Pyrido[2,3-d]pyrimidine-7(8H)-one as a CDK inhibitor

Abstract

The present invention provides pyrido[2,3-d]pyrimidine-7(8H)-one compounds, pharmaceutically acceptable salts, solvates, prodrugs, and active metabolites that may be potent CDK2, CDK4, and CDK6 inhibitors. [Solution] A pharmaceutical composition comprising pyrido[2,3-d]pyrimidine-7(8H)-one of formula 1 and a compound of formula 1 as a CDK inhibitor is disclosed herein. Methods and uses of the compound of formula 1 in the treatment and manufacture of cancer are also disclosed. TIFF2026053649000070.tif60166

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority under U.S. Patent Application No. 62 / 989,448, filed on 13 March 2020, all of which are incorporated herein by reference. [Background technology]

[0002] Cyclin-dependent kinase (CDK) inhibitors have therapeutic potential for several diseases, including cancer, diabetes, kidney disease, neurodegenerative diseases, and infections. However, their development has focused on anticancer agents, with a particular emphasis on the cell cycle and transcriptional CDKs.

[0003] Cancer represents the pathological manifestation of uncontrolled cell division. Therefore, it has long been hoped that understanding the fundamental principles of cell cycle regulation would enable effective cancer treatment. In particular, CDKs such as CDK4 and CDK6, which promote cell cycle transitions, were expected to be key therapeutic targets because many tumorigenic events activate these kinases during the G1 phase of the cell cycle, inducing DNA synthesis (S phase) and ultimately leading to proliferation. Furthermore, perturbations of genomic stability during the S phase or mitotic (M) phase, two phases regulated by CDK1 and CDK2, are important tumorigenic events. CDK4 and CDK6 are considered highly effective targets for anticancer drugs because they play a crucial role in controlling cell cycle progression during the transition from G1 to S phase. However, historically, translating this knowledge into successful clinical development of CDK inhibitors has been difficult. For example, suppression of CDK4 and CDK6 appears to have little clinical effect in certain cancers, such as colorectal cancer, triple-negative breast cancer, and melanoma. Therefore, the search continues for CDK inhibitors that are less toxic and offer broader and more effective cancer treatment. [Overview of the project] [Means for solving the problem]

[0004] Described herein are pyrido[2,3-d]pyrimidin-7(8H)-one compounds, pharmaceutically acceptable salts, solvates, prodrugs, and active metabolites that can be potent CDK2, CDK4, and CDK6 inhibitors. These compounds can be used to treat various types of cancer that require treatment, including administering a therapeutically effective amount of a pyrido[2,3-d]pyrimidin-7(8H)-one compound.

[0005] Some embodiments include a compound of formula 1

Chemical formula

[0006] Some embodiments include compositions comprising the subject compound. The subject compound is a compound of formula 1, formula 1A, formula 1B, formula 1C, formula 2, formula 2A, formula 3, formula 3A, formula 4, formula 4A, formula 5, formula 5A, formula 6, formula 6A, formula 7, formula 7A, formula 8, or formula 9, or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, as described herein.

[0007] Some embodiments include pharmaceutical dosage forms containing the subject compound.

[0008] The compounds or compositions of the subject may be used to inhibit CDK2, CDK4 and / or CDK6, or to treat cancer. The compounds or compositions of the subject may also be used to treat diseases or disorders such as breast cancer, melanoma, kidney cancer, squamous cell carcinoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, prostate cancer, colorectal cancer, esophageal cancer, head cancer, cervical cancer, neuroblastoma, myeloma, glioma, lymphoma, and leukemia.

[0009] Some embodiments include methods for treating diseases or disorders associated with CDK2, CDK4, and / or CDK6 inhibitors, comprising administering an effective amount of the compound of the subject to a mammal in need of treatment.

[0010] Some embodiments involve the use of the subject compound in the manufacture of a pharmaceutical product for the treatment of a disease or disorder associated with CDK2, CDK4, and / or CDK6 inhibitors. [Brief explanation of the drawing]

[0011] [Figure 1]The DNA content profiles of MDA-MB-231 human breast cancer cells treated with the subject compound or a commercially available CDK inhibitor are shown, along with the percentage of cells in different cell cycle phases 48 hours after the treatment (n=6 technical replicates). [Figure 2] Representative images of β-galactosidase staining of MDA-MB-231 human breast cancer cells treated with available CDK inhibitors or the compound of the subject, and β-Gal activity after 14 days of treatment are shown (arrows indicate positively stained cells). [Figure 3] The results of β-galactosidase staining of MDA-MB-231 human breast cancer cells treated with available CDK inhibitors or the compound of the subject are shown, along with quantification of the percentage of β-galactosidase-positive cells (shown as blue columns) and total cell count (shown as black dots) 3 and 14 days after treatment with the compound (n=2 independent experiments). [Figure 4] This report demonstrates the specific effects of selected subject compounds on Cdk-deficient mouse fetal fibroblasts (MEFs). The relative cell counts are shown for Cdk2-, Cdk4 / 6-, or Cdk2 / 4 / 6-null MEFs at day 6 versus day 3 after treatment. Data are mean ± sem (3 technical replicates). [Figure 5] This study shows cell proliferation in luminal and non-luminal breast cancer cell lines in the presence of palbociclib or PS009. Relative cell counts (GI50 dose in each case) are shown 6 days after the start of treatment with palbociclib or PS009 in the luminal breast cancer cell line group (ZR75-1, T47D, MCF7) and the non-luminal breast cancer cell line group (HCC1143, MDA-MB-231, BT549, MDA-MB468). Data are mean ± sem (3 technical replicates). It should be noted that palbociclib shows clear pRB dependence in non-luminal breast cancer cell lines, while PS009 is effective in both pRB wild-type and mutant cell lines. [Figure 6]This study demonstrates the effects of the subject compound on various cell cycle markers. Biochemical analyses were performed on pRB-rich (pRB-proficient) and pRB-deficient (pRB-deficient) breast cancer cells treated with the indicated compound at the corresponding GI50 dose. Actin was used as a loading control. The blots show representative results from more than three independent experiments. [Figure 7] This study demonstrates the effects of antibodies against phospho RB1 Ser807 / 811 on the phosphorylation of retinoblastoma proteins PS004, PS006, and PS009 in various tissues. Microscopic images are representative of three mice per treatment. [Figure 8A] This study demonstrates the therapeutic effect of the subject compound in xenografting of MDA-MB-231 breast cancer cells. Mice carrying MDA-MB-231-derived xenografts were treated with the compound for two weeks (a total of four doses per treatment). Tumor weight (g) was measured at the end of each treatment. DMSO treatment served as a control for intraperitoneal administration of the PS compound, and lactate buffer served as a control for oral administration of palbociclib. Data are mean ± sem (each dot represents the analysis of one mouse). **P<0.01; ***P<0.001 (Student's t-test). [Figure 8B] This study demonstrates the therapeutic effect of the compound in question on tumor doubling after treatment with the compound in xenografting of MDA-MB-231 breast cancer cells. Mice carrying MDA-MB-231-derived xenografts were treated with the compound for two weeks (a total of four doses per treatment). The mean values ​​for DMSO treatment and lactate buffer at each time point in Figure 8A are shown as "Vehicle". Data are mean ± sem (each dot represents the analysis of one mouse). **P<0.01;***P<0.001 (Student's t-test). [Figure 9A]This section quantifies cells positive for the phosphorylated form of RB1(pRb) in tumor analysis. Data are mean ± sem (n=6 mice per treatment). *P<0.05; ***P<0.001 (Student's t-test). [Figure 9B] This section quantifies cells that were positive for Ki67 in tumor analysis. Data are mean ± sem (n=6 mice per treatment). *P<0.05; ***P<0.001 (Student's t-test). [Figure 10] This study shows the effects of various compound treatments on mice, including their total weight and the number of various cell populations in their peripheral blood, such as red blood cells or white blood cells. The data corresponds to 6 mice and 13 control mice per treatment. [Figure 11] Representative micrographs of lung, bone marrow, and intestinal sections of mice treated with the compound indicated are shown. Sections were stained with hematoxylin and eosin. Samples are representative of at least three mice per treatment. [Modes for carrying out the invention]

[0012] Unless otherwise specified, when a compound or chemical structural feature such as pyrido[2,3-d]pyrimidine-7(8H)-one, aryl, heteroaryl, etc. is referred to as "optionally substituted," it includes features that are unsubstituted (i.e., unsubstituted) or features that have one or more substituents. The term "substituent" has a broad meaning known to those skilled in the art and includes a portion that replaces one or more hydrogen atoms bonded to the parent compound or structural feature. In some embodiments, the substituent may be a common part of any organic compound known in the art and may have molecular weights (sum of atomic masses of the substituent atoms) of 15Da to 50Da, 15Da to 100Da, 15Da to 150Da, 15Da to 200Da, 15Da to 300Da, or 15Da to 500Da. In some embodiments, the substituent comprises or consists of 0 to 30, 0 to 20, 0 to 10, or 0 to 5 carbon atoms and 0 to 30, 0 to 20, 0 to 10, or 0 to 5 heteroatoms, each heteroatom independently of N, O, S, P, Si, F, Cl, Br, or I, wherein the substituent comprises one C, N, O, S, P, Si, F, Cl, Br, or I. Examples of substituents include, but are not limited to, hydrocarbyl substituents such as alkyl, alkenyl, alkynyl, and aryl substituents; heterohydrocarbyl substituents such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, alkylthio, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, isocyanate, thiocyanate, isothiocyanate, haloalkyl, haloalkoxyl, trihalomethanesulfonyl, and trihalomethanesulfonamide; or substituents such as hydroxy, thiol, cyano, F, Cl, Br, I, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, amino, phosphono, and phosphoric acidyl substituents, which are not necessarily hydrocarbyl or heterocarbyl substituents but include other O, S, N, Si, P, or halo-based substituents.

[0013] For convenience, the term "molecular weight" is used in relation to a part or part of a molecule to indicate the sum of the atomic masses of a part or part of a molecule, even if it is not a complete molecule.

[0014] The following are structures related to some of the chemical names mentioned herein. These structures may be unsubstituted, as shown below, and may have substituents independently at any position that would normally be occupied by a hydrogen atom if unsubstituted. [ka] If no bond point is specified, the bond may occur at any position typically occupied by a hydrogen atom.

[0015] [ka]

[0016] As used herein, the term “alkyl” has the broad meaning commonly understood in the art and may include a carbon-hydrogen moiety that does not contain double or triple bonds. Alkyl may be a linear alkyl, a branched alkyl, a cycloalkyl, or a combination thereof, and in some embodiments may contain 1 to 35 carbon atoms. In some embodiments, alkyl may be C such as methyl (-CH3), methylene (-CH2-), ethyl (-CH2CH3), ethylene (-C2H4-), propylene (-C3CH6-), n-butyl (-CH2CH2CH2CH3), n-pentyl (-CH2CH2CH2CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), etc. 1-10 Linear alkyl groups; C3H7 (e.g., isopropyl), C4H9 (e.g., branched butyl isomers), C5H 11 (For example, branched pentyl isomer), C6H 13 (For example, branched hexyl isomer), C7H 15 C (e.g., heptyl isomer) 3-10Branched alkyl groups; C3H5 (e.g., cyclopropyl), C4H7 (e.g., cyclobutyl, methylcyclopropyl, and other cyclobutyl isomers), C5H9 (e.g., cyclopentyl, methylcyclobutyl, dimethylcyclopropyl, and other cyclopentyl isomers), C6H 11 (For example, cyclohexyl isomer), C7H 13 (For example, cycloheptyl isomers) 3-10 May include cycloalkyl groups, etc.

[0017] As used herein, "aryl" has a broad meaning as commonly understood in the art and may include aromatic rings or aromatic ring systems such as phenyl and naphthyl.

