CN106336412A - 2-(N-Oxyaryl-2-ylamino)-pyrrolopyrimidines and purines as CDK4/6 inhibitors - Google Patents

Abstract

2-(N-Oxyaryl-2-ylamino)-pyrrolopyrimidine and purine compounds as CDK4/6 inhibitors. The present invention relates to pyrrolopyrimidine and purine compounds of formula (I) and salts thereof, including pharmaceutically acceptable salts, and the preparation method and use of pharmaceutical compositions thereof. The compound of the present invention is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, and can be used for treating diseases and disorders mediated by CDK4/6, such as cancer and the like. .

Description

2-(N-Oxyaryl-2-ylamino)-pyrrolopyrimidines and purines as CDK4/6 inhibitors

technical field

The present invention relates to novel pyrrolopyrimidine and purine compounds and pharmaceutical compositions thereof, especially 2-(N-oxidized aromatic ring-2 base amino)-pyrrolopyrimidine and purine compounds and their pharmaceutical compositions as CDK4/6 inhibitors pharmaceutical composition. The invention also relates to the use of these compounds and compositions in the treatment of CDK4/6 hyperproliferative disorders such as cancer.

Background technique

The life of a cell begins with the cell cycle, and the normal operation of the cell cycle depends on fine regulatory mechanisms. Cyclin-dependent kinases (cyclin-dependent kinases, CDKs) are central to cell cycle regulation. CDKs are a class of serine (Ser)/threonine (Thr) kinases, as important signal transduction molecules in cells, and the CDK-cyclin complex formed by cyclin (cyclin), involved in cell growth, proliferation, dormancy or into apoptosis.

Studies have found that the abnormality of CDKs in cell cycle regulation is closely related to the occurrence and development of tumors. About 90% of tumors have enhanced activity of CDKs. Therefore, abnormal regulation of CDKs has become a sign of tumorigenesis. Small molecule CDK inhibitors can effectively inhibit the growth of various tumor cells. It can also be used to treat cardiovascular disorders and diseases caused by various infectious agents, including fungi, protozoan parasites and DNA and RNA viruses. At the same time, selective CDK small molecule inhibitors can improve the consequences of various autoimmune disorders, etc. Therefore, the research and development of drugs targeting CDK4/6 protein kinase is a field of great significance.

Small molecule inhibitors of cyclin-dependent kinases have been reported [Clinical Cancer Research, 2013, 19, 6173-6182]. The present invention designs and synthesizes small-molecule inhibitors targeting CDK kinases on the basis of existing discoveries, and the series of compounds have the potential to treat various diseases.

Contents of the invention

The life of a cell begins with the cell cycle, and the normal operation of the cell cycle depends on fine regulatory mechanisms. Cyclin-dependent kinases (cyclin-dependent kinases, CDKs) are central to cell cycle regulation. CDKs are a class of serine (Ser)/threonine (Thr) kinases, as important signal transduction molecules in cells, and the CDK-cyclin complex formed by cyclin (cyclin), involved in cell growth, proliferation, dormancy or into apoptosis.

Studies have found that the abnormality of CDKs in cell cycle regulation is closely related to the occurrence and development of tumors. About 90% of tumors have enhanced activity of CDKs. Therefore, abnormal regulation of CDKs has become a sign of tumorigenesis. Small molecule CDK inhibitors can effectively inhibit the growth of various tumor cells. It can also be used to treat cardiovascular disorders and diseases caused by various infectious agents, including fungi, protozoan parasites and DNA and RNA viruses. At the same time, selective CDK small molecule inhibitors can improve the consequences of various autoimmune disorders, etc. Therefore, the research and development of drugs targeting CDK4/6 protein kinase is a field of great significance.

Small molecule inhibitors of cyclin-dependent kinases have been reported [Clinical Cancer Research, 2013, 19, 6173-6182]. The present invention designs and synthesizes small-molecule inhibitors targeting CDK kinases on the basis of existing discoveries, and the series of compounds have the potential to treat various diseases.

