WO2018233684A1 - 7-位取代吡咯并三嗪类化合物或其药学上可用的盐,及其制备方法和用途 - Google Patents
7-位取代吡咯并三嗪类化合物或其药学上可用的盐,及其制备方法和用途 Download PDFInfo
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- WO2018233684A1 WO2018233684A1 PCT/CN2018/092419 CN2018092419W WO2018233684A1 WO 2018233684 A1 WO2018233684 A1 WO 2018233684A1 CN 2018092419 W CN2018092419 W CN 2018092419W WO 2018233684 A1 WO2018233684 A1 WO 2018233684A1
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- 0 CC1C(**)OC(*)C(*)*1 Chemical compound CC1C(**)OC(*)C(*)*1 0.000 description 4
- DRTOPLRMDZJIGV-UHFFFAOYSA-N CC(CC1)CCC1=C Chemical compound CC(CC1)CCC1=C DRTOPLRMDZJIGV-UHFFFAOYSA-N 0.000 description 1
- BWBIOTXJBUATMO-BKPODWGBSA-N C[C@@H](COCC1)N1/C(/c1cc(C#N)c(C)[nH]1)=N/C(/c(c(C(F)(F)F)c1)cnc1NC(C(C)(C)C)=O)=N\C Chemical compound C[C@@H](COCC1)N1/C(/c1cc(C#N)c(C)[nH]1)=N/C(/c(c(C(F)(F)F)c1)cnc1NC(C(C)(C)C)=O)=N\C BWBIOTXJBUATMO-BKPODWGBSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to the field of medicinal chemistry, and in particular to a 7-position substituted pyrrolotriazine compound or a pharmaceutically usable salt thereof, and a process for the preparation thereof and use thereof.
- the PI3K-Akt-mTOR signaling pathway is one of the major pathways that transmit signals from receptor tyrosine kinases and G-protein coupled receptors and plays an important role in a variety of cellular functions. Recent studies have found that in a variety of human tumors, multiple key nodal proteins in the PI3K-Akt-mTOR signaling pathway are over-activated by mutation or amplification of the coding gene [Vivancod et al., Nat Rev Cancer 2 (2002) , pp. 489-501]. PI3K, a bridge molecule that links extracellular signals and cellular responses, is a key factor regulating cell growth, metabolism, and survival. Its overactivation is closely related to the occurrence of multiple tumors in humans [Sabbah et al., Curr Med Chem 18 (2011). ), pp. 5528-5544].
- PI3K belongs to intracellular phosphatidylinositol kinase with phosphatidylinositol kinase activity and silk/threonine kinase activity. According to gene family homology, substrate specificity and function, PI3K superfamily is mainly divided into three types: type I, type II, type III [Engelman et al., Nat Rev Genet 7 (2006), pp. 606-619. ]. Type I PI3K is the most widely studied class to date, and this type of PI3K can be divided into four subtypes of PI3K ⁇ , PI3K ⁇ , PI3K ⁇ and PI3K ⁇ .
- Type I PI3K is a heterodimeric enzyme consisting of a 110 kDa catalytic subunit and an 85 kDa regulatory subunit. Due to the difference in regulatory subunits and activation mechanisms, these four subtypes can be grouped into two categories: Class IA, Class IB. Among them, PI3K ⁇ , PI3K ⁇ and PI3K ⁇ belong to Class IA and are activated by receptor tyrosine kinase (RTKs); PI3K ⁇ belongs to Class IB and is activated by G-protein coupled receptor.
- RTKs receptor tyrosine kinase
- Type I PI3K phosphorylates the 3rd position of phosphatidylinositol-4,5-phosphate (PIP2) to form phosphatidylinositol-3,4,5-triphosphate ( Phosphatidylinositol-3,4,5-phosphate, PIP3).
- PIP3 can bind and activate a variety of intracellular target proteins (such as AKT and PDK1) to form a signal cascade complex that ultimately regulates cell proliferation, differentiation, survival and migration.
- Type II PI3K is a monomeric structure, lacks regulatory subunits, and is divided into three subtypes of PI3KC2 ⁇ , PI3KC2 ⁇ , and PI3KC2 ⁇ ; it is mainly involved in the transport of intracellular substances, cell survival, and internalization of membrane receptor proteins.
- Type III PI3K has only one subtype, Vps34 (vacuole protein sorting defective 34), which is well known for its endocytosis and Golgi vesicle transport functions [Backer, Biochem J 410 (2008), pp. 1-17 ]. Recent studies have shown that Vps34 plays an important role in autophagy [Ma et al, Cell Res 24 (2014), pp. 912-924].
- PI3K inhibitors there are dozens of PI3K inhibitors in clinical research, which can be roughly divided into three categories: non-selective PI3K inhibitors, type I PI3K selective inhibitors and subtype-selective type I PI3K inhibitors. From the analysis of existing clinical data, although non-selective PI3K inhibitors first entered clinical studies, they progressed slowly due to dose limitation and toxicity. Subtype-selective PI3K inhibitors have the fastest progress, especially PI3K ⁇ inhibitors, of which the first marketed PI3K inhibitor, Idelalisib, is a PI3K ⁇ inhibitor, and another ⁇ / ⁇ selective inhibitor, Duvelisib, is already in phase III clinical [Winkler et al.