[0018] The term "heteroaryl" also has a meaning that will be understood by those skilled in the art, and includes "aryls" having one or more heteroatoms in a ring or ring system, such as pyridinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, oxadiazolyl, isoxazolyl, indolyl, quinolinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, and benzimidazolyl.

[0019] Unless otherwise specified, references to the compounds described herein by structure, name, or other means include pharmaceutically acceptable salts such as HCl, HBr, HI, H2SO4, acetates, citrates, sodium, potassium, and ammonium salts; prodrugs such as ester prodrugs; alternative solid forms such as polymorphs, solvates, and hydrates; tautomers; or any other chemical species that can be rapidly converted to the compounds described herein under the conditions under which the compounds are used as described.

[0020] If stereochemistry is not indicated, the name or structural expression includes any stereoisomer or mixture of stereoisomers.

[0021] Some embodiments include compounds represented by 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9.

[0022] [ka] [ka] [ka] [ka]

[0023] With respect to any related structural representation of formula I, 1A, 1B, or 1C, 2, 3, 4, 5, 6, 7, etc., A is an optionally substituted aryl or heteroaryl. In some embodiments, A is an optionally substituted aryl such as optionally substituted p-phenylene. In some embodiments, A is an unsubstituted aryl. In some embodiments, A is an optionally substituted heteroaryl. In some embodiments, A is an unsubstituted heteroaryl. If the aryl or heteroaryl is substituted, it has 1, 2, 3, or 4 substituents, each substituent may be identical or different from the others. The substituents may be contained on the aryl or heteroaryl. In some embodiments, some or all substituents on the aryl or heteroaryl have 0 to 10 carbon atoms and 0 to 10 heteroatoms, each heteroatom independently being O, N, S, F, Cl, Br, or I, and / or having a molecular weight of 15 g / mol to 500 g / mol. In some embodiments, some or all of the substituents each consist of a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to 50 Da, and 2 to 5 chemical elements, which are independently C, H, O, N, S, F, Cl, or Br.

[0024] For example, with respect to any related structural representation of formula I, 1A, 1B or 1C, 2, 3, 4, 5, 6, 7, etc., the substituents of A may optionally be substituted with CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , Ring C5H9, C6H 13 , Ring C6H 11 C as arbitrarily substituted, etc. 1-10 Alkyl; OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 , ring-shaped OC5H9, OC6H 13 , ring-shaped OC6H 11 C 1-10 Optionally substituted alkoxys; halos such as F, Cl, Br, I; OH; CN; NO2; C such as CF3, CF2H, C2F5. 1-6 Fluoroalkyls such as OCF3, OCF2H, OC2F5, etc. 1-6 Fluoroalkoxys such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl, etc. 1-10 Esters; C such as -COCH3, -COC2H5, -COC3H7, -CO-phenyl 1-10 Ketones; or C such as NH2, NH(CH3), N(CH3)2, N(CH3)C2H5, etc. 1-10 It may also be an amine. In some embodiments, the substituents of A are F, Cl, Br, I, CN, NO2, C 1-4 Alkyl, C 1-4 alkyl-OH, C 1-3 O-alkyl, CF3, C(O)H, C 1-4 CO-alkyl, CO2H, C 1-4 CO2-alkyl, NH2, or C 1-4 Alkylamino compounds are also acceptable.

[0025] With respect to any related structural representations such as Formulas 1, 1A, 1B, 1C, 2, 3, 4, 5, 6, or 7, in some embodiments, A is optionally substituted p-phenylene or optionally substituted pyridine 2,5-yl, with the 2-position bonded to NH and the 5-position bonded to D.

[0026] With respect to any related structural representation of formulas such as 1, 1A, 1B, 1C, 2, 3, 4, 5, 6, or 7, if A is substituted phenylene, then R has 1, 2, 3, or 4 substituents, for example, represented by the following structure. 2a , R 2b , R 2c and R 2d Not all of them have to be H.

[0027] [ka]

[0028] In some embodiments, A is unsubstituted phenylene, [ka] That is the case.

[0029] With respect to any related structural representation of formulas such as 1, 1A, 1B, 1C, 2, 3, 4, 5, 6, or 7, in some embodiments, A is fluoro-p-phenylene, [ka] That is the case.

[0030] With respect to any related structural representation such as 1, 1A, 1B, 1C, 2, 3, 4, 5, 6, or 7, in some embodiments, A is an optionally substituted pyridinyl such as optionally substituted pyridine-2,5-yl. In some embodiments, A is an unsubstituted pyridinyl. With respect to any related structural representation such as formula 1, 1A, 1B, 1C, 2, 3, 4, 5, 6, or 7, in some embodiments, A is an unsubstituted 2-pyridinyl, [ka] That is the case.

[0031] With respect to any related structural representation of formulas 1A, 1B, 1C, 2A, 3A, 4A, 5A, 6A, 7A, 8, or 9, in some embodiments, D is optionally substituted piperidine-1,4-yl or optionally substituted piperazine-1,4-yl. In some embodiments, D is optionally substituted piperazine-1,4-yl. In some embodiments, D is optionally substituted piperidine-1,4-yl. In some embodiments, D is optionally substituted piperidine-1,4-yl, with A bonded at position 1.

[0032] When D is substituted piperidine-1,4-yl or substituted piperazine-1,4-yl, it has 1, 2, 3, 4, 5, 6, 7, or 8 substituents, each substituent may be identical or different from the others. In some embodiments, some or all substituents of D have 0 to 10 carbon atoms and 0 to 10 heteroatoms, each heteroatom independently being O, N, S, F, Cl, Br, or I (with at least one non-hydrogen atom present) and / or a molecular weight of 15 g / mol to 500 g / mol. In some embodiments, some or all substituents have molecular weights of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to 50 Da, and 2 to 5 chemical elements, each chemical element independently being C, H, O, N, S, F, Cl, or Br.

[0033] For example, with respect to any related structural representation of formula 1A, 1B, 1C, 2A, 3A, 4A, 5A, 6A, 7A, 8, or 9, the substituents of D are CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , Ring C5H9, C6H 13 , Ring C6H 11 Arbitrarily substituted alkyl groups such as OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 , ring-shaped OC5H9, OC6H 13 , ring-shaped OC6H 11 C 1-10Optionally substituted alkoxys; halos such as F, Cl, Br, I; OH; CN; NO2; C such as CF3, CF2H, C2F5. 1-6 Fluoroalkyls such as OCF3, OCF2H, OC2F5, etc. 1-6 Fluoroalkoxys such as -O2CCH3, -CO2CH3, -OCOC2H5, -CO2C2H5, -OCO-phenyl, -CO2-phenyl, etc. 1-10 Esters; C such as -COCH3, -COC2H5, -COC3H7, -CO-phenyl 1-10 Ketones; or C such as NH2, NH(CH3), N(CH3)2, N(CH3)C2H5, etc. 1-10 It may also be an amine.

[0034] With respect to any related structural representation of formulas such as 1A, 1B, 1C, 2A, 3A, 4A, 5A, 6A, 7A, 8, or 9, in some embodiments, D is [ka] That is the case.

[0035] With respect to any related structural representation of formulas 1A, 1B, 1C, 2A, 3A, 4A, 5A, 6A, 7A, 8, or 9, in some embodiments, D is optionally substituted piperidine-1,4-yl. In some embodiments, D is unsubstituted piperidine-1,4-yl: [ka] That is the case.

[0036] With respect to any related structural representation of formulas 1A, 1B, 1C, 2A, 3A, 4A, 5A, 6A, 7A, 8, or 9, in some embodiments, D is optionally substituted piperazine-1,4-yl. In some embodiments, D is unsubstituted piperazine-1,4-yl: [ka] That is the case.

[0037] With respect to any related structural representation such as formula 3 or 4, A is optionally substituted p-phenylene or optionally substituted pyridine-2,5-yl, with the 2 position bonded to NH and the 5 position bonded to D, and D is optionally substituted piperidine-1,4-yl, with the 1 position bonded to A.

[0038] In relation to any related structural representations such as Equation 5, A is an optionally substituted p-phenylene and D is an optionally substituted piperazine-1,4-yl.

[0039] With respect to any related structural representations such as Formula 6, A is a substituted p-phenylene or an optionally substituted pyridine-2,5-yl, with the 2-position bonded to NH and the 5-position bonded to D, and D is an optionally substituted piperidine-1,4-yl, with the 1-position bonded to A.

[0040] With respect to any related structural representation such as Formula 7, A is optionally substituted pyridine-2,5-yl, with the 2-position bonded to NH and the 5-position bonded to D, where D is optionally substituted piperazine-1,4-yl; or A is optionally substituted phenyl and D is unsubstituted piperazine-1,4-yl.

[0041] Regarding any related structural representation of formulas such as 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9, generally R 1-28 R may be H or any substituent having 0 to 12 atoms or 0 to 10 carbon atoms and 0 to 5 heteroatoms, where each heteroatom is independently O, N, S, F, Cl, Br, or I, and / or has a molecular weight of 15 g / mol to 300 g / mol. 1-28is one or more functional groups such as b) C═C, C≡C, CO, CO2, CON, NCO2, OH, SH, O, S, N, N═C, F, Cl, Br, I, CN, NO2, CO2H, NH2, etc., and contains a) an optionally substituted or one or more alkyl moieties optionally linked by or to these, or may be a substituent without an alkyl moiety such as F, Cl, Br, I, NO2, CN, NH2, OH, COH, CO2H, etc. In some embodiments, R 1-28 each of which is independently H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 300 Da, 15 Da to 200 Da, 15 Da to 100 Da or 15 Da to 60 Da and consisting of 2 to 5 chemical elements, the chemical elements being independently C, H, O, N, S, F, Cl, or Br.

[0042] Regarding any related structural representations such as Formula 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9, etc., R 1-28 Some non-limiting examples of which include R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1-4 hydroxyalkyl, NO2, NR A R B , COR A , CO2R A , OCOR A , NR A [[ID=*28]]COR B , CONR A R B etc. may be included. In some embodiments, R 1-28 is H; F; Cl; Br; CN; C 1-3 fluoroalkyl such as CHF2, CF3, etc.; OH; NH2; C 1-6Alkyl; -O-methyl, -O-ethyl, isomers of -O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc., C 1-6 Alkoxy; -CH2OH, -C2H4-OH, -C3H6-OH, C4H8-OH, etc., C 1-4 Hydroxyalkyl; -CO2-CH3, -CO2-C2H5, -CO2-C3H7, -CO2-C4H9, etc., C 2-5 It may be -CO2-alkyl.

[0043]

Chemical formula

[0044] For any related structural representation, R A is independently H, or a straight-chain or branched alkyl having the formula C a H 2a+1 or a cycloalkyl having the formula C a H 2a-1 where the alkyl contains C 1-12 and a may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. For example, straight-chain or branched alkyl such as the formula CH3, C2H5, C3H7, C4H9, C5H 11 , C6H 13 , C7H 15 , C8H 17 , C9H 19 , C 10 H 21 etc., or cycloalkyl such as the formula C3H5, C4H7, C5H9, C6H 11 , C7H 13 , C8H 15 , C9H 17 , C 10 H 19 etc. may be used. In some embodiments, R A may be H or C 1-6 alkyl. In some embodiments, R A may be H or C 1-3It may be alkyl. In some embodiments, R A This may be H or CH3. In some embodiments, R A H may also be used.

