CN111285887B - Spiro compound - Google Patents
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- 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
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention discloses a spiro compound, application thereof and a pharmaceutical composition containing the same. The structure of the compound is shown as formula I, and the compound has a good inhibitory effect on RET kinase.
Description
Technical Field
The invention relates to a spiro compound, application thereof and a pharmaceutical composition containing the same.
Background
The RET gene was found in the transformed mouse NTH3T3 cells by Takahashi et al (Takahashi M, Ritz J, Cooper GM. activation of a novel human transformation gene, RET, by DNARRANGEMENT. cell,1985,42 (2): 581-588) and was designated as RET gene. The RET gene is a protooncogene (10q11.2) located on the long arm of chromosome 10, and the encoded RET protein is a tyrosine kinase receptor, is composed of three parts, namely a cysteine-rich cadherin-like extracellular region, a transmembrane region and an intracellular region with tyrosine kinase activity, and has 37% amino acid identity with an ALK kinase region. RET proteins stimulate receptor dimerization through ligand binding to the receptor, and intracellular domain autophosphorylation and intracellular substrate phosphorylation activate downstream signals, playing an important role in the processes of proliferation, migration and differentiation of cells.
RET is involved in renal development and development of the gastrointestinal nervous system under normal physiological conditions, however, mutation of the RET gene results in abnormal activation of ligand-independent, constitutive RET kinases, leading to tumorigenesis. There are two major mechanisms for activation of RET kinase: RET gene point mutation; RET gene rearrangement. Missense mutations in RET may occur at extracellular Cys residues (e.g., C620R, C634R/W), leading to aberrant kinase activation. Mutations may also occur in the intracellular kinase activity domain (e.g., V804L/M, M918T) which will promote ligand-independent RET kinase activation (Romei C, Ciampi R, Elisei R.A comprehensive overview of the roll of the RET proto-oncogene in tyrosine kinase. Nat Rev Endocrinol 2016; 12: 192. sup. 202.). Point mutations of RET in Medullary Thyroid Carcinoma (MTC) are very common, occurring in approximately 50% of sporadic MTC and almost all familial MTC. RET gene is recombined in a mode of connecting with other genes through self-breaking to form a new fusion gene, so that the activation of RET tyrosine kinase escapes the regulation and control of ligand, and autophosphorylation is further carried out, thereby enhancing the signal transduction function, promoting the activation of kinase and initiating the generation of tumor. RET fusions are present in 10-20% of Papillary Thyroid Cancers (PTCs), 1-2% of non-small cell lung cancers (NSCLCs) and many other cancers, such as colon and breast cancers. The above results show that: dysregulation of the RET signaling pathway is an important driver of many neoplastic diseases.
No specific inhibitors against RET are currently on the market, but several multi-targeted tyrosine kinase inhibitors have been used in clinical studies of patients with RET gene mutations, such as: vandetanib, cabozantinib and lenvatinib, and the like. The current multi-target tyrosine kinase inhibitor treatment for RET fusion NSCLC patients is inferior to other NSCLC driving genes in efficiency and survival data. In addition, patients are exposed to RET TKIs for a long time, and the incidence of grade 3-4 toxicity is high due to the inhibition effect on VEGFR kinase. Therefore, the development of RET specific inhibitors with higher selectivity and stronger activity increases the curative effect and limits the toxicity, and is expected to become a new means for treating various malignant tumors such as thyroid cancer, NSCLC and the like.
Disclosure of Invention
The invention aims to solve the technical problem that the structure of the existing RET kinase inhibitor is single, and therefore, the invention provides a spiro compound with a brand-new structure, application thereof and a pharmaceutical composition containing the same. The compound has better inhibitory effect on RET kinase.
The invention provides a compound shown as a formula I or a pharmaceutically acceptable salt thereof;
wherein R is1And R2Each independently selected from hydrogen or C1～C4An alkyl group; said C is1～C4Alkyl is optionally selected fromSubstituted from the following groups: 6-membered aryl, 5-to 6-membered heteroaryl; the 6-membered aryl, 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from: halogen, C1～C4Alkyl or C1～C4An alkoxy group.
In an alternative embodiment, R1Is C1～C4An alkyl group; said C is1～C4Alkyl is substituted with one group selected from: 6-membered aryl, 5-to 6-membered heteroaryl; the 6-membered aryl, 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from: halogen, C1～C4Alkyl or C1～C4An alkoxy group; r2Is hydrogen or C1～C4An alkyl group. Preferably, R1Is C1～C2An alkyl group; said C is1～C2Alkyl is substituted with one group selected from: phenyl or pyridyl; said phenyl or pyridyl being optionally substituted with one or more groups selected from: halogen, C1～C4Alkyl or C1～C4An alkoxy group; r2Is hydrogen, methyl, ethyl, propyl or isopropyl.
