CN111875620B - Pyrazolopyrimidine macrocyclic derivative and application thereof - Google Patents

Pyrazolopyrimidine macrocyclic derivative and application thereof Download PDF

Info

Publication number
CN111875620B
CN111875620B CN202011037533.9A CN202011037533A CN111875620B CN 111875620 B CN111875620 B CN 111875620B CN 202011037533 A CN202011037533 A CN 202011037533A CN 111875620 B CN111875620 B CN 111875620B
Authority
CN
China
Prior art keywords
fluoro
pyrazolo
pyrimidine
mmol
pyridine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202011037533.9A
Other languages
Chinese (zh)
Other versions
CN111875620A (en
Inventor
任峰
王显连
陈春麟
周南梅
蔡金娜
潘桂梅
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medicilon Puya Medical Technology (shanghai) Co ltd
Shanghai Medicilon Inc
Original Assignee
Medicilon Puya Medical Technology (shanghai) Co ltd
Shanghai Medicilon Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medicilon Puya Medical Technology (shanghai) Co ltd, Shanghai Medicilon Inc filed Critical Medicilon Puya Medical Technology (shanghai) Co ltd
Priority to CN202011037533.9A priority Critical patent/CN111875620B/en
Publication of CN111875620A publication Critical patent/CN111875620A/en
Application granted granted Critical
Publication of CN111875620B publication Critical patent/CN111875620B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention relates to a novel pyrazolopyrimidine macrocyclic derivative, a preparation method thereof and application thereof in medicines. In particular, the invention relates to a novel pyrazolopyrimidine macrocyclic derivative shown in a general formula (I), a preparation method thereof and application of the macrocyclic derivative or a pharmaceutical composition containing the macrocyclic derivative as a therapeutic agent, in particular to application of the macrocyclic derivative or the pharmaceutical composition as a tropomyosin-related kinase (TRK) inhibitor in treating or preventing TRK-mediated related diseases such as tumors. Wherein each substituent (R) in the general formula (I)1、R2) And the group (X) is as defined in the specification.

