CN112759594B - Substituted pyrazolopyrimidine TAM inhibitors and uses thereof - Google Patents
Substituted pyrazolopyrimidine TAM inhibitors and uses thereof Download PDFInfo
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to the technical field of medicines, in particular to a substituted pyrazolopyrimidine TAM inhibitor compound, pharmaceutically acceptable salt thereof, ester thereof or stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salt thereof, the ester thereof or stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt thereof, the ester thereof or stereoisomer thereof, and application of the compound, the pharmaceutically acceptable salt thereof, the ester thereof or stereoisomer thereof.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a substituted pyrazolopyrimidine TAM inhibitor compound, pharmaceutically acceptable salt thereof, ester thereof or stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salt thereof, the ester thereof or stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt thereof, the ester thereof or stereoisomer thereof, and application of the compound, the pharmaceutically acceptable salt thereof, the ester thereof or stereoisomer thereof.
Background
The TAM receptor is a subfamily of receptor tyrosine kinases (Receptor Tyrosine Kinases, RTKs) comprising three members of Mer, axl and Tyro3, which are functionally similar in structure, having the common ligand Gas6 and Protein S. TAM receptors play an important role in the embryonic development process, and exist as homeostasis regulators in the adult tissue and organ system, maintaining the stability of the internal immune environment in vivo by phagocytizing apoptotic cells or inhibiting the innate immune response.
As the cDNAs of Axl and Mer are isolated from myeloid leukemia and lymphoblastic cell lines, the link between TAM receptors and cancer is gradually discovered. TAMs have been reported to exhibit over-or ectopic expression in a variety of tumors, including leukemia, non-small cell lung cancer, glioblastoma, melanoma, prostate cancer, breast cancer, colon cancer, gastric cancer, pituitary adenoma, and rhabdomyoma, etc., by activating a variety of classical oncogenic signaling pathways to promote tumor development and development.
Mer (also known as MERTK) is abnormally expressed in various tumors to activate various downstream oncogenic signaling pathways, up-regulate oncogenic related gene transcription, promote the progression of tumor cell survival, proliferation, migration, etc. The extracellular ligand Gas6 or Protein S is combined with phosphatidylserine everting an apoptotic cell membrane, has the activity of activating MERTK, and can transmit extracellular signals into a cascade reaction of intracellular signaling after being combined with the MERTK. MERTK regulates expression of oncogenes such as STAT5/6, CREB and NF-kB on the one hand or regulates proliferation of tumor cells through Shc-Raf-MEK-Erk-c-Fos/c-Jun, PI3K-Akt-mTOR-p70s6 signaling pathway; on the other hand, the expression of the apoptosis-related genes is regulated to resist the progress of tumor cell apoptosis, including promoting the expression of the apoptosis-related genes Bcl-xl and Survivin and inhibiting the expression of the pro-apoptosis-related gene Bcl-2; or the biological occurrence of tumor cell migration and invasion is promoted by regulating and controlling tumor migration signal channels, including activation of Rho/FAK/PCLy and other signal channels.
Abnormal expression of Axl is also associated with poor prognosis of tumors, such as acute myeloid leukemia, glioblastoma multiforme, pancreatic cancer, esophageal cancer, and the like. In non-small cell lung cancer, aberrant expression and activation of Axl is a mechanism of resistance to epidermal growth factor receptor inhibitors and PI3K inhibitors. Overexpression of Axl and Gas6 is positively correlated with tumor migration, a mechanism that was demonstrated in a mouse model of breast cancer metastasis.
Tyro3 shares much similarity with Axl in terms of signal transduction, on the one hand being able to be activated by the extracellular ligand Gas6/Protein S to cause phosphorylation of the downstream signal pathway PI3K/Akt, and on the other hand not binding to the ligand in case of Tyro3 overexpression, self dimerization and phosphorylation can occur. There is relatively little current study on Tyro3, but Tyro3 has been demonstrated in tumor cells to regulate tumor progression through both PI3K-Akt and Raf-MAPK pathways.
Based on the knowledge of the action mechanism of Mer, axl and Tyro3 in tumor progression, the TaM receptor small molecule inhibitor is specifically developed, so that the influence on a downstream signal path can be effectively reduced, the proliferation and migration of tumor cells are inhibited, the occurrence of apoptosis is promoted, and the anti-tumor effect is realized. The target is currently studied in a clinical test stage, and no drug is yet marketed. In combination with the latest research progress, the target drug is expected to solve the drug resistance of the Ornitinib in the non-small cell lung cancer. Meanwhile, TAM has been reported to play an important role in tumor immunosuppression. Therefore, the development of TAM receptor small molecule inhibitors has broad market prospect in single use or combined with other pharmaceutical applications. Therefore, development of a TAM receptor small molecule inhibitor with high activity, selectivity and drug-like property is a difficult problem which needs to be solved in clinic at present, and has important clinical significance for research and development of the target specific small molecule drug.
Disclosure of Invention
The invention aims to provide a substituted pyrazolopyrimidine TAM small molecule inhibitor and application thereof. The specific technical scheme is as follows:
the present invention provides a compound of the general formula (I), a pharmaceutically acceptable salt, ester or stereoisomer thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
each R 1 Independently selected from hydrogen, halogen, nitro, cyano, hydroxy, carboxyl, amino, mercapto, aminoacyl, C 1-6 Alkylaminoacyl group (C) 1-6 Alkyl group 2 Aminoacyl, C 1-6 Alkylamido, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylamino, C 1-6 Alkylamino, (C) 1-6 Alkyl group 2 Amino, C optionally substituted by one or more Q1 s 1-6 Alkyl or C 1-6 An alkoxy group;
each Q1 is independently selected from halogen, nitro, cyano, hydroxy, carboxyl, amino, mercapto, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylamino, C 1-6 Alkylamino or C 1-6 An alkylcarbonyl group;
each R 2 Independently selected from hydrogen, halogen, cyano, C optionally substituted with one or more Q2 1-6 Alkyl, C 1-6 Alkoxy, amino C 1-6 Alkyl, C 1-6 Alkyl ammoniaRadical (C) 1-6 Alkyl group 2 Amino, aminoacyl, C 1-6 Alkylaminoacyl group (C) 1-6 Alkyl group 2 Aminoacyl, C 1-6 Alkylamido or C 1-6 Alkylsulfonylamino;
each Q2 is independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl;
R 3 selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, carboxyl, mercapto C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl group, C 1-6 Alkylsulfonyl, (C) 1-6 Alkyl group 2 Amino, (C) 1-6 Alkyl group 2 Aminocarbonyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, N (C) 1-6 Alkyl group 2 C(O)-、C 3-8 Cyclic hydrocarbylcarbonyl, 3-12 membered cyclic hydrocarbyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl or 6-12 membered aryl;
ring A and ring B are each independently selected from 3-12 membered cyclic hydrocarbyl, 3-12 membered heterocyclic group, 6-12 membered aryl or 5-12 membered heteroaryl;
each E, F, L is independently selected from the group consisting of-C (O) -, -O-, -S-, -SO 2 -、-NR 4 -or-CR 4 R 4 -；
Each R 4 Are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, (C) 1-6 Alkyl group 2 Amino, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halogen, nitro, amino, hydroxy, mercapto or carboxyl;
m, n, q, d are each independently an integer selected from 0 to 5;
p is selected from integers from 1 to 5.
In certain embodiments, the compounds of the foregoing general formula (I), pharmaceutically acceptable salts thereof, esters thereof, or stereoisomers thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
each R 1 Independently selected from hydrogen, halogen, nitro, cyano, hydroxy, carboxyl, amino, mercapto, C 1-6 Alkylaminoacyl, C 1-6 Alkylamido, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylamino, C 1-6 Alkylamino, C optionally substituted with 1-4Q 1 s 1-6 Alkyl or C 1-6 An alkoxy group;
each Q1 is independently selected from halogen, nitro, cyano, hydroxy, carboxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylamino, C 1-6 Alkylamino or C 1-6 An alkylcarbonyl group;
each R 2 Independently selected from hydrogen, halogen, cyano, C optionally substituted with 1-4Q 2 1-6 Alkyl, C 1-6 Alkoxy, amino C 1-6 Alkyl, C 1-6 Alkylamino, aminoacyl, C 1-6 Alkylaminoacyl, C 1-6 Alkylamido or C 1-6 Alkylsulfonylamino;
each Q2 is independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl or 6-8 membered aryl;
R 3 selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl group, C 1-6 Alkylsulfonyl, (C) 1-6 Alkyl group 2 Amino, (C) 1-6 Alkyl group 2 Aminocarbonyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, N (C) 1-6 Alkyl group 2 C (O) -, 3-8 membered cycloalkyl or 3-8 membered heterocyclyl;
ring A and ring B are each independently selected from 3-10 membered cyclic hydrocarbyl, 3-10 membered heterocyclic group, 6-10 membered aryl or 5-10 membered heteroaryl;
each E, F, L is independently selected from the group consisting of-C (O) -, -O-, -NR 4 -or-CR 4 R 4 -；
Each R 4 Are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halogen, nitro, amino, hydroxy or carboxyl;
m, n, q, d are each independently an integer selected from 0 to 4;
p is selected from integers from 1 to 4.