Contents of the invention

The compounds of the present invention are CDK4/6 inhibitors and are useful in the treatment of diseases and disorders mediated by CDK4/6, such as cancer, including mantle cell lymphoma, liposarcoma, non-small cell lung cancer, melanoma, squamous cell esophagus cancer and breast cancer. The invention also relates to the use of the compounds of the invention or pharmaceutical compositions comprising the compounds of the invention for the treatment of disorders associated therewith.

The present invention relates to novel pyrrolopyrimidine and purine compounds and their salts, including pharmaceutically acceptable salts, having the formula (I):

in:

R ¹ is selected from , , , , , , , , , , alkenyl, alkynyl, heterocyclyl, aryl, heteroaromatic ring, wherein R ⁴ and R ⁵ are respectively hydrogen, hydrocarbyl, cycloalkyl, heteroatom cycloalkyl, aryl or heteroaryl ring;

R ² is C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or C ₃ -C ₇ heterocyclocycloalkyl, optionally substituted by 1 to 3 halogens, OH or NH ₂ ; optionally substituted by one Phenyl substituted with a substituent selected from C _1-6 alkyl, C(CH ₃ ) ₂ CN and OH; piperidinyl optionally substituted by a cyclopropyl or C _1-6 alkyl; optionally substituted by a Cyclopropyl or C _1-6 alkyl substituted tetrahydropyranyl; or bicyclo [2.2.1] heptyl;

R ³ is selected from NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkoxyalkyl, C ₁ -C ₈ haloalkyl, optionally with halogen, OH, NH ₂ , alkoxy or alkylamino;

R ⁶ and R ⁷ are respectively a hydrogen group, a hydrocarbon group, a cycloalkyl group, a heteroatom cycloalkyl group, an aryl group or a heteroaryl ring; or when R ⁶ and R ⁷ are connected to the same C, N or O atom to form a heterocycle, Forming a ring containing 3-8 atoms, such as piperidine, piperazine and morpholine, etc., the heterocycle can be independently selected from 1-3 halogen, alkyl, cycloalkyl, alkoxy, hydroxyl, trifluoro Methyl, aminoalkyl, amino, cyano, 1-2 alkylamino or alkylcarbonyl substitutions;

A ¹ - A ⁴ are N or CR ⁸ respectively, wherein R ⁸ is selected from H, F, Cl, CH ₃ , CFH ₂ , CF ₂ H or CF ₃ ;

L is a bond, C(O) , O or S(O) _1~2 .

The pyrrolopyrimidine and purine compounds of the present invention can be mixed with pharmaceutical carriers or excipients (such as pharmaceutically acceptable carriers and excipients) according to conventional pharmaceutical preparation techniques to form pharmaceutical preparations. The pyrrolopyrimidine compound can be mixed as an active ingredient in any commonly used oral dosage form, including tablets, capsules and liquid preparations (such as elixirs and suspensions), which contain coloring agents, flavoring agents, additives, stabilizers and taste-masking substances. For mixed oral dosage forms, the pyrrolopyrimidine compound as an active ingredient can be mixed with various common tableting materials such as starch, calcium carbonate, lactose, sucrose and dicalcium phosphate to facilitate tableting and filling into capsules. The pyrrolopyrimidine compound can be dissolved or suspended in a pharmaceutically acceptable sterile liquid carrier such as sterile water, sterile organic solvent or a mixture of both. The liquid carrier can be a carrier suitable for injection, such as physiological saline, propylene glycol or polyethylene glycol aqueous solution. In other cases, it may also be prepared by dispersing the micronized active ingredient in an aqueous solution of starch or sodium carboxymethylcellulose or in a suitable oil such as peanut oil. Liquid pharmaceutical preparations (meaning sterile solutions or suspensions) can be used for intravenous, intramuscular, intraperitoneal or subcutaneous injection.