Description

Pyrazolopyrimidine macrocyclic derivative and application thereof
Technical Field
The present invention relates to a novel class of pyrazolopyrimidine macrocyclic derivatives, to a process for their preparation and to their use as therapeutic agents, in particular as inhibitors of tropomyosin-related kinase (TRK), or of pharmaceutical compositions containing them.
Background
Tropomyosin-related kinases (TRKs, also known as "tropomyosin receptor kinases") are a class of nerve growth factor receptors, are present in a variety of tissues, and play an important role in the processes of proliferation, differentiation, and survival of cells. TRK belongs to receptor tyrosine kinase family, mainly comprises TRKA, TRKB and TRKC, and is respectively encoded by NTRK1, NTRK2 and NTRK3 genes.
Each TRK has a neurotrophic factor ligand associated with it. The ligand of TRKA is NGF (nerve growth factor), the ligand of TRKB comprises BDGF (woven-derived growth factor) and NT-4/5 (neurotropin-4/5), and the ligand of TRKC is NT-3. These neurotrophic factors specifically bind to TRKs, trigger receptor dimerization and phosphorylation of specific tyrosine residues of kinases, thereby activating downstream signal pathways including Ras/MAPK, PLC gamma/PKC and PI3K/AKT, and further regulating a series of physiological processes such as proliferation, differentiation, metabolism, apoptosis and the like of cells.
The TRK signaling pathway is normally precisely regulated and, when abnormally activated by gene fusion, overexpression of proteins, or single nucleotide mutations, etc., leads to the development of various tumors independently of the tissue origin and type of the tumor. The rapid development of genomics allows more and more NTRK fusion genes to be discovered, such as ETV6-NTRK3, MPRIP-NTRK1, CD74-NTRK1, and the like. The development of the TRK inhibitor can treat various tumors of NTRK fusion protein, such as lung cancer, malignant hematological diseases, prostatic cancer, breast cancer, ovarian cancer, brain glioma, pancreatic cancer, hepatobiliary duct type liver cancer, papillary thyroid cancer, colon cancer, head and neck squamous cell carcinoma, melanoma and the like, and has huge potential and wide market prospect. However, in clinical trials it has been found that some patients develop resistance when they are administered continuously and have been shown to be caused by mutations in NTRK, such as the G595R or G667C mutations in NTRK 1. The development of a new generation of TRK kinase inhibitor is expected to solve the problems.
Disclosure of Invention
In view of the above problems, the present invention aims to develop a new generation of TRK kinase inhibitor compounds with novel structural types and better drug properties. The compound with the structure shown in the general formula (I) or diastereoisomer and pharmaceutically acceptable salt thereof are found to have excellent effect and action as a new generation of TRK kinase inhibitor.
In a first aspect, the present invention provides a compound represented by general formula (I) or a tautomer, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof:
Figure 80807DEST_PATH_IMAGE001
wherein:
x is selected from O, NRaOr CHRbWherein R isa、RbEach independently selected from hydrogen atom or C1~3An alkyl group;
R1selected from hydrogen atoms or C1~3An alkyl group;
R2selected from hydrogen atoms, halogens, C1~3Alkyl or C1~3An alkoxy group;
wherein R is1、R2May form, together with the atoms to which they are attached, a four-to eight-membered heterocyclic group.
Preferably, X is selected from O or NH;
R1selected from hydrogen atoms or C1~3An alkyl group;
R2selected from hydrogen atoms or C1~3An alkyl group;
wherein R is1、R2May form a five-or six-membered heterocyclic group together with the atoms to which they are attached.
Further preferably, X is selected from O;
R1selected from a hydrogen atom, a methyl group or an ethyl group;
R2selected from a hydrogen atom, a methyl group or an ethyl group;
wherein R is1、R2May form, together with the atoms to which they are attached, a tetrahydropyrrole or a piperidine.
Even more preferably, said compound is selected from:
（R，23E，24E）-45-fluoro-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane;
（R，23E，24E）-45-fluoro-8-methyl-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole 3 (1, 2) -pyrrolidinylcyclooctane;
（23E，24E，32R，7R）-45-fluoro-7-methyl-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane;
（23E，24E，32R，7S）-45-fluoro-7-methyl-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane;
（R，23E，24E）-45-fluoro-7- (3, 5) pyrrole-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane;
(R，23E，24E）-45-fluoro-7- (3, 6) piperidine-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane.
In a second aspect, the present invention provides a pharmaceutical composition, comprising a compound represented by general formula (I) or a tautomer, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
In a third aspect, the invention provides a compound shown in the general formula (I) or a diastereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, and an application of the compound or the diastereoisomer or the pharmaceutically acceptable salt in preparation of a medicament for preventing and/or treating tropomyosin-related kinase-mediated diseases.
The drug may be a tropomyosin-related kinase inhibitor. Also, the medicament can be used for preventing and/or treating diseases related to functional abnormality of tropomyosin-related kinase caused by amplification, overexpression, mutation, or fusion of tropomyosin-related kinase gene. Also, the diseases include, but are not limited to, cancers such as lung cancer, hematologic malignancies, prostate cancer, breast cancer, ovarian cancer, brain glioma, pancreatic cancer, hepatobiliary duct type cancer, papillary thyroid cancer, colon cancer, head and neck squamous cell carcinoma, melanoma.
Detailed Description
The present invention is further illustrated by the following examples, which are to be understood as merely illustrative of, and not restrictive on, the present invention.
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight or branched chain groups of 1 to 10 carbon atoms. Alkyl groups having 1 to 5 carbon atoms are preferred. More preferred are alkyl groups having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl.
The carbon atom content of various hydrocarbon-containing moieties is represented by the prefix designating the minimum and maximum number of carbon atoms for that moiety, i.e., prefix Ci~jThe number of carbon atoms representing the moiety is from the integer "i" to the integer "j" (inclusive). Thus, for example, C1~3Alkyl refers to alkyl groups of 1 to 3 carbon atoms (including 1 and 3).
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
Unless otherwise specified, all occurrences of a compound in the present invention are intended to include all possible isomers, such as tautomers, enantiomers, diastereomers, and mixtures thereof.
The term "compound of the present invention" means a compound represented by the general formula (I). The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of general formula (I).
The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid.
The term "pharmaceutically acceptable carrier" refers to carriers that can be used in the preparation of pharmaceutical compositions, which are generally safe, non-toxic, not biologically or otherwise undesirable, and includes carriers that are pharmaceutically acceptable to animals and humans. As used in the specification and claims, a "pharmaceutically acceptable carrier" includes one or more of such carriers.
The terms "comprising," "including," or "including" mean that the various ingredients may be used together in a mixture or composition of the invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "comprising.
The term "preventing" refers, for example, to the prevention of the development of clinical symptoms of a disease in a mammal that may be exposed to or predisposed to the disease but has not yet experienced or exhibited symptoms of the disease.
The term "treating" may refer to inhibiting a disease, e.g., arresting or reducing the development of a disease or clinical symptoms thereof, or ameliorating a disease, e.g., causing regression of a disease or clinical symptoms thereof.
A compound of the general formula (I)
Figure 60264DEST_PATH_IMAGE002
Wherein:
x is selected from O, NRaOr CHRbWherein R isa、RbEach independently selected from hydrogen atom or C1~3An alkyl group;
R1selected from hydrogen atoms or C1~3An alkyl group;
R2selected from hydrogen atoms, halogens, C1~3Alkyl or C1~3An alkoxy group;
wherein R is1、R2May form, together with the atoms to which they are attached, a four-to eight-membered heterocyclic group.
In some embodiments of the invention, X is selected from O or NH. In a more preferred embodiment, X is selected from O.
In some embodiments of the invention, R1Selected from hydrogen atoms or C1~3An alkyl group. In a more preferred embodiment, R1Selected from a hydrogen atom, a methyl group or an ethyl group.
In some embodiments of the invention, R2Selected from hydrogen atoms or C1~3An alkyl group. In a more preferred embodiment, R2Selected from a hydrogen atom, a methyl group or an ethyl group.
In some embodiments of the invention, R1、R2May form a five-or six-membered heterocyclic group together with the atoms to which they are attached. In a more preferred embodiment, R1、R2May form, together with the atoms to which they are attached, a tetrahydropyrrole or a piperidine.
