Pyrido[2,3-d]pyrimidin-7(8H)-ones as CDK inhibitors

Abstract

To provide pyrido[2,3-d]pyrimidin-7(8H)-one compounds, pharmaceutically acceptable salts, solvates, prodrugs and active metabolites, which can be strong CDK2, CDK4, and CDK6 inhibitors.SOLUTION: Pyrido[2,3-d]pyrimidin-7(8H)-ones of a formula (1) and pharmaceutical compositions containing compounds of the formula (1) as CDK inhibitors are disclosed herein. Methods and uses of compounds of the formula 1 in the treatment of cancer and manufacturing are also disclosed.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Patent Application No. 62 / 989,448, filed March 13, 2020, all of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Cyclin-dependent kinase (CDK) inhibitors have therapeutic potential for several diseases, including cancer, diabetes, kidney disease, neurodegenerative diseases, and infectious diseases. However, development as anticancer drugs has been focused on cell cycle and transcription CDKs.

[0003] Cancer represents a pathological manifestation of uncontrolled cell division. Therefore, understanding the fundamental principles of cell cycle regulation has long been expected to 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 oncogenic events activate these kinases during the G1 phase of the cell cycle, inducing DNA synthesis (S phase), ultimately leading to proliferation. Furthermore, perturbation of genome stability during S phase or mitosis (M), two phases regulated by CDK1 and CDK2, is a key oncogenic event. Due to their crucial role in regulating cell cycle progression during the G1-S phase transition, CDK4 and CDK6 are considered highly effective targets for anticancer drugs. However, translating this knowledge into successful clinical development of CDK inhibitors has historically been difficult. For example, inhibition of CDK4 and CDK6 appears to have little clinical benefit in certain cancers, such as colorectal cancer, triple-negative breast cancer, and melanoma. Therefore, there is an ongoing search for CDK inhibitors that are less toxic and more broadly effective in cancer treatment. Summary of the Invention [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 inhibitors of CDK2, CDK4, and CDK6. These compounds can be used to treat various types of cancers in need of treatment, including administering a therapeutically effective amount of the pyrido[2,3-d]pyrimidin-7(8H)-one compounds.

[0005] Some embodiments are represented by Formula 1 [ka] The compound includes a compound represented by During the ceremony, R 1 is an arbitrarily substituted C 1-6 Alkyl, or optionally substituted C 3-10 is cycloalkyl; R 1a is R 8 , or COR 8 and;R 1b is R 8 and;R 1c is R 8 , CN, OR 8 , N.R. 9 R 8 , optionally substituted C 6-10 Aryl, or optionally substituted C 1-10 A is an optionally substituted aryl or an optionally substituted heteroaryl; D is an optionally substituted piperidin-1,4-yl or an optionally substituted piperazin-1,4-yl; R 11 is R 8 , OR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 , CO2R 8 , or CONR 8 R 9 and 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 C optionally substituted with geminal-alkyl-O-alkyl- 1-6 Hydrocarbyl; ring, etc.

[0006] Some embodiments include a subject composition, which is a composition comprising a subject compound, wherein the subject compound is a compound described herein, such as 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.

[0007] Some embodiments include pharmaceutical dosage forms comprising the subject compounds.

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

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

[0010] Some embodiments include the use of a subject compound in the manufacture of a medicament for the treatment of a disease or disorder associated with a CDK2, CDK4 and / or CDK6 inhibitor. [Brief explanation of the drawings]

[0011] [Figure 1]1 shows the DNA content profile of MDA-MB-231 human breast cancer cells treated with the subject compounds or a commercially available CDK inhibitor, showing the percentage of cells in different cell cycle phases 48 hours after the indicated treatment (n=6 technical replicates). [Figure 2] Representative photographs of β-galactosidase staining of MDA-MB-231 human breast cancer cells treated with available CDK inhibitors or the subject compounds, and β-Gal activity after 14 days of treatment are shown (arrows point to positively stained cells). [Figure 3] β-galactosidase staining of MDA-MB-231 human breast cancer cells treated with available CDK inhibitors or the subject compounds is shown, with quantification of the percentage of β-galactosidase-positive cells (shown as blue columns) and total cell number (shown as black dots) after 3 and 14 days of treatment with the indicated compounds (n=2 independent experiments). [Figure 4] Figure 1 shows the specific effects of selected subject compounds in Cdk-deficient mouse embryonic fibroblasts (MEFs). Relative cell numbers in Cdk2-, Cdk4 / 6-, or Cdk2 / 4 / 6-null MEFs at day 6 vs. day 3 after the indicated treatments. Data are means ± sem (three technical replicates). [Figure 5] Cell proliferation in luminal and non-luminal breast cancer cell lines in the presence of palbociclib or PS009 is shown. Relative cell counts (GI50 dose in each case) are shown for a group of luminal breast cancer cell lines (ZR75-1, T47D, MCF7) and a group of non-luminal breast cancer cell lines (HCC1143, MDA-MB-231, BT549, MDA-MB468) 6 days after the start of treatment with palbociclib or PS009. Data are mean ± sem (three technical replicates). Note that palbociclib shows clear pRB dependency in non-luminal breast cancer cell lines, while PS009 is effective in both pRB wild-type and mutant cell lines. [Figure 6]Figure 1 shows the effect of the subject compounds on various cell cycle markers. Biochemical analysis of pRB-proficient and pRB-deficient breast cancer cells treated with the indicated compounds at the corresponding GI50 doses. Actin was used as a loading control. Blots are representative of more than three independent experiments. [Figure 7] The effect of PS004, PS006, and PS009 on retinoblastoma protein phosphorylation in various tissues is shown using an antibody against phospho-RB1 Ser807 / 811. Photomicrographs are representative of three mice per treatment. [Figure 8A] The therapeutic effect of the subject compounds in xenografts of MDA-MB-231 breast cancer cells is shown. Mice bearing MDA-MB-231-derived xenografts were treated with the subject compounds for 2 weeks (a total of 4 doses per treatment). Tumor weights (g) were measured at the end of various treatments. DMSO treatment served as a control for intraperitoneal administration of PS compounds, 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] Figure 8 shows the therapeutic effect of the subject compound on time-lapse analysis of tumor doubling growth after treatment with the compound in xenografts of MDA-MB-231 breast cancer cells. Mice bearing MDA-MB-231-derived xenografts were treated with the compound for two weeks (a total of four doses per treatment). The average of DMSO treatment and lactate buffer at each time point in Figure 8A is represented 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]Quantification of cells positive for the phosphorylated form of RB1 (pRb) in tumor analysis is shown. Data are mean ± sem (n = 6 mice per treatment). *P < 0.05; ***P < 0.001 (Student's t-test). [Figure 9B] Quantification of cells positive for the presence of Ki67 in tumor analysis is shown. Data are mean ± sem (n = 6 mice per treatment). *P < 0.05; ***P < 0.001 Student's t test). [Figure 10] The effect of treating mice with various compounds on various parameters, including total mouse weight and the number of various cell populations, such as red blood cells or white blood cells, in peripheral blood, is shown. Data correspond to 6 mice per treatment and 13 control mice. [Figure 11] Representative photomicrographs of lung, bone marrow, and intestine sections after treatment of mice with the indicated compounds are shown. Sections were stained with hematoxylin and eosin. Samples are representative of at least three mice per treatment. DETAILED DESCRIPTION OF THE INVENTION

[0012] Unless otherwise specified, when a compound or chemical structural feature, such as a pyrido[2,3-d]pyrimidin-7(8H)-one, aryl, or heteroaryl, is referred to as "optionally substituted," it includes the "substituted" feature, meaning a feature that has no substituents (i.e., unsubstituted), or a feature that has one or more substituents. The term "substituent" has a broad meaning known to those skilled in the art and includes a moiety that replaces one or more hydrogen atoms bonded to a parent compound or structural feature. In some embodiments, the substituent may be a conventional moiety of any organic compound known in the art and may have a molecular weight (sum of the atomic masses of the atoms of the substituent) of 15 Da to 50 Da, 15 Da to 100 Da, 15 Da to 150 Da, 15 Da to 200 Da, 15 Da to 300 Da, or 15 Da to 500 Da. In some embodiments, a substituent comprises or consists of 0-30, 0-20, 0-10, or 0-5 carbon atoms and 0-30, 0-20, 0-10, or 0-5 heteroatoms, each of which may independently be N, O, S, P, Si, F, Cl, Br, or I, provided that the substituent comprises one C, N, O, S, P, Si, F, Cl, Br, or I. Examples of substituents include, but are not limited to, hydrocarbyls such as alkyl, alkenyl, alkynyl, aryl, etc.; heterohydrocarbyls such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, alkylthio, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanate, isothiocyanate, haloalkyl, haloalkoxyl, trihalomethanesulfonyl, trihalomethanesulfonamido; or other O, S, N, Si, P, or halo-based substituents that are not necessarily hydrocarbyl or heterocarbyl, such as hydroxy, thiol, cyano, F, Cl, Br, I, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, amino, phosphono, phosphoric acidyl, etc.

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

[0014] Structures associated with some of the chemical names referred to herein are shown below: These structures may be unsubstituted as shown below, or may independently have substituents at any position normally occupied by a hydrogen atom when unsubstituted. [ka] If the point of attachment is not specified by , the bond may occur at any position normally occupied by a hydrogen atom.