In an alternative embodiment, R2Is C1～C4An alkyl group; said C is1～C4Alkyl is substituted with one group selected from: 6-membered aryl, 5-to 6-membered heteroaryl; the 6-membered aryl, 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from: halogen, C1～C4Alkyl or C1～C4An alkoxy group; r1Is hydrogen or C1～C4An alkyl group. Preferably, R2Is C1～C2An alkyl group; said C is1～C2Alkyl is substituted with one group selected from: phenyl or pyridyl; said phenyl or pyridyl being optionally substituted with one or more groups selected from: halogen, C1～C4Alkyl or C1～C4An alkoxy group; r1Is hydrogen, methyl, ethyl, propyl or isopropyl.
In an alternative embodiment, R1And R2Are respectively C1～C4An alkyl group.
In the compound or the pharmaceutically acceptable salt thereof, the compound I can be any one of the following compounds:
the invention also provides application of the compound shown as the formula I or pharmaceutically acceptable salt thereof in preparing RET inhibitors.
The invention also provides application of the compound shown as the formula I or pharmaceutically acceptable salts thereof in preparing medicines for preventing or treating diseases mediated by abnormal RET expression.
The "disease mediated by aberrant expression of RET" is, for example, cancer, in turn, for example Papillary Thyroid Cancer (PTC), Medullary Thyroid Cancer (MTC), Pheochromocytoma (PC), ductal pancreatic adenocarcinoma, multiple endocrine tumors (MEN2A or MEN2B), breast cancer (also, for example, metastatic breast cancer), testicular cancer, small cell lung cancer, non-small cell lung cancer, chronic myelomonocytic leukemia, colon cancer, rectal cancer, ovarian cancer, or salivary gland cancer.
The invention also provides a pharmaceutical composition, which comprises the compound shown as the formula I or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
Unless otherwise specified, the terms in the present invention have the following meanings:
the term "alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon group having 1 to 12 carbon atoms. Preferably, the alkyl group is an alkyl group having 1 to 6 carbon atoms. More preferably, the alkyl group is an alkyl group having 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, and the like, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, 1-heptyl, 1-octyl, 1-nonyl, 1-decyl and the like.
As used herein, the term "aryl" refers to a group of a carbocyclic aromatic system having 6 to 14 ring carbon atoms that is monocyclic or polycyclic (e.g., bicyclic or tricyclic) ("C6-14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl).
As used herein, the term "halogen" refers to fluorine, chlorine, bromine, iodine.
As used herein, the term "alkoxy" refers to an alkyl-O-group.
As used herein, the term "heteroaryl" refers to an aryl ring system containing one or more heteroatoms selected from N, O and S, wherein the ring nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. Heteroaryl groups may be monocyclic or polycyclic, such as monocyclic heteroaryl groups fused to one or more carbocyclic aromatic groups or other monocyclic heteroaryl groups. Examples include, but are not limited to, 5-to 6-membered heteroaryl groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2, 4-triazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl); an oxygen atom-containing 5 to 6-membered heteroaryl group, for example, pyranyl, 2-furyl, 3-furyl and the like; a 5-to 6-membered heteroaryl group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; a 5-to 6-membered heteroaryl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group (e.g., 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl); 5-to 6-membered heteroaryl groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl).
The term "optionally substituted" as used herein means that a given structure or group is unsubstituted or substituted with one or more specific substituents. Unless otherwise indicated, optional substitution may be at any position of the substituted group.
As used herein, the term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention. Exemplary salts include, but are not limited to: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, methanesulfonate (methanesulfonate), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate; or ammonium salts (e.g., primary amine salts, secondary amine salts, tertiary amine salts, quaternary ammonium salts), metal salts (e.g., sodium salts, potassium salts, calcium salts, magnesium salts, manganese salts, iron salts, zinc salts, copper salts, lithium salts, aluminum salts).
As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
Certain compounds of the present invention have chiral carbon atoms, double bonds, carbocyclic rings or heterocyclic rings, and thus each configurational isomer { optical isomers (e.g., enantiomers, diastereomers, etc.), cis-trans isomers, etc. } and mixtures thereof (e.g., racemates) are within the scope of the present invention. When certain compounds of the present invention indicate a particular configuration, it is meant that the configurational isomer is present and the compound is substantially free of other isomers.
As used herein, the term "inhibitor" refers to a molecule that is reducing, blocking, preventing, delaying activation, inactivating, desensitizing, or down regulating, for example, a gene, protein, ligand, receptor, or cell.
As used herein, the term "aberrant expression of RET" means an increase in RET activity caused by signaling through RET.
As used herein, the term "prevention" refers to a reduced risk of acquiring or developing a disease or disorder.
