CN106336412A - 2-(N-oxidized aromatic ring-2 amino)-pyrrolopyrimidinyl and purines compound as CDK4/6 inhibitor - Google Patents
2-(N-oxidized aromatic ring-2 amino)-pyrrolopyrimidinyl and purines compound as CDK4/6 inhibitor Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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Abstract
The invention relates to a 2-(N-oxidized aromatic ring-2 amino)-pyrrolopyrimidinyl and purines compound as a CDK4/6 inhibitor. The invention relates to the pyrrolopyrimidinyl and purines compound as CDK4/6 inhibitor, its salt, medicinal salt, and a pharmaceutical composition preparation method and a purpose. The compound is the cyclin-dependent kinases 4/6 (CDK4/6) inhibitor, which can be used for treating disease and disorder mediated by CDK4/6, such as cancer.
Description
Technical field
The present invention relates to new pyrrolopyrimidine and purine compound and its pharmaceutical composition, 2- (n- aoxidizes aromatic ring -2 base the amino)-pyrrolopyrimidine especially as cdk4/6 inhibitor and purine compound and its pharmaceutical composition.The invention still further relates to these compounds and compositionss purposes in treatment cdk4/6 hyperproliferative disorders are as cancer.
Background technology
The life of cell starts from cell cycle, and the normal operation of cell cycle depends on fine regulatory mechanism.Have been found that cell cycle protein dependent kinase (cyclin-dependent kinase,
Cdk) be cell cycle regulating core.Cdks is a class serine (ser)/threonine (thr) kinases, as intracellular important signal transducers, and the cdk-cyclin complex that cycle element (cyclin) is formed, participate in growth, propagation, dormancy or the entrance apoptosis of cell.
Research finds that in cell cycle regulating, the exception of cdks is closely related with the generation of tumor, development.There is cdks increased activity in about 90% tumor, therefore, the regulation and control of cdks become a tumorigenic mark extremely.Small molecule cdk inhibitor can effectively suppress the growth of kinds of tumor cells.Can be used for treating the disease that cardiovascular disorder and multi-infection agent lead to, including funguses, protozoon parasite and dna and rna virus.Meanwhile, selectivity cdk micromolecular inhibitor can improve consequence of various autoimmune disorders etc..Therefore, the research and development of targeting cdk4/6 protein kinase medicine are far reaching fields.
With regard to cell cycle protein dependent kinase micromolecular inhibitor had document report [clinical cancer research, 2013,19,
6173-6182].The present invention be it has been found that on the basis of, the micromolecular inhibitor of the targeting cdk kinases of design synthesis, this series compound has the potentiality treating multiple diseases.
Content of the invention
The life of cell starts from cell cycle, and the normal operation of cell cycle depends on fine regulatory mechanism.Have been found that cell cycle protein dependent kinase (cyclin-dependent kinase,
Cdk) be cell cycle regulating core.Cdks is a class serine (ser)/threonine (thr) kinases, as intracellular important signal transducers, and the cdk-cyclin complex that cycle element (cyclin) is formed, participate in growth, propagation, dormancy or the entrance apoptosis of cell.
Research finds that in cell cycle regulating, the exception of cdks is closely related with the generation of tumor, development.There is cdks increased activity in about 90% tumor, therefore, the regulation and control of cdks become a tumorigenic mark extremely.Small molecule cdk inhibitor can effectively suppress the growth of kinds of tumor cells.Can be used for treating the disease that cardiovascular disorder and multi-infection agent lead to, including funguses, protozoon parasite and dna and rna virus.Meanwhile, selectivity cdk micromolecular inhibitor can improve consequence of various autoimmune disorders etc..Therefore, the research and development of targeting cdk4/6 protein kinase medicine are far reaching fields.
With regard to cell cycle protein dependent kinase micromolecular inhibitor had document report [clinical cancer research, 2013,19,
6173-6182].The present invention be it has been found that on the basis of, the micromolecular inhibitor of the targeting cdk kinases of design synthesis, this series compound has the potentiality treating multiple diseases.
