CN115215799B - Urea multi-target tyrosine kinase inhibitor and multiple medical applications thereof - Google Patents

Urea multi-target tyrosine kinase inhibitor and multiple medical applications thereof Download PDF

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CN115215799B
CN115215799B CN202210968135.1A CN202210968135A CN115215799B CN 115215799 B CN115215799 B CN 115215799B CN 202210968135 A CN202210968135 A CN 202210968135A CN 115215799 B CN115215799 B CN 115215799B
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詹正云
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Abstract

The invention discloses a compound shown in a formula IIIb, cis-trans isomer, racemate, deuterated or pharmaceutically acceptable salt or a mixture thereof, a pharmaceutical composition containing the compound and application of the compound as a plurality of important tyrosine kinase (RTK) target inhibitors and for treating various diseases such as tumors accompanied with angiogenesis. The compound can be used as an RTK targeted polyclonal drug with better inhibition activity for effectively treating various cancer diseases such as pancreatic cancer, lung cancer, kidney cancer, liver cancer, stomach cancer, cervical cancer, leukemia and the like, wherein E、G1、G2、G3、G4、G5、R1、R2、R3、X1、X2、X3、X4 and possible isotope substitution marks of elements in the compound are defined in the specification.

Description

Urea multi-target tyrosine kinase inhibitor and multiple medical applications thereof
Technical Field
The invention relates to a novel urea compound formed by polysubstituted aromatic amine and alkylamine. More particularly, the present invention relates to polysubstituted arylamino urea compounds useful as inhibitors of multi-target tyrosine kinases and a variety of medical applications thereof.
Background
Protein tyrosine kinases (protein tyrosine kinases, PTKs) are the largest superfamily of proteins known, and protein tyrosine kinases are important hubs for extracellular signaling into cells. Tyrosine kinases play an important role in regulating proliferation and differentiation of cells, and abnormal expression of PTKs activates a series of downstream signaling pathways, causing cascade reactions, leading to disturbance of cell proliferation regulation and eventually tumor formation. Tyrosine kinases can be classified into receptor-type tyrosine kinases (RTKs) and non-receptor-type tyrosine kinases (nRTK), the receptor-type tyrosine kinases (RTKs) including vascular endothelial growth factor receptor (VEGFR, vascular Endothelial Growth Factor Receptor), fibroblast growth factor receptor (FGFR, fibroblast growth gactor receptor), epidermal growth factor receptor [ EPIDERMAL GROWTH FACTOR RECEPTOR, abbreviated as EGFR, HER1, or ErbB-1, which are members of the epidermal growth factor receptor (HER) family, tyrosine kinase membrane receptor (c-Met), platelet-derived growth factor receptor (PDGFR alpha), and RET, which are closely related to tumor diseases and their targeted therapies.
To date, more than 80% of kinases have been targeted for therapeutic drug development, and it has been reported that pathological increases in vascular endothelial formation are associated with the onset or progression of various diseases, and that proliferation of solid tumors is dependent on angiogenesis, so drugs that effectively inhibit tyrosine kinase (RTK) targets such as some of the above-mentioned tyrosine kinases VEGFR1-3, FGFR1-4, EGFR, RET, c-MET have become the primary targeted therapeutic approaches against refractory solid tumors. Most of the molecular targeted antitumor drugs currently on the market are protein Tyrosine Kinase Inhibitors (TKIs) targeting PTKs.