As used herein, the term "treating" any disease or disorder refers in one embodiment to ameliorating the disease or disorder (i.e., arresting the disease, or, reducing the degree or severity of presenting with its clinical symptoms). In another embodiment, "treating" refers to improving at least one physical parameter, which may not be perceptible by the subject. In another embodiment, "treating" or "treatment" refers to modulating a disease or disorder, or both, physically (e.g., stabilizing distinguishable symptoms), physiologically (e.g., stabilizing physical parameters). In another embodiment, "treating" or "treatment" refers to slowing the progression of the disease.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
EXAMPLE 1 preparation of SZ-9307
(S) -6- (1-methyl-1H-pyrazol-4-yl) -4- (6- (4-carbonyl-3- (1-phenylethyl) -1,3, 8-triazaspiro [4.5] dec-1-en-8-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1;
compound 1(17g,69.6mmol) and anhydrous dichloromethane (500ml) were added to a reaction flask, stirred, N-isopropylamine (22.5g,174mmol) was added, stirred at room temperature for 30 minutes, trimethylchlorosilane (15.1g,140mmol) was slowly added dropwise, and then heated to reflux for 3 hours during which argon was bubbled for 30 seconds every 30 minutes to remove hydrogen chloride gas generated by the reaction. The reaction was cooled to-10 ℃ and Fmoc-Cl (16.7g, 64.6mmol), EDCI & HCl (21.1g,0.11mol) were added and stirring was continued for 3h during which argon bubbling was carried out for 30 seconds every 30 minutes to remove the hydrogen chloride gas generated by the reaction. The reaction solution was added with 2.5% aqueous Na2CO3 solution (1000ml), extracted with ether (100ml x 2), the aqueous phase was adjusted to pH 2 with 2N hydrochloric acid, extracted with ethyl acetate (300ml x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give compound 9307a1(24.4g, 85%, white foamy solid) which was not purified for the next reaction. LCMS De-Boc [ M + H ] + 367.08.
Step 2;
the reaction flask was charged with 9307A1(4.5g,9.6mmol) and DMF (30ml), stirred, then added with S- (-) -phenethylamine (1.17g,9.6mmol), DIPEA (2.5g,19.3mmol) and finally HATU (4.4g,11.6mmol) and reacted at 20 ℃ for 2 h. The reaction was extracted with water (400ml), EA (50ml x 3), combined with organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product which was purified by flash silica gel column chromatography (EA/PE 0-50%) to give 9307a2(4.5g, 82%, white foam solid). LCMS [ + Na ] + 592.18.
Step 3;
9307A2(4.5g,7.9mmol) and methanol (30ml) were charged in a reaction flask, and after stirring, ethylenediamine (30ml) was added thereto, and the reaction was carried out at 20 ℃ for 2 hours. The reaction was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 9307A3(2.5g, 91%, colorless oily liquid). LCMS [ M + H ] + 348.12.
Step 4;
compound 9307A3(2.5g,7.2mmol) was dissolved in acetic acid (3mL) and triethyl orthoformate (6mL) and stirred at 100 degrees under microwave for 1 hour, the solvent was removed by concentration, and the residue was purified by flash silica gel column chromatography (PE/EA 50% -100%) to give compound 9307a4(2.3g, 89%, colorless oily liquid). LCMS [ M + H ] + 358.09.
Step 5;
the compound 9307A4(1g, 2.8mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was added, stirred at room temperature for 2 hours, and the solvent was removed by concentration and reacted in the next step without purification. LCMS [ M + H + ] 258.07.
In a 100mL single-neck flask were added 3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazoline [1,5-a ] pyridin-4-yl trifluoromethanesulfonate (2.12g, 5.7mmol,1.0eq.) (prepared according to WO 2017011776), (6-fluoropyridin-3-yl) boronic acid (1.92g, 13.5mmol,2.4eq.), palladium tetratriphenylphosphine (330mg, 0.26mmol,0.05eq.), 1, 4-dioxane (55mL) and 2M aqueous sodium carbonate (14.3mL), and the reaction mixture was reacted overnight at 110 ℃ under argon protection. And (3) cooling after the reaction is finished, pouring the reaction liquid into ice water, separating out solids, performing suction filtration and washing for multiple times, and crystallizing dichloromethane to obtain 2(390 mg).
Step 6;
compound 9307A5(357mg,1mol), compound 2(318mg,1mmol) and potassium carbonate (552mg,4mmol) were added to DMSO (5mL) and stirred at 110 ℃ for 16 h. Water (50mL) was added to the system, extracted with ethyl acetate (10 mL. times.3), and the organic phase was concentrated under reduced pressure to give the crude product, which was purified by medium pressure reverse phase column chromatography (ACN-0.1% HCO2H aq) and lyophilized to give SZ-9307(120mg, 22%, white solid). LCMS [ M + H ] + 556.16. 1H NMR (400MHz, CDCl3)8.63(d, J ═ 1.1Hz,1H),8.37(d, J ═ 2.4Hz,1H),8.25(s,1H),7.80(s,1H),7.75(dd, J ═ 8.8,2.5Hz,1H),7.69(d, J ═ 1.5Hz,2H),7.43-7.27(m,6H),6.83(d, J ═ 8.9Hz,1H),5.25(q, J ═ 7.1Hz,1H),4.34(ddd, J ═ 13.1,9.1,4.3Hz,2H),3.9(s,3H),3.60(td, J ═ 14.0,2.9, 2H), 2.11.95 (d, 1.3H), 3.5.5 (J ═ 14.0, 2H), 3.5.5.5.5 (J ═ 13.1 Hz,1H).
