Geminal disubstituted heterocyclic compounds and their use as IDH inhibitors

Abstract

The present invention relates to certain gem - disubstituted heterocyclic compounds that modulate the activity of isocitrate dehydrogenase (IDH). Accordingly, the compounds of the present invention are useful in treating diseases caused by mutant IDH1 enzyme and / or mutant IDH2 enzyme and / or IDH1 wild - type (wt) enzyme. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases using the pharmaceutical compositions comprising these compounds.

Description

[0001] The present invention relates to certain gem - disubstituted heterocyclic compounds that modulate the activity of isocitrate dehydrogenase (IDH). Accordingly, the compounds of the present invention are useful in treating diseases caused by mutant IDH1 enzyme and / or mutant IDH2 enzyme and / or IDH1 wild - type (wt) enzyme. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases using the pharmaceutical compositions comprising these compounds. BACKGROUND OF THE INVENTION

[0003] Isocitrate dehydrogenase (IDH) represents a family of metal - dependent redox enzymes involved in cellular metabolism. These enzymes catalyze the oxidative decarboxylation of isocitrate to α - ketoglutarate, during which carbon dioxide and NADH or NADPH are produced.

[0004] Three distinct members 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 alternatively uses NAD + as an electron acceptor.

[0005] IDH1 is located in the cytoplasm and peroxisomes and represents the major source of NADPH production in the cell, while IDH2 is located in the mitochondria as a component of the tricarboxylic acid cycle (TCA). The human IDH1 gene encodes a 414 - amino - acid protein, the amino acid sequence of which can be found as UniProtKB accession number O75874. The human IDH2 gene encodes a 452 - amino - acid protein, the amino acid sequence of which can be found as UniProtKB accession number P48735.

[0006] Somatic heterozygous mutations in isocitrate dehydrogenase 1 (IDH1) have been identified in approximately 80% of grade 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 cholangiocarcinomas (see Borger DR, Oncol. 2012, 17, 72–9), and at lower frequencies (<5%) in other solid tumors (e.g., glioblastoma, colorectal cancer, esophageal cancer, bladder cancer, melanoma, prostate cancer, breast adenocarcinoma) (see Cerami E, Cancer Discov. 2012, 2, 401–4).

[0007] IDH1 and IDH2 mutations have also been observed in many hematopoietic tumors, most commonly in 10%–15% of acute myeloid leukemia (AML) (see, e.g., Mardis ER, N Engl 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 in 20% of angioimmunoblastic T-cell lymphoma (see Cairns RA, Blood 2012, 119, 1901–3).

[0008] Interestingly, the same mutations in IDH1 or IDH2 have been identified in the majority of enchondromas and spindle cell hemangiomas in patients with Ollier disease and Maffucci syndrome (non-hereditary skeletal disorders) (see Amary et al., Nature Genetics, 2011, 1261-1265; and Pansuriya TC, Nat. Genet. 2011, 43, 1256–61).

[0009] All mutations have been found in heterozygosity in a mutually exclusive manner and in specific tissues. These mutations are present in the catalytic domain of the enzymes responsible for 2-oxoglutarate coordination and mainly involve 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 also been identified in IDH1, although at very low frequencies (e.g., Arg 100 and Gly 97; Dang L, Nature, 2009, 462, 739-44). In all cases, these mutation sites from Arg to Cys, His, Lys, Leu, or Ser abolish magnesium binding and prevent the conversion of isocitrate to α-ketoglutarate. Instead, the mutant enzymes acquire a neomorphic activity to convert α-ketoglutarate to R(-)-2-hydroxyglutarate (R-2-HG) (see P.S. Ward et al., Cancer Cell, 2010, 17, 225). In general, the production of 2-HG is enantiomer-specific, resulting in the production 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 by inhibiting several DNA and histone demethylases. The result at the cellular level is epigenetic reprogramming, leading to different transcriptional profiles, which induce dedifferentiation and tumorigenesis.

[0010] In glioblastoma (GBM) and other solid and systemic cancer models, IDH1 overexpression has been shown to maintain a less differentiated tumor cell state, promote growth, accelerate tumor progression, and reduce susceptibility to RTK-targeted therapies. At the molecular level, attenuated IDH1 activity results in reduced α-ketoglutarate (α-KG) and NADPH production, depletion of reduced glutathione, increased levels of reactive oxygen species (ROS), and enhanced histone methylation and expression of differentiation markers. Pharmacological inhibition of IDH1 with small molecules reduces GBM tumor burden and increases the survival rate of PDX mice. These data also suggest that cancer-associated IDH1 upregulation represents an actionable ("druggable") pro-cancer mechanism and provides a rationale for evaluating wild-type IDH1 inhibitors as anti-tumor agents (see Calvert et al., 2017, Cell Reports 19, 1858–1873).

[0011] Accordingly, inhibition of the IDH enzyme activity is a potential therapeutic treatment option for tumors and other IDH-related disorders.

[0012] Accordingly, there is a strong medical need for therapeutic agents that are active against diseases caused by and / or associated with mutant IDH enzymes and / or over-function of IDH wt, and some efforts are being made to develop inhibitors with their α-hydroxy neomorphic activity, especially small molecule inhibitors.

[0013] Certain biologically active pyrido-pyridin-7-one derivatives as kinase inhibitors are disclosed in WO2005 / 047284 in the name of Hoffmann La Roche.

[0014] Other pyrido-pyrimidin-7-one compounds useful as kinase inhibitors are disclosed in WO2007044813 and WO20087021389 in the name of Exelixis Inc., in WO1998 / 33798 in the name of Warner Lambert Co, and in WO2008 / 034008 in the name of Deciphera Pharmaceuticals Lcc.

[0015] Certain biologically active pyrimido-oxazin-2-one derivatives as IDH inhibitors are disclosed in WO2016 / 171755A1 in the name of Forma Therapeutics.

[0016] The present inventors have now found that the compounds of formula (I) described below are inhibitors of mutant IDH1 enzyme and / or mutant IDH2 enzyme and / or IDH1 wt enzyme, and can thus be used to treat diseases caused by high levels of 2-HG or by over-function of IDH wt.

[0017] Accordingly, a first object of the present invention is a substituted gem-disubstituted heterocyclic derivative of formula (I):

[0018]

[0019] Wherein:

[0020] X is nitrogen or -CH-;

[0021] U is CH, CH2 or CMe;

[0022] Y is CH, CF or O;

[0023] Indicates a single bond or a double bond;

[0024] R1a and R1b are each independently hydrogen, a linear or branched (C1-C6) alkyl group which is optionally substituted, or together with the atom to which they are attached may form a (C3-C6) cycloalkyl group;

[0025] A is a (C3-C6) cycloalkyl group, an aryl group or a heteroaryl group;

[0026] R4 is hydrogen, halogen, cyano or a linear or branched (C1-C6) alkyl group which is optionally substituted;

[0027] R5a and R5b are each independently a group selected from a linear or branched (C1-C6) alkyl group which is optionally substituted, a (C3-C6) cycloalkyl group, or together with the atom to which they are attached may form a 3- to 7-membered cycloalkylalkyl or heterocyclic group, the heterocyclic group containing a heteroatom selected from O, S, N-R6;

[0028] wherein:

[0029] R6 is a linear or branched (C1-C6) alkyl group which is optionally substituted, -COOR7 or -COR8;

[0030] wherein:

[0031] R7 and R8 are linear or branched (C1-C6) alkyl groups which are optionally substituted;

[0032] M is a bond, NH, NR6 or O, where R6 is as defined above;

[0033] G1 is N, CH, CH2 or CO;

[0034] Z1 is CR9aR9b;

[0035] Z2 is CR10aR10b;

[0036] wherein:

[0037] R9a, R9b, R10a and R10b are independently hydrogen or a linear or branched

[0038] (C1-C6) alkyl group which is optionally substituted;

[0039] m1 is 1, 2 or 3;

[0040] m2 is 0, 1, 2 or 3;

[0041] E is CN, or a linear or branched (C1-C6) alkyl group, a (C2-C6) alkenyl group, a (C2-C6) alkynyl group or a group of the formula -COR11 which is optionally substituted;

[0042] wherein:

[0043] R11 is an optionally substituted straight-chain or branched (C2-C6) alkyl, (C2-C6) alkenyl or (C2-C6) alkynyl;

[0044] R2 is an optionally substituted group selected from: straight-chain or branched (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, aryl-(C1-C6) alkyl and heterocyclic-(C1-C6) alkyl;

[0045] R3 is hydrogen, chlorine, cyano, CONH2, NH2, NR12aR12b, OR13 or an optionally substituted group selected from straight-chain or branched (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, aryl and heteroaryl;

[0046] wherein:

[0047] R12a and R12b are each independently selected from hydrogen or an optionally substituted straight-chain or branched (C1-C6) alkyl;

[0048] R13 is an optionally substituted straight-chain or branched (C1-C6) alkyl;

[0049] or a pharmaceutically acceptable salt thereof.

[0050] Preferred compounds of formula (I) are those wherein:

[0051] Y is CH or O;

[0052] R3 is hydrogen, chlorine, cyano, CONH2, NH2, NR12aR12b, OR13 or an optionally substituted group selected from straight-chain or branched (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl;

[0053] wherein:

[0054] R12a and R12b are each independently selected from hydrogen or an optionally substituted straight-chain or branched (C1-C6) alkyl;

[0055] R13 is an optionally substituted straight-chain or branched (C1-C6) alkyl;

[0056] m1 is 1 or 2;

[0057] m2 is 0, 1 or 2; and

[0058] X, U, R1a, R1b, A, R4, R5a, R5b, M, G1, Z1, Z2, E and R2 are as defined above.

[0059] In one embodiment, more preferred compounds of formula (I) are compounds wherein:

[0060] A is aryl or heteroaryl;

[0061] R4 is hydrogen, halogen or a straight-chain or branched (C1-C6) alkyl optionally substituted;

[0062] R3 is hydrogen, chlorine, cyano, CONH2, NH2, NR12aR12b or a group selected from straight-chain or branched (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl optionally substituted;

[0063] wherein:

[0064] R12a, R12b are each independently selected from hydrogen or a straight-chain or branched (C1-C6) alkyl optionally substituted; and

[0065] X, U, Y, R1a, R1b, R5a, R5b, M, G1, Z1, Z2, m1, m2, E and R2 are as defined above.

[0066] In another embodiment, more preferred compounds of formula (I) are compounds wherein:

[0067] R4 is hydrogen or halogen;

[0068] R3 is hydrogen, chlorine, cyano, CONH2, NH2, NR12aR12b or a group selected from straight-chain or branched (C1-C6) alkyl optionally substituted;

[0069] wherein:

[0070] R12a, R12b are each independently selected from hydrogen or a straight-chain or branched (C1-C6) alkyl optionally substituted; and

[0071] X, U, Y, R1a, R1b, A, R5a, R5b, M, G1, Z1, Z2, m1, m2, E and R2 are as defined above.

[0072] In another embodiment, more preferred compounds of formula (I) are compounds wherein:

[0073] R1a, R1b are each independently hydrogen, a straight-chain or branched (C1-C3) alkyl, or together with the atom to which they are attached can form a cyclopropyl group;

[0074] A is a phenyl group, a pyridyl group or a pyrimidinyl group;

[0075] R5a and R5b are each independently a group selected from linear or branched (C1-C6) alkyl groups, or together with the atom to which they are attached can form a 3- to 7-membered cycloalkylalkyl or heterocyclic group, said heterocyclic group containing a heteroatom selected from O or N-R6;

[0076] wherein:

[0077] R6 is linear or branched (C1-C6) alkyl or COR8;

[0078] wherein:

[0079] R8 is linear or branched (C1-C6) alkyl;

[0080] R2 is linear or branched (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl;

[0081] R3 is hydrogen, chlorine, cyano, NH2, NR12aR12b or linear or branched (C1-C6) alkyl; and

[0082] X, U, Y, R4, M, G1, Z1, Z2, m1, m2, E, R12a and R12b are as defined above.

[0083] In another embodiment, more preferred compounds of formula (I) are the following compounds, wherein:

[0084] R1a, R1b are each independently hydrogen, methyl, ethyl, or together with the atom to which they are attached can form a cyclopropyl group;

[0085] A is a phenyl group or a pyridyl group;

[0086] R4 is hydrogen;

[0087] R5a and R5b are each independently a group selected from methyl or ethyl, or together with the atom to which they are attached can form an optionally substituted (C3-C6) cycloalkyl group selected from cyclopentyl, cyclohexyl, 4,4-difluorocyclohexyl or a heterocyclic group selected from pyranyl, oxetanyl, N-methylpiperidinyl, N-acetylpiperidinyl;

[0088] R2 is methyl, ethyl, isopropyl or cyclopentyl;

[0089] R3 is hydrogen, cyano, methyl, NH2, NHMe or N(Me)2;

[0090] X, U, Y, M, G1, Z1, Z2, m1, m2 and E are as defined above.

[0091] Preferred compounds of formula (I) or pharmaceutically acceptable salts thereof are the compounds listed below:

[0092] 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 1);

[0093] 2-{[(1S)-1-{4-[2-(4-Acryloylpiperazin-1-yl)propan-2-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 2);

[0094] 2-{[(1S)-1-{4-[3-(4-Acryloylpiperazin-1-yl)oxetan-3-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 3);

[0095] 2-{[(1S)-1-{4-[3-(4-Acryloylpiperazin-1-yl)pentan-3-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 4);

[0096] 2-{[(1S)-1-(4-{4-[4-(But-2-ynoyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 5);

[0097] 2-{[(1S)-1-{4-[1-Acetyl-4-(4-acryloylpiperazin-1-yl)piperidin-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 6);

[0098] 2-{[4-(4-{4-[(1S)-1-{[7-Oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazin-1-yl]methyl}prop-2-enoic acid (cpd 7);

[0099] 2-{[(1S)-1-{4-[4-(4-Propionylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 8);

[0100] 2-{[(1R)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 9);

[0101] 2-{[(1S)-1-(4-{4-[4-(2,3-dihydroxypropanoyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 10);

[0102] 7-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one (cpd 11);

[0103] 2-{[(1S)-1-{6-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]pyridin-3-yl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 12);

[0104] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-4-methyl-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 13);

[0105] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one (cpd 14);

[0106] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (cpd 15);

[0107] 2-{[(1S)-1-{4-[1-(4-acryloylpiperazin-1-yl)cyclopentyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 16);

[0108] 2-{[(1S)-1-{4-[3-(4-acryloylpiperazin-1-yl)tetrahydrofuran-3-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 17);

[0109] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-5-methyl-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 18);

[0110] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-4-amino-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 19);

[0111] 2-{[(1S)-1-{4-[1-(4-acryloylpiperazin-1-yl)cyclohexyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 20);

[0112] 2-{[(1S)-1-(4-{4-[4-(2-methylacryloyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 21);

[0113] 2-{[(1S)-1-(4-{4-[4-(chloroacetyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 22);

[0114] 2-{[(1S)-1-(4-{4-[4-(3-chloropropanoyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 23);

[0115] 7-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (cpd 24);

[0116] 7-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-1-(propan-2-yl)-1,4-dihydro-2H-pyrido[4,3-d][1,3]oxazin-2-one (cpd 25);

[0117] 2-{[(1S)-1-{4-[1-(4-Acryloylpiperazin-1-yl)-4,4-difluorocyclohexyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 26);

[0118] 2-{[(1S)-1-{5-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]pyridin-2-yl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 27);

[0119] 2-{[(1S)-1-(4-{4-[(1-Acryloylazetidin-3-yl)(methyl)amino]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 28);

[0120] 2-{[(1S)-1-(4-{4-[(1-Acryloylazetidin-3-yl)oxy]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 29);

[0121] 2-[(1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}cyclopropyl)amino]-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 30);

[0122] 2-({4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]benzyl}amino)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 31);

[0123] 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)-1-methylpiperidin-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 32);

[0124] 2-{[(1S)-1-{4-[(2R)-2-(4-acryloylpiperazin-1-yl)butan-2-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 33);

[0125] 2-{[(1S)-1-{4-[(2S)-2-(4-acryloylpiperazin-1-yl)butan-2-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 34);

[0126] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(pentan-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 35);

[0127] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-4-(dimethylamino)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 36);

[0128] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-4-(methylamino)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 37);

[0129] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidine-4-carbonitrile (cpd 38);

[0130] 2-{[(1S)-1-(4-{4-[(1-acryloylpiperidin-4-yl)oxy]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 39);

[0131] 2-[(2-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}propan-2-yl)amino]-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 40);

[0132] 7-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-5-amino-1-(propan-2-yl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (cpd 41);

[0133] 2-{[(1S)-1-{4-[(2S)-2-(4-acryloylpiperazin-1-yl)-1-(morpholin-4-yl)propan-2-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 42);

[0134] 2-{[(1S)-1-{4-[(2R)-2-(4-acryloylpiperazin-1-yl)-1-(morpholin-4-yl)propan-2-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 43);

[0135] 7-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-1-ethyl-1,4-dihydro-2H-pyrido[4,3-d][1,3]oxazin-2-one (cpd 44);

[0136] 7-{[(1S)-1-{4-[4-(4-ethylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (cpd 45);

[0137] 2-{[(1S)-1-{4-[2-(4-acryloylpiperazin-1-yl)butan-2-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 46);

[0138] 7-{[(1S)-1-{4-[1-(4-acryloylpiperazin-1-yl)-4,4-difluorocyclohexyl]phenyl}ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one (cpd 47);

[0139] 7-{[(1S)-1-(4-{4-[(1-acryloylazetidin-3-yl)(methyl)amino]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one (cpd 48);

[0140] 2-[(1-{4-[1-(4-acryloylpiperazin-1-yl)cyclopentyl]phenyl}cyclopropyl)amino]-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 49);

[0141] 2-{[(1S)-1-(4-{1-[(1-acryloylazetidin-3-yl)(methyl)amino]-4,4-difluorocyclohexyl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 50);

[0142] 8-(propan-2-yl)-2-({(1S)-1-[4-(4-{4-[( 2 H3)acryloyl]piperazin-1-yl}tetrahydro-2H-pyran-4-yl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 51);

[0143] 2-[(2-{4-[1-(4-acryloylpiperazin-1-yl)-4,4-difluorocyclohexyl]phenyl}propan-2-yl)amino]-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 52);

[0144] 2-{[(1S)-1-(4-{1-[{1-[chloro(fluoro)acetyl]azetidin-3-yl}(methyl)amino]-4,4-difluorocyclohexyl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd53);

[0145] 2-{[(1S)-1-(4-{4-[4-(2-fluoropropenoyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 54);

[0146] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-[( 2 H7)propan-2-yl]pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 55);

[0147] N-{2-[(4,4-difluoro-1-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}cyclohexyl)amino]-2-oxoethyl}prop-2-enamide (cpd 56);

[0148] N2 - acryloyl - N - (4,4 - difluoro - 1 - {4 - [(1S) - 1 - {[7 - oxo - 8 - (propan - 2 - yl) - 7,8 - dihydropyrido[2,3 - d]pyrimidin - 2 - yl]amino}ethyl]phenyl}cyclohexyl) - D - alanine amide (cpd 57);

[0149] N2 - acryloyl - N - (4,4 - difluoro - 1 - {4 - [(1S) - 1 - {[7 - oxo - 8 - (propan - 2 - yl) - 7,8 - dihydropyrido[2,3 - d]pyrimidin - 2 - yl]amino}ethyl]phenyl}cyclohexyl) - L - alanine amide (cpd 58);

[0150] N - {2 - [(4 - {4 - [(1S) - 1 - {[7 - oxo - 8 - (propan - 2 - yl) - 7,8 - dihydropyrido[2,3 - d]pyrimidin - 2 - yl]amino}ethyl]phenyl}tetrahydro - 2H - pyran - 4 - yl)amino]ethyl}prop - 2 - enamide (cpd 59);

[0151] 7 - {[(1S) - 1 - (4 - {1 - [4 - (2,3 - dihydroxypropanoyl)piperazin - 1 - yl] - 4,4 - difluorocyclohexyl}phenyl)ethyl]amino} - 1 - (propan - 2 - yl) - 1,6 - naphthyridin - 2(1H) - one (cpd 60);

[0152] 7 - {[(1S) - 1 - (4 - {1 - [(1 - acryloylazetidin - 3 - yl)(methyl)amino] - 4,4 - difluorocyclohexyl}phenyl)ethyl]amino} - 1 - (propan - 2 - yl) - 1,6 - naphthyridin - 2(1H) - one (cpd 61);

[0153] N - (1 - acryloylazetidin - 3 - yl) - N - (4,4 - difluoro - 1 - {4 - [(1S) - 1 - {[2 - oxo - 1 - (propan - 2 - yl) - 1,2 - dihydronaphthyridin - 7 - yl]amino}ethyl]phenyl}cyclohexyl)acetamide (cpd62);

[0154] 7 - {[(1R) - 1 - {4 - [1 - (4 - acryloylpiperazin - 1 - yl) - 4,4 - difluorocyclohexyl]phenyl}ethyl]amino} - 1 - (propan - 2 - yl) - 1,6 - naphthyridin - 2(1H) - one (cpd 63);

[0155] 2 - {[(1S) - 1 - (4 - {4,4 - difluoro - 1 - [4 - (4 - hydroxybutyl)piperazin - 1 - yl]cyclohexyl}phenyl)ethyl]amino} - 8 - (propan - 2 - yl)pyrido[2,3 - d]pyrimidin - 7(8H) - one (cpd 64);

[0156] 4-(4-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carbonitrile (cpd 65);

[0157] N-{2-[(4-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)(trifluoroacetyl)amino]ethyl}prop-2-enamide (cpd 66) and

[0158] 7-{[(1S)-1-{4-[4,4-difluoro-1-(4-propionylpiperazin-1-yl)cyclohexyl]phenyl}ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one (cpd 67).

[0159] If a stereogenic center or another form of asymmetric center is present in the compounds of the present invention, then all forms of one or more such optical isomers, including enantiomers and diastereomers, are intended to be included herein. Compounds containing a stereogenic center can be used as racemic mixtures, enantiomerically enriched mixtures, or the racemic mixtures can be separated using well-known techniques and the individual enantiomers can be used. In cases where the compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of the present invention.

[0160] In cases where the compounds can exist in tautomeric forms such as keto-enol tautomers, each tautomeric form is expected to be included within the present invention, whether present in equilibrium or predominantly in one form.

[0161] Pharmaceutically acceptable salts of the compounds of formula (I) include salts with inorganic or organic acids, such as nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, oxalic acid, fumaric acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, and salicylic acid.

[0162] Pharmaceutically acceptable salts of the compounds of formula (I) also include salts with inorganic or organic bases, such as hydroxides, carbonates, or bicarbonates of alkali metals or alkaline earth metals, especially sodium, potassium, calcium, ammonium, or magnesium, acyclic amines, or cyclic amines.

[0163] Another object of the present invention is a compound of formula (I) wherein one or more hydrogens are replaced by one or more deuterium atoms.

[0164] When m2 is 0, it is intended that the group Z2 is absent and the groups G1 and N are saturated with hydrogen.

[0165] For the term "(C1-C6)alkyl", we mean an aliphatic (C1-C6) hydrocarbon chain containing only carbon-carbon single bonds which may be straight-chain or branched-chain. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl and the like.

[0166] For the term "(C3-C6)cycloalky", unless otherwise provided, we mean a 3- to 6-membered fully carbon monocyclic ring which may contain one or more double bonds but does not have a fully conjugated π-electron system.

[0167] Examples of (C3-C6)cycloalkyl groups are, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cyclohexadienyl. The (C3-C6)cycloalkyl ring may optionally be further fused or linked to aromatic and non-aromatic carbocyclic or heterocyclic rings.

[0168] For the term "heterocyclyl", we mean a 3- to 7-membered saturated or partially unsaturated carbocyclic ring wherein one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups are, for example, pyranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolinyl, imidolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, thiazolinyl, thiazolidinyl, dihydrofuryl, tetrahydrofuryl, tetrahydropyridyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl and the like. The heterocyclyl ring may optionally be further fused or linked to aromatic and non-aromatic carbocyclic or heterocyclic rings.

[0169] For the term "(C2-C6)alkenyl", we mean an aliphatic straight-chain or branched-chain (C2-C6) hydrocarbon chain containing at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl or 2-butenyl and the like.

[0170] For the term "(C2-C6)alkynyl", we mean an aliphatic straight-chain or branched-chain (C2-C6) hydrocarbon chain containing at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl or 2-butynyl and the like.

[0171] For the term “(C1-C6) alkoxy”, we mean any of the above-defined (C1-C6) alkyl groups attached to the remainder of the molecule through an oxygen atom (-O-).

[0172] The term “aryl” refers to monocyclic, bicyclic, or polycyclic carbocyclic hydrocarbons having from 1 to 4 ring systems, optionally further fused or linked to each other by single bonds, where at least one of the carbocyclic rings is “aromatic”, where the term “aromatic” refers to a completely conjugated π-electron bond system. Non-limiting examples of such aryl groups are phenyl group, α-naphthyl group or β-naphthyl group, α-tetrahydronaphthyl group or β-tetrahydronaphthyl group, biphenyl group, and indanyl group.

[0173] The term “heteroaryl” refers to aromatic heterocycles, typically 5- to 7-membered heterocycles having from 1 to 3 heteroatoms selected from N, O, or S; the heteroaryl rings can be optionally further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings. Non-limiting examples of such heteroaryl groups are, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, thiadiazolyl, oxadiazolyl, indazolyl, cinnolinyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, benzothiazolyl, benzothienyl, benzofuryl, isoindolinyl, benzimidazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, benzopyranyl, 2,3-dihydrobenzoxazinyl, 2,3-dihydroquinoxalinyl, and similar groups.

[0174] For the term “halogen”, we mean fluorine, chlorine, bromine, or iodine.

[0175] For the term “polyfluorinated (C1-C6) alkyl” or “polyfluorinated (C1-C6) alkoxy”, we mean any of the above-defined (C1-C6) alkyl groups or (C1-C6) alkoxy groups substituted by more than one fluorine atom, such as, for example, trifluoromethyl, trifluoroethyl, 1,1,1,3,3,3-hexafluoropropyl, trifluoromethoxy, and similar groups.

[0176] For the term “hydroxy (C1-C6) alkyl”, we mean any of the above-defined (C1-C6) alkyl groups having a hydroxy group, such as, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and similar groups.

[0177] According to the present invention and unless otherwise provided, R1a, R1b, R2, R3, R4, R5a, R5b, R9a, R9b, R10a, R10b and E may optionally be substituted at any of their free positions by one or more groups, such as from 1 to 6 groups, independently selected from: hydroxy, hydroxy(C1-C6)alkyl, halogen, nitro, oxo group(=O), cyano, (C1-C6)alkyl, polyfluorinated(C1-C6)alkyl, polyfluorinated(C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(C1-C6)alkyl, (C1-C6)alkylaryl, aryl(C1-C6)alkoxy, heteroaryl, heteroaryl(C1-C6)alkyl, (C1-C6)alkylheteroaryl, heterocyclic group, heterocyclic group(C1-C6)alkyl, (C1-C6)alkylheterocyclic group, (C1-C6)alkylheterocyclic group(C1-C6)alkyl, tris(C1-C6)alkylsilyl, (C3-C7)cycloalkyl, (C1-C6)alkoxy, aryloxy, heterocyclic group oxy, methylenedioxy, (C1-C6)alkylcarbonyloxy, arylcarbonyloxy, di(C1-C6)alkylaminoheterocyclic group(C1-C6)alkyl, (C3-C7)cycloalkenyloxy, heterocyclic group carbonyloxy, (C1-C6)alkylenaminooxy, carboxyl, (C1-C6)alkoxycarbonyl, aryloxycarbonyl, (C3-C7)cycloalkyl oxycarbonyl, amino, heterocyclic group(C1-C6)alkoxycarbonylamino, ureido, (C1-C6)alkylamino, amino(C1-C6)alkyl, di(C1-C6)alkylamino, arylamino, diarylamino, heterocyclic group amino, formylamino, (C1-C6)alkylcarbonylamino, arylcarbonylamino, heterocyclic group carbonylamino, aminocarbonyl, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, arylaminocarbonyl(C1-C6)alkyl, (C3-C7)cycloalkylaminocarbonyl, heterocyclic group aminocarbonyl, (C1-C6)alkoxycarbonylamino, hydroxyaminocarbonyl, (C1-C6)alkoxyimino, (C1-C6)alkylsulfonylamino, arylsulfonylamino, heterocyclic group sulfonylamino, formyl, (C1-C6)alkylcarbonyl, arylcarbonyl, (C3-C7)cycloalkylcarbonyl, heterocyclic group carbonyl, heterocyclic group carbonyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, polyfluorinated(C1-C6)alkylsulfonyl, arylsulfonyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl, arylaminosulfonyl, heterocyclic group aminosulfonyl, arylthio, (C1-C6)alkylthio; at any appropriate time, each of the substituents mentioned above may in turn be further substituted by one or more of the groups mentioned previously.

[0178] From all of the above, it will be clear to the person skilled in the art that any group whose name is a composite name, such as for example "aryl amino", must be intended to be interpreted conventionally by the moiety from which it is derived, for example by an amino group substituted by an aryl group, where the aryl group is as defined above.

[0179] Likewise, any terms such as for example (C1-C6) alkylthio, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C1-C6) alkoxycarbonyl, (C1-C6) alkoxycarbonylamino, heterocyclic carbonyl, heterocyclic carbonylamino, (C3-C7) cycloalkyloxycarbonyl and similar groups, including groups where the (C1-C6) alkyl moiety, (C1-C6) alkoxy moiety, aryl moiety, (C3-C7) cycloalkyl moiety and heterocyclic moiety are as defined above.

[0180] The present invention also provides a process for preparing a compound of general formula (I) as defined above, said process being carried out by using the reaction routes and synthetic schemes described below, with techniques available in the art and starting materials that are readily available. The preparation of certain embodiments of the present invention is described in the subsequent examples, but those of ordinary skill in the art will recognize that the described preparation can be readily adapted to prepare other embodiments of the present invention. For example, the synthesis of non-exemplary compounds according to the present invention can be carried out by modifications that will be apparent to those skilled in the art, such as by appropriately protecting interfering groups, by suitably replacing reagents with other reagents known in the art or by making conventional modifications to the reaction conditions. Alternatively, other reactions mentioned herein or known in the art will be considered to be suitable for preparing other compounds of the present invention.

[0181] The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. Unless otherwise indicated, the starting materials are known compounds or can be prepared from known compounds according to well-known procedures. It should be understood that when describing typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure), different process conditions can also be used unless otherwise stated. The optimal reaction conditions can vary depending on the reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0182] The compounds of general formula (I) as defined above can be prepared starting from intermediate compounds of formula (II) according to the general synthetic process described in Scheme 1:

[0183] Scheme 1

[0184]

[0185] Step 1a) React a compound of formula (II):

[0186]

[0187] wherein X is nitrogen or -CH-; U is CH, CH2 or CMe; Y is CH, CF or O; represents a single bond or a double bond; R2 is an optionally substituted group selected from: straight-chain or branched (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, aryl-(C1-C6) alkyl and heterocyclic-(C1-C6) alkyl; R3 is hydrogen, chlorine, cyano, CONH2, NH2, NR12aR12b, OR13 or an optionally substituted group selected from straight-chain or branched (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, aryl and heteroaryl; wherein: R12a, R12b are each independently selected from hydrogen or an optionally substituted straight-chain or branched (C1-C6) alkyl; R13 is an optionally substituted straight-chain or branched (C1-C6) alkyl; R1a and R1b are each independently hydrogen or an optionally substituted straight-chain or branched (C1-C6) alkyl, or together with the atom to which they are attached can form a (C3-C6) cycloalkyl; A is a (C3-C6) cycloalkyl, aryl or heteroaryl; R4 is hydrogen, halogen, cyano or an optionally substituted straight-chain or branched (C1-C6) alkyl; R5a and R5b are each independently a group selected from optionally substituted straight-chain or branched (C1-C6) alkyl, (C3-C6) cycloalkyl, or together with the atom to which they are attached can form a 3- to 7-membered cycloalkylalkyl or heterocyclic group, said heterocyclic group containing a heteroatom selected from O, S, N-R6; wherein: R6 is an optionally substituted straight-chain or branched (C1-C6) alkyl, -COOR7 or -COR8; wherein: R7 and R8 are optionally substituted straight-chain or branched (C1-C6) alkyl; M is a bond, NH, wherein R6 is NR6 as defined above, or O; G1 is N, CH, CH2 or CO; Z1 is CR9aR9b; Z2 is CR10aR10b; wherein: R9a, R9b, R10a and R10b are independently hydrogen or an optionally substituted straight-chain or branched (C1-C6) alkyl; m1 is 1, 2 or 3, and m2 is 0, 1, 2 or 3;

[0188] with a compound of formula (III):

[0189]

[0190] wherein E is CN or optionally substituted straight-chain or branched (C1-C6) alkyl, (C2-C6) alkenyl, or a group of formula -COR11; R11 is optionally substituted straight-chain or branched (C2-C6) alkyl or (C2-C6) alkenyl or (C2-C6) alkynyl; and Q is hydroxy, or chlorine, or bromine, to produce a compound of general formula (I), wherein X, U, Y, R2, R3, R1a, R1b, A, R4, R5a, R5b, M, G1, Z1, Z2 and E are as defined above.

