A combination of anti-HER2 antibodies and CDK inhibitors to treat tumors.

Abstract

The present invention provides a pharmaceutical comprising a HER2 inhibitor or a CDK inhibitor that inhibits CDK4 and / or CDK6. The present invention further provides the use of a HER2 inhibitor in combination with a CDK inhibitor for treating tumors, and their use in preparing a medicament for treating tumors. The combination of the present invention significantly enhances tumor inhibition.

Description

[Background technology]

[0001] HER2 belongs to the receptor tyrosine kinase family that drives constitutive signaling via AKT and mTOR. Cyclin D1-CDK4 / 6 can be involved in HER2 signaling by inducing phosphorylation and inactivation of the mTORC1 inhibitor TSC2. In preclinical models, CDK4 / 6 inhibitors have been shown to enhance HER2 activity and increase sensitivity to HER2 kinase inhibitors or anti-HER2 antibodies.

[0002] Furthermore, it is urgent and necessary to explore the antitumor activity of HER2 biblockade and CDK4 / 6 inhibitors against HER2-positive metastatic breast cancer (MBC) in clinical trials. [Overview of the project]

[0003] The present invention provided a pharmaceutical comprising a HER2 inhibitor and a CDK inhibitor that inhibits CDK4 and / or CDK6. The present invention further provides a HER2 inhibitor in combination with the present CDK inhibitor for use in the preparation of pharmaceuticals for treating cancer in subjects in need. The combination of the present HER2 inhibitor and CDK inhibitor significantly enhances tumor inhibition.

[0004] On the other hand, the present invention provides a pharmaceutical product comprising a HER2 inhibitor capable of binding to a first HER2 antigen and a second HER2 antigen, and a CDK inhibitor capable of inhibiting CDK4 and / or CDK6.

[0005] In some embodiments, the above-mentioned pharmaceutical is a composition.

[0006] In some embodiments, the above-mentioned HER2 is human HER2.

[0007] In some embodiments, the first HER2 antigen described above comprises an epitope within the HER2 extracellular domain 2 (ECD2).

[0008] In some embodiments, the second HER2 antigen described above comprises an epitope within the HER2 extracellular domain 2 (ECD2).

[0009] In some embodiments, the second HER2 antigen described above comprises an epitope within the HER2 extracellular domain 4 (ECD4).

[0010] In some embodiments, the HER2 inhibitor described above is a bispecific antibody or its antigen-binding moiety.

[0011] In some embodiments, the antigen-binding moieties described above include Fab, Fab', F(ab)2, Fv fragment, F(ab')2, scFv, di-scFv, and / or dAb.

[0012] In some embodiments, the HER2 inhibitor is a bispecific antibody or its antigen-binding moiety, the bispecific antibody or its antigen-binding moiety comprising a first light chain and a second light chain, wherein the first light chain and the second light chain have the same amino acid sequence.

[0013] In some embodiments, the HER2 inhibitor is a bispecific antibody or its antigen-binding moiety, which comprises a first heavy chain and a second heavy chain, respectively, which can properly assemble with a light chain under physiological conditions or during protein expression in vitro.

[0014] In some embodiments, the first and second light chains can be assembled with the heavy chain of di-scFv and the heavy chain of trastuzumab, respectively.

[0015] In some embodiments, the variable regions of the first and / or second light chains have an amino acid sequence represented by SEQ ID NO: 1 to 6.

[0016] In some embodiments, the variable regions of the first and / or second light chains have an amino acid sequence represented by SEQ ID NO:1.

[0017] In some embodiments, the first and second light chains are selected from the light chains of pertuzumab or its variants, and the light chains of trastuzumab or its variants, respectively.

[0018] In some embodiments, the first light chain has an amino acid sequence represented by any of SEQ ID NO: 7 to 12, and / or the second light chain has an amino acid sequence represented by any of SEQ ID NO: 7 to 12.

[0019] In some embodiments, the heavy chain variable regions are the heavy chain variable region of pertuzumab and the heavy chain variable region of trastuzumab, respectively.

[0020] In some embodiments, the variable region of the first heavy chain has an amino acid sequence represented by SEQ ID NO:13, and the variable region of the second heavy chain has an amino acid sequence represented by SEQ ID NO:14.

[0021] In some embodiments, the first and second heavy chains described above include a constant region derived from the human IgG constant region.

[0022] In some embodiments, the Fc fragment sequence of the heavy chain described above has a sequence represented by SEQ ID NO: 19-49 or 51-52.

[0023] In some embodiments, the two heavy chains have sequences represented by SEQ ID NO: 15-18.

[0024] In some embodiments, the above CDK4 is human CDK4, and / or the above CDK6 is human CDK6.

[0025] In some embodiments, the above CDK inhibitor has the structure of Formula I:

[0026]

Chemical formula

[0027] where: X is CR 9 or N; R 1 is C 1-8 alkyl, CN, C(O)OR 4 or CONR 5 R 6 , 5- to 14-member heteroaryl or 3- to 14-member cycloheteroalkyl; R 2 is C 1-8 alkyl, C3-14 cycloalkyl or 5- to 14-member heteroaryl, where R 2 may be substituted with one or more of C 1-8 alkyl or OH; L is a bond, C 1-8 alkylene, C(O) or C(O)NR 10 , where L may or may not be substituted; Y is H, R 11 , NR 12 R 13 , OH, or a part of the following group:

[0028]

Chemical formula

[0029] where: Y is CR 9 or N; where 0 to 3 R 8 may be present, and R 8 is C 1-8 alkyl, oxo, halogen, or two or more R 8 may form a bridged alkyl; W is CR 9 or N; R 3 is H, C 1-8 alkyl, C 1-8 alkyl R 14, C3-i4 cycloalkyl, C(O)C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 AlkylOH, C(O)NR 14 R 15 Ci-g cyanoalkyl, C(O)R 14 , C 0-8 Alkyl C(0)C0-8 alkylNR 14 R 15 , C 0-8 Alkyl C(O)OR 14 , NR 14 R 15 SO2C 1-8 Alkyl, C 1-8 Alkyl C3-i4 cycloalkyl, C(O)C 1-8 Alkyl C3-i4 cycloalkyl, C 1-8 Alkoxy, OH, or R 3 If it is not H, it may be substituted or not; R 9 is H or halogen; R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 H and C are respectively 1-8 Alkyl, C3-H cycloalkyl, 3-14 member cycloheteroalkyl, Cβ-u aryl, 5-14 member heteroaryl, alkoxy, C(O)H, C(N)OH, C(N)OCH3, C(O)C 1-3 Alkyl, C 1-8 Alkyl NH2, C 1-6 Selected independently from alkylOH, where R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 If not H, then it may be substituted or not; m and n are independently 0 to 2; where L and R3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 is C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C3 -14 cycloalkyl, 5- to 14-membered heteroaryl, C 6-14 aryl, 3- to 14-membered cycloheteroalkyl, OH, (O), CN, alkoxy, halogen or NH2, and may be substituted with one or more of them.

[0030] In some embodiments, R is H, C 1-8 alkyl, C3-i4 cycloalkyl, C(O)Ci-S alkyl, Ci-8 alkyl OH, Ci-g cyanoalkyl, C 0-8 alkyl C(0)C 0-8 alkyl NR 14 R 15 , C 0-8 alkyl C(O)OR 14 , NR 14 R 15 , C 1-8 alkyl C3-i4 cycloalkyl, C(O)C 1-8 alkyl C3- 14 cycloalkyl, C 0-8 alkoxy, C 1-8 alkyl R 14 , C 1-8 haloalkyl or C(O)R, and may be substituted with one or more of OH, CN, F or NH2, where R and R are each independently selected from H, C 1-8 alkyl, C3-i4 cycloalkyl, alkoxy, C(O)C1-3 alkyl, C1-8 alkyl NH2 or C1-6 alkyl OH.

[0031] In some embodiments, R is H, C 1-8Alkyl, C3-i4 cycloalkyl, C(O)Ci-S alkyl, Ci-8 alkylOH, Ci-g cyanoalkyl, C 0-8 Alkyl C(0)C 0-8 Alkyl NR 14 R 15 , C 0-8 Alkyl C(O)OR 14 , NR 14 R 15 , C 1-8 Alkyl C3-i4 cycloalkyl, C(O)C 1-8 Alkyl C3- 14 Cycloalkyl, C 0-8 Alkoxy, C 1-8 Alkyl R 14 , C 1-8 The compound is a haloalkyl or C(O)R, which may be substituted with one or more of OH, CN, F, or NH2, where R and R are H and C, respectively. 1-8 A molecule is independently selected from alkyl, C3-i4 cycloalkyl, alkoxy, C(O)C1-3 alkyl, C1-8 alkylNH2, or C1-6 alkylOH.

[0032] In some embodiments, Y is H, OH, or some of the following groups:

[0033] [ka]

[0034] And, Here, Y is N and W is CR 9 or N; where there may be 0 to 2 Rs, R is C 1-8 R may be alkyl, oxo, or two or more R may form a cross-linked alkyl group.

[0035] In some embodiments, L is a bond, Ci-s alkylene, or C(O)NH or C(O).

[0036] In some embodiments, R 2 C3- HIt is a cycloalkyl group.

[0037] In some embodiments, R is cyclopentane.

[0038] In some embodiments, R 1 , CN, C(O)OR 4 CONR 5 It is either R or a 5- to 14-membered heteroaryl.

[0039] In some embodiments, R is CONRR, and R 5 and R 6 C 1-8 It is alkyl.

[0040] In some embodiments, X is CR.

[0041] In some embodiments, one X is N and the other X is CR.

[0042] In some embodiments, X is CR and Y is

[0043] [ka]

[0044] And, Here, m and n are 1, and Y and W are N.

[0045] In some embodiments, the above CDK inhibitor has the structure of formula Ia:

[0046] [ka]

[0047] It has, R 50 is CONR 54 R 55 or CN; R 51C may be non-substituted, 1-3 C3- substituted with alkyl or OH H It may be a cycloalkyl group; Z is CH or N; and V is NR 56 or CHR 57 And; R 54 and R 55 H and C are independent of each other. 1-3 It is alkyl, R 52 , R 53 R 56 and R 57 H and C are independent of each other. 1-8 Alkyl, C3-i4 cycloalkyl, C 1-8 Haloalkyl, NR 58 R 59 , C(O)OR 60 , C(O)C 1-8 Alkyl, C 0-8 Alkyl C(0)C 0-8 Alkyl-NR 61 R 62 , C 1-8 Alkoxy, C 1-8 Alkyl 0R 63 , C(O)-5-H cycloheteroalkyl, C3- H If they are cycloalkyl and each of them is not H, then C 1-8 It may be substituted with one or more alkyl, OH, or CN groups; R 58 , R 59 , R 60 , R 61 , R 62 and R 63 It is H or C1-8 alkyl.

[0048] In some embodiments, the CDK inhibitor is 7-cyclopentyl-2-[5-(3-methylpiperazin-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3d]pyrimidine-6-carbonitride; 7-cyclopentyl-2-{5-[4-(2-fluoroethyl)-piperazin-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-(4-dimethylamino-3,4,5,6-tetrahydro-2H-[l ,3']bipyridinyl-6'-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;2-[5-(4-carbamoylmethylpiperazine-1-yl)-pyridine-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;2-{5-[4-(2-aminoacetyl)-piperazine-1-yl]-pyridine-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid di Methylamide; 2-[5-(3-amino-pyrroridine-1-yl)-pyridine-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-{5-[4-(2-methoxyethyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[4-(2-hydroxyethyl)-3,4,5,6-tetrahydro-2H-[l ,2']bipyradinyl-5'-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[5-((R)-3-methylpiperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[5-((S)-3-methylpiperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[5-(3-methylpiperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-{5-[4-(3-hydroxypropyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-{5-[4-(pyrroridine-1-carbonyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-{5-[4-(2-hydroxyethyl)-piperazine-1- [Il]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-{5-[4-((S)-2,3-dihydroxypropyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-(5-{4-[2-(2-hydroxyethoxy)-ethyl]-piperazine-1-yl}pyridine-2-ylamino)-7H-pyrrolo[2, 3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-{5-[4-(2-hydroxy-l-methylethyl)-piperazine-1-yl]-pyrididine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-{6-[4-(2-hydroxyethyl)-piperazine-1-yl]-pyridazine-3-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2 -{5-[4-(2,3-dihydroxypropyl)-piperazine-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-{5-[4-((R)-2,3-dihydroxypropyl)-piperazine-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-(4-dimethylamino-3,4,5,6-tetrahydro-2H-[l,3']bipyridinyl-6'-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel;7-Cyclopentyl-2-(3,4,5,6-tetrahydro-2H-[1,2']bipyradinyl-5'-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-[5-(piperazine-1-carbonyl)-pyridine-2-ylamino]-7H-pyrrolo[2,3d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-[5-(4-dimethylaminopiperidine-1-carbonyl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-(1',2',3',4',5',6'-hexahydro-[3 ,4']bipyridinyl-6-ylamino)-7H-pyrrolo2,3d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-[5-((S)-3-methylpiperazine-1-ylmethyl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-{5-[4-((S)-2-hydroxypropyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-{5-[4-((R)-2-hydroxypropyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2 ,3-d]pyrimidine-6-carboxylate dimethylamide;7-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate methylamide;7-cyclopentyl-2-[5-(4-isopropyl-piperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3d]pyrimidine-6-carboxylate dimethylamide 7-Cyclopentyl-2-[5-(4-isopropyl-piperazine-1-carbonyl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-{5-[4-(4-methyl-pentyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-[6-(4-isopropyl-piperazine-1-yl)-pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-{5-[4-(2-hydroxy-2methylpropyl)-piperazine-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-[5-(3,3-dimethyl-piperazine-1-yl)-pyridin-2-yl [7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octo-3-ylmethyl)pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[5-(4- Ethyl-piperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[5-(4-cyclopentyl-piperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-(1'-isopropyl-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-6-ylamino)-7H-pyrrolo[2 ,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-{5-[(R)-4-(2-hydroxyethyl)-3-methyl-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-{5-[(S)-4-(2-hydroxymethyl)-3-methyl-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-{5-[4-(2-hydroxyethyl)-piperazine-1-ylmethyl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-{5-[4-(2-dimethylaminoethyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-{5-[4-(2-ethyl-butyl)piperazine-1-yl]- Pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate dimethylamide; 2-{5-[4-(2-cyclohexyl-acetyl)piperazine-1-yl]-pyridine-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate dimethylamide; 7-cyclopentyl-2-{5-[4-(3-cyclopentyl-propionyl)-piperazine-1-yl]-pyridine-2-ylamino}7H-pyrrolo[2,3-d]pyrimidine-6-carbone Dimethyl acid amide; 7-Cyclopentyl-2-[5-(4-Isobutylpiperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3d]pyrimidine-6-carboxylic acid dimethylamide; {4-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)pyridine-3-yl]-piperazine-1-yl}-methyl acetate; 7-Cyclopentyl-2-{5-[4-(2-Isopropoxyethyl)-piperazine-1-yl]-pyridine-2- Ilamino}-7Hpyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; {4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)pyridine-3-yl]-piperazine-1-yl}-ethyl acetate; 4-(6-{7-cyclopentyl-6-[(2-hydroxyethyl)methylcarbamoyl]-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino}pyridine-3-yl)piperazine-l-carboxylic acid tert-butyl;7-Cyclopentyl-2-{5-[4-(2-methyl-butyl)piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-[1'-(2-hydroxyethyl)-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-6-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; Selected from {4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]piperazine-1-yl}acetic acid; and 2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]piperazine-1-yl}propionic acid, or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the above CDK inhibitor has the structure of formula II:

[0050] [ka]

[0051] It has, R1 is a C3-C5 alkyl, C3-C5 cycloalkyl, or cyclopropyl-methyl; R2 and R3 are H or fluorine, where at least one of R2 or R3 is fluorine; R4 is H or CH3; R5 is a Ci-C6 alkyl or -NR6R7, where R6 and R7 are C1-C3 alkyl; Q is CH2, O, S, or a direct bond; and W and Y are C or N, where at least one of W or Y is N, where Q is O or S, W is C, or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, R1 is isopropyl, cyclopropyl, cyclopentyl, or cyclopropyl-methyl.

[0053] In some embodiments, R1 is isopropyl.

[0054] In some embodiments, R2 and R3 are fluorine, respectively.

[0055] In some embodiments, R4 is H.

[0056] In some embodiments, R5 is a C1-C3 alkyl group.

[0057] In some embodiments, Q is CH2 or a direct bond.

[0058] In some embodiments, Q is CH2.

[0059] In some embodiments, Y is N.

[0060] In some embodiments, W is N.

[0061] In some embodiments, the above-mentioned CDK inhibitor is

[0062] [ka]

[0063] TIFF0007857866000008.tif197170

[0064] Selected from the group consisting of .

[0065] In some embodiments, the above-mentioned CDK inhibitor is

[0066] [ka]

[0067] That is the case.

[0068] In some embodiments, the above-mentioned CDK inhibitor has the structure of formula III:

[0069] [ka]

[0070] It has, Here, the HER2 inhibitor comprises a first antigen-binding domain capable of specifically binding to the first HER2 antigen and a second antigen-binding domain capable of specifically binding to the second HER2 antigen, wherein the first HER2 antigen is not identical to the second HER2 antigen; X 1 , X 2 and X 3 These are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, CN, NO2, OR 5 , NR 5 R 6 CO2R 5 COR 5 , S(O) n R 5 CONR 5 R 6 , NR 5 COR 6 , NR 5 SO2R 6 SO2NR 5 R 6 and P(O)(OR 5 )(OR 6 ) and; however, X 1 , X 2 and X 3 The prerequisite is that at least one of them is hydrogen; n is selected from 0, 1, and 2; R 1 In each case, R is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C3-C7 cycloalkyl; R 2 and R 4These are hydrogen, halogen, C1-C8 alkyl, C3-C7 cycloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C2-C8 alkenyl, C2-C8 alkynyl, nitrile, nitro, OR 5 , SR 5 , NR 5 R 6 , N(O)R 5 R 6 , P(O)(OR 5 )(OR 6 ), (CR 5 R 6 ) m NR 7 R 8 COR 5 , (CR 4 R 5 ) m C(O)R 7 CO2R 5 CONR 5 R 6 , C(O)NR 5 SO2R 6 , NR 5 SO2R 6 , C(O)NR 5 Ure 6 , S(O) n R 5 SO2NR 5 R 6 , P(O)(OR 5 )(OR 6 ), (CR 5 R 6 ) m P(O)(OR 7 )(OR 8 ), (CR 5 R 6 ) m -Ayl, (CR 5 R 6 ) m - Heteroaryl, T(CH2) m QR 5 ,-C(O)T(CH2) m QR 5 , NR 5 C(O)T(CH2) m QR 5 and -CR 5=CR 6 C(O)R 7 Selected independently of; or R 1 and R 2 The carbocyclic group may have 3 to 7 ring members, preferably 5 to 6 ring members, and up to 4 of these may be substituted with heteroatoms independently selected from oxygen, sulfur, and nitrogen, where the carbocyclic group is unsubstituted or has halogen, hydroxy, hydroxyalkyl, nitrile, lower C1-C8 alkyl, lower C1-C8 alkyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl, N-hydroxyacetamide, trifluoromethylalkyl, amino, and mono or dialkylamino, (CH2) m C(O)NR 5 R 6 and O(CH2) m C(O)OR 5 Substituted by one, two, or three groups independently selected from, provided that there is at least one carbon atom in the carbocyclic ring and two or more ring oxygen atoms, provided that the above ring oxygen atoms are not adjacent to each other; T is O, S, NR 7 , N(O)R 7 , NR 7 R 8 W or CR 7 R 8 Q is O, S, NR 7 , N(O)R 7 , NR 7 R 8 W, CO2, O(CH2) m - Heteroaryl, O(CH2) m S(O) n R 8, (CH2)-heteroaryl or a carbocyclic group having 3 to 7 ring members, where up to 4 of the ring members may be substituted with heteroatoms independently selected from oxygen, sulfur, and nitrogen, provided that there is at least one carbon atom in the carbocyclic ring and two or more ring oxygen atoms, provided that the above ring oxygen atoms are not adjacent to each other, where the carbocyclic group is unsubstituted or substituted with 1, 2, or 3 groups independently selected from alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl, N-hydroxyacetamide, trifluoromethylalkyl, amino, and mono or dialkylamino; W is an anion selected from the group consisting of chloride, bromide, trifluoroacetate, and triethylammonium; m is selected from 0, 1, 2, 3, 4, 5, and 6; R 4 and X 1 , X 2 and X 3 One of them contains up to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, and optionally halogens, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, mono or dialkylamino, N-hydroxyacetamide, aryl, heteroaryl, carboxyalkyl, nitrile, NR 7 SO2R 8 , C(O)NR 7 R 8 , NR 7 C(O)R 8 , C(O)OR 7 , C(O)NR 7 SO2R 8 , (CH2) m S(O) n R 7 , (CH2) m - Heteroaryl, O(CH2) m -heteroaryl, (CH2),C(O)NR 7 R 8 , O(CH2)m C(O)OR 7 , (CH2) m SO2NR 7 R 8 and C(O)R 7 Aromatic rings may be formed by substitution of up to four groups independently selected from; R 3 R is hydrogen, aryl, C1-C8 alkyl, C1-C8 alkyl, C3-C7 cycloalkyl or C3-C7 heterocyclyl; 5 and R 6 Each is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; or R 5 and R 6 If bonded to the same nitrogen atom, they may form a heterocycle containing 3 to 8 ring members together with the nitrogen to which they are bonded, where up to 4 of the ring members may be substituted with heteroatoms independently selected from oxygen, sulfur, S(O), S(O)2, and nitrogen, provided that there is at least one carbon atom in the heterocycle and two or more ring oxygen atoms, provided that the above ring oxygen atoms are not adjacent to each other, where the heterocyclic group is unsubstituted or is a halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, nitrile, mono or dialkylamino, N-hydroxyacetamide, aryl, heteroaryl, carboxyalkyl, NR 7 SO2R 8 , C(O)NR 7 R 8 , NR 7 C(O)R 8 , C(O)OR 7 , C(O)NR 7 SO2R 8 , (CH2) m S(O) n R 7 , (CH2)m - Heteroaryl, O(CH2) m - Heteroaryl, (CH2) m C(O)NR 7 R 8 , O(CH2) m C(O)OR 7 and (CH2)SO2NR 7 R 8 It is replaced by one, two, or three groups independently selected from; R 7 and R 8 Each is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; or R 7 and R 8 If bonded to the same nitrogen atom, they may form a heterocycle containing 3 to 8 ring members together with the nitrogen to which they are bonded, where up to 4 of the ring members are heteroatoms independently selected from oxygen, sulfur, S(O), S(O)2, and nitrogen, provided that there is at least one carbon atom in the heterocycle and if there are two or more ring oxygen atoms, the above ring oxygen atoms are not adjacent to each other, where the heterocyclic group is unsubstituted or substituted with 1, 2, or 3 groups independently selected from halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, nitrile, mono or dialkylamino, N-hydroxy, aryl, heteroaryl, and carboxyalkyl; and their pharmaceutically acceptable salts, esters, amides, and prodrugs.

