WO2018192273A1 - 一种新型细胞周期蛋白依赖性激酶cdk9抑制剂 - Google Patents
一种新型细胞周期蛋白依赖性激酶cdk9抑制剂 Download PDFInfo
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- WO2018192273A1 WO2018192273A1 PCT/CN2018/070108 CN2018070108W WO2018192273A1 WO 2018192273 A1 WO2018192273 A1 WO 2018192273A1 CN 2018070108 W CN2018070108 W CN 2018070108W WO 2018192273 A1 WO2018192273 A1 WO 2018192273A1
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- 0 *C*c1nc(-c2cc(N*)ncc2*)c[s]1 Chemical compound *C*c1nc(-c2cc(N*)ncc2*)c[s]1 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present application relates to compounds which are inhibitors of the cyclin-dependent kinase CDK9, pharmaceutical compositions comprising these compounds, and methods and uses for inhibiting serine acid kinase activity using these compounds or compositions.
- CDK cyclin-dependent kinases
- CKI cyclin-dependent kinases
- CDK9 belongs to the serine kinase, and its complex with the corresponding cyclin is called positive transcription elongation factor b (P-TEFb).
- P-TEFb positive transcription elongation factor b
- This complex is capable of phosphorylating RNA polymerase II (RNA polymerase II) and some negative sexual transcription elongation factor (NELF and N-TEF) allows transcription to be extended from the initiation site and is a core molecule for transcriptional elongation (Sims RJ 3 rd et al. Genes Dev, 2004, 18: 2437-68; Yamaguchi Y et al. Mol Cell Biol, 2002, 22: 2918-27).
- CDK9 abnormal expression levels of CDK9 or (and) kinase activity cause abnormal expression of various proteins in the cell or (and) its mRNA levels.
- anti-apoptotic proteins such as Bcl-2
- cell cycle-associated regulatory proteins such as cyclin D1
- p53 pathway-related proteins certain proteins of the NF- ⁇ B pathway, and related to the tumor microenvironment
- proteins such as VEGF and the like. It can be said that CDK9 is one of the most critical molecules in the development of tumors (Shapiro GI. J Clin Oncol, 2006, 24: 1770-83).
- the invention relates to inhibitors of cyclin dependent kinases.
- the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
- Y is selected from fluorobenzoyl group, an optionally substituted N R 3 groups of trans-4- aminocyclohexyl, N, and optionally substituted with a group R 3 trans-4- aminocyclohexyl methyl;
- Z is selected from the group consisting of NH, S and O;
- R 1 is selected from the group consisting of hydrogen and halogen
- R 2 is selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, optionally substituted R 4 groups C3-C6 heterocycloalkyl, and optionally substituted with R 4 a phenyl group;
- R 3 is selected from the group consisting of C 2 -C 6 alkanoyl and C 1 -C 3 alkoxy (C 1 -C 3 )alkyl;
- R 4 is selected from the group consisting of cyano and halogen.
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier or excipient And optionally other therapeutic agents.
- the invention further relates to the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, for use in the treatment, prevention or amelioration of, or effected by, modulation of serine kinase activity Or use in a medicament in which a disease, disorder or condition of cyclin-dependent kinase activity is involved.
- the disease, disorder or condition is preferably cancer.
- Figures 1a-1d show the effect of Compound 1 on cellular signaling pathways in MV4-11 (Figure 1a), OCI-AML-3 ( Figure 1b), HL-60 ( Figure 1c) and NB4 ( Figure 1d) cell lines;
- Figures 2a-2d show that Compound 1 is involved in apoptosis-associated proteins in MV4-11 (Fig. 2a), OCI-AML-3 (Fig. 2b), HL-60 (Fig. 2c) and NB4 (Fig. 2d) cell lines. influences;
- Figures 3a-3c show the effect of Compound 1 on cell cycle in MV4-11 (Figure 3a), HL-60 ( Figure 3b) and NB4 ( Figure 3c) cell lines.
- Figures 4a-4c show the results of an experiment in which Compound 1 inhibits tumor growth in a tumor mouse model, wherein Figure 4a shows the relative body weight of the mice injected subcutaneously into leukemia cells (calculated based on the body weight on the day of administration) as a function of time. Figure 4b shows the change in tumor-loaded tumor size over time; Figure 4c shows the final calculated tumor inhibition rate (TGI) for each group, and the values for each data point shown in the graph reflect the mean of each experimental group. .
- TGI tumor inhibition rate
- the present invention employs conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology within the skill of the art.
- naming and laboratory operations and techniques chemically related to analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are known to those skilled in the art.
- the foregoing techniques and procedures can be carried out by conventional methods well known in the art and described in various general and more specific documents, which are cited and discussed in this specification.
- Alkyl means an aliphatic hydrocarbon group which may be a branched or straight chain alkyl group. Depending on the structure, the alkyl group may be a monovalent group or a divalent group (i.e., an alkylene group). In the present invention, the alkyl group is preferably a "lower alkyl group” having 1 to 6 carbon atoms, and even more preferably a "lower alkyl group” having 1 to 3 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.
- Alkoxy means an -O-alkyl group wherein alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
- aryl means that the planar ring has a delocalized ⁇ -electron system and contains 4n+2 ⁇ electrons, where n is an integer.
- the aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms.
- the aryl group can be optionally substituted.
- aryl includes carbocyclic aryl (eg phenyl) and heterocyclic aryl (or "heteroaryl” or “heteroaryl”) groups (eg pyridine).
- the term includes monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.
- aryl as used herein means that each of the atoms constituting the ring in the aryl ring is a carbon atom.
- the aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms.
- the aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, and fluorenyl.
- the aryl group may be a monovalent group or a divalent group (i.e., an arylene group).
- Alkyl (aryl) means an alkyl group, as defined herein, substituted by an aryl group, as defined herein.
- Non-limiting alkyl (aryl) groups include benzyl, phenethyl and the like.
- cycloalkyl refers to a monocyclic or polycyclic group containing only carbon and hydrogen.
- the cycloalkyl group includes a group having 3 to 10 ring atoms.
- the cycloalkyl group may be a monovalent group or a divalent group (for example, a cycloalkylene group).