[0015] [ka]

[0016] As used herein, the term "alkyl" has the broad meaning commonly understood in the art and can include a moiety composed of carbon and hydrogen that does not contain double or triple bonds. Alkyl can be a straight chain alkyl, branched alkyl, cycloalkyl, or a combination thereof, and in some embodiments, can contain 1 to 35 carbon atoms. In some embodiments, alkyl is a C alkyl group such as methyl (-CH), methylene (-CH-), ethyl (-CHCH), ethylene (-CH-), propylene (-CCH-), n-butyl (-CHCHCHCHCH), n-pentyl (-CHCHCHCHCHCH), n-hexyl (-CHCHCHCHCHCHCHCH), etc. 1-10 Straight chain alkyl; C3H7 (e.g., isopropyl), C4H9 (e.g., branched butyl isomers), C5H 11 (e.g., branched pentyl isomers), CH 13 (e.g., branched hexyl isomers), C7H 15 (e.g., heptyl isomers) etc. 3-10Branched alkyl; C3H5 (e.g., cyclopropyl), C4H7 (e.g., cyclobutyl isomers such as cyclobutyl, methylcyclopropyl, etc.), C5H9 (e.g., cyclopentyl isomers such as cyclopentyl, methylcyclobutyl, dimethylcyclopropyl, etc.), C6H 11 (e.g., cyclohexyl isomers), C7H 13 (e.g., cycloheptyl isomers) etc. 3-10 cycloalkyl; and the like.

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

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

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

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

[0021] Some embodiments include compounds designated 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. When an aryl or heteroaryl is substituted, it has 1, 2, 3, or 4 substituents, and each substituent may be the same as or different from the other substituents. Substituents may be included on the aryl or heteroaryl. In some embodiments, some or all of the substituents on the aryl or heteroaryl have 0-10 carbon atoms and 0-10 heteroatoms, each of which is independently O, N, S, F, Cl, Br, or I, and / or has a molecular weight of 15 g / mol to 500 g / mol. In some embodiments, some or all of the substituents each 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 C, H, O, N, S, F, Cl, or Br.

[0024] For example, with respect to the representation of any related structure of formula I, 1A, 1B, or 1C, 2, 3, 4, 5, 6, 7, etc., the substituents of A are optionally substituted CH, C2H, C3H, cyclic C3H, C4H, cyclic C4H, C5H 11 , cyclic C5H9, C6H 13 , cyclic CH 11 Any substituted C such as 1-10 Alkyl; OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 , cyclic OC5H9, OC6H 13 , cyclic OC6H 11 etc., C 1-10 optionally substituted alkoxy; halo such as F, Cl, Br, I; OH; CN; NO; C such as CF, CFH, CF 1-6 Fluoroalkyl; C such as OCF3, OCF2H, OC2F5 1-6 Fluoroalkoxy; -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl, etc. 1-10 Esters: -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc. 1-10 Ketones; or C such as NH2, NH(CH3), N(CH3)2, N(CH3)C2H5 1-10 In some embodiments, the substituents of A are F, Cl, Br, I, CN, NO, C 1-4 Alkyl, C 1-4 Alkyl-OH, C 1-3 O-Alkyl, CF3, C(O)H, C 1-4 CO-Alkyl, COH, C 1-4 CO2-alkyl, NH2, or C 1-4 It may also be alkylamino.

[0025] 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 optionally substituted p-phenylene or an optionally substituted pyridin-2,5-yl, with the 2-position attached to NH and the 5-position attached to D.

[0026] With respect to any related structural representation of formula 1, 1A, 1B, 1C, 2, 3, 4, 5, 6, or 7, when A is a substituted phenylene, it may have 1, 2, 3, or 4 substituents, for example, as represented by the following structures: 2a , R 2b , R 2c and R 2d does not have to be all H.

[0027] [ka]

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

[0029] 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 fluoro-p-phenylene, [ka] is.

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

[0031] With respect to any related structural representation, such as Formula 1A, 1B, 1C, 2A, 3A, 4A, 5A, 6A, 7A, 8, or 9, in some embodiments, D is an optionally substituted piperidin-1,4-yl or an optionally substituted piperazin-1,4-yl. In some embodiments, D is an optionally substituted piperazin-1,4-yl. In some embodiments, D is an optionally substituted piperidin-1,4-yl. In some embodiments, D is an optionally substituted piperidin-1,4-yl that is attached to A at the 1-position.

[0032] When D is substituted piperidin-1,4-yl or substituted piperazin-1,4-yl, it has 1, 2, 3, 4, 5, 6, 7, or 8 substituents, each of which may be the same as or different from the other substituents. In some embodiments, some or all of the substituents of D have 0-10 carbon atoms and 0-10 heteroatoms, each heteroatom independently being O, N, S, F, Cl, Br, or I (provided that 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 of the substituents have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to 50 Da, and 2-5 chemical elements independently being C, H, O, N, S, F, Cl, or Br.

[0033] For example, with respect to any relevant structural representation of formula 1A, 1B, 1C, 2A, 3A, 4A, 5A, 6A, 7A, 8, or 9, the substituents of D can be CH3, C2H5, C3H7, cyclicC3H5, C4H9, cyclicC4H7, C5H 11 , cyclic C5H9, C6H 13 , cyclic CH 11 Optionally substituted alkyl such as OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 , cyclic OC5H9, OC6H 13 , cyclic OC6H 11 etc., C 1-10optionally substituted alkoxy; halo such as F, Cl, Br, I; OH; CN; NO; C such as CF, CFH, CF 1-6 Fluoroalkyl; C such as OCF3, OCF2H, OC2F5 1-6 Fluoroalkoxy; -O2CCH3, -CO2CH3, -OCOC2H5, -CO2C2H5, -OCO-phenyl, -CO2-phenyl, etc. 1-10 Esters: -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc. 1-10 Ketones; or C such as NH2, NH(CH3), N(CH3)2, N(CH3)C2H5 1-10 It may also be an amine.

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

[0035] With respect to any related structural representation, such as Formula 1A, 1B, 1C, 2A, 3A, 4A, 5A, 6A, 7A, 8, or 9, in some embodiments, D is an optionally substituted piperidin-1,4-yl. In some embodiments, D is an unsubstituted piperidin-1,4-yl: [ka] is.

[0036] With respect to any related structural representation, such as Formula 1A, 1B, 1C, 2A, 3A, 4A, 5A, 6A, 7A, 8, or 9, in some embodiments, D is an optionally substituted piperazin-1,4-yl. In some embodiments, D is an unsubstituted piperazin-1,4-yl: [ka] is.

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

[0038] With respect to any related structural representation, such as Formula 5, A is optionally substituted p-phenylene and D is optionally substituted piperazin-1,4-yl.

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

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

[0041] For any related structural representation of formula 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9, R 1-28 may be H or any substituent, such as a substituent having 0-12 atoms or 0-10 carbon atoms and 0-5 heteroatoms, each heteroatom being independently O, N, S, F, Cl, Br, or I, and / or having a molecular weight of 15 g / mol to 300 g / mol. 1-28is a) optionally substituted with, or optionally linked by or to, one or more alkyl moieties, such as, b) one or more functional groups, such as C=C, C≡C, CO, CO2, CON, NCO2, OH, SH, O, S, N, N=C, F, Cl, Br, I, CN, NO2, CO2H, NH2, 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 are each 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, which chemical elements are independently C, H, O, N, S, F, Cl, or Br.

[0042] For any relevant structural representation of formula 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9, R 1-28 Some non-limiting examples of A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A ,OCOR A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-28 is H; F; Cl; Br; CN; C such as CHF2, CF3 1-3 Fluoroalkyl; OH; NH; C such as methyl, ethyl, propyl isomers (e.g., n-propyl and isopropyl), cyclopropyl, butyl isomers, cyclobutyl isomers (e.g., cyclobutyl and methylcyclopropyl), pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc. 1-6Alkyl; C such as -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 1-6 Alkoxy; C such as -CHOH, -CH-OH, -CH-OH, -CH-OH, 1-4 Hydroxyalkyl; C such as -CO2-CH3, -CO2-C2H5, -CO2-C3H7, -CO2-C4H9 2-5 It may also be -CO2-alkyl.

[0043] [ka]

[0044] For representations of any relevant structure, R A independently, H, or C a H 2a+1 or a linear or branched alkyl having the formula C a H 2a-1 C including cycloalkyl having 1-12 alkyl, where a can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, for example, alkyl of the formula CH3, C2H5, C3H7, C4H9, C5H 11 , C6H 13 , C7H 15 , C8H 17 , C9H 19 , C 10 H 21 or a linear or branched alkyl of the formula C3H5, C4H7, C5H9, C6H 11 , C7H 13 , C8H 15 , C9H 17 , C 10 H 19 In some embodiments, R A is H or C 1-6 In some embodiments, R A is H or C 1-3In some embodiments, R A may be H or CH. In some embodiments, R A may be H.

[0045] For representations of any relevant structure, R B independently, H, or C a H 2a+1 or a linear or branched alkyl having the formula C a H 2a-1 C including cycloalkyl having 1-12 alkyl, where a can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, for example, alkyl of the formula CH3, C2H5, C3H7, C4H9, C5H 11 , C6H 13 , C7H 15 , C8H 17 , C9H 19 , C 10 H 21 or a linear or branched alkyl of the formula C3H5, C4H7, C5H9, C6H 11 , C7H 13 , C8H 15 , C9H 17 , C 10 H 19 In some embodiments, R B is H or C 1-3 In some embodiments, R B may be H or CH. In some embodiments, R B may be H.