[0071] In some embodiments, the compound has the structure of formula IV:

[0072] [ka]

[0073] It has, Here, X 1 , X 2 and X 3 These are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, CN, NO2, OR 5 , NR 5 R 6 CO2R 5 COR 5 , S(O) n R 5 CONR 5 R 6 , NR 5 COR 6 , NR 5 SO2R 6 SO2NR 5 R 6 and P(O)(OR 5 )(OR 6 ) and; however, X 1 , X 2 and X 3 The prerequisite is that at least one of them is hydrogen; n is selected from 0, 1, and 2; R 1 In each case, R is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C3-C7 cycloalkyl; R 2 and R 4 These are hydrogen, halogen, C1-C8 alkyl, C3-C7 cycloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C2-C8 alkenyl, C2-C8 alkynyl, nitrile, nitro, OR 5 , SR 5 , NR 5 R 6 , N(O)R 5 R 6 , P(O)(OR 5 )(OR 6 ), (CR 5 R 6 ) m NR 7 R 8COR 5 , (CR 4 R 5 ) m C(O)R 7 CO2R 5 CONR 5 R 6 , C(O)NR 5 SO2R 6 , NR 5 SO2R 6 , C(O)NR 5 Ure 6 , S(O) n R 5 SO2NR 5 R 6 , P(O)(OR 5 )(OR 6 ), (CR 5 R 6 ) m P(O)(OR 7 )(OR 8 ), (CR 5 R 6 ) m -Ayl, (CR 5 R 6 ) m - Heteroaryl, T(CH2) m QR 5 ,-C(O)T(CH2) m QR 5 , NR 5 C(O)T(CH2) m QR 5 , and -CR 5 =CR 6 C(O)R 7 Selected independently of; or R 1 and R 2The carbocyclic group may have 3 to 7 ring members, preferably 5 to 6 ring members, and up to 4 of these may be substituted with heteroatoms independently selected from oxygen, sulfur, and nitrogen, where the carbocyclic group is unsubstituted or has halogen, hydroxy, hydroxyalkyl, nitrile, lower C1-C8 alkyl, lower C1-C8 alkyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl, N-hydroxyacetamide, trifluoromethylalkyl, amino, and mono or dialkylamino, (CH2) m C(O)NR 5 R 6 and O(CH2) m C(O)OR 5 Substituted by one, two, or three groups independently selected from, provided that there is at least one carbon atom in the carbocyclic ring and two or more ring oxygen atoms, provided that the above ring oxygen atoms are not adjacent to each other; T is O, S, NR 7 , N(O)R 7 , NR 7 R 8 W or CR 7 R 8 Q is O, S, NR 7 , N(O)R 7 , NR 7 R 8 W, CO2, O(CH2) m - Heteroaryl, O(CH2) m S(O) n R 8, (CH2)-heteroaryl or a carbocyclic group comprising 3 to 7 ring members, where up to 4 of the ring members may be optionally substituted with heteroatoms independently selected from oxygen, sulfur, and nitrogen, provided that there is at least one carbon atom in the heterocycle and two or more ring oxygen atoms, provided that the above ring oxygen atoms are not adjacent to each other, where the carbocyclic group is unsubstituted or substituted with 1, 2, or 3 groups independently selected from alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl, N-hydroxyacetamide, trifluoromethylalkyl, amino, and mono or dialkylamino; W is an anion selected from the group consisting of chloride, bromide, trifluoroacetate, and triethylammonium; m is selected from 0, 1, 2, 3, 4, 5, and 6; R 4 and X 1 , X 2 and X 3 One of them contains up to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, and optionally halogens, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, mono or dialkylamino, N-hydroxyacetamide, aryl, heteroaryl, carboxyalkyl, nitrile, NR 7 SO2R 8 , C(O)NR 7 R 8 , NR 7 C(O)R 8 , C(O)OR 7 , C(O)NR 7 SO2R 8 , (CH2) m S(O) n R 7 , (CH2) m - Heteroaryl, O(CH2) m -heteroaryl, (CH2),C(O)NR 7 R 8, O(CH2) m C(O)OR 7 , (CH2) m SO2NR 7 R 8 and C(O)R 7 Aromatic rings may be formed by substitution of up to four groups independently selected from; R 3 R is hydrogen, aryl, C1-C8 alkyl, C1-C8 alkyl, C3-C7 cycloalkyl or C3-C7 heterocyclyl; 5 and R 6 Each is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; or R 5 and R 6 If bonded to the same nitrogen atom, they may form a heterocycle containing 3 to 8 ring members together with the nitrogen to which they are bonded, where up to 4 of the ring members may be substituted with heteroatoms independently selected from oxygen, sulfur, S(O), S(O)2, and nitrogen, provided that there is at least one carbon atom in the heterocycle and two or more ring oxygen atoms, provided that the above ring oxygen atoms are not adjacent to each other, where the heterocyclic group is unsubstituted or is a halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, nitrile, mono or dialkylamino, N-hydroxyacetamide, aryl, heteroaryl, carboxyalkyl, NR 7 SO2R 8 , C(O)NR 7 R 8 , NR 7 C(O)R 8 , C(O)OR 7 , C(O)NR 7 SO2R 8 , (CH2) m S(O) n R 7, (CH2) m - Heteroaryl, O(CH2) m - Heteroaryl, (CH2) m C(O)NR 7 R 8 , O(CH2) m C(O)OR 7 and (CH2)SO2NR 7 R 8 It is replaced by one, two, or three groups independently selected from; R 7 and R 8 Each is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; or R 7 and R 8 If bonded to the same nitrogen atom, they may form a heterocycle containing 3 to 8 ring members together with the nitrogen to which they are bonded, where up to 4 of the ring members may be optionally substituted with heteroatoms independently selected from oxygen, sulfur, S(O), S(O)2, and nitrogen, provided that there is at least one carbon atom in the heterocycle and two or more ring oxygen atoms, provided that the ring oxygen atoms are not adjacent to each other, where the heterocyclic group is unsubstituted or substituted with 1, 2, or 3 groups independently selected from halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, nitrile, mono or dialkylamino, N-hydroxyacetamide, aryl, heteroaryl, and carboxyalkyl; and their pharmaceutically acceptable salts, esters, amides, and prodrugs.

[0074] In some embodiments, R 3 It is cyclopentyl.

[0075] In some embodiments, R1 It is an alkyl group.

[0076] In some embodiments, R 1 It is methyl.

[0077] In some embodiments, R 2 It is (CO)CH3.

[0078] In some embodiments, the above compounds are 8-cyclopentyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-cyclopentyl-6-ethyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-cyclopentyl-7-one Xo-2-(5-piperazine-1-ylpyridine-2-ylamino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate ethyl hydrochloride, 6-amino-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 6-bromo-8-cyclopentyl-2-[5-((R)-1-methyl-1-pyrrolidine-2-yl)pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 6-Bromo-8-cyclohexyl-2-(pyridine-2-yl-amino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-yl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(3,3-dimethyl-piperazine-1-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one n, 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-[5-(3-amino-pyrroridine-1-yl)-pyridine-2-ylamino]-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(5-morpholine-4-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[bis-(2-methoxyethyl)-amino]-pyridine-2-ylamino}-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(5-morpholine-4-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-{5-[bis-(2-methoxyethyl)-amino]-pyridine-2-ylamino}-8-cyclopentyl-5-methyl-8H-pyrido do[2,3-d]pyrimidine-7-one, 4-[6-(8-cyclopentyl-6-iodo-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-piperazine-1-carboxylate tert-butyl, 8-cyclopentyl-6-iodo-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-{6-[8-cyclopentyl-6-(2-ethoxyethoxy)-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidine-2-ylamino]-pyridine-3-yl}piperazine-1-carboxylate tert-butyl, 8-cyclopentyl-6-(2-ethoxy-ethoxy)-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[bis-(2-methoxyethyl)-amino]-pyridine-2-ylamino}-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-{5-[bis-(2-methoxyethyl) 8-Isopropyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyridol-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(8-isopropyl-7-oxo-7,8-dihydro-pyrido[2,3]pyrimidine-2-ylamino)-pyridin-3-yl]piperazine-1-carboxylate tert-butyl, 8-isopropyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-piperazine-1-carboxylate tert-butyl, 8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(8-cyclohexyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-piperazine-1-carboxylate tert-butyl, 8-cyclohexyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H -Pyrido[2,3-d]pyrimidine-7-one, 4-[6-(8-cyclopropyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-piperazine-1-carboxylate tert-butyl, 8-cyclopropyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(pyridine-2,6-yldiamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl Ptyl-5-methyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-[5-(4-methyl-piperazine-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, (1-{6-[8-cyclopentyl-6 -(1-ethoxyvinyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino]-pyridine-3-yl}-pyrrolidine-3-yl)-carbamate tert-butyl, 6-acetyl-8-cyclopentyl-2-(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]azepan-1-carboxylic acid tert-butyl, 6-bromo-8-cyclopentyl-2-(5-[1,4]diazepan-1-ylpyridine-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 4-{6-[8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino]-pyridine-3-yl}-[1,4]diazepan-1-carboxylic acid tert-butyl, 6-acetyl-8-cyclopentyl-2-(5-[1,4]diazepan-1-ylpyridine-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-piperazine-1-carbone tert-butyl carboxylate, 8-cyclopentyl-5-methyl-2-(5-piperazine-4-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-2,2-dimethylpiperazine-1-carboxylate tert-butyl, 6-bromo-8-cyclopentyl-2-[5-(3,3-dimethylpiperazine-1-yl)-pyridine- 2-ylamino]-5-methyl-8H-pyrido[2,3d]pyrimidine-7-one, 4-{6-[8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino]-pyridine-3-yl}-2,2-dimethylpiperazine-1-carboxylate tert-butyl, 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-2,6-dimethylpiperazine-1-carboxylate tert-butyl, 6-bromo-8-cyclopentyl-2-[5-(3,5-dimethylpiperazine-1-yl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 4-{6-[8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino]-pyridine-3-yl}-2,6-dimethylpiperazine-1-carboxylate tert-butyl, 8-cyclo Lopentyl-6-(1-ethoxyvinyl)-5-methyl-2-(5-morpholine-4-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′ -ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-{6-[8-cyclopentyl-6-(2-ethoxyethyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino]-pyridine-3-yl}piperazine-1-carboxylate tert-butyl, 8-cyclopentyl-6-(2 -Ethoxyethyl)-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-{6-[8-cyclopentyl-6-(2-methoxy-ethoxymethyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino]-pyridine-3-yl}piperazine-1-carboxylate tert-butyl, 8-cyclopentyl-6-(2-methoxy-ethoxymethyl)-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(8-cyclopentyl-6-ethoxymethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]piperazine-1-carboxylate tert-butyl, 8-cyclopentyl-6-ethoxymethyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(8-cyclopentyl-6-methoxymethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-7-one [Midine-2-ylamino)-pyridine-3-yl]-piperazine-1-carboxylate tert-butyl, 8-cyclopentyl-6-methoxymethyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(2,6-dimethyl-morpholine-4-yl)pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethoxymethyl-2-(3,4,5,6-tetramethyl Hydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethoxymethyl-2-(5-morpholine-4-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, [8-cyclopentyl-7-oxo-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-ylmethyl]-benzylcarbamate, 8-cyclopentyl Tyl-2-[5-(2,6-dimethyl-morpholine-4-yl)-pyridine-2-ylamino]-6-(1-ethoxy-vinyl)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(2,6-dimethyl-morpholine-4-yl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-6-propionyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-fluoro-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-cyclopentyl-6-methyl-2 -(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-cyclopentyl-6-isobutoxy-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 6-benzyl-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-cyclopentyl-6-hydroxymethyl-2-( 5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 2-[5-(4-tert-butoxycarbonylpiperazine-1-yl)-pyridine-2-ylamino]-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate ethyl, 6-acetyl-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7 -one, 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(3,5-di, [methyl-piperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(3,3-dimethyl-piperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-yl)-pyridine-2-ylamino] ]-6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(3-ethylamino-pyrrolidine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-pyrrolidine-1-yl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[3-(1-amino-1-methylethyl)-pyrrolidine-1-yl]-pyridine-2-ylamino}-6-bromo- 8-Cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 1-[6-(6-bromo-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]pyrroridine-2-carboxylic acid, 6-bromo-8-cyclopentyl-2-[5-(4-diethylamino-butylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(3-ethylamino-pyrimidine-1-yl)-pyridine-2 -ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(5-pyrrolidine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-{5-[3-(1-amino-1-methylethyl)-pyrrolidine-1-yl]-pyridine-2-ylamino}-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 1-[6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-pyrroridine-2-carboxylic acid, 6-acetyl-8-cyclopentyl-2-[5-(4-diethylamino-butylamino)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-[5-(3,5-dimethylpiperazine-1-yl)-pyridine-2-ylamino]-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-[5-(3,3- Dimethyl-piperazine-1-yl)-pyridine-2-ylamino]-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-yl)-pyridine-2-ylamino]-8-cyclopentyl-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(3-ethyl [amino-pyrrolidine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-(5-pyrrolidine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[3-(1-amino-1-methylethyl)-pyrrolidine-1-yl]-pyridine-2-ylamino}-8-cyclopentyl-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 1-[6-(8-cyclopentyl-6-ethyl-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-pyrroridine-2-carboxylic acid, 8-cyclopentyl-2-[5-(4-diethylamino-butylamino)-pyridine-2-ylamino]-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-[5-(3,5-dimethylpiperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-[5-(3,3-dimethylpiperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-[5-(4-methylpiperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-yl)-pyridine-2-ylamino]-6-benzyl-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-[5-( 3-ethylamino-pyrrolidine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-(5-pyrrolidine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[3-(1-amino-1-methylethyl)-pyrrolidine-1-yl]-pyridine-2-ylamino}6-benzyl-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 1-[6-(6-benzyl-8- Cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-pyrroridine-2-carboxylic acid, 6-benzyl-8-cyclopentyl-2-[5-(4-diethylamino-butylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-[5-(3,5-dimethylpiperazine-1-yl)-pyridine-2-ylamino]-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one , 8-cyclopentyl-2-[5-(3,3-dimethylpiperazine-1-yl)-pyridine-2-ylamino]-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-hydroxymethyl-2-[5-(4-methylpiperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-yl)-pyridine-2-ylamino]-8-cyclopentyl-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-[5-(3-ethylamino-pyrrolidine-1-yl)-pyridine-2-ylamino]-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-hydroxymethyl-2-(5-pyrrolidine-1-yl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[3-(1-amino-1-methylethyl)-pyrrolidine-1-yl]-pyridine-2-ylamino}8-cyclopentyl-6-hydroxymethyl- 8H-pyrido[2,3-d]pyrimidine-7-one, 1-[6-(8-cyclopentyl-6-hydroxymethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]pyrroridine-2-carboxylic acid, 8-cyclopentyl-2-[5-(4-diethylamino-butylamino)-pyridine-2-ylamino]-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-yl)-pyridine-2 -ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-[5-(3,3-dimethylpiperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-[5-(4-methylpiperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3d]pyrimidine-7-one, 6-amino-2-[5-(3-amino-pyrroridine-1-yl)-pyridine-2-ylamino]-8-cyclopentyl-8H-py Lido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-[5-(3-ethylamino-pyrrolidine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-(5-pyrrolidine-1-ylpyridine-2-ylamino)-81H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-2-{5-[3-(1-amino-1-methylethyl)-pyrrolidine-1-yl]-pyridine-2-ylamino}-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 1-[6-(6-amino-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]pyrroridine-2-carboxylic acid, 6-amino-8-cyclopentyl-2-[5-(4-diethylamino-butylamino)-pyridinyl-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2, 3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-morpholine-4-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-diethylaminopyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[bis-(2-hydroxyethyl)-amino]-pyridine-2-ylamino}-6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[bis-(2-methoxyethyl) [6-(6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(2-amino-ethylamino)-pyridin-2-ylamino]-6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-dimethylamino-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-bromo-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d ]pyrimidine-2-ylamino)-pyridine-3-yl]-N-methyl-acetamide, 6-bromo-8-cyclopentyl-2-[5-(2-methoxy-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(2-methoxy-ethoxymethyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(2-diethylamino-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-pyrroridine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(6-methyl-5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d] Pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-diethylamino-pyridine-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[bis-(2-hydroxyethyl)-amino]-pyridine-2-ylamino}-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(2-amino-ethylamino)-pyridine-2-ylamino]-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d] Pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-dimethylaminopyridine-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-N-methylacetamide, 6-bromo-8-cyclopentyl-2-[5-(2-methoxyethoxy)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2, 3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(2-methoxy-ethoxymethyl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(2-diethylamino-ethoxy)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(5-pyrrolidine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(6-methyl-5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2 -(5-diethylamino-pyridine-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-{5-[bis-(2-hydroxyethyl)-amino]-pyridine-2-ylamino}-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-[5-(2-amino-ethylamino)-pyridine-2-ylamino]-8-cyclopentyl-5-methyl-8H-pyridin do[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-(5-dimethylaminopyridine-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-N-methylacetamide, 6-acetyl-8-cyclopentyl-2-[ 5-(2-methoxy-ethoxy)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(2-methoxy-ethoxymethyl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(2-diethylamino-ethoxy)-pyridine-2-ylamino]-5-methyl-8H-, Pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(5-pyrroridine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(6-methyl-5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6 ′-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-(5-morpholine-4-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-(5-diethylaminopyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-{5-[bis-(2-hydroxyethyl)-amino]-pyridine-2-ylamino}-8-cyclopentyl-8H-py Lido[2,3-d]pyrimidine-7-one, 6-acetyl-2-{5-[bis-(2-methoxyethyl)-amino]-pyridine-2-ylamino}-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-[5-(2-amino-ethylamino)-pyridine-2-ylamino]-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-(5-dimethylamino-pyridine-2-ylamino)-8H-pyrido[2,3-d] Pyrimidine-7-one, N-[6-(6-acetyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-N-methyl-acetamide, 6-acetyl-8-cyclopentyl-2-[5-(2-methoxy-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(2-methoxy-ethoxymethyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(2-diethylamino-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-(5-pyrrolidine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-(6-methyl-5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7- ONE, 6-bromo-8-cyclopentyl-2-[5-(2-methoxy-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3d]pyrimidine-7-ONE, 6-bromo-8-cyclopentyl-2-[5-(2-methoxy-ethylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-ONE, 2-(5-azetidine-1-ylpyridine-2-ylamino)-6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-ONE, 2-(5-azepan-1-ylpyridin N-2-ylamino)-6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-bromo-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]acetamide, 6-bromo-8-cyclopentyl-2-(5-phenylaminopyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(4-fluorobenzylamino)-pyrimidine-7-one [Din-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-bromo-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]methanesulfonamide, 6-bromo-8-cyclopentyl-2-(5-methanesulfonyl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-phenyl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-[5-(2-methoxy-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-[5-(2-methoxy-ethylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-2-(5-azetidine-1-ylpyridine-2-ylamino)-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-2- (5-azepan-1-ylpyridine-2-ylamino)-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-amino-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]acetamide, 6-amino-8-cyclopentyl-2-(5-phenylaminopyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-[5-(4-fluorobenzyl [Mino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-amino-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-methanesulfonamide, 6-amino-8-cyclopentyl-2-(5-methanesulfonylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-(5-phenylpyridine-2-ylamino)-8H-pyrid [2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(2-methoxy-ethoxy)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(2-methoxy-ethylamino)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-(5-azetidine-1-ylpyridine-2-ylamino)-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-(5-azepan-1-ylpyridine-2-ylamino)-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]acetamide, 6-acetyl-8-cyclopentyl-5-methyl-2-(5-phenylaminopyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7- ONE, 6-acetyl-8-cyclopentyl-2-[5-(4-fluoro-benzylamino)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-ONE, N-[6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-methanesulfonamide, 6-acetyl-8-cyclopentyl-2-(5-methanesulfonyl-pyridin-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-O 6-acetyl-8-cyclopentyl-5-methyl-2-(5-phenylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-[5-(2-methoxy-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-[5-(2-methoxy-ethylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-(5-azetidine-1-ylpyridine-2-yl Amino)-6-benzyl-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-(5-azepan-1-ylpyridine-2-ylamino)-6-benzyl-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-benzyl-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]acetamide, 6-benzyl-8-cyclopentyl-2-(5-phenylaminopyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-[5-(4-fluoro-benzylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-benzyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]methanesulfonamide, 6-benzyl-8-cyclopentyl-2-(5-methanesulfonyl-pyridine-2-ylamino)-8H-py Lido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-(5-phenylpyridine--2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-hydroxymethyl-2-[5-(2-methoxy-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-hydroxymethyl-2-[5-(2-methoxy-ethylamino)-pyridine-2-ylamino]-8H-pyrido [2,3-d]pyrimidine-7-one, 2-(5-azetidine-1-ylpyridine-2-ylamino)-8-cyclopentyl-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-(5-azepan-1-ylpyridine-2-ylamino)-8-cyclopentyl-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(8-cyclopentyl-6-hydroxymethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2 -ylamino)-pyridine-3-yl]-acetamide, 8-cyclopentyl-6-hydroxymethyl-2-(5-phenylaminopyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-[5-(4-fluorobenzylamino)-pyridine-2-ylamino]-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(8-cyclopentyl-6-hydroxymethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-methanesulfonamide, 8-cyclopentyl-6-hydroxymethyl-2-(5-methanesulfonyl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-hydroxymethyl-2-(5-phenyl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(2-methoxy-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2, 3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(2-methoxy-ethylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-(5-azetidine-1-yl-pyridine-2-ylamino)-8-cyclopentyl-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-(5-azepan-1-yl-pyridine-2-ylamino)-8-cyclopentyl-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(8-cyclopentyl Lu-6-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]acetamide, 8-cyclopentyl-6-ethyl-2-(5-phenylaminopyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(4-fluorobenzylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(8-cyclopentyl-6-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-7-one, N-[6-(8-cyclopentyl-6-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino] Dro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-methanesulfonamide, 8-cyclopentyl-6-ethyl-2-(5-methanesulfonyl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-(5-phenyl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(piperazine-1-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-carbonyl)-pyridine-2-ylamino]-6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(morpholine-4-carbonyl)-pyridine-2-ylamino] -8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-[5-(piperazine-1-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-carbonyl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-carbonyl)-pyridine-2-ylamino] [6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-[5-(morpholine-4-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(piperazine-1-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl Lu-2-[5-(3,5-dimethylpiperazine-1-carbonyl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-[5-(3-amino-pyrroridine-1-carbonyl)-pyridine-2-ylamino]-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(morpholine-4-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2, 3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(piperazine-1-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-carbonyl)-pyridine-2-ylamino]-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-carbonyl)-pyridine-2-ylamino]-8-cyclopentyl-6-ethyl-8H-pyrido[2,3- d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(morpholine-4-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(piperazine-1-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(morpholine-4-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5 -(3-amino-pyrroridine-1-sulfonyl)-pyridine-2-ylamino]-6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(3,5-dimethylpiperazine-1-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-[5-(piperazine-1-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-[5-(morpholine-4-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-sulfonyl)-pyridine-2-ylamino]-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-sulfonyl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(piperazine-1-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(morpholine-4-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-sulfonyl)-pyridine-2-ylamino]-8-cyclopentyl-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8 -Cyclopentyl-2-[5-(3,5-dimethylpiperazine-1-sulfonyl)-pyridine-2-ylamino]-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(piperazine-1-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(morpholine-4-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-Acetyl-2-[5-(3-amino-pyrroridine-1-sulfonyl)-pyridine-2-ylamino]-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-Acetyl-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-sulfonyl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one and 6-Acetyl-8-cyclopentyl-5-methyl-2-([1,6]naphthyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine- 7-ONE, 6-acetyl-8-cyclopentyl-2-[5-(1,1-dioxo-116-thiomorpholin-4-yl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-ONE, 8-cyclopentyl-6-hydroxymethyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-ONE, 6-acetyl-2-(3-chloro-5-piperazine-1-ylpyridine-2-ylamino)-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-acetyl-5-methyl-7-oxo-2-(pyridine-2-ylamino)-7H-pyrido[2,3-d]pyrimidine-8-yl]-cyclohexanecarboxylic acid, 4-[6-acetyl-2-(5-dimethylaminopyridine-2-ylamino)-5-methyl-7-oxo-7H-pyrido[2,3-d]pyrimidine-8-yl]-cyclohexanecarboxylic acid, 6-bromo-8-cyclopentyl-5-methyl-2-[5-(piperazine-1-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d] Pyrimidine-7-one, 6-(8-cyclopentyl-6-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-3-piperazine-1-ylpyridine-2-carboxylic acid, 2-(6-acetyl-5-piperazine-1-ylpyridine-2-ylamino)-8-cyclopentyl-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 3-{2-[6-(8-cyclopentyl-6-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yloxy )-ethoxy}-propionic acid, [6-(8-cyclopentyl-6-ethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridin-3-yloxy)-acetic acid, 8-cyclopentyl-2-(5-{2-[2-(5-methyl-pyridin-2-yl)-ethoxy]-ethoxy}pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-benzenesulfonyl-propoxy)-pyridin-2-ylamino]-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine- 7-one, 8-cyclopentyl-6-ethyl-2-{5-[2-(2-methoxy-ethoxy)-ethoxy]-pyridine-2-ylamino}-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-(5-{[3-(3,5-dimethyl-piperazine-1-yl)-propyl]-methyl-amino}pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-{5-[(3-imidazole-1-yl-propyl)-methyl-amino]pyridin-2-ylamino}-8H-pyrido[2,Selected from the group consisting of 3-d]pyrimidine-7-one, 6-acetyl-5-methyl-2-(5-methylpyridine-2-ylamino)-8-piperidine-4-yl-8H-pyrido[2,3-d]pyrimidine-7-one, and 6-acetyl-2-[5-(3,4-dihydroxypyrrolidine-1-yl)-pyridine-2-ylamino]-8-methoxymethyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one.

[0079] In some embodiments, the above compound is 8-Cyclopentyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-Cyclopentyl-6-ethyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-Cyclopentyl-7-oxo-2-(5-piperazine-1-ylpyridine-2-ylamino)-7 ,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate ethyl hydrochloride, 6-amino-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 6-bromo-8-cyclopentyl-2-[5-((R)-methyl-1-pyrroridine-2-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 6-bromo-8-cyclohexyl-2-(pyridine-2-yl-amino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 6-bromo-8-cyclohexyl-2-(pyridine-2-yl-amino)-8H-pyrido[2,3-d]pyrimidine-6-carboxylate ethyl hydrochloride, 6-amino-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylpentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride Limidine-7-one, 6-bromo-8-cyclopentyl-2-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-fluoro-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-cyclopentyl-6-methyl-2-(5-piperazine-1-ylpyridine-2 -ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-cyclopentyl-6-isobutoxy-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 6-benzyl-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-cyclopentyl-6-hydroxymethyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 2-[5-(4-tert-butoxycarbonylpiperazine-1-yl)-pyridine-2-ylamino]-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate ethyl, 6-acetyl-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl- Selected from the group consisting of 8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, and 6-bromo-8-cyclopentyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one.