- the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, more preferably a "lower cycloalkyl group” having 3 to 6 carbon atoms.
- Alkyl (cycloalkyl) means an alkyl group, as defined herein, substituted by a cycloalkyl group, as defined herein.
- Non-limiting alkyl (cycloalkyl) groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.
- halo or halogen refers to fluoro, chloro, bromo and iodo.
- haloalkyl and haloalkoxy include structures of alkyl, or alkoxy, wherein at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by a halogen atom, the halogen atoms are the same or different from each other.
- cyano refers to a radical of the formula -CN.
- alkanoyl or “alkylcarbonyl” refers to a carbonyl group further substituted with an alkyl group. Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, and the like.
- amino refers to the group -NH 2.
- alkylamino refers to an amino substituent further substituted with one or two alkyl groups, in particular a group -NRR', wherein R and R' are each independently selected from hydrogen or lower alkyl, provided that - NRR' is not -NH 2 .
- aminoalkyl refers to an alkyl substituent further substituted with one or more amino groups.
- cyanoalkyl refers to an alkyl substituent further substituted with one or more cyano groups.
- heteroalkyl as used herein means that one or more of the backbone chains of the alkyl groups defined herein are heteroatoms such as oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof.
- the heteroatom(s) may be located anywhere within the heteroalkyl group or at a position where the heteroalkyl group is attached to the remainder of the molecule.
- heteroaryl refers to a ring heteroatom comprising one or more selected from the group consisting of nitrogen, oxygen and sulfur in the aryl group.
- the N-containing "heteroaryl” moiety means that at least one of the backbone atoms in the ring of the aryl group is a nitrogen atom.
- the heteroaryl group may be a monovalent group or a divalent group (i.e., a heteroarylene group).
- heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazole , isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, oxazolyl, pyridazinyl, pyridazinyl, pyridazinyl, isoindole Sulfhydryl, pteridinyl, fluorenyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazinyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl , naph
- heterocycloalkyl as used herein means that one or more of the atoms constituting the ring in the non-aryl ring is a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur.
- the heterocycloalkyl ring may be composed of three, four, five, six, seven, eight, nine or more than nine atoms.
- the heterocycloalkyl ring can be optionally substituted.
- heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic gums, cyclic thioimines, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4- Oxetane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, bar Bitoteric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, Te
- alkyl refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein.
- alkyl refers to an alkyl group, as defined herein, substituted by a heterocycloalkyl group, as defined herein.
- optionally substituted or “substituted” means that the group mentioned may be substituted by one or more additional groups, each of which is independently and independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, hydroxy, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methylsulfonyl and the like.
- GI 50 refers to the concentration of a drug required to inhibit 50% of cell growth, that is, the concentration of a drug when the growth of 50% of cells (such as cancer cells) is inhibited or controlled.
- IC 50 refers to obtain 50% of the maximum amount of a particular inhibitory effect of the test compound, the concentration or effect of a certain dose of analytical measurements.
- CDK9 kinase inhibitor of the invention CDK9 kinase inhibitor of the invention
- the present invention relates to inhibitors of the cyclin dependent kinase CDK9.
- the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
- Y is selected from fluorobenzoyl group, an optionally substituted N R 3 groups of trans-4- aminocyclohexyl, N, and optionally substituted with a group R 3 trans-4- aminocyclohexyl methyl;
- Z is selected from the group consisting of NH, S, and O;
- R 1 is selected from the group consisting of hydrogen and halogen
- R 2 is selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, optionally substituted R 4 groups C3-C6 heterocycloalkyl, and optionally substituted with R 4 a phenyl group;
- R 3 is selected from the group consisting of C 2 -C 6 alkanoyl and C 1 -C 3 alkoxy (C 1 -C 3 )alkyl;
- R 4 is selected from the group consisting of cyano and halogen.
- Y is selected from the following structures:
- R 1 is chlorine
- R 2 is selected from the group consisting of hydrogen, methyl, cyclopropyl, cyclohexyl, 4-tetrahydropyranyl optionally substituted by cyano, and phenyl optionally substituted by fluorine.
- R 3 is selected from the group consisting of acetyl, 2-methoxyethyl, (R)-1-methyl-2-methoxyethyl, and (S)-1-methyl 2-methoxyethyl.
- particularly preferred compounds include:
- Described herein are novel kinase inhibitors.
- Pharmaceutically acceptable salts, solvates, esters, acids, pharmaceutically active metabolites and prodrugs of this compound are also described herein.
- the compounds described herein are administered to a subject in need thereof to be metabolized in their bodies to produce metabolites which are then used to produce the desired effect, including the desired therapeutic effect.
- compositions described herein can be made and/or used as pharmaceutically acceptable salts.
- pharmaceutically acceptable salts include, but are not limited to, (1) acid addition salts formed by reacting the free base form of the compound with a pharmaceutically acceptable mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reaction with an organic acid such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, lemon Acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonate Acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic
- organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like.
- Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
- Corresponding counterions of pharmaceutically acceptable salts can be analyzed and characterized using a variety of methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any of them. combination.
- the salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or lyophilization using an aqueous solution.
- Screening and characterization of pharmaceutically acceptable salts, polymorphs, and/or solvates can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, microscopy, elemental analysis.
- Various spectral techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state).
- Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.
- the present application also provides a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, pharmaceutically active metabolite or prodrug of said compound, and pharmaceutically acceptable A carrier or excipient, and optionally other therapeutic agents.
- the drug comprising a compound of the invention may be administered to a patient by at least one of injection, oral, inhalation, rectal and transdermal administration.
- the amount of a given drug when treating a patient in accordance with the present invention depends on a number of factors, such as the particular dosage regimen, the type of disease or disorder and its severity, and the subject in need of treatment. Or the uniqueness of the host (eg, body weight), however, depending on the particular circumstances, including, for example, the particular drug that has been employed, the route of administration, the condition being treated, and the subject or host being treated, the dosage administered can be known in the art. The method is routinely decided. Generally, the dosage administered will typically range from 0.02 to 5000 mg/day, for example from about 1 to 1500 mg per day, for dosages used in adult treatment.