In certain embodiments, the compounds of the foregoing general formula (I), pharmaceutically acceptable salts thereof, esters thereof, or stereoisomers thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
ring A and ring B are each independently selected from 3-8 membered cyclic hydrocarbyl, 3-8 membered heterocyclic group, 6-8 membered aryl or 5-8 membered heteroaryl;
each E, L is independently selected from C (O) -, -NR 4 -or-CR 4 R 4 -；
Each F is independently selected from-CR 4 R 4 -；
Each R 4 Are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, (C) 1-6 Alkyl group 2 Amino, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halogen, nitro, amino, hydroxy or carboxyl.
In certain embodiments, a compound represented by the foregoing general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, has the structure of the following formula (I'):
wherein, the liquid crystal display device comprises a liquid crystal display device,
each R 1 Independently selected from hydrogen, halogen, cyano, hydroxy, carboxyl, amino, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, amino C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylaminoacyl, C 1-6 Alkylamido, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylamino, C 1-6 Alkylamino or (C) 1-6 Alkyl group 2 An amino group;
each R 2 Independently selected from hydrogen, halogen, cyano, C optionally substituted with 1-2Q 2 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, amino C 1-6 Alkyl, C 1-6 Alkylamino, (C) 1-6 Alkyl group 2 Amino, aminoacyl, C 1-6 Alkylaminoacyl group (C) 1-6 Alkyl group 2 Aminoacyl, C 1-6 Alkylamido or C 1-6 Alkylsulfonylamino;
Each Q2 is independently selected from 5-6 membered cyclic hydrocarbon groups or 5-6 membered heterocyclic groups;
R 3 selected from hydrogen, halogen, cyano, amino, hydroxy, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl group, C 1-6 Alkylsulfonyl, di (C) 1-6 Alkyl) amino, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or carboxyl C 1-6 An alkyl group;
ring A is selected from 5-6 membered cyclic hydrocarbon group or 5-6 membered heterocyclic group;
ring B is selected from phenyl or 5-6 membered heteroaryl;
each L is independently selected from C (O) -or-CR 4 R 4 -；
Each R 4 Are independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy group；
m, n, q, d are independently selected from 0, 1, 2 and 3.
In certain embodiments, the compounds of the foregoing general formula (I) or (I'), pharmaceutically acceptable salts thereof, esters thereof, or stereoisomers thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
each R 1 Are independently selected from hydrogen, hydroxy, carboxyl, amino and C 1-4 Alkyl, hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, amino C 1-4 Alkyl, C 1-4 Alkylaminoacyl, C 1-4 Alkylamido, C 1-4 Alkylsulfonylamino, C 1-4 Alkylamino or (C) 1-4 Alkyl group 2 An amino group;
each R 2 Independently selected from hydrogen, halogen, cyano, C optionally substituted with 1-2Q 2 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, amino C 1-4 Alkyl, C 1-4 Alkylamino, (C) 1-4 Alkyl group 2 Amino, aminoacyl, C 1-4 Alkylaminoacyl group (C) 1-4 Alkyl group 2 Aminoacyl, C 1-4 Alkylamido or C 1-4 Alkylsulfonylamino;
each Q2 is independently selected from 5-6 membered cyclic hydrocarbyl;
R 3 selected from hydrogen, amino, hydroxy, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Alkylcarbonyl, C 1-4 Alkoxycarbonyl, di (C) 1-4 Alkyl) amino, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl or carboxyl C 1-4 An alkyl group;
ring A is selected from 5-6 membered cycloalkyl;
ring B is selected from phenyl;
each L is independently selected from-C (O) -or-CR 4 R 4 -；
Each R 4 Are independently selected from hydrogen, C 1-4 Alkyl or C 1-4 An alkoxy group;
m, n, q, d are independently selected from 0, 1 and 2.
In certain embodiments, the compounds of the foregoing general formula (I) or (I'), pharmaceutically acceptable salts thereof, esters thereof, or stereoisomers thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
each R 1 Each independently selected from hydrogen, hydroxy, carboxy, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, aminomethyl, methylamino, carboxamido, methylsulfonylamino, methylamino, ethylamino, or dimethylamino;
Each R 2 Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, aminoethyl, methylamino, ethylamino, formylamino, acetamido or methylsulfonylamino optionally substituted with 1-2Q 2;
each Q2 is independently selected from cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1, 3-diene, or cyclohex-1, 4-diene;
R 3 selected from hydrogen, amino, hydroxy, carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, formyl, methoxycarbonyl, dimethylamino, hydroxymethyl, aminomethyl, aminoethyl or carboxymethyl;
Ring a is selected from cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexa-1, 3-diene or cyclohexa-1, 4-diene;
ring B is selected from phenyl;
each L is independently selected from C (O) -or-CR 4 R 4 -；
Each R 4 Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, or isopropoxy;
m, n, q, d are independently selected from 0, 1 and 2.
In certain embodiments, the compounds of the foregoing general formula (I) or (I'), pharmaceutically acceptable salts thereof, esters thereof, or stereoisomers thereof,
each R 1 Independently selected from hydrogen, hydroxy, carboxy, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, aminomethyl, methylamino, ethylamino, or dimethylamino;
each R 2 Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, 1-trifluoroethyl, trifluoromethoxy, amino, aminomethyl, aminoethyl, methylamino or ethylamino optionally substituted with 1-2Q 2;
Each Q2 is independently selected from cyclopentyl or cyclohexyl;
R 3 selected from the group consisting of hydrogen, amino, hydroxyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, formyl, dimethylamino, aminomethyl or aminoethyl;
ring a is selected from cyclopentyl or cyclohexyl;
ring B is selected from phenyl;
each L is independently selected from-C (O) -or-CR 4 R 4 -；
Each R 4 Are respectively independent ofVertical is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy or isopropoxy;
m, n, q, d are independently selected from 0, 1 and 2.
In certain embodiments, each R 1 Independently selected from hydrogen, amino, C 1-4 Alkyl, C 1-4 Alkoxy, amino C 1-4 Alkyl, C 1-4 Alkylamino or (C) 1-4 Alkyl group 2 Amino group.
In certain embodiments, each R 1 Each independently selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, aminomethyl, aminoethyl, methylamino, ethylamino, or dimethylamino.
In certain embodiments, each R 2 Independently selected from halogen, C optionally substituted with 1-2Q 2 1-4 Alkyl, C 1-4 Alkoxy, amino C 1-4 Alkyl or C 1-4 An alkylamino group; each Q2 is independently selected from 5-6 membered cyclic hydrocarbyl groups.
In certain embodiments, each R 2 Each independently selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, amino, aminomethyl, aminoethyl, methylamino or ethylamino optionally substituted with 1-2Q 2; each Q2 is independently selected from cyclopentyl or cyclohexyl.
In certain embodiments, R 3 Selected from amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, (C) 1-4 Alkyl group 2 Amino or amino C 1-4 An alkyl group.
In certain embodiments, R 3 Selected from amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylAmino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, dimethylamino, aminomethyl or aminoethyl.
In certain embodiments, ring a is selected from 5-6 membered cycloalkyl.
In certain embodiments, ring a is selected from cyclopentane or cyclohexane.
In certain embodiments, ring B is selected from phenyl.
In certain embodiments, each L is independently selected from-C (O) -or-CR 4 R 4 -; each R 4 Are independently selected from hydrogen, C 1-4 Alkyl or C 1-4 An alkoxy group.
In certain embodiments, m, n, q, d is independently selected from 0, 1, 2.
In certain embodiments, m, n, q, d is independently selected from 0, 1.
Any substituent groups in any embodiment of the invention can be mutually combined, and the combined technical scheme is still included in the protection scope of the invention.
In some embodiments of the present invention, the structure of the compound of the foregoing general formula (I) or (I'), pharmaceutically acceptable salts, esters, or stereoisomers thereof, is shown in the following table:
the term "pharmaceutically acceptable salt" as used herein refers to pharmaceutically acceptable acid and base addition salts.
The "ester" as used herein refers to pharmaceutically acceptable esters, particularly esters which hydrolyze in vivo and include esters which readily decompose in humans to leave the parent compound (the compound of formula (I) or (I') or a salt thereof). In some embodiments of the invention, wherein the pharmaceutically acceptable ester comprises: derived from pharmaceutically acceptable aliphatic carboxylic acids and phosphoric acid.