EXAMPLE 2 preparation of SZ-9317
(S) -4- (6- (3- (1- (3-fluorophenyl) ethyl) -4-carbonyl-1, 3, 8-triazaspiro [4.5] dec-1-en-8-yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:
tert-butyl (S) -4- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4- ((1- (3-fluorophenyl) ethyl) carbamoyl) piperidine-1-carboxylate
9307A1(932mg,2.0mmol) and DMF (30ml) were added to the reaction flask, stirred, and then (S) -1- (3-fluorophenyl) ethylamine (279mg,2.0mmol), DIPEA (774mg,3.0mmol) and finally HATU (912mg,2.4mmol) were added and reacted at 20 ℃ for 2 hours. Water (100ml) was added to the reaction mixture, and EA (50 ml. multidot.3) was used for extraction; the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product, which was purified by flash silica gel column chromatography (EA/PE 0-50%) to afford 9317A1(1.0g, 85%, white foam solid). LCMS [ + Na ] +610.16@4.18 min.
Step 2:
tert-butyl (S) -4-amino-4- ((1- (3-fluorophenyl) ethyl) carbamoyl) piperidine-1-carboxylate
9317A1(1.0g,1.7mmol) and methanol (5ml) were added to a reaction flask, and after stirring, ethylenediamine (10ml) was added thereto, and the reaction was carried out at 20 ℃ for 2 hours. The reaction solution is decompressed and concentrated to obtain crude product 9317A2, which is not purified to be directly used for the next reaction. LCMS [ + H ] +366.10@2.88 min.
And 3, step 3:
tert-butyl (S) -3- (1- (3-fluorophenyl) ethyl) -4-carbonyl-1, 3, 8-triazaspiro [4.5] dec-1-ene-8-carboxylic acid ester
Compound 9317a2(0.5g,0.85mmol) was dissolved in acetic acid (3mL) and triethyl orthoformate (6mL) and stirred at 100 degrees under microwave for 1 hour, the solvent was removed by concentration, and the residue was purified by flash silica gel column chromatography (PE/EA 50% -100%) to give compound 9317A3(290mg, 90%, colorless oily liquid). LCMS [ + H ] +376.10@3.66 min.
And 4, step 4:
(S) -3- (1- (3-fluorophenyl) ethyl) -1,3, 8-triazaspiro [4.5] dec-1-en-4-one
The compound 9317A3(150mg, 0.41mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was added, stirred at room temperature for 2 hours, and the solvent was removed by concentration and reacted in the next step without purification. LCMS [ + H ] +276.03@2.59 min.
And 5, step 5:
(S) -4- (6- (3- (1- (3-fluorophenyl) ethyl) -4-carbonyl-1, 3, 8-triazaspiro [4.5] dec-1-en-8-yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Compound 9317A4(112mg,0.41mol), compound 2(130mg,0.41mmol) and potassium carbonate (226mg,1.64mmol) were added to DMSO (5mL) and stirred at 110 ℃ for 16 h. Water (50mL) was added to the system, extracted with ethyl acetate (20mL × 3), the organic phase was concentrated under reduced pressure to give the crude product, which was purified by flash silica gel column chromatography (DCM/EA 50%), the product was dissolved in acetonitrile and water, and lyophilized to give SZ-9317(101mg, 43%, white solid). LCMS [ + H ] +574.13@3.78 min. 1H NMR (400MHz, DMSO-d6)9.24(d, J ═ 1.1Hz,1H),8.65(s,1H),8.48(s,1H),8.41-8.39(m,2H),8.13(s,1H),7.90(dd, J ═ 8.9,2.5Hz,1H),7.83(d, J ═ 1.3Hz,1H),7.47-7.40(m,1H),7.24-7.19(m,1H),7.18-7.11(m,3H),5.14(q, J ═ 7.3Hz,1H),4.38-4.28(m,2H),3.88(s,3H),3.57-3.49(m,2H),1.85-1.74(m,2H),1.70 (m, 1.70H), 1.39H, 3H, 1H), 3.55H (d, 1H).
EXAMPLE 3 preparation of SZ-9318
(S) -6- (1-methyl-1H-pyrazol-4-yl) -4- (6- (4-carbonyl-3- (1- (pyridin-3-yl) ethyl) -1,3, 8-triazaspiro [4.5] dec-1-en-8-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:
(R) -2-methylpropane-2-sulfonimide (4.5g,37mmol) and 3-acetylpyridine (5.0g,41mmol) and THF (50mL) were added to a reaction flask and stirred, the system was cooled to 0 deg.C, tetraethyltitanate (16.9g,74mmol) was added dropwise, and the temperature was raised to 65 deg.C after the addition was completed and reacted for 12 hours. The system was cooled to-78 deg.C, L-selectride (100mL,100mmol) was slowly added dropwise over about 1h, and the reaction was allowed to warm to room temperature for 15 min. The reaction was then quenched with methanol at-50 deg.C, water (20mL), EA (200mL) was added, stirred well and filtered. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash silica gel column chromatography (DCM/MeOH ═ 20/1) to give 9318a1(8.0g, 95%, colorless oily liquid). LCMS [ M + H ] + 227.01.