- the desired dose may conveniently be presented as a single dose, or concurrently (or in a short period of time) or in divided doses at appropriate intervals, such as two, three, four or more divided doses per day. It will be understood by those skilled in the art that although the above dosage ranges are given, the specific effective amount can be appropriately adjusted depending on the condition of the patient and in connection with the diagnosis of the physician.
- a compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to inhibit cyclin-dependent kinases (CDK)
- CDK cyclin-dependent kinases
- the activity of cyclins is especially the activity of CDK9.
- the compound of the formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof can be used for the treatment or prevention of one or more diseases selected from the group consisting of non-small cell lung cancer, small Cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, prostate cancer, bladder cancer, liver cancer, skin cancer, glioma, breast cancer, melanoma, glioblastoma, rhabdomyosarcoma, ovarian cancer, astrocytes Tumor, Ewing's sarcoma, retinoblastoma, epithelial cell carcinoma, colon cancer, kidney cancer, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, and nasopharyngeal carcinoma.
- diseases selected from the group consisting of non-small cell lung cancer, small Cell lung cancer, lung adenocarcinoma, lung squamous cell
- the compound of formula (I) described herein, or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, or a pharmaceutical composition comprising the same can be used as an inhibitor of CDK9, It can be used alone or in combination with other therapeutic agents for the treatment of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, prostate cancer, bladder cancer, liver cancer, skin cancer, glial Tumor, breast cancer, melanoma, malignant glioma, rhabdomyosarcoma, ovarian cancer, astrocytoma, Ewing's sarcoma, retinoblastoma, epithelial cell carcinoma, colon cancer, kidney cancer, gastrointestinal stromal tumor, Leukemia, histiocytic lymphoma, and nasopharyngeal carcinoma.
- the reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments which are subsequently added by the methods described herein and/or methods known in the art.
- provided herein are methods of making a serine kinase inhibitor compound described herein and methods of use thereof.
- the compounds described herein can be synthesized using the protocols synthesized below.
- Compounds can be synthesized by methods analogous to those described below, using the appropriate starting materials.
- reaction product can be isolated and purified using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. These products can be characterized using conventional methods, including physical constants and map data.
- Step 1 Synthesis of 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
- Step 3 Synthesis of (1r,4R)-N 1 -((R)-1-methoxypropan-2-yl)cyclohexane-1,4-diamine
- Step 4 Synthesis of tert-butyl 5-bromothiazol-2-ylcarbamate
- 5-Bromothiazol-2-amine hydrobromide (105 g, 403 mmol) was suspended in 500 mL of tetrahydrofuran, and dimethylaminopyridine (2.41 g, 20 mmol) was added to form white turbid, and di-tert-butyl dicarbonate was slowly added dropwise. A solution of (105.6 g, 484.6 mmol) in tetrahydrofuran was reacted at room temperature for two days.
- Step 5 Synthesis of tert-butyl 4-bromothiazol-2-ylcarbamate
- Step 8 Synthesis of (4-bromothiazol-2-yl)((4-cyanotetrahydro-2H-pyran-4-yl)methyl)carbamic acid tert-butyl ester
- Step 9 (4-(5-Chloro-2-fluoropyridin-4-yl)thiazol-2-yl)((4-cyano-tetrahydro-2H-pyran-4-yl)methyl)carbamic acid Synthesis of tert-butyl ester
- reaction solution was cooled to room temperature, ethyl acetate and methanol were added, filtered, and the filter cake was washed with ethyl acetate.
- the filtrate was concentrated, and the residue was dissolved in dichloromethane, washed with saturated brine, and then evaporated.
- Step 10 4-(((4R,4r)-4-(((R)-1-methoxypropan-2-yl)amino)cyclohexyl)amino) Synthesis of pyridin-4-yl)thiazol-2-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile
- Step 2 Synthesis of (4-(5-chloro-2-fluoropyridin-4-yl)thiazol-2-yl)(tert-butyl (tetrahydro-2H-pyran-4-yl)methyl)carbamate
- Step 3 ((1r,4r)-4-((5-chloro-4-(2-((tetrahydro-2H-pyran-4-yl)methyl)amino)thiazol-4-yl)pyridine) Synthesis of tert-butyl 2-yl)amino)cyclohexyl)carbamate
- Step 4 (1r,4r)-N 1 -(5-chloro-4-(2-((tetrahydro-2H-pyran-4-yl)methyl)amino)thiazol-4-yl)pyridine- Synthesis of 2-yl)cyclohexane-1,4-diamine
- Step 2 (1S,4r)-N 1 -(5-chloro-4-(2-((tetrahydro-2H-pyran-4-yl)methyl)amino)thiazol-4-yl)pyridine- Synthesis of 2-yl)-N4-((S)-1-methoxypropan-2-yl)cyclohexyl-1,4-diamine
- Step 2 (1R,4r)-N 1 -(5-chloro-4-(2-((tetrahydro-2H-pyran-4-yl)methyl)amino)thiazol-4-yl)pyridine- Synthesis of 2-yl)-N 4 -((R)-1-methoxypropan-2-yl)cyclohexane-1,4-diamine
- Example 7 4-(2-(((1r,4r)-4-aminocyclohexyl)methyl)amino)-5-chloropyridine-4- Synthesis of s-N-((tetrahydro-2H-pyran-4-yl)methyl)thiazol-2-amine