"stereoisomers" of the compounds of the general formulae (I) or (I ') according to the invention mean that enantiomers are produced when asymmetric carbon atoms are present in the compounds of the general formulae (I) or (I'); when the compound has a carbon-carbon double bond or a cyclic structure, a cis-trans isomer is produced; tautomers may occur when compounds exist as ketones or oximes, and in some embodiments of the invention stereoisomers include, but are not limited to: enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof.
The examples of the present invention also provide two methods for preparing the above compounds, but are not limited to the following methods, the reaction equations are as follows:
the preparation method comprises the following steps:
reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV);
the compound shown in the formula (IV) is subjected to a functional group conversion reaction to obtain a compound shown in the formula (V);
deprotection of a compound of formula (V) to give a compound of formula (I');
wherein X is selected from halogen, G is a protecting group, Y is selected from halogen, hydrogen atom, C 1-6 Alkyl or C 1-6 Alkoxy, R 1’ Represents R 1 Is substituted by other substituents, L' is selected from the group consisting of-C (O) -, R 1 、R 2 、R 3 The definitions of the L, m, n, q, d, the ring A and the ring B are described in the technical scheme.
In certain embodiments, the compound of formula (IV) is reacted under basic conditions by functional group conversion to provide a compound of formula (V).
The preparation method comprises the following steps:
reacting a compound of formula (II-1) with a compound of formula (III-1) to obtain a compound of formula (V);
deprotection of a compound of formula (V) to give a compound of formula (I');
wherein G is a protecting group, R 1’ Represents R 1 Is substituted by other substituents, R 1 、R 2 、R 3 The definitions of the L, m, n, q, d, the ring A and the ring B are described in the technical scheme.
The alkaline condition refers to a condition containing an organic base or an inorganic base, wherein the organic base comprises, but is not limited to, pyridine, triethylamine, N-butylamine, N-dimethylaniline, sodium methoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide, potassium acetate, N-diisopropylethylamine and the like; inorganic bases are preferred, including but not limited to potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium acetate, sodium acetate, potassium phosphate, sodium phosphate, and the like.
The protecting group includes, but is not limited to, (1) alkoxycarbonyl-type protecting groups such as benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc), carbomethoxy carbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), etc.; (2) Acyl-type protecting groups such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o (p) nitrobenzenesulfonyl (Ns), pivaloyl, and the like; (3) Alkyl protecting groups, trityl (Trt), 2, 4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB), benzyl (Bn), and the like.
The "functional group conversion reaction" may be achieved by known chemical synthesis methods, including but not limited to substitution, addition, elimination, dehydration, hydrolysis, oxidation, esterification, etc., which are well known to those skilled in the chemical arts, and the present invention is not limited thereto; in the specific implementation process, the method can be realized through a one-step reaction or a multi-step reaction.
The raw materials and/or intermediates directly adopted in the preparation method of the invention can be purchased commercially or self-made, and the intermediate can be obtained by a person skilled in the art according to the known conventional chemical reaction preparation method, and the preparation method is also within the protection scope of the invention.
The invention also provides an intermediate for synthesizing a compound shown in a general formula (I'), which has the following structural formula:
wherein X is selected from halogen, G is a protecting group, R 1’ Represents R 1 Is substituted by other substituents, R 2 、R 3 The technical proposal is that the parts of the ring A, the ring B and the L, m, n, q, d are as described in the above technical proposal.
The invention also provides a pharmaceutical composition comprising a compound of the general formula (I) or (I'), a pharmaceutically acceptable salt, ester or stereoisomer thereof, and one or more second therapeutically active agents, optionally together with one or more pharmaceutically acceptable carriers and/or diluents.
The second therapeutically active agent is selected from anticancer agents, antiviral agents, immunopotentiators, immunosuppressants, etc.
The invention also provides a pharmaceutical preparation which contains the compound shown in the general formula (I) or (I'), pharmaceutically acceptable salt, ester or stereoisomer thereof and one or more medicinal carriers and/or diluents; the pharmaceutical preparation is any clinically or pharmaceutically acceptable dosage form.
In some embodiments of the invention, the above-described pharmaceutical formulations may be administered orally, parenterally, rectally, or pulmonary, etc., to a patient or subject in need of such treatment. For oral administration, the pharmaceutical composition may be formulated into oral preparations, for example, into conventional oral solid preparations such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparation such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. may be added. For parenteral administration, the pharmaceutical preparations may also be formulated as injections, including injectable solutions, injectable sterile powders, and injectable concentrated solutions. When the injection is prepared, the conventional method in the existing pharmaceutical field can be adopted for production. When the injection is prepared, an additive may not be added, or a suitable additive may be added according to the nature of the drug. For rectal administration, the pharmaceutical composition may be formulated as suppositories and the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalant or spray, etc.
The pharmaceutically acceptable carrier and/or diluent useful in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent in the pharmaceutical formulation arts, and the choice of the particular carrier and/or diluent will depend on the mode of administration or type and state of disease for the particular patient being treated. The preparation of suitable pharmaceutical compositions for specific modes of administration is well within the knowledge of those skilled in the pharmaceutical arts. For example, pharmaceutically acceptable carriers and/or diluents may include solvents, diluents, dispersing agents, suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, binders, lubricants, stabilizers, hydration agents, emulsifying accelerators, buffers, absorbents, colorants, ion-exchange agents, mold release agents, coating agents, flavoring agents, antioxidants and the like which are conventional in the pharmaceutical arts. Flavoring agent, antiseptic, sweetener, etc. can be added into the pharmaceutical composition if necessary.
The invention also provides application of the compound shown in the general formula (I) or (I'), pharmaceutically acceptable salt, ester or stereoisomer thereof, the medicinal preparation or the medicinal composition in preparing medicines for treating and/or preventing cancers or benign tumors.
The invention also provides application of the compound shown in the general formula (I) or (I'), pharmaceutically acceptable salt, ester or stereoisomer thereof, the medicinal preparation or the medicinal composition in preparation of medicaments for treating and/or preventing TAM related diseases.
In some embodiments of the invention, the TAM-related disease is selected from cancer or benign tumor.
The invention also provides the use of a compound of the general formula (I) or (I'), a pharmaceutically acceptable salt, ester or stereoisomer thereof, a pharmaceutical preparation or a pharmaceutical composition for treating and/or preventing diseases related to Axl and/or Mer kinase.
In some embodiments of the invention, the Axl and/or Mer kinase related disease is selected from cancer or benign tumor.
The invention also provides application of the compound shown in the general formula (I) or (I'), pharmaceutically acceptable salt, ester or stereoisomer thereof, the medicinal preparation or the medicinal composition in treating and/or preventing cancers or benign tumors.
The present invention also provides a method of treating a disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the foregoing general formula (I) or (I'), a pharmaceutically acceptable salt, ester or stereoisomer thereof, a pharmaceutical formulation of the foregoing, or a pharmaceutical composition of the foregoing, wherein the disease is cancer or benign tumor.
The compounds of the invention are also useful for inhibiting tumor metastasis.
In the description and claims of the present application, compounds are named according to chemical structural formulas, and if the same compound is indicated, the naming and chemical structural formulas of the compounds are not identical, the chemical structural formulas are used as references.
In this application, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art, however, for a better understanding of the invention, the following definitions of some terms are provided. When the definition of a term or an explanation provided herein is inconsistent with the definition of that term or the explanation provided herein, which is commonly understood by those skilled in the art, the definition of the term or the explanation provided herein controls.
"halogen" as used herein refers to fluorine, chlorine, bromine and iodine.
"halo" as used herein means that any hydrogen in a substituent may be substituted with one or more of the same or different halogens. "halogen" is as defined above.
"C" as described in the present invention 1-6 Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms and includes, for example," C 1-5 Alkyl "," C 1-4 Alkyl "," C 1-3 Alkyl "," C 1-2 Alkyl "," C 2-6 Alkyl "," C 2-5 Alkyl "," C 2-4 Alkyl "," C 2-3 Alkyl "," C 3-6 Alkyl "," C 3-5 Alkyl "," C 3-4 Alkyl "," C 4-6 Alkyl "," C 4-5 Alkyl "," C 5-6 Alkyl ", and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" as described in the present invention 1-4 Alkyl "means C 1-6 Specific examples of the alkyl group include 1 to 4 carbon atoms.