The present invention also provides a pharmaceutical composition, which comprises at least one of the pyrrolopyrimidine and purine compounds described in the present invention as an active ingredient. In addition, the pharmaceutical composition may also contain one or more inorganic or organic, solid or liquid pharmaceutically acceptable carriers or excipients. The term "pharmaceutically acceptable" refers to an additive or composition that is physiologically tolerable and generally does not produce allergic or similar adverse reactions (such as dizziness, etc.) when administered to animals such as mammals (such as humans). Pharmaceutical carriers and excipients may include, but are not limited to, diluents such as lactose, dextrose, mannose and/or glycerin; lubricants; polyethylene glycols; binders such as magnesium aluminum silicate, starch, gelatin, methyl Cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; and, if desired, disintegrants such as starch, agar, alginic acid or a salt thereof such as sodium alginate; and/or adsorbents, colorants preservatives, stabilizers, flavoring and sweetening agents.

detailed description

Various aspects and features of the present invention are further described below.

Abbreviations used herein are generally known to those skilled in the art, or may be easily understood based on basic knowledge.

The starting materials used in the preparation of the compounds of the present invention are known, can be prepared according to known methods, or are commercially available.

The invention also relates to novel intermediates and/or starting materials. Particular preference is given to reaction conditions and novel intermediates which are the same or similar to those mentioned in the examples.

Both intermediates and final products can be worked up and/or purified according to conventional methods including pH adjustment, extraction, filtration, drying, concentration, chromatography, trituration, crystallization, and the like.

In addition, the compounds of the present invention can be prepared by various methods known in the art or variations on the methods described herein.

The following examples are only used to illustrate the present invention and do not limit the present invention in any way.

Example 1 2-((7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-5-(piperazin-1-yl ) Preparation of pyridine-1-oxide.

Step 1.1: 5-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-2-((7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3- d] Preparation of pyrimidin-2-ylamino)pyridine-1-oxides.

Add 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (835 mg, 2.85 mmol) into a 100 mL two-necked bottle, 2-Amino-5-(4-tert-butoxycarbonylpiperazin-1-yl)pyridine nitroxide (840 mg, 2.85 mmol), palladium acetate (16 mg, 0.071 mmol), BINAP (89 mg, 0.143 mmol), Cesium carbonate (1.39 g, 4.3 mmol) was evacuated and replaced with argon three times, then 20 mL of dioxane was added, heated to 100°C, and reacted overnight. TLC detection, after the reaction was completed, 300 mL of ethyl acetate was added, washed successively with saturated aqueous sodium bicarbonate solution, water, and saturated brine, the organic phase was dried, filtered, and the organic solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain brown yellow Solid 1.067 g, yield = 68%. ¹ H NMR (400 MHz, Chloroform- d ) δ 9.63 (s, 1H), 8.73 (d, J = 1.3 Hz, 1H), 8.65 (d, J = 9.4 Hz, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.05 (dd, J = 9.5, 2.5 Hz, 1H), 6.46 (d, J = 1.3 Hz, 1H), 4.86 – 4.72 (m, 1H), 3.59 (t, J = 5.0 Hz, 4H ), 3.15 (s, 6H), 3.06 (t, J = 5.0 Hz, 4H), 2.66 – 2.43 (m, 2H), 2.15 – 1.96 (m, 4H), 1.85 – 1.64 (m, 2H), 1.48 ( s, 9H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 163.83, 154.53, 153.19, 151.76, 151.55, 141.72, 139.75, 132.98, 126.73, 118.85, 113.68, 113.18, 100.74, 80.24, 58.01, 49.49, 39.42, 35.20, 30.20, 28.41 , 24.61.

Step 1.2: 5-(Piperazin-1-yl)-2-((7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino ) Preparation of pyridine-1-oxide.

Add 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-((7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[ 2,3-d] Pyrimidin-2-ylamino)pyridine-1-oxide (700 mg, 1.27 mmol) and 10 mL of tetrahydrofuran, stirred at 0°C for 15 minutes, added 6 mL of concentrated hydrochloric acid dropwise, and the addition was completed Back moved to room temperature and stirred for 2 hours.After the completion of the reaction, adjust the pH>8 with saturated aqueous sodium carbonate solution, remove the solvent, dissolve the product with absolute ethanol, remove ethanol, and the residue is purified by column chromatography to obtain light yellow solid 510.2 mg, Yield = 89%. ¹ H NMR (400 MHz, Chloroform- d ) δ 9.60 (s, 1H), 8.72 (s, 1H), 8.63 (d, J = 9.4 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.03 (dd, J = 9.5, 2.4 Hz, 1H), 6.45 (s, 1H), 4.77 (p, J = 8.9 Hz, 1H), 3.29 – 3.17 (m, 8H), 3.14 ( s, 6H), 2.94 (s, 1H), 2.86 (s, 1H), 2.60 – 2.45 (m, 2H), 2.14 – 1.91 (m, 4H), 1.83 – 1.62 (m, 2H).