[0080] In some embodiments, the above compound is 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one.

[0081] In some embodiments, the pharmaceutical further comprises fulvestrant.

[0082] In some embodiments, the HER2 inhibitor and the CDK inhibitor described above are not mixed with each other in the composition.

[0083] In some embodiments, the HER2 inhibitor, the CDK inhibitor, and the fulvestrant are not mixed with each other in the composition.

[0084] On the other hand, the present invention provides a HER2 inhibitor of the present invention for preventing, mitigating, or treating tumors, or inhibiting tumor growth, in combination with a CDK inhibitor of the present invention.

[0085] On the other hand, the present invention provides the use of a combination of the CDK inhibitor and the HER2 inhibitor of the present invention in the preparation of a pharmacopoeia for the prevention, mitigation, or treatment of tumors, or for the inhibition of tumor growth, in subjects in need.

[0086] On the other hand, the present invention provides a method for preventing, alleviating, or treating a tumor in a subject in need, or for inhibiting tumor growth, the method comprising administering a combination of the HER2 inhibitor and the CDK inhibitor of the present invention to the subject.

[0087] On the other hand, the present invention provides a method for preventing, alleviating, or treating a tumor in a subject in need, or for inhibiting tumor growth, the method comprising administering the composition of the present invention to the subject.

[0088] In some embodiments, the above-mentioned tumor includes a solid tumor.

[0089] In some embodiments, the tumors described above include metastatic tumors, early-stage tumors, and / or locally advanced tumors.

[0090] In some embodiments, the tumors described above include HER2-positive tumors and / or HER2-low-expressing tumors.

[0091] In some embodiments, the tumors described above include breast cancer and / or gastric cancer.

[0092] In some embodiments, the breast cancers described above include HER2-positive breast cancers and / or HER2-low-expressing breast cancers.

[0093] In some embodiments, the tumor described above is HR-negative or HR-positive breast cancer.

[0094] In some embodiments, the breast cancer described above includes early-stage breast cancer, locally advanced breast cancer, and / or metastatic breast cancer, and / or the gastric cancer described above includes early-stage gastric cancer, locally advanced gastric cancer, and / or metastatic gastric cancer.

[0095] In some embodiments, the tumors described above are selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, esophageal cancer, gastric cancer, skin cancer, lung cancer, bone cancer, colorectal cancer, pancreatic cancer, thyroid cancer, biliary tract cancer, buccal and pharyngeal cancer (oral cavity), lip cancer, tongue cancer, oral cancer, pharyngeal cancer, small intestine cancer, colorectal cancer, colon cancer, rectal cancer, brain and central nervous system cancer, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminomas, melanoma, sarcoma, bladder cancer, liver cancer, renal cell carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's disease, pilocytic cell carcinoma, and leukemia.

[0096] In some embodiments, the above-mentioned HER2 inhibitors are formulated for intravenous injection.

[0097] In some embodiments, the above-mentioned HER2 inhibitors are administered to subjects in need at doses ranging from approximately 1 mg / kg to approximately 30 mg / kg.

[0098] In some embodiments, the above-mentioned HER2 inhibitor is administered to subjects who require it every two weeks.

[0099] In some embodiments, the above-mentioned CDK inhibitors are formulated for oral administration.

[0100] In some embodiments, the above-mentioned CDK inhibitors are administered to subjects in need at doses ranging from approximately 10 mg / kg to approximately 50 mg / kg.

[0101] In some embodiments, the above-mentioned CDK inhibitor is administered daily to subjects in need for three weeks.

[0102] In some embodiments, the above method further includes administering an effective amount of fulvestrant to a subject.

[0103] In some embodiments, the fulvestrant in the above-mentioned pharmaceutical is formulated for intramuscular injection.

[0104] In some embodiments, the fulvestrant in the above-mentioned pharmaceutical is administered to subjects in need at doses ranging from approximately 400 mg to approximately 600 mg.

[0105] In some embodiments, the fulvestrant in the above-mentioned pharmaceutical is administered to subjects who require it on days 1 and 15 of cycle 1, and on day 1 of each subsequent 28-day cycle.

[0106] In some embodiments, the subjects described above do not respond to conventional therapies for HER2-related tumors.

[0107] In some embodiments, conventional treatments for the above-mentioned HER2-related tumors include administering HER2-ADC, MBC hormone, taxane, pirotinib, neratinib, tucatinib, trastuzumab, and / or pertuzumab.

[0108] In some embodiments, conventional treatments for the above-mentioned HER2-related tumors include administering docetaxel, capecitabine, and / or lapatinib.

[0109] Additional aspects and advantages of the present application will be readily apparent to those skilled in the art from the following detailed description, which illustrates and describes only exemplary embodiments of the present application. As realized, other different embodiments of the present application are possible, and some of their details can be modified in various obvious ways without departing from the present disclosure. Accordingly, the accompanying drawings and description are to be considered exemplary in nature and not restrictive. Embedding by reference All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent that individual publications, patents, and patent applications are specifically and individually represented so as to be incorporated by reference. [Brief explanation of the drawing]

[0110] Novel features of the present invention are described in detail in the appended claims. A better understanding of the features and advantages of the present invention can be obtained by referring to the following detailed description and accompanying drawings (also referred to herein as “Figures” and “FIG”) illustrating exemplary embodiments in which the principles of the present invention are employed, among which, [Figure 1] Figure 1 is a schematic diagram illustrating the study design of the studies described in Examples 1 and 2, where HBI represents the HER2 inhibitor of the present invention. [Figure 2] Figure 2 illustrates tumor volume in an HCC1954 XENO model after treatment with the drug of the present invention, where HBI represents the HER2 inhibitor of the present invention. [Figure 3] Figure 3 illustrates ER, PR, EGFR, and HER2 biomarkers in an HCC1954 XENO model after treatment with the present invention. [Figure 4] Figure 4 illustrates tumor volume in an MCF-7 XENO model after treatment with the drug of the present invention, where HBI represents the HER2 inhibitor of the present invention. [Modes for carrying out the invention]

[0111] While various embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Those skilled in the art can conceive of numerous variations, modifications, and substitutions without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be employed.

[0112] In this application, the term “HER2” as used herein generally refers to a type I transmembrane protein belonging to the epidermal growth factor receptor family, also known as c-erbB2, ErbB2, or Neu. In the context of this application, the term “HER2” also includes isoforms, including homologs, mutants, and splice isoforms of HER2. The term “HER2” also includes proteins having one or more sequences of HER2 homologs, mutants, and isoforms and fragments of such sequences, provided that the mutant protein (including isoforms), homologous protein, and / or fragments are recognized by one or more HER2-specific antibodies such as pertuzumab, trastuzumab, and margetsuzumab. HER2 may be human HER2. The human HER2 gene is mapped to chromosome position 17q12, and the genomic sequence of the HER2 gene is listed in GenBank NG-007503.1. In humans, there are five HER2 isoforms: A, B, C, D, and E. The term "HER2" is used herein to refer collectively to all HER2 isoforms.

[0113] In this application, the term “antibody” as used herein generally means immunoglobulin or a fragment or derivative thereof, encompassing any polypeptide containing an antigen-binding site, whether produced in vitro or in vivo. The term includes, but is not limited to, polyclonal, monoclonal, monospecific, multispecific, nonspecific, humanized, single-stranded, chimeric, synthetic, recombinant, hybrid, mutant, and transplant. For the purposes of this disclosure, unless the term “intact” is otherwise modified, such as “intact antibody,” the term “antibody” also includes antibody fragments such as Fab, F(ab')2, Fv, scFv, Fd, dAb, and other antibody fragments that retain antigen-binding function, i.e., the ability to specifically bind to HER2. Typically, such fragments include an antigen-binding domain.

[0114] In this application, the term "antigen-binding portion" of an antibody refers to one or more portions of a full-length antibody, and the antigen-binding portion maintains the ability to bind to the same antigen (such as HER2) to which the antibody binds, and competes with the full-length antibody for specific binding to the antigen. A general reference is Fundamental Immunology, Ch. 7 (Paul, W., ed., II edition, Raven Press, NY (1989)), which is incorporated herein by reference in its entirety for all purposes. Antigen-binding moieties can be produced using recombinant DNA technology or by enzymatic or chemical cleavage of full-length antibodies. In some cases, the antigen-binding moiety consists of polypeptides such as Fab, Fab′, F(ab′)2, Fd, Fv, dAb, complementary determination region (CDR) fragments, single-chain antibodies (such as scFv), chimeric antibodies, and biantibodies, and includes at least a portion of an antibody that sufficiently confers specific antigen-binding ability to the polypeptide. Antigen-binding moieties of antibodies (such as the antibody fragments mentioned above) can be obtained from a given antibody using conventional techniques well known to those skilled in the art (such as recombinant DNA technology, enzymatic or chemical cleavage processes), and their specificity can be screened in a manner similar to that of screening full-length antibodies.

[0115] In this application, the terms “variable region” or “variable domain” of an antibody as used herein generally refer to the amino-terminal domain of the heavy or light chain of the antibody. The variable domains of the heavy and light chains are sometimes referred to as “VH” and “VL,” respectively. These domains are generally the most variable parts of the antibody (compared to other antibodies of the same class) and contain the antigen-binding site.

[0116] In this application, the term “bispecific antibody” refers to an antibody capable of binding to two different antigens or their antigenic epitopes. For example, a bispecific antibody may comprise at least one light chain or fragment thereof, and at least one heavy chain or fragment thereof. For example, a bispecific antibody may comprise one light chain or fragment thereof capable of specifically binding to both a first antigen or its antigenic epitope and a second antigen or its antigenic epitope. For example, a bispecific antibody may comprise two heavy chains or fragment thereof capable of binding to a first antigen or its antigenic epitope and a second antigen or its antigenic epitope, respectively. For example, the first antigen or its antigenic epitope and the second antigen or its antigenic epitope may be two different HER2 antigens.

[0117] In this application, the term “antigen” as used herein generally refers to a structure that is specifically bound by an antibody and / or a B cell antigen receptor. An antigen can induce an immune system response through interaction with an antibody that matches the structure of the antigen molecule. In one embodiment, the antigen may be HER2, for example, the extracellular domain of HER2 (e.g., ECD2 and / or ECD4). The epitope of pertuzumab may refer to Discovery of epitopes for targeting the human epidermal growth factor receptor 2 (HER2) with antibodies, Mol Oncol. 2009 Jun;3(3): 238-247; the epitope of trastuzumab may refer to Matching of trastuzumab (Herceptin) epitope mimics onto the surface of Her-2 / neu - a new method of epitope definition, Mol Immunol. 2005 May;42(9):1121-4.

[0118] In this application, the term “CDK inhibitor” as used herein generally refers to inhibitors of cyclin-dependent kinases (CDKs). CDKs are thought to be involved in the regulation of transcription, mRNA processing, and neuronal differentiation. Among the various CDKs, CDK4 and / or CDK6 have numerous inhibitors, including palbociclib (for CDK4 and CDK6), flavopyridol (arbocidib) (for CDK 1, 2, 4, 6, 7, and 9), aminothiazole (for CDK4), benzocarbazole (for CDK4), and pyrimidine (for CDK4).

[0119] In this application, the term “ribociclib” as used herein generally refers to an inhibitor of cyclin D1 / CDK4 and CDK6 used to treat certain types of breast cancer. Developed by Novartis and Astex, its trade name is Kisqali. Ribociclib has the following structure (C 23 H 30 It has N8O and its CAS number is 1211441-98-3.

[0120] [ka]

[0121] In this application, the term “abemaciclib” as used herein generally refers to a CDK inhibitor selective for CDK4 and CDK6, used for the treatment of advanced or metastatic breast cancer. Developed by Eli Lilly, its trade name is Verzenio or Verzenios. Abemaciclib has the following structure (C 27 H 32 It has the F2N8 designation and its CAS number is 1231929-97-7.

[0122] [ka]

[0123] In this application, the term “palbociclib” as used herein generally refers to an orally active pyridopyrimidine, a first-in-class compound that is a potent and highly selective reversible inhibitor of cyclin-dependent kinase (CDK) 4 / 6. Palbociclib is also known as Ibrance, Palbonix, or PD-0332991. The compound inhibits the synthesis of deoxyribonucleic acid (DNA) in cells by inhibiting the progression of the cell cycle from G1 to S phase. Palbociclib has the following structure (C 24 H 29 It has the N7O2 compound and its CAS number is 571190-30-2. It was approved by the FDA in March 2015 for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer.

[0124] [ka]

[0125] In this application, the term “fulvestrant” as used herein generally refers to a potent anti-estrogen agent that binds to and degrades endocrine receptors (ERs). Fulvestrant is currently indicated for the treatment of postmenopausal women with metastatic HR-positive breast cancer. Fulvestrant has the following structure (C 32 H 47 It has the F5O3S designation and its CAS number is 129453-61-8.

[0126] [ka]

[0127] In this application, the term “breast cancer” as used herein generally refers to cancer that originates from breast tissue. Breast cancer cells may or may not have three important receptors: the estrogen receptor (ER), the progesterone receptor (PR), and HER2.

[0128] In this application, the terms “HER2-positive” or “HER2-enhanced” as used herein generally refer to tumors containing cells on which the HER2 protein is present on the cell surface. The HER2 protein can be overexpressed, for example, by gene amplification. Solid tumors that overexpress HER2 can be biochemically determined by an immunohistochemical score according to the copy number of HER2 molecules expressed per cell (see Hudziak et al., Proc. Natl. Acad. Sci. USA 84:7159-7163

[1987] ). For example, HER2-positive solid tumors may include HER2-positive breast cancer. HER2-positive breast cancer may be estrogen receptor positive and may be HER2-non-amplified invasive breast cancer. HER2-positive breast cancer may be progressive. HER2-positive breast cancer may be metastatic.

[0129] In this application, the term "HER2 low expression" refers to tumors containing cells that express very low levels of HER2. HER2 low expression is IHC 1 + or 2 + and FISH - This may refer to HER2-negative tumors that are being tested for. HER2 expression levels can be measured by immunohistochemistry or FISH. For example, a group with low HER2 levels is likely to be high-grade EGFR-positive and ER / HER3 / HER4-negative.

[0130] In this application, the term "solid tumor" generally refers to an abnormal mass of tissue that does not contain a fluid area. Solid tumors may be malignant or cancerous. Different types of solid tumors are named according to the type of cells that form them. For example, solid tumors may include breast cancer.

[0131] In this application, the term “metastatic” means that a tumor has spread from its place of origin to another part of the body. Many types of tumors are also called stage IV (4) tumors. Metastatic tumors develop when tumor cells detach from the primary tumor and enter the bloodstream or lymphatic system. For example, breast cancer that has metastasized to the lungs is sometimes called metastatic breast cancer.

[0132] In this application, the term “early tumor” refers to a tumor that has not spread deeply into neighboring tissues. Early tumors may also be called early cancers and / or stage I (1) tumors. Early tumors may not have spread very far.

[0133] In this application, the term "locally advanced tumor" refers to a tumor that has grown outside the site of origin and has not yet metastasized to other sites. For example, locally advanced breast cancer may be a subset of breast cancer characterized by the most advanced breast tumors without distant metastasis.

[0134] In this application, the term “treatment” as used herein generally refers to a clinical intervention in an attempt to alter the natural course of the individual being treated, which may be carried out for preventive purposes or during the course of a clinical condition. Desired effects of treatment may include prevention of disease onset or recurrence, relief of symptoms, reduction of direct or indirect pathological consequences of the disease, prevention of metastasis, slowing of the rate of disease progression, improvement or mitigation of the disease state, remission, or improvement of prognosis. For example, HER2 inhibitors are used to delay the onset of disease or to slow the progression of disease.

[0135] In this application, the term “prevent” as used herein generally means delaying the onset of, preventing the progression of, preventing the appearance of, defending against, suppressing or eliminating the appearance of, or reducing the incidence of any injury, effect, or symptom of a disease or disorder.

[0136] In this application, the term “alleviate” as used herein generally refers to the process by which the severity of the signs or symptoms of a disorder is reduced. Alleviation may include the alleviation, but not elimination, of the signs or symptoms of a disease or disorder.

[0137] In this application, the term “subject” as used herein generally refers to an animal, such as a human. For example, subjects may include “non-human animals” consisting of mammals such as rats, mice, rabbits, sheep, cats, dogs, cattle, pigs, and non-human primates.

[0138] In this application, the term “conventional treatments for HER2-related tumors” as used herein generally means administering any substance or agent that blocks HER2-related tumor growth. Conventional treatments for HER2-related tumors can interfere with the function of certain molecules involved in the growth and survival of HER2-related (e.g., HER2-positive and / or HER2-low-expressing) tumor cells. Conventional treatments for HER2-related tumors may include any approved agents specific to the treatment of HER2-related tumors (e.g., HER2-related tumors may be solid tumors, and e.g., HER2-related tumors may be at any stage). Conventional treatments for HER2-related tumors may include first-line and / or second-line agents approved for the treatment of HER2-related tumors (e.g., those approved for the treatment of HER2-positive breast cancer). Conventional treatments for HER2-related tumors may include any approved agents suitable for the treatment of HER2-related tumors, such as agents used in general oncology treatments such as chemotherapy.

[0139] In this application, the term "HR" as used herein generally refers to hormone receptors. In breast cancer, HR-positive (HR + ) indicates the expression of hormone receptors, and HR-negative (HR - ) may indicate the absence of hormone receptor expression. Hormone receptors may include estrogen receptors (ER) and progesterone receptors (PR).

[0140] In this application, the term “trastuzumab” as used herein generally refers to a whole-human HER2 monoclonal antibody used to treat breast cancer and gastric cancer. Its trade names are Herceptin, Herzma, or Ogibri. Trastuzumab may be used particularly for HER2 receptor-positive cancers.

[0141] In this application, the term “MBC hormone” as used herein generally refers to hormone therapy for the treatment of breast cancer. In some embodiments, the hormone therapy may prevent hormones (e.g., estrogen or progesterone) from binding to receptors within breast cancer cells. For example, the hormone therapy may include administering tamoxifen and / or toremifene.

[0142] In this application, the term “taxane” as used herein generally refers to a type of diterpene. Taxanes are also used in the treatment of metastatic breast cancer. The CAS number of a taxane may be 1605-68-1. A taxane is given by the following formula:

[0143] [ka]

[0144] It may have.

[0145] In this application, the term “HER2-ADC” as used herein generally refers to an antibody-drug conjugate that targets HER2 and is capable of binding to HER2 on the surface of tumor cells. For example, a HER2-ADC may include trastuzumab emtansine (T-DM1), which may be indicated for the treatment of HER2-positive metastatic breast cancer. For example, a HER2-ADC may include trastuzumab deruxtecan (Ds-8201a), which may be indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer. For example, a HER2-ADC may include SYD985, in which trastuzumab is linked via a cleavable linker to the duocalmycin prodrug seco-ducalmycin-hydroxybenzamide-azaindole or seco-duvá.

[0146] In this application, the term “pirotinib” as used herein generally refers to an irreversible bimodal pan-ErbB receptor tyrosine kinase inhibitor. Pilotinib may target EGFR, HER2, and HER4. Pilotinib may be used to treat HER2-positive advanced solid tumors. Pilotinib brasemiform is a racemic mixture of pirotinib and has the following formula:

[0147] [ka]

[0148] It is a compound that has [a certain characteristic].

[0149] In this application, the term “neratinib” as used herein generally refers to a tyrosine kinase inhibitor. Neratinib may be used as an adjuvant therapy for adults with early-stage hormone receptor-positive HER2-overexpressing / amplifying breast cancer. Neratinib is expressed by the following formula:

[0150] [ka]

[0151] It is a compound that has [a certain characteristic].

[0152] In this application, the term "tucatinib" as used herein generally refers to a small molecule inhibitor of HER2. Tucatinib may be used for advanced, unresectable, or metastatic HER2-positive breast cancer. Tucatinib is expressed by the following formula:

[0153] [ka]

[0154] It is a compound that has [a certain characteristic].

[0155] In this application, the term “pertuzumab” as used herein generally refers to a monoclonal antibody used for the treatment of HER2-positive breast cancer. The amino acid sequences of the variable light chain and variable heavy chain of pertuzumab (OMNITARG®) can be referenced to WO2006033700A2.

[0156] In this application, the term "trastuzumab" as used herein generally refers to a monoclonal antibody (trade names: Harcron, Herceptin) that interferes with the HER2 / neu receptor (Hudis, 2007, N. Engl. J. Med. 3577(1):39-51).

[0157] In this application, the term “docetaxel” as used herein generally refers to the active ingredient of TAXOTERE® or TAXOTERE® itself. Docetaxel is given by the following formula:

[0158] [ka]

[0159] It is a compound that has [a certain characteristic].

[0160] In this application, the term “capecitabine” as used herein generally refers to a chemotherapeutic agent that is a prodrug converted to 5-FU in tissues. The chemical name of capecitabine is pentyl[1-(3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1H-pyrimidine-4-yl]carbamate.

[0161] In this application, the term “lapatinib” as used herein generally refers to an orally active drug for breast cancer and other solid tumors. It is a dual tyrosine kinase inhibitor that blocks the HER2 / neu and epidermal growth factor receptor (EGFR) pathways. It functions as a dual reversible TKI against these receptors, thus blocking the downstream MAPK / Erk1 / 2 and PI3K / AKT pathways. Lapatinib is given by the following formula:

[0162] [ka]

[0163] It is a compound that has [a certain characteristic].

[0164] In this application, the term “effective amount” of the compound of the present invention generally means the amount of the compound of the present invention that induces a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity, or improvement of symptoms, alleviation of disease, delay or prevention of disease progression.

[0165] In this application, the term “1” as used herein is not generally intended to be singular. In some embodiments, the term “1” may refer to a plural. Where used throughout this disclosure, the singular “1” and “the” include plural references unless the context explicitly indicates otherwise.

[0166] In this application, the term “about” as used herein generally means variation within the normal acceptable range in the art, and generally means variation within 10% of the stated value, for example, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01%. Unless otherwise evident from the context, all numerical values ​​provided herein are modified by the term “about.” Pharmaceuticals On the other hand, the present invention provides pharmaceuticals comprising a HER2 inhibitor capable of binding to a first HER2 antigen and a second HER2 antigen, and a CDK inhibitor that inhibits CDK4 and / or CDK6.

[0167] For example, the above-mentioned pharmaceutical product may be a composition.

[0168] For example, the HER2 mentioned above could be human HER2.

[0169] For example, the first HER2 antigen described above may include an epitope within the HER2 extracellular domain 2 (ECD2).

[0170] For example, the second HER2 antigen described above may include an epitope within the HER2 extracellular domain 2 (ECD2).

[0171] For example, the second HER2 antigen described above may include an epitope within the HER2 extracellular domain 4 (ECD4).

[0172] For example, the HER2 inhibitor mentioned above may be a bispecific antibody or its antigen-binding moiety.

[0173] For example, the antigen-binding moiety described above may include Fab, Fab', F(ab)2, Fv fragment, F(ab')2, Fv fragment, di-scFv and / or dAb.

[0174] For example, the HER2 inhibitor described above may be a bispecific antibody or its antigen-binding moiety, and the bispecific antibody or its antigen-binding moiety includes a first light chain and a second light chain, wherein the first light chain and the second light chain may have the same amino acid sequence.

[0175] For example, the HER2 inhibitor described above may be a bispecific antibody or its antigen-binding moiety, which comprises a first heavy chain and a second heavy chain, the first and second heavy chains being able to properly assemble with the light chain, respectively, under physiological conditions or during in vitro protein expression.

[0176] For example, the HER2 inhibitor described above may be a bispecific antibody or its antigen-binding moiety, and the bispecific antibody or its antigen-binding moiety may include a first light chain and a second light chain having the same amino acid sequence. For example, the bispecific antibody or its antigen-binding moiety may include a common light chain because the first and second light chains have the same amino acid sequence.

[0177] For example, the common light chain described above may be engineered from two different original monoclonal antibodies capable of binding to different epitopes of human HER2, respectively. In some cases, the common light chain described above may also be derived from the light chain of either of the two original monoclonal antibodies. In some cases, the common light chain described above may be modified based on the light chain of either of the two original monoclonal antibodies.

[0178] For example, the modification may involve an insertion, deletion, and / or substitution at at least one amino acid position in the amino acid sequence of the light chain of either of the two original monoclonal antibodies. In some cases, the purpose of the modification is to maintain the affinity between the bispecific antibody or its antigen-binding moiety and the corresponding epitope.