In some embodiments of the invention, the compound of formula (I) is selected from the compounds shown in Table 1.
TABLE 1
Figure 840001DEST_PATH_IMAGE003
The preparation of the compounds of formula (I) is described in more detail in the examples.
General synthetic scheme 1
Figure 235211DEST_PATH_IMAGE004
General synthetic scheme 2
Figure 111900DEST_PATH_IMAGE005
In the above synthetic route, R1Selected from hydrogen atoms or C1~3An alkyl group. In a more preferred embodiment, R1Selected from a hydrogen atom, a methyl group or an ethyl group. R2Selected from hydrogen atoms or C1~3An alkyl group. In a more preferred embodiment, R2Selected from a hydrogen atom, a methyl group or an ethyl group. R1、R2May form a five-or six-membered heterocyclic group together with the atoms to which they are attached. In a more preferred embodiment, R1、R2May form, together with the atoms to which they are attached, a tetrahydropyrrole or a piperidine.
Use of compounds of general formula (I)
The compounds of formula (I) are useful as inhibitors of tropomyosin-related kinase (TRK).
The compound of the general formula (I) can be used for preventing and/or treating TRK dysfunction related diseases caused by TRK gene amplification, overexpression, mutation or fusion.
The compounds of formula (I) are useful for the prevention and/or treatment of TRK mediated diseases, including, but not limited to, cancer such as lung cancer, hematologic malignancies, prostate cancer, breast cancer, ovarian cancer, brain glioma, pancreatic cancer, hepatobiliary duct type cancer, papillary thyroid cancer, colon cancer, head and neck squamous cell carcinoma, melanoma.
Pharmaceutical composition
The pharmaceutical composition comprises an effective amount of the compound shown in the general formula (I) or tautomers, enantiomers, diastereomers and mixture forms thereof, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or excipients or diluents thereof.
By "effective amount" is meant a compound of the invention: (i) treating a particular disease, condition, or disorder, (ii) attenuating, ameliorating, or eliminating one or more symptoms of a particular disease, condition, or disorder, or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein.
Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween 80, Tween 20), wetting agents (e.g., sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
Another aspect of the present invention relates to a method of inhibiting tropomyosin-related kinase (TRK), which comprises administering to a patient in need of treatment an effective amount of a compound represented by the general formula (I) or a tautomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
The structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS), and the purity of the compound is determined by liquid high pressure chromatography (HPLC). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d6) Or deuterated methanol (MeOH-)d4) Internal standard is Tetramethylsilane (TMS) and chemical shifts are in ppm. MS was determined using an Agilent 6120 mass spectrometer. HPLC was measured using agilent 1200DAD high pressure liquid chromatograph.
In the case where the present invention is not specifically described, the eluent gradient refers to the volume ratio of the eluent.
Example 1
（R，23E，24E）-45-fluoro-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane
Figure 934362DEST_PATH_IMAGE006
Figure 201396DEST_PATH_IMAGE008
First step 4-chloro-N-methoxy-N-methylbutanamide
4-chlorobutyryl chloride (13 g, 0.0929 mol) was dissolved in dichloromethane (100 mL), N, O-dimethylhydroxylamine hydrochloride (10 g, 0.102 mol) and triethylamine (20.2 g, 0.200 mol) were added at 0 ℃ and after the addition was complete, stirring was carried out at room temperature for 4 hours. The reaction was quenched with water, extracted with dichloromethane, the organic phases combined, dried over anhydrous sodium sulfate filtered, and the organic phase concentrated under reduced pressure to give 4-chloro-N-methoxy-N-methylbutanamide (10.4 g, yellow oily liquid) in yield: 89.0 percent. MS (ESI) M/z =166.0[ M + H ]]+。
Second step 4-chloro-1- (5-fluoro-2-methoxypyridin-3-yl) butan-1-one
3-bromo-5-fluoro-2-methoxypyridine (10 g, 48.6 mmol) was dissolved in tetrahydrofuran (100 mL) and a solution of isopropyl magnesium bromide in tetrahydrofuran (58.4 mL, 58.4 mmol, 1M) was added dropwise at-78 ℃ under a nitrogen atmosphere, after which time the mixture was slowly warmed to 0 ℃ and stirred for 1 hour. After cooling again to-78 ℃, 4-chloro-N-methoxy-N-methylbutanamide (8.8 g, 53.4 mmol) was dissolved in tetrahydrofuran (20 mL) and added dropwise slowly to the reaction, which was allowed to warm to room temperature and stirred at room temperature overnight. Quenching with saturated ammonium chloride solution, extracting with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure, and purifying the residue by silica gel column chromatography (eluent gradient, petroleum ether: ethyl acetate =10: 1) to give 4-chloro-1- (5-fluoro-2-methoxypyridin-3-yl) butan-1-one (4.23 g, yellow oily liquid), yield: 37.8 percent. MS (ESI) M/z =232.1[ M + H ]]+ 。
The third step (R, Z) -N- (4-chloro-1- (5-fluoro-2-methoxypyridin-3-yl) butylidene) -2-methylpropane-2-sulfinyl
4-chloro-1- (5-fluoro-2-methoxypyridin-3-yl) butan-1-one (4.23 g, 18.3 mmol), (R) -2-methylpropane-2-sulfinamide (2.21 g, 18.3 mmol) was dissolved in tetrahydrofuran (50 mL), tetraethyltitanate (8.34 g, 36.6 mmol) was added in portions, and the reaction was stirred at reflux overnight. Diluting with ethyl acetate, washing with water and saturated brine in this order, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography (eluent gradient, ethyl acetate: petroleum ether = 1: 1) to give (R, Z) -N- (4-chloro-1- (5-fluoro-2-methoxypyridin-3-yl) butylidene) -2-methylpropane-2-sulfinamide (3.1 g, yellow oily liquid), yield: 50.1 percent. MS (ESI) M/z =335.0 [ M + H ]]+。
The fourth step (R) -N- ((R) -4-chloro-1- (5-fluoro-2-methoxypyridin-3-yl) butyl) -2-methylpropane-2-sulfinamide
(R) -N- ((R) -4-chloro-1- (5-fluoro-2-methoxypyridin-3-yl) butyl) -2-methylpropane-2-sulfinamide (3.1 g, 9.25 mmol) was dissolved in tetrahydrofuran (25 mL), lithium triethylborohydride (10.2 mL, 10.2 mmol, 1M in THF) was added dropwise under a nitrogen atmosphere at-78 ℃ and the reaction was stirred at-78 ℃ for 1 hour until the reaction was complete. Quenching with saturated ammonium chloride solution, extracting with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating the organic phase under reduced pressure to give crude (R) -N- ((R) -4-chloro-1- (5-fluoro-2-methoxypyridin-3-yl) butyl) -2-methylpropane-2-sulfinamide (2.78 g, yellow oily liquid) in yield: 88.9 percent. MS (ESI) M/z =337.0 [ M + H ]]+。
The fifth step 3- ((R) -1- ((R) -tert-butylsulfinyl) pyrrolidin-2-yl) -5-fluoro-2-methoxypyridine
(R) -N- ((R) -4-chloro-1- (5-fluoro-2-methoxypyridin-3-yl) butyl) -2-methylpropane-2-sulfinamide (2.78 g, 8.25 mmol) was dissolved in tetrahydrofuran (30 mL) and portionwisePotassium tert-butoxide (1.39 g, 12.4 mmol) was added, and the reaction mixture was stirred at room temperature overnight. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent gradient, ethyl acetate: petroleum ether = 2: 1) to give 3- ((R) -1- ((R) -tert-butylsulfinyl) pyrrolidin-2-yl) -5-fluoro-2-methoxypyridine (2.14 g, yellow oily liquid), yield: 86.1 percent. MS (ESI) M/z =301.2 [ M + H ]]+。
The sixth step (R) -5-fluoro-2-methoxy-3- (pyrrolidin-2-yl) pyridine
3- ((R) -1- ((R) -tert-Butylsulfinyl) pyrrolidin-2-yl) -5-fluoro-2-methoxypyridine (2.14 g, 7.13 mmol) was dissolved in dichloromethane (10 mL), a solution of hydrogen chloride in dioxane (10 mL, 4M) was added, and the reaction was stirred at room temperature for 2 hours until completion. Concentration under reduced pressure gave crude (R) -5-fluoro-2-methoxy-3- (pyrrolidin-2-yl) pyridine (1.4 g, quantitative, yellow oily liquid). MS (ESI) M/z =197.2 [ M + H ]]+。
Seventh step (R) -5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -3-iodopyrazolo [1,5-a ] pyrimidine
Mixing (R) -5-fluoro-2-methoxy-3- (pyrrolidin-2-yl) pyridine (1.4 g, 7.13 mmol) and 5-chloro-3-iodopyrazolo [1,5-a ]]Pyrimidine (2.01 g, 7.13 mmol) was dissolved in dichloromethane (20 mL), triethylamine (2.16 g, 21.4 mmol) was added at room temperature, and the reaction was stirred at room temperature overnight. Quenching with water, extracting with dichloromethane, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure, and purifying the residue by silica gel column chromatography (eluent gradient, ethyl acetate: petroleum ether = 1: 2) to obtain (R) -5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -3-iodopyrazolo [1, 5-a)]Pyrimidine (1.2 g, yellow oily liquid), yield: 44.0 percent. MS (ESI) M/z =440.2 [ M + H ]]+。
Eighth step (R) -5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -3- (1H-imidazol-2-yl) pyrazolo [1,5-a ] pyrimidine
Mixing (R) -5- (2- (5-fluoro-2-methoxypyridin-3-yl)Pyrrolidin-1-yl) -3-iodopyrazolo [1,5-a]Pyrimidine (1.12 g, 2.5 mmol), sodium carbonate (795 mg, 7.5 mmol) and (1H-imidazol-2-yl) boronic acid (425 mg, 3.8 mmol) were added to a solution of dioxane/water (25 mL/5 mL) followed by Pd (dppf) Cl2(185 mg, 0.25 mmol). After the oxygen is removed by replacing the reaction liquid with nitrogen, the mixture is heated to 100 ℃ under the protection of nitrogen and reacts overnight. After the reaction, the reaction solution was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (100 mL), then washed with saturated aqueous sodium chloride (2X 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid. The solid was separated by column chromatography (eluent gradient: dichloromethane: methanol =10: 1) to give (R) -5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -3- (1H-imidazol-2-yl) pyrazolo [1,5-a]Pyrimidine (616 mg, off-white solid), yield: 65.1 percent. MS (ESI) M/z =380.3 [ M + H ]]+。
