WO2023169453A1 - Composé alcynyle contenant un cycle hétéroaromatique, son procédé de préparation et son utilisation - Google Patents
Composé alcynyle contenant un cycle hétéroaromatique, son procédé de préparation et son utilisation Download PDFInfo
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- WO2023169453A1 WO2023169453A1 PCT/CN2023/080231 CN2023080231W WO2023169453A1 WO 2023169453 A1 WO2023169453 A1 WO 2023169453A1 CN 2023080231 W CN2023080231 W CN 2023080231W WO 2023169453 A1 WO2023169453 A1 WO 2023169453A1
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- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- alkyl
- methyl
- unsubstituted
- membered
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 142
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Definitions
- the present invention relates to KIT mutation inhibitors, in particular to a class of compounds containing heteroaromatic ring alkynyl groups and their preparation methods and uses. More specifically, the present invention relates to a compound that can inhibit the proliferation of KIT mutant cell lines, a preparation method of such compounds, and pharmaceutical uses for mutant KIT-related diseases.
- KIT also known as CD117 or stem cell factor receptor
- RTK Receptor Tyrosine Kinase
- KIT belongs to the third type of RTK, which consists of 5 immunoglobulin-like domains (D1 ⁇ D5), 1 transmembrane domain, and 1 juxtamembrane domain (JMD) and tyrosine kinase (TK) domain. composed of cytoplasmic region.
- PDGFR ⁇ platelet-derived growth factor receptor ⁇
- PDGFR ⁇ platelet-derived growth factor receptor ⁇
- FLT3 FLT3
- CSF-1R colony-stimulating factor 1 receptor
- the ligand stem cell factor binds to the extracellular domain to dimerize the receptor, leading to tyrosine autophosphorylation in the TK domain in the cytoplasmic region, further causing downstream signaling pathways (such as PI3K, JAK-STAT , Ras-Erk, Src family kinases and PLC signaling pathways), and trigger a variety of physiological processes, such as cell proliferation, division, and tissue growth and survival.
- SCF ligand stem cell factor
- KIT gain-of-function mutations are associated with various diseases such as tumors, inflammation, and autoimmune diseases.
- GIST gastrointestinal stromal tumors
- systemic mastocytosis a small amount of acute myeloid leukemia
- glioma a small amount of acute myeloid leukemia
- lung cancer a small amount of acute myeloid leukemia
- KIT mutations Its role in GIST has been studied most extensively and deeply. About 85% of GISTs are caused by KIT mutations. GIST is the most common mesenchymal tumor of the gastrointestinal tract, with an incidence rate of approximately 1/100,000 to 2/100,000, accounting for 1 to 3% of all gastrointestinal tumors.
- Imatinib As a first-line drug for the treatment of GIST, Imatinib is effective against most GISTs with primary KIT mutations, but 90% of patients will eventually develop drug resistance due to secondary mutations in KIT, leading to tumor recurrence.
- These resistance mutations mainly occur in the ATP binding pocket of KIT (exon 13, such as K642E, V654A; exon 14, such as T670I) and activation loop (A-loop; exon 17, such as D816H, D816V, D820A, N822K, N822H, N822V ).
- Sunitinib and Regorafenib as second- and third-line treatments for GIST, can only overcome a small number of Imatinib-resistant mutations (such as V654A and T670I mutations that occur in the ATP-binding pocket), and the clinical response rate is low. It is reported that among Imatinib-resistant cases, 50% of patients have secondary mutations in A-loop (Demetri GD, et al. Lancet. 2006, 368: 1329-1338; Nishida T, et al. Int.J. Clin.Oncol.2009,14:143-149). Therefore, the development of new KIT inhibitors that can reverse drug resistance caused by A-loop (exon 17) mutations has important clinical significance.
- CN104211639A, CN108456163A and CN111662227A all relate to heteroaryl ring alkynyl compounds, which involve compounds whose connecting chain L is -C(O)NH-, -NHC(O)-, ether chain or amino chain.
- the connecting chain of the heteroaryl ring alkynyl compound disclosed in WO2015089210A1 includes -C(O)NHCH 2 -, its pyridine ring must have a sulfone imine as the dominant structure in the meta position, and the middle benzene ring must be unsubstituted. situation; in addition, its focus is on VEGFR and PDGFR, and does not involve the inhibitory activity against KIT mutant cell lines.
- the present invention provides a class of heteroaryl ring alkynyl small molecule kinase inhibitors with novel structures. These compounds have very strong proliferation inhibitory activity on KIT mutant cell lines (including various mutant forms including KIT D816V). At the same time, this type of compound has high selectivity, has no obvious cytotoxicity to non-tumor cells (32D cells) and KIT wild-type cells (NCI-H526, Moe7), and has weak inhibitory activity against EGFR and PDGFR-dependent cells, which reflects the Compounds with higher selectivity. In addition, representative compounds have significant anti-tumor effects in vivo and have low toxicity.