Content of the invention
The compound of the present invention is cdk4/6 inhibitor, can be used for treating the disease being mediated by cdk4/6 and disorder, such as cancer, inclusion lymphoma mantle cell, liposarcoma, nonsmall-cell lung cancer, melanoma, the squamous cell esophageal carcinoma and breast carcinoma.The invention still further relates to treating associated disorder using the compound of the present invention or the pharmaceutical composition of the compound comprising the present invention.
The present invention relates to new pyrrolopyrimidine and purine compound and its salt, the inclusion officinal salt with formula (i):
Wherein:
r1It is selected from、、、、、、、、、, thiazolinyl, alkynyl, heterocyclic radical, aryl, hetero-aromatic ring, wherein r4And r5It is hydrogen-based, alkyl, cycloalkyl, heteroatomic ring alkyl, aryl or hetero-aromatic ring respectively；
r2It is c1-c6Alkyl, c3-c7
Cycloalkyl or c3-c7
Heterocycloall yl groups, optional have 1 to 3 halogen, oh or nh2Replace；Optionally it is selected from c by one1-6Alkyl, c (ch3)2cn
The phenyl replacing with the substituent group of oh；Optionally by a cyclopropyl or c1-6The piperidyl that alkyl replaces；Optionally by a cyclopropyl or c1-6The THP trtrahydropyranyl that alkyl replaces；Or bicyclo- [2.2.1] heptane base；
r3Selected from nr6r7、c1-c6Alkyl, c3-c7
Cycloalkyl, c1-c8Alkoxyl, c1-c8Alkoxyalkyl, c1-c8Haloalkyl, optional have halogen, oh, nh2, alkoxyl or alkylamino；
r6And r7It is hydrogen-based, alkyl, cycloalkyl, heteroatomic ring alkyl, aryl or hetero-aromatic ring respectively；Or work as r6And r7Connect same c, n or o atom, form heterocycle, form annular atom and comprise 3-8 atom, as piperidines, piperazine and morpholine etc., heterocycle can be replaced independently selected from halogen, alkyl, cycloalkyl, alkoxyl, hydroxyl, trifluoromethyl, aminoalkyl, amino, cyano group, 1-2 alkylamino or alkyl carbonyl by 1-3；
a1– a4It is n or cr respectively8, wherein r8Selected from h, f, cl, ch3、cfh2、cf2H or cf3；
L is valence link, c (o), o or s (o)1~2.
Pyrrolopyrimidine of the present invention and purine compound can be mixed to form pharmaceutical preparation according to conventional medicine preparation technique with pharmaceutical carrier or excipient (such as pharmaceutically acceptable carrier and excipient).Described Pyrrolopyrimidine compounds can be blended in any commonly employed peroral dosage form as active component, described peroral dosage form includes tablet, capsule and liquid preparation (such as elixir and suspensoid), wherein comprises the material of coloring agent, correctivess, stabilizer and taste masking.For mixing peroral dosage form, described Pyrrolopyrimidine compounds can be mixed with various conventional tablet materials (such as starch, Calcium Carbonate, Lactose, sucrose and dicalcium phosphate) to help tabletting as active component and load capsule.By dissolving in described Pyrrolopyrimidine compounds pharmaceutically acceptable sterile liquid carrier such as sterilized water, sterile organic solvent or both mixture or can be suspended.Liquid-carrier can be the carrier being suitable for injection, such as normal saline, propylene glycol or Aqueous Solutions of Polyethylene Glycol.In other cases, micronized active component can also be dispersed in starch or the aqueous solution of sodium carboxymethyl cellulose or be dispersed in and to be obtained in suitable oil (such as Oleum Arachidis hypogaeae semen).Liquid pharmaceutical formulation (referring to sterile solution or suspensoid) can be used for intravenous injection, intramuscular injection, peritoneal injection or subcutaneous injection.
Present invention also offers a kind of pharmaceutical composition, this pharmaceutical composition comprises at least one pyrrolopyrimidine of the present invention as active component and purine compound.In addition, described pharmaceutical composition can also comprise pharmaceutically acceptable carrier or the excipient of one or more inorganic or organic, solid or liquid.Term " pharmaceutically acceptable " refers to physiologically to can tolerate and generally will not produce additive or the compositionss of allergy or similar untoward reaction (such as dizziness etc.) when being administered to animal such as mammal (the such as mankind).Pharmaceutical carrier and excipient can include but is not limited to diluent, such as Lactose, glucose, mannose and/or glycerol；Lubricant；Polyethylene Glycol；Binding agent, such as Magnesiumaluminumsilicate, starch, gelatin, methylcellulose, sodium carboxymethyl cellulose and/or Polyvinylpyrrolidone；And, if necessary, also include disintegrating agent, such as starch, agar, alginic acid or its salt such as sodium alginate；And/or adsorbent, coloring agent, preservative, stabilizer, correctivess and sweeting agent.
Specific embodiment
It is further described with feature to various aspects of the present invention below.
Abbreviation used herein is usually well-known to those skilled in the art, or can be understandable according to rudimentary knowledge.
Initiation material employed in the preparation of the compounds of this invention is known, can be prepared or commercially available according to known method.
The invention still further relates to new intermediate and/or initiation material.Those the same or like reaction conditions mentioned particularly preferably and in embodiment and new intermediate.
Intermediate and end-product can carry out post processing and/or purification according to conventional methods, and described conventional method includes adjusting ph, extraction, filtration, drying, concentration, chromatography, grinding, crystallization etc..
In addition, the compounds of this invention can also be prepared by the alternative of various methods known in the art or methods described herein.
The following example is only used for illustrating the present invention, limits the invention never in any form.
The embodiment 1 2- (preparation of (7- cyclopenta-6- dimethylcarbamoyl-7h- pyrrolo- [2,3-d] pyrimidine -2 --amino)-5- (piperazine-1- base) pyridine-1- oxide.
Step 1.1:5- (4- (tertbutyloxycarbonyl) piperazine-1- base)-2- (preparation of (7- cyclopenta-6- dimethylcarbamoyl-7h- pyrrolo- [2,3-d] pyrimidine -2 --amino) pyridine-1- oxide.
2- chloro- 7- cyclopenta-n is added in 100 ml two-mouth bottles, n- dimethyl -7h- pyrrolo- [2,3-d] pyrimidine -6- Methanamide (835 mg, 2.85 mmol), 2- amino -5- (4- tert-butoxycarbonyl-piperazine -1- base) nitrogen oxidation pyridine (840 mg, 2.85 mmol), palladium (16 mg, 0.071 mmol), binap(89 mg, 0.143 mmol), cesium carbonate (1.39 g, 4.3 mmol), evacuation displacement argon three times, it is subsequently adding dioxane 20 ml, is heated to 100 DEG C, reaction is overnight.Tlc detects, adds ethyl acetate 300ml after completion of the reaction, uses saturated sodium bicarbonate aqueous solution, water successively, saturated common salt water washing, organic faciess are dried, and filter, organic solvent is removed under reduced pressure, residue passes through column chromatography purification, obtains yellow-brown solid 1.067 g, yield=68%.1h 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).13c nmr (101 mhz, cdcl3)
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- (piperazine-1- base)-2- (preparation of (7- cyclopenta-6- dimethylcarbamoyl-7h- pyrrolo- [2,3-d] pyrimidine -2 --amino) pyridine-1- oxide.
5- (4- (tertbutyloxycarbonyl) piperazine-1- base)-2- ((7- cyclopenta-6- dimethylcarbamoyl-7h- pyrrolo- [2 is added in 50 ml single port bottles; 3-d] pyrimidine -2 --amino) pyridine-1- oxide (700 mg; 1.27 mmol) and oxolane 10 ml; put into and stir 15 minutes at 0 DEG C; Deca concentrated hydrochloric acid 6 ml, moves to after completion of dropping and is stirred at room temperature 2 hours.After completion of the reaction, adjust ph with saturated aqueous sodium carbonate > 8, remove solvent, use anhydrous alcohol solution product, remove ethanol, residue passes through column chromatography purification, obtains faint yellow solid 510.2 mg, yield=89%.1h 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).
Embodiment 2 5- (the n- methylpiperazine-1-yl)-2- (preparation of (7- cyclopenta-6- dimethylcarbamoyl-7h- pyrrolo- [2,3-d] pyrimidine -2 --amino) pyridine-1- oxide.