[0191] The compound of general formula (II) as defined above can be prepared starting from the intermediate compound of formula (IV) according to the general synthetic process described in Scheme 2:

[0192] Scheme 2

[0193]

[0194] Therefore, the process of the present invention comprises the following steps:

[0195] Step 2a) reacting a compound of formula (IV):

[0196]

[0197] wherein G is chlorine, MeS(O)2-, MeS(O)- or OTrif; X, U, Y, R2 and R3 are as defined under step 1a, with a compound of formula (V):

[0198]

[0199] wherein R1a, R1b, A, R4, R5a, R5b, M, G1, Z1, Z2, m1 and m2 are as defined above under step 1a, and PG is a protecting group selected from tert-butyl formate, benzyl formate, phenyl formate;

[0200] Step 2b) reacting the compound of formula (VI) with a suitable deprotecting agent:

[0201]

[0202] wherein PG is as defined above in step 2a;

[0203] to produce a compound of formula (II), wherein X, U, Y, A, R1a, R1b, R2, R3, R4, R5a, R5b, M, G1, Z1, Z2, m1 and m2 are as defined above.

[0204] wherein G is MeS(O)2- or MeS(O)-, X is N, R3 is hydrogen or chlorine and U, Y, and R2, the compound of formula (IV) as defined in step 1a can be prepared according to Scheme 3:

[0205] Scheme 3

[0206]

[0207] Step 3a) The chlorine of the intermediate compound of formula (VII):

[0208]

[0209] wherein R3 is hydrogen, chlorine or an optionally substituted straight-chain or branched (C1-C6) alkyl, is substituted with an amine intermediate compound of formula (VIII):

[0210] R2-NH2

[0211] (VIII)

[0212] wherein R2 is as defined in step 1a above;

[0213] Step 3b) React the compound of formula (IX) with a reducing agent:

[0214]

[0215] wherein R2 and R3 are as defined above;

[0216] Step 3c) React the resulting compound of formula (X) with a suitable oxidizing agent:

[0217]

[0218] wherein R2 and R3 are as defined above;

[0219] Step 3d) React the resulting compound of formula (XI) with a reagent of formula T-CH2COOEt (XIV) wherein T is hydrogen or fluorine:

[0220]

[0221] wherein R2 and R3 are as defined above;

[0222] Step 3e) Mix the resulting intermediate compound of formula (XII) with an oxidizing agent:

[0223]

[0224] wherein U, Y and is as defined in step 1a, and R2 and R3 are as defined above, to give a compound of formula (IV) wherein G is MeS(O)2- or MeS(O)-, X is N, and R2, R3, U, Y and is as defined above;

[0225] or

[0226] Step 3f) React a compound of formula (X) with carbonyldiimidazole or triphosgene:

[0227]

[0228] wherein R2 and R3 are as defined above in step 3e to give a compound of formula (XII) wherein U is CH2, Y is O, is a single bond, and R2 and R3 are as defined above;

[0229] or

[0230] Step 3g) Alkylate the intermediate compound of formula (XIII) with an alkylating agent of formula R2-Lg (XV) wherein Lg is bromine, iodine, -OMs, –OTs or hydroxyl and R2 is as defined above:

[0231]

[0232] wherein R3, U, Y, are as defined above in step 3e to give a compound of formula (XII) wherein R2, R3, U, Y and are as defined above.

[0233] A compound of formula (IV) wherein G is chlorine and R3, X, U, Y and R2 are as defined above in step 1a can be prepared according to Scheme 4:

[0234] Scheme 4

[0235]

[0236] Step 4a) Substitute the chlorine of the intermediate compound of formula (XVI):

[0237]

[0238] wherein X and R3 are as defined above in step 1a, with an amine intermediate compound of formula (VIII):

[0239] R2-NH2

[0240] (VIII)

[0241] wherein R2 is as defined above in step 1a;

[0242] Step 4b) React the compound of formula (XVII) with a reducing agent:

[0243]

[0244] wherein X, R3 and R2 are as defined above;

[0245] Step 4c) React the resulting compound of formula (XVIII) with a suitable oxidizing agent:

[0246]

[0247] wherein X, R3 and R2 are as defined above;

[0248] Then

[0249] Step 4d) React the resulting compound of formula (XIX) with a compound of formula T-CH2COOEt (XIV) wherein T is hydrogen or fluorine:

[0250]

[0251] wherein X, R2 and R3 are as defined above to give a compound of formula (IV) wherein G is chlorine, U, Y, X, R3 and R2 are as defined above in step 1a;

[0252] Or

[0253] Step 4e) React the resulting compound of formula (XVIII) with carbonyldiimidazole or triphosgene:

[0254]

[0255] wherein X, R3 and R2 are as defined above to give a compound of formula (IV) wherein G is chlorine, U is CH2, Y is O, is a single bond, and X and R2 are as defined above.

[0256] If desired, convert the first compound of formula (XII) to the second compound of formula (XII) by operating according to well-known synthetic conditions.

[0257] Examples of possible conversions are those reported below:

[0258] Transformation A) The compound of formula (XII) in which R3 is chlorine is converted to the compound of formula (XII) in which R3 is CN by reaction with a source of cyanide under conditions known in the art for the palladium-catalyzed cyanation of aryl halides:

[0259]

[0260] Transformation B) The compound of formula (XII) in which R3 is chlorine is converted to the compound of formula (XII) in which R3 is NHPG by reaction with the amine PG-NH2:

[0261]

[0262] Transformation C) The compound of formula (XII) in which R3 is chlorine is converted to the compound of formula (XII) in which R3 is NR12aR12b by reaction with the amine HNR12aR12b in which R12a and R12b are each independently selected from hydrogen or optionally substituted straight-chain or branched (C1-C6) alkyl:

[0263]

[0264] Transformation D) The compound of formula (XII) in which R3 is chlorine is converted to the compound of formula (XII) in which R3 is OR13 by reaction with the alcohol R13-OH in which R13 is optionally substituted straight-chain or branched (C1-C6) alkyl:

[0265]

[0266] Transformation E) The compound of formula (XII) in which R3 is cyano is converted to the compound of formula (XII) in which R3 is CONH2 by hydrolysis with a suitable agent:

[0267]

[0268] If desired, the first compound of formula (IV) is converted to the second compound of formula (IV) by operating according to well-known synthetic conditions.

[0269] Examples of possible transformations are the examples reported below:

[0270] Transformation A1) The compound of formula (IV) in which G is MeS(O)2- is converted to the compound of formula (IV) in which G is -OTrif (triflate) by a two-step sequence with a suitable reagent:

[0271]

[0272] Wherein R1a, R1b, A, R4, R5a, R5b, M, G1, Z1, Z2, m1 and m2 are as reported in step 1a above and PG is a protecting group, the compound of formula (V) can be prepared according to Synthesis Scheme 5 reported below:

[0273] Scheme 5

[0274]

[0275] Step 5a) React a compound of formula (XX) with ClCH2CN under Ritter reaction conditions:

[0276]

[0277] wherein W1 is bromine, cyano, COR1a and A, R4, R5a, R5b and R1a are as defined in step 1a above, and then deprotect the amide intermediate under acidic conditions, basic conditions or with thiourea to obtain a compound of formula (XXI).

[0278] Step 5b) React the amino intermediate of formula (XXI):

[0279]

[0280] wherein W1, A, R4, R5a and R5b are as defined in step 5a above, with a compound of formula (XXII):

[0281]

[0282] wherein Z1, Z2, m1 and m2 are as reported in step 1a above, PG is a protecting group, and Hal is a halogen, to produce a compound of formula (XXIII), wherein W1, A, R4, R5a, R5b, Z1, Z2 and PG are as defined above, m1 and m2 are 1, 2 or 3, G1 is N, and M is a bond;

[0283] or

[0284] Step 5b’) React the amino intermediate of formula (XXI) with a heterocyclic halide of formula (XXIIa),

[0285]

[0286] wherein Z1, Z2, m1, m2 and PG are as reported above in step 5b and Hal is a halogen, and then the obtained intermediate is reacted by reductive amination with formaldehyde or with a suitable alkyl aldehyde derivative or by acylation with a suitable haloacyl derivative R8CO-hal or by reaction with an alkyl chloroformate derivative R7OCO-Cl, wherein R7 and R8 are as defined in step 1a; to form a compound of formula (XXIII), wherein PG is as defined above, W1, A, R4, R5a, R5b, Z1, Z2, m1 and m2 are as defined in step 1a, and G1 is CH and M is NR6, wherein R6 is as defined in step 1a;

[0287] or

[0288] Step 5b”) reacting the amino intermediate of formula (XXI) with a protected aminoalkyl of formula (XXIIb)

[0289]

[0290] wherein Z1, m1 and PG are as reported above in step 5b and FG is a functional group selected from aldehyde (-CHO) or carboxylic acid (-COOH), to yield a compound of formula (XXIII), wherein m2 is 0, PG is as defined above, W1, A, R4, R5a, R5b, Z1 and m1 are as defined in step 1a, G1 is CH2 or CO, and M is NH or NR6, wherein R6 is as defined in step 1a;

[0291] or

[0292] Step 5a’) a compound of formula (XX):

[0293]

[0294] wherein W1, A, R4, R5a and R5b are as defined above in step 5a, is reacted with a heterocyclic halide of formula (XXIIa):

[0295]

[0296] wherein Hal, Z1, Z2, m1, m2 and PG are as defined above in step 5b’; to form a compound of formula (XXIII), wherein W1, A, R4, R5a, R5b are as defined above in step 5a; Z1, Z2, m1, m2 and PG are as defined above in step 5b’; G1 is CH and M is O;

[0297] then

[0298] Step 5c) React the compound of formula (XXIII) obtained from step 5b or step 5b' or step 5b'' or step 5a' with ethylmagnesium bromide and boron trifluoride diethyl etherate:

[0299]

[0300] wherein W1 is cyano, and A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2 and PG are as reported above, to give the desired compound of formula (V), wherein A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2 and PG are as defined above, and R1a and R1b are the same and are as defined in step 1a, or R1a and R1b together are cyclopropyl;

[0301] or

[0302] Step 5c') React the compound of formula (XXIII) obtained from step 5b or step 5b' or step 5b'' or step 5a' with tert-butanesulfinamide:

[0303]

[0304] wherein W1 is COR1a, wherein A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2, PG and R1a are as defined above in step 5b or step 5b' or step 5b'' or step 5a', to yield a compound of formula (XXIV), wherein R1b is hydrogen, and A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2, PG and R1a are as defined above;

[0305] or

[0306] Step 5c'') React the compound of formula (XXIII) obtained from step 5b or step 5b' or step 5b'' or step 5a' with tert-butanesulfinamide:

[0307]

[0308] wherein W1 is COR1a, and A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2, PG and R1a are as defined above in step 5b or step 5b' or step 5b'' or step 5a', to yield a compound of formula (XXV);

[0309] Then

[0310] Step 5e) React the obtained compound of formula (XXV) with an alkyl Grignard reagent:

[0311]

[0312] wherein R1a, A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2 and PG are as defined above in step 5b or step 5b' or step 5b'' or step 5a' to give the desired compound of formula (XXIV);

[0313] Finally

[0314] Step 5d) React the compound of formula (XXIV) obtained according to step 5c' or step 5e with an acidic deprotecting reagent or with iodine:

[0315]

[0316] wherein R1b, R1a, A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2 and PG are as defined above in step 5c' or step 5e to give the desired compound of formula (V), wherein R1b, R1a, A, R4, R5a, R5b, M, G1, Z1, Z2, m1 and m2 are as defined in step 1a and PG is a protecting group;

[0317] Optionally, the compound of formula (XXIII) can also be obtained by converting another compound of formula (XXIII) as described in the following conversions:

[0318] Conversion F) A compound of formula (XXIII) wherein W1 is cyano is obtained by converting the corresponding compound of formula (XXIII) wherein W1 is bromine obtained from step 5b or step 5b' or step 5b'' or step 5a' with a source of cyanide under the conditions of palladium-catalyzed cyanation of aryl halides known in the art;

[0319]

[0320] Conversion G) A compound of formula (XXIII) wherein W1 is COR1a, where R1a is as defined in step 1a, is obtained by converting the compound of formula (XXIII) wherein W1 is bromine obtained from step 5b or step 5b' or step 5b'' or step 5a' with a suitable enol ether organometallic derivative and then hydrolyzing;

[0321]

[0322] The compound of formula (I) prepared according to Scheme 1 can be further converted into another compound of formula (I) by procedures well known to those skilled in the art.

[0323] Transformation 1) The compound of formula (I) in which E is an acrylamide group is transformed into a compound in which E is a dihydroxypropionic acid group

[0324]

[0325] According to Step 1, the reaction of the compound of formula (II) with the compound of formula (III) in which E is -COR11 can be carried out in a variety of ways and operating conditions, which are widely known in the field of amide preparation. As an example, when using an acyl chloride, the reaction is carried out as follows: in a suitable solvent such as, for example, DCM, THF, 1,4-dioxane, ACN or DMF or the like, at a temperature in the range from 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 scavenger such as triethylamine, N,N-diisopropylethylamine or pyridine; or when involving a carboxylic acid, the reaction is carried out as follows: in the presence of a coupling agent such as, for example, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N-cyclohexylcarbodiimide-N'-propylmethylpolystyrene or N-cyclohexylcarbodiimide-N'-methylpolystyrene, in a suitable solvent such as, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, at a temperature in the range from about -10 °C to reflux, and for a time from about 30 minutes to about 48 hours. The reaction is optionally carried out in the presence of a suitable catalyst such as 4-dimethylaminopyridine or in the presence of an additional coupling agent such as N-hydroxybenzotriazole.

[0326] Alternatively, when E is an optionally substituted straight-chain or branched (C1-C6) alkyl, (C2-C6) alkenyl, the alkylation of the intermediate of formula (II) can be carried out in the presence of a suitable base such as Na2CO3, K2CO3, Cs2CO3, NaH, KH and the like, in a suitable solvent such as DMF, DMA, ACN, acetone, THF and the like, at a temperature in the range from 0 °C to reflux.

[0327] According to step 2a, the replacement of the leaving group such as methyl sulfone, methyl sulfoxide or chlorine or trifluoromethanesulfonate of the intermediate from formula (IV) by the group of formula (V) is carried out as follows: using an organic base such as DIPEA, optionally with CsF as a reaction promoter, in a suitable solvent such as ACN, DMSO, 1,4-dioxane, and at a temperature in the range from room temperature to 90 °C under conventional heating or microwave irradiation, for a time in the range from 1 h to 24 h;

[0328] Optionally, and more particularly when G is chlorine and X is -CH, the reaction can be completed under conditions well known to those skilled in the art. For example, the halide can be replaced by: a Buchwald-Hartwig amination reaction using a suitable palladium source such as a PEPPSI precatalyst and a base such as Cs2CO3, in a solvent such as toluene or ACN, at a temperature in the range from 60 °C to 110 °C under conventional heating or microwave irradiation, and for a time in the range from 1 h to 24 h.

[0329] According to step 2b, when the protecting group is phenyl carbamate, the deprotection of the compound of formula (VI) can be carried out as follows: under basic conditions by using, for example, NaOH, KOH, in a solvent such as ethanol, isopropanol, 1,4-dioxane, under reflux for a time in the range from 6 h to 18 h. Optionally, when the protecting group is Boc, the reaction is carried out as follows: under acidic conditions such as, for example, TFA, 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 a mixture of EtOH / water, at a temperature in the range from room temperature to reflux, and for a time in the range from 1 h to about 12 h. Optionally, when the protecting group is benzyl carbamate, the reaction is carried out as follows: using Pd / C, in the presence of a hydrogen source such as ammonium formate, cyclohexene, 1,3-cyclohexadiene, in a suitable solvent such as EtOH or isopropanol, at reflux temperature for a time in the range from 1 h to about 18 h.

[0330] According to step 3a, the replacement of the chlorine of the compound of formula (VII) by the amine of formula R2-NH2 (VIII) can be carried out in pure form, or in the presence of a suitable base such as Na2CO3, K2CO3, Cs2CO3, TEA, DIPEA and the like, in a suitable solvent such as DMF, DMA, ACN, DMSO and the like, at a temperature in the range from room temperature to reflux.

[0331] According to step 3b of the process, the reduction of the ester of formula (IX) to obtain the compound of formula (X) can be carried out in different ways and experimental conditions well-known in the art. Reducing agents such as lithium aluminum hydride or the like can be used, in a suitable solvent such as THF, at a temperature in the range from 0 °C to room temperature for a period of from 2 h to about 24 h. Preferably, the reaction is conveniently carried out with lithium aluminum hydride in THF at room temperature.

[0332] According to step 3c of the process, the oxidation of the intermediate of formula (X) to the aldehyde of formula (XI) can be carried out using manganese(II) dioxide, pyridinium chlorochromate, iodobenzene diacetate (IBX), tetrapropylammonium perruthenate (TPAP), 4-methylmorpholine N-oxide or sodium hypochlorite / TEMPO / Bu4NHSO4, in a solvent such as DCM, ACN, THF, EtOAc, acetone or chloroform at room temperature.

[0333] According to step 3d, the Claisen–Schmidt condensation of the intermediate of formula (XI) with the intermediate of formula (XIV) can be carried out as follows: in the presence of a suitable base such as Na2CO3, K2CO3, LiOH, Cs2CO3, potassium tert-butoxide, LiHMDS, KHMDS and the like, in a suitable solvent such as THF, DMF, DMA and the like, at a temperature in the range from -50 °C to reflux, under classical thermal conditions or in a microwave device for a period of time in the range from 1 h to 24 h.

[0334] According to step 3e, the oxidation of the methylthio group of the intermediate of formula (XII) to produce the compound of formula (IV) in which G is MeS(O)2- or MeS(O) can be carried out as follows: in the presence of oxidizing agents well-known to those skilled in the art such as, for example, potassium monopersulfate (oxone) or meta-chloroperoxybenzoic acid and the like, in a suitable solvent such as DCM, or at room temperature for a period of time in the range from 1 h to 16 h.

[0335] According to step 3f, the cyclization of the intermediate of formula (X) to oxazin-2-one under carbamylation conditions can be accomplished by using triphosgene, carbonyldiimidazole or phosgene in the presence of a base such as DIPEA or TEA, at a temperature of about -30 °C to room temperature for a period of time in the range from 1 h to 6 h.

[0336] According to step 3g, alkylation of the intermediate of formula (XIII) with the intermediate of formula (XV) wherein Lg is bromine, iodine, -OMs or -OTs can be carried out in the presence of a suitable base such as Na2CO3, K2CO3, Cs2CO3, NaH, KH and the like, in a suitable solvent such as DMF, DMA, ACN, acetone, THF and the like, at a temperature ranging from 0°C to reflux. When an intermediate of formula (XV) in which Lg is hydroxy is used, the reaction is preferentially 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 and the like, at a temperature ranging from 0°C to 65°C.

[0337] According to step 4a, the substitution of the chlorine of the compound of formula (XVI) by the amine of formula (VIII) can be carried out as described above in step 3a.

[0338] According to step 4b of the process, the reduction of the ester of formula (XVII) to obtain the compound of formula (XVIII) can be carried out as described above in step 3b.

[0339] According to step 4c of the process, oxidation of the intermediate of formula (XVIII) to the aldehyde of formula (XIX) can be carried out as described above in step 3c.

[0340] According to step 4d, compounds of formula (XIX) are cyclized under the Claisen-Schmidt condensation conditions reported in step 3d to provide compounds of formula (IV) wherein G is chloro and X is nitrogen or -CH-.

[0341] According to step 4e, the compound of formula (XVIII) is cyclized under the conditions reported in step 3f for the carbamylation to oxazin-2-one to provide a compound of formula (IV) wherein G is chloro and X is nitrogen or -CH-, U is CH2, and Y is O.

[0342] According to transformation A of the process, the heteroaryl chloride of formula (XII) can be reacted with a source of cyanide such as sodium cyanide, potassium cyanide according to nucleophilic aromatic substitution reaction in different ways and experimental conditions known in the art, or alternatively by the following reaction: using ZnCN, CuCN or potassium hexacyanoferrate (II) as the source of cyanide, in the presence of palladium(II) acetate as the catalyst, sodium carbonate, potassium carbonate or cesium carbonate as the base, in a suitable solvent such as DMF, N-methylpyrrolidone or DMA, from 80 °C to reflux, for a time in the range from 4 hours to about 24 hours (J. Org. Chem. 2005, 70, 1508 - 1510, Org. Lett., 2011, 13(4), pp. 648–651, Org Lett. 2015 17(2), pp. 202–205).

[0343] According to transformation B of the process, the heteroaryl chloride of formula (XII) can be reacted with the amine PG-NH2 in acetonitrile under reflux for a time in the range from 1 hour to about 24 hours in different ways and experimental conditions.

[0344] According to transformation C of the process, the heteroaryl chloride of formula (XII) can be reacted with the amine of formula NR12aR12b in a suitable solvent such as acetonitrile, DMF, DMA from rt to reflux for a time in the range from 2 hours to about 24 hours in different ways and experimental conditions.

[0345] According to transformation D of the process, the heteroaryl chloride of formula (XII) can be reacted with the alcohol of formula OR13 in a suitable solvent such as acetonitrile, THF in the presence of potassium carbonate, cesium carbonate from rt to reflux for a time in the range from 2 hours to about 24 hours in different ways and experimental conditions.

[0346] According to transformation E of the process, the heteroaryl nitrile of formula (XII) can be reacted with acetamide in the presence of 1,4-dioxane in the presence of Pd(OAc)2 under reflux for a time in the range from 4 h to about 24 h.

[0347] According to transformation A1 of the process, the transformation of the compound of formula (IV) to the corresponding trifluoromethanesulfonate derivative of formula (IV) can be accomplished in different ways and experimental conditions known in the art. The compound of formula (IV) is first reacted with NaOH, KOH or the like in a suitable solvent such as water, acetonitrile, dioxane, DMSO at a temperature ranging from room temperature to 90 °C for a time within the range from 1 h to about 4 h. Then, the obtained hydroxy derivative is reacted with trifluoromethanesulfonic anhydride or N-phenylbis(trifluoromethanesulfonyl)imide (N-phenyltriflimide) in the presence of a base such as DIPEA, TEA, 2,6-dimethylpyridine in a solvent such as DCM, THF at a temperature of about -10 °C to room temperature for a time within the range from 1 h to 6 h.

[0348] According to step 5a of the process, the conversion of the compound of formula (XX) to the derivative of formula (XXI) can be accomplished under acid-induced nucleophilic addition of nitrile, followed by hydrolysis to the corresponding amide. This reaction is known as the Ritter reaction and is carried out with H2SO4 and chloroacetonitrile at a temperature within the range from 0 °C to 20 °C for 6 h to 12 h. The amide thus obtained is further reacted with thiourea in ethanol and acetic acid at 60 °C for 6 h to 12 h to produce the derivative of formula (XXI).

[0349] According to step 5b, the reaction of the compound of formula (XXI) with a suitable substituted alkyldihalide of formula (XXII) to give the corresponding derivative of formula (XXIII) is accomplished using a solvent such as DIPEA in the presence of NaI under reflux for 24 h to 72 h.

[0350] According to step 5a', the reaction of the compound of formula (XX) with a suitable substituted heterocyclic halide of formula (XXIIa) is accomplished by using a suitable base such as NaH, K2CO3, Cs2CO3, LiHMDS in a suitable solvent such as DMF, acetonitrile, THF, DIPEA in the presence of NaI at a temperature within the range from rt to reflux and for a time within the range from 4 h to about 24 h to give the corresponding derivative of formula (XXIII).

[0351] According to step 5b', the reaction of the compound of formula (XXI) with a suitable substituted heterocyclic halide of formula (XXIIa) is accomplished by using a suitable base such as NaH, K2CO3, Cs2CO3, LiHMDS in a suitable solvent such as DMF, acetonitrile, THF, DIPEA in the presence of NaI at a temperature within the range from rt to reflux, and for a time within the range from 4 h to about 24 h.

[0352] Alternatively, the reaction of a compound of formula (XXI) with a suitable heterocyclic ketone of formula (XXIIa) is carried out in the presence of titanium tetraethoxide or titanium tetraisopropoxide as a suitable catalyst in a suitable solvent such as THF, toluene, 1,4-dioxane at a temperature in the range from 70 °C to reflux for a time in the range from 16 h to 24 h. The obtained intermediate is directly treated with a reducing agent such as NaCNBH3 (sodium cyanoborohydride) at a temperature in the range from 20 °C to 70 °C for a time in the range from 1 hour to 4 hours to produce an intermediate compound, which is then reacted with formaldehyde or an alkyl aldehyde under reductive amination conditions in the presence of a reducing agent such as NaCNBH3, NaBH(OAc)3 and the like, in a solvent such as MeOH, EtOH, 2,2,2-trifluoroethanol and the like, at a temperature in the range from rt to 40 °C for a time in the range from 1 h to about 24 h. The reduction reaction can optionally be carried out in the presence of a suitable catalyst such as AcOH, TFA and the like, or reacted with a suitable haloacyl derivative in a solvent such as DCM, THF, DMF and the like, optionally in the presence of a base, at a temperature in the range from rt to 40 °C for a time in the range from 1 h to about 24 h, or reacted with an alkyl chloroformate derivative in a solvent such as DCM, THF, DMF, dioxane and the like, optionally in the presence of a base, at a temperature in the range from rt to 40 °C for a time in the range from 1 h to about 24 h to produce a compound of formula (XXIII).

[0353] According to step 5b", the reaction of a compound of formula (XXI) with a protected aminoalkyl aldehyde of formula (XXIIb) is carried out by using a reducing agent such as NaCNBH3 (sodium cyanoborohydride), NaBH(OAc)3 (sodium triacetoxyborohydride), in a solvent such as DCM, THF and the like at a temperature in the range from 20 °C to 50 °C for a time in the range from 1 hour to 4 hours. The reduction reaction can optionally be carried out in the presence of a suitable catalyst such as AcOH, TFA to produce an intermediate compound, which is further reacted with trifluoroacetic anhydride in the presence of pyridine and the like at room temperature for a time in the range from 1 h to about 24 h to produce a compound of formula (XXIII).

[0354] Alternatively, the reaction of a compound of formula (XXI) with a protected aminoalkyl carboxylic acid of formula (XXIIb) in which FG is -COOH can be carried out in a variety of ways and operating conditions, which are widely known in the field of amide preparation. As an example, the reaction is carried out as follows: in the presence of a coupling agent such as, for example, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), T3P (1-propane phosphonic anhydride), in a suitable solvent such as, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, ethyl acetate, at a temperature in the range from about -10 °C to reflux, and for a time ranging from about 30 minutes to about 48 hours.

[0355] According to step 5c, the compound of formula (XXIII) is subjected to the Kulinkovich-Szymoniak reaction, which allows the preparation of primary cyclopropylamines by reaction of ethyl Grignard reagent in the presence of a stoichiometric amount of titanium(IV) isopropoxide and is then exposed to boron trifluoride diethyl ether in a subsequent step. The reaction is carried out in diethyl ether, methyl tert-butyl ether (MTBE) at a temperature in the range from -70 °C to 0 °C for a time in the range from 1 hour to 4 hours to give the corresponding derivative of formula (V).

[0356] According to step 5c’, the compound of formula (XXIII) is reacted with tert-butanesulfinamide in the presence of tetraethoxytitanium or tetraisopropoxytitanium as a suitable catalyst in a suitable solvent such as THF, toluene, 1,4-dioxane at a temperature in the range from 50 °C to reflux for a time in the range from 4 h to 16 h. The obtained intermediate is directly treated with a reducing agent such as NaBH4 (sodium borohydride), lithium tri-sec-butylborohydride (L-selectride) at a temperature in the range from -70 °C to 0 °C for a time in the range from 1 hour to 4 hours to produce the compound of formula (XXIV).

[0357] According to step 5c”, the compound of formula (XXIII) is reacted with tert-butanesulfinamide in the presence of tetraethoxytitanium or tetraisopropoxytitanium as a suitable catalyst in a suitable solvent such as THF, toluene, 1,4-dioxane at a temperature in the range from 50 °C to reflux for a time in the range from 4 h to 16 h.

[0358] According to step 5e, the compound of formula (XXV) is reacted with methylmagnesium reagent or ethylmagnesium reagent in diethyl ether or THF at a temperature in the range from 0 °C to room temperature for 1 h to 4 h to give the compound of formula (XXIV).

[0359] According to step 5d, the compound of formula (XXIV) is reacted with a strong acid such as, for example, hydrochloric acid in 1,4-dioxane or in methanol at room temperature for a time in the range from 1 hour to 24 hours to produce the compound of formula (V).

[0360] Alternatively, the compound of formula (XXIV) is reacted with iodine in a solvent such as a mixture of THF and H2O at a temperature in the range from room temperature to 80 °C for a time in the range from 1 hour to 24 hours to produce the compound of formula (V).

[0361] Examples of possible transformations are reported below:

[0362] According to transformation F, the compound of formula (XXIII) is reacted with a suitable source of cyanide such as ZnCN, CuCN, K3[Fe(CN)6] or the like in the presence of a suitable palladium catalyst such as Pd(OAc)2, PdCl2(PPh3)3, Pd(dppf)Cl2 and the like. The reaction is carried out in the presence of a suitable base such as sodium carbonate, potassium carbonate or cesium carbonate and the like, in a solvent such as THF, dioxane, DMF, acetonitrile, at a temperature in the range from 80 °C to reflux for a time in the range from 4 hours to about 24 hours.

[0363] According to transformation G, the compound of formula (XXIII) is cross-coupled with a suitable enol ether organometallic derivative such as 1-ethoxyvinyltributyltin in the presence of a suitable palladium catalyst such as PdCl2(PPh3)3, Pd(dppf)Cl2 and the like. The reaction is carried out in the presence of a suitable base such as TEA, DIPEA and the like, at a temperature in the range from r.t. to reflux for a time in the range from 1 hour to about 24 hours. The intermediate thus obtained is further hydrolyzed with aqueous HCl 6N at room temperature for a time in the range from 1 h to about 24 h to produce the compound of formula (V).

[0364] According to transformation 1), the acrylamide of formula (I) is reacted with osmium tetroxide in pyridine and tert-butanol (as reported in WO211046964) at room temperature for a time in the range from 8 hours to 24 hours.

[0365] From all of the above, it will be clear to the person skilled in the art that any compound of formula (I) having a functional group that can be further derivatized into another functional group is intended to be included within the scope of the present invention, the derivatization being effected by operating according to methods well known in the art to obtain other compounds of formula (I).

[0366] When preparing the compounds of general formula (I) according to any of the above variants of the process, any optional functional groups present in the starting materials, reagents or intermediates thereof and which may give rise to unwanted side reactions need to be appropriately protected according to conventional techniques (see, for example, Green, Theodora W. and Wuts, Peter G.M. – Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons Inc., New York (NY), 2012). Similarly, the conversion of these protected compounds into the free, deprotected compounds can be carried out according to known procedures.

[0367] Each compound of the general formula can be further converted into other compounds of the same general formula according to methods well known from the literature, as reported in the experimental part.

[0368] According to any variant of the process for preparing the compounds of formula (I), the starting materials and any other reactants are known or can be readily prepared according to known methods.

[0369] The intermediate of formula (XI) in which R3 is chlorine is prepared as reported in WO2016204429A1.

[0370] The compounds of formula (XXI) can also be prepared as described in Tetrahedron, Vol. 72, 2016, 1941 - 1953.

[0371] The compounds of formula (XX) can be prepared as described in WO2014086316.

[0372] The compounds of formula (XXII) can be prepared as described in WO2009065622A1.

[0373] The compounds of formula (III, VII, VIII, XII, XIV, XV, XVI, XXIIa, XXIIb) are commercially available or can be prepared by known methods.

[0374] The final compounds can be isolated and purified using conventional procedures, such as chromatography and / or crystallization and salt formation.

[0375] 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 their pharmaceutically acceptable salts can subsequently be formulated together with a pharmaceutically acceptable carrier or diluent to provide a pharmaceutical composition.