[0045] With respect to the representation of any related structure, R B Independently, H, or formula C a H 2a+1 Having a linear or branched alkyl group, or formula C a H 2a-1 C containing a cycloalkyl group 1-12 Alkyl, where a may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, for example, formulas CH3, C2H5, C3H7, C4H9, C5H 11 , C6H 13 , C7H 15 C8H 17 C9H 19 , C 10 H 21 Linear or branched alkyl groups such as C3H5, C4H7, C5H9, C6H 11 , C7H 13 C8H 15 C9H 17 , C 10 H 19 These may be cycloalkyls, etc. In some embodiments, R B is H or C 1-3 It may be alkyl. In some embodiments, R B This may be H or CH3. In some embodiments, R B H may also be used.

[0046] With respect to any related structural representation of formulas such as 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9, R 1 is an arbitrarily substituted C 1-6 Alkyl or optionally substituted C 3-10 It is a cycloalkyl group. 1 C is arbitrarily substituted 3-10If it is a cycloalkyl, it may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 substituents. 1 R may include any substituents. In some embodiments, some or all R 1 The substituents may have 0 to 10 carbon atoms and 0 to 10 heteroatoms, each heteroatom independently of O, N, S, F, Cl, Br, or I (where at least one non-hydrogen atom is present) and / or have a molecular weight of 15 g / mol to 500 g / mol. In some embodiments, some or all substituents have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to 50 Da, and 2 to 5 chemical elements, which are independently of C, H, O, N, S, F, Cl, or Br. In some embodiments, R 1 These include CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, and C5H 11 , Ring C5H9, C6H 13 , Ring C6H 11 , Ring C7H 13 , Ring C8H 15 , Ring C9H 17 , cyclic C 10 H 19 C as arbitrarily substituted, etc. 1-6 Alkyl or optionally substituted C 3-10 Cycloalkyl; OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 , ring-shaped OC5H9, OC6H 13 , ring-shaped OC6H 11 C 1-10 Optionally substituted alkoxys; halos such as F, Cl, Br, I; OH; CN; NO2; C such as CF3, CF2H, C2F5. 1-6 Fluoroalkyls such as OCF3, OCF2H, OC2F5, etc. 1-6 Fluoroalkoxys such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl, etc. 1-10 Esters; C such as -COCH3, -COC2H5, -COC3H7, -CO-phenyl 1-10Ketones; or C such as NH2, NH(CH3), N(CH3)2, N(CH3)C2H5, etc. 1-10 It is an amine. In some embodiments, the substituents of D are F, Cl, Br, I, CN, NO2, C 1-4 Alkyl, C 1-4 alkyl-OH, C 1-3 O-alkyl, CF3, C(O)H, C 1-4 CO-alkyl, CO2H, C 1-4 CO2-alkyl, NH2, or C 1-4 Alkylamino compounds are also acceptable.

[0047] With respect to any related structural representation of formulas such as 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9, in some embodiments, R 1 is optionally substituted bicycloheptanyl or optionally substituted cyclopentanyl. In some embodiments, R 1 is optionally substituted bicycloheptanyl. In some embodiments, R 1 This is an optionally substituted bicyclo[2.2.1]heptanyl [ka] That is the case.

[0048] With respect to any related structural representation of formulas such as 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9, in some embodiments, R 1 This is unsubstituted bicyclo[2.2.1]heptanyl [ka] That is the case.

[0049] With respect to any related structural representation of formulas such as 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9, in some embodiments, R 1 is optionally substituted cyclopentanyl. In some embodiments, R1 is unsubstituted cyclopentanyl [ka] That is the case.

[0050] With respect to any related structural representation such as formulas 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 8, or 9, in some embodiments, R 1a H, COR 8 , arbitrarily substituted C 1-6 Alkyl or optionally substituted C 3-6 It is alkylcycloalkyl. In some embodiments, R 1a is H, COCH3, or CH3. In some embodiments, R 1a is H or CH3. In some embodiments, R 1a is H. In some embodiments, R 1a It is COCH3.

[0051] With respect to any related structural representation such as formulas 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 8, or 9, R 1b H, and C as arbitrarily substituted. 1-6 Alkyl or optionally substituted C 3-6 It is alkylcycloalkyl. In some embodiments, R 1b is H or CH3. In some embodiments, R 1b is H or CH3. In some embodiments, R 1b is H. In some embodiments, R 1b It is CH3.

[0052] With respect to any related structural representation such as Formula 1, 1A, 1B, or 1C, in some embodiments, R 1c This includes H, CN, OH, optionally substituted hydrocarbyl, alkoxy, and NR. 9 R 8 , optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R 1cis H, OH, CH3, OCH3, or NH2. In some embodiments, R 1c is H, OH, or CH3. In some embodiments, R 1b is H. In some embodiments, R 1c is CH3.

[0053] For any relevant structural representations such as Formula 1, 5, 5A, 7, or 7A, in some embodiments, R 11 is R 8 , -OR 8 , SO2R 8 , SO2NR<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​1-5 It is an -O-alkylene. In some embodiments, E is -O-(CH2)CH(CH3)-.

[0056] Regarding E-Hy, Hy is either OH or H. In some embodiments, Hy is OH. In some embodiments, Hy is H.

[0057] In some embodiments, R 11 H is a substituted C 1-4 Alkyl or optionally substituted C 1-4 It is a hydroxyalkyl group. In some embodiments, R 11 is H. In some embodiments, R 11 is an arbitrarily substituted C 1-4 It is alkyl. In some embodiments, R 11 is an arbitrarily substituted C 1-4 It is a hydroxyalkyl group. In some embodiments, R 11 teeth, [ka] That is the case.

[0058] In some embodiments, R 11 teeth, [ka] That is the case.

[0059] In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] That is the case.

[0060] With respect to any related structural representation of formulas such as 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9, in some embodiments, R 2 H, F, Cl, Br, I, cyano, OH, SOR 8 SO2R 8 SO2NR 9 R 8 COR 8 CO2R 8 CONR 9 R 8 , NR 9 R 8 , NR 9 COR 8 , NR 9 SO2R 8 , NR 9 CO2R 8 , NR 9 CONR 8 OCOR 8 In some embodiments, R 8 and R 9 It does not have substituents containing heteroatoms. In some embodiments, R 2 is F or Cl. In some embodiments, R 2 It is F.

[0061] In some embodiments, R 2a is F or H, and R 2b , R 2c , and R 2d R 2 It is one of the above bases regarding R. In some embodiments, R 2a F is R 2b , R 2c , and R 2d R 2It is one of the above bases regarding R. In some embodiments, R 2a H is R 2b , R 2c , and R 2d R 2 It is one of the above bases regarding.

[0062] In some embodiments, R 2b is F or H, and R 2a , R 2c , and R 2d R 2 It is one of the above bases regarding R. In some embodiments, R 2b F is R 2a , R 2c , and R 2d R 2 It is one of the above bases regarding R. In some embodiments, R 2b H is R 2a , R 2c , and R 2d R 2 It is one of the above bases regarding.

[0063] With respect to any related structural representation of formulas such as 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9, in some embodiments, R 3 H, F, Cl, Br, I, cyano, OH, SOR 8 SO2R 8 SO2NR 9 R 8 COR 8 CO2R 8 CONR 9 R 8 , NR 9 R 8 , NR 9 COR 8 , NR 9 SO2R 8 , NR 9 CO2R 8 , NR 9 CONR 8 OCOR 8 In some embodiments, R8 and R 9 has no substituent containing a heteroatom. In some embodiments, one, two, three, or four R 3 groups are H.

[0064] In some embodiments, R 3a is H, and R 3b , R 3c , and R 3d are any of the above groups for R 3 .

[0065] In some embodiments, R 3b is H, and R 3a , R 3c , and R 3d are any of the above groups for R 3 .

[0066] For any relevant structural representation such as Formula 1A, 1B, or 1C, in some embodiments, R 4 is H or CH3. In some embodiments, R 4 is H. In some embodiments, R 4 is CH3.

[0067] For any relevant structural representation such as Z in Formula 1A or 1C, in some embodiments, R 5 is R 8 , F, Cl, Br, I, cyano, -OR 8 , SOR 8 , SO2R 8 , SO2NR 9 R 8 , COR 8 , CO2R 8 , CONR 9 R 8 , NR 9 R 8 , NR 9 , COR 8 , NR 9 , SO2R 8 , NR 9 , CO2R 8 , NR 9 , CONR8 , or OCOR 8 That is the case.

[0068] With respect to any related structural representation such as W in formula 1A or 1C, in some embodiments, R 6 R 8 F, Cl, Br, I, Cyano, -OR 8 SOR 8 SO2R 8 SO2NR 9 R 8 COR 8 CO2R 8 CONR 9 R 8 , NR 9 R 8 , NR 9 COR 8 , NR 9 SO2R 8 , NR 9 CO2R 8 , NR 9 CONR 8 , or OCOR 8 That is the case.

[0069] With respect to the representation of any related structure, in some embodiments, R 7 R 8 F, Cl, Br, I, Cyano, -OR 8 SOR 8 SO2R 8 SO2NR 9 R 8 COR 8 CO2R 8 CONR 9 R 8 , NR 9 R 8 , NR 9 COR 8 , NR 9 SO2R 8 , NR 9 CO2R 8 , NR 9 CONR 8 , or OCOR 8 That is the case.

[0070] With respect to any related structural representation of formulas such as 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9, in some embodiments, R 8 is H or R 8 F, Cl, Br, I, amino, hydroxyl, C 1-6 C may be optionally substituted with an alkoxy or cyano group. 1-6 Hydrocarbil (C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenil, C 3-6 Cycloalkenyl, C 2-6 Alkinyl, C 3-6 These include cycloalkenyls, etc.

[0071] With respect to any related structural representation of formulas such as 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9, in some embodiments, R 9 is H or R 9 F, Cl, Br, I, amino, hydroxyl, C 1-6 C may be optionally substituted with an alkoxy or cyano group. 1-6 Hydrocarbil (C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenil, C 3-6 Cycloalkenyl, C 2-6 Alkinyl, C 3-6 These include cycloalkenyls, etc.

[0072] With respect to the representation of any related structure, in some embodiments, R 12 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 13 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 14 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 15H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 16 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 17 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 18 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 19 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 20 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 21 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 22 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 23 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 24 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 25 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 26 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 27 H is R 1-28 The remaining group is one of the relevant groups described above. In some embodiments, R 28 H is R 1-28 The remaining group is one of the related groups mentioned above.

[0073] With respect to any related structural representation of formulas such as 2A, 3A, 4A, 6A, 7A, 8, or 9, X is either CH or N. In some embodiments, X is CH. In some embodiments, X is N.

[0074] With respect to any related structural representation of formulas such as 1A, 1C, 2, 2A, 4, 4A, 6, 6A, or 8, n is 1, 2, or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0075] For some compounds represented by formulas 1A, 1B, or 1C: R 1 is an arbitrarily substituted C 1-6 Alkyl or optionally substituted C 3-10 It is a cycloalkyl group; A is optionally 1-4R 2 , (identical or different) substituted aryl, or optionally 1-3R 2 (The same or different) substituted heteroaryl; R 1a is H or COCH3; R 1b is H or CH3; R 1c is H, OH, or optionally substituted hydrocarbyl; Z is C(R 5 )2; W is C(R 6 ) is 2; m=1 or 2; n=0, 1, or 2; and R 4 is hydrogen or R 4 And, R in formulas 1, 1A, 1B, or 1C 3a , R 3b , R 3c , R 3d Each of these independently comprises H, or one or two identical or different R 7 C arbitrarily replaced by 1-6 Hydrocarbil, R 4 is H or CH3, R in formulas 1, 1A, 1B, or 1C 2 , R 5 , R 6 , R 7 Each of these independently, R8 F, Cl, Br, I, Cyano, -OR 8 , C 1-6 Hydrocarbyl, C 1-6 Alkoxy, SOR 8 SO2R 8 SO2NR 9 R 8 COR 8 CO2R 8 CONR 9 R 8 , NR 9 R 8 , NR 9 COR 8 , NR 9 SO2R 8 , NR 9 CO2R 8 , NR 9 CONR 8 OCOR 8 Selected from, C 1-6 Hydrocarbyl, C 1-6 Alkoxy, SOR 8 SO2R 8 SO2NR 9 R 8 COR 8 CO2R 8 CONR 9 R 8 , NR 9 R 8 , NR 9 COR 8 , NR 9 SO2R 8 , NR 9 CO2R 8 , NR 9 CONR 8 , or OCOR 8 These are each of them. R 8 and R 9 H or C 1-6 It is hydrocarbyl, C 1-6 Each of the hydrocarbyl compounds is F, Cl, Br, I, amino, hydroxyl, C 1-6 It may be optionally substituted with an alkoxy or cyano compound.

