isocitrate dehydrogenase). 14. Use according to any one of claims 10-13, where the cancer is selected from the group consisting of carcinomas; hematopoietic tumors of the lymphoid cell line; hematopoietic tumors of the myeloid cell line; tumors of mesenchymal origin; tumors of the central and peripheral nervous system; melanoma; seminomas; teratocarcinomas; osteosarcomas; pigment xeroderma; keratoxanthomas; thyroid cancer; Kaposi's sarcoma; chondrosarcomas and cholangiocarcinomas. 15. Use according to claim 14, wherein said carcinomas are selected from the group consisting of cancer of the bladder, breast, kidney, liver, colon, lung, esophagus, gallbladder, ovary, pancreas, stomach, cervix, prostate and skin carcinomas. 16. Use according to claim 14, wherein said hematopoietic tumors of a lymphoid cell line are selected from the group consisting of leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, angioimmunoblastic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy lymphoma cells and Burkitt's lymphoma. - 122 046117 17. Use according to claim 14, wherein said hematopoietic tumors of the myeloid cell line are selected from the group consisting of acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia. 18. Use according to claim 14, wherein said tumors of mesenchymal origin are selected from the group consisting of fibrosarcoma and rhabdomyosarcoma. 19. Use according to claim 14, wherein said tumors of the central and peripheral nervous system are selected from the group consisting of glioma, glioblastoma, glioblastoma multiforme, astrocytoma, oligodendroglioma, paraglioma, neuroblastoma and schwannoma. 20. Use according to claim 14, wherein said thyroid cancer is selected from the group consisting of papillary thyroid carcinoma and medullary thyroid carcinoma. 21. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in combination with a pharmaceutically acceptable excipient, carrier or diluent. 22. The pharmaceutical composition according to claim 21, further containing one or more chemotherapeutic agents. 23. A kit containing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and one or more chemotherapeutic agents in the form of a combined preparation for simultaneous, separate or sequential use in anticancer therapy.