"C" as described herein 1-6 Alkoxy, C 1-6 Alkylamino, (C) 1-6 Alkyl group 2 Amino, C 1-6 Alkylcarbonyl, C 1-6 Alkyloxycarbonyl, C 1-6 Alkylsulfonyl, (C) 1-6 Alkyl group 2 Aminoacyl, C 1-6 Alkylaminoacyl, C 1-6 Alkylamido, C 1-6 Alkylsulfonylamino "means as C 1-6 alkyl-O-, C 1-6 alkyl-NH- (C) 1-6 Alkyl group 2 -N-、C 1-6 alkyl-C (O) -, C 1-6 alkyl-O-C (O) -, C 1-6 alkyl-S (O) 2 -、(C 1-6 Alkyl group 2 -N-C(O)-、C 1-6 alkyl-NH-C (O) -, C 1-6 alkyl-C (O) -NH-, C 1-6 alkyl-S (O) 2 -NH-formed group, wherein "C 1-6 The definition of alkyl "is as described above.
Described herein"C of (C) 1-4 Alkoxy, C 1-4 Alkylamino, (C) 1-4 Alkyl group 2 Amino, C 1-4 Alkylcarbonyl, C 1-4 Alkyloxycarbonyl, C 1-4 Alkylsulfonyl, (C) 1-4 Alkyl group 2 Aminoacyl, C 1-4 Alkylaminoacyl, C 1-4 Alkylamido, C 1-4 Alkylsulfonylamino "means as C 1-4 alkyl-O-, C 1-4 alkyl-NH- (C) 1-4 Alkyl group 2 -N-、C 1-4 alkyl-C (O) -, C 1-4 alkyl-O-C (O) -, C 1-4 alkyl-S (O) 2 -、(C 1-4 Alkyl group 2 -N-C(O)-、C 1-4 alkyl-NH-C (O) -, C 1-4 alkyl-C (O) -NH-, C 1-4 alkyl-S (O) 2 -NH-formed group, wherein "C 1-4 The definition of alkyl "is as described above.
"halo C" as described herein 1-6 Alkyl, halogenated C 1-6 Alkylene, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, halogenated C 1-6 Alkoxy "means that one to more, for example 1 to 4, 1 to 3, 1 to 2, halogen atoms, hydroxy, amino, carboxyl groups are substituted for C respectively 1-6 Alkyl, C 1-6 Alkylene, C 1-6 A group formed by a hydrogen atom in an alkoxy group.
"halo C" as described herein 1-4 Alkyl, halogenated C 1-4 Alkylene, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, halogenated C 1-4 Alkoxy "means that one to more, for example 1 to 4, 1 to 3, 1 to 2, halogen atoms, hydroxy, amino, carboxyl groups are substituted for C respectively 1-4 Alkyl, C 1-4 Alkylene, C 1-4 A group formed by a hydrogen atom in an alkoxy group.
As used herein, "3-12 membered cyclic hydrocarbon group" means a saturated or partially saturated cyclic hydrocarbon group having 3 to 12 carbon atoms and having no aromaticity, and includes "3 to 8 membered cyclic hydrocarbon group" and "8 to 12 membered condensed ring hydrocarbon group", preferably "3 to 10 membered cyclic hydrocarbon group".
The "3-8 membered cyclic hydrocarbon group" as used herein refers to a saturated or partially saturated monocyclic cyclic alkyl group having 3 to 8 carbon atoms and having no aromaticity, and includes "3-8 membered saturated cyclic hydrocarbon group" and "3-8 membered partially saturated cyclic hydrocarbon group"; preferred are "3-4 membered cyclic hydrocarbon group", "3-5 membered cyclic hydrocarbon group", "3-6 membered cyclic hydrocarbon group", "3-7 membered cyclic hydrocarbon group", "4-5 membered cyclic hydrocarbon group", "4-6 membered cyclic hydrocarbon group", "4-7 membered cyclic hydrocarbon group", "4-8 membered cyclic hydrocarbon group", "5-6 membered cyclic hydrocarbon group", "5-7 membered cyclic hydrocarbon group", "5-8 membered cyclic hydrocarbon group", "6-7 membered cyclic hydrocarbon group", "6-8 membered cyclic hydrocarbon group", "7-8 membered cyclic hydrocarbon group", "3-6 membered saturated cyclic hydrocarbon group", "5-8 membered saturated cyclic hydrocarbon group", "5-7 membered saturated cyclic hydrocarbon group", "5-6 membered partially saturated cyclic hydrocarbon group", etc. Specific examples of the "3-8 membered saturated cyclic hydrocarbon group" include, but are not limited to: cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl), cyclooctyl (cyclooctyl), and the like; specific examples of the "3-8 membered partially saturated cyclic hydrocarbon group" include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1, 3-diene, cyclohex-1, 4-diene, cycloheptenyl, cyclohepta-1, 3-dienyl, cyclohepta-1, 4-dienyl, cyclohepta-1, 3, 5-trienyl, cyclooctenyl, cycloocta-1, 3-dienyl, cycloocta-1, 4-dienyl, cycloocta-1, 5-dienyl, cycloocta-1, 3, 5-trienyl, cyclooctatetraenyl and the like.
The invention relates to an 8-12 membered condensed ring group, which is a saturated or partially saturated non-aromatic cyclic group containing 8-12 ring atoms and formed by sharing two adjacent carbon atoms by two or more cyclic structures, wherein one ring in the condensed ring can be an aromatic ring, but the whole condensed ring does not have aromaticity; including "8-11 membered condensed ring group", "8-10 membered condensed ring group", "8-9 membered condensed ring group", "9-10 membered condensed ring group", etc., the manner of condensation may be: 5-6 membered cyclic hydrocarbon group, benzo 5-6 membered saturated cyclic hydrocarbon group, etc. Examples include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [4.1.0] heptyl, bicyclo [2.2.0] hexyl, bicyclo [3.2.0] heptyl, bicyclo [4.2.0] octyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, decatetrahydrophenanthryl, bicyclo [3.1.0] hex-2-enyl, bicyclo [4.1.0] hept-3-enyl, bicyclo [3.2.0] hept-3-enyl, bicyclo [4.2.0] oct-3-enyl, 1,2,3 a-tetrahydropentalenyl, 2, 3a,4,7 a-hexahydro-1H-indenyl, 1,2,3, 4a,5,6, 4 a-octahydronaphthyl, 1,2,4a,5,6,8 a-hexahydronaphthyl, 1,2,3,4, 6,7,8, 10-benzopentalenyl, benzocyclohexyl, benzopentalenyl, and the like.
"3-to 12-membered heterocyclic group" as used herein means a saturated or partially saturated and non-aromatic cyclic group containing at least one heteroatom (e.g., containing 1,2, 3,4 or 5) and having 3 to 12 ring atoms, the heteroatom being a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom in the cyclic structure (e.g., carbon atom, nitrogen atom or sulfur atom) may be oxo. The "3-12 membered heterocyclic group" includes "3-8 membered heterocyclic group" and "8-12 membered condensed heterocyclic group", preferably 3-10 membered heterocyclic group ".
"3-8 membered heterocyclic group" as used herein refers to a saturated or partially saturated and non-aromatic monocyclic ring group containing at least one heteroatom (e.g., containing 1,2, 3,4 or 5) and having 3 to 8 ring atoms, the heteroatom being a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom in the ring structure (e.g., carbon atom, nitrogen atom or sulfur atom) may be oxo. The "3-8 membered heterocyclic group" as used herein includes "3-8 membered saturated heterocyclic group" and "3-8 membered partially saturated heterocyclic group". Preferably, the "3-8 membered heterocyclic group" according to the present invention contains 1 to 3 hetero atoms; preferably, the "3-8 membered heterocyclic group" according to the present invention contains 1 to 2 hetero atoms, and the hetero atoms are selected from nitrogen atoms and/or oxygen atoms; preferably, the "3-8 membered heterocyclic group" according to the present invention contains 1 nitrogen atom. The "3-8 membered heterocyclic group" is preferably "3-7 membered heterocyclic group", "3-6 membered heterocyclic group", "4-7 membered heterocyclic group", "4-6 membered heterocyclic group", "6-8 membered heterocyclic group", "5-7 membered heterocyclic group", "5-6 membered heterocyclic group", "3-6 membered saturated heterocyclic group", "5-6 membered saturated heterocyclic group", "3-6 membered nitrogen-containing heterocyclic group", "3-6 membered saturated nitrogen-containing heterocyclic group", "5-6 membered saturated nitrogen-containing heterocyclic group" or the like. Specific examples of "3-8 membered heterocyclyl" include, but are not limited to: aziridinyl, 2H-aziridinyl, diazabicycloalkyl, 3H-diazapropenyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuranyl, dihydropyrrole, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidonyl, tetrahydropyridinonyl, dihydropyridinonyl, piperazinyl, morpholinyl, 4, 5-dihydro-oxazolyl, 4, 5-dihydro-isoxazolyl, 2, 3-dihydro-isoxazolyl, oxazolidinyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl, and the like.