5- (piperazine-1- base)-2- ((7- cyclopenta-6- dimethylcarbamoyl-7h- pyrrolo- [2 is added in 50ml two-mouth bottle; 3-d] pyrimidine -2 --amino) pyridine-1- oxide (200 mg, 0.44 mmol) and methanol 5 ml.Add formalin (37%, 330ul), stirring added sodium cyanoborohydride (195 mg, 3.1 mmol) after 10 minutes.It is stirred overnight at room temperature.After completion of the reaction, remove solvent, residue passes through faint yellow solid 88.5 mg of column chromatography purification, yield=43%.1h 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).13c nmr (101 mhz, cdcl3)
δ 163.88, 153.36, 151.78,
151.63, 141.75, 139.32, 132.80, 126.27, 117.87, 113.55, 113.04, 100.74, 57.98,
54.61, 49.12, 46.01, 39.41, 30.17, 24.59.
The preparation of embodiment 3 2- { [7- cyclopenta -6- (oxazole -5- base) -7h- pyrrolo- [2,3-d] pyrimidine -2-base] amino } -5- (piperazine -1- base) pyridine -1- oxide.
The preparation of step 3.1:5- (2- chloro- 7- cyclopenta -7h- pyrrolo- [2,3-d] pyrimidine -6- base) oxazole.
Add 2- chloro- 7- cyclopenta -7h- pyrrolo- [2,3-d] pyrimidine -6- formaldehyde (100 mg) in 50 ml single port bottles, to Methyl benzenesulfonyl methyl isocyanide (86 mg, 0.44 mmol), potassium carbonate (72 mg, 0.52 mmol) and methanol 5 ml, it is heated to 65 DEG C, stir 4 hours.Reaction removes solvent after terminating, add 100 ml saturated sodium bicarbonate aqueous solutions, extracted 3 times with dichloromethane, merge organic faciess, saturated aqueous common salt washed once, anhydrous magnesium sulfate is dried, filter, remove organic solvent, residue obtains faint yellow solid 109.9 mg, yield=95% by column chromatography purification.1h 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).13c nmr (101 mhz, cdcl3)
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.
The preparation of step 3.2:5- (4- tert-butoxycarbonyl-piperazine -1- base) -2- ((7- cyclopenta -6- (oxazole -5- base) -7h-7h- pyrrolo- [2,3-d] pyrimidine -2-base) amino) nitrogen oxidation pyridine.
Method is with step 1.1, yield 62 %.1h 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).13c 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.
The preparation of step 3.3 2- { [7- cyclopenta -6- (oxazole -5- base) -7h- pyrrolo- [2,3-d] pyrimidine -2-base] amino } -5- (piperazine -1- base) pyridine -1- oxide.
Method same 1.2, yield=75%,1h 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).13c 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 assay.
Using the inhibitory activity to cdk4/6 enzyme for the caliper mobility shift assay method test compound, the basic concept of capillary electrophoresis is applied in microfluidic environment this technology, and in the case of being added without stopping reagent, detection zymetology is tested.Substrate for experiment is with fluorescently-labeled polypeptide, in the presence of enzyme in reaction system, substrate is changed into product, the electric charge that it is carried also there occurs corresponding change, mobility-shift assay utilizes the charged difference of substrate and product institute, the two is carried out separating, and is detected respectively.
Experiment 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 technique: measure the apparent km of atp on mobility shift, add 2 × enzyme ＆ peptide mixed liquor in 5 μ l/ holes in 384 microwell plates.Add 2 × atp solution of 5 μ l/ hole three times gradient dilutions, start reaction.Room temperature is centrifuged 1min, after putting into 23 ° of c incubator reaction 60min, adds 5 ul/ hole 3 × stop buffer(100 mm hepes, ph 7.5；0.015% brij-35；0.2% coating reagent #3；50 mm edta) terminating reaction, it is placed in and detected on caliper ez reader i；In 96 microwell plates, in 5 μm of concentration, 4 times of gradient dilutions are carried out to compound, add 100 μ l, 100%dmso, as no compound no kinase control group, takes 10 μ l compounds to be added to 96 new hole microwell plates, add 90 μ l, 1 × kinase base buffer (20 mm
hepes, ph 7.5 ; 0.01% triton x-100; 10 mm mgcl2;2 mm dtt), this plate is placed on shaking table upper 10 minute to mix compound；Every hole takes 5 μ l mixed liquors to be added in 384 hole microwell plates.The each Kong Zhongjia of 384 hole microwell plates 10 μ l, 2.5 × enzyme solution.Under room temperature, incubation adds 10 μ l in each Kong Zhongzai after 10 minutes again, 2.5 × polypeptide solution (adding fam-labeled peptide and atp in 1 × kinase base buffer).Kinase reaction, it is intended that the time stops, being incubated 30 DEG C.Plus 25 μ l stop buffer terminating reactions.It is placed in and detected on caliper ez reader i.