- Step 1 ((1r,4r)-4-(((5-chloro-4-(2-((tetrahydro-2H-pyran-4-yl)methyl)amino)thiazol-4-yl)) Synthesis of tert-butyl pyridin-2-yl)amino)methyl)cyclohexyl)carbamate
- Step 2 4-(2-(((1r,4r)-4-aminocyclohexyl)methyl)amino)-5-chloropyridin-4-yl)-N-((tetrahydro-2H-pyran) Synthesis of -4-yl)methyl)thiazole-2-amine
- Step 1 Synthesis of ((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)carbamic acid tert-butyl ester
- Step 2 Synthesis of (1r,4r)-N 1 -(2-methoxyethyl)cyclohexane-1,4-diamine
- Step 3 Synthesis of tert-butyl (4-(5-chloro-2-fluoropyridin-4-yl)thiazol-2-yl)carbamate
- Step 4 Synthesis of tert-butyl (4-(5-chloro-2-fluoropyridin-4-yl)thiazol-2-yl)(methyl)carbamate
- Step 5 (1r,4r)-N 1 -(5-chloro-4-(2-(methylamino)thiazol-4-yl)pyridin-2-yl)-N 4 -(2-methoxy B Synthesis of cyclohexane-1,4-diamine
- Step 1 Synthesis of tert-butyl (4-(5-chloro-2-fluoropyridin-4-yl)thiazol-2-yl)(cyclohexylmethyl)carbamate
- Step 2 (1r, 4r)-N 1 -(5-chloro-4-(2-((cyclohexylmethyl)amino)thiazol-4-yl)pyridin-2-yl)-N 4 -(2- Synthesis of methoxyethyl)cyclohexane-1,4-diamine
- Step 1 Synthesis of benzyl (4-(5-chloro-2-fluoropyridin-4-yl)thiazol-2-yl)carbamic acid tert-butyl ester
- Step 2 (1r,4r)-N 1 -(4-(2-(Benzylamino)thiazol-4-yl)-5-chloropyridin-2-yl)-N 4 -(2-methoxyethyl Synthesis of cyclohexane-1,4-diamine
- Benzyl (4-(5-chloro-2-fluoropyridin-4-yl)thiazol-2-yl)carbamic acid tert-butyl ester (240 mg, 0.57 mmol), (1r,4r)-N 1 -(2- Methoxyethyl)cyclohexane-1,4-diamine (280 mg, 1.14 mmol), diisopropylethylamine DIEA (369 mg, 2.86 mol), cesium fluoride (268 mg, 1.71 mmol) dissolved in dimethyl In sulfoxide (8 mL), the reaction was stirred at 120 ° C for 3 days. The reaction was detected by LCMS and product was formed.
- Step 1 Synthesis of (4-(5-chloro-2-fluoropyridin-4-yl)thiazol-2-yl)(4-fluorobenzyl)carbamic acid tert-butyl ester
- Step 2 (1r,4r)-N 1 -(5-chloro-4-(2-((4-fluorobenzyl)amino)thiazol-4-yl)pyridin-2-yl)-N 4 -(2 Synthesis of -methoxyethyl)cyclohexane-1,4-diamine
- Step 1 Synthesis of tert-butyl (4-(5-chloro-2-fluoropyridin-4-yl)thiazol-2-yl)(cyclopropylmethyl)carbamate
- Step 2 (1r,4r)-N 1 -(5-chloro-4-(2-((cyclopropylmethyl)amino)thiazol-4-yl)pyridin-2-yl)-N 4 -(2 Synthesis of -methoxyethyl)cyclohexane-1,4-diamine
- Example 15 4-(((4-S5-chloro-2-((S)-1-methoxypropan-2-yl)amino)) Cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl)-tetrahydro-2H-pyran-4-carbonitrile synthesis
- Step 1 Synthesis of (1r,4S)-N 1 -((S)-1-methoxypropan-2-yl)cyclohexane-1,4-diamine
- Step 2 4-((4-(5-Chloro-2-((1S,4r)-4-((S)-1-methoxypropan-2-yl)amino)cyclohexyl)amino) Synthesis of pyridin-4-yl)thiazol-2-yl)amino)methyl)-tetrahydro-2H-pyran-4-carbonitrile
- Step 2 Synthesis of 4-(5-chloro-2-fluoropyridin-4-yl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)thiazole
- Step 3 (1r,4r)-N 1 -(5-chloro-4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)thiazol-4-yl)pyridine-2- Synthesis of )-N 4 -(2-methoxyethyl)cyclohexane-1,4-diamine
- Step 2 Synthesis of thioacetic acid-S-(tetrahydro-2H-pyran-4-yl)methyl ester
- Step 5 Synthesis of 4-(5-chloro-2-fluoropyridin-4-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)indenyl)thiazole
- Step 6 (1r,4r)-N 1 -(5-chloro-4-(2-((tetrahydro-2H-pyran-4-yl)methyl)indolyl)thiazol-4-yl)pyridine- Synthesis of 2-yl)-N 4 -(2-methoxyethyl)cyclohexane-1,4-diamine
- Step 1 Synthesis of (4-(2-chloropyridin-4-yl)thiazol-2-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamic acid tert-butyl ester
- Step 2 ((1r,4r)-4-((4-(2-((tetrahydro-2H-pyran-4-yl)methyl)amino)thiazol-4-yl)pyridin-2-yl) Synthesis of tert-butyl amino)cyclohexyl)carbamate
- Step 3 (1r,4r)-N 1 -(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)amino)thiazol-4-yl)pyridin-2-yl) Synthesis of cyclohexane-1,4-diamine
- Step 4 (1r,4r)-N 1 -(2-methoxyethyl)-N 4 -(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)amino) Synthesis of thiazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine
- acute myelocytic leukemia OCI-AML-3, acute promyelocytic leukemia cell line NB-4, MDS-RAEB (myelodysplastic syndrome - blasts Type) SKM-1, human leukemia cell Nomo-1, acute myeloid leukemia cell line MOLM14, acute myeloid leukemia cell line MOLM13, acute myeloid leukemia cell line MV4-11, acute myeloid leukemia cell line HL-60 Acute myeloid leukemia cell line OCI-AML-2, histiocytic lymphoma U-937, acute B cell leukemia cell line MEC-1, acute B cell leukemia cell line MEC-2, acute megakaryoblastic leukemia CMK, hamster lung Cell CHL, hamster ovary cell CHO, human non-small cell lung cancer cell H1975, human non-small cell lung cancer cell H358, human small cell lung cancer cell H209, human lung adenocar
- the compounds of the present invention tested were found to have strong inhibitory effects on cancer cells tested, such as leukemia cells and lymphoma cells, and compounds 1 and 14 also showed good selectivity: It has no inhibitory effect on normal cell CHL and CHO cells, while the comparators Dinaciclib and HY-16462 have certain inhibitory effects on CHL and CHO.