[0179] In this application, the constant light chain region of the bispecific antibody or its antigen-binding portion may be of the κ type, which may include various allotypes such as Km1, Km2, and Km3, or the λ type, which may include various allotypes such as CL1, CL2, CL3, CL6, and CL7.

[0180] In this application, the HER2 inhibitor may be a bispecific antibody or its antigen-binding moiety, and the bispecific antibody or its antigen-binding moiety may have a first heavy chain and a second heavy chain.

[0181] In this application, the first and second heavy chains described above can be correctly assembled with the light chain, respectively, under physiological conditions or during protein expression in vitro.

[0182] For example, the first and second light chains described above can be combined with the heavy chain of pertuzumab and the heavy chain of trastuzumab, respectively.

[0183] For example, the variable regions of the first and / or second light chains described above may have an amino acid sequence represented by SEQ ID NO:1.

[0184] For example, the first and second light chains described above may be selected from the light chains of pertuzumab or its variants, and the light chains of trastuzumab or its variants, respectively.

[0185] For example, the variable regions of the first light chain and the second light chain described above may be the variable regions of the trastuzumab light chain.

[0186] For example, the first and second light chains described above may have amino acid sequences represented by SEQ ID NO: 7 to 12. For example, the first and second light chains described above may have amino acid sequences represented by SEQ ID NO: 7.

[0187] For example, the variable region of the first heavy chain described above may be the variable region of the pertuzumab heavy chain, and the variable region of the second heavy chain described above may be the variable region of the trastuzumab heavy chain. For example, the variable region of the first heavy chain described above may have an amino acid sequence represented by SEQ ID NO:13, and the variable region of the second heavy chain described above may have an amino acid sequence represented by SEQ ID NO:14.

[0188] In this application, the first heavy chain and / or the second heavy chain may include a constant region. For example, the constant region may be derived from the human IgG constant region. For example, the constant regions of the first heavy chain and the second heavy chain may be identical or different. In some cases, the amino acid sequences of the variable regions and CH1 domains of the first and second heavy chains may be identical to the amino acid sequences of the original monoclonal antibody.

[0189] In this application, the above-described bispecific antibody or its antigen-binding moiety can block both ligand-dependent and ligand-independent HER2 signaling pathways. For example, the IgG1 Fc fragment of the above-described bispecific antibody or its antigen-binding moiety can bind to FcRγIIIa and mediate a potent ADCC effect. For example, the above-described bispecific antibody or its antigen-binding moiety may promote HER2 internalization and / or exhibit superior antitumor activity in preclinical models compared to the use of the original monoclonal antibody (e.g., trastuzumab and pertuzumab) alone.

[0190] In some cases, the light chain constant region and / or heavy chain constant region of the bispecific antibody or its antigen-binding moiety may include modifications to obtain better ADCC, CDC, endocytosis, stability, immunogenicity and / or half-life, and furthermore, such modifications may also promote the formation of heterodimeric proteins during antibody expression. In this application, techniques for modifying the Fc fragment of the heavy chain are known in the art.

[0191] For example, the Fc fragment of the first heavy chain described above may have an amino acid sequence represented by SEQ ID NO: 19-49 or 51-52; the Fc fragment of the second heavy chain described above may have an amino acid sequence represented by SEQ ID NO: 19-49 or 51-52.

[0192] For example, the Fc fragment of the first heavy chain described above may have an amino acid sequence represented by SEQ ID NO:19; and the Fc fragment of the second heavy chain described above may have an amino acid sequence represented by SEQ ID NO:20.

[0193] For example, the Fc fragment of the first heavy chain described above may have an amino acid sequence represented by SEQ ID NO: 51; and the Fc fragment of the second heavy chain described above may have an amino acid sequence represented by SEQ ID NO: 52.

[0194] For example, the first heavy chain described above may have an amino acid sequence represented by SEQ ID NO:17; the second heavy chain described above may have an amino acid sequence represented by SEQ ID NO:18.

[0195] For example, the first heavy chain described above may have an amino acid sequence represented by SEQ ID NO:15; the second heavy chain described above may have an amino acid sequence represented by SEQ ID NO:16.

[0196] In this application, the HER2 inhibitor may include a first light chain, a second light chain, a first heavy chain, and a second heavy chain, wherein the variable region of the first light chain and / or the second light chain may have a sequence represented by SEQ ID NO:1; the variable region of the first heavy chain may have an amino acid sequence represented by SEQ ID NO:13; and the variable region of the second heavy chain may have an amino acid sequence represented by SEQ ID NO:14. The first heavy chain may have an amino acid sequence represented by SEQ ID NO:15; and the second heavy chain may have an amino acid sequence represented by SEQ ID NO:16.

[0197] The amino acid sequence according to the present invention is also an amino acid sequence that is identical to at least 80% (for example, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100%) the amino acid sequence represented by any of the SEQ ID NOs: 1 to 104 of the sequence list. For example, the amino acid sequence according to the present invention may have an amino acid sequence that has one or more (for example, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10 or more) amino acid deletions, insertions, and / or substitutions to the amino acid sequence represented by any of the SEQ ID NOs: 1 to 104 of the sequence list.

[0198] In this application, the HER2 inhibitor described above may be any HER2 inhibitor capable of binding to at least two different epitopes of HER2. For example, the HER2 inhibitor described above may be the HER2 inhibitor described in WO2015077891A1. In some cases, the HER2 inhibitor described above may be variants 5019, 7091, and 10000 described in WO2015077891A1. For example, the HER2 inhibitor described above may be the HER2 inhibitor described in US10000576B1. For example, the HER2 inhibitor described above may be the HER2 inhibitors described in WO2015091738A1, WO2015157592A1, WO2015077891A1, and WO2018014864A1.

[0199] In this application, the above-mentioned HER2 inhibitors can block both ligand-dependent and ligand-independent HER2 signaling pathways. For example, the IgG1 Fc fragment of the above-mentioned HER2 inhibitors can bind to FcRγIIIa and mediate a potent ADCC effect. For example, the above-mentioned HER2 inhibitors may promote HER2 internalization and exhibit superior antitumor activity compared to the use of trastuzumab or pertuzumab alone in preclinical models.

[0200] In this application, the above DK4 may be human CDK4, and / or the above CDK6 may be human CDK6.

[0201] In this application, the above-mentioned CDK inhibitors may further include palbociclib (PD-0332991), dinaciclib, P276-00, ronaciclib (BAY 1000394), P1446A-05, AT7519M, SNS-032, SCH 727965, and AG-024322. The above AG-024322 represents N-[[5-[(3E)-3-(4,6-difluorobenzimidazole-2-ylidene)-1,2-dihydroindazole-5-yl]-4-methylpyridine-3-yl]methyl]ethanamine, the above AT7519M represents 4-[(2,6-dichlorobenzoyl)amino]-N-piperidine-4-yl-1H-pyrazole-5-carboxamide, methanesulfonic acid, and the above P1446A-05 represents voruciclib, 2-(2-chloro-4-(trifluoromethyl)-phenyl)-5,7-dihydroxy-8-((2R,3S)-2-(hydroxymethyl)-1-methylpyrrolidine-3-yl)-4H-chromen-4- P276-00 above represents 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methylpyrrolidine-3-yl]chromen-4-one; SCH727965 above represents dinaciclib, 2-[(2S)-1-[3-ethyl-7-[(1-oxidepyridine-1-ium-3-yl)methylamino]pyrazolo[1,5-a]pyrimidine-5-yl]piperidine-2-yl]ethanol; SNS-032 above represents N-[5-[(5-tert-butyl-1,3-oxazole-2-yl)methylsulfanyl]-1,3-thiazole-2-yl]piperidine-4-carboxamide.

[0202] For example, the above-mentioned CDK inhibitors may be those listed in Table 1 of "Cyclone-dependent kinase inhibitors as anticancer drugs," Mol Pharmacol. 2015 Nov;88(5): 846-852.

[0203] In this application, the above-mentioned CDK inhibitors may further include SHR6390, Pirostini, D-0316, BPI-13650, TQ05510, FCN-437c, HEC80797, and BEBT-209.

[0204] For example, the above CDK inhibitor has the structure of formula I:

[0205] [ka]

[0206] Having Here, X is CR 9 or N; R 1 is C 1-8 Alkyl, CN, C(O)OR 4 or CONR 5 R 6 , 5-14 member heteroaryl or a 3-14 member cycloheteroalkyl; R 2 is C 1-8 Alkyl, C3-i4 cycloalkyl, or 5-14 member heteroaryl, where R 2 is one or more C 1-8 It may be substituted with alkyl or OH groups; L is a bond, C 1-8 Alkylene, C(O) or C(O)NR 10 Here, L may or may not be substituted; Y is H, R 11 , NR 12 R 13 , OH, or part of the following groups:

[0207] [ka]

[0208] And, Here, Y is CR 9 or N; where 0 to 3 R 8 It may exist, R 8 is C 1-8 Alkyl, oxo, halogen, or two or more R8 It may form a crosslinked alkyl group; W is CR 9 or N; R 3 H, C 1-8 Alkyl, C 1-8 Alkyl R 14 , C3-i4 cycloalkyl, C(O)C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 AlkylOH, C(O)NR 14 R 15 Ci-g cyanoalkyl, C(O)R 14 , C 0-8 Alkyl C(0)C0-8 alkylNR 14 R 15 , C 0-8 Alkyl C(O)OR 14 , NR 14 R 15 SO2C 1-8 Alkyl, C 1-8 Alkyl C3-i4 cycloalkyl, C(O)C 1-8 Alkyl C3-i4 cycloalkyl, C 1-8 It is an alkoxy or OH, and R 3 If it is not H, then it may be substituted or not, R 9 is H or halogen; R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 H and C are respectively 1-8 Alkyl, C3-H cycloalkyl, 3-14 member cycloheteroalkyl, Cβ-u aryl, 5-14 member heteroaryl, alkoxy, C(O)H, C(N)OH, C(N)OCH3, C(O)C 1-3 Alkyl, C 1-8 Alkyl NH2, C 1-6 Selected independently from alkylOH, where R 4 , R 5 , R 6 , R 7 , R 10 , R11 , R 12 , R 13 , R 14 and R 15 If not H, then it may be substituted or not; m and n are independently 0 to 2; where L and R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 is C 1-8 Alkyl, C 2-8 Alkenil, C 2-8 Alkinyl, C 3-14 Cycloalkyl, 5-14 member heteroaryl, C6- 14 It may be substituted with one or more of the following: aryl, 3-14 membered cycloheteroalkyl, OH, (O), CN, alkoxy, halogen, or NH2.

[0209] For example, R is H, C 1-8 Alkyl, C3-i4 cycloalkyl, C(O)Ci-S alkyl, Ci-8 alkylOH, Ci-g cyanoalkyl, C 0-8 Alkyl C(O)C 0-8 Alkyl NR 14 R 15 , C 0-8 Alkyl C(O)OR 14 , NR 14 R 15 , C 1-8 Alkyl C3-i4 cycloalkyl, C(O)C 1-8 Alkyl C3- 14 Cycloalkyl, C 0-8 Alkoxy, C 1-8 Alkyl R 14 , C 1-8 The compound is a haloalkyl or C(O)R, which may be substituted with one or more of OH, CN, F, or NH2, where R and R are H and C, respectively. 1-8A molecule is independently selected from alkyl, C3-i4 cycloalkyl, alkoxy, C(O)C1-3 alkyl, C1-8 alkylNH2, or C1-6 alkylOH.

[0210] For example, R is H, C 1-8 Alkyl, C3-i4 cycloalkyl, C(O)Ci-S alkyl, Ci-8 alkylOH, Ci-g cyanoalkyl, C 0-8 Alkyl C(0)C 0-8 Alkyl NR 14 R 15 , C 0-8 Alkyl C(O)OR 14 , NR 14 R 15 , C 1-8 Alkyl C3-i4 cycloalkyl, C(O)C 1-8 Alkyl C3- 14 Cycloalkyl, C 0-8 Alkoxy, C 1-8 Alkyl R 14 , C 1-8 The compound is a haloalkyl or C(O)R, which may be substituted with one or more of OH, CN, F, or NH2, where R and R are H and C, respectively. 1-8 A molecule is independently selected from alkyl, C3-i4 cycloalkyl, alkoxy, C(O)C1-3 alkyl, C1-8 alkylNH2, or C1-6 alkylOH.

[0211] For example, Y is either H, OH, or part of the following groups:

[0212] [ka]

[0213] And, Here, Y is N and W is CR 9 or N; where there may be 0 to 2 Rs, and R is C 1-8 The R elements may be alkyl, oxo, or two or more R elements may form a cross-linked alkyl group.

[0214] For example, L may be a bond, a Ci-s alkylene, or C(O)NH or C(O).

[0215] For example, R 2 C3- H It may be a cycloalkyl group.

[0216] For example, R 1 , CN, C(O)OR 4 CONR 5 It may be R or a 5- to 14-membered heteroaryl.

[0217] For example, R can be CONR R, and R 5 and R 6 C 1-8 It may be alkyl.

[0218] For example, X can be CR.

[0219] For example, one X may be N, and the other X may be CR.

[0220] For example, X may be CR, and Y may be

[0221] [ka]

[0222] It is fine to be that way, Here, m and n are 1, and Y and W are N. For example, the above CDK inhibitor has the structure of formula Ia:

[0223] [ka]

[0224] It has, R 50 is CONR 54 R 55 or CN; R 51 C may be non-substitutive,1-3 C3- substituted with alkyl or OH H It may be a cycloalkyl group; Z is CH or N; V is NR 56 or CHR 57 And; R 54 and R 55 H and C are independent of each other. 1-3 It is alkyl, R 52 , R 53 , R 56 and R 57 H and C are independent of each other. 1-8 Alkyl, C3-i4 cycloalkyl, C 1-8 Haloalkyl, NR 58 R 59 , C(O)OR 60 , C(O)C 1-8 Alkyl, C 0-8 Alkyl C(0)C 0-8 Alkyl-NR 61 R 62 , C 1-8 Alkoxy, C 1-8 Alkyl 0R 63 , C(O)-5-H cycloheteroalkyl, C3- H If they are cycloalkyl and each of them is not H, then C 1-8 It may be substituted with one or more alkyl, OH, or CN groups; R 58 , R 59 , R 60 , R 61 , R 62 and R 63 It is H or C1-8 alkyl.

[0225] For example, the above CDK inhibitors, 7-Cyclopentyl-2-[5-(3-methylpiperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3d]pyrimidine-6-carbonitride;7-Cyclopentyl-2-{5-[4-(2-fluoroethyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-(4-dimethylamino-3,4,5,6-tetrahydro-2H-[l ,3']bipyridinyl-6'-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;2-[5-(4-carbamoylmethylpiperazine-1-yl)-pyridine-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;2-{5-[4-(2-aminoacetyl)-piperazine-1-yl]-pyridine-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid di Methylamide; 2-[5-(3-amino-pyrroridine-1-yl)-pyridine-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-{5-[4-(2-methoxyethyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[4-(2-hydroxyethyl)-3,4,5,6-tetrahydro-2H-[l ,2']bipyradinyl-5'-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[5-((R)-3-methylpiperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[5-((S)-3-methylpiperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[5-(3-methylpiperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-{5-[4-(3-hydroxypropyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-{5-[4-(pyrroridine-1-carbonyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-{5-[4-(2-hydroxyethyl)-piperazine-1- [Il]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-{5-[4-((S)-2,3-dihydroxypropyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-(5-{4-[2-(2-hydroxyethoxy)-ethyl]-piperazine-1-yl}pyridine-2-ylamino)-7H-pyrrolo[2, 3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-{5-[4-(2-hydroxy-l-methylethyl)-piperazine-1-yl]-pyrididine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-{6-[4-(2-hydroxyethyl)-piperazine-1-yl]-pyridazine-3-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2 -{5-[4-(2,3-dihydroxypropyl)-piperazine-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-{5-[4-((R)-2,3-dihydroxypropyl)-piperazine-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-cyclopentyl-2-(4-dimethylamino-3,4,5,6-tetrahydro-2H-[l,3']bipyridinyl-6'-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel;7-Cyclopentyl-2-(3,4,5,6-tetrahydro-2H-[1,2']bipyradinyl-5'-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-[5-(piperazine-1-carbonyl)-pyridine-2-ylamino]-7H-pyrrolo[2,3d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-[5-(4-dimethylaminopiperidine-1-carbonyl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-(1',2',3',4',5',6'-hexahydro-[3,4']bi Pyridinyl-6-ylamino)-7H-pyrrolo2,3d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[5-((S)-3-methylpiperazine-1-ylmethyl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-{5-[4-((S)-2-hydroxypropyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-{5-[4-((R)-2-hydroxypropyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2 ,3-d]pyrimidine-6-carboxylate dimethylamide;7-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate methylamide;7-cyclopentyl-2-[5-(4-isopropyl-piperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3d]pyrimidine-6-carboxylate dimethylamide 7-Cyclopentyl-2-[5-(4-isopropyl-piperazine-1-carbonyl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-{5-[4-(4-methyl-pentyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-[6-(4-isopropyl-piperazine-1-yl)-pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-{5-[4-(2-hydroxy-2methylpropyl)-piperazine-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-[5-(3,3-dimethyl-piperazine-1-yl)-pyridin-2-yl [7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octo-3-ylmethyl)pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[5-(4- Ethyl-piperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-[5-(4-cyclopentyl-piperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-(1'-isopropyl-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-6-ylamino)-7H-pyrrolo[2 ,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-{5-[(R)-4-(2-hydroxyethyl)-3-methyl-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-cyclopentyl-2-{5-[(S)-4-(2-hydroxyethyl)-3-methyl-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-{5-[4-(2-hydroxyethyl)-piperazine-1-ylmethyl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-{5-[4-(2-dimethylaminoethyl)-piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;7-Cyclopentyl-2-{5-[4-(2-ethyl-butyl)piperazine-1-yl]- Pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate dimethylamide; 2-{5-[4-(2-cyclohexyl-acetyl)piperazine-1-yl]-pyridine-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate dimethylamide; 7-cyclopentyl-2-{5-[4-(3-cyclopentyl-propionyl)-piperazine-1-yl]-pyridine-2-ylamino}7H-pyrrolo[2,3-d]pyrimidine-6-carbone Dimethyl acid amide; 7-Cyclopentyl-2-[5-(4-Isobutylpiperazine-1-yl)-pyridine-2-ylamino]-7H-pyrrolo[2,3d]pyrimidine-6-carboxylic acid dimethylamide; {4-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)pyridine-3-yl]-piperazine-1-yl}-methyl acetate; 7-Cyclopentyl-2-{5-[4-(2-Isopropoxyethyl)-piperazine-1-yl]-pyridine-2- Ilamino}-7Hpyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; {4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)pyridine-3-yl]-piperazine-1-yl}-ethyl acetate; 4-(6-{7-cyclopentyl-6-[(2-hydroxyethyl)methylcarbamoyl]-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino}pyridine-3-yl)piperazine-l-carboxylic acid tert-butyl;7-Cyclopentyl-2-{5-[4-(2-methyl-butyl)piperazine-1-yl]-pyridine-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-[1'-(2-hydroxyethyl)-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-6-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; {4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]piperazine-1-yl}acetic acid and Selected from 2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-piperazine-1-yl}propionic acid, or a pharmaceutically acceptable salt thereof.

[0226] For example, the CDK inhibitor mentioned above could be ribociclib.

[0227] For example, the above-mentioned CDK inhibitors are used to modulate the activity of protein kinases such as CDK1, CDK2, CDK4, CDK5, CDK6, CDK7, CDK8, and CDK9. For example, the compounds may be those described in WO2010020675A1.

[0228] For example, the above CDK inhibitor has the structure of formula II:

[0229] [ka]

[0230] Having R1 is a C3-C5 alkyl, C3-C5 cycloalkyl, or cyclopropyl-methyl; R2 and R3 are H or fluorine, where at least one of R2 or R3 is fluorine; R4 is H or CH3; R5 is a Ci-C6 alkyl or -NR6R7, where R6 and R7 are C1-C3 alkyl; Q is CH2, O, S, or a direct bond; W and Y are C or N, where at least one of W or Y is N, where Q is O or S, W is C, or a pharmaceutically acceptable salt thereof.

[0231] For example, R may be isopropyl, cyclopropyl, cyclopentyl, or cyclopropyl-methyl.

[0232] For example, R may be isopropyl.

[0233] For example, R2 and R3 may each be fluorine.

[0234] For example, R4 can be H.

[0235] For example, R5 may be a C1-C3 alkyl group.

[0236] For example, Q may be a CH2 or a direct bond.

[0237] For example, Q can be CH2.

[0238] For example, Y can be N.

[0239] For example, W can be N.

[0240] For example, the above CDK inhibitors,

[0241] [ka] TIFF0007857866000029.tif245170

[0242] TIFF0007857866000030.tif137170

[0243] Selected from the group consisting of .

[0244] For example, the above CDK inhibitors,

[0245] [ka]

[0246] That's fine.

[0247] For example, the CDK inhibitor mentioned above could be abemaciclib.

[0248] For example, the above-mentioned CDK inhibitor may be a CDK4 / 6 inhibitor that has secondary inhibitory activity against other non-Cdk kinases. For example, the compound may be one described in WO2010075074A1.

[0249] For example, the above CDK inhibitor has the structure of formula III, i.e.

[0250] [ka]

[0251] It has, Here, the HER2 inhibitor comprises a first antigen-binding domain capable of specifically binding to the first HER2 antigen and a second antigen-binding domain capable of specifically binding to the second HER2 antigen, wherein the first HER2 antigen is not identical to the second HER2 antigen; X 1 , X 2 and X 3 These are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, CN, NO2, OR 5 , NR5 R 6 CO2R 5 COR 5 , S(O) n R 5 CONR 5 R 6 , NR 5 COR 6 , NR 5 SO2R 6 SO2NR 5 R 6 and P(O)(OR 5 )(OR 6 ) and; however, X 1 , X 2 and X 3 The prerequisite is that at least one of them is hydrogen; n is selected from 0, 1, and 2; R 1 In each case, R is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C3-C7 cycloalkyl; R 2 and R 4 These are hydrogen, halogen, C1-C8 alkyl, C3-C7 cycloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C2-C8 alkenyl, C2-C8 alkynyl, nitrile, nitro, OR 5 , SR 5 , NR 5 R 6 , N(O)R 5 R 6 , P(O)(OR 5 )(OR 6 ), (CR 5 R 6 ) m NR 7 R 8 COR 5 , (CR 4 R 5 ) m C(O)R 7 CO2R 5 CONR 5 R 6 , C(O)NR 5 SO2R 6 , NR 5 SO2R6 , C(O)NR 5 Ure 6 , S(O) n R 5 SO2NR 5 R 6 , P(O)(OR 5 )(OR 6 ), (CR 5 R 6 ) m P(O)(OR 7 )(OR 8 ), (CR 5 R 6 ) m -Ayl, (CR 5 R 6 ) m - Heteroaryl, T(CH2) m QR 5 ,-C(O)T(CH2) m QR 5 , NR 5 C(O)T(CH2) m QR 5 and -CR 5 =CR 6 C(O)R 7 Selected independently of; or R 1 and R 2 The carbon-cyclic group may have 3 to 7 ring members, preferably 5 to 7 ring members, and up to 4 of these may be substituted with heteroatoms independently selected from oxygen, sulfur, and nitrogen, where the carbon-cyclic group is unsubstituted or contains halogens, hydroxy, hydroxyalkyl, nitriles, lower C1-C8 alkyl, lower C1-C8 alkyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl, N-hydroxyacetamide, trifluoromethylalkyl, amino and mono or dialkylamino, (CH2) m C(O)NR 5 R 6 and O(CH2) m C(O)OR 5Substituted by one, two, or three groups independently selected from, provided that there is at least one carbon atom in the carbocyclic ring and two or more ring oxygen atoms, provided that the above ring oxygen atoms are not adjacent to each other; T is O, S, NR 7 , N(O)R 7 , NR 7 R 8 W or CR 7 R 8 Q is O, S, NR 7 , N(O)R 7 , NR 7 R 8 W, CO2, O(CH2) m - Heteroaryl, O(CH2) m S(O) n R 8 , (CH2)-heteroaryl or a carbocyclic group comprising 3 to 7 ring members, where up to 4 of the ring members may be optionally substituted with heteroatoms independently selected from oxygen, sulfur, and nitrogen, provided that there is at least one carbon atom in the carbocyclic ring and two or more ring oxygen atoms, provided that the above ring oxygen atoms are not adjacent to each other, where the carbocyclic group is unsubstituted or substituted with 1, 2, or 3 groups independently selected from alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl, N-hydroxyacetamide, trifluoromethylalkyl, amino, and mono or dialkylamino; W is an anion selected from the group consisting of chloride, bromide, trifluoroacetate, and triethylammonium; m is selected from 0, 1, 2, 3, 4, 5, and 6; R 4 and X 1 , X 2 and X 3One of them contains up to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, and optionally halogens, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, mono or dialkylamino, N-hydroxyacetamide, aryl, heteroaryl, carboxyalkyl, nitrile, NR 7 SO2R 8 , C(O)NR 7 R 8 , NR 7 C(O)R 8 , C(O)OR 7 , C(O)NR 7 SO2R 8 , (CH2) m S(O) n R 7 , (CH2) m - Heteroaryl, O(CH2) m -heteroaryl, (CH2),C(O)NR 7 R 8 , O(CH2) m C(O)OR 7 , (CH2) m SO2NR 7 R 8 and C(O)R 7 Aromatic rings may be formed by substitution of up to four groups independently selected from; R 3 R is hydrogen, aryl, C1-C8 alkyl, C1-C8 alkyl, C3-C7 cycloalkyl or C3-C7 heterocyclyl; 5 and R 6 Each is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; or R 5 and R 6If bonded to the same nitrogen atom, they may form a heterocycle containing 3 to 8 ring members together with the nitrogen to which they are bonded, where up to 4 of the ring members may be substituted with heteroatoms independently selected from oxygen, sulfur, S(O), S(O)2, and nitrogen, provided that there is at least one carbon atom in the heterocycle and two or more ring oxygen atoms, provided that the above ring oxygen atoms are not adjacent to each other, where the heterocyclic group is unsubstituted or is a halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, nitrile, mono or dialkylamino, N-hydroxyacetamide, aryl, heteroaryl, carboxyalkyl, NR 7 SO2R 8 , C(O)NR 7 R 8 , NR 7 C(O)R 8 , C(O)OR 7 , C(O)NR 7 SO2R 8 , (CH2) m S(O) n R 7 , (CH2) m - Heteroaryl, O(CH2) m - Heteroaryl, (CH2) m C(O)NR 7 R 8 , O(CH2) m C(O)OR 7 and (CH2)SO2NR 7 R 8 It is replaced by one, two, or three groups independently selected from; R 7 and R 8 Each is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; or R 7 and R 8If bonded to the same nitrogen atom, they may form a heterocycle containing 3 to 8 ring members together with the nitrogen to which they are bonded, where up to 4 of the ring members may be optionally substituted with heteroatoms independently selected from oxygen, sulfur, S(O), S(O)2, and nitrogen, provided that there is at least one carbon atom in the heterocycle and two or more ring oxygen atoms, provided that the above ring oxygen atoms are not adjacent to each other, where the heterocyclic group is unsubstituted or substituted with 1, 2, or 3 groups independently selected from halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, nitrile, mono or dialkylamino, N-hydroxyacetamide, aryl, heteroaryl, and carboxyalkyl; and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

[0252] For example, the compound has the structure of formula IV:

[0253] [ka]

[0254] It has, Here, X 1 , X 2 and X 3 These are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, CN, NO2, OR 5 , NR 5 R 6 CO2R 5 COR 5 , S(O) n R 5 CONR 5 R 6 , NR 5 COR 6 , NR 5 SO2R6 SO2NR 5 R 6 and P(O)(OR 5 )(OR 6 ) and; however, X 1 , X 2 and X 3 The prerequisite is that at least one of them is hydrogen; n is selected from 0, 1, and 2; R 1 In each case, R is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C3-C7 cycloalkyl; R 2 and R 4 These are hydrogen, halogen, C1-C8 alkyl, C3-C7 cycloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C2-C8 alkenyl, C2-C8 alkynyl, nitrile, nitro, OR 5 , SR 5 , NR 5 R 6 , N(O)R 5 R 6 , P(O)(OR 5 )(OR 6 ), (CR 5 R 6 ) m NR 7 R 8 COR 5 , (CR 4 R 5 ) m C(O)R 7 CO2R 5 CONR 5 R 6 , C(O)NR 5 SO2R 6 , NR 5 SO2R 6 , C(O)NR 5 Ure 6 , S(O) n R 5 SO2NR 5 R 6 , P(O)(OR 5 )(OR 6 ), (CR 5 R 6 )m P(O)(OR 7 )(OR 8 )、(CR 5 R 6 ) m -aryl, (CR 5 R 6 ) m -heteroaryl, T(CH2) m QR 5 , -C(O)T(CH2) m QR 5 , NR 5 C(O)T(CH2) m QR 5 and -CR 5 =CR 6 C(O)R 7 is independently selected from; or R 1 and R 2 may form a carbocyclic group containing 3 to 7 ring members, preferably 5 to 6 ring members, up to 4 of which may be optionally substituted with heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein the carbocyclic group is unsubstituted or halogen, hydroxy, hydroxyalkyl, nitrile, lower C1-C8 alkyl, lower C1-C8 alkyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl, N-hydroxyacetamide, trifluoromethylalkyl, amino and mono- or dialkylamino, (CH2) m C(O)NR 5 R 6 and O(CH2) m C(O)OR 5 is substituted with 1, 2 or 3 groups independently selected from, provided that there is at least one carbon atom in the carbocyclic ring and when there are two or more ring oxygen atoms, the above ring oxygen atoms are not adjacent to each other; T is O, S, NR 7 , N(O)R 7 , NR 7 R 8 W or CR 7 R 8 ; Q is O, S, NR 7 , N(O)R 7 , NR 7 R8 W, CO2, O(CH2) m - Heteroaryl, O(CH2) m S(O) n R 8 , (CH2)-heteroaryl or a carbocyclic group having 3 to 7 ring members, where up to 4 of the ring members may be substituted with heteroatoms independently selected from oxygen, sulfur, and nitrogen, provided that there is at least one carbon atom in the heterocycle and two or more ring oxygen atoms, provided that the above ring oxygen atoms are not adjacent to each other, where the carbocyclic group is unsubstituted or substituted with 1, 2, or 3 groups independently selected from alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, trifluoromethyl, N-hydroxyacetamide, trifluoromethylalkyl, amino, and mono or dialkylamino; W is an anion selected from the group consisting of chloride, bromide, trifluoroacetate, and triethylammonium; m is selected from 0, 1, 2, 3, 4, 5, and 6; R 4 and X 1 , X 2 and X 3 One of them contains up to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, and optionally halogens, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, mono or dialkylamino, N-hydroxyacetamide, aryl, heteroaryl, carboxyalkyl, nitrile, NR 7 SO2R 8 , C(O)NR 7 R 8 , NR 7 C(O)R 8 , C(O)OR 7 , C(O)NR 7 SO2R 8 , (CH2) m S(O) n R 7 , (CH2)m - Heteroaryl, O(CH2) m -heteroaryl, (CH2),C(O)NR 7 R 8 , O(CH2) m C(O)OR 7 , (CH2) m SO2NR 7 R 8 and C(O)R 7 Aromatic rings may be formed by substitution of up to four groups independently selected from; R 3 R is hydrogen, aryl, C1-C8 alkyl, C1-C8 alkyl, C3-C7 cycloalkyl or C3-C7 heterocyclyl; 5 and R 6 Each is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl; or R 5 and R 6 If bonded to the same nitrogen atom, they may form a heterocycle containing 3 to 8 ring members together with the nitrogen to which they are bonded, where up to 4 of the ring members may be substituted with heteroatoms independently selected from oxygen, sulfur, S(O), S(O)2, and nitrogen, provided that there is at least one carbon atom in the heterocycle and two or more ring oxygen atoms, provided that the above ring oxygen atoms are not adjacent to each other, where the heterocyclic group is unsubstituted or is a halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, nitrile, mono or dialkylamino, N-hydroxyacetamide, aryl, heteroaryl, carboxyalkyl, NR 7 SO2R 8 , C(O)NR 7 R 8 , NR 7 C(O)R 8 , C(O)OR 7, C(O)NR 7 SO2R 8 , (CH2) m S(O) n R 7 , (CH2) m -heteroaryl, O(CH2) m -heteroaryl, (CH2) m C(O)NR 7 R 8 , O(CH2) m C(O)OR 7 and (CH2)SO2NR 7 R 8 is substituted with 1, 2 or 3 groups independently selected from; R 7 and R 8 are each independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or heteroarylalkyl; or R 7 and R 8 when attached to the same nitrogen atom, may together with the nitrogen to which they are attached form a heterocyclic ring containing 3 to 8 ring members, where up to 4 of the ring members may optionally be substituted with heteroatoms independently selected from oxygen, sulfur, S(O), S(O)2 and nitrogen, provided that there is at least one carbon atom in the heterocyclic ring and when there are two or more ring oxygen atoms, the above ring oxygen atoms are not adjacent to each other, where the heterocyclic group is unsubstituted or substituted with 1, 2 or 3 groups independently selected from halogen, hydroxy, hydroxyalkyl, lower alkyl, lower alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, aminoalkylcarbonyl, trifluoromethyl, trifluoromethylalkyl, trifluoromethylalkylaminoalkyl, amino, nitrile, mono or dialkylamino, N-hydroxyacetamide, aryl, heteroaryl, carboxyalkyl; and its pharmaceutically acceptable salts, esters, amides and prodrugs.

[0255] For example, R 3It may be cyclopentyl.

[0256] For example, R 1 It may be an alkyl group.

[0257] For example, R 1 It may be methyl.

[0258] For example, R 2 (CO)CH3 may be used.

[0259] For example, the above compounds are 8-cyclopentyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-cyclopentyl-6-ethyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, and 8-cyclopentyl-7-oxo-2-(5 -Piperadin-1-ylpyridine-2-ylamino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate ethyl hydrochloride, 6-amino-8-cyclopentyl-2-(5-piperazin-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 6-bromo-8-cyclopentyl-2-[5-((R)-1-methyl-1-pyrrolidine-2-yl)pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 6-bromo -8-Cyclohexyl-2-(pyridine-2-yl-amino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-Acetyl-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-yl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-Acetyl-8-cyclopentyl-2-[5-(3,3-dimethyl-piperazine-1-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6 -Acetyl-8-cyclopentyl-5-methyl-2-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-[5-(3-amino-pyrroridine-1-yl)-pyridine-2-ylamino]-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(5-morpholine-4-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[bis-(2-methoxyethyl)-amino]-pyridine-2-ylamino}-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(5-morpholine-4-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-{5-[bis-(2-methoxyethyl)-amino]-pyridine-2-ylamino}-8-cyclopentyl-5-methyl-8H-pyrido do[2,3-d]pyrimidine-7-one, 4-[6-(8-cyclopentyl-6-iodo-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-piperazine-1-carboxylate tert-butyl, 8-cyclopentyl-6-iodo-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-{6-[8-cyclopentyl-6-(2-ethoxyethoxy)-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidine-2-ylamino]-pyridine-3-yl}piperazine-1-carboxylate tert-butyl, 8-cyclopentyl-6-(2-ethoxy-ethoxy)-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[bis-(2-methoxyethyl)-amino]-pyridine-2-ylamino}-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-{5-[bis-(2-methoxyethyl) 8-Isopropyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyridol-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(8-isopropyl-7-oxo-7,8-dihydro-pyrido[2,3]pyrimidine-2-ylamino)-pyridin-3-yl]piperazine-1-carboxylate tert-butyl, 8-isopropyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-piperazine-1-carboxylate tert-butyl, 8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(8-cyclohexyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-piperazine-1-carboxylate tert-butyl, 8-cyclohexyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H -Pyrido[2,3-d]pyrimidine-7-one, 4-[6-(8-cyclopropyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-piperazine-1-carboxylate tert-butyl, 8-cyclopropyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(pyridine-2,6-yldiamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl Ptyl-5-methyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-[5-(4-methyl-piperazine-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, (1-{6-[8-cyclopentyl-6 -(1-ethoxyvinyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino]-pyridine-3-yl}-pyrrolidine-3-yl)-carbamate tert-butyl, 6-acetyl-8-cyclopentyl-2-(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]azepan-1-carboxylic acid tert-butyl, 6-bromo-8-cyclopentyl-2-(5-[1,4]diazepan-1-ylpyridine-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 4-{6-[8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino]-pyridine-3-yl}-[1,4]diazepan-1-carboxylic acid tert-butyl, 6-acetyl-8-cyclopentyl-2-(5-[1,4]diazepan-1-ylpyridine-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-piperazine-1-carbone tert-butyl carboxylate, 8-cyclopentyl-5-methyl-2-(5-piperazine-4-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-2,2-dimethylpiperazine-1-carboxylate tert-butyl, 6-bromo-8-cyclopentyl-2-[5-(3,3-dimethylpiperazine-1-yl)-pyridine- 2-ylamino]-5-methyl-8H-pyrido[2,3d]pyrimidine-7-one, 4-{6-[8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino]-pyridine-3-yl}-2,2-dimethylpiperazine-1-carboxylate tert-butyl, 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-2,6-dimethylpiperazine-1-carboxylate tert-butyl, 6-bromo-8-cyclopentyl-2-[5-(3,5-dimethylpiperazine-1-yl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 4-{6-[8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino]-pyridine-3-yl}-2,6-dimethylpiperazine-1-carboxylate tert-butyl, 8-cyclo Lopentyl-6-(1-ethoxyvinyl)-5-methyl-2-(5-morpholine-4-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′ -ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-{6-[8-cyclopentyl-6-(2-ethoxyethyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino]-pyridine-3-yl}piperazine-1-carboxylate tert-butyl, 8-cyclopentyl-6-(2 -Ethoxyethyl)-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-{6-[8-cyclopentyl-6-(2-methoxy-ethoxymethyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino]-pyridine-3-yl}piperazine-1-carboxylate tert-butyl, 8-cyclopentyl-6-(2-methoxy-ethoxymethyl)-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(8-cyclopentyl-6-ethoxymethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]piperazine-1-carboxylate tert-butyl, 8-cyclopentyl-6-ethoxymethyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-(8-cyclopentyl-6-methoxymethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-7-one [Midine-2-ylamino)-pyridine-3-yl]-piperazine-1-carboxylate tert-butyl, 8-cyclopentyl-6-methoxymethyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(2,6-dimethyl-morpholine-4-yl)pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethoxymethyl-2-(3,4,5,6-tetramethyl Hydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethoxymethyl-2-(5-morpholine-4-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, [8-cyclopentyl-7-oxo-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-ylmethyl]-benzylcarbamate, 8-cyclopentyl Tyl-2-[5-(2,6-dimethyl-morpholine-4-yl)-pyridine-2-ylamino]-6-(1-ethoxy-vinyl)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(2,6-dimethyl-morpholine-4-yl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-6-propionyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-fluoro-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-cyclopentyl-6-methyl-2-(5 -piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-cyclopentyl-6-isobutoxy-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 6-benzyl-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-cyclopentyl-6-hydroxymethyl-2-(5-piperazine (1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 2-[5-(4-tert-butoxycarbonylpiperazine-1-yl)-pyridin-2-ylamino]-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate ethyl, 6-acetyl-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl Lu-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-, [Iyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(3,3-dimethyl-piperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-yl)-pyridine-2-ylamino]-6-bromo-8-cyclo Lopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(3-ethylamino-pyrrolidine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-pyrrolidine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[3-(1-amino-1-methylethyl)-pyrrolidine-1-yl]-pyridine-2-ylamino}-6-bromo-8-cyclopentyl-8H -Pyrido[2,3-d]pyrimidine-7-one, 1-[6-(6-bromo-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]pyrroridine-2-carboxylic acid, 6-bromo-8-cyclopentyl-2-[5-(4-diethylamino-butylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(3-ethylamino-pyrimidine-1-yl)-pyridine-2-ylamino]-5-methyl -8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(5-pyrrolidine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-{5-[3-(1-amino-1-methylethyl)-pyrrolidine-1-yl]-pyridine-2-ylamino}-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 1-[6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]pyrroridine-2-carboxylic acid, 6-acetyl-8-cyclopentyl-2-[5-(4-diethylamino-butylamino)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-yl)-pyridine-2-ylamino]-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-[5-(3,3-dimethyl-piperazine -1-yl)-pyridine-2-ylamino]-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrrolidine-1-yl)-pyridine-2-ylamino]-8-cyclopentyl-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(3-ethylamino-pyro Lysine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-(5-pyrrolidine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[3-(1-amino-1-methylethyl)-pyrrolidine-1-yl]-pyridine-2-ylamino}-8-cyclopentyl-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 1-[6-(8-cyclopentyl-6-ethyl-7-oxo-7,8 -Dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-pyrroridine-2-carboxylic acid, 8-cyclopentyl-2-[5-(4-diethylamino-butylamino)-pyridine-2-ylamino]-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-[5-(3,5-dimethylpiperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-[5-(3,3-dimethylpiperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-[5-(4-methylpiperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-yl)-pyridine-2-ylamino]-6-benzyl-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-[5-( 3-ethylamino-pyrrolidine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-(5-pyrrolidine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[3-(1-amino-1-methylethyl)-pyrrolidine-1-yl]-pyridine-2-ylamino}6-benzyl-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 1-[6-(6-benzyl-8- Cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-pyrroridine-2-carboxylic acid, 6-benzyl-8-cyclopentyl-2-[5-(4-diethylamino-butylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-[5-(3,5-dimethylpiperazine-1-yl)-pyridine-2-ylamino]-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one , 8-cyclopentyl-2-[5-(3,3-dimethylpiperazine-1-yl)-pyridine-2-ylamino]-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-hydroxymethyl-2-[5-(4-methylpiperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-yl)-pyridine-2-ylamino]-8-cyclopentyl-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-[5-(3-ethylamino-pyrrolidine-1-yl)-pyridine-2-ylamino]-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-hydroxymethyl-2-(5-pyrrolidine-1-yl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[3-(1-amino-1-methylethyl)-pyrrolidine-1-yl]-pyridine-2-ylamino}8-cyclopentyl-6-hydroxymethyl- 8H-pyrido[2,3-d]pyrimidine-7-one, 1-[6-(8-cyclopentyl-6-hydroxymethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]pyrroridine-2-carboxylic acid, 8-cyclopentyl-2-[5-(4-diethylamino-butylamino)-pyridine-2-ylamino]-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-yl)-pyridine-2 -ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-[5-(3,3-dimethylpiperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-[5-(4-methylpiperazine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3d]pyrimidine-7-one, 6-amino-2-[5-(3-amino-pyrroridine-1-yl)-pyridine-2-ylamino]-8-cyclopentyl-8H-py Lido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-[5-(3-ethylamino-pyrrolidine-1-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-(5-pyrrolidine-1-ylpyridine-2-ylamino)-81H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-2-{5-[3-(1-amino-1-methylethyl)-pyrrolidine-1-yl]-pyridine-2-ylamino}-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 1-[6-(6-amino-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]pyrroridine-2-carboxylic acid, 6-amino-8-cyclopentyl-2-[5-(4-diethylamino-butylamino)-pyridinyl-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2, 3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-morpholine-4-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-diethylaminopyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[bis-(2-hydroxyethyl)-amino]-pyridine-2-ylamino}-6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[bis-(2-methoxyethyl) [6-(6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(2-amino-ethylamino)-pyridin-2-ylamino]-6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-dimethylamino-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-bromo-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d ]pyrimidine-2-ylamino)-pyridine-3-yl]-N-methyl-acetamide, 6-bromo-8-cyclopentyl-2-[5-(2-methoxy-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(2-methoxy-ethoxymethyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(2-diethylamino-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-pyrroridine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(6-methyl-5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d] Pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-diethylamino-pyridine-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-{5-[bis-(2-hydroxyethyl)-amino]-pyridine-2-ylamino}-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(2-amino-ethylamino)-pyridine-2-ylamino]-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d] Pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-dimethylaminopyridine-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-N-methylacetamide, 6-bromo-8-cyclopentyl-2-[5-(2-methoxyethoxy)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2, 3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(2-methoxy-ethoxymethyl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(2-diethylamino-ethoxy)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(5-pyrrolidine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(6-methyl-5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-(5 -Diethylamino-pyridine-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-{5-[bis-(2-hydroxyethyl)-amino]-pyridine-2-ylamino}-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-[5-(2-amino-ethylamino)-pyridine-2-ylamino]-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d ]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-(5-dimethylaminopyridine-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridin-3-yl]-N-methyl-acetamide, 6-acetyl-8-cyclopentyl-2-[5-(2-methoxy- Ethoxy)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(2-methoxy-ethoxymethyl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(2-diethylamino-ethoxy)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine, n-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(5-pyrroridine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(6-methyl-5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidine-7- 6-acetyl-8-cyclopentyl-2-(5-morpholine-4-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-(5-diethylaminopyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-{5-[bis-(2-hydroxyethyl)-amino]-pyridine-2-ylamino}-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-{5-[bis-(2-hydroxyethyl)-amino]-pyridine-2-ylamino}-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-{5-[bis-(2-methoxyethyl) N-[6-(6-acetyl-8-cyclopentyl-2-ylamino)-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-[5-(2-amino-ethylamino)-pyridin-2-ylamino]-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-(5-dimethylamino-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-acetyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-7-one] Midine-2-ylamino)-pyridine-3-yl]-N-methyl-acetamide, 6-acetyl-8-cyclopentyl-2-[5-(2-methoxy-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(2-methoxy-ethoxymethyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(2-diethylamino-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-(5-pyrrolidin-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-(6-methyl-5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(2-methoxyethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3d]pyrimidine-7-one, 6 -Bromo-8-cyclopentyl-2-[5-(2-methoxy-ethylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-(5-azetidine-1-yl-pyridine-2-ylamino)-6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-(5-azepan-1-yl-pyridine-2-ylamino)-6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-bromo-8-cyclopentyl-7- Oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridin-3-yl]acetamide, 6-bromo-8-cyclopentyl-2-(5-phenylaminopyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(4-fluorobenzylamino)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-bromo-8-cyclopentyl-7-oxo-7,8-dihydro-py Lido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-methanesulfonamide, 6-bromo-8-cyclopentyl-2-(5-methanesulfonyl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-phenyl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-[5-(2-methoxyethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-[5-(2-methoxy-ethylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-2-(5-azetidine-1-ylpyridine-2-ylamino)-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-2-(5-azepan-1-ylpyridine-2-ylamino)-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-amino-8 -Cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]acetamide, 6-amino-8-cyclopentyl-2-(5-phenylaminopyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-[5-(4-fluorobenzylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-amino-8-cyclopentyl-7-oxo-7,8- Dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-methanesulfonamide, 6-amino-8-cyclopentyl-2-(5-methanesulfonyl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-amino-8-cyclopentyl-2-(5-phenyl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(2-methoxyethoxy)-pyridine-2-ylamino]-5-methyl-8 H-Pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(2-methoxy-ethylamino)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-(5-azetidine-1-ylpyridine-2-ylamino)-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-(5-azepan-1-ylpyridine-2-ylamino)-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]acetamide, 6-acetyl-8-cyclopentyl-5-methyl-2-(5-phenylaminopyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(4-fluorobenzylamino)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]py Limidine-7-one, N-[6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]methanesulfonamide, 6-acetyl-8-cyclopentyl-2-(5-methanesulfonyl-pyridin-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-(5-phenyl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6- Benzyl-8-cyclopentyl-2-[5-(2-methoxy-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-[5-(2-methoxy-ethylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-(5-azetidine-1-ylpyridine-2-ylamino)-6-benzyl-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-(5-azepan-1-ylpyridine-2-ylamino)-6- Benzyl-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-benzyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]acetamide, 6-benzyl-8-cyclopentyl-2-(5-phenylaminopyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-[5-(4-fluoro-benzylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(6-benzyl-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]methanesulfonamide, 6-benzyl-8-cyclopentyl-2-(5-methanesulfonylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-benzyl-8-cyclopentyl-2-(5-phenylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-hyd Roxymethyl-2-[5-(2-methoxy-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-hydroxymethyl-2-[5-(2-methoxy-ethylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-(5-azetidine-1-ylpyridine-2-ylamino)-8-cyclopentyl-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-(5-azepan-1-ylpyridine-2-ylamino)-8 -Cyclopentyl-6-hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(8-cyclopentyl-6-hydroxymethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]acetamide, 8-cyclopentyl-6-hydroxymethyl-2-(5-phenylaminopyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-[5-(4-fluorobenzylamino)-pyridine-2-ylamino]-6- Hydroxymethyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(8-cyclopentyl-6-hydroxymethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]methanesulfonamide, 8-cyclopentyl-6-hydroxymethyl-2-(5-methanesulfonyl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-hydroxymethyl-2-(5-phenyl-pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(2-methoxy-ethoxy)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(2-methoxy-ethylamino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-(5-azetidine-1-ylpyridine-2-ylamino)-8-cyclopentyl-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-(5-azepa N-1-ylpyridine-2-ylamino)-8-cyclopentyl-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(8-cyclopentyl-6-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]acetamide, 8-cyclopentyl-6-ethyl-2-(5-phenylaminopyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(4-fluorobenzyl [Mino)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, N-[6-(8-cyclopentyl-6-ethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yl]-methanesulfonamide, 8-cyclopentyl-6-ethyl-2-(5-methanesulfonyl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-(5-phenyl-pyridine-2-ylamino)-8H-pyrido[ 2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(piperazine-1-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-carbonyl)-pyridine-2-ylamino]-6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(morpholine-4-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-[5-(piperazine-1-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-( 3,5-dimethylpiperazine-1-carbonyl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-carbonyl)-pyridine-2-ylamino]-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-[5-(morpholine-4-cal [bonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(piperazine-1-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-carbonyl)-pyridine-2-ylamino]-5-methyl-8 H-Pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-2-[5-(3-amino-pyrroridine-1-carbonyl)-pyridine-2-ylamino]-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(morpholine-4-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, , 8-cyclopentyl-6-ethyl-2-[5-(piperazine-1-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-carbonyl)-pyridine-2-ylamino]-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-carbonyl)-pyridine-2-ylamino]-8-cyclopentyl-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7- ONE, 8-cyclopentyl-6-ethyl-2-[5-(morpholine-4-carbonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-ONE, 6-bromo-8-cyclopentyl-2-[5-(piperazine-1-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-ONE, 6-bromo-8-cyclopentyl-2-[5-(morpholine-4-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-ONE, 2-[5-(3-amino -Pyrrolidine-1-sulfonyl)-pyridine-2-ylamino]-6-bromo-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(3,5-dimethylpiperazine-1-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-[5-(piperazine-1-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bro Mo-8-cyclopentyl-5-methyl-2-[5-(morpholine-4-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-sulfonyl)-pyridine-2-ylamino]-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-sulfonyl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(piperazine-1-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-ethyl-2-[5-(morpholine-4-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-amino-pyrroridine-1-sulfonyl)-pyridine-2-ylamino]-8-cyclopentyl-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 8 -Cyclopentyl-2-[5-(3,5-dimethylpiperazine-1-sulfonyl)-pyridine-2-ylamino]-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(piperazine-1-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(morpholine-4-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one, 6-Acetyl-2-[5-(3-amino-pyrroridine-1-sulfonyl)-pyridine-2-ylamino]-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-Acetyl-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazine-1-sulfonyl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one and 6-Acetyl-8-cyclopentyl-5-methyl-2-([1,6]naphthyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine- 7-ONE, 6-acetyl-8-cyclopentyl-2-[5-(1,1-dioxo-116-thiomorpholin-4-yl)-pyridine-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-ONE, 8-cyclopentyl-6-hydroxymethyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-ONE, 6-acetyl-2-(3-chloro-5-piperazine-1-ylpyridine-2-ylamino)-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 4-[6-acetyl-5-methyl-7-oxo-2-(pyridine-2-ylamino)-7H-pyrido[2,3-d]pyrimidine-8-yl]-cyclohexanecarboxylic acid, 4-[6-acetyl-2-(5-dimethylaminopyridine-2-ylamino)-5-methyl-7-oxo-7H-pyrido[2,3-d]pyrimidine-8-yl]-cyclohexanecarboxylic acid, 6-bromo-8-cyclopentyl-5-methyl-2-[5-(piperazine-1-sulfonyl)-pyridine-2-ylamino]-8H-pyrido[2,3-d] Pyrimidine-7-one, 6-(8-cyclopentyl-6-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-3-piperazine-1-ylpyridine-2-carboxylic acid, 2-(6-acetyl-5-piperazine-1-ylpyridine-2-ylamino)-8-cyclopentyl-6-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, 3-{2-[6-(8-cyclopentyl-6-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-ylamino)-pyridine-3-yloxy )-ethoxy}-propionic acid, [6-(8-cyclopentyl-6-ethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-ylamino)-pyridin-3-yloxy)-acetic acid, 8-cyclopentyl-2-(5-{2-[2-(5-methyl-pyridin-2-yl)-ethoxy]-ethoxy}pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 2-[5-(3-benzenesulfonyl-propoxy)-pyridin-2-ylamino]-8-cyclopentyl-8H-pyrido[2,3-d]pyrimidine- 7-one, 8-cyclopentyl-6-ethyl-2-{5-[2-(2-methoxy-ethoxy)-ethoxy]-pyridine-2-ylamino}-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-(5-{[3-(3,5-dimethyl-piperazine-1-yl)-propyl]-methyl-amino}pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-2-{5-[(3-imidazole-1-yl-propyl)-methyl-amino]pyridin-2-ylamino}-8H-pyrido[2,Selected from the group consisting of 3-d]pyrimidine-7-one, 6-acetyl-5-methyl-2-(5-methylpyridine-2-ylamino)-8-piperidine-4-yl-8H-pyrido[2,3-d]pyrimidine-7-one, and 6-acetyl-2-[5-(3,4-dihydroxypyrrolidine-1-yl)-pyridine-2-ylamino]-8-methoxymethyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one.

