CN117886813A - SHP2 phosphatase allosteric inhibitors - Google Patents

SHP2 phosphatase allosteric inhibitors Download PDF

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CN117886813A
CN117886813A CN202310682599.0A CN202310682599A CN117886813A CN 117886813 A CN117886813 A CN 117886813A CN 202310682599 A CN202310682599 A CN 202310682599A CN 117886813 A CN117886813 A CN 117886813A
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compound
pharmaceutically acceptable
cancer
acceptable salt
mixtures
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梁永宏
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Yaoya Technology Shanghai Co ltd
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Yaoya Technology Shanghai Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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

Abstract

The invention discloses an SHP2 phosphatase allosteric inhibitor and application thereof. The related compound, a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a protein tyrosine phosphatase SHP-2 inhibitor in medicaments for treating leukemia, neuroblastoma, melanoma, acute bone leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma, gastric cancer, liver cancer, anaplastic large cell lymphoma and glioblastoma are disclosed.

Description

SHP2 phosphatase allosteric inhibitors
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a novel SHP2 phosphatase inhibitor, and a preparation method and application thereof.
Background
The present invention relates generally to novel compounds, methods for their preparation and use as SHP2 phosphatase inhibitors (e.g., for the treatment of cancer).
SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, containing two N-terminal Src homology 2 (SH 2) domains, a Protein Tyrosine Phosphatase (PTP) domain, and a poorly sequenced C-terminal end. X-ray crystallography studies indicate that SHP2 inhibits its own phosphatase activity by blocking access to the catalytic site on the PTP domain using the N-terminal SH2 domain. Casein or peptide bisphosphate (e.g., IRS-1) has been demonstrated to bind to the SH2 domain of SHP2, disrupting the N-terminal SH2-PTP domain interaction. This binding allows the substrate to enter the catalytic site and activate the phosphatase.
SHP2 is recruited by RTKs to induce cellular signaling and is involved in multiple intracellular oncogenic signaling cascades, such as Jak/STAT, PI3K/AKT, RAS/Raf/MAPK, PD-1/PD-L1, and the mTOR pathway. The key gtpase RAS, in which extracellular signals are transmitted into the nucleus, plays a oncogenic role in its GTP binding mode regulated (tyrosine dephosphorylation in adaptor/scaffold proteins) by SHP2 into an activated state; on the other hand, SHP2 activation of RAS signaling in acquired resistance promotes compensatory activation of signaling pathways (e.g., negative feedback regulation of MEK activates RTKs, activating SHP2 to activate downstream pathways), in which case inhibition of SHP2 may eliminate reactivation of the RAS/Raf/ERK pathway and represent a potential therapeutic strategy as a new strategy to address RTK resistance issues.
Moreover, germ line or somatic mutations in PTPN11 that lead to overactivation of SHP2 have been identified in a variety of pathophysiological states: the dysplastic Noonan syndrome, hematological malignancies include juvenile myelomonocytic leukemia, myelodysplastic syndrome, B-cell acute lymphoblastic leukemia and acute myelogenous leukemia and low frequency solid tumors. Thus, SHP2 is one of the most attractive targets for the development of new therapies for the treatment of various diseases.
Currently, there are already SHP2 phosphatase inhibitors at clinical stage: TNO155 from North, JAB-3312 from JACOBIO, RMC-4630 from Revol, and GDC-1971 from Gentech, all of which are in phase I or II clinical stages, there is no such target product on the market. At the same time, the oncogenic mutation E76K causes SHP2 to adopt an "open" conformation, completely exposing the PTP catalytic pocket. Therefore, it is of great importance to develop inhibitors that inhibit the target more efficiently while having strong activity against the SHP2 phosphomutant E76K enzyme.
Disclosure of Invention
To solve the above problems, the present invention provides a compound or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, polymorph or isomer thereof,
another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients, wherein the therapeutically effective amount of the present disclosure is optionally from 0.1 to 2000mg.
The present disclosure also relates to a method of preparing the pharmaceutical composition comprising admixing an inventive compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a compound of formula (la), or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier, diluent or excipient.
The present disclosure further relates to the use of the inventive compounds or their tautomers, meso, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for the preparation of SHP2 inhibitors.
The present disclosure further relates to the use of the inventive compounds, or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a disease or disorder mediated by SHP2 activity.
The disclosure further relates to the use of the inventive compounds, or a tautomer, meso, racemate, enantiomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, as an SHP2 inhibitor in the manufacture of a medicament for the prevention and/or treatment of tumors or cancers.
The present disclosure further relates to the use of a compound of the general formula, or a tautomer, meso, racemate, enantiomer, diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the prevention or treatment of noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute bone leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma, gastric cancer, liver cancer, anaplastic large cell lymphoma, and glioblastoma.
The disclosure further relates to the inventive compounds, or tautomers, meso, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament.
The disclosure also relates to inventive compounds, or tautomers, meso, racemate enantiomers, diastereomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, as SHP2 inhibitors.
The disclosure also relates to inventive compounds or their tautomers, meso racemates, enantiomers, diastereomers, atropisomers or mixtures thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, as SHP2 inhibitors for the prevention and/or treatment of tumors or cancers.
The present disclosure also relates to a method of treatment for prophylaxis and/or treatment of tumors or cancers comprising administering to a patient in need thereof a therapeutically effective dose of a compound of the general formula as an inhibitor of SHP2, or a tautomer meso, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as a tablet dragee, lozenge, aqueous or oil suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or agent, the oral composition may be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants and preservatives to provide a pleasant and palatable pharmaceutical formulation, the tablet containing the active ingredient and nontoxic pharmaceutically acceptable excipients for the mixed preparation of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or oil vehicle.
The aqueous suspension contains the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.
The oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of anti-hydrogenation.
The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion, the oil phase may be a vegetable oil, or a mineral oil or a mixture thereof, the suitable emulsifier may be a naturally occurring phospholipid, and the emulsion may also contain a sweetener, a flavoring agent, a preservative and an antioxidant. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which is prepared by injecting the injectable solution or microemulsion in a topically high amount into the bloodstream of a patient, or which is preferably administered in a manner which will maintain a constant circulating concentration of the compound of the present disclosure. To maintain such constant concentrations, an example of such a device that may be used with a continuous intravenous delivery device is the Deltec CADD-plus. TM.5400 model intravenous pump.
The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The mixture may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above, and the sterile injectable preparation may be a sterile injectable solution or suspension in a parenterally-acceptable non-toxic diluent or solvent, which may be in the form of a sterile fixed oil as a solvent or suspending medium thereof, for which purpose any tempering fixed oil may be employed in addition to fatty acids.
The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the inventive compound or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
Thus, references in the present application to "a compound", "a compound of the invention" or "a compound of the invention" include all such compound forms, e.g., prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers, meso, racemates, enantiomers, diastereomers, and mixtures thereof.
Herein, the term "tumor" includes benign tumors and malignant tumors (e.g., cancers).
As used herein, the term "cancer" includes various malignant tumors in which SHP2 phosphatase participates, including but not limited to non-small cell lung cancer, esophageal cancer, melanoma, striated muscle grenade, cell cancer, multiple myeloma, breast cancer ovarian cancer, endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer, and liver cancer (e.g., hepatocellular cancer), more particularly liver cancer, gastric cancer, and bladder cancer.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The term "polymorph" or "polymorphic form" as used herein means that a compound of the present invention has a plurality of crystalline forms, some compounds of the present invention may have more than one crystalline form, and the present invention encompasses all polymorphic forms or mixtures thereof.
Intermediate compounds of the invention and polymorphs thereof are also within the scope of the present invention.
Crystallization often yields solvates of the compounds of the present invention, and the term "solvate" as used herein refers to a complex composed of one or more molecules of the compounds of the present invention and one or more molecules of a solvent.
The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent is also possible. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may simply accidentally retain water or a mixture of water with some other solvent, the compounds of the invention may be reacted in one solvent or precipitated or crystallized in one solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
The term "acceptable" in relation to a formulation, composition or ingredient as used herein means that there is no sustained detrimental effect on the overall health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
"pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizer isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administration for use in humans and domestic animals.
The terms "subject," "patient," "subject," or "individual" as used herein refer to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals, examples of which include, but are not limited to, any member of the class mammalia: human, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.
The term "treatment" as used herein refers to the treatment of a disease condition associated with a mammal, particularly a human, including
(i) Preventing the occurrence of a disease or condition in a mammal, particularly a mammal that has been previously exposed to a disease or condition but has not been diagnosed with the disease or condition;
(ii) Inhibiting the disease or disorder, i.e., controlling its progression;
(iii) Alleviating the disease or condition, i.e., slowing the regression of the disease or condition;
(iv) Relieving symptoms caused by diseases or symptoms.
The terms "disease" and "disorder" as used herein may be used interchangeably or differently and, because some specific diseases or disorders have not yet been known to cause a disease (and therefore the cause of the disease is not yet known), they cannot be considered as a disease but rather can be considered as an unwanted condition or syndrome, more or less specific symptoms of which have been confirmed by clinical researchers.
The terms "administering," "administering," and the like as used herein refer to methods that enable delivery of a compound or composition to a desired site for biological action. Including, but not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
Detailed description of the preferred embodiments
The invention also provides a method for preparing the compound. The preparation of the compounds of the general formulae (I) and (II) according to the invention can be carried out by the following exemplary methods and examples, which are not to be regarded in any way as limiting the scope of the invention. The compounds of the present invention may also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of methods known in the art and methods described herein. The product obtained in each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis can be synthesized conventionally according to the literature (reaxys) or purchased.
Unless otherwise indicated, temperatures are degrees celsius. Reagents were purchased from commercial suppliers of chembilocks Inc, shanghai, and the like, and these reagents were used directly without further purification unless otherwise indicated.
Unless otherwise indicated, the following reactions were carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or argon, or using dry tubes; glassware drying and/or heat drying.
Column chromatography purification uses 200-300 mesh silica gel from the Qingdao marine chemical plant unless otherwise indicated; preparation of thin layer chromatography A thin layer chromatography silica gel prefabricated plate (HSGF 254) manufactured by Kagaku chemical industry research institute of tobacco, inc.; MS was determined using a Therno LCD Fleet type (ESI) liquid chromatograph-mass spectrometer.
Nuclear magnetic data [ ] 1 H NMR) using Bruker Avance-400MHz or Varian Oxford-400Hz nuclear magnetic instruments with CDCl as solvent for the nuclear magnetic data 3 、CD 3 OD、D 2 O、DMSO-d 6 Etc., based on tetramethylsilane (0.000 ppm) or on residual solvent (CDCl) 3: 7.26ppm；CD 3 OD:3.31ppm；D 2 O:4.79ppm；DMSO-d 6 2.50 ppm) when peak shape diversity is indicated, the following abbreviations represent the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet), dt (doublet). If the coupling constant is given, it is in Hertz (Hz).
The invention will be further described by the following examples, which should not be construed as limiting the scope of the invention.
Preparation of intermediate N- (2-chloro-3-mercaptophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide
Compound 3- (3- (tert-butylmercapto) -2Chloroaniline (1.08 g,5 mmol) and the compound 2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ]]And pyrimidine-3-carboxylic acid ethyl ester (1.43 g,6 mmol) was dissolved in chlorobenzene 20mL and heated to reflux and stirred for reaction for 3 hours. Cooling to room temperature, filtering, and drying to obtain the compound N- (3- (tert-butylmercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ]]And pyrimidine-3-carboxamide (1.18 g, 58% yield). 1 H NMR(400MHz,DMSO)δ:14.85(br,1H),12.33(s,1H),8.43(d,1H),7.43-7.52(m,2H),3.88(br,2H),2.92-2.89(m,2H),1.93-1.81(m,4H),1.29(s,9H),LC/MS(ESI):m/z＝408.1[M+H] + .
The compound N- (3- (tert-butylmercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ]]And pyrimidine-3-carboxamide (1.02 g,2.5 mmol) was dissolved in 10mL of concentrated hydrochloric acid, and the temperature was raised to 50℃and the reaction was stirred for 3 hours. Cooled to room temperature, quenched to neutrality with sodium bicarbonate and the aqueous phase extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue is purified by column chromatography to obtain the compound N- (2-chloro-3-mercaptophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ]]And pyrimidine-3-carboxamide (0.57 g, 65% yield). 1 H NMR(400MHz,DMSO)δ:12.21(s,1H),8.14(d,1H),7.40(d,1H),7.27-7.25(m,1H),6.06(s,1H),3.89-3.86(m,2H),2.92-2.89(m,2H),1.82-1.93(m,4H).LC/MS(ESI):m/z＝353.0[M+H] + .
Preparation of intermediate (S) -1'- (6-bromo-1, 2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-amine
3, 6-dibromo-1, 2, 4-triazine (7.14 g,30 mmol) was dissolved in 50mL of methylene chloride, and (1S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ] -1-amine dihydrochloride (7.11 g,30 mmol) and triethylamine (9.11 g,90 mmol) were added thereto and the reaction was stirred at room temperature overnight. The reaction solution was diluted with methylene chloride, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure. The residue was purified by column chromatography to give the compound (S) -1'- (6-bromo-1, 2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-amine (8.34 g).
LC/MS(ESI):m/z 361.1[M+H] + .
Preparation of intermediate (S) -1'- (6-bromo-1, 2, 4-triazin-3-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4' -piperidin ] -5-amine
3, 6-dibromo-1, 2, 4-triazine (7.14 g,30 mmol) was dissolved in 50mL of methylene chloride, and (5S) -spiro [5, 7-dihydropyranyl [ B ] pyridin-6, 4' -piperidin ] -5-amine (7.14 g,30 mmol), triethylamine (9.11 g,90 mmol) was added and the reaction was stirred at room temperature overnight. The reaction solution was diluted with methylene chloride, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure. The residue was purified by column chromatography to give the compound (S) -1'- (6-bromo-1, 2, 4-triazin-3-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4' -piperidin ] -5-amine (8.71 g).
LC/MS(ESI):m/z 362.1[M+H] + .
Preparation of intermediate (R) -1'- (6-bromo-1, 2, 4-triazin-3-yl) -3H-spiro [ benzofuran-2, 4' -piperidin ] -3-amine
3, 6-dibromo-1, 2, 4-triazine (7.14 g,30 mmol) was dissolved in 50mL of methylene chloride, and (R) -3H-spiro [ benzofuran-2, 4' -piperidine ] -3-amine dihydrochloride (8.31 g,30 mmol), triethylamine (9.11 g,90 mmol) was added and the reaction was stirred at room temperature overnight. The reaction solution was diluted with methylene chloride, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure. The residue was purified by column chromatography to give the compound (R) -1'- (6-bromo-1, 2, 4-triazin-3-yl) -3H-spiro [ benzofuran-2, 4' -piperidin ] -3-amine (8.62 g).
LC/MS(ESI):m/z 363.1[M+H] + .
Example 1
Preparation of (S) -N- (3- ((3- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -1,2, 4-triazin-6-yl) mercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (Compound 1)
(S) -1'- (6-bromo-1, 2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-amine (576 mg,1.6 mmol) was dissolved in NMP (10 ml) and the intermediate N- (2-chloro-3-mercaptophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a was added]And pyrimidine-3-carboxamide (845 mg,2.4 mmol), pd2 (dba) 3 (145 mg,0.16 mmol), xantphos (92 mg,0.16 mmol) and DIEA (1.29 g 10 mmol). After heating to 120 ℃ under nitrogen and stirring for 1h, after TLC reaction was completed, the reaction mixture was added to 75ml of saturated sodium chloride solution, then extracted with EtOAc (25 ml×3), the organic phases were combined, washed with saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, spin-dried and concentrated, and the residue was isolated and purified by preparative high performance liquid chromatography to give compound 1 (428 mg, pale yellow solid). 1 H NMR(400MHz,CDCl 3 )δ:12.14(s,1H),8.42(d,1H),8.16(s,1H),7.38-7.29(m,5H),7.13(d,1H),4.68(m,2H),4.06-4.04(m,3H),3.38-3.35(m,2H),3.19-3.15(m,1H),3.04-3.01(m,2H),2.84-2.81(m,1H),2.06-1.69(m,8H).LC/MS(ESI):m/z 632[M+H] + .
Example 2
Preparation of (S) -N- (3- ((3- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) -1,2, 4-triazin-6-yl) mercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridin [1,2-a ] pyrimidine-3-carboxamide (Compound 2)
(S) -1' - (6-bromo-1, 2, 4-triazin-3-yl) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine (578 mg,1.6 mmol) was dissolved in NMP (10 ml) and the intermediate N- (2-chloro-3-mercaptophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a was added]And pyrimidine-3-carboxamide (845 mg,2.4 mmol), pd2 (dba) 3 (145 mg,0.16 mmol), xantphos (92 mg,0.16 mmol) and DIEA (1.29 g 10 mm)And (3) an ol). After heating to 120 ℃ under nitrogen and stirring for 1h, after TLC reaction was completed, the reaction mixture was added to 75ml of saturated sodium chloride solution, then extracted with EtOAc (25 ml×3), the organic phases were combined, washed with saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, spin-dried and concentrated, and the residue was isolated and purified by preparative high performance liquid chromatography to give compound 2 (494 mg, pale yellow solid). 1 HNMR(400MHz,MeOD)δ:8.56(d,1H),8.45(d,1H),8.34(s,2H),7.99(d,1H),7.44-7.40(m,1H),7.28-7.32(m,1H),7.07(d,1H),4.79-4.66(m,2H),4.53(m,1H),3.98(br,2H),3.45(m,2H),3.37-3.25(m,2H),2.97-2.95(m,1H),2.05-1.69(m,9H).LC/MS(ESI):m/z 633[M+H]+.
Example 3
Preparation of (R) -N- (3- ((3- (3-amino-3H-spiro [ benzofuran-2, 4 '-piperidine ] -1' -yl) -1,2, 4-triazin-6-yl) mercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (Compound 3)
(R) -1'- (6-bromo-1, 2, 4-triazin-3-yl) -3H-spiro [ benzofuran-2, 4' -piperidine]-3-amine (589 mg,1.6 mmol) was dissolved in NMP (10 ml) and the intermediate N- (2-chloro-3-mercaptophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a was added]And pyrimidine-3-carboxamide (845 mg,2.4 mmol), pd2 (dba) 3 (145 mg,0.16 mmol), xantphos (92 mg,0.16 mmol) and DIEA (1.29 g 10 mmol). After heating to 120 ℃ under nitrogen and stirring for 1h, after TLC reaction was completed, the reaction mixture was added to 75ml of saturated sodium chloride solution, then extracted with EtOAc (25 ml×3), the organic phases were combined, washed with saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, spin-dried and concentrated, and the residue was isolated and purified by preparative high performance liquid chromatography to give compound 3 (462 mg, pale yellow solid). 1 H NMR(400MHz,CDCl 3 )δ:12.15(s,1H),8.43(d,1H),8.17(s,1H),7.37(d,1H),7.29-7.24(m,2H),7.17(d,1H),6.98(m,1H),6.67(d,1H),4.84-4.70(m,2H),4.18(s,2H),4.05-4.03(m,2H),3.62(m,2H)3.04-3.01(m,2H),2.07-1.62(m,8H).LC/MS(ESI):m/z 634[M+H]+.
Reference compound TNO-155 (WO 2015/107495), GDC-1971 (WO 2019/183367), RMC-4630 (WO 2018/13597), PY-1 (WO 2022/237676) was synthesized according to the reported route.
Example 4 biological Activity test
The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.
SHP2 allosteric inhibition assay
1. Determination of the inhibitory Effect of Compounds on SHP2 kinase Activity
The purpose of this test is to measure the ability of a compound to inhibit the allosteric activity of the SHP2 full-length protein. Experimental instrument: centrifuge (5810R) was purchased from Eppendorf corporation, pipettor from Rainin corporation of Eppendorf domain, and microplate reader was purchased from BioTek corporation of America, model number SynergyHl full function microplate reader.
The experimental method comprises the following steps: in vitro SHP2 activity assays were performed using the Homogeneous Full Length SHP-2Assay Kit (BPS Bioscience, # 79330). First, 18. Mu.L of Master Mix was added to a 96-well low adsorption microplate (NUNC, # 267342), namely, SHP-2activating Peptide containing 0.5 and 5mM DTT in a reaction buffer having a final concentration of 1X, 5 dishes of test compound/DMSO (final DMSO content: 1%, V/V) was added to each well, the test compound was dissolved in DMSO to ImM, three-fold serial dilutions were performed, 10 concentrations were carried out, the final concentration of the reaction system ranged from 1. Mu.M to 0.05 nM), SHP2 was diluted in a reaction buffer having a final concentration of 0.06nM, and then added to the reaction microplate, 2. Mu.L of each well was placed on the reaction plate, and after centrifugation of the whole activity control (compound only DMSO) and whole inhibition control (no SHP-2) were added, the reaction mixture was incubated at room temperature for 60 minutes.
After the incubation, 25. Mu.L of Substrate solution per well, containing the final concentration of 10. Mu.M of Substrate and 5mM of DTT, was added and incubation was continued for 30 minutes at room temperature after centrifugation. After the reaction, the excitation wavelength of 340nM, the emission wavelength of 455nM and the gain value of 75 were set on a Synergy Hl full-function microplate reader (Biotek).
The experimental data processing method comprises the following steps:
the percent inhibition ratio data {% inhibition = 100- [ (test compound-Min mean)/(Max mean-Min mean) ] X100} for wells treated with compound were calculated from positive control wells (DMSO control wells) and negative control wells (no kinase added) on the reaction plate based on the values of total active control and total inhibitory control as Max and Min. IC50 values for test compounds were calculated using GraphPad prism fit percent inhibition and ten-point concentration data to a 4-parameter nonlinear logistic equation.
Conclusion of experiment:
from the above schemes, it was found that the example compounds of the present invention showed the biological activities in the SHP2 kinase activity assay as shown in Table 1 below.
IC of Table 1 Compounds inhibiting SHP2 50 Value of
Numbering device IC 50 nM Numbering device IC 50 nM Numbering device IC 50 nM
Compound 1 3.62 Compound 3 1.03 RMC-4630 1.36
Compound 2 0.33 TNO-155 1.69 PY-1 0.50
From the experimental results in Table 1, the compounds of the invention show very excellent SHP2 enzyme inhibition activity in the aspect of enzymology, and the IC50 reaches the nM level, thus having great development and application prospects.
2. Determination of the inhibition of the Activity of SHP2 mutant enzyme E76K by Compounds
The experimental method comprises the following steps:
1. transfer 50nL of compound to 384 assay plates with Echo 655, centrifuge at 1000rpm for 1min (ensuring 1% DMSO concentration);
2. serial dilutions of 10 gradients in DMSO at a ratio of 1:4;
3. transfer 0.1 μl of diluted compound solution into 384 assay plates using Echo, each well containing 2 replicates;
4. transfer 4. Mu.L of enzyme and 4. Mu.L of SHP2-E76K activation peptide solution to 384 well assay plates, centrifuge at 1000rpm for 1 minute;
incubation at 5.25 ℃ for 60 minutes;
6. transfer 2. Mu.L of substrate (DiFMUP) into 384 well assay plates and centrifuge at 1000rpm for 1 min;
incubating at 7.25 ℃ for 30 minutes;
8. ex360nm and Em460nm fluorescence signal values were read using a BMG microplate reader.
The experimental data processing method comprises the following steps:
the percent inhibition ratio data {% inhibition = 100- [ (test compound-Min mean)/(Max mean-Min mean) ] X100} for wells treated with compound were calculated from positive control wells (DMSO control wells) and negative control wells (no kinase added) on the reaction plate based on the values of total active control and total inhibitory control as Max and Min. IC50 values for test compounds were calculated using GraphPad prism fit percent inhibition and ten-point concentration data to a 4-parameter nonlinear logistic equation.
Conclusion of experiment:
from the above schemes, it was found that the example compounds of the present invention showed the biological activities in the SHP2 kinase activity assay as shown in Table 2 below.
IC of Table 2 Compounds inhibiting SHP2 mutant enzyme E76K 50 Value of
Numbering device IC 50 nM Numbering device IC 50 nM Numbering device IC 50 nM
Compound 1 154.7 Compound 3 135.4 GDC-1971 240.7
Compound 2 38.15 TNO-155 >1000 PY-1 >1425
From the experimental results in table 2, it can be seen that the compound of the present invention shows very excellent inhibitory activity against SHP2 mutant enzyme E76K, which is higher than that of the reference compound, wherein the inhibitory activity of compound 3 reaches 38nM.
3. Cell antiproliferative activity assay
Experimental materials:
NCI-H358 (ATCC-30-2001), KYSE520 (Kebai, CBP 60658) and HCC827 (ATCC, CRL-2868).
The experimental method comprises the following steps:
KYSE520 (Kebai, CBP 60658) and HCC827 (ATCC, CRL-2868) were inoculated into 96-well plates (Corning, 3603) at appropriate cell densities, NCI-H358 (ATCC, CRL-5807) was inoculated into 384-well plates (Corning, 3764) at appropriate cell densities, and cultured overnight in a 37℃cell incubator; the test compound is added into the pore plates for 5 days after being diluted in a gradient manner on the next day, and the final concentration of DMSO in each pore plate is 0.1%; after the incubation time was completed, cellTiter-Glo reagent (CTG, promega, G7573) and the cells were removed for 30 minutes and allowed to return to room temperature, an equal volume of CTG reagent was added to the cells and shaken for 2 minutes to fully lyse the cells. After 30 minutes of standing at room temperature, the fluorescence signal values were read with a microplate reader (PHERAstar FSX). Medium wells were set as negative controls, DMSO wells were positive controls, and the percentage of inhibitory activity of the compounds was normalized by the readings of the negative and positive controls.
Data analysis:
inhibition ratio (%) = (positive control fluorescence value-experimental fluorescence value)/(positive control fluorescence value-negative control fluorescence value) ×100%. Table 3 provides the inhibitory activity of the compounds of the invention on cell proliferation.
TABLE 3 anti-cell proliferation Activity data (IC 50) for the compounds of the invention
Numbering device IC 50 (NCI-H358，nm) IC 50 (KYSE-520，nm) IC 50 (HCC-827，nm)
Compound 1 66.59 221.76 652.76
Compound 2 16.77 25.85 93.06
Compound 3 49.24 92.21 359.92
TNO-155 185.43 336.13 613.13
RMC-4630 152.88 241.51 549.06
PY-1 73.02 140.25 388.22
As can be seen from the experimental results in Table 3, the compounds of the present invention have strong inhibitory activities on H358, KYSE-520, HCC-827, wherein the inhibitory activity of compound 3 is more than 10 times that of the reference compounds TNO-155 and RMC-4630.
4. Determination of hERG Potassium ion channel blocking
The experimental procedure is summarized as follows:
extracellular fluid: 140mM NaCl, 3.5mM KCl, 1mM MgCl2, 2mM CaCl2, 10mM D-glucose, 10mM HEPES, 1.25mM NaH2PO4, pH=7.4.
Electrode inner liquid: 20mM KCl, 115mM K-aspartate, 1mM MgCl2, 5mM EGTA, 10mM HEPES, 2mM Na2-ATP, pH=7.2
Cell culture: HEK293 cell line stably expressing hERG potassium channel was used, and hERG potassium channel cells were purchased from Creacell Inc. (cat# A-0320) and cultured in DMEM medium containing 10% fetal bovine serum and 0.8mg/mL G418 at 37℃and carbon dioxide concentration of 5%. The old medium was removed and washed once with PBS, then 2mL of TrypLE was added TM Express solution, incubated at 37℃for about 1 min. When the cells were detached from the bottom of the dish, about 5ml of complete medium, pre-warmed at 37℃was added. The cell suspension was gently swirled with a pipette to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000rpm for 5min to collect the cells. Cells were seeded in 10cm cell culture dishes, each cell culture dish was seeded with 6105cells (final volume: 10 mL). To maintain the cell's electrophysiological activity, the cell density must not exceed 80%.
The voltage stimulation protocol for whole cell patch clamp recording whole cell hERG potassium current is as follows: the cell membrane voltage was clamped at-80 mV after the whole cell seal was formed. The clamp voltage is divided from-80 mV to-50 mV for 0.5s (used as leakage current detection), then is stepped to 30mV for 2.5s, and then is quickly restored to-50 mV for 4s, so that the tail current of the hERG channel can be excited. Data were collected repeatedly every 10s and the effect of drug on hERG tail current was observed. The leakage current was measured with a stimulus of-50 mV for 0.5 s. Test data is collected by Qpatch and stored in a connected service station.
Each drug concentration was set for two administrations for at least 5 minutes. The test compound and the external liquid without the compound sequentially act on cells from low concentration to high concentration, and the current detected by each cell in the external liquid without the compound is used as a control group of the cell, so that two cells are independently and repeatedly detected. All electrophysiological experiments were performed at 24 ℃.
The current after each drug concentration was first normalized to the current for the blankThen calculating the inhibition rate corresponding to each drug concentration>Average and standard errors were calculated for each concentration and the semi-inhibitory concentration for each compound was calculated using the following equation:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 x) HillSlope) non-linear fit to the dose-dependent effect using the above equation, where C represents the concentration of the test agent, IC 50 H represents the Hill coefficient for the half-inhibitory concentration. Curve fitting and IC 50 Is done using Graphpad software.
TABLE 4 Compounds of the invention inhibit cardiac hERG potassium ion channel IC 50
Numbering device IC 50 Numbering device IC 50 Numbering device IC 50
Compound 1 >30μm Compound 2 >30μm Compound 3 >30μm
Experimental conclusion inhibition of cardiac hERG potassium ion channel by drugs is the main cause of QT prolongation syndrome by drugs. From experimental results, the compound provided by the embodiment of the invention has no obvious inhibition effect on the heart hERG potassium ion channel, and the risk of toxic and side effects of the heart is low.
5. Pharmacokinetic experiments
1. Experimental materials
Using the compounds prepared in the above examples, oral drug was formulated as 0.3mg/mL clear solution (2% DMSO+30% PEG300+2% Tween80+66% H2O) and intravenous drug was formulated as 0.2mg/mL clear solution (2% DMSO+30% PEG300+2% Tween80+66% H2O).
2. Experimental animal
Male SD rats, 3 each, weighing 218-233g, were offered by Shanghai Laike laboratory animal liability Co. The SD rats tested were given an environmental adaptation period of 2-4 days prior to the experiment, fasted for 8-12 hours prior to administration, fed water 2 hours after administration, and fed after 4 hours.
3. Experimental method
1) After SD rats fasted but were free to drink water for 12 hours, 0 time blank plasma was taken;
2) Taking the SD rat in the step 1), and orally (PO) administering 3mg/kg of the compound to be tested; intravenous (IV) administration of 1mg/kg of test compound;
3) Continuously taking blood from eyeground venous plexus at 5min, 15min, 30min, 1h, 2h, 4h, 8h, 10h and 24h after oral administration, placing in an EP tube distributed with heparin, centrifuging at 8000rpm for 5min, taking upper plasma, freezing at-20deg.C, and analyzing by LC-MS/MS;
4) According to the blood concentration-time data obtained in the step 3), the pharmacokinetic parameters are calculated by using WinNonlin software, and the specific data are shown in Table 5.
TABLE 5 pharmacokinetic data for the compounds of the invention
As shown in table 5, the compounds of the present invention were given orally or intravenously to rats with very high exposure in animal plasma, and compound 1 and compound 3 were more than 10 times as much as positive control TNO-155. Meanwhile, the clearance rate is low, and the medicine can be orally taken.
6. In vivo pharmacodynamic experiments
In vivo pharmacodynamic experiments
1. Purpose of experiment
The in vivo efficacy of the test compounds on a human esophageal cancer KYSE-520 subcutaneous allograft tumor model was evaluated.
2. Experimental animal
BALB/nude mice, female, 6-8 weeks old, weighing 18-24 g, total 40, offered by Beijing Vitolihua technology Co.
3. Experimental method
KYSE-520 tumor cells were resuspended in PBS to prepare a cell suspension with a density of 10X 10<6> cells/mL, and 0.2mL of the cell suspension was inoculated subcutaneously on the right back of each mouse (matrigel addition, volume ratio 1:1), and tumor growth was awaited. When the average tumor volume reached about 141mm <3>, randomized group dosing was started. After administration, tumor diameter was measured twice weekly with vernier calipers and tumor volume was calculated as follows:
v=0.5a×b <2>, where a and b represent the long and short diameters of the tumor, respectively.
The tumor-inhibiting effect of the compound was evaluated with TGI (%), which reflects the tumor growth inhibition ratio, calculated as follows:
TGI (%) = [ (1- (mean tumor volume at the end of dosing of a treatment group-mean tumor volume at the beginning of dosing of a treatment group)/(mean tumor volume at the end of treatment of a solvent control group-mean tumor volume at the beginning of treatment of a solvent control group) ]x100%.
4. Experimental results
After 21 days of starting administration, compound 3 has a significantly better tumor inhibition effect than that of the positive control TNO-155 (30 mg/kg) under the condition that the dose of the compound 3 is one tenth of that of the positive control (3.0 mg/kg), and the TGI (%) reaches 97.6%, which is obviously better than that of the positive control TNO155 by 81.1%.
Although the invention has been described in detail hereinabove, those skilled in the art will appreciate that various modifications and changes can be made thereto without departing from the spirit and scope of the invention. The scope of the invention is not limited by the detailed description set forth above, but rather is to be attributed to the claims.

Claims (7)

1. A compound selected from the group consisting of:
or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof.
2. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 or a pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof.
3. A pharmaceutical formulation comprising a compound of claim 1 or a pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof or a pharmaceutical composition of claim 2, said formulation being any one of a tablet, capsule, injection, granule, powder, suppository, pill, cream, paste, gel, powder, oral solution, inhalant, suspension, dry suspension, patch, lotion.
4. A compound as claimed in claim 1 or a pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof, or a pharmaceutical composition as claimed in claim 6 or a pharmaceutical formulation as claimed in claim 3 for use in the prevention and treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or condition.
5. Use of a compound as claimed in claim 1 or a pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof, or a pharmaceutical composition as claimed in claim 2, or a pharmaceutical formulation as claimed in claim 3, for the prevention and/or treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or condition.
6. Use of a compound as claimed in claim 1 or a pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof, or a pharmaceutical formulation as claimed in claim 3 in the manufacture of a medicament for the prophylaxis and/or treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or condition.
7. The use of a compound according to claim 1, or a tautomer, meso, racemate, enantiomer, diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the prevention or treatment of noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute bone leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma, gastric cancer, liver cancer, anaplastic large cell lymphoma and glioblastoma.
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