- the results in Table 3 also show that Compound 1 of the present invention also exhibits significant inhibitory effects on human non-small cell lung cancer cells, human small cell lung cancer cells, lung adenocarcinoma cells, and breast cancer cells, while Palbociclib is against cancer cells tested. There is no obvious inhibition.
- Example 20 Enzyme inhibition assay for inhibiting CDK protein in vitro
- Compound 1 in DMSO was diluted with Compound 14 were detected and CDK protein (Invitrogen, USA) were mixed, incubated for 30 min at room temperature; adding Kinase / Z'-LYTE TM Peptide Substrate Mixture (Invitrogen, USA) was mixed with 4 ⁇ ATP, the The mixed system was transferred to a 384-well white opaque plate for 1 hour at room temperature; 5 ⁇ L of Development Solution (Invitrogen, USA) was added to react at room temperature for 1 hour, and finally Stop Reagent (Invitrogen, USA) was added to terminate the reaction using MD SpectraMax I3X microplate reader (Molecular Devices, USA) read fluorescence values. Based on the read fluorescence values using Prism 5.0 (GraphPad Software, San Diego , CA) plotted calculated Compound 1 and Compound IC 50 value of 14 pairs tested CDK protein, shown in Table 4.
- IC 50 Compound 1 Compound 14 CDK1/cyclin B 5410 1340 CDK2/cyclin A 6850 2860 CDK3/cyclin E1 >10,000 >10,000 CDK5/p25 6950 4640 CDK7/cyclin HMNAT1 3700 1720 CDK8/cyclin C >10,000 >10,000 CDK9/cyclin T1 0.928 1.27 CDK11 (inactive) >10,000 >10,000 CDK14/cyclin Y 2710 1680 CDK16/cyclin Y 195 292
- Acute myelocytic leukemia (AML) OCI-AML-3, acute promyelocytic leukemia cell line NB-4, acute myelocytic leukemia (AML) HL-60 and acute A total of four cells (all purchased from ATCC) were obtained from the MV4-11 cell line of acute myelocytic leukemia (AML) cell line.
- AML acute myelocytic leukemia
- Compound 1 was evaluated for CDK9 in cells.
- other protein kinases associated with its signaling pathway such as RNAPII, XIAP, MCL-1, c-MYC, BCL-2, etc.
- Compound 1 (in DMSO) with different concentrations of 0 ⁇ M, 0.03 ⁇ M, 0.1 ⁇ M, 0.3 ⁇ M, 1 ⁇ M, 3 ⁇ M, 1 ⁇ M of the comparators Dinaciclib and HY-16462 (CDK9-IN-2) (purchased from Shanghai Qianyuan) After treating these cell lines in DMSO for 2 hours, samples were collected. The effect of Compound 1 on the phosphorylation of CDK9, RNAPII, XIAP, MCL-1, c-MYC, BCL-2 in these cell lines was determined (Fig. 1a-d).
- Acute myelocytic leukemia (AML) OCI-AML-3, acute promyelocytic leukemia cell line NB-4, acute myelocytic leukemia (AML) HL-60 and acute Compound 1 of the myeloid leukemia (AML) MV4-11 cells was found to have a significant inhibitory effect on the phosphorylation of CDK9 protein directly downstream of RNAPII, MCL-1, and c-MYC.
- Example 22 Effect of novel kinase inhibitors on apoptosis
- AML acute myelocytic leukemia
- AML acute promyelocytic leukemia cell line NB-4
- acute myeloid leukemia Cell strain acute myelocytic leukemia, AML
- HL-60 acute myelocytic leukemia
- AML acute myelocytic leukemia
- AML acute myelocytic leukemia MV4-11 (all purchased from ATCC) were tested for compound 1 in cells.
- Apoptosis is closely related to the DNA repair enzyme polyadenylation diphosphate-ribose polymerase PARP, cysteine-containing aspartate proteolytic enzyme Caspase3 protein cleavage effect.
- FIGS 2a-d The results are shown in Figures 2a-d: acute myelocytic leukemia (AML) OCI-AML-3, acute promyelocytic leukemia cell line NB-4, acute myeloid leukemia cell line (acute) Myelocytic leukemia, AML) HL-60 and acute myelocytic leukemia (AML) MV4-11 four cells in the four cells, 24 hours after the obvious, some DNA repair enzyme polyadenylate diphosphate-ribose Cleavage of downstream Caspase 3 by polymerase PARP or PARP.
- AML acute myelocytic leukemia
- NB-4 acute promyelocytic leukemia cell line
- AML acute myeloid leukemia cell line (acute) Myelocytic leukemia, AML) HL-60
- AML acute myelocytic leukemia
- compound 1 is in acute myelocytic leukemia (AML) OCI-AML-3, acute promyelocytic leukemia cell line NB-4, acute myelocytic leukemia (AML). HL-60, acute myelocytic leukemia (AML) MV4-11 can cause apoptosis in the four cells.
- AML acute myelocytic leukemia
- NB-4 acute promyelocytic leukemia
- AML acute myelocytic leukemia
- HL-60 acute myelocytic leukemia
- AML acute myelocytic leukemia
- Example 23 Effect of novel kinase inhibitors on cell cycle
- AML acute myelocytic leukemia
- AML acute myeloid leukemia cell line
- Example 24 Compound 1 in a human acute myeloid leukemia MV4-11 mouse model Experimental result
- mice 24 4-6 week old Bal b/c female mice were purchased from Shanghai Slack Laboratory Animals Co., Ltd. and kept in SPF laboratory. The drinking water and litter were aseptically treated by autoclaving. All operations were carried out under aseptic conditions.
- 5 x 10 6 MV4-11 acute granulocyte leukemia cells purchased from ATCC
- mice were subcutaneously injected into the left side of all mice. Starting on day 15, all mice were divided into four groups (6 mice per group), methyl cellulose (HKI) solvent was orally administered to the first group of mice per day; dose was orally administered to the second group of mice.
- HKI methyl cellulose
- Compound 1 which is 10 mg/kg murine weight; Compound 1 is administered orally to a third group of mice at a dose of 20 mg/kg; and a dose of 30 mg/kg of mouse compound 1 is orally administered to the fourth group of mice.