Example 2 5-(N-methylpiperazin-1-yl)-2-((7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 2-ylamino)pyridine-1-oxides.

Add 5-(piperazin-1-yl)-2-((7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidine-2 -Amino)pyridine-1-oxide (200 mg, 0.44 mmol) and 5 mL of methanol. Add formaldehyde aqueous solution (37%, 330uL), stir for 10 minutes and then add sodium cyanoborohydride (195 mg, 3.1 mmol). Stir overnight at room temperature. After the reaction was completed, the solvent was removed, and the residue was purified by column chromatography as a light yellow solid 88.5 mg, yield = 43%. ¹ H NMR (400 MHz, Chloroform- d ) δ 9.62 (s, 1H), 8.71 (s, 1H), 8.60 (d, J = 9.4 Hz, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.01 (dd, J = 9.4, 2.5 Hz, 1H), 6.45 (s, 1H ), 4.77 (p, J = 9.0 Hz, 1H), 3.23 – 3.06 (m, 11H), 2.59 (t, J = 5.0 Hz, 4H), 2.56 – 2.48 (m, 2H), 2.35 (s, 2H) , 2.12 – 1.96 (m, 4H), 1.78 – 1.62 (m, 2H) ^.13 C NMR (101 MHz, CDCl ₃ ) δ 163.88, 153.36, 151.78, 151.63, 141.75, 139.32, 135,117.27, 7 113.04, 100.74, 57.98, 54.61, 49.12, 46.01, 39.41, 30.17, 24.59.

Example 3 2-{[7-cyclopentyl-6-(oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-5-(piperazine- Preparation of 1-yl)pyridine-1-oxides.

Step 3.1: Preparation of 5-(2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)oxazole.

Add 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (100 mg), p-toluenesulfonylmethylisocyanide (86 mg, 0.44 mmol), potassium carbonate (72 mg, 0.52 mmol) and 5 mL of methanol, heated to 65°C and stirred for 4 hours. After the reaction was completed, the solvent was removed, 100 mL of saturated aqueous sodium bicarbonate was added, extracted three times with dichloromethane, the organic phases were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, the organic solvent was removed, and the residue was passed through the column layer Analysis and purification gave 109.9 mg of light yellow solid, yield = 95%. ¹ H NMR (400 MHz, Chloroform- d ) δ 8.81 (d, J = 1.1 Hz, 1H), 8.06 (s, 1H), 7.38 (s, 1H), 6.76 (s, 1H), 4.93 (p, J = 8.5 Hz, 1H), 2.50 – 2.36 (m, 3H), 2.17 – 2.00 (m, 4H), 1.78 – 1.61 (m, 2H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 153.53, 152.86, 151.80, 151.43, 143.20, 129.59, 126.69, 117.57, 101.82, 57.83, 31.01, 24.96.

Step 3.2: 5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-((7-cyclopentyl-6-(oxazol-5-yl)-7H-7H-pyrrolo[2, 3-d] Preparation of pyrimidin-2-yl)amino)pyridine nitroxides.