[0260] For example, the above compound is 8-Cyclopentyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-Cyclopentyl-6-ethyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7 -One hydrochloride, 8-cyclopentyl-7-oxo-2-(5-piperazine-1-ylpyridine-2-ylamino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate ethyl hydrochloride, 6-amino-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 6-bromo-8-cyclopentyl-2-[5-((R) -methyl-1-pyrroridine-2-yl)-pyridine-2-ylamino]-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 6-bromo-8-cyclohexyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-2-methyl-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 8-cyclopentyl-6-fluoro-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3- d] Pyrimidine-7-one hydrochloride, 8-cyclopentyl-6-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-cyclopentyl-6-isobutoxy-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 6-benzyl-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 8-cyclopentyl-6-hydroxymethyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one hydrochloride, 2-[5-(4-tert-butoxycarbonylpiperazine-1-yl)-pyridine-2-ylamino]-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate ethyl, 6-acetyl-8-cyclopentyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-acetyl- Selected from the group consisting of 8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, 6-bromo-8-cyclopentyl-5-methyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, and 6-bromo-8-cyclopentyl-2-(pyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one.

[0261] For example, the compound is 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one.

[0262] For example, the compound may be a substituted 2-aminopyridine useful for treating cell proliferation disorders, which is a potent inhibitor of cyclin-dependent kinase 4 (cdk4). For example, this compound may be described in US6936612B2 and / or US20030149001A1.

[0263] In this application, the pharmaceutical product may be a combination of the HER2 inhibitor and the CDK inhibitor in the present invention. For example, a prescription for treating cancer may include both a HER2 inhibitor and a CDK inhibitor. For example, the specifications / labels for the HER2 inhibitor in this application may include a recommendation to take a CDK inhibitor or CDK4 inhibitor before, after, or concurrently with the HER2 inhibitor. As a further example, the specifications / labels for the CDK inhibitor in this application may include a recommendation to take a HER2 inhibitor before, after, or concurrently with the HER2 inhibitor in this application.

[0264] In this application, the above-mentioned pharmaceutical product may be a composition. For example, the above-mentioned HER2 inhibitor and CDK inhibitor do not have to be mixed with each other in the composition. For example, the above-mentioned HER2 inhibitor and CDK inhibitor may be packaged in different isolated packages and / or containers.

[0265] In this application, the above compositions are typically sterile and stable under manufacturing and storage conditions. The above compositions can be formulated as solutions, microemulsions, liposomes, or other ordered structures suitable for high drug concentrations. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, or liquid polyethylene glycol) and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by the use of a coating agent such as lecithin, maintaining the required particle size in the case of a dispersion, or by the use of a surfactant. Often, the above compositions preferably contain an isotonic agent, such as sugars, polyhydric alcohols such as mannitol or sorbitol, or sodium chloride. Long-lasting absorption of the injectable composition can be achieved by including an absorption-delaying agent in the composition, such as monostearate or gelatin.

[0266] For example, the above composition may include other compounds, drugs, and / or agents used in the treatment of cancer. Such compounds, drugs, and / or agents may include, for example, chemotherapeutic agents, small molecule drugs, or antibodies that stimulate an immune response against a given cancer. In some cases, the above composition may include, for example, one or more of the agents listed in the section on combination therapies. For example, a combination therapy may include at least one other anticancer agent and / or T-cell stimulant (e.g., an activator).

[0267] For example, the above-mentioned pharmaceutical product may further contain fulvestrant.

[0268] For example, the HER2 inhibitor, CDK inhibitor, and fulvestrant described above do not need to be mixed with each other in the composition. For example, the HER2 inhibitor, CDK inhibitor, and fulvestrant described above may be packaged in different isolated packages and / or containers. Usage and Instructions On the other hand, the present invention provides a HER2 inhibitor of the present invention for preventing, mitigating, or treating tumors, or inhibiting tumor growth, in combination with a CDK inhibitor of the present invention.

[0269] On the other hand, the present invention provides a pharmaceutical product for preventing, alleviating, or treating tumors, or for inhibiting tumor growth.

[0270] On the other hand, the present invention provides the use of a combination of the CDK inhibitor and the HER2 inhibitor of the present invention in the preparation of a pharmacopoeia for the prevention, mitigation, or treatment of tumors, or for the inhibition of tumor growth, in subjects in need.

[0271] For example, the present invention can provide the use of the pharmaceutical product of the present invention in the preparation of a pharmacopoeia for the purpose of preventing, alleviating, or treating tumors, or inhibiting tumor growth, in subjects in need.

[0272] On the other hand, the present invention provides a method for preventing, alleviating, or treating a tumor in a subject in need, or for inhibiting tumor growth, the method comprising administering to the subject a HER2 inhibitor of the present invention in combination with a CDK inhibitor of the present invention.

[0273] For example, the present invention may provide a method for preventing, alleviating, or treating a tumor in a subject in need, or for inhibiting tumor growth, the method comprising administering the composition of the present invention to the subject.

[0274] For example, the above method may further include administering an effective dose of fulvestrant to subject (c).

[0275] For example, the subjects described above may not respond to conventional therapies for HER2-related tumors. For example, conventional therapies for HER2-related tumors may include administering HER2-targeting specific agents. For example, these may include HER2 antigen-binding proteins (e.g., anti-HER2 antibodies), their conjugates, and / or HER2-specific inhibitors. For example, conventional therapies for HER2-related tumors may include administering HER2-ADCs, MBC hormones, taxanes, pirotinib, neratinib, tucatinib, trastuzumab, and / or pertuzumab. For example, conventional therapies for HER2-related tumors may include administering drugs commonly used to treat tumors. For example, these may include any available chemotherapeutic agents. For example, conventional therapies for HER2-related tumors may include administering docetaxel, capecitabine, and / or lapatinib.

[0276] In this application, "not responding" means that the subject's tumor syndrome is not significantly alleviated by administration of a conventional treatment for HER2-related tumors. For example, the syndrome may include a decrease in tumor volume. For example, the syndrome may include an expansion of OS, ORR, and / or PFS.

[0277] In this application, the subjects in need are those who have failed with conventional therapies for HER2-related tumors, and conventional therapies for HER2-related tumors may include the administration of trastuzumab, MBC hormone and / or taxanes.

[0278] For example, subjects in need may have failed conventional therapies for HER2-related tumors. Conventional therapies for HER2-related tumors may include trastuzumab, HER2 TKIs, and HER2 ADCs. For example, the median prior history of conventional HER2-targeted therapy may be 2 (range: 1–12) in subjects in need.

[0279] For example, eligible subjects may have HER2-positive metastatic breast cancer that has progressed after treatment with trastuzumab and / or taxanes.

[0280] For example, subjects who require it may be receiving conventional hormone therapy. For example, hormone therapy may include administering drugs that block estrogen receptors. For example, hormone therapy may include treatment with tamoxifen and / or toremifene. For example, taxanes may include paclitaxel (Taxol) and docetaxel (Taxotere).

[0281] For example, a subject in need might have been treated first with hormone therapy, and then with trastuzumab and / or taxanes. Alternatively, a subject in need might have been treated first with trastuzumab and / or taxanes, and then with hormone therapy.

[0282] In this application, tumors may include solid tumors. For example, the above tumors may include metastatic tumors, early-stage tumors and / or locally advanced tumors. For example, the above tumors may include HER2-positive tumors and / or HER2-low-expressing tumors.

[0283] For example, the tumors described above may include breast cancer and / or gastric cancer. For example, the breast cancer described above may include HER2-positive breast cancer and / or HER2-low-expressing breast cancer. For example, the breast cancer described above may include early-stage breast cancer, locally advanced breast cancer and / or metastatic breast cancer. For example, the gastric cancer described above may include early-stage gastric cancer, locally advanced gastric cancer and / or metastatic gastric cancer. For example, a subject who requires such a diagnosis may have a histologically or cytologically proven diagnosis of HER2-positive breast cancer if they are diagnosed with locally advanced, unresectable or metastatic disease.

[0284] For example, the tumors listed above may be selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, esophageal cancer, gastric cancer, skin cancer, lung cancer, bone cancer, colorectal cancer, pancreatic cancer, thyroid cancer, biliary tract cancer, oral and pharyngeal cancer (mouth), lip cancer, tongue cancer, oral cancer, pharyngeal cancer, small intestine cancer, colorectal cancer, colon cancer, rectal cancer, brain and central nervous system cancer, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenocarcinoma, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminomas, melanoma, sarcoma, bladder cancer, liver cancer, renal cell carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's disease, pilocytic cell carcinoma, and leukemia.

[0285] For example, the breast cancer mentioned above is HR-negative (HR - ) or HR positive (HR + ) It could be breast cancer. For example, cancer is HR - It could be HER2-positive breast cancer. Also, for example, cancer is HR + It could be HER2-positive breast cancer.

[0286] In this application, subjects who require treatment may be treated with HER2 inhibitors in a planned regimen until disease progression, unacceptable toxicity, or withdrawal of informed consent occurs, whichever comes first.

[0287] The HER2 inhibitor of the present invention may be administered by the same route of administration or by different routes of administration. For example, the HER2 inhibitor may be administered by intravenous injection.

[0288] For example, the above-mentioned HER2 inhibitor may be administered as an initial dose via intravenous infusion over 90 minutes. For example, the above-mentioned HER2 inhibitor may have subsequent doses administered via intravenous infusion over a shorter period of 60 minutes.

[0289] In this application, the cycle may be defined as 28 days for Q2W (once every two weeks) medication and 21 days for Q3W (once every three weeks) medication.

[0290] For example, the above-mentioned HER2 inhibitors may be administered to subjects in need at doses ranging from approximately 1 mg / kg to approximately 30 mg / kg (e.g., at least approximately 1 mg / kg, at least approximately 1.5 mg / kg, at least approximately 2 mg / kg, at least approximately 2.5 mg / kg, at least approximately 5 mg / kg, at least approximately 6 mg / kg, at least approximately 7 mg / kg, at least approximately 8 mg / kg, at least approximately 9 mg / kg, at least approximately 10 mg / kg, at least approximately 15 mg / kg, at least approximately 20 mg / kg, at least approximately 25 mg / kg, or at least approximately 30 mg / kg). For example, the above-mentioned HER2 inhibitors may be administered to subjects in need at doses of approximately 10 mg / kg, approximately 5 mg / kg, and approximately 2.5 mg / kg, each in three consecutive doses.

[0291] For example, the above-mentioned HER2 inhibitor may be administered to subjects who require it once every two weeks. For example, the above-mentioned HER2 inhibitor may be administered to subjects who require it at a loading dose of 20 mg / kg on days 1 and 8 of cycle 1.

[0292] For example, the above-mentioned HER2 inhibitor may be administered to subjects who require it within 10 days. For example, the above-mentioned HER2 inhibitor may be administered to subjects on day 10, day 3, and day 10.

[0293] For example, the above-mentioned CDK inhibitors can be formulated for oral use.

[0294] For example, the above-mentioned CDK inhibitors may be administered to subjects who require them in doses ranging from 80 mg to 150 mg (e.g., 80 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, or 150 mg / day).

[0295] For example, the above-mentioned CDK inhibitor may be administered to subjects in need at doses ranging from approximately 10 mg / kg to approximately 50 mg / kg (e.g., at least approximately 10 mg / kg, at least approximately 15 mg / kg, at least approximately 20 mg / kg, at least approximately 25 mg / kg, at least approximately 30 mg / kg, at least approximately 35 mg / kg, at least approximately 40 mg / kg, at least approximately 45 mg / kg, or at least approximately 50 mg / kg). For example, the above-mentioned CDK inhibitor may be administered to subjects in need at doses of approximately 40 mg / kg, approximately 20 mg / kg, and approximately 10 mg / kg, each in three consecutive doses.

[0296] For example, the above-mentioned CDK inhibitor may be administered daily for three weeks to subjects who require it. For example, the above-mentioned CDK inhibitor may be administered continuously for three weeks to subjects who require it, followed by a one-week rest period.

[0297] For example, the above-mentioned CDK inhibitor may be administered to subjects who require it for at least two consecutive weeks. For example, the above-mentioned CDK inhibitor may be administered to subjects on days 0-6, days 7-13, and from day 14 onward.

[0298] For example, fulvestrant, which is included in pharmaceuticals, can be formulated for intramuscular injection.

[0299] For example, fulvestrant contained in a pharmaceutical product may be administered to subjects in need at doses of 400 mg to 600 mg (e.g., a dose of 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg).

[0300] For example, fulvestrant contained in a pharmaceutical product may be administered to subjects who require it on days 1 and 15 of cycle 1, and on day 1 of each subsequent 28-day cycle. Examples The following examples are provided to those skilled in the art to give a complete disclosure and explanation of how the invention can be carried out and used, and are not intended to limit the scope of what the inventors consider to be the invention, nor are they intended to represent all or only experiments. Efforts have been made to ensure accuracy with respect to the numerical values ​​used (e.g., quantity, temperature, etc.), but some experimental errors and deviations should be taken into consideration. Unless otherwise specified, parts refer to parts by weight, molecular weight to weight-average molecular weight, temperature to Celsius, and pressure to atmospheric pressure or near atmospheric pressure. Standard abbreviations may be used, for example, bp to base pair, kb to kilobase, pl to picoliters, s or sec to seconds, min to minutes, h or hr to hours, aa to amino acid, nt to nucleotide, im to intramuscular, ip to intraperitoneal, and sc to subcutaneous.

[0301] In the examples, the HER2 inhibitor used was to represent the HER2 inhibitor according to the present invention described above. The HER2 inhibitor targets different extracellular domains of HER2: domain 2 (pertuzumab binding site) and domain 4 (trastuzumab binding site). It blocks both ligand-dependent and ligand-independent HER2 signaling pathways. The HER2 inhibitor comprises a first light chain, a second light chain, a first heavy chain, and a second heavy chain. The first and second light chains have the same amino acid sequence represented by SEQ ID No. 1; the variable regions of the first and second heavy chains are represented by SEQ ID No. 13 and SEQ ID No. 14, respectively. The HER2 inhibitor was an IgG1 antibody. Example 1: Study Design This study is an open-label, multicenter, dose-escalation, and parallel-group expansion phase 1b / 2 clinical trial evaluating the efficacy, safety, and tolerability of HER2 inhibitors and CDK inhibitors in combination with or without fulvestrant in at least all breast cancer settings in women or men with HER2-positive metastatic breast cancer that has progressed after treatment with trastuzumab and taxanes. Patients may have previously received one hormone therapy for MBC.

[0302] Eligible patients must have a diagnosis of histologically or cytologically confirmed HER2-positive breast cancer at the time of diagnosis of locally advanced, unresectable, or metastatic disease. HER2 status is confirmed in the central laboratory using archival paraffin-embedded tumor tissue. The tumor is considered HER2-positive if the central laboratory reports grade 3+ staining intensity (on a scale of 0 to 3+) by gene amplification by IHC analysis or FISH.

[0303] Dose escalation was carried out at the following two dose levels: Dose level 1 For HR- / HER2-positive MBC patients, the following was performed: HER2 inhibitor 20 mg / kg IV Q2W (20 mg / kg load on days 1 and 8 of cycle 1) + CDK inhibitor 100 mg / day orally for 3 weeks, followed by a 1-week rest period; For HR+ / HER2-positive MBC patients, the following was performed: HER2 inhibitor 20 mg / kg IV Q2W (20 mg / kg load on days 1 and 8 of cycle 1) + CDK inhibitor 100 mg / day orally for 3 weeks, followed by a 1-week rest period + fulvestrant 500 mg intramuscularly administered on days 1 and 15 of cycle 1, and then intramuscularly administered on day 1 of each 28-day cycle; Dose level 2 For HHR- / HER2-positive MBC patients, the following was performed: HER2 inhibitor 20 mg / kg IV Q2W (20 mg / kg load on days 1 and 8 of cycle 1) + CDK inhibitor 125 mg / day orally for 3 weeks, followed by a 1-week rest period; For HR+ / HER2-positive MBC patients, the following was performed: HER2 inhibitor 20 mg / kg IV Q2W (20 mg / kg load on days 1 and 8 of cycle 1) + CDK inhibitor 125 mg / day orally for 3 weeks, followed by a 1-week rest period + fulvestrant 500 mg intramuscularly administered on days 1 and 15 of cycle 1, and then intramuscularly administered on day 1 of each 28-day cycle; The dose escalation phase utilized an mTPI-2 (modified toxicity probability interval) design. Each treatment cohort enrolled 3–6 subjects. Decisions to escalate to the next dose level were based on safety assessments after all subjects in the treatment cohort had reached day 28 (dose-limiting toxicity observation period). A Scientific Monitoring Committee (SMC), responsible for determining dose escalation, maximum tolerated dose (MTD), or recommended phase 2 dose (RP2D), was established before the first patient administration. Based on safety and efficacy data obtained from the HER2 inhibitor program, the SMC could decide to explore higher, lower, or intermediate doses. Once the MTD or RP2D combination was established, the study proceeded to a parallel-group expansion phase.

[0304] In the parallel-group expansion phase, 30 HR- / HER2-positive and 30 HR+ / HER2-positive MBC patients were enrolled and were scheduled to receive RP2D combination therapy. HR- / HER2-positive MBC patients received a combination of a HER2 inhibitor and a CDK inhibitor, while HR+ / HER2-positive MBC patients received a triple combination of a HER2 inhibitor, a CDK inhibitor, and fulvestrant.

[0305] After the initial parallel-group expansion was completed, further expansions to include HR- / HER2-positive, HR+ / HER2-positive, or HER2-intermediate or low-expression (defined as HER2 IHC1+ or 2+ and FISH-negative) MBC patients may have been added. Protocol modifications were to be issued to further expand the study, subject to approval by the relevant committee.

[0306] Patients were required to have at least one measurable disease in the non-irradiated area at baseline, or to have disease progression in the previously irradiated field. Patients underwent tumor assessments every 8 weeks for the first 12 months, and every 12 weeks thereafter, calculated from the date of the first investigational treatment. Tumor assessments continued until the first of the following occurred: progression of disease according to RECIST 1.1, initiation of new chemotherapy, death, or withdrawal of consent.

[0307] Patients continued the designated investigational treatment until one of the following occurred first: progressive disease based on RECIST 1.1, clinical deterioration, unacceptable toxicity, initiation of new anticancer therapy, death, or withdrawal of consent. If treatment discontinuation of the prospective study was necessary due to CDK inhibitor, HER2 inhibitor, or fulvestrant-related toxicity, patients may continue administration of other investigational drugs.