[0076] With respect to any related structural representation such as Formula 2 or Formula 2A, in some embodiments, R 1a is H or COCH3, and R 1b is H or CH3, and n is 1 or 2.

[0077] With respect to any related structural representation such as Equation 3, Equation 3A, or Equation 9, R 1a is H or COCH3, and R 1b It is either H or CH3.

[0078] With respect to any related structural representation such as Equation 6A, in some embodiments, X is CH or N, and if X is CH, R 2 At least one of them is not H.

[0079] With respect to any related structural representation such as Equation 7A, X is either CH or N, and if X is CH, then R 2 H is H.

[0080] With regard to any related structural representation such as Equation 7 or Equation 7A, R 1 This is a bicycloheptanyl that has been optionally substituted.

[0081] With respect to any related structural representation such as Equation 8, X is CH or N, and R 1a is H or COCH3, and R 1b is H or CH3, and n is 1 or 2.

[0082] With respect to any related structural representation such as Equation 1B, in some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0083] With respect to any relevant structural representation of formulas such as 1A, 1C, 2, 2A, 4, 4A, 6, 6A, or 8, n may be 1 or 2. In some embodiments, n may be 0, as in the compound represented by formula 1A or 1C. In some embodiments, n may be 3, as in the compound represented by formula 4 or 4A.

[0084] Some embodiments include one or more of the following: [ka] TIFF2026053649000026.tif55 [ka] [ka] [ka] [ka]

[0085] Some embodiments include optionally substituted 8-((2R)-bicyclo[2.2.1]heptan-2-yl)-2-((2-fluoro-4-(4-(3-hydroxypropyl)piperidine-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one; optionally substituted 8-((2R)-bicyclo[2.2.1]heptan-2-yl)-2-((3-fluoro-4-(4-(3-hydroxypropyl)piperidine-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one; optionally substituted 8-(( 8-((2R)-bicyclo[2.2.1]heptan-2-yl)-2-((4-(4-(3-hydroxybutyl)piperidine-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one; optionally substituted 8-((2R)-bicyclo[2.2.1]heptan-2-yl)-2-((4-(4-(3-hydroxybutyl)piperazine-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one; optionally substituted 8-((2R)-bicyclo[2.2.1]heptan-2-yl)-2-((4-(4-(2-H Droxypropoxy)piperidine-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one; optionally substituted 8-((2R)-bicyclo[2.2.1]heptan-2-yl)-2-((4-(piperazine-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one; optionally substituted 6-acetyl-8-((2R)-bicyclo[2.2.1]heptan-2-yl)-2-((4-(4-(3-hydroxypropyl)piperidine-1-yl)phenyl)amino)-5-methylpyrido[2,3-d ]pyrimidine-7(8H)-one; optionally substituted 6-acetyl-8-cyclopentyl-2-((4-(4-(3-hydroxypropyl)piperidine-1-yl)phenyl)amino)-5-methylpyrido[2,3-d]pyrimidine-7(8H)-one; or optionally substituted 6-acetyl-8-((2R)-bicyclo[2.2.1]heptan-2-yl)-5-methyl-2-((4-(piperazine-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one; or optionally substituted 8-((2R)-bicyclo[2.2.Contains 1]heptan-2-yl)-2-((4-(4-((3-(hydroxymethyl)oxetan-3-yl)methoxy)piperidine-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one.

[0086] The compounds of the subject may be used to treat disorders or diseases associated with CDK inhibitors. Treatment of disorders includes the diagnosis, treatment, mitigation, management, or prevention of disorders in humans or animals. In some embodiments, the disease is cancer. In some embodiments, the disease or disorder may include breast cancer, melanoma, renal cancer, squamous cell carcinoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, prostate cancer, colorectal cancer, esophageal cancer, head cancer, cervical cancer, neuroblastoma, myeloma, glioma, lymphoma, and leukemia.

[0087] Suitable additives for use in the subject composition may include, for example, one or more carriers, binders, fillers, vehicles, disintegrants, surfactants, dispersion or suspension aids, concentrators or emulsifiers, isotonic agents, preservatives, lubricants, etc., or combinations thereof, suitable for a specific dosage form. Remington Pharmaceutical Sciences, 16th Edition, EW Martin (Mack Press, Easton, Pa, 1980) discloses various carriers used in formulations of pharmaceutically acceptable compositions and known techniques for their preparation.

[0088] The subject composition may be formulated for any desired delivery route, including, but is not limited to, parenteral, intravenous, intradermal, subcutaneous, oral, inhalation, transdermal, topical, transmucosal, rectal, cisterna magna, vaginal, intraperitoneal, buccal, and intraocular.

[0089] Parenteral, intradermal, or subcutaneous formulations may be sterile, injectable aqueous or oily suspensions or solutions. Acceptable vehicles, solutions, suspensions, and solvents may include, but are not limited to, water or other sterile diluents; physiological saline; Ringer's solution; sodium chloride; fixative oils such as mono- or diglycerides; fatty acids such as oleic acid; polyethylene glycol; glycerin; propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfate; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and agents for adjusting tonicity such as sodium chloride or dextrose. pH can be adjusted with an acid or base such as hydrochloric acid or sodium hydroxide. Parenteral formulations may be sealed in ampoules, disposable glass or plastic syringes, or multi-dose vials.

[0090] Suitable pharmaceutical compositions for injectable use may include sterile aqueous solutions or dispersants and sterile powders for the immediate preparation of sterile injectable solutions or dispersants. Suitable carriers for intravenous administration include, but are not limited to, physiological saline, bacteriostatic water, CREMOPHOR EL® (BASF, Parsippani, NJ), or phosphate-buffered saline (PBS). Solvents or dispersion media may include, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersants, and by the use of surfactants. Prevention of microbial growth can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. Compositions may also include, for example, sugars; polyalcohols such as mannitol; or isotonic agents such as sodium chloride. The sustained absorption of injectable compositions can be improved by adding absorption-delaying agents, such as aluminum monostearate or gelatin.

[0091] Oral compositions may contain inert diluents or edible carriers. These may be encapsulated in gelatin capsules or compressed into tablets. Tablets, pills, capsules, lozenges, etc., may contain the following ingredients or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; flow enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0092] In addition to oral or injectable administration, systemic administration may also be by mucosal or transdermal means. For mucosal or transdermal administration, penetrating agents may be used. Such penetrating agents are commonly known in the art and include, for example, surfactants, bile salts, and fusidic acid derivatives. Transdermal administration may contain bioactive substances and can be formulated into ointments, gels, or creams, as is commonly known in the art. Mucosal administration may be done through the use of nasal sprays or suppositories.

[0093] The compound of the subject may be administered in a therapeutically effective dose according to an appropriate dose regimen. As understood by a skilled technician, the exact required dose may vary depending on the subject's species, age, and overall symptoms, the severity of the infection, the specific drug, and the method of administration. In some embodiments, to obtain the desired therapeutic effect, a pharmaceutical composition of about 0.01 mg / kg to about 50 mg / kg based on the subject's body weight is administered once or more daily. In other embodiments, to obtain the desired therapeutic effect, a pharmaceutical composition of about 0.001 mg / kg to about 25 mg / kg based on the subject's body weight is administered once or more daily.

[0094] The total daily dose of the compound in question can be determined by the attending physician within the bounds of normal medical judgment. The specific therapeutically effective dose level for a particular patient or subject depends on a variety of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's or subject's age, weight, overall health, sex, and diet; the timing of administration, route of administration, and elimination rate of the specific compound used; the duration of treatment; any drugs used in combination with or concurrently with the specific compound used; and other factors well known in the medical field.

[0095] In this specification, the following embodiments are specifically envisioned.

[0096] Embodiment 1. formula: [ka] A compound represented by, or a salt thereof, During the ceremony, R 1 is an arbitrarily substituted C 1-6 Alkyl or optionally substituted C 3-10 It is a cycloalkyl; R 1a is H or COCH3; R 1b is H or CH3; R 1c is H; A is an arbitrarily substituted aryl or an arbitrarily substituted heteroaryl; D is optionally substituted piperidine-1,4-yl or optionally substituted piperazine-1,4-yl; R 11 is R 8 , OR 8 SO2R 8 SO2NR 8 R 9 COR 8 CO2R 8 , or CONR 8 R 9 And R 8 and R9 These are independently H, or F, Cl, Br, I, amino, OH, C 1-6 -O-alkyl, cyano, or C 1-6 C optionally substituted with geminal-alkyl-O-alkyl- 1-6 It is hydrocarbil. A compound, or a salt thereof.

[0097] Embodiment 2. formula: [ka] A compound further represented by, or a salt thereof, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridine-2,5-yl, with the 2-position bonded to NH and the 5-position bonded to D; D is an optionally substituted piperidine-1,4-yl, with the 1-position bonded to A; R 1a is H or COCH3; R 1b is H or CH3; n is either 1 or 2. The compound of Embodiment 1, or a salt thereof.

[0098] Embodiment 3. formula: [ka] A compound further represented by, or a salt thereof, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridine-2,5-yl, with the 2-position bonded to NH and the 5-position bonded to D; D is an optionally substituted piperidine-1,4-yl, with the 1-position bonded to A; R 1a is H or COCH3; R 1b is H or CH3. The compound of Embodiment 1, or a salt thereof.

[0099] Embodiment 4. formula: [ka] A compound further represented by, or a salt thereof, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridine-2,5-yl, with the 2-position bonded to NH and the 5-position bonded to D; D is an optionally substituted piperidine-1,4-yl, with the 1-position bonded to A; n is 1, 2, or 3. The compound of Embodiment 1, or a salt thereof.

[0100] Embodiment 5. formula: [ka] A compound further represented by, or a salt thereof, During the ceremony, R 1 is an optionally substituted bicycloheptanyl; A is a optionally substituted p-phenylene; D is unsubstituted piperazine-1,4-yl. The compound of Embodiment 1, or a salt thereof.

[0101] Embodiment 6. formula: [ka] A compound further represented by, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridine-2,5-yl, with the 2-position bonded to NH and the 5-position bonded to D; D is an optionally substituted piperidine-1,4-yl, with the 1-position bonded to A; n is either 1 or 2. The compound of Embodiment 1.

[0102] Embodiment 7. formula: [ka] A compound further represented by, or a salt thereof, During the ceremony, R 1 is an optionally substituted bicycloheptanyl; A is an optionally substituted pyridine-2,5-yl, with the 2-position bonded to NH and the 5-position bonded to D, where D is an optionally substituted piperazine-1,4-yl; or, A is an optionally substituted phenyl compound, and D is an unsubstituted piperazine-1,4-yl compound. The compound of Embodiment 1, or a salt thereof.

[0103] Embodiment 8. R 1 The compound of Embodiments 1, 2, 3, 4, 5, 6, or 7, wherein is optionally substituted cyclopentanyl.

[0104] Embodiment 9. R 1 The compound of Embodiment 8, wherein is an unsubstituted cyclopentanyl.