- the catalytic subunit p110 ⁇ of PI3K ⁇ is different from P110 ⁇ and P110 ⁇ widely expressed in various tissues of the whole body, and is mainly selectively expressed in the immune system, such as B cells, T cells, etc., and hematological malignancies. It is closely related to diseases such as inflammation and immunity [Fruman et al., N Engl J Med 370 (2014), pp. 1061-1062].
- Idelalisib is approved by the US FDA as a drug for the treatment of recurrent chronic lymphocytic leukemia (CLL), recurrent follicular B-cell non-Hodgkin's lymphoma (FL) and recurrent small lymphocytic lymphoma. . This highlights the significance of PI3K ⁇ inhibitors in the treatment of hematological malignancies.
- R 1 is halogen, or a C 1-6 alkyl group or a C 3-8 cycloalkyl group which is unsubstituted or substituted with at least one substituent, the substituent being a halogen;
- R 2 is -C(OH)R 5 R 6 , -COC 1-6 alkyl, -CN, unsubstituted or substituted with at least one substituent: C 1-6 alkyl, -CH 2 NH- C 1-6 alkyl, -CH 2 N(C 1-6 alkyl)(C 1-6 alkyl), -CH 2 - (saturated heterocyclic group containing 1-2 hetero atoms and 3-6 carbon atoms) ), -CH 2 - (containing a 1-2 hetero atom and a saturated heterocyclic group of 3 to 6 carbon atoms) - (containing a 1-2 hetero atom and a saturated heterocyclic group of 3 to 6 carbon atoms), -CH 2 - (containing a 1-2 hetero atom and a saturated spiro group of 4 to 12 carbon atoms), -CH 2 - (a saturated bridged ring group containing 1-2 hetero atoms and 3 to 12 carbon atoms) - (including 1-2 hetero a saturated hetero
- the hetero atom is selected from at least one of N, O and S,
- the R 5 and R 6 are each independently hydrogen or C 1-6 alkyl
- R 3 is Wherein R 7 , R 8 , R 9 , R 10 are each independently hydrogen or C 1-6 alkyl which is unsubstituted or substituted with at least one substituent, the substituent being a halogen or a hydroxy group;
- R 4 is -NH 2 , -NHCONHR 11 or -NHCO 2 R 12 , wherein R 11 and R 12 are each independently a C 1-6 alkyl group, a C 3-8 cycloalkane which is unsubstituted or substituted with at least one substituent. Or a phenyl group, the substituent being selected from at least one of halogen and -C(O)OR 13 , wherein R 13 is a C 1-6 alkyl group which is unsubstituted or substituted with at least one substituent, said R The substituent in 13 is a halogen.
- the R 1 is halogen, or C 1-4 alkyl or C 3-6 cycloalkyl, unsubstituted or substituted with at least one substituent.
- the R 1 is -Cl, -F, methylalkyl, trifluoromethyl or difluoromethylalkyl.
- the R 2 is -C(OH)R 5 R 6 , -COC 1-4 alkyl, -CN, unsubstituted or substituted with at least one substituent: C 1 -4 alkyl, -CH 2 NH-C 1-4 alkyl, -CH 2 N(C 1-4 alkyl)(C 1-4 alkyl), -X- (saturation containing 1-2 heteroatoms) Four to six-membered heterocyclic group), -X- (saturated four to six-membered heterocyclic group containing 1-2 hetero atoms) - (saturated four to six-membered heterocyclic group containing 1-2 hetero atoms), -X- (including 1-2 heteroatoms and saturated bicyclospirocyclyl groups of 4-8 carbon atoms), -X- (saturated bicyclic bridged ring groups containing 1-2 heteroatoms and 3-8 carbon atoms)-(including 1-2 a saturated tetra- to six-membere
- the R 5 and R 6 are each independently hydrogen, methyl or ethyl.
- the substituent in R 2 is -F, -Cl, -Br, -I, -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -C(CH 3 )(CF 3 )OH, -C(CF 3 ) 2 OH, -C(CH 3 ) 2 OCH 3 , -C(CH 3 2 NH 2 , -CH 2 C(CH 3 ) 2 OH, -CH(OH)CH(CH 3 ) 2 , -C(CH 3 ) 2 CH 2 OH, -C(CH 3 ) 2 CH 2 OCH 3 , -C(CH
- the R 2 is Rx and Ry are each -N(CH 3 ) 2 , -S(O) 2 CH 3 or a C 1-4 alkyl group which is unsubstituted or substituted with at least one substituent which is halogen, hydroxy, -CONH 2 , -CF 3 , amino or -OCH 3 .
- the R 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 3 is wherein R 7 , R 8 , R 9 and R 10 are each independently hydrogen or C 1-4 alkyl.