- the length/width of the subcutaneous tumor was measured with a vernier caliper every day, and the body weight of the mouse was recorded every day, and the effect of Compound 1 on the body weight of the mouse was observed.
- On day 43 the mice were sacrificed, subcutaneous tumors were removed, and tumors were weighed and compared, and then a sample of protein lysate was prepared from the tumor sample tissue for use. The trend of subcutaneous tumor growth was counted within 16-43 days, and the tumor volume was calculated as: length ⁇ width ⁇ width / 2 mm 3 .
- the results of the experiment are shown in the figure.
- the results show that the inhibitor compound 1 disclosed in the present invention, the high dose group (20, 30 mg/kg) affects the body weight of Bal b/c mice, but the low dose group (10 mg/kg) is obviously
- the weight of the subcutaneous tumor has been significantly reduced and has no significant effect on the body weight of the mouse; the tumor inhibition rate (TGI) of the high dose group (20, 30 mg/kg) can reach 98.7%.
- TGI tumor inhibition rate
- Compound 1 is effective in inhibiting the growth of subcutaneous tumors (Fig. 4a-c).
- the present invention provides an inhibitor of the cyclin-dependent kinase CDK9 which can be used to reduce or inhibit the treatment, prevention or amelioration of or which is regulated by or involved in serine kinase activity, or which is involved in cyclin-dependent kinase activity.
- a disease, disorder, or condition can be made into a corresponding drug suitable for industrial applications.
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Abstract
Description
化合物编号 | CHO | CHL | CMK | HL-60 | MOLM-13 | MOLM-14 | MV4-11 | NB4 |
1 | 1.6 | 1.1 | 0.049 | 0.032 | 0.025 | 0.025 | 0.014 | 0.035 |
2 | 2.8 | 3.5 | 0.37 | 0.55 | 0.15 | 0.14 | 0.14 | 0.056 |
5 | 1.2 | 3.6 | 1.5 | 0.39 | 0.64 | 0.49 | 0.44 | 0.46 |
6 | 0.4 | 1.1 | 0.35 | 0.065 | 0.13 | 0.11 | 0.14 | 0.11 |
8 | 1.6 | 0.93 | 0.15 | 0.31 | 0.2 | 0.53 | 0.55 | 0.22 |
9 | 1.2 | 1.9 | 1.8 | 0.42 | 1 | 0.68 | 0.53 | 0.7 |
10 | 0.78 | 8 | 0.98 | 0.41 | 0.82 | 0.33 | 1.1 | 0.49 |
11 | 0.37 | 1 | 0.47 | 0.073 | 0.28 | 0.16 | 0.33 | 0.27 |
12 | 0.47 | 1.1 | 0.72 | 0.19 | 0.29 | 0.31 | 0.88 | 0.41 |
13 | 0.77 | 1.4 | 1.1 | 0.32 | 0.44 | 0.33 | 0.74 | 0.34 |
14 | 1.1 | 1.2 | 0.036 | 0.056 | 0.012 | 0.0011 | 0.041 | 0.0079 |
16 | 1.3 | 3.3 | 1.4 | 0.45 | 0.57 | 0.62 | 0.63 | 0.58 |
17 | 0.61 | 5.6 | 1.1 | 0.16 | 0.34 | 0.36 | 1.1 | 0.35 |
18 | 4.1 | 1.2 | 4 | 0.98 | 1.2 | 1.2 | 0.91 | 1.3 |
HY-16462 | 0.29 | 0.2 | 0.042 | 0.037 | 0.032 | 0.033 | 0.027 | 0.032 |
Dinaciclib | 0.16 | 0.18 | 0.0099 | 0.008 | 0.0033 | 0.0045 | 0.0076 | 0.01 |
化合物编号 | Nomo-1 | OCI-AML2 | OCI-AML3 | SKM-1 | U-937 | MEC-1 | MEC-2 |
1 | 0.045 | 0.033 | 0.033 | 0.033 | 0.017 | 0.047 | 0.025 |
2 | 0.59 | 9.1 | 0.14 | 0.085 | 0.12 | 0.27 | 0.14 |
5 | 1 | 0.47 | 0.82 | 0.35 | 0.43 | 1.3 | 0.77 |
6 | 0.29 | 0.12 | 0.15 | 0.097 | 0.11 | 0.31 | 0.13 |
8 | 1 | 2.9 | 0.72 | 0.15 | 1.4 | 3.6 | 0.83 |
9 | 1.3 | 0.65 | 1.1 | 0.75 | 0.85 | 1.4 | 1.1 |
10 | 0.6 | 0.6 | 0.56 | 0.33 | 0.34 | 0.85 | 0.66 |
11 | 0.96 | 0.33 | 0.22 | 0.17 | 0.22 | 0.47 | 0.32 |
12 | 0.92 | 0.41 | 0.39 | 0.2 | 0.39 | 0.45 | 0.48 |
13 | 0.87 | 0.6 | 0.42 | 0.26 | 0.32 | 0.89 | 0.66 |
14 | 0.11 | 0.0066 | 0.012 | 0.002 | 0.011 | 0.037 | 0.023 |
16 | 1.5 | 2.1 | 0.63 | 0.5 | 0.6 | 1.4 | 0.97 |
17 | 0.93 | 0.8 | 0.98 | 0.33 | 0.3 | 0.8 | 0.7 |
18 | 3 | 1.1 | 2.1 | 1.1 | 1.1 | 2.5 | 1.7 |
HY-16462 | 0.063 | 0.071 | 0.047 | 0.04 | 0.031 | 0.048 | 0.036 |
Dinaciclib | 0.034 | 0.013 | 0.011 | 0.01 | 0.0036 | 0.011 | 0.01 |
IC 50(μM) | 化合物1 | Palbociclib | Dinaciclib |
H358 | 0.043 | 6.6 | 0.043 |
H209 | 0.086 | >10 | 0.077 |
H1395 | 0.12 | >10 | 0.056 |
H3122 | 0.011 | 1.2 | 0.011 |
PC-9 | 0.09 | >10 | 0.013 |
H1975 | 0.042 | >10 | 0.029 |
H2122 | 0.049 | 1.6 | 0.039 |
H1915 | 0.037 | 3.6 | 0.023 |
H1355 | 0.1 | ~10 | 0.025 |
HCC827 | 0.06 | >10 | 0.028 |
MDA-MB-231 | 0.074 | 5.1 | 0.063 |
MDA-MB-468 | 0.018 | 2.7 | 0.013 |
MCF-7 | 0.006 | 1.7 | 0.0082 |
T47D | 0.055 | 4.1 | 0.054 |
SK-Br-3 | 0.04 | 3.2 | 0.015 |
IC 50(nM) | 化合物1 | 化合物14 |
CDK1/细胞周期蛋白B | 5410 | 1340 |
CDK2/细胞周期蛋白A | 6850 | 2860 |
CDK3/细胞周期蛋白E1 | >10,000 | >10,000 |
CDK5/p25 | 6950 | 4640 |
CDK7/细胞周期蛋白HMNAT1 | 3700 | 1720 |
CDK8/细胞周期蛋白C | >10,000 | >10,000 |
CDK9/细胞周期蛋白T1 | 0.928 | 1.27 |
CDK11(非活性) | >10,000 | >10,000 |
CDK14/细胞周期蛋白Y | 2710 | 1680 |
CDK16/细胞周期蛋白Y | 195 | 292 |
Claims (14)
- 根据权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中R 1为氯。
- 根据权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中R 2选自氢、甲基、环丙基、环己基、任选被氰基取代的4-四氢吡喃基、和任选被氟取代的苯基。
- 根据权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中R 3选自乙酰基、2-甲氧基乙基、(R)-1-甲基-2-甲氧基乙基、和(S)-1-甲基-2-甲氧基乙基。
- 根据权利要求1-4中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中所述化合物选自:4-(((4-(5-氯-2-(((1R,4r)-4-(((R)-1-甲氧基丙基-2-基)氨基)环己基)氨基)吡啶-4-基)噻唑-2-基)氨基)甲基)四氢-2H-吡喃-4-甲腈;(1r,4r)-N 1-(5-氯-4-(2-(((四氢-2H-吡喃-4-基)甲基)氨基)噻唑-4-基)吡啶-2-基)环己烷-1,4-二胺;N-((1r,4r)-4-((5-氯-4-(2-(((四氢-2H-吡喃-4-基)甲基)氨基)噻唑-4-基)吡啶-2-基)氨基)环己基)乙酰胺;(1r,4r)-N 1-(5-氯-4-(2-(((四氢-2H-吡喃-4-基)甲基)氨基)噻唑-4-基)吡啶-2-基)-N 4-(2-甲氧基乙基)环己基-1,4-二胺;(1S,4r)-N 1-(5-氯-4-(2-(((四氢-2H-吡喃-4-基)甲基)氨基)噻唑-4-基)吡啶-2-基)-N4-((S)-1-甲氧基丙-2-基)环己基-1,4-二胺;(1R,4r)-N 1-(5-氯-4-(2-(((四氢-2H-吡喃-4-基)甲基)氨基)噻唑-4-基)吡啶-2-基)-N 4-((R)-1-甲氧基丙-2-基)环己烷-1,4-二胺;4-(2-((((1r,4r)-4-氨基环己基)甲基)氨基)-5-氯吡啶-4-基)-N-((四氢-2H-吡喃-4-基)甲基)噻唑-2-胺;N-(5-氯-4-(2-(((四氢-2H-吡喃-4-基)甲基)氨基)噻唑-4-基)吡啶-2-基)-4-氟苯甲酰胺;(1r,4r)-N 1-(5-氯-4-(2-(甲基氨基)噻唑-4-基)吡啶-2-基)-N 4-(2-甲氧基乙基)环己烷-1,4-二胺;(1r,4r)-N 1-(5-氯-4-(2-((环己基甲基)氨基)噻唑-4-基)吡啶-2-基)-N 4-(2-甲氧基乙基)环己烷-1,4-二胺;(1r,4r)-N 1-(4-(2-(苄氨基)噻唑-4-基)-5-氯吡啶-2-基)-N 4-(2-甲氧基乙基)环己烷-1,4-二胺;(1r,4r)-N 1-(5-氯-4-(2-((4-氟苄基)氨基)噻唑-4-基)吡啶-2-基)-N 4-(2-甲氧基乙基)环己烷-1,4-二胺;(1r,4r)-N 1-(5-氯-4-(2-((环丙基甲基)氨基)噻唑-4-基)吡啶-2-基)-N 4-(2-甲氧基乙基)环己烷-1,4-二胺;4-((4-(5-氯-2-(((1r,4r)-4-((2-甲氧基乙基)氨基)环己基)氨基)吡啶-4-基)噻唑-2-基氨基)甲基)-四氢-2H-吡喃-4-甲腈;4-(((4-(5-氯-2-(((1S,4r)-4-(((S)-1-甲氧基丙-2-基)氨基)环己基)氨基)吡啶-4-基)噻唑-2-基)氨基)甲基)-四氢-2H-吡喃-4-甲腈;(1r,4r)-N 1-(5-氯-4-(2-((四氢-2H-吡喃-4-基)甲氧基)噻唑-4-基)吡啶-2-基)-N 4-(2-甲氧基乙基)环己烷-1,4-二胺;(1r,4r)-N 1-(5-氯-4-(2-(((四氢-2H-吡喃-4-基)甲基)巯基)噻唑-4-基)吡 啶-2-基)-N 4-(2-甲氧基乙基)环己烷-1,4-二胺;和(1r,4r)-N 1-(2-甲氧基乙基)-N 4-(4-(2-(((四氢-2H-吡喃-4-基)甲基)氨基)噻唑-4-基)吡啶-2-基)环己烷-1,4-二胺。
- 一种药物组合物,其包括根据权利要求1-5中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,以及药学上可接受的载体或赋形剂,以及任选的其它治疗剂。
- 根据权利要求1-5中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药在制备用于治疗、预防或改善由丝氨酸激酶活性调节的或者受其影响的或者其中涉及细胞周期蛋白依赖性激酶活性的疾病、障碍或病症的药物中的用途。
- 根据权利要求7所述的用途,其中所述疾病、障碍或病症是癌症。
- 根据权利要求8所述的用途,所述癌症选自:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、***癌、膀胱癌、肝癌、皮肤癌、神经胶质瘤、乳腺癌、黑色素瘤、恶性胶质瘤、横纹肌肉瘤、卵巢癌、星形细胞瘤、尤因氏肉瘤、成视网膜细胞瘤、上皮细胞癌、结肠癌、肾癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、和鼻咽癌。
- 根据权利要求7所述的用途,其中所述疾病、障碍或病症选自:MDS-RAEB(骨髓增生异常综合征-原始细胞增多型)、组织细胞性淋巴瘤、急性B细胞白血病、急性巨核细胞白血病、急性髓系白血病、和急性早幼粒细胞白血病。