The method is the same as step 1.1, and the productive rate is 62%. ¹ H NMR (500 MHz, Chloroform- d ) δ 9.11 (d, J = 1.5 Hz, 1H), 7.92 (s, 1H), 7.56 (d, J = 1.4 Hz, 1H), 7.31 (s, 1H), 7.08 (d, J = 1.5 Hz, 1H), 6.68 – 6.58 (m, 2H), 6.53 (s, 1H), 4.68 (t, J = 6.9 Hz, 1H), 3.57 (t, J = 5.2 Hz, 4H ), 3.02 (t, J = 5.2 Hz, 4H), 2.26 – 2.01 (m, 2H), 2.03 – 1.90 (m, 4H), 1.90 – 1.76 (m, 2H), 1.47 (s, 9H). ¹³ C NMR (125 MHz, Common NMR Solvents) δ 178.26, 158.97, 154.80, 151.62, 151.59, 150.83, 149.42, 140.54, 128.51, 127.19, 126.29, 122.52, 118.79, 116.08, 105.92, 79.29, 60.32, 47.61, 45.83, 33.50, 28.27, 26.20.

Step 3.3 2-{[7-cyclopentyl-6-(oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-5-(piperazine-1 -yl)pyridine-1-oxide preparation.

The method is the same as 1.2, yield = 75%, ¹ H NMR (500 MHz, Chloroform- d ) δ 9.10 (d, J = 1.5 Hz, 1H), 7.92 (s, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.30 (s, 1H), 7.07 (d, J = 1.7 Hz, 1H), 6.83 (dd, J = 7.5, 1.5 Hz, 1H), 6.62 (d, J = 7.4 Hz, 1H), 6.50 ( s, 1H), 4.66 (td, J = 8.9, 8.0, 5.7 Hz, 1H), 3.57 (t, J = 5.1 Hz, 4H), 2.89 (t, J = 5.1 Hz, 4H), 2.22 – 2.03 (m , 2H), 1.94 (dddd, J = 13.8, 9.0, 4.8, 2.0 Hz, 4H), 1.80 (ddd, J = 8.9, 5.8, 3.4 Hz, 2H). ¹³ C NMR (125 MHz, Common NMR Solvents) δ 178.26, 158.97, 151.62, 151.59, 150.83, 149.42, 140.54, 128.51, 127.19, 126.29, 122.52, 118.79, 116.08, 105.92, 60.32, 49.57, 45.55, 33.50, 26.20。

CDK4/6 enzyme activity assay.

The Caliper Mobility Shift Assay method was used to test the inhibitory activity of compounds on CDK4/6 enzymes. This technology applies the basic concept of capillary electrophoresis to the microfluidic environment to detect enzymatic experiments without adding stop reagents. The substrate used in the experiment is a fluorescently labeled polypeptide. Under the action of the enzyme in the reaction system, the substrate is converted into a product, and its charge also changes accordingly. The Mobility-Shift Assay uses the substrate and product According to the difference in charge, the two are separated and detected separately.

Experimental material: CDK4/CycD3 (Carna, Cat.No 04-105, Lot. No 10CBS-0429 C, GST-CDK4(1-303end)/GSTCycD3(1-292end)); Peptide FAM-P8 (GL Biochem, Cat. No. 112396, Lot. No. P100804-XZ112396); ATP (Sigma, Cat. No. A7699-1G, CAS No. 987-65-5); DMSO (Sigma, Cat. No. D2650, Lot. No. 474382); EDTA (Sigma, Cat. No. E5134, CAS No. 60-00-4); 96-well plate (Corning, Cat. No. 3365, Lot. No. 22008026); 384-well plate (Corning, Cat. No. 3573, Lot. No. 12608008).

Experimental method: To measure the apparent Km of ATP on the Mobility Shift, add 5 μL/well of 2× enzyme & peptide mixture into a 384 microwell plate. Add 5 μL/well of three-fold serially diluted 2×ATP solution to start the reaction. Centrifuge at room temperature for 1 min, put in 23°C incubator for 60 min, add 5 uL/well 3×stop buffer (100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% Coating Reagent #3; 50 mM EDTA) to stop The reaction was placed on the Caliper EZ Reader I for detection; the compound was diluted 4-fold in a 96-microwell plate at a concentration of 5 μM, and 100 μL of 100% DMSO was added as a no-compound-no-kinase control group, and 10 μL of the compound was added to a new 96-well microplate, then add 90μL, 1×kinase base buffer (20 mM HEPES, pH 7.5; 0.01% Triton X-100; 10 mM MgCl ₂ ; 2 mM DTT), and place the plate on the shaker for 10 minutes To mix the compound; take 5 μL of the mixture per well and add it to a 384-well microplate. Add 10 μL of 2.5×enzyme solution to each well of a 384-well microplate. After incubating at room temperature for 10 minutes, add 10 μL, 2.5× peptide solution (add FAM-labeled peptide and ATP to 1× kinase base buffer) in each well. Kinase reaction, stop at specified time, incubate at 30°C. Add 25μL stop buffer to terminate the reaction. Placed on Caliper EZ Reader I for detection.