Step 2:
9318A1(4.0g,17.7mmol) and methanol (40mL) were added to the reaction flask, and stirred, and hydrogen chloride dioxane solution (4mol/L,20mL,80mmol) was slowly added dropwise, followed by reaction at room temperature for 1 hour after the addition. The system was filtered slightly, the filtrate slowly added dropwise to vigorously stirred MTBE (300mL), filtered, and the filter cake washed with MTBE to give product 9318A2(2.0g, 92%, white solid). LCMS [ M + H ] + 122.96.
And 3, step 3:
the reaction flask was charged with 9307A1(460mg,1.0mmol) and DMF (10ml), stirred, added with 9318A2(244mg,2.0mmol), DIEA (516mg,4.0mmol) and finally HATU (456mg,1.2mmol) and reacted at 20 ℃ for 2 h. Water (100ml) was added to the reaction solution, and EA (50ml) was extracted three times; the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 9318A3(500mg, 87%, white foam solid). LCMS [ M + H ] + 571.21.
And 4, step 4:
9318A3(500mg,0.87mmol) and methanol (2ml) were added to a reaction flask, and after stirring, ethylenediamine (4ml) was added thereto, and the reaction was carried out at 20 ℃ for 2 hours. The reaction solution is decompressed and concentrated to obtain crude product 9318A4, which is not purified to be directly used for the next reaction.
LCMS:[M+H]+349.09。
And 5, step 5:
compound 9318a4(0.5g,0.85mmol) was dissolved in acetic acid (3mL) and triethyl orthoformate (6mL) and stirred at 100 degrees under microwave for 1h, the solvent was removed by spinning off and the residue was purified by flash silica gel column chromatography (PE/EA 50% -100%) to give compound 9318a5(290mg, 90%, colorless oily liquid). LCMS [ M + H ] + 359.08.
And 6, step 6:
compound 9318a5(60mg, 0.17mmol) was dissolved in dichloromethane (5mL) and trifluoroacetic acid (1mL) was added, stirred at room temperature for 2 hours and the solvent was dried by spinning to give 9318a6, which was directly followed without purification.
And 7, step 7:
(S) -6- (1-methyl-1H-pyrazol-4-yl) -4- (6- (4-carbonyl-3- (1- (pyridin-3-yl) ethyl) -1,3, 8-triazaspiro [4.5] dec-1-en-8-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Compound 9318A6(45mg,0.17mol), compound 2(50mg,0.17mmol) and potassium carbonate (83mg,0.6mmol) were added to DMSO (5mL) and stirred at 110 ℃ for 16 h. To the system was added 50mL of water, extracted three times with ethyl acetate (20mL), the organic phase was pressure spun dried to give the crude product, purified by flash silica gel column chromatography (DCM/MeOH 20/1) and the product was dissolved in acetonitrile and water and lyophilized to give SZ-9318(50mg, 53%, white solid). LCMS [ M + H ] + 557.13.
1H NMR(400MHz,DMSO)9.23(d,J＝1.2Hz,1H),8.65(s,1H),8.57(d,J＝2.1Hz,1H),8.52(dd,J＝4.7,1.3Hz,1H),8.40(t,J＝4.2Hz,3H),8.13(s,1H),7.82(m,2H),7.76(d,J＝8.0Hz,1H),7.42(dd,J＝7.9,4.8Hz,1H),7.06(d,J＝8.9Hz,1H),5.17(q,J＝7.2Hz,1H),4.32(dd,J＝16.5,8.2Hz,2H),3.88(s,3H),3.47(dd,J＝20.6,10.2Hz,2H),1.73(m,5H),1.41(m,2H)。
EXAMPLE 4 preparation of SZ-9320
Step 1:
compound 9307A3(0.5g,1.44mmol) was dissolved in acetic acid (6mL) and methyl orthoacetate (2mL) and stirred at 100 degrees under microwave for 1 hour, the solvent was removed by concentration, and the residue was purified by flash silica gel column chromatography (PE/EA 50% -100%) to give compound 9320a1(110mg, 22%, white solid). LCMS [ M + H ] + 372.15.
Step 2:
compound 9320a1(110mg,0.29mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was added, stirred at room temperature for 2 hours, and the solvent was removed by concentration to give 9320a2, which was directly used in the next reaction without purification.