Ninth step (R) -5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -3- (5-iodo-1H-imidazol-2-yl) pyrazolo [1,5-a ] pyrimidine
Mixing (R) -5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -3- (1H-imidazol-2-yl) pyrazolo [1,5-a]Pyrimidine (570 mg, 1.5 mmol) was dissolved in dichloromethane (30 mL), N-iodosuccinimide (510 mg, 2.25 mmol) was added in portions at 0 deg.C, and the mixture was stirred at that temperature for 2 hours. After completion of the reaction, the reaction mixture was washed with a saturated aqueous solution of sodium sulfite (2 × 50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give (R) -5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -3- (5-iodo-1H-imidazol-2-yl) pyrazolo [1,5-a]Pyrimidine (454 mg, yellow solid), yield: 60.1 percent. MS (ESI) M/z =506.7 [ M + H ]]+。
The tenth step (R) -2- ((2- (5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -1H-imidazol-5-yl) amino) ethan-1-ol
Mixing (R) -5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -3- (5-iodo-1H-imidazol-2-yl) pyri dineAzolo [1,5-a ]]Pyrimidine (100 mg, 0.2 mmol) was dissolved in a 1, 4-dioxane (3.0 mL) solution, ethanolamine (61 mg, 1.0 mmol), tris (dibenzylideneacetone) dipalladium (14 mg, 0.015 mmol), 2-dicyclohexylphosphonium-2 ',4',6' -triisopropylbiphenyl (14 mg, 0.029 mmol), sodium tert-butoxide (42 mg, 0.44 mmol) were added in this order, and the mixture was reacted overnight at 100 ℃ under an argon atmosphere. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with ethyl acetate (3X 30 mL). The organic phases were combined and washed with saturated brine (2X 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to preparative HPLC (mobile phase: acetonitrile/water (containing 0.05% NH)3) Purifying to obtain (R) -2- ((2- (5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidine-1-yl) pyrazolo [1, 5-a)]Pyrimidin-3-yl) -1H-imidazol-5-yl) amino) ethan-1-ol (62 mg, white solid), yield: 70.1 percent. MS m/z (ESI): 439.6 [ M +1 ]]+。
Eleventh step (R) -5-fluoro-3- (1- (3- (5- (((2-hydroxyethyl) amino) -1H-imidazol-2-yl) pyrazolo [1,5-a ] pyrimidin-5-yl) pyrrolidin-2-yl) pyridin-2-ol
Mixing (R) -2- ((2- (5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1, 5-a)]Pyrimidin-3-yl) -1H-imidazol-5-yl) amino) ethan-1-ol (62 mg, 0.14 mmol) was dissolved in acetic acid (5.0 mL), a solution of 33% by mass hydrogen bromide in acetic acid (1.83 mL, 9.5 mmol) was added at room temperature, and the reaction was stirred at 90 ℃ for 2 hours until the reaction was complete. Cooling to room temperature, quenching with water, extracting with ethyl acetate, washing the organic phase with saturated sodium bicarbonate, combining the aqueous phases, extracting again with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and subjecting the residue to preparative HPLC (mobile phase: acetonitrile/water (containing 0.05% NH)3) Purifying to obtain (R) -5-fluoro-3- (1- (3- (5- (((2-hydroxyethyl) amino) -1H-imidazol-2-yl) pyrazolo [1, 5-a)]Pyrimidin-5-yl) pyrrolidin-2-yl) pyridin-2-ol (48 mg, yellow solid), yield: 80.0 percent. MS m/z (ESI): 425.4 [ M +1 ]]+。
Twelfth step (R, 2)3E，24E）-45-fluorine-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane
Reacting (R) -5-fluoro-3- (1- (3- (5- (((2-hydroxyethyl) amino) -1H-imidazol-2-yl) pyrazolo [1, 5-a)]Pyrimidin-5-yl) pyrrolidin-2-yl) pyridin-2-ol (48 mg, 0.11 mmol) in anhydrous DMF (10 mL) was added followed by N, N-diisopropylethylamine (150 mg, 1.15 mmol). After cooling the reaction to 0 ℃, add Kate condensing agent (BOP) (66 mg, 0.15 mmol) and stir the reaction overnight at ambient temperature. After the reaction was completed, the reaction mixture was poured into a 10% citric acid aqueous solution (10 mL) and extracted with ethyl acetate (3X 10 mL). The combined organic phases were washed successively with water (20 mL), saturated sodium bicarbonate (20 mL), water (20 mL) and brine (3X 20 mL). Dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to preparative HPLC (mobile phase: acetonitrile/water (containing 0.05% NH)3) Purification to obtain (R, 2)3E，24E）-45-fluoro-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane (18 mg, white solid), yield: 39.1 percent. 1H NMR (400 MHz, MeOD-d 4 ) 8.85 (d, J = 9.2 Hz, 1H), 8.52 (d, J = 7.6 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H), 8.08 (s, 1H), 7.39 (dd, J = 9.6, 2.8 Hz, 1H), 7.30 (s, 1H), 6.63 (d, J = 7.6 Hz, 1H), 4.23 (t, J = 6.4 Hz, 2H), 3.86 - 3.75 (m, 2H), 3.11 - 3.05 (m, 1H), 2.95 - 2.84 (m, 1H), 2.59 - 2.54 (m, 1H), 1.94 - 1.78 (m, 2H), 1.27 - 1.10 (m, 2H)。MS (ESI) m/z =407.1 [M+H]+ 。
Example 2 (R, 2)3E，24E）-45-fluoro-8-methyl-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole 3 (1, 2) -pyrrolidinylcyclooctane
Figure 462613DEST_PATH_IMAGE009
Figure 131491DEST_PATH_IMAGE010
Will be (R, 2)3E，24E）-45-fluoro-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane (10 mg, 0.025 mmol) was dissolved in methylene chloride (10 mL), and paraformaldehyde (50 mg) was added thereto, followed by stirring at room temperature for 3 hours. Sodium cyanoborohydride (62 mg, 10 mmol) was then added and the reaction was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3X 30 mL). The organic phases were combined and washed with saturated brine (2X 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to preparative HPLC (mobile phase: acetonitrile/water (containing 0.05% NH)3) Purifying to obtain (R) -2- ((2- (5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidine-1-yl) pyrazolo [1, 5-a)]Pyrimidin-3-yl) -1H-imidazol-5-yl) amino) ethan-1-ol (4.8 mg, white solid), yield: 46.2 percent. 1H NMR (400 MHz, MeOD-d 4 ) 8.75 (d, J = 9.2 Hz, 1H), 8.48 (d, J = 7.6 Hz, 1H), 8.30 (m, 1H), 8.09 (s, 1H), 7.35-7.33 (m, 1H), 7.28 (s, 1H), 6.63 (d, J = 7.6 Hz, 1H), 4.27 (t, J = 6.4 Hz, 2H), 3.85 - 3.82 (m, 2H), 3.13 - 3.05 (m, 1H), 2.90 - 2.84 (m, 1H), 2.59 - 2.57 (m, 1H), 2.23 (s, 3H), 1.90 - 1.78 (m, 2H), 1.28 - 1.20 (m, 2H)。MS (ESI) m/z =421.0 [M+H]+。
Examples 3 and 4
（23E，24E，32R，7R）-45-fluoro-7-methyl-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane and (2)3E，24E，32R，7S）-45-fluoro-7-methyl-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -Pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane
Figure 124855DEST_PATH_IMAGE011
Figure 813938DEST_PATH_IMAGE012
The first step is 2- ((2- (5- ((R) -2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -1H-imidazol-5-yl) amino) propan-1-ol
Mixing (R) -5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -3- (5-iodo-1H-imidazol-2-yl) pyrazolo [1,5-a]Pyrimidine (300 mg, 0.6 mmol) was dissolved in a 1, 4-dioxane (10.0 mL) solution, and 2-aminopropanol (225 mg, 3.0 mmol), tris (dibenzylideneacetone) dipalladium (42 mg, 0.045 mmol), 2-dicyclohexylphosphonium-2 ',4',6' -triisopropylbiphenyl (12 mg, 0.025 mmol), sodium tert-butoxide (126 mg, 1.32 mmol) were added in this order, and the mixture was reacted at 100 ℃ overnight under an argon atmosphere. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with ethyl acetate (3X 30 mL). The organic phases were combined and washed with saturated brine (2X 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent gradient, dichloromethane: methanol =10: 1) to give 2- ((2- (5- ((R) -2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1, 5-a)]Pyrimidin-3-yl) -1H-imidazol-5-yl) amino) propan-1-ol (165 mg, white solid), yield: 61.3 percent. MS m/z (ESI): 453.8 [ M +1 ]]+。
The second step is 5-fluoro-3- ((2R) -1- (3- (5- ((1-hydroxypropan-2-yl) amino) -1H-imidazol-2-yl) pyrazolo [1,5-a ] pyrimidin-5-yl) pyrrolidin-2-yl) pyridin-2-ol
2- ((2- (5- ((R) -2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a]Pyrimidin-3-yl) -1H-imidazol-5-yl) amino) propan-1-ol (160 mg, 0.36 mmol) was dissolved in acetic acid (5.0 mL), a solution of 33% by mass hydrogen bromide in acetic acid (1.83 mL, 9.5 mmol) was added at room temperature, and the reaction mixture was stirred at 90 ℃ for 2 hours until completion of the reaction. Cooling to room temperature, quenching with water, extracting with ethyl acetate, washing the organic phase with saturated sodium bicarbonate, combining the aqueous phases, extracting again with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and subjecting the residue to preparative HPLC (mobile phase: acetonitrile/water (containing 0.05% NH)3) Purifying to obtain 5-fluoro-3- ((2R) -1- (3- (5- ((1-hydroxypropane-2-yl) amino) -1H-imidazole-2-yl) pyrazolo [1,5-a]Pyrimidin-5-yl) pyrrolidin-2-yl) pyridin-2-ol (128 mg, yellow solid), yield: 82.5 percent. MS m/z (ESI): 439.5 [ M +1 ]]+。
Third step (2)3E，24E，32R，7R）-45-fluoro-7-methyl-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane and (2)3E，24E，32R，7S）-45-fluoro-7-methyl-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane
Mixing (5-fluoro-3- ((2R) -1- (3- (5- ((1-hydroxypropan-2-yl) amino) -1H-imidazol-2-yl) pyrazolo [1, 5-a)]Pyrimidin-5-yl) pyrrolidin-2-yl) pyridin-2-ol (128 mg, 0.29 mmol) in anhydrous DMF (10 mL) was added followed by N, N-diisopropylethylamine (150 mg, 1.15 mmol). After cooling the reaction to 0 ℃, add Kate condensing agent (BOP) (200 mg, 0.45 mmol) and stir the reaction overnight at ambient temperature. After completion of the reaction, the reaction mixture was poured into 10% aqueous citric acid (10 mL) and extracted with ethyl acetate (3X 10 mL). The combined organic phases were washed successively with water (20 mL), saturated sodium bicarbonate (20 mL), water (20 mL) and brine (3X 20 mL). Dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to preparative HPLC (mobile phase: acetonitrile/water (containing 0.05% NH)3) Purification yielded two components: (Peek 1, 6.6 mg, white)Color solid), yield: 5.3% and (Peek 2, 4.5 mg, white solid), yield 3.7%. These two compounds are a group of diastereomers, and the structures are shown as: (23E，24E，32R，7R）-45-fluoro-7-methyl-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane and (2)3E，24E，32R，7S）-45-fluoro-7-methyl-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane.