- the invention provides a compound of formula (I), or its deuterated compound, pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug:
- X is selected from -(C(R a )(R b )) q -;
- R a and R b are each independently selected from hydrogen, deuterium, halogen, and C1-4 alkyl; or R a and R b connected to the same carbon atom together with the carbon atom form a 3-5-membered carbon ring;
- q is selected from 1 and 2;
- R 1 is selected from hydrogen, halogen, C1-6 alkyl
- Ring M1 is selected from the following structures:
- a 1 and A 2 are independent CR H4 or N atoms
- a 3 is CR H2 or N atom
- a 4 is CR H3 , NR H3 or N atom
- R 2 and the atom connected thereto form a substituted or unsubstituted 3-7 membered carbocyclic ring or heterocyclic ring, and the substitution refers to being substituted by 1-5 R 3 ;
- R H1 , R H2 and R H4 are each independently selected from hydrogen, halogen, amino, cyano, hydroxyl, -N(R 4 )(R 5 );
- the R 4 and R 5 are each independently selected from hydrogen, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C1-6 alkyl acyl, C3- 6 cycloalkyl acyl;
- the substitution means each is independently substituted by 1-5 R 6 ; in cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, one or more
- R 6 and the atoms to which they are connected together form a substituted or unsubstituted 5-7 membered carbocyclic ring or 5-7 membered heterocyclic ring, and the substitution refers to being substituted by 1 to 5 R 7 groups;
- Ring M 2 is selected from unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-7 membered heteroaryl, unsubstituted or substituted 5-7 heterocyclyl; the substitution means that each is independently replaced by Replaced by 1-5 R M ;
- R M Two R M and the atoms connected to them together form a substituted or unsubstituted 3-7 membered carbocyclic ring or heterocyclic ring, and the substitution refers to being substituted by 1-5 R 8 groups;
- the R 8 are each independently selected from hydroxyl, cyano, amino, halogen, -NH (C1-6 alkyl), C1-6 alkyl, C1-6 heteroalkyl, C1-6 haloalkyl, C1-6 hydroxyl Alkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl.
- the compound has the structure of the following formula (II):
- R 1 is selected from halogen, C1-3 alkyl; preferably selected from methyl, F, Cl;
- R a and R b are each independently selected from hydrogen, deuterium, halogen, and methyl; or R a and R b and the carbon atoms connected to them together form a three-membered carbon ring;
- Ring M1 is selected from the following structures:
- a 1 , A 2 , A 3 , A 4 , rings W, Z and R H1 are each as defined above;
- Ring M2 is defined as above.
- ring M1 is selected from the following structures:
- C,N on the ring atom indicates that it is CH or N.
- R 2 , RH1 , RH2 and RH3 are each defined as described above.
- Ring M 2 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted pyridyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted benzothienyl; the substitution means that each is independently substituted by 1-5 R M ;
- R M Two R M and the atoms connected to them form a substituted or unsubstituted 3-7 membered carbocyclic ring or heterocyclic ring, and the substitution refers to being substituted by 1-5 R 8 groups;
- the R 8 are each independently selected from hydroxyl, cyano, amino, halogen, -NH (C1-6 alkyl), C1-6 alkyl, C1-6 heteroalkyl, C1-6 haloalkyl, C1-6 hydroxyl Alkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl.
- the alkyl group is a saturated aliphatic linear or branched alkyl group with 1 to 8 carbon atoms; typical alkyl groups include but are not limited to: methyl, ethyl, propyl, isopropyl, and cyclopropyl , n-butyl, isobutyl, tert-butyl, etc.
- halogens are each independently selected from F, Cl, Br, I;
- the haloalkyl group means that at least one hydrogen atom in the alkyl group is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are the same as or different from each other;
- the heteroalkyl group means that at least one skeleton C atom in the alkyl group is replaced by a heteroatom (N, O, S).
- examples of the heteroalkyl group may include alkoxy, alkylamino, alkylthio, etc.
- the heteroatoms are the same or different from each other;
- the cycloalkyl group is a saturated or partially unsaturated 3-10 membered monocyclic or polycyclic alicyclic ring, and can be a monovalent group or a bivalent group (ie, cycloalkylene group);
- the heterocycloalkyl group is a saturated 3-10 membered monocyclic or polycyclic alicyclic heterocyclic ring containing one or more heteroatoms selected from N, O, and S, and can be a monovalent group or a bivalent group. (i.e. heterocycloalkylene);
- the aryl group means that each atom constituting the ring in the aryl ring is a carbon atom, including a single ring or a condensed polycyclic ring, and it can be a monovalent group or a bivalent group (i.e., arylene group).
- the aryl ring preferably has 5 to 10 carbon atoms, and more preferably an aryl group has 5 to 7 carbon atoms.
- the heteroaryl group is an aromatic group containing one or more heteroatoms selected from N, O, and S on the ring.
- a heteroaryl group can be a monovalent group or a bivalent group (i.e., a heteroarylene group).
- heterocyclyl groups are monocyclic or polycyclic, and at least one of them is a non-aromatic ring group containing one or more heteroatoms selected from N, O, and S on the ring.
- a heterocyclyl group may be a monovalent group or a bivalent group (i.e., a heterocyclylene group).
- the above-mentioned compound of formula (I) is selected from the group consisting of compounds of the following formula:
- the present invention also provides a method for preparing the above-mentioned compound of formula (I), which includes the following steps: performing a coupling reaction between a compound of formula (A) and a compound of formula (B) to obtain a compound of formula (I).
- ring M 1 , ring M 2 , X and R 1 are each independently defined as above; TMS is -Si(CH 3 ) 3 ;
- the coupling reaction is carried out in the presence of a palladium metal catalyst and a copper metal catalyst, and in the presence of a base.
- the palladium metal catalyst includes Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 , and Pd(PPh 3 ) One or more of 4 ;
- the copper metal catalyst includes CuI and/or CuCl;
- the base includes CsF, Cs 2 CO 3 , KF, K 2 CO 3 , NaHCO 3 , One or more of Na 2 CO 3 , Et3N, ( i Pr) 2 EtN, and DMAP;
- the coupling reaction is performed in the presence of a solvent, and the solvent includes one or more of acetonitrile, 1,4-dioxane, and DMF.
- the method includes the following steps: the compound of formula (A) and the compound of formula (B) are carried out in the presence of cesium fluoride, Pd(PPh 3 ) 2 Cl 2 , CuI and triethylamine in an acetonitrile solvent.
- the coupling reaction gives compounds of formula (I).
- the present invention provides an instructive synthetic scheme (as shown in synthetic route I). It will be appreciated that the reagents/reaction conditions shown in the synthetic schemes can be modified or optimized using general knowledge of organic chemistry to prepare different compounds of the invention.
- the A 1 , A 2 , ring M 2 , X, Z, R H1 and R 1 are independently as mentioned above.
- the synthetic route I includes the following steps:
- Step 1 Mix compounds I-1, I-2 and Et 3 N, add palladium metal catalyst and copper metal catalyst, and react under argon protection (for example, at room temperature) to obtain compound I-3;
- Step 2 Add compounds I-3 and I-4 to a suitable solvent, add palladium metal catalyst, K 2 CO 3 , and heat the reaction under argon protection to obtain important intermediate A; in addition, suitable ligands can also be added ;
- Step 3 Condensation reaction occurs between compounds I-5 and I-6, wherein X is as described above. After mixing compound I-5, HATU, DIPEA and DMF (for example, stirring at room temperature for 30 to 60 minutes), add compound I-6 and react (for example, at room temperature for 6 to 12 hours) to obtain intermediate B;
- Step 4 Mix intermediates A, B, base and MeCN, add palladium metal catalyst and copper metal catalyst, and react under argon protection (for example, in the case of I substitution, react at room temperature, and in the case of Br substitution (reaction at 80°C, reaction time (for example, 2 to 6 hours)) to obtain compound I-7;
- argon protection for example, in the case of I substitution, react at room temperature, and in the case of Br substitution (reaction at 80°C, reaction time (for example, 2 to 6 hours)
- the palladium metal catalyst described in steps 1 and 4 is Pd(PPh 3 ) 2 Cl 2 , and the copper metal catalyst is CuI;
- the solvent in step 2 is one or more of toluene, ethanol, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane and water;
- the palladium metal catalyst is Pd(PPh 3 ) 4 , Pd Any one of (OAC) 2 and (dppf) PdCl 2 ;
- the base is any one of K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 and Na 2 CO 3 ;
- the ligand is X- Any of Phos and PPh 3 ;
- the base in step 4 is cesium fluoride and/or triethylamine
- synthetic route I includes the following steps:
- Step 1 Add compound I-1 and Et 3 N to the round-bottomed flask, replace the oxygen with argon, add Pd(PPh 3 ) 2 Cl 2 and CuI, repeat the operation of removing oxygen, and react at room temperature for about 15 minutes. , add I-2, and continue the reaction at room temperature for 3 hours
- compound I-3 can be obtained after purification; among them, the equivalents of compound I-1, I-2, Pd(PPh 3 ) 2 Cl 2 and CuI can be about 1.0, 1.0 ⁇ 1.5, 0.05 ⁇ 0.1, 0.1 ⁇ respectively. 0.2.
- Step 2 Add compounds I-3, I-4, K 2 CO 3 , THF and water to the round bottom flask, replace the oxygen with argon, add Pd(OAc) 2 and X-Phos, and repeat the operation of removing oxygen. Heating to 80°C for reaction, the reaction is completed in 4-8 hours, and compound A can be obtained after purification; the equivalents of I-3, I-4, K 2 CO 3 , Pd(OAc) 2 and X-Phos can be 1.0 respectively. 1.0-1.5, 2.0-3.0, 0.05-0.1, 0.1-0.2; the volume ratio of THF/H 2 O is 4/1.
- Step 3 Add compound I-5, HATU, DIPEA and DMF to the round-bottomed flask, stir at room temperature for 30 minutes, then add compound I-6, and react at room temperature; after 12 hours of reaction, compound B can be obtained after purification;
- the equivalents of compounds I-5, I-6, HATU and DIPEA may be about 1.0, 1.0 ⁇ 1.2, 1.0 ⁇ 1.5, 2.0 ⁇ 4.0 respectively.
- Step 4 Add compounds A, B, Et 3 N, CsF and MeCN to the round-bottomed flask, replace oxygen with argon, add Pd(PPh 3 ) 2 Cl 2 , CuI, repeat the operation of removing oxygen, and heat to room temperature or to Reaction at 80°C, the reaction is completed in 3-6 hours, and compound I-7 can be obtained after purification; the equivalents of compounds A, B, cesium fluoride, Pd(PPh 3 ) 2 Cl 2 , CuI and Et 3 N can be approximately 1.0 respectively. ,1.0 ⁇ 1.5,2.5 ⁇ 3.0,0.05 ⁇ 0.1,0.1 ⁇ 0.2,2.5 ⁇ 3.0.
- the present invention also provides a pharmaceutical composition, which includes: one selected from the group consisting of the above-mentioned compound of formula (I), its deuterated compound, pharmaceutically acceptable salt, solvate, ester, acid, metabolite and prodrug. or more, and pharmaceutically acceptable excipients.
- the present invention also provides the above-mentioned compound of formula (I) or its deuterated compound, pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug or the above-mentioned pharmaceutical composition for preparing KIT (mutant type) inhibitor. uses in.
- the present invention also provides the above-mentioned compound of formula (I) or its deuterated compound, pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug, or the above-mentioned pharmaceutical composition prepared for treatment, prevention or Use in a medicament to improve one or more diseases or conditions selected from the group consisting of tumors, inflammation, autoimmune and neurological diseases.
- the tumor is a gastrointestinal stromal tumor, in particular a gastrointestinal stromal tumor involving a KIT mutation, more particularly a gastrointestinal stromal tumor caused by a KIT mutation that is resistant to Imatinib and/or Sunitinib tumor.
- the compound of formula (I) of the present invention has a potent killing effect on tumor cells carrying primary KIT mutations and drug-resistant KIT mutations.
- the compound containing a heteroaryl ring alkynyl structure according to the present invention shows that the tumor cell lines carrying different mutant forms of KIT, D816V, V559D, V559D-V654A, V559D/Y823D and V559D/N822K It has strong inhibitory activity on cell proliferation.
- the compound containing a heteroaryl ring alkynyl structure according to the present invention has low cytotoxicity to normal 32D cells and the KIT wild-type cell line NCI-H526 cell line, showing the toxicity of the compound.
- compounds containing heteroaryl ring alkynyl structures according to the present invention have low inhibitory activity against BCR-ABL, EGFR, and PDGFR-dependent cell lines, showing that such compounds have relative selectivity.
- the compound containing a heteroaryl ring alkynyl structure according to the present invention shows obvious activity in inhibiting the growth of related tumors in a long-term animal efficacy model, which is significantly better than the positive drug Ripretinib.
- the animals are in good condition (including no significant decrease in body weight), and there is no animal death.
- Figure 1 is a graph showing the effects of compounds 77, 85 and Ripretinib on 32D KIT D816V cell KIT and its downstream signaling pathways.
- Figure 2 is a graph showing the effects of compounds 27, 48 and Ripretinib on 32D KIT V559D cell KIT and its downstream signaling pathways.
- Figure 3 is a graph showing the effects of compounds 27, 48 and Ripretinib on KIT and its downstream signaling pathways in 32D KIT V559D-V654A cells.
- Figure 4 is a graph showing the efficacy of compounds 77, 85, and Ripretinib on subcutaneous transplanted tumors of 32D KIT D816V nude mice.
- Figure 5 is a graph showing the effects of compounds 77, 85, and Ripretinib on the body weight of tumor-bearing (32D KIT D816V) nude mice.
- Step 1 Add 2-amino-5-bromo-3-iodopyridine (1.0g, 3.35mmol), trimethylsilyl acetylene (427.2mg, 4.35mmol) and Et 3 N (50mL) into a round-bottomed flask.
- Step 2 Add 2-amino-5-bromo-3-trimethylethynylpyridine (300mg, 1.11mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (348mg, 1.67 mmol), K 2 CO 3 (385mg, 2.79mmol) and THF/H 2 O (8/2mL), replace oxygen with argon, add Pd(OAc) 2 (25mg, 0.11mmol) and X-Phos (106 mg, 0.22mmol), heated to 70°C for 4 hours. After the reaction, the reaction solution was extracted with ethyl acetate (15 mL ⁇ 3) and water (10 mL).
- Step 3 Add compound 4-methyl-3-iodobenzoic acid (2.0g, 7.63mmol), HATU (3.8g, 9.92mmol), DIPEA (2.5g, 19.08mmol) and DMF (40mL) into the round-bottomed flask. After stirring at room temperature for 30 minutes, the compound benzylamine (818 mg, 7.63 mmol) was added, and the reaction was carried out at room temperature for 12 hours. After the reaction, the reaction solution was extracted with ethyl acetate (50 mL ⁇ 3) and water (40 mL), and the organic phase was washed with tap water. (30 mL g (yield: 93%).
- Step 4 Add compound N-benzyl-3-iodo-4-methylbenzamide (100 mg, 0.28 mmol), 5-(1-methyl-1H-pyrazol-4-yl) into the round-bottomed flask. -3-((Trimethylsilyl)ethynyl)-2-aminopyridine (100 mg, 0.37 mmol), Et 3 N (86 mg, 0.85 mmol), CsF (108 mg, 0.71 mmol) and MeCN (20 mL), using Replace oxygen with argon, add Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.014 mmol) and CuI (5.4 mg, 0.028 mmol), repeat the oxygen removal operation, and react at room temperature for 3 hours.
- Pd(PPh 3 ) 2 Cl 2 10 mg, 0.014 mmol
- CuI 5.4 mg, 0.028 mmol
- the synthesis method is as in Example 1 except that phenylethylamine is used instead of benzylamine.
- the synthesis method was as in Example 1 except that 1-phenylcyclopropylamine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 5-fluoro-3-iodobenzoic acid was used instead of 4-methyl-3-iodobenzoic acid.
- the synthesis method was as in Example 1 except that 5-fluoro-3-iodobenzoic acid was used instead of 4-methyl-3-iodobenzoic acid and 3-aminomethylthiophene was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 5-fluoro-3-iodobenzoic acid was used instead of 4-methyl-3-iodobenzoic acid and 3-aminomethylpyridine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 5-fluoro-3-iodobenzoic acid was used instead of 4-methyl-3-iodobenzoic acid and 6-fluoro-3-aminomethylpyridine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 4-chlorobenzylamine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 2-trifluoromethylbenzylamine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 2-methoxybenzylamine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 3-methoxybenzylamine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 4-methoxybenzylamine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 4-fluorobenzylamine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 2,4-difluorobenzylamine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 2-fluoro-4-chlorobenzylamine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 3-aminomethylpyridine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 4-aminomethylpyridine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 5-aminomethylpyrimidine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 3-aminomethyl-6-methoxypyridine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 3-aminomethyl-6-chloropyridine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 3-aminomethyl-6-fluoropyridine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 3-aminomethyl-6-methylaminopyridine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that (6-(1H-pyrazol-1yl)pyridin-3-yl)methanamine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 3-fluorobenzylamine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 3-aminomethylthiophene was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 2-aminomethylthiophene was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 4-aminomethylthiazole was used instead of benzylamine.
- Step 1 Add 2-chloro-5-bromo-3-iodopyridine (1.0g, 3.14mmol) and MeNH2 (2.0M, 5mL) to the sealed tube, heat to 80°C and react overnight. After the reaction, the solvent was evaporated to dryness under reduced pressure, and 650 mg of 2-methylamino-5-bromo-3-iodopyridine was obtained by column chromatography (yield: 66%).
- Step 2 Add 2-methylamino-5-bromo-3-iodopyridine (300 mg, 0.96 mmol), trimethylsilyl acetylene (122.4 mg, 1.25 mmol) and Et 3 N (20 mL) into a round-bottomed flask. Replace oxygen with argon, add Pd(PPh 3 ) 2 Cl 2 (34 mg, 0.048 mmol) and CuI (18 mg, 0.096 mmol), repeat the operation of removing oxygen, and react at room temperature for 4 hours; after the reaction, add 20 mL of ethyl acetate. Dilute the reaction solution and filter to obtain the product 2-methylamino-5-bromo-3-trimethyl.
- Step 3 Add 2-amino-5-bromo-3-trimethylethynylpyridine (200mg, 0.71mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (294mg, 1.41 mmol), K 2 CO 3 (244mg, 1.77mmol) and THF/H 2 O (8/2mL), replace oxygen with argon, add Pd(OAc) 2 (16mg, 0.071mmol) and X-Phos (50mg, 0.11mmol), heated to 70°C for 3 hours. After the reaction, the reaction solution was extracted with ethyl acetate (15 mL ⁇ 3) and water (10 mL).
- Step 4 Add 4-methyl-3-iodobenzoic acid (2.0g, 7.63mmol), HATU (3.8g, 9.92mmol), DIPEA (2.5g, 19.08mmol) and DMF (40mL) into the round-bottomed flask at room temperature. After stirring for 30 minutes, add 3-aminomethylpyridine (825 mg, 7.63 mmol) and react at room temperature for 12 hours; after the reaction, extract the reaction solution with ethyl acetate (50 mL ⁇ 3) and water (40 mL), and use the organic phase with Wash with water (30 mL methyl)benzamide 2.5g (yield: 93%).
- Step 5 Add 3-iodo-4-methyl-N-(pyridin-3-ylmethyl)benzamide (100 mg, 0.28 mmol), 5-(1-methyl-1H-pyridin) into the round-bottomed flask.
- Azol-4-yl)-3-((trimethylsilyl)ethynyl)-2-methylaminopyridine 101 mg, 0.35 mmol
- Et 3 N 86 mg, 0.85 mmol
- CsF 108 mg, 0.71 mmol
- MeCN 15 mL
- replace oxygen with argon add Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.014 mmol), CuI (5.4 mg, 0.028 mmol), repeat the operation of removing oxygen, and react at room temperature for 3 hours.
- the synthesis method was as in Example 30 except that ethylamine was used instead of methylamine.
- the synthesis method was as in Example 30, except that ethylamine was used instead of methylamine and 3-aminomethylthiophene was used instead of 3-aminomethylpyridine.
- the synthesis method was as in Example 30 except that cyclopropylamine was used instead of methylamine and 3-aminomethylthiophene was used instead of 3-aminomethylpyridine.
- the synthesis method was as in Example 1, except that 1-trifluoromethyl-1H-pyrazolyl-4-boronic acid zanacol ester was used instead of 1-methyl-1H-pyrazolyl-4-boronic acid zanacol ester.
- the synthesis method was as in Example 1, except that 1-difluoromethyl-1H-pyrazolyl-4-boronic acid zanacol ester was used instead of 1-methyl-1H-pyrazolyl-4-boronic acid zanacol ester.
- the synthesis method was as in Example 1 except that thiophen-3-ylmethylene-d2-amine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that 6-fluoropyridin-3-ylmethylene-d2-amine was used instead of benzylamine.
- the synthesis method was as in Example 1 except that (5-cyclopropylthiophen-2-yl)methylamine was used instead of (5-methylthiophen-2-yl)methylamine.
- the synthesis method was as in Example 61 except that 5-chlorothiophene-2-aldehyde was used instead of 5-cyclopropylthiophene-2-aldehyde.
- Step 1 Add 4-methyl-3-iodobenzoic acid (2.0g, 7.63mmol), HATU (3.8g, 9.92mmol), DIPEA (2.5g, 19.08mmol) and DMF (40mL) into a round-bottomed flask at room temperature. After stirring at low temperature for 30 minutes, 3-aminomethylthiophene (864 mg, 7.63 mmol) was added, and the reaction was carried out at room temperature for 12 hours. After the reaction, the reaction solution was extracted with ethyl acetate (50 mL ⁇ 3) and water (40 mL).
- Step 2 Add 3-iodo-4-methyl-N-(thiophen-3-ylmethyl)benzamide (100 mg, 0.28 mmol), 5-bromo-3-(trimethyl Silyl)ethynyl)-2-aminopyridine (90mg, 0.34mmol), Et 3 N (85mg, 0.84mmol), CsF (128mg, 0.84mmol) and MeCN (20mL), replace oxygen with argon, add Pd ( PPh 3 ) 2 Cl 2 (10 mg, 0.014 mmol), CuI (5.3 mg, 0.028 mmol), repeat the operation of removing oxygen, and react at room temperature for 3 hours.
- Pd ( PPh 3 ) 2 Cl 2 10 mg, 0.014 mmol
- CuI 5.3 mg, 0.028 mmol
- Step 3 Add 3-((2-amino-5-bromopyridin-3-yl)ethynyl)-4-methyl-N-(thiophen-3-ylmethyl)benzamide ( 80mg, 0.19mmol), 4-cyclopropylimidazole (30mg, 0.28mmol), CuI (7mg, 0.038mmol), Cs2CO3 (122mg, 0.38mmol) and DMF (2mL), reacted at 120°C for 30h under argon protection. Cool to room temperature, add 10 mL of ethyl acetate to dilute the reaction solution, filter, and wash the filter cake with ethyl acetate.
- the synthesis method was as in Example 1 except that 5-iodo-pyrimidin-2-amine was used instead of 5-bromo-3-iodopyridin-2-amine and 3-aminomethylthiophene was used instead of benzylamine.
- Step 1 Removal of (2-((tert-butoxyformyl)((4-cyanotetrahydro-2H-pyran-4-yl)methyl)amino)thiazole-4-boronic acid zonal ester (
- N-methylpyrazole-4-boronic acid pinacol ester is replaced and 3-aminomethylthiophene is used instead of benzylamine
- Intermediate 67-IM can be prepared by referring to the synthesis method of Example 1.
- Step 2 Add intermediate 67-IM (50 mg, 0.075 mmol) and DCM (2 mL) into a round-bottomed flask, add TFA (0.5 mL), and react at room temperature overnight. Pour the reaction solution into NaHCO 3 aqueous solution, and extract with DCM. Combine the organic phases, wash with NaCl aqueous solution, dry over anhydrous Na 2 SO 4 , evaporate the solvent to dryness under reduced pressure, and separate by column chromatography to obtain Product 40 mg (light yellow solid; yield: 94%).
- the synthesis method was as follows except that 6-chloro-3-iodoimidazole[1,2-b]pyrazine was used instead of 5-bromo-3-iodopyridin-2-amine and 3-aminomethylthiophene was used instead of benzylamine. example 1.
- the synthesis method was as in Example 80 except that compound 83 was used instead of compound 79.
- the synthesis method was as in Example 1, except that 3-bromoimidazole[1,2-a]pyrimidine was used instead of 5-bromo-3-iodopyridin-2-amine and 3-aminomethylthiophene was used instead of benzylamine.
- Step 1 Add 5-iodo-7H-pyrrole[2,3-d]pyrimidin-4amine (1.0g, 3.85mmol), K 2 CO 3 (1.59g, 11.54mmol) and anhydrous to a round-bottomed flask. DMF (10 mL), add methyl iodide (0.29 mL, 4.61 mmol) dropwise, and react at room temperature for 8 hours.
- Step 2 Add 5-iodo-7-methyl-7H-pyrrole[2,3-d]pyrimidin-4-amine (0.5g, 1.82mmol) and trimethylsilylacetylene (233mg, 2.37mmol), Et 3 N (5mL) and MeCN (20mL), replace the oxygen with argon, add Pd(PPh 3 ) 2 Cl 2 (64mg, 0.091mmol), CuI (17.4mg, 0.091mmol), and repeat the oxygen removal Operation, react overnight at room temperature; after the reaction is completed, add 50 mL of ethyl acetate to dilute the reaction solution, filter, evaporate the solvent to dryness under reduced pressure, and separate by column chromatography to obtain the product 7-methyl-5-((trimethylsilyl) Ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 420 mg (yield: 94.2%).
- Step 3 Add 3-iodo-4-methyl-N-(thiophen-3-ylmethyl)benzamide (90 mg, 0.25 mmol), 7-methyl-5-(trimethyl (silyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (62 mg, 0.25 mmol), Et 3 N (76 mg, 0.76 mmol), CsF (115 mg, 0.76 mmol), and MeCN (10 mL), replace oxygen with argon, add Pd(PPh 3 ) 2 Cl 2 (9 mg, 0.013 mmol) and CuI (5 mg, 0.025 mmol), repeat the operation of removing oxygen, and react at room temperature for 3 hours.
- Pd(PPh 3 ) 2 Cl 2 9 mg, 0.013 mmol
- CuI 5 mg, 0.025 mmol
- the synthesis method was as in Example 72 except that deuterated methyl iodide was used instead of methyl iodide.
- Step 1 Add compound 90 (0.3g, 0.55mmol) and DCM (5mL) into a round-bottomed flask, add HCl.dioxane solution (0.5mL, 2mmol), and stir at room temperature overnight. After the reaction, the solvent was evaporated to dryness under reduced pressure to obtain 0.26g of yellow solid 91-IM (yield: 98.2%), which was directly used in the next step without further purification.
- Step 2 Add 106-IM (80mg, 0.17mmol), K 2 CO 3 (115mg, 0.84mmol) and anhydrous DMF (2mL) obtained in the previous step into the round-bottomed flask, and add IEt (16 ⁇ L, 0.2mmol) dropwise. , react at room temperature overnight. After the reaction, pour the reaction solution into water, extract with ethyl acetate, combine the organic phases, wash with H 2 O and NaCl aqueous solution respectively, dry over anhydrous Na 2 SO 4 , evaporate the solvent to dryness under reduced pressure, and perform column chromatography.
- Step 1 Add 7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.0g, 7.45mmol), DMF-DMA (1.07g, 8.95mmol) and DMF (20mL) into a round-bottomed flask at room temperature. Reaction was allowed to take place overnight. The solvent was evaporated to dryness under reduced pressure to obtain a crude product, which was redissolved in DCM, washed with H 2 O and NaCl aqueous solutions, dried over anhydrous Na 2 SO 4 , and separated by column chromatography to obtain 950 mg of compound 115-2 (yield: 67.4%). .
- Step 2 Add compound 115-2 (250 mg, 1.32 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (333 mg, 1.59 mmol), and copper acetate (291 mg) into the round-bottomed flask. ,1.59mmol), 2,2'-bipyridine (248mg, 1.59 mmol), anhydrous Na 2 CO 3 (420 mg, 3.96 mmol) and DMAC (10 mL). Stir at 90°C for 4 hours, add DCM and wash with water three times. The organic phase was dried over anhydrous Na 2 SO 4 and evaporated to dryness under reduced pressure to obtain intermediate 115-3 without further purification.
- Step 3 Add EtOH (10 mL) and ethylenediamine (0.2 mL) to intermediate 115-3 in the previous step, and react under reflux for 16 h. After the reaction, the solvent was evaporated to dryness under reduced pressure, redissolved in DCM, washed with NaCl aqueous solution, and dried over anhydrous Na 2 SO 4. The solvent was evaporated to dryness under reduced pressure and separated by column chromatography to obtain 160 mg of compound 115-4 (two-step total product). rate: 56%).
- Step 4 Add compound 115-4 (160 mg, 0.74 mmol), NIS (183 mg, 0.81 mmol) and DMF (3 mL) into the round-bottomed flask, and react at room temperature for 4 hours. After the reaction, the solvent was evaporated to dryness under reduced pressure, and 7-(3,6-dihydro-2H-pyran-4-yl)-5-iodo-7H-pyrrolo[2,3-d] was separated by column chromatography. Pyrimidine-4-amine 180 mg (yield: 71%).
- Step 1 Add 115-2 (0.5g, 2.64mmol) and anhydrous THF (30mL) to the round-bottomed flask, add NaH (60%, 211mg) under ice bath, stir for 30 minutes, add ethyl chloroformate (430mg, 3.96mmol), react at room temperature for 2 hours. After the reaction, the reaction was quenched by adding dropwise a saturated aqueous ammonium chloride solution in an ice bath, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 142-1 (400 mg, Yellow oil, yield 57.9%).
- Step 2 and step 3 can be obtained by referring to step 3 and step 4 of Example 115 respectively to obtain 126-3 as a brown solid.
- MTT assay was used to detect the effects of compounds on cell proliferation. Collect the cells in good condition, inoculate them into a 96-well plate, add different concentrations of compounds, and culture them in a 37°C, 5% CO 2 , saturated humidity incubator for 72 hours (h). After the drug effect ends, add MTT to each well and continue culturing for 4 hours in a 37°C, 5% CO 2 , saturated humidity incubator. Add triple solution (10% SDS, 5% isobutanol, 0.01mol/L HCl) and place it in a 37°C incubator for 12 hours to ensure that the blue-violet formazan is completely dissolved; measure the OD value at 570nm and 690nm wavelengths on a microplate reader. . Calculate the inhibitory rate of the compound on cells according to the following formula:
- Inhibition rate (%) (OD value of control hole - OD value of administration hole)/OD value of control hole ⁇ 100%
- Compound IC 50 was calculated using Graphpad Prism 8.0 software, and a concentration (log)-inhibition rate plot was generated.
- the heteroaromatic alkynyl compounds in the embodiments of the present invention all have significant inhibitory activity on the proliferation of 32D KIT D816V cells, and 33 of them are better than Ripretinib.
- the IC 50 value of Examples 76, 77, 99 and 120 against the proliferation of 32D KIT D816V cells is less than 1 nM, which is significantly better than the positive drug Ripretinib, showing that this type of compound has a strong advantage in inhibiting the proliferation of cells carrying KIT D816V drug-resistant mutations. .