The "8-12 membered fused heterocyclic group" as used herein refers to a saturated or partially saturated, non-aromatic cyclic group containing 8-12 ring atoms and at least one ring atom being a heteroatom, formed by two or more cyclic structures sharing two adjacent atoms with each other, one of which may be an aromatic ring but the whole of which is not aromatic, and the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo-substituted, including, but not limited to, "8-9 membered fused heterocyclic group", "9-10 membered fused heterocyclic group" and the like, and the manner of the fusion may be 5-6 membered heterocyclic group and 5-6 membered heterocyclic group, benzo 5-6 membered saturated heterocyclic group, 5-6 membered heteroaryl and 5-6 membered saturated heterocyclic group; a 5-6 membered heteroaryl group as defined hereinbefore; specific examples of the "8-to 10-membered fused heterocyclic group" include, but are not limited to: pyrrolidinyl, cyclopentylazacyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, pyrrolidinyl-pentalinyl, piperidinyl-pentalinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidinyl, benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzopyranyl, pyridocyclopentyl, pyridocyclohexyl, benzofuranyl-pentalinyl, and benzopiperidinyl-pentalinyl pyridotetrahydrofuranyl, pyridopyrrolidinyl, pyridoimidazolidinyl, pyridooxazolidinyl, pyridothiazolidinyl, pyridoisoxazolidinyl, pyridoisothiazolidinyl, pyridopiperidinyl, pyridomorpholinyl, pyridopiperazinyl, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidoethylphenyl, pyrimidopyrrolidinyl, pyrimidoimidazolidinyl, pyrimidooxazolidinyl, pyrimidoidinyl, pyrimidoidithiazolidinyl, pyrimidopiperidyl, pyrimidomomorpholinyl, pyrimidopiperidinyl, pyrimidoetetrahydropyranyl; tetrahydroimidazo [4,5-c ] pyridinyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo [ d ] [1,3] dioxolyl, 2H-chromene-2-onyl, 4H-chromene, 4H-chromen-4-onyl, 4H-1, 3-benzoxazolyl, 4, 6-dihydro-1H-furo [3,4-d ] imidazolyl, 3a,4,6 a-tetrahydro-1H-furo [3,4-d ] imidazolyl, 4, 6-dihydro-1H-thieno [3,4-d ] imidazolyl, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazolyl, octahydro-benzo [ d ] imidazolyl, decahydroquinolinyl, hexahydrothienoimidazoyl, hexahydrofuroimidazoyl, 4,5,6, 7-tetrahydro-1H-benzo [3,4-d ] imidazolyl, octahydro-pyrrolo [3,4-d ] pyrrolyl, and the like.
As used herein, "6-12 membered aryl" refers to an aromatic cyclic group containing 6-12 ring carbon atoms, and includes "6-8 membered monocyclic aryl" and "8-12 membered fused ring aryl", preferably 6-10 membered aryl.
"6-8 membered monocyclic aryl" as used herein refers to monocyclic aryl groups containing 6-8 ring carbon atoms, examples of which include, but are not limited to: phenyl, cyclooctatetraenyl, and the like; phenyl is preferred.
The term "8-to 12-membered condensed ring aryl" as used herein refers to an unsaturated, aromatic cyclic group containing 8 to 12 ring carbon atoms, preferably "9-to 10-membered condensed ring aryl", which is formed by sharing two or more adjacent atoms with each other by two or more cyclic structures, and specific examples thereof are naphthyl and the like.
"5-12 membered heteroaryl" as used herein refers to a cyclic group having aromatic character containing 5-12 ring atoms, wherein at least one ring atom is a heteroatom such as nitrogen, oxygen or sulfur. Including "5-8 membered mono heteroaryl" and "8-12 membered fused heteroaryl", preferably 5-10 membered heteroaryl.
"5-8 membered mono-heteroaryl" as used herein refers to an aromatic monocyclic ring group containing 5-8 ring atoms, at least one of which is a heteroatom, such as nitrogen, oxygen or sulfur. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. "5-8 membered mono-heteroaryl" includes, for example, "5-7 membered mono-heteroaryl", "5-6 membered nitrogen containing mono-heteroaryl", "6 membered nitrogen containing mono-heteroaryl", etc., wherein the heteroatom in the "nitrogen containing heteroaryl" contains at least one nitrogen atom, e.g., contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms), or contains 2 nitrogen atoms and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms). Specific examples of "5-8 membered monocyclic heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepanyl, 1, 3-diazinoheptenyl, azocyclotetraenyl and the like. The "5-6 membered single heteroaryl" refers to a specific example in which 5-8 membered heteroaryl contains 5-6 ring atoms.
The "8-12 membered fused heteroaryl group" as used herein refers to an unsaturated aromatic ring structure containing 8 to 12 ring atoms (at least one of which is a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom) formed by two or more ring structures sharing two adjacent atoms with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. Including "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", and the like, which may be fused in such a manner as to be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, and the like; specific examples include, but are not limited to: pyrrolopyrroles, pyrrolofurans, pyrazolopyrroles, pyrazolothiophenes, furanthiophenes, pyrazolooxazoles, benzofuranyl, benzisofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolonyl, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like.
The term "optionally substituted" as used herein includes both "substituted" and "unsubstituted".
The "each independently selected" of the present invention is used for different symbols (e.g. R 1 And R is 2 ) The groups represented may be selected from the same substituent or different substituents; for the same symbol (e.g. a plurality of R 1 ) The groups represented may be the same substituent or different substituents.
The term "therapeutically effective amount" as used herein refers to an amount of a compound, pharmaceutical formulation, pharmaceutical composition, as described above, that is capable of at least alleviating the symptoms of a disorder in a patient when administered to the patient. The actual amount comprising a "therapeutically effective amount" will vary depending on a variety of circumstances including, but not limited to, the particular disorder being treated, the severity of the disorder, the physical and health of the patient, and the route of administration. The skilled medical practitioner can readily determine the appropriate amount using methods known in the medical arts.
Advantageous effects of the invention
(1) The compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof has excellent Axl and Mer inhibition activity, has better selectivity to Tyro3 and can treat and/or prevent cancers or benign tumors;
(2) The compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof has good pharmacokinetic properties, longer action and high bioavailability;
(3) The compound has the advantages of simple preparation process, high purity of the medicine, stable quality and easy mass industrial production.
The advantageous effects of the compounds provided by the examples of the present invention are further illustrated by the experiments below, but this should not be construed as the compounds provided by the examples of the present invention only have the following advantageous effects.
Abbreviations used in the following experiments represent the following meanings:
DMSO: dimethyl sulfoxide (Dimethyl sulfoxide)
Kinase buffer: HEPES kinase buffer
Precision: automatic pipetting system
ATP: adenine nucleoside triphosphate (Adenosine Triphosphate)
Kinase submount 22: kinase substrate No. 22 peptide
Staurosporine: staurosporine
1 x of which "×": multiple times
Experimental example 1: detection of kinase Activity inhibition of the inventive Compounds on Axl, tyro3 and Mer
Experimental reagent and consumable:
| name of the name | Suppliers of goods | Goods number | Lot number |
| Axl | Carna | 08-107 | 16CBS-0641E |
| Tyro3 | Carna | 08-109 | 17CBS-0178C |
| MerTK | Invitrogen | PR6317A | 1691294AJ |
| Kinase substrate22 | GL | 112393 | P190329-SL112393 |
| DMSO | Sigma | D8418-1L | SHBG3288V |
| 384-wel white plate | PerkinElmer | 6007290 | 810712 |
The experimental method comprises the following steps:
1. compound formulation
The compounds were dissolved in 100% dmso to prepare 10mM stock solutions.
2. Kinase reaction process
(1) 1 XKinase buffer was prepared.
(2) Preparing a compound concentration gradient: test compounds were tested at 1000nM, diluted to 100-fold final concentration in 100% dmso solution in 384source plates, and diluted 4-fold with Precision to 10 concentrations, 10 concentrations being 100000n m, 25000n m, 6250n m, 1562.5n m, 390.6n m, 97.7n m, 24.4n m, 6.1n m, 1.5n m, 0.38n m, respectively. 250nL of 100-fold final concentration of compound was transferred to the destination plate OptiPlate-384F using a dispenser Echo 550.
(3) AXL Kinase solution with a final concentration of 2.5nM and TYRO3 Kinase solution with a final concentration of 0.5nM and merTK Kinase solution with a final concentration of 2.5nM were prepared in a 1 XKinase buffer.
(4) Adding 10 mu L of kinase solution with 2.5 times of final concentration to each of the compound well and the positive control well; to the negative control wells, 10. Mu.L of 1 XKinase buffer was added.
(5) Centrifugation at 1000rpm for 30 seconds, the reaction plate was shaken and mixed well and incubated at room temperature for 10 minutes.