[0046] For any relevant structural representation of formula 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 Cycloalkyl. R 1 is arbitrarily substituted C 3-10When R is cycloalkyl, it may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 substituents. 1 may contain optional substituents. In some embodiments, some or all of R 1 The substituents may have 0-10 carbon atoms and 0-10 heteroatoms, each independently O, N, S, F, Cl, Br, or I (provided that 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 of the 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 C, H, O, N, S, F, Cl, or Br. In some embodiments, R 1 are CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , cyclic C5H9, C6H 13 , cyclic CH 11 , cyclic CH 13 , cyclic CH 15 , cyclic CH 17 , cyclic C 10 H 19 Any substituted C such as 1-6 Alkyl, or optionally substituted C 3-10 Cycloalkyl; OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 , cyclic OC5H9, OC6H 13 , cyclic OC6H 11 etc., C 1-10 optionally substituted alkoxy; halo such as F, Cl, Br, I; OH; CN; NO; C such as CF, CFH, CF 1-6 Fluoroalkyl; C such as OCF3, OCF2H, OC2F5 1-6 Fluoroalkoxy; -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl, etc. 1-10 Esters: -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc. 1-10Ketones; or C such as NH2, NH(CH3), N(CH3)2, N(CH3)C2H5 1-10 In some embodiments, the substituents of D are F, Cl, Br, I, CN, NO, C 1-4 Alkyl, C 1-4 Alkyl-OH, C 1-3 O-Alkyl, CF3, C(O)H, C 1-4 CO-Alkyl, COH, C 1-4 CO2-alkyl, NH2, or C 1-4 It may also be alkylamino.

[0047] With respect to any related structural representation, such as formula 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 an optionally substituted bicycloheptanyl or an optionally substituted cyclopentanyl. In some embodiments, R 1 is an optionally substituted bicycloheptanyl. In some embodiments, R 1 is an optionally substituted bicyclo[2.2.1]heptanyl [ka] is.

[0048] With respect to any related structural representation, such as formula 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 an unsubstituted bicyclo[2.2.1]heptanyl [ka] is.

[0049] With respect to any related structural representation, such as formula 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 an optionally substituted cyclopentanyl. In some embodiments, R1 is unsubstituted cyclopentanyl [ka] is.

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

[0051] For any relevant structural representation of formula 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 8, or 9, R 1b is H, optionally substituted C 1-6 Alkyl, or optionally substituted C 3-6 In some embodiments, R 1b is H or CH. In some embodiments, R 1b is H or CH. In some embodiments, R 1b is H. In some embodiments, R 1b is CH3.

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

[0053] With respect to any related structural representation, such as formula 1, 5, 5A, 7, or 7A, in some embodiments, R 11 is R 8 , -OR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 , CO2R 8 , or CONR 8 R 9 and R 8 and R 9 are independently H, 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 a hydrocarbyl.

[0054] With respect to any related structural representation, such as formula 1, 5, 5A, 7, or 7A, in some embodiments, R 11 is E-Hy.

[0055] With respect to E-Hy, E is a bond; C alkylene such as C alkylene, C alkylene, C alkylene (including -(CH2)3-), C alkylene (including -(CH2)2CH(CH3)-), or C alkylene. 1-5 alkylene; or C such as C1-O-alkylene, C2-O-alkylene, C3-O-alkylene (including -O-(CH2)CH(CH3)-), C4-O-alkylene, or C5-O-alkylene. 1-5 In some embodiments, E is -O-alkylene. In some embodiments, E is -(CH2)3-. In some embodiments, E is -(CH2)2CH(CH3)-. In some embodiments, E is C1-5 In some embodiments, E is —O-alkylene. In some embodiments, E is —O—(CH 2 )CH(CH 3 )—.

[0056] With respect to E-Hy, Hy is OH or H. In some embodiments, Hy is OH. In some embodiments, Hy is H.

[0057] In some embodiments, R 11 is H, optionally substituted C 1-4 Alkyl, or optionally substituted C 1-4 In some embodiments, R 11 is H. In some embodiments, R 11 is an arbitrarily substituted C 1-4 In some embodiments, R 11 is an arbitrarily substituted C 1-4 In some embodiments, R 11 teeth, [ka] is.

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

[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] is.

[0060] With respect to any related structural representation, such as formula 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9, in some embodiments, R 2 are H, F, Cl, Br, I, cyano, OH, SOR 8 , SO2R 8 , SO2NR 9 R 8 , C.O.R. 8 , CO2R 8 ,CONR 9 R 8 , N.R. 9 R 8 , N.R. 9 COR 8 , N.R. 9 SO2R 8 , N.R. 9 CO2R 8 , N.R. 9 CONR 8 ,OCOR 8 In some embodiments, R 8 and R 9 In some embodiments, R does not have a substituent that contains a heteroatom. 2 is F or Cl. In some embodiments, R 2 is F.

[0061] In some embodiments, R 2a is F or H, and R 2b , R 2c , and R 2d is R 2 In some embodiments, R 2a is F and R 2b , R 2c , and R 2d is R 2In some embodiments, R 2a is H and R 2b , R 2c , and R 2d is R 2 is any of the groups described above for

[0062] In some embodiments, R 2b is F or H, and R 2a , R 2c , and R 2d is R 2 In some embodiments, R 2b is F and R 2a , R 2c , and R 2d is R 2 In some embodiments, R 2b is H and R 2a , R 2c , and R 2d is R 2 is any of the groups described above for

[0063] With respect to any related structural representation, such as formula 1, 1A, 1B, 1C, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, or 9, in some embodiments, R 3 are H, F, Cl, Br, I, cyano, OH, SOR 8 , SO2R 8 , SO2NR 9 R 8 , C.O.R. 8 , CO2R 8 ,CONR 9 R 8 , N.R. 9 R 8 , N.R. 9 COR 8 , N.R. 9 SO2R 8 , N.R. 9 CO2R 8 , N.R. 9 CONR 8 ,OCOR 8 In some embodiments, R8 and R 9 In some embodiments, one, two, three, or four R 3 The group is H.

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

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

[0066] With respect to any related structural representation, such as formula 1A, 1B, or 1C, in some embodiments, R 4 is H or CH. In some embodiments, R 4 is H. In some embodiments, R 4 is CH3.

[0067] With respect to any related 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 , C.O.R. 8 , CO2R 8 ,CONR 9 R 8 , N.R. 9 R 8 , N.R. 9 COR 8 , N.R. 9 SO2R 8 , N.R. 9 CO2R 8 , N.R. 9 CONR8 , or OCOR 8 is.

[0068] With respect to any relevant structural representation such as W in Formula 1A or 1C, in some embodiments, R 6 is R 8 , F, Cl, Br, I, cyano, -OR 8 , SOR 8 , SO2R 8 , SO2NR 9 R 8 , C.O.R. 8 , CO2R 8 ,CONR 9 R 8 , N.R. 9 R 8 , N.R. 9 COR 8 , N.R. 9 SO2R 8 , N.R. 9 CO2R 8 , N.R. 9 CONR 8 , or OCOR 8 is.

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

[0070] With respect to any related structural representation, such as formula 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 are F, Cl, Br, I, amino, hydroxyl, C 1-6 C optionally substituted with alkoxy or cyano 1-6 Hydrocarbyl (C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 3-6 Cycloalkenyl, C 2-6 Alkynyl, C 3-6 cycloalkenyl, etc.).

[0071] With respect to any related structural representation, such as formula 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 are F, Cl, Br, I, amino, hydroxyl, C 1-6 C optionally substituted with alkoxy or cyano 1-6 Hydrocarbyl (C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 3-6 Cycloalkenyl, C 2-6 Alkynyl, C 3-6 cycloalkenyl, etc.).

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

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

[0074] With respect to any related structural representation, such as Formula 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 Formula 1A, 1B, or 1C: R 1 is an arbitrarily substituted C 1-6 Alkyl or optionally substituted C 3-10 A is optionally 1-4R 2 , (identical or different) substituted aryl, or optionally 1-3R 2 (identical 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 )2; m=1 or 2; n=0, 1, or 2; and R 4 is hydrogen or R 4 and R of Formula 1, 1A, 1B or 1C 3a , R 3b , R 3c , R 3d each independently represents H or one or two identical or different R 7 C optionally substituted with 1-6 is hydrocarbyl, and R 4 is H or CH3, R of Formula 1, 1A, 1B or 1C 2 , R 5 , R 6 , R 7 Each of the groups independently represents R8 , F, Cl, Br, I, cyano, -OR 8 , C 1-6 Hydrocarbyl, C 1-6 Alkoxy, SOR 8 , SO2R 8 , SO2NR 9 R 8 , C.O.R. 8 , CO2R 8 ,CONR 9 R 8 , N.R. 9 R 8 , N.R. 9 COR 8 , N.R. 9 SO2R 8 , N.R. 9 CO2R 8 , N.R. 9 CONR 8 ,OCOR 8 Selected from C 1-6 Hydrocarbyl, C 1-6 Alkoxy, SOR 8 , SO2R 8 , SO2NR 9 R 8 , C.O.R. 8 , CO2R 8 ,CONR 9 R 8 , N.R. 9 R 8 , N.R. 9 COR 8 , N.R. 9 SO2R 8 , N.R. 9 CO2R 8 , N.R. 9 CONR 8 , or OCOR 8 Each of the following. R 8 and R 9 are independently H or C 1-6 Hydrocarbyl, C 1-6 Each of the hydrocarbyls is selected from the group consisting of F, Cl, Br, I, amino, hydroxyl, C 1-6 It may be optionally substituted with alkoxy or cyano.