- the R 7 , R 8 , R 9 , R 10 are each independently H or methyl.
- the R 3 is morpholinyl or (S)-3-methylmorpholinyl.
- the R 4 is -NH 2 , -NHCONHR 11 or -NHCO 2 R 12 , wherein R 11 and R 12 are each independently C 1 - unsubstituted or substituted with at least one substituent a 4- alkyl group, a C 3-6 cycloalkyl group or a phenyl group, the substituent being selected from at least one of fluorine, chlorine, bromine and -C(O)OR 13 , wherein R 13 is a C 1-4 alkyl group .
- the R 11 and R 12 are each independently methyl, ethyl, isopropyl, cyclopropyl, phenyl, -Ph-CO 2 Et-p or 4-fluorophenyl .
- the pharmaceutically acceptable salts include organic acid salts and inorganic acid salts including, but not limited to, maleate, succinate, citrate, tartrate, fumarate, acetate, methanesulfonate, Hydrochloride, phosphate, nitrate or sulfate.
- Another object of the present invention is to provide a process for the preparation of a 7-substituted pyrrole [2,1-f][1,2,4]-triazine compound represented by the general formula I, which is prepared by the following route:
- reagents and conditions required for each step include:
- Step a dropwise adding chlorosulfonyl isocyanate to a solution of the compound Aa1', dimethylformamide (DMF) in anhydrous acetonitrile to obtain the compound Aa2', or step b: dissolving the compound Aa1" in chloroform, and adding N-chlorosuccinimide is reacted to obtain compound Aa2";
- Step c adding 5% by mass of sodium hypochlorite solution to the solution of the compound Aa2', K 2 CO 3 , NH 4 Cl, concentrated aqueous ammonia, methyl trioctyl ammonium chloride in methyl tert-butyl ether, and reacting Compound Aa3, or step d: the compound Aa2" is dissolved in anhydrous dimethylformamide, NaH is added, and after stirring, O-(2,4-dinitrophenyl)-hydroxylamine is added to obtain the compound Aa3;
- Step e the compound Aa3 is dissolved in a saturated ammonia methanol solution or ammonia in methanol to obtain a compound Aa4;
- Step f mixing compound Aa4 with aldehyde, anhydrous copper chloride, dimethyl sulfoxide, the reaction to obtain compound Aa5;
- Step g adding phosphorus oxychloride to a mixture of compound Aa5 and N,N-dimethylaminopyridine or dimethylaminopyridine to obtain compound Aa6;
- Step h to the compound Aa6, the addition of anhydrous tetrahydrofuran and morpholine, the reaction to obtain the compound Aa7;
- Step i adding Raney nickel to the acetic acid/water/pyridine suspension of the compound Aa7 and sodium hypophosphite, the reaction gives the compound Aa8;
- Step j suspending the compound Aa8, sodium cyanoborohydride and an amine in methanol, adding acetic acid to obtain a product; or step j: adding methyl magnesium bromide to a solution of the compound Aa8 in anhydrous tetrahydrofuran to obtain a product; Or step j: adding diethylaminosulfur trifluoride (DAST) to a solution of the compound Aa8 in anhydrous dichloromethane to obtain a product.
- DAST diethylaminosulfur trifluoride
- compound P-28 is prepared by the following route:
- Step 1 Compound P-28-1 was dissolved in a mixture of dichloromethane and water, followed by sodium trifluoromethylsulfinate, and the system was cooled and a 70% aqueous solution of t-butoxyethanol was slowly added dropwise, followed by Adding dimethyl sulfoxide and raising the temperature to obtain compound P-28-2;
- Step 2 The compound P-28-2 and phosphorus oxychloride are added to toluene, followed by the addition of N,N-dimethylaniline, and the reaction is carried out under reflux to obtain a crude chloro compound, and the crude chloro compound is dissolved in anhydrous tetrahydrofuran. Add morpholine at 0 ° C, stir at room temperature until the reaction of the starting material is complete, and concentrate to obtain the crude product directly in the next reaction;
- Step 3 The crude product obtained in Step 2 is added to methanol to dissolve, then water and sodium hydroxide are added, and the reaction is carried out under reflux until the starting material completely disappears, concentrated, water is added, the pH is adjusted to precipitate a solid, and dried, and the next reaction is directly carried out;
- Step 4 The crude product of Step 3, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), triethylamine and 2-(4-piperidinyl) 2-propanol is added to N,N-dimethylformamide (DMF) to give the compound P-28-5;
- HBTU benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
- DMF N,N-dimethylformamide
- Step 5 Dissolve P-28-5 in anhydrous tetrahydrofuran, then slowly add borane/tetrahydrofuran (BH 3 /THF) dropwise. After the addition is completed, the reaction system is heated to carry out the reaction, then the reaction system is cooled and slowly added dropwise. Concentrated hydrochloric acid was added dropwise, and the temperature was raised to give the compound P-28.