Peek 1 (example 3):
1H NMR (400 MHz, MeOD-d 4 ) 8.77 (d, J = 9.2 Hz, 1H), 8.52 (d, J = 7.6 Hz, 1H), 8.35 (m, 1H), 8.11 (s, 1H), 7.35-7.33 (m, 1H), 7.28 (s, 1H), 6.65 (d, J = 7.6 Hz, 1H), 4.03 (m, 2H), 3.87- 3.85 (m, 1H), 3.23 - 3.15 (m, 1H), 2.92 - 2.88 (m, 1H), 2.59 - 2.57 (m, 1H), 1.90 - 1.78 (m, 2H), 1.28 - 1.24 (m, 2H), 1.17 (d, J = 7.8 Hz, 3H)。
LCMS: tR = 1.787 min in A90B10_2.6min_214&254_Shimadzu.lcm, chromatography (SunFire C18 50*4.6mm 5um), MS (ESI) m/z =421.0 [M+H]+。
peek 2 (example 4):
1H NMR (400 MHz, MeOD-d 4 ) 8.79 (d, J = 9.2 Hz, 1H), 8.53 (d, J = 7.6 Hz, 1H), 8.32 (m, 1H), 8.14 (s, 1H), 7.35-7.33 (m, 1H), 7.28 (s, 1H), 6.65 (d, J = 7.6 Hz, 1H), 4.03 (m, 2H), 3.87- 3.85 (m, 1H), 3.23 - 3.15 (m, 1H), 2.92 - 2.88 (m, 1H), 2.59 - 2.57 (m, 1H), 1.91 - 1.78 (m, 2H), 1.28 - 1.25 (m, 2H), 1.16 (d, J = 7.8 Hz, 3H)。
LCMS: tR = 1.789 min in A90B10_2.6min_214&254_Shimadzu.lcm, chromatography (SunFire C18 50*4.6mm 5um), MS (ESI) m/z =421.1 [M+H]+。
example 5 (R, 2)3E，24E）-45-fluoro-7- (3, 5) pyrrole-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane
Figure 633775DEST_PATH_IMAGE013
Figure 157160DEST_PATH_IMAGE015
First step (R) -tert-butyl 2- (2-chloro-5-fluoropyridin-3-yl) pyrrolidine-1-carboxylate
A solution of tert-butyl pyrrolidine-1-carboxylate (10 mL, 57.0 mmol) and (-) -aspartic acid (13.1 mL, 57.0 mmol) in anhydrous methyl tert-butyl ether (300 mL) was first cooled to-78 deg.C under nitrogen and then a solution of sec-butyllithium in n-hexane (40.7 mL, 1.4M, 57.0 mmol) was added dropwise over 15 minutes using a constant pressure dropping funnel, maintaining the temperature below-75 deg.C. The pale yellow solution was stirred at-78 ℃ for 3 hours and then treated dropwise with 10% by mass aqueous zinc chloride (38.0 mL, 1.0M, 38.0 mmol) over 15 minutes while maintaining the temperature below-73 ℃. The mixture was stirred at-78 ℃ for 30 minutes, then placed in a water bath at ambient temperature and stirred for an additional 1 hour. At this time, a large amount of white precipitate was formed, and the mixture was treated with a solution of 3-bromo-2-chloro-5-fluoropyridine (10.00 g, 47.5 mmol) in methyl t-butyl ether (50 mL), followed by addition of palladium acetate (530 mg, 2.40 mmol) and tri-t-butylphosphine tetrafluoroborate (830 mg, 2.80 mmol). The mixture was heated to 50 ℃ with stirring overnight. After completion of the reaction, the mixture was treated with aqueous ammonia (10 mL), stirred for 30 minutes, filtered and the solid was washed with methyl tert-butyl ether. The filtrate was washed with a 10% aqueous solution of citric acid (300 mL) and the aqueous layer was back-extracted with tert-butyl methyl ether (2X 300 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product as a dark yellow oil. Separating and purifying the crude product by column chromatography (eluent gradient, petroleum ether: ethyl acetate =10: 1) to obtainTo (R) -tert-butyl 2- (2-chloro-5-fluoropyridin-3-yl) pyrrolidine-1-carboxylate (5.0 g, colorless oil), yield: 35.0 percent. MS m/z (ESI): 301.1 [ M + H]+. , 201.1 [M+H-Boc]+。
Second step (R) -2-chloro-5-fluoro-3- (pyrrolidin-2-yl) pyridine dihydrochloride
To a solution of (R) -tert-butyl 2- (2-chloro-5-fluoropyridin-3-yl) pyrrolidine-1-carboxylate (5.00 g, 16.6 mmol) in dioxane (50 mL) was added a solution of dioxane hydrochloride (4M, 50 mL) and the mixture was stirred at ambient temperature overnight. The mixture was concentrated and treated with ether, then dried in vacuo to give (R) -2-chloro-5-fluoro-3- (pyrrolidin-2-yl) pyridine dihydrochloride (3.6 g, white solid) in yield: 80.1 percent. MS m/z (ESI): 201.1 [ M + H]+。
The third step is (R) -5- (2- (2-chloro-5-fluoropyridin-3-yl) pyrrolidin-1-yl) -3-iodopyrazolo [1,5-a ] pyrimidine
(R) -2-chloro-5-fluoro-3- (pyrrolidin-2-yl) pyridine dihydrochloride (1.69 g, 7.13 mmol) and 5-chloro-3-iodopyrazolo [1, 5-a)]Pyrimidine (2.00 g, 7.13 mmol) was dissolved in dichloromethane (50 mL), triethylamine (2.16 g, 21.4 mmol) was added at room temperature, and the reaction was stirred at room temperature overnight. Quenching with water, extracting with dichloromethane, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure, and purifying the residue by silica gel column chromatography (eluent gradient, ethyl acetate: petroleum ether = 1: 2) to obtain (R) -5- (2- (2-chloro-5-fluoropyridin-3-yl) pyrrolidin-1-yl) -3-iodopyrazolo [1, 5-a)]Pyrimidine (2.02 g, yellow solid), yield: and (3.9). MS m/z (ESI): 444.5 [ M + H]+。
The fourth step (R) -5- (2- (2-chloro-5-fluoropyridin-3-yl) pyrrolidin-1-yl) -3- (1H-imidazol-2-yl) pyrazolo [1,5-a ] pyrimidine
Reacting (R) -5- (2- (2-chloro-5-fluoropyridin-3-yl) pyrrolidin-1-yl) -3-iodopyrazolo [1,5-a]Pyrimidine (1.11 g, 2.5 mmol), sodium carbonate (795 mg, 7.5 mmol) and (1H-imidazol-2-yl) boronic acid (425 mg, 3.8 mmol) were added to a solution of dioxane/water (25 mL/5 mL)Adding Pd (dppf) Cl2(185 mg, 2.5 mmol). After the oxygen is removed by replacing the reaction liquid with nitrogen, the mixture is heated to 100 ℃ under the protection of nitrogen and reacts overnight. After the reaction, the reaction solution was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (100 mL), then washed with saturated aqueous sodium chloride (2X 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid. The solid was separated by column chromatography (eluent gradient, dichloromethane: methanol =10: 1) to give (R) -5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -3- (1H-imidazol-2-yl) pyrazolo [1,5-a]Pyrimidine (550 mg, off-white solid), yield: 56.9 percent. MS (ESI) M/z =384.6 [ M + H ]]+。
The fifth step tert-butyl 2- ((((3- ((R) -1- (3- (1H-imidazol-2-yl) pyrrolo [1,5-a ] pyrimidin-5-yl) pyrrolidin-2-yl ] -5-fluoropyridin-2-yl) oxy) methylpyrrolidine-1-carboxylate
Tert-butyl 2- (hydroxymethyl) pyrrolidine-1-carboxylate (402 mg, 2.0 mmol) was dissolved in DMF (10 mL), cooled to 0 ℃ in an ice bath, sodium hydride (60% by mass in mineral oil) (88 mg, 2.2 mmol) was added and the temperature was stirred for 30 minutes. Followed by addition of (R) -5- (2- (2-chloro-5-fluoropyridin-3-yl) pyrrolidin-1-yl) -3- (1H-imidazol-2-yl) pyrazolo [1,5-a]Pyrimidine (550 mg, 1.44 mmol), the reaction was allowed to warm slowly to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was poured into a 10% citric acid aqueous solution (10 mL) and extracted with ethyl acetate (3X 10 mL). The combined organic phases were washed successively with water (20 mL), saturated sodium bicarbonate (20 mL), water (20 mL) and brine (3X 20 mL). Dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (eluent gradient, petroleum ether: ethyl acetate = 5: 1) to give tert-butyl 2- ((((3- ((R) -1- (3- (1H-imidazol-2-yl) pyrrolo [1, 5-a)]Pyrimidin-5-yl) pyrrolidin-2-yl]-5-fluoropyridin-2-yl) oxy) methylpyrrolidine-1-carboxylate (410 mg, off-white solid), yield: 52.3 percent. MS (ESI) M/z =549.6 [ M + H ]]+。
Sixth step tert-butyl 2- ((((5-fluoro-3- (R) -1- (3- (5-iodo-1H-imidazol-2-yl) pyrazolo [1,5-a ] pyrimidin-5-yl) pyrrolidin-2-yl) pyridin-2-yl) oxy) methylpyrrolidine-1-carboxylic acid
Reacting tert-butyl 2- ((((3- ((R) -1- (3- (1H-imidazol-2-yl) pyrrolo [1, 5-a))]Pyrimidin-5-yl) pyrrolidin-2-yl]-5-Fluoropyridin-2-yl) oxy) methylpyrrolidine-1-carboxylate (410 mg, 0.75 mmol) was dissolved in dichloromethane (30 mL), N-iodosuccinimide (255 mg, 1.12 mmol) was added portionwise at 0 deg.C, and the mixture was stirred at this temperature for 2 hours. After completion of the reaction, the reaction mixture was washed with a saturated aqueous solution of sodium sulfite (2X 50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give tert-butyl 2- ((((5-fluoro-3- (R) -1- (3- (5-iodo-1H-imidazol-2-yl) pyrazolo [1, 5-a)]Pyrimidin-5-yl) pyrrolidin-2-yl) pyridin-2-yl) oxy) methylpyrrolidine-1-carboxylic acid (385 mg, yellow solid), yield: 76.3 percent. MS (ESI) M/z =675.6 [ M + H ]]+。
Seventh step 5- ((2R) -2- (5-fluoro-2- (pyrrolidin-2-ylmethoxy) pyridin-3-yl) pyrrolidin-1-yl) -3- (5-iodo-1H-imidazol-2-yl) pyrazolo [1,5-a ] pyrimidine
Reacting tert-butyl 2- ((((5-fluoro-3- (R) -1- (3- (5-iodo-1H-imidazol-2-yl) pyrazolo [1, 5-a)]Pyrimidin-5-yl) pyrrolidin-2-yl) pyridin-2-yl) oxy) methylpyrrolidine-1-carboxylic acid (385 mg, 0.57 mmol) was dissolved in dichloromethane (10 mL), a dioxane solution of hydrogen chloride (10 mL, 4M) was added, and the reaction was stirred at room temperature for 2 hours until the reaction was complete. Concentration under reduced pressure gave the crude product which was dissolved in dichloromethane (30 mL) and washed successively with saturated sodium bicarbonate (20 mL) and brine (3X 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 5- ((2R) -2- (5-fluoro-2- (pyrrolidin-2-ylmethoxy) pyridin-3-yl) pyrrolidin-1-yl) -3- (5-iodo-1H-imidazol-2-yl) pyrazolo [1,5-a]Pyrimidine (290 mg, yellow solid), yield: 89.8 percent. MS (ESI) M/z =575.3 [ M + H ]]+。
Eighth step (R, 2)3E，24E）-45-fluoro-7- (3, 5) pyrrole-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane
Mixing 5- ((2R) -2- (5-fluoro-2- (pyrrolidin-2-ylmethoxy) pyridin-3-yl) pyrrolidin-1-yl) -3- (5-iodo-1H-imidazol-2-yl) pyrazolo [1,5-a]Pyrimidine (290 mg, 0.5 mmol) was dissolved in a 1, 4-dioxane (50 mL) solution, and tris (dibenzylideneacetone) dipalladium (42 mg, 0.045 mmol), 2-dicyclohexylphosphonium-2 ',4',6' -triisopropylbiphenyl (42 mg, 0.087 mmol), sodium tert-butoxide (126 mg, 1.32 mmol) were added in this order, and the reaction was carried out overnight at 90 ℃ under an argon atmosphere. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with ethyl acetate (3X 30 mL). The organic phases were combined and washed with saturated brine (2X 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to preparative HPLC (mobile phase: acetonitrile/water (containing 0.05% NH)3) Purification to obtain (R, 2)3E，24E）-45-fluoro-7- (3, 5) pyrrole-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane (15 mg, white solid), yield: 6.66 percent. 1H NMR (400 MHz, MeOD-d 4 ) 8.82 (d, J = 9.2 Hz, 1H), 8.56 (d, J = 7.6 Hz, 1H), 8.35 (m, 1H), 8.17 (s, 1H), 7.36-7.34 (m, 1H), 7.30 (s, 1H), 6.65 (d, J = 7.6 Hz, 1H), 4.13 (m, 2H), 3.87- 3.85 (m, 1H), 3.24 - 3.17 (m, 1H), 2.94 - 2.88 (m, 1H), 2.59 - 2.55 (m, 1H), 2.33-2.29 (m, 2H), 1.90 - 1.76 (m, 2H), 1.28 - 1.25 (m, 2H), 1.16 (m, 3H)。MS (ESI) m/z =447.1 [M+H]+。
Example 6 (R, 2)3E，24E）-45-fluoro-7- (3, 6) piperidine-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane
Figure 649321DEST_PATH_IMAGE016
Figure 890946DEST_PATH_IMAGE017
First step tert-butyl 2- ((((3- ((R) -1- (3- (1H-imidazol-2-yl) pyrrolo [1,5-a ] pyrimidin-5-yl) pyrrolidin-2-yl ] -5-fluoropyridin-2-yl) oxy) methylpiperidine-1-carboxylic acid
Tert-butyl 2- (hydroxymethyl) pyrrolidine-1-carboxylate (430 mg, 2.0 mmol) was dissolved in DMF (10 mL), cooled to 0 ℃ in an ice bath, sodium hydride (60% by mass in mineral oil) (88 mg, 2.2 mmol) was added and the temperature was stirred for 30 minutes. Followed by addition of (R) -5- (2- (2-chloro-5-fluoropyridin-3-yl) pyrrolidin-1-yl) -3- (1H-imidazol-2-yl) pyrazolo [1,5-a]Pyrimidine (500 mg, 1.30 mmol), the reaction was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was poured into a 10% citric acid aqueous solution (10 mL) and extracted with ethyl acetate (3X 10 mL). The combined organic phases were washed successively with water (20 mL), saturated sodium bicarbonate (20 mL), water (20 mL) and brine (3X 20 mL). Dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (eluent gradient, petroleum ether: ethyl acetate = 5: 1) to give tert-butyl 2- ((((3- ((R) -1- (3- (1H-imidazol-2-yl) pyrrolo [1, 5-a)]Pyrimidin-5-yl) pyrrolidin-2-yl]-5-fluoropyridin-2-yl) oxy) methylpiperidine-1-carboxylic acid (475 mg, off-white solid), yield: 65.1 percent. MS (ESI) M/z =563.4 [ M + H ]]+。
Second step tert-butyl 2- ((((5-fluoro-3- ((R) -1- (3- (5-iodo-1H-imidazol-2-yl)) pyrazolo [1,5-a ] pyrimidin-pyrrolidin-2-yl) pyridin-2-yl) oxy) methylpiperidine-1-carboxylic acid
Reacting tert-butyl 2- ((((3- ((R) -1- (3- (1H-imidazol-2-yl) pyrrolo [1, 5-a))]Pyrimidin-5-yl) pyrrolidin-2-yl]-5-Fluoropyridin-2-yl) oxy) methylpiperidine-1-carboxylic acid (475 mg, 0.84 mmol) is dissolved in dichloromethane (30 mL), N-iodosuccinimide (295 mg, 1.30 mmol) is added portionwise at 0 ℃ and the mixture is stirred at this temperature for 2 hours. Inverse directionAfter completion, the reaction mixture was washed with a saturated aqueous solution of sodium sulfite (2 × 50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give tert-butyl 2- ((((5-fluoro-3- ((R) -1- (3- (5-iodo-1H-imidazol-2-yl)) pyrazolo [1, 5-a)]Pyrimidin-pyrrolidin-2-yl) pyridin-2-yl) oxy) methylpiperidine-1-carboxylic acid (370 mg, yellow solid), yield: and (4) 64.3%. MS (ESI) M/z =689.2 [ M + H ]]+。
The third step is 5- ((2R) -2- (5-fluoro-2- (piperidin-2-ylmethoxy) pyridin-3-yl) pyrrolidin-1-yl) -3- (5-iodo-1H-imidazol-2-yl) pyrazolo [1,5-a ] pyrimidine
Tert-butyl-2- ((((5-fluoro-3- ((R) -1- (3- (5-iodo-1H-imidazol-2-yl)) pyrazolo [1, 5-a)]Pyrimidine-pyrrolidin-2-yl) pyridin-2-yl) oxy) methylpiperidine-1-carboxylic acid (370 mg, 0.54 mmol) was dissolved in dichloromethane (10 mL), a dioxane solution of hydrogen chloride (10 mL, 4M) was added, and the reaction solution was stirred at room temperature for 2 hours until the reaction was complete. Concentration under reduced pressure gave the crude product which was dissolved in dichloromethane (30 mL) and washed successively with saturated sodium bicarbonate (20 mL) and brine (3X 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 5- ((2R) -2- (5-fluoro-2- (piperidin-2-ylmethoxy) pyridin-3-yl) pyrrolidin-1-yl) -3- (5-iodo-1H-imidazol-2-yl) pyrazolo [1,5-a]Pyrimidine (310 mg, yellow solid), yield: 98.8 percent. MS (ESI) M/z =589.3 [ M + H ]]+。
The fourth step (R, 2)3E，24E）-45-fluoro-7- (3, 6) piperidine-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane
Mixing 5- ((2R) -2- (5-fluoro-2- (piperidine-2-yl methoxyl) pyridine-3-yl) pyrrolidine-1-yl) -3- (5-iodine-1H-imidazole-2-yl) pyrazolo [1,5-a]Pyrimidine (310 mg, 0.53 mmol) was dissolved in 1, 4-dioxane (50 mL), and tris (dibenzylideneacetone) dipalladium (42 mg, 0.045 mmol), 2-dicyclohexylphosphonium-2 ',4',6' -triisopropylbiphenyl (42 mg, 0.087 mmol), sodium tert-butoxide (126 mg, 1.32 m)mol), reacting overnight at 90 ℃ in an argon atmosphere. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with ethyl acetate (3X 30 mL). The organic phases were combined and washed with saturated brine (2X 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to preparative HPLC (mobile phase: acetonitrile/water (containing 0.05% NH)3) Purification to obtain (R, 2)3E，24E）-45-fluoro-7- (3, 6) piperidine-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane (25 mg, white solid), yield: 10.3 percent. 1H NMR (400 MHz, MeOD-d 4 ) 8.80 (d, J = 9.2 Hz, 1H), 8.53 (d, J = 7.6 Hz, 1H), 8.40 (m, 1H), 8.20 (s, 1H), 7.36-7.33 (m, 1H), 7.31 (s, 1H), 6.68 (d, J = 7.6 Hz, 1H), 4.14 (m, 2H), 3.89- 3.86 (m, 1H), 3.25-3.20 (m, 1H), 2.97-2.93 (m, 1H), 2.85-2.79 (m, 2H), 2.59 - 2.55 (m, 1H), 2.35-2.29 (m, 2H), 1.91 - 1.78 (m, 3H), 1.28 - 1.25 (m, 2H), 1.16 (m, 2H)。MS (ESI) m/z =461.0 [M+H]+。
Test example: determination of inhibitory Effect of Compounds on TRKA kinase Activity
The following experiments were conducted to determine the inhibitory effect of the compounds of the present invention on TRKA kinase activity.
1. Experimental Material
TABLE 2
Figure 166070DEST_PATH_IMAGE018
2. Laboratory apparatus
The full-automatic multi-functional multichannel ELIASA: MD, SpectraMax i3x
3. Reagent preparation
(1) 1-fold working solution of Kinase Buffer (1 × Kinase Buffer) was prepared: 200. mu.l of 5-fold Kinase Buffer (5 XKinase Buffer) and 1M MgCl were taken2Mu.l of stock solution and 1. mu.l of 1M DTT stock solution are dissolved in 794. mu.l of double distilled water and mixed evenly, thus obtaining 1 time of kinase buffer solution.
(2) Preparation of 5. mu.M tyrosine kinase Substrate solution (Substrate-TK solution): Substrate-TK was diluted to 5. mu.M with 1 XKinase Buffer. Add 4. mu.l/well to the reaction plate with a final concentration of 1. mu.M of Substrate-TK.
(3) Compound solution preparation: a2.5 Xcompound solution was prepared using a 1 XKinase Buffer. Add 4. mu.l/well to the plate.
(4) 75 μ M ATP: ATP was diluted 75. mu.M with 1 XKinase Buffer. Add 4. mu.l/well to the plate and ATP is added to a final concentration of 15. mu.M.
(5) Preparing TRKA: TRKA enzyme was formulated at 1.5 ng/. mu.l using 1 XKinase Buffer. Add 2. mu.l/well to the plate and TRKA was added to the plate at a final concentration of 3 ng/well.
(6) And (3) preparing streptavidin: stock solutions of fluorescein XL 166-labeled Streptavidin (Streptavidin-XL 66) were diluted to 500 nM with Detection Buffer. Add 5. mu.l/well to the plate.
(7) Preparing a tyrosine phosphorylation antibody: the Cryptate (Cryptate) -labeled tyrphostin (TK-Ab-Cryptate) stock solution was diluted 100-fold with Detection Buffer. Add 5. mu.l/well to the plate.
3. Experimental procedure
(1) Preparing a reagent: the reagents were prepared as described above, TRKA kinase enzyme (Carna, cat # 08-186) was allowed to stand at 4 ℃ for use, and the remaining reagents were equilibrated to room temperature.
(2) Substrate phosphorylation: substrate-TK-biotin, ATP, enzyme and compound with a certain concentration are mixed evenly in 1 x Kinase Buffer (the volume percentage concentration of DMSO in the reaction system is controlled to be 1 percent), and the reaction is carried out for 40 minutes at room temperature.
(3) Specific binding reaction: mu.l of Detection solution mixed by Streptavidin-XL665 diluted by Detection Buffer and TK antibody europi mu M cryptate is added into each reaction well, and reaction is carried out for 1h at room temperature.
(4) And (3) computer detection: fluorescence signals (excitation 320 nm, emission 615 nm, 665 nm) were detected in multiplex using an M.mu.ltilabel Reader (MD, SpectraMax i3 x).
(5) Data analysis and mapping: the background signal value is deducted by using a background signal hole, and the result is compared with a full-activity enzyme live hole (a solvent control hole), and the inhibition effect of each compound on the TRKA enzyme activity is calculated; and plotted using plot analysis software PRISM 6.0.
4. Data analysis
Excitation Ratio (ER) = 665 nm emission light signal value/615 nm emission light signal value
Inhibition rate = (ER)Solvent set―ER Sample (I))/(ERSolvent set―ERBlank space)×100%
5. Results of the experiment
Inhibition ratio (IC) of each example compound50) Shown in table 3.
TABLE 3
Figure 871858DEST_PATH_IMAGE019
As can be seen from table 3, the compounds of the present invention have excellent TRKA kinase inhibitory activity.