- KIT mutant cells 32D KIT V559D, 32D KIT V559D-V654A, 32D KIT V559D-Y823D and 32D KIT V559D-N822K
- KIT wild-type cells NCI-H526, Mo7e , HMC-1
- 32D cell proliferation inhibitory activity the results are shown in Table 3.
- the representative compounds have strong inhibitory activity on the proliferation of cells carrying different mutant KITs of V559D, V559D-V654A, V559D-Y823D and V559D-N822K, reflecting the advantages of this type of compound in inhibiting mutant KIT in a broad spectrum; at the same time, Representative compounds have weak activity against wild-type KIT-dependent cell lines and have a high therapeutic index compared with mutant KIT. For example, the selection index for KIT D861V is higher than 490 times and is better than the positive drug ripretinib. In addition, the compounds are not cytotoxic to 32D normal cells, indicating that these compounds have good selectivity and can avoid potential off-target toxic side effects.
- results show that the representative compounds are not cytotoxic to wild-type PDGFR and EGFR-dependent cell lines, and initially show good target selectivity; while the positive drug ripretinib has relatively obvious inhibitory activity against PDGFR-dependent U118MG cells, and treatment The index is lower.
- Cells were seeded in six-well plates, added with different concentrations of drugs, and treated in a 37°C, 5% CO 2 , saturated humidity incubator for 4 hours. Cells were lysed on ice with 1 ⁇ SDS gel loading buffer (50mM Tris-HCl (pH 6.8), 100mM DTT, 2% SDS, 10% glycerol, 0.1% bromophenol blue). The cell lysate was denatured by heating in a boiling water bath for 10 minutes. Perform SDS-PAGE electrophoresis. After electrophoresis, transfer the protein to a PVDF membrane and place it in blocking solution (5% skimmed milk powder diluted in TBST) at room temperature for 1 hour. After washing the membrane, add the corresponding I and II antibodies and use ECL to The reagent develops color, and is finally observed and photographed in the ECL chemiluminescence imaging system.
- 1 ⁇ SDS gel loading buffer 50mM Tris-HCl (pH 6.8), 100mM DTT, 2% S
- mice BALB/c-nu nude mice, 5-6 weeks, ⁇ . Each nude mouse was subcutaneously inoculated with 32D KIT D816V cells. After the average tumor volume reached ⁇ 100 mm 3 , the animals were divided into groups (D0) according to tumor volume. Mice were administered intragastrically (ig) (twice a day) with a volume of 10 mL/kg; the solvent group was given the same volume of "solvent"; the tumor volume was measured twice a week, the mice were weighed, and the data were recorded.
- Compound 85 (30, 100 mg/kg, i.g., BID ⁇ 12) dose-dependently inhibited the growth of subcutaneous transplanted tumors in 32D KIT D816V nude mice, with tumor inhibition rates of 20% and 50% respectively; compound 77 (20, 40 mg/kg, i.g., BID ⁇ 12) also dose-dependently inhibited the growth of subcutaneous transplanted tumors in 32D KIT D816V nude mice, with tumor inhibition rates of 45% and 71% respectively; Ripretinib (30, 100 mg/kg, i.g., BID ⁇ 12) has an inhibitory effect on 32D KIT The tumor inhibition rates of subcutaneously transplanted tumors in D816V nude mice were 13% and 21% respectively; the tumor-bearing mice could tolerate the above drugs well, and no obvious symptoms such as weight loss occurred. In comparison, the efficacy of compounds 77 and 85 on subcutaneous transplanted tumors in 32D KIT D816V nude mice were significantly stronger than Ripret
- the compounds containing heteroaryl ring alkynyl groups in the embodiments of the present invention have strong inhibitory activity against 32D KIT D816V cells; at the same time, representative compounds 27, 48, 77 and 85 have strong inhibitory activity against V559D, V559D-V654A, V559D/Y823D and V559D /N822K Different mutant forms of KIT all have potent inhibitory activity, indicating that this type of compound has the advantage of potent and broad-spectrum inhibition of different types of mutant KIT.
- Representative compounds 27, 48, 77 and 85 have weak inhibitory effects on 32D normal cells and cells carrying wild-type KIT, PDGRF ⁇ and EGFR, indicating that these compounds have high selectivity and can avoid related off-target toxic side effects; the important thing is , the representative compounds 77 and 85 have obvious medicinal effects on the 32D KIT D816V nude mouse subcutaneous transplant tumor model; their medicinal efficacy is significantly stronger than the reference compound Ripretinib (P ⁇ 0.05), indicating that the compounds containing heteroaryl ring alkynyl groups It has the advantage of stronger medicinal effect in the body.
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Abstract
La présente invention concerne un composé alcynyle contenant un cycle hétéroaromatique, son procédé de préparation et son utilisation. Le composé alcynyle contenant un cycle hétéroaromatique est un composé représenté par la formule (I), ou un composé deutéré, un sel pharmaceutiquement acceptable, un solvate, un ester, un acide, un métabolite ou un promédicament de celui-ci. Le composé tel que représenté par la formule (I) selon la présente invention a un effet destructeur puissant sur des cellules tumorales portant une mutation KIT primaire et une mutation KIT résistante aux médicaments.
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