At present, most of the molecular targeted antitumor drugs on the market at home and abroad are protein Tyrosine Kinase Inhibitors (TKI) with PTK as a target, for example, micromolecular urea compound antitumor drugs with good inhibition effect on tyrosine kinase VEGFR1-3, which are clinically used for treating liver cancer, comprise sorafenib (Sorafenib, ref-1), regorafenib (Regorafenib, ref-2) and lenvatinib (Lenvatinib, lenvatinib, ref-3) with good inhibition effect on tyrosine kinase VEGFR1-3 and FGFR1-4, and have good antitumor effect in clinical treatment.
The invention aims to develop a novel multi-target Tyrosine Kinase Inhibitor (TKI) with higher tyrosine kinase activity and lower toxic and side effects through innovative design of a small molecular structure and functional groups thereof, and the novel multi-target Tyrosine Kinase Inhibitor (TKI) is more effectively used for treating various tumors such as pancreatic cancer, lung cancer, kidney cancer, liver cancer, gastric cancer, cervical cancer, leukemia and the like and related cancer diseases.
The invention relates to a novel polysubstituted anilino group-containing polysubstituted anilino urea compound with a formula IIIb as an innovative key point, which is used as a multi-target Tyrosine Kinase Inhibitor (TKI), can inhibit vascular endothelial growth factor receptors (VEGFR 1, VEGFR2, VEGFR 3) and fibroblast growth factor receptors (FGFR 1-4) with high efficiency, can inhibit a plurality of important Receptor Tyrosine Kinases (RTKs) which can cause angiogenesis and tumor growth pathogenicity except normal cell functions, such as tyrosine kinases including EGFR, RET, PDGFR α and the like, so that the novel polysubstituted anilino urea compound can generate a relatively strong angiogenesis inhibition effect, and has better application in more effectively preventing and treating diseases such as various tumors with abnormal proliferation of angiogenesis.
The structure of the urea compound containing the polysubstituted anilino group disclosed by the invention is that according to the structural characteristics of tyrosine kinase targets, structural modification innovation and optimization are carried out by introducing more substituents into aniline, so that a multi-target Tyrosine Kinase Inhibitor (TKI) with better inhibition effect is developed, and various types of tumors can be treated more effectively.
Disclosure of Invention
The invention solves the core problem of developing a novel urea compound with multi-substituent aniline as innovative characteristics, which has better inhibition effect on pancreatic cancer (BXPC 3), lung cancer (A549), kidney cancer (Caki-1), liver cancer (Hep3B2.1-7), gastric cancer (SNU 16), cervical cancer (Hela), leukemia (K562) and other tumor cell lines and VEGFR1-3, FGFR1-4, EGFR, RET and other kinase targets, and has better inhibition effect, better application prospect and better safety.
A first aspect of the invention provides a compound of formula IIIb, which is a cis, trans, enantiomer, diastereomer, racemate, tautomer, or pharmaceutically acceptable salt or hydrate thereof, and a deuterated or isotopically substituted compound:
wherein,
E is nitrogen (N), or CH;
G 1 is hydrogen, deuterium (D), halogen, -CN, C 1-20 alkyl, C 1-20 alkoxy, or C 1-20 alkylamino;
G 2 is halogen, -CN, C 1-20 alkylamino, C 1-20 hydroxyalkylamino, C 1-20 nitriloalkylamino, C 1-20 aminoalkylamino, C 3-20 aminocycloalkylamino, C 1-20 carboxyalkyleneamino, C 3-20 carboxycycloalkylamino, 3-6 membered heterocycloalkylamino, OR-OR 6; wherein R 6 is selected from: hydrogen, deuterium, C 1-20 alkyl, C 1-20 haloalkyl, C 1-20 cyanoalkylene, C 3-20 cyanocycloalkylene, C 2-20 hydroxyalkylene, C 2-20 aminoalkylene, C 3-20 aminocycloalkylene, C 2-20 carboxyalkylene, C 3-20 carboxycycloalkylene, C 3-6 cycloalkyl, C 3-6 aminocycloalkylene, C 1-20 amino (C 3-20 cycloalkyl) alkylene, 3-6 membered heterocyclyl, or 3-6 membered heterocyclylalkylene;