(6) A5/3-fold final concentration of a mixed solution of ATP and Kinase substrate22 was prepared using a 1 XKinase buffer.
(7) The reaction was initiated by adding 15. Mu.L of a 5/3-fold final concentration of the mixed solution of ATP and substrate.
(8) The 384-well plate was centrifuged at 1000rpm for 30 seconds, and after shaking and mixing, incubated at room temperature for a corresponding period of time.
(9) The kinase reaction was stopped by adding 30. Mu.L of the stop detection solution containing EDTA, centrifuging at 1000rpm for 30 seconds, and shaking and mixing.
(10) The conversion was read using a Caliper EZ ReaderEZ Reader ii microfluidic system.
3. Data analysis
(1) Calculation formula
% inhibition= (Conversion% _max-Conversion% _sample)/(Conversion% _max-Conversion% _min), wherein: conversion% _sample is a Conversion reading of the sample; convertion% _min: negative control Kong Junzhi, representing conversion reading without enzyme wells; convesion% _max: positive control Kong Junzhi, represents a conversion reading without compound inhibition wells.
(2) Fitting dose-response curve
The log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and a log (inhibitor) vs. response-Variable slope fit quantitative effect curve of analysis software GraphPad Prism 5 is adopted, so that the IC of each compound on the enzyme activity is obtained 50 Values. The calculation formula is as follows: y=bottom+ (Top-Bottom)/(1+10
4. Results
IC for the inhibition of kinase Activity of Axl, tyro3 and Mer by Compounds of the invention 50 When the value is less than 100nm, the value is expressed by A; IC (integrated circuit) 50 The value is more than 100nm and less than 1000nm, and is represented by B; IC (integrated circuit) 50 The value is greater than 1000nm and is denoted by C.
TABLE 1 inhibition of kinase Activity of the inventive compounds against Axl, tyro3 and Mer
The results show that: the compounds of the embodiments of the present invention have certain inhibitory effects on Axl and Mer kinase activities.
Detailed Description
The technical solution of the present invention will be described below with reference to specific embodiments, and the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Abbreviations used in the following experiments represent the following meanings:
PE: petroleum ether
EA: acetic acid ethyl ester
DCM: dichloromethane (dichloromethane)
THF: tetrahydrofuran (THF)
MeOH: methanol
DIEA: n, N-diisopropylethylamine
TEA: triethylamine
DMAP: 4-dimethylaminopyridine
DMSO: dimethyl sulfoxide
Preparation example
Preparation example 1 preparation of benzyl trans (4- (3-amino-6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) carbamate
(1) Preparation of 2, 4-dichloropyrimidine-5-carboxamide
2, 4-dichloropyrimidine-5-carbonyl chloride (12.5 g,60 mmol) was dissolved in DCM (300 mL), ammonia water (14 mL) was added dropwise at-20deg.C, the addition was completed, the reaction was carried out for 3 hours at-20deg.C, the filtrate was filtered, washed with water (100 mL), the filter cake was added to ethyl acetate (300 mL), stirred at 60deg.C for 10min, hot-filtered, the filter cake was repeatedly operated for 1 time, the ethyl acetate layer and dichloromethane layer were combined, and the product was concentrated to give 10g in 88.1% yield.
(2) Preparation of tert-butyl trans-2- ((4- (((benzyloxy) carbonyl) amino) cyclohexyl) -2- (5-carbamoyl-2-chloropyrimidin-4-yl) hydrazine-1-carboxylate
Trans 2- ((4- (((benzyloxy) carbonyl) amino) cyclohexyl) hydrazine-1-carboxylic acid tert-butyl ester hydrochloride (1.4 g,3.64 mmol), 2, 4-dichloropyrimidine-5-carboxamide (0.7 g,3.64 mmol) and DIEA (2 g,15.48 mmol) were added sequentially to CH 3 CN (60 mL) was reacted at 60℃for 4 hours, filtered, and the cake was dried to give 1.4g of the product in 74% yield.
(3) Preparation of trans 1- ((4- (((benzyloxy) carbonyl) amino) cyclohexyl) -6-chloro-3-imino-1, 3-dihydro-2H-pyrazolo [3,4-d ] pyrimidine-2-carboxylic acid tert-butyl ester
Trans 2- ((4- (((benzyloxy) carbonyl) amino) cyclohexyl) -2- (5-carbamoyl-2-chloropyrimidin-4-yl) hydrazine-1-carboxylic acid tert-butyl ester (6.7 g,12.9 mmol), PCl 5 (2.7 g,12.9 mmol) was added sequentially to toluene (200 mL), reacted at 110℃for 3 hours, poured into water (200 mL), extracted with EA (100 mL. Times.3), concentrated, and chromatographed (EA: PE=1:2) to give 800mg of crude product.
(4) Preparation of benzyl trans (4- (3-amino-6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) carbamate
Trans 1- ((4- (((benzyloxy) carbonyl) amino) cyclohexyl) -6-chloro-3-imino-1, 3-dihydro-2H-pyrazolo [3,4-d ] pyrimidine-2-carboxylic acid tert-butyl ester (500 mg, crude) was dissolved in DCM (40 mL), TFA (4 mL) was added, reacted for 4 hours at 25 ℃, concentrated, TEA (4 mL) was added and stirred, column chromatography (EA: pe=1:1) afforded 200mg of product in 3.9% yield in two steps.
Example 1 trans 1- (4-aminocyclohexyl) -N 6 -butyl-N 3 - (4-fluorobenzyl) -1H-pyrazolo [3,4-d]Preparation of pyrimidine-3, 6-diamine (Compound 1)
(1) Preparation of benzyl trans (4- (6-chloro-3- ((4-fluorobenzyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) carbamate
Trans (4- (3-amino-6-chloro-1H-pyrazolo [3, 4-d)]Benzyl pyrimidyl-1-yl) carbamate (340 mg,0.85 mmol) and p-fluorobenzaldehyde (316 mg,2.55 mmol) were dissolved in THF (40 mL), tetraethyltitanate (3838 mg,1.7 mmol) was added and reacted at 25℃for 48 hours, naBH (OAc) was added 3 (610 mg,2.88 mmol), at 25℃for 16 hours, concentrated, added THF (40 mL) and MeOH (40 mL), and added NaBH again 3 CN (300 mg,4.78 mmol), at 25℃for 12 hours, concentrated,column chromatography (EA: pe=10:1-1:1) afforded 180mg of product in 41.7% yield.
(2) Preparation of benzyl trans ((4- (6- (butylamino) -3- ((4-fluorobenzyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) carbamate
Benzyl trans (4- (6-chloro-3- ((4-fluorobenzyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) carbamate (180 mg,0.35 mmol), n-butylamine (52 mg,0.7 mmol), DIEA (160 mg,1.24 mmol) were added to dioxane (10 mL), reacted for 16H at 110 ℃, concentrated, column chromatographed (EA: pe=10:1-1:1) to give 110mg of product in 57% yield.
(3) Trans 1- (4-aminocyclohexyl) -N 6 -butyl-N 3 - (4-fluorobenzyl) -1H-pyrazolo [3,4-d]Preparation of pyrimidine-3, 6-diamines
Benzyl trans ((4- (6- (butylamino) -3- ((4-fluorobenzyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) carbamate (60 mg,0.11 mmol), pd/C (20 mg) was added to methanol (20 mL), hydrogen balloon stirred at 25 ℃ for 3H, filtered, and the filtrate concentrated to give 12mg of product in 26.5% yield by preparative HPLC separation (methanol/water=10% -100%).
Molecular formula C 22 H 30 FN 7 Molecular weight 411.5LC-MS (M/e): 412.3 (M+H) + )
1 H-NMR(400MHz,MeOD)δ:8.49(s,1H),7.41-7.45(m,2H),7.02-7.07(m,2H),4.47(s,2H),4.31-4.39(m,1H),3.41(t,J＝3.2Hz,2H),2.71-2.81(m,1H),2.09-2.20(m,2H),2.01-2.04(m,2H),1.86-1.91(m,2H),1.59-1.65(m,2H),1.39-1.50(m,2H),1.31-1.37(m,2H),0.99(t,J＝7.2Hz,3H).
Example 2 preparation of trans N- (1- (4-aminocyclohexyl) -6- (butylamino) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -4-fluorobenzamide (compound 2)
(1) Preparation of trans (-4- (6-chloro-3- (4-fluorobenzamido) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) aminomethyl ester
Benzyl trans (4- (3-amino-6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) carbamate (200 mg,0.5 mmol) was dissolved in DCM (4 mL), triethylamine (150 mg,1.48 mmol) -p-fluorobenzoyl chloride (120 mg,0.75 mmol) was added dropwise at 5℃and reacted for 16H at 25℃followed by DIEA (191 mg,1.48 mmol), p-fluorobenzoyl chloride (120 mg,0.75 mmol) and reacted for 4H at 25℃and concentrated to give 220mg of the product with a yield of 84.3% (EA: PE=10:1-2:1).