[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] For any related structural representation such as Formula 3, Formula 3A, or Formula 9, R 1a is H or COCH3, and R 1b is H or CH3.

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

[0079] For any related structural representation, such as Formula 7A, X is CH or N, and when X is CH, R 2 is H.

[0080] For any related structural representation such as Formula 7 or Formula 7A, R 1 is an optionally substituted bicycloheptanyl.

[0081] For any related structural representation, such as Formula 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 Formula 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 related structural representation, such as Formula 1A, 1C, 2, 2A, 4, 4A, 6, 6A, or 8, n can be 1 or 2. In some embodiments, n can be 0, such as in compounds represented by Formula 1A or 1C. In some embodiments, n can be 3, such as in compounds represented by Formula 4 or 4A.

[0084] Some embodiments include one or more of the following. [ka] TIFF0007798981000026.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)piperidin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one; optionally substituted 8-((2R)-bicyclo[2.2.1]heptan-2-yl)-2-((3-fluoro-4-(4-(3-hydroxypropyl)piperidin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one; optionally substituted 8-(( 2R)-Bicyclo[2.2.1]heptan-2-yl)-2-((4-(4-(3-hydroxybutyl)piperidin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one; optionally substituted 8-((2R)-bicyclo[2.2.1]heptan-2-yl)-2-((4-(4-(3-hydroxybutyl)piperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one; optionally substituted 8-((2R)-bicyclo[2.2.1]heptan-2-yl)-2-((4-(4-(2-hydroxybutyl)piperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one optionally substituted 6-acetyl-8-((2R)-bicyclo[2.2.1]heptan-2-yl)-2-((4-(4-(3-hydroxypropyl)piperidin-1-yl)phenyl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one; optionally substituted 6-acetyl-8-((2R)-bicyclo[2.2.1]heptan-2-yl)-2-((4-(4-(3-hydroxypropyl)piperidin-1-yl)phenyl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one; optionally substituted 6-acetyl-8-((2R)-bicyclo[2.2.1]heptan-2-yl)-2-((4-(4-(3-hydroxypropyl)piperidin-1-yl)phenyl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one; ]pyrimidin-7(8H)-one; optionally substituted 6-acetyl-8-cyclopentyl-2-((4-(4-(3-hydroxypropyl)piperidin-1-yl)phenyl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one; or optionally substituted 6-acetyl-8-((2R)-bicyclo[2.2.1]heptan-2-yl)-5-methyl-2-((4-(piperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one; or optionally substituted 8-((2R)-bicyclo[2.2.1]heptan-2-yl)-2-((4-(4-((3-(hydroxymethyl)oxetan-3-yl)methoxy)piperidin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one.

[0086] The subject compounds can be used to treat disorders or diseases associated with CDK inhibitors. Disorder treatment includes diagnosis, cure, mitigation, treatment, or prevention of human or animal disorders. In some embodiments, the disease is cancer. In some embodiments, the disease or disorder can include breast cancer, melanoma, kidney cancer, squamous cell carcinoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, prostate cancer, colon cancer, esophageal cancer, head cancer, neck cancer, neuroblastoma, myeloma, glioma, lymphoma, and leukemia.

[0087] Suitable excipients for use in the subject compositions may include, for example, one or more carriers, binders, fillers, vehicles, disintegrants, surfactants, dispersing or suspending aids, thickening or emulsifying agents, isotonicity agents, preservatives, lubricants, and the like, or combinations thereof, appropriate to the particular dosage form desired. Remington's Pharmaceutical Sciences, 16th Edition, E. W. Martin (Mack Publishing Company, Easton, Pa., 1980), discloses various carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation.

[0088] The subject compositions may be formulated for any desired route of delivery, including, but not limited to, parenteral, intravenous, intradermal, subcutaneous, oral, inhalation, transdermal, topical, transmucosal, rectal, intracisternal, intravaginal, 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; saline; Ringer's solution; sodium chloride; fixed 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 methylparabens; 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 acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral formulations may be enclosed in ampoules, disposable syringes made of glass or plastic, or multiple-dose vials.

[0090] Pharmaceutical compositions suitable for injectable use may include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include, but are not limited to, physiological saline, bacteriostatic water, CREMOPHOR EL® (BASF, Parsippany, 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. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, 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, thimerosal, and the like. The compositions may also include isotonic agents, for example, sugars; polyalcohols such as mannitol; or sodium chloride. Prolonged absorption of the injectable compositions can be increased by the addition of agents that delay absorption, such as aluminum monostearate or gelatin.

[0091] Oral compositions may contain an inert diluent or an edible carrier. These may be enclosed in gelatin capsules or compressed into tablets. Tablets, pills, capsules, troches, etc. may contain the following ingredients, or compounds of similar nature: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; disintegrating agents such as alginic acid, Primogel, or cornstarch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring.

[0092] In addition to oral or injection administration, systemic administration can also be via transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants can be used. Such penetrants are generally known in the art and include, for example, surfactants, bile salts, and fusidic acid derivatives. Transdermal administration can contain physiologically active substances and can be formulated into ointments, salves, gels, or creams as generally known in the art. Transmucosal administration can be achieved through the use of nasal sprays or suppositories.

[0093] The subject compounds may be administered in therapeutically effective amounts according to an appropriate dosage regimen. As will be appreciated by skilled artisans, the exact amount required may vary from subject to subject, depending on the subject's species, age, and general condition, the severity of the infection, the particular agent, and the method of administration. In some embodiments, to achieve the desired therapeutic effect, about 0.01 mg / kg to about 50 mg / kg of the subject's body weight is administered one or more times daily. In another embodiment, to achieve the desired therapeutic effect, about 0.001 mg / kg to about 25 mg / kg of the subject's body weight is administered one or more times daily.

[0094] The total daily dose of the subject compound can be determined by the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for a specific patient or subject will depend on various factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex, and diet of the patient or subject; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or simultaneously with the specific compound used; and other factors well known in the medical field.

[0095] The following embodiments are specifically contemplated herein.

[0096] Embodiment 1. formula: [ka] or a salt thereof, During the ceremony, R 1 is an arbitrarily substituted C 1-6 Alkyl, or optionally substituted C 3-10 is cycloalkyl; R 1a is H or COCH3; R 1b is H or CH3; R 1c is H; A is optionally substituted aryl or optionally substituted heteroaryl; D is optionally substituted piperidin-1,4-yl or optionally substituted piperazin-1,4-yl; R 11 is R 8 , OR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 , CO2R 8 , or CONR 8 R 9 and R 8 and R9 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 is a hydrocarbyl, compound, or a salt thereof.

[0097] Embodiment 2. formula: [ka] or a salt thereof, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridin-2,5-yl, with the 2-position attached to NH and the 5-position attached to D; D is an optionally substituted piperidin-1,4-yl, attached at position 1 to A; R 1a is H or COCH3; R 1b is H or CH3; n is 1 or 2; The compound of embodiment 1, or a salt thereof.

[0098] Embodiment 3. formula: [ka] or a salt thereof, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridin-2,5-yl, with the 2-position attached to NH and the 5-position attached to D; D is an optionally substituted piperidin-1,4-yl, attached at position 1 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] or a salt thereof, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridin-2,5-yl, with the 2-position attached to NH and the 5-position attached to D; D is an optionally substituted piperidin-1,4-yl, attached at position 1 to A; n is 1, 2, or 3; The compound of embodiment 1, or a salt thereof.

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

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

[0102] Embodiment 7. formula: [ka] or a salt thereof, During the ceremony, R 1 is optionally substituted bicycloheptanyl; A is an optionally substituted pyridin-2,5-yl, the 2-position of which is bonded to NH and the 5-position of which is bonded to D, and D is an optionally substituted piperazin-1,4-yl; or A is optionally substituted phenyl and D is unsubstituted piperazin-1,4-yl; The compound of embodiment 1, or a salt thereof.

[0103] Embodiment 8. R 1 The compound of embodiment 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 unsubstituted cyclopentanyl.

[0105] Embodiment 10. R 1 The compound of embodiment 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, wherein is unsubstituted bicyclo[2.2.1]heptanyl.

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

[0108] Embodiment 13. R 1a 12. The compound of embodiment 1, 2, 3, 8, 9, 10, or 11, wherein is COCH3.

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

[0110] Embodiment 15. R 1b 14. The compound of embodiment 1, 2, 3, 8, 9, 10, 11, 12, or 13, wherein

[0111] Embodiment 16. The compound of embodiment 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. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein A is unsubstituted p-phenylene.

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

[0114] Embodiment 19. 19. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein D is optionally substituted piperidin-1,4-yl.

[0115] Embodiment 20. 19. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein D is unsubstituted piperidin-1,4-yl.

[0116] Embodiment 21. 19. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein D is an optionally substituted piperazin-1,4-yl.

[0117] Embodiment 22. 19. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein D is unsubstituted piperazin-1,4-yl.

[0118] Embodiment 23. R 11 is E-Hy, where E is a bond, C 1-5 Alkylene, C 1-5 -O-alkylene, or [ka] and Hy is OH or H.