[0105] Embodiment 10. R 1 The compound of Embodiments 1, 2, 3, 4, 5, 6, or 7, wherein is optionally substituted bicyclo[2.2.1]heptanyl.

[0106] Embodiment 11. R 1 The compound of Embodiment 10 is an unsubstituted bicyclo[2.2.1]heptanyl.

[0107] Embodiment 12. R 1a The compound of Embodiments 1, 2, 3, 8, 9, 10, or 11, wherein is H.

[0108] Embodiment 13. R 1a The compound of Embodiments 1, 2, 3, 8, 9, 10, or 11, wherein COCH3 is present.

[0109] Embodiment 14. R 1b The compound of Embodiments 1, 2, 3, 8, 9, 10, 11, 12, or 13, wherein is H.

[0110] Embodiment 15. R 1b The compound of Embodiments 1, 2, 3, 8, 9, 10, 11, 12, or 13, wherein is CH3.

[0111] Embodiment 16. Compounds of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein A is optionally substituted p-phenylene.

[0112] Embodiment 17. A is an unsubstituted p-phenylene compound of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0113] Embodiment 18. A is fluoro-p-phenylene, a compound of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0114] Embodiment 19. Compounds of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, in which D is optionally substituted piperidine-1,4-yl.

[0115] Embodiment 20. The compounds of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein D is unsubstituted piperidine-1,4-yl.

[0116] Embodiment 21. Compounds of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein D is optionally substituted piperazine-1,4-yl.

[0117] Embodiment 22. Compounds of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, in which D is unsubstituted piperazine-1,4-yl.

[0118] Embodiment 23. R 11 E-Hy is E, where E is the bond and C is the bond. 1-5 Alkylene, C 1-5 -O-alkylene, or [ka] The compounds of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, or 22, wherein Hy is OH or H.

[0119] Embodiment 24. E is an arbitrarily substituted C 1-5 The compound of embodiment 23, which is alkylene.

[0120] Embodiment 25. The compound of Embodiment 23, where E is (CH2)3-.

[0121] Embodiment 26. The compound of Embodiment 23, where E is (CH2)2CH(CH3)-.

[0122] Embodiment 27. E is C 1-5 The compound of Embodiment 23, which is an -O-alkylene.

[0123] Embodiment 28. The compound of Embodiment 23, where E is (CH2)CH(CH3)-.

[0124] Embodiment 29. E is [ka] The compound of Embodiment 23.

[0125] Embodiment 30. Compounds of Embodiments 23, 24, 25, 26, 27, 28, or 29, where Hy is OH.

[0126] Embodiment 31. The compound of embodiment 23, 24, 25, 26, 27, 28, or 29, wherein Hy is H.

[0127] Embodiment 32. [ka] [ka] A compound selected from or a salt thereof.

[0128] Embodiment 33. A pharmaceutically acceptable composition comprising the compound of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32.

[0129] Embodiment 34. A pharmaceutically acceptable dosage form comprising the compound of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32.

[0130] Embodiment 35. A method for treating a CDK inhibitor-related disorder, comprising administering an effective amount of the compound of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32.

[0131] Embodiment 36. The compound of Embodiment 35, wherein the aforementioned disorder is cancer.

[0132] Embodiment 37. Use of the compounds of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 in the manufacture of pharmaceuticals for the treatment of cancer.

[0133] Embodiment 38. The method or use of Embodiment 36 or 37, wherein the cancer includes breast cancer, kidney cancer, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, prostate cancer, colorectal cancer, esophageal cancer, head cancer, cervical cancer, or leukemia.

[0134] Embodiment 39. The method of embodiment 35 further comprises administering an additional therapeutic agent.

[0135] Embodiment 40. The method of Embodiment 39, wherein the further therapeutic agent is an antibiotic, antiemetic, antidepressant, antifungal, anti-inflammatory, antiviral, anticancer, immunomodulator, alkylating agent, or hormone.

[0136] (Experiment Section) (Reference substance) The control commercially available CDK inhibitors were obtained from Selleckchem: palbociclib (PD-0332991)-HCl (#S1116), abemaciclib (LY2835219) (#S7158), and ribociclib (LEE011) (#S7440). PD-0183812, RO-3306 (#217699), and roscovitine (#R7772) were obtained from WuXi AppTec, Merck Millipore, and Sigma Aldrich, respectively. All compounds were dissolved in 5 mM DMSO (Sigma Aldrich) (storage solution).

[0137] (Preparation of compounds) In the synthesis scheme described below, all temperatures are expressed in Celsius unless otherwise specified, and all values ​​are expressed in parts by weight and weight percent. Reagents and solvents were purchased from suppliers such as Aldrich Chemical Company and used without further purification unless otherwise specified. Tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) were purchased from Aldrich in Sure Seal bottles and used as is.

[0138] The reactions described below were typically carried out in anhydrous solvents at ambient temperature (unless otherwise specified), under positive pressure of argon or nitrogen. Glassware was oven-dried and / or heat-dried. Reactions were assayed by TLC and / or analyzed by LC-MS, and terminated based on the consumption of starting materials. Thin-layer chromatography (TLC) for analysis was performed on 60 F254 0.25 mm plates (EM Science), which are glass plates pre-coated with silica gel, and visualized by heating with UV light (254 nm) and / or with commercially available ethanolic phosphomolybdic acid. Preparative thin-layer chromatography (TLC) was performed on 60 F254 0.5 mm plates (20 × 20 cm, Thomson Instrument Company), which are glass plates pre-coated with silica gel, and visualized with UV light (254 nm).

[0139] Workup was typically performed by doubling the reaction volume with the reaction or extraction solvent, unless otherwise specified, followed by washing with a specified aqueous solution equivalent to 25% of the extracted volume. The product solution was dried with anhydrous Na₂SO₄ and / or Mg₂SO₄ before filtration and evaporation of the solvent under reduced pressure in a rotary evaporator, and recorded as the solvent removed under vacuum. Column chromatography was performed under positive pressure using 230–400 mesh silica gel.

[0140] 1 H-NMR spectrum and 13 ¹¹C-NMR spectra were recorded using a Varian Mercury-VX400 instrument operating at 400 MHz. NMR spectra were obtained as CDCl3 solutions (reported in ppm) using chloroform (7.27 ppm for protons, 77.00 ppm for carbon), CD3OD (3.4 and 4.8 ppm for protons, 49.3 ppm for carbon), DMSO-d6 (2.49 ppm for protons), or internal tetramethylsilane (0.00 ppm) as reference standards, as appropriate. Other NMR solvents were used as needed.

[0141] The compounds disclosed can be prepared using procedures known in the art. The reaction schemes below illustrate typical procedures, but those skilled in the art will recognize that other procedures may also be suitable for preparing these compounds. For example, those skilled in the art will recognize that any changes to the required reagents can be made at appropriate stages of the synthetic methods outlined below. Reactions may require monitoring of the consumption of starting materials, and there are many monitoring methods, including, but not limited to, thin-layer chromatography (TLC) and liquid chromatography-mass spectrometry (LCMS). Those skilled in the art will understand that any synthetic method specified in the examples shown below may be appropriately replaced by other, non-limiting methods.

[0142] In some embodiments, the pyrido[2,3-d]pyrimidine-7-one analogs described herein are prepared by general routes shown in schemes 1 and 2. As shown in scheme 1, commercially available 4-chloro-2-methylthio-5-pyrimidinecarboxylate ethyl ester (1) is condensed with a primary amine in triethylamine-containing THF to obtain the intermediate of structure 2. After reducing ester 2 to alcohol 3 using lithium aluminum hydride, reoxidation with MnO2 yields aldehyde 4. Reacting aldehyde 4 with (carbethoxymethylene)triphenylphosphorane in THF under reflux yields (E)-acrylic acid ester 5, which is not the target product. Heating this in the presence of DBU allows for convenient isomerization with ring closure to obtain the pyrido[2,3-d]pyrimidine core molecule 6. Oxidation of methyl sulfide in compound 6 with (+ / -)-trans-2-(phenylsulfonyl)-3-phenyloxaziridine or m-chloroperbenzoic acid yields the corresponding sulfoxide 7 or sulfone 8. The introduction of an amine to the C2-position is achieved by heating the sulfoxide or sulfone with two equivalents or more of an aromatic amine, etc., in or without a solvent at a temperature of 100°C to 175°C to obtain the general structure 9.

[0143] [ka]

[0144] As shown in Scheme 2, if step 1 of the synthesis is carried out with ammonium hydroxide, compound 14 can be produced in the same manner as the synthesis of compound 6 shown in Scheme 1. Intermediate 14 is oxidized with oxaziridine to form 15 and / or 16, which then react with an aromatic amine to produce analog 17, which is then alkylated with N8 by treatment with sodium hydride and alkyl halide to produce the target product 18. Alternatively, compound 14 is alkylated with N8 to obtain structure 6, which is then oxidized to 7 and / or 8, which is then treated with an amine to produce the target product 18.

[0145] [ka]

[0146] (Example 1) Examples of compounds can be prepared by some of these routes, which are detailed below. One example of the synthesis of PS004 is shown in Scheme 3 below.

[0147] [ka]

[0148] Step 1: Preparation of Compound 19 To a room temperature solution of ethyl 4-chloro-2-methanesulfanylpyrimidine-5-carboxylate (1) (1 equivalent) in tetrahydrofuran (approximately 0.3 M), triethylamine (3 equivalents) is added, followed by (1S,2S,4R)-bicyclo[2.2.1]heptan-2-amine (excess). The solution is stirred for approximately 30 minutes, then concentrated under vacuum and separated into chloroform and saturated aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate, filtered, and concentrated to obtain compound 19, which is used directly in the next step without further purification.

[0149] Step 2: Preparation of Compound 20 A solution of compound 19 (1 equivalent) in tetrahydrofuran (approximately 0.4 M) is added dropwise to a room temperature suspension of lithium aluminum hydride (1.6 equivalents) in tetrahydrofuran. After 10 minutes, the reaction is carefully quenched with water and 15% NaOH, and the mixture is stirred for approximately 1.5 hours. The white precipitate is removed by filtration and washed with ethyl acetate. The filtrate is concentrated under vacuum and 1:1 hexane:ethyl acetate is added. The solid is collected to obtain compound 20.

[0150] Step 3: Preparation of Compound 21 Add manganese oxide (approximately 7 equivalents) to compound 20 (1 equivalent) in chloroform (approximately 0.05 M). Stir the suspension at room temperature for approximately 2 hours, then add manganese oxide (approximately 2 equivalents). Continue stirring for approximately 4-5 hours. Filter the mixture through Celite and wash with chloroform. Concentrate the filtrate under vacuum to obtain compound 21.

[0151] Step 4: Preparation of Compound 22 To a room temperature solution of compound 21 (1 equivalent) in tetrahydrofuran (approximately 0.3 M), (carbetoxymethylene)triphenylphosphorane (1.3 equivalents) is added. The reaction mixture is heated under reflux for approximately 70 minutes. The reaction mixture is concentrated under vacuum, and the residue is purified by flash chromatography eluting with ethyl acetate to obtain compound 22.

[0152] Step 5: Preparation of Compound 23 To a solution of compound 22 (1 equivalent) in N,N-diisopropylethylamine (7 equivalents) at room temperature, 1,8-diazabicyclo[5.4.0]undes-7-ene (1.15 equivalents) is added. The reaction mixture is heated overnight under reflux and then cooled to room temperature. The resulting solid is collected by filtration and washed with 1:1 hexane:ethyl acetate to obtain compound 23. The filtrate is concentrated under vacuum, and hexane is added to form a solid, which is collected, washed with hexane, and purified by flash chromatography with ethyl acetate elution to obtain an additional amount of the title product 23.