[0376] According to the synthetic processes described above, the synthesis of the compounds of general formula (I) can be carried out in a stepwise manner, whereby, if desired, each intermediate is separated and purified by standard purification techniques such as, for example, column chromatography before the subsequent reaction is carried out. Alternatively, two or more steps of the synthetic sequence can be carried out in a so-called "one-pot" procedure known in the art, whereby only the compound obtained from two or more steps is separated and purified.

[0377] In cases where the compounds of general formula (I) contain one or more asymmetric centers, the compounds can be separated into individual stereoisomers by procedures known to those skilled in the art. Such procedures include standard chromatographic techniques or crystallization, and standard chromatographic techniques include chromatography using a chiral stationary phase. General methods for separating compounds containing one or more asymmetric centers are reported, for example, in Jacques, Jean; Collet, André; Wilen, Samuel H., Enantiomers, Racemates, and Resolutions, John Wiley & Sons Inc., New York (NY), 1981.

[0378] The present invention also provides a method for treating a disease caused by and / or associated with an increased level of 2-hydroxyglutaric acid, the method comprising administering to a mammal, preferably a human, in need thereof an effective amount of a compound of formula (I) as defined above.

[0379] Furthermore, the present invention provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in a method for treating a disease caused by and / or associated with an increased level of 2-hydroxyglutaric acid, the method comprising administering to a mammal, preferably a human, in need thereof an effective amount of a compound of formula (I) as defined above.

[0380] Furthermore, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a disease caused by and / or associated with an increased level of 2-hydroxyglutaric acid, which comprises administering to a mammal, preferably a human, in need thereof an effective amount of a compound of formula (I) as defined above.

[0381] In yet another aspect, the present invention provides the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease caused by and / or associated with increased levels of 2-hydroxyglutaric acid, which comprises administering to a mammal, preferably a human, in need thereof an effective amount of a compound of formula (I) as defined above.

[0382] In addition, the present invention provides a method for treating a disease caused by and / or associated with a mutant IDH enzyme or IDH wt overfunction, which method comprises administering to a mammal, preferably a human, in need thereof an effective amount of a compound of formula (I) as defined above.

[0383] Furthermore, the present invention provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in a method for treating a disease caused by and / or associated with a mutant IDH enzyme or IDH wt overfunction, which method comprises administering to a mammal, preferably a human, in need thereof an effective amount of a compound of formula (I) as defined above.

[0384] In addition, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disease caused by and / or associated with a mutant IDH enzyme or IDH wt overfunction, which comprises administering to a mammal, preferably a human, in need thereof an effective amount of a compound of formula (I) as defined above.

[0385] In yet another aspect, the present invention provides the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease caused by and / or associated with a mutant IDH enzyme or IDH wt overfunction, which comprises administering to a mammal, preferably a human, in need thereof an effective amount of a compound of formula (I) as defined above.

[0386] Preferably, the disease is selected from the group consisting of: cancer, cell proliferative disorders, immune-related disorders. More preferably, the disease is cancer.

[0387] According to the most preferred embodiments of the present invention, the cancer is selected from the group consisting of: carcinomas, such as bladder cancer, breast cancer, kidney cancer, liver cancer, colon cancer, lung cancer including small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, prostate cancer, and skin cancer including squamous cell carcinoma; lymphoid hematopoietic tumors, including leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, B-cell lymphoma, angioimmunoblastic T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt's lymphoma; myeloid hematopoietic tumors, including acute and chronic myelogenous leukemia, myelodysplastic syndromes, and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous systems, including glioma, glioblastoma, glioblastoma multiforme, astrocytoma, oligodendroglioma, paraganglioma, neuroblastoma, and schwannoma; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid cancer such as papillary thyroid carcinoma and medullary thyroid carcinoma, Kaposi sarcoma, chondrosarcoma, and cholangiocarcinoma.

[0388] Other preferred diseases caused by and / or associated with mutant IDH enzymes or overactive IDH wt are proliferative disorders, such as, for example, benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, and postoperative stenosis and restenosis.

[0389] Additional preferred diseases caused by and / or associated with mutant IDH enzymes or increased 2-hydroxyglutarate levels are, for example, Ollier disease and Maffucci syndrome.

[0390] Other preferred diseases caused by and / or associated with mutant IDH enzymes or overactive IDH wt are immune-related disorders, including but not limited to: transplant rejection, skin disorders such as psoriasis, allergy, asthma, and autoimmune-mediated diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Crohn's disease, and amyotrophic lateral sclerosis. Optionally, the methods of the present invention further include treating a mammal in need thereof in combination with a radiotherapy or chemotherapy regimen.

[0391] Furthermore, the present invention provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in a method of treating a mammal in need thereof in combination with radiotherapy or in combination with a chemotherapy regimen.

[0392] In one embodiment, the chemotherapy regimen comprises at least one cytostatic or cytotoxic agent.

[0393] Cytostatic or cytotoxic agents include, but are not limited to, antibiotic agents, alkylating agents, antimetabolites, hormonal agents, immunological agents, interferon agents, cyclooxygenase inhibitors (e.g., COX-2 inhibitors), matrix metalloproteinase inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenic agents (e.g., angiogenesis inhibitors), farnesyl transferase 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, inhibitors of mTOR, histone deacetylase inhibitors, hypoxia response inhibitors, PD-1 antagonists or antigen-binding fragments thereof that specifically bind to PD-1 or PD-L1.

[0394] If formulated as a fixed dose, such combination products employ the compound of the present invention in the dosage ranges described below and other pharmaceutically active agents in the approved dosage ranges.

[0395] When combination formulations are not appropriate, the compound of formula (I) can be used sequentially with known anticancer agents.

[0396] The compound of formula (I) of the present invention suitable for administration to a mammal such as 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.

[0397] For example, suitable dosages for oral administration of the compound of formula (I) can range from about 10 mg to about 1000 mg per dose, from 1 to 5 times daily. The compounds of the present invention can be administered in a variety of dosage forms, e.g., orally, in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories; parenterally, e.g., intramuscularly, or by intravenous and / or intrathecal and / or intraspinal injection or infusion.

[0398] Pharmaceutical compositions comprising the compounds of the present invention are generally prepared by conventional methods and are administered in a suitable pharmaceutical form.

[0399] For example, solid oral forms can contain a diluent together with the active compound, such as lactose, dextrose, sucrose (saccharose), sucrose (sucrose), cellulose, corn starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium stearate or calcium stearate and / or polyethylene glycol; binders such as starch, gum arabic, gelatin, methylcellulose, 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 sulphate; and non-toxic and pharmacologically inactive substances commonly used in pharmaceutical formulations. These pharmaceutical products can be manufactured in a known manner, for example by means of mixing processes, granulation processes, tabletting processes, sugar coating processes or film coating processes.

[0400] Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions.

[0401] As an example, syrups can contain sucrose as a carrier or sucrose together with glycerol and / or mannitol and sorbitol.

[0402] As examples of carriers, suspensions and emulsions can contain natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

[0403] Suspensions or solutions for intramuscular injection can contain a pharmaceutically acceptable carrier together with the active compound, such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride.

[0404] Solutions for intravenous injection or infusion can contain sterile water as a carrier, or preferably they can be in the form of a sterile solution, aqueous solution, isotonic solution, saline solution, or they can contain propylene glycol as a carrier.

[0405] Suppositories can contain a pharmaceutically acceptable carrier together with the active compound, such as cocoa butter, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester surfactants or lecithin.

[0406] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, carrier or diluent.

[0407] The present invention also provides a pharmaceutical composition of a compound of formula (I), which further comprises one or more chemotherapeutic agents. Chemotherapeutic agents include, but are not limited to, cytostatic or cytotoxic agents, antibiotic agents, alkylating agents, antimetabolic agents, hormonal agents, immunological agents, interferon agents, cyclooxygenase inhibitors (such as COX-2 inhibitors), matrix metalloproteinase inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenic agents (such as angiogenesis inhibitors), farnesyl transferase 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, inhibitors of mTOR, histone deacetylase inhibitors, hypoxia response inhibitors, PD-1 antagonists or antigen-binding fragments thereof that specifically bind to PD-1 or PD-L1, and analogs.

[0408] In addition, the present invention provides an in vitro method for inhibiting the activity of a mutant IDH protein, which method comprises contacting said protein with an effective amount of a compound of formula (I) as defined above.

[0409] Furthermore, the present invention provides a product comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof and one or more chemotherapeutic agents, for use simultaneously, separately or sequentially in anticancer therapy as a combination product.

[0410] In yet another aspect, the present invention provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use as a medicament.

[0411] Finally, the present invention provides the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament having anticancer activity.

[0412] Experimental Section

[0413] The short forms and abbreviations used herein have the following meanings:

[0414]

[0415]

[0416]

[0417] Biochemical Assays

[0418] IDH1m (R132H or R132C) and IDH2 R172K In Vitro Assays of Inhibitors

[0419] The enzymatic activity of IDH mutations that convert α-ketoglutaric acid to 2-hydroxyglutaric acid is measured using NADPH consumption assays. In the assay, at the end of the reaction, the remaining cofactor is measured in the presence of catalytically excessive amounts of diaphorase and resazurin to generate a fluorescent signal proportional to the amount of remaining NADPH. IDH1WT enzyme as well as mutant subtypes IDH1 R132H enzyme, IDH1 R132C enzyme, and IDH2 R172K enzymes are commercially available proteins (see, for example, SinoBiological, Abcam, Active Motif or Creative BioMart).

[0420] The IDH1 R132H homodimeric enzyme is diluted to 8 nM 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 β-mercaptoethanol); 0.2 μL of a test compound, which was previously serially diluted 1 to 3-fold from 1 mM in DMSO, >10 experimental points, is added and the mixture is incubated at room temperature for 15 minutes. The reaction is initiated by adding 10 μL of a substrate mixture (12 μM NADPH, 3.4 mM α-ketoglutaric acid in assay buffer) and the mixture is incubated at room temperature for 60 minutes. The reaction is terminated by adding 5 μl of detection buffer (100 μg / mL diaphorase, 30 μM resazurin in IX assay buffer) and incubated for 15 minutes before reading at Ex544 / Em590 on a ViewLux as a plate reader.

[0421] The activity of the compound against IDH1 R132C is assayed according to the same assay as above, with the following modifications: the final concentrations of IDH1 R132C and α-ketoglutaric acid in the assay buffer are 2 nM and 0.14 mM, respectively.

[0422] The activity of the compound against IDH2 R172K is assayed according to the same assay as above, with the following modifications: the final concentrations of IDH2 R172K and α-ketoglutaric acid in the assay buffer are 16 nM and 0.55 mM, respectively.

[0423] Enzyme assay of IDH1 wild type (wt)

[0424] The IDH1 WT enzyme activity that converts isocitrate to α-ketoglutarate was measured using a NADPH formation assay. In the assay, the forming cofactor was continuously measured in the presence of catalytically excess amounts of diaphorase and resazurin to generate a fluorescent signal proportional to the amount of NADPH formed.

[0425] The compound was pre-incubated with the enzyme and then the reaction was initiated by adding NADP + , isocitrate, diaphorase, and the corresponding substrate resazurin. Diaphorase reduces resazurin to highly fluorescent resorufin, concomitant with the oxidation of NADPH to NADP. Specifically, 0.2 μL of the test compound (previously serially diluted 1 to 3-fold from 1 mM in DMSO, 10 experimental points) was added to 0.016 nM IDH1 WT 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 β-mercaptoethanol); the mixture was incubated at room temperature for 15 minutes. The reaction was initiated by adding 10 μL of the substrate mixture (400 μM NADP + , 40 μM isocitrate, 5 μg / mL diaphorase, and 7 μM resazurin in assay buffer), the mixture was incubated at room temperature, and the reaction was continuously read at Ex544 / Em590 on a ViewLux as a plate reader.

[0426] Biochemical activity

[0427] The biochemical potencies of representative compounds determined according to the assay described above against mutant IDH1 R132H , IDH1 R132C and IDH2 R172K are reported in Table 1 as IC 50 values (μM), while the biochemical potencies against the IDH1 wild-type enzyme determined according to the assay described above are reported in Table 2 as IC 50 values (μM).

[0428] Table 1

[0429]

[0430]

[0431] Table 2

[0432]

[0433] Cell assays of IDHm inhibitors

[0434] The cell line HT-1080 (commercially available) was maintained in E-MEM 10% FCS and incubated at 37 °C in a humidified 5% CO2 atmosphere.

[0435] Cells were seeded at a density of 500 cells / well in 100 μL of complete medium in 96-well black flat-bottom plates. After 24 hours, the medium was replaced with 200 μL of fresh medium, and the compounds (dissolved in DMSO) were administered to the cells using a D300E digital dispenser (Tecan).

[0436] After incubation for 72 hours, 100 μL was collected from each well and used for 2HG (R(-)-2-hydroxyglutaric acid) quantification.

[0437] The level of 2-HG in the cell culture medium was determined by LC-MS / MS. The cell supernatant (100 μL / well) was treated in 96-well plates with 1 M aqueous trichloroacetic acid (20 μL / well) containing 130 μM of the internal standard 2-HG-d3. The plates were sealed, gently vortexed for 60 minutes, centrifuged at 4,000 RPM for 15 minutes, placed in a refrigerated autosampler taking care not to shake them, and an aliquot of the upper part of the sample was directly injected into the chromatographic system. Calibration standards were obtained by ten-fold dilution of the aqueous 2-HG stock solution with blank cell culture medium and were denatured exactly in the same manner as described above for the samples. Samples and standards were assayed for 2-HG by reversed-phase chromatography on a C18 column eluted with 0.15% aqueous formic acid and briefly washed with 90% methanol at the end of the run. 2-HG was determined by an internal standard method based on a triple quadrupole mass spectrometer monitoring the MRM transitions 147>129 (2-HG) and 150>132 (2-HG-d3) by negative ion electrospray ionization.

[0438] 2-HG inhibition was calculated by comparing the processed data to the control data using Assay Explore (Symyx) software, where the IC 50 was determined using a sigmoidal fitting algorithm.

[0439] Table 3 reports the IC R132C values (μM) of the inhibition of 2HG by representative compounds determined according to the assay described above in the cell line HT-1080 (IDH1 50 ).

[0440] Table 3

[0441]

[0442] As reported in Table 3, when tested in cell lines with the mutant form of IDH1, representative compounds of the invention showed dose-dependent inhibition of 2-HG production, with potencies below 5 μM. As expected, even at the highest dose (10 μM), the compounds showed no effect on cell proliferation.

[0443] Preparation of Compounds of Formula (I)

[0444] For any particular compound of formula (I) of the invention, optionally in the form of a pharmaceutically acceptable salt, see the experimental section and the claims. With reference to the following examples, the compounds of the invention were synthesized using the methods described herein or other methods well known in the art.

[0445] The following examples are given for the purpose of better illustrating the invention without imposing any limitation on the invention.

[0446] As used herein, the symbols and conventions used in the processes, protocols, and examples are consistent with those used in contemporary scientific literature such as the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0447] Compound names are IUPAC names generated using ACD Name (by Advanced Chemistry Development, Inc.).

[0448] Unless otherwise stated, all materials, including anhydrous solvents such as DMF, THF, DCM, were obtained from commercial suppliers, were of the best grade, and were used without further purification. All reactions involving air-sensitive or moisture-sensitive compounds were carried out under a nitrogen or argon atmosphere.

[0449] General Purification and Analysis Methods

[0450] Flash chromatography was performed on silica gel (Merck grade 9395, 60 Å).

[0451] The HPLC equipment consisted of a Waters Alliance TM HT 2795 system equipped with a Waters 996 PDA detector and a Waters mod. ZQ2000 single quadrupole mass spectrometer equipped with an electrospray (ESI) ion source. Instrument control, data acquisition, and data processing were provided by Empower 2 software and MassLynx 4.1 software.

[0452] HPLC was performed using a YMC-Triart C18 column (4.6×50 mm, 3 μm) at 25 °C with a flow rate of 1.2 mL / min. Mobile phase B was 5 mM ammonium acetate buffer (pH = 5.2) with acetonitrile (95:5), and mobile phase C was H2O / acetonitrile (5:95); the gradient was from 10% C to 90% C in 5 minutes, then ramped to 100% C in 0.1 minute. The injection volume was 10 μL. The mass spectrometer was operated in positive ion mode and in negative ion mode, with the capillary voltage set at 3.5 kV (ES + ) and 2.8 kV (ES - ); the cone voltage was 14 V (ES + ) and 28 V (ES - ); the source temperature was 120 °C; a full scan from 100 amu to 800 amu was set.

[0453] The preparative HPLC equipment consisted of a Shimadzu HPLC system equipped with an SCL-8A system controller, two LC-8A pumps, an SPD-6A UV spectrophotometric detector, and a manual Rheodyne injection system. Data acquisition (analog signals) and data processing were provided by Empower 2 software. Purification was performed using a Waters X-Terra MS RP18 column (150×30 mm, 10 μm) at 25 °C with a flow rate of 15 mL / min. Mobile phase A was 0.1% TFA in water / acetonitrile (95:5), or alternatively, mobile phase A was 0.05% NH3 in water / acetonitrile (95:5), and mobile phase B was H2O / acetonitrile (5:95); the gradient was from 10% B to 90% B in 15 minutes, then ramped to 100% B in 0.1 minute. The maximum injection volume was 500 μL.

[0454] 1 1H-NMR spectra were 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 1H{ 15 15N- 31 31P} z-axis PFG indirect detection probe, and were recorded on a Varian INOVA500 spectrometer operating at 499.7 MHz and equipped with a 5 mm 1 1H{ 13 13C- 15 15N} triple resonance indirect detection probe. Chemical shifts were referenced to the residual solvent signal (DMSO-d6: 1The signal at 2.50 ppm was referenced. The data were reported as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br.s = broad singlet, dd = double doublet, ddd = double double doublet, m = multiplet), coupling constant (J, Hz), and number of protons.

[0455] As previously reported (M. Colombo, F. R. Sirtori, V. Rizzo, Rapid Commun Mass Spectrom 2004, 18(4), 511 - 517), ESI(+) high-resolution mass spectrometry (HRMS) was obtained on a Q-Tof Ultima (Waters, Manchester, UK) mass spectrometer directly connected to an Agilent 1100 micro-HPLC system (Palo Alto, US).

[0456] Preparation 1

[0457] Ethyl 2-(methylthio)-4-(propan-2-ylamino)pyrimidine-5-carboxylate [(IX), R2 = propan-2-yl, R3 = H] Steps 3a and 4a

[0458]

[0459] Commercially available ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (12 g, 51.4 mmol) was dissolved in 300 ml of ACN, and isopropylamine (8.8 mL, 102.8 mmol) was added at 0 °C and stirred at rt for 3 h. The precipitated salt was filtered and washed with EtOAc, and the solvent was evaporated under reduced pressure. The resulting oil was dissolved in Et2O, washed with NH4Cl, and then dried over Na2SO4. The salt was filtered, and the solvent was evaporated in vacuo to give the product (7.0 g, 53% yield), which was used without further purification.

[0460]

[0461] For C 11 H 16 ClN2O2[M + H] + HRMS (ESI) calculated for 243.0895, found 243.0901.

[0462] According to the same method, the following compounds were prepared:

[0463] Ethyl 6-chloro-4-ethylamino-nicotinate [(XVII), R2 = ethyl, X = CH]

[0464]

[0465] The title compound was obtained as a pale yellow oil (80% yield).

[0466] 1 1H NMR (DMSO-d6) 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), 3.25 - 3.32 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H). At r.t., 6.27 min, LCMS: m / z 229 [M+H] + 。

[0467] For C 10 H 14 ClN2O2 [M+H] + The HRMS (ESI) calculated value for C

[0468] Ethyl 6-chloro-4-isopropylamino-nicotinate [(XVII), R2 = propan-2-yl, X = CH]

[0469]

[0470] 1 1H NMR (DMSO-d6) δ = 8.53 (s, 1H), 7.98 (d, J = 7.9 Hz, 1H), 6.84 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.80 - 3.93 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 6.4 Hz, 6H). At r.t., 6.72 min, LCMS: m / z 243 [M+H] + 。

[0471] Preparation 2

[0472] [2-(Methylthio)-4-(propan-2-ylamino)pyrimidin-5-yl]methanol [(X), R2 = propan-2-ylamino, R3 = H] Steps 3b and 4b

[0473]

[0474] At -5 °C for 15 minutes, LiAlH4 (29 mL, 4% in THF) was added to a solution of ethyl 2-(methylthio)-4-(propan-2-ylamino)pyrimidine-5-carboxylate (7 g, 27.4 mmol) in THF (70 mL). The cold bath was removed and the mixture was allowed to reach room temperature, then stirred for 2 h. It was then cooled to 0 °C and saturated NaHCO3 solution (31 mL) was added slowly (exothermic reaction). After 30 minutes, the quenched reaction mixture was filtered and the cake was washed with AcOEt (50 mL). The combined organic washes were dried over Na2SO4 and filtered. The solvent was evaporated in vacuo to give the product (5.84 g, 96% yield), which was used without further purification.

[0475] The following compounds were prepared essentially by the same procedure:

[0476] (6-Chloro-4-ethylamino-pyridin-3-yl)-methanol [(XVIII), R2 = ethyl, X = CH]

[0477]

[0478] 1 H NMR (DMSO-d6) 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 (qd, J = 7.1, 5.7 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H). At r.t., 4.06 min, LCMS: m / z 187 [M+H] + 。

[0479] For C8H 12 N2OCl [M+H] + The HRMS (ESI) calculated for 187.0633, found 187.0638.

[0480] (6-Chloro-4-isopropylamino-pyridin-3-yl)-methanol [(XVIII), R2 = propan-2-yl, X = CH]

[0481]

[0482] 11H NMR (DMSO-d6) 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). At r.t., 2.74 min, LCMS: m / z 201 [M+H] + 。

[0483] For C9H 14 ClN2O [M+H] + The HRMS (ESI) calculated value for 201.0789, found 201.0787.

[0484] Preparation 3

[0485] 2-(Methylthio)-4-(propan-2-ylamino)pyrimidine-5-carbaldehyde [(XI), R2 = 2,2-dimethyl-propyl, R3 = H] Steps 3c and 4c

[0486]

[0487] Dissolve [2-(methylthio)-4-(propan-2-ylamino)pyrimidin-5-yl]methanol (5.3 g, 24.84 mmol) in DCM (120 mL), and add thereto MnO2 (17.27 g, 198.7 mmol) pre-activated in an oven at 50 °C for 4 h. Stir the resulting suspension overnight. The solid is removed by filtration through a pad of diatomaceous earth, which is washed with additional DCM, and the solvent is evaporated in vacuo. The crude product is purified on a silica gel column eluted with (n-Hex / EtOAc 9 / 1) to afford the title product (4.08 g, 78% yield).

[0488] 1 1H NMR (500 MHz, DMSO-d6) 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). At r.t., 5.9 min, LCMS: m / z 212 [M+H] + 。For C9H 14 N3OS [M+H] + The HRMS (ESI) calculated value for 212.0852, found 212.0856.

[0489] According to the same method, the following compounds were prepared:

[0490] 2-Chloro-4-(propan-2-ylamino)pyrimidine-5-carbaldehyde [(XIX), X = N, R2 = propan-2-yl]

[0491]

[0492] At r.t., 4.87 min, LCMS: m / z 200 [M+H] + 。

[0493] 6-Chloro-4-ethylamino-pyridine-3-carbaldehyde [(XIX), R2 = propan-2-yl, X = CH]

[0494]

[0495] 1 H NMR (DMSO-d6) 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). At r.t., 4.89 min, LCMS: m / z 185 [M+H] + 。

[0496] For C8H 10 ClN2O [M+H] + The HRMS (ESI) calculated value for 185.0476, found 185.0481.

[0497] 6-Chloro-4-isopropylamino-pyridine-3-carbaldehyde [(XIX), R2 = propan-2-yl, X = CH]

[0498]

[0499] 1 H NMR (DMSO-d6) 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). At r.t., 7.84 min, LCMS: m / z 199 [M+H] + 。For C9H 12 ClN2O [M+H] + The HRMS (ESI) calculated value for 199.0633, found 199.0632.

[0500] Prepare 4

[0501] 2-(methylthio)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U = Y = CH, X = N, R2 = propan-2-yl, R3 = H] Steps 3d and 4d

[0502]

[0503] At -78 °C, LiHMDS (47 mL of 1 M THF solution, 47 mmol) was added to THF (78 mL), and treated with EtOAc (5.8 mL, 53.92 mmol). The solution was stirred at -78 °C for 10 min, then solid 2-(methylthio)-4-(propan-2-ylamino)pyrimidine-5-carbaldehyde (2.6 g, 12.30 mmol) was added in one portion, and the solution was stirred at -78 °C for 10 min, then removed from the cooling bath and warmed to RT over 2 h, and stirred at room temperature for an additional 4 h. The reaction was cooled in an ice bath and quenched with saturated NH4Cl solution (60 ml), and extracted with EtOAc (2 × 1 mL), dried over Na2SO4, filtered and concentrated to give an off-white solid (2.8 g) of the title compound.

[0504] 1 1H NMR (500 MHz, DMSO-d6) δ = 8.86 (s, 1H), 7.88 (d, J = 9.46 Hz, 1H), 6.57 (d, J = 9.46 Hz, 1H), 5.68 (br.s., 1H), 2.60 (s, 3H), 1.54 (d, J = 7.02 Hz, 6H). At r.t., 9.10 min, LCMS: m / z 236 [M+H] + . For C 11 H 14 N3OS [M+H] + The HRMS (ESI) calculated value for 236.0852, found 236.0861.

[0505] According to the same method, the following compounds were prepared:

[0506] 2-chloro-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(IV), U = Y = CH, X = N, R2 = propan-2-yl, R3 = H, G = Cl]

[0507]

[0508] At r.t., 4.26 min, LCMS: m / z 224 [M+H] + .

[0509] 7-chloro-1-ethyl-1H-[1,6]naphthyridin-2-one [(IV), U = Y = CH, X = CH, R2 = ethyl, R3 = H, G = Cl]

[0510]

[0511] 1 H NMR (500 MHz, DMSO-d6) 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 (q, J = 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H). At r.t., 4.28 min, LCMS: m / z 209 [M+H] + 。

[0512] For C 10 H 10 ClN2O [M+H] + the HRMS (ESI) calculated value for 209.0476, found 209.0485.

[0513] 7-chloro-1-isopropyl-1H-[1,6]naphthyridin-2-one [(IV), U = Y = CH, X = CH, R2 = propan-2-yl, R3 = H, G = Cl]

[0514]

[0515] 1 H NMR (500 MHz, DMSO-d6) δ = 8.71 (s, 1H), 7.96 (d, J = 9.5 Hz, 1H), 7.79 (br.s., 1H), 6.63 (d, J = 9.5 Hz, 1H), 5.14 (br.s., 1H), 1.50 (d, J = 6.9 Hz, 6H). At r.t., 7.11 min, LCMS: m / z 223 [M+H] + 。

[0516] For C 11 H 12 ClN2O [M+H] + the HRMS (ESI) calculated value for 223.0633, found 223.0633.

[0517] Prepare 5

[0518] 2-(methylthio)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U = Y = CH, X = N, R2 = propan-2-yl, R3 = H] Step 3g

[0519]

[0520] A mixture of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.52 mmol), cesium carbonate (337 mg, 1.04 mmol) and isopropyl iodide (77.8 μl, 0.78 mmol) in anhydrous DMF (2 mL) was purged with nitrogen and heated in a sealed tube at 70 °C for 2 h. The reaction mixture was allowed to cool to room temperature and diluted with water. The product was precipitated, filtered and washed with water. To give the title compound as a pale yellow solid (86 mg, 70% yield). 1 1H NMR (401 MHz, DMSO-d6) 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). At r.t., 5.53 min, LCMS: m / z 236 [M+H] + 。For C 11 H 14 N3OS [M+H] + The HRMS (ESI) calculated value for C

[0521] According to the same method, the following compounds were prepared:

[0522] 8-Ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U = Y = CH, X = N, R2 = ethyl, R3 = H]

[0523]

[0524] 1 1H NMR (401 MHz, DMSO-d6) δ = 8.88 (s, 1H), 7.93 (d, J = 9.40 Hz, 1H), 6.62 (d, J = 9.52 Hz, 1H), 4.32 (q, J = 7.04 Hz, 2H), 2.60 (s, 3H), 1.22 (t, J = 7.02 Hz, 3H). At r.t., 4.95 min, LCMS: m / z 222 [M+H]+ 。For C 10 H 12 N3OS[M+H] + The calculated HRMS(ESI) value of 222.0696 and the measured value of 222.07.

[0525] 4-Methyl-2-(methylthio)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U = Y = CH, X = N, R2 = propan-2-yl, R3 = methyl]

[0526]

[0527] 1 H NMR(500 MHz, DMSO-d6) δ = 8.04(d, J = 9.61 Hz, 1H), 6.54(d, J = 9.46 Hz, 1H), 5.73(br.s, 1H), 2.61 - 2.64(m, 3H), 2.58(s, 3H), 1.54(d, J = 6.86 Hz, 6H). At r.t., 5.85 min, LCMS: m / z 250[M+H] + 。

[0528] 1-Ethyl-7-(methylthio)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one [(XII), U = CH2, Y = O, X = N, R2 = ethyl, R3 = H]

[0529]

[0530] 1 H NMR(500 MHz, DMSO-d6) δ = 8.33(s, 1H), 5.30(d, J = 0.61 Hz, 2H), 3.94(q, J = 7.02 Hz, 2H), 2.51(br.s., 3H), 1.19(t, J = 7.02 Hz, 3H).

[0531] 5-Methyl-2-(methylthio)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U = CMe, Y = CH, X = N, R2 = propan-2-yl, R3 = H]

[0532]

[0533] 11H NMR (500 MHz, DMSO-d6) δ = 8.90 (s, 1H), 6.44 (s, 1H), 5.67 (br.s., 1H), 2.60 (s, 3H), 2.40 (d, J = 1.22 Hz, 3H), 1.53 (d, J = 7.02 Hz, 6H). At r.t., 6.67 min, LCMS: m / z 250 [M+H] + 。For C 12 H 16 N3OS [M+H] + The HRMS (ESI) calculated value for C

[0534] Preparation 6

[0535] 2-(Methylthio)-7-oxo-8-(2,2-dimethylpropyl)-7,8-dihydropyrido[2,3-d]pyrimidine-4-carbonitrile [(XII), U = Y = CH, X = N, R2 = 2,2-dimethylpropyl, R3 = CN] Transformation A

[0536]

[0537] 4-Chloro-8-(2,2-dimethyl-propyl)-2-methylthio-8H-pyrido[2,3-d]pyrimidin-7-one (60 mg, 0.2 mmol) was dissolved in DMSO (4.5 mL), to which triethylamine (300 μL) and NaCN (18 mg, 0.2 mmol) were added, and the mixture was stirred at 50 °C for 1 h. Then 10 mL of water was added and the mixture was extracted twice with AcOEt. The organic phase was washed with brine and then dried over Na2SO4. The salts were filtered off and the solvent was evaporated in vacuo. The crude product was purified by elution with hexane / AcOEt 8 / 2 on a SiO2 column to give the product (12 mg, 20% yield).

[0538] 1 1H NMR (500 MHz, DMSO-d6) δ = 7.94 (d, J = 9.61 Hz, 1H), 6.83 (d, J = 9.61 Hz, 1H), 4.28 (br.s., 2H), 2.63 (s, 3H), 0.91 (s, 3H). At r.t., 7.09 min, LCMS: m / z 289 [M+H] + 。For C 14 H 17 N4OS [M+H] + The HRMS (ESI) calculated value for C

[0539] Preparation 7

[0540] 4-[(2,4-Dimethoxybenzyl)amino]-2-(methylthio)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U = Y = CH, X = N, R2 = propan-2-yl, R3 = NH-2,4-dimethoxybenzyl] Conversion B

[0541]

[0542] To a solution of 4-chloro-8-isopropyl-2-methylthio-8H-pyrido[2,3-d]pyrimidin-7-one (370 mg, 1.37 mmol) in CH3CN (15 mL) was added 2,4-dimethoxybenzylamine (0.288 mL, 1.92 mmol) and triethylamine (0.268 mL, 1.92 mmol). The solution was heated at 50 °C for 3 h. The reaction mixture was evaporated to dryness and the residue was purified on silica gel (AcOEt / hexane: 1 / 1) to give a pale yellow solid (325 mg).

[0543] 1 1H NMR (500 MHz, DMSO-d6) δ = 8.37 (t, J = 5.57 Hz, 1H), 8.11 (d, J = 9.61 Hz, 1H), 7.08 (d, J = 8.24 Hz, 1H), 6.56 (d, J = 2.29 Hz, 1H), 6.46 (dd, J = 2.29, 8.39 Hz, 1H), 6.32 (d, J = 9.46 Hz, 1H), 5.70 (br.s., 1H), 4.55 (d, J = 5.64 Hz, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 2.44 (s, 3H), 1.49 (d, J = 6.86 Hz, 6H). At r.t., 3.43 min, LCMS: m / z 423 [M+Na] + For C 20 H 25 N4NaO4S [M+Na] + HRMS (ESI) calcd for C20H25N4NaO4S [M+Na] 423.1440, found 423.1444.

[0544] Preparation 8

[0545] 4-(Methylamino)-2-(methylthio)-8-(2,2-dimethylpropyl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U = Y = CH, X = N, R2 = 2,2-dimethylpropyl, R3 = NHMe, R4 = R5 = H] Conversion C

[0546]

[0547] 4-Chloro-8-(2,2-dimethylpropyl)-2-(methylthio)-8H-pyrido[2,3-d]pyrimidin-7-one (40 mg, 0.13 mmol) was dissolved in THF (4 mL), 1.0 M methylamine in EtOH (100 μL) was added thereto, and the mixture was stirred at room temperature for 12 h. Then 10 mL of water was added and the mixture was extracted twice with AcOEt. The organic phase was washed with brine and then dried over Na2SO4. The salts were filtered off and the solvent was evaporated in vacuo. The crude product was purified on a SiO2 column with DCM / MeOH 98 / 2 to give the product (33 mg, 85% yield).

[0548] 1 H NMR (500 MHz, DMSO-d6) 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 (br.s., 2H), 2.93 (d, J = 4.42 Hz, 3H), 2.52 (s, 3H), 0.89 (s, 9H). At r.t., 6.63 min, LCMS: m / z 293 [M+H] + For C 14 H 21 N4OS [M+H] + HRMS (ESI) calcd for C13H20N4OS [M+H] 293.1431, found 293.1436.

[0549] Following the same method, the following compounds were prepared:

[0550] 4-(Dimethylamino)-2-(methylthio)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U = Y = CH, X = N, R2 = propan-2-yl, R3 = N(Me)2]

[0551]

[0552] 1 H NMR (500 MHz, DMSO-d6) δ = 7.93 (d, J = 9.76 Hz, 1H), 6.25 (d, J = 9.76 Hz, 1H), 5.72 (br.s., 1H), 3.21 (s, 6H), 2.50 (s, 3H), 1.50 (d, J = 7.02 Hz, 6H). At r.t., 6.48 min, LCMS: m / z 279 [M+H] + For C13 H 19 N4OS[M+H] + The calculated HRMS(ESI) value of [M+H] for N4OS is 279.1274, and the measured value is 279.1276.

[0553] Preparation 9

[0554] 2-(Methylsulfonyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(IV), U = Y = CH, X = N, R2 = propan-2-yl, R3 = H, G = MeS(O)2-] Step 3e

[0555]

[0556] Dissolve 2-(methylthio)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (3.1 mg, 13.17 mmol) in 62 mL of DCM. Add m-CPBA 55% (10.32 g, 32.93 mmol) to the stirred solution. Allow the reaction to stir at room temperature for 2 h. LCMS indicates that the reaction is complete. Dilute the sample with 50 mL of DCM and wash twice with saturated NaHCO3 (170 ml) and then wash with 50 ml × 2, followed by washing with brine (50 ml). Separate the organic phase, dry over Na2SO4, filter and concentrate in vacuo. Purify by column eluent EtOAc / acetone 100:1 to give the title compound 2-(methylsulfonyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (2.29 mg, 65% yield) as an off-white solid.

[0557] 1 H NMR (500 MHz, DMSO-d6) 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). At r.t., 4.48 min, LCMS: m / z 268 [M+H] + . For C 11 H 13 N3O3S[M+H] + The calculated HRMS(ESI) value of [M+H] for C H N3O3S is 268.0751, and the measured value is 268.0746.

[0558] According to the same method, the following compounds were prepared:

[0559] 8-Ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one [(IV), U = Y = CH, X = N, R2 = ethyl, R3 = H, G = MeS(O)2-]

[0560]

[0561] 1 H NMR (500 MHz, DMSO-d6) δ = 9.30 (s, 1H), 8.12 (d, J = 9.61 Hz, 1H), 6.93 (d, J = 9.46 Hz, 1H), 4.35 (q, J = 7.02 Hz, 2H), 3.48 (s, 3H), 1.24 (t, J = 7.09 Hz, 3H). At r.t., 3.53 min, LCMS: m / z 254 [M+H] + 。For C 10 H 11 N3O3S [M+H] + The HRMS (ESI) calculated value for C

[0562] 4-Methyl-2-(methylsulfonyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(IV), U = Y = CH, X = N, R2 = propan-2-yl, R3 = methyl, G = MeS(O)2-]

[0563]

[0564] 1 H NMR (500 MHz, DMSO-d6) δ = 8.22 (d, J = 9.76 Hz, 1H), 6.84 (d, J = 9.76 Hz, 1H), 5.59 - 5.77 (m, 1H), 3.44 (s, 3H), 2.81 (s, 3H), 1.55 (d, J = 7.02 Hz, 6H). At r.t., 4.34 min, LCMS: m / z 282 [M+H] + 。

[0565] 5-Methyl-2-(methylsulfonyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(IV), U = CMe, Y = CH, X = N, R2 = propan-2-yl, R3 = H, G = MeS(O)2-]

[0566]

[0567] 11H NMR (500 MHz, DMSO-d6) δ = 8.90 (s, 1H), 6.44 (s, 1H), 5.67 (br.s., 1H), 2.60 (s, 3H), 2.40 (d, J = 1.22 Hz, 3H), 1.53 (d, J = 7.02 Hz, 6H). At r.t., 4.73 min, LCMS: m / z 282 [M+H] + 。For C 12 H 16 N3O3S [M+H] + The HRMS (ESI) calculated value for 282.0907, found value 282.0907.

[0568] 1-Ethyl-7-(methylsulfonyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one [(IV), U = CH2, Y = O, X = N, R2 = ethyl, R3 = H, G = MeS(O)2-]

[0569]

[0570] 1 1H NMR (500 MHz, DMSO-d6) δ = 8.68 (s, 1H), 5.48 (d, J = 0.61 Hz, 2H), 3.99 (q, J = 7.02 Hz, 2H), 3.41 (s, 3H), 1.22 (t, J = 7.02 Hz, 3H). At r.t., 3.43 min, LCMS: m / z 258 [M+H] + 。For C9H 11 N3O4S [M+H] + The HRMS (ESI) calculated value for 258.0543, found value 258.054.

[0571] 4-[(2,4-Dimethoxybenzyl)amino]-2-(methylsulfinyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(IV), U = Y = CH, X = N, R2 = propan-2-yl, R3 = 4-[(2,4-dimethoxybenzyl)amino], G = MeSO-]

[0572]

[0573] 11H NMR (500 MHz, DMSO-d6) δ = 8.74 (t, J = 5.57 Hz, 1H), 8.22 (d, J = 9.76 Hz, 1H), 7.16 (d, J = 8.24 Hz, 1H), 6.56 (d, J = 2.44 Hz, 1H), 6.53 (d, J = 9.61 Hz, 1H), 6.45 (dd, J = 2.36, 8.31 Hz, 1H), 5.75 (s, 1H), 4.48 - 4.67 (m, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 2.78 (s, 3H), 1.51 (d, J = 7.02 Hz, 6H). At r.t., 3.43 min, LCMS: m / z 258 [M+H] + For C 20 H 25 N4NaO4S [M+Na] + The calculated value of HRMS (ESI) for it is 423.1440, and the measured value is 423.1444.

[0574] Preparation 10

[0575] 7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl trifluoromethanesulfonate [(IV), U = Y = CH, X = N, R2 = propan-2-yl, R3 = H, G = O-trifluoromethanesulfonate] Conversion A1

[0576]

[0577] Step 1 At rt, to a solution of 2-(methylsulfonyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (5 g, 18.7 mmol) in 1,4-dioxane (86 mL) was added NaOH 1N (37.4 ml, 37.4 mmol). The mixture was stirred at 40 °C for 1 h. The mixture was cooled to rt and diluted with DCM (80 ml), the aqueous phase was separated and saved. The organic phase was washed with NaOH 0.5M (20 mL), and the aqueous phase was added to the previous aqueous phase. The aqueous solution was acidified with HCl 1N and partitioned with a solution of DCM / i-pr-OH (4 × 50 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give 2-hydroxy-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one as an off-white solid (2.65 g, Y = 65%). 1HNMR(500MHz, DMSO-d6) δ = 12.26 (br.s., 1H), 8.46 (s, 1H), 7.58 (d, J = 9.46 Hz, 1H), 6.17 (d, J = 9.46 Hz, 1H), 5.59 (br.s., 1H), 1.44 (d, J = 7.02 Hz, 6H). LCMS: m / z 204 [M-H] - 。

[0578] Step 2 Under a nitrogen atmosphere at 2 °C (internal temperature), 2,6-dimethylpyridine (2.65 mL, 22.8 mmol, 1.2 equiv) was added to a solution of 2-hydroxy-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (3.90 g, 19.02 mmol) in dry DCM (78 mL). Then, trifluoromethanesulfonic anhydride (3.83 mL, 22.8 mmol, 1.2 equiv) was added dropwise over 5 minutes, maintaining the internal temperature between 2 °C and 10 °C. After 1 h, the reaction was complete and diluted with DCM and water. The organic phase was separated, washed with brine and dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (DCM:EA = 99 / 1 to 97.5 / 2.5) to afford the title compound as an off-white solid (5.53 g, 86% yield). 1 1H NMR(500MHz, DMSO-d6) δ = 9.16 (s, 1H), 8.4 (d, J = 9.46 Hz, 1H), 6.80 (d, J = 9.46 Hz, 1H), 5.52 (m, 1H), 1.52 (d, J = 7.02 Hz, 6H). LCMS: m / z 338 [M+H] + 。For C 11 H 11 F3N3O4S [M+H] + The HRMS (ESI) calculated value for C13H15F3N3O4S [M+H] is 338.0417, found 338.0412.

[0579] Preparation 11

[0580] 4-(4-{4-[(1S)-1-Aminoethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenylcarboxylate] Steps 5a - 5e

[0581]

[0582] Step 1. Synthesis of 4-(4-bromophenyl)tetrahydro-2H-pyran-4-carboxylic acid

[0583]

[0584] To a solution of ethyl 4-(4-bromophenyl)tetrahydro-2H-pyran-4-carboxylate (383.2 g, 1.22 mol) in THF / MeOH / H2O (1 L / 1 L / 1 L) was added LiOH.H2O (308.5 g, 7.35 mol). The mixture was stirred at 30 °C for 2 days. Most of the solvent was removed in vacuo, the pH was adjusted to 2 with 2N HCl solution and partitioned with EtOAc (2 L). The solvent was removed in vacuo to give 4-(4-bromophenyl)tetrahydro-2H-pyran-4-carboxylic acid as a white solid (314 g, 90% yield).

[0585]

[0586] According to the same method, the following compounds were prepared:

[0587] 1-(4-bromophenyl)cyclopentanecarboxylic acid

[0588]

[0589]

[0590] 1-(4-bromophenyl)cyclohexanecarboxylic acid

[0591]

[0592]

[0593] Step 2. Synthesis of 4-(4-bromophenyl)tetrahydro-2H-pyran-4-amine [(XXI) W1 = Br, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl]

[0594]

[0595] A mixture of 4-(4-bromophenyl)tetrahydro-2H-pyran-4-carboxylic acid (314 g, 1.10 mol), TEA (189.2 g, 1.87 mol) and DPPA (diphenylphosphoryl azide) (424 g, 1.54 mol) in anhydrous toluene (3 L) was purged with nitrogen and stirred at 90 °C for 3 h. The reaction mixture was allowed to cool to ambient temperature and diluted with water (1 L). The aqueous phase was extracted with EtOAc (1 L * 2), and the combined organic phases were washed twice with saturated NaHCO3, then with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was suspended in 3.2 L of HCl (aqueous, 20%) and refluxed for 3 h. Toluene was added to the cold solution, and the azeotropic mixture was evaporated. Diluted with EtOAc and saturated NaHCO3, the organic phase was separated, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel with DCM / EtOH = 50 / 1 - 30 / 1 to afford 4-(4-bromophenyl)tetrahydro-2H-pyran-4-amine as a pale yellow solid (215.6 g, 76% yield).

[0596]

[0597] According to the same method, the following compounds were prepared:

[0598] 1-(4-bromophenyl)cyclopentanamine [(XXI) W1 = Br, A = phenyl, R4 = H, R5a and R5b = cyclopent-3-yl]

[0599]

[0600]

[0601] 1-(4-bromophenyl)cyclohexanamine [(XXI) W1 = Br, A = phenyl, R4 = H, R5a and R5b = cyclohexyl]

[0602]

[0603]

[0604] 4-(5-bromopyridin-2-yl)tetrahydro-2H-pyran-4-amine [(XXI) W1 = Br, A = pyrimidin-2-yl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl]

[0605]

[0606]

[0607] Step 3. Synthesis Step 5b of phenyl 4-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate [(XXIII) W1 = Br, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl carbonate]

[0608]

[0609] To a suspension of 4-(4-bromophenyl)tetrahydro-2H-pyran-4-amine (215.6 g, 0.84 mol) in DIEA (4 L) was added phenyl bis(2-chloroethyl)carbamate (prepared as reported in WO2009065622) (308 g, 1.18 mol). The mixture was stirred at 130 °C for 72 h and evaporated in vacuo. The residue was dissolved in DCM (2 L), washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel with DCM / acetone = 100 / 0 to 20 / 1 to afford phenyl 4-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (149 g, 40% yield) as an off-white solid.

[0610]

[0611] According to the same method, the following compounds were prepared:

[0612] Phenyl 4-[1-acetyl-4-(4-bromophenyl)piperidin-4-yl]piperazine-1-carboxylate [(XXIII) W1 = Br, A = phenyl, R4 = H, R5a and R5b = 1-acetylpiperidin-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl carbonate]

[0613]

[0614]

[0615] Phenyl 4-[1-(4-bromophenyl)cyclopentyl]piperazine-1-carboxylate [(XXIII) W1 = Br, A = phenyl, R4 = H, R5a and R5b = cyclopentyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl carbonate]

[0616]

[0617]

[0618] 4-[4-(5-Bromopyridin-2-yl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylic acid phenyl ester [(XXIII) W1 = Br, A = pyrimidin-2-yl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0619]

[0620]

[0621] 4-[3-(4-Bromophenyl)tetrahydrofuran-3-yl]piperazine-1-carboxylic acid phenyl ester [(XXIII) W1 = Br, A = phenyl, R4 = H, R5a and R5b = tetrahydrofuran-3-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0622]

[0623]

[0624] 4-[4-(6-Chloropyridin-3-yl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylic acid phenyl ester [(XXIII) W1 = Cl, A = pyrimidin-3-yl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0625]

[0626] 1 HNMR(400MHz, chloroform-d) δ = 8.33 (d, J = 2.50Hz, 1H) 7.54 (dd, J = 8.38, 2.50Hz, 1H) 7.29 - 7.40 (m, 3H) 7.15 - 7.22 (m, 1H) 7.05 (d, J = 8.13Hz, 2H) 3.92 - 4.05 (m, 2H) 3.46 - 3.72 (m, 6H) 2.39 (brt, J = 4.50Hz, 4H) 2.21 - 2.33 (m, 2H) 2.09 - 2.21 (m, 2H).

[0627] Step 4. Synthesis of 4-[4-(4-Acetylphenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylic acid phenyl ester [(XXIII) W1 = methyl ketone, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]. Transformation of G

[0628]

[0629] Under N2, tributyl(1-ethoxyvinyl)tin (242 g, 0.67 mol) and Pd(PPh3)2Cl2 (2.35 g, 3.35 mmol) were added to a solution of 4-[4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carbamate (149 g, 0.34 mol) in DMF (1.2 L). The mixture was stirred overnight at 90 °C. After cooling, the reaction mixture was diluted with an aqueous solution of KF and stirred at r.t. for 1 h, and then the precipitate was filtered and washed with EtOAc. After separation, the aqueous phase was extracted with EtOAc (500 mL * 5). The combined organic phases were dried over Na2SO4 and concentrated. The crude product was suspended in 2 L of DCM and 1 L of 2N HCl (aqueous) and stirred at r.t. for 2 h. The reaction mixture was diluted with DCM (2 L) and washed with saturated NaHCO3. After separation, the aqueous phase was extracted with DCM (500 mL * 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with DCM / acetone = 100 / 0 to 10 / 1 to afford phenyl 4-(4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (63 g, 45% yield) as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ = 8.00 - 7.98 (d, J = 8.4 Hz, 2H), 7.36 - 7.29 (m, 4H), 7.18 - 7.16 (m, 1H), 7.03 - 7.01 (d, J = 7.6 Hz, 2H), 3.99 - 3.96 (t, J = 5.8 Hz, 2H), 3.61 - 3.53 (m, 6H), 2.63 (s, 3H), 2.37 (s, 4H), 2.24 - 2.23 (m, 4H). At Rt = 6.19 min, LCMS 409; for C 24 H 29 N2O4[M + H] + The HRMS (ESI) calculated value for C

[0630] According to the same method, the following compounds were prepared:

[0631] Phenyl 4-[3-(4-acetylphenyl)pent-3-yl]piperazine-1-carboxylate [(XXIII) W1 = methyl ketone, A = phenyl, R4 = H, R5a and R5b = ethyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl carbamate]

[0632]

[0633]

[0634] Phenyl 4-[1-acetyl-4-(4-acetylphenyl)piperidin-4-yl]piperazine-1-carboxylate [(XXIII) W1 = methyl ketone, A = phenyl, R4 = H, R5a and R5b = 1-acetylpiperidin-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0635]

[0636]

[0637] Phenyl 4-[1-(4-acetylphenyl)cyclopentyl]piperazine-1-carboxylate [(XXIII) W1 = methyl ketone, A = phenyl, R4 = H, R5a and R5b = cyclopentyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0638]

[0639]

[0640] Phenyl 4-[4-(5-acetylpyridin-2-yl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylate [(XXIII) W1 = methyl ketone, A = pyridin-2-yl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0641]

[0642]

[0643] Phenyl 4-[3-(4-acetylphenyl)tetrahydrofuran-3-yl]piperazine-1-carboxylate [(XXIII) W1 = methyl ketone, A = pyridin-2-yl, R4 = H, R5a and R5b = tetrahydrofuran-3-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0644]

[0645]

[0646] Phenyl 4-[4-(5-acetylpyridin-3-yl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylate [(XXIII) W1 = methyl ketone, A = pyridin-3-yl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl carboxylate]

[0647]

[0648] 1 HNMR(400Mhz, chloroform-d) δ = 8.64(d, 1H, J = 2.0Hz), 8.09(d, 1H, J = 8.4Hz), 7.71(dd, 1H, J = 2.2, 8.4Hz), 7.3 - 7.4(m, 2H), 7.1 - 7.2(m, 1H), 7.03(d, 2H, J = 7.9Hz), 3.9 - 4.1(m, 2H), 3.5 - 3.7(m, 6H), 2.75(s, 3H), 2.40(br t, 4H, J = 4.3Hz), 2.2 - 2.4(m, 4H).

[0649] Benzyl 3-{[4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl](methyl)amino}azetidine-1-carboxylate [(XXIII) W1 = methyl ketone, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = N(R6), R6 = methyl, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, PG = benzyl carboxylate]

[0650]

[0651] At r.t., 2.29 min, LCMS: m / z 423 [M + H] + .

[0652] Step 5. Synthesis of step 5c' of phenyl 4-(4-{4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate [(XXIV) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl carboxylate]

[0653]

[0654] A mixture of titanium(IV) tetraethoxide (3 equiv, 400 μL, 1.908 mmol), (S)-2-methylpropane-2-sulfinamide (2 equiv, 154 mg, 1.272 mmol), and phenyl 4-[4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylate (260 mg, 0.636 mmol) in THF (20 mL) was heated at 80 °C overnight and then cooled to room temperature. At -50 °C, NaBH4 (5 equiv, 120 mg, 3.18 mmol) was added to the mixture. The mixture was then slowly warmed to room temperature (2 h). MeOH (2 mL) was added to quench the excess NaBH4, and then water was added. The resulting mixture was filtered to remove the solid, and the aqueous phase was extracted twice with EtOAc, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using gradient elution (100% DCM, then 0%-20% acetone / DCM) to afford phenyl 4-(4-{4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (225 mg, 69% yield).

[0655]

[0656] Following the same procedure, the following compounds were prepared:

[0657] Phenyl 4-(3-{4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]phenyl}pentan-3-yl)piperazine-1-carboxylate [(XXIV) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = ethyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl carboxylate]

[0658]

[0659] 1 1H NMR (500 MHz, DMSO-d6) δ = 7.29 - 7.40 (m, 6H), 7.17 - 7.21 (m, 1H), 7.07 (dd, J = 0.99, 8.46 Hz, 2H), 5.61 (d, J = 7.02 Hz, 1H), 4.37 (quintet, J = 6.75 Hz, 1H), 3.52 (br.s., 2H), 3.33 (m, 2H), 2.47 (br.s., 4H), (1.79 - 1.97 (m, 4H), 1.41 (d, J = 6.86 Hz, 3H), 1.09 - 1.16 (m, 9H), 0.76 (t, J = 6.94 Hz, 6H).

[0660] 4-(4-{5-[(1S)-1-{[(S)-tert-Butylsulfinyl]amino}ethyl]pyridin-2-yl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester [(XXIV) R1a = methyl, R1b = H, A = pyridin-2-yl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0661]

[0662]

[0663] 4-(1-{4-[(1S)-1-{[(S)-tert-Butylsulfinyl]amino}ethyl]phenyl}cyclopentyl)piperazine-1-carboxylic acid phenyl ester [(XXIV) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = cyclopentyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0664]

[0665]

[0666] 4-(4-{4-[(1R)-1-{[(R)-tert-Butylsulfinyl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester [(XXIV) R1a = H, R1b = methyl, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0667]

[0668]

[0669] 4-(3-{4-[(1S)-1-{[(S)-tert-Butylsulfinyl]amino}ethyl]phenyl}tetrahydrofuran-3-yl)piperazine-1-carboxylic acid phenyl ester [(XXIV) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = tetrahydrofuran-3-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0670]

[0671]

[0672] Phenyl 4-(4-{5-[(1S)-1-{[(R)-tert-Butanesulfinyl]amino}ethyl]pyridin-3-yl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate [(XXIV) R1a = methyl, R1b = H, A = pyridin-2-yl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl carboxylate]

[0673]

[0674] 1 HNMR(400MHz, chloroform-d) δ = 8.50 (d, 1H, J = 1.8Hz), 7.54 (dd, 1H, J = 2.1, 8.1Hz), 7.3 - 7.4 (m, 3H), 7.1 - 7.2 (m, 1H), 7.03 (d, 2H, J = 8.0Hz), 4.67 (quintet, 1H, J = 6.7Hz), 4.13 (q, 1H, J = 7.1Hz), 3.9 - 4.0 (m, 3H), 3.5 - 3.7 (m, 6H), 2.39 (br s, 4H), 2.1 - 2.3 (m, 4H), 1.66 (d, 3H, J = 6.8Hz), 1.23 (s, 8H).

[0675] Benzyl 3-[(4-{4-[(1S)-1-{[(S)-tert-Butanesulfinyl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)(methyl)amino]azetidine-1-carboxylate [(XXIV) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = N(R6), R6 = methyl, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, PG = benzyl carboxylate]

[0676]

[0677] 1 HNMR(400MHz, chloroform-d) δ = 7.27 (s, 9H), 5.03 (s, 2H), 4.56 (br dd, J = 2.8, 6.5Hz, 1H), 4.03 - 3.92 (m, 1H), 3.89 - 3.80 (m, 2H), 3.76 - 3.59 (m, 4H), 3.55 - 3.43 (m, 2H), 3.41 (d, J = 2.4Hz, 1H), 2.25 (s, 3H), 2.15 (br s, 4H), 1.51 (d, J = 6.4Hz, 3H), 1.24 (s, 9H).

[0678] Benzyl 3-[acetyl(4-{4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)amino]azetidine-1-carboxylate [(XXIV) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = N(R6), R6 = acetyl, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, PG = benzyl formate]

[0679]

[0680]

[0681] Step 6. Synthesis step 5e of phenyl 4-(4-{4-[(1S)-1-aminoethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0682]

[0683] To a solution of phenyl 4-(4-{4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (220 mg, 0.432 mmol) in MeOH (5 mL) was added HCl (2 mL, 8.0 mmol, 4 M in 1,4-dioxane). The mixture was stirred at room temperature for 2 h. DCM and saturated NaHCO3 solution were added to the mixture, and the aqueous phase was extracted twice with DCM, dried over Na2SO4 and concentrated to afford phenyl 4-(4-{4-[(1S)-1-aminoethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (200 mg, 99% yield).

[0684]

[0685] According to the same method, the following compounds were prepared:

[0686] Phenyl 4-(4-{4-[(1R)-1-aminoethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate [(V) R1a = H, R1b = methyl, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0687]

[0688]

[0689] 4-(1-acetyl-4-{4-[(1S)-1-aminoethyl]phenyl}piperidin-4-yl)piperazine-1-carboxylic acid phenyl ester [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = 1-acetylpiperidin-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0690]

[0691]

[0692] 4-(4-{5-[(1S)-1-aminoethyl]pyridin-2-yl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester [(V) R1a = methyl, R1b = H, A = pyridin-2-yl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0693]

[0694]

[0695] 4-(1-{4-[(1S)-1-aminoethyl]phenyl}cyclopentyl)piperazine-1-carboxylic acid phenyl ester [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = cyclopentyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0696]

[0697]

[0698] 4-(3-{4-[(1S)-1-aminoethyl]phenyl}tetrahydrofuran-3-yl)piperazine-1-carboxylic acid phenyl ester [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = cyclopentyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0699]

[0700]

[0701] Phenyl 4-(4-{5-[(1S)-1-aminoethyl]pyridin-3-yl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate [(V) R1a = methyl, R1b = H, A = pyridin-2-yl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenylcarboxylate]

[0702]

[0703] 1 HNMR(400MHz, chloroform-d) δ = 8.50 (d, J = 1.96Hz, 1H) 7.53 (dd, J = 8.19, 2.32Hz, 1H) 7.33 (dd, J = 16.44, 8.38Hz, 3H) 7.13 - 7.22 (m, 1H) 7.04 (d, J = 7.70Hz, 2H) 4.19 (q, J = 6.60Hz, 1H) 3.91 - 4.07 (m, 2H) 3.46 - 3.72 (m, 6H) 2.39 (br t, J = 4.52Hz, 4H) 2.14 - 2.32 (m, 4H) 1.47 (d, J = 6.72Hz, 3H).

[0704] Phenyl 4-(4-{5-[(1R)-1-aminoethyl]pyridin-3-yl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate [(V) R1a = H, R1b = methyl, A = pyridin-2-yl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenylcarboxylate]

[0705]

[0706]

[0707] Benzyl 3-[(4-{4-[(1S)-1-aminoethyl]phenyl}tetrahydro-2H-pyran-4-yl)(methyl)amino]azetidine-1-carboxylate [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = N(R6), R6 = methyl, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, PG = benzylcarboxylate]

[0708]

[0709]

[0710] Benzyl 3-[(1-{4-[(1S)-1-aminoethyl]phenyl}-4,4-difluorocyclohexyl)(methyl)amino]azetidine-1-carboxylate [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = N(R6), R6 = methyl, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, PG = benzyl formate]

[0711]

[0712]

[0713] Benzyl 4-(1-{4-[(1S)-1-aminoethyl]phenyl}-4,4-difluorocyclohexyl)piperazine-1-carboxylate [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = benzyl formate]

[0714]

[0715]

[0716] Phenyl 4-(1-{4-[(1S)-1-aminoethyl]phenyl}-4,4-difluorocyclohexyl)piperazine-1-carboxylate [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0717]

[0718]

[0719] Phenyl 4-(1-{4-[(1R)-1-aminoethyl]phenyl}-4,4-difluorocyclohexyl)piperazine-1-carboxylate [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0720]

[0721]

[0722] Preparation 12

[0723] 4-(4-{4-[(1S)-1-Aminoethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate] Steps 5a - 5e

[0724]

[0725] Step a Synthesis of 4-[4-(4-{(1E)-N-[(S)-tert-butylsulfinyl]ethylideneamino}phenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylic acid phenyl ester [(XXV) R1a = methyl, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate] Step 5c”

[0726]

[0727] A mixture of titanium tetraethoxide (2.5 eq., 1.57 mL, 7.5 mmol), (S)-2-methylpropane-2-sulfinamide (1.5 eq., 545 mg, 4.5 mmol), and 4-[4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylic acid phenyl ester (1.22 g, 3.0 mmol) in THF (80 mL) was heated at 80 °C overnight and then cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient (100% DCM then 0% - 20% acetone / DCM) to afford the title compound (966 mg, 63% yield).

[0728]

[0729] Step b Synthesis of 4-{4-[4-(2-{[(S)-tert-butylsulfinyl]amino}propan-2-yl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylic acid phenyl ester [(XXIV) R1a = R1b = methyl, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate] Step 5e

[0730]

[0731] At -48 °C, 0.375 mL (1.125 mmol, 1.5 equiv) of 3.0 M methylmagnesium bromide ether solution was added to a solution of 4-[4-(4-{(1E)-N-[(S)-tert-butylsulfinyl]ethylideneamino}phenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylic acid phenyl ester (384 mg, 0.75 mmol) in 5 mL of dry DCM. The mixture was allowed to warm to room temperature and stirred for 6 h. The reaction mixture was quenched with saturated aqueous NaHCO3, and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient (100% DCM then 0%-4% ethanol / DCM) to afford the title compound (182 mg, 46% yield).

[0732]

[0733] Step c Synthesis of 4-{4-[4-(2-aminopropan-2-yl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylic acid phenyl ester [(V) R1a = R1b = methyl, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenylcarboxylate] Step 5d

[0734]

[0735] At 0 °C, 37% HCl (0.25 mL) was added to a solution of 4-{4-[4-(2-{[(S)-tert-butylsulfinyl]amino}propan-2-yl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylic acid phenyl ester (180 mg, 0.341 mmol) in MeOH (5 mL). The mixture was stirred at room temperature for 1 h. DCM and saturated NaHCO3 solution were added to the mixture, and the aqueous phase was extracted twice with DCM, dried over Na2SO4 and concentrated to afford 4-{4-[4-(2-aminopropan-2-yl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylic acid phenyl ester (143 mg, 99% yield).

[0736]

[0737] The following compounds were prepared according to the same method:

[0738] 4-{1-[4-(2-Aminopropan-2-yl)phenyl]-4,4-difluorocyclohexyl}piperazine-1-carboxylic acid phenyl ester [(V) R1a = R1b = methyl, A = phenyl, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester] Step 5d

[0739]

[0740]

[0741] Preparation 13

[0742] Synthesis of 3-(4-bromophenyl)pentan-3-amine [(XXI) W1 = Br, A = phenyl, R4 = H, R5a and R5b = ethyl] Step 5a

[0743]

[0744] Step a Synthesis of N-[3-(4-bromophenyl)pentan-3-yl]-2-chloroacetamide

[0745] To the alcohol 3-(4-bromophenyl)pentan-3-ol (2.5 g, 10 mmol) and ClCH2CN (1.5 g, 20 mmol) was added AcOH (25 mL), and the mixture was cooled to 0 °C. H2SO4 (1.6 mL, 30 mmol) was added dropwise while maintaining the temperature below 10 °C. The reaction mixture was allowed to reach r.t., stirred for 4 h and poured into ice water (20 mL). A light pink precipitate formed and was filtered. To obtain N-[3-(4-bromophenyl)pentan-3-yl]-2-chloroacetamide (2.7 g, 85% yield) as a light pink solid.

[0746]

[0747] According to the same method, the following compounds were prepared:

[0748] 2-Chloro-N-[4-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-yl]acetamide [(XXI) W1 = Cl, A = pyridin-3-yl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl] Step 5a

[0749]

[0750] 11H NMR (400 MHz, chloroform-d) δ = 8.51 (d, J = 2.45 Hz, 1H) 7.79 (dd, J = 8.38, 2.51 Hz, 1H) 7.33 (d, J = 8.44 Hz, 1H) 3.84 - 4.01 (m, 4H) 2.08 - 2.17 (m, 2H) 1.70 (br d, J = 13.08 Hz, 2H).

[0751] Step b Synthesis of 3-(4-bromophenyl)pentan-3-amine [(XXI) W1 = Br, A = phenyl, R4 = H, R5a and R5b = ethyl]

[0752]

[0753] Chloroacetamide (2.7 g, 8.5 mmol) and thiourea (800 mg, 10 mmol) were dissolved in a 1:5 AcOH / EtOH mixture (22 mL) and refluxed for 10 h. The cooled reaction was diluted in water and the precipitate was filtered off. The filtrate was basified with NaOH and extracted with ethyl acetate. The product was purified on silica using hexane / AcOEt 1:1 to give 3-(4-bromophenyl)pentan-3-amine (1.4 g, 68% yield).

[0754]

[0755] Following the same method, the following compounds were prepared:

[0756] 4-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-amine [(XXI) W1 = Cl, A = pyridin-3-yl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl]

[0757]

[0758] 1 1H NMR (400 MHz, chloroform-d) δ = 8.54 (d, J = 2.65 Hz, 1H) 7.79 (dd, J = 8.38, 2.65 Hz, 1H) 7.32 (d, J = 8.38 Hz, 1H) 3.77 - 4.01 (m, 4H) 2.08 - 2.26 (m, 2H) 1.64 (dd, J = 13.89, 2.43 Hz, 2H).

[0759] Preparation 14

[0760] Synthesis steps 5a and 5b of phenyl 4-(4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate [(XXIII) W1 = methyl ketone, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0761]

[0762] Step 1 Preparation of 2-(4-bromophenyl)-2-methyl-1,3-dioxolaneAt 25 °C to 30 °C under N2, PTSA (0.669 g, 3.52 mmol, 0.1 eq) was added in one portion to a mixture of 1-(4-bromophenyl)ethanone (7.0 g, 35.2 mmol, 1 eq) and ethylene glycol (9.8 g, 158 mmol, 4.5 eq) in toluene (35 mL). The mixture was stirred at reflux for 36 h and water was removed via a Dean-Stark trap. The mixture was cooled to 50 °C and concentrated under reduced pressure at 50 °C. The residue was poured into saturated aqueous Na2CO3 (40 mL) and stirred for 20 min. The aqueous phase was extracted with a mixed solvent (petroleum ether / ethyl acetate = 5 / 1, 40 mL, 30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (9.0 g, purity 80%). The crude product was used in the next step without purification. At r.t., 8.51 min, LCMS: m / z 244 [M+H] + 。

[0763] Step 2 Preparation of 4-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)tetrahydro-2H-pyran-4-ol [(XX) W1 = 2-methyl-1,3-dioxolan-2-yl, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl]

[0764] Under N₂, over a 30 min period at -65 °C, a solution of 2-(4-bromophenyl)-2-methyl-1,3-dioxolane (6.4 g, 26.33 mmol, 1 equiv) in THF (10.0 mL) was added dropwise to a solution of n-BuLi (2.5 M, 12.6 mL, 1.2 equiv) in THF (13 mL). Over 20 min at -65 °C, tetrahydropyran-4-one (2.50 g, 25.01 mmol, 2.30 mL, 0.95 equiv) was added to the above mixture. The reaction mixture was stirred at -65 °C for 30 min. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.24) showed that the starting material was completely consumed. The reaction mixture was quenched with saturated aqueous NH₄Cl at 0 °C and stirred at 20 °C for 30 min (a white precipitate formed during stirring) and filtered to give a white solid. The white solid was dissolved in DCM (150 mL), the organic phase was washed with saturated aqueous Na₂CO₃, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude product was triturated with MTBE at 20 °C for 30 min, filtered and dried in a drying oven at 50 °C for 10 h to give a white powder (3.43 g, 37% yield for two steps). At r.t., 6.35 min, LCMS: m / z 265 [M+H] + 。

[0765] Following the same method, the following compounds were prepared:

[0766] 4,4-Difluoro-1-[4-(2-methyl-1,3-dioxolan-2-yl)phenyl]cyclohexanol [(XX) W1 = 2-methyl-1,3-dioxolan-2-yl, A = phenyl, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl]

[0767]

[0768] 1 H NMR (400 MHz, chloroform-d) δ = 12.23 (d, J = 8.3 Hz, 2H), 12.17 - 12.09 (m, 2H), 9.93 (s, 1H), 8.79 - 8.68 (m, 2H), 8.50 - 8.39 (m, 2H), 7.11 - 6.86 (m, 2H), 6.70 (br t, J = 12.0 Hz, 4H), 6.52 (br d, J = 12.6 Hz, 2H), 6.30 (s, 3H).

[0769] Step 3 Preparation Step 5a of 4-(4-Bromophenyl)tetrahydro-2H-pyran-4-amine [(XXI) W1 = Br, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl]

[0770] Under N2 at 0 °C over a period of 30 min, AcOH (1.36 g, 22.0 mmol, 1.30 mL, 1.0 equiv) and H2SO4 (2.23 g, 22.7 mmol, 1.21 mL, 1.0 equiv) were added dropwise successively to a mixture of 4-(4-(2-Methyl-1,3-dioxolan-2-yl)phenyl)tetrahydro-2H-pyran-4-ol (6.00 g, 22.7 mmol, 1.0 equiv) and 2-chloroacetonitrile (28.5 g, 378 mmol, 24 mL, 16.7 equiv) in a 50 mL round-bottom flask. The mixture was stirred at 20 °C for 10 h. The mixture was poured into ice-water (w / w = 1 / 1) (50 mL) and basified to pH 9 with saturated aqueous Na2CO3 (3.9 g). The aqueous phase was extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was triturated with MTBE (20 mL) at 20 °C for 10 min and filtered to give a white solid (4.0 g, 60.0% yield).

[0771] Under N2 at 20 °C, thiourea (1.85 g, 24.34 mmol, 1.2 equiv) was added to a solution of N-(4-(4-Acetylphenyl)tetrahydro-2H-pyran-4-yl)-2-chloroacetamide (6.00 g, 20.29 mol, 1 equiv) in EtOH (30 mL). At 20 °C, AcOH (3.65 g, 60.8 mmol, 3.48 mL, 3 equiv) was added to the above mixture. The reaction mixture was stirred at 100 °C for 10 h. The mixture was cooled to 60 °C and concentrated under reduced pressure at 55 °C. The mixture was poured into ice-water (w / w = 1 / 1) (10 mL) and basified to pH 9 with saturated aqueous Na2CO3. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was triturated with MTBE (10 mL) at 25 °C for 10 min and filtered to give the title compound as a pale yellow solid (4.0 g, 90.0% yield). At r.t., 4.85 min, LCMS: m / z 220 [M + H] + 。

[0772] The following compounds were prepared according to the same method:

[0773] 1-[4-(1-Amino-4,4-difluorocyclohexyl)phenyl]ethanone (XXI) [(XXI) W1 = methyl ketone, A = phenyl, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl]

[0774]

[0775]

[0776] Step 4 Preparation of phenyl 4-(4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate Step 5b

[0777] At 20 °C under N2, NaI (150.0 mg) was added to a solution of 1-(4-(4-aminotetrahydro-2H-pyran-4-yl)phenyl)ethanone (1.50 g, 6.84 mmol, 1.0 equiv) in DIPEA (5 mL). At 20 °C, bis(2-chloroethyl)phenylcarbamate (2.33 g, 8.89 mmol, 1.3 equiv) was added to the above mixture. The reaction mixture was stirred at 140 °C for 10 h. The mixture was cooled to 40 °C and separated in a 100 mL separatory funnel. The lower layer was acidified to pH 6 with HCl (2N) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1, 0 / 1) to afford the crude product, which was triturated with MTBE (20 mL) at 25 °C for 10 min and filtered to give a white solid (1.28 g, 45.0% yield). 1 H NMR (500 MHz, DMSO-d6) δ = 7.97 (d, J = 8.39 Hz, 2H), 7.46 (d, J = 8.54 Hz, 2H), 7.30 - 7.35 (m, 2H), 7.13 - 7.21 (m, 1H), 6.99 - 7.06 (m, 2H), 3.80 - 3.90 (m, 2H), 3.46 - 3.60 (m, 2H), 3.33 - 3.40 (m, 4H), 2.59 (s, 3H), 2.09 - 2.32 (m, 8H). At r.t., 6.02 min, LCMS: m / z 409 [M+H] + 。For C 24 H 29 N2O4 [M+H] + The HRMS (ESI) calculated value for C22H28N2O4 [M+H] is 409.2122, found 409.2113.

[0778] Preparation 15

[0779] Synthesis steps 5a - 5d of phenyl 4-{4-[4-(aminomethyl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylate [(V) R1a = R1b = H, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0780]

[0781] Step a Preparation of 4-[4-(dimethoxymethyl)phenyl]tetrahydro-2H-pyran-4-ol [(XX) W1 = dimethoxymethyl, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl]

[0782] Under N2 at -65 °C over a 30 min period, a solution of 1-bromo-4-(dimethoxymethyl)benzene (6.4 g, 26.33 mmol, 1 equiv) in THF (10.0 mL) was added dropwise to a solution of n-BuLi (2.5 M, 12.6 mL, 1.2 equiv) in THF (13 mL). At -65 °C within 20 min, tetrahydropyran-4-one (2.50 g, 25.01 mmol, 2.30 mL, 0.95 equiv) was added to the above mixture. The reaction mixture was stirred at -65 °C for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl at 0 °C and stirred at 20 °C for 30 min (a white precipitate formed during stirring) and filtered to give a white solid. The white solid was dissolved in DCM (150 mL), the organic phase was washed with saturated aqueous Na2CO3, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was a white powder (3.98 g, 60% yield).

[0783] 1 H NMR (500 MHz, DMSO-d6) δ = 7.47 - 7.51 (m, 2H), 7.33 (d, J = 8.24 Hz, 2H), 5.35 (s, 1H), 5.04 (s, 1H), 3.74 - 3.81 (m, 2H), 3.67 - 3.72 (m, 2H), 3.23 (s, 6H), 1.95 (dt, J = 5.11, 12.77 Hz, 2H), 1.52 (d, J = 12.20 Hz, 2H). At r.t., 6.35 min, LCMS: m / z 253 [M + H] + 。

[0784] Step b Preparation of 2-chloro-N-[4-(4-formylphenyl)tetrahydro-2H-pyran-4-yl]acetamide, Step 5a

[0785] Under N2, over a period of 30 min at 0 °C, AcOH (1.36 g, 22.0 mmol, 1.30 mL, 1.0 equiv) and H2SO4 (2.23 g, 22.7 mmol, 1.21 mL, 1.0 equiv) were added dropwise successively to a mixture of 4-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)tetrahydro-2H-pyran-4-ol (6.00 g, 22.7 mmol, 1.0 equiv) and 2-chloroacetonitrile (28.5 g, 378 mmol, 24 mL, 16.7 equiv) in a 50 mL round-bottom flask. The mixture was stirred at 20 °C for 10 h. The mixture was poured into ice-water (w / w = 1 / 1) (50 mL) and basified to pH 9 with saturated aqueous Na2CO3 (3.9 g). The aqueous phase was extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was triturated with MTBE (20 mL) at 20 °C for 10 min and filtered to give a white solid (4.0 g, 60.0% yield). 1 1H NMR (500 MHz, DMSO-d6) δ = 9.98 (s, 1H), 8.57 (s, 1H), 7.87 (d, J = 8.39 Hz, 2H), 7.60 (d, J = 8.39 Hz, 2H), 4.13 (s, 2H), 3.76 (dd, J = 2.75, 11.74 Hz, 2H), 3.60 - 3.69 (m, 2H), 2.24 (d, J = 12.96 Hz, 2H), 1.92 - 2.02 (m, 2H). At r.t., 4.07 min, LCMS: m / z 282 [M + H] + 。

[0786] Step c Preparation of N-(4-{4-[(E)-{[(S)-tert-Butylsulfinyl]imino}methyl]phenyl}tetrahydro-2H-pyran-4-yl)-2-chloroacetamide

[0787] A mixture of titanium tetraethoxide (2.5 eq, 4.0 mL, 19.08 mmol), (S)-2-methylpropane-2-sulfinamide (1.5 eq, 1.38 g, 11.4 mmol), and 2-chloro-N-[4-(4-formylphenyl)tetrahydro-2H-pyran-4-yl]acetamide (2.15 g, 7.63 mmol) in toluene (20 mL) was heated at 80 °C overnight and then cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography system with gradient elution (100% DCM, then 0 - 20% acetone / DCM) to afford the title compound (1.76 mg, 60% yield). At r.t., 6.85 min, LCMS: m / z 385 [M+H] + .

[0788] Step d Preparation of N-{(E)-[4-(4-aminotetrahydro-2H-pyran-4-yl)phenyl]methylene}-2-methylpropane-2-sulfinamide [(XXI) W1 = (S)-tert-butylsulfinamidomethylene, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl], Step 5a

[0789] Under N2 at 20 °C, thiourea (0.418 g, 5.50 mmol, 1.2 eq) was added to a solution of N-(4-{4-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]phenyl}tetrahydro-2H-pyran-4-yl)-2-chloroacetamide (1.76 g, 4.58 mmol, 1 eq) in EtOH (30 mL). At 20 °C, AcOH (0.824 mL, 13.74 mmol, 3 eq) was added to the above mixture. The reaction mixture was stirred at 100 °C for 10 h. The mixture was cooled to 60 °C and concentrated under reduced pressure. The mixture was poured into ice-water (w / w = 1 / 1) (10 mL) and basified to pH 9 with saturated aqueous Na2CO3. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was triturated with MTBE (10 mL) at 25 °C for 10 min and filtered to give the title compound as an off-white solid (1.27 g, 90.0% yield).

[0790]

[0791] At r.t., 2.32 min, LCMS: m / z 309 [M+H] + .

[0792] Step e Preparation step 5b of 4-(4-{4-[(E)-{[(S)-tert-Butylsulfinyl]imino}methyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester [(XXIII); W1 = (S)-tert-butylsulfinamide methylene, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl]

[0793] At 20 °C under N2, NaI (130.0 mg) was added to a solution of N-{(E)-[4-(4-aminotetrahydro-2H-pyran-4-yl)phenyl]methylene}-2-methylpropane-2-sulfinamide (1.20 g, 3.89 mmol, 1.0 equiv) in DIPEA (5 mL). At 20 °C, bis(2-chloroethyl) phenyl carbamate (1.32 g, 5.1 mmol, 1.3 equiv) was added to the above mixture. The reaction mixture was stirred at 140 °C for 48 h. The mixture was cooled to 40 °C and separated in a 100 mL separatory funnel. The lower layer was acidified to pH 6 with HCl (2N) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1, 0 / 1) to afford the crude product, which was triturated with MTBE (20 mL) at 25 °C for 10 min and filtered to give a white solid (0.967 g, 50.0% yield). LCMS: m / z 498 [M + H] at r.t., 6.58 min + .

[0794] Step f Synthesis step 5d of 4-{4-[4-(aminomethyl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylic acid phenyl ester [(V); R1a = R1b = H, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0795]

[0796] At 0 °C, 37% HCl (0.25 mL) was added to a solution of phenyl 4-(4-{4-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (910 mg, 1.82 mmol) in MeOH (5 mL). The mixture was stirred at room temperature for 1 h. DCM and saturated Na2CO3 solution were added to the mixture, and the aqueous phase was extracted twice with DCM, dried over Na2SO4 and concentrated to afford the title compound as an off-white solid (715 mg, 99% yield). At r.t., 2.35 min, LCMS: m / z 396 [M+H] + .

[0797] Preparation 16

[0798] Phenyl 4-{4-[4-(1-aminocyclopropyl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylate [(V) R1a and R1b = cyclopropyl, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate] Conversion F - Step 5c

[0799]

[0800] Step a Synthesis of phenyl 4-[4-(4-cyanophenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylate [(XXIII) W1 = -CN, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate] Conversion F

[0801]

[0802] Under N2, X-phos (1 g, 2.08 mmol, 0.5 equiv), K3[Fe(CN)6] (6.8 g, 22.29 mmol, 5 equiv), K2CO3 (1.15 g, 8.32 mmol, 2 equiv), and Pd(OAc)2 (233.47 mg, 4.16 mmol, 0.25 equiv) were successively added to a mixture of 4-[4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylic acid phenyl ester (2 g, 4.15 mmol, 1 equiv) in H2O (4 mL) and dioxane (40 mL). The mixture was stirred at 100 °C for 16 h. TLC (PE:EA = 1:1, Rf = 0.41) indicated the completion of the reaction, and a major new spot with a relatively large polarity was detected. For this step, the reaction of 2 g * 4 was run in parallel. The four reaction mixtures were filtered through the added THF (200 mL), quenched by the addition of H2O (100 mL), and extracted with EtOAc (100 mL * 3). The combined organic layers were washed with 30 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was suspended in DMF (50 mL) and stirred for 2 h. The mixture was filtered, and the filter cake was concentrated to give the title compound [5 g (total from 2 g * 4 of the bromo derivative), 72.93% yield].

[0803]

[0804] Step b Synthesis step 5c of 4-{4-[4-(1-aminocyclopropyl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylic acid phenyl ester [(V) R1a and R1b = cyclopropyl, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0805]

[0806] In a 3-necked flask, 4-[4-(4-cyanophenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylic acid phenyl ester (1 g, 2.43 mmol, 1 equiv) was dissolved in THF (35 mL) and Et2O (20 mL), and a cloudy suspension was obtained. At 20 °C, Ti(Oi-Pr)4 (875 mg, 3.08 mmol, 908.62 μL, 1.27 equiv) was added. The reaction was cooled to -65 °C under N2. At -65 °C, EtMgBr (3 M, 2.25 mL, 2.78 equiv) was added over 10 min and stirred for an additional 10 min, then allowed to warm to 20 °C. The yellow mixture slowly turned black and was stirred at 20 °C for 1 h. Then BF3.Et2O (750 mg, 5.28 mmol, 652.17 μL, 2.18 equiv) was added at 0 °C and stirred at 20 °C for 1 h. LCMS showed a mixture containing the desired product (RT = 0.77, m / z = 422.3, M+H). For this step, a reaction of 1 g * 5 was run in parallel, and for the 5 reactions, 15% - 30% of the desired compound was detected by LCMS. The reaction mixture was quenched by adding HCl (1 M, 7.5 mL) at 0 °C, then diluted with NaOH (10%, 25 mL) and extracted three times with EtOAc (100 mL * 3). The combined organic layers were washed with 30 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by neutral preparative HPLC (HPLC: column: Agela DuraShell C18 250 * 25 mm * 10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 15% - 45%, 22 min). Lyophilization gave the amine as a white solid [676 mg (total from 5 g of starting material), 12.5% yield].

[0807]

[0808] According to the same method, the following compounds were prepared:

[0809] 4-{1-[4-(1-aminocyclopropyl)phenyl]cyclopentyl}piperazine-1-carboxylic acid phenyl ester [(V) R1a and R1b = cyclopropyl, A = phenyl, R4 = H, R5a and R5b = cyclopentyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0810]

[0811]

[0812] Prepare 17

[0813] Benzyl 3-{[4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl](methyl)amino}azetidine-1-carboxylate [(XXIII) W1 = Br, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = N(R6), R6 = methyl, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, PG = benzyl formate] - Step 5b’

[0814]

[0815] Step 1 At 25 °C, Ti(OEt)4 (18.70 g, 81.99 mmol, 17.00 mL, 1.5 eq) was added to a solution of compound 4-(4-bromophenyl)tetrahydro-2H-pyran-4-amine (14 g, 54.66 mmol, 1 eq) and benzyl 3-oxoazetidine-1-carboxylate (16.82 g, 81.99 mmol, 1.5 eq) in anhydrous THF (150 mL). The reaction was stirred at 70 °C for 16 h. Then the reaction was cooled to 30 °C, and NaBH3CN (10.30 g, 163.97 mmol, 3 eq) was added. Then the reaction was stirred at 70 °C for 2 h. LCMS (t = 1.818 min, Ms+H = 445.1, 447.1) showed the reaction was complete. The reaction mixture was quenched by adding 100 mL of H2O and 50 mL of 1 M HCl at 25 °C, and then diluted with 200 mL of EtOAc. Then, 50 mL of saturated Na2CO3 was added to the residue, and the mixture was stirred at 20 °C for 3 h. The residue was filtered through diatomaceous earth and extracted with 200 mL (100 mL * 2) of EtOAc. The combined organic layers were washed with 200 mL (100 mL * 2) of saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography (eluent with a 0% - 70% ethyl acetate / petroleum ether gradient, containing 10% DCM, at 100 mL / min), giving benzyl 3-{[4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl]amino}azetidine-1-carboxylate (20 g, 44.91 mmol, 82.16% yield) as a pale yellow oil. 1 HNMR (400 MHz, chloroform-d) δ = 7.52 - 7.45 (m, 2H), 7.37 - 7.31 (m, 5H), 7.25 - 7.14 (m, 2H), 5.03 (s, 2H), 4.29 - 4.20 (m, 1H), 3.87 - 3.80 (m, 2H), 3.75 - 3.34 (m, 6H), 2.12 - 2.06 (m, 2H), 1.81 (brd, J = 13.9 Hz, 2H).

[0816] Step 2. At 0 °C, NaBH3CN (11.29 g, 179.63 mmol, 5 equiv) was added to a solution of 3-{[4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl]amino}azetidine-1-carboxylic acid benzyl ester (16 g, 35.93 mmol, 1 equiv), formaldehyde (8.72 g, 290.42 mmol, 8.00 mL, 8.08 equiv), and AcOH (8.40 g, 139.88 mmol, 8.00 mL, 3.89 equiv) in anhydrous MeOH (160 mL). The reaction was stirred at 20 °C for 16 h. HPLC (t = 2.757 min) showed completion of the reaction. The reaction was concentrated in vacuo and then diluted with 100 mL of EtOAc. At 0 °C, 100 mL of saturated Na2CO3 was added to the residue to pH = 8, and the mixture was extracted with 100 mL (50 mL × 2) of EtOAc. The combined organic layers were washed with 50 mL (25 mL × 2) of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (eluent with a 0% - 100% ethyl acetate / petroleum ether gradient, containing 20% DCM, at 100 mL / min), giving the title compound as a pale yellow oil (15 g, 32.65 mmol, 90.89% yield). 1 1H NMR (400 MHz, chloroform-d) δ = 7.52 - 7.43 (m, 2H), 7.37 - 7.29 (m, 6H), 7.18 - 7.07 (m, 2H), 5.06 - 4.99 (m, 2H), 4.27 - 4.19 (m, 1H), 3.89 - 3.82 (m, 2H), 3.77 - 3.60 (m, 4H), 3.51 - 3.40 (m, 2H), 2.12 (br t, J = 5.0 Hz, 4H), 1.27 (t, J = 7.2 Hz, 3H).

[0817] Preparation 18

[0818] Benzyl 3-[acetyl(1-{4-[(1S)-1-aminoethyl]phenyl}-4,4-difluorocyclohexyl)amino]azetidine-1-carboxylate [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = N(R6), R6 = acetyl, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, PG = benzyl formate] Step 5e

[0819]

[0820] To a solution of benzyl 3-[acetyl(4-{4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)amino]azetidine-1-carboxylate (140.00 mg, 237.39 μmol, 1 equiv) in THF (1 mL) and H2O (0.2 mL) was added I2 (6.03 mg, 23.74 μmol, 4.78 μL, 0.1 equiv). The reaction was then stirred at 50 °C for 16 h. LCMS showed the reaction was complete. At 0 °C, Na2SO3 (1 M, 2 mL) was slowly added to the reaction to quench the excess I2. The reaction mixture was concentrated to dryness in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-55%, 8 min) to afford the title compound as a white solid (60 mg, 123.57 μmol, 52.05% yield, 100% purity).

[0821]

[0822] Preparation 19

[0823] Benzyl {2-[(1-{4-[(1S)-1-aminoethyl]phenyl}-4,4-difluorocyclohexyl)amino]-2-oxoethyl}carbamate [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = NH, G1 = CO, Z1 = -CH2-, m1 = 1, PG = benzyl carbamate], Step 5b, Step 5c', and Step 5d

[0824]

[0825] (Step 5b”) At 0 °C, a solution of T3P (14.70 g, 23.10 mmol, 13.74 mL, 50% purity, 1.5 equiv) was added to a solution of 1-[4-(1-amino-4,4-difluorocyclohexyl)phenyl]ethanone (3.9 g, 15.40 mmol, 1 equiv), DIEA (15.92 g, 123.18 mmol, 21.46 mL, 8 equiv) and 2-(benzyloxycarbonylamino)acetic acid (3.87 g, 18.48 mmol, 1.2 equiv) in DCM (30 mL). The resulting mixture was stirred at 25 °C for 3 h. TLC (PE:EA = 3:1) showed the reaction was complete, indicating the end of the reaction, and the desired product was observed on LCMS. The reaction mixture was concentrated and diluted with EA (100 mL), washed with H2O (35 mL), saturated aqueous brine (40 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash silica chromatography (ISCO; 40 g SepaFlash silica quick column, eluent with 0% - 60% EA / PE gradient, at 100 mL / min). Benzyl (2-{[1-(4-acetylphenyl)-4,4-difluorocyclohexyl]amino}-2-oxoethyl)carbamate (4.5 g, 8.99 mmol, 58.39% yield, 88.8% purity) was obtained as a yellow solid. According to LCMS (Rt = 1.201 min, Ms+1 = 445.3) it was 88.8%.

[0826] (Step 5c’) At 20 °C, Ti(OEt)4 (5.93 g, 25.99 mmol, 5.39 mL, 3 eq) was added to a solution of benzyl (2-{[1-(4-acetylphenyl)-4,4-difluorocyclohexyl]amino}-2-oxoethyl)carbamate (3.85 g, 8.66 mmol, 1 eq) and (S)-tert-butanesulfinamide (3.67 g, 30.32 mmol, 3.5 eq) in anhydrous THF (80 mL). The reaction was stirred at 80 °C for 16 h. TLC (SiO2, PE:EtOAc = 1:1) and LCMS showed the reaction was complete. Then the reaction was cooled to -70 °C. At -70 °C, NaBH4 (655.37 mg, 17.32 mmol, 2 eq) was slowly added to the reaction. Then the reaction was warmed to 20 °C and stirred for 2 h. TLC (PE:EtOAc = 1:1) and LCMS (Rt = 1.199 min, Ms+1 = 550.3) showed the reaction was complete. At 0 °C, MeOH (5 mL) was slowly added to the reaction to quench the excess NaBH4, and then H2O (25 mL) was added. The reaction mixture was filtered through celite, and the cake was washed with EtOAc 100 mL (50 mL * 2). The residue was extracted with EtOAc 40 mL (20 mL * 2). The organic phases were combined, dried over Na2SO4, filtered and concentrated to dryness in vacuo. The crude product was purified by preparative HPLC (column: Agela DuraShell C18 250*70 mm*10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 45%-63%, 20 min); benzyl {2-[(1-{4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]phenyl}-4,4-difluorocyclohexyl)amino]-2-oxoethyl}carbamate (3.8 g, 6.77 mmol, 78.21% yield, 98% purity) was obtained as a yellow solid. The purity was 98% according to HPLC (Rt = 3.424 min).

[0827] (Step 5d) Dissolve benzyl {2-[(1-{4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]phenyl}-4,4-difluorocyclohexyl)amino]-2-oxoethyl}carbamate (3.8 g, 6.91 mmol, 1 eq) in HCl / MeOH (4 M, 307.27 mL, 177.79 eq). Stir the reaction at 25 °C for 2 h. LCMS (Rt = 0.952 min, Ms+1 = 446.3) shows the reaction is complete. Concentrate the reaction mixture under reduced pressure. The resulting residue is purified by preparative HPLC (column: Agela DuraShell C18 250*70 mm*10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 28% - 55%, 20 min); benzyl {2-[(1-{4-[(1S)-1-aminoethyl]phenyl}-4,4-difluorocyclohexyl)amino]-2-oxoethyl}carbamate (1.75 g, 3.93 mmol, 56.82% yield, 100% purity) is obtained as a white solid. It is 100% pure according to LCMS (Rt = 0.952 min, Ms+1 = 446.3).

[0828]

[0829] According to the same method, the following compounds are prepared:

[0830] Benzyl {(2R)-1-[(1-{4-[(1S)-1-aminoethyl]phenyl}-4,4-difluorocyclohexyl)amino]-1-oxopropan-2-yl}carbamate [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = NH, G1 = CO, Z1 = CR9aR9b, R9a = CH3, R9b = H, m1 = 1, PG = benzyl carbamate]

[0831]

[0832]

[0833] Benzyl {(2S)-1-[(1-{4-[(1S)-1-aminoethyl]phenyl}-4,4-difluorocyclohexyl)amino]-1-oxopropan-2-yl}carbamate [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = NH, G1 = CO, Z1 = CR9aR9b, R9a = CH3, R9b = H, m1 = 1, PG = benzyl carbamate]

[0834]

[0835]

[0836] Prepare 20

[0837] Benzyl {2-[(4-{4-[(1S)-1-aminoethyl]phenyl}tetrahydro-2H-pyran-4-yl)(trifluoroacetyl)amino]ethyl}carbamate [(V) R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = NR6, R6 = trifluoroacetyl, G1 = CH2, Z1 = CH2, m1 = 1, PG = benzyl carbamate], Step b", Step c' and Step d

[0838]

[0839] Step b" To a solution of 1-[4-(4-aminotetrahydro-2H-pyran-4-yl)phenyl]ethanone (9 g, 41.04 mmol, 1 equiv) and benzyl N-(2-oxoethyl)carbamate (8.72 g, 45.15 mmol, 1.1 equiv) in DCM (90 mL) was added HOAc (3.70 g, 61.57 mmol, 3.52 mL, 1.5 equiv) and the mixture was stirred at 25 °C for 0.5 h. At 25 °C, NaBH(OAc)3 (17.40 g, 82.09 mmol, 2 equiv) was added to the above mixture. The reaction mixture was stirred at 25 °C for 2 h. TLC (n-hexane:EtOAc = 0:1) indicated completion of the reaction. The reaction mixture was quenched with H2O (25 mL), filtered through a Celite pad, and then extracted with DCM (55 mL * 2), washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash silica chromatography (ISCO; 80 g SepaFlash silica quick column, eluent with 60% - 75% EtOAc / n-hexane gradient, at 145 mL / min). Benzyl (2-{[4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl]amino}ethyl)carbamate (4.5 g, 10.21 mmol, 24.89% yield, 90% purity) was obtained as a yellow solid.

[0840] 11H NMR (400 MHz, chloroform-d) δ = 9.83 (br s, 2H), 8.06 (d, J = 8.38 Hz, 2H), 7.82 (br d, J = 8.13 Hz, 2H), 7.29 - 7.36 (m, 5H), 4.94 (s, 2H), 6.70 (br s, 1H), 4.01 (br d, J = 12.01 Hz, 2H), 3.25 - 3.55 (m, 4H), 2.73 (br s, 2H), 2.54 - 2.65 (m, 7H).

[0841] At 0 °C, pyridine (4.19 g, 52.97 mmol, 4.28 mL, 6 eq) and trifluoroacetic anhydride (7.42 g, 35.31 mmol, 4.91 mL, 4 eq) were added to a solution of benzyl (2-{[4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl]amino}ethyl)carbamate (3.5 g, 8.83 mmol, 1 eq) in DCM (20 mL), and the mixture was stirred for 1 h. Then the reaction mixture was stirred at 25 °C for 5 h. LCMS showed the reaction was complete and the desired product was observed. The reaction mixture was diluted with H2O (15 mL), then extracted with DCM (100 mL × 2), washed with K2CO3 (50 mL) and brine (25 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude was purified by flash silica chromatography (ISCO; 80 g SepaFlash silica quick column, eluent with 20% - 25% EtOAc / hexane gradient, at 100 mL / min). Benzyl (2-{[4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl](trifluoroacetyl)amino}ethyl)carbamate (3 g, 5.79 mmol, 65.55% yield, 95% purity) was obtained as a yellow oil.

[0842]

[0843] Step c': At 25 °C, Ti(OEt)4 (3.89 g, 17.06 mmol, 3.54 mL, 3 equiv) was added to a solution of (2-{[4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl](trifluoroacetyl)amino}ethyl)carbamic acid benzyl ester (2.8 g, 5.69 mmol, 1 equiv) and (R)-2-methylpropane-2-sulfinamide (2.41 g, 19.90 mmol, 3.5 equiv) in anhydrous THF (70 mL). The reaction was stirred at 80 °C for 16 h. LCMS showed the reaction was complete. Then the reaction was cooled to -70 °C. At -70 °C, lithium tri-sec-butylborohydride (1 M, 17.06 mL, 3 equiv) was slowly added to the reaction and stirred for 2 h. LCMS HPLC showed the reaction was complete. At 0 °C, MeOH (5 mL) was slowly added to the reaction to quench the excess lithium tri-sec-butylborohydride, then H2O (15 mL) was added. The reaction mixture was filtered through Celite; the cake was washed with EtOAc 30 mL (15 mL * 2). The residue was extracted with EtOAc 20 mL (10 mL * 2). The organic phases were combined, dried over Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by preparative HPLC (column: Agela DuraShell C18 250 * 80 mm * 10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-65%, 20 min). Benzyl {2-[(4-{4-[(1S)-1-{[(R)-tert-butylsulfinyl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)(trifluoroacetyl)amino]ethyl}carbamate (2.8 g, 4.64 mmol, 81.57% yield, 99% purity) was obtained as a colorless oil. 99% ee.

[0844] Step d Then, I2 (1.68 g, 6.63 mmol, 1.33 mL, 2 eq) was added to a solution of benzyl {2-[(4-{4-[(1S)-1-{[(R)-tert-butanesulfinyl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)(trifluoroacetyl)amino]ethyl}carbamate (2 g, 3.31 mmol, 99% purity, 1 eq) in THF (20 mL) and H2O (20 mL). The reaction was stirred at 25 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was quenched with Na2SO3 (2 mL) and H2O (10 mL), and then extracted with DCM (25 mL * 2), washed with brine (15 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250 * 70 mm #10 μm; mobile phase: [water (0.05% NH3H2O + 10 mM NH4HCO3)-ACN]; B%: 35%-65%, 25 min).

[0845] Benzyl {2-[(4-{4-[(1S)-1-aminoethyl]phenyl}tetrahydro-2H-pyran-4-yl)(trifluoroacetyl)amino]ethyl}carbamate (1.25 g, 2.48 mmol, 74.93% yield, 98% purity) was obtained as a white solid.

[0846]

[0847] Preparation 21

[0848] 4-(4-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl carbonate] Synthesis step 2a

[0849]

[0850] Dissolve phenyl 4-(4-{4-[(1S)-1-aminoethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (377.17 mg, 0.921 mmol, 1.1 eq) in DMSO (11 ml). Then, sequentially add 2-(methylsulfonyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (223.7 mg, 0.837 mmol), CsF (140 mg, 0.920 mmol) and DIPEA (0.175 ml, 0.1 mmol) to this solution. Then heat the reaction mixture at 75 °C for 4 h and then place it at room temperature. Slowly pour the reaction mixture onto cold water / brine. Filter the precipitated solid, wash it with water and dry it under vacuum. The obtained dry solid, phenyl 4-(4-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (349 mg, 70%) was used without further purification.

[0851] 1 H NMR (500 MHz, DMSO-d6) δ = 8.57 (s, 1H), 8.38 (d, J = 6.86 Hz, 1H), 7.63 (d, J = 9.15 Hz, 1H), 7.30 - 7.42 (m, 4H), 7.24 (d, J = 8.24 Hz, 2H), 7.14 - 7.21 (m, 1H), 6.92 - 7.06 (m, 2H), 6.18 (d, J = 9.00 Hz, 1H), 5.47 (br.s., 1H), 5.01 (t, J = 6.56 Hz, 1H), 3.81 (dd, J = 4.96, 10.90 Hz, 2H), 3.43 - 3.57 (m, 2H), 3.36 - 3.40 (m, 4H), 1.94 - 2.32 (m, 8H), 1.50 (d, J = 7.02 Hz, 3H), 1.24 - 1.45 (m, 6H). At r.t., 8.67 min, LCMS: m / z 597 [M+H] + 。For C 34 H 41 N6O4 [M+H] + The HRMS (ESI) calculated value for C

[0852] Following the same method, the following compounds were prepared:

[0853] 4-(3-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}pentan-3-yl)piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = ethyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0854]

[0855]

[0856] 4-(3-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}oxetan-3-yl)piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = oxetan-3-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0857]

[0858] At r.t., 8.95 min, LCMS: m / z 569 [M+H] + 。

[0859] 4-(2-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}propan-2-yl)piperazine-1-carboxylic acid ethyl ester [(VI) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = methyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = ethyl ester]

[0860]

[0861]

[0862] 4-(1-Acetyl-4-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}piperidin-4-yl)piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 1-acetylpiperidin-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0863]

[0864] 1 H NMR (500 MHz, DMSO-d6) δ = 8.52 - 8.60 (m, 1H), 8.36 (d, J = 6.25 Hz, 1H), 7.57 - 7.66 (m, 1H), 7.25 - 7.41 (m, 6H), 7.14 - 7.21 (m, 1H), 6.90 - 7.05 (m, 2H), 6.17 (d, J = 5.49 Hz, 1H), 5.46 (br.s, 1H), 4.97–5.01 (m, 1H), 3.70–3.76 (m, 2H), 3.53–3.62 (m, 2H), 3.15–3.35 (m, 2H), 2.15–2.33 (m, 8H), 1.98 (s, 3H), 1.77–1.96 (m, 2H) 1.30 - 1.52 (m, 9H). At r.t., 8.70 min, LCMS: m / z 638 [M+H] + 。For C 36 H 43 N7O4 [M+H] + The HRMS (ESI) calculated value for C

[0865] 4-(4-{4-[(1R)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = Y = CH, R1a = H, R1b = methyl, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0866]

[0867] 1 1H NMR (500 MHz, DMSO-d6) δ = 8.57 (s, 1H), 8.36 (d, J = 6.86 Hz, 1H), 7.63 (d, J = 9.30 Hz, 1H), 7.30 - 7.42 (m, 4H), 7.21 - 7.27 (m, 2H), 7.17 (t, J = 7.32 Hz, 1H), 6.90 - 7.05 (m, 2H), 6.18 (d, J = 9.30 Hz, 1H), 5.450 - 5.46 (m, 1H), 4.96 - 5.03 (m, 1H), 3.76 - 3.91 (m, 3H), 3.23 - 3.39 (m, 6H), 2.02 - 2.31 (m, 7H), 1.47 (d, J = 6.86 hz, 3H), 1.25 - 1.46 (m, 6H). At r.t., 8.58 min, LCMS: m / z 597 [M + H] + 。For C 34 H 41 N6O4 [M + H] + The calculated value of HRMS (ESI) for C27H35N6O4 [M + H] is 597.3184, and the measured value is 597.3185.

[0868] 4-(4-{5-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]pyridin-2-yl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = Y = CH, R1a = methyl, R1b = H, A = pyrimidin-2-yl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0869]

[0870] 11H NMR (DMSO-d6) δ = 8.55 - 8.63 (m, 2H), 8.20 - 8.47 (m, 1H), 7.72 - 7.89 (m, 1H), 7.65 (d, J = 9.30 Hz, 1H), 7.27 - 7.39 (m, 2H), 7.15 - 7.22 (m, 1H), 6.91 - 7.07 (m, 2H), 6.20 (d, J = 8.39 Hz, 1H), 5.42 - 5.79 (m, 1H), 4.97 - 5.38 (m, 1H), 3.75 - 3.88 (m, 2H), 3.40 - 3.54 (m, 2H), 3.18 - 3.30 (4H), 2.18 - 2.34 (m, 6H), 1.97 - 2.07 (m, 2H), 1.53 (d, J = 7.02 Hz, 3H), 1.22 - 1.31 (m, 6H). At r.t., 5.95 min, LCMS: m / z 598 [M+H] + 。

[0871] 4-(4-{4-[(1S)-1-{[4-Methyl-7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = methyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0872]

[0873] 1 1H NMR (DMSO-d6) δ = 8.00 - 8.37 (m, 1H), 7.81 (d, J = 9.61 Hz, 1H), 7.30 - 7.45 (m, 4H), 7.23 (d, J = 8.24 Hz, 2H), 7.14 - 7.20 (m, 1H), 6.88 - 7.07 (m, 2H), 6.14 - 6.20 (m, 1H), 5.45–5.60 (br.m, 1H), 4.48–5.05 (br.M, 1H), 3.81 (dd, J = 4.96, 10.75 Hz, 4H), 3.48 (br.m, 4H), 2.54 (s, 3H), 2.01 - 2.33 (m, 8H), 1.48 (d, J = 7.02 Hz, 3H), 0.90–1.42 (br m, 6H). At r.t., 6.8 min, LCMS: m / z 611 [M+H] + 。

[0874] 4-[4-(4-{(1S)-1-[(8-Ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]ethyl}phenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = ethyl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0875]

[0876] 1 H NMR (DMSO-d6) δ = 8.59 (s, 1H), 8.44 (d, J = 7.02 Hz, 1H), 7.68 (d, J = 9.30 Hz, 1H), 7.22 - 7.40 (m, 4H), 7.18 (dd, J = 7.47, 7.32 Hz, 1H), 7.02 (, dd, J = 2.90, 6.71 Hz, 1H), 6.97 (d, J = 7.78 Hz, 1H), 6.22 (d, J = 9.30 Hz, 1H), 5.04 (t, J = 6.94 Hz, 1H), 4.01 - 4.27 (m, 2H), 3.72 - 3.92 (m, 2H), 3.46 - 3.55 (m, 6H), 3.37 - 3.41 (m, 2H), 1.94 - 2.33 (m, 8H), 1.49 (d, J = 7.02 Hz, 3H), 0.83 (t, J = 6.86 Hz, 3H). At r.t., 6.26 min, LCMS: m / z 583 [M + H] + .

[0877] 4-[4-(4-{(1S)-1-[(8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]ethyl}phenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = methyl, Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = cyclopentyl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0878]

[0879] 11H NMR (DMSO-d6) δ = 8.66 (s, 1H), 8.36 (d, J = 6.86 Hz, 1H), 7.29 - 7.42 (m, 4H), 7.23 (d, J = 8.24 Hz, 2H), 7.15 - 7.20 (m, 1H), 6.96 (d, J = 7.93 Hz, 2H), 6.05 (d, J = 1.07 Hz, 1H), 5.55 (d, J = 8.85 Hz, 1H), 4.90 - 5.37 (m, 1H), 3.72 - 3.89 (m, 2H), 3.49 (br.s., 2H), 3.39 (br.s., 2H), 2.30 (s, 3H), 1.93 - 2.28 (m, 8H), 1.67 - 1.86 (m, 5H), 1.50 (d, J = 7.02 Hz, 3H), 1.23 - 1.47 (m, 4H). At r.t., 10.06 min, LCMS: m / z 636 [M+H] + 。

[0880] 4-(3-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydrofuran-3-yl)piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydrofuran-3-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0881]

[0882] 1 1H NMR (DMSO-d6) δ = 8.57 (s, 1H), 8.38 (br.s., 1H), 7.63 (d, J = 9.15 Hz, 1H), 7.27 - 7.43 (m, 6H), 7.13 - 7.23 (m, 1H), 6.93 - 7.09 (m, 2H), 6.17 (d, J = 7.78 Hz, 1H), 5.42 - 5.83 (m, 1H), 4.89 - 5.35 (m, 1H), 4.01 - 4.13 (m, 1H), 3.88 - 3.98 (m, 2H), 3.58 - 3.68 (m, 1H), 3.43 - 3.56 (m, 2H), 3.28 - 3.32 (m, 2H), 2.14 - 2.46 (m, 6H), 1.49 (d, J = 7.02 Hz, 3H), 1.30 - 1.45 (m, 6H). At r.t., 10.41 min, LCMS: m / z 583 [M+H] + 。

[0883] 4-(4-{4-[(1S)-1-{[5-Methyl-7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = CMe, Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0884]

[0885]

[0886] At r.t., 9.02 min, LCMS: m / z 611 [M+H] + 。

[0887] 4-(1-{4-[(1S)-1-{[7-Oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}cyclopentyl)piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = cyclopentyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0888]

[0889] 11H NMR (DMSO-d6) δ = 8.57 (s, 1H), 8.37 (d, J = 6.86 Hz, 1H), 7.63 (d, J = 9.30 Hz, 1H), 7.27 - 7.40 (m, 6H), 7.15 - 7.21 (m, 1H), 6.91 - 7.06 (m, 2H), 6.17 (d, J = 8.24 Hz, 1H), 5.47 (br.s., 1H), 4.99 (t, J = 6.86 Hz, 1H), 3.42 - 3.55 (m, 3H), 3.25 - 3.33 (m, 2H), 2.17 - 2.35 (m, 5H), 1.91 - 2.13 (m, 4H), 1.71 (br.s., 2H), 1.49 (d, J = 6.86 Hz, 3H), 1.33 - 1.44 (m, 6H). At r.t., 9.06 min, LCMS: m / z 581 [M + H] + 。

[0890] 4-(4-{4-[(1S)-1-{[7-Oxo-8-(pentan-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = methyl, Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = pentan-3-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0891]

[0892]

[0893] 4-(4-{4-[(1S)-1-{[4-(Dimethylamino)-7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = methyl, Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = N(Me)2, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl ester]

[0894]

[0895]

[0896] Preparation of 22

[0897] 4-{4-[4-(2-{[7-Oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}propan-2-yl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = Y = CH, R1a = R1b = methyl, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate] in Step 2a of synthesis

[0898]

[0899] Dissolve 4-{4-[4-(2-aminopropan-2-yl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylic acid phenyl ester (143 mg, 0.34 mmol, 1 equiv) in 1,4-dioxane (6 ml). Then, sequentially add 2-(methylsulfonyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (104 mg, 0.308 mmol, 0.9 equiv) and DIPEA (0.088 ml, 1.5 equiv) to the solution. Then heat the reaction mixture at 60 °C for 48 h and then allow to warm to room temperature. Pour the reaction mixture slowly onto cold water / brine. Filter the precipitated solid, wash with water and dry under vacuum. The title compound is obtained as a solid (144 mg, 77%) and is used without further purification.

[0900]

[0901] At r.t., 3.98 min, LCMS: m / z 611 [M+H] + 。

[0902] According to the same method, the following compounds are prepared:

[0903] 4-{4-[4-(1-{[7-Oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}cyclopropyl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = Y = CH, R1a and R1b = cyclopropyl, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0904]

[0905]

[0906] Preparation 23

[0907] Phenyl 4-(4-{4-[(1S)-1-{[2-oxo-1-(propan-2-yl)-1,2-dihydro-1,6-naphthyridin-7-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate [(VI) X = CH, U = Y = CH, Synthesis Step 2a of R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0908]

[0909] Under nitrogen, dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (0.06 g, 0.08 mmol) was added to a solution of phenyl 4-(4-{4-[(1S)-1-aminoethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (0.25 g, 0.61 mmol), 7-chloro-1-isopropyl-1H-[1,6]naphthyridin-2-one (0.17 g, 0.76 mmol) and cesium carbonate (0.50 g, 1.53 mmol) in toluene (7 mL), and the mixture was heated at 100 °C overnight. After cooling to room temperature, the mixture was filtered through a silica plug and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0% to 40% acetone / EtOAc).

[0910] 11H NMR (DMSO-d6) δ = 8.31 (s, 1H), 7.62 (d, J = 9.30 Hz, 1H), 7.45 - 7.49 (m, 1H), 7.40 (d, J = 8.24 Hz, 2H), 7.30 - 7.36 (m, 2H), 7.27 (d, J = 8.24 Hz, 2H), 7.14 - 7.20 (m, 1H), 6.95 - 7.02 (m, 2H), 6.43 (br.m, 1H), 6.12 (d, J = 9.46 Hz, 1H), 4.85 - 5.07 (m, 2H), 3.76 - 3.88 (m, 2H), 3.36 - 3.53 (m, 6H), 2.01 - 2.30 (m, 8H), 1.48 (d, J = 6.86 Hz, 3H), 1.41 (d, J = 6.56 Hz, 3H), 1.22–1.28 (br.m, 3H). At r.t., 7.39 min, LCMS: m / z 596 [M+H] + 。For C 35 H 42 N5O4 [M+H] + The HRMS (ESI) calcd for C29H36N5O4 [M+H] 596.3232, found 596.3244.

[0911] According to the same method, the following compounds were prepared:

[0912] Benzyl 4-(4,4-difluoro-1-{4-[(1S)-1-{[2-oxo-1-(propan-2-yl)-1,2-dihydro-1,6-naphthyridin-7-yl]amino}ethyl]phenyl}cyclohexyl)piperazine-1-carboxylate [(VI) X = CH, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = benzyl formate]

[0913]

[0914] 1 1H NMR (DMSO-d6) δ = 8.29 (s, 1H), 7.61 (d, J = 9.30 Hz, 1H), 7.45 (d, J = 6.25 Hz, 1H), 7.34 - 7.40 (m, 2H), 7.23 - 7.34 (m, 7H), 6.17 - 6.41 (m, 1H), 6.11 (d, J = 9.15 Hz, 1H), 4.86 - 5.04 (m, 3H), 2.07 - 2.28 (m, 8H), 1.72 - 1.92 (m, 8H), 1.09 - 1.60 (m, 9H).

[0915] Benzyl 4-(4,4-difluoro-1-{4-[(1S)-1-{[2-oxo-1-(propan-2-yl)-1,2-dihydro-1,6-naphthyridin-7-yl]amino}ethyl]phenyl}cyclohexyl)piperazine-1-carboxylate [(VI) X = CH, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenyl formate]

[0916]

[0917]

[0918] 7-{[(1S)-1-(4-{1-[(1-benzylazetidin-3-yl)(methyl)amino]-4,4-difluorocyclohexyl}phenyl)ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one [(VI) X = CH, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = NR6, R6 = methyl, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, PG = benzyl formate]

[0919]

[0920]

[0921] 7-{[(1S)-1-(4-{1-[(1-benzylazetidin-3-yl)(methyl)amino]-4,4-difluorocyclohexyl}phenyl)ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one [(VI) X = CH, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = NR6, R6 = acetyl, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, PG = benzyl formate]

[0922]

[0923]

[0924] Preparation 24

[0925] 4-(4-{4-[(1S)-1-{[4-Methyl-7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester [(VI) X = N, U = Y = CH, Synthesis of

[0926]

[0927] To a solution of 4-(4-{4-[(1S)-1-({4-[(2,4-Dimethoxybenzyl)amino]-7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl}amino)ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylic acid phenyl ester (175 mg, 0.227 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (2 mL). The yellow solution was stirred overnight at room temperature. 15 mL of CH2Cl2 was added, and the organic solution was washed with saturated NaHCO3 solution, dried over Na2SO4 and evaporated to dryness to give 170 mg of the title compound. The solvent was evaporated and the residue was suspended. The reaction mixture was evaporated to dryness and the residue was purified on silica gel (AcOEt / hexane: 1 / 1) to give a white solid (170 mg). 1 1H NMR (DMSO-d6) δ = 7.84 (d, J = 9.6 Hz, 1H), 7.51 - 7.39 (m, 1H), 7.38 - 7.06 (m, 7H), 7.03 - 6.87 (m, 3H), 5.00 (br.s., 1H), 3.90 - 3.73 (m, 3H), 3.56 - 3.43 (m, 3H), 2.33 - 1.98 (m, 8H).

[0928] Preparation of 25

[0929] 2-{[(1S)-1-{4-[4-(Piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(II) X = N, U = Y = CH, Step 2b of

[0930]

[0931] To a solution of phenyl 4-(4-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (149.0 mg, 0.25 mmol) in a mixture of isopropanol (4.0 mL) was added NaOH (1.0 mL, 12.5 mmol). The mixture was stirred at 80 °C for 8 h and then concentrated to dryness, with 5%-10% of isopropyl carbamate remaining in the mixture. The crude product was dissolved in DCM and water at pH 10, the organic phase was separated and washed with brine, dried (Na2SO4) and the volatiles were removed in vacuo to afford 2-{[(1S)-1-{4-[4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one as a pale yellow oil (109.0 mg, 92%).

[0932]

[0933] Following the same method, the following compounds were prepared:

[0934] 2-{[(1R)-1-{4-[4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(II) X = N, U = Y = CH, R1a = H, R1b = methyl, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2]

[0935]

[0936]

[0937] 8-ethyl-2-{[(1S)-1-{4-[4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one [(II) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = ethyl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2

[0938]

[0939]

[0940] 2-{[(1S)-1-{6-[4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl]pyridin-3-yl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(II) X = N, U = Y = CH, R1a = methyl, R1b = H, A = pyrimidin-2-yl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2

[0941]

[0942]

[0943] 4-methyl-2-{[(1S)-1-{4-[4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(II) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = methyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2

[0944]

[0945]

[0946] 8-cyclopentyl-5-methyl-2-{[(1S)-1-{4-[4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one [(II) X = N, U = CMe, Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = cyclopentyl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2

[0947]

[0948]

[0949] 2-{[(1S)-1-{4-[3-(Piperazin-1-yl)tetrahydrofuran-3-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(VI) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydrofuran-3-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2]

[0950]

[0951]

[0952] 5-Methyl-2-{[(1S)-1-{4-[4-(Piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(VI) X = N, U = C-Me, Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2]

[0953]

[0954]

[0955] 2-{[(1S)-1-{4-[1-(Piperazin-1-yl)cyclopentyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(II) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = cyclopentyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2]

[0956]

[0957]

[0958] 4-Amino-2-{[(1S)-1-{4-[4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(II) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = NH2, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2]

[0959]

[0960] At r.t., 6.16 min, LCMS: m / z 514 [M+Na] + 。For C 27 H 38 N7NaO2 [M+Na] + The calculated value of HRMS(ESI) for C

[0961] 8-(Pentan-3-yl)-2-{[(1S)-1-{4-[4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one [(II) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = pentan-3-yl, R3 = R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2]

[0962]

[0963]

[0964] 4-(Dimethylamino)-8-(pentan-3-yl)-2-{[(1S)-1-{4-[4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one [(II) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = N(Me)2, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2]

[0965]

[0966] At r.t., 7.77 min, LCMS: m / z 520 [M+H] + 。For C 29 H 42 N7O2 [M+Na] + The calculated HRMS(ESI) value for C

[0967] Preparation 26

[0968] 2-{[(1S)-1-(4-{4-[Azetidin-3-yl(methyl)amino]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(II) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = NR6, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, R6 = methyl] Step 2b

[0969]

[0970] Under a nitrogen atmosphere, ammonium formate (1.4 ml of a 25% aqueous solution) was added to a stirred solution of benzyl 3-[methyl(4-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)amino]azetidine-1-carboxylate (200.0 mg, 0.327 mmol) in THF (30.0 mL), followed by the addition of 10% Pd / C (120 mg). The suspension was stirred at 60 °C for 1 hour. The catalyst was removed by filtration through a pad of diatomaceous earth and the filtrate was evaporated to dryness under vacuum to give the title product (150 mg, 96% yield).

[0971] 11H NMR (500 MHz, DMSO-d6) δ = 8.53 - 8.58 (m, 1H), 8.37 (d, J = 7.02 Hz, 1H), 7.58 - 7.67 (m, 1H), 7.31 - 7.37 (m, 2H), 7.26 (d, J = 7.93 Hz, 2H), 6.65 (s, 1H), 6.16 (d, J = 9.46 Hz, 1H), 5.49 (br.s, 1H), 5.03 (br.m, 1H), 3.69 (m, 2H), 3.06 - 3.27 (m, 7H), 2.18 (s, 2H), 2.04 - 2.15 (m, 3H), 1.86 - 1.97 (m, 2H), 1.50 (d, J = 6.10 Hz, 3H), 1.35 (m, 6H). At r.t., 6.28 min, LCMS: m / z 477 [M+H] + 。For C 27 H 37 N6O2 [M+H] + The HRMS (ESI) calculated value for C24H32N6O2 [M+H] is 477.2973, and the measured value is 477.2971.

[0972] According to the same method, the following compounds were prepared:

[0973] 2-{[(1S)-1-{4-[4,4-difluoro-1-(piperazin-1-yl)cyclohexyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(II) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2]

[0974]

[0975] 1 1H NMR (500 MHz, DMSO-d6) δ = 8.56 (s, 1H), 8.37 (d, J = 6.71 Hz, 1H), 7.62 (d, J = 9.30 Hz, 1H), 7.22 - 7.42 (m, 4H), 6.16 (d, J = 9.30 Hz, 1H), 5.41 - 5.79 (m, 1H), 4.96 - 5.33 (m, 1H), 2.55 - 2.64 (m, 4H), 2.00 - 2.22 (m, 8H), 1.66 - 1.79 (m, 4H), 1.17 - 1.50 (m, 9H). At r.t., 8.63 min, LCMS: m / z 511 [M+H] + 。

[0976] For C 28 H 37 F2N6O2[M+H] + The calculated HRMS(ESI) value of 511.2992 and the measured value of 511.2987.

[0977] 7-{[(1S)-1-{4-[4,4-difluoro-1-(piperazin-1-yl)cyclohexyl]phenyl}ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one [(II) X = CH, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2]

[0978]

[0979]

[0980] N-(4,4-difluoro-1-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}cyclohexyl)-D-alanine amide [(II) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = N(Me)2, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = NH, G1 = CO, Z1 = CR9aR9b, R9a = CH3, R9b = H, m1 = 1]

[0981]

[0982] At r.t., 9.60 min, LCMS: m / z 513 [M+H] + 。For C 27 H 35 F2N6O2[M+H] + The calculated HRMS(ESI) value of 513.2784 and the measured value of 513.2774.

[0983] N-(4,4-difluoro-1-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}cyclohexyl)-L-alanine amide [(II) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = N(Me)2, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = NH, G1 = CO, Z1 = CR9aR9b, R9a = CH3, R9b = H, m1 = 1

[0984]

[0985] At r.t., 9.58 min, LCMS: m / z 513 [M+H] + 。For C 27 H 35 F2N6O2 [M+H] + The HRMS(ESI) calculated value for C25H31F2N6O2 [M+H] is 513.2784, found 513.2772.

[0986] Example 1

[0987] 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 1, step 1a

[0988]

[0989] At 0 °C, acryloyl chloride (0.01 mL, 0.13 mmol) was added to a solution of 2-{[(1S)-1-{4-[4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (57.0 mg, 0.12 mmol) in DCM (1.0 mL). After 30 minutes, the reaction was quenched with water. The mixture was extracted with DCM, dried over Na2SO4, filtered and concentrated to give a yellow oil. The crude product was purified by silica gel chromatography (1% to 10% MeOH / DCM) to give the title product as a white foam (40 mg, 66% yield).

[0990] 11H NMR (500 MHz, DMSO-d6) δ = 8.55 (s, 1H), 8.31 (d, J = 6.71 Hz, 1H), 7.61 (d, J = 9.28 Hz, 1H), 7.33 (d, J = 7.81 Hz, 2H), 7.21 (d, J = 8.18 Hz, 2H), 6.63 (dd, J = 10.50, 16.72 Hz, 1H), 6.15 (d, J = 9.28 Hz, 1H), 5.91 - 6.03 (m, 1H), 5.55 (d, J = 10.62 Hz, 1H), 5.42 (br.m.1H), 5.00 (t, J = 6.65 Hz, 1H), 3.79 (d, J = 7.08 Hz, 2H), 3.34 - 3.54 (m, 6H), 2.12 (br.s., 8H), 1.49 (d, J = 6.96 Hz, 3H), 1.42 - 1.21 (br.m.6H). At r.t., 6.03 min, LCMS: m / z 531 [M+H] + 。For C 30 H 39 N6O3 [M+H] + The calculated value of HRMS (ESI) for C26H33N6O3 [M+H] is 531.3078, and the measured value is 531.3067.

[0991] According to the same method, the following compounds were prepared:

[0992] 2-{[(1S)-1-{4-[2-(4-acryloylpiperazin-1-yl)propan-2-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = methyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd2

[0993]

[0994] 11H NMR (500 MHz, DMSO-d6) δ = 8.56 (s, 1H), 8.35 (d, J = 6.86 Hz, 1H), 7.62 (d, J = 9.30 Hz, 1H), 7.38 - 7.46 (m, 2H), 7.24 - 7.36 (m, 2H), 6.73 (dd, J = 10.45, 16.70 Hz, 1H), 6.15 (d, J = 9.30 Hz, 1H), 5.99 - 6.10 (m, 1H), 5.63 (dd, J = 2.14, 10.52 Hz, 1H), 5.40 - 5.56 (br.s., 1H), 4.98 (q, J = 6.71 Hz, 1H), 3.46 (br.s., 4H), 2.22 - 2.41 (m, 4H), 1.47 (d, J = 6.71 Hz, 3H), 1.29 - 1.44 (br.m, 6H), 1.25 (s, 3H), 1.24 (s, 3H). At r.t., 6.49 min, LCMS: m / z 489 [M+H] + 。For C 28 H 37 N6O2 [M+H] + The calculated value of HRMS (ESI) for C

[0995] 2-{[(1S)-1-{4-[3-(4-acryloylpiperazin-1-yl)oxetan-3-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = oxetan-3-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 3

[0996]

[0997] 11H NMR (500 MHz, DMSO-d6) δ = 8.51 - 8.59 (m, 1H), 8.15 - 8.40 (m, 1H), 7.60 - 7.64 (m, 1H), 7.33 - 7.43 (m, 2H), 7.03 - 7.10 (m, 2H), 6.66 (dd, J = 10.45, 16.70 Hz, 1H), 6.15 (d, J = 9.30 Hz, 1H), 5.93 - 6.00 (m, 1H), 5.56 (d, J = 10.37 Hz, 1H), 5.35 - 5.42 (br., m, 1H), 4.99 (q, J = 7.30 Hz, 1H), 4.69 - 4.75 (m, 4H), 3.52 (br.s., 4H), 1.99 - 2.22 (m, 4H), 1.48 (d, J = 7.30 Hz, 3H), 1.17 - 1.32 (br., m, 6H). At r.t., 8.72 min, LCMS: m / z 503 [M+H] + 。For C 28 H 35 N6O3 [M+H] + The calculated value of HRMS (ESI) for C

[0998] 2-{[(1S)-1-{4-[3-(4-acryloylpiperazin-1-yl)pent-3-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = ethyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd4

[0999]

[1000] 11H NMR (500 MHz, DMSO-d6) δ = 8.56 (s, 1H), 8.34 (d, J = 6.86 Hz, 1H), 7.62 (d, J = 9.30 Hz, 1H), 7.18 - 7.39 (m, 4H), 6.68 (dd, J = 10.45, 16.55 Hz, 1H), 6.15 (d, J = 9.30 Hz, 1H), 6.02 (dd, J = 1.91, 16.55 Hz, 1H), 5.59 (dd, J = 1.91, 10.29 Hz, 1H), 5.37 - 5.42 (br., m, 1H), 4.99 (t, J = 6.63 Hz, 1H), 3.37 - 3.51 (m, 4H), 2.25 - 2.41 (m, 4H), 1.75 - 1.94 (m, 4H), 1.48 (d, J = 7.02 Hz, 3H), 1.35 - 1.44 (br., m, 6H), 0.70 (q, J = 6.96 Hz, 6H). At r.t., 7.73 min, LCMS: m / z 517 [M+H] + 。For C 30 H 41 N6O2 [M+H] + The HRMS (ESI) calculated value for C

[1001] 2-{[(1S)-1-{4-[1-Acetyl-4-(4-acryloylpiperazin-1-yl)piperidin-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = N-acetylpiperidin-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 6

[1002]

[1003] 11H NMR (500 MHz, DMSO-d6) δ = 8.48 - 8.59 (m, 1H), 8.34 (d, J = 6.71 Hz, 1H), 7.62 (d, J = 9.30 Hz, 1H), 7.32 (d, J = 8.08 Hz, 2H), 7.23 (d, J = 8.08 Hz, 2H), 6.64 (dd, J = 10.45, 16.70 Hz, 1H), 6.15 (d, J = 9.30 Hz, 1H), 5.97 (d, J = 16.47 Hz, 1H), 5.56 (d, J = 10.68 Hz, 1H), 5.36 - 5.42 (br., m, 1H), 4.99 (t, J = 6.62 Hz, 1H), 3.37 - 3.57 (m, 8H), 2.08 - 2.33 (m, 4H), 1.97 (s, 3H), 1.74 - 1.94 (m, 4H), 1.48 (d, J = 7.02 Hz, 3H), 1.35 - 1.44 (br., m, 6H). At r.t., 6.71 min, LCMS: m / z 572 [M+H] + 。For C 32 H 42 N7O3 [M+H] + The HRMS (ESI) calculated value for C

[1004] 2-{[(1S)-1-{4-[4-(4-propionylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = propionyl] cpd 8

[1005]

[1006] 11H NMR (500 MHz, DMSO-d6) δ = 8.56 (s, 1H), 8.13 - 8.38 (m, 1H), 7.62 (d, J = 9.30 Hz, 1H), 7.30 - 7.43 (m, 2H), 7.20 (d, J = 8.08 Hz, 2H), 6.15 (d, J = 9.30 Hz, 1H), 5.35 - 5.85 (m, 1H), 4.90 - 5.32 (m, 1H), 3.79 (dd, J = 5.41, 10.75 Hz, 2H), 3.26 - 3.32 (m, 6H), 1.93 - 2.28 (m, 10H), 1.48 (d, J = 7.02 Hz, 3H), 1.35 - 1.44 (br., m, 6H), 0.81 - 0.88 (m, 3H). At r.t., 6.38 min, LCMS: m / z 533 [M+H] + For C 30 H 41 N6O3 [M+H] + the HRMS (ESI) calculated value for is 533.3235, found 533.3232.

[1007] 2-{[(1R)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = Y = CH, R1a = H, R1b = methyl, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 9

[1008]

[1009]

[1010] At r.t., 6.36 min, LCMS: m / z 531 [M+H] + For C 30 H 39 N6O3 [M+H] + the HRMS (ESI) calculated value for is 531.3078, found 531.3077.

[1011] 2-{[(1S)-1-{6-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]pyridin-3-yl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = Y = CH, R1a = methyl, R1b = H, A = pyridin-3-yl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 12

[1012]

[1013]

[1014] At r.t., 4.69 min, LCMS: m / z 532 [M+H] + 。

[1015] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-4-methyl-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = methyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 13

[1016]

[1017]

[1018] At r.t., 4.69 min, LCMS: m / z 545 [M+H] + 。For C 31 H 41 N7O3 [M+H] + The calculated value of HRMS(ESI) for C

[1019] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = ethyl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 14

[1020]

[1021]

[1022] At r.t., 4.93 min, LCMS: m / z 517 [M+H] + 。For C 29 H 37 N6O3 [M+H] + The calculated HRMS(ESI) value for C

[1023] 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = CMe, Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = cyclopentyl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 15

[1024]

[1025]

[1026] At r.t., 8.0 min, LCMS: m / z 571 [M+H] + 。

[1027] 7-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one [X = CH, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 11

[1028]

[1029] 11H NMR (500 MHz, DMSO-d6) δ = 8.29 (s, 1H), 7.61 (d, J = 9.30 Hz, 1H), 7.43 (d, J = 6.71 Hz, 1H), 7.37 (d, J = 8.24 Hz, 2H), 7.23 (d, J = 8.24 Hz, 2H), 6.66 (dd, J = 10.52, 16.62 Hz, 1H), 6.30 (br.s., 1H), 6.10 (d, J = 9.30 Hz, 1H), 5.98 (dd, J = 2.29, 16.62 Hz, 1H), 5.55 - 5.60 (m, 1H), 4.94 (br.s., 2H), 3.74 - 3.86 (m, 2H), 3.46 (br.s., 6H), 2.00 - 2.21 (m, 8H), 1.46 (d, J = 6.71 Hz, 3H), 1.23 - 1.40 (m, 6H). At r.t., 4.72 min, LCMS: m / z 530 [M+H] + 。For C 31 H 40 N5O3 [M+H] + The calculated value of HRMS (ESI) for C

[1030] 2-{[(1S)-1-{4-[3-(4-acryloylpiperazin-1-yl)tetrahydrofuran-3-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydrofuran-3-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 17

[1031]

[1032]

[1033] At r.t., 7.77 min, LCMS: m / z 517 [M+H] + 。

[1034] 2-{[(1S)-1-{4-[1-(4-acryloylpiperazin-1-yl)cyclopentyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = cyclopentyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 16

[1035]

[1036] 1 H NMR (500 MHz, DMSO-d6) δ = 8.55 (s, 1H), 8.33 (d, J = 6.86 Hz, 1H), 7.62 (d, J = 9.30 Hz, 1H), 7.20 - 7.37 (m, 4H), 6.64 (dd, J = 10.37, 16.62 Hz, 1H), 6.15 (d, J = 9.30 Hz, 1H), 5.97 (dd, J = 1.91, 16.70 Hz, 1H), 5.52 - 5.61 (m, 1H), 5.42 (br.s, 1H), 4.98 (t, J = 7.02 Hz, 1H), 3.39 - 3.52 (m, 4H), 2.09 - 2.29 (m, 4H), 1.91 - 2.08 (m, 4H), 1.68 (br.s., 2H), 1.31 - 1.51 (m, 9H). At r.t., 7.01 min, LCMS: m / z 515 [M+H] + 。

[1037] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-5-methyl-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = C-Me, Y = CH、 R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 18

[1038]

[1039] 11H NMR (500 MHz, DMSO-d6) δ = 8.62 (s, 1H), 8.31 (d, J = 6.71 Hz, 1H), 7.27 - 7.42 (m, 2H), 7.13 - 7.26 (m, 2H), 6.63 (dd, J = 10.52, 16.62 Hz, 1H), 6.03 (s, 1H), 5.85 - 5.99 (m, 1H), 5.51 - 5.60 (m, 1H), 5.39 (br.s, 1H), 4.99 (t, J = 6.86 Hz, 1H), 3.79 (dd, J = 5.57, 11.06 Hz, 2H), 3.40 - 3.49 (m, 2H), 3.28 - 3.33 (m, 4H), 2.28 (s, 3H), 2.08 (d, J = 9.91 Hz, 8H), 1.47 (d J = 7.0 Hz, 3H), 1.23 - 1.39 (m, 6H). At r.t., 6.81 min, LCMS: m / z 545 [M+H] + 。

[1040] 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-4-amino-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = NH2, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 19

[1041]

[1042] 1 1H NMR (500 MHz, DMSO-d6) δ = 7.83 (d, J = 9.61 Hz, 1H), 7.35 - 7.47 (m, 1H), 7.16 - 7.33 (m, 4H), 6.97 (br.s., 2H), 6.64 (dd, J = 10.60, 16.40 Hz, 1H), 5.83 - 6.06 (m, 2H), 5.56 (d, J = 10.07 Hz, 1H), 4.90 - 5.32 (m, 2H), 3.71 - 3.90 (m, 2H), 3.40 - 3.51 (m, 4H), 3.28 - 3.32 (m, 2H), 1.92 - 2.27 (m, 8H), 1.43 (d, J = 7.02 Hz, 3H), 1.21 - 1.35 (m, 6H). At r.t., 5.88 min, LCMS: m / z546 [M+H] + 。

[1043] 2-{[(1S)-1-(4-{4-[4-(2-Methylacryloyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = 2-methylacryloyl] cpd 21

[1044]

[1045] 1 H NMR (500 MHz, DMSO-d6) δ = 8.56 (s, 1H), 8.36 (d, J = 7.02 Hz, 1H), 7.62 (d, J = 9.30 Hz, 1H), 7.33 (d, J = 7.93 Hz, 2H), 7.20 (d, J = 8.08 Hz, 2H), 6.15 (d, J = 9.15 Hz, 1H), 5.37 - 5.87 (m, 1H), 5.05 (s, 1H), 4.99 (d, J = 6.71 Hz, 1H), 4.73 (s, 1H), 3.71 - 3.84 (m, 2H), 3.28 - 3.33 (m, 6H), 1.94 - 2.33 (m, 8H), 1.62 - 1.78 (m, 3H), 1.48 (d, J = 6.76 Hz, 3H), 1.23 - 1.41 (m, 6H). At r.t., 6.93 min, LCMS: m / z 545 [M + H] + 。For C 31 H 41 N6O3 [M + H] + The calculated value of HRMS (ESI) for C

[1046] 2-{[(1S)-1-(4-{4-[4-(Chloroacetyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = chloroacetyl] cpd 22

[1047]

[1048] 1 1H NMR (500 MHz, DMSO-d6) δ = 8.56 (s, 1H), 8.35 (d, J = 7.17 Hz, 1H), 7.62 (d, J = 9.15 Hz, 1H), 7.31 - 7.43 (m, 2H), 7.21 (d, J = 8.08 Hz, 2H), 6.15 (d, J = 9.30 Hz, 1H), 5.38 - 5.76 (m, 1H), 4.88 - 5.33 (m, 1H), 4.11 - 4.33 (m, 2H), 3.71 - 3.86 (m, 2H), 3.28 - 3.33 (m, 6H), 1.94 - 2.29 (m, 8H), 1.48 (d, J = 6.86 Hz, 3H), 1.23 - 1.41 (m, 6H). At r.t., 6.64 min, LCMS: m / z 554 [M+H] + 。

[1049] 2-{[(1S)-1-(4-{4-[4-(3-Chloropropanoyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = 3-chloropropanoyl] cpd 23

[1050]

[1051] 1 1H NMR (500 MHz, DMSO-d6) δ = 8.57 (br.s, 1H), 8.43 (br.s, 1H), 7.62 (d, J = 9.15 Hz, 1H), 7.45 - 7.57 (m, 2H), 7.21 - 7.33 (m, 2H), 6.17 (d, J = 9.15 Hz, 1H), 5.42 (br.s, 1H), 5.05 (br.s, 1H), 4.33 - 4.43 (m, 2H), 3.73 - 3.99 (m, 2H), 3.55 - 3.70 (m, 4H), 3.28 - 3.32 (m, 2H), 2.65 - 2.96 (m, 2H), 1.99 - 2.29 (m, 8H), 1.50 (br.s, 3H), 1.21 - 1.41 (m, 6H). At r.t., 6.93 min, LCMS: m / z 567 [M+H]+ 。For C 30 H 40 ClN6O3[M+H] + The calculated HRMS(ESI) value of 567.2845 for

[1052] 2-{[(1S)-1-{4-[1-(4-acryloylpiperazin-1-yl)cyclohexyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = cyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 20

[1053]

[1054]

[1055] At r.t., 7.28 min, LCMS: m / z 529 [M+H] + 。For C 31 H 41 N6O3[M+H] + The calculated HRMS(ESI) value of 529.3286 for

[1056] 7-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one [(I) X = N, U = CH2, Y = O, -, R1a = methyl, R1b = H, A = phenyl, R2 = ethyl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 24

[1057]

[1058]

[1059] At r.t., 4.06 min, LCMS: m / z 521 [M+H] + 。For C 28 H 37 N6O4[M+H] +HRMS(ESI) calculated value: 521.2871, measured value: 521.2867.

[1060] 7-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-1-(propan-2-yl)-1,4-dihydro-2H-pyrido[4,3-d][1,3]oxazin-2-one [(I) X = CH, U = CH2, Y = O, -, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 25

[1061]

[1062] At r.t., 6.65 min, LCMS: m / z 534 [M+H] + 。

[1063] 7-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-1-ethyl-1,4-dihydro-2H-pyrido[4,3-d][1,3]oxazin-2-one [(I) X = CH, U = CH2, Y = O, -, R1a = methyl, R1b = H, A = phenyl, R2 = ethyl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 44

[1064]

[1065]

[1066] At r.t., 2.49 min, LCMS: m / z 520 [M+H] + 。For C 29 H 38 N5O4 [M+H] + HRMS(ESI) calculated value: 520.2919, measured value: 520.2924.

[1067] 2-{[(1S)-1-{4-[1-(4-Acryloylpiperazin-1-yl)-4,4-difluorocyclohexyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 26

[1068]

[1069]

[1070] At r.t., 8.60 min, LCMS: m / z 565 [M+H] + 。For C 31 H 37 F2N6O2 [M+H] + The HRMS (ESI) calculated value for C

[1071] 7-{[(1S)-1-{4-[1-(4-acryloylpiperazin-1-yl)-4,4-difluorocyclohexyl]phenyl}ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one [(I) X = CH, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 47

[1072]

[1073] 11H NMR (500 MHz, DMSO-d6) δ = 8.28 (s, 1H), 7.60 (d, J = 9.30 Hz, 1H), 7.43 (d, J = 6.71 Hz, 1H), 7.37 (d, J = 8.39 Hz, 2H), 7.37 (d, J = 8.39 Hz, 2H), 6.66 (dd, J = 10.45, 16.70 Hz, 1H), 6.15 - 6.52 (br.s, 1H), 6.10 (d, J = 9.30 Hz, 1H), 5.98 (dd, J = 2.36, 16.70 Hz, 1H), 5.60 (dd, J = 2.3, 10.50 Hz, 1H), 4.57 - 5.44 (m, 2H), 3.40 - 3.49 (m, 2H), 3.29 - 3.32 (m, 2H), 2.52 - 2.59 (m, 4H), 2.16 (br.s., 4H), 1.78 (br.s., 4H), 1.48 (d, J = 6.71 Hz, 3H), 1.34 - 1.41 (m, 3H), 1.03 (d, J = 6.10 Hz, 3H). At r.t., 6.62 min, LCMS: m / z 564 [M+H] + 。For C 32 H 40 F2N5O2 [M+H] + The HRMS (ESI) calculated value for C

[1074] 7-{[(1R)-1-{4-[1-(4 - acryloylpiperazin - 1 - yl)-4,4 - difluorocyclohexyl]phenyl}ethyl]amino}-1-(propan - 2 - yl)-1,6 - naphthyridin - 2(1H)-one [(I) X = CH, U = Y = CH, R1a = H, R1b = methyl, A = phenyl, R2 = propan - 2 - yl, R3 = H, R4 = H, R5a and R5b = 4,4 - difluorocyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 63

[1075]

[1076] At r.t., 6.62 min, LCMS: m / z 564 [M+H] + 。For C 32 H 40 F2N5O2 [M+H] + The HRMS (ESI) calculated value for C

[1077] 7-{[(1S)-1-{4-[4,4-difluoro-1-(4-propionylpiperazin-1-yl)cyclohexyl]phenyl}ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one [(I) X = CH, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = propionyl] cpd 67

[1078]

[1079] At r.t., 6.67 min, LCMS: m / z 566 [M+H] + 。For C 32 H 42 F2N5O2 [M+H] + The HRMS(ESI) calculated value for C

[1080] 2-{[(1S)-1-{5-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]pyridin-2-yl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = pyridin-2-yl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 27

[1081]

[1082]

[1083] At r.t., 5.54 min, LCMS: m / z 532 [M+H] + 。For C 29 H 38 N7O2 [M+H] + The HRMS(ESI) calculated value for C

[1084] 2-{[(1S)-1-(4-{4-[(1-Acryloylazetidin-3-yl)(methyl)amino]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = NR6, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, R6 = methyl, E = acryloyl] cpd 28

[1085]

[1086]

[1087] At r.t., 7.25 min, LCMS: m / z 531 [M+H] + 。For C 30 H 39 N6O3 [M+H] + The HRMS(ESI) calculated value for C

[1088] 7-{[(1S)-1-(4-{4-[(1-Acryloylazetidin-3-yl)(methyl)amino]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one [(I) X = CH, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = NR6, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, R6 = methyl, E = acryloyl] cpd 48

[1089]

[1090] 11H NMR (500 MHz, DMSO-d6) δ = 8.29 (s, 1H), 7.61 (dd, J = 2.67, 9.23 Hz, 1H), 7.25 - 7.52 (m, 5H), 5.86 - 6.13 (m, 3H), 5.44 - 5.60 (m, 1H), 5.00 (br.s, 1H), 4.05 - 4.15 (m, 1H), 3.84 (dd, J = 7.93 and 8.39 Hz, 1H), 3.65 - 3.76 (m, 4H), 3.51 - 3.57 (m, 1H), 3.39 - 3.44 (m, 2H), 3.24 - 3.32 (m, 2H), 2.08 (s, 3H), 1.99 - 2.05 (m, 4H), 1.48 (d, J = 6.86 Hz, 3H), 1.22 - 1.41 (m, 6H). At r.t., 5.62 min, LCMS: m / z 530 [M+H] + 。For C 31 H 40 N5O3 [M+H] + The HRMS (ESI) calculated value for C

[1091] 2-{[(1S)-1-(4-{1-[(1-Acryloylazetidin-3-yl)(methyl)amino]-4,4-difluorocyclohexyl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = NR6, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, R6 = methyl, E = acryloyl] cpd 50

[1092]

[1093]

[1094] At r.t., 9.57 min, LCMS: m / z 565 [M+H] + 。For C 31 H 39 F2N6O2 [M+H] + The HRMS (ESI) calculated value for C

[1095] 7-{[(1S)-1-(4-{1-[(1-acryloylazetidin-3-yl)(methyl)amino]-4,4-difluorocyclohexyl}phenyl)ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one [(I) X = CH, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = NR6, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, R6 = methyl, E = acryloyl] cpd 61

[1096]

[1097]

[1098] At r.t., 8.12 min, LCMS: m / z 564 [M+H] + 。For C 32 H 40 F2N6O2 [M+H] + The HRMS (ESI) calculated value for C

[1099] N-(1-acryloylazetidin-3-yl)-N-(4,4-difluoro-1-{4-[(1S)-1-{[2-oxo-1-(propan-2-yl)-1,2-dihydro-1,6-naphthyridin-7-yl]amino}ethyl]phenyl}cyclohexyl)acetamide [(I) X = CH, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = NR6, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, R6 = acetyl, E = acryloyl] cpd 62

[1100]

[1101]

[1102] At r.t., 8.79 min, LCMS: m / z 592 [M+H] + 。For C 33 H 40 F2N6O3 [M+H] + The HRMS (ESI) calculated value for C

[1103] 2-{[(1S)-1-(4-{4-[(1-acryloylazetidin-3-yl)oxy]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = pyridin-2-yl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = O, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, E = acryloyl] cpd 29

[1104]

[1105] At r.t., 6.28 min, LCMS: m / z 518 [M+H] + 。

[1106] 2-[(1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}cyclopropyl)amino]-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a and R1b = -CH2-CH2-, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 30

[1107]

[1108] 1 H NMR (500 MHz, DMSO-d6) δ = 8.61 (s, 1H), 8.59 (s, 1H), 7.65 (d, J = 9.30 Hz, 1H), 7.03 - 7.18 (m, 4H), 6.64 (dd, J = 10.37, 16.62 Hz, 1H), 6.20 (d, J = 9.30 Hz, 1H), 5.99 (dd, J = 2.29, 16.62 Hz, 1H), 5.53 - 5.59 (m, 1H), 5.27 (br.s., 1H), 3.77 (dd, J = 3.43, 7.40 Hz, 2H), 3.43 (d, J = 3.05 Hz, 4H), 3.19 - 3.31 (m, 2H), 1.96 - 2.23 (m, 8H), 1.01 - 1.52 (m, 10H). At r.t., 6.31 min, LCMS: m / z 543 [M+H] + 。For C 31 H39 N6O3[M+H] + HRMS(ESI) calculated value for N6O3[M+H] is 543.3078, found value is 543.3087.

[1109] 2-({4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]benzyl}amino)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 31

[1110]

[1111] 1 H NMR (500 MHz, DMSO-d6) δ = 8.57 (s, 1H), 8.38 (t, J = 5.95 Hz, 1H), 7.64 (d, J = 9.30 Hz, 1H), 7.18 - 7.33 (m, 4H), 6.65 (dd, J = 10.45, 16.85 Hz, 1H), 6.18 (d, J = 9.15 Hz, 1H), 5.98 (d, J = 16.62 Hz, 1H), 5.57 (d, J = 10.68 Hz, 1H), 5.39 - 5.53 (br.s 1H), 4.56 - 4.60 (m, 1H), 4.53 (d, J = 5.64 Hz, 1H), 3.76 - 3.83 (m, 2H), 3.40 - 3.48 (m, 4H), 3.28 - 3.32 (m, 2H), 2.03 - 2.18 (m, 8H), 1.20 - 1.28 (m, 3H), 1.03 (d, J = 6.10 Hz, 3H). At r.t., 5.54 min, LCMS: m / z 517 [M+H] + 。For C 29 H 37 N6O3[M+H] + HRMS(ESI) calculated value for N6O3[M+H] is 517.2922, found value is 517.2921.

[1112] 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)-1-methylpiperidin-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 1-methylpiperidin-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 32

[1113]

[1114] 1 H NMR (500 MHz, DMSO-d6) δ = 8.56 (s, 1H), 8.34 (d, J = 7.02 Hz, 1H), 7.62 (d, J = 9.30 Hz, 1H), 7.30 (d, J = 7.93 Hz, 2H), 7.19 (d, J = 7.93 Hz, 2H), 6.63 (dd, J = 10.45, 16.85 Hz, 1H), 6.15 (d, J = 9.30 Hz, 1H), 5.96 (d, J = 16.62 Hz, 1H), 5.55 (d, J = 10.68 Hz, 1H), 5.24 - 5.45 (m, 1H), 4.99 (q, J = 7.47 Hz, 1H), 3.38 - 3.48 (m, 4H), 3.26 - 3.32 (m, 4H), 1.96 - 2.22 (m, 11H), 1.48 (d, J = 7.02 Hz, 3H), 1.23 - 1.44 (m, 3H), 1.03 (d, J = 6.10 Hz, 3H). At r.t., 6.18 min, LCMS: m / z 544 [M+H] + 。For C 31 H 41 N7O2 [M+H] + The HRMS (ESI) calculated value for C

[1115] 2-{[(1S)-1-{4-[(2R)-2-(4-acryloylpiperazin-1-yl)butan-2-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a = methyl, R5b = ethyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 33

[1116]

[1117] At r.t., 7.02 min, LCMS: m / z 503 [M+H] + 。

[1118] 2-{[(1S)-1-{4-[(2S)-2-(4-Acryloylpiperazin-1-yl)butan-2-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a = ethyl, R5b = methyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 34

[1119]

[1120] At r.t., 7.02 min, LCMS: m / z 503 [M+H] + 。

[1121] 2-{[(1S)-1-{4-[2-(4-Acryloylpiperazin-1-yl)butan-2-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a = ethyl, R5b = methyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 46

[1122]

[1123] 11H NMR (500 MHz, DMSO-d6) δ = 8.56 (s, 1H), 8.35 (t, J = 7.47 Hz, 1H), 7.62 (d, J = 9.30 Hz, 2H), 7.36 (d, J = 7.02 Hz, 2H), 7.30 (d, J = 8.02 Hz, 1H), 6.73 (ddd, J = 3.81, 10.45, 16.70 Hz, 1H), 6.16 (d, J = 9.00 Hz, 1H), 6.07 (dd, J = 2.06, 16.70 Hz, 1H), 5.63 (d, J = 10.52 Hz, 1H), 5.25 - 5.55 (br.s, 1H), 5.00 (d, J = 6.56 Hz, 1H), 3.49 (d, J = 7.47 Hz, 2H), 3.30 - 3.33 (m, 2H), 2.17 - 2.47 (m, 4H), 1.64 - 1.75 (m, 1H), 1.53 - 1.58 (m, 1H), 1.48 (d, J = 6.86 Hz, 3H), 1.15 - 1.40 (m, 6H), 1.10 (s, 3H), 0.45 - 0.52 (m, 3H). At r.t., 7.02 min, LCMS: m / z 503 [M+H] + 。For C 29 H 39 N6O2 [M+H] + The calculated value of HRMS (ESI) for C

[1124] 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(pentan-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = pentan-3-yl, R3 = R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 35

[1125]

[1126]

[1127] At r.t., 7.02 min, LCMS: m / z 559 [M+H] + 。For C 32 H 43 N6O3 [M+H] +HRMS(ESI) calculated value: 559.3391, measured value: 559.3392.

[1128] 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-4-(dimethylamino)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = N(Me)2, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 36

[1129]

[1130] 1 H NMR (500 MHz, DMSO-d6) δ = 7.67 - 7.74 (m, 1H), 7.64 (d, J = 7.17 Hz, 1H), 7.28 - 7.37 (m, 2H), 7.19 (d, J = 8.39 Hz, 2H), 6.59 - 6.74 (m, 1H), 5.84 - 6.04 (m, 2H), 5.53 - 5.61 (m, 1H), 5.47 (br.s, 1H), 4.93 - 5.11 (m, 1H), 3.72 - 3.85 (m, 2H), 3.44 (dd, J = 5.11, 6.94 Hz, 4H), 3.29 - 3.32 (m, 2H), 2.94 - 3.11 (m, 6H), 2.00 - 2.24 (m, 8H), 1.20 - 1.50 (m, 9H). At r.t., 7.57 min, LCMS: m / z 574 [M+H] + 。For C 32 H 44 N7O3 [M+H] + HRMS(ESI) calculated value: 574.35, measured value: 574.3489.

[1131] 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-4-(methylamino)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = NHMe, R4 = H, R5a = ethyl, R5b = methyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 37

[1132]

[1133]

[1134] At r.t., 6.98 min, LCMS: m / z 560 [M+H] + 。For C 31 H 42 N7O3 [M+H] + The calculated value of HRMS(ESI) for C

[1135] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidine-4-carbonitrile [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = CN, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 38

[1136]

[1137] At r.t., 7.25 min, LCMS: m / z 556 [M+H] + 。

[1138] 2-{[(1S)-1-(4-{4-[(1-acryloylpiperidin-4-yl)oxy]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = O, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 39

[1139]

[1140] At r.t., 7.82 min, LCMS: m / z 546 [M+H] + 。

[1141] 2-[(2-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}propan-2-yl)amino]-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = R1b = Me, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 40

[1142]

[1143] 1 H NMR (500 MHz, DMSO-d6) δ = 8.55 (s, 1H), 8.17 (br.s., 1H), 7.59 (d, J = 9.15 Hz, 1H), 7.34 (d, J = 8.39 Hz, 2H), 7.18 (d, J = 8.39 Hz, 2H), 6.65 (dd, J = 10.37, 16.62 Hz, 1H), 6.10 (d, J = 7.78 Hz, 1H), 5.92 - 6.05 (m, 1H), 5.54 - 5.62 (m, 1H), 5.04 (br.s., 1H), 3.79 (t, J = 8.46 Hz, 2H), 3.36 - 3.48 (m, 6H), 2.15 (br.s., 6H), 1.95 (br.s., 2H), 1.68 (s, 6H), 1.05 (br.s., 6H). At r.t., 6.59 min, LCMS: m / z 545 [M+H] + 。For C 31 H 41 N6O3 [M+H] + The calculated value of HRMS (ESI) for C

[1144] 2-[(2-{4-[1-(4-Acryloylpiperazin-1-yl)-4,4-difluorocyclohexyl]phenyl}propan-2-yl)amino]-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = R1b = Me, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 52

[1145]

[1146]

[1147] At r.t., 9.96 min, LCMS: m / z 579 [M+H] + 。For C 32 H 41 F2N6O2 [M+H] + The HRMS(ESI) calculated value for C

[1148] 7-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-5-amino-1-(propan-2-yl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one [(I) X = N, U = CH2, Y = O, -, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = NH2, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 41

[1149]

[1150] At r.t., 5.78 min, LCMS: m / z 550 [M+H] + 。

[1151] 2-{[(1S)-1-{4-[(2S)-2-(4-acryloylpiperazin-1-yl)-1-(morpholin-4-yl)propan-2-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = R4 = H, R5a = methyl, R5b = morpholin-4-yl-methyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 42

[1152]

[1153] At r.t., 6.98 min, LCMS: m / z 574 [M+H] + .

[1154] 2-{[(1S)-1-{4-[(2S)-2-(4-Acryloylpiperazin-1-yl)-1-(morpholin-4-yl)propan-2-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = R4 = H, R5a = morpholin-4-yl-methyl, R5b = methyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 43

[1155]

[1156]

[1157] At r.t., 7.14 min, LCMS: m / z 574 [M+H] + 。For C 32 H 44 N7O3 [M+H] + The HRMS(ESI) calculated value for C

[1158] 2-[(1-{4-[1-(4-Acryloylpiperazin-1-yl)cyclopentyl]phenyl}cyclopropyl)amino]-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a and R1b = -CH2-CH2-, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = cyclopentyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 49

[1159]

[1160]

[1161] At r.t., 7.63 min, LCMS: m / z 527 [M+H] + 。For C 31 H 39 N6O2 [M+H] + The HRMS(ESI) calculated value for C

[1162] 8-(propan-2-yl)-2-({(1S)-1-[4-(4-{4-[( 2 H3)acryloyl]piperazin-1-yl}tetrahydro-2H-pyran-4-yl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = -[( 2 H3)acryloyl]] cpd 51

[1163]

[1164]

[1165] At r.t., 7.60 min, LCMS: m / z 534 [M+H] + 。For C 30 H 39 N6O3 [M+H] + The HRMS (ESI) calculated value for 534.3267, found 534.3265.

[1166] 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-[( 2 H7)propan-2-yl]pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = -( 2 H7)propan-2-yl, R3 = R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] cpd 55

[1167]

[1168] 11H NMR (500 MHz, DMSO-d6) δ = 8.55 (s, 1H), 8.31 (d, J = 6.59 Hz, 1H), 7.61 (d, J = 9.52 Hz, 1H), 7.33 (d, J = 7.93 Hz, 2H), 7.20 (d, J = 8.30 Hz, 2H), 6.63 (dd, J = 10.62, 16.60 Hz, 1H), 6.15 (d, J = 9.15 Hz, 1H), 5.96 (d, J = 15.50 Hz, 1H), 5.55 (d, J = 10.99 Hz, 1H), 5.00 (br.s., 1H), 3.79 (d, J = 7.20 Hz, 2H), 3.44 (br.s., 4H), 3.23 - 3.28 (m, 2H), 2.11 (br.s., 8H), 1.48 (d, J = 7.20 Hz, 3H). At r.t., 6.74 min, LCMS: m / z 538 [M + H] + 。For C 30 H 39 N6O3 [M + H] + The calculated value of HRMS (ESI) for C

[1169] Example 2

[1170] N-{2-[(4,4-difluoro-1-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}cyclohexyl)amino]-2-oxoethyl}prop-2-enamide [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = NH, G1 = CO, Z1 = CR9aR9b, R9a = R9b = H, m1 = 1, E = acryloyl] cpd 56, step 1a

[1171]

[1172] At -10 °C, acryloyl chloride (27 μL, 0.3 mmol) was added to a solution of N-(4,4-difluoro-1-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}cyclohexyl)glycine amide (150 mg, 0.30 mmol) and DIPEA (100 μL, 0.6 mmol) in DCM (10.0 mL). After 30 minutes, the reaction was quenched with water. The mixture was extracted with DCM, dried over Na2SO4, filtered and concentrated to give a yellow oil. The crude product was purified by silica gel chromatography (1% to 10% MeOH / DCM) to give the title product as a white foam (99 mg, 60% yield). 1 1H NMR (500 MHz, DMSO-d6) δ = 8.54 (s, 1H), 8.35 (d, J = 7.02 Hz, 1H), 8.26 (t, J = 5.80 Hz, 1H), 8.05 - 8.12 (m, 1H), 7.61 (d, J = 9.15 Hz, 1H), 7.22 - 7.39 (m, 4H), 6.27 (dd, J = 10.22, 17.08 Hz, 1H), 6.15 (d, J = 9.30 Hz, 1H), 6.08 (dd, J = 2.14, 17.08 Hz, 1H), 5.58 (dd, J = 2.14, 10.22 Hz, 1H), 5.52 (br.s, 1H), 4.99 (br.m, 1H), 3.87 (d, J = 5.64 Hz, 2H), 2.37 - 2.46 (m, 2H), 1.78 - 2.14 (m, 6H), 1.22 - 1.52 (m, 9H). At r.t., 11.08 min, LCMS: m / z 553 [M+H] + For C 29 H 35 F2N6O3 [M+H] + The HRMS (ESI) calculated value for C

[1173] Following the same method, the following compounds were prepared:

[1174] N2-Acryloyl-N-(4,4-difluoro-1-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}cyclohexyl)-D-alanine amide [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = NH, G1 = CO, Z1 = CR9aR9b, R9a = CH3, R9b = H, m1 = 1, E = acryloyl] cpd 57

[1175]

[1176] 1 H NMR (500 MHz, DMSO-d6) δ = 8.54 (s, 1H), 8.34 (d, J = 7.02 Hz, 1H), 8.21 (d, J = 6.86 Hz, 1H), 8.08 (s, 1H), 7.61 (d, J = 9.15 Hz, 1H), 7.25 - 7.34 (m, 4H), 6.29 (dd, J = 10.29, 17.16 Hz, 1H), 6.15 (d, J = 9.46 Hz, 1H), 6.09 (dd, J = 1.98, 17.23 Hz, 1H), 5.58 (dd, J = 2.14, 10.22 Hz, 1H), 5.53 (br.s, 1H), 4.99 (br.m, 1H), 4.45 (dq, J = 8.13 and 6.86 Hz, 1H), 2.37 - 2.46 (m, 2H), 1.77 - 2.11 (m, 6H), 1.22 - 1.52 (m, 12H). At r.t., 11.27 min, LCMS: m / z 567 [M+H] + 。For C 30 H 37 F2N6O3 [M+H] + The HRMS (ESI) calculated value for C

[1177] N2-Acryloyl-N-(4,4-difluoro-1-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}cyclohexyl)-L-alanine amide [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = NH, G1 = CO, Z1 = CR9aR9b, R9a = H, R9b = CH3, m1 = 1, E = acryloyl] cpd 58

[1178]

[1179]

[1180] At r.t., 11.30 min, LCMS: m / z 567 [M+H] + 。

[1181] N-{2-[(4-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)(trifluoroacetyl)amino]ethyl}prop-2-enamide [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = NR6, R6 = trifluoroacetyl, G1 = -CH2, Z1 = -CH2, m1 = 1, E = acryloyl] cpd66

[1182]

[1183] At r.t., 4.59 min, LCMS: m / z 601 [M+H] + 。

[1184] N-{2-[(4-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)amino]ethyl}prop-2-enamide [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = NH, G1 = CH2, Z1 = -CH2, m1 = 1, E = acryloyl] cpd 59

[1185]

[1186] At r.t., 8.25 min, LCMS: m / z 505 [M+H] + 。

[1187] Example 3

[1188] 2-{[(1S)-1-(4-{4-[4-(but-2-ynoyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = but-2-ynoyl] cpd 5

[1189]

[1190] To a solution of 2-{[(1S)-1-{4-[4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (166.0 mg, 0.349 mmol), DIPEA (140 μL, 0.803 mmol) and 2-butynoic acid (36 mg, 0.419 mmol) in DMF (4.0 mL) was added HATU (163 mg, 0.419 mmol). The mixture was stirred at room temperature for 2 h. The mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (1% to 5% EtOH / DCM) to give the title product as a white solid (84.6 mg, 44% yield).

[1191] 1 1H NMR (500 MHz, DMSO-d6) δ = 8.57 (s, 1H), 8.35 (d, J = 7.17 Hz, 1H), 7.63 (d, J = 9.15 Hz, 1H), 7.29 - 7.41 (m, 2H), 7.20 (d, J = 8.08 Hz, 2H), 6.16 (d, J = 9.15 Hz, 1H), 5.43 (br.s., 1H), 5.00 (t, J = 6.79 Hz, 1H), 3.79 (dd, J = 4.96, 10.75 Hz, 2H), 3.50 - 3.60 (m, 2H), 3.36 - 3.40 (br., m, 4H), 1.99 - 2.27 (m, 8H), 1.93 (s, 3H), 1.49 (d, J = 7.02 Hz, 3H), 1.17 - 1.45 (br., m, 6H). At r.t., 6.92 min, LCMS: m / z 543 [M+H] + 。For C 31 H 39 N6O3 [M+H] + The HRMS (ESI) calculated for C

[1192] Example 4

[1193] 2-{[4-(4-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazin-1-yl]methyl}prop-2-enoic acid [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = methylprop-2-enoic acid] cpd 7

[1194]

[1195] At rt, in the presence of K2CO3 (35.5 mg, 0.257 mmol), 2-bromomethylacrylic acid (28 μL, 0.166 mmol) was added to a solution of 2-{[(1S)-1-{4-[4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (60.0 mg, 0.126 mmol) in acetonitrile (6.0 mL). After 2 h, the reaction was filtered and washed with acetonitrile. The organic portion was evaporated in vacuo to give a yellow oil. The crude product was purified by silica gel chromatography (1% to 7% MeOH / DCM with 1% water) to give the title product as a white foam (44 mg, 58% yield).

[1196] 1 H NMR (500 MHz, DMSO-d6) δ = 8.57 (s, 1H), 8.36 (d, J = 7.47 Hz, 1H), 7.63 (d, J = 9.30 Hz, 1H), 7.32 - 7.42 (m, 2H), 7.22 (d, J = 8.24 Hz, 2H), 6.16 (d, J = 9.30 Hz, 1H), 6.00 (s, 1H), 5.52 (br.s., 1H), 5.27 - 5.50 (br., m, 1H), 5.04 (t, J = 6.71 Hz, 1H), 3.75 (d, J = 9.30 Hz, 2H), 3.26 (br., m, 6H), 3.12 (s, 2H), 2.41 (br., m, 4H), 1.90 - 2.13 (m, 4H), 1.50 (d, J = 6.86 Hz, 3H), 1.24 - 1.45 (br., m, 6H). At r.t., 7.44 min, LCMS: m / z 561 [M + H] + 。For C 31 H 41 N6O4 [M + H]+ HRMS(ESI) calculated value for it is 561.3184, found value is 561.3181.

[1197] According to the same method, the following compounds were prepared:

[1198] 7-{[(1S)-1-{4-[4-(4-Ethylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one [(I) X = N, U = CH2, Y = O, -, R1a = methyl, R1b = H, A = phenyl, R2 = ethyl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = ethyl] cpd 45

[1199]

[1200] 1 H NMR (500 MHz, DMSO-d6) δ = 7.99 (s, 1H), 7.88 (br.s., 1H), 7.34 (d, J = 7.78 Hz, 2H), 7.19 (d, J = 8.24 Hz, 2H), 5.10 (s, 2H), 4.94 (br.s., 1H), 3.54 - 4.03 (m, 6H), 1.91 - 2.32 (m, 10H), 1.44 (d, J = 7.02 Hz, 3H), 1.23 (br.s, 3H), 0.88 (t, J = 7.17 Hz, 3H). At r.t., 4.57 min, LCMS: m / z 495 [M+H] + For C 27 H 39 N6O3 [M+H] + HRMS(ESI) calculated value for it is 495.3078, found value is 495.3079.

[1201] 2-{[(1S)-1-(4-{4,4-Difluoro-1-[4-(4-hydroxybutyl)piperazin-1-yl]cyclohexyl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluoro-cyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = 4-hydroxybutyl] cpd 64

[1202]

[1203]

[1204] At r.t., 9.36 min, LCMS: m / z 583 [M+H] + 。For C 32 H 45 F2N6O2 [M+H] + The calculated value of HRMS(ESI) for it is 583.3567, and the measured value is 583.3566.

[1205] Example 5

[1206] 4-(4-{4-[(1S)-1-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carbonitrile [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = carbonitrile] cpd 65

[1207]

[1208] At 0 °C in the presence of DIPEA (19 μL, 0.113 mmol), cyanogen bromide (12 μL, 0.113 mmol) was added to a solution of 2-{[(1S)-1-{4-[4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (54.0 mg, 0.113 mmol) in DCM (10.0 mL). After 1 h, the reaction was brought to room temperature for 2 h and then diluted with water and DCM. The organic portion was dried over Na2SO4 and evaporated in vacuo to give a yellow oil. The crude product was purified by silica gel chromatography (1% to 7% EtOH / DCM 2 / 98 to 10 / 90) to give the title product as a white foam (30 mg, 52% yield).

[1209]

[1210] At r.t., 6.94 min, LCMS: m / z 502 [M+H] + 。For C 28 H 36 N7O2 [M+H] +HRMS (ESI) calcd for 502.2925, found 502.2917.

[1211] Example 6

[1212] 2-{[(1S)-1-(4-{4-[4-(2,3-dihydroxypropanoyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = 2,3-dihydroxypropanoyl] cpd 10

[1213]

[1214] A mixture of 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (52 mg, 0.099 mmol), OsO4 (2.5 wt% in t-BuOH, 1.52 mL, 0.122 mmol) and pyridine (9 μL) was stirred at room temperature for 18 h. The mixture was treated with saturated aqueous NaHSO3 solution (1.5 mL) and stirred for an additional hour. The aqueous mixture was extracted with EtOAc (30 mL, 15 mL and 5 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The crude was dissolved in a small amount of dichloromethane and purified by flash chromatography (silica, 5% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2) to afford the title compound as a white solid (34 mg, 65% yield).

[1215] 11H NMR (500 MHz, DMSO-d6) δ = 8.56 (s, 1H), 8.13 - 8.36 (m, 1H), 7.62 (d, J = 9.30 Hz, 1H), 7.30 - 7.44 (m, 2H), 7.22 (d, J = 8.24 Hz, 2H), 6.16 (d, J = 9.30 Hz, 1H), 5.37 - 5.79 (m, 1H), 4.94 - 5.32 (m, 1H), 4.71 - 4.84 (m, 1H), 4.57 (q, J = 6.00 Hz, 1H), 4.17 (br.s., 1H), 3.79 (d, J = 5.64 Hz, 2H), 3.36 - 3.50 (m, 4H), 3.24 - 3.32 (m, 4H), 1.96 - 2.33 (m, 8H), 1.48 (d, J = 7.02 Hz, 3H), 1.26 - 1.43 (br., m, 6H). At r.t., 5.84 min, LCMS: m / z 565 [M+H] + 。For C 30 H 41 N6O4 [M+H] + The HRMS (ESI) calculated value for C

[1216] According to the same method, the following compounds were prepared:

[1217] 7-{[(1S)-1-(4-{1-[4-(2,3-dihydroxypropanoyl)piperazin-1-yl]-4,4-difluorocyclohexyl}phenyl)ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one [X = CH, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = 2,3-dihydroxypropanoyl] cpd 60

[1218]

[1219]

[1220] At r.t., 5.83 min, LCMS: m / z 598 [M+H] + 。For C 32 H 42 F2N6O4 [M+H] + The HRMS (ESI) calculated value for C

[1221] Example 7

[1222] 2-{[(1S)-1-(4-{1-[{1-[Chloro(fluoro)acetyl]azetidin-3-yl}(methyl)amino]-4,4-difluorocyclohexyl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = H, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl, M = NR6, G1 = CH, Z1, Z2 = -CH2-, m1 = m2 = 1, R6 = methyl, E = acryloyl] cpd 53

[1223]

[1224] At ambient temperature, DIPEA (50.0 μL, 0.294 mmol) and T3P (50 wt.% in AcOEt, 262.0 μL, 0.441 mmol) were added to a stirred solution of 2-{[(1S)-1-(4-{1-[azetidin-3-yl(methyl)amino]-4,4-difluorocyclohexyl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (150 mg, 0.294 mmol) and sodium chlorofluoroacetate (80 mg, 0.588 mmol) in dry CH2Cl2 (5.0 mL). After stirring for 3 h, the reaction mixture was diluted with AcOEt and saturated NaHCO3. The organic layer was separated, and the aqueous phase was extracted three times with AcOEt. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (CH2Cl2 / EtOH = 98:2 to 9:1) to give the title compound as an off-white solid (79.2 mg, 45% yield).

[1225] 11H NMR (500 MHz, DMSO-d6) δ = 8.56 (s, 1H), 8.12 - 8.42 (m, 1H), 7.61 (d, J = 9.30 Hz, 1H), 7.36 (s, 4H), 6.58 - 6.79 (m, 1H), 6.16 (d, J = 9.30 Hz, 1H), 5.34 - 5.84 (m, 1H), 4.88 - 5.32 (m, 1H), 4.21 - 4.36 (m, 2H), 3.44 - 4.00 (m, 4H), 2.07 - 2.42 (m, 4H), 1.95 (d, J = 8.69 Hz, 4H), 1.71 (br.s., 2H), 1.48 (d, J = 6.70 Hz, 3H), 1.16 - 1.43 (m, 3H), 1.03 (d, J = 6.10 Hz, 3H). At r.t., 10.97 min, LCMS: m / z 605 [M+H] + 。For C 30 H 37 ClF3N6O2 [M+H] + The calculated value of HRMS (ESI) for C

[1226] According to the same method, but using 2-{[(1S)-1-{4-[4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one and 2-fluoroacrylic acid, the following compound was prepared:

[1227] 2-{[(1S)-1-(4-{4-[4-(2-fluoropropanoyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(I) X = N, U = Y = CH, R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = 2-fluoropropanoyl] cpd 54

[1228]

[1229] 11H NMR (500 MHz, DMSO-d6) δ = 8.58 (s, 1H), 8.36 (d, J = 6.71 Hz, 1H), 7.64 (d, J = 9.30 Hz, 1H), 7.34 (d, J = 7.93 Hz, 2H), 7.22 (d, J = 7.93 Hz, 2H), 6.17 (d, J = 9.15 Hz, 1H), 5.24 - 5.56 (m, 1H), 5.18 (dd, J = 3.97, 18.15 Hz, 1H), 4.89 - 5.08 (m, 2H), 3.71 - 3.85 (m, 2H), 3.51 - 3.65 (m, 4H), 3.26 - 3.32 (m, 2H), 1.95 - 2.31 (m, 8H), 1.26 - 1.61 (m, 9H). At r.t., 7.19 min, LCMS: m / z 549 [M + H] + For C 30 H 38 FN6O3 [M + H] + HRMS (ESI) calcd for 549.2984, found 549.2984.

Claims

1. A compound of formula (I): Wherein: X is nitrogen or -CH-; U is CH or CMe; Y is CH; Indicates a single or double bond; R1a and R1b are each independently hydrogen, a straight-chain (C1-C6) alkyl group, or together with the atom to which they are attached can form a cyclopropyl group; A is a phenyl, pyridyl or pyrimidinyl group; R4 is hydrogen; R5a and R5b together with the atom to which they are attached can form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic group, said heterocyclic group containing a heteroatom selected from O or N-R6; Wherein: R6 is an optionally substituted straight-chain or branched (C1-C6) alkyl group or -COR8; Wherein: R8 is an optionally substituted straight-chain or branched (C1-C6) alkyl group; M is a bond, NH or NR6, where R6 is as defined above; G1 is N, CH or CO; Z1 is CR9aR9b; Z2 is CR10aR10b; Wherein: R9a, R9b, R10a and R10b are independently hydrogen or an optionally substituted straight-chain (C1-C6) alkyl group; m1 is 1 or 2; m2 is 0, 1 or 2; E is CN or a group of formula -COR11; Wherein: R11 is an optionally substituted straight-chain or branched (C2-C6) alkyl group or (C2-C6) alkenyl group or (C2-C6) alkynyl group; R2 is an optionally substituted group selected from: straight-chain or branched (C1-C6) alkyl group or cyclopentyl; R3 is hydrogen, cyano, NH2 or NR12aR12b; wherein: R12a, R12b are each independently selected from hydrogen or a straight-chain (C1-C6) alkyl group; Or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R1a and R1b are each independently hydrogen, a straight-chain (C1-C3) alkyl group, or together with the atom to which they are attached can form a cyclopropyl group; A is a phenyl group or a pyridyl group; R5a and R5b together with the atom to which they are attached can form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic group, said heterocyclic group containing a heteroatom selected from O or N-R6; Wherein: R6 is a straight-chain or branched (C1-C6) alkyl group or -COR8; Wherein: R8 is a straight-chain or branched (C1-C6) alkyl group; R2 is a straight-chain or branched (C1-C6) alkyl group or cyclopentyl; R3 is hydrogen, cyano, NH2 or NR12aR12b; and X, U, Y, R4, M, G1, Z1, Z2, m1, m2, E, R12a and R12b are as defined in claim 1.

3. The compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof, wherein: R1a and R1b are each independently hydrogen, methyl, ethyl, or together with the atom to which they are attached can form a cyclopropyl group; A is a phenyl group; R4 is hydrogen; R5a and R5b together with the atom to which they are attached can form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic group selected from cyclopentyl, cyclohexyl, 4,4-difluorocyclohexyl, pyranyl, oxetanyl, N-methylpiperidinyl and N-acetylpiperidinyl; R2 is methyl, ethyl, isopropyl or cyclopentyl; R3 is hydrogen, NH2, NHMe or N(Me)2; E is a group of the formula -COR11; wherein: R11 is a straight-chain or branched (C2-C6) alkyl or (C2-C6) alkenyl or (C2-C6) alkynyl which is optionally substituted; X, U, Y, M, G1, Z1, Z2, m1 and m2 are as defined in claim 1.

4. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 1); 2-{[(1S)-1-{4-[3-(4-acryloylpiperazin-1-yl)oxetan-3-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 3); 2-{[(1S)-1-(4-{4-[4-(but-2-ynoyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 5); 2-{[(1S)-1-{4-[1-acetyl-4-(4-acryloylpiperazin-1-yl)piperidin-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 6); 2-{[(1S)-1-{4-[4-(4-propionylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 8); 2-{[(1R)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 9); 2-{[(1S)-1-(4-{4-[4-(2,3-dihydroxypropionyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 10); 7-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one (cpd 11); 2-{[(1S)-1-{6-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]pyridin-3-yl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 12); 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-4-methyl-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 13); 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one (cpd 14); 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (cpd 15); 2-{[(1S)-1-{4-[1-(4-Acryloylpiperazin-1-yl)cyclopentyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 16); 2-{[(1S)-1-{4-[3-(4-Acryloylpiperazin-1-yl)tetrahydrofuran-3-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 17); 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-5-methyl-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 18); 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-4-amino-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 19); 2-{[(1S)-1-{4-[1-(4-Acryloylpiperazin-1-yl)cyclohexyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 20); 2-{[(1S)-1-(4-{4-[4-(2-Methylacryloyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 21); 2-{[(1S)-1-(4-{4-[4-(Chloroacetyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 22); 2-{[(1S)-1-(4-{4-[4-(3-chloropropanoyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 23); 2-{[(1S)-1-{4-[1-(4-acryloylpiperazin-1-yl)-4,4-difluorocyclohexyl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 26); 2-{[(1S)-1-{5-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]pyridin-2-yl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 27); 2-{[(1S)-1-(4-{4-[(1-acryloylazetidin-3-yl)(methyl)amino]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 28); 2-[(1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}cyclopropyl)amino]-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 30); 2-({4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]benzyl}amino)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 31); 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)-1-methylpiperidin-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 32); 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(pentan-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 35); 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-4-(dimethylamino)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 36); 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-4-(methylamino)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 37); 2-{[(1S)-1-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidine-4-carbonitrile (cpd 38); 2-[(2-{4-[4-(4-Acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}propan-2-yl)amino]-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 40); 7-{[(1S)-1-{4-[1-(4-Acryloylpiperazin-1-yl)-4,4-difluorocyclohexyl]phenyl}ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one (cpd 47); 7-{[(1S)-1-(4-{4-[(1-Acryloylazetidin-3-yl)(methyl)amino]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one (cpd 48); 2-[(1-{4-[1-(4-Acryloylpiperazin-1-yl)cyclopentyl]phenyl}cyclopropyl)amino]-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 49); 2-{[(1S)-1-(4-{1-[(1-Acryloylazetidin-3-yl)(methyl)amino]-4,4-difluorocyclohexyl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 50); 8-(propan-2-yl)-2-({(1S)-1-[4-(4-{4-[( 2 H3)acryloyl]piperazin-1-yl}tetrahydro-2H-pyran-4-yl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 51); 2-[(2-{4-[1-(4-Acryloylpiperazin-1-yl)-4,4-difluorocyclohexyl]phenyl}propan-2-yl)amino]-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 52); 2-{[(1S)-1-(4-{1-[{1-[Chloro(fluoro)acetyl]azetidin-3-yl}(methyl)amino]-4,4-difluorocyclohexyl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd53); 2-{[(1S)-1-(4-{4-[4-(2-Fluoropropenoyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 54); 2-{[(1S)-1-{4-[4-(4-acryloylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-[( 2 H7)propyl]pyrido[2,3-d]pyrimidin-7(8H)-one (cpd 55); N-{2-[(4,4-Difluoro-1-{4-[(1S)-1-{[7-Oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl]phenyl}cyclohexyl)amino]-2-oxoethyl}prop-2-enamide (cpd 56); N2 - acryloyl - N - (4,4 - difluoro - 1 - {4 - [(1S) - 1 - {[7 - oxo - 8 - (propan - 2 - yl) - 7,8 - dihydropyrido[2,3 - d]pyrimidin - 2 - yl]amino}ethyl]phenyl}cyclohexyl) - D - alanine amide (cpd 57); N2 - acryloyl - N - (4,4 - difluoro - 1 - {4 - [(1S) - 1 - {[7 - oxo - 8 - (propan - 2 - yl) - 7,8 - dihydropyrido[2,3 - d]pyrimidin - 2 - yl]amino}ethyl]phenyl}cyclohexyl) - L - alanine amide (cpd 58); 7 - {[(1S) - 1 - (4 - {1 - [4 - (2,3 - dihydroxypropanoyl)piperazin - 1 - yl] - 4,4 - difluorocyclohexyl}phenyl)ethyl]amino} - 1 - (propan - 2 - yl) - 1,6 - naphthyridin - 2(1H) - one (cpd 60); 7 - {[(1S) - 1 - (4 - {1 - [(1 - acryloylazetidin - 3 - yl)(methyl)amino] - 4,4 - difluorocyclohexyl}phenyl)ethyl]amino} - 1 - (propan - 2 - yl) - 1,6 - naphthyridin - 2(1H) - one (cpd 61); N - (1 - acryloylazetidin - 3 - yl) - N - (4,4 - difluoro - 1 - {4 - [(1S) - 1 - {[2 - oxo - 1 - (propan - 2 - yl) - 1,2 - dihydronaphthyridin - 7 - yl]amino}ethyl]phenyl}cyclohexyl)acetamide (cpd62); 7 - {[(1R) - 1 - {4 - [1 - (4 - acryloylpiperazin - 1 - yl) - 4,4 - difluorocyclohexyl]phenyl}ethyl]amino} - 1 - (propan - 2 - yl) - 1,6 - naphthyridin - 2(1H) - one (cpd 63); 4 - (4 - {4 - [(1S) - 1 - {[7 - oxo - 8 - (propan - 2 - yl) - 7,8 - dihydropyrido[2,3 - d]pyrimidin - 2 - yl]amino}ethyl]phenyl}tetrahydro - 2H - pyran - 4 - yl)piperazine - 1 - carbonitrile (cpd 65); N - {2 - [(4 - {4 - [(1S) - 1 - {[7 - oxo - 8 - (propan - 2 - yl) - 7,8 - dihydropyrido[2,3 - d]pyrimidin - 2 - yl]amino}ethyl]phenyl}tetrahydro - 2H - pyran - 4 - yl)(trifluoroacetyl)amino]ethyl}prop - 2 - enamide (cpd 66) and 7 - {[(1S) - 1 - {4 - [4,4 - difluoro - 1 - (4 - propionylpiperazin - 1 - yl)cyclohexyl]phenyl}ethyl]amino} - 1 - (propan - 2 - yl) - 1,6 - naphthyridin - 2(1H) - one (cpd 67).

5. A process for preparing a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, said process comprising the following steps: Step 1a) reacting a compound of formula (II): wherein X, U, Y, R2, R3, R1a, R1b, A, R4, R5a, R5b, M, G1, Z1, Z2, m1 and m2 are as defined in claim 1, with a compound of formula (III): wherein E is as defined in claim 1, and Q is hydroxy, or chlorine, or bromine, to produce a compound of formula (I), wherein X, U, Y, R2, R3, R1a, R1b, A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2 and E are as defined above; The compound of formula (II) can be prepared from a compound of formula (IV) by a process comprising the following steps: Step 2a) A compound of formula (IV): wherein G is Cl, MeS(O)2-, MeS(O)- or OTrif, and X, U, Y, R2 and R3 are as defined in claim 1, and react with a compound of formula (V): wherein R1a, R1b, A, R4, R5a, R5b, M, G1, Z1, Z2, m1 and m2 are as defined in claim 1, and PG is a protecting group selected from tert-butyl formate, benzyl formate, phenyl formate; Step 2b) Reacting a compound of formula (VI) with a suitable deprotecting agent: wherein PG is as defined above in step 2a; A compound of formula (II) wherein X, U, Y, A, R1a, R1b, R2, R3, R4, R5a, R5b, M, G1, Z1, Z2, m1 and m2 are as defined above in step 2a; Said compound of formula (IV): wherein G is MeS(O)2- or MeS(O)-, X is N, R3 is hydrogen or chlorine, and U, Y, and R2 are as defined in claim 1 and can be prepared by a process comprising the following steps: Step 3a) Substituting the chlorine of the intermediate compound of formula (VII): wherein R3 is hydrogen or chlorine, with an amine intermediate compound of formula (VIII): R2-NH2 (VIII) wherein R2 is as defined in claim 1; Step 3b) Reacting a compound of formula (IX) with a reducing agent: wherein R2 and R3 are as defined above in step 3a; Step 3c) Reacting the resulting compound of formula (X) with a suitable oxidizing reagent: wherein R2 and R3 are as defined above in step 3a; Step 3d) Reacting the resulting compound of formula (XI) with a reagent of formula T-CH2COOEt (XIV) wherein T is hydrogen or fluorine: wherein R2 and R3 are as defined above in step 3a; Step 3e) Mixing the resulting intermediate compound of formula (XII) with an oxidizing reagent: Among them, U, Y, and as defined in claim 1, and R2 and R3 are as defined above in step 3a to give a compound of formula (IV) wherein G is MeS(O)2- or MeS(O)-, X is N, and R2, R3, U, Y and are as defined above; or Step 3f) Reacting said compound of formula (X) with carbonyldiimidazole or triphosgene: wherein R2 and R3 are as defined above in step 3e to give a compound of formula (XII) wherein U is CH2, Y is O, is a single bond, and R2 and R3 are as defined above; or Step 3g) Alkylating the intermediate compound of formula (XIII) with an alkylating agent of formula R2-Lg (XV) wherein Lg is bromine, iodine, -OMs, -OTs or hydroxyl and R2 is as defined above in step 3e: wherein R3, U, Y, are as defined in step 3e above to give the compound of formula (XII), wherein R2, R3, U, Y and are as defined above; wherein G is chlorine, R3, X, U, Y, and R2, a compound of formula (IV) as defined in claim 1, can be prepared by a process comprising the following steps: Step 4a) Substituting the chlorine of the intermediate compound of formula (XVI): wherein X and R3 are as defined in claim 1, with an amine intermediate compound of formula (VIII): R2-NH2 (VIII) wherein R2 is as defined in claim 1; Step 4b) Reacting a compound of formula (XVII) with a reducing agent: wherein X, R3 and R2 are as defined above in step 4a; Step 4c) Reacting the resulting compound of formula (XVIII) with a suitable oxidizing reagent: wherein X, R3 and R2 are as defined above in step 4b; Then Step 4d) Reacting the resulting compound of formula (XIX) with a compound of formula T-CH2COOEt (XIV) wherein T is hydrogen or fluorine: wherein X, R2 and R3 are as defined above in step 4c to give a compound of formula (IV) wherein G is chlorine, U, Y, X, R3 and R2 are as defined in claim 1; or Step 4e) Reacting the resulting compound of formula (XVIII) with carbonyldiimidazole or triphosgene: wherein X, R3 and R2 are as defined above in step 4c to give a compound of formula (IV) wherein G is chlorine, U is CH2, Y is O, is a single bond, and X, R3 and R2 are as defined above; If desired, converting a first compound of formula (XII) to a second compound of formula (XII) according to a process comprising the following transformation: Transformation A) Converting a compound of formula (XII) wherein R3 is chlorine to a compound of formula (XII) wherein R3 is CN by reaction with a source of cyanide: Transformation B) The compound of formula (XII) in which R3 is chlorine is converted to the compound of formula (XII) in which R3 is NHPG by reaction with the amine PG-NH2: Transformation C) The compound of formula (XII) in which R3 is chlorine is converted to the compound of formula (XII) in which R3 is NR12aR12b by reaction with the amine HNR12aR12b in which R12a and R12b are each independently selected from hydrogen or a straight-chain or branched (C1-C6) alkyl optionally substituted: If desired, the first compound of formula (IV) is converted to the second compound of formula (IV) according to a process comprising the following transformations: Transformation A1) The compound of formula (IV) in which G is MeS(O)2- is converted to the compound of formula (IV) in which G is -OTrif (triflate) by a two-step sequence with a suitable reagent: The compound of formula (V) in which R1a, R1b, A, R4, R5a, R5b, M, G1, Z1, Z2, m1 and m2 are as reported in claim 1 and PG is a protecting group can be prepared according to a process comprising the following steps: Step 5a) Reacting a compound of formula (XX) with ClCH2CN: where W1 is bromine, cyano, COR1a and A, R4, R5a, R5b and R1a are as defined in claim 1, followed by deprotection of the amide intermediate under acidic conditions, basic conditions or with thiourea to obtain a compound of formula (XXI); Step 5b) The amino intermediate of formula (XXI): where W1, A, R4, R5a and R5b are as defined above in step 5a, is reacted with a compound of formula (XXII): where Z1, Z2, m1 and m2 are as reported in claim 1, PG is a protecting group, and Hal is a halogen, to produce a compound of formula (XXIII) in which W1, A, R4, R5a, R5b, Z1, Z2 and PG are as defined above, m1 and m2 are 1 or 2, G1 is N, and M is a bond; or Step 5b’) Reacting the amino intermediate of formula (XXI) with a heterocyclic halide of formula (XXIIa), where Z1, Z2, m1, m2 and PG are as reported above in step 5b and Hal is a halogen, and then reacting the obtained intermediate by reductive amination with formaldehyde or a suitable alkyl aldehyde derivative or by acylation with a suitable haloacyl derivative R8CO-hal, where R8 is as defined in claim 1; to form a compound of formula (XXIII) in which PG is as defined above, W1, A, R4, R5a, R5b, Z1, Z2, m1 and m2 are as defined above; G1 is CH and M is NR6, where R6 is as defined in claim 1; or Step 5b”) Reacting the amino intermediate of formula (XXI) with a protected aminoalkyl of formula (XXIIb) wherein Z1, m1 and PG are as reported in step 5b above and FG is a functional group selected from aldehyde (-CHO) or carboxylic acid (-COOH) to produce a compound of formula (XXIII), wherein m2 is 0, G1 is CO, M is NH or NR6, PG is as defined in step 5b above, and W1, A, R4, R5a, R5b, Z1, m1 and R6 are as defined above; or Step 5a') React a compound of formula (XX): wherein W1, A, R4, R5a and R5b are as defined in step 5a above, with a heterocyclic halide of formula (XXIIa): wherein Hal, Z1, Z2, m1, m2 and PG are as defined in step 5b'; to form a compound of formula (XXIII), wherein W1, A, R4, R5a, R5b are as defined in step 5a; Z1, Z2, m1, m2 and PG are as defined in step 5b' above; G1 is CH and M is O; Then Step 5c) React the compound of formula (XXIII) obtained from step 5b or step 5b' or step 5b'' or step 5a' with ethylmagnesium bromide and boron trifluoride diethyl ether: wherein W1 is cyano, and A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2 and PG are as reported in step 5b or step 5b' or step 5b'' or step 5a' to give the desired compound of formula (V), wherein A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2 and PG are as defined in step 5b or step 5b' or step 5b'' or step 5a' above, and R1a and R1b are the same and are as defined in claim 1; or R1a and R1b together are cyclopropyl; or Step 5c') React the compound of formula (XXIII) obtained from step 5b or step 5b' or step 5b'' or step 5a' with tert-butanesulfinamide: wherein W1 is COR1a, wherein A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2, PG and R1a are as defined in step 5b or step 5b' or step 5b'' or step 5a' above to produce a compound of formula (XXIV), wherein R1b is hydrogen, and A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2, PG and R1a are as defined above; or Step 5c'') React the compound of formula (XXIII) obtained from step 5b or step 5b' or step 5b'' or step 5a' with tert-butanesulfinamide: wherein W1 is COR1a, and A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2, PG and R1a are as defined in step 5b or step 5b' or step 5b'' or step 5a' above to produce a compound of formula (XXV); Then Step 5e) React the obtained compound of formula (XXV) with an alkyl Grignard reagent: wherein R1a, A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2, and PG are as defined above in Step 5b or Step 5b' or Step 5b'' or Step 5a' to give the desired compound of formula (XXIV); Finally Step 5d) React the compound of formula (XXIV) obtained according to that described in Step 5c' or Step 5e with an acidic deprotecting reagent or with iodine: wherein R1b, R1a, A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2, and PG are as defined above in Step 5c' or Step 5e to give the desired compound of formula (V), wherein R1b, R1a, A, R4, R5a, R5b, M, G1, Z1, Z2, m1, and m2 are as defined in claim 1 and PG is a protecting group; Optionally, the compound of formula (XXIII) can also be obtained by converting another compound of formula (XXIII), the corresponding conversion being as follows: Conversion F) A compound of formula (XXIII) wherein W1 is cyano is obtained by converting the corresponding compound of formula (XXIII) wherein W1 is bromo, obtained from Step 5b or Step 5b' or Step 5b'' or Step 5a', with a source of cyanide under the conditions of palladium-catalyzed cyanation of aryl halides known in the art; Conversion G) A compound of formula (XXIII) wherein W1 is COR1a, wherein R1a is as defined in claim 1, is obtained by converting the said compound of formula (XXIII) wherein W1 is bromo, obtained from Step 5b or Step 5b' or Step 5b'' or Step 5a', with a suitable enol ether organometallic derivative, followed by hydrolysis; The compound of formula (I) prepared according to Step 1a can be further converted into another compound of formula (I) according to a process comprising the following conversions: Conversion 1) Convert a compound of formula (I) in which E is an acrylamide group into a compound in which E is a dihydroxypropionic acid group and X, U, Y, R2, R3, R1a, R1b, A, R4, R5a, R5b, M, G1, Z1, Z2, m1 and m2 are as defined in claim 1:

6. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient, carrier, or diluent.

7. Use of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease caused by and / or associated with increased levels of 2-hydroxyglutaric acid.

8. Use of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease caused by and / or associated with a mutant IDH enzyme or IDH wt overfunction.

9. Use of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of acute and chronic myeloid leukemia, fibrosarcoma, glioma, glioblastoma, and cholangiocarcinoma.

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