- borane/tetrahydrofuran BH 3 /THF
- Another object of the present invention is to provide a 7-substituted pyrrole [2,1-f][1,2,4]-triazine compound represented by the formula I or a pharmaceutically acceptable salt thereof for preparing a PI3K activity inhibitor Use in.
- the PI3K activity inhibitor has a selective inhibitory effect on PI3K ⁇ .
- the PI3K activity inhibitor is for use in a medicament for treating a disease associated with a PI3K channel.
- the diseases associated with the PI3K channel include tumors, leukemias, and autoimmune diseases.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a 7-substituted pyrrole [2,1-f][1,2,4]-triazine compound represented by Formula I or a pharmaceutical thereof
- a useful salt for the treatment of a disease associated with the PI3K channel is a 7-substituted pyrrole [2,1-f][1,2,4]-triazine compound represented by Formula I or a pharmaceutical thereof.
- the inventors of the present invention have obtained a novel class of 7-substituted pyrrole [2,1-f][1,2,4]-triazine compounds by rational design and comprehensive consideration of the pharmacokinetic factors of the compounds.
- the compounds exhibit better PI3K inhibitory activity, can effectively inhibit PI3K kinase activity, and have greatly improved and improved pharmacokinetic properties such as bioavailability due to the introduction of the 7-position group;
- the compounds exhibit unpredictable high selectivity and strong inhibitory activity against PI3K ⁇ , and thus these compounds can be used to treat diseases associated with the PI3K channel, particularly for anti-cancer or for the treatment of tumors, leukemias and autoimmune diseases. After further optimization and screening, it is expected to develop into a new type of anti-tumor drugs.
- alkyl refers to a straight or branched alkyl group.
- substituted refers to the replacement of one or more hydrogen atoms.
- the halogen herein may be selected from at least one of F, Cl, Br and I, preferably at least one of F and Cl.
- Step a Preparation of ethyl 4-cyano-5-methyl-1H-pyrrole-2-carboxylate (Aa2')
- Step c Preparation of ethyl 1-amino-4-cyano-5-methyl-1H-pyrrole-2-carboxylate (Aa3')
- the compound Aa3' (800 mg, 4.1 mmol) was dissolved in 100 mL of a saturated ammonia methanol solution or a methanol solution of ammonia, and the mixture was sealed at 80 ° C for 2 days, cooled to room temperature, and concentrated to give a yellow solid (680 mg, 100%).
- Step b Preparation of ethyl 4-cyano-5-chloro-1H-pyrrole-2-carboxylate (Aa2")
- Step d Preparation of ethyl 1-amino-4-cyano-5-chloro-1H-pyrrole-2-carboxylate (Aa3")
- Phosphorus oxychloride was added to a mixture of Compound Aa5 (1.0 equiv.), 4-dimethylaminopyridine (2.0 equiv.), and refluxed for 10 hours. After cooling, phosphorus oxychloride was removed under reduced pressure, and anhydrous tetrahydrofuran and morpholine were added in that order and refluxed for 2 hours. The tetrahydrofuran was evaporated under reduced pressure, and the mixture was evaporated. EtOAcjjjjjjjjjj .
- Step j Synthesis of the compounds P-(1-9), 12, (29-32), (34-35), (38-43), (45-46)
- Methanesulfonic acid (370 ⁇ L, 0.3 mmol) was added to a solution of the compound P-9 (160 mg, 0.3 mmol) in chloroform (10 mL), and the mixture was reacted at room temperature for 2 hours, then diluted with anhydrous diethyl ether (50 mL), filtered and dried. Yellow compound P-9 methanesulfonate (145 mg, 77%).
- Step j Synthesis of compound P-33, 36, 37
- the obtained product was dissolved in methanol (15 mL), and 10 equivalents of a 1M potassium hydroxide solution was added and refluxed. After completion of the reaction, it was concentrated and purified by column chromatography (dichloromethane / methanol: 40/1).
- the obtained product was dissolved in concentrated hydrochloric acid (10 mL) and refluxed for 7 days. After completion of the reaction, it was neutralized and purified by column chromatography (dichloromethane / methanol: 10/1).
- the obtained product was dissolved in methanol (15 mL), and 10 equivalents of a 1M potassium hydroxide solution was added and refluxed. After completion of the reaction, it was concentrated and purified by column chromatography (dichloromethane / methanol: 40/1).
- the obtained product was dissolved in methanol (15 mL), and 10 equivalents of a 1M potassium hydroxide solution was added and refluxed. After completion of the reaction, it was concentrated and purified by column chromatography (dichloromethane / methanol: 40/1).
- a method for preparing a methanesulfonate of the reference compound P-9 was used to give the yellow compound P-17 methanesulfonate (190 mg, 81%).
- a method for preparing a methanesulfonate of the reference compound P-9 was used to give yellow compound P-21 methanesulfonate (70 mg, 81%).