[0153] Step 6: Preparation of Compound 25 To a room temperature solution of compound 23 (1 equivalent) in chloroform (0.1 M), (+ / -)-trans-2-(phenylsulfonyl)-3-phenyloxaziridine (1.2 equivalents) is added. The solution is stirred overnight at room temperature, and then concentrated under vacuum. The residue is treated with ethyl acetate to obtain a solid, which is recovered by filtration and washed with ethyl acetate to obtain compound 25.

[0154] Step 7: Preparation of PS004 To compound 25 (1 equivalent), more than 1 equivalent of amine 27 is added, and the reaction mixture is heated at 100°C to 175°C for less than 1 hour. In a typical workup, the cooled reaction mixture is diluted with ethyl acetate and then washed with aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate, filtered, and evaporated to dry. The crude product is purified by crystallization from ethyl acetate and hexane, or by silica gel chromatography, to obtain the target product PS004.

[0155] Other analog compounds such as PS002, PS003, PS005, PS006, PS007, PS016, and other compounds described herein can be similarly prepared, for example, using some optionally substituted reagents shown below, which are either commercially available or synthesized using synthetic methods available in the art. In some cases, protection and deprotection of certain groups of the reagents are required during synthesis.

[0156] [ka]

[0157] For example, one of the aromatic amines mentioned above can be prepared or purchased as shown in Scheme A below. In this case, Boc-protected substituted aniline (4-(4-aminophenyl)piperazine-1-carboxylate tert-butyl) is used as a reagent during synthesis, and the Boc-protecting group is removed after synthesis. Other substituted anilines can be prepared similarly using appropriate reagents.

[0158] [ka]

[0159] In some embodiments, the pyrido[2,3-d]pyrimidine-7-one analogs described herein are prepared by general routes described in Schemes 4, 5, and 6. As shown in Scheme 4, compound 29 can be prepared by treating compound 4, which can be made according to the method described in Scheme 1, with reagent 28. Compound 30 can be prepared by oxidizing the hydroxyl group of compound 29 to a ketone. Oxidation of the methyl sulfide in compound 30 with oxaziridine yields the corresponding sulfoxide or sulfone, which, when substituted with an amine under heating conditions, forms compound 31. The C5-C6 double bond of the pyrido[2,3-d]pyrimidinone ring system can be introduced by treating the ketone at the C5 position of the substituted 4-aminopyrimidine 31 with reagent 32, along with similar chemical reactions such as Wittig, Horner-Wadsworth-Emmons, Kneefenagel, or enolate anion chemistry.

[0160] [ka]

[0161] These reactions proceed under conditions well known to those skilled in the art, using appropriate bases such as NaH, NaOEt, LDA, BuLi, and HMDS. If the double bond configuration is such that the pyrimidine ring and ester group are in a cis relationship with respect to the newly formed double bond, cyclization to form the target product 33 usually occurs spontaneously under the reaction conditions. Otherwise, it may be necessary to accelerate cyclization by gently heating to a temperature below 100°C in a suitable organic solvent. If the double bond configuration is such that the pyrimidine and ester are in a trans relationship with respect to the double bond, cyclization occurs, for example, by heating to a temperature between 100°C and 200°C in DBU, or by isomerization of the double bond by treatment with a radical source such as iodine and UV light under conditions well known to those skilled in the art. The order of ring formation and side chain introduction may be reversed, as shown in Scheme 5 below.

[0162] [ka]

[0163] Alternatively, the synthesis of the compounds of this disclosure, as shown in Scheme 5, proceeds via a substituted 2-chloropyrimidine intermediate 34, which can be prepared using methods known in the art. Compound 35 is prepared by a Wittig, Horner-Wadsworth-Emmons, Kneefenagel reaction between the ketone at the C5 position of 34 and reagent 32, followed by the spontaneous ring closure described above. The introduction of the C2 side chain of compound 35 proceeds typically by catalyst with [(t-Bu)2P(OH)]2PdCl2(POPd), Pd(OAc)2, or Pd2dba3 and a suitable ligand such as BINAP, xanthophos, or a similar phosphine-based Pd ligand, to produce the target product 33.

[0164] [ka]

[0165] Another alternative route for preparing the compounds of this disclosure, as shown in Scheme 6, may proceed through intermediate 31, which can be prepared as described above. Treatment of compound 31 with reagent 36 via the Wittig, Horner-Wadsworth-Emmons, Kneefenagel reaction, and spontaneous ring closure can form pyrido[2,3-d]pyrimidinone 37 without substitution at the C6 position. The introduction of Br to the C6 position of 37 can be achieved by treatment with NBS, forming 38. Compound 40 can be formed by a Still coupling reaction with compound 38 using reagent 39 and a catalyst, which can then be treated with HCl to form a ketone substituent at the C6 position, yielding the target product 41. The Still reaction of Scheme 6 is typically carried out under palladium catalysis using reagents such as Pd(OAc)2, Pd2(dba)3, or Pd(PPh3)4, and PdC12(PPh3)2. Typical solvents include dimethoxyethane, tetrahydrofuran, acetonitrile, and toluene, and the reaction may be heated to a temperature in the range of 100–200°C.

[0166] [ka]

[0167] (Example 2) Examples of compounds can be prepared using some of the routes described above. An example of the synthesis of PS009 is shown in Scheme 7 below.

[0168] Starting with commercially available compound 1, Cl is substituted with amine 42 to obtain compound 43. The ester group of 43 is then reduced to a hydroxyl group to form 44. The hydroxyl group of 44 is then oxidized to an aldehyde group to form 45. The aldehyde of 45 is then converted to a ketone via a two-step synthesis to form 48. Compound 48 can be converted to 49 via the Wittig, Horner-Wadsworth-Emmons, Kneefenergel reaction and spontaneously occurring ring closure. After introducing Br at the C6 position of 49 to form 50, the methyl sulfide group of 50 is then oxidized with reagent 24 to form a sulfoxide and / or sulfone, which is then substituted with amine 53 to form 54. Compound 54 can be converted to 55 via Still coupling with reagent 39 in the presence of a palladium catalyst such as Pd(PPh3)4. Finally, treatment of 55 with HCl yields the desired compound PS009.

[0169] [ka]

[0170] Other compounds described herein, such as PS008 and PS010, can be similarly prepared using appropriate reagents and the method described in Scheme 7. In some cases, protection and deprotection of specific groups of reagents may be required during synthesis.

[0171] (Biological assay and test results) (Cell lines and cell cultures) The following human tumor cell lines were all retinoblastoma (Rb)-proficient and used in this study: MDA-MB231 (breast cancer), MDA-MB453 (breast cancer), U87MG (glioblastoma), and H460 (lung cancer). Rb-deficient cells MDA-MB468 (breast cancer) and SW1783 (glioblastoma) were also included in this study, as were the MCF10A untransformed mammary epithelial cell lines. Tumor cell lines were maintained in DMEM or PRMI-1640 medium supplemented with 10% FBS, depending on the cell line. MCF10A cells were grown in complete mammary epithelial growth medium (MEGM, Lonza). Cell lines were identified by short tandem repeat (STR) gene profiling using the GenePrint® 10 System (Promega).

[0172] (Kinase profiling) Kinase profiling of compounds was performed using 27 types of protein kinases. For each compound, IC was performed. 50 A 200 μM stock solution (5 mM) in 100% DMSO was prepared as the highest concentration (50 μM) 100× stock solution for use in determining the following: Semi-logarithmic dilutions were performed stepwise, and 27 kinases were tested in single runs: AKT1, CDC7 / DBF4, CDK1 / CycA2, CDK1 / CycB1, CDK1 / CycE1, CDK12 / CycK, CDK19 / CycC, CDK2 / CycA2, CDK2 / CycE1, CDK3 / CycC, CDK3 / CycE1, CDK4 / CycD1, CDK4 / CycD3, CDK5 / p25NCK, CDK5 / p35NCK, CDK6 / CycD1, CDK6 / CycD3, CDK7 / CycH / MAT 1, CDK8 / CycC, CDK9 / CycK, CDK9 / CycT1, DYRK1A, DYRK2, ERK1, HIPK2, PCTAIRE1 / CycY, PIM1. I C 50 The values ​​are summarized in Table 1 below. Lower IC 50 The value correlates with a higher binding affinity between the kinase and the compound.

[0173] [Table 1-1] [Table 1-2]

[0174] As shown in Table 1, most of the tested compounds showed high affinity for CDK and CDK6, and some of them (PS008, PS009, and PS016, etc.) showed even greater affinity for CDK1 / 2. PS006, PS0010, and PS016 also showed affinity for CDK5. PS005 and PS007 appear to bind to many other members of the CDK family.

[0175] (Cell culture, GI50, and cell proliferation analysis) All human cancer cell lines (Table 2) were obtained from a US cell culture preservation institution and maintained in DMEM (Hyclone) or RPMI-1640 medium (Sigma) supplemented with 10% fetal bovine serum (Sigma). Untransformed MCF10 cell lines were maintained in MEGM mammary epithelial cell proliferation medium (Lonza). Immortalized mouse embryonic fibroblasts (MEFs) were maintained in DMEM supplemented with 10% fetal bovine serum.

[0176] [Table 2]

[0177] (Growth assay: GI) 50 Determining the value) GI 50To determine the 50% growth inhibitory concentration, cells were seeded in 96-well plates at 20–40% confluence (10,000–20,000 cells / well, pre-optimized for each cell line) and treated with 11 inhibitor concentrations ranging from 10 μM to 0.033 μM. After 48 hours, cells were fixed with 4% PFA for 15 minutes, then fixed with 10 μg / ml Hoechst3334 (Molecular Probes, Thermo Fisher) for 30 minutes, and washed twice with PBS. Cells were imaged using a high-content screening system (Opera Phoenix®, Perkin Elmer) with a 20X dry objective lens (30 fields / well). Cell counts were determined using Opera software (Perkin Elmer), and data were further processed with SPSS software. GI 50 This involves using Prism6 (Graphpad Software Inc.), a dose-response inhibitory tool, to perform IC (Intracytocorticosteroid) testing. 50 It was calculated by estimating the absolute value of [the variable].

[0178] Cdk-deficient MEF cells were seeded in a 3-row configuration in a 10cm dish (100,000 cells / well), and the GI was determined in advance using the MDA-MB-231 cell line. 50 The cells were treated with a selected compound at a specified concentration based on the given criteria. At 3 and 6 days post-treatment, cells were counted using a light microscope to estimate relative cell proliferation under each condition.

[0179] For a detailed comparison of the antiproliferative effects of PS009 and palbociclib, several breast cancer cell lines were subjected to both inhibitors, with each GI being measured. 50 Cells were treated for 6 days (determined using the MDA-MB-231 cell line as a reference). Relative cell proliferation was calculated on day 6 by counting the number of treated cells versus cells treated with the vehicle (DMSO).

[0180] (The compound in question inhibits the proliferation of human cancer cell lines.) The cell proliferation inhibition of the subject compounds was tested in several human cancer cell lines and with wild-type retinoblastoma protein: MDA-MB-231 (breast cancer), U87-MG (glioblastoma), H460 (lung cancer); and MCF10 (as an example of non-transformed human cells) and mutant cells. Table 3 shows the proliferation inhibitory concentration (GI) required for a 50% reduction in proliferation of the compounds tested in this set of human cancer cell lines. 50 This is a summary of the findings. As shown in Table 3, most of the subject compounds, with the exception of PS002, suppressed cell proliferation with comparable efficacy to clinically known CDK4 / 6 inhibitors such as palbociclib, ribociclib, abemaciclib, RO-3306, or PD-0183812 (reference compound).