LCMS:[M+H]+272.0。
And 3, step 3:
compound 9320A2(70mg,0.22mol), compound 2(80mg,0.25mmol) and potassium carbonate (140mg,1mmol) were mixed in DMSO (3mL) and stirred at 115 ℃ for 16 h. Water (10mL) was added to the system, extracted with ethyl acetate (10mL x 3), the organic phase was concentrated and purified by flash silica gel column chromatography (PE/EA 50% -100%) to give SZ-9320(15.1mg, 11%, white solid). LCMS [ M + H ] + 570.11. 1H NMR (DMSO-d6) ppm 9.23(d, J ═ 1.5Hz,1H),8.64(s,1H),8.40-8.41(m,2H),8.31(s,1H),7.82-7.85(m,2H),7.37-7.41(m,2H),7.27-7.30(m,3H),7.05(d, J ═ 11Hz,1H),5.25(q, J ═ 9Hz,1H),4.30-4.36(m,2H),3.88(s,3H),3.44-3.50(m,2H),2.03(s,3H),1.73-1.79(m,5H),1.38-1.46(m, 2H).
EXAMPLE 5 preparation of SZ-9321
Step 1:
compound 9307A3(1.0g,2.88mmol) was dissolved in acetic acid (3mL) and methyl orthoisobutyrate (6mL) and stirred at 100 degrees under microwave for 1 hour, concentrated to remove solvent, and the residue was purified by flash silica gel column chromatography (PE/EA 50% -100%) to give compound 9321a1(300mg, 28%, oil). LCMS [ + H ] + 400.1.
Step 2:
the compound 9321A1(125mg,0.31mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was added, stirred at room temperature for 2 hours, and the solvent was removed by concentration to give 9321A2, which was reacted in the next step without purification. LCMS [ + H ] + 300.1.
And 3, step 3:
compound 9321A2(100mg,0.29mol), Compound 2(90mg,0.29mmol), and potassium carbonate (150mg,1.1mmol) were combined in DMSO (3mL) and stirred at 115 ℃ for 16 h. Water (15mL) and ethyl acetate (15mL) were added to the system, the layers were separated, the organic layer was concentrated, and purified by flash silica gel column chromatography (EA/MeOH 0% -10%) to give SZ-9321(29.4mg, 18%, white solid). LCMS [ M + H ] + 598.16. 1H NMR (DMSO-d6) ppm 9.23(d, J ═ 1.5Hz,1H),8.65(s,1H),8.40-8.41(m,2H),8.13(s,1H),7.82-7.86(m,2H),7.36-7.40(m,2H),7.26-7.30(m,3H),7.05(d, J ═ 11Hz,1H),5.26(q, J ═ 9Hz,1H),4.28-4.33(m,2H),3.88(s,3H),3.50-3.56(m,2H),2.70-2.76(m,1H),1.71-1.82(m,5H),1.34-1.43(m,2H),1.13(d, J ═ 8.0, 1H),1.01, 1H, 1.8 (d, 8H), 1H, 0.
Example 6 preparation of SZ-9382
Step 1:
9307A1(3.0g,6.43mmol) was dissolved in DMF (40mL), EDCI.HCl (1.8g,9.65mmol), HOBT.H2O (1.3g,9.65mmol), ammonium chloride (1.3g,25.75mmol) and N-methylmorpholine (3.6g,32.18mmol) were added sequentially and stirred at room temperature overnight. After completion of the reaction, DMF was removed under reduced pressure and purified by flash silica gel column chromatography (100% EA) to give 9382A1 as a white foamy solid (1.6g, 53%).
Step 2:
9382A1(1.6g) was dissolved in methanol (10mL), diethylamine (4mL) was added and stirred at room temperature for 2 hours, after completion of the reaction the methanol was removed under reduced pressure and purified by flash column chromatography on silica gel (MeOH/EA 0% -10%) to give 9382A2(1.2g, 144%) as a white foamy solid.
And 3, step 3:
9382A2(500g,2.05mmol) was dissolved in 10mL of DMF and (S) -2-phenylpropionic acid (300mg,2.10mmol), HATU (1.2g,3.08mmol) and DIPEA (1mL) were added sequentially and stirred at room temperature overnight. After completion of the reaction, DMF was removed under reduced pressure, water (20mL) and ethyl acetate (20mL) were added and the organic phase was purified by flash silica gel column chromatography (MeOH/EA 0% -10%) to give 9382A3(600mg, 77%) as a white foamy solid.
And 4, step 4:
9382A3(200mg) was dissolved in DCM (10mL), TFA (2mL) was added and stirred at room temperature for 2h, after completion of the reaction, it was directly concentrated to dryness under reduced pressure to give 9382A4(150mg, 81%).
And 5, step 5:
9382A4(150mg,0.54mmol) and Compound 2(200mg,0.62mmol) and potassium carbonate (342mg,2.5mmol) in DMSO heated to 115 deg.C and stirred for 24 h, after the reaction was completed water (20mL) and ethyl acetate (20mL) were added and the organic phase was spin dried to give 9282A5(500mg, light yellow solid) which was used in the next step without further purification.
And 6, step 6:
9382A5(500mg), methanol (12mL) and 6N sodium hydroxide (1mL) were mixed and stirred at 70 ℃ overnight, after completion of the reaction, methanol was removed under reduced pressure and washed with flash silica gel column chromatography (100% EA) to give SZ-9382(35mg, 11% second yield). LCMS [ M + H ] + 555.19. 1H NMR (DMSO-d6) ppm 9.23(d, J ═ 1.5Hz,1H),8.64(s,1H),8.40-8.41(m,2H),8.13(s,1H),7.82-7.85(m,2H),7.33-7.38(m,4H),7.25-7.29(m,1H),7.05(d, J ═ 11Hz,1H),4.32(d, J ═ 17Hz,2H),3.88-3.90(m,4H),3.53-3.55(m,2H),1.68-1.76(m,2H),1.50(d, J ═ 9.5Hz,3H),1.37-1.40(m, 2H).
Example 7 preparation of SZ-9365
4- (6- (2, 3-dimethyl-4-carbonyl-1, 3, 8-triazaspiro [4.5] dec-1-en-8-yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:
9307A1(300mg,0.64mmol) and DMF (10ml) were added to a reaction flask and stirred, followed by methylamine hydrochloride (52mg,0.77mmol), DIEA (330mg,2.6mmol) and finally HATU (243mg,0.64mmol) added and reacted at 20 ℃ for 2 hours. Water (100ml) was added to the reaction solution, and EA (50ml) was extracted three times; the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash silica gel column chromatography (DCM/MeOH 20/1) to afford 9365A1(300mg, 98%, white foam solid). LCMS [ M + H ] + 502.06.
Step 2:
9365A1(300mg,0.62mmol) and methanol (2ml) were added to a reaction flask, and after stirring, ethylenediamine (4ml) was added thereto, and the reaction was carried out at 20 ℃ for 2 hours. The reaction solution is decompressed and concentrated to obtain crude product 9365A2, which is not purified to be directly used for the next reaction.
LCMS:[M+H]+258.06。
And 3, step 3:
compound 9365a2(150mg,0.58mmol) was dissolved in acetic acid (3mL) and triethyl orthoacetate (6mL) and stirred at 100 degrees under microwave for 1h, the solvent was spun off and the residue was purified by flash silica gel column chromatography (DCM/MeOH 20/1) to give compound 9365A3(60mg, 37%, colorless oily liquid). LCMS [ M + H ] + 282.06.
And 4, step 4:
compound 9365A3(60mg, 0.21mmol) was dissolved in dichloromethane (5mL) and trifluoroacetic acid (1mL) was added, stirred at room temperature for 2 hours and the solvent was dried by spinning to give 9365a4, which was directly followed without purification. LCMS [ M + H ] + 182.04.
And 5, step 5:
4- (6- (2, 3-dimethyl-4-carbonyl-1, 3, 8-triazaspiro [4.5] dec-1-en-8-yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Compound 9365A4(28mg,0.15mol), compound 2(50mg,0.15mmol) and potassium carbonate (83mg,0.6mmol) were added to DMSO (5mL) and stirred at 110 ℃ for 16 h. To the system was added 50mL of water, extracted three times with ethyl acetate (20mL), the organic phase was pressure spun dried to give the crude product, purified by flash silica gel column chromatography (DCM/MeOH 20/1) and the product was dissolved in acetonitrile and water and lyophilized to give SZ-9365(50mg, 69%, white solid). LCMS [ M + H ] + 480.08.
1H NMR(400MHz,DMSO)9.23(d,J＝1.4Hz,1H),8.65(s,1H),8.40(s,2H),8.13(s,1H),7.83(d,J＝1.2Hz,2H),7.05(d,J＝8.9Hz,1H),4.32(d,J＝13.3Hz,2H),3.88(s,3H),3.54–3.41(m,2H),2.99(s,3H),2.21(s,3H),1.73(td,J＝13.3,4.0Hz,2H),1.35(d,J＝12.6Hz,2H)。
Effect examples RET activity inhibition assay
The purpose of the test is as follows: staurosporine was used as a positive control compound. IC detection of compounds on RET kinase Using the method of Mobility shift assay50The value is obtained.
The test conditions are as follows:
enzyme concentration: 2.5nM
ATPKm：16uM
Pre-incubation: for 10min
Reaction time: 60min
Compound starting concentration 1 μ M, 3-fold dilution, 10 concentrations, duplicate wells.
The test method comprises the following steps:
1. compound preparation the compound powder was dissolved in 100% DMSO to prepare a 10mM stock solution.
2. Kinase reaction process
(1) A1 XKinase buffer was prepared.
(2) Preparation of compound concentration gradient: compounds were tested at 1 μ M concentration, diluted in 384 plates to 100-fold final concentration of 100% DMSO solution, followed by 3-fold dilutions of compounds at 10 concentrations. Using a dispenser to transfer 250nL of 100 times final concentration of compound to the target plate.
(3) A2.5 fold final concentration of Kinase solution was prepared using a1 XKinase buffer.
(4) Add 10. mu.L of 2.5 fold final concentration kinase solution to the compound well and positive control well, respectively; mu.L of 1 XKinase buffer was added to the negative control wells.
(5) Centrifuge at 1000rpm for 30 seconds, shake the plate and incubate at room temperature for 10 minutes.
(6) A mixture of ATP and Kinase substrate 2 was made up to a final concentration of 5/3 times using a1 XKinase buffer.