Table 1 is the suppression effect to cdk4 kinases for the compound.
Table 2 is the suppression effect to cdk6 kinases for the compound.
Table 1
Table 2
Claims (10)
1. formula (i) compound or pharmaceutically acceptable salt thereof
Wherein:
r1It is selected from、、、、、、、、、, thiazolinyl, alkynyl, heterocyclic radical, aryl, hetero-aromatic ring, wherein r4And r5It is hydrogen-based, alkyl, cycloalkyl, heteroatomic ring alkyl, aryl or hetero-aromatic ring respectively；
r2It is c1-c6Alkyl, c3-c7Cycloalkyl or c3-c7Heterocycloall yl groups, optional have 1 to 3 halogen, oh or nh2Replace；Optionally it is selected from c by one1-6Alkyl, c (ch3)2The phenyl that the substituent group of cn and oh replaces；Optionally by a cyclopropyl or c1-6The piperidyl that alkyl replaces；Optionally by a cyclopropyl or c1-6The THP trtrahydropyranyl that alkyl replaces；Or bicyclo- [2.2.1] heptane base；
r3Selected from nr6r7、c1-c6Alkyl, c3-c7Cycloalkyl, c1-c8Alkoxyl, c1-c8Alkoxyalkyl, c1-c8Haloalkyl, optional have halogen, oh, nh2, alkoxyl or alkylamino；
r6And r7It is hydrogen-based, alkyl, cycloalkyl, heteroatomic ring alkyl, aryl or hetero-aromatic ring respectively；Or work as r6And r7Connect same c, n or o atom, form heterocycle, form annular atom and comprise 3-8 atom, as piperidines, piperazine and morpholine etc., heterocycle can be replaced independently selected from halogen, alkyl, cycloalkyl, alkoxyl, hydroxyl, trifluoromethyl, aminoalkyl, amino, cyano group, 1-2 alkylamino or alkyl carbonyl by 1-3；
a1-a4It is n or cr respectively8, wherein r8Selected from h, f, cl, ch3、cfh2、cf2H or cf3；
L is valence link, c (o), o or s (o)1~2.
2. formula (i) compound according to claim 1, r1It is selected from、、、、；r2Selected from cyclopenta；r3It is selected from、、、、、；L is valence link.
3. the method for the treatment disease, obstacle or syndrome related to cdk4/6 inhibitory action, methods described includes applying the compound of any one or the pharmaceutical composition of its prodrug or contained i compound or its prodrug and pharmaceutically acceptable excipient according to claim 1-2 to its individuality of needs.
4. the Therapeutic Method as described in claim 3, wherein said disease, obstacle or syndrome are excess proliferatives in individuality, and selected from cancer and inflammation, wherein individuality is the animal including people.
5. the method for suppression cyclin dependent kinase (for example, cdk4/6), methods described is included described kinases and is contacted with the compound of the suppression kinases of any one according to claim 1 to 2.
6. the method for regulating cell process (for example, cell division), it suppresses the activity of the kinases of cyclin dependence by using the compound of any one according to claim 1 to 12.
7. the compound of any one according to claim 1 to 2, the prevention for morbid state as described herein or treatment.
8. the compound of any one according to claim 1 to 2 is used for the purposes of medicine preparation, and wherein said medicine is for any one or more purposes defined herein.
9. pharmaceutical composition, the compound or pharmaceutically acceptable salt thereof comprising any one of the claims and comprise pharmaceutically useful carrier or excipient.
10. the method for the treatment of cancer in the patient that it is treated in needs, the method includes the compound or pharmaceutically acceptable salt thereof of any one of the claims of effective dose.
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Application publication date: 20170118 |