G 3 is-CN, -C (O) OR, -C (O) NH 2, deuterated-C (O) ND 2、C1-20 alkoxy, C 1-20 alkylamino, OR-C (O) NR 4R5; wherein R is hydrogen, or C 1-20 alkyl, R 4 and R 5 are each independently selected from: hydrogen, deuterium, C 1-20 alkyl, C 1-20 haloalkyl, C 1-20 cyanoalkylene, C 3-20 cyanocycloalkylene, C 2-20 hydroxyalkylene, C 3-20 hydroxycycloalkylene, C 2-20 aminoalkylene, C 3-20 aminocycloalkylene, C 2-20 carboxyalkylene, C 3-20 carboxycycloalkylene, C 3-20 cycloalkenyl, C 3-20 cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclylalkylene, C 6-20 aryl, C 3-20 heterocyclylaryl, C 1-20 alkylsulfonyl, C 3-20 cycloalkylsulfonyl, or C 2-20 heterocyclylalkylsulfonyl; r 4 and R 5 are connected with each other or form a 3-8 membered heterocyclic group or heterocyclic aryl group containing 1-3 hetero atoms;
Each of G 4 and G 5 is independently selected from: hydrogen, deuterium (D), halogen, -CN, C 1-20 alkyl, C 1-20 alkoxy, or C 1-20 alkylamino;
R 1 is selected from: hydrogen, deuterium, C 1-20 alkyl, C 3-20 cycloalkyl, or C 3-20 deuterated cycloalkyl;
R 2 and R 3 are each independently selected from: hydrogen, deuterium, C 1-20 alkyl, C 3-20 cycloalkyl, C 3-20 deuterated cycloalkyl, or a 3-to 6-membered heterocyclyl;
X 1、X2 and X 3 are each independently selected from: halogen, -CN, -NH 2、C1-20 alkoxy, or C 1-20 alkylamino;
X 4 is selected from: hydrogen, deuterium, halogen, -CN, -NH 2、C1-20 alkoxy, or C 1-20 alkylamino.
In some preferred embodiments of the present invention,
E is nitrogen (N), or CH;
G 1 is hydrogen, deuterium (D), halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino;
G 2 is halogen, -CN, C 1-6 alkylamino, C 1-6 hydroxyalkylamino, C 1-6 nitriloalkylamino, C 1-6 aminoalkylamino, C 3-6 aminocycloalkylamino, C 1-6 carboxyalkyleneamino, C 3-6 carboxycycloalkylamino, 3-6 membered heterocycloalkylamino, OR-OR 6; wherein R 6 is selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene, C 2-6 hydroxyalkylene, C 2-6 aminoalkylene, C 3-6 aminocycloalkylene, C 2-6 carboxyalkylene, C 3-6 carboxycycloalkylene, C 3-6 cycloalkyl, C 3-6 aminocycloalkylene, C 1-6 amino (C 3-6 cycloalkyl) alkylene, 3-6 membered heterocyclyl, or 3-6 membered heterocyclylalkylene;
G 3 is-CN, -C (O) OR, -C (O) NH 2, deuterated-C (O) ND 2、C1-6 alkoxy, C 1-6 alkylamino, OR-C (O) NR 4R5; wherein R is hydrogen, or C 1-6 alkyl, R 4 and R 5 are each independently selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene, C 2-6 hydroxyalkylene, C 3-6 hydroxycycloalkylene, C 2-6 aminoalkylene, C 3-6 aminocycloalkylene, C 2-6 carboxyalkylene, C 3-6 carboxycycloalkylene, C 3-6 cycloalkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclylalkylene, C 6-10 aryl, C 3-10 heterocyclylaryl, C 1-6 alkylsulfonyl, C 3-6 cycloalkylsulfonyl, or C 2-6 heterocyclylalkylsulfonyl; r 4 and R 5 are connected with each other or form a 3-8 membered heterocyclic group or heterocyclic aryl group containing 1-3 hetero atoms;
each of G 4 and G 5 is independently selected from: hydrogen, deuterium (D), halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino;
R 1 is selected from: hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, or C 3-6 deuterated cycloalkyl;
R 2 and R 3 are each independently selected from: hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 deuterated cycloalkyl, or a 3-to 6-membered heterocyclyl;
X 1、X2 and X 3 are each independently selected from: halogen, -CN, -NH 2、C1-6 alkoxy, or C 1-6 alkylamino;
X 4 is selected from: hydrogen, deuterium, halogen, -CN, -NH 2、C1-6 alkoxy, or C 1-6 alkylamino.
In some of the more preferred embodiments of the present invention,
E is CH;
G 1 is hydrogen;
G 2 is-OR 6, wherein R 6 is selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene, C 2-6 hydroxyalkylene, C 2-6 aminoalkylene, C 3-6 aminocycloalkylene, C 2-6 carboxyalkylene, C 3-6 cycloalkyl, C 3-6 aminocycloalkylene, C 1-6 amino (C 3-6 cycloalkyl) alkylene, 3-6 membered heterocyclyl, or 3-6 membered heterocyclylalkylene;
G 3 is-C (O) OR, -C (O) NH 2, OR-C (O) NR