(7) The reaction was initiated by adding 15. mu.L of a mixed solution of ATP and substrate at 5/3-fold final concentration.
(8) The 384 well plates were centrifuged at 1000rpm for 30 seconds, shaken well and incubated for 60 minutes at room temperature.
(9) Add 30. mu.L of termination detection solution to stop the kinase reaction, centrifuge at 1000rpm for 30 seconds, shake and mix.
(10) The conversion was read using a Caliper EZ Reader.
3. Data analysis
Calculating the formula: % Inhibition ═ 100%
Wherein: conversion% _ sample is the Conversion reading for the sample;
conversion% _ min: negative control well mean, representing conversion readings without enzyme live wells;
conversion% _ max: positive control wells are averaged for conversion readings in wells without compound inhibition.
Fitting a dose-response curve: the log value of the concentration is taken as an X axis, the percentage inhibition rate is taken as a Y axis, and an analysis software GraphPad Prism 5 is adopted to fit a dose-effect curve, so that the IC of each compound on the enzyme activity is obtained50The value is obtained.
The test results are shown in table 1:
TABLE 1
Claims (13)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein R is1And R2Each independently selected from hydrogen or C1～C4An alkyl group; said C is1～C4Alkyl is optionally substituted with one group selected from: 6-membered aryl, 5-to 6-membered heteroaryl; the 6-membered aryl, 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from: halogen, C1～C4Alkyl or C1～C4An alkoxy group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, R1Is C1～C4An alkyl group; said C is1～C4Alkyl is substituted with one group selected from: 6-membered aryl, 5-to 6-membered heteroaryl; said 6-membered aryl, 5-to 6-membered heteroaryl being optionally substituted by one or more groups selected fromThe following groups: halogen, C1～C4Alkyl or C1～C4An alkoxy group; r2Is hydrogen or C1～C4An alkyl group.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, R1Is C1～C2An alkyl group; said C is1～C2Alkyl is substituted with one group selected from: phenyl or pyridyl; said phenyl or pyridyl being optionally substituted with one or more groups selected from: halogen, C1～C4Alkyl or C1～C4An alkoxy group; r2Is hydrogen, methyl, ethyl, propyl or isopropyl.
4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is C1～C2An alkyl group; said C is1～C2Alkyl is substituted with one group selected from: phenyl or pyridyl; said phenyl or pyridyl being optionally substituted by one or more fluorine atoms.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, R2Is C1～C4An alkyl group; said C is1～C4Alkyl is substituted with one group selected from: 6-membered aryl, 5-to 6-membered heteroaryl; the 6-membered aryl, 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from: halogen, C1～C4Alkyl or C1～C4An alkoxy group; r1Is hydrogen or C1～C4An alkyl group.
6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, R2Is C1～C2An alkyl group; said C is1～C2Alkyl is substituted with one group selected from: phenyl or pyridyl; said phenyl or pyridyl being optionally substituted with one or more groups selected from: halogen, halogen,C1～C4Alkyl or C1～C4An alkoxy group; r1Is hydrogen, methyl, ethyl, propyl or isopropyl.
7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, R2Is C1～C2An alkyl group; said C is1～C2Alkyl is substituted with one group selected from: phenyl or pyridyl; said phenyl or pyridyl being optionally substituted by one or more fluorine atoms.
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, R1And R2Are respectively C1～C4An alkyl group.
9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is any one of the following:
10. a pharmaceutical composition comprising a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of a disease mediated by aberrant expression of RET.
12. The use of claim 11, wherein the disease mediated by aberrant expression of RET is cancer.
13. The use of claim 12, wherein the cancer is papillary thyroid cancer, medullary thyroid cancer, pheochromocytoma, ductal pancreatic adenocarcinoma, multiple endocrine tumors, breast cancer, testicular cancer, small cell lung cancer, non-small cell lung cancer, chronic myelomonocytic leukemia, colon cancer, rectal cancer, ovarian cancer, or salivary gland cancer.
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| CN110177786A (en) * | 2016-10-10 | 2019-08-27 | 阿雷生物药品公司 | Pyrazolo [1,5-A] pyridine compounds being substituted are as RET kinase inhibitor |
| CN110267960A (en) * | 2017-01-18 | 2019-09-20 | 阿雷生物药品公司 | Substituted pyrazolo [1,5-a] pyrazine compound as RET kinase inhibitor |
| CN110382494A (en) * | 2016-10-10 | 2019-10-25 | 阿雷生物药品公司 | Pyrazolo [1,5-A] pyridine compounds being substituted are as RET kinase inhibitor |
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| CN110177786A (en) * | 2016-10-10 | 2019-08-27 | 阿雷生物药品公司 | Pyrazolo [1,5-A] pyridine compounds being substituted are as RET kinase inhibitor |
| CN110382494A (en) * | 2016-10-10 | 2019-10-25 | 阿雷生物药品公司 | Pyrazolo [1,5-A] pyridine compounds being substituted are as RET kinase inhibitor |
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