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

[0120] Embodiment 25. 24. The compound of embodiment 23, wherein E is (CH2)3-.

[0121] Embodiment 26. 24. The compound of embodiment 23, wherein E is (CH2)2CH(CH3)-.

[0122] Embodiment 27. E is C 1-5 24. The compound of embodiment 23, wherein the alkyl group is -O-alkylene.

[0123] Embodiment 28. 24. The compound of embodiment 23, wherein E is (CH2)CH(CH3)-.

[0124] Embodiment 29. E is [ka] 24. The compound of embodiment 23, wherein

[0125] Embodiment 30. The compound of embodiment 23, 24, 25, 26, 27, 28, or 29, wherein 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] or a salt thereof.

[0128] Embodiment 33. 36. A pharmaceutically acceptable composition comprising 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.

[0129] Embodiment 34. 34. A pharmaceutically acceptable dosage form comprising 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.

[0130] Embodiment 35. 36. A method of treating a disorder associated with a CDK inhibitor, 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 disorder is cancer.

[0132] Embodiment 37. 36. Use of a 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 in the manufacture of a medicament for the treatment of cancer.

[0133] Embodiment 38. 38. The method or use of embodiment 36 or 37, wherein said cancer comprises breast cancer, kidney cancer, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, prostate cancer, colon cancer, esophageal cancer, head cancer, neck cancer, or leukemia.

[0134] Embodiment 39. 36. The method of embodiment 35, further comprising administering an additional therapeutic agent.

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

[0136] (Experimental Section) (Reference substance) 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 DMSO (Sigma-Aldrich) at a concentration of 5 mM (stock solution).

[0137] (Preparation of Compounds) In the synthetic schemes described below, all temperatures are in degrees Celsius and all parts and percentages by weight are given unless otherwise noted. Reagents and solvents were purchased from commercial suppliers such as Aldrich Chemical Company and used without further purification unless otherwise noted. Tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) were purchased from Aldrich in Sure Seal bottles and used as received.

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

[0139] Workup was typically performed by doubling the reaction volume with the reaction or extraction solvent, unless otherwise noted, followed by washing with the indicated aqueous solution at a volume equal to 25% of the extraction volume. Product solutions were dried over anhydrous NaSO and / or MgSO before filtration and evaporation of the solvent under reduced pressure on a rotary evaporator, with the solvent removed in vacuo recorded. Column chromatography was performed using 230-400 mesh silica gel under positive pressure.

[0140] 1 H-NMR spectrum and 13 C-NMR was recorded on 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 proton, 77.00 ppm for carbon), CD3OD (3.4 and 4.8 ppm for proton, 49.3 ppm for carbon), DMSO-d6 (2.49 ppm for proton), or internal tetramethylsilane (0.00 ppm) as reference standards, as appropriate. Other NMR solvents were used as needed.

[0141] The disclosed compounds can be made using procedures known in the art. The following reaction schemes illustrate typical procedures, but those skilled in the art will recognize that other procedures may also be suitable for use in preparing these compounds. For example, those skilled in the art will recognize that necessary reagent modifications can be made at appropriate stages of the synthetic methods outlined below. Reactions may require monitoring of the consumption of starting materials, and many monitoring methods exist, including but not limited to thin layer chromatography (TLC) and liquid chromatography-mass spectrometry (LCMS). Those skilled in the art will recognize that any synthetic method set forth in the examples below can be substituted with other, non-limiting methods as appropriate.

[0142] In some embodiments, the pyrido[2,3-d]pyrimidin-7-one analogs described herein are prepared via the general route shown in Schemes 1 and 2. As shown in Scheme 1, commercially available 4-chloro-2-methylthio-5-pyrimidinecarboxylic acid ethyl ester (1) is condensed with a primary amine in THF containing triethylamine to afford the intermediate of structure 2. Reduction of ester 2 to alcohol 3 using lithium aluminum hydride, followed by reoxidation with MnO2, affords aldehyde 4. Reaction of aldehyde 4 with (carbethoxymethylene)triphenylphosphorane in THF under reflux affords the undesired (£)-acrylate ester 5, which is conveniently isomerized upon heating in the presence of DBU during ring closure to afford the pyrido[2,3-d]pyrimidine core molecule 6. Oxidation of the methyl sulfide in compound 6 with (+ / -)-trans-2-(phenylsulfonyl)-3-phenyloxaziridine or m-chloroperbenzoic acid can give the corresponding sulfoxide 7 or sulfone 8. Introduction of an amine at the C2-position can be achieved by heating the sulfoxide or sulfone with two or more equivalents of an amine, such as an aromatic amine, at temperatures between 100°C and 175°C, in the presence or absence of a solvent, to give the general structure 9.

[0143] [ka]

[0144] As shown in Scheme 2, when step 1 of the synthesis is performed with ammonium hydroxide, compound 14 can be prepared similarly to the synthesis of compound 6 shown in Scheme 1. Intermediate 14 was oxidized with oxaziridine to form 15 and / or 16, which was then reacted with an aromatic amine to generate analog 17, which was then alkylated at N8 by treatment with sodium hydride and an alkyl halide to generate desired product 18. Alternatively, compound 14 was alkylated at N8 to give structure 6, which was then oxidized to 7 and / or 8, which was then treated with an amine to generate desired product 18.

[0145] [ka]

[0146] Example 1 Exemplary compounds can be prepared by several of these routes and are detailed below. An exemplary synthesis of PS004 is shown in Scheme 3 below.

[0147] [ka]

[0148] Step 1: Preparation of compound 19 To a room temperature solution of 4-chloro-2-methanesulfanylpyrimidine-5-carboxylic acid ethyl ester (1) (1 equivalent) in tetrahydrofuran (approximately 0.3 M) was added triethylamine (3 equivalents), followed by (1S,2S,4R)-bicyclo[2.2.1]heptan-2-amine (excess). The solution was stirred for approximately 30 minutes, then concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give compound 19, which was 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 in vacuo, and 1:1 hexane:ethyl acetate is added. The solid is collected to give compound 20.

[0150] Step 3: Preparation of compound 21 To compound 20 (1 equivalent) in chloroform (approximately 0.05 M) is added manganese oxide (approximately 7 equivalents). The suspension is stirred at room temperature for approximately 2 hours, and then additional manganese oxide (approximately 2 equivalents) is added. Stirring is continued for approximately 4-5 hours. The mixture is filtered through Celite and washed with chloroform. The filtrate is concentrated in vacuo to give 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) is added (carbethoxymethylene)triphenylphosphorane (1.3 equivalents). The reaction mixture is heated at reflux for approximately 70 minutes. The reaction mixture is concentrated in vacuo, and the residue is purified by flash chromatography eluting with ethyl acetate to give compound 22.

[0152] Step 5: Preparation of Compound 23 To a room temperature solution of compound 22 (1 equivalent) in N,N-diisopropylethylamine (7 equivalents) is added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.15 equivalents). The reaction mixture is heated at reflux overnight and then cooled to room temperature. The resulting solid is collected by filtration and washed with 1:1 hexane:ethyl acetate to give compound 23. The filtrate is concentrated in vacuo, and upon addition of hexane a solid forms, which is collected, washed with hexane, and purified by flash chromatography eluting with ethyl acetate to give a further quantity 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) is added (+ / -)-trans-2-(phenylsulfonyl)-3-phenyloxaziridine (1.2 equivalents). The solution is stirred at room temperature overnight and then concentrated in vacuo. The residue is treated with ethyl acetate to give a solid, which is collected by filtration and washed with ethyl acetate to give compound 25.

[0154] Step 7: Preparation of PS004 To compound 25 (1 equivalent), 1 equivalent more 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, followed by an aqueous wash with sodium bicarbonate solution. The organic layer is dried over magnesium sulfate, filtered, and evaporated to dryness. The crude product is purified by crystallization from ethyl acetate and hexane or by silica gel chromatography to give the desired product, PS004.

[0155] Other analog compounds such as PS002, PS003, PS005, PS006, PS007, PS016, and other compounds described herein can be similarly prepared using, for example, several 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 on the reagents during synthesis may be necessary.

[0156] [ka]

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

[0158] [ka]

[0159] In some embodiments, the pyrido[2,3-d]pyrimidin-7-one analogs described herein are prepared via the general routes illustrated in Schemes 4, 5, and 6. As shown in Scheme 4, compound 29 can be prepared from compound 4, which can be prepared according to the method described in Scheme 1, by treatment with reagent 28. The hydroxy group in compound 29 can be oxidized to a ketone to produce compound 30. Oxidation of the methyl sulfide in compound 30 with oxaziridine provides the corresponding sulfoxide or sulfone, which can be displaced by an amine under heating to form compound 31. Treatment of the ketone at the C5 position of substituted 4-aminopyrimidine 31 with reagent 32 using similar chemistry, such as Wittig, Horner-Wadsworth-Emmons, Knoevenagel, or enolate anion chemistry, can introduce the C5-C6 double bond of the pyrido[2,3-d]pyrimidinone ring system (position shown below).

[0160] [ka]

[0161] These reactions proceed using a suitable base, such as NaH, NaOEt, LDA, BuLi, or HMDS, under conditions that will be familiar to those skilled in the art. When the double bond configuration is such that the pyrimidine ring and ester group are in a cis relationship across the newly formed double bond, ring closure to form target 33 usually occurs spontaneously under the reaction conditions. Otherwise, it may be necessary to facilitate closure by gentle heating to temperatures below 100°C in a suitable organic solvent. When the double bond configuration is such that the pyrimidine and ester are in a trans relationship across the double bond, ring closure occurs, for example, by heating to temperatures 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 that will be familiar to those skilled in the art. The order of ring formation and side chain introduction can also be reversed, as shown in Scheme 5 below.

[0162] [ka]

[0163] Alternatively, the synthesis of compounds of the present disclosure, as shown in Scheme 5, can proceed via substituted 2-chloropyrimidine intermediate 34, which can be prepared using methods known in the art. Compound 35 can be prepared by Wittig, Horner-Wadsworth-Emmons, or Knoevenagel reaction of the ketone at the C5 position of 34 with reagent 32, followed by spontaneous ring closure as described above. Installation of the C2 side chain of compound 35 typically proceeds via catalysis with [(t-Bu)P(OH)]PdCl(POPd), Pd(OAc), or Pddba with an appropriate ligand, such as BINAP, Xantphos, or a similar phosphine-based Pd ligand, to generate the desired product 33.

[0164] [ka]

[0165] Another alternative route for preparing compounds of the present disclosure, as shown in Scheme 6, can proceed through intermediate 31, which can be prepared as described above. Treatment of compound 31 with reagent 36 via the Wittig, Horner-Wadsworth-Emmons, or Knoevenagel reaction, followed by spontaneous ring closure, can form pyrido[2,3-d]pyrimidinone 37, which lacks C6 substitution. Introduction of Br at the C6 position of 37 can be achieved by treatment with NBS, forming 38. A Stille coupling reaction can be performed with compound 38 using reagent 39 and a catalyst to form compound 40, which can be treated with HCl to form a ketone substituent at C6 and afford the desired product 41. The Stille reaction in Scheme 6 is typically carried out under palladium catalysis using reagents such as Pd(OAc)2, Pd2(dba)3, or Pd(PPh3)4 and PdCl2(PPh3)2. Typical solvents include dimethoxyethane, tetrahydrofuran, acetonitrile, and toluene, which may be heated to a temperature ranging from 100 to 200° C. during the reaction.

[0166] [ka]

[0167] Example 2 Example compounds can be prepared by several of these routes described above. An example synthesis of PS009 is shown below in Scheme 7.

[0168] Starting with commercially available compound 1, Cl is displaced with amine 42 to give compound 43. The ester group of 43 is then reduced to a hydroxy group to form 44. The hydroxy 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 Wittig, Horner-Wadsworth-Emmons, or Knoevenagel reactions and spontaneous 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 displaced by amine 53 to form 54. Compound 54 can be converted to 55 via a Stille 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, PS010, etc., can be similarly made using the appropriate reagents and the methods described in Scheme 7. In some cases, protection and deprotection of certain groups on the reagents during synthesis is necessary.

[0171] (Biological Assay and Test Results) (Cell lines and cell cultures) The following human tumor cell lines, all retinoblastoma (Rb)-proficient, were 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 was the MCF10A nontransformed mammary epithelial cell line. 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 confirmed by short tandem repeat (STR) gene profiling using the GenePrint® 10 System (Promega).

[0172] (Kinase profiling) Kinase profiling of compounds was performed using 27 protein kinases. For each compound, IC 50 A 200 μM stock solution (5 mM) in 100% DMSO was prepared as the highest concentration (50 μM) of 100x stock solution used for determination of ATP. Serial half-log dilutions were performed and tested in single runs against 27 kinases: AKT1, CDC7 / DBF4, CDK1 / CycA2, CDK1 / CycB1, CDK1 / CycE1, CDK12 / CycK, CDK19 / CycC, CDK2 / CycA2, CDK2 / CycE1, CDK3 / CycC, CDK3 / CycE1, and CDK4 / CycA2. 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 CDKs and CDK6, and some of them (such as PS008, PS009, and PS016) showed additional affinity for CDK1 / 2. PS006, PS0010, and PS016 also had 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 the American Type Culture Collection and maintained in DMEM (Hyclone) or RPMI-1640 medium (Sigma) supplemented with 10% fetal bovine serum (Sigma). The non-transformed MCF10 cell line was maintained in MEGM mammary epithelial cell growth medium (Lonza). Immortalized mouse embryonic fibroblasts (MEFs) were maintained in DMEM supplemented with 10% fetal bovine serum.

[0176] [Table 2]

[0177] (Proliferation assay: GI 50 Determining the value) G.I. 50To determine the 50% growth inhibitory concentration (GIC), cells were seeded at 20-40% confluence in 96-well plates (10,000-20,000 cells / well, previously optimized for each cell line) and treated with inhibitors at 11 concentrations ranging from 10 μM to 0.033 μM. After 48 hours, cells were fixed with 4% PFA for 15 minutes, 10 μg / ml Hoechst 3334 (Molecular Probes, Thermo Fisher Scientific) for 30 minutes, and washed twice with PBS. Cells were imaged using a 20X dry objective (30 fields / well) on a high-content screening system (Opera Phoenix®, Perkin Elmer). Cell numbers were determined using Opera software (Perkin Elmer), and data were further processed using SPSS software. GI 50 were calculated using the dose-response inhibition tool in Prism6 (Graphpad Software Inc.). 50 was calculated by estimating the absolute value of

[0178] Cdk-deficient MEFs were plated in triplicate in 10-cm dishes (100,000 cells / well) and incubated with the MDA-MB-231 cell line for 12 h. 50 The cells were treated with selected compounds at the indicated concentrations based on the 3 and 6 days after treatment, and the cells were counted under a light microscope to estimate the relative cell proliferation in each condition.

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

[0180] (The subject compounds inhibit the growth of human cancer cell lines) The cell growth inhibition of the subject compounds was tested in several human cancer cell lines, including wild-type retinoblastoma protein: MDA-MB-231 (breast cancer), U87-MG (glioblastoma), H460 (lung cancer); and MCF10 (as examples of non-transformed human cells) and mutant cells. Table 3 shows the growth inhibitory concentrations (GI) required for a 50% reduction in growth for compounds tested in this set of human cancer cell lines. 50 As shown in Table 3, most of the subject compounds, except for PS002, inhibited cell proliferation with potency comparable to that of clinically known CDK4 / 6 inhibitors such as palbociclib, ribociclib, abemaciclib, RO-3306, or PD-0183812 (reference compound).

[0181] [Table 3]

[0182] (Cell cycle analysis) Cells were grown in 6 cm dishes and treated with the indicated compounds using GI 50 Cells were treated with 250 μg / ml RNase (Qiagen) for 24 hours. Cells were harvested by trypsinization, washed with PBS, and fixed with cold 70% ethanol. Cells were treated with 250 μg / ml RNase (Qiagen) for 30 minutes at 37°C and stained with 10 μg / ml propidium iodide (Sigma). Cell cycle analysis was performed by flow cytometry using an LSR Fortessa Analyzer. Cell cycle profiles were generated and analyzed using FlowJo software.

[0183] (Flow cytometry) After treatment with the indicated compounds, cells were harvested by multiple rounds of trypsinization and then fixed in cold 70% ethanol. DNA content was determined by staining with propidium iodide (10 μg / ml, Sigma-Aldrich). Data collection was performed on an LSR Fortessa analyzer (BD Biosciences) and analyzed using FlowJo software.

[0184] Current CDK4 / 6 inhibitors suppress proliferation by preventing cells from entering S phase. Cell cycle analysis for DNA content confirmed a robust G0 / G1 arrest in cells treated with palbociclib, ribociclib, or abemaciclib, consistent with the suppression of CDK4 / 6 activity (Figure 1). On the other hand, PD-0183812 arrested cells with a 4N DNA content, suggesting a G2 / M arrest or mitotic defect leading to tetraploid formation. PS008 and PS009 induced cell accumulation in G0 / G1, similar to CDK4 / 6-specific inhibitors, whereas other PS compounds, such as PS003, PS006, or PS016, induced G2 / M arrest, as detected by a 4N DNA content. PS004, PS005, PS007, and PS010 exhibited a mixed phenotype, causing cell accumulation in both G1 and G2 / M phases. Some compounds, such as PS005, PS007, and PS010, caused cell death, as indicated by increased sub-G1 accumulation (Fig. 1).

[0185] (Aging assay) MDA-MB-231 cells were seeded in 6-well plates (65,000 cells / well) and incubated with the selected compounds at their respective GI 50 On days 3, 7, and 14 after treatment, cells were stained overnight at 37°C with the Senescence β-Galactosidase Staining Kit (Cell Signaling). Blue-stained senescent cells were counted under a light microscope. The medium and compounds were renewed every 3 days.

[0186] Cell cycle arrest can be irreversible in the case of senescence induction. Cellular senescence is defined by several non-exclusive characteristics, including flattened cell morphology, positive staining for senescence-associated beta-galactosidase (SA-βGAL) at pH 6.0, DNA damage, and a specific secretory phenotype. To test senescence induction by the subject compounds, 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, indicative of senescence, with high efficiency compared to the reference CDK4 / 6 inhibitor.

[0187] (Antibodies and immunoblotting) MDA-MB-231 and MDA-MB-468 cells were cultured with GI, a marker corresponding to the MDA-MB-231 cell line. 50 Cells were treated with the indicated compounds using a 500-well plate and lysed in Laemmli buffer (60 mM Tris-Cl pH 6.8, 10% glycerol, 2% SDS) for 48 hours. Protein concentration was determined using the BCA method (Pierce). Whole-cell lysates (25 μg) were separated on TGX Criterion 4-15% Bis-Tris acrylamide gels (BioRad), transferred to nitrocellulose membranes (BioRad), and probed with the following specific antibodies: β-actin from Sigma-Aldrich; phosphorylated histone H3 (Ser10) from Millipore; retinoblastoma from BD Pharmingen; phosphorylated Rb (S807 / 811) and cyclin B from Cell Signaling; and cyclin A, p21, and FOXM1 from Santa Cruz Biotechnology.

[0188] (The subject compounds do not solely rely 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 explore the relative functional dependency of the subject compounds on CDK2 versus CDK4 or CDK6, the specific effects of PS004, PS006, and PS009 were tested in CDK-deficient mouse embryonic fibroblasts (MEFs) derived 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 a strong reliance on CDK4 / 6 activity (green columns in Figure 4) to exert its antiproliferative effects. The subject compound, however, effectively inhibited cell proliferation in Cdk4;Cdk6-deficient cells (green column) and to some extent in Cdk2;Cdk4;Cdk6 triple mutant cells (purple column), suggesting some dependence on the activity of CDK2 and other related kinases.

[0189] CDK4 / 6 kinases drive cell cycle progression by phosphorylating retinoblastoma protein (pRB), relieving its repressive activity on transcription. Therefore, CDK4 / 6-specific inhibitors are ineffective in pRB-deficient cells, as cell cycle transcription is induced independently of CDK4 / 6 activity. We assessed the extent to which the subject compounds depend on the presence of functional pRB. Two sets of human cancer cell lines, representing breast cancer and glioblastoma, were tested: pRB wild-type and pRB-deficient. As expected, as shown in Table 4 below, comparing pRB-mutant cells with functional pRB-retaining cells, palbociclib significantly reduced GI activity in both brain tumors (19.9 vs. 5.7 μM) and breast cancers (9.5 vs. 1.7 μM). 50PS004 was also less effective 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 pRB-proficient brain and breast cancer cells, suggesting that their effects are independent of the presence of this tumor suppressor. Consistent with these data, DNA content analysis showed that most compounds efficiently arrested pRB-deficient tumor cells in G2 / M(4N) cells, suggesting that these subject compounds may target other G0 / G1-independent activities in cells where the G1 checkpoint is blocked.

[0190] [Table 4]

[0191] Palbociclib is known to have a more potent antiproliferative effect in luminal-like cells compared to non-luminal breast cancer cell lines. This is thought to be due to the presence of active pRB signaling in luminal cells, which induces a strong dependency on CDK4 / 6 activity. Therefore, we tested our compounds in a panel of breast cancer cell lines to determine whether they have a broader inhibitory spectrum than known CDK4 / 6 inhibitors. Figure 5 shows the relative cell proliferation of a panel of human breast cancer cell lines, both luminal (ZR75-1, T47D, and MCF7) and non-luminal (HCC1143, MDA-MB-231, BT549, and MDA-MB-468) cell lines, after 5 days of treatment with palbociclib or PS009. While two of the four non-luminal cell lines were resistant to palbociclib, consistent with the pRB mutations in these cells, PS009 was able to efficiently inhibit both luminal and non-luminal breast cancer cells, including pRB-mutated luminal cells, confirming that PS009 has a broader spectrum than the known CDK4 / 6 inhibitor palbociclib and that PS009 does not depend on a functional pRB pathway to exert its antiproliferative effects.

[0192] In addition, cyclins A and B, FOXM1, and the cell cycle inhibitor p21 Cip1 We biochemically assessed the levels of various proteins involved in cell cycle progression, such as pRB (serine 807) and histone H3 (serine 10), as well as the phosphorylation status of pRB (serine 807) and histone H3 (serine 10). As shown in Figure 6, treatment with PS009 and palbociclib (or "palvo" for short) caused a strong inhibition of pRB phosphorylation and reduced the levels of most cell cycle markers, whereas with other compounds, these defects were less dramatic.

[0193] In Vivo Evaluation of Selected Subject Compounds For histological analysis, mouse tissues and human xenografts were fixed in 10% buffered formalin (Sigma) and embedded in paraffin wax. 3- or 5-μm-thick sections were stained with hematoxylin and eosin. Further immunohistochemistry was performed using specific antibodies against phosphorylated Rb (Ser807 / 811; Cell Signaling) or Ki67 (DAKO).

[0194] (tumor xenografts) Athymic nude mice (6-week-old females provided by Harlan Laboratories / ENVIGO) were treated with 5 × 10 cells in 100 μl PBS-0.1% glucose. 6 MDA-MB-231 cells were injected subcutaneously into both flanks. Approximately two weeks after injection, tumors grew to 100 mm 3Upon reaching 12 days of age, mice 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 in sesame oil and administered intraperitoneally at 100 mg / kg twice a week for 2 weeks. Palbociclib was dissolved in lactate buffer (50 mM sodium lactate, pH 4) and delivered orally at 100 mg / kg, 5 days a week, followed by a 2-day break for 12 days. Tumor growth was monitored using a caliper, and tumor size was estimated using the following formula: tumor volume (mm 3 ) = d2·D / 2, where d and D are the minimum and maximum diameters (mm), respectively. After treatment was completed, the mice were sacrificed, and 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 for comparative data were performed using two-tailed, unpaired Student's t-test or ANOVA for differential comparisons between two or more groups, respectively. Data with p<0.05 were considered statistically significant (*, p<0.05; **, p<0.01; ***, p<0.001).

[0196] Efficacy of the Subject Compounds For in vivo evaluation, we first tested the target engagement of the subject compounds in vivo. Phosphorylated RB staining in bone marrow, intestine, and spleen showed clear RB target inhibition in vivo, especially after treatment with PS004 and PS009 (Figure 7).

[0197] The therapeutic effects of the subject compounds were then tested by treating mice that had previously been subcutaneously injected with MDA-MB-231 breast cancer cells. Palbociclib (oral administration) was used as a reference, and once tumors became apparent, the subject compounds PS004, PS006, and PS009 were injected intraperitoneally. A 100 mg / kg dose was administered twice weekly for a total of two weeks of treatment. During the two-week treatment period, 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 antitumor effects as determined by overall tumor fold growth 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, although this did not reach statistical significance (Figure 9A). Furthermore, treatment with PS004 or palbociclib slightly reduced Ki67 levels, but these data did not reach statistical significance (Figure 9B).

[0199] Solubility and Stability of the Subject Compounds Given the generally low or lack of activity observed in vivo for several of the subject compounds tested, the solubility and stability of these compounds were tested in vivo. As shown in Table 5, while palbociclib is generally soluble and stable in vivo, the subject compounds exhibit clear deficiencies in their chemical formulation 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 or lack of activity observed in vivo for some of the subject compounds tested is believed to be due to their low solubility and / or poor stability. Therefore, it is difficult to evaluate such compounds in vivo in their current formulations. It is also believed that other formulations, such as combinations with cyclodextrins, may improve the solubility and / or stability of the subject compounds, resulting in advantageous or superior efficacy in vivo.

[0201] [Table 5]

[0202] (In vivo toxicity assessment) For toxicity studies, athymic nude mice (6-week-old females provided by Harlan Laboratories / ENVIGO) were treated with vehicle (DMSO) or PS compounds (PS004, PS006, and PS009). Stock solutions were diluted to 10 mg / ml in sesame oil and administered intraperitoneally (IP) at two doses (50 or 100 mg / kg) twice weekly for a 2-week period (3 mice per group). After treatment, mice were sacrificed, weighed, and several tissues (lungs, intestines, bone marrow, and spleen) were removed and fixed in 10% buffered formalin for histological examination. Blood counts were analyzed using a differential hematology analyzer (Abacus, Diatron).

[0203] To evaluate the toxicity of selected compounds, healthy female athymic nude mice were first intraperitoneally injected with PS004, PS006, PS009, and PD-0183812 (50 mg / kg or 100 mg / kg each) twice weekly for two weeks, and various parameters were measured at the endpoint. The reference compound, PD-0183812, induced significant weight loss and reduced total leukocyte and lymphocyte levels compared with the control DMSO (Figure 10). PS009 caused weight loss without abnormalities in blood counts, whereas PS004 reduced lymphocyte counts but without other significant changes. Both PD-0183812 (6 of 6 mice) and, to a lesser extent, PS004 (4 of 6 mice) induced pulmonary toxicity, inducing extensive hemorrhage in the lungs. PS006 and PS009 induced pulmonary hemorrhage accompanied by edema in one of six mice tested for each compound. Further histopathological analysis also revealed abnormal mitotic figures in the intestine and bone marrow hypoplasia / reactivity 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 subject compound) Inhibition of CDK4 / 6 holds important therapeutic potential in hormone-positive, HER2-negative advanced breast cancer, and three specific inhibitors have recently been approved for clinical use. However, these inhibitors are relatively ineffective in hormone-negative breast cancer tumors, and their potential use in other tumor types is still under preclinical or clinical evaluation. Because the CDK family consists of 20 different kinases and complementary roles are expected between different family members, the application of inhibitors that specifically inhibit CDK4 / 6 may be limited.

[0205] The subject compounds described herein exhibit relative specificity for CDK4 / 6 kinase and significant in vitro potency, similar to that achieved by known CDK4 / 6 inhibitors such as palbociclib. Furthermore, some of the subject compounds can bind to other related CDKs, such as CDK2 or CDK9, which have suggested therapeutic potential in certain settings. Specific inhibitors such as palbociclib and ribociclib are used in combination with hormonal therapy to treat breast cancer, while abemaciclib, a CDK4 / 6 inhibitor that may also have activity against CDK9, is effective as monotherapy. Among the subject compounds, PS004 has a high potential for inhibiting cell proliferation and arresting cells in the G1 / G2 / M phases of the cell cycle, and has affinity for not only CDK4 / 6 but also CDK2 / 9. This property opens up a new, unexplored mechanism of action for CDK inhibitors, distinct from the commercially available CDK4 / 6 inhibitors palbociclib, abemaciclib, and ribociclib. PS006 induced enhanced senescence compared to its counterparts, exhibited high affinity for CDK6 / 2 / 5 / 9, arrested cells in the G2 / M phase, and caused potent cell growth inhibition. PS009 arrested cells primarily in G1, exhibited very high SA-BGAL induction, and bound primarily to CDK4 / 6, but also showed an intriguing preference for CDK2 and CDK9 among other CDKs. Interestingly, some of these compounds were effective in inhibiting tumor cell growth 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 growth in Cdk4:Cdk6 double mutants or Cdk4:Cdk6:Cdk2 triple mutants, whereas the reference compound palbociclib showed no activity in those cells. Furthermore, PS009, but not palbociclib, was able to inhibit the growth of non-luminal pRB-mutant breast cancer cell lines. With these unique properties, the subject compounds described herein may offer great therapeutic potential.

[0206] Unless otherwise indicated, all numbers expressing quantities of ingredients, molecular weights, reaction conditions, and so forth used in the specification and claims are to be understood in all instances as modified by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, no attempt is made to limit the scope of the claims to equivalents, and each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0207] As used in the context of describing the present invention (particularly in the context of the claims below), the terms "a," "an," "the," and similar references should be construed to cover both the singular and the plural unless otherwise indicated or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. Any and all examples provided herein, or the use of exemplary language (e.g., "such as"), are intended to better clarify the invention and do not limit the scope of the claims. Nothing in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0208] Groupings of alternative elements or embodiments disclosed herein should not be construed as limiting. The members of each group may be referenced and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that for reasons of convenience or patentability, one or more members of a group may be included in, or deleted from, a group. When such inclusion or deletion occurs, the specification is deemed to include the modified group, and fulfills all recitations of a Markush group as used in the appended claims.

[0209] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to employ such variations as they see fit, and the inventors intend to practice the invention otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, combinations of the above-described elements in all possible variations are contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

[0210] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, and not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the scope of the claims should not be limited to the precise embodiments shown and described.

[0211] (Addendum) (Appendix 1) formula: [ka] or a salt thereof, During the ceremony, R 1 is an arbitrarily substituted C 1-6 Alkyl, or optionally substituted C 3-10 is cycloalkyl; R 1a is H or COCH3; R 1b is H or CH3; A is optionally substituted aryl or optionally substituted heteroaryl; D is optionally substituted piperidin-1,4-yl or optionally substituted piperazin-1,4-yl; R 11is R 8 , OR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 , CO2R 8 , or CONR 8 R 9 and 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 C optionally substituted with geminal-alkyl-O-alkyl- 1-6 is a hydrocarbyl, compound, or a salt thereof.

[0212] (Appendix 2) formula: [ka] or a salt thereof, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridin-2,5-yl, with the 2-position attached to NH and the 5-position attached to D; D is an optionally substituted piperidin-1,4-yl, attached at position 1 to A; R 1a is H or COCH3; R 1b is H or CH3; n is 1 or 2; A compound according to Appendix 1, or a salt thereof.

[0213] (Appendix 3) formula: [ka] or a salt thereof, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridin-2,5-yl, with the 2-position attached to NH and the 5-position attached to D; D is an optionally substituted piperidin-1,4-yl, attached at position 1 to A; R 1a is H or COCH3; R 1b is H or CH3, A compound according to Appendix 1, or a salt thereof.

[0214] (Appendix 4) formula: [ka] or a salt thereof, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridin-2,5-yl, with the 2-position attached to NH and the 5-position attached to D; D is an optionally substituted piperidin-1,4-yl, attached at position 1 to A; n is 1, 2, or 3; A compound according to Appendix 1, or a salt thereof.

[0215] (Appendix 5) formula: [ka] or a salt thereof, During the ceremony, R 1 is optionally substituted bicycloheptanyl; A is optionally substituted p-phenylene; D is unsubstituted piperazin-1,4-yl; A compound according to Appendix 1, or a salt thereof.

[0216] (Appendix 6) formula: [ka] or a salt thereof, During the ceremony, A is optionally substituted p-phenylene or optionally substituted pyridin-2,5-yl, with the 2-position attached to NH and the 5-position attached to D; D is an optionally substituted piperidin-1,4-yl, attached at position 1 to A; n is 1 or 2; A compound according to Appendix 1, or a salt thereof.

[0217] (Appendix 7) formula: [ka] or a salt thereof, During the ceremony, R 1 is optionally substituted bicycloheptanyl; A is an optionally substituted pyridin-2,5-yl, the 2-position of which is bonded to NH and the 5-position of which is bonded to D, and D is an optionally substituted piperazin-1,4-yl; or A is optionally substituted phenyl and D is unsubstituted piperazin-1,4-yl; A compound according to Appendix 1, or a salt thereof.

[0218] (Appendix 8) R 1 is unsubstituted cyclopentanyl or unsubstituted bicyclo[2.2.1]heptanyl.

[0219] (Appendix 9) The compound of claim 1, wherein A is optionally substituted p-phenylene.

[0220] (Appendix 10) The compound of Appendix 1, wherein D is unsubstituted piperidin-1,4-yl.

[0221] (Appendix 11) The compound of Appendix 1, wherein D is unsubstituted piperazin-1,4-yl.

[0222] (Appendix 12) R 11 is E-Hy, where E is a bond, C 1-5 Alkylene, C 1-5 -O-alkylene, or [ka] and Hy is OH or H.

[0223] (Appendix 13) E is an optionally substituted C 1-5 The compound of claim 12, wherein the alkylene is alkylene.

[0224] (Appendix 14) The compound of claim 12, wherein E is —(CH 2 ) 3 —.

[0225] (Appendix 15) The compound of claim 12, wherein E is —(CH 2 ) 2 CH(CH 3 )—.

[0226] (Appendix 16) The compound of claim 12, wherein E is —O—(CH 2 )CH(CH 3 )—.

[0227] (Appendix 17) E is [ka] 13. The compound of claim 12, wherein

[0228] (Appendix 18) 13. The compound of claim 12, wherein Hy is OH.

[0229] (Appendix 19) 13. The compound of claim 12, wherein Hy is H.

[0230] (Appendix 20) [ka] [ka] or a salt thereof.

[0231] (Appendix 21) A method of treating a cancer associated with a CDK inhibitor, comprising administering an effective amount of a compound of claim 1.

Claims

1. formula: 【Chemistry 1】 or a salt thereof, During the ceremony, R １ is an optionally substituted C5-7 cycloalkyl; R １ａ is H or COCH ３ and R １ｂ is H or CH ３ and A is optionally substituted aryl; D is optionally substituted piperidin-1,4-yl; R １１ is one of the following groups: 【Chemistry 2】 That is, compound, or a salt thereof.

2. The compound of claim 1, further comprising the following formula: 【Transformation 3】 or a salt thereof, During the ceremony, R １ is an optionally substituted C5-7 cycloalkyl; A is optionally substituted p-phenylene or optionally substituted pyridin-2,5-yl; the 2-position is bonded to NH and the 5-position is bonded to D; D is an optionally substituted piperidin-1,4-yl, attached at the 1-position to A; R １ａ is H or COCH ３ and R １ｂ is H or CH ３ and n is 1 or 2; compound, or a salt thereof.

3. The compound of claim 1, further comprising the following formula: 【Chemistry 4】 or a salt thereof, During the ceremony, R 1 is optionally substituted C 5-7 cycloalkyl; A is optionally substituted p-phenylene or optionally substituted pyridin-2,5-yl, with the 2-position bonded to NH and the 5-position bonded to D; D is an optionally substituted piperidin-1,4-yl, attached at the 1-position to A; R １ａ is H or COCH ３ and R １ｂ is H or CH ３ That is, compound, or a salt thereof.

4. The compound of claim 1, further comprising the following formula: 【Transformation 5】 or a salt thereof, During the ceremony, R １ is optionally substituted bicycloheptanyl; A is an optionally substituted pyridin-2,5-yl; the 2-position is bonded to NH and the 5-position is bonded to D; D is an optionally substituted piperazin-1,4-yl; or A is optionally substituted p-phenylene and D is unsubstituted piperazin-1,4-yl; R 11 is 【Transformation 6】 That is, The compound of claim 1, or a salt thereof.

5. R １ 2. The compound of claim 1, wherein: is unsubstituted cyclopentanyl or unsubstituted bicyclo[2.2.1]heptanyl.

6. The compound of claim 1, wherein A is optionally substituted p-phenylene.

7. The compound of claim 1, wherein D is unsubstituted piperidin-1,4-yl.

8. The compound of claim 1, wherein D is unsubstituted piperazin-1,4-yl.

9. A compound according to any one of claims 1 to 8 for the treatment of cancers associated with CDK inhibitors.

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