- Step 1 P-28-1 (437.0 mg, 1.0 mmol, preparation method see CN201210177980.3) was dissolved in a mixture of dichloromethane:water (10:1, 20 mL), followed by the addition of trifluoromethyl Sodium sulfonate (936.0 mg, 6 mmol), the above system was cooled to 0 ° C, and a 70% aqueous solution of t-butoxy-butanol (1.4 mL, 10.0 mmol) was slowly added dropwise. After the addition was completed, stirring was continued for 30 min; Sulfoxide (4.0 mL) was heated to 40 ° C overnight, and the end of the reaction was analyzed by LC-MS.
- Step 2 P-28-2 (300 mg, 0.6 mmol) and phosphorus oxychloride (1.85 g, 11.9 mmol) were added to toluene (20 mL) followed by N,N-dimethylaniline (215.6 mg, 18.0) Methyl) was reacted overnight under reflux. The reaction was completed by TCL, and the reaction mixture was concentrated, then ethyl acetate and iced water were added and stirred, and the ethyl acetate phase was separated, and the ethyl acetate phase was dried and concentrated to give crude chlorobenzene. The crude chloroform was dissolved in anhydrous tetrahydrofuran (10 mL), and morpholine (155.0 mg, 1.8 mmol) was added at 0 ° C and stirred at room temperature until the reaction was completed.
- Step 3 The crude product obtained in Step 2 was dissolved in methanol (20 mL), then water (1 mL) and sodium hydroxide (237.6 mg) were added and reacted under reflux until the starting material disappeared completely, concentrated, water was added, and the pH was adjusted to 5-6. Solid, dry, directly next.
- Step 4 The crude product from Step 3, HBTU (455.0mg, 1.2mmol), triethylamine (121mg, 1,2mmol) and 2-(4-piperidinyl)-2-propanol (Aa9, 93.2mg, 0.65 mmol) was added to DMF (10 mL) and allowed to react at room temperature overnight, and the reaction was completed by LC-MS. The reaction mixture was poured into EtOAc (EtOAc)EtOAc.
- EtOAc EtOAc
- test compound was dissolved in DMSO (dimethyl sulfoxide) to 100 ⁇ M or 10 ⁇ M as a stock solution, and each 2 ⁇ L was added to 48 ⁇ L of 1 ⁇ reaction buffer (1 ⁇ Reaction Buffer) to obtain 1 ⁇ M or 100 nM.
- 1 ⁇ reaction buffer 1 ⁇ Reaction Buffer
- a 4% DMSO solution of the compound was mixed and diluted with 4% DMSO in 1 time reaction buffer (in 1 ⁇ Reaction Buffer) to obtain a 100 nM or 20 nM compound solution.
- IC 50 assay concentration setting 10 ⁇ M and 100 ⁇ M were selected for the starting concentrations for different enzymes. Dissolve in DMSO to 1 mM or 10 mM as a working solution, and add 1 ⁇ L to 24 ⁇ l of 1X Kinase Buffer A (1 ⁇ Kinase Buffer A) to obtain 40 ⁇ M or 400 ⁇ M compound solution containing 4% DMSO, and serially dilute by 4 times. At 10 dilutions, 2.5 ⁇ L of each diluted solution was added to a 384-well plate such that the final concentration of the compound in the final 10 ⁇ L of the kinase reaction system was 10 ⁇ M, 2.5 ⁇ M, 0.625 ⁇ M and contained 1% DMSO.
- Emission Ratio(ER) 665nM Emission signal/620nm Emission signal
- the inhibition rate is calculated using the following formula:
- Inhibition rate (ER sample - ER 0% ) / (ER 100% - ER 0% ) ⁇ 100%
- the compounds in the table all showed a good inhibitory effect on PI3K kinase, and in particular, the compound P-5/6/7 showed an inhibitory effect on the selectivity of PI3K ⁇ .
- GDC0941 is a positive compound, the chemical name is 2-(1H-carbazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-? Phenyl)thieno[3,2-D]pyrimidine(4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d ]pyrimidin-4-yl]morpholine).
- Administration by intragastric administration 0.25 h, 0.5 h, 1.0 h, 2.0 h, 3.0 h, 4.0 h, 6.0 h, 8.0 h and 24 h after administration.
- Intravenous administration 5 min after administration, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h and 24 h.
- venous blood was taken from the posterior venous plexus of the rat eye, placed in a heparinized tube, centrifuged at 11,000 rpm for 5 min, and the plasma was separated and frozen in a refrigerator at -20 °C.
- the concentration of the compound in rat plasma was determined by LC/MS/MS.
- the pharmacokinetic parameters after administration were calculated using a non-compartmental model of Phoenix 1.3 software (Pharsight, USA).