- 根据权利要求1-5中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其用于治疗、预防或改善由丝氨酸激酶活性调节的或者受其影响的或者其中涉及细胞周期蛋白依赖性激酶活性的疾病、障碍或病症。
- 根据权利要求11所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中所述疾病、障碍或病症是癌症。
- 根据权利要求12所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中所述疾病、障碍或病症选自:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、***癌、膀胱癌、肝癌、皮肤癌、神经胶质瘤、乳腺癌、黑色素瘤、恶性胶质瘤、横纹肌肉瘤、卵巢癌、星形细胞瘤、尤因氏肉瘤、成视网膜细胞瘤、上皮细胞癌、结肠癌、肾癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、和鼻咽癌。
- 根据权利要求11中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中所述疾病、障碍或病症选自:MDS-RAEB(骨髓增生异常综合征-原始细胞增多型)、组织细胞性淋巴瘤、急性B细胞白血病、急性巨核细胞白血病、急性髓系白血病、急性早幼粒细胞白血病。
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CA3059622A CA3059622C (en) | 2017-04-19 | 2018-01-03 | Inhibitor of cyclin-dependent kinase cdk9 |
DK18787869.9T DK3613737T3 (da) | 2017-04-19 | 2018-01-03 | Hidtil ukendt inhibitor af cyclin-afhængig kinase CDK9 |
US16/606,136 US10952999B2 (en) | 2017-04-19 | 2018-01-03 | Inhibitor of cyclin-dependent kinase CDK9 |
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ES18787869T ES2909301T3 (es) | 2017-04-19 | 2018-01-03 | Nuevo inhibidor de la quinasa CDK9 dependiente de ciclina |
KR1020197033935A KR102309986B1 (ko) | 2017-04-19 | 2018-01-03 | 사이클린 의존성 키나아제 cdk9의 신규 인히비터 |
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WO2020259556A1 (zh) * | 2019-06-27 | 2020-12-30 | 南京明德新药研发有限公司 | 作为cdk9抑制剂的氮杂吲哚连吡唑类化合物 |
US10952999B2 (en) | 2017-04-19 | 2021-03-23 | Genfleet Therapeutics (Shanghai) Inc. | Inhibitor of cyclin-dependent kinase CDK9 |
WO2021227906A1 (zh) | 2020-05-12 | 2021-11-18 | 苏州阿尔脉生物科技有限公司 | 一种作为cdk抑制剂的吡啶乙酰胺类衍生物、其制备方法及用途 |
WO2021227904A1 (zh) | 2020-05-12 | 2021-11-18 | 苏州阿尔脉生物科技有限公司 | 一种作为cdk9抑制剂的多环酰胺类衍生物、其制备方法及用途 |
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WO2020244612A1 (zh) | 2019-06-06 | 2020-12-10 | 劲方医药科技(上海)有限公司 | Cdk9抑制剂的多晶型物及其制法和用途 |
TWI809330B (zh) * | 2020-11-20 | 2023-07-21 | 大陸商勁方醫藥科技(上海)有限公司 | Cdk9抑制劑的多晶型物及其製法和用途 |
CN116270644A (zh) * | 2023-05-22 | 2023-06-23 | 劲方医药科技(上海)有限公司 | Cdk9抑制剂与bcl-2抑制剂联用的药物组合及其用途 |
CN116270658B (zh) * | 2023-05-24 | 2023-10-27 | 劲方医药科技(上海)有限公司 | Cdk9抑制剂与btk抑制剂联用的药物组合及其用途 |
CN116496267B (zh) * | 2023-06-26 | 2023-09-22 | 劲方医药科技(上海)有限公司 | Cdk9抑制剂及其制备方法和用途 |
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WO2020259556A1 (zh) * | 2019-06-27 | 2020-12-30 | 南京明德新药研发有限公司 | 作为cdk9抑制剂的氮杂吲哚连吡唑类化合物 |
WO2021227906A1 (zh) | 2020-05-12 | 2021-11-18 | 苏州阿尔脉生物科技有限公司 | 一种作为cdk抑制剂的吡啶乙酰胺类衍生物、其制备方法及用途 |
WO2021227904A1 (zh) | 2020-05-12 | 2021-11-18 | 苏州阿尔脉生物科技有限公司 | 一种作为cdk9抑制剂的多环酰胺类衍生物、其制备方法及用途 |
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BR112019021794A2 (pt) | 2020-05-05 |
KR102309986B1 (ko) | 2021-10-12 |
RU2738654C1 (ru) | 2020-12-15 |
JP2020517595A (ja) | 2020-06-18 |
PT3613737T (pt) | 2022-03-11 |
AU2018253655A1 (en) | 2019-10-17 |
CA3059622C (en) | 2021-09-07 |
ES2909301T3 (es) | 2022-05-06 |
US20200078343A1 (en) | 2020-03-12 |
EP3613737A4 (en) | 2020-08-26 |
EP3613737B1 (en) | 2021-12-29 |
JP6866967B2 (ja) | 2021-04-28 |
CN108727363B (zh) | 2020-06-19 |
AU2018253655B2 (en) | 2020-12-17 |
US10952999B2 (en) | 2021-03-23 |
EP3613737A1 (en) | 2020-02-26 |
KR20200039616A (ko) | 2020-04-16 |
DK3613737T3 (da) | 2022-03-07 |
CN108727363A (zh) | 2018-11-02 |
CA3059622A1 (en) | 2018-10-25 |
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