[0181] [Table 3]

[0182] (Cell cycle analysis) The cells were grown in a 6cm dish, and the indicator compound was applied to the GI. 50 Cells were treated at the specified concentration for 24 hours. Cells were harvested by trypsin treatment, washed with PBS, and fixed with cooled 70% ethanol. The cells were treated with 250 μg / ml RNase (Qiagen) at 37°C for 30 minutes and stained with 10 μg / ml propidium iodide (Sigma). The cell cycle was analyzed by flow cytometry using an LSR Fortessa Analyzer. Cell cycle profiles were created and analyzed using FlowJo software.

[0183] (Flow cytometry) After treatment with the indicator compound, cells were collected by several trypsin treatments and then fixed with cooled 70% ethanol. DNA content was determined by staining with propidium iodide (10 μg / ml, Sigma Aldrich). Data collection was performed using an LSR Fortessa analyzer (BD Biosciences), and analysis was performed using FlowJo and WEAR.

[0184] Current CDK4 / 6 inhibitors suppress cell proliferation by inhibiting cell entry into the S phase. Cell cycle analysis based on DNA content revealed robust G0 / G1 phase arrest in cells treated with palbociclib, ribociclib, or abemaciclib, consistent with suppression of CDK4 / 6 activity (Figure 1). On the other hand, PD-0183812 arrested cells with 4N DNA content, suggesting mitotic defects leading to G2 / M arrest or tetraploidy. PS008 and PS009 induced cell accumulation in G0 / G1, similar to CDK4 / 6-specific inhibitors, while other PS compounds such as PS003, PS006, or PS016 induced G2 / M arrest, as detected by 4N DNA content. PS004, PS005, PS007, and PS010 exhibited a mixed phenotype, causing cell accumulation in both G1 and G2 / M phases. Several compounds, including PS005, PS007, and PS010, induced cell death, as indicated by increased sub-G1 accumulation (Figure 1).

[0185] (Aging assay) MDA-MB-231 cells were seeded in 6-well plates (65,000 cells / well), and each GI was treated with the selected compound. 50 Cells were treated with [method / component name]. On days 3, 7, and 14 after treatment, cells were stained overnight at 37°C with Senescence β-Galactosidase Staining Kit (Cell Signaling). Blue-stained senescent cells were counted under a light microscope. The culture medium and compound were replaced every 3 days.

[0186] Cell cycle arrest can be irreversible in cases of senescence induction. Cellular senescence is defined by several non-exclusive features, including flattened cell morphology, positive staining of senescence-associated beta-galactosidase (SA-βGAL) at pH 6.0, DNA damage, and specific secretory phenotypes. To test senescence induction by the compounds of the subject, MDA-MB-231 cells were stained with SA-βGAL after short-term (3 days) or long-term (14 days) exposure to various inhibitors. As shown in Figures 2 and 3, PD-0183812, PS003, PS006, PS008, and PS009, among others, induced high levels of SA-βGAL staining indicating senescence with high efficiency compared to the reference CDK4 / 6 inhibitor.

[0187] (Antibodies and immunoblotting) MDA-MB-231 and MDA-MB-468 cells are GI-based on the MDA-MB-231 cell line. 50 The cells were treated with indicator compounds using [a specific method] and dissolved in Laemmli buffer (60 mM Tris-Cl pH 6.8, 10% glycerol, 2% SDS) after 48 hours. Protein concentrations were determined using the BCA method (Pierce). Whole cell lysates (25 μg) were separated on TGX Criterion 4-15% Bis-Tris acrylamide gel (BioRad), transferred to nitrocellulose membranes (BioRad), and probed using the following specific antibodies: Sigma Aldrich β-actin; Millipore phosphorylated histone H3 (Ser10); BD Pharmingen retinoblastoma; Cell Signaling phosphorylated Rb (S807 / 811) and cyclin B; and Santa Cruz Biotechnology cyclin A, p21, and FOXM1.

[0188] (The compound in question does not depend solely on CDK4 / 6 activity.) As shown in Table 1 above, most compounds bind with high affinity to CDK4 / 6, in addition to other CDKs, including CDK2. To further investigate the relative functional dependence of the compounds in question on CDK2 versus CDK4 or CDK6, the specific effects of PS004, PS006, and PS009 were tested in CDK-deficient mouse embryonic fibroblasts (MEFs) obtained from Cdk2 knockout, Cdk4;Cdk6 double knockout, and Cdk2;Cdk4;Cdk6 triple knockout mice. Figure 4 shows the relative cell numbers in MEF cultures after exposure to various compounds. The reference compound palbociclib did not reduce cell proliferation in Cdk4;Cdk6 double knockout cells, suggesting that its antiproliferative effect is strongly dependent on CDK4 / 6 activity (green column in Figure 4). The compound in question, however, effectively inhibited cell proliferation in Cdk4;Cdk6-deficient cells (green column) and suppressed Cdk2;Cdk4;Cdk6 triple mutant cells (purple column) to some extent, suggesting that its activity is somewhat dependent on CDK2 and other related kinases.

[0189] CDK4 / 6 kinases drive cell cycle progression by phosphorylating retinoblastoma protein (pRB), thereby releasing its repressive activity against transcription. Therefore, in pRB-deficient cells, cell cycle transcription is induced independently of CDK4 / 6 activity, rendering CDK4 / 6-specific inhibitors ineffective. We evaluated the extent to which the compound in question depends on the presence of functional pRB. Two sets of human cancer cell lines, representing breast cancer and glioblastoma, were tested, one with pRB wild-type and the other with pRB deficiency. As expected, when comparing pRB-mutant cells with cells possessing pRB function, palbociclib showed GI in both brain tumors (19.9 vs. 5.7 μM) and breast cancer (9.5 vs. 1.7 μM), as shown in Table 4 below. 50A significant increase was observed. PS004 was also less efficient in pRB-deficient glioblastoma cells, but showed comparable efficacy when comparing pRB-deficient and pRB wild-type breast cancer cells. Finally, PS006 and PS009 were equally effective in pRB-deficient or highly pRB-active brain tumor and breast cancer cells, suggesting that they are independent of the presence of this tumor suppressor. Consistent with these data, DNA content analysis showed that most compounds efficiently terminated pRB-deficient tumor cells in G2 / M(4N) cells, suggesting that these subject compounds may target other G0 / G1-independent activities in cells with inhibited G1 checkpoints.

[0190] [Table 4]

[0191] Palbociclib is known to exert a more potent antiproliferative effect in lumen-like cells compared to non-lumen breast cancer cell lines, which is thought to be due to the presence of active pRB signaling in lumen cells, thereby inducing a strong dependence on CDK4 / 6 activity. Therefore, we tested whether the target compound has a broad inhibitory range in a panel of breast cancer cell lines compared to known CDK4 / 6 inhibitors. Figure 5 shows the relative cell proliferation 5 days after treatment with palbociclib or PS009 in a panel of both lumen-like (ZR75-1, T47D, and MCF7) and non-lumen (HCC1143, MDA-MB-231, BT549, MDA-MB-468) human breast cancer cell lines. Two of the four non-lumen cell lines were resistant to palbociclib, consistent with pRB mutations in these cells. However, PS009 was able to efficiently inhibit both lumen and non-lumen breast cancer cells, including pRB-mutated lumen cells. This indicates that PS009 has a broader range than palbociclib, a known CDK4 / 6 inhibitor, and that it does not depend on the functional pRB pathway to produce its antiproliferative effect.

[0192] Furthermore, cyclins A and B, FOXM1, and the cell cycle inhibitor p21 Cip1 The levels of various proteins involved in cell cycle progression, such as pRB (serine 807) and histone H3 (serine 10), and their phosphorylation status were biochemically evaluated. As shown in Figure 6, treatment with PS009 and palbociclib (or simply "parvo") induced potent inhibition of pRB phosphorylation and reduced the levels of most cell cycle markers, while other compounds did not produce such dramatic defects.

[0193] (In vivo evaluation of selected compounds) For histological analysis, mouse tissues and human xenografts were fixed in 10% buffered formalin (Sigma) and embedded in paraffin wax. Sections 3 or 5 μm thick were stained with hematoxylin and eosin. Further immunohistochemical analysis was performed using specific antibodies against phosphorylated Rb (Ser807 / 811; Cell Signaling) or Ki67 (DAKO).

[0194] (Tumor xenograft) Thymus-deficient nude mice (6-week-old females provided by Harlan Laboratories / ENVIGO) were given 5 × 10 in 100 μl PBS-0.1% glucose. 6 Individual MDA-MB-231 cells were subcutaneously injected into both flanks. Approximately two weeks after the injection, the tumor had grown to 100 mm. 3When the mice reached a certain stage, they were randomly assigned to six different treatment groups (8 mice / group): DMSO (vehicle for PS compounds), PS004, PS006, PS009, lactate buffer (vehicle for palbociclib), and palbociclib. DMSO, PS004, PS006, and PS009 were diluted with sesame oil and administered intraperitoneally at 100 mg / kg twice weekly for two weeks. Palbociclib was dissolved in lactate buffer (50 mM sodium lactate, pH 4) and delivered orally at 100 mg / kg every five days / week, followed by a two-day rest period, which was repeated for 12 days. Tumor growth was monitored using a calipas analyzer, and tumor size was estimated using the following formula: tumor volume (mm²). 3 ) = d²·D / 2, where d and D are the minimum and maximum diameters (mm), respectively. After processing, mice were sacrificed, the tumors were excised, weighed, and fixed for histological analysis.

[0195] (statistical analysis) Statistical analysis was performed using Prism6 (Graphpad Software Inc.). All statistical tests on comparative data were performed using two-sided, unpaired Student's t-tests or ANOVA for difference comparisons between two or more groups. Data with p<0.05 are considered statistically significant (*, p<0.05; **, p<0.01; ***, p<0.001).

[0196] (Efficacy of the subject compound) For in vivo evaluation, we first examined the in vivo target involvement of the subject compound. Phosphorylated RB staining in bone marrow, intestine, and spleen showed clear in vivo RB target inhibition, particularly after treatment with PS004 and PS009 (Figure 7).

[0197] Subsequently, the therapeutic effects of the subject compounds were tested by treating mice that had been pre-injected subcutaneously with MDA-MB-231 breast cancer cells. Palbociclib (oral administration) was used as a reference, and when tumors were identified, the subject compounds PS004, PS006, and PS009 were administered intraperitoneally. The doses of 100 mg / kg in these cases were administered twice a week for a total of two weeks of treatment. During the two weeks of treatment, the subject compound PS004 and the reference compound palbociclib significantly reduced tumor growth and tumor weight compared to their respective controls (Figures 8A and 8B), while compounds PS006 and PS009 did not produce an antitumor effect, as determined by gastric-ply tumor polyploidy and final tumor weight.

[0198] Biomarker analysis revealed that both PS006 and palbociclib significantly reduced phosphorylated RB levels in xenografts, while PS004 and PS009 also reduced phosphorylation of phosphorylated Rb, though not statistically significant (Figure 9A). Furthermore, treatment with PS004 or palbociclib slightly reduced Ki67 levels, but these data were not statistically significant (Figure 9B).

[0199] (Solubility and stability of the subject compound) Considering that the activity observed in vivo for several subject compounds was generally low or absent, the solubility and stability of these compounds were tested in vivo. As shown in Table 5, palbociclib is generally soluble and stable in vivo, while the subject compounds show clear deficiencies in their formulations to maintain good solubility or stability in vivo. In particular, PS006 and PS009 are highly unstable and insoluble, which may explain their low activity in vivo.

[0200] Therefore, the low activity or lack of activity observed in vivo for some of the subject compounds tested is thought to be due to their low solubility and / or low stability. Consequently, in vivo evaluation of such compounds with current formulations is difficult. It is also thought that other formulations, such as combinations with cyclodextrins, may improve the solubility and / or stability of the subject compounds, potentially leading to favorable or superior efficacy in vivo.