Claims (7)

1. A compound shown in a general formula (I) and pharmaceutically acceptable salts thereof,
Figure 468731DEST_PATH_IMAGE001
wherein:
x is selected from O;
R1selected from a hydrogen atom, a methyl group or an ethyl group; r2Selected from a hydrogen atom, a methyl group or an ethyl group; or R1、R2Together with the atoms to which they are attached form a pyrrolidine or piperidine.
2. The compound of claim 1, and pharmaceutically acceptable salts thereof, wherein the compound is selected from the group consisting of:
（R，23E，24E）-45-fluoro-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5)) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane;
（R，23E，24E）-45-fluoro-8-methyl-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole 3 (1, 2) -pyrrolidinylcyclooctane;
（23E，24E，32R，7R）-45-fluoro-7-methyl-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane;
（23E，24E，32R，7S）-45-fluoro-7-methyl-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane;
（R，23E，24E）-45-fluoro-7- (3, 5) pyrrole-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane;
(R，23E，24E）-45-fluoro-7- (3, 6) piperidine-11H-5-oxo-8-aza-2 (3, 5) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine-1 (2, 5) -imidazole-3 (1, 2) -pyrrolidinylcyclooctane.
3. A pharmaceutical composition comprising a compound of claim 1 or 2, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
4. Use of a compound according to claim 1 or 2, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the prevention and/or treatment of tropomyosin-related kinase-mediated diseases.
5. Use according to claim 4, wherein the medicament is an inhibitor of tropomyosin-related kinase.
6. Use according to claim 4, wherein the disease is a disease associated with dysfunction of tropomyosin-related kinase resulting from amplification, overexpression, mutation or fusion of the tropomyosin-related kinase gene.
7. The use according to claim 4, wherein the disease is cancer selected from lung cancer, hematologic malignancies, prostate cancer, breast cancer, ovarian cancer, brain glioma, pancreatic cancer, hepatobiliary carcinoma, papillary thyroid carcinoma, colon cancer, head and neck squamous cell carcinoma and melanoma.
CN202011037533.9A 2020-09-28 2020-09-28 Pyrazolopyrimidine macrocyclic derivative and application thereof Active CN111875620B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011037533.9A CN111875620B (en) 2020-09-28 2020-09-28 Pyrazolopyrimidine macrocyclic derivative and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011037533.9A CN111875620B (en) 2020-09-28 2020-09-28 Pyrazolopyrimidine macrocyclic derivative and application thereof