Abstract
Description
Claims (17)
- 一种通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐:其中,R 1为卤素,或未取代或被至少一个取代基取代的C 1-6烷基或C 3-8环烷基,所述取代基为卤素;R 2为-C(OH)R 5R 6、-COC 1-6烷基、-CN、未取代或被至少一个取代基取代的如下基团:C 1-6烷基、-CH 2NH-C 1-6烷基、-CH 2N(C 1-6烷基)(C 1-6烷基)、-CH 2-(含1-2杂原子及3-6碳原子的饱和杂环基)、-CH 2-(含1-2杂原子及3-6碳原子的饱和杂环基)-(含1-2杂原子及3-6碳原子的饱和杂环基)、-CH 2-(含1-2杂原子及4-12碳原子的饱和螺环基)、-CH 2-(含1-2杂原子及3-12碳原子的饱和桥环基)-(含1-2杂原子及3-6碳原子的饱和杂环基),或-CH 2-(含1-2杂原子及3-12碳原子的饱和桥环基),所述取代基为卤素、-N(C 1-4烷基)(C 1-4烷基)、-O-C 1-4烷基、-CN、-COOH、-CHO、-NHS(O) 2-C 1-4烷基、-N(C 1-4烷基)C(C 1-4烷基)(C 1-4烷基)-CONH 2、=O、-OH、-S(O) 2N(C 1-4烷基)(C 1-4烷基)、-S-C 1-4烷基、-S(O) 2-C 1-4烷基、-CO-C 3-6环烷基、氧杂环丁烷基、吗啉基、C 3-6环烷基、-C 1-4烷基-N(C 1-4烷基)(C 1-4烷基)、未取代或被至少一个甲基取代的C 1-4烷基-O-C 1-4烷基、未取代或被至少一个甲基取代的-CONH 2、未取代或被至少一个甲基取代的C 1-4烷基-CONH 2、未取代或被至少一个甲基取代的-COO-C 1-4烷基、未取代或被至少一个甲基取代的-NH 2、未取代或被至少一个甲基取代的-NHCO-C 1-4烷基、未取代或被至少一个取代基A取代的-CO-C 1-4烷基,所述取代基A为羟基或甲基,或者未取代或被至少一个取代基B取代的C 1-4烷基,所述取代基B为-NH 2、-OCH 3、-CONH 2、-OH或-CF 3;所述R 2中,所述杂原子选自N、O和S中的至少一种,所述R 5和R 6各自独立地为氢或C 1-6烷基;R 4为-NH 2、-NHCONHR 11或-NHCO 2R 12,其中R 11和R 12各自独立地为未取代或被至少一个取代基取代的C 1-6烷基、C 3-8环烷基或苯基,所述取代基选自卤素和-C(O)OR 13中的至少一种,其中R 13为未取代或被至少一个取代基取代的C 1-6烷基,所述R 13中的所述取代基为卤素。
- 根据权利要求1所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐,其特征在于,所述R 1为卤素,或未取代或被至少一个取代基取代的C 1-4烷基或C 3-6环烷基。
- 根据权利要求2所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐,其特征在于,所述R 1为-Cl、-F、甲烷基、三氟甲烷基或二氟甲烷基。
- 根据权利要求1所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐,其特征在于,所述R 2为-C(OH)R 5R 6、-COC 1-4烷基、-CN、未取代或被至少一个取代基取代的如下基团:C 1-4烷基、-CH 2NH-C 1-4烷基、-CH 2N(C 1-4烷基)(C 1-4烷基)、-X-(含1-2杂原子的饱和四至六元杂环基)、-X-(含1-2杂原子的饱和四至六元杂环基)-(含1-2杂原子的饱和四至六元杂环基)、-X-(含1-2杂原子及4-8碳原子的饱和二环螺环基)、-X-(含1-2杂原子及3-8碳原子的饱和二环桥环基)-(含1-2杂原子的饱和四至六元杂环基),或-X-(含1-2杂原子及3-8碳原子的饱和二环桥环基),其中X为CH 2,所述杂环基、螺环基和桥环基 以N原子与X相连,所述R 5和R 6各自独立地为氢或C 1-4烷基。
- 根据权利要求4所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐,其特征在于,所述R 2中的所述取代基为-F、-Cl、-Br、-I、-CH 3、-CH 2CH 3、-CH 2CH(CH 3) 2、-CH 2NH 2、-CH 2N(CH 3) 2、-CH 2CH 2NH 2、-CH 2CH 2N(CH 3) 2、-CH 2OH、-CH 2OCH 3、-CH 2CH 2OH、-C(CH 3) 2OH、-C(CH 3)(CF 3)OH、-C(CF 3) 2OH、-C(CH 3) 2OCH 3、-C(CH 3) 2NH 2、-CH 2C(CH 3) 2OH、-CH(OH)CH(CH 3) 2、-C(CH 3) 2CH 2OH、-C(CH 3) 2CH 2OCH 3、-CN、-CF 3、-CO 2H、-CHO、-COCH 3、-CO 2CH 3、-CO 2C(CH 3) 3、-COCH 2OH、-COC(OH)(CH 3) 2、-COCH(OH)CH 3、-CONH 2、-CONHCH 3、-CON(CH 3) 2、-CH 2CONH 2、-CH 2CON(CH 3) 2、-C(CH 3) 2CONH 2、-NH 2、-NHCH 3、-N(CH 3) 2、-NHCOCH 3、-N(CH 3)COCH 3、-NHS(O) 2CH 3、-N(CH 3)C(CH 3) 2CONH 2、=O、-OH、-OCH 3、-S(O) 2N(CH 3) 2、-SCH 3、-S(O) 2CH 3、-C(O)-环丙基、环丙基、环丁基、氧杂环丁烷基或吗啉基取代。
- 根据权利要求8所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐,其特征在于,所述R 3为吗啉基或(S)-3-甲基吗啉基。
- 根据权利要求1所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐,其特征在于,所述R 4为-NH 2、-NHCONHR 11或-NHCO 2R 12,其中R 11和R 12各自独立地为未取代或被至少一个取代基取代的C 1-4烷基、C 3-6环烷基或苯基,所述取代基选自氟、氯、溴和-C(O)OR 13中的至少一种,其中R 13为C 1-4烷基。
- 根据权利要求10所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐,其特征在于,所述R 11和R 12各自独立地为甲基、乙基、异丙基、环丙基、苯基、-Ph-CO 2Et-p或4-氟苯基。
- 一种权利要求1至12中任意一项所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐在制备PI3K活性抑制剂中的用途。
- 根据权利要求13所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐在制备PI3K活性抑制剂中的用途,其特征在于,所述PI3K活性抑制剂对PI3Kδ具有选择性抑制作用。
- 根据权利要求13所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐在制备PI3K活性抑制剂中的用途,其特征在于,所述PI3K活性抑制剂用在治疗与PI3K通道相关的疾病的药物中。