[0308] Each enrolled subject was scheduled to undergo a screening period (from 21 days to 1 day before the first trial treatment), a treatment period, an end-of-treatment (EOT) visit, a 30-day safety follow-up, an 84-day safety follow-up, and an overall survival follow-up. The study concluded 12 months after all subjects had completed their final dose of the investigational drug. Example 2: Introduction to the Research Research subject Main purpose Dose escalation phase The following MTD or RP2D decision: Combination therapy with HER2 inhibitors and CDK inhibitors in HR- / HER2-positive MBCs; and combination therapy with HER2 inhibitors and CDK inhibitors, along with fulvestrant, in HR+ / HER2-positive MBCs; Parallel intergroup expansion stage Evaluation of the antitumor activity of combination therapy with HER2 inhibitors and CDK inhibitors in HR- / HER2-positive MBC; Evaluation of the antitumor activity of combination therapy with HER2 inhibitors, CDK inhibitors, and fulvestrant in HR- / HER2-positive MBC; Secondary objectives: □Evaluate the safety and tolerability of HER2 inhibitors and CDK inhibitors when used in combination with and without fulvestrant; □Characterize the pharmacokinetics of HER2 inhibitors; □Evaluate the immunogenicity of HER2 inhibitors. Exploratory objectives: □ Exploration of the relationship between HER2 inhibitor exposure levels and efficacy / safety findings; □ Exploration of gene, protein, and ribonucleic acid (RNA) changes related to the cell cycle, drug targets, tumor sensitivity, and / or resistance. Research endpoints Main endpoints Dose escalation phase; Dose-limiting toxicity (DLT); Parallel-group expansion period: Objective response rate as assessed by the principal investigator according to RECIST 1.1; Secondary endpoints: □Duration of response (DOR) and time to response (TTR); □PFS and OS rates at 6 and 12 months; □Clinical benefit rate (CBR) is defined as the proportion of complete responses (CR), partial responses (PR), or stable disease (SD) for 24 weeks or longer; □Disease control rate (DCR) is defined as the proportion of CR, PR, or SD; □Morbidity and severity (grading based on CTCAE v5.0), relationship between severity and investigational treatment, and any abnormal findings in clinical and physical examinations. All cardiac AEs that occurred during the study period and within 12 months after the last HER2 inhibitor administration must be reported, regardless of causality (related or unrelated) or severity (serious or non-serious); □PK parameters of HER2 inhibitors obtained from population PK analysis are AUC, C max , C min , CL and T 1 / 2 This includes, but is not limited to, antibodies against HER2 inhibitors, their neutralizing ability (positive or negative), and serum titers; Exploratory endpoints include tumor tissue biomarkers such as genes (HER2 mutations, copy numbers of HER2, CCND1, and CDKN2A, PIK3CA mutations, etc.), proteins (Ki67, pRb, CCNE1, etc.), and RNA expression (cdk4, cdk6, etc.). Target population for the survey Study patient eligibility criteria I01. Signing of informed consent; I02. Postmenopausal female or male subjects aged 18 years or older. A postmenopausal woman is defined by at least one of the following criteria: □ Age 60 years or older; □ Age under 60 years, with cessation of regular menstruation for at least 12 consecutive months, without other pathological or physiological causes, and with serum estradiol and FSH levels within laboratory reference ranges; □ Documented bilateral oophorectomy; □ Medically confirmed ovarian failure; I03. A histologically or cytologically confirmed diagnosis of breast cancer with evidence of metastatic or locally advanced disease, where curative excision or radiotherapy is not applicable; I04. HER2-positive tumors based on tumor tissue taken at the time of diagnosis of locally advanced, unresectable, or metastatic disease. HER2 positivity is defined as IHC 3+ and / or HER2 gene amplification by FISH. While the HER2 status determined in the local laboratory may be used to determine eligibility for this study, tissue samples must be submitted to a sponsor-designated central laboratory for confirmation of the HER2 status; I05. Adjuvants, prior treatment for locally advanced, unresectable, or metastatic breast cancer should include taxanes and trastuzumab; I06. Progression of documented locally advanced, unresectable or metastatic breast cancer, or progression within 6 months after documented completion of adjuvant therapy; I07. Baseline measurable disease progression from a non-irradiated area or within a previous irradiation field, based on RECIST 1.1; I08. Left ventricular ejection fraction (LVEF) ≥ 50% at baseline (within 42 days of the first investigational treatment) as determined by either ECHO (preferred) or MUGA; I09. ECOG state 0 or 1; I10. Adequate organ function assessed within 7 days prior to the initial clinical trial treatment: □Hematological function□ANC ≥ 1.5 x 10⁹ / L; □Hemoglobin ≥ 9 g / dL; □Platelets ≥ 100 x 10⁹ / L; □Renal function□Calculated creatinine clearance ≥ 60 mL / min (Cockcroft-Gault method); □Hepatic function□Total bilirubin ≤ 1.5 x ULN (or 2.5 x ULN in the case of documented Gilbert's syndrome); □ALT / AST ≤ 3.0 x ULN (or 5.0 x ULN in the case of documented liver metastases); □INR or aPTT ≤ 1.5 x ULN; I11. The average life expectancy is at least 3 months; I12. For male subjects with a childbearing partner, if they intend to use a highly effective method of contraception (annual failure rate of less than 1.0%) from the initial study treatment until 24 weeks after the end of the trial treatment. Exclusion criteria E01. Untreated active CNS metastases or leptomeningeal metastases. Subjects are eligible if they have received treatment for at least 4 weeks, are clinically stable, have no evidence of new or expanding brain metastases, and have discontinued steroids for the treatment of brain metastases for 7 days prior to the initial investigational treatment; E02. Uncontrolled tumor-related pain. Patients requiring narcotic analgesics must have been using a stable regimen for at least two weeks prior to the first investigational treatment; E03. Having received other antitumor treatments, including traditional Chinese medicines approved for antitumor effects, within 4 weeks prior to the initial trial treatment; E04. If a subject undergoes major surgery for any reason other than a diagnostic biopsy within four weeks of the start of the first dose of the investigational treatment, and / or if the subject has not fully recovered from surgery within four weeks of the start of the first dose of the investigational treatment; E05. If curative radiation is administered within 3 months of the start of the first dose of the investigational treatment. Radiation of more than 30% of the bone marrow or broad-spectrum radiation should not be performed within 4 weeks prior to the first dose of the investigational treatment. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) or asymptomatic metastatic lesions (e.g., those likely to cause functional impairment or intractable pain if further growth occurs) are suitable for palliative radiotherapy and should be treated before the first investigational treatment, and the patient must have recovered from the effects of radiation; E06. Uncontrolled hypercalcemia (ionized calcium > 1.5 mmol / L or calcium > 12 mg / dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued bisphosphonate treatment; E07. Currently participating in a clinical trial and receiving the investigational drug, or participating in a clinical trial of the investigational drug within 4 weeks prior to the start of the first dose of the investigational drug, or within 5 half-lives, whichever is shorter; E08. Patients with a history of treatment with CDK inhibitors, everolimus, or drugs that inhibit the PI3K-mTOR pathway; E09. During the current use of foods or drugs known to be potent CYP3A4 inhibitors, potent CYP3A4 inducers, and drugs known to prolong the QT interval; E10. History of exposure to the following cumulative doses of anthracycline drugs: • Doxorubicin or liposomal doxorubicin > 360 mg / m2; • Epirubicin > 720 mg / m2; • Mitoxantrone > 120 mg / m2, and idarubicin > 90 mg / m2; • Other anthracycline drugs > 360 mg / m2 equivalent of doxorubicin. When using one or more anthracycline drugs, the cumulative dose must not exceed 360 mg / m2 equivalent of doxorubicin; E11. History of malignancies other than the target malignancies studied in this study. However, this excludes well-treated non-melanoma skin cancer, prostate / cervical cancer in situ, superficial bladder cancer, or other malignancies that have been treated with surgery and / or curative radiotherapy at least 5 years prior and for which there is no evidence of subsequent recurrence; E12. A history of uncontrolled complications, including but not limited to: • Active HBV / HCV infection; • A history of known HIV infection or known acquired immunodeficiency syndrome (AIDS); • Active tuberculosis infection; • An active infection requiring the use of systemic antibiotics within two weeks prior to the first investigational treatment; • A history of interstitial lung disease or pneumonia requiring oral or intravenous glucocorticoids as an adjunct to treatment; • A history of active cardiovascular disease or cardiovascular dysfunction, including any of the following: • A history of angina pectoris, symptomatic pericarditis, myocardial infarction, coronary / peripheral artery bypass surgery, cerebrovascular disease (including transient ischemic attack), or symptomatic pulmonary embolism within six months prior to the first investigational treatment; • A history of documented congestive heart failure (New York Heart Association functional class III-IV); documented cardiomyopathy; • A history of LVEF reduction to 50% or less, or absolute reduction to 15% or more, during or after treatment with HER2-targeted therapy (neo / adjuvant, locally advanced or metastatic disease); severe arrhythmias requiring drug therapy (including fridericia, pacemaker, history of QT prolongation, corrected QT interval prolongation of 470 ms or more based on Brugada syndrome or inverted ventricular tachycardia <3 ECG mean values>, other progressive cardiac arrhythmias of CTCAE grade 2 or higher, and progressive atrial fibrillation of any grade); hypertension uncontrolled with standard treatment (not stabilized to 150 / 90 mmHg); gastrointestinal (GI) dysfunction or GI disease that may significantly alter the absorption of CDK inhibitors, such as a history of GI surgery causing enterocecal malformation, clinically significant gastroparesis, short bowl syndrome, unresolved nausea, vomiting, active inflammatory bowel disease, or diarrhea of ​​CTCAE grade 1 or higher); A history of hematopoietic stem cell transplantation or solid organ transplantation; E13. Persistent toxicity associated with prior treatment (including prior treatment with the investigational drug) of CTCAE grade 2 or higher, or related toxicity of any grade that has not returned to baseline except for alopecia; E14. A known severe allergic reaction to an antibody drug (CTCAE grade ≥ 3), a history of anaphylaxis, uncontrolled asthma (i.e., three or more features of partially controlled asthma), or a history of severe drug hypersensitivity (e.g., immune-mediated hepatotoxicity, immune-mediated thrombocytopenia, or anemia); E15. Any other medical condition that, in the opinion of the principal investigator, would interfere with the requirements of the trial in terms of safety or efficacy evaluation or adherence to treatment. This includes, but is not limited to, mental disorders or substance abuse disorders, moderate to severe pleural, pericardial, or ascites effusion, or recurrent or refractory pleural, pericardial, or ascites effusion. statistical methods This study was planned to enroll 30 MBC subjects who were HR- / HER2 positive and 30 who were HR+ / HER2 positive. Based on the sample size of 30 subjects, the table below shows the number of responders, estimated ORR, and relevant 95% confidence intervals using the Clopper-Pearson method.

[0309] [Table 1]

[0310] Example 3 Evaluation According to the study in Example 2, the results of the clinical trial are shown in the following table.

[0311] [Table 2]

[0312] TIFF0007857866000036.tif218170

[0313] TIFF0007857866000037.tif49170

[0314] 1. Informed consent must be obtained before any procedures or treatments related to the clinical trial take place; 2. Demographic data includes date of birth, sex, race, and ethnicity; 3. The medical history includes past and concomitant non-malignant diseases and treatments, and past and concomitant malignant diseases and treatments; 4. Oncological history includes histopathological diagnosis, grading, and staging according to AJCC version 8 at the time of initial diagnosis and diagnosis of locally advanced, unresectable, or metastatic disease; all therapies used in the past for treating cancer (including surgery, radiotherapy, chemotherapy, and immunotherapy); other diseases treated with chemotherapy, radiotherapy, or immunotherapy; current signs and symptoms of cancer, and adverse event effects from current and / or past anticancer drug treatments; and a detailed medical history of the indications for this study, including the current state of cancer. 5. Record all medications (including herbal medicines) taken and procedures performed within 28 days prior to the first clinical trial treatment; record any radiotherapy performed within 3 months prior to the first clinical trial treatment for conditions other than those targeted by this study; 6. All adverse events (AEs) will be documented from the time of signing informed consent until the 30-day safety follow-up period. After this visit, all relevant SAEs (cardiac or non-cardiac) must be collected and reported, regardless of the time elapsed since the last HER2 inhibitor dose. All cardiogenic AEs occurring during the study and within 12 months of the last HER2 inhibitor dose must be reported, regardless of causality (related or unrelated) and severity (serious or non-serious); 7. A general physical examination including an examination of the general appearance, skin, neck (including the thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, limbs, and assessment of the basic nervous system; 8. Signs of vital signs such as body temperature, respiratory rate, pulse rate, and blood pressure; 9. After the subject breathes quietly for 5 minutes, a 12-lead electrocardiogram (ECG) is performed in the supine position; the ECG results are used to assess heart rate, atrial-ventricular conduction, QR and QT intervals, and the likelihood of arrhythmias. Interpretation of the ECG traces must be performed by a qualified physician and recorded in an ECG eCRF. Each ECG trace must be labeled with the study number, subject identification number, and date and stored in the facility's source documentation; 10. Hematological tests such as absolute lymphocyte count, absolute neutrophil count, hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell percentage, red blood cell morphology, reticulocyte count, mean corpuscular hemoglobin volume, and mean corpuscular hemoglobin concentration; 11. Serological chemistry tests including measurement of albumin, alkaline phosphatase, alanine aminotransferase, amylase, aspartate aminotransferase, gamma-glutamyltransferase, blood urea nitrogen / total urea, calcium, chloride, creatine kinase, creatinine, glucose, lactate dehydrogenase, lipase, phosphorus / phosphate, magnesium, potassium, sodium, troponin, total bilirubin, and total protein; 12. A urine test includes bilirubin, blood, glucose, ketones, pH, protein, specific gravity, and color and appearance. If a urine test is positive for protein, a segmental and 24-hour urine protein test should be performed. 13. Tests for HBV, HCV, and HIV include HBsAb, HCV Ab, and anti-HIV 1 / 2. If HBsAb is positive, HBsAg, HBeAb, HBcAb, and HBV DNA should be measured and active HBV infection should be ruled out according to clinical instructions. If HCV Ab is positive, HCV RNA should be measured and active HCV infection should be ruled out according to clinical instructions; 14. In subjects with a history of latent or active tuberculosis infection due to untreated or inadequate treatment, recent contact with a person infected with tuberculosis, or clinical symptoms and signs indicating tuberculosis infection, if the QuantiFERON®-TB Gold In-Tube test (TB Quantiferon test) is negative, or unusable or indeterminate upon retesting, the results of a Mantoux Purified Derivative skin test with a nodules less than 5 mm in size, performed within 3 months prior to screening according to local standards, are acceptable to declare that there is no suspicion of latent or active tuberculosis infection; In subjects with a history of latent or active tuberculosis infection due to untreated or inadequate treatment, recent contact with a person infected with tuberculosis, or signs or symptoms of tuberculosis infection, the following measures are recommended to rule out latent tuberculosis infection: • A negative result on a Mantoux Purified Derivative skin test with a nodule less than 5 mm in size, performed according to local standards within 3 months prior to screening (Note: Subjects who have received the BCG vaccine must be tested with the QuantiFERON®-TB Gold In-Tube test); • No indication of latent or active tuberculosis infection on a chest X-ray taken at the time of examination or within 3 months prior to examination; In subjects who have previously received an appropriate course of treatment for either latent (9 months of isoniazid or other acceptable regimens in a local setting with a multidrug-resistant tuberculosis infection rate of less than 5%) or active (with an acceptable regimen), a chest X-ray should be performed at the time of examination or within 3 months prior to examination to rule out latent or active tuberculosis infection. In such situations, neither PPD testing nor the QuantiFERON®-TB Gold In-Tube test is necessary; 15. Baseline LVEF assessment should be performed as soon as possible immediately before the first investigational treatment, but no later than 42 days prior to the first investigational treatment. During the treatment period, LVEF should be assessed every 12 weeks. For cardiac safety, LVEF assessments may be performed more frequently if necessary. If LVEF assessment needs to be brought forward or delayed, subsequent assessments should be performed according to the original schedule from the date of the first investigational treatment. Patients whose investigational treatment is permanently discontinued due to a decrease in LVEF should continue to have their LVEF monitored according to clinical instructions until their LVEF value returns to 50% or higher, or after one year, whichever comes first. 16. For eligibility purposes, the recording of HR and HER2 status in tumor tissue collected at the time of diagnosis of locally advanced, unresectable, or metastatic disease is based on local laboratory test results determined using institutional criteria. On the other hand, tumor tissue collected at the time of diagnosis of locally advanced, unresectable, or metastatic disease must be submitted to a central laboratory designated by the sponsor for confirmation of HER2 status based on IHC and FISH methods. Archived formalin-fixed paraffin-embedded (FFPE) specimens are collected. If archived FFPE specimens of metastatic or locally advanced, unresectable tumors are unavailable, de novo biopsy is required. A minimum of five slides are required; 17. Tumor biopsies should be taken at the time of screening, unless tissue (block or slide) from a preserved specimen (biopsy or surgery) is available and was taken within two years prior to screening. Core needle biopsy, excision biopsy, punch biopsy, and surgical specimens are appropriate. Microneedle aspiration biopsy is not appropriate. Biopsies should only be taken from tumor tissue / sites that are safely accessible. Priority 1: FFPE tissue block containing the tumor; Priority 2: If all FFPE tissue blocks containing the tumor cannot be provided, fresh (within one week) 4μm thick sections should be provided from this block and mounted on SuperFrost Plus microscope slides. Subjects are encouraged to provide as many slides as possible, preferably around 5-10 slides in total; 18. Approximately 10 mL of peripheral blood samples will be collected at screening and during disease progression. ERBB2 amplification will be measured and tumor single-cell sequencing will be performed to develop HER2 CDx and explore the mechanisms of drug resistance. 19. During the treatment period, pharmacokinetic samples of the HER2 inhibitor were collected before administration on day 1 of cycles 1, 2, 3, and 5; every other cycle for the first 12 months; and every four cycles thereafter (60 minutes before HER2 inhibitor administration); before administration on days 8 and 15 of cycle 1; at the end of infusion on days 1 and 8 of cycle 1 and on day 1 of cycles 3 and 5 (within 30 minutes after the end of HER2 inhibitor infusion); and during 30-day and 84-day safety follow-up studies; 20. During the treatment period, ADA samples of HER2 inhibitors were collected before administration of cycles 1, 2, 3, and 5, every other cycle for the first 12 months, and every four cycles thereafter, along with PK sample collection (60 minutes before administration of KN046); and during 30-day and 84-day safety follow-up; 21. Tumor evaluation will be performed using CT / MRI of the chest, abdomen, and pelvis. If MRI is used, chest CT is mandatory. Screening tumor evaluation will be performed within 21 days after the first investigational treatment to record the baseline status of tumor disease using RECIST 1.1 targeted and non-targeted lesions. During the treatment period, the visit time frame for tumor evaluation is ±7 days. CT or MRI examinations (if MRI is used, chest CT is mandatory) should always be used in the same way as during the screening period. If a tumor response is documented during the study, follow-up should be performed preferably at 4-6 week intervals according to RECIST 1.1, however, the response should be confirmed within 4 weeks and within 8 weeks of the first documented CR or PR. PR / CR confirmation can be performed after the first documented PR / CR, but after the next evaluation. Tumor evaluation will be performed every 8 weeks for 12 months until disease progression, initiation of new anticancer drug therapy, death, or withdrawal of informed consent, whichever occurs first, according to RECIST 1.1, and then every 12 weeks thereafter. If treatment is discontinued for reasons other than progressive disease as defined in RECIST 1.1, oncological evaluation must be continued until one of the following occurs first: progressive disease as defined in RECIST 1.1, initiation of new anticancer treatment, death, or withdrawal of informed consent; 22. A brain CT / MRI scan (preferably with contrast) is required at screening if it has not been performed within 42 days prior to the first clinical trial treatment. During the treatment period, a brain CT / MRI scan will be performed if clinically required due to the development of new specific symptoms. 23. Bone scans must be performed if they have not been performed within 3 months prior to the initial investigational treatment. Bone scans should be performed during the treatment period as clinically directed. If suspicious abnormalities are identified in baseline or subsequent bone scans, confirmation should be made by X-ray, bone-windowed CT scan, or MRI. The same modality must be used throughout the study period to identify lesions and patients. Bone lesions identified at baseline will be followed up according to the same tumor evaluation schedule; 24. Clinical evaluation of superficial lesions shall be performed on the same day as imaging studies and shall include photographs of all superficial metastatic lesions. All lesions must be recorded in the eCRF; 25. The first dose of a HER2 inhibitor should be administered intravenously over 90 minutes (±15 minutes). If no fluid-related reactions occur after the first dose, subsequent doses may be administered intravenously over 60 minutes (±15 minutes). 26. The CDK inhibitor will be administered orally at a dose of 125 mg per day for 3 weeks, followed by a 1-week rest period. The patient is required to complete a patient diary regarding medication information on day 1 of each cycle and return all CDK inhibitor bottles. 27. Test results must be obtained before administering the investigational drug. 28. The results of the examination or test must be obtained within 7 days of the first clinical trial treatment. 29. This should only be performed if a clinically significant abnormality is found during the EOT visit; Example 4 The HER2 inhibitor and CDK inhibitor ribociclib of the present invention was used to treat breast cancer in an MCF-7 XENO model. The four groups were equally divided (n=6): Group 1: Vehicles, PO, QD; Group 2: HER2 inhibitors, 10 mg / kg (D0), 5 mg / kg (D3), 2.5 mg / kg (D10-), IP, QW; Group 3: Ribociclib, 40 mg / kg (D0-D6), 20 mg / kg (D7-D13), 10 mg / kg (D14-), PO, QD; Group 4: HER2 inhibitors, 10 mg / kg (D0), 5 mg / kg (D3), 2.5 mg / kg (D10-), IP, QW; ribociclib 40 mg / kg (D0-D6), 20 mg / kg (D7-D13), 10 mg / kg (D14-), PO, QD.

[0315] The tumor volume in the MCF-7 XENO model is shown in Figure 4. It can be seen that the combination of a HER2 inhibitor and the CDK inhibitor ribociclib can significantly reduce tumor volume. Example 5: Study Design This study is an open-label, multicenter, dose-escalation, and parallel-group expansion phase 1b / 2 clinical trial evaluating the efficacy, safety, and tolerability of HER2 inhibitors in combination with palbociclib, with or without fulvestrant, in at least all breast cancer settings in women or men with HER2-positive metastatic breast cancer whose disease has progressed after treatment with trastuzumab and taxanes. Patients may have previously received one hormone therapy for MBC.

[0316] Eligible patients must have a diagnosis of histologically or cytologically confirmed HER2-positive breast cancer at the time of diagnosis of locally advanced, unresectable, or metastatic disease. HER2 status is confirmed in the central laboratory using archival paraffin-embedded tumor tissue. The tumor is considered HER2-positive if the central laboratory reports grade 3+ staining intensity (on a scale of 0 to 3+) by gene amplification by IHC analysis or FISH.

[0317] Dose escalation was carried out at the following two dose levels: Dose level 1 For HR- / HER2-positive MBC patients, the following was performed: HER2 inhibitor 20 mg / kg IV Q2W (20 mg / kg load on days 1 and 8 of cycle 1) + palbociclib 100 mg / day orally for 3 weeks, followed by a 1-week rest period; For HR+ / HER2-positive MBC patients, the following was performed: HER2 inhibitor 20 mg / kg IV Q2W (20 mg / kg load on days 1 and 8 of cycle 1) + palbociclib 100 mg / day orally for 3 weeks, followed by a 1-week rest period + fulvestrant 500 mg intramuscularly administered on days 1 and 15 of cycle 1, and then intramuscularly administered on day 1 of each 28-day cycle; Dose level 2 For HHR- / HER2-positive MBC patients, the following was performed: HER2 inhibitor 20 mg / kg IV Q2W (20 mg / kg load on days 1 and 8 of cycle 1) + palbociclib 125 mg / day orally for 3 weeks, followed by a 1-week rest period; For HR+ / HER2-positive MBC patients, the following was performed: HER2 inhibitor 20 mg / kg IV Q2W (20 mg / kg load on days 1 and 8 of cycle 1) + palbociclib 125 mg / day orally for 3 weeks, followed by a 1-week rest period + fulvestrant 500 mg intramuscularly administered on days 1 and 15 of cycle 1, and then intramuscularly administered on day 1 of each 28-day cycle; The dose escalation phase utilized an mTPI-2 (modified toxicity probability interval) design. Each treatment cohort enrolled 3–6 subjects. Decisions to escalate to the next dose level were based on safety assessments after all subjects in the treatment cohort had reached day 28 (dose-limiting toxicity observation period). A Scientific Monitoring Committee (SMC), responsible for determining dose escalation, maximum tolerated dose (MTD), or recommended phase 2 dose (RP2D), was established before the first patient administration. Based on safety and efficacy data obtained from the HER2 inhibitor program, the SMC could decide to explore higher, lower, or intermediate doses. Once the MTD or RP2D combination was established, the study proceeded to a parallel-group expansion phase.

[0318] In the parallel-group expansion phase, 30 HR- / HER2-positive and 30 HR+ / HER2-positive MBC patients were enrolled and were scheduled to receive RP2D combination therapy. HR- / HER2-positive MBC patients received a combination of a HER2 inhibitor and palbociclib, while HR+ / HER2-positive MBC patients received a triple combination of a HER2 inhibitor, palbociclib, and fulvestrant.

[0319] After the initial parallel-group expansion was completed, further expansions to include HR- / HER2-positive, HR+ / HER2-positive, or HER2-intermediate or low-expression (defined as HER2 IHC1+ or 2+ and FISH-negative) MBC patients may have been added. Protocol modifications were to be issued to further expand the study, subject to approval by the relevant committee.

[0320] Patients were required to have at least one measurable disease in the non-irradiated area at baseline, or to have disease progression in the previously irradiated field. Patients underwent tumor assessments every 8 weeks for the first 12 months, and every 12 weeks thereafter, calculated from the date of the first investigational treatment. Tumor assessments continued until the first of the following occurred: progression of disease according to RECIST 1.1, initiation of new chemotherapy, death, or withdrawal of consent.

[0321] Patients continued the designated investigational treatment until one of the following occurred first: progressive disease based on RECIST 1.1, clinical deterioration, unacceptable toxicity, initiation of new anticancer therapy, death, or withdrawal of consent. If treatment discontinuation of the prospective study was necessary due to palbociclib, HER2 inhibitor, or fulvestrant-related toxicity, patients may continue administration of other investigational drugs.