Table 1 shows the inhibitory efficacy of compounds on CDK4 kinase.

Table 2 shows the inhibitory efficacy of the compounds on CDK6 kinase.

Table 1

Table 2

Claims (10)

1. Formula (I) compound or its pharmaceutically acceptable salt in: R ¹ is selected from , , , , , , , , , , alkenyl, alkynyl, heterocyclyl, aryl, heteroaromatic ring, wherein R ⁴ and R ⁵ are respectively hydrogen, hydrocarbyl, cycloalkyl, heteroatom cycloalkyl, aryl or heteroaryl ring; R ² is C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or C ₃ -C ₇ heterocyclocycloalkyl, optionally substituted by 1 to 3 halogens, OH or NH ₂ ; optionally substituted by one Phenyl substituted with a substituent selected from C _1-6 alkyl, C(CH ₃ ) ₂ CN and OH; piperidinyl optionally substituted by a cyclopropyl or C _1-6 alkyl; optionally substituted by a Cyclopropyl or C _1-6 alkyl substituted tetrahydropyranyl; or bicyclo [2.2.1] heptyl; R ³ is selected from NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkoxyalkyl, C ₁ -C ₈ haloalkyl, optionally with halogen, OH, NH ₂ , alkoxy or alkylamino; R ⁶ and R ⁷ are respectively hydrogen group, hydrocarbon group, cycloalkyl, heteroatom cycloalkyl, aryl or heteroaromatic ring; or when R ⁶ and R ⁷ are connected to the same C, N or O atom to form a heterocyclic ring , forming a ring containing 3-8 atoms, such as piperidine, piperazine and morpholine, etc., the heterocycle can be independently selected from 1-3 halogen, alkyl, cycloalkyl, alkoxy, hydroxyl, tri Fluoromethyl, aminoalkyl, amino, cyano, 1-2 alkylamino or alkylcarbonyl substitutions; A ¹ -A ⁴ are N or CR ⁸ , wherein R ⁸ is selected from H, F, Cl, CH ₃ , CFH ₂ , CF ₂ H or CF ₃ ; L is a bond, C(O) , O or S(O) _1~2 . 2. The compound of formula (I) according to claim ¹ , R selected from , , , , ; R ² is selected from cyclopentyl; R ³ is selected from , , , , , ; L is the valence bond. 3. A method of treating a disease, disorder or syndrome associated with CDK4/6 inhibition, said method comprising administering to an individual in need thereof a compound or a prodrug thereof according to any one of claims 1-2 or comprising a compound of formula I A pharmaceutical composition of a compound or its prodrug and a pharmaceutically acceptable excipient. 4. A method of treatment as claimed in claim 3, wherein said disease, disorder or syndrome is hyperproliferative in an individual selected from cancer and inflammation, wherein the individual is an animal including a human. 5. A method of inhibiting a cyclin-dependent kinase (eg, CDK4/6), said method comprising contacting said kinase with a kinase-inhibiting compound according to any one of claims 1-2. 6. A method of regulating a cellular process (eg cell division) by inhibiting the activity of a cyclin-dependent kinase using a compound according to any one of claims 1 to 12. 7. A compound according to any one of claims 1 to 2, for use in the prevention or treatment of a disease state as described herein. 8. Use of a compound according to any one of claims 1 to 2 for the manufacture of a medicament, wherein said medicament is for any one or more of the uses defined herein. 9. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 10. A method of treating cancer in a patient in need thereof, the method comprising an effective amount of a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.