- 根据权利要求15所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐在制备PI3K活性抑制剂中的用途,其特征在于,所述与PI3K通道相关的疾病为肿瘤、白血病及自身免疫性疾病中的至少一种。
- 一种用于治疗与PI3K通道相关的疾病的药物组合物,其特征在于,该组合物包含治疗有效量的根据权利要求1至12中任意一项所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐。
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SG11201912827TA SG11201912827TA (en) | 2017-06-23 | 2018-06-22 | 7-substituted pyrrolotriazine compounds or pharmaceutically acceptable salts thereof, and preparation methods and uses thereof |
CN201880042091.1A CN110869371B (zh) | 2017-06-23 | 2018-06-22 | 7-位取代吡咯并三嗪类化合物或其药学上可用的盐,及其制备方法和用途 |
EP18820615.5A EP3643717B1 (en) | 2017-06-23 | 2018-06-22 | 7-substituted pyrrole triazine compounds or pharmaceutically acceptable salts thereof, and preparation method therefor and uses thereof |
ES18820615T ES2887629T3 (es) | 2017-06-23 | 2018-06-22 | Compuestos de pirrol-triazina sustituidos con 7 o sales aceptables para uso farmacéutico, y procedimiento de preparación y usos de los mismos |
KR1020207002152A KR102413943B1 (ko) | 2017-06-23 | 2018-06-22 | 7-부위 치환된 피롤로트라이아진 화합물 또는 이의 약학적으로 허용되는 염, 및 이의 제조 방법 및 용도 |
AU2018287971A AU2018287971B9 (en) | 2017-06-23 | 2018-06-22 | 7-site substituted pyrrole triazine compounds or pharmaceutically acceptable salts thereof, and preparation method therefor and uses thereof |
CA3068114A CA3068114C (en) | 2017-06-23 | 2018-06-22 | 7-substituted pyrrolotriazine compounds or pharmaceutically acceptable salts thereof, and preparation methods and uses thereof |
JP2019571243A JP6852199B2 (ja) | 2017-06-23 | 2018-06-22 | 7−置換ピロロトリアジン系化合物又はその薬学的に許容される塩、並びにその調製方法及び使用 |
US16/626,254 US11214572B2 (en) | 2017-06-23 | 2018-06-22 | 7-site substituted pyrrole triazine compounds or pharmaceutically acceptable salts thereof, and preparation method thereof and uses thereof |
RU2020101594A RU2745548C1 (ru) | 2017-06-23 | 2018-06-22 | Соединения на основе 7-замещенного пирролотриазина или их фармацевтически приемлемые соли и способы их получения и применения |
BR112019027545-2A BR112019027545A2 (pt) | 2017-06-23 | 2018-06-22 | compostos de pirrolotriazina 7-substituídos ou sais farmaceuticamente aceitáveis dos mesmos, e métodos e preparação e usos dos mesmos |
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010138589A1 (en) | 2009-05-27 | 2010-12-02 | Genentech, Inc. | Bicyclic pyrimidine pi3k inhibitor compounds selective for p110 delta, and methods of use |
CN102675323A (zh) | 2012-06-01 | 2012-09-19 | 南京药石药物研发有限公司 | 吡咯并[2,1-f][1,2,4]三嗪衍生物及其抗肿瘤用途 |
WO2013134226A1 (en) | 2012-03-06 | 2013-09-12 | Boehringer Ingelheim International Gmbh | Benzodioxanes for inhibiting leukotriene production |
WO2013177983A1 (zh) * | 2012-05-31 | 2013-12-05 | 中国科学院上海药物研究所 | 吡咯[2,1-f][1,2,4]并三嗪类化合物,其制备方法及用途 |
WO2014043068A1 (en) | 2012-09-11 | 2014-03-20 | Genzyme Corporation | Glucosylceramide synthase inhibitors |
US20140121224A1 (en) | 2004-05-13 | 2014-05-01 | Icos Corporation | Quinazolinones as inhibitors of human phosphatidyositol 3-kinase delta |
WO2017219800A1 (en) * | 2016-06-25 | 2017-12-28 | Suzhou Kintor Pharmaceuticals, Inc. | Mechanistic target of rapamycin signaling pathway inhibitors and therapeutic applications thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20140036269A (ko) | 2011-07-01 | 2014-03-25 | 바이엘 인텔렉쳐 프로퍼티 게엠베하 | Alk1 억제제로서의 히드록시메틸아릴-치환된 피롤로트리아진 |