[0322] Each enrolled subject was scheduled to undergo a screening period (from 21 days to 1 day before the first trial treatment), a treatment period, an end-of-treatment (EOT) visit, a 30-day safety follow-up, an 84-day safety follow-up, and an overall survival follow-up. The study concluded 12 months after all subjects had completed their final dose of the investigational drug. Example 6: Introduction to the Research Research subject Main purpose Dose escalation stage □ Determination of MTD or RP2D below: □ Combination therapy of a HER2 inhibitor and palbociclib in HR- / HER2-positive MBC; and □ Combination therapy of a HER2 inhibitor and palbociclib and fulvestrant in HR+ / HER2-positive MBC; Parallel-group expansion phase: Evaluation of antitumor activity of combination therapy with a HER2 inhibitor and palbociclib in HR- / HER2-positive MBC; Evaluation of antitumor activity of combination therapy with a HER2 inhibitor, palbociclib, and fulvestrant in HR+ / HER2-positive MBC; Secondary Objectives: □Evaluation of safety and tolerability of HER2 inhibitors in combination with palbociclib, both when used in combination with and without fulvestrant; □Characterization of the pharmacokinetics of HER2 inhibitors; □Evaluation of the immunogenicity of HER2 inhibitors. Exploratory Objectives: □ Exploration of the relationship between HER2 inhibitor exposure levels and efficacy / safety findings; □ Exploration of gene, protein, and ribonucleic acid (RNA) changes related to the cell cycle, drug targets, tumor sensitivity, and / or resistance. Research endpoints Main endpoints Dose escalation phase; Dose-limiting toxicity (DLT); Objective response rate as assessed by the principal investigator according to the parallel-group expansion phase R□ECIST 1.1; Secondary endpoints: □Duration of response (DOR) and time to response (TTR); □PFS and OS rates at 6 and 12 months; □Clinical benefit rate (CBR) is defined as the proportion of complete responses (CR), partial responses (PR), or stable disease (SD) for 24 weeks or longer; □Disease control rate (DCR) is defined as the proportion of CR, PR, or SD; □Morbidity and severity (grading based on CTCAE v5.0), relationship between severity and investigational treatment, and any abnormal findings in clinical and physical examinations. All cardiac AEs that occurred during the study period and within 12 months after the last HER2 inhibitor administration must be reported, regardless of causality (related or unrelated) or severity (serious or non-serious); □PK parameters of HER2 inhibitors obtained from population PK analysis are AUC, C max , C min , CL and T 1 / 2 This includes, but is not limited to, antibodies against HER2 inhibitors, their neutralizing ability (positive or negative), and serum titers; Exploratory endpoints include tumor tissue biomarkers such as genes (HER2 mutations, copy numbers of HER2, CCND1, and CDKN2A, PIK3CA mutations, etc.), proteins (Ki67, pRb, CCNE1, etc.), and RNA expression (cdk4, cdk6, etc.). Target population for the survey Study patient eligibility criteria I01. Signing of informed consent; I02. Postmenopausal female or male subjects aged 18 years or older. A postmenopausal woman is defined by at least one of the following criteria: □ Age 60 years or older; □ Age under 60 years, with cessation of regular menstruation for at least 12 consecutive months, without other pathological or physiological causes, and with serum estradiol and FSH levels within laboratory reference ranges; □ Documented bilateral oophorectomy; □ Medically confirmed ovarian failure; I03. A histologically or cytologically confirmed diagnosis of breast cancer with evidence of metastatic or locally advanced disease, where curative excision or radiotherapy is not applicable; I04. HER2-positive tumors based on tumor tissue taken at the time of diagnosis of locally advanced, unresectable, or metastatic disease. HER2 positivity is defined as IHC 3+ and / or HER2 gene amplification by FISH. While the HER2 status determined in the local laboratory may be used to determine eligibility for this study, tissue samples must be submitted to a sponsor-designated central laboratory for confirmation of the HER2 status; I05. Adjuvants, prior treatment for locally advanced, unresectable, or metastatic breast cancer should include taxanes and trastuzumab; I06. Progression of documented locally advanced, unresectable or metastatic breast cancer, or progression within 6 months after documented completion of adjuvant therapy; I07. Baseline measurable disease progression from a non-irradiated area or within a previous irradiation field, based on RECIST 1.1; I08. Left ventricular ejection fraction (LVEF) ≥ 50% at baseline (within 42 days of the first investigational treatment) as determined by either ECHO (preferred) or MUGA; I09. ECOG state 0 or 1; I10. Adequate organ function assessed within 7 days prior to the initial clinical trial treatment: □ Hematological function □ ANC ≥ 1.5 x 10⁹ / L; □ Hemoglobin ≥ 9 g / dL; □ Platelets ≥ 100 x 10⁹ / L; □ Renal function □ Calculated creatinine clearance ≥ 60 mL / min (Cockcroft-Gault method); □ Hepatic function □ Total bilirubin ≤ 1.5 x ULN (or 2.5 x ULN in the case of documented Gilbert's syndrome); □ ALT / AST ≤ 3.0 x ULN (or 5.0 x ULN in the case of documented liver metastases); □ INR or aPTT ≤ 1.5 x ULN; I11. The average life expectancy is at least 3 months; I12. For male subjects with a childbearing partner, if they intend to use a highly effective method of contraception (annual failure rate of less than 1.0%) from the initial study treatment until 24 weeks after the end of the trial treatment. Exclusion criteria E16. Untreated active CNS metastases or leptomeningeal metastases. Subjects are eligible if they have been treated for at least 4 weeks, are clinically stable, have no evidence of new or expanding brain metastases, and have discontinued steroids for the treatment of brain metastases for 7 days prior to the initial investigational treatment; E17. Uncontrolled tumor-related pain. Patients requiring narcotic analgesics must have been using a stable regimen for at least two weeks prior to the first investigational treatment; E18. Having received other antitumor treatments, including traditional Chinese medicines approved for antitumor effects, within 4 weeks prior to the initial investigational treatment; E19. If a subject undergoes major surgery for any reason other than a diagnostic biopsy within four weeks of the start of the first dose of the investigational treatment, and / or if the subject has not fully recovered from surgery within four weeks of the start of the first dose of the investigational treatment; E20. If curative radiation is administered within 3 months of the start of the first dose of the investigational treatment. Radiation of more than 30% of the bone marrow or broad-spectrum radiation should not be performed within 4 weeks prior to the first dose of the investigational treatment. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) or asymptomatic metastatic lesions (e.g., those likely to cause functional impairment or intractable pain if further growth occurs) are suitable for palliative radiotherapy and should be treated before the first investigational treatment, and the patient must have recovered from the effects of radiation; E21. Uncontrolled hypercalcemia (ionized calcium > 1.5 mmol / L or calcium > 12 mg / dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued bisphosphonate treatment; E22. Currently participating in a clinical trial and receiving the investigational drug, or participating in a clinical trial of the investigational drug within 4 weeks prior to the start of the first dose of the investigational drug, or within 5 half-lives, whichever is shorter; E23. Patients with a history of treatment with CDK inhibitors, everolimus, or drugs that inhibit the PI3K-mTOR pathway; E24. Current use of foods or drugs known to be potent CYP3A4 inhibitors, potent CYP3A4 inducers, and drugs known to prolong the QT interval; E25. History of exposure to the following cumulative doses of anthracycline drugs Doxorubicin or liposomal doxorubicin > 360 mg / m2; • Epirubicin > 720 mg / m2; • Mitoxantrone > 120 mg / m2, and idarubicin > 90 mg / m2; • Other anthracycline drugs > Equivalent to 360 mg / m2 of doxorubicin.

[0323] When using one or more anthracycline drugs, the cumulative dose must not exceed the equivalent of 360 mg / m2 of doxorubicin; E26. History of malignancies other than the target malignancies studied in this study. However, this excludes well-treated non-melanoma skin cancer, prostate / cervical cancer in situ, superficial bladder cancer, or other malignancies that have been treated with surgery and / or curative radiotherapy at least 5 years prior and for which there is no evidence of recurrence; E27. A history of uncontrolled comorbidities, including but not limited to the following: • Active HBV / HCV infection; • A known history of HIV infection or a known history of acquired immunodeficiency syndrome (AIDS); • Active tuberculosis infection; • Active infection requiring the use of systemic antibiotics within two weeks prior to the first treatment of the study; • History of interstitial lung disease or pneumonia requiring oral or intravenous glucocorticoids as an adjunct to treatment; • History of active cardiovascular disease or cardiovascular dysfunction including any of the following: • History of angina pectoris, symptomatic pericarditis, myocardial infarction, coronary / peripheral artery bypass surgery, cerebrovascular disease (including transient ischemic attack), or symptomatic pulmonary embolism within six months prior to the first treatment of the study; • History of documented congestive heart failure (New York Heart Association functional class III-IV); documented cardiomyopathy; • History of LVEF reduction to 50% or less, or absolute reduction to 15% or more, during or after previous HER2-targeted therapy (neo / adjuvant, locally advanced or metastatic disease); • Severe arrhythmias requiring drug treatment (including fridericia, pacemaker, history of QT prolongation, corrected QT interval prolongation of 470 milliseconds or more calculated based on Brugada syndrome or inverted ventricular tachycardia <average of 3 ECGs>, other progressive cardiac arrhythmias of CTCAE grade 2 or higher, and progressive atrial fibrillation of any grade); • Hypertension that is uncontrolled with standard treatment (not stabilized to 150 / 90 mmHg); • Gastrointestinal (GI) dysfunction or GI disease that may significantly alter palbociclib absorption, such as a history of GI surgery causing enterocecal malformation, clinically significant gastroparesis, short bowl syndrome, unresolved nausea, vomiting, active inflammatory bowel disease, or diarrhea of ​​CTCAE grade 1 or higher; • History of hematopoietic stem cell transplantation or solid organ transplantation; E28. Persistent toxicity associated with prior treatment (including prior treatment with the investigational drug) of CTCAE grade 2 or higher, or related toxicity of any grade except alopecia that has not returned to baseline; E29. A known severe allergic reaction to an antibody drug (CTCAE grade ≥ 3), a history of anaphylaxis, uncontrolled asthma (i.e., three or more features of partially controlled asthma), or a history of severe drug hypersensitivity (e.g., immune-mediated hepatotoxicity, immune-mediated thrombocytopenia, or anemia); E30. Any other medical condition that, in the opinion of the principal investigator, would interfere with the requirements of the trial in terms of safety or efficacy evaluation or adherence to treatment. This includes, but is not limited to, mental disorders or substance abuse disorders, moderate to severe pleural, pericardial, or ascites effusion, or recurrent or refractory pleural, pericardial, or ascites effusion. statistical methods This study was planned to enroll 30 MBC subjects who were HR- / HER2 positive and 30 who were HR+ / HER2 positive. Based on the sample size of 30 subjects, the table below shows the number of responders, estimated ORR, and relevant 95% confidence intervals using the Clopper-Pearson method.

[0324] [Table 3]

[0325] Example 7 Evaluation According to the study in Example 6, the results of the clinical trial are shown in the following table.

[0326] [Table 4]

[0327] TIFF0007857866000040.tif219170

[0328] TIFF0007857866000041.tif62170

[0329] 1. Informed consent must be obtained before any procedures or treatments related to the clinical trial take place; 2. Demographic data includes date of birth, sex, race, and ethnicity; 3. The medical history includes past and concomitant non-malignant diseases and treatments, and past and concomitant malignant diseases and treatments; 4. Oncological history includes histopathological diagnosis, grading, and staging according to AJCC version 8 at the time of initial diagnosis and diagnosis of locally advanced, unresectable, or metastatic disease; all therapies used in the past for treating cancer (including surgery, radiotherapy, chemotherapy, and immunotherapy); other diseases treated with chemotherapy, radiotherapy, or immunotherapy; current signs and symptoms of cancer, and adverse event effects from current and / or past anticancer drug treatments; and a detailed medical history of the indications for this study, including the current state of cancer. 5. Record all medications (including herbal medicines) taken and procedures performed within 28 days prior to the first clinical trial treatment; record any radiotherapy performed within 3 months prior to the first clinical trial treatment for conditions other than those targeted by this study; 6. All adverse events (AEs) will be documented from the time of signing informed consent until the 30-day safety follow-up period. After this visit, all relevant SAEs (cardiac or non-cardiac) must be collected and reported, regardless of the time elapsed since the last HER2 inhibitor dose. All cardiogenic AEs occurring during the study and within 12 months of the last HER2 inhibitor dose must be reported, regardless of causality (related or unrelated) and severity (serious or non-serious); 7. A general physical examination including an examination of the general appearance, skin, neck (including the thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, limbs, and assessment of the basic nervous system; 8. Signs of vital signs such as body temperature, respiratory rate, pulse rate, and blood pressure; 9. After the subject breathes quietly for 5 minutes, a 12-lead electrocardiogram (ECG) is performed in the supine position; the ECG results are used to assess heart rate, atrial-ventricular conduction, QR and QT intervals, and the likelihood of arrhythmias. Interpretation of the ECG traces must be performed by a qualified physician and recorded in an ECG eCRF. Each ECG trace must be labeled with the study number, subject identification number, and date and stored in the facility's source documentation; 10. Hematological tests such as absolute lymphocyte count, absolute neutrophil count, hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell percentage, red blood cell morphology, reticulocyte count, mean corpuscular hemoglobin volume, and mean corpuscular hemoglobin concentration; 11. Serological chemistry tests including measurement of albumin, alkaline phosphatase, alanine aminotransferase, amylase, aspartate aminotransferase, gamma-glutamyltransferase, blood urea nitrogen / total urea, calcium, chloride, creatine kinase, creatinine, glucose, lactate dehydrogenase, lipase, phosphorus / phosphate, magnesium, potassium, sodium, troponin, total bilirubin, and total protein; 12. A urine test includes bilirubin, blood, glucose, ketones, pH, protein, specific gravity, and color and appearance. If a urine test is positive for protein, a segmental and 24-hour urine protein test should be performed. 13. Tests for HBV, HCV, and HIV include HBsAb, HCV Ab, and anti-HIV 1 / 2. If HBsAb is positive, HBsAg, HBeAb, HBcAb, and HBV DNA should be measured and active HBV infection should be ruled out according to clinical instructions. If HCV Ab is positive, HCV RNA should be measured and active HCV infection should be ruled out according to clinical instructions; 14. In subjects with a history of latent or active tuberculosis infection due to untreated or inadequate treatment, recent contact with a person infected with tuberculosis, or clinical symptoms and signs indicating tuberculosis infection, if the QuantiFERON®-TB Gold In-Tube test (TB Quantiferon test) is negative, or unusable or indeterminate upon retesting, the results of a Mantoux Purified Derivative skin test with a nodules less than 5 mm in size, performed within 3 months prior to screening according to local standards, are acceptable to declare that there is no suspicion of latent or active tuberculosis infection; In subjects with a history of latent or active tuberculosis infection due to untreated or inadequate treatment, recent contact with a person infected with tuberculosis, or signs or symptoms of tuberculosis infection, the following measures are recommended to rule out suspected latent tuberculosis infection: The Mantoux Purified Derivative skin test, performed within 3 months prior to screening according to local standards, must be negative (Note: Subjects who have received the BCG vaccine must be tested with the QuantiFERON®-TB Gold In-Tube test); a chest X-ray taken at the time of screening or within 3 months prior to screening must not suggest latent or active tuberculosis infection; In subjects who have previously received an appropriate course of treatment for either latent (9 months of isoniazid or other acceptable regimens in a local setting with a multidrug-resistant tuberculosis infection rate of less than 5%) or active (with an acceptable regimen), a chest X-ray should be performed at the time of examination or within 3 months prior to examination to rule out latent or active tuberculosis infection. In such situations, neither PPD testing nor the QuantiFERON®-TB Gold In-Tube test is necessary; 15. Baseline LVEF assessment should be performed as soon as possible immediately before the first investigational treatment, but no later than 42 days prior to the first investigational treatment. During the treatment period, LVEF should be assessed every 12 weeks. For cardiac safety, LVEF assessments may be performed more frequently if necessary. If LVEF assessment needs to be brought forward or delayed, subsequent assessments should be performed according to the original schedule from the date of the first investigational treatment. Patients whose investigational treatment is permanently discontinued due to a decrease in LVEF should continue to have their LVEF monitored according to clinical instructions until their LVEF value returns to 50% or higher, or after one year, whichever comes first. 16. For eligibility purposes, the recording of HR and HER2 status in tumor tissue collected at the time of diagnosis of locally advanced, unresectable, or metastatic disease is based on local laboratory test results determined using institutional criteria. On the other hand, tumor tissue collected at the time of diagnosis of locally advanced, unresectable, or metastatic disease must be submitted to a central laboratory designated by the sponsor for confirmation of HER2 status based on IHC and FISH methods. Archived formalin-fixed paraffin-embedded (FFPE) specimens are collected. If archived FFPE specimens of metastatic or locally advanced, unresectable tumors are unavailable, de novo biopsy is required. A minimum of five slides are required; 17. Tumor biopsies should be taken at the time of screening, unless tissue (block or slide) from a preserved specimen (biopsy or surgery) is available and was taken within two years prior to screening. Core needle biopsy, excision biopsy, punch biopsy, and surgical specimens are appropriate. Microneedle aspiration biopsy is not appropriate. Biopsies should only be taken from tumor tissue / sites that are safely accessible. Priority 1: FFPE tissue block containing the tumor; Priority 2: If all FFPE tissue blocks containing the tumor cannot be provided, fresh (within one week) 4μm thick sections should be provided from this block and mounted on SuperFrost Plus microscope slides. Subjects are encouraged to provide as many slides as possible, preferably around 5-10 slides in total; 18. Approximately 10 mL of peripheral blood samples will be collected at screening and during disease progression. ERBB2 amplification will be measured and tumor single-cell sequencing will be performed to develop HER2 CDx and explore the mechanisms of drug resistance. 19. During the treatment period, pharmacokinetic samples of the HER2 inhibitor were collected before administration on day 1 of cycles 1, 2, 3, and 5; every other cycle for the first 12 months; and every four cycles thereafter (60 minutes before HER2 inhibitor administration); before administration on days 8 and 15 of cycle 1; at the end of infusion on days 1 and 8 of cycle 1 and on day 1 of cycles 3 and 5 (within 30 minutes after the end of HER2 inhibitor infusion); and during 30-day and 84-day safety follow-up studies; 20. During the treatment period, ADA samples of HER2 inhibitors were collected before administration of cycles 1, 2, 3, and 5, every other cycle for the first 12 months, and every four cycles thereafter, along with PK sample collection (60 minutes before administration of KN046); and during 30-day and 84-day safety follow-up; 21. Tumor evaluation will be performed using CT / MRI of the chest, abdomen, and pelvis. If MRI is used, chest CT is mandatory. Screening tumor evaluation will be performed within 21 days after the first investigational treatment to record the baseline status of tumor disease using RECIST 1.1 targeted and non-targeted lesions. During the treatment period, the visit time frame for tumor evaluation is ±7 days. CT or MRI examinations (if MRI is used, chest CT is mandatory) should always be used in the same way as during the screening period. If a tumor response is documented during the study, follow-up should be performed preferably at 4-6 week intervals according to RECIST 1.1, however, the response should be confirmed within 4 weeks and within 8 weeks of the first documented CR or PR. PR / CR confirmation can be performed after the first documented PR / CR, but after the next evaluation. Tumor evaluation will be performed every 8 weeks for 12 months until disease progression, initiation of new anticancer drug therapy, death, or withdrawal of informed consent, whichever occurs first, according to RECIST 1.1, and then every 12 weeks thereafter. If treatment is discontinued for reasons other than progressive disease as defined in RECIST 1.1, oncological evaluation must be continued until one of the following occurs first: progressive disease as defined in RECIST 1.1, initiation of new anticancer treatment, death, or withdrawal of informed consent; 22. A brain CT / MRI scan (preferably with contrast) is required at screening if it has not been performed within 42 days prior to the first clinical trial treatment. During the treatment period, a brain CT / MRI scan will be performed if clinically required due to the development of new specific symptoms. 23. Bone scans must be performed if they have not been performed within 3 months prior to the initial investigational treatment. Bone scans should be performed during the treatment period as clinically directed. If suspicious abnormalities are identified in baseline or subsequent bone scans, confirmation should be made by X-ray, bone-windowed CT scan, or MRI. The same modality must be used throughout the study period to identify lesions and patients. Bone lesions identified at baseline will be followed up according to the same tumor evaluation schedule; 24. Clinical evaluation of superficial lesions shall be performed on the same day as imaging studies and shall include photographs of all superficial metastatic lesions. All lesions must be recorded in the eCRF; 25. The first dose of a HER2 inhibitor should be administered intravenously over 90 minutes (±15 minutes). If no fluid-related reactions occur after the first dose, subsequent doses may be administered intravenously over 60 minutes (±15 minutes). 26. Palbociclib is administered orally at a dose of 125 mg per day for 3 weeks, followed by a 1-week rest period. Patients are required to complete a patient diary regarding medication information on day 1 of each cycle and return all palbociclib bottles. 27. Test results must be obtained before administering the investigational drug. 28. The results of the examination or test must be obtained within 7 days of the first clinical trial treatment. 29. This should only be performed if a clinically significant abnormality is found during the EOT visit; Even though preferred embodiments of the present invention are shown and described herein, it will be apparent to those skilled in the art that these embodiments are merely given as examples. The present invention is not limited to the embodiments described herein. Although the present invention has been described herein above, the description of embodiments and the drawings herein are not to be constrained. Those skilled in the art will be able to conceive of various changes, modifications and substitutions as long as they do not depart from the present invention. It should be understood that the present invention is not in any respect limited to the specific description, arrangement or relative proportions of the various conditions and variables described herein. It should be understood that various alternative forms of the embodiments described herein may be used when the present invention is put into practice. Therefore, it is expected that the present invention will cover all such alternatives, modifications, variations or equivalents. The following claims limit the scope of the present invention and include methods and structures within the scope of these claims and their equivalents.

Claims

1. A pharmaceutical composition used to prevent, alleviate, or treat tumors or inhibit tumor growth in subjects in need, comprising a HER2 inhibitor capable of binding to a first HER2 antigen and a second HER2 antigen, and a CDK inhibitor capable of inhibiting CDK4 and / or CDK6. Here, the HER2 inhibitor is a bispecific antibody or its antigen-binding portion, the HER2 inhibitor comprises a first light chain, a second light chain, a first heavy chain, and a second heavy chain, the variable region of the first light chain and the variable region of the second light chain are represented by SEQ ID NO: 1, the variable regions of the first heavy chain and the second heavy chain are represented by SEQ ID NO: 13 and SEQ ID NO: 14, respectively, the CDK inhibitor comprises ribociclib, and the tumor is breast cancer.

2. The first light chain has an amino acid sequence represented by SEQ ID NO: 7, and the second light chain has an amino acid sequence represented by SEQ ID NO:

7. The pharmaceutical composition according to claim 1.

3. The pharmaceutical composition according to claim 1, wherein the two heavy chains have a sequence represented by any of SEQ ID NO: 15 to 18.

4. Furthermore, including fulvestrant, The pharmaceutical composition according to claim 1.

5. The aforementioned breast cancers include HER2-positive breast cancers and / or HER2-low-expressing breast cancers. The pharmaceutical composition according to claim 1.

6. The aforementioned tumor is either HR-negative or HR-positive breast cancer. The pharmaceutical composition according to claim 1.

7. The aforementioned breast cancer includes early-stage breast cancer, locally advanced breast cancer, and / or metastatic breast cancer. The pharmaceutical composition according to claim 1.

8. The aforementioned HER2 inhibitor is formulated for intravenous injection. The pharmaceutical composition according to claim 1.

9. The aforementioned HER2 inhibitor is administered to subjects who require it at doses ranging from approximately 1 mg / kg to approximately 30 mg / kg. The pharmaceutical composition according to claim 1.

10. The HER2 inhibitor is administered to subjects who require it every two weeks. The pharmaceutical composition according to claim 1.

11. The aforementioned CDK inhibitor is formulated for oral use. The pharmaceutical composition according to claim 1.

12. The aforementioned CDK inhibitor is administered to subjects who require it at doses ranging from approximately 10 mg / kg to approximately 50 mg / kg. The pharmaceutical composition according to claim 1.

13. The aforementioned CDK inhibitor is administered daily for three weeks to subjects who require it. The pharmaceutical composition according to claim 1.

14. The fulvestrant in the aforementioned pharmaceutical is formulated for intramuscular injection. The pharmaceutical composition according to claim 4.

15. The fulvestrant in the aforementioned pharmaceutical is administered to subjects in need at doses of approximately 400 mg to approximately 600 mg. The pharmaceutical composition according to claim 4.

16. The fulvestrant in the aforementioned pharmaceutical is administered to subjects who require it on day 1 and day 15 of cycle 1, and on day 1 of each subsequent 28-day cycle. The pharmaceutical composition according to claim 4.

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