[0201] [Table 5]

[0202] (In vivo toxicity assessment) For toxicity studies, thymus-deficient nude mice (6-week-old females provided by Harlan Laboratories / ENVIGO) were treated with either a vehicle (DMSO) or PS compounds (PS004, PS006, and PS009). The stock solution was diluted to 10 mg / ml with sesame oil and administered intraperitoneally twice a week at two doses (50 or 100 mg / kg) for a period of two weeks (3 mice / group). After treatment, the mice were sacrificed, weighed, and several tissues (lungs, intestines, bone marrow, and spleen) were excised and fixed in 10% buffered formalin for histological examination. Blood cell counts were analyzed using differential hematology analyzers (Abacus, Diatron).

[0203] To evaluate the toxicity of the selected compounds, healthy female thymus-deficient nude mice were first intraperitoneally injected with PS004, PS006, PS009, and PD-0183812 (50 mg / kg or 100 mg / kg each) twice a week for two weeks, and various parameters were measured at the endpoint. The reference compound PD-0183812 induced significant weight loss and decreased total leukocyte or lymphocyte levels compared to the control DMSO (Figure 10). PS009 caused weight loss but no abnormalities in blood cell counts, while PS004 decreased lymphocyte counts but no other significant changes. Both PD-0183812 (6 out of 6 mice) and lower doses of PS004 (4 out of 6 mice) induced pulmonary toxicity, resulting in massive pulmonary hemorrhage. PS006 and PS009 induced pulmonary hemorrhage with edema in 1 out of 6 mice tested for each compound. Further histopathological analysis revealed abnormal mitotic figures in the intestines and hypoplasia / reactivity of the bone marrow in PD-0183812 and PS004-treated mice, as well as active extramedullary hematopoiesis in the spleen of PD-0183812, PS004, or PS006-treated mice.

[0204] (Advantages of the compound in question) Inhibition of CDK4 / 6 offers significant therapeutic potential in hormone-positive, HER2-negative advanced breast cancer, and recently, three specific inhibitors have been approved for clinical use. However, these inhibitors have been relatively ineffective in hormone-negative breast cancer tumors, and their potential use in other tumor types is still in the preclinical or clinical evaluation stage. Because the CDK family consists of 20 different kinases, and complementary roles are expected among different family members, the application of inhibitors that specifically inhibit CDK4 / 6 may be limited.

[0205] The series of subject compounds described herein exhibit relative specificity to CDK4 / 6 kinases and significant in vitro efficacy, similar to that achieved by known CDK4 / 6 inhibitors such as palbociclib. Furthermore, some of the subject compounds can conjugate to other relevant CDKs, such as CDK2 or CDK9, for which therapeutic potential has been proposed in certain situations. Specific inhibitors such as palbociclib and ribociclib are used in combination with hormone therapy to treat breast cancer, while abemaciclib, a CDK4 / 6 inhibitor that may also have activity in CDK9, is effective as monotherapy. Among the subject compounds, PS004 has a high potential to inhibit cell proliferation and arrest cells in the G1 / G2 / M phase of the cell cycle, and exhibits affinity not only for CDK4 / 6 but also for CDK2 / 9. This property opens up a novel and unexplored mechanism of action for CDK inhibitors, distinct from the commercially available CDK4 / 6 inhibitors palbociclib, abemaciclib, and ribociclib. PS006 induced higher senescence compared to its counterparts, showed high affinity for CDK6 / 2 / 5 / 9, arrested cells in the G2 / M phase, and caused potent inhibition of cell proliferation. PS009 arrested cells primarily in the G1 phase, showed very high SA-BGAL induction, and primarily bound to CDK4 / 6, but also showed interesting preference for other CDKs, including CDK2 and CDK9. Interestingly, some of these compounds were effective in inhibiting tumor cell proliferation in pRB mutant cells, further suggesting that their activity is not solely dependent on CDK4 / 6 kinases. In line with these findings, the subject compounds PS004, PS006, and PS009 were effective in inhibiting cell proliferation in Cdk4:Cdk6 double mutants or Cdk4:Cdk6:Cdk2 triple mutants, while the reference compound palbociclib showed no activity in those cells. Furthermore, PS009, rather than palbociclib, was able to inhibit the proliferation of non-luminal pRB-mutated breast cancer cell lines. These unique properties suggest that the subject compounds described herein may offer significant therapeutic potential.

[0206] Unless otherwise specified, all figures representing quantities such as ingredient amounts, molecular weights, and reaction conditions used in the specification and claims should be understood in all cases to be approximate. Therefore, unless otherwise indicated, the numerical parameters shown herein and in the appended claims are approximations that may vary depending on the desired properties to be obtained. At the very least, without attempting to limit the application as equivalents to the claims, each numerical parameter should be interpreted, at least in light of the number of significant figures reported, by applying ordinary rounding methods.

[0207] The terms “a,” “an,” “the,” and similar references used in the context describing the present invention (particularly in the context of the following claims) should be construed to cover both singular and plural forms unless otherwise stated or unless clearly contradicted by the context. All methods described herein may be performed in any suitable order unless otherwise stated herein or unless clearly contradicted by the context. All embodiments or use of exemplary language (e.g., “like”) provided herein are intended to better illustrate the present invention and not to limit the scope of the claims. Nothing described herein should be construed to indicate non-claimed elements essential to the practice of the present invention.

[0208] The grouping of alternative elements or embodiments disclosed herein should not be construed as limitation. Each group's components may be referenced and claimed individually or in any combination with other components of the group or other elements found herein. For convenience or patentability reasons, it is anticipated that one or more components of a group may be included in or removed from the group. If such inclusion or removal occurs, this specification shall be deemed to include the modified group and shall satisfy all descriptions of the Markush group used in the appended claims.

[0209] This specification describes several embodiments, including the best mode for carrying out the invention as known to the inventor. Of course, variations of these described embodiments will be obvious to those skilled in the art by reading the preceding description. The inventor expects those skilled in the art to use such variations appropriately, and the inventor intends to carry out the invention in ways other than those specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter described in the claims, as permitted by applicable law. Furthermore, unless otherwise stated herein, or unless it is clearly inconsistent with the context, any combination of the above elements in any conceivable variation is assumed.

[0210] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be adopted are within the scope of the claims. Therefore, alternative embodiments can be utilized in accordance with the teachings herein, not as limitations but as examples. Accordingly, the claims are not strictly limited to the embodiments shown and described.

[0211] (Note) (Note 1) formula: [ka] A compound represented by, or a salt thereof, During the ceremony, R 1 is an arbitrarily substituted C 1-6 Alkyl or optionally substituted C 3-10 It is a cycloalkyl; R 1a is H or COCH3; R 1b is H or CH3; A is an arbitrarily substituted aryl or an arbitrarily substituted heteroaryl; D is optionally substituted piperidine-1,4-yl or optionally substituted piperazine-1,4-yl; R 11R 8 , OR 8 SO2R 8 SO2NR 8 R 9 COR 8 CO2R 8 , or CONR 8 R 9 And R 8 and R 9 These are independently H, or F, Cl, Br, I, amino, OH, C 1-6 -O-alkyl, cyano, or C 1-6 C optionally substituted with geminal-alkyl-O-alkyl- 1-6 It is hydrocarbil. A compound, or a salt thereof.

[0212] (Note 2) formula: [ka] A compound further represented by, or a salt thereof, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridine-2,5-yl, with the 2-position bonded to NH and the 5-position bonded to D; D is an optionally substituted piperidine-1,4-yl, with the 1-position bonded to A; R 1a is H or COCH3; R 1b is H or CH3; n is either 1 or 2. The compounds listed in Appendix 1, or their salts.

[0213] (Note 3) formula: [ka] A compound further represented by, or a salt thereof, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridine-2,5-yl, with the 2-position bonded to NH and the 5-position bonded to D; D is an optionally substituted piperidine-1,4-yl, with the 1-position bonded to A; R 1a is H or COCH3; R 1b is H or CH3. The compounds listed in Appendix 1, or their salts.

[0214] (Note 4) formula: [ka] A compound further represented by, or a salt thereof, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridine-2,5-yl, with the 2-position bonded to NH and the 5-position bonded to D; D is an optionally substituted piperidine-1,4-yl, with the 1-position bonded to A; n is 1, 2, or 3. The compounds listed in Appendix 1, or their salts.

[0215] (Note 5) formula: [ka] A compound further represented by, or a salt thereof, During the ceremony, R 1 is an optionally substituted bicycloheptanyl; A is a optionally substituted p-phenylene; D is unsubstituted piperazine-1,4-yl. The compounds listed in Appendix 1, or their salts.

[0216] (Note 6) formula: [ka] A compound further represented by, or a salt thereof, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridine-2,5-yl, with the 2-position bonded to NH and the 5-position bonded to D; D is an optionally substituted piperidine-1,4-yl, with the 1-position bonded to A; n is either 1 or 2. The compounds listed in Appendix 1, or their salts.

[0217] (Note 7) formula: [ka] A compound further represented by, or a salt thereof, During the ceremony, R 1 is an optionally substituted bicycloheptanyl; A is an optionally substituted pyridine-2,5-yl, with the 2-position bonded to NH and the 5-position bonded to D, where D is an optionally substituted piperazine-1,4-yl; or, A is an optionally substituted phenyl compound, and D is an unsubstituted piperazine-1,4-yl compound. The compounds listed in Appendix 1, or their salts.

[0218] (Note 8) R 1 The compounds described in Appendix 7, wherein the compound is unsubstituted cyclopentanyl or unsubstituted bicyclo[2.2.1]heptanyl.

[0219] (Note 9) A is a compound as described in Appendix 1, wherein A is a optionally substituted p-phenylene.

[0220] (Note 10) D is the unsubstituted piperidine-1,4-yl compound as described in Appendix 1.

[0221] (Note 11) D is the unsubstituted piperazine-1,4-yl compound as described in Appendix 1.

[0222] (Note 12) R 11 E-Hy is E, where E is the bond and C is the bond. 1-5 Alkylene, C 1-5 -O-alkylene, or [ka] The compound described in Appendix 1, wherein Hy is either OH or H.

[0223] (Note 13) E is an arbitrarily substituted C 1-5 The alkylene compound described in Appendix 12.

[0224] (Note 14) E is -(CH2)3-, the compound described in Appendix 12.

[0225] (Note 15) E is -(CH2)2CH(CH3)-, as described in Appendix 12.

[0226] (Note 16) E is -O-(CH2)CH(CH3)-, the compound described in Appendix 12.

[0227] (Note 17) E is [ka] The compound described in Appendix 12.

[0228] (Note 18) The compound described in Appendix 12 has Hy as OH.

[0229] (Note 19) Hy is H, as described in Appendix 12 of the compounds.

[0230] (Note 20) [ka] [ka] A compound selected from or a salt thereof.

[0231] (Note 21) A method for treating cancer associated with CDK inhibitors, comprising administering an effective amount of the compound described in Appendix 1.

Claims

[Claim 1] formula: 【Chemistry 1】 A compound represented by, or a salt thereof, During the ceremony, R １ is an arbitrarily substituted C １－６ Alkyl or optionally substituted C ３－１０ It is a cycloalkyl; R １ａ is H or COCH ３ And; R １ｂ is H or CH ３ And; A is an arbitrarily substituted aryl or an arbitrarily substituted heteroaryl; D is optionally substituted piperidine-1,4-yl or optionally substituted piperazine-1,4-yl; R １１ is R ８ , OR ８ , SO ２ R ８ , SO ２ NR ８ R ９ , COR ８ , CO ２ R ８ , or CONR ８ R ９ where R ８ and R ９ are independently H, or F, Cl, Br, I, amino, OH, C １－６ -O-alkyl, cyano, or C １－６ geminal-alkyl-O-alkyl-substituted C １－６ hydrocarbyl, A compound, or a salt thereof.

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