US9745321B2 (en) | 2013-09-30 | 2017-08-29 | Shanghai Yingli Pharmaceutical Co., Ltd | Fused pyrimidine compound, intermediate, preparation method therefor, and composition and application thereof |
-
2017
- 2017-06-23 CN CN201710493411.2A patent/CN109111447A/zh active Pending
-
2018
- 2018-06-22 US US16/626,254 patent/US11214572B2/en active Active
- 2018-06-22 ES ES18820615T patent/ES2887629T3/es active Active
- 2018-06-22 SG SG11201912827TA patent/SG11201912827TA/en unknown
- 2018-06-22 WO PCT/CN2018/092419 patent/WO2018233684A1/zh unknown
- 2018-06-22 BR BR112019027545-2A patent/BR112019027545A2/pt active Search and Examination
- 2018-06-22 KR KR1020207002152A patent/KR102413943B1/ko active IP Right Grant
- 2018-06-22 RU RU2020101594A patent/RU2745548C1/ru active
- 2018-06-22 AU AU2018287971A patent/AU2018287971B9/en active Active
- 2018-06-22 CA CA3068114A patent/CA3068114C/en active Active
- 2018-06-22 EP EP18820615.5A patent/EP3643717B1/en active Active
- 2018-06-22 CN CN201880042091.1A patent/CN110869371B/zh active Active
- 2018-06-22 JP JP2019571243A patent/JP6852199B2/ja active Active
- 2018-06-22 PT PT188206155T patent/PT3643717T/pt unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140121224A1 (en) | 2004-05-13 | 2014-05-01 | Icos Corporation | Quinazolinones as inhibitors of human phosphatidyositol 3-kinase delta |
WO2010138589A1 (en) | 2009-05-27 | 2010-12-02 | Genentech, Inc. | Bicyclic pyrimidine pi3k inhibitor compounds selective for p110 delta, and methods of use |
WO2013134226A1 (en) | 2012-03-06 | 2013-09-12 | Boehringer Ingelheim International Gmbh | Benzodioxanes for inhibiting leukotriene production |
WO2013177983A1 (zh) * | 2012-05-31 | 2013-12-05 | 中国科学院上海药物研究所 | 吡咯[2,1-f][1,2,4]并三嗪类化合物,其制备方法及用途 |
CN102675323A (zh) | 2012-06-01 | 2012-09-19 | 南京药石药物研发有限公司 | 吡咯并[2,1-f][1,2,4]三嗪衍生物及其抗肿瘤用途 |
WO2014043068A1 (en) | 2012-09-11 | 2014-03-20 | Genzyme Corporation | Glucosylceramide synthase inhibitors |
WO2017219800A1 (en) * | 2016-06-25 | 2017-12-28 | Suzhou Kintor Pharmaceuticals, Inc. | Mechanistic target of rapamycin signaling pathway inhibitors and therapeutic applications thereof |
Non-Patent Citations (10)
Title |
---|
BACKER, BIOCHEM J, vol. 410, 2008, pages 1 - 17 |
ENGELMAN ET AL., NAT REV GENET, vol. 7, 2006, pages 606 - 619 |
FOLKES ET AL., J MED CHEM, vol. 51, 2008, pages 5522 - 5532 |
FRUMAN ET AL., N ENGL J MED, vol. 370, 2014, pages 1061 - 1062 |
MA ET AL., CELL RES, vol. 24, 2014, pages 912 - 924 |
MURRAY ET AL., J MED CHEM, vol. 55, 2012, pages 7866 - 7695 |
SABBAH ET AL., CURR MED CHEM, vol. 18, 2011, pages 5528 - 5544 |
See also references of EP3643717A4 |
VIVANCOD ET AL., NAT REV CANCER, vol. 2, 2002, pages 489 - 501 |
WINKLER ET AL., CHEM BIOL, vol. 20, 2013, pages 1362 - 1372 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111909153A (zh) * | 2020-04-16 | 2020-11-10 | 山东鲁西药业有限公司 | 7-碘吡咯并[2,1-f][1,2,4]三嗪-4-胺的合成工艺 |
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ES2887629T3 (es) | 2021-12-23 |
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