(2) Preparation of benzyl trans (4- (6- (butylamino) -3- (4-fluorobenzamido) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) carbamate
Benzyl trans (4- (6-chloro-3- (4-fluorobenzamido) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) carbamate (200 mg,0.38 mmol), n-butylamine (56 mg,0.77 mmol), DIEA (250 mg,1.93 mmol) were added to dioxane (40 mL), reacted for 4 hours at 110℃and concentrated, column chromatography (EA: PE=1:1) to give 200mg of product in 93.4% yield.
(3) Preparation of trans N- (1- (4-aminocyclohexyl) -6- (butylamino) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -4-fluorobenzamide
Benzyl trans (4- (6- (butylamino) -3- (4-fluorobenzamido) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) carbamate (80 mg,0.14 mmol), pd/C (40 mg) was added to methanol (30 mL), hydrogen balloon stirred at 25 ℃ for 3H, filtered, the filtrate concentrated, reverse column chromatography (methanol/water=10% -100%) concentrated, crude was slurried with acetonitrile (20 mL), filtered, and the filter cake dried to give 10mg of product in 16.4% yield.
Molecular formula C 22 H 28 FN 7 Molecular weight of O425.5 LC-MS (M/e): 426.3 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:9.33(s,1H),8.57(s,1H),7.92-7.96(m,2H),7.14-7.19(m,2H),5.20-5.35(m,1H),4.45-4.59(m,1H),3.40-3.50(m,2H),2.75-2.85(m,1H),1.90-2.01(m,6H),1.32-1.72(m,8H),0.96(t,J＝7.2Hz,3H).
Example 3 trans 1- ((4-aminocyclohexyl) methyl) -N 6 -butyl-N 3 - (4-fluorophenyl) -1H-pyrazolo [3,4-d ]]Preparation of pyrimidine-3, 6-diamine (Compound 3)
(1) Preparation of methyl trans (4- ((tert-butoxycarbonyl) amino) cyclohexyl) 4-methylbenzenesulfonate
Tert-butyl trans (4- (hydroxymethyl) cyclohexyl) carbamate (0.5 g,2.18 mmol), TEA (0.95 g,9.39 mmol) and DMAP (53 mg,0.43 mmol) were dissolved in DCM (20 mL), p-toluenesulfonyl chloride (0.89 g,4.67 mmol) was added and reacted at 25℃for 16 h, water (50 mL) and DCM (50 mL) were added, the organic layer was separated, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated by column chromatography (EA/PE=0% -40%) to give 400mg of product in 47.8% yield.
(2) Preparation of tert-butyl 2- (2-chloro-5- ((4-fluorophenyl) carbamoyl) pyrimidin-4-yl) hydrazine-1-carboxylate
2, 4-dichloro-N- (4-fluorophenyl) pyrimidine-5-carboxamide (1 g,3.5 mmol), NH 2 NHBoc (463 mg,3.5 mmol) and TEA (0.53 g,5.23 mmol) were added sequentially to tetrahydrofuran (30 mL), reacted at 25℃for 16 hours, concentrated, acetonitrile (20 mL) was added, filtered and the filter cake dried to give 0.7g of product in 52.4% yield.
(3) Preparation of 6-chloro-N- (4-fluorophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-amine
Tert-butyl 2- (2-chloro-5- ((4-fluorophenyl) carbamoyl) pyrimidin-4-yl) hydrazine-1-carboxylate (2.5 g,6.56 mmol), PCl 5 (1.36 g,6.54 mmol) was added sequentially to toluene (80 mL), reacted at 120℃for 1.5 hours, concentrated, and reversed-phase column chromatography (MeOH/H) 2 O=1:2), to give 650mg of crude product.
(4)N 6 -butyl-N 3 - (4-fluorophenyl) -1H-pyrazolo [3,4-d ]]Preparation of pyrimidine-3, 6-diamines
6-chloro-N- (4-fluorophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-amine (650 mg, crude) N-butylamine (360 mg,4.9 mmol), DIEA (1.6 g,12.4 mmol) was added to dioxane (20 mL), reacted at 110℃for 3 hours, concentrated, and column chromatographed (EA/PE=10% -50%) to give 200mg of product in 10.2% two-step yield.
(5) Preparation of tert-butyl trans (4- ((6- (butylamino) -3- ((4-fluorophenyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) cyclohexyl) carbamate
Will N 6 -butyl-N 3 - (4-fluorophenyl) -1H-pyrazolo [3,4-d ]]Pyrimidine-3, 6-diamine (120 mg,0.4 mmol), trans (4- ((tert-butoxycarbonyl) amino) cyclohexyl) 4-methylbenzenesulfonic acid methyl ester (155 mg,0.4 mmol), and Cs 2 CO 3 (260 mg,0.8 mmol) in DMF (6 mL), 80 ℃ for 3 hours, water (100 mL) was poured, extracted with EA (50 mL. Times.3), the organic layers were combined, concentrated, and column chromatographed (EA/PE=10% -50%) to give 80mg of product in 39.1% yield.
(6) Trans 1- ((4-aminocyclohexyl) methyl)-N 6 -butyl-N 3 - (4-fluorophenyl) -1H-pyrazolo [3,4-d ]]Preparation of pyrimidine-3, 6-diamines
Tert-butyl trans (4- ((6- (butylamino) -3- ((4-fluorophenyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) cyclohexyl) carbamate (80 mg,0.156 mmol) was added to DCM (5 mL) and TFA (1 mL), reacted for 1 hour at 25 ℃, concentrated, saturated sodium carbonate solution (10 mL) and DCM (50 mL) were added, filtered, the filter cake was washed with water, the filter cake was slurried with acetonitrile (10 mL), filtered, and the filter cake dried to give 40mg of product in 62.2% yield.
Molecular formula C 22 H 30 FN 7 Molecular weight 411.5LC-MS (M/e): 412.3 (M+H) + )
1 H-NMR(400MHz,MeOD)δ:8.66(s,1H),7.57-7.60(m,2H),6.95-7.00(m,2H),3.99(d,J＝6.8Hz,2H),3.40(t,J＝7.2Hz,2H),2.99-3.05(m,1H),1.96-2.02(m,3H),1.78-1.81(m,2H),1.56-1.64(m,2H),1.30-1.44(m,4H),1.15-1.30(m,2H),0.95(t,J＝7.2Hz,3H).
EXAMPLE 4 trans 1- (4-aminocyclohexyl) -N 6 -butyl-N 3 - (4-fluorophenyl) -1H-pyrazolo [3,4-d ]]Preparation of pyrimidine-3, 6-diamine trifluoroacetate salt (Compound 6)
(1) Preparation of tert-butyl 2- (4- ((((benzyloxy) carbonyl) amino) cyclohexylidene) hydrazine-1-carboxylate
Benzyl (4-oxocyclohexyl) carbamate (11.3 g,45.7 mmol) and NH 2 NHBoc (6.6 g,49.9 mmol) was dissolved in methanol (140 mL), reacted for 16 hours at 25℃and concentrated to give crude product.
(2) Preparation of trans-2- ((4- (((benzyloxy) carbonyl) amino) cyclohexyl) hydrazine-1-carboxylic acid tert-butyl ester hydrochloride
Tert-butyl 2- (4- ((((benzyloxy) carbonyl) amino) cyclohexylidene) hydrazine-1-carboxylate (crude product in the previous step) is added into acetic acid (135 mL) and water (135 mL), sodium cyanoborohydride (2.9 g,46.2 mmol) is added in portions, the reaction is carried out for 3 hours at 25 ℃, 35% NaOH (150 mL) is used for adjusting pH=6-7 after the reaction is finished, filtration is carried out, the filter cake is washed by water (50 mL), drying is carried out to obtain crude product, the crude product is added into ethyl acetate (300 mL), HCl-dioxane (5 mL) is slowly dripped into the solution, the reaction is carried out for 10 minutes at 25 ℃, white solid is separated out, filtration is carried out, filter cake is washed by ethyl acetate (50 mL), and the product 8g is obtained after the two-step yield is 43.9%.
(3) Preparation of 2, 4-dichloropyrimidine-5-carbonyl chloride
2, 4-dihydroxypyrimidine-5-carboxylic acid (5.0 g,32.0 mmol) was added in portions to POCl at 0deg.C 3 (23 mL) and then PCl was added 5 (23.3 g) was then allowed to react at 105℃for 16 hours, concentrated, n-heptane (20 mL) was added, filtered, and the filtrate was concentrated to give 6.5g of the product in 96% yield.
(4) Preparation of 2, 4-dichloro-N- (4-fluorophenyl) pyrimidine-5-carboxamide
2, 4-dichloropyrimidine-5-carbonyl chloride (5 g,23.6 mmol) was dissolved in DCM (100 mL), p-fluoroaniline (2.5 g,22.5 mmol) was added dropwise at-5℃followed by triethylamine (2.3 g,22.7 mmol), -reaction at 5℃for 1 hour and then reaction at 25℃for 1 hour. Concentration and column chromatography (PE: ea=2:1) gave 4.2g of product in 62.1% yield.
(5) Preparation of tert-butyl trans-2- ((4- (((benzyloxy) carbonyl) amino) cyclohexyl) -2- (2-chloro-5- ((4-fluorophenyl) carbamoyl) pyrimidin-4-yl) hydrazine-1-carboxylate
Trans 2- ((4- (((benzyloxy) carbonyl) amino) cyclohexyl) hydrazine-1-carboxylic acid tert-butyl ester hydrochloride (400 mg,1 mmol),
2, 4-dichloro-N- (4-fluorophenyl) pyrimidine-5-carboxamide (284 mg,1 mmol) and DIEA (390 mg,3 mmol) were added sequentially to CH 3 CN (10 mL) was reacted at 65℃for 4 hours, concentrated to 2.5mL, filtered, and the cake was dried to give 100mg of the product in 16.4% yield.
(6) Preparation of trans-benzyl (4- (6-chloro-3- ((4-fluorophenyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) carbamate
Trans-2- ((4- (((benzyloxy) carbonyl) amino) cyclohexyl) -2- (2-chloro-5- ((4-fluorophenyl) carbamoyl) pyrimidin-4-yl) hydrazine-1-carboxylic acid tert-butyl ester (1 g,1.6 mmol), PCl 5 (0.68 g,3.2 mmol) was added sequentially to toluene (50 mL), reacted at 110℃for 16 hours, concentrated, methanol (50 mL) was added, filtered, and the cake was washed with methanol (10 mL) and dried to give 550mg of the title compound in a yield of 68.1%.
(7) Preparation of trans-benzyl (4- (6- (butylamino) -3- ((4-fluorophenyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) carbamate
Trans benzyl (4- (6-chloro-3- ((4-fluorophenyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) carbamate (500 mg,1 mmol), n-butylamine (220 mg,3 mmol), DIEA (650 mg,5 mmol) were added to acetonitrile (50 mL), reacted at 80 ℃ for 16 hours, further DMSO (10 mL), DIEA (650 mg,5 mmol), n-butylamine (220 mg,3 mmol) were added, reacted at 90 ℃ for 8 hours, concentrated, dropped into water (50 mL), solid was precipitated, filtered, and the filter cake was dried to give 500mg of crude product.
(8) Trans 1- (4-aminocyclohexyl) -N 6 -butyl-N 3 - (4-fluorophenyl) -1H-pyrazolo [3,4-d ]]Preparation of pyrimidine-3, 6-diamine trifluoroacetate salt
Trans benzyl (4- (6- (butylamino) -3- ((4-fluorophenyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) carbamate (200 mg, crude), pd/C (80 mg) was added to methanol (20 mL), hydrogen balloon stirred at 25 ℃ for 8H, filtered, the filtrate concentrated, reverse column chromatography (acetonitrile/water=10% -100%, column washed with 1% trifluoroacetic acid in methanol), concentrated, crude slurried with acetonitrile (15 mL), filtered, filter cake dried to give 10mg of product.
Molecular formula C 21 H 28 FN 7 Molecular weight of xTFA 397.5LC-MS (M/e): 398.3 (M+H) + )
1 H-NMR(400MHz,MeOD)δ:8.79(s,1H),7.66-7.70(m,2H),7.07(t,J＝8.8Hz,2H),4.50-4.60(m,1H),3.52(t,J＝7.2Hz,2H),3.21-3.23(m,1H),2.20-2.30(m,4H),2.05-2.15(m,2H),1.65-1.75(m,4H),1.40-1.55(m,2H),1.03(t,J＝7.2Hz,3H).
The TAM inhibitors provided by the present invention and their use are described in detail above. The principles and embodiments of the present invention have been described herein with reference to specific examples, the description of which is intended only to aid in the understanding of the method of the present invention and its central ideas. It should be noted that it will be apparent to those skilled in the art that various changes and modifications can be made herein without departing from the principles of the invention, which also falls within the scope of the appended claims.
Claims (8)
1. A compound represented by the general formula (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
each R 1 Independently selected from hydrogen, halogen, cyano, hydroxy, carboxyl, amino, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, amino C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino or (C) 1-6 Alkyl group 2 An amino group;
each R 2 Independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, amino C 1-6 Alkyl, C 1-6 Alkylamino, (C) 1-6 Alkyl group 2 An amino group;
R 3 selected from hydrogen, halogen, cyano, amino, hydroxy, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, (C) 1-6 Alkyl group 2 Amino, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or carboxyl C 1-6 An alkyl group;
ring A is selected from 5-6 membered cycloalkyl;
ring B is selected from phenyl;
each L is independently selected from-CR 4 R 4 -；
Each R 4 Are independently selected from hydrogen, C 1-6 Alkyl or C 1-6 An alkoxy group;
m and d are independently selected from 0 and 1 respectively;
n and q are respectively and independently selected from 0, 1, 2 and 3;
except for the following compounds:
2. the compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
each R 1 Are independently selected from hydrogen, hydroxy, carboxyl, amino and C 1-4 Alkyl, hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, amino C 1-4 Alkyl, C 1-4 Alkylamino or (C) 1-4 Alkyl group 2 An amino group;
each R 2 Independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, amino C 1-4 Alkyl, C 1-4 Alkylamino, (C) 1-4 Alkyl group 2 An amino group;
R 3 selected from hydrogen, amino, hydroxy, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, (C) 1-4 Alkyl group 2 Amino, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl or carboxyl C 1-4 An alkyl group;
ring A is selected from 5-6 membered cycloalkyl;
ring B is selected from phenyl;
Each L is independently selected from-CR 4 R 4 -；
Each R 4 Are independently selected from hydrogen, C 1-4 Alkyl or C 1-4 An alkoxy group;
m and d are independently selected from 0 and 1 respectively;
n and q are independently selected from 0, 1 and 2.
3. The compound of claim 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
each R 1 Each independently selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, aminomethyl, methylamino, ethylamino, or dimethylamino;
each R 2 Each independently selected from hydrogen, fluorine, chlorine, bromine, and iodine;
R 3 selected from methylamino, ethylamino, propylamino, isopropylamino, butylAmino, isobutylamino, sec-butylamino, tert-butylamino;
ring a is selected from cyclopentyl or cyclohexyl;
ring B is selected from phenyl;
each L is independently selected from-CR 4 R 4 -；
Each R 4 Each independently selected from hydrogen;
m and d are independently selected from 0 and 1 respectively;
n and q are independently selected from 0, 1 and 2.
4. A compound selected from the group consisting of:
5. a pharmaceutical formulation comprising a compound of any one of claims 1-4, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or diluents; the pharmaceutical preparation is any clinically or pharmaceutically acceptable dosage form.
6. Use of a compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical formulation according to claim 5 for the manufacture of a medicament for the treatment and/or prophylaxis of cancer or benign tumors.
7. A process for the preparation of a compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, comprising the steps of:
reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV);
the compound shown in the formula (IV) is subjected to functional group conversion reaction to obtain a compound shown in the formula (V), and the compound shown in the formula (V) is subjected to deprotection to obtain a compound shown in the general formula (I');
wherein X is selected from halogen, G is a protecting group, Y is selected from halogen, hydrogen atom, C 1-6 Alkyl or C 1-6 Alkoxy, R 1’ Represents R 1 Is substituted by G, L' is-C (O) -, R 1 、R 2 、R 3 L, m, n, q, d, ring a, ring B as claimed in any one of claims 1 to 3.
8. An intermediate for preparing a compound represented by the general formula (I'), which has the following structure:
wherein G is a protecting group, R 1’ Represents R 1 Is substituted by G, R 1 、R 2 、R 3 L, m, n, q, d, ring a, ring B as claimed in any one of claims 1 to 3.
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| "CAS登记号2251800-14-1、2251800-16-3、2251800-74-3、1099657-69-8、210414-99-6、210415-01-3";STN Registry数据库;《美国化学会》;第1-6页 * |
| "Identification and optimization of N 3,N6-diaryl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamines as a novel class of ACK1 inhibitors";David J. Kopecky et al.;《Bioorganic & Medicinal Chemistry Letters》;第18卷;第6352-6356页 * |
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| CN112759594A (en) | 2021-05-07 |
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