Gem-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 for treating diseases caused by mutant IDH1 enzymes and / or mutant IDH2 enzymes and / or wild-type (wt) IDH1 enzymes. The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for treating diseases using pharmaceutical compositions containing these compounds.

Description

[Technical Field]

[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 for treating diseases caused by mutant IDH1 enzymes and / or mutant IDH2 enzymes and / or wild-type (wt) IDH1 enzymes. The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for treating diseases using pharmaceutical compositions containing these compounds. [Background technology]

[0002] Isocitrate dehydrogenase (IDH) belongs to a family of metal-dependent oxidoreductase enzymes involved in cellular metabolism. These enzymes catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate, generating carbon dioxide and NADH or NADPH in the process.

[0003] Three distinct members of this family have been identified: structurally related homodimers, NADP + IDH1 and IDH2 use NAD as an electron acceptor, and they are heterotrimeric complexes. + is IDH3, which uses ATP as an electron acceptor.

[0004] IDH1 is localized in the cytoplasm and peroxisomes and is the major source of NADPH production in the cell, while IDH2 is localized in the mitochondria as a key part of the tricarboxylic acid cycle (TCA).

[0005] The human IDH1 gene encodes a 414 amino acid protein, the amino acid sequence of which is available under UniProtKB accession number O75874. The human IDH2 gene encodes a 452 amino acid protein, the amino acid sequence of which is available under 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 secondary glioblastomas (see Balss, J. Acta Neuropathol, 2008, 116, 597-602; Watanabe, T., Am. J. Pathol, 2009, 174, 1149-1153; Yan, HN Engl. J. Med. 2009, 360, 765-773). IDH1 mutations have also been detected in 50% of chondrosarcomas (see Amary MF, J. Pathol 2011, 224, 334-43) and 15%-20% of intrahepatic cholangiocarcinomas (see Borger DR, Oncol. 2012, 17, 72-9), and have also been identified, albeit less frequently (<5%), in other solid tumors (e.g., glioblastoma, rectal cancer, esophageal cancer, bladder cancer, melanoma, prostate cancer, and breast cancer) (see Cerami E, Cancer Discov. 2012, 2, 401-4).

[0007] Mutations in IDH1 and IDH2 have also been detected in a number of hematopoietic malignancies, most commonly in acute myeloid leukemia (AML) in 10%-15% of cases (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, e.g., Cairns RA, Blood 2012, 119, 1901-3).

[0008] Interestingly, identical 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 detected in a mutually exclusive heterozygous state in specific tissues. These mutations are located in the catalytic domains of the enzymes responsible for 2-oxoglutarate coordination, primarily resulting in substitutions of Arg132 (R132) in IDH1 and Arg140 (R140) or Arg172 (R172) in IDH2. Other mutations have also been identified in IDH1, albeit at very low frequencies (e.g., Arg100 and Gly97; Dang L, Nature, 2009, 462, 739-44). In all cases, these point mutations result in substitutions of Arg with Cys, His, Lys, Leu, or Ser, resulting in an inability to bind magnesium and convert isocitrate to α-ketoglutarate. Instead, the mutated enzyme acquires neomorphic activity, converting α-ketoglutarate to R(-)-2-hydroxyglutarate (R-2-HG) (see P.S. Ward et al., Cancer Cell, 2010, 17, 225). Generally, the production of 2-HG is enantiospecific, resulting in the D-isomer (also known as the R-isomer or R-2-HG). R(-)-2-hydroxyglutarate has been shown to act as an oncometabolite, primarily through the inhibition of several DNA and histone demethylases. The cellular consequence is epigenetic reprogramming, leading to differential transcriptional outcomes and inducing dedifferentiation and tumorigenesis.

[0010] IDH1 overexpression has been shown to maintain a poorly differentiated tumor cell state, promote proliferation, accelerate tumor progression, and reduce sensitivity to RTK-targeted therapy in glioblastoma (GBM) and other solid and systemic tumor models. At the molecular level, reduced IDH1 activity leads to decreased production of α-ketoglutarate (α-KG) and NADPH, depletion of reduced glutathione, elevated reactive oxygen species (ROS) levels, and increased expression of histone methylation and differentiation markers. Pharmacological inhibition of IDH1 with small molecules reduces GBM tumor burden and improves survival in PDX mice. These data also suggest that cancer-associated IDH1 upregulation represents an actionable ("druggable") cancer-promoting mechanism and warrants the evaluation of wild-type IDH1 inhibitors as antitumor agents (see Calvert et al., 2017, Cell Reports 19, 1858-1873).

[0011] Therefore, inhibiting the activity of the IDH enzyme is a potential therapeutic treatment option for tumors and other IDH-associated diseases.

[0012] Thus, there is a great medical need for effective therapeutic agents against diseases caused by and / or associated with mutant IDH enzymes and / or wild-type IDH hyperfunction, and various efforts are ongoing to develop inhibitors, particularly small molecule inhibitors, of the α-hydroxyl neomorphic activity of these enzymes.

[0013] WO2005 / 047284 in the name of Hoffmann La Roche discloses certain pyridopyridin-7-one derivatives which have biological activity as kinase inhibitors.

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

[0015] WO2016 / 171755A1 in the name of Forma Therapeutics discloses certain pyrimidooxazin-2-one derivatives that have biological activity as IDH inhibitors. [Prior art documents] [Patent documents]

[0016] [Patent Document 1] International Publication No. 2005 / 047284 [Patent Document 2] International Publication No. 2007 / 044813 [Patent Document 3] International Publication No. 2008 / 7021389 [Patent Document 4] International Publication No. 1998 / 033798 [Patent Document 5] International Publication No. 2008 / 034008 [Patent Document 6] International Publication No. 2016 / 171755 [Non-patent literature]

[0017] [Non-Patent Document 1] Balss, J. Acta Neuropathol, 2008, 116, 597-602 [Non-patent document 2] Watanabe, T., Am. J. Pathol, 2009, 174, 1149-1153 [Non-patent document 3] Yan,HNEngl.J.Med.2009,360,765-773

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[0019] Therefore, a first object of the present invention is to provide a compound of formula (I):

[0020] [ka] or a pharmaceutically acceptable salt thereof, In the above formula, X is nitrogen or -CH-; U is CH, CH, or CMe; Y is CH, CF or O;

[0021] [ka] represents a single or double bond; R1a, R1b are each independently hydrogen, an optionally substituted straight or branched chain (C1-C6) alkyl, or together with the atom to which they are attached may form a (C3-C6) cycloalkyl; A is (C3-C6)cycloalkyl, aryl, or heteroaryl; R4 is hydrogen, halogen, cyano, or optionally substituted straight or branched chain (C1-C6) alkyl; R5a and R5b are each independently a group selected from optionally substituted straight-chain or branched-chain (C1-C6) alkyl, (C3-C6) cycloalkyl, or together with the atom to which they are attached, may form a 3- to 7-membered cycloalkyl group or a heterocyclyl group containing one heteroatom selected from O, S, and N-R6; R6 is an optionally substituted straight or branched chain (C1-C6) alkyl, -COOR7, or -COR8; R7 and R8 are optionally substituted straight or branched chain (C1-C6) alkyl; M is a bond, NH, NR6, or O, where R6 is as defined above; G1 is N, CH, CH2 or CO; Z1 is CR9aR9b; Z2 is CR10aR10b; R9a, R9b, R10a, and R10b are independently hydrogen or optionally substituted straight or branched (C1-C6) alkyl; m1 is 1, 2 or 3; m2 is 0, 1, 2 or 3; E is CN, or an optionally substituted straight or branched chain (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, or a group of formula -COR11; R11 is an optionally substituted straight or branched chain (C2-C6) alkyl or (C2-C6) alkenyl or (C2-C6) alkynyl; R2 is an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, aryl-(C1-C6) alkyl, and heterocyclyl-(C1-C6) alkyl; R3 is hydrogen, chloro, cyano, CONH2, NH2, NR12aR12b, OR13, or an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, aryl, and heteroaryl; R12a, R12b are each independently selected from hydrogen or optionally substituted straight or branched (C1-C6) alkyl; R13 is an optionally substituted straight or branched chain (C1-C6) alkyl.

[0022] Preferred compounds of formula (I) are Y is CH or O; R3 is hydrogen, chloro, cyano, CONH2, NH2, NR12aR12b, OR13, or an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C3-C6)cycloalkyl-(C1-C6) alkyl; R12a, R12b are each independently selected from hydrogen or optionally substituted straight or branched (C1-C6) alkyl; R13 is an optionally substituted straight or branched chain (C1-C6) alkyl; m1 is 1 or 2; m2 is 0, 1 or 2; X, U,

[0023] [ka] , R1a, R1b, A, R4, R5a, R5b, M, G1, Z1, Z2, E and R2 are as described above.

[0024] In one embodiment, more preferred compounds of formula (I) are: A is aryl or heteroaryl; R4 is hydrogen, halogen, or optionally substituted straight or branched (C1-C6) alkyl; R3 is hydrogen, chloro, cyano, CONH2, NH2, NR12aR12b, or an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C3-C6)cycloalkyl-(C1-C6) alkyl; R12a, R12b are each independently selected from hydrogen or optionally substituted straight or branched (C1-C6) alkyl; X, U, Y,

[0025] [ka] , R1a, R1b, R5a, R5b, M, G1, Z1, Z2, m1, m2, E and R2 are as described above.

[0026] In another embodiment, more preferred compounds of formula (I) are R4 is hydrogen or halogen; R3 is an optionally substituted group selected from hydrogen, chloro, cyano, CONH2, NH2, NR12aR12b, or straight or branched chain (C1-C6) alkyl; R12a, R12b are each independently selected from hydrogen or optionally substituted straight or branched (C1-C6) alkyl; X, U, Y,

[0027] [ka] , R1a, R1b, A, R5a, R5b, M, G1, Z1, Z2, m1, m2, E and R2 are as described above.

[0028] In another embodiment, more preferred compounds of formula (I) are R1a, R1b are each independently hydrogen, straight or branched (C1-C3) alkyl, or together with the atom to which they are attached may form a cyclopropyl group; A is a phenyl group, a pyridyl group, or a pyrimidinyl group; R5a and R5b are each independently a group selected from a straight-chain or branched-chain (C1-C6) alkyl, or together with the atom to which they are attached, may form a 3- to 7-membered cycloalkyl group or a heterocyclyl group containing one heteroatom selected from O or N-R6; R6 is a straight or branched chain (C1-C6) alkyl or COR8; R8 is a straight or branched chain (C1-C6) alkyl; R2 is a straight or branched chain (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl; R3 is hydrogen, chloro, cyano, NH2, NR12aR12b, or straight or branched (C1-C6) alkyl; X, U, Y,

[0029] [ka] , R4, M, G1, Z1, Z2, m1, m2, E, R12a and R12b are as defined above.

[0030] In another embodiment, more preferred compounds of formula (I) are R1a and R1b are each independently hydrogen, methyl, or ethyl, or may be taken together with the atom to which they are attached to form a cyclopropyl group; A is a phenyl group or a pyridyl group; R4 is hydrogen; R5a and R5b are each independently a group selected from methyl or ethyl, or together with the atom to which they are attached, may form an optionally substituted (C3-C6)cycloalkyl group selected from cyclopentyl, cyclohexyl, 4,4-difluorocyclohexyl, or a heterocyclyl group selected from pyranyl, oxetyl, N-methylpiperidinyl, N-acetylpiperidinyl; R2 is methyl, ethyl, isopropyl, or cyclopentyl; R3 is hydrogen, cyano, methyl, NH2, NHMe, or N(Me)2; X, U, Y,

[0031] [ka] , M, G1, Z1, Z2, m1, m2 and E are as described above.

[0032] Certain preferred compounds of formula (I), or pharmaceutically acceptable salts thereof, are the following compounds: 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 (compound 1); 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 (compound 2); 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 (compound 3); 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 (compound 4); 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 (compound 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 (compound 6); 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}prope-2-enoic acid (compound 7); 2-{[(1S)-1-{4-[4-(4-propanoylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (compound 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 (compound 9); 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 23); 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 (compound 24); 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 (compound 25); 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 (compound 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 (compound 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 (compound 28); 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 (compound 29); 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 (compound 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 (compound 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 (compound 32); 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 (compound 33); 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 (compound 34); 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 (compound 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 (compound 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 (compound 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 (compound 38); 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 (compound 39); 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 (compound 40); 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 (compound 41); 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 (compound 42); 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 (compound 43); 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 (compound 44); 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 (compound 45); 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 (compound 46); 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 (compound 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 (compound 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 (compound 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 (compound 50); 8-(propan-2-yl)-2-({(1S)-1-[4-(4-{4-[( 2 H3) propenoyl]piperazin-1-yl}tetrahydro-2H-pyran-4-yl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one (compound 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 (compound 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 (compound 53); 2-{[(1S)-1-(4-{4-[4-(2-fluoroacryloyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (compound 54); 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 (compound 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 (compound 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-alaninamide (compound 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-alaninamide (compound 58); 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 (compound 59); 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 (compound 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 (compound 61); 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 (compound 62); 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 (compound 63); 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 (compound 64); 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 (compound 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 (Compound 66); and 7-{[(1S)-1-{4-[4,4-difluoro-1-(4-propanoylpiperazin-1-yl)cyclohexyl]phenyl}ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one (compound 67). DETAILED DESCRIPTION OF THE INVENTION

[0033] When a stereocenter (also referred to as an asymmetric center) is present in a compound of the present invention, all forms of such optical isomers, including enantiomers and diastereomers, are intended to be included herein. Compounds containing a stereocenter can be used as racemic mixtures or as enantiomer-enriched mixtures, or racemic mixtures can be separated using well-known techniques and the individual enantiomers used. When a compound contains an unsaturated carbon-carbon double bond, both the cis (Z) and trans (E) forms are included within the scope of the present invention.

[0034] Compounds may also exist as tautomers, such as keto-enol tautomers, and in such cases, each tautomer is intended to be included within the scope of the present invention, regardless of whether both isomers exist in equilibrium or whether one predominates.

[0035] Pharmaceutically acceptable salts of the compounds of formula (I) include salts with inorganic or organic acids (e.g., 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, isethionic acid, and salicylic acid).

[0036] 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 or alkaline earth metals, in particular sodium, potassium, calcium, ammonium or magnesium, and salts with acrylamines or cyclic amines.

[0037] Another object of the invention are compounds of formula (I) in which one or more hydrogens have been replaced by one or more deuterium atoms.

[0038] When m2 is 0, the Z2 group is absent and the G1 and N groups are saturated with hydrogen.

[0039] The term "(C1-C6) alkyl" means an aliphatic (C1-C6) hydrocarbon chain that contains only carbon-carbon single bonds and may be straight or branched. 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.

[0040] The term "(C3-C6)cycloalkyl," unless otherwise specified, means an all-carbon 3- to 6-membered monocyclic ring that may contain one or more double bonds but does not have a completely conjugated π-electron system.

[0041] Examples of (C3-C6)cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexanyl, cyclohexenyl, and cyclohexadienyl. The (C3-C6)cycloalkyl rings may optionally be fused or linked to further aromatic and non-aromatic carbocyclic or heterocyclic rings.

[0042] The term "heterocyclyl" refers to a 3- to 7-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, or sulfur. Non-limiting examples of heterocyclyl groups include pyranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, thiazolinyl, thiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyridinyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, and the like. Heterocyclyl rings may optionally be fused or linked to further aromatic and non-aromatic carbocyclic or heterocyclic rings.

[0043] The term "(C2-C6) alkenyl" refers to an aliphatic straight or branched (C2-C6) hydrocarbon chain containing at least one carbon-carbon double bond. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1- or 2-butenyl, and the like.

[0044] The term "(C2-C6)alkynyl" refers to an aliphatic straight or branched (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- or 2-butynyl, and the like.

[0045] The term "(C1-C6)alkoxy" means any of the above (C1-C6)alkyl groups linked to the rest of the molecule via an oxygen atom (-O-).

[0046] The term "aryl" refers to a monocyclic, bicyclic, or polycyclic carbocyclic hydrocarbon group consisting of 1 to 4 ring systems, optionally further fused or linked together by single bonds, in which at least one of the carbocyclic rings is "aromatic," where "aromatic" refers to a completely conjugated π-electron bonding system. Non-limiting examples of such aryl groups are phenyl, α- or β-naphthyl, α- or β-tetrahydronaphthalenyl, biphenyl, and indanyl.

[0047] The term "heteroaryl" refers to an aromatic heterocycle, typically a 5- to 7-membered heterocycle, containing 1 to 3 heteroatoms selected from N, O, or S, which heteroaryl ring may optionally be fused or linked to further 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, furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiophenyl, thiadiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, indazolyl, cinnolinyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, benzothiazolyl, benzothiophenyl, benzofuranyl, isoindolinyl, benzimidazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl, benzopyranyl, 2,3-dihydrobenzoxazinyl, 2,3-dihydroquinoxalinyl, and the like.

[0048] The term "halogen" means fluoro, chloro, bromo or iodo.

[0049] The term "polyfluorinated (C1-C6) alkyl" or "polyfluorinated (C1-C6) alkoxy" means any of the above (C1-C6) alkyl or (C1-C6) alkoxy groups substituted with two or more fluorine atoms (e.g., trifluoromethyl, trifluoroethyl, 1,1,1,3,3,3-hexafluoropropyl, trifluoromethoxy, etc.).

[0050] The term "hydroxy(C1-C6)alkyl" means any of the above (C1-C6)alkyl groups bearing a hydroxyl group (eg, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, etc.).

[0051] According to the present invention, unless otherwise specified, R1a, R1b, R2, R3, R4, R5a, R5b, R9a, R9b, R10a, R10b, and E may optionally be substituted at any of their open positions with one or more groups, for example, independently hydroxyl, 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)alkynyl ... alkyl, (C1-C6)alkylaryl, aryl(C1-C6)alkoxy, heteroaryl, heteroaryl(C1-C6)alkyl, (C1-C6)alkylheteroaryl, heterocyclyl, heterocyclyl(C1-C6)alkyl, (C1-C6)alkylheterocyclyl, (C1-C6)alkylheterocyclyl(C1-C6)alkyl, tri(C1-C6)alkylsilyl, (C3-C7)cycloalkyl, (C1-C6)alkoxy, aryloxy, heterocyclyloxy, methylenedioxy, (C1-C6)alkylcarbonyl oxy, arylcarbonyloxy, di(C1-C6)alkylaminoheterocyclyl(C1-C6)alkyl, (C3-C7)cycloalkenyloxy, heterocyclylcarbonyloxy, (C1-C6)alkylideneaminooxy, carboxy, (C1-C6)alkoxycarbonyl, aryloxycarbonyl, (C3-C7)cycloalkyloxycarbonyl, amino, heterocyclyl(C1-C6)alkoxycarbonylamino, ureido, (C1-C6)alkylamino, amino(C1-C6)alkyl, di(C1-C6)alkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, (C1-C6)alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, arylaminocarbonyl(C1-C6)alkyl, (C3-C7)cycloalkylaminocarbonyl, heterocyclylaminocarbonyl, (C1-C6)alkoxycarbonylamino,It may be substituted with 1 to 6 groups selected from hydroxyaminocarbonyl, (C1-C6)alkoxyimino, (C1-C6)alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, formyl, (C1-C6)alkylcarbonyl, arylcarbonyl, (C3-C7)cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, polyfluorinated (C1-C6)alkylsulfonyl, arylsulfonyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, and (C1-C6)alkylthio, and if necessary, each of the above substituents may be further substituted with one or more of the above groups.

[0052] From the above, it will be apparent to those skilled in the art that when the name of a group is a compound word, the component words should be interpreted in the conventional manner, e.g., "arylamino" means an amino group substituted with an aryl, wherein the aryl is as defined above.

[0053] Similarly, for example, terms such as (C1-C6)alkylthio, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, (C3-C7)cycloalkyloxycarbonyl, and the like all include groups in which the (C1-C6)alkyl moiety, (C1-C6)alkoxy moiety, aryl moiety, (C3-C7)cycloalkyl moiety, and heterocyclyl moiety are as defined above.

[0054] The present invention also provides methods for preparing compounds of the above general formula (I) by utilizing techniques available in the art and readily available starting materials, using the following reaction pathways and synthetic schemes. The following examples describe the preparation of certain embodiments of the present invention, but those skilled in the art will understand that the preparations described in the examples can be readily adapted to prepare other embodiments of the present invention. For example, modifications obvious to those skilled in the art can be used to synthesize compounds of the present invention other than those exemplified, such as appropriate protection of interfering groups, appropriate substitution of reagents with other reagents known in the art, and routine modification of reaction conditions. Alternatively, it will be understood that other reactions mentioned herein or known in the art can be adapted to prepare other compounds of the present invention.

[0055] The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. Unless otherwise specified, starting materials are known compounds or can be prepared from known compounds according to well-known procedures. It will be understood that where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures) are described, alternative process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0056] The compounds of general formula (I) above can be prepared according to the general synthetic method described in Scheme 1, starting from an intermediate compound of formula (II).

[0057] Scheme 1

[0058] [ka]

[0059] Step 1a) Formula (II):

[0060] [ka] wherein X is nitrogen or -CH-; U is CH, CH2, or CMe; Y is CH, CF, or O;

[0061] [ka] represents a single or double bond; R2 is an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, aryl-(C1-C6) alkyl, and heterocyclyl-(C1-C6) alkyl; R3 is hydrogen, chloro, cyano, CONH2, NH2, NR12aR12b, OR13, or an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, aryl, and heteroaryl. is a substituted group, wherein R12a, R12b are each independently selected from hydrogen or optionally substituted straight or branched (C1-C6) alkyl; R13 is an optionally substituted straight or branched (C1-C6) alkyl; R1a and R1b are each independently hydrogen or optionally substituted straight or branched (C1-C6) alkyl, or together with the atom to which they are attached may form a (C3-C6) cycloalkyl; A is a (C3-C6) cycloalkyl, aryl, or heteroaryl; R4 is hydrogen, halogen, cyano, or optionally substituted straight or branched chain (C1-C6) alkyl; R5a and R5b are each independently a group selected from optionally substituted straight or branched chain (C1-C6) alkyl, (C3-C6) cycloalkyl, or may together with the atom to which they are attached form a 3- to 7-membered cycloalkyl group or a heterocyclyl group containing one or more heteroatoms selected from O, S, N—R6; R6 is optionally substituted straight or branched chain (C1-C6) alkyl. R7 and R8 are optionally substituted straight or branched chain (C1-C6) alkyl; M is a bond, NH, NR6 (wherein R6 is as defined above), or O; G1 is N, CH, CH2, or CO; Z1 is CR9aR9b; Z2 is CR10aR10b; R9a, R9b, R10a, and R10b are independently hydrogen or optionally substituted straight or branched chain (C1-C6) alkyl; m1 is 1, 2, or 3, and m2 is 0, 1, 2, or 3.

[0062] [ka] [wherein E is CN, or an optionally substituted straight or branched chain (C1-C6) alkyl, (C2-C6) alkenyl, or a group of the formula -COR11; R11 is an optionally substituted straight or branched chain (C2-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl; and Q is hydroxy, chloro, or bromo.], to form a compound of formula -COR11,

[0063] [ka] , a compound of general formula (I) is obtained in which R2, R3, R1a, R1b, A, R4, R5a, R5b, M, G1, Z1, Z2 and E are as defined above.

[0064] The compounds of general formula (II) above can be prepared according to the general synthetic method described in Scheme 2, starting from the intermediate compound of formula (IV).

[0065] Scheme 2

[0066] [ka]

[0067] Thus, the method of the present invention comprises the following steps: Step 2a) Formula (IV):

[0068] [ka] wherein G is chloro, MeS(O)2-, MeS(O)- or OTrif; and X, U, Y,

[0069] [ka] , R2 and R3 are as defined in step 1a.] is reacted with a compound of formula (V):

[0070] [ka] wherein R1a, R1b, A, R4, R5a, R5b, M, G1, Z1, Z2, m1 and m2 are as defined above in step 1a, and PG is a protecting group selected from tert-butyl carboxylate, benzyl carboxylate, phenyl carboxylate; Step 2b) Formula (VI):

[0071] [ka] wherein PG is as defined above in step 2a) is reacted with a suitable deprotecting agent to afford X, U, Y,

[0072] [ka] , A, R1a, R1b, R2, R3, R4, R5a, R5b, M, G1, Z1, Z2, m1 and m2 are as defined above to obtain a compound of formula (II).

[0073] G is MeS(O)2- or MeS(O)-, X is N, R3 is hydrogen or chloro, U, Y,

[0074] [ka] Compounds of formula (IV), wherein R2 is as defined in step 1a, can be prepared according to scheme 3.

[0075] Scheme 3

[0076] [ka]

[0077] Step 3a) Formula (VII):

[0078] [ka] wherein R3 is hydrogen, chloro, or an optionally substituted straight or branched chain (C1-C6) alkyl, by converting the chlorine of an intermediate compound of formula (VIII):

[0079] [ka] wherein R2 is as defined above in step 1a;

[0080] Step 3b) Formula (IX):

[0081] [ka] (wherein R2 and R3 are as defined above) is reacted with a reducing agent;

[0082] Step 3c) Obtained formula (X):

[0083] [ka] (wherein R2 and R3 are as defined above) is reacted with a suitable oxidizing agent;

[0084] Step 3d) Obtained formula (XI):

[0085] [ka] wherein R and R are as defined above, is reacted with a reagent of formula T-CHCOOEt (XIV), wherein T is hydrogen or fluoro:

[0086] Step 3e) Obtained formula (XII):

[0087] [ka] (Wherein U, Y and

[0088] [ka] is as defined in step 1a, and R2 and R3 are as defined above.) is mixed with an oxidizing agent reagent, and an intermediate compound of formula (I) is prepared by adding an oxidizing agent reagent to the intermediate compound of formula (I), wherein G is MeS(O)2- or MeS(O)-, X is N, and R2, R3, U, Y and

[0089] [ka] to obtain a compound of formula (IV) wherein

[0090] Alternative Step 3f) Formula (X):

[0091] [ka] wherein R2 and R3 are as defined above in step 3e, is reacted with carbonyldiimidazole or triphosgene to form a compound of formula (I), wherein U is CH2 and Y is O;

[0092] [ka] is a single bond, and R2 and R3 are as defined above;

[0093] Alternative Step 3g) Formula (XIII):

[0094] [ka] (In the formula, R3, U, Y,

[0095] [ka] is as defined above in step 3e.) with an alkylating agent of formula R2-Lg(XV), where Lg is bromine, iodine, -OMs, -OTs or hydroxy, and R2 is as defined above, to give the intermediate compound of formula R2-Lg(XV), where R2, R3, U, Y and

[0096] [ka] to obtain a compound of formula (XII) wherein

[0097] Compounds of formula (IV) wherein G is chloro and R3, X, U, Y and R2 are as defined above in step 1a may be prepared according to Scheme 4.

[0098] Scheme 4

[0099] [ka]

[0100] Step 4a) Formula (XVI):

[0101] [ka] wherein X and R3 are as defined above in step 1a, by converting the chlorine of the intermediate compound of formula (VIII):

[0102] [ka] wherein R2 is as defined above in step 1a;

[0103] Step 4b) Formula (XVII):

[0104] [ka] (wherein X, R3 and R2 are as defined above) is reacted with a reducing agent;

[0105] Step 4c) Obtained formula (XVIII):

[0106] [ka] wherein X, R3 and R2 are as defined above, reacting the compound of formula (I) with a suitable oxidizing agent;

[0107] Next process Step 4d) Obtained formula (XIX):

[0108] [ka] wherein X, R2 and R3 are as defined above, is reacted with a compound of formula T-CH2COOEt(XIV) wherein T is hydrogen or fluoro, and G is chloro and U, Y, X,

[0109] [ka] , to obtain a compound of formula (IV), wherein R3 and R2 are as defined above in step 1a;

[0110] Alternative Step 4e) Obtained formula (XVIII):

[0111] [ka] wherein X, R3 and R2 are as defined above, is reacted with carbonyldiimidazole or triphosgene to form a compound of formula (I), wherein G is chloro, U is CH2, Y is O,

[0112] [ka] is a single bond, and X and R2 are as defined above to obtain a compound of formula (IV).

[0113] If necessary, the first compound of formula (XII) is converted to a second compound of formula (XII) by operating according to well-known synthetic conditions.

[0114] Examples of possible transformations are listed below.

[0115] Conversion A):

[0116] [ka] converting a compound of formula (XII) wherein R3 is chloro to a compound of formula (XII) wherein R3 is CN by reaction with a cyanide source according to conditions known in the art for palladium-catalyzed cyanation of aryl halides;

[0117] Conversion B):

[0118] [ka] Converting a compound of formula (XII) in which R3 is chloro to a compound of formula (XII) in which R3 is NHPG by reacting with the amine PG-NH2;

[0119] Conversion C):

[0120] [ka] converting a compound of formula (XII) wherein R3 is chloro to a compound of formula (XII) wherein R3 is NR12aR12b by reacting with an amine HNR12aR12b, wherein R12a and R12b are each independently selected from hydrogen or an optionally substituted straight or branched chain (C1-C6) alkyl;

[0121] Conversion D):

[0122] [ka] converting a compound of formula (XII) in which R3 is chloro to a compound of formula (XII) in which R3 is OR13 by reacting with an alcohol R13-OH, where R13 is an optionally substituted linear or branched (C1-C6) alkyl;

[0123] Conversion E):

[0124] [ka] Compounds of formula (XII) where R3 is cyano are converted to compounds of formula (XII) where R3 is CONH2 by hydrolysis with an appropriate reagent.

[0125] If necessary, the first compound of formula (IV) is converted to a second compound of formula (IV) by operating according to well-known synthetic conditions.

[0126] Examples of possible transformations are listed below.

[0127] Conversion A1):

[0128] [ka] A two-step sequence using appropriate reagents converts compounds of formula (IV) where G is MeS(O)2- to compounds of formula (IV) where G is -OTrif (triflate).

[0129] The compound of formula (V) wherein R1a, R1b, A, R4, R5a, R5b, M, G1, Z1, Z2, m1 and m2 are as described above in Step 1a, and PG is a protecting group, can be prepared according to the following synthesis scheme 5.

[0130] Scheme 5

[0131] [ka]

[0132] Step 5a) Formula (XX):

[0133] [ka] (wherein W1 is bromo, cyano, COR1a, and A, R4, R5a, R5b and R1a are as defined above in step 1a) is reacted with ClCH2CN under Ritter reaction conditions, followed by deprotection of the amide intermediate under acidic conditions, basic conditions or with thiourea to give a compound of formula (XXI).

[0134] Step 5b) Formula (XXI):

[0135] [ka] wherein W1, A, R4, R5a and R5b are as defined above in step 5a, are reacted with an amino intermediate of formula (XXII):

[0136] [ka] (wherein Z1, Z2, m1 and m2 are as defined above in step 1a, PG is a protecting group, and Hal is a halogen) to obtain 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;

[0137] Alternative Step 5b') reacting the amino intermediate of formula (XXI) with a compound of formula (XXIIa):

[0138] [ka] (wherein Z1, Z2, m1, m2 and PG are as defined above in step 5b, and Hal is a halogen), followed by reaction of the resulting intermediate by reductive amination with formaldehyde or 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), where PG is as defined above, W1, A, R4, R5a, R5b, Z1, Z2, m1 and m2 are as defined in step 1a, G1 is CH, and M is NR6 (wherein R6 is as defined in step 1a);

[0139] Alternative Step 5b"): The amino intermediate of formula (XXI) is reacted with a compound of formula (XXIIb):

[0140] [ka] [wherein Z1, m1, and PG are as defined above in Step 5b, and FG is a functional group selected from an aldehyde (—CHO) or a carboxylic acid (—COOH)] to obtain 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);

[0141] Alternative Step 5a') Formula (XX):

[0142] [ka] wherein W1, A, R4, R5a and R5b are as defined above in step 5a, by reacting a compound of formula (XXIIa)

[0143] [ka] (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;

[0144] Next process Step 5c) Compounds of formula (XXIII) obtained from step 5b or 5b' or 5b" or 5a':

[0145] [ka] (wherein W1 is cyano, and A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2 and PG are as defined above) is reacted with ethylmagnesium bromide and boron trifluoride diethyl etherate to obtain the target 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 as defined in step 1a, or R1a and R1b together form a cyclopropyl group;

[0146] Alternative Step 5c') Compound of formula (XXIII) obtained from step 5b or 5b' or 5b" or 5a':

[0147] [ka] (wherein W1 is COR1a, and R1a, A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2, PG and R1a are as defined above in step 5b or 5b' or 5b" or 5a') is reacted with tert-butanesulfinamide to obtain a compound of formula (XXIV), wherein R1b is hydrogen, and R1a, A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2, PG and R1a are as defined above;

[0148] Alternative Step 5c"): Compound of formula (XXIII) obtained from step 5b or 5b' or 5b" or 5a':

[0149] [ka] (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 5b' or 5b" or 5a') is reacted with tert-butanesulfinamide to obtain a compound of formula (XXV);

[0150] Next process Step 5e) Obtained formula (XXV):

[0151] [ka] (wherein R1a, A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2 and PG are as defined above in step 5b or 5b' or 5b" or 5a') is reacted with an alkyl Grignard reagent to obtain the target compound of formula (XXIV);

[0152] Final process Step 5d) Compounds of formula (XXIV) obtained as described in step 5c' or 5e:

[0153] [ka] (wherein R1b, R1a, A, R4, R5a, R5b, M, G1, Z1, Z2, m1, m2 and PG are as defined above in Step 5c' or 5e) is reacted with an acidic deprotecting reagent or iodine to obtain the target 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.

[0154] Alternatively, compounds of formula (XXIII) can be obtained by conversion of another compound of formula (XXIII), as described in the example conversions below.

[0155] Conversion F):

[0156] [ka]

[0157] Compounds of formula (XXIII) in which W1 is cyano can be obtained by converting the corresponding compound of formula (XXIII) obtained from step 5b or 5b' or 5b" or 5a' (in which W1 is bromo) using a cyanide source according to conditions known in the art for palladium-catalyzed cyanation of aryl halides;

[0158] Conversion G):

[0159] [ka]

[0160] Compounds of formula (XXIII), wherein W1 is COR1a, where R1a is as defined in step 1a, can be obtained by conversion of compounds of formula (XXIII), wherein W1 is bromo, obtained from step 5b or 5b' or 5b" or 5a' using an appropriate enol ether organometallic derivative, followed by hydrolysis.

[0161] Compounds of formula (I) prepared according to Scheme 1 may be further converted to other compounds of formula (I) according to procedures well known to those skilled in the art.

[0162] Conversion 1):

[0163] [ka]

[0164] A compound of formula (I) in which E is an acrylamide group is converted to a compound in which E is a dihydroxypropionic acid group.

[0165] According to Step 1, the reaction of a compound of formula (II) with a compound of formula (III) where E is -COR11 can be carried out by a variety of methods and operating conditions widely known in the art for the preparation of amides. For example, when an acyl chloride is used, the reaction is carried out in a suitable solvent such as DCM, THF, 1,4-dioxane, ACN, or DMF at a temperature ranging from about -10°C to reflux for a suitable time, e.g., about 30 minutes to about 96 hours. The reaction is carried out in the presence of a suitable proton scavenger, e.g., triethylamine, N,N-diisopropylethylamine, or pyridine. Alternatively, when a carboxylic acid is utilized, the reaction is carried out in a suitable solvent, e.g., dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, or the like, e.g., 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 1-[bis(dimethylamino)methylene]-1H-1, The reaction is carried out in the presence of a coupling agent such as 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 at a temperature ranging from about -10°C to reflux for about 30 minutes to about 48 hours. The reaction is optionally carried out in the presence of a suitable catalyst (e.g., 4-dimethylaminopyridine) or another coupling agent such as N-hydroxybenzotriazole.

[0166] Alternatively, when E is an optionally substituted straight or branched chain (C1-C6) alkyl, (C2-C6) alkenyl, the reaction can be carried out by addition of Na2CO3, K2CO3, or the like in a suitable solvent such as DMF, DMA, ACN, acetone, or THF at a temperature ranging from 0°C to reflux.3、 Alkylation of the intermediate of formula (II) can be carried out in the presence of a suitable base such as Cs2CO3, NaH, KH, and the like.

[0167] According to step 2a, the leaving group such as methyl sulfone, methyl sulfoxide, chloro or triflate from the intermediate of formula (IV) is replaced with a group of formula (V) using an organic base such as DIPEA, optionally in the presence of CsF as a reaction promoter, in a suitable solvent such as ACN, DMSO, 1,4-dioxane, etc., at temperatures ranging from room temperature to 90°C under conventional heating or microwave irradiation for 1 to 24 hours.

[0168] Alternatively, particularly when G is chloro and X is -CH, the reaction can be carried out under conditions well known to those skilled in the art. For example, the halide can be displaced by a Buchwald-Hartwig amination reaction using a suitable palladium source, such as PEPPSI precatalyst, and a base, such as CsCO, in a solvent such as toluene or ACN at temperatures ranging from 60 to 110 °C under conventional heating or microwave irradiation for 1 to 24 hours.

[0169] According to step 2b, when the protecting group is a phenyl carbamate, deprotection of the compound of formula (VI) can be carried out under alkaline conditions, e.g., using NaOH or KOH, in a solvent such as ethanol, isopropanol, or 1,4-dioxane at reflux for 6 to 18 hours. Alternatively, when the protecting group is Boc, the reaction can be carried out under acidic conditions, e.g., TFA or HCl, in a solvent such as DCM or 1,4-dioxane at temperatures ranging from room temperature to reflux for 1 to about 12 hours, or using a catalytic amount of CuCl in a suitable solvent such as MeOH, EtOH, or an EtOH / water mixture. Alternatively, when the protecting group is a benzyl carbamate, the reaction can be carried out using Pd / C in the presence of a hydrogen source, e.g., ammonium formate, cyclohexene, or 1,3-cyclohexadiene, in a suitable solvent such as EtOH or isopropanol at reflux for 1 to about 18 hours.

[0170] According to step 3a, NaCO, KCO, or the like can be reacted neat or in a suitable solvent such as DMF, DMA, ACN, or DMSO at temperatures ranging from room temperature to reflux. 3、 The chlorine in the compound of formula (VII) can be displaced with an amine of formula R2-NH2 (VIII) in the presence of a suitable base such as Cs2CO3, TEA, DIPEA, etc.

[0171] According to step 3b of the present process, the ester of formula (IX) can be reduced to give the compound of formula (X) by a variety of methods and experimental conditions known in the art. A reducing agent such as lithium aluminum hydride can be used in a suitable solvent such as THF at temperatures ranging from 0°C to room temperature for 2 to about 24 hours. Preferably, the reaction is conveniently carried out using lithium aluminum hydride in THF at room temperature.

[0172] According to step 3c of the present process, oxidation of the intermediate of formula (X) to the aldehyde of formula (XI) can be carried out using manganese dioxide (II), pyridinium chlorochromate, o-iodoxybenzoic acid (IBX), tetrapropylammonium perruthenate (TPAP), 4-methylmorpholine N-oxide or sodium hypochlorite / TEMPO / BuNHSO at room temperature in a solvent such as DCM, ACN, THF, EtOAc, acetone or chloroform.

[0173] According to step 3d, NaCO, KCO, etc. can be prepared in a suitable solvent such as THF, DMF, DMA, etc. at temperatures ranging from −50° C. to reflux under classical thermal conditions or in a microwave apparatus for 1 to 24 hours. 3、 Claisen-Schmidt condensation of intermediates of formula (XI) and formula (XIV) can be carried out in the presence of a suitable base such as LiOH, Cs2CO3, potassium t-butoxide, LiHMDS, KHMDS, and the like.

[0174] According to step 3e, the methylthio group of the intermediate of formula (XII) can be oxidized in the presence of an oxidizing agent well known to those skilled in the art, such as, for example, oxone or m-chloroperbenzoic acid, in a suitable solvent, such as DCM, at room temperature for 1-16 hours, to give compounds of formula (IV) where G is MeS(O)- or MeS(O).

[0175] According to step 3f, cyclization of intermediates of formula (X) to oxazin-2-ones can be carried out under carbamoylation conditions using triphosgene, carbonyldiimidazole or phosgene in the presence of a base such as DIPEA or TEA at temperatures from about −30° C. to room temperature for 1 to 6 hours.

[0176] According to step 3g, NaCO, KCO are reacted with NaCO in a suitable solvent such as DMF, DMA, ACN, acetone, THF, etc. at temperatures ranging from 0°C to reflux. 3、 The intermediate of formula (XIII) can be alkylated with an intermediate of formula (XV) where Lg is bromine, iodine, -OMs, or -OTs in the presence of a suitable base such as CsCO, NaH, KH, etc. When an intermediate of formula (XV) where Lg is hydroxy is used, the reaction is preferentially carried out under Mitsunobu alkylation conditions in the presence of a suitable reagent such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate (DBAD), 1,1'-(azodicarbonyl)dipiperidine (ADDP), and a phosphine reagent such as trimethylphosphine, tri-tert-butylphosphine, or triphenylphosphine in a suitable solvent such as THF, DMF, DCM, or toluene at a temperature ranging from 0°C to 65°C.

[0177] According to step 4a, the chlorine of a compound of formula (XVI) can be displaced with an amine of formula (VIII), as described above in step 3a.

[0178] According to step 4b of the process, the ester of formula (XVII) can be reduced to give the compound of formula (XVIII), as described above in step 3b.

[0179] 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.

[0180] According to step 4d, compounds of formula (XIX) are cyclized under the Claisen-Schmidt condensation conditions reported in step 3d to give compounds of formula (IV) where G is chloro and X is nitrogen or -CH-.

[0181] According to step 4e, compounds of formula (XVIII) are cyclized under the carbamoylation conditions to oxazin-2-ones reported in step 3f to give compounds of formula (IV) in which G is chloro, X is nitrogen or -CH-, U is CH2 and Y is O.

[0182] According to Transformation A of the present method, heteroaryl chlorides of formula (XII) can be reacted in a suitable solvent such as DMF, N-methylpyrrolidone, or DMA at temperatures from 80° C. to reflux for 4 to about 24 hours in the presence of palladium(II) acetate as a catalyst and sodium carbonate, potassium carbonate, or cesium carbonate as a base, using a cyanide source such as sodium cyanide, potassium cyanide, or ZnCN, CuCN, or potassium hexacyanoferrate(II) as a cyanide source, according to various methods and experimental conditions known in the art for aromatic nucleophilic substitution (J. Org. Chem. 2005, 70, 1508-1510; Org. Lett. 2011, 13(4), pp. 648-651; Org Lett. 2015, 17(2), pp. 202-205).

[0183] According to transformation B of the present method, heteroaryl chlorides of formula (XII) can be reacted with amines PG-NH2 in acetonitrile under reflux for 1 to about 24 hours using a variety of methods and experimental conditions.

[0184] According to transformation C of the present method, a heteroaryl chloride of formula (XII) can be reacted with an amine of formula NR12aR12b in a suitable solvent such as acetonitrile, DMF, DMA, etc. at temperatures ranging from room temperature to reflux for a period of 2 to about 24 hours using a variety of methods and experimental conditions.

[0185] According to transformation D of the present method, a heteroaryl chloride of formula (XII) can be reacted with an alcohol of formula OR13 in the presence of potassium carbonate, cesium carbonate, in a suitable solvent such as acetonitrile or THF at temperatures ranging from room temperature to reflux for a period of 2 to about 24 hours, using a variety of methods and experimental conditions.

[0186] According to transformation E of the present method, a heteroaryl nitride of formula (XII) can be reacted with acetamide in the presence of 1,4-dioxane under reflux with the addition of Pd(OAc) 2 for a period of 4 to about 24 hours.

[0187] According to Conversion A1 of this method, the compound of formula (IV) can be converted to the corresponding triflate derivative of formula (IV) by various methods and experimental conditions known in the art. First, the compound of formula (IV) is reacted with NaOH, KOH, or the like in a suitable solvent such as water, acetonitrile, dioxane, or DMSO at room temperature to 90°C for 1 to about 4 hours. The resulting hydroxyl derivative is then reacted with triflic anhydride or N-phenyltriflimide in the presence of a base such as DIPEA, TEA, or 2,6-lutidine in a solvent such as DCM or THF at a temperature from about -10°C to room temperature for 1 to 6 hours.

[0188] According to step 5a of the present process, compounds of formula (XX) can be converted to derivatives of formula (XXI) by acid-catalyzed nucleophilic addition of the nitrile followed by hydrolysis to the corresponding amide. This reaction, commonly known as the Ritter reaction, is carried out using H2SO4 and chloroacetonitrile at temperatures ranging from 0°C to 20°C for 6-12 hours. The amide thus obtained is further reacted with thiourea in ethanol and acetic acid at 60°C for 6-12 hours to give derivatives of formula (XXI).

[0189] According to step 5b, the compound of formula (XXI) is reacted with an appropriately substituted alkyl dihalide of formula (XXII) using a solvent such as DIPEA with the addition of NaI under reflux for 24-72 hours to give the corresponding derivative of formula (XXIII).

[0190] According to step 5a', the compound of formula (XX) is reacted with an appropriate substituted heterocyclyl halide of formula (XXIIa) by using an appropriate base such as NaH, K2CO3, Cs2CO3, LiHMDS, etc. in a suitable solvent such as DMF, acetonitrile, THF, DIPEA, etc. at room temperature to reflux for 4 to about 24 hours with the addition of NaI to give the corresponding derivative of formula (XXIII).

[0191] According to step 5b', the compound of formula (XXI) is reacted with an appropriate substituted heterocyclyl halide of formula (XXIIa) using an appropriate base such as NaH, K2CO3, Cs2CO3, LiHMDS, etc., with the addition of NaI, in an appropriate solvent such as DMF, acetonitrile, THF, DIPEA, etc., at room temperature to reflux, for 4 to about 24 hours.

[0192] Alternatively, a compound of formula (XXI) is reacted with an appropriate heterocyclyl ketone of formula (XXIIa) in the presence of a suitable catalyst, such as tetraethoxytitanium or tetraisopropoxytitanium, in a suitable solvent such as THF, toluene, or 1,4-dioxane at temperatures ranging from 70°C to reflux for 16 to 24 hours. The resulting intermediate is directly treated with a reducing agent such as NaCNBH3 (sodium cyanoborohydride) at temperatures ranging from 20°C to 70°C for 1 to 4 hours to give 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, in a solvent such as MeOH, EtOH, or 2,2,2-trifluoroethanol at temperatures ranging from room temperature to 40°C for 1 to about 24 hours. The reduction reaction can be carried out optionally in the presence of a suitable catalyst such as AcOH or TFA, or by reacting the intermediate compound with a suitable haloacyl derivative, optionally in the presence of a base, in a solvent such as DCM, THF, or DMF at a temperature ranging from room temperature to 40° C. for 1 to about 24 hours, or by reacting the intermediate compound with an alkyl chloroformate derivative, optionally in the presence of a base, in a solvent such as DCM, THF, DMF, or dioxane at a temperature ranging from room temperature to 40° C. for 1 to about 24 hours, to obtain a compound of formula (XXIII).

[0193] According to step 5b", the compound of formula (XXI) is reacted with a protected aminoalkylaldehyde of formula (XXIIb) using a reducing agent such as NaCNBH3 (sodium cyanoborohydride), NaBH(OAc)3 (sodium triacetoxyborohydride) in a solvent such as DCM, THF, etc. at a temperature ranging from 20°C to 50°C for 1 to 4 hours. The reduction reaction can be optionally carried out in the presence of a suitable catalyst such as AcOH, TFA, etc., and the resulting intermediate compound is further reacted with trifluoroacetic anhydride in the presence of pyridine, etc. at room temperature for 1 to about 24 hours to give the compound of formula (XXIII).

[0194] Alternatively, the reaction of a compound of formula (XXI) with a protected aminoalkylcarboxylic acid of formula (XXIIb) where FG is -COOH can be carried out by a variety of methods and operating conditions widely known in the art for the preparation of amides. For example, the reaction is carried out in the presence of a coupling agent such as 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-propanephosphonic anhydride), or the like, in a suitable solvent such as dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, ethyl acetate, or the like, at a temperature ranging from about -10°C to reflux for about 30 minutes to about 48 hours.

[0195] According to step 5c, the compound of formula (XXIII) is subjected to the Kulinkovich-Szymoniak reaction with an ethyl Grignard reagent in the presence of a stoichiometric amount of titanium(IV) isopropoxide, followed by exposure to boron trifluoride diethyl etherate in diethyl ether, methyl tert-butyl ether (MTBE) at temperatures ranging from -70°C to 0°C for 1 to 4 hours to give the corresponding derivative of formula (V).

[0196] 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, etc. at a temperature ranging from 50°C to reflux for 4 to 16 hours. The resulting intermediate is directly treated with a reducing agent such as NaBH4 (sodium borohydride), L-selectride, etc. at a temperature ranging from -70°C to 0°C for 1 to 4 hours to give the compound of formula (XXIV).

[0197] 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, etc. at a temperature ranging from 50° C. to reflux for a period of 4 to 16 hours.

[0198] According to step 5e, the compound of formula (XXV) is reacted with a methyl or ethyl Grignard reagent in diethyl ether or THF at a temperature ranging from 0° C. to room temperature for 1 to 4 hours to give the compound of formula (XXIV).

[0199] According to step 5d, the compound of formula (XXIV) is reacted with a strong acid, such as hydrochloric acid, in 1,4-dioxane or methanol at room temperature for 1 to 24 hours to give the compound of formula (V).

[0200] Alternatively, the compound of formula (XXIV) is reacted with iodine in a solvent mixture such as a mixture of THF and HO at a temperature ranging from room temperature to 80° C. for 1 to 24 hours to give the compound of formula (V).

[0201] Examples of possible transformations are listed below.

[0202] According to transformation F, a compound of formula (XXIII) is reacted with a suitable cyanide source, such as ZnCN, CuCN, K3[Fe(CN)6], etc., in the presence of a suitable palladium catalyst, such as Pd(OAc)2, PdCl2(PPh3)3, or Pd(dppf)Cl2. The reaction is carried out in the presence of a suitable base, such as sodium carbonate, potassium carbonate, or cesium carbonate, in a solvent, such as THF, dioxane, DMF, or acetonitrile, at a temperature ranging from 80° C. to reflux for a period of 4 to about 24 hours.

[0203] According to transformation G, a compound of formula (XXIII) is crosslinked with a suitable enol ether organometallic derivative, such as 1-ethoxyvinyltri-n-butyltin, in the presence of a suitable palladium catalyst, such as PdCl(PPh) or Pd(dppf)Cl. The reaction is carried out in the presence of a suitable base, such as TEA or DIPEA, at temperatures ranging from room temperature to reflux for 1 to about 24 hours. The resulting intermediate is further hydrolyzed with 6N aqueous HCl at room temperature for 1 to about 24 hours to give a compound of formula (V).

[0204] According to transformation 1), acrylamide of formula (I) is reacted with osmium tetroxide in pyridine and tert-butanol at room temperature (as reported in WO211046964) for 8-24 hours.

[0205] From the foregoing, it will be apparent to one skilled in the art that compounds of formula (I) contain functional groups that can be further derivatized to other functional groups by manipulation according to methods well known in the art to provide other compounds of formula (I), and such compounds are also intended to be within the scope of the present invention.

[0206] When preparing compounds of general formula (I) according to any of the above-described various aspects of the method, the starting materials, reagents, or intermediates may contain functional groups that may undergo undesired side reactions and therefore need to be appropriately protected according to conventional techniques (see, for example, Green, Theodora W. and Wuts, Peter GM - Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons Inc., New York (NY), 2012). Similarly, these compounds can be converted into the free, deprotected compounds according to known procedures.

[0207] Compounds of all general formulae can be further transformed into other compounds of the same general formula according to methods well known from the literature, as reported in the experimental section.

[0208] In any embodiment of the process for preparing the compounds of formula (I), the starting materials and all other reactants are known or readily prepared according to known methods.

[0209] The intermediate of formula (XI) where R3 is chloro is prepared as reported in WO2016204429A1.

[0210] The compound of formula (XXI) can also be prepared as described in Tetrahedron, Vol. 72, 2016, 1941-1953.

[0211] Compounds of formula (XX) can be prepared as described in WO2014086316.

[0212] Compounds of formula (XXII) can be prepared as described in WO2009065622A1.

[0213] Compounds of formula (III, VII, VIII, XII, XIV, XV, XVI, XXIIa, XXIIb) are commercially available or can be prepared by known methods.

[0214] The final compound can be isolated and purified using conventional procedures (e.g., chromatography and / or crystallization and salt formation).

[0215] The compound of general formula (I) can be converted into a pharmaceutically acceptable salt. The compound of general formula (I) or a pharmaceutically acceptable salt thereof can then be formulated with a pharmaceutically acceptable carrier or diluent to provide a pharmaceutical composition.

[0216] The synthesis of compounds of general formula (I) using the above synthetic methods can be carried out in a stepwise manner, whereby each intermediate can be isolated and purified, as necessary, by standard purification techniques, such as column chromatography, before carrying out the subsequent reaction. Alternatively, two or more steps of the synthetic sequence can be carried out in a so-called "one-pot" manner known in the art, whereby only the compound resulting from said two or more steps is isolated and purified.

[0217] When a compound of general formula (I) contains one or more asymmetric centers, the compound can be separated into individual stereoisomers by procedures known to those skilled in the art. Such procedures include standard chromatographic techniques, including chromatography using chiral stationary phases, or crystallization. General methods for separating compounds containing one or more asymmetric centers are reported, for example, in Jacques, Jean; Collet, Andre; Wilen, Samuel H., Enantiomers, Racemates, and Resolutions, John Wiley & Sons Inc., New York (NY), 1981.

[0218] The present invention further provides a method comprising administering to a mammal, preferably a human, in need of treatment for a disease caused by and / or associated with elevated levels of 2-hydroxyglutaric acid an effective amount of a compound of formula (I) above.

[0219] Furthermore, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method comprising administering an effective amount of a compound of formula (I) to a mammal, preferably a human, in need of treatment for a disease caused by and / or associated with elevated levels of 2-hydroxyglutaric acid.

[0220] Furthermore, the present invention provides a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease caused by and / or associated with elevated levels of 2-hydroxyglutaric acid, the composition comprising administering an effective amount of the compound of formula (I) to a mammal, preferably a human, in need of said treatment.

[0221] 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 elevated levels of 2-hydroxyglutaric acid, which comprises administering an effective amount of a compound of formula (I) as defined above to a mammal, preferably a human, in need of said treatment.

[0222] The present invention also provides a method for treating a disease caused by and / or associated with a mutant IDH enzyme or hyperactivity of a wild-type IDH, comprising administering an effective amount of a compound of formula (I) to a mammal, preferably a human, in need of treatment.

[0223] Furthermore, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method comprising administering an effective amount of a compound of formula (I) to a mammal, preferably a human, in need of treatment for a disease caused by and / or associated with a mutant IDH enzyme or hyperactivity of wild-type IDH.

[0224] Furthermore, the present invention provides a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease caused by and / or associated with a mutant IDH enzyme or hyperactivity of a wild-type IDH, the pharmaceutical composition comprising administering an effective amount of the compound of formula (I) to a mammal, preferably a human, in need of said treatment.

[0225] In yet another aspect, the present invention provides the use of a compound of formula (I) 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 hyperactivity of wild-type IDH, which comprises administering an effective amount of a compound of formula (I) above to a mammal, preferably a human, in need of said treatment.

[0226] The disease is preferably selected from the group consisting of cancer, cell proliferative disorders, and immune-related disorders, and more preferably cancer.

[0227] According to the most preferred embodiment of the present invention, the cancer is 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 such as leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, angioimmunoblastic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma; Myeloid hematopoietic tumors such as acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; mesenchymal cell-derived tumors such as fibrosarcoma and rhabdomyosarcoma; central and peripheral nervous system tumors such as glioma, glioblastoma, glioblastoma multiforme, astrocytoma, oligodendroglioma, paraganglioma, neuroblastoma, and schwannoma; and other tumors such as melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxantoma, thyroid cancers such as papillary thyroid carcinoma and medullary thyroid carcinoma, Kaposi's sarcoma, chondrosarcoma, and cholangiocarcinoma.

[0228] Other preferred diseases caused by and / or associated with mutant IDH enzymes or hyperfunction of wild-type IDH are cell proliferative diseases such as, for example, benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, and postoperative stenosis and restenosis.

[0229] Other preferred diseases caused by and / or associated with mutant IDH enzymes with elevated 2-hydroxyglutarate levels are, for example, Ollier disease or Maffucci syndrome.

[0230] Other preferred diseases caused by and / or associated with mutant IDH enzymes or wild-type IDH hyperfunction are immune-related diseases, including, but not limited to, transplant rejection, skin diseases such as psoriasis, allergies, asthma, and autoimmune 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 comprise treating the mammal in need thereof with a radiation or chemotherapy regimen in combination.

[0231] The present invention further provides a compound of formula (I) above or a pharmaceutically acceptable salt thereof for use in a method of treating a mammal in need thereof in combination with a radiotherapeutic or chemotherapy regimen.

[0232] In one embodiment, the chemotherapy regimen comprises at least one cytostatic or cytotoxic agent.

[0233] Cytostatic or cytotoxic agents include, but are not limited to, antibiotic-type agents, alkylating agents, antimetabolites, hormonal agents, immunological agents, interferon-type 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), farnesyltransferase inhibitors, ras-raf signaling pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, aromatase inhibitors, kinesin inhibitors, therapeutic monoclonal antibodies, mTOR inhibitors, histone deacetylase inhibitors, hypoxia response inhibitors, PD-1 antagonists, or antigen-binding fragments thereof that specifically bind to PD-1 or PD-L1.

[0234] If formulated as a fixed dose, such combination products utilize the compounds of this invention within the dosage ranges described below and the other pharmaceutically active agent within an accepted dosage range.

[0235] Compounds of formula (I) may also be used sequentially with known anti-cancer agents when a combination formulation is inappropriate.

[0236] Compounds of formula (I) of the present invention suitable for administration to mammals (e.g., humans) can be administered by any conventional route, with dosage levels varying depending on the age, weight and health condition of the patient and the route of administration.

[0237] For example, a suitable dosage adopted for oral administration of a compound of formula (I) can be about 10 to about 1000 mg per dose, 1 to 5 times per day. The compounds of the present invention can be administered in various dosage forms, for example, orally as tablets, capsules, sugar-coated tablets, film-coated tablets, solutions or suspensions, rectally as suppositories, or parenterally, for example, by intramuscular, intravenous and / or intrathecal and / or intraspinal injection or infusion.

[0238] Pharmaceutical compositions containing the compounds of the invention are normally prepared following conventional methods and administered in a suitable pharmaceutical form.

[0239] For example, oral solid dosage forms may contain, together with the active compound, diluents (e.g., lactose, dextrose, saccharose, sucrose, cellulose, corn starch, or potato starch); lubricants (e.g., silica, talc, stearic acid, magnesium stearate, calcium stearate, and / or polyethylene glycol); binders (e.g., starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone); disintegrating agents (e.g., starch, alginic acid, alginates, or sodium starch glycolate); effervescent mixtures; dyes; sweeteners; wetting agents (e.g., lecithin, polysorbates, lauryl sulfate); and non-toxic, pharmacologically inactive substances generally used in pharmaceutical preparations. These pharmaceutical preparations can be produced by known methods, for example, by mixing, granulating, tabletting, sugar-coating, or film-coating processes.

[0240] The liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions.

[0241] For example, syrups may contain sucrose or sucrose with glycerine and / or mannitol and sorbitol as bases.

[0242] The suspensions and the emulsions may contain, as examples of bases, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

[0243] Intramuscular injection suspensions or solutions may contain the active compound together with a pharmaceutically acceptable base such as sterile water, olive oil, ethyl oleate, glycols (e.g., propylene glycol), and, if desired, an appropriate amount of lidocaine hydrochloride.

[0244] Solutions for intravenous injection or infusion may contain sterile water as a base, or preferably in the form of sterile aqueous isotonic saline solutions, or may contain propylene glycol as a base.

[0245] The suppositories may contain, together with the active compound, a pharmaceutically acceptable base such as cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

[0246] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) above or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, carrier, or diluent.

[0247] The present invention further provides pharmaceutical compositions of compounds of Formula (I) further comprising one or more chemotherapeutic agents, including, but not limited to, cytostatic or cytotoxic agents, antibiotic-type agents, alkylating agents, antimetabolites, hormonal agents, immunological agents, interferon-type 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), farnesyltransferase inhibitors, ras-raf signaling pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, aromatase inhibitors, kinesin inhibitors, therapeutic monoclonal antibodies, mTOR inhibitors, histone deacetylase inhibitors, hypoxia response inhibitors, PD-1 antagonists, or antigen-binding fragments thereof that specifically bind to PD-1 or PD-L1.

[0248] Furthermore, the present invention provides an in vitro method for inhibiting the activity of a mutant IDH protein, which comprises contacting said protein with an effective amount of a compound of formula (I) above.

[0249] The present invention also provides a product comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anti-cancer therapy.

[0250] In yet another aspect, the present invention provides a compound of formula (I) above or a pharmaceutically acceptable salt thereof for use in a medicine.

[0251] Finally, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament having anti-cancer activity.

[0252] Experimental Section The abbreviations used in this application have the following meanings:

[0253] [Table 1]

[0254] Biochemical assays IDH1m (R132H or R132C) and IDH2 R172K In vitro assay of inhibitors The NADPH depletion assay measures the activity of IDH mutant enzymes in converting α-ketoglutarate to 2-hydroxyglutarate. In this assay, catalytic excesses of diaphorase and resazurin are added, generating a fluorescent signal proportional to the amount of NADPH remaining, and measuring the amount of cofactor remaining at the end of the reaction. The IDH1 wild-type enzyme and the mutant isoform IDH1 R132H 、 IDH1 R132C , and IDH2 R172K The enzymes are commercially available proteins (see, for example, Sino Biological, Abcam, Active Motif or Creative BioMart).

[0255] IDH1 R132H The homodimeric enzyme was 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 test compound, previously diluted 1-3 times in DMSO starting from 1 mM with >10 experimental points, was added and the mixture was incubated for 15 min at room temperature. The reaction was initiated by adding 10 μL of substrate mix (12 μM NADPH, 3.4 mM α-ketoglutarate in assay buffer). The mixture was incubated for 60 min at room temperature. The reaction was terminated by adding 5 μL of detection buffer (100 μg / mL diaphorase, 30 μM resazurin in 1x assay buffer). After 15 min of incubation, the plate was read on an Ex544 / Em590 plate reader using a ViewLux.

[0256] IDH1 in assay buffer R132CIDH1 was assayed according to the same assay as above, except that the final concentrations of α-ketoglutarate and α-ketoglutarate were 2 nM and 0.14 mM, respectively. R132C Compounds are assayed for activity against

[0257] IDH2 in assay buffer R172K The same assay as above was followed, except that the final concentrations of IDH2 and α-ketoglutarate were 16 nM and 0.55 mM, respectively. R172K Compounds are assayed for activity against

[0258] Enzyme assay of wild-type (wt) IDH1 An NADPH formation assay is used to measure the activity of the IDH1WT enzyme, which converts isocitrate to α-ketoglutarate. In this assay, catalytic excesses of diaphorase and resazurin are added to generate a fluorescent signal proportional to the amount of NADPH formed, thereby measuring the amount of cofactor formed.

[0259] After preincubation of the compounds with the enzyme, NADP + The reaction was initiated by adding isocitrate, diaphorase, and the corresponding substrate, resazurin. Diaphorase reduces resazurin to highly fluorescent resorufin while simultaneously oxidizing NADPH to NADP. Specifically, the IDH1WT enzyme was prepared at 0.016 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 test compound, previously diluted 1-3 times in DMSO starting from 1 mM in 10 experimental points, was added, and the mixture was incubated at room temperature for 15 min. The substrate mixture (400 μM NADP in assay buffer) was added. + The reaction is initiated by adding 10 μL of a 500 μL buffer (40 μM isocitrate, 5 μg / mL diaphorase, and 7 μM resazurin), the mixture is incubated at room temperature, and the reaction is read continuously at Ex544 / Em590 using a ViewLux as a plate reader.

[0260] biochemical activity Mutant IDH1 R132H , IDH1 R132C and IDH2 R172K The biochemical potency of representative compounds against β-glucan was determined according to the above assay and is shown in Table 1. 50 The biochemical potency against wild-type IDH1 enzyme was measured according to the assay described above and is reported as IC values ​​(μM) in Table 2. 50 Values ​​are reported as μM.

[0261] [Table 2] TIFF0007744336000067.tif84166

[0262] [Table 3]

[0263] Cellular assay of IDHm inhibitors The cell line HT-1080 (commercially available) is maintained in E-MEM supplemented with 10% FCS and incubated at 37°C in a humidified 5% CO2 atmosphere.

[0264] Cells were seeded at a density of 500 cells / well in 100 μL of complete medium in a 96-well black flat-bottom plate. After 24 hours, the medium was replaced with 200 μL of fresh medium and compounds (dissolved in DMSO) were administered to the cells using a D300E digital dispenser (Tecan).

[0265] After 72 hours of incubation, 100 uL of the solution was removed from each well and used for 2HG (R(-)-2-hydroxyglutaric acid) quantification.

[0266] The concentration of 2-HG in cell culture medium was measured by LC-MS / MS. Cell supernatants (100 μL / well) were treated with 1 M aqueous trichloroacetic acid supplemented with 130 μM internal standard 2-HG-d3 (20 μL / well) in a 96-well plate. The plate was sealed, gently vortexed for 60 minutes, centrifuged at 4,000 RPM for 15 minutes, and then placed in a refrigerated autosampler, taking care to avoid shaking. An aliquot of the top portion of the sample was injected directly into the chromatography system. Calibration standards were obtained by diluting the 2-HG stock solution 10-fold with blank cell culture medium and denaturing it exactly 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% formic acid, with a brief wash at the end of the run with 90% methanol. 2-HG is determined by negative ion electrospray ionization using an internal standard on a triple quadrupole mass spectrometer monitoring the MRM transitions 147>129 (2-HG) and 150>132 (2-HG-d3).

[0267] The 2-HG inhibition rate was calculated by comparing the data from the treated and control groups using Assay Explore (Symyx) software, and the IC50 was determined using a sigmoidal fitting algorithm.

[0268] Cell line HT-1080(IDH1 R132C IC of representative compounds for inhibition of 2HG production in 50 Values ​​(μM) were determined according to the above assay and are reported in Table 3.

[0269] [Table 4]

[0270] Representative compounds of the present invention were tested in cell lines with mutant IDH1 and showed dose-dependent inhibition of cellular production of 2-HG at potencies below 5 μM, as reported in Table 3. As expected, these compounds also showed some effect on cell proliferation at the highest dose (10 μM).

[0271] Preparation of Compounds of Formula (I) For specific compounds of formula (I) of the present invention, optionally in the form of a pharmaceutically acceptable salt, see the experimental section and claims. In the following examples, compounds of the present invention were synthesized using methods described herein or other methods known in the art.

[0272] The following examples are intended to more clearly illustrate the present invention and are not intended to limit the present invention.

[0273] The symbols and notations used in the methods, schemes, and examples herein correspond to those used in the current scientific literature (e.g., Journal of the American Chemical Society or Journal of Biological Chemistry).

[0274] The compound names are IUPAC names created by using ACD Name (a product of Advanced Chemistry Development, Inc.).

[0275] Unless otherwise specified, all materials, including anhydrous solvents such as DMF, THF, DCM, etc., were obtained from commercial suppliers of the best grade and used without further purification. All reactions involving air- or moisture-sensitive compounds were carried out under a nitrogen or argon atmosphere.

[0276] General purification and analysis methods Flash chromatography was performed on silica gel (Merck grade 9395, 60A).

[0277] The HPLC system consisted of a Waters Alliance™ HT2795 system equipped with a Waters 996 PDA detector and a Waters mod. ZQ 2000 single quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source. Instrument control, data acquisition, and data processing were performed using Empower 2 and MassLynx 4.1 software.

[0278] HPLC was performed using a YMC-Triart C18 (4.6 × 50 mm, 3 μm) column at 25 °C with a flow rate of 1.2 mL / min. Mobile phase B was a mixture of 5 mM ammonium acetate buffer (pH = 5.2) and acetonitrile (95:5), and mobile phase C was H2O / acetonitrile (5:95). The gradient was 10 to 90% C over 5 min, then gradually increased to 100% C over 0.1 min. The injection volume was 10 μL. The mass spectrometer was operated in positive and negative ion modes, with a capillary voltage of 3.5 kV (ES + ) and 2.8kV(ES - ) and the cone voltage is set to 14V (ES + ) and 28V(ES - ), the ion source temperature was set to 120°C, and the full scan mass range was set to 100 to 800 amu.

[0279] The preparative HPLC system consisted of a Shimadzu HPLC system equipped with an SCL-8A system controller, two LC-8A pumps, an SPD-6A UV spectrophotometer, and a manual Rheodyne injection system. Data acquisition (analog signal) and data processing were performed using Empower 2 software. Purification was performed using a Waters X-Terra MS RP18 (150 × 30 mm, 10 μm) column at 25 °C with a flow rate of 15 mL / min. Mobile phase A was water / acetonitrile (95:5) supplemented with 0.1% TFA, or mobile phase A was water / acetonitrile (95:5) supplemented with 0.05% NH3, and mobile phase B was HO / acetonitrile (5:95). The gradient was 10 to 90% B over 15 min, gradually increasing to 100% B over 0.1 min. The maximum injection volume was 500 μL.

[0280] It operates at 400.5MHz and has a 5mm 1 H{ 15 N- 31 P} A Varian INOVA 400 spectrometer equipped with a z-axis PFG indirect detection probe, operating at 499.7 MHz and measuring 5 mm 1 H{ 13 C- 15 A Varian INOVA 500 spectrometer equipped with a {N} triple resonance indirect detection probe was used at a constant temperature of 28°C. 1 H-NMR spectra were recorded. Chemical shifts were referenced to residual signals in the solvent (2.50 ppm in DMSO-d6). 1 H as the reference. Data are reported as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br.s = broad singlet, dd = doublet of doublet, ddd = doublet of doublet of doublet, m = multiplet), coupling constant (J, Hz) and number of protons.

[0281] As previously reported (M. Colombo, FR Sirtori, V. Rizzo, Rapid Commun Mass Spectrom 2004, 18(4), 511-517), ESI(+) high-resolution mass spectra (HRMS) were acquired on a Q-Tof Ultima (Waters, Manchester, UK) mass spectrometer directly connected to an Agilent 1100 micro HPLC system (Palo Alto, US).

[0282] Manufacturing Example 1 Ethyl 2-(methylsulfanyl)-4-(propan-2-ylamino)pyrimidine-5-carboxylate [(IX), R2 = propan-2-yl, R3 = H] (Steps 3a and 4a)

[0283] [ka]

[0284] Commercially available 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester (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. The mixture was stirred at room temperature for 3 h. The precipitated salt was filtered, washed with EtOAc, and the solvent was evaporated under reduced pressure. The resulting oil was dissolved in EtO, washed with NH Cl, and then dried over Na SO . The salt was filtered and the solvent was evaporated under reduced pressure to give the product (7.0 g, 53% yield), which was used without further purification. 1 H NMR(500MHz,DMSO-d6)δ=8.55(s,1H),8.09(d,J=7.32Hz,1H),4.31-4.37(m,1 H),4.25-4.30(m,2H),2.48(s,3H),1.27-1.32(m,3H),1.23(d,J=6.56Hz,6H). HRMS(ESI)C 11 H 16 ClN2O2[M+H] + Calculated value: 243.0895, measured value: 243.0901.

[0285] Following the same method, the following compounds were prepared:

[0286] 6-Chloro-4-ethylaminonicotinic acid ethyl ester [(XVII), R2 = ethyl, X = CH]

[0287] [ka]

[0288] The title compound was obtained as a pale yellow oil (80% yield). 1 H NMR(DMSO-d6)δ=8.52(s,1H),8.05(t,J=5.2Hz,1H),6.80(s,1H),4.29(q,J= 7.2Hz, 2H), 3.25-3.32 (m, 2H), 1.31 (t, J=7.1Hz, 3H), 1.17 (t, J=7.2Hz, 3H). LCMS:m / z229[M+H] + @rt6.27 minutes. HRMS(ESI)C 10 H 14 ClN2O2[M+H] + Calculated value 229.0739, measured value 229.0745.

[0289] 6-Chloro-4-isopropylaminonicotinic acid ethyl ester [(XVII), R2 = propan-2-yl, X = CH]

[0290] [ka]

[0291] 1 H NMR(DMSO-d6)δ=8.53(s,1H),7.98(d,J=7.9Hz,1H),6.84(s,1H),4.29(q,J= 7.1Hz, 2H), 3.80-3.93 (m, 1H), 1.31 (t, J = 7.1Hz, 3H), 1.19 (d, J = 6.4Hz, 6H). LCMS:m / z243[M+H] + @rt6.72 minutes.

[0292] Manufacturing Example 2 [2-(methylsulfanyl)-4-(propan-2-ylamino)pyrimidin-5-yl]methanol [(X), R2 = propan-2-ylamino, R3 = H] (Steps 3b and 4b)

[0293] [ka]

[0294] To a solution of ethyl 2-(methylsulfanyl)-4-(propan-2-ylamino)pyrimidine-5-carboxylate (7 g, 27.4 mmol) in THF (70 mL) was added LiAlH (4% solution in THF, 29 mL) over 15 min at -5 °C. The cooling bath was removed, and the mixture was allowed to warm to room temperature and then stirred for 2 h. The mixture was then cooled to 0 °C, and saturated NaHCO solution (31 mL) was added slowly (exothermic reaction). After 30 min, the quenched reaction mixture was filtered, and the filter cake was washed with AcOEt (50 mL). The combined organic solvent washes were dried over NaSO and filtered. The solvent was evaporated under reduced pressure to give the product (5.84 g, 96% yield), which was used without further purification.

[0295] The following compounds are prepared by essentially the same preparative method:

[0296] (6-chloro-4-ethylaminopyridin-3-yl)-methanol [(XVIII), R = ethyl, X = CH]

[0297] [ka]

[0298] 1H NMR(DMSO-d6)δ=7.77(s,1H),6.49(s,1H),6.11(t,J=5.1Hz,1H),5.18(t,J=5.4H z,1H),4.37(d,J=5.3Hz,2H),3.17(qd,J=7.1,5.7Hz,2H),1.15(t,J=7.2Hz,3H). LCMS:m / z187[M+H] + @rt4.06 minutes. HRMS(ESI)C8H 12 NOCl[M+H] + Calculated value: 187.0633, measured value: 187.0638.

[0299] (6-chloro-4-isopropylaminopyridin-3-yl)-methanol [(XVIII), R = propan-2-yl, X = CH]

[0300] [ka]

[0301] 1 H NMR(DMSO-d6)δ=7.76(s,1H),6.53(s,1H),5.81(d,J=7.8Hz,1H),5.24(t,J= 5.4Hz, 1H), 4.38 (d, J=5.2Hz, 2H), 3.65-3.77 (m, 1H), 1.16 (d, J=6.4Hz, 6H). LCMS:m / z201[M+H] + @rt2.74min. HRMS(ESI)C9H 14 ClNO[M+H] + Calculated value 201.0789, measured value 201.0787.

[0302] Manufacturing Example 3 2-(Methylsulfanyl)-4-(propan-2-ylamino)pyrimidine-5-carbaldehyde [(XI), R2 = 2,2-dimethylpropyl, R3 = H] (Steps 3c and 4c)

[0303] [ka]

[0304] [2-(Methylsulfanyl)-4-(propan-2-ylamino)pyrimidin-5-yl]methanol (5.3 g, 24.84 mmol) was dissolved in DCM (120 mL) and MnO (17.27 g, 198.7 mmol) preactivated in an oven at 50 °C for 4 h was added. The resulting suspension was stirred overnight. The solid was filtered off through a pad of Celite, washed with DCM, and the solvent was evaporated under reduced pressure. The crude product was purified on a silica gel column eluting with n-Hex / EtOAc 9 / 1 to give the title product (4.08 g, 78% yield). 1 H NMR (500MHz, DMSO-d6) δ=9.74(s,1H),8.53(s,1H),8.45(d,J=7.32Hz,1H),4.28-4.44(m,1H),2.50(s,3H),1.24(d,J=6.56Hz,6H). LCMS:m / z212[M+H] + @rt5.9 minutes. HRMS(ESI)C9H 14 N3OS[M+H] + Calculated value 212.0852, actual value 212.0856.

[0305] Following the same method, the following compounds were prepared:

[0306] 2-Chloro-4-(propan-2-ylamino)pyrimidine-5-carbaldehyde [(XIX), X = N, R2 = propan-2-yl]

[0307] [ka]

[0308] LCMS: m / z 200 [M+H] + @rt4.87 minutes.

[0309] 6-Chloro-4-ethylaminopyridine-3-carbaldehyde [(XIX), R2 = propan-2-yl, X = CH]

[0310] [ka]

[0311] 1 H NMR(DMSO-d6)δ=9.86(d,J=0.6Hz,1H),8.56(t,J=4.7Hz,1H),8.44(s,1H),6.85(s,1H),3.34(s,2H),1.17(t,J=7.2Hz,3H). LCMS:m / z185[M+H] + @rt4.89 minutes. HRMS(ESI)C8H 10 ClNO[M+H] + Calculated value: 185.0476, measured value: 185.0481.

[0312] 6-Chloro-4-isopropylaminopyridine-3-carbaldehyde [(XIX), R2 = propan-2-yl, X = CH]

[0313] [ka]

[0314] 1 H NMR(DMSO-d6)δ=9.85(d,J=0.5Hz,1H),8.40-8.49(m,2H),6.90(s,1H),3.90(dt,J=7.9,6.5Hz,1H),1.20(d,J=6.4Hz,6H). LCMS:m / z199[M+H] + @rt7.84 minutes. HRMS(ESI)C9H 12 ClNO[M+H] + Calculated value: 199.0633, measured value: 199.0632.

[0315] Manufacturing Example 4 2-(methylsulfanyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U=Y=CH, X=N,

[0316] [ka] , R2 = propan-2-yl, R3 = H] (Steps 3d and 4d)

[0317] [ka]

[0318] LiHMDS (47 mL in 1M THF, 47 mmol) was added to THF (78 mL) at −78 °C and treated with EtOAc (5.8 mL, 53.92 mmol). After stirring the solution at −78 °C for 10 min, solid 2-(methylsulfanyl)-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 allowed to warm to room temperature over 2 h and stirred at room temperature for an additional 4 h. The reaction was cooled in an ice bath, quenched with saturated NH4Cl solution (60 mL), extracted with EtOAc (2 × 1 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (2.8 g) as an off-white solid. 1 H NMR (500MHz, DMSO-d6) δ=8.86(s,1H),7.88(d,J=9.46Hz,1H),6.57(d,J=9.46Hz,1H),5.68(br.s.,1H),2.60(s,3H),1.54(d,J=7.02Hz,6H). LCMS:m / z236[M+H] + @rt9.10 minutes. HRMS(ESI)C 11 H 14 N3OS[M+H] + Calculated value 236.0852, measured value 236.0861.

[0319] Following the same method, the following compounds were prepared:

[0320] 2-chloro-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(IV), U=Y=CH, X=N,

[0321] [ka] , R2=propan-2-yl, R3=H, G=Cl]

[0322] [ka] LCMS: m / z 224 [M+H] + @rt4.26 minutes.

[0323] 7-chloro-1-ethyl-1H-[1,6]naphthyridin-2-one [(IV), U=Y=CH, X=CH,

[0324] [ka] , R2=ethyl, R3=H, G=Cl]

[0325] [ka]

[0326] 1 H NMR(500MHz,DMSO-d6)δ=8.74(s,1H),8.02(d,J=9.6Hz,1H),7.69(s,1H),6.71(d,J=9.6Hz,1H),4.21(q,J=7.2Hz,2H),1.17(t,J=7.2Hz,3H). LCMS:m / z209[M+H] + @rt4.28 minutes. HRMS(ESI)C 10 H 10 ClNO[M+H] + Calculated value 209.0476, measured value 209.0485.

[0327] 7-Chloro-1-isopropyl-1H-[1,6]naphthyridin-2-one [(IV), U=Y=CH, X=CH,

[0328] [ka] , R2=propan-2-yl, R3=H, G=Cl]

[0329] [ka]

[0330] 1 H NMR (500MHz, DMSO-d6) δ=8.71(s,1H),7.96(d,J=9.5Hz,1H),7.79(br.s.,1H),6.63(d,J=9.5Hz,1H),5.14(br.s.,1H),1.50(d,J=6.9Hz,6H). LCMS:m / z223[M+H] + @rt7.11 minutes. HRMS(ESI)C 11 H 12 ClNO[M+H] + Calculated value 223.0633, actual value 223.0633.

[0331] Production Example 5 2-(methylsulfanyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U=Y=CH, X=N,

[0332] [ka] , R2 = propan-2-yl, R3 = H] (Step 3g)

[0333] [ka]

[0334] A mixture of 2-(methylsulfanyl)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 to 70° C. in a sealed tube 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 H NMR(401MHz,DMSO-d6)δ=8.85(s,1H),7.87(d,J=9.52Hz,1H),6.57(d,J=9.40 Hz,1H),5.69(td,J=6.93,13.73Hz,1H),2.60(s,3H),1.54(d,J=6.96Hz,6H). LCMS:m / z236[M+H] + rt5.53 minutes. HRMS(ESI)C 11 H 14 N3OS[M+H] + Calculated value 236.0852, measured value 236.0861.

[0335] Following the same method, the following compounds were prepared:

[0336] 8-Ethyl-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U=Y=CH, X=N,

[0337] [ka] , R2=ethyl, R3=H]

[0338] [ka]

[0339] 1 H NMR (401MHz, DMSO-d6)δ=8.88(s,1H),7.93(d,J=9.40Hz,1H),6.62(d,J=9.52Hz,1H),4.32(q,J=7.04Hz,2H),2.60(s,3H),1.22(t,J=7.02Hz,3H). LCMS:m / z222[M+H] + rt4.95 minutes. HRMS(ESI)C 10 H 12 N3OS[M+H] + Calculated value 222.0696, actual value 222.07.

[0340] 4-Methyl-2-(methylsulfanyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U=Y=CH, X=N,

[0341] [ka] , R2=propan-2-yl, R3=methyl]

[0342] [ka]

[0343] 1 H NMR (500MHz, DMSO-d6) δ=8.04(d,J=9.61Hz,1H),6.54(d,J=9.46Hz,1H),5.73(br.s,1H),2.61-2.64(m,3H),2.58(s,3H),1.54(d,J=6.86Hz,6H). LCMS:m / z250[M+H] + rt5.85 mins.

[0344] 1-Ethyl-7-(methylsulfanyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one [(XII), U=CH2, Y=O, X=N,

[0345] [ka] , R2=ethyl, R3=H]

[0346] [ka]

[0347] 1 H NMR (500MHz, DMSO-d6) δ=8.33(s,1H),5.30(d,J=0.61Hz,2H),3.94(q,J=7.02Hz,2H),2.51(br.s.,3H),1.19(t,J=7.02Hz,3H).

[0348] 5-Methyl-2-(methylsulfanyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U = CMe, Y = CH, X = N,

[0349] [ka] , R2=propan-2-yl, R3=H]

[0350] [ka]

[0351] 1 H NMR (500MHz, DMSO-d6) δ=8.90(s,1H),6.44(s,1H),5.67(br.s.,1H),2.60(s,3H),2.40(d,J=1.22Hz,3H),1.53(d,J=7.02Hz,6H). LCMS:m / z250[M+H] + @rt6.67 minutes. HRMS(ESI)C 12 H 16 N3OS[M+H] + Calculated value 250.1009, measured value 250.101.

[0352] Manufacturing Example 6 2-(methylsulfanyl)-7-oxo-8-(2,2 dimethylpropyl)-7,8-dihydropyrido[2,3-d]pyrimidine-4-carbonitrile [(XII), U=Y=CH, X=N,

[0353] [ka] , R2 = 2,2-dimethylpropyl, R3 = CN] (Transformation A)

[0354] [ka]

[0355] 4-Chloro-8-(2,2-dimethylpropyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (60 mg, 0.2 mmol) was dissolved in DMSO (4.5 mL), triethylamine (300 μL) and NaCN (18 mg, 0.2 mmol) were added, and the mixture was stirred at 50 °C for 1 h. 10 mL of water was then added, followed by extraction with AcOEt twice. The organic phase was washed with brine and then dried over NaSO. The salts were filtered, and the solvent was evaporated under reduced pressure. The crude product was purified on a SiO chromatography column using hexane / AcOEt 8 / 2 as the eluent to give the product (12 mg, 20% yield). 1 H NMR (500MHz, DMSO-d6) δ=7.94(d,J=9.61Hz,1H),6.83(d,J=9.61Hz,1H),4.28(br.s.,2H),2.63(s,3H),0.91(s,3H). LCMS:m / z289[M+H] + @rt7.09 minutes. HRMS(ESI)C 14 H 17 N4OS[M+H] + Calculated value: 289.1118, measured value: 289.1122.

[0356] Manufacturing Example 7 4-[(2,4-dimethoxybenzyl)amino]-2-(methylsulfanyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U=Y=CH, X=N,

[0357] [ka] , R2 = propan-2-yl, R3 = NH-2,4-dimethoxybenzyl] (Transformation B)

[0358] [ka]

[0359] To a solution of 4-chloro-8-isopropyl-2-methylsulfanyl-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 to 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). 1 H NMR(500MHz,DMSO-d6)δ=8.37(t,J=5.57Hz,1H),8.11(d,J=9.61Hz,1H),7.08(d,J=8.24Hz,1H),6.56(d,J=2.29Hz,1H),6.46(dd,J=2.29,8 .39Hz,1H),6.32(d,J=9.46Hz,1H),5.70(br.s.,1H),4.55(d,J=5.64Hz,2H),3.80(s,3H),3.73(s,3H),2.44(s,3H),1.49(d,J=6.86Hz,6H). LCMS:m / z423[M+Na] + @rt3.43 min. HRMS(ESI)C 20 H 25 N4NaO4S[M+Na] + Calculated value: 423.1440, measured value: 423.1444.

[0360] Manufacturing Example 8 4-(methylamino)-2-(methylsulfanyl)-8-(2,2-dimethylpropyl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U=Y=CH, X=N,

[0361] [ka] , R2 = 2,2-dimethylpropyl, R3 = NHMe, R4 = R5 = H] (Conversion C)

[0362] [ka]

[0363] 4-Chloro-8-(2,2-dimethylpropyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (40 mg, 0.13 mmol) was dissolved in THF (4 mL) and 1.0 M methylamine in EtOH (100 μL) was added and stirred at room temperature for 12 h. Then, 10 mL of water was added and extracted twice with AcOEt. The organic phase was washed with brine and then dried over NaSO. The salts were filtered, and the solvent was evaporated under reduced pressure. The crude product was purified on a SiO chromatography column using DCM / MeOH 98 / 2 as the eluent to give the product (33 mg, 85% yield). 1 H NMR(500MHz,DMSO-d6)δ=8.11(q,J=4.02Hz,1H),8.01(d,J=9.61Hz,1H),6.39(d,J =9.61Hz,1H),4.27(br.s.,2H),2.93(d,J=4.42Hz,3H),2.52(s,3H),0.89(s,9H). LCMS:m / z293[M+H] + @rt6.63 minutes. HRMS(ESI)C 14 H 21 N4OS[M+H] + Calculated value: 293.1431, measured value: 293.1436.

[0364] Following the same method, the following compounds were prepared:

[0365] 4-(dimethylamino)-2-(methylsulfanyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(XII), U=Y=CH, X=N,

[0366] [ka] , R2 = propan-2-yl, R3 = N(Me)2]

[0367] [ka]

[0368] 1 H NMR (500MHz, DMSO-d6) δ=7.93(d,J=9.76Hz,1H),6.25(d,J=9.76Hz,1H),5.72(br.s.,1H),3.21(s,6H),2.50(s,3H),1.50(d,J=7.02Hz,6H). LCMS:m / z279[M+H] + @rt6.48 minutes. HRMS(ESI)C 13 H 19 N4OS[M+H] + Calculated value: 279.1274, measured value: 279.1276.

[0369] Manufacturing Example 9 2-(methylsulfonyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(IV), U=Y=CH, X=N,

[0370] [ka] , R2 = propan-2-yl, R3 = H, G = MeS(O)2-] (Step 3e)

[0371] [ka]

[0372] 2-(Methylsulfanyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (3.1 mg, 13.17 mmol) was dissolved in 62 mL of DCM. To this solution was added 55% m-CPBA (10.32 g, 32.93 mmol) with stirring. The reaction was stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete. The sample was diluted with 50 mL of DCM and washed twice with saturated NaHCO (170 mL), followed by two 50 mL washes and then brine (50 mL). The organic phase was separated, dried over NaSO, filtered, and concentrated under reduced pressure. Purification on a chromatography column eluted with 100:1 EtOAc / acetone afforded the title compound 2-(methylsulfonyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one as an off-white solid (2.29 mg, 65% yield). 1 H NMR(500MHz,DMSO-d6)δ=9.27(s,1H),8.07(d,J=9.46Hz,1H),6.88(d,J=9.46Hz,1H),5.65(spt,J=6.80Hz,1H),3.46(s,3H),1.56(d,J=7.02Hz,6H). LCMS:m / z268[M+H] + @rt4.48 minutes. HRMS(ESI)C 11 H 13 N3O3S[M+H] + Calculated value: 268.0751, measured value: 268.0746.

[0373] Following the same method, the following compounds were prepared:

[0374] 8-Ethyl-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one [(IV), U=Y=CH, X=N,

[0375] [ka] , R2 = ethyl, R3 = H, G = MeS(O)2-]

[0376] [ka]

[0377] 1 H NMR(500MHz,DMSO-d6)δ=9.30(s,1H),8.12(d,J=9.61Hz,1H),6.93(d,J=9.46Hz,1H),4.35(q,J=7.02Hz,2H),3.48(s,3H),1.24(t,J=7.09Hz,3H). LCMS:m / z254[M+H] + @rt 3.53 min. HRMS(ESI)C 10 H 11 N3O3S[M+H] + Calculated value 254.0594, measured value 254.0595.

[0378] 4-Methyl-2-(methylsulfonyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(IV), U=Y=CH, X=N,

[0379] [ka] , R2 = propan-2-yl, R3 = methyl, G = MeS(O)2-]

[0380] [ka]

[0381] 1 H NMR (500MHz, DMSO-d6) δ=8.22(d,J=9.76Hz,1H),6.84(d,J=9.76Hz,1H),5.59-5.77(m,1H),3.44(s,3H),2.81(s,3H),1.55(d,J=7.02Hz,6H). LCMS:m / z282[M+H] + rt4.34 minutes.

[0382] 5-Methyl-2-(methylsulfonyl)-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [(IV), U = CMe, Y = CH, X = N,

[0383] [ka] , R2=propan-2-yl, R3=H, G=MeS(O)2-]

[0384] [ka]

[0385] 1 H NMR (500MHz, DMSO-d6) δ=8.90(s,1H),6.44(s,1H),5.67(br.s.,1H),2.60(s,3H),2.40(d,J=1.22Hz,3H),1.53(d,J=7.02Hz,6H). LCMS:m / z282[M+H] + @rt4.73 minutes. HRMS(ESI)C 12 H 16 N3O3S[M+H] + Calculated value 282.0907, measured value 282.0907.

[0386] 1-Ethyl-7-(methylsulfonyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one [(IV), U=CH2, Y=O, X=N,

[0387] [ka] , R2 = ethyl, R3 = H, G = MeS(O)2-]

[0388] [ka]

[0389] 1H NMR (500MHz, DMSO-d6) δ=8.68(s,1H),5.48(d,J=0.61Hz,2H),3.99(q,J=7.02Hz,2H),3.41(s,3H),1.22(t,J=7.02Hz,3H). LCMS:m / z258[M+H] + @rt 3.43 min. HRMS(ESI)C9H 11 N3O4S[M+H] + Calculated value: 258.0543, measured value: 258.054.

[0390] 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,

[0391] [ka] , R2 = propan-2-yl, R3 = 4-[(2,4-dimethoxybenzyl)amino], G = MeSO)-]

[0392] [ka]

[0393] NMR(500MHz,DMSO-d6)δ=8.74(t,J=5.57Hz,1H),8.22(d,J=9.76Hz,1H),7.16(d,J=8.24Hz,1H),6.56(d,J=2.44Hz,1H),6.53(d,J=9.6 1Hz,1H),6.45(dd,J=2.36,8.31Hz,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=7.02Hz,6H). LCMS:m / z258[M+H] + @rt3.43 min. HRMS(ESI)C 20 H 25 N4NaO4S[M+Na] + Calculated value: 423.1440, measured value: 423.1444.

[0394] Manufacturing Example 10 7-Oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl trifluoromethanesulfonate [(IV), U=Y=CH, X=N,

[0395] [ka] , R2 = propan-2-yl, R3 = H, G = O-triflate] (Transformation A1)

[0396] [ka]

[0397] Step 1: 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 1N NaOH (37.4 mL, 37.4 mmol) at room temperature. The mixture was stirred at 40°C for 1 hour. The mixture was allowed to cool to room temperature and diluted with DCM (80 mL). The aqueous phase was separated and saved. The organic phase was washed with 0.5 M NaOH (20 mL) and the aqueous phase was added to it. The aqueous solution was acidified with 1N HCl and partitioned between DCM / i-pr-OH solution (4 x 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%). 1 H NMR (500MHz, DMSO-d6) δ=12.26(br.s.,1H),8.46(s,1H),7.58(d,J=9.46Hz,1H),6.17(d,J=9.46Hz,1H),5.59(br.s.,1H),1.44(d,J=7.02Hz,6H). LCMS:m / z204[MH] - .

[0398] Step 2: 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 anhydrous DCM (78 mL) was added 2,6-lutidine (2.65 mL, 22.8 mmol, 1.2 equiv.) under a nitrogen atmosphere at 2 °C (internal temperature). Next, triflic anhydride (3.83 mL, 22.8 mmol, 1.2 equiv.) was added dropwise over 5 min while maintaining the internal temperature between 2 and 10 °C. The reaction was complete after 1 h and diluted with DCM and water. The organic phase was separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (DCM:EA = 99 / 1 to 97.5 / 2.5) to afford the title compound (5.53 g, 86% yield) as an off-white solid. 1 H NMR (500MHz, DMSO-d6) δ=9.16(s,1H),8.4(d,J=9.46Hz,1H),6.80(d,J=9.46Hz,1H),5.52(m,1H),1.52(d,J=7.02Hz,6H). LCMS:m / z338[M+H] + . HRMS(ESI)C 11 H 11 F3N3O4S[M+H] + Calculated value: 338.0417, measured value: 338.0412.

[0399] Manufacturing Example 11 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 = phenylcarboxylate] (Steps 5a to 5e)

[0400] [ka]

[0401] Step 1: Synthesis of 4-(4-bromophenyl)tetrahydro-2H-pyran-4-carboxylic acid

[0402] [ka]

[0403] To a solution of ethyl 4-(4-bromophenyl)tetrahydro-2H-pyran-4-carboxylate (383.2 g, 1.22 mol) in THF / MeOH / HO (1 L / 1 L / 1 L) was added LiOH.HO (308.5 g, 7.35 mol). The mixture was stirred at 30 °C for 2 days. Most of the solvent was removed under reduced pressure, and the mixture was adjusted to pH = 2 with 2 N HCl solution and partitioned with EtOAc (2 L). Removal of the solvent under reduced pressure gave 4-(4-bromophenyl)tetrahydro-2H-pyran-4-carboxylic acid (314 g, 90% yield) as a white solid. 1 HNMR(400MHz,DMSO-d6)δ=12.77(s,1H),7.60-7.58(d,J=10.8Hz,2H),7.40-7.37(d,J=10.8H z,2H),3.85-3.76(m,2H),3.51-3.38(m,2H),1.94-1.84(t,J=21.0Hz,2H),1.27-1.09(m,2H).

[0404] Following the same method, the following compounds were prepared:

[0405] 1-(4-Bromophenyl)cyclopentanecarboxylic acid

[0406] [ka]

[0407] 1 HNMR (500MHz, DMSO-d6) δ = 12.37 (br.s., 1H), 7.50-7.52 (m, 2H), 7.27-7.32 (m, 2H), 1.51-1.86 (m, 6H).

[0408] 1-(4-Bromophenyl)cyclohexanecarboxylic acid

[0409] [ka]

[0410] 1 HNMR(500MHz,DMSO-d6)δ=12.47(br.s.,1H),7.51-7.57(m,2H),7.28-7.37(m,2H) ,2.29(d,J=12.81Hz,2H),1.51-1.73(m,5H),1.34-1.47(m,2H),1.16-1.30(m,1H).

[0411] 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]

[0412] [ka]

[0413] 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 under reduced pressure. The crude product was suspended in 3.2 L of HCl (20% aqueous solution) and refluxed for 3 h. Toluene was added to the cooled solution, and the azeotrope was evaporated. After dilution with EtOAc and saturated NaHCO₃, the organic phase was separated, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography using DCM / EtOH=50 / 1 to 30 / 1 to give 4-(4-bromophenyl)tetrahydro-2H-pyran-4-amine (215.6 g, 76% yield) as a pale yellow solid. 1 H-NMR(400MHz, CDCl3)δ=7.49-7.47(d,J=8.4Hz,2H),7.37-7.34(d,J=8.4Hz,2H),3. 94-3.88(m,2H),3.82-3.77(m,2H),2.18-2.11(m,2H),1.63-1.60(d,J=12.8Hz,2H).

[0414] Following the same method, the following compounds were prepared:

[0415] 1-(4-Bromophenyl)cyclopentanamine [(XXI), W1 = Br, A = phenyl, R4 = H, R5a and R5b = cyclopentan-3-yl]

[0416] [ka]

[0417] 1 HNMR (500MHz, DMSO-d6) δ = 7.44 (d, J = 2.29Hz, 4H), 1.57-1.93 (m, 10H).

[0418] 1-(4-Bromophenyl)cyclohexanamine [(XXI), W1 = Br, A = phenyl, R4 = H, R5a and R5b = cyclohexyl]

[0419] [ka]

[0420] 1 HNMR(500MHz,DMSO-d6)δ=7.42(dd,J=8.42,2.29Hz,2H),7.32(dd,J=8.4,2.3Hz ,2H),1.84(br.s,2H),1.60-1.64(m,4H),1.39-1.47(m,4H),1.20-1.23(m,2H).

[0421] 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]

[0422] [ka]

[0423] 1 HNMR(500MHz,DMSO-d6)δ=8.67(d,J=2.29Hz,1H),8.05(dd,J=2.36,8.46Hz,1H),7.66(d,J=8.54Hz,1H),3 .82(dt,J=2.52,10.87Hz,2H),3.59(td,J=4.29,11.40Hz,2H),2.10-2.20(m,2H),1.54(d,J=13.27Hz,2H).

[0424] Step 3: Synthesis 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 = phenylcarboxylate] (Step 5b)

[0425] [ka]

[0426] 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 (308 g, 1.18 mol) (prepared as reported in WO2009065622). The mixture was stirred at 130 °C for 72 h and evaporated under reduced pressure. The residue was dissolved in DCM (2 L), washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography using DCM / acetone = 100 / 0 to 20 / 1 to give phenyl 4-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (149 g, 40% yield) as an off-white solid. 1 H-NMR(400MHz, CDCl3)δ=7.53-7.51(d,J=8.4Hz,2H),7.34-7.30(t,J=7.8Hz,2H),7.18-7.11(m,3H) ,7.05-7.03(d,J=7.6Hz,2H),3.98-3.92(m,2H),3.60-3.51(m,6H),2.35(s,4H),2.20-2.17(m,4H).

[0427] Following the same method, the following compounds were prepared:

[0428] 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 = phenylcarboxylate]

[0429] [ka]

[0430] 1HNMR(500MHz,DMSO-d6)δ=7.58(d,J=8.54Hz,2H),7.32-7.36(m,2H),7.30(d,J=8.69Hz,2H),7 .16-7.21(m,1H),7.01-7.07(m,2H),3.36-3.58(m,7H),2.21-2.35(m,6H),1.98-2.03(m,3H).

[0431] 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 = phenylcarboxylate]

[0432] [ka]

[0433] 1 HNMR(500MHz,DMSO-d6)δ=7.51-7.58(m,2H),7.30-7.38(m,4H),7.16-7.22(m,1H),7.01-7.07(m, 2H), 3.51 (br.s., 4H), 2.30 (br.s., 4H), 1.98-2.08 (m, 4H), 1.66-1.80 (m, 2H), 1.35-1.49 (m, 2H).

[0434] Phenyl 4-[4-(5-bromopyridin-2-yl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylate [(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 = phenylcarboxylate]

[0435] [ka]

[0436] 1HNMR(500MHz,DMSO-d6)δ=8.74(d,J=2.29Hz,1H),8.07(dd,J=2.52,8.46Hz,1H),7.40(d,J=8.39Hz,1H),7.29-7.37(m,2H),7.1 5-7.22(m,1H),7.01-7.07(m,2H),3.76-3.88(m,2H),3.51(br.s.,2H),3.20-3.31(m,4H),2.23-2.37(m,6H),1.95-2.10(m,2H).

[0437] Phenyl 4-[3-(4-bromophenyl)tetrahydrofuran-3-yl]piperazine-1-carboxylate [(XXIII), W1 = Br, A = phenyl, R4 = H, R5a and R5b = tetrahydrofuran-3-yl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenylcarboxylate]

[0438] [ka]

[0439] 1 HNMR(500MHz,DMSO-d6)δ=7.56(d,J=8.54Hz,2H),7.32-7.39(m,4H),7.19(dd,J=7.47,7.32Hz,1H),7.04-7.08(m,2H),4.07(d,J= 9.15Hz,1H),3.95-3.97(m,1H),3.93(d,J=9.15Hz,1H),3.64-3.68(m,1H),3.54(br.s,2H),3.33-3.35(m,1H),2.24-2.45(m,7H).

[0440] Phenyl 4-[4-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylate [(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 = phenylcarboxylate]

[0441] [ka]

[0442] 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(br t,J=4.50Hz,4H)2.21-2.33(m,2H)2.09-2.21(m,2H).

[0443] Step 4: Synthesis 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 = phenylcarboxylate] (Conversion G)

[0444] [ka]

[0445] 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) was added tributyl(1-ethoxyvinyl)tin (242 g, 0.67 mol) and Pd(PPh3)2Cl2 (2.35 g, 3.35 mmol) under N2. The mixture was stirred at 90 °C overnight. After cooling, the reaction mixture was diluted with aqueous KF solution and stirred at room temperature for 1 h. The precipitate was filtered and washed with EtOAc. After separation, the aqueous phase was extracted with EtOAc (5 x 500 mL). The combined organic phases were dried over Na2SO4 and concentrated. The crude product was suspended in 2 L of DCM and 1 L of 2 N HCl (aq) and stirred at room temperature 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 NaSO, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using DCM / acetone = 100 / 0 to 10 / 1 to give phenyl 4-(4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (63 g, 45% yield) as a white solid. 1 H-NMR(400MHz,CDCl3)δ=8.00-7.98(d,J=8.4Hz,2H),7.36-7.29(m,4H),7.18-7.16(m,1H),7.03-7.01(d, J=7.6Hz,2H),3.99-3.96(t,J=5.8Hz,2H),3.61-3.53(m,6H),2.63(s,3H),2.37(s,4H),2.24-2.23(m,4H). LCMS:409 Rt=6.19min;HRMS(ESI)C 24 H 29 N2O4[M+H] + Calculated value: 409.2122, measured value: 409.2118.

[0446] Following the same method, the following compounds were prepared:

[0447] Phenyl 4-[3-(4-acetylphenyl)pentan-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 = phenylcarboxylate]

[0448] [ka]

[0449] 1 HNMR(400MHz,DMSO-d6)δ=7.93(d,J=8.54Hz,2H),7.57(d,J=8.54Hz,2H),7.32-7.39(m,2H),7.16-7.23(m,1H),7. 03-7.10(m,2H),3.53(br.s.,2H),3.37(d,J=2.29Hz,1H),2.57(s,3H),1.81-2.07(m,4H),0.76(t,J=7.32Hz,6H).

[0450] 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 = phenylcarboxylate]

[0451] [ka]

[0452] 1 HNMR(500MHz,DMSO-d6)δ=7.97(d,J=8.54Hz,2H),7.46-7.52(m,2H),7.29-7.37(m,2H),7.15-7.2 0(m,1H),6.99-7.06(m,2H),3.37-3.65(m,8H),2.59(s,3H),2.23-2.46(m,8H),1.95-2.07(m,3H).

[0453] 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 = phenylcarboxylate]

[0454] [ka]

[0455] 1 HNMR(500MHz,DMSO-d6)δ=7.94(d,J=8.39Hz,2H),7.49-7.54(m,2H),7.30-7.36(m,2H),7.14-7.22(m,1H),6.98-7.0 6(m,2H),3.52(br.s.,4H),2.58(s,3H),2.27-2.38(m,4H),2.04-2.13(m,4H),1.71-1.78(m,2H),1.37-1.51(m,2H).

[0456] 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 = phenylcarboxylate]

[0457] [ka]

[0458] 1HNMR(500MHz,DMSO-d6)δ=9.16(d,J=1.68Hz,1H),8.30(dd,J=2.36,8.31Hz,1H),7.55-7.58(m,1H),7.30-7.37(m,2H),7.16-7.20(m ,1H),7.00-7.05(m,2H),3.80-3.89(m,2H),3.52(br.s.,2H),3.23-3.32(m,4H),2.64(s,3H),2.28-2.42(m,6H),2.04-2.13(m,2H).

[0459] 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 = phenylcarboxylate]

[0460] [ka]

[0461] 1 HNMR(500MHz,DMSO-d6)δ=7.96(d,J=8.39Hz,2H),7.56(d,J=8.54Hz,2H),7.32-7.37(m,2H),7.16-7.22(m,1H),7.01-7.09(m,2H), 4.13(d,J=9.15Hz,1H),3.93-4.01(m,2H),3.65-3.73(m,1H),3.50-3.60(m,2H),3.36-3.45(m,2H),2.59(s,3H),2.26-2.49(m,6H).

[0462] 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 = phenylcarboxylate]

[0463] [ka]

[0464] 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).

[0465] 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]

[0466] [ka]

[0467] LCMS: m / z 423 [M+H] + rt2.29 min.

[0468] Step 5: Synthesis 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 = phenylcarboxylate] (Step 5c′)

[0469] [ka]

[0470] A mixture of tetraethoxytitanium (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 to 80 °C overnight and then cooled to room temperature. To this mixture was added NaBH (5 equiv., 120 mg, 3.18 mmol) at -50 °C. The mixture was then allowed to warm slowly to room temperature (2 h). MeOH (2 mL) was added to quench excess NaBH, followed by the addition of water. The resulting mixture was filtered to remove solids, and the aqueous phase was extracted twice with EtOAc, dried over NaSO, and concentrated. The residue was purified on a silica gel column chromatography system using gradient elution (100% DCM followed by 0→20% acetone / DCM) to give phenyl 4-(4-{4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (225 mg, 69% yield). 1 H NMR(500MHz,DMSO-d6)δ=7.41(d,J=8.24Hz,2H),7.31-7.36(m,2H),7.26(d, J=8.39Hz,2H),7.15-7.21(m,1H),7.00-7.05(m,2H),5.64(d,J=6.86Hz,1H), 4.39(s,1H),3.83(d,J=7.78Hz,2H),3.52(br.s.,2H),3.36-3.43(m,3H),2. 26(br.s.,4H),2.04-2.21(m,4H),1.42(d,J=6.71Hz,3H),1.10-1.13(m,9H).

[0471] Following the same method, the following compounds were prepared:

[0472] 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 = phenylcarboxylate]

[0473] [ka]

[0474] 1 HNMR(500MHz,DMSO-d6)δ=7.29-7.40(m,6H),7.17-7.21(m,1H),7.07(dd,J=0.99,8.46Hz,2H),5.61(d,J=7.02Hz,1H),4.37(quin,J=6.75Hz) ,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=6.86Hz,3H),1.09-1.16(m,9H),0.76(t,J=6.94Hz,6H).

[0475] Phenyl 4-(4-{5-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]pyridin-2-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 = phenylcarboxylate]

[0476] [ka]

[0477] 1HNMR(500MHz,DMSO-d6)δ=8.62(d,J=2.14Hz,1H),7.83(dd,J=2.29,8.24Hz,1H),7.3 7(d,J=8.24Hz,1H),7.30-7.35(m,2H),7.16-7.20(m,1H),7.01-7.05(m,2H),5.79(d, J=7.17Hz,1H),4.46(t,J=6.86Hz,1H),3.79-3.88(m,2H),3.51(br.s.,2H),3.24-3. 32(m,4H),2.27-2.37(m,6H),2.02-2.10(m,2H),1.45(d,J=6.86Hz,3H),1.12(s,9H).

[0478] Phenyl 4-(1-{4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]phenyl}cyclopentyl)piperazine-1-carboxylate [(XXIV), R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = cyclopentyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenylcarboxylate]

[0479] [ka]

[0480] 1 H NMR(500MHz,DMSO-d6)δ=7.36-7.39(m,2H),7.27-7.35(m,4H),7.15-7.20(m,1H),7.00-7.06(m,2H),5.61(d,J=6.86Hz,1H),4.38(t,J=6.71Hz, 1H),3.51(br.s.,4H),2.31(br.s.,4H),2.06(d,J=8.54Hz,4H),1.73(b r.s.,2H),1.43-1.50(m,2H),1.41(d,J=6.86Hz,3H),1.10-1.14(m,9H).

[0481] Phenyl 4-(4-{4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate [(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 = phenylcarboxylate]

[0482] [ka]

[0483] 1 H NMR(500MHz,DMSO-d6)δ=7.41(d,J=8.24Hz,2H),7.30-7.36(m,2H),7.26(d,J =8.24Hz,2H),7.15-7.20(m,1H),7.00-7.05(m,2H),5.64(d,J=6.86Hz,1H),4. 39(t,J=6.86Hz,1H),3.84(t,J=8.08Hz,2H),3.53(br.s.,2H),3.35-3.43(m, 4H), 2.26 (br.s., 4H), 2.05-2.21 (m, 4H), 1.42 (d, J=6.71Hz, 3H), 1.12 (s, 9H).

[0484] Phenyl 4-(3-{4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]phenyl}tetrahydrofuran-3-yl)piperazine-1-carboxylate [(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 = phenylcarboxylate]

[0485] [ka]

[0486] 1H NMR(500MHz,DMSO-d6)δ=7.38-7.42(m,2H),7.29-7.37(m,4H),7.16-7.21(m,1H),7.02-7.07(m,2H),5.63(d,J=6.86Hz,1H),5.31(s,1H),4.07-4 .11(m,1H),3.94-3.98(m,2H),3.67(q,J=7.52Hz,1H),3.54(br.s.,2H), 3.38 (br.s., 2H), 2.24-2.44 (m, 6H), 1.41 (d, J=6.71Hz, 3H), 1.12 (s, 9H).

[0487] Phenyl 4-(4-{5-[(1S)-1-{[(R)-tert-butylsulfinyl]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 = phenylcarboxylate]

[0488] [ka]

[0489] 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(quin,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).

[0490] Benzyl 3-[(4-{4-[(1S)-1-{[(S)-tert-butylsulfinyl]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]

[0491] [ka]

[0492] 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).

[0493] 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 carboxylate]

[0494] [ka]

[0495] 1H NMR(500MHz,DMSO-d6)δ=7.29-7.39(m,7H),7.24(d,J=8.38Hz,2H),5.62(d ,J=7.00Hz,1H),5.02(s,2H),4.60-4.71(m,1H),3.97-4.41(m,6H),2.64(br s, 2H), 2.09 (s, 3H), 1.95-2.05 (m, 5H), 1.65-1.89 (m, 2H), 1.38 (d, J=6.75Hz, 3H), 1.10 (s, 9H).

[0496] Step 6: Synthesis 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 = phenylcarboxylate] (Step 5e)

[0497] [ka]

[0498] 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 of a 4 M solution in 1,4-dioxane, 8.0 mmol). 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 give phenyl 4-(4-{4-[(1S)-1-aminoethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (200 mg, 99% yield). 1H NMR(500MHz,DMSO-d6)δ=7.37(d,J=8.39Hz,2H),7.31-7.34(m,2H),7.23(d,J=8.39Hz,2H),7.16-7.20(m,1H),7.00-7.06(m,2H),3.98 (q,J=6.56Hz,1H),3.79-3.87(m,2H),3.52(br.s.,2H),2.25(br.s.,4H),2.03-2.20(m,5H),1.81-2.01(m,1H),1.25(d,J=6.71Hz,3H).

[0499] Following the same method, the following compounds were prepared:

[0500] 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 = phenylcarboxylate]

[0501] [ka]

[0502] 1 H NMR(500MHz,DMSO-d6)δ=7.39(d,J=8.24Hz,2H),7.31-7.35(m,2H),7.25(d,J=8.24Hz,2H),7.16-7.20(m,1H),7.00-7.06(m,2H),4.04(d,J=6 .56Hz,1H),3.79-3.88(m,2H),3.52(br.s.,2H),3.35-3.40(m,6H),2.25(br.s.,4H),2.13(dt,J=13.42,17.46Hz,4H),1.29(d,J=6.56Hz,3H).

[0503] Phenyl 4-(1-acetyl-4-{4-[(1S)-1-aminoethyl]phenyl}piperidin-4-yl)piperazine-1-carboxylate [(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 = phenylcarboxylate]

[0504] [ka]

[0505] 1 H NMR(500MHz,DMSO-d6)δ=7.38(d,J=8.24Hz,2H),7.31-7.36(m,2H),7.27(d,J=8.39Hz,2H),7.15-7.20(m,1H),6.99-7.08(m,2H),4.02(d, J=6.41Hz,1H),3.37-3.65(m,8H),2.21-2.40(m,8H),1.99(s,3H),1.94(d,J=2.90Hz,1H),1.84(d,J=12.96Hz,1H),1.27(d,J=6.71Hz,3H).

[0506] Phenyl 4-(4-{5-[(1S)-1-aminoethyl]pyridin-2-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]

[0507] [ka]

[0508] 1HNMR(500MHz,DMSO-d6)δ=8.70(d,J=2.14Hz,1H),7.94(dd,J=2.36,8.31Hz,1H),7.46-7.50(m,1H),7.31-7.36(m,2H),7.16-7.21(m,1H),6.98-7. 05(m,2H),4.40-4.51(m,1H),3.81-3.89(m,2H),3.52(br.s.,2H),3.24-3 .32(m,2H),2.27-2.40(m,6H),2.01-2.14(m,2H),1.52(d,J=6.86Hz,3H).

[0509] Phenyl 4-(1-{4-[(1S)-1-aminoethyl]phenyl}cyclopentyl)piperazine-1-carboxylate [(V), R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = cyclopentyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenylcarboxylate]

[0510] [ka]

[0511] 1 HNMR(500MHz,DMSO-d6)δ=7.31-7.36(m,4H),7.27(d,J=8.24Hz,2H),7.18(dd,J=7.4 and 7.3Hz,1H),7.03(d,J=8.54Hz,2H),3.96(q,J=6.56Hz,1H),3.51(br.s.,2H),3.37-3.40(m,2H),2.31(br. s.,4H),1.99-2.12(m,4H),1.87(br.s.,2H),1.67-1.76(m,2H),1.37-1.48(m,2H),1.25(d,J=6.56Hz,3H).

[0512] Phenyl 4-(3-{4-[(1S)-1-aminoethyl]phenyl}tetrahydrofuran-3-yl)piperazine-1-carboxylate [(V), R1a = methyl, R1b = H, A = phenyl, R4 = H, R5a and R5b = cyclopentyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenylcarboxylate]

[0513] [ka]

[0514] 1 HNMR(500MHz,DMSO-d6)δ=7.28-7.39(m,6H),7.16-7.21(m,1H),7.01-7.08(m,2H),4.09(d,J=9.15Hz,1H),3.96-4.0 2(m,1H),3.94(d,J=8.85Hz,2H),3.66(q,J=7.78Hz,1H),3.54(br.s.,4H),2.23-2.46(m,6H),1.25(d,J=6.71Hz,3H).

[0515] 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]

[0516] [ka]

[0517] 1HNMR(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,3 H)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).

[0518] 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]

[0519] [ka]

[0520] 1 HNMR(500MHz,DMSO-d6)δ=8.46(d,J=1.98Hz,1H),7.68(dd,J=2.29,8.24Hz,1H),7.42-7.53(m,1H),7.29-7.37(m,2H),7.15-7.22(m,1H),7 .00-7.07(m,2H),3.99(q,J=6.71Hz,1H),3.81-3.90(m,2H),3.54(br.s.,2H),3.37-3.42(m,4H),2.01-2.31(m,8H),1.29(d,J=6.56Hz,3H).

[0521] 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 = benzyl carboxylate]

[0522] [ka]

[0523] 1 HNMR(500MHz,DMSO-d6)δ=7.23-7.37(m,9H),4.94(br.s.,2H),4.07-4.15(m,1H),3.97(q,J=6.46Hz,1H),3.66-3.73(m,2H),3.5 3-3.65(m,2H),3.36-3.53(m,2H),3.25-3.33(m,2H),2.13-2.19(m,2H),2.11(s,3H),1.96-2.06(m,2H),1.22(d,J=6.56Hz,3H).

[0524] 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 carboxylate]

[0525] [ka]

[0526] 1HNMR(500MHz,DMSO-d6)δ=7.25-7.36(m,9H),4.95(br.s.,2H),4.19(t,J=6.10Hz,1H),3.97(q,J=6.66Hz,1H),3.59-3.7 8(m,2H),3.39-3.51(m,2H),2.30-2.44(m,2H),2.14(s,4H),1.87-2.02(m,4H),1.73(br.s.,2H),1.22(d,J=6.56Hz,3H).

[0527] 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 carboxylate]

[0528] [ka]

[0529] 1 HNMR(500MHz,DMSO-d6)δ=7.21-7.37(m,9H),4.98(s,2H),3.96(q,J=6.56Hz,2 H),2.06-2.28(m,8H),1.89(s,3H),1.79(d,J=9.46Hz,5H),1.20-1.25(m,3H).

[0530] 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 = phenylcarboxylate]

[0531] [ka]

[0532] 1 HNMR(500MHz,DMSO-d6)δ=7.35-7.39(m,2H),7.31-7.35(m,2H),7.27-7.31(m,2H),7.12-7.20(m,1H),6.96-7.07(m,2H),3.97(q,J=6.56Hz ,1H),3.53(d,J=3.51Hz,2H),2.53-2.61(m,2H),2.28(br.s.,4H),2.08-2.22(m,4H),1.71-2.03(m,J=6.10Hz,4H),1.24(d,J=6.56Hz,3H).

[0533] 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 = phenylcarboxylate]

[0534] [ka]

[0535] 1 HNMR(500MHz,DMSO-d6)δ=7.37-7.40(m,2H),7.32-7.36(m,2H),7.29-7.32(m,2H),7.16-7.22(m,1H),6.98-7.08(m,2H),3.99( q,J=6.56Hz,1H),3.55(br.s.,2H),2.54-2.62(m,2H),2.08-2.36(m,6H),1.63-1.99(m,J=6.10Hz,6H),1.26(d,J=6.71Hz,3H).

[0536] Manufacturing Example 12 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 = phenylcarboxylate] (Steps 5a to 5e)

[0537] [ka]

[0538] Step a: Synthesis of phenyl 4-[4-(4-{(1E)-N-[(S)-tert-butylsulfinyl]ethanimidoyl}phenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylate [(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 = phenylcarboxylate] (Step 5c″)

[0539] [ka]

[0540] A mixture of tetraethoxytitanium (2.5 equiv., 1.57 mL, 7.5 mmol), (S)-2-methylpropane-2-sulfinamide (1.5 equiv., 545 mg, 4.5 mmol), and phenyl 4-[4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylate (1.22 g, 3.0 mmol) in THF (80 mL) was heated to 80 °C overnight, then cooled to room temperature and concentrated. The residue was purified on a silica gel column chromatography system using gradient elution (100% DCM followed by 0 → 20% acetone / DCM) to give the title compound (966 mg, 63% yield). 1H NMR(500MHz,DMSO-d6)δ=7.94(d,J=8.39Hz,2H),7.44(d,J=8.54Hz,2H),7.29-7.34(m,2H),7.14-7.21(m,1H),7.00-7.07(m, 2H),3.79-3.89(m,2H),3.53(br.s.,2H),3.36-3.42(m,3H),2.73(s,3H),2.24-2.34(m,4H),2.12-2.21(m,4H),1.23(s,9H).

[0541] Step b: Synthesis of phenyl 4-{4-[4-(2-{[(S)-tert-butylsulfinyl]amino}propan-2-yl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylate [(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 = phenylcarboxylate] (Step 5e)

[0542] [ka]

[0543] To a solution of phenyl 4-[4-(4-{(1E)-N-[(S)-tert-butylsulfinyl]ethanimidoyl}phenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylate (384 mg, 0.75 mmol) in anhydrous DCM (5 mL) was added 0.375 mL (1.125 mmol, 1.5 equiv.) of 3.0 M methylmagnesium bromide ether solution at −48° C. The mixture was warmed 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 using gradient elution (100% DCM followed by 0 to 4% ethanol / DCM) to give the title compound (182 mg, 46% yield). 1H NMR(500MHz,DMSO-d6)δ=7.47-7.53(m,2H),7.30-7.36(m,2H),7.25(d,J=8.54Hz,2H),7.16-7.20(m,1H),6.99-7.04(m,2H),5.36(s,1H),3.84 (dd,J=7.93,10.22Hz,2H),3.53(br.s.,2H),3.36-3.43(m,3H),2.25(br.s.,3H),2.03-2.21(m,4H),1.58(d,J=4.27Hz,5H),1.09-1.13(m,8H).

[0544] Step c: Synthesis of phenyl 4-{4-[4-(2-aminopropan-2-yl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylate [(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)

[0545] [ka]

[0546] To a solution of phenyl 4-{4-[4-(2-{[(S)-tert-butylsulfinyl]amino}propan-2-yl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylate (180 mg, 0.341 mmol) in MeOH (5 mL) was added 37% HCl (0.25 mL) at 0 °C. The mixture was stirred at room temperature for 1 h. DCM and saturated NaHCO solution were added to the mixture, and the aqueous phase was extracted twice with DCM, dried over NaSO, and concentrated to give phenyl 4-{4-[4-(2-aminopropan-2-yl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylate (143 mg, 99% yield). 1H NMR(500MHz,DMSO-d6)δ=7.52(d,J=8.39Hz,2H),7.30-7.36(m,2H),7.22(d,J=8.39Hz,2H),7.14-7.20(m,1H),7.00-7.06(m,2H), 3.79-3.86(m,2H),3.52(br.s.,2H),3.36-3.44(m,3H),2.26(br.s.,4H),2.04-2.20(m,4H),1.90(br.s.,2H),1.34-1.40(m,6H).

[0547] Following the same method, the following compounds were prepared:

[0548] Phenyl 4-{1-[4-(2-aminopropan-2-yl)phenyl]-4,4-difluorocyclohexyl}piperazine-1-carboxylate [(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 = phenylcarboxylate] (Step 5d)

[0549] [ka]

[0550] 1 H NMR(500MHz,DMSO-d6)δ=7.52(d,J=8.39Hz,2H),7.31-7.37(m,2H),7.29(d,J=8.39Hz,2H),7.13-7.22(m,1H),7.03(dd,J=0.92,8.5 4Hz,2H),3.53(br.s.,2H),3.38(br.s.,2H),2.54-2.62(m,2H),2.28(br.s.,2H),2.05-2.24(m,4H),1.68-1.92(m,4H),1.37(s,6H).

[0551] Manufacturing Example 13 Synthesis of 3-(4-bromophenyl)pentan-3-amine [(XXI), W1 = Br, A = phenyl, R4 = H, R5a and R5b = ethyl] (Step 5a)

[0552] [ka]

[0553] Step a: Synthesis of N-[3-(4-bromophenyl)pentan-3-yl]-2-chloroacetamide To the alcohol 3-(4-bromophenyl)pentan-3-ol (2.5 g, 10 mmol) and ClCHCN (1.5 g, 20 mmol) was added AcOH (25 mL), and the mixture was cooled to 0 °C. HSO (1.6 mL, 30 mmol) was added dropwise, maintaining the temperature below 10 °C. The reaction mixture was allowed to warm to room temperature, stirred for 4 h, and poured into ice water (20 mL). A pale pink precipitate formed, which was filtered to give N-[3-(4-bromophenyl)pentan-3-yl]-2-chloroacetamide (2.7 g, 85% yield) as a pale pink solid. 1 H NMR (500MHz, DMSO-d6)δ=8.11(s,1H),7.44-7.49(m,2H),7.19-7.24(m,2H),4.05-4.11(m,2H),1.75-2.10(m,4H),0.64(t,J=7.40Hz,6H).

[0554] Following the same method, the following compounds were prepared:

[0555] 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)

[0556] [ka]

[0557] 1H NMR(400MHz,chloroform-d)δ=8.51(d,J=2.45Hz,1H)7.79(dd,J=8.38,2.51Hz,1H)7.33(d,J=8.44Hz,1H)3.84-4.01(m,4H)2.08-2.17(m,2H)1.70(br d,J=13.08Hz,2H).

[0558] Step b: Synthesis of 3-(4-bromophenyl)pentan-3-amine [(XXI), W1 = Br, A = phenyl, R4 = H, R5a and R5b = ethyl]

[0559] [ka]

[0560] Chloroacetamide (2.7 g, 8.5 mmol) and thiourea (800 mg, 10 mmol) were dissolved in 22 mL of a 1:5 AcOH / EtOH mixture and refluxed for 10 h. The cooled reaction was diluted with 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 1:1 hexane / AcOEt to give 3-(4-bromophenyl)pentan-3-amine (1.4 g, 68% yield). 1 H NMR (500MHz, DMSO-d6) δ = 7.46-7.52 (m, 2H), 7.35-7.39 (m, 2H), 1.54-1.79 (m, 4H), 0.62 (t, J = 7.40Hz, 6H).

[0561] Following the same method, the following compounds were prepared:

[0562] 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]

[0563] [ka]

[0564] 1 H NMR(400MHz,chloroform-d)δ=8.54(d,J=2.65Hz,1H)7.79(dd,J=8.38,2.65Hz,1H)7.32( d,J=8.38Hz,1H)3.77-4.01(m,4H)2.08-2.26(m,2H)1.64(dd,J=13.89,2.43Hz,2H).

[0565] Manufacturing Example 14 Synthesis 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 = phenylcarboxylate] (Steps 5a, 5b)

[0566] [ka]

[0567] Step 1: Preparation of 2-(4-bromophenyl)-2-methyl-1,3-dioxolane To a mixture of 1-(4-bromophenyl)ethanone (7.0 g, 35.2 mmol, 1 equiv.) and ethylene glycol (9.8 g, 158 mmol, 4.5 equiv.) in toluene (35 mL) was added PTSA (0.669 g, 3.52 mmol, 0.1 equiv.) in one portion at 25-30 °C under N2. The mixture was stirred at reflux for 36 h, and water was removed using 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 phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (9.0 g, 80% purity) as a pale yellow oil. The crude product was used in the next step without further purification. LCMS: LCMS: m / z 244 [M+H] +rt8.51 minutes.

[0568] 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] To a solution of n-BuLi (2.5 M, 12.6 mL, 1.2 equiv.) in THF (13 mL) was added dropwise over 30 min at −65° C. under N. Tetrahydropyran-4-one (2.50 g, 25.01 mmol, 2.30 mL, 0.95 equiv.) in THF (10.0 mL). Tetrahydropyran-4-one (2.50 g, 25.01 mmol, 2.30 mL, 0.95 equiv.) was added to the above mixture at −65° C. over 20 min. The reaction mixture was stirred at −65° C. for 30 min. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.24) confirmed complete consumption of the starting material. The reaction mixture was quenched with saturated aqueous NH4Cl at 0° C., 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), and the organic phase was washed with saturated aqueous Na2CO3, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. 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 over two steps). LCMS: m / z 265 [M+H] + rt6.35 minutes.

[0569] Following the same method, the following compounds were prepared:

[0570] 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]

[0571] [ka]

[0572] 1 H NMR(400MHz,chloroform-d)δ=12.23(d,J=8.3Hz,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=12.0Hz,4H),6.52(br d,J=12.6Hz,2H),6.30(s,3H).

[0573] Step 3: Preparation of 4-(4-bromophenyl)tetrahydro-2H-pyran-4-amine [(XXI), W1 = Br, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl] (Step 5a) 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 was added AcOH (1.36 g, 22.0 mmol, 1.30 mL, 1.0 equiv.) and HSO (2.23 g, 22.7 mmol, 1.21 mL, 1.0 equiv.) dropwise over 30 min at 0 °C under N. 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 NaCO (3.9 g). The aqueous phase was extracted with dichloromethane (15 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. 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).

[0574] 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) was added thiourea (1.85 g, 24.34 mmol, 1.2 equiv) at 20 °C under N. To the above mixture was added AcOH (3.65 g, 60.8 mmol, 3.48 mL, 3 equiv) at 20 °C. 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 NaCO. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was triturated with MTBE (10 mL) at 25° C. for 10 minutes and filtered to give the title compound as a pale yellow solid (4.0 g, 90.0% yield). LCMS: m / z 220 [M+H] + rt4.85 minutes.

[0575] Following the same method, the following compounds were prepared:

[0576] 1-[4-(1-amino-4,4-difluorocyclohexyl)phenyl]ethanone (XXI) [(XXI), W1 = methyl ketone, A = phenyl, R4 = H, R5a and R5b = 4,4-difluorocyclohexyl]

[0577] [ka]

[0578] 1 H NMR(500MHz,DMSO-d6)δ=7.90(d,J=8.6Hz,2H),7.68(d,J=8.6Hz,2H),2.56(s,3H),2.42-2.23(m,2H),2.03(br s,2H),1.99(s,1H),2.00-1.92(m,1H),1.92-1.82(m,2H),1.92-1.82(m,1H),1.79-1.65(m,2H).

[0579] Step 4: Preparation of phenyl 4-(4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (Step 5b) 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) was added NaI (150.0 mg) at 20 °C under N2. To the above mixture was added phenyl bis(2-chloroethyl)carbamate (2.33 g, 8.89 mmol, 1.3 equiv) at 20 °C. The reaction mixture was stirred at 140 °C for 10 h. The mixture was cooled to 40 °C and separated into layers in a 100 mL separatory funnel. The lower layer was acidified to pH 6 with HCl (2 N) and extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1, 0 / 1) to give 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, yield 45.0%). 1 H NMR(500MHz,DMSO-d6)δ=7.97(d,J=8.39Hz,2H),7.46(d,J=8.54Hz,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). LCMS:m / z409[M+H] + @rt6.02 minutes. HRMS(ESI)C 24 H 29 N2O4[M+H] + Calculated value: 409.2122, measured value: 409.2113.

[0580] Manufacturing Example 15 Synthesis 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 = phenylcarboxylate] (Steps 5a-5d)

[0581] [ka]

[0582] 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] To a solution of n-BuLi (2.5 M, 12.6 mL, 1.2 equiv.) in THF (13 mL) was added dropwise over 30 min at −65 °C under N. Tetrahydropyran-4-one (2.50 g, 25.01 mmol, 2.30 mL, 0.95 equiv.) in THF (10.0 mL) was added dropwise over 30 min. Tetrahydropyran-4-one (2.50 g, 25.01 mmol, 2.30 mL, 0.95 equiv.) was added to the above mixture at −65 °C over 20 min. The reaction mixture was stirred at −65 °C for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl at 0 °C, 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), and the organic phase was washed with saturated aqueous Na2CO3, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was a white powder (3.98 g, 60% yield). 1H NMR(500MHz,DMSO-d6)δ=7.47-7.51(m,2H),7.33(d,J=8.24Hz,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=5.11,12.77Hz,2H),1.52(d,J=12.20Hz,2H). LCMS:LCMS:m / z253[M+H] + rt6.35 minutes.

[0583] Step b: Preparation of 2-chloro-N-[4-(4-formylphenyl)tetrahydro-2H-pyran-4-yl]acetamide (Step 5a) 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 was added AcOH (1.36 g, 22.0 mmol, 1.30 mL, 1.0 equiv.) and HSO (2.23 g, 22.7 mmol, 1.21 mL, 1.0 equiv.) dropwise over 30 min at 0 °C under N. 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 NaCO (3.9 g). The aqueous phase was extracted with dichloromethane (15 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. 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 H NMR(500MHz,DMSO-d6)δ=9.98(s,1H),8.57(s,1H),7.87(d,J=8.39Hz,2H),7.60(d,J=8.39Hz,2H),4.13 (s,2H),3.76(dd,J=2.75,11.74Hz,2H),3.60-3.69(m,2H),2.24(d,J=12.96Hz,2H),1.92-2.02(m,2H). LCMS:m / z282[M+H] + rt4.07 minutes.

[0584] Step c: Preparation of N-(4-{4-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]phenyl}tetrahydro-2H-pyran-4-yl)-2-chloroacetamide A mixture of tetraethoxytitanium (2.5 equiv., 4.0 mL, 19.08 mmol), (S)-2-methylpropane-2-sulfinamide (1.5 equiv., 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 to 80 °C overnight, then cooled to room temperature and concentrated. The residue was purified on a silica gel column chromatography system using gradient elution (100% DCM followed by 0 → 20% acetone / DCM) to give the title compound (1.76 mg, 60% yield). LCMS: m / z 385 [M+H] + rt6.85 minutes.

[0585] Step d: Preparation of N-{(E)-[4-(4-aminotetrahydro-2H-pyran-4-yl)phenyl]methylidene}-2-methylpropane-2-sulfinamide [(XXI), W1 = (S)-tert-butylsulfinamidomethylidene, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl] (Step 5a) 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 equiv.) in EtOH (30 mL) was added thiourea (0.418 g, 5.50 mmol, 1.2 equiv.) at 20 °C under N. To the above mixture was added AcOH (0.824 mL, 13.74 mmol, 3 equiv.) at 20 °C. 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 NaCO. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. 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). 1 H NMR(500MHz,DMSO-d6)δ=8.52(s,1H),7.89(d,J=8.39Hz,2H),7.69(d,J=8.54Hz,2H),3.82 -3.91(m,2H),3.60-3.69(m,2H),1.89-2.02(m,3H),1.53(d,J=11.74Hz,2H),1.18(s,9H). LCMS: m / z 309 [M+H] + rt2.32 min.

[0586] Step e: Preparation of phenyl 4-(4-{4-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate [(XXIII), W1 = (S)-tert-butylsulfinamidomethylidene, A = phenyl, R4 = H, R5a and R5b = tetrahydro-2H-pyran-4-yl] (Step 5b) To a solution of N-{(E)-[4-(4-aminotetrahydro-2H-pyran-4-yl)phenyl]methylidene}-2-methylpropane-2-sulfinamide (1.20 g, 3.89 mmol, 1.0 equiv.) in DIPEA (5 mL) was added NaI (130.0 mg) at 20°C under N2. To the above mixture was added phenyl bis(2-chloroethyl)carbamate (1.32 g, 5.1 mmol, 1.3 equiv.) at 20°C. The reaction mixture was stirred at 140°C for 48 hours. The mixture was cooled to 40°C and separated into layers using a 100 mL separatory funnel. The lower layer was acidified to pH 6 with HCl (2N) and extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1, 0 / 1) to give 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] + @rt6.58 minutes.

[0587] Step f: Synthesis 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 = phenylcarboxylate] (Step 5d)

[0588] [ka]

[0589] 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) was added 37% HCl (0.25 mL) at 0 °C. 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 give the title compound as an off-white solid (715 mg, 99% yield). LCMS: m / z 396 [M+H] + @rt2.35min.

[0590] Manufacturing Example 16 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 = phenylcarboxylate] (Conversion F—Step 5c)

[0591] [ka]

[0592] 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 = phenylcarboxylate] (Conversion F)

[0593] [ka]

[0594] To a mixture of phenyl 4-[4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylate (2 g, 4.15 mmol, 1 equiv.) in HO (4 mL) and dioxane (40 mL) 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 added sequentially. The mixture was stirred at 100 °C for 16 h. TLC (PE:EA = 1:1, Rf = 0.41) confirmed the reaction was complete, with one major new, highly polar spot detected. In this step, four 2g reactions were carried out in parallel. The four reaction mixtures were added with THF (200 mL), filtered, quenched by adding HO (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with 30 mL of brine, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that 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 four 2g bromo derivatives), 72.93% yield]. 1 H NMR(500MHz,DMSO-d6)δ=7.37-7.27(t,4H),7.24-7.13(m,3H),7.03(d,J=7.9Hz,2H) ,3.90-3.80(m,2H),3.51-3.38(m,6H),2.36-2.26(m,4H),2.21-2.06(m,4H),0.95(br d,J=15.8Hz,4H).

[0595] Step b: Synthesis of 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 = phenylcarboxylate] (Step 5c)

[0596] [ka]

[0597] In a three-neck flask, phenyl 4-[4-(4-cyanophenyl)tetrahydro-2H-pyran-4-yl]piperazine-1-carboxylate (1 g, 2.43 mmol, 1 equiv.) was dissolved in THF (35 mL) and EtO (20 mL) to give a cloudy suspension. Ti(Oi-Pr) (875 mg, 3.08 mmol, 908.62 µL, 1.27 equiv.) was added at 20 °C. The reaction mixture was cooled to -65 °C under N. EtMgBr (3 M, 2.25 mL, 2.78 equiv.) was added at -65 °C for 10 min. After stirring for an additional 10 min, the mixture was warmed to 20 °C. The yellow mixture slowly turned black and was stirred at 20 °C for 1 h. Next, 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 confirmed the mixture contained the desired product (RT = 0.77, m / z = 422.3, M+H). Five 1g reactions were performed in parallel, and 15%–30% of the desired compound was detected by LCMS. The reaction mixture was quenched by adding HCl (1M, 7.5 mL) at 0 °C, diluted with NaOH (10%, 25 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. 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) and lyophilized to give the amine [676 mg (total from 5 g starting material), 12.5% ​​yield] as a white solid. 1H NMR(500MHz,DMSO-d6)δ=7.39-7.26(m,4H),7.24-7.13(m,3H),7.03(br d,J=7.9Hz,2H),3.92-3.76(m,2H),3.40-3.29(m,6H),2.35(br d,J=15.2Hz,2H),2.29-2.07(m,8H),1.03-0.84(m,4H).

[0598] Following the same method, the following compounds were prepared:

[0599] Phenyl 4-{1-[4-(1-aminocyclopropyl)phenyl]cyclopentyl}piperazine-1-carboxylate [(V), R1a and R1b = cyclopropyl, A = phenyl, R4 = H, R5a and R5b = cyclopentyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, PG = phenylcarboxylate]

[0600] [ka]

[0601] 1 H NMR(500MHz,DMSO-d6)δ=7.30-7.36(m,2H),7.25(s,4H),7.15-7.20(m,1H),7.04(dd,J=0.99,8.62Hz,2H),3.51(br.s.,2H),3.32-3.34(br. s.,2H),2.30(br.s.,4H),2.04-2.14(m,2H),1.94-2.04(m,2H),1.62- 1.81(m,2H),1.34-1.50(m,2H),0.92-0.97(m,2H),0.86-0.92(m,2H).

[0602] Manufacturing Example 17 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 carboxylate] (Step 5b′)

[0603] [ka]

[0604] Step 1: To a solution of 4-(4-bromophenyl)tetrahydro-2H-pyran-4-amine (14 g, 54.66 mmol, 1 equiv.) and benzyl 3-oxoazetidine-1-carboxylate (16.82 g, 81.99 mmol, 1.5 equiv.) in anhydrous THF (150 mL) was added Ti(OEt) (18.70 g, 81.99 mmol, 17.00 mL, 1.5 equiv.) at 25 °C. The reaction was stirred at 70 °C for 16 h. The reaction was then cooled to 30 °C, and NaBHCN (10.30 g, 163.97 mmol, 3 equiv.) was added. The reaction was then stirred at 70 °C for 2 h. LCMS (t = 1.818 min, Ms + H = 445.1, 447.1) indicated the reaction was complete. The reaction mixture was quenched at 25 °C by the addition of 100 mL of HO and 50 mL of 1 M HCl and then diluted with 200 mL of EtOAc. Next, 50 mL of saturated NaCO was added to the residue, and the mixture was stirred at 20 °C for 3 h. The residue was filtered through Celite and extracted with 200 mL of EtOAc (2 x 100 mL). The combined organic layers were washed with 200 mL of saturated NaCl (2 x 100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography at 100 mL / min using a gradient elution of 0–70% ethyl acetate / petroleum ether containing 10% DCM to afford 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 H NMR(400MHz, 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(br d,J=13.9Hz,2H).

[0605] Step 2: To a solution of compound benzyl 3-{[4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl]amino}azetidine-1-carboxylate (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) was added NaBHCN (11.29 g, 179.63 mmol, 5 equiv.) at 0 °C. The reaction was stirred at 20 °C for 16 h. HPLC (t = 2.757 min) showed the reaction to be complete. The reaction mixture was concentrated under reduced pressure and then diluted with 100 mL of EtOAc. 100 mL of saturated Na2CO3 was added to the residue at 0 °C until the pH reached 8, and the mixture was extracted with 100 mL of EtOAc (50 mL × 2). The combined organic layers were washed with 50 mL of brine (25 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a gradient elution of 0–100% ethyl acetate / petroleum ether containing 20% ​​DCM at 100 mL / min to afford the title compound (15 g, 32.65 mmol, 90.89% yield) as a pale yellow oil. 1 H NMR (400MHz, 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=5.0Hz,4H),1.27(t,J=7.2Hz,3H).

[0606] Manufacturing Example 18 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 carboxylate] (Step 5e)

[0607] [ka]

[0608] 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 HO (0.2 mL) was added I (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. To the reaction was slowly added NaSO (1 M, 2 mL) to quench the excess I at 0 °C. The reaction mixture was concentrated to dryness under reduced pressure. 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 give the title compound (60 mg, 123.57 μmol, yield 52.05%, purity 100%) as a white solid. 1 HNMR(500MHz,DMSO-d6)δ=7.26-7.42(m,7H),7.20(d,J=8.39Hz,2H),4.93-5.09(m,2H),4.57-4.73(m,1H),4.02-4.34(m, 4H),3.94(q,J=6.76Hz,1H),2.61(br.s.,2H),2.07(s,3H),1.93-2.06(m,4H),1.61-1.87(m,3H),1.21(d,J=6.56Hz,3H).

[0609] Manufacturing Example 19 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 carboxylate] (Step 5b″, Step 5c′ and Step 5d)

[0610] [ka]

[0611] (Step 5b)" To a DCM (30 mL) solution of 1-[4-(1-amino-4,4-difluorocyclohexyl)phenyl]ethanone (3.9 g, 15.40 mmol, 1 equivalent), DIEA (15.92 g, 123.18 mmol, 21.46 mL, 8 equivalents), and 2-(benzyloxycarbonylamino)acetic acid (3.87 g, 18.48 mmol, 1.2 equivalents) was added a T3P solution (14.70 g, 23.10 mmol, 13.74 mL, 50% pure) at 0°C. , 1.5 equiv.) was added. The resulting mixture was stirred at 25 °C for 3 h. The reaction was confirmed to be complete by TLC (PE:EA = 3:1), and the desired product was detected by LCMS. The reaction mixture was concentrated, 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 gel chromatography (ISCO; 40 g Purification was performed on a SepaFlash silica flash column using a gradient elution of 0–60% EA / PE 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. LCMS (Rt = 1.201 min, Ms+1 = 445.3) indicated a purity of 88.8%.

[0612] (Step 5c') To a solution of benzyl (2-{[1-(4-acetylphenyl)-4,4-difluorocyclohexyl]amino}-2-oxoethyl)carbamate (3.85 g, 8.66 mmol, 1 equiv.) and (S) tert-butanesulfinamide (3.67 g, 30.32 mmol, 3.5 equiv.) in anhydrous THF (80 mL) was added Ti(OEt) (5.93 g, 25.99 mmol, 5.39 mL, 3 equiv.) at 20 °C. The reaction mixture was stirred at 80 °C for 16 h. TLC (SiO, PE: EtOAc = 1:1) and LCMS confirmed the reaction was complete. The reaction mixture was then cooled to -70 °C. NaBH (655.37 mg, 17.32 mmol, 2 equiv.) was slowly added to the reaction mixture at -70 °C. The reaction mixture was then warmed to 20°C and stirred for 2 hours. TLC (PE: EtOAc = 1:1) and LCMS (Rt = 1.199 min, Ms+1 = 550.3) confirmed the reaction was complete. MeOH (5 mL) was slowly added to the reaction mixture to quench excess NaBH4 at 0°C, followed by the addition of H2O (25 mL). The reaction mixture was filtered through Celite, and the filter cake was washed with 100 mL of EtOAc (50 mL x 2). The residue was extracted with 40 mL of EtOAc (20 mL x 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. 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) to give 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) as a yellow solid. HPLC (Rt = 3.424 min) showed 98% purity.

[0613] (Step 5d) 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 equiv) was dissolved in HCl / MeOH (4 M, 307.27 mL, 177.79 equiv). The reaction was stirred at 25° C. for 2 hours. LCMS (Rt=0.952 min, Ms+1=446.3) indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The resulting residue was 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) to give the compound 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) as a white solid. LCMS (Rt = 0.952 min, Ms+1 = 446.3) showed 100% purity. 1 HNMR(500MHz,DMSO-d6)δ=8.00(s,1H),7.40(s,1H),7.28-7.38(m,4H),7.27(s,4H),7.17-7.24(m,J=5.95Hz,1H),5.02(s,2 H),3.93(q,J=6.66Hz,1H),3.70(d,J=6.25Hz,2H),2.39-2.48(m,J=12.81Hz,2H),1.77-2.16(m,8H),1.21(d,J=6.56Hz,3H).

[0614] Following the same method, the following compounds were prepared:

[0615] 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 carboxylate]

[0616] [ka]

[0617] 1 HNMR(500MHz,DMSO-d6)δ=8.03(s,1H),7.15-7.44(m,10H),4.94-5.08(m,2H),4.03-4.23(m ,1H),3.93(q,J=6.41Hz,1H),2.44(br.s.,2H),1.72-2.19(m,6H),1.22(dd,J=6.79Hz,6H).

[0618] 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 carboxylate]

[0619] [ka]

[0620] 1HNMR(500MHz,DMSO-d6)δ=8.03(s,1H),7.15-7.42(m,10H),4.98-5.07(m,2H),4.11-4.21( m,1H),3.93(q,J=6.56Hz,1H),2.44(br.s.,2H),1.75-2.18(m,6H),1.22(t,J=6.25Hz,6H).

[0621] Manufacturing Example 20 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 carboxylate] (Step b", Step c' and Step d)

[0622] [ka]

[0623] (Step b)" To a solution of 1-[4-(4-aminotetrahydro-2H-pyran-4-yl)phenyl]ethanone (9 g, 41.04 mmol, 1 equivalent) and benzyl N-(2-oxoethyl)carbamate (8.72 g, 45.15 mmol, 1.1 equivalent) in DCM (90 mL) was added HOAc (3.70 g, 61.57 mmol, 3.52 mL, 1.5 equivalents), and the mixture was stirred at 25°C for 0.5 hours. To the above mixture was added NaBH(OAc) (17.40 g, 82.09 mmol, 2 equivalents) at 25°C. The reaction mixture was stirred at 25°C for 2 hours. TLC (n-hexane: EtOAc = 0:1) confirmed that the reaction was complete. The reaction mixture was quenched with HO (25 mL), filtered through a pad of Celite, extracted with DCM (55 mL × 2), washed with brine (15 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (ISCO; 80 g, SepaFlash silica flash column, gradient elution of 60–75% EtOAc / n-hexane 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. 1 H NMR(400MHz,chloroform-d)δ=9.83(br s,2H),8.06(d,J=8.38Hz,2H),7.82(br d,J=8.13Hz,2H),7.29-7.36(m,5H),4.94(s,2H)6.70(br s,1H),4.01(br d,J=12.01Hz,2H),3.25-3.55(m,4H),2.73(br s,2H)2.54-2.65(m,7H).

[0624] Benzyl (2-{[4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl]amino}ethyl)carbamate (3.5 g, 8.83 mmol, 1 equiv.) was dissolved in DCM (20 mL). Pyridine (4.19 g, 52.97 mmol, 4.28 mL, 6 equiv.) and trifluoroacetic anhydride (7.42 g, 35.31 mmol, 4.91 mL, 4 equiv.) were added to the above mixture at 0 °C and stirred for 1 h. The reaction mixture was then stirred at 25 °C for 5 h. LCMS confirmed the reaction was complete and the desired product was detected. The reaction mixture was diluted with HO (15 mL), extracted with DCM (100 mL × 2), washed with KCO (50 mL) and brine (25 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO; 80 g, SepaFlash silica flash column, gradient elution of 20–25% EtOAc / n-hexane at 100 mL / min) to afford benzyl (2-{[4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl](trifluoroacetyl)amino}ethyl)carbamate (3 g, 5.79 mmol, 65.55% yield, 95% purity) as a yellow oil. 1 HNMR(500MHz,DMSO-d6)δ=7.90(br d,J=8.31Hz,2H),7.64(br d,J=8.44Hz,3H),7.25-7.42(m,1H),7.25-7.43(m,4H),5.06(s,2H),3.64-3.86(m,4H),3.26-3.34(m,3H),2.75(br d,J=11.98Hz,1H),2.57(s,3H),2.26-2.41(m,2H).

[0625] (Step c') To a solution of benzyl (2-{[4-(4-acetylphenyl)tetrahydro-2H-pyran-4-yl](trifluoroacetyl)amino}ethyl)carbamate (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) was added Ti(OEt) (3.89 g, 17.06 mmol, 3.54 mL, 3 equiv.) at 25 °C. The reaction mixture was stirred at 80 °C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was then cooled to -70 °C. Lithium tri-sec-butylborohydride (1 M, 17.06 mL, 3 equiv.) was slowly added to the reaction mixture at -70 °C, and the mixture was stirred for 2 hours. LCMS and HPLC confirmed the reaction was complete. MeOH (5 mL) was slowly added to the reaction mixture to quench excess trisec-butylborohydride at 0°C, followed by the addition of HO (15 mL). The reaction mixture was filtered through Celite, and the filter cake was washed with 30 mL of EtOAc (15 mL x 2). The residue was extracted with 20 mL of EtOAc (10 mL x 2). The combined organic phase was dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Agela DuraShell C18 250 x 80 mm x 10 μm; mobile phase: [water (10 mM NHHCO)-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).

[0626] (Step d) Benzyl {2-[(4-{4-[(1S)-1-{[(R)-tert-butylsulfinyl]amino}ethyl]phenyl}tetrahydro-2H-pyran-4-yl)(trifluoroacetyl)amino]ethyl}carbamate (2 g, 3.31 mmol, 99% purity, 1 equiv.) was dissolved in THF (20 mL) and HO (20 mL), and then I (1.68 g, 6.63 mmol, 1.33 mL, 2 equiv.) was added to the solution. The reaction was stirred at 25 °C for 16 h. LCMS confirmed the reaction was complete. The reaction mixture was quenched with NaSO (2 mL) and HO (10 mL), extracted with DCM (25 mL × 2), washed with brine (15 mL), dried over NaSO, 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) to give benzyl {2-[(4-{4-[(1S)-1-aminoethyl]phenyl}tetrahydro-2H-pyran-4-yl)(trifluoroacetyl)amino]ethyl}carbamate (1.25 g, 2.48 mmol, yield 74.93%, purity 98%) as a white solid. 1 HNMR(500MHz,DMSO-d6)δ=7.60(t,J=5.80Hz,1H),7.16-7.46(m,9H),5.04(s,2H),3.96(q,J=6.66Hz,1H),3.72-3.80(m,J=1 2.05Hz,2H),3.63(t,J=7.63Hz,2H),3.19-3.28(m,3H),2.70(d,J=11.74Hz,2H),2.03-2.40(m,3H),1.24(d,J=6.56Hz,3H).

[0627] Manufacturing Example 21 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 [(VI), X = N, U = Y = CH,

[0628] [ka] , 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 = phenylcarboxylate (Step 2a)

[0629] [ka]

[0630] Phenyl 4-(4-{4-[(1S)-1-aminoethyl]phenyl}tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (377.17 mg, 0.921 mmol, 1.1 equiv.) was dissolved in DMSO (11 mL). 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) were added sequentially to this solution. The reaction mixture was then heated to 75°C for 4 hours and then allowed to stand at room temperature. The reaction mixture was slowly poured into cold water / brine. The precipitated solid was filtered, washed with water, and dried under reduced pressure. The resulting 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 for testing without further purification. 1H NMR(500MHz,DMSO-d6)δ=8.57(s,1H),8.38(d,J=6.86Hz,1H),7.63(d,J=9.15Hz,1H),7.30 -7.42(m,4H),7.24(d,J=8.24Hz,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=6.56Hz,1H),3.81(dd,J=4.96,10.90Hz,2H),3.43-3. 57(m,2H),3.36-3.40(m,4H),1.94-2.32(m,8H),1.50(d,J=7.02Hz,3H),1.24-1.45(m,6H). LCMS:m / z597[M+H] + @rt8.67 minutes. HRMS(ESI)C 34 H 41 N6O4[M+H] + Calculated value: 597.3184, measured value: 597.3157.

[0631] Following the same method, the following compounds were prepared:

[0632] Phenyl 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-carboxylate [(VI), X = N, U = Y = CH,

[0633] [ka] , 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 = phenylcarboxylate]

[0634] [ka]

[0635] 1H NMR(500MHz,DMSO-d6)δ=8.57(s,1H),8.36(d,J=7.02Hz,1H),7.63(d,J=9.15Hz,1H),7. 28-7.38(m,6H),7.19(dd,J=7.32Hz,1H),6.99-7.09(m,2H),6.16(d,J=9.00Hz,1H),5.4 1-5.86(m,1H),5.00(t,J=6.86Hz,1H),3.42-3.57(m,2H),3.32(m,2H),2.34-2.49(m,4H ),1.77-1.95(m,4H),1.49(d,J=7.02Hz,3H),1.23-1.45(m,6H),0.73(q,J=7.17Hz,6H).

[0636] Phenyl 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-carboxylate [(VI), X = N, U = Y = CH,

[0637] [ka] , 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 = phenylcarboxylate]

[0638] [ka]

[0639] LCMS: m / z 569 [M+H] + @rt8.95 minutes.

[0640] Ethyl 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-carboxylate [(VI), X = N, U = Y = CH,

[0641] [ka] , 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 carboxylate]

[0642] [ka]

[0643] 1 H NMR(500MHz,DMSO-d6)δ=8.55(s,1H),8.35(d,J=7.17Hz,1H),7.62(d,J=9.30Hz,1H),7.41(d,J=8.24Hz,2H),7.30(d,J=7.93Hz,2H),6.15(d, J=9.30Hz,1H),5.41-5.67(m,1H),4.98(m,1H),3.95-4.03(m,2H),3.29 (br.,s,4H),2.25-2.39(m,4H),1.21-1.53(m,15H),1.10-1.16(m,3H).

[0644] Phenyl 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-carboxylate [(VI), X = N, U = Y = CH,

[0645] [ka] , 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 = phenylcarboxylate]

[0646] [ka]

[0647] 1 H NMR(500MHz,DMSO-d6)δ=8.52-8.60(m,1H),8.36(d,J=6.25Hz,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=5.49Hz,1 H),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). LCMS:m / z638[M+H] + @rt8.70 minutes. HRMS(ESI)C 36 H 43 N7O4[M+H] + Calculated value 638.3450, actual value 638.34.

[0648] Phenyl 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-carboxylate [(VI), X = N, U = Y = CH,

[0649] [ka] , 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 = phenylcarboxylate]

[0650] [ka]

[0651] 1 H NMR(500MHz,DMSO-d6)δ=8.57(s,1H),8.36(d,J=6.86Hz,1H),7.63(d,J=9. 30Hz,1H),7.30-7.42(m,4H),7.21-7.27(m,2H),7.17(t,J=7.32Hz,1H),6.9 0-7.05(m,2H),6.18(d,J=9.30Hz,1H),5.450-5.46(m,1H),4.96-5.03(m,1 H),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). LCMS:m / z597[M+H] + @rt8.58 minutes. HRMS(ESI)C 34 H 41 N6O4[M+H] + Calculated value: 597.3184, measured value: 597.3185.

[0652] Phenyl 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-carboxylate [(VI), X = N, U = Y = CH,

[0653] [ka] , 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 = phenylcarboxylate]

[0654] [ka]

[0655] 1 H 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=9.3 0Hz,1H),7.27-7.39(m,2H),7.15-7.22(m,1H),6.91-7.07(m,2H),6.20(d,J=8.39Hz,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),3.18-3.3 0(4H),2.18-2.34(m,6H),1.97-2.07(m,2H),1.53(d,J=7.02Hz,3H),1.22-1.31(m,6H). LCMS:m / z598[M+H] + @rt5.95min.

[0656] Phenyl 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-carboxylate [(VI), X = N, U = Y = CH,

[0657] [ka] , 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 = phenylcarboxylate]

[0658] [ka]

[0659] 1 H NMR(DMSO-d6)δ=8.00-8.37(m,1H),7.81(d,J=9.61Hz,1H),7.30-7.45(m,4H),7. 23(d,J=8.24Hz,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=4.96,10.75Hz,4H),3.48( br.m,4H),2.54(s,3H),2.01-2.33(m,8H),1.48(d,J=7.02Hz,3H),0.90-1.42(br m,6H). LCMS:LCMS:m / z611[M+H] + @rt6.8 minutes.

[0660] Phenyl 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-carboxylate [(VI), X = N, U = Y = CH,

[0661] [ka] , 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 = phenylcarboxylate]

[0662] [ka]

[0663] 1 H NMR(DMSO-d6)δ=8.59(s,1H),8.44(d,J=7.02Hz,1H),7.68(d,J=9.30Hz,1H),7.22-7.40(m,4 H),7.18(dd,J=7.47,7.32Hz,1H),7.02(,dd,J=2.90,6.71Hz,1H),6.97(d,J=7.78Hz,1H),6.2 2(d,J=9.30Hz,1H),5.04(t,J=6.94Hz,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=7.02Hz,3H),0.83(t,J=6.86Hz,3H). LCMS:m / z583[M+H] + @rt6.26 minutes.

[0664] Phenyl 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-carboxylate [(VI), X = N, U = methyl, Y = CH,

[0665] [ka] , 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 = phenylcarboxylate]

[0666] [ka]

[0667] 1 H NMR(DMSO-d6)δ=8.66(s,1H),8.36(d,J=6.86Hz,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=7.93Hz,2H),6.05(d,J=1.07Hz,1H),5.55(d,J=8.8 5Hz,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=7.02Hz,3H),1.23-1.47(m,4H). LCMS:m / z636[M+H] + @rt10.06min.

[0668] Phenyl 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-carboxylate [(VI), X = N, U = Y = CH,

[0669] [ka] , 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 = phenylcarboxylate]

[0670] [ka]

[0671] 1H NMR(DMSO-d6)δ=8.57(s,1H),8.38(br.s.,1H),7.63(d,J=9.15Hz,1H),7.27-7.43(m,6 H),7.13-7.23(m,1H),6.93-7.09(m,2H),6.17(d,J=7.78Hz,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=7.02Hz,3H),1.30-1.45(m,6H). LCMS:m / z583[M+H] + @rt10.41min.

[0672] Phenyl 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-carboxylate [(VI), X = N, U = CMe, Y = CH,

[0673] [ka] , 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 = phenylcarboxylate]

[0674] [ka]

[0675] 1H NMR(DMSO-d6)δ=8.64(s,1H),8.35(d,J=6.86Hz,1H),7.22-7.45(m,6H),7.14 -7.21(m,1H),6.90-7.06(m,2H),6.05(br.s.,1H),5.45(br.s.,1H),4.94-5. 33(m,1H),3.81(dd,J=5.26,10.75Hz,2H),3.43-3.54(m,2H),3.29-3.33(m,4 H),2.29(s,3H),2.02-2.28(m,8H),1.49(d,J=7.02Hz,3H),1.23-1.44(m,6H). LCMS: m / z 611 [M+H] + @rt9.02min.

[0676] Phenyl 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-carboxylate [(VI), X=N, U=Y=CH,

[0677] [ka] , 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 = phenylcarboxylate]

[0678] [ka]

[0679] 1H NMR(DMSO-d6)δ=8.57(s,1H),8.37(d,J=6.86Hz,1H),7.63(d,J=9.30Hz,1H),7.27- 7.40(m,6H),7.15-7.21(m,1H),6.91-7.06(m,2H),6.17(d,J=8.24Hz,1H),5.47(br. s.,1H),4.99(t,J=6.86Hz,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=6.86Hz,3H),1.33-1.44(m,6H). LCMS:m / z581[M+H] + @rt9.06min.

[0680] Phenyl 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-carboxylate [(VI), X = N, U = methyl, Y = CH,

[0681] [ka] , 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 = phenylcarboxylate]

[0682] [ka]

[0683] 1H NMR(DMSO-d6)δ=8.58(s,1H),8.30-8.44(m,1H),7.66(d,J=9.30Hz,1H),7.29-7.43(m,4 H),7.24(d,J=8.24Hz,2H),7.13-7.21(m,1H),6.90-7.03(m,2H),6.08-6.26(m,1H),4.8 9-5.36(m,2H),3.81(dd,J=3.20,7.17Hz,2H),3.46-3.55(m,2H),1.71-2.25(m,12H),1. 48(d,J=7.02Hz,3H),0.63-0.81(m,3H),0.31(t,J=7.32Hz,2H),0.19(t,J=7.32Hz,1H).

[0684] Phenyl 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-carboxylate [(VI), X = N, U = methyl, Y = CH,

[0685] [ka] , 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 = phenylcarboxylate]

[0686] [ka]

[0687] 1H NMR(DMSO-d6)δ=7.64-7.75(m,1H),7.30-7.40(m,4H),7.23(d,J=8.24Hz,2H ),7.16-7.20(m,1H),6.93-7.05(m,2H),5.85-5.99(m,1H),5.54(br.s.,1H), 4.92-5.15(m,1H),3.76-3.88(m,2H),3.50(br.s.,2H),3.36-3.40(m,2H),2. 97-3.13(m,6H),1.97-2.33(m,8H),1.46(d,J=6.87Hz,3H),1.04-1.40(m,6).

[0688] Manufacturing Example 22 Phenyl 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-carboxylate [(VI), X=N, U=Y=CH,

[0689] [ka] , 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 = phenylcarboxylate (Step 2a)

[0690] [ka]

[0691] Phenyl 4-{4-[4-(2-aminopropan-2-yl)phenyl]tetrahydro-2H-pyran-4-yl}piperazine-1-carboxylate (143 mg, 0.34 mmol, 1 equiv.) was dissolved in 1,4-dioxane (6 mL). 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.) were then added sequentially to this solution. The reaction mixture was then heated to 60°C for 48 hours and then allowed to warm to room temperature. The reaction mixture was slowly poured into cold water / brine. The precipitated solid was filtered, washed with water, and dried under vacuum. The title compound was obtained as a solid (144 mg, 77%) and was used without further purification. 1 H NMR(DMSO-d6)δ=8.57(s,1H),8.21(br.s.,1H),7.61(d,J=8.85Hz,1H),7.32 -7.39(m,4H),7.16-7.24(m,3H),6.94-7.05(m,2H),6.12(d,J=9.15Hz,1H),4 .98-5.28(m,1H),3.81(t,J=8.46Hz,2H),3.49(br.s.,2H),3.36-3.43(m,4H ),2.12-2.34(m,6H),1.99(br.s.,2H),1.65-1.77(m,6H),0.91-1.35(m,6H). LCMS: m / z 611 [M+H] + @rt3.98min.

[0692] Following the same method, the following compounds were prepared:

[0693] Phenyl 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-carboxylate [(VI), X=N, U=Y=CH,

[0694] [ka] , 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 = phenylcarboxylate]

[0695] [ka]

[0696] 1 H NMR(DMSO-d6)δ=8.65(s,1H),8.61(s,1H),7.67(d,J=9.30Hz,1H),7.30-7.40(m,1H),7.15-7.22(m,3H),7.08-7.14(m,2H),6.98(d,J=7.78Hz) ,2H),6.23(d,J=9.30Hz,1H),5.37(br.s,1H),3.72-3.85(m,2H),3.48 (br.s.,2H),3.25-3.32(m,4H),1.94-2.31(m,8H),1.03-1.54(m,10H).

[0697] Manufacturing Example 23 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,

[0698] [ka] , 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 = phenylcarboxylate (Step 2a)

[0699] [ka]

[0700] 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) 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, and the mixture was heated to 100 °C overnight. After cooling to room temperature, the mixture was filtered through a silica gel plug and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-40% acetone / EtOAc). 1 H NMR(DMSO-d6)δ=8.31(s,1H),7.62(d,J=9.30Hz,1H),7.45-7.49(m,1H),7.40(d,J=8.24Hz ,2H),7.30-7.36(m,2H),7.27(d,J=8.24Hz,2H),7.14-7.20(m,1H),6.95-7.02(m,2H),6.43 (br.m,1H),6.12(d,J=9.46Hz,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=6.86Hz,3H),1.41(d,J=6.56Hz,3H),1.22-1.28(br.m,3H). LCMS:m / z596[M+H] + @rt7.39 minutes. HRMS(ESI)C 35 H 42 N5O4[M+H] + Calculated value: 596.3232, measured value: 596.3244.

[0701] Following the same method, the following compounds were prepared:

[0702] 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,

[0703] [ka] , 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 carboxylate]

[0704] [ka]

[0705] 1 H NMR(DMSO-d6)δ=8.29(s,1H),7.61(d,J=9.30Hz,1H),7.45(d,J=6.25Hz,1H),7.34-7.40(m,2H),7.23-7.34(m,7H),6 .17-6.41(m,1H),6.11(d,J=9.15Hz,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).

[0706] 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,

[0707] [ka] , 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 = phenylcarboxylate]

[0708] [ka]

[0709] 1 H NMR(DMSO-d6)δ=8.30(s,1H),7.62(d,J=9.46Hz,1H),7.43-7.53(m,1H),7.37-7.43(m,2H) ,7.28-7.37(m,4H),7.12-7.20(m,1H),6.99(d,J=7.78Hz,2H),6.17-6.54(m,1H),6.12(d, J=8.85Hz,2H),4.73-5.18(m,2H),3.50(d,J=3.97Hz,2H),3.25-3.33(m,2H),2.55(d,J=11 .90Hz,2H),2.03-2.34(m,6H),1.80(br.s.,4H),1.48(d,J=6.86Hz,3H),1.18-1.44(m,6H).

[0710] 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,

[0711] [ka] , 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 carboxylate]

[0712] [ka]

[0713] 1 H NMR(DMSO-d6)δ=8.26(s,1H),7.57(d,J=9.30Hz,1H),7.43(d,J=7.17Hz,1H),7.23-7.37(m,10H),6.31-6.47(m,1H),6.09(d,J=9.15Hz,1H),4.9 4(br.s.,3H),4.15(t,J=6.86Hz,1H),3.40-3.72(m,4H),2.31-2.40(m,2 H),2.11(s,3H),1.88-2.02(m,4H),1.71(br.s.,2H),1.21-1.47(m,9H).

[0714] 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,

[0715] [ka] , 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 carboxylate]

[0716] [ka]

[0717] 1H NMR(DMSO-d6)δ=8.26(s,1H),7.59(d,J=9.30Hz,1H),7.44(d,J=7.02Hz,1H),7. 27-7.38(m,7H),7.23(d,J=8.39Hz,2H),6.26-6.57(m,1H),6.10(d,J=9.30Hz,1 H),4.83-5.13(m,J=5.19Hz,3H),4.51-4.72(m,1H),4.05-4.34(m,4H),2.54-2. 65(m,2H),2.06(s,3H),1.89-2.04(m,4H),1.64-1.86(m,2H),1.21-1.53(m,9H).

[0718] Manufacturing Example 24 Phenyl 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-carboxylate [(VI), X = N, U = Y = CH,

[0719] [ka] , 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, PG = phenylcarboxylate

[0720] [ka]

[0721] To a solution of phenyl 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-carboxylate (175 mg, 0.227 mmol) in CHCl (5 mL) was added trifluoroacetic acid (2 mL). The yellow solution was stirred at room temperature overnight. 15 mL of CHCl was added, and the organic solution was washed with saturated NaHCO solution, dried over NaSO, 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 H NMR(DMSO-d6)δ=7.84(d,J=9.6Hz,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).

[0722] Manufacturing Example 25 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,

[0723] [ka] , 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] (Step 2b)

[0724] [ka]

[0725] 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 i-propanol (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. 5-10% of the isopropyl carbamate was still present in the mixture. The crude product is dissolved in DCM and water (pH 10), the organic phase is separated, washed with brine, dried (NaSO), and the volatiles are removed in vacuo to give 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%). 1 H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.13-8.41(m,1H),7.63(d,J=9.30Hz,1H),7.29-7.42(m,2H),7.13-7.24(m,2H),6.16(d,J=9.30H) z,1H),5.49(br.s.,1H),4.91-5.35(m,1H),3.76(d,J=7.47Hz,2H),3.36(m,3H),2.55-2.62(m,4H),1.85-2.20(m,8H)1.49(d,J=6.81Hz) 3H),1.21-1.43(m,6H).

[0726] Following the same method, the following compounds were prepared:

[0727] 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,

[0728] [ka] , 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]

[0729] [ka]

[0730] 1 H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.34(d,J=7.17Hz,1H),7.63(d,J=9.1 5Hz,1H),7.30-7.39(m,2H),7.15-7.24(m,2H),6.16(d,J=9.15Hz,1H),5.42 -5.56(m,1H),5.02-5.04(m,1H),3.71-3.80(m,2H),3.28-3.37(m,2H),2.55 -2.61(m,4H),1.95-2.15(m,8H),1.47(d,J=6.86Hz,3H),1.03-1.44(m,6H).

[0731] 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,

[0732] [ka] , 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]

[0733] [ka]

[0734] 1 H NMR(500MHz,DMSO-d6)δ=8.58(s,1H),8.42(d,J=7.02Hz,1H),7.68(d,J=9.30H z,1H),7.32-7.42(m,2H),7.15-7.25(m,2H),6.21(d,J=9.30Hz,1H),5.06(t,J =7.09Hz,1H),4.05-4.30(m,2H),3.64-3.87(m,2H),3.26-3.31(m,2H),2.57-2 .69(m,4H),1.88-2.22(m,8H),1.49(d,J=6.86Hz,3H),0.91(t,J=6.71Hz,3H).

[0735] 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,

[0736] [ka] , 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]

[0737] [ka]

[0738] 1H 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=9.3 0Hz,1H),7.27-7.39(m,3H),7.15-7.22(m,1H),6.91-7.07(m,2H),6.20(d,J=8.39Hz,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),3.19-3.3 0(m,2H),2.16-2.35(m,4H),1.97-2.07(m,2H),1.53(d,J=7.0Hz,3H),1.22-1.45(m,6H).

[0739] 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,

[0740] [ka] , 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]

[0741] [ka]

[0742] 1H NMR(500MHz,DMSO-d6)δ=8.29(d,J=7.32Hz,1H),7.80(d,J=9.61Hz,1H),7.2 7-7.43(m,2H),7.16-7.23(m,2H),6.12(d,J=9.76Hz,1H),5.47-5.57(m,1H), 4.98-5.03(m,1H),3.76(d,J=7.17Hz,2H),3.25-3.33(m,2H),2.58(br.s.,4H) ),2.48(s,3H),1.89-2.22(m,8H),1.47(d,J=7.02Hz,3H),1.12-1.41(m,6H).

[0743] 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,

[0744] [ka] , 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]

[0745] [ka]

[0746] 1H NMR(DMSO-d6)δ=8.64(s,1H),8.35(d,J=6.86Hz,1H),7.31(d,J=7.78Hz,2H),7.19 (d,J=7.93Hz,2H),6.01-6.07(m,1H),5.53-5.92(m,1H),4.99(t,J=6.86Hz,1H),3. 67-3.90(m,2H),3.27-3.31(m,2H),2.58(br.s.,3H),2.29(s,5H),1.92-2.17(m,8 H),1.67-1.88(m,4H),1.55(br.s.,2H),1.49(d,J=7.02Hz,3H),1.35-1.42(m,2H).

[0747] 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,

[0748] [ka] , 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]

[0749] [ka]

[0750] 1 H NMR(DMSO-d6)δ=8.50-8.59(m,1H),8.37(br.s.,1H),7.62(d,J=9.30Hz,1H),7.20-7.42(m,4H),6.16(d,J=9.00Hz,1H),5.49(b r.s.,1H),5.02(br.s.,1H),3.80-4.05(m,5H),2.61-2.71(m,4H),2.08-2.36(m,6H),1.48(d,J=7.02Hz,3H),1.12-1.42(m,6H).

[0751] 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,

[0752] [ka] , 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]

[0753] [ka]

[0754] 1 H NMR(DMSO-d6)δ=8.63(s,1H),8.10-8.38(m,1H),7.27-7.43(m,2H),7.11-7.25(m,2H),6.03(s,1H),5.48(br.s.,1H),5.03(br.s.,1H), 3.76(d,J=6.71Hz,2H),3.26-3.33(m,2H),2.58(br.s.,5H),2.29(s,3H),1.83-2.24(m,8H),1.49(d,J=6.86Hz,3H),1.27-1.43(m,6H).

[0755] 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,

[0756] [ka] , 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]

[0757] [ka]

[0758] 1 H NMR(DMSO-d6)δ=8.56(s,1H),8.14-8.39(m,1H),7.62(d,J=9.15Hz,1H),7.28-7.39(m,2H),7.23-7.27(m,2H),6.15(d,J=9.15Hz,1H) ),5.50(br.s.,1H),4.94-5.35(m,1H),2.58(br.s.,4H),2.06-2.29(m,4H),1.82-2.03(m,5H),1.65(br.s.,2H),0.82-1.54(m,11H).

[0759] 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,

[0760] [ka] , 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]

[0761] [ka]

[0762] LCMS: m / z 514 [M+Na] +@rt6.16 minutes. HRMS(ESI)C 27 H 38 N7NaO2[M+Na] + Calculated value 514.2907, measured value 514.2907.

[0763] 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,

[0764] [ka] , 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]

[0765] [ka]

[0766] 1 H NMR(DMSO-d6)δ=8.53-8.61(m,1H),8.28-8.42(m,1H),7.66(d,J=9.30Hz,1 H),7.27-7.41(m,2H),7.19(d,J=8.08Hz,2H),6.08-6.27(m,1H),4.83-5.39 (m,2H),3.71-3.86(m,3H),3.29-3.33(m,2H),2.56-2.66(m,4H),1.70-2.1 8(m,12H),1.48(d,J=7.0Hz,3H),0.62-0.81(m,3H),0.35(t,J=7.47Hz,3H).

[0767] 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,

[0768] [ka] , 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]

[0769] [ka]

[0770] LCMS: m / z 520 [M+H] + @rt7.77 minutes. HRMS(ESI)C 29 H 42 N7O2[M+Na] + Calculated value: 520.3395, measured value: 520.3393.

[0771] Manufacturing Example 26 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,

[0772] [ka] , 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)

[0773] [ka]

[0774] To a 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) was added ammonium formate (1.4 mL of a 25% aqueous solution) under a stirred nitrogen atmosphere, followed by 10% Pd / C (120 mg). The suspension was stirred at 60°C for 1 hour. The catalyst was removed by filtration through a Celite pad, and the filtrate was evaporated to dryness under reduced pressure to give the title product (150 mg, 96% yield). 1 H NMR(500MHz,DMSO-d6)δ=8.53-8.58(m,1H),8.37(d,J=7.02Hz,1H),7.58-7.67( m,1H),7.31-7.37(m,2H),7.26(d,J=7.93Hz,2H),6.65(s,1H),6.16(d,J=9.46H z,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=6.10Hz,3H),1.35(m,6H). LCMS: m / z 477 [M+H] + @rt6.28 minutes. HRMS(ESI)C 27 H 37 N6O2[M+H] + Calculated value: 477.2973, measured value: 477.2971.

[0775] Following the same method, the following compounds were prepared:

[0776] 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,

[0777] [ka] , 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]

[0778] [ka]

[0779] 1 H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.37(d,J=6.71Hz,1H),7.62(d,J=9.30Hz,1H),7.22-7.42(m,4H),6.16(d,J=9.30H) z,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). LCMS:m / z511[M+H] + @rt8.63 minutes. HRMS(ESI)C 28 H 37 F2N6O2[M+H] + Calculated value: 511.2992, measured value: 511.2987.

[0780] 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,

[0781] [ka] , 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]

[0782] [ka]

[0783] 1 H NMR(DMSO-d6)δ=8.19-8.38(m,1H),7.61(d,J=9.30Hz,1H),7.26-7.47(m,5H),6.11(d,J=9.30Hz,1 H),4.79-5.16(m,1H),2.67-2.72(m,4H),2.02-2.20(m,8H),1.66-1.82(m,4H),1.15-1.52(m,9H).

[0784] 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-alaninamide [(II), X = N, U = Y = CH,

[0785] [ka] , 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]

[0786] [ka]

[0787] LCMS: m / z 513 [M+H] +@rt9.60 minutes. HRMS(ESI)C 27 H 35 F2N6O2[M+H] + Calculated value: 513.2784, measured value: 513.2774.

[0788] 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-alaninamide [(II), X = N, U = Y = CH,

[0789] [ka] , 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]

[0790] [ka]

[0791] LCMS: m / z 513 [M+H] + @rt9.58 minutes. HRMS(ESI)C 27 H 35 F2N6O2[M+H] + Calculated value: 513.2784, measured value: 513.2772. [Example]

[0792] [Example 1] 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,

[0793] [ka] , 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] (Compound 1, Step 1a)

[0794] [ka]

[0795] 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) was added acryloyl chloride (0.01 mL, 0.13 mmol) at 0 °C. After 30 min, 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 (1-10% MeOH / DCM) to give the title product (40 mg, 66%) as a white foam. 1 H NMR(500MHz,DMSO-d6)δ=8.55(s,1H),8.31(d,J=6.71Hz,1H),7.61(d,J=9.28Hz,1H),7.33(d,J =7.81Hz,2H),7.21(d,J=8.18Hz,2H),6.63(dd,J=10.50,16.72Hz,1H),6.15(d,J=9.28Hz,1H), 5.91-6.03(m,1H),5.55(d,J=10.62Hz,1H),5.42(br.m.1H),5.00(t,J=6.65Hz,1H),3.79(d,J= 7.08Hz,2H),3.34-3.54(m,6H),2.12(br.s.,8H),1.49(d,J=6.96Hz,3H),1.42-1.21(br.m.6H). LCMS:m / z531[M+H] + @rt6.03 minutes. HRMS(ESI)C30 H 39 N6O3[M+H] + Calculated value: 531.3078, measured value: 531.3067.

[0796] Following the same method, the following compounds were prepared:

[0797] 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,

[0798] [ka] , 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] (Compound 2)

[0799] [ka]

[0800] 1 H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.35(d,J=6.86Hz,1H),7.62(d,J=9.30Hz,1H),7.38-7.46 (m,2H),7.24-7.36(m,2H),6.73(dd,J=10.45,16.70Hz,1H),6.15(d,J=9.30Hz,1H),5.99-6.10(m ,1H),5.63(dd,J=2.14,10.52Hz,1H),5.40-5.56(br.s.,1H),4.98(q,J=6.71Hz,1H),3.46(br.s. ,4H),2.22-2.41(m,4H),1.47(d,J=6.71Hz,3H),1.29-1.44(br.m,6H),1.25(s,3H),1.24(s,3H). LCMS:m / z489[M+H] + rt6.49 minutes. HRMS(ESI)C28 H 37 N6O2[M+H] + Calculated value: 489.2973, measured value: 489.2979.

[0801] 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,

[0802] [ka] , 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] (Compound 3)

[0803] [ka]

[0804] 1 H NMR(500MHz,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=10.45,16.70Hz,1H),6.15(d,J=9.30Hz,1H),5.93-6. 00(m,1H),5.56(d,J=10.37Hz,1H),5.35-5.42(br.,m,1H),4.99(q,J=7.30Hz,1H),4.69-4.7 5(m,4H),3.52(br.s.,4H),1.99-2.22(m,4H),1.48(d,J=7.30Hz,3H),1.17-1.32(br.,m,6H). LCMS:m / z503[M+H] + @rt8.72 minutes. HRMS(ESI)C 28 H 35 N6O3[M+H] +Calculated value: 503.2765, measured value: 503.2758.

[0805] 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 [X=N, U=Y=CH,

[0806] [ka] , 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] (Compound 4)

[0807] [ka]

[0808] 1 H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.34(d,J=6.86Hz,1H),7.62(d,J=9.30Hz,1H),7.18-7.39(m, 4H),6.68(dd,J=10.45,16.55Hz,1H),6.15(d,J=9.30Hz,1H),6.02(dd,J=1.91,16.55Hz,1H),5.59(d d,J=1.91,10.29Hz,1H),5.37-5.42(br.,m,1H),4.99(t,J=6.63Hz,1H),3.37-3.51(m,4H),2.25-2. 41(m,4H),1.75-1.94(m,4H),1.48(d,J=7.02Hz,3H),1.35-1.44(br.,m,6H),0.70(q,J=6.96Hz,6H). LCMS:m / z517[M+H] + @rt7.73 minutes. HRMS(ESI)C 30 H 41 N6O2[M+H] + Calculated value: 517.3286, measured value: 517.3271.

[0809] 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,

[0810] [ka] , 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] (Compound 6)

[0811] [ka]

[0812] 1 H NMR(500MHz,DMSO-d6)δ=8.48-8.59(m,1H),8.34(d,J=6.71Hz,1H),7.62(d,J=9.30Hz ,1H),7.32(d,J=8.08Hz,2H),7.23(d,J=8.08Hz,2H),6.64(dd,J=10.45,16.70Hz,1H), 6.15(d,J=9.30Hz,1H),5.97(d,J=16.47Hz,1H),5.56(d,J=10.68Hz,1H),5.36-5.42( br.,m,1H),4.99(t,J=6.62Hz,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=7.02Hz,3H),1.35-1.44(br.,m,6H). LCMS:m / z572[M+H] + @rt6.71 minutes. HRMS(ESI)C 32 H 42 N7O3[M+H] + Calculated value: 572.3344, measured value: 572.3356.

[0813] 2-{[(1S)-1-{4-[4-(4-propanoylpiperazin-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,

[0814] [ka] , 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 = propanoyl] (Compound 8).

[0815] [ka]

[0816] 1 H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.13-8.38(m,1H),7.62(d,J=9.30Hz,1H), 7.30-7.43(m,2H),7.20(d,J=8.08Hz,2H),6.15(d,J=9.30Hz,1H),5.35-5.85(m, 1H),4.90-5.32(m,1H),3.79(dd,J=5.41,10.75Hz,2H),3.26-3.32(m,6H),1.93- 2.28(m,10H),1.48(d,J=7.02Hz,3H),1.35-1.44(br.,m,6H),0.81-0.88(m,3H). LCMS:m / z533[M+H] + @rt6.38 minutes. HRMS(ESI)C 30 H 41 N6O3[M+H] + Calculated value: 533.3235, measured value: 533.3232.

[0817] 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,

[0818] [ka] , 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] (Compound 9).

[0819] [ka]

[0820] 1 H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.34(d,J=6.86Hz,1H),7.62(d,J=9.30Hz,1H),7.29-7.42(m,2 H),7.18-7.24(m,2H),6.64(dd,J=10.52,16.78Hz,1H),6.15(d,J=9.30Hz,1H),5.96(dd,J=1.98,16. 78Hz,1H),5.55(dd,J=1.98,10.52Hz,1H),5.32-5.47(m,1H),4.94-5.12(m,1H),3.79(dd,J=4.96,10 .60Hz,2H),3.39-3.49(br.,m,6H),2.10(br.s.,8H),1.48(d,J=7.02Hz,3H),1.23-1.40(br.,m,6H). LCMS: m / z 531 [M+H] + @rt6.36 minutes. HRMS(ESI)C 30 H 39 N6O3[M+H] + Calculated value: 531.3078, measured value: 531.3077.

[0821] 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,

[0822] [ka] , 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] (Compound 12)

[0823] [ka]

[0824] 1 H NMR(500MHz,DMSO-d6)δ=8.50-8.64(m,2H),8.41(d,J=6.71Hz,1H),7.69-7.85(m,1H),7.63(d,J=9. 30Hz,1H),7.31(d,J=8.24Hz,1H),6.64(dd,J=10.29,16.55Hz,1H),6.17(d,J=9.30Hz,1H),5.97(d, J=16.17Hz,1H),5.56(d,J=10.52Hz,1H),5.41(br.s,1H),5.04(q,J=6.71Hz,1H),3.74-3.82(m,2H) ,3.37-3.45(m,4H),3.15-3.28(m,2H),1.96-2.32(m,8H),1.50(d,J=7.02Hz,3H),1.20-1.42(m,6H). LCMS: m / z 532 [M+H] + @rt4.69 minutes.

[0825] 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,

[0826] [ka] , 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] (Compound 13)

[0827] [ka]

[0828] 1 H NMR(500MHz,DMSO-d6)δ=8.27(d,J=6.86Hz,1H),7.80(d,J=9.46Hz,1H),7.31(d,J=7.93Hz,2H),7.19( d,J=8.08Hz,2H),6.63(dd,J=10.37,16.78Hz,1H),6.12(d,J=9.30Hz,1H),5.96(dd,J=2.06,16.70Hz,1 H),5.55(dd,J=2.14,10.22Hz,1H),5.44(br.s,1H),4.98(q,J=6.56Hz,1H),3.75-3.82(m,2H),3.38-3. 46(m,4H),3.27-3.32(m,2H),2.48(s,3H),2.0-2.18(m,8H),1.47(d,J=7.02Hz,3H),1.18-1.42(m,6H). LCMS: m / z 545 [M+H] + @rt4.69 minutes. HRMS(ESI)C 31 H 41 N7O3[M+H] + Calculated value: 545.3235, measured value: 545.3232.

[0829] 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,

[0830] [ka] , 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] (Compound 14)

[0831] [ka]

[0832] 1 H NMR(500MHz,DMSO-d6)δ=8.58(s,1H),8.40(d,J=7.17Hz,1H),7.67(d,J=9.30Hz,1H),7.35(d,J= 8.10Hz,2H),7.21(d,J=8.10Hz,2H),6.64(dd,J=10.52,16.62Hz,1H),6.20(d,J=9.30Hz,1H),5.9 6(dd,J=2.13,16.62Hz,1H),5.51-5.64(m,1H),5.03(t,J=6.94Hz,1H),3.91-4.16(m,2H),3.74-3 .86(m,2H),3.40-3.47(m,6H),1.94-2.24(m,8H),1.47(d,J=7.17Hz,3H),0.79(t,J=6.86Hz,3H). LCMS: m / z 517 [M+H] + @rt4.93 minutes. HRMS(ESI)C 29 H 37 N6O3[M+H] + Calculated value: 517.3078, measured value: 517.3077.

[0833] 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,

[0834] [ka] , 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] (Compound 15)

[0835] [ka]

[0836] 1 H NMR(500MHz,DMSO-d6)δ=8.64(s,1H),8.32(d,J=7.02Hz,1H),7.29(d,J=8.08Hz,2H),7.20(d,J=8.08 Hz,2H),6.64(dd,J=10.37,16.62Hz,1H),6.03(s,1H),5.97(dd,J=1.83,16.62Hz,1H),5.54-5.64(m, 1H),5.51(q,J=9.01Hz,1H),4.96(q,J=6.94Hz,1H),3.70-3.86(m,2H),3.41-3.51(m,4H),3.29-3.32 (m,2H),2.29(s,3H),1.97-2.22(m,8H),1.64-1.92(m,4H),1.47(d,J=7.17Hz,3H),1.23-1.45(m,4H). LCMS: m / z 571 [M+H] + @rt8.0 minutes.

[0837] 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,

[0838] [ka] , 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] (Compound 11)

[0839] [ka]

[0840] 1 H NMR(500MHz,DMSO-d6)δ=8.29(s,1H),7.61(d,J=9.30Hz,1H),7.43(d,J=6.71Hz,1H),7.37(d, J=8.24Hz,2H),7.23(d,J=8.24Hz,2H),6.66(dd,J=10.52,16.62Hz,1H),6.30(br.s.,1H),6.1 0(d,J=9.30Hz,1H),5.98(dd,J=2.29,16.62Hz,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=6.71Hz,3H),1.23-1.40(m,6H). LCMS:m / z530[M+H] + @rt4.72 minutes. HRMS(ESI)C 31 H 40 N5O3[M+H] + Calculated value: 530.3126, measured value: 530.3128.

[0841] 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,

[0842] [ka] , 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] (Compound 17)

[0843] [ka]

[0844] 1 H NMR(500MHz,DMSO-d6)δ=8.51-8.60(m,1H),8.12-8.38(m,1H),7.62(d,J=9.30Hz,1H),7. 20-7.35(m,4H),6.60-6.72(m,1H),6.15(d,J=9.30Hz,1H),5.91-6.09(m,1H),5.55-5.61( m,1H),5.43(br.s,1H),4.93-5.05(m,1H),3.99-4.10(m,1H),3.85-3.98(m,2H),3.56-3.6 5(m,1H),3.39-3.53(m,4H),2.09-2.42(m,6H),1.47(d,J=7.02Hz,3H),1.23-1.39(m,6H). LCMS: m / z 517 [M+H] + @rt7.77 minutes.

[0845] 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,

[0846] [ka] , 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] (Compound 16)

[0847] [ka]

[0848] 1 H NMR(500MHz,DMSO-d6)δ=8.55(s,1H),8.33(d,J=6.86Hz,1H),7.62(d,J=9.30Hz,1H),7 .20-7.37(m,4H),6.64(dd,J=10.37,16.62Hz,1H),6.15(d,J=9.30Hz,1H),5.97(dd,J= 1.91,16.70Hz,1H),5.52-5.61(m,1H),5.42(br.s,1H),4.98(t,J=7.02Hz,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). LCMS:m / z515[M+H] + @rt7.01 minutes.

[0849] 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,

[0850] [ka] , 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] (Compound 18)

[0851] [ka]

[0852] 1 H NMR(500MHz,DMSO-d6)δ=8.62(s,1H),8.31(d,J=6.71Hz,1H),7.27-7.42(m,2H),7.1 3-7.26(m,2H),6.63(dd,J=10.52,16.62Hz,1H),6.03(s,1H),5.85-5.99(m,1H),5.5 1-5.60(m,1H),5.39(br.s,1H),4.99(t,J=6.86Hz,1H),3.79(dd,J=5.57,11.06Hz,2 H),3.40-3.49(m,2H),3.28-3.33(m,4H),2.28(s,3H),2.08(d,J=9.91Hz,8H),1.47(d J=7.0Hz,3H),1.23-1.39(m,6H). LCMS:m / z545[M+H] + @rt6.81 minutes.

[0853] 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,

[0854] [ka] , 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] (Compound 19)

[0855] [ka]

[0856] 1 H NMR(500MHz,DMSO-d6)δ=7.83(d,J=9.61Hz,1H),7.35-7.47(m,1H),7.16-7.33( m,4H),6.97(br.s.,2H),6.64(dd,J=10.60,16.40Hz,1H),5.83-6.06(m,2H),5. 56(d,J=10.07Hz,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=7.02Hz,3H),1.21-1.35(m,6H). LCMS: m / z 546 [M+H] + @rt5.88min.

[0857] 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,

[0858] [ka] , 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] (Compound 21)

[0859] [ka]

[0860] 1 H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.36(d,J=7.02Hz,1H),7.62(d,J=9.30Hz,1H), 7.33(d,J=7.93Hz,2H),7.20(d,J=8.08Hz,2H),6.15(d,J=9.15Hz,1H),5.37-5.87(m,1 H),5.05(s,1H),4.99(d,J=6.71Hz,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=6.76Hz,3H),1.23-1.41(m,6H). LCMS:m / z545[M+H] + @rt6.93 minutes. HRMS(ESI)C 31 H 41 N6O3[M+H] + Calculated value: 545.3078, measured value: 545.306.

[0861] 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,

[0862] [ka] , 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] (Compound 22)

[0863] [ka]

[0864] 1 H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.35(d,J=7.17Hz,1H),7.62(d,J=9.15 Hz,1H),7.31-7.43(m,2H),7.21(d,J=8.08Hz,2H),6.15(d,J=9.30Hz,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),3.2 8-3.33(m,6H),1.94-2.29(m,8H),1.48(d,J=6.86Hz,3H),1.23-1.41(m,6H). LCMS: m / z 554 [M+H] + @rt6.64 minutes.

[0865] 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,

[0866] [ka] , 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] (Compound 23)

[0867] [ka]

[0868] 1H NMR(500MHz,DMSO-d6)δ=8.57(br.s,1H),8.43(br.s,1H),7.62(d,J=9.15Hz,1H) ,7.45-7.57(m,2H),7.21-7.33(m,2H),6.17(d,J=9.15Hz,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). LCMS:m / z567[M+H] + @rt6.93 minutes. HRMS(ESI)C 30 H 40 ClN6O3[M+H] + Calculated value: 567.2845, measured value: 567.2852.

[0869] 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,

[0870] [ka] , 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] (Compound 20)

[0871] [ka]

[0872] 1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.33(d,J=7.17Hz,1H),7.62(d,J=9.15Hz,1H),7. 18-7.32(m,4H),6.63(dd,J=10.45,16.55Hz,1H),6.15(d,J=9.30Hz,1H),5.96(dd,J=1. 83,16.78Hz,1H),5.51-5.58(m,1H),5.25-5.40(m,1H),4.95-5.01(m,1H),3.39-3.46(m ,2H),1.85-2.25(m,10H),1.58-168(m,2H),1.47(d,J=7.02Hz,3H),1.20-1.44(m,10H). LCMS: m / z 529 [M+H] + @rt7.28 minutes. HRMS(ESI)C 31 H 41 N6O3[M+H] + Calculated value 529.3286, measured value 529.3282.

[0873] 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,

[0874] [ka] , 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] (Compound 24)

[0875] [ka]

[0876] 1H NMR(500MHz,DMSO-d6)δ=7.99(br.s.,1H),7.86(br.s.,1H),7.32(d,J=6.86Hz,2H), 7.19(d,J=8.39Hz,2H),6.66(dd,J=10.45,16.70Hz,1H),5.99(dd,J=2.29,16.62Hz,1 H),5.58(dd,J=2.29,10.37Hz,1H),5.09(s,2H),4.92(br.s,1H),3.80(d,J=7.63Hz, 3H),3.36-3.48(m,6H),1.99-2.22(m,8H),1.43(d,J=7.02Hz,3H),0.77-0.88(m,3H). LCMS: m / z 521 [M+H] + @rt4.06 minutes. HRMS(ESI)C 28 H 37 N6O4[M+H] + Calculated value: 521.2871, measured value: 521.2867.

[0877] 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 = CH, Y = O,

[0878] [ka] , 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] (Compound 25)

[0879] [ka]

[0880] LCMS: m / z 534 [M+H] + @rt6.65 minutes.

[0881] 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,

[0882] [ka] , 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] (Compound 44)

[0883] [ka]

[0884] 1 H NMR(500MHz,DMSO-d6)δ=7.72(s,1H),7.34(d,J=8.39Hz,2H),7.21(d,J=8.24Hz,2H),7.0 5(d,J=7.47Hz,1H),6.67(dd,J=10.45,16.70Hz,1H),6.03-6.07(m,1H),6.00(dd,J=2.44, 16.62Hz,1H),5.57-5.60(m,1H),5.06(s,2H),4.98(br.s.,1H),3.76-3.85(m,2H),3.56-3 .73(m,2H),3.41-3.50(m,6H),2.00-2.22(m,8H),1.41(d,J=6.86Hz,3H),1.23(br.s,3H). LCMS: m / z 520 [M+H] + @rt 2.49 min. HRMS(ESI)C 29 H 38 N5O4[M+H] + Calculated value: 520.2919, measured value: 520.2924.

[0885] 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,

[0886] [ka] , 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] (Compound 26)

[0887] [ka]

[0888] 1 H NMR(500MHz,DMSO-d6)δ=8.50-8.58(m,1H),8.34(d,J=6.86Hz,1H),7.62(d,J=9.15Hz,1 H),7.23-7.40(m,4H),6.64(dd,J=10.52,16.62Hz,1H),6.15(d,J=9.15Hz,1H),5.96(dd ,J=1.83,16.47Hz,1H),5.52-5.61(m,1H),5.40(br.s,1H),4.98(t,J=6.63Hz,1H),3.39 -3.50(m,4H),2.14(br.s,8H),1.78(br.s,4H),1.47(d,J=7.02Hz,3H),0.9-1.42(m,6H). LCMS: m / z 565 [M+H] + @rt8.60 minutes. HRMS(ESI)C 31 H 37 F2N6O2[M+H] + Calculated value: 565.3097, measured value: 565.3086.

[0889] 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,

[0890] [ka] , 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] (Compound 47)

[0891] [ka]

[0892] 1 H NMR(500MHz,DMSO-d6)δ=8.28(s,1H),7.60(d,J=9.30Hz,1H),7.43(d,J=6.71Hz,1H),7.37(d,J=8.39Hz,2H),7.3 7(d,J=8.39Hz,2H),6.66(dd,J=10.45,16.70Hz,1H),6.15-6.52(br.s,1H),6.10(d,J=9.30Hz,1H),5.98(dd,J=2. 36,16.70Hz,1H),5.60(dd,J=2.3,10.50Hz,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=6.71Hz,3H),1.34-1.41(m,3H),1.03(d,J=6.10Hz,3H). LCMS:m / z564[M+H] + @rt6.62 minutes. HRMS(ESI)C 32 H 40 F2N5O2[M+H] + Calculated value: 564.3145, measured value: 564.3157.

[0893] 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,

[0894] [ka] , 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] (Compound 63)

[0895] [ka]

[0896] LCMS: m / z 564 [M+H] + @rt6.62 minutes. HRMS(ESI)C 32 H 40 F2N5O2[M+H] + Calculated value: 564.3145, measured value: 564.3150.

[0897] 7-{[(1S)-1-{4-[4,4-difluoro-1-(4-propanoylpiperazin-1-yl)cyclohexyl]phenyl}ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one [(I), X=CH, U=Y=CH,

[0898] [ka] , 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 = propanoyl] (Compound 67)

[0899] [ka]

[0900] LCMS: m / z 566 [M+H] + @rt6.67 minutes. HRMS(ESI)C 32 H 42 F2N5O2[M+H] + Calculated value: 566.6970, measured value: 566.6968.

[0901] 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,

[0902] [ka] , 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] (Compound 27)

[0903] [ka]

[0904] 1H NMR(500MHz,DMSO-d6)δ=8.57-8.61(m,1H),8.43-8.50(m,1H),8.31-8.37(m,1H),7.58-7.68(m,2H),7 .26-7.32(m,1H),6.61-6.69(m,1H),6.10-6.22(m,1H),5.94-6.02(m,1H),5.54-5.60(m,1H),5.34(br s,1H),4.97-5.07(m,1H),3.74-3.87(m,2H),3.39-3.53(m,4H),3.26- 3.32 (m, 2H), 1.99-2.26 (m, 8H), 1.46-1.56 (m, 3H), 1.01-1.05 (m, 6H). LCMS: m / z 532 [M+H] + @rt5.54 minutes. HRMS(ESI)C 29 H 38 N7O2[M+H] + Calculated value: 532.3031, measured value: 532.3035.

[0905] 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,

[0906] [ka] , 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] (Compound 28)

[0907] [ka]

[0908] 1H NMR(500MHz,DMSO-d6)δ=8.57(d,J=3.66Hz,1H),8.13-8.44(m,1H),7.64(dd,J=3.9 7,9.30Hz,1H),7.25-7.43(m,4H),6.16(d,J=9.46Hz,1H),5.91-6.02(m,2H),5.43-5 .58(m,1H),5.00-5.09(m,1H),4.02-4.12(m,2H),3.76-3.82(m,1H),3.64-3.75(m,4 H),3.38-3.63(m,2H),3.19-3.31(m,2H),1.95-2.21(m,6H),1.50(d,J=6.67Hz,3H), 1.15-1.44(m,3H),0.91(d,J=7.51Hz,3H). LCMS: m / z 531 [M+H] + @rt7.25 minutes. HRMS(ESI)C 30 H 39 N6O3[M+H] + Calculated value: 531.3078, measured value: 531.3077.

[0909] 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,

[0910] [ka] , 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] (Compound 48).

[0911] [ka]

[0912] 1H NMR(500MHz,DMSO-d6)δ=8.29(s,1H),7.61(dd,J=2.67,9.23Hz,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 8.39Hz,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=6.86Hz, 3H), 1.22-1.41 (m, 6H). LCMS:m / z530[M+H] + @rt5.62 minutes. HRMS(ESI)C 31 H 40 N5O3[M+H] + Calculated value: 530.3126, measured value: 530.3127.

[0913] 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,

[0914] [ka] , 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] (Compound 50).

[0915] [ka]

[0916] 1H NMR(500MHz,DMSO-d6)δ=8.57(d,J=3.36Hz,1H),8.33-8.44(m,1H),8.20(br.s.,1H),7.63(d,J=9.15Hz ,1H),7.27-7.43(m,4H),6.16(d,J=9.30Hz,1H),6.01-6.10(m,1H),5.97(d,J=19.37Hz,1H),5.41-5.59( m,2H),5.04(br.s.,1H),4.16(br.s.,1H),3.49-3.96(m,3H),3.37-3.49(m,1H),2.07-2.42(m,4H),1.9 5(d,J=8.69Hz,4H),1.70(br.s.,2H),1.49(d,J=6.71Hz,3H),1.07-1.43(m,3H),1.03(d,J=6.10Hz,3H). LCMS: m / z 565 [M+H] + @rt9.57 minutes. HRMS(ESI)C 31 H 39 F2N6O2[M+H] + Calculated value: 565.3097, measured value: 565.3077.

[0917] 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,

[0918] [ka] , 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] (Compound 61)

[0919] [ka]

[0920] 1H NMR(500MHz,DMSO-d6)δ=8.29(s,1H),7.61(dd,J=1.98,9.30Hz,1H),7.41-7.51(m,1H),7.2 8-7.41(m,4H),6.18-6.53(m,1H),6.04-6.16(m,2H),5.89-6.03(m,2H),5.45-5.64(m,1H), 4.75-5.20(m,1H),4.09-4.25(m,1H),3.87-3.93(m,1H),3.76-3.84(m,1H),3.57-3.52(m,2 H),2.29-2.43(m,2H),2.12(s,3H),1.84-2.05(m,4H),1.73(br.s.,2H),1.13-1.57(m,9H). LCMS: m / z 564 [M+H] + @rt8.12 minutes. HRMS(ESI)C 32 H 40 F2N6O2[M+H] + Calculated value: 564.3145, measured value: 564.3140.

[0921] 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,

[0922] [ka] , 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] (Compound 62)

[0923] [ka]

[0924] 1 H NMR(500MHz,DMSO-d6)δ=8.26(s,1H),7.60(d,J=9.15Hz,1H),7.40-7.47(m,1H),7.36(d,J=8.24Hz,2H), 7.24(d,J=8.39Hz,2H),6.33-6.53(m,1H),6.20-6.31(m,1H),5.94-6.14(m,2H),5.60-5.68(m,1H),4.86- 5.21(m,1H),4.57-4.73(m,J=5.26,9.38Hz,1H),4.50(t,J=6.18Hz,1H),4.31-4.44(m,1H),4.20(t,J=7. 55Hz, 1H), 3.97-4.15 (m, 1H), 2.56-2.68 (m, 2H), 1.93-2.11 (m, 7H), 1.65-1.86 (m, 2H), 1.09-1.59 (m, 9H). LCMS:m / z592[M+H]+@rt8.79min. HRMS(ESI)C 33 H 40 Calculated F2N6O3[M+H]+ 592.3094, found 592.3092.

[0925] 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,

[0926] [ka] , 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] (Compound 29)

[0927] [ka]

[0928] LCMS: m / z 518 [M+H] + @rt6.28 minutes.

[0929] 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,

[0930] [ka] , 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] (Compound 30)

[0931] [ka]

[0932] 1 H NMR(500MHz,DMSO-d6)δ=8.61(s,1H),8.59(s,1H),7.65(d,J=9.30Hz,1H),7.03-7. 18(m,4H),6.64(dd,J=10.37,16.62Hz,1H),6.20(d,J=9.30Hz,1H),5.99(dd,J=2.2 9,16.62Hz,1H),5.53-5.59(m,1H),5.27(br.s.,1H),3.77(dd,J=3.43,7.40Hz,2H) ,3.43(d,J=3.05Hz,4H),3.19-3.31(m,2H),1.96-2.23(m,8H),1.01-1.52(m,10H). LCMS:m / z543[M+H] + @rt6.31 minutes. HRMS(ESI)C 31 H 39 N6O3[M+H] + Calculated value: 543.3078, measured value: 543.3087.

[0933] 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,

[0934] [ka] , 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] (Compound 31)

[0935] [ka]

[0936] 1 H NMR(500MHz,DMSO-d6)δ=8.57(s,1H),8.38(t,J=5.95Hz,1H),7.64(d,J=9.30Hz,1H),7.18-7.33(m,4H),6.65(dd, J=10.45,16.85Hz,1H),6.18(d,J=9.15Hz,1H),5.98(d,J=16.62Hz,1H),5.57(d,J=10.68Hz,1H),5.39-5.53(br.s 1H),4.56-4.60(m,1H),4.53(d,J=5.64Hz,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=6.10Hz,3H). LCMS:m / z517[M+H] + @rt5.54 minutes. HRMS(ESI)C 29 H 37 N6O3[M+H] + Calculated value: 517.2922, measured value: 517.2921.

[0937] 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,

[0938] [ka] , 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] (Compound 32)

[0939] [ka]

[0940] 1 H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.34(d,J=7.02Hz,1H),7.62(d,J=9.30Hz,1H),7.30 (d,J=7.93Hz,2H),7.19(d,J=7.93Hz,2H),6.63(dd,J=10.45,16.85Hz,1H),6.15(d,J=9.30 Hz,1H),5.96(d,J=16.62Hz,1H),5.55(d,J=10.68Hz,1H),5.24-5.45(m,1H),4.99(q,J=7.4 7Hz,1H),3.38-3.48(m,4H),3.26-3.32(m,4H),1.96-2.22(m,11H),1.48(d,J=7.02Hz,3H), 1.23-1.44(m,3H),1.03(d,J=6.10Hz,3H). LCMS:m / z544[M+H] + @rt6.18 minutes. HRMS(ESI)C 31 H 41 N7O2[M+H] + Calculated value: 544.3395, measured value: 544.3405.

[0941] 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,

[0942] [ka] , 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] (Compound 33)

[0943] [ka]

[0944] LCMS:LCMS:m / z503[M+H]+@rt7.02 minutes.

[0945] 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,

[0946] [ka] , 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] (Compound 34)

[0947] [ka]

[0948] LCMS: m / z 503 [M+H]+ @rt7.02 minutes.

[0949] 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,

[0950] [ka] , 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] (Compound 46)

[0951] [ka]

[0952] 1 H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.35(t,J=7.47Hz,1H),7.62(d,J=9.30Hz,2H),7.36(d,J=7.02Hz,2H),7.30(d,J =8.02Hz,1H),6.73(ddd,J=3.81,10.45,16.70Hz,1H),6.16(d,J=9.00Hz,1H),6.07(dd,J=2.06,16.70Hz,1H),5.63(d, J=10.52Hz,1H),5.25-5.55(br.s,1H),5.00(d,J=6.56Hz,1H),3.49(d,J=7.47Hz,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=6.86Hz,3H),1.15-1.40(m,6H),1.10(s,3H),0.45-0.52(m,3H). LCMS:m / z503[M+H] + @rt7.02 minutes. HRMS(ESI)C 29 H 39N6O2[M+H] + Calculated value: 503.3129, measured value: 503.3109.

[0953] 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,

[0954] [ka] , 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] (Compound 35)

[0955] [ka]

[0956] 1 H NMR(500MHz,DMSO-d6)δ=8.6(s,1H),8.25-8.45(m,1H),7.65(d,J=9.30Hz,1H),7.26-7.40(m ,2H),7.20(d,J=8.24Hz,2H),6.55-6.70(m,1H),6.08-6.23(m,1H),5.96(d,J=16.47Hz,1H), 5.56(d,J=10.52Hz,1H),4.87-5.31(m,2H),3.72-3.85(m,2H),3.45(br.s.,4H),3.29-3.32( m,2H),1.69-2.25(m,12H),1.46(d,J=7.02Hz,3H),0.63-0.78(m,3H),0.12(t,J=7.32Hz,3H). LCMS: m / z 559 [M+H] + @rt7.02 minutes. HRMS(ESI)C 32 H 43 N6O3[M+H] +Calculated value: 559.3391, measured value: 559.3392.

[0957] 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,

[0958] [ka] , 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] (Compound 36)

[0959] [ka]

[0960] 1 H NMR(500MHz,DMSO-d6)δ=7.67-7.74(m,1H),7.64(d,J=7.17Hz,1H),7.28-7.37(m, 2H),7.19(d,J=8.39Hz,2H),6.59-6.74(m,1H),5.84-6.04(m,2H),5.53-5.61(m,1 H),5.47(br.s,1H),4.93-5.11(m,1H),3.72-3.85(m,2H),3.44(dd,J=5.11,6.94H z,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). LCMS:m / z574[M+H] + @rt7.57 minutes. HRMS(ESI)C 32 H 44 N7O3[M+H] + Calculated value: 574.35, measured value: 574.3489.

[0961] 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,

[0962] [ka] , 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] (Compound 37)

[0963] [ka]

[0964] 1 H NMR(500MHz,DMSO-d6)δ=7.70-7.80(m,1H),7.50-7.62(m,2H),7.27-7.42(m,2H) ),7.19(d,J=7.78Hz,2H),6.64(dd,J=10.52,16.62Hz,1H),5.86-6.04(m,2H),5 .52-5.65(m,2H),4.94-5.20(m,1H),3.79(d,J=5.64Hz,2H),3.40-3.47(m,4H), 3.28-3.32(m,4H),2.89(d,J=3.97Hz,3H),2.11(br.s.,6H),1.21-1.63(m,9H). LCMS: m / z 560 [M+H] + @rt6.98 minutes. HRMS(ESI)C 31 H 42 N7O3[M+H] + Calculated value: 560.3344, measured value: 560.3359.

[0965] 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,

[0966] [ka] , 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] (Compound 38)

[0967] [ka]

[0968] LCMS:m / z556[M+H]+@rt7.25 minutes.

[0969] 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,

[0970] [ka] , 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] (Compound 39)

[0971] [ka]

[0972] LCMS:m / z546[M+H]+@rt7.82 minutes.

[0973] 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,

[0974] [ka] , 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] (Compound 40)

[0975] [ka]

[0976] 1 H NMR(500MHz,DMSO-d6)δ=8.55(s,1H),8.17(br.s.,1H),7.59(d,J=9.15Hz,1H),7.34(d ,J=8.39Hz,2H),7.18(d,J=8.39Hz,2H),6.65(dd,J=10.37,16.62Hz,1H),6.10(d,J=7.7 8Hz,1H),5.92-6.05(m,1H),5.54-5.62(m,1H),5.04(br.s.,1H),3.79(t,J=8.46Hz,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). LCMS:m / z545[M+H] + @rt6.59 minutes. HRMS(ESI)C 31 H 41 N6O3[M+H] + Calculated value: 545.3235, measured value: 545.3246.

[0977] 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,

[0978] [ka] , 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] (Compound 52)

[0979] [ka]

[0980] 1 H NMR(500MHz,DMSO-d6)δ=8.55(s,1H),8.18(br.s,1H),7.59(d,J=9.00Hz,1H),7.33(d,J=8.39Hz,2H),7 .25(d,J=8.39Hz,2H),6.65(dd,J=10.45,16.70Hz,1H),6.09(d,J=9.00Hz,1H),5.99(dd,J=1.98,16.62H z,1H),5.58(dd,J=1.91,10.45Hz,1H),4.99(br.s.,1H),3.39-3.53(m,4H),3.29-3.31(m,2H),2.52-2. 61(m,2H),2.01-2.33(m,6H),1.70-1.88(m,2H),1.67(s,6H),1.44-1.56(m,3H),1.03(d,J=6.10Hz,3H). LCMS: m / z 579 [M+H] + @rt9.96 minutes. HRMS(ESI)C 32 H 41 F2N6O2[M+H] + Calculated value: 579.3254, measured value: 579.3255.

[0981] 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,

[0982] [ka] , 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] (Compound 41)

[0983] [ka]

[0984] LCMS: m / z550[M+H]+@rt5.78 minutes.

[0985] 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,

[0986] [ka] , R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = R4 = H, R5a = methyl, R5b = morpholin-4-ylmethanyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] (Compound 42)

[0987] [ka]

[0988] LCMS: m / z574[M+H]+@rt6.98 minutes.

[0989] 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,

[0990] [ka] , R1a = methyl, R1b = H, A = phenyl, R2 = propan-2-yl, R3 = R4 = H, R5a = morpholin-4-ylmethanyl, R5b = methyl, M = bond, G1 = N, Z1, Z2 = -CH2-, m1 = m2 = 2, E = acryloyl] (Compound 43)

[0991] [ka]

[0992] 1H NMR(500MHz,DMSO-d6)δ=8.47-8.57(m,1H),8.36(d,J=7.47Hz,1H),7.62(d,J=9.30Hz,1H),7.43(d,J=8.08Hz,2H),7 .30(d,J=8.08Hz,2H),6.72(dd,J=10.45,16.55Hz,1H),6.14(d,J=8.69Hz,1H),6.06(dd,J=2.29,16.62Hz,1H),5.63 (dd,J=2.14,10.52Hz,1H),5.53(br.s.,1H),4.98(br.s.,1H),3.42-3.55(m,4H),2.96-3.21(m,4H),2.59(d,J=13.2 7Hz,1H),2.38-2.47(m,1H),2.23-2.33(m,3H),2.07(br.s.,2H),1.62-1.78(m,2H),1.32-1.53(m,9H),1.27(s,3H). LCMS: m / z 574 [M+H] + @rt7.14 minutes. HRMS(ESI)C 32 H 44 N7O3[M+H] + Calculated value: 574.35, measured value: 574.3479.

[0993] 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,

[0994] [ka] , 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] (Compound 49)

[0995] [ka]

[0996] 1 H NMR(500MHz,DMSO-d6)δ=8.62(s,1H),8.60(s,1H),7.66(d,J=9.30Hz,1H),7.20(d,J=8.39Hz,2H),7. 02-7.12(m,2H),6.65(dd,J=10.52,16.62Hz,1H),6.21(d,J=9.15Hz,1H),6.00(dd,J=2.36,16.70Hz,1 H),5.58(dd,J=2.36,10.45Hz,1H),5.29(br.s.,1H),3.39-3.52(m,4H),3.27-3.32(m,2H),2.07-2.22 (m,4H),1.87-1.93(m,2H),1.63-1.73(m,2H),1.50-1.57(m,2H),1.25-1.41(m,4H),0.93-1.1(m,6H). LCMS: m / z 527 [M+H] + @rt7.63 minutes. HRMS(ESI)C 31 H 39 N6O2[M+H] + Calculated value: 527.3129, measured value: 527.3132.

[0997] 8-(propan-2-yl)-2-({(1S)-1-[4-(4-{4-[( 2 H3) propenoyl]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,

[0998] [ka] , 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] (Compound 51)

[0999] [ka]

[1000] 1 H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.09-8.41(m,1H),7.62(d,J=9.30Hz,1H),7 .26-7.44(m,2H),7.20(d,J=8.24Hz,2H),6.16(d,J=9.15Hz,1H),5.33-5.84(m,1H) ,4.99(q,J=6.71Hz,1H),3.70-3.87(m,2H),3.38-3.51(m,4H),3.28-3.32(m,2H),2 .10(br.s.,8H),1.48(d,J=7.02Hz,3H),1.10-1.43(m,3H),1.03(d,J=6.10Hz,3H). LCMS: m / z 534 [M+H] + @rt7.60 minutes. HRMS(ESI)C 30 H 39 N6O3[M+H] + Calculated value: 534.3267, measured value: 534.3265.

[1001] 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,

[1002] [ka] , 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 (Compound 55)

[1003] [ka]

[1004] 1 H NMR(500MHz,DMSO-d6)δ=8.55(s,1H),8.31(d,J=6.59Hz,1H),7.61(d,J=9.52Hz,1H),7.3 3(d,J=7.93Hz,2H),7.20(d,J=8.30Hz,2H),6.63(dd,J=10.62,16.60Hz,1H),6.15(d,J=9. 15Hz,1H),5.96(d,J=15.50Hz,1H),5.55(d,J=10.99Hz,1H),5.00(br.s.,1H),3.79(d,J=7 .20Hz,2H),3.44(br.s.,4H),3.23-3.28(m,2H),2.11(br.s.,8H),1.48(d,J=7.20Hz,3H). LCMS:m / z538[M+H] + @rt6.74 minutes. HRMS(ESI)C 30 H 39 N6O3[M+H] + Calculated value: 538.7073, measured value: 538.7072.

[1005] [Example 2] 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,

[1006] [ka] , 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] (Compound 56, Step 1a)

[1007] [ka]

[1008] 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)glycinamide (150 mg, 0.30 mmol) and DIPEA (100 µL, 0.6 mmol) in DCM (10.0 mL) was added acryloyl chloride (27 µL, 0.3 mmol) at -10 °C. After 30 min, the reaction was quenched by the addition of 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 (1-10% MeOH / DCM) to give the title product as a white foam (99 mg, 60% yield). 1 H NMR(500MHz,DMSO-d6)δ=8.54(s,1H),8.35(d,J=7.02Hz,1H),8.26(t,J=5.80Hz,1H),8.05-8.1 2(m,1H),7.61(d,J=9.15Hz,1H),7.22-7.39(m,4H),6.27(dd,J=10.22,17.08Hz,1H),6.15(d,J= 9.30Hz,1H),6.08(dd,J=2.14,17.08Hz,1H),5.58(dd,J=2.14,10.22Hz,1H),5.52(br.s,1H),4 .99(br.m,1H),3.87(d,J=5.64Hz,2H),2.37-2.46(m,2H),1.78-2.14(m,6H),1.22-1.52(m,9H). LCMS:m / z553[M+H] + @rt11.08 minutes. HRMS(ESI)C 29 H 35 F2N6O3[M+H] + Calculated value: 553.2733, measured value: 553.2726.

[1009] Following the same method, the following compounds were prepared:

[1010] 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-alaninamide [X=N, U=Y=CH,

[1011] [ka] , 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] (Compound 57)

[1012] [ka]

[1013] 1 H NMR(500MHz,DMSO-d6)δ=8.54(s,1H),8.34(d,J=7.02Hz,1H),8.21(d,J=6.86 Hz,1H),8.08(s,1H),7.61(d,J=9.15Hz,1H),7.25-7.34(m,4H),6.29(dd,J=10 .29,17.16Hz,1H),6.15(d,J=9.46Hz,1H),6.09(dd,J=1.98,17.23Hz,1H),5.5 8(dd,J=2.14,10.22Hz,1H),5.53(br.s,1H),4.99(br.m,1H),4.45(dq,J=8.13 and 6.86Hz, 1H), 2.37-2.46(m, 2H), 1.77-2.11(m, 6H), 1.22-1.52(m, 12H). LCMS:m / z567[M+H] + @rt11.27 minutes. HRMS(ESI)C 30 H 37 F2N6O3[M+H] + Calculated value: 567.2890, measured value: 567.2887.

[1014] 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-alaninamide [X=N, U=Y=CH,

[1015] [ka] , 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] (Compound 58)

[1016] [ka]

[1017] 1 H NMR(500MHz,DMSO-d6)δ=8.54(s,1H),8.14-8.40(m,2H),8.10(s,1H),7.61(d,J =9.30Hz,1H),7.16-7.39(m,4H),6.29(dd,J=10.29,17.16Hz,1H),6.14(d,J=9.1 5Hz,1H),6.09(dd,J=2.14,17.08Hz,1H),5.37-5.74(m,2H),4.99(br.s.,1H),4 .45(t,J=7.02Hz,1H),2.36-2.47(m,2H),1.69-2.16(m,6H),1.03-1.58(m,12H). LCMS: m / z 567 [M+H] + @rt11.30min.

[1018] 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,

[1019] [ka] , 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] (Compound 66).

[1020] [ka]

[1021] LCMS: m / z 601 [M+H] + @rt4.59 minutes.

[1022] 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}propen-2-enamide [X=N, U=Y=CH,

[1023] [ka] , 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] (Compound 59)

[1024] [ka]

[1025] LCMS: m / z 505 [M+H] + @rt8.25 minutes.

[1026] [Example 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 [X=N, U=Y=CH,

[1027] [ka] , 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] (Compound 5)

[1028] [ka]

[1029] 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 under reduced pressure. The residue was purified by silica gel chromatography (1-5% EtOH / DCM) to give the title product as a white solid (84.6 mg, 44% yield). 1H NMR(500MHz,DMSO-d6)δ=8.57(s,1H),8.35(d,J=7.17Hz,1H),7.63(d,J=9.15Hz,1H),7 .29-7.41(m,2H),7.20(d,J=8.08Hz,2H),6.16(d,J=9.15Hz,1H),5.43(br.s.,1H),5.0 0(t,J=6.79Hz,1H),3.79(dd,J=4.96,10.75Hz,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=7.02Hz,3H),1.17-1.45(br.,m,6H). LCMS:m / z543[M+H] + @rt6.92 minutes. HRMS(ESI)C 31 H 39 N6O3[M+H]+ calculated value 543.3078, found value 543.306.

[1030] [Example 4] 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}prope-2-enoic acid [X=N, U=Y=CH,

[1031] [ka] , 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] (Compound 7).

[1032] [ka]

[1033] 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) was added 2-bromomethylacrylic acid (28 μL, 0.166 mmol) in the presence of KCO (35.5 mg, 0.257 mmol) at room temperature. After 2 h, the reaction was filtered and washed with acetonitrile. The organic portion was evaporated under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography (1–7% MeOH / DCM + 1% water) to give the title product as a white foam (44 mg, 58% yield). 1 H NMR(500MHz,DMSO-d6)δ=8.57(s,1H),8.36(d,J=7.47Hz,1H),7.63(d,J=9.30Hz,1H),7.32- 7.42(m,2H),7.22(d,J=8.24Hz,2H),6.16(d,J=9.30Hz,1H),6.00(s,1H),5.52(br.s.,1H),5 .27-5.50(br.,m,1H),5.04(t,J=6.71Hz,1H),3.75(d,J=9.30Hz,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=6.86Hz,3H),1.24-1.45(br.,m,6H). LCMS:m / z561[M+H] + @rt7.44 minutes. HRMS(ESI)C 31 H 41 N6O4[M+H] + Calculated value: 561.3184, measured value: 561.3181.

[1034] Following the same method, the following compounds were prepared:

[1035] 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,

[1036] [ka] , 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] (Compound 45)

[1037] [ka]

[1038] 1 H NMR(500MHz,DMSO-d6)δ=7.99(s,1H),7.88(br.s.,1H),7.34(d,J=7.78Hz,2H),7.19(d,J=8.24Hz,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=7.02Hz,3H),1.23(br.s,3H),0.88(t,J=7.17Hz,3H). LCMS:m / z495[M+H] + @rt4.57 minutes. HRMS(ESI)C 27 H 39 N6O3[M+H] + Calculated value: 495.3078, measured value: 495.3079.

[1039] 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,

[1040] [ka] , 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 = 4-hydroxybutyl] (Compound 64)

[1041] [ka]

[1042] 1 H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.13-8.42(m,1H),7.62(d,J=9.15Hz,1H),7.30-7.43(m,2H),7.18-7.31(m,2H),6.15(d,J=9.15Hz) ,1H),5.47(br.s.,1H),4.88-5.35(m,1H),4.39(br.s.,1H),3.30(br.s.,2H),1.90-2.48(m,14H),1.74(br.s.,4H),0.92-1.55(m,13H). LCMS: m / z 583 [M+H] + @rt9.36 minutes. HRMS(ESI)C 32 H 45 F2N6O2[M+H] + Calculated value: 583.3567, measured value: 583.3566.

[1043] [Example 5] 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,

[1044] [ka] , 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] (Compound 65)

[1045] [ka]

[1046] 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) was added cyanogen bromide (12 μL, 0.113 mmol) in the presence of DIPEA (19 μL, 0.113 mmol) at 0 °C. After 1 h, the reaction was allowed to warm to room temperature for 2 h before diluting with water and DCM. The organic portion was dried over Na2SO4 and evaporated under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography (1-7% EtOH / DCM2 / 98-10 / 90) to give the title product as a white foam (30 mg, 52% yield). 1 H NMR(500MHz,DMSO-d6)δ=8.57(s,1H),8.37(d,J=7.02Hz,1H),7.63(d,J=9. 15Hz,1H),7.36(d,J=7.78Hz,1H),7.22(d,J=8.24Hz,1H),6.16(d,J=9.15H z,1H),5.25-5.52(m,1H),5.03(t,J=6.79Hz,1H),3.68-3.82(m,2H),3.27- 3.32(m,2H),3.07-3.13(m,4H),1.99-2.27(m,8H),1.50(d,J=7.02Hz,3H), LCMS: m / z 502 [M+H] + @rt6.94 minutes. HRMS(ESI)C 28 H 36 N7O2[M+H] +Calculated value: 502.2925, measured value: 502.2917.

[1047] [Example 6] 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,

[1048] [ka] , 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] (Compound 10).

[1049] [ka]

[1050] 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), OsO (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 worked up with saturated aqueous NaHSO (1.5 mL) and stirred for an additional 1 h. The aqueous mixture was extracted with EtOAc (30 mL, 15 mL, and 5 mL). The combined organic extracts were dried (NaSO), filtered, and evaporated under reduced pressure. The crude product was dissolved in a small amount of dichloromethane and purified by flash chromatography (silica, 5% MeOH / CH2Cl2 to 10% MeOH / CH2Cl2) to give the title compound as a white solid (34 mg, 65% yield). 1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.13-8.36(m,1H),7.62(d,J=9.30Hz,1H),7.30-7.44( m,2H),7.22(d,J=8.24Hz,2H),6.16(d,J=9.30Hz,1H),5.37-5.79(m,1H),4.94-5.32(m,1H),4 .71-4.84(m,1H),4.57(q,J=6.00Hz,1H),4.17(br.s.,1H),3.79(d,J=5.64Hz,2H),3.36-3.50 (m,4H),3.24-3.32(m,4H),1.96-2.33(m,8H),1.48(d,J=7.02Hz,3H),1.26-1.43(br.,m,6H). LCMS:m / z565[M+H] + @rt5.84 minutes. HRMS(ESI)C 30 H 41 N6O4[M+H] + Calculated value: 565.3133, measured value: 565.3141.

[1051] Following the same method, the following compounds were prepared:

[1052] 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,

[1053] [ka] , 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] (Compound 60)

[1054] [ka]

[1055] 1 H NMR(500MHz,DMSO-d6)δ=8.28(s,1H),7.60(d,J=9.30Hz,1H),7.42(d,J=6.10Hz,1H),7.33-7.39(m,2H),7 .28-7.33(m,2H),6.36(br.s.,1H),6.10(d,J=9.30Hz,1H),4.99(d,J=5.19Hz,1H),4.79(dd,J=2.90,7.17H z,1H),4.53-4.63(m,1H),4.13-4.23(m,1H),3.45-3.56(m,2H),3.39-3.45(m,2H),3.25-3.32(m,4H),2.54 (br.s.,1H),2.28(br.s.,2H),1.96-2.20(m,4H),1.69-1.86(m,4H),1.11-1.51(m,6H),0.99-1.07(m,3H). LCMS: m / z598[M+H]+@rt5.83 minutes. HRMS(ESI)C 32 H 42 Calculated for F2N6O4 [M+H]+ 598.32, found 598.3192.

[1056] [Example 7] 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,

[1057] [ka] , 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] (Compound 53)

[1058] [ka]

[1059] To a 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 anhydrous CHCl (5.0 mL) was added DIPEA (50.0 μL, 0.294 mmol) and T3P (50 wt % in AcOEt, 262.0 μL, 0.441 mmol) under stirring at ambient temperature. 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 with AcOEt. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (CH2Cl2 / EtOH = 98:2 to 9:1) to give the title compound (79.2 mg, yield 45%) as an off-white solid. 1 H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.12-8.42(m,1H),7.61(d,J=9.30Hz,1H),7.3 6(s,4H),6.58-6.79(m,1H),6.16(d,J=9.30Hz,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=8.69Hz,4H) ,1.71(br.s.,2H),1.48(d,J=6.70Hz,3H),1.16-1.43(m,3H),1.03(d,J=6.10Hz,3H). LCMS:m / z605[M+H] + @rt10.97 minutes. HRMS(ESI)C 30 H 37 ClF3N6O2[M+H] + Calculated value 605.2613, measured value 605.2617.

[1060] The following compound was prepared according to the same method, except that 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 were used.

[1061] 2-{[(1S)-1-(4-{4-[4-(2-fluoroacryloyl)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,

[1062] [ka] , 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-fluoroacryloyl] (Compound 54)

[1063] [ka]

[1064] 1 H NMR(500MHz,DMSO-d6)δ=8.58(s,1H),8.36(d,J=6.71Hz,1H),7.64(d,J=9.30Hz ,1H),7.34(d,J=7.93Hz,2H),7.22(d,J=7.93Hz,2H),6.17(d,J=9.15Hz,1H),5.2 4-5.56(m,1H),5.18(dd,J=3.97,18.15Hz,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). LCMS: m / z 549 [M+H] + @rt7.19 minutes. HRMS(ESI)C30 H 38 FN6O3[M+H] + Calculated value 549.2984, measured value 549.2984.

Claims

1. Formula (I): 【Chemical 1】 [In the formula, X is nitrogen or —CH—; U is CH, CH2 or CMe; Y is CH, CF or O; The partial structure of the formula: 【Chemistry 2】 represents a single or double bond; R1a, R1b are each independently hydrogen, an optionally substituted straight or branched chain (C1-C6) alkyl, or together with the atom to which they are attached may form a (C3-C6) cycloalkyl; A is (C3-C6)cycloalkyl, aryl, or heteroaryl; R4 is hydrogen, halogen, cyano, or optionally substituted straight or branched (C1-C6) alkyl; R5a and R5b are each independently a group selected from optionally substituted straight or branched chain (C1-C6) alkyl and (C3-C6) cycloalkyl, or together with the atom to which they are attached, may form a 3- to 7-membered cycloalkyl group or a heterocyclyl group containing one heteroatom selected from O, S, and N-R6; R6 is an optionally substituted straight or branched chain (C1-C6) alkyl, —COOR7, or —COR8; R7 and R8 are optionally substituted straight or branched chain (C1-C6) alkyl; M is a bond, NH, NR6, or O, where R6 is as defined above; G1 is N, CH, CH2 or CO; Z １ is CR9aR9b; Z ２ is CR10aR10b; R9a, R9b, R10a and R10b are independently hydrogen or optionally substituted straight or branched (C1-C6) alkyl; m1 is 1, 2 or 3; m2 is 0, 1, 2 or 3; E is CN, optionally substituted straight or branched (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl; or a group of formula -COR11; R11 is an optionally substituted straight or branched chain (C2-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl; R2 is an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, aryl-(C1-C6) alkyl, and heterocyclyl-(C1-C6) alkyl; R3 is hydrogen, chloro, cyano, CONH2, NH2, NR12aR12b, OR13, or an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, aryl, and heteroaryl; R12a, R12b are each independently selected from hydrogen and optionally substituted straight or branched (C1-C6) alkyl; R13 is an optionally substituted straight or branched chain (C1-C6) alkyl. or a pharmaceutically acceptable salt thereof.

2. Y is CH or O; R3 is hydrogen, chloro, cyano, CONH2, NH2, NR12aR12b, OR13, or an optionally substituted group selected from linear or branched (C1-C6) alkyl, and (C3-C6) cycloalkyl-(C1-C6) alkyl; R12a, R12b are each independently selected from hydrogen and optionally substituted straight or branched (C1-C6) alkyl; R13 is an optionally substituted straight or branched chain (C1-C6) alkyl; m1 is 1 or 2; m2 is 0, 1 or 2; X, U, a partial structure of the following formula: 【Chemistry 3】 , R1a, R1b, A, R4, R5a, R5b, M, G 1, Z １ , Z ２ 2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R, E, and R2 are as defined in claim 1.

3. A is aryl or heteroaryl; R4 is hydrogen, halogen, or optionally substituted straight or branched (C1-C6) alkyl; R3 is hydrogen, chloro, cyano, CONH2, NH2, NR12aR12b, or an optionally substituted group selected from linear or branched (C1-C6) alkyl, and (C3-C6) cycloalkyl-(C1-C6) alkyl; R12a, R12b are each independently selected from hydrogen and optionally substituted straight or branched (C1-C6) alkyl; X, U, Y, a partial structure of the following formula: 【Chemistry 4】 , R1a, R1b, R5a, R5b, M, G 1, Z １ , Z ２ 3. A compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, wherein m1, m2, E, and R2 are as defined in claim 2.

4. R4 is hydrogen or halogen; R3 is an optionally substituted group selected from hydrogen, chloro, cyano, CONH2, NH2, NR12aR12b, or straight or branched (C1-C6) alkyl; R12a, R12b are each independently selected from hydrogen and optionally substituted straight or branched (C1-C6) alkyl; X, U, Y, a partial structure of the following formula: 【Chemistry 5】 , R1a, R1b, A, R5a, R5b, M, G 1, Z １ , Z ２ 4. A compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, wherein m1, m2, E, and R2 are as defined in claim 3.

5. R1a, R1b each independently represent hydrogen, a straight or branched chain (C1-C3) alkyl, or together with the atom to which they are attached may form a cyclopropyl group; A is a phenyl group, a pyridyl group, or a pyrimidinyl group; R5a and R5b are each independently a group selected from a straight-chain or branched-chain (C1-C6) alkyl, or together with the atom to which they are attached, may form a 3- to 7-membered cycloalkyl group, or a heterocyclyl group containing one heteroatom selected from O and N-R6; R6 is a straight or branched chain (C1-C6) alkyl or COR8; R8 is a straight or branched chain (C1-C6) alkyl; R2 is a straight or branched chain (C1-C6) alkyl, or (C3-C6) cycloalkyl-(C1-C6) alkyl; R3 is hydrogen, chloro, cyano, NH2, NR12aR12b, or straight or branched (C1-C6) alkyl; X, U, Y, a partial structure of the following formula: 【Chemistry 6】 , R4, M, G 1, Z １ , Z ２ 5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein m1, m2, E, R12a, and R12b are as defined in claim 4.

6. R1a and R1b are each independently hydrogen, methyl, ethyl, or together with the atom to which they are attached may form a cyclopropyl group; A is a phenyl group or a pyridyl group; R4 is hydrogen; R5a and R5b are each independently a group selected from methyl and ethyl, or together with the atoms to which they are attached may form an optionally substituted (C3-C6)cycloalkyl group selected from cyclopentyl, cyclohexyl, and 4,4-difluorocyclohexyl, or a heterocyclyl group selected from pyranyl, oxetyl, N-methylpiperidinyl, and N-acetylpiperidinyl; R2 is methyl, ethyl, isopropyl, or cyclopentyl; R3 is hydrogen, cyano, methyl, NH2, NHMe or N(Me)2; X, U, Y, a partial structure of the following formula: 【Chemistry 7】 , M, G 1, Z １ , Z ２ 6. A compound of formula (I) according to claim 5, or a pharmaceutically acceptable salt thereof, wherein m1, m2 and E are as defined in claim 5.

7. 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 (Compound 1); 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 (Compound 2); 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 (compound 3); 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 (compound 4); 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 (compound 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 (compound 6); 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}prope-2-enoic acid (Compound 7); 2-{[(1S)-1-{4-[4-(4-propanoylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]phenyl}ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (compound 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 (compound 9); 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 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 (compound 23); 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 (compound 24); 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 (compound 25); 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 (compound 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 (compound 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 (compound 28); 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 (compound 29); 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 (compound 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 (compound 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 (compound 32); 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 (compound 33); 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 (compound 34); 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 (compound 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 (compound 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 (compound 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 (compound 38); 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 (compound 39); 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 (compound 40); 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 (compound 41); 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 (compound 42); 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 (compound 43); 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 (compound 44); 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 (compound 45); 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 (compound 46); 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 (compound 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 (compound 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 (compound 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 (compound 50); 8-(propan-2-yl)-2-({(1S)-1-[4-(4-{4-[( ２ H3) prop-2-enoyl]piperazin-1-yl}tetrahydro-2H-pyran-4-yl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 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 (compound 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 (compound 53); 2-{[(1S)-1-(4-{4-[4-(2-fluoroacryloyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}phenyl)ethyl]amino}-8-(propan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (compound 54); 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 (compound 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 (Compound 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-alaninamide (Compound 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-alaninamide (Compound 58); 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 (compound 59); 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 (compound 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 (compound 61); 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 (compound 62); 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 (compound 63); 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 (compound 64); 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 (compound 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 (Compound 66); and 7-{[(1S)-1-{4-[4,4-difluoro-1-(4-propanoylpiperazin-1-yl)cyclohexyl]phenyl}ethyl]amino}-1-(propan-2-yl)-1,6-naphthyridin-2(1H)-one (Compound 67) 2. The compound of formula (I) according to claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

8. 10. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, the method comprising the steps of: Step 1a) Formula (II): 【Chemistry 8】 (Wherein X, U, Y, a partial structure of the following formula: 【Chemistry 9】 , R2, R3, R1a, R1b, A, R4, R5a, R5b, M, G 1, Z １ and Z ２ is as defined in claim 1. with a compound of formula (III): 【Chemistry 10】 wherein E is as defined in claim 1 and Q is hydroxy, chloro, or bromo. to form a compound of formula (I) (Wherein X, U, Y, a partial structure of the following formula: 【Chemistry 11】 , R2, R3, R1a, R1b, A, R4, R5a, R5b, M, G 1, Z １ , Z ２ , and E are as described above.) obtaining Including, The compound of formula (II) can be produced from a compound of formula (IV) by the following steps: Step 2a) Formula (IV): 【Chemistry 12】 (Wherein G is chloro, MeS(O) ２ -, MeS(O)- or OTrif, and X, U, Y, a partial structure of the following formula: 【Chemistry 13】 , R2 and R3 are as defined in claim 1. with a compound of formula (V): 【Chemistry 14】 (In the formula, R1a, R1b, A, R4, R5a, R5b, M, G1, Z １ , Z ２ , m1 and m2 are as defined in claim 1, and PG is a protecting group selected from tert-butyl carboxylate, benzyl carboxylate, and phenyl carboxylate. with a compound of formula (I); Step 2b) Obtained formula (VI): 【Chemistry 15】 wherein PG is as defined above in Step 2a. with a deprotecting agent to give a compound of formula (II) (Wherein X, U, Y, a partial structure of the following formula: 【Chemistry 16】 , A, R1a, R1b, R2, R3, R4, R5a, R5b, M, G 1, Z １ , Z ２ , m1 and m2 are as defined above in step 2a. obtaining Produced according to a process comprising: The formula (IV): 【Chemistry 17】 (Wherein G is MeS(O) ２ - or MeS(O)-, X is N, R3 is hydrogen or chloro, U, Y, a partial structure of the following formula: 【Chemistry 18】 and R2 are as defined in claim 1. The compound of formula (I) can be prepared by the following steps: Step 3a) Formula (VII): 【Chemistry 19】 wherein R3 is hydrogen, chloro, or an optionally substituted straight or branched chain (C １ -C ６ ) alkyl. by converting the chlorine of the intermediate compound of formula (VIII): 【Chemistry 20】 (Wherein R2 is as defined in claim 1.) with an amine intermediate compound of formula (I); Step 3b) Obtained formula (IX): 【Chemical 21】 wherein R2 and R3 are as defined above in step 3a. reacting the compound of formula (I) with a reducing agent; Step 3c) Obtained formula (X): 【Chemical 22】 wherein R2 and R3 are as defined above in step 3a. reacting the compound of formula (I) with an oxidant reagent; Step 3d) Obtained formula (XI): 【Chemical 23】 wherein R2 and R3 are as defined above in step 3a. is reacted with a compound of formula T-CH ２ reacting with a reagent of COOEt (XIV) (wherein T is hydrogen or fluoro): Step 3e) The compound of formula (XII): 【Chemistry 24】 (Wherein U, Y, and the partial structure of the following formula: 【Chemistry 25】 is as defined in claim 1, and R2 and R3 are as defined above in step 3a. with an oxidizing agent to produce a compound of formula (IV) (Wherein G is MeS(O) ２ - or MeS(O)-, X is N, and R2, R3, U, Y, and a partial structure of the formula: 【Chemical 26】 is as above.) obtaining and (c) producing the product according to a method comprising: or Step 3f) Formula (X): 【Chemical 27】 wherein R2 and R3 are as defined above in step 3e. with carbonyldiimidazole or triphosgene to give a compound of formula (XII) wherein U is CH2, Y is O, and the partial structure of the formula: 【Chemical Formula 28】 is a single bond, and R2 and R3 are as defined above. obtaining or Step 3g) Formula (XIII): 【Chemical Formula 29】 (Wherein R3, U, Y, a partial structure of the following formula: 【Chemistry 30】 is as defined above in step 3e. to an intermediate compound of formula R2-Lg(XV), wherein Lg is bromine, iodine, —OMs, —OTs or hydroxy, and R2 is as defined above in step 3e. to give a compound of formula (XII) (In the formula, R2, R3, U, Y, and the partial structure of the following formula: 【Chemical 31】 is as above.) obtaining Including; The compound of formula (IV) (wherein G is chloro and R3, X, U, Y and R2 are as defined in claim 1) can be prepared by the following process: Step 4a) Formula (XVI): 【Chemical 32】 (wherein X and R3 are as defined in claim 1). by converting the chlorine of the intermediate compound of formula (VIII): 【Chemical 33】 (Wherein R2 is as defined in claim 1.) with an amine intermediate compound of formula (I); Step 4b) Obtained formula (XVII): 【Chemical 34】 wherein X, R3, and R2 are as defined above in step 4a. reacting the compound of formula (I) with a reducing agent; Step 4c) Obtained formula (XVIII): 【Chemistry 35】 wherein X, R3 and R2 are as defined above in step 4b. reacting the compound of formula (I) with an oxidant reagent; Next Step 4d) Obtained formula (XIX): 【Chemical 36】 wherein X, R2 and R3 are as defined above in step 4c. is reacted with a compound of formula T-CH ２ COOEt (XIV) (wherein T is hydrogen or fluoro) to give a compound of formula (IV) (wherein G is chloro and U, Y, X, and the partial structure 【Chemical 37】 , R3 and R2 are as defined in claim 1; and (c) producing the product according to a method comprising: or Step 4e) Obtained formula (XVIII): 【Chemical Formula 38】 wherein X, R3 and R2 are as defined above in step 4c. with carbonyldiimidazole or triphosgene to give a compound of formula (IV) ２ and Y is O, and the partial structure of the formula: 【Chemical 39】 is a single bond, and X and R2 are as defined above; The method is produced according to a method comprising:

9. 9. The method of claim 8, further comprising converting a first compound of formula (XII) to a second compound of formula (XII): Transformation A): 【Chemistry 40】 Converting a compound of formula (XII) wherein R3 is chloro to a compound of formula (XII) wherein R3 is CN by reacting with a cyanide source; or Transformation B): 【Chemistry 41】 Converting a compound of formula (XII) in which R3 is chloro to a compound of formula (XII) in which R3 is NHPG by reacting with an amine PG-NH2; or Conversion C): 【Chemistry 42】 Amines HNR12aR12b, where R12a and R12b are each independently hydrogen and optionally substituted straight or branched chain (C １ -C ６ ) alkyl; or Conversion D): 【Chemistry 43】 Alcohol R13-OH, where R13 is an optionally substituted straight or branched chain (C １ -C ６ ) is alkyl; or Transformation E): 【Chemical 44】 Compounds of formula (XII) where R3 is cyano can be converted by hydrolysis to compounds of formula (XII) where R3 is CONH ２ converting the compound of formula (XII) The method is transformed according to a method including:

10. 10. The method of claim 8 or 9, further comprising converting a first compound of formula (IV) to a second compound of formula (IV), wherein said conversion is: Transformation A1): 【Chemistry 45】 A two-step sequence allows G to be converted to MeS(O) ２ - to a compound of formula (IV) wherein G is -OTrif (triflate); Including; The compound of formula (V) (wherein R1a, R1b, A, R4, R5a, R5b, M, G1, Z １ , Z ２ , m1 and m2 are as defined in claim 1, and PG is a protecting group, by the following steps: Step 5a) Formula (XX): 【Chemistry 46】 (Wherein W1 is bromo, cyano, or COR1a, and A, R4, R5a, R5b, and R1a are as defined in claim 1.) The compound ２ CN followed by deprotection of the amide intermediate under acidic conditions, basic conditions or thiourea to give a compound of formula (XXI); Step 5b) Formula (XXI): 【Chemistry 47】 (Where W1, A, R4, R5a and R5b are as defined above in Step 5a.) by reacting an amino intermediate of formula (XXII): 【Chemistry 48】 (In the formula, Z １ , Z ２ , m1 and m2 are as defined in claim 1, PG is a protecting group, and Hal is a halogen. to give a compound of formula (XXIII) (wherein W 1, A, R 4, R 5a, R 5b, Z １ , Z ２ and PG are as defined above, m1 and m2 are 1, 2 or 3, G1 is N, and M is a bond; or Step 5b') reacting the amino intermediate of formula (XXI) with a reaction product of formula (XXIIa) 【Chemistry 49】 (In the formula, Z １ , Z ２ , m1, m2 and PG are as described above in step 5b, and Hal is a halogen. and then reacting the resulting intermediate by reductive amination with formaldehyde or an alkyl aldehyde derivative or by acylation with a haloacyl derivative RCO-hal or by reaction with an alkyl chloroformate derivative RCO-Cl, where R and R are as defined in claim 1, to give a compound of formula (XXIII), where PG is as defined above and W, A, R, R, R, R, Z １ , Z ２ , m1 and m2 are as defined in claim 1, G1 is CH, and M is NR6 (wherein R6 is as defined in claim 1); or Step 5b") The amino intermediate of formula (XXI) is reacted with a reaction product of formula (XXIIb) 【Chemistry 50】 (In the formula, Z １ , m1 and PG are as defined above in step 5b, and FG is a functional group selected from aldehyde (—CHO) and carboxylic acid (—COOH), to give a compound of formula (XXIII) (wherein m2 is 0, G1 is CH2 or CO, M is NH or NR6, PG is as defined above in step 5b, W1, A, R4, R5a, R5b, Z １ , m1 and R6 are as defined in claim 1; or Step 5a') Formula (XX): 【Chemistry 51】 wherein W1, A, R4, R5a and R5b are as defined above in step 5a, by reacting a compound of formula (XXIIa) 【Chemistry 52】 (In the formula, Hal, Z １ , Z ２ , m1, m2 and PG are as defined in Step 5b') to give a compound of formula (XXIII) (wherein W1, A, R4, R5a, R5b are as defined in Step 5a) and Z １ , Z ２ , m1, m2 and PG are as defined above in step 5b', G1 is CH and M is O; Next Step 5c) Compounds of formula (XXIII) obtained from step 5b or 5b' or 5b" or 5a': 【Chemistry 53】 (Wherein W1 is cyano, A, R4, R5a, R5b, M, G1, Z １ , Z ２ , m1, m2 and PG are as described in step 5b or 5b' or 5b" or 5a') is reacted with ethylmagnesium bromide and boron trifluoride diethyl etherate to give the target compound of formula (V) (wherein A, R4, R5a, R5b, M, G1, Z １ , Z ２ , m1, m2 and PG are as defined above in step 5b or 5b' or 5b" or 5a', and R1a and R1b are the same and as defined in claim 1, or R1a and R1b together form cyclopropyl; and (c) producing the product according to a method comprising: or Step 5c') Compounds of formula (XXIII) obtained from step 5b or 5b' or 5b" or 5a': 【Chemical 54】 (Wherein W1 is COR1a, A, R4, R5a, R5b, M, G1, Z １ , Z ２ , m1, m2, PG and R1a are as defined above in step 5b or 5b' or 5b" or 5a') with tert-butanesulfinamide to give a compound of formula (XXIV) (wherein R1b is hydrogen and R1a, A, R4, R5a, R5b, M, G1, Z １ , Z ２ , m1, m2, PG and R1a are as defined above; or Step 5c") Compounds of formula (XXIII) obtained from step 5b or 5b' or 5b" or 5a': 【Chemistry 55】 (Wherein W1 is COR1a, A, R4, R5a, R5b, M, G1, Z １ , Z ２ , m1, m2, PG and R1a are as defined above in step 5b or 5b' or 5b" or 5a') with tert-butanesulfinamide to obtain a compound of formula (XXV); Next Step 5e) Obtained formula (XXV): 【Chemical 56】 (In the formula, R1a, A, R4, R5a, R5b, M, G1, Z １ , Z ２ , m1, m2 and PG are as defined above in Step 5b or 5b' or 5b" or 5a') with an alkyl Grignard reagent to obtain the target compound of formula (XXIV); lastly Step 5d) Compounds of formula (XXIV) obtained as described in step 5c' or 5e: 【Chemical 57】 (In the formula, R1b, R1a, A, R4, R5a, R5b, M, G1, Z １ , Z ２ , m1, m2 and PG are as defined above in step 5c' or 5e.) is reacted with an acidic deprotecting reagent or iodine to give the target compound of formula (V) (wherein R1b, R1a, A, R4, R5a, R5b, M, G1, Z １ , Z ２ , m1 and m2 are as defined in claim 1, and PG is a protecting group; Produced according to a process comprising: Alternatively, a compound of formula (XXIII) can be reacted with another compound of formula (XXIII) as follows: Transformation F): 【Chemistry 58】 Conversion of a compound of formula (XXIII) (wherein W1 is cyano) into the corresponding compound of formula (XXIII) (wherein W1 is bromo) obtained from step 5b or 5b' or 5b" or 5a' using a cyanide source according to the conditions of palladium-catalyzed cyanation of aryl halides; or Transformation G): 【Chemical Formula 59】 hydrolysis of a compound of formula (XXIII), wherein W 1 is COR1a, wherein R1a is as defined in claim 1, using an enol ether organometallic derivative, followed by conversion of a compound of formula (XXIII), wherein W 1 is bromo, obtained from step 5b or 5b' or 5b" or 5a'; Follow the instructions to get it.

11. 11. The method according to any one of claims 8 to 10, wherein the compound of formula (I) prepared according to step 1a is further converted into another compound of formula (I), said conversion being carried out by the following reaction: Conversion 1): 【Chemistry 60】 A compound of formula (I) in which E is an acrylamide group is treated with a compound of formula (I) in which E is a dihydroxypropionic acid group and X, U, Y and a partial structure of the following formula: 【Hua 61】 , R2, R3, R1a, R1b, A, R4, R5a, R5b, M, G 1, Z １ , Z ２ , m1 and m2 are as defined in claim 1; The method is transformed according to a method including:

12. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient, carrier or diluent.

13. 13. The pharmaceutical composition of claim 12, further comprising one or more chemotherapeutic agents.

14. A pharmaceutical composition comprising the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for treating a disease selected from the group consisting of cancer, cell proliferative disorders and immune-related disorders.

15. The pharmaceutical composition of claim 14, wherein the disease is cancer.

16. The cancer may be 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, stomach cancer, cervical cancer, prostate cancer, and skin cancer including squamous cell carcinoma; lymphoid hematopoietic tumors such as leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, angioimmunoblastic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma; acute and chronic myeloid leukemia, myelodysplastic syndromes, myeloapoptosis, and myeloapoptosis.

16. The pharmaceutical composition of claim 15, wherein the tumor is selected from the group consisting of myeloid hematopoietic tumors such as myeloid leukemia, myeloma, myelomatous leukemia ...

17. 15. The pharmaceutical composition of claim 14, further comprising exposing the mammal in need of treatment to radiation therapy or a chemotherapy regimen in combination with at least one cytostatic or cytotoxic agent.

18. 10. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

19. 10. A product or kit comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and one or more chemotherapeutic agents, said product or kit being a combined preparation for simultaneous, separate or sequential use in anti-cancer therapy.

20. 10. Use of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament having anti-cancer activity.

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