Publications (2)

Publication Number Publication Date
CN111875620A CN111875620A (en) 2020-11-03
CN111875620B true CN111875620B (en) 2020-12-11

Family

ID=73199669

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011037533.9A Active CN111875620B (en) 2020-09-28 2020-09-28 Pyrazolopyrimidine macrocyclic derivative and application thereof

Country Status (1)

Country Link
CN (1) CN111875620B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112979646B (en) * 2021-03-08 2022-01-14 北京富龙康泰生物技术有限公司 Imidazopyridine derivative
CN113475740B (en) * 2021-07-10 2022-10-21 深圳市真味生物科技有限公司 Preparation method of chiral synthetic nicotine
CN117586277A (en) * 2022-08-09 2024-02-23 苏州朗睿生物医药有限公司 Macrocyclic triazole derivative and preparation method and application thereof

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR122019024201B1 (en) * 2010-05-20 2021-08-03 Array Biopharma Inc MACROCYCLIC COMPOUND AS TRK KINASE INHIBITORS, ITS USE, AND PHARMACEUTICAL COMPOSITION
AU2018320021C1 (en) * 2017-08-23 2023-02-23 Centaurus Biopharma Co., Ltd. Macrocycle containing aminopyrazole and pyrimidine and pharmaceutical composition and use thereof
EP3706749B1 (en) * 2017-11-10 2024-03-13 Angex Pharmaceutical, Inc. Macrocyclic compounds as trk kinase inhibitors and uses thereof
CN109956957B (en) * 2017-12-22 2021-11-09 广州白云山医药集团股份有限公司白云山制药总厂 Imidazo [1,2-b ] pyridazine large-ring kinase inhibitor
CN111848622A (en) * 2018-01-23 2020-10-30 深圳市塔吉瑞生物医药有限公司 Macrocyclic compounds of the substituted pyrazolo [1,5-a ] pyrimidines
US11555042B2 (en) * 2018-03-28 2023-01-17 Fochon Biosciences, Ltd. Macrocyclic compounds as TRK kinases inhibitors
CA3099493C (en) * 2018-04-18 2023-08-22 Hitgen Inc. Macrocyclic kinase inhibitor
CN111171049B (en) * 2018-11-09 2021-06-04 山东轩竹医药科技有限公司 Tyrosine kinase inhibitors and uses thereof
CN113166155A (en) * 2018-11-09 2021-07-23 山东轩竹医药科技有限公司 Macrocyclic tyrosine kinase inhibitors and uses thereof
US20220112201A1 (en) * 2018-11-19 2022-04-14 Dana-Farber Cancer Institute, Inc. Macrocyclic inhibitors of dyrk1a
CN111592541B (en) * 2019-02-21 2021-09-10 山东轩竹医药科技有限公司 Macrocyclic kinase inhibitors and uses thereof

Also Published As

Publication number Publication date
CN111875620A (en) 2020-11-03

Similar Documents

Publication Publication Date Title
CN111875620B (en) Pyrazolopyrimidine macrocyclic derivative and application thereof
EP2606051B1 (en) Pyrrolopyrimidine compounds and uses thereof
CA3013618C (en) Substituted pyrazolo[1,5-a]pyrimidine compounds as trk kinase inhibitors
EP3677583A1 (en) Nitrogenous heterocyclic compound, preparation method, intermediate, composition, and application
AU2019296085B2 (en) Heterocyclic compound as TRK inhibitor
KR20160144378A (en) Polyfluorinated compounds acting as bruton's tyrosine kinase inhibitors
KR20220118500A (en) Substituted straight chain spiro derivatives
AU2015407300A1 (en) 2-Arylamino pyridine, pyridine or triazine derivative, preparation method and use thereof
EP4008719A2 (en) Pyrazolone and pyrimidine compound, and preparation method and use therefor
JP7248256B2 (en) JAK Kinase Inhibitors, Preparation Methods Thereof, and Uses Thereof in the Pharmaceutical Field
CN113527299B (en) Nitrogen-containing condensed ring compound, preparation method and application
CN116323625A (en) Heterocyclic derivative, preparation method and medical application thereof
EP4328228A1 (en) Heterocyclic compound for inhibiting shp2 activity, preparation method therefor and use thereof
KR20210105375A (en) Macrocyclic compounds as CDK inhibitors, methods for their preparation, and their use in medicine
JP2023538096A (en) Heteroaromatic ring compounds as RET kinase inhibitors and their production and use
KR20200052321A (en) Cycloolefin substituted heteroaromatic compounds and uses thereof
CN115485281B (en) FGFR and mutation inhibitor thereof, and preparation method and application thereof
JP7335972B2 (en) Piperazinamide derivatives, their preparation and their use in medicine
CN111138459B (en) Optical isomer of FGFR4 inhibitor and application thereof
CN114315900B (en) 3-aryl pyrazolopyrimidine derivative and application thereof
RU2803817C2 (en) Heterocyclic compounds as trk inhibitors
CN114315899A (en) 3- (aromatic benzimidazolyl) pyrazolopyrimidine derivative and application thereof
KR20230159367A (en) Uses and methods of heterocyclic compounds in the treatment of diseases associated with kinase drug resistance mutations
CN117412971A (en) Pyrrolopyrimidine derivatives containing pyrazine structures
JP2011516522A (en) Pyrrolo [2,3-d] pyrimidin-2-yl-amine derivatives as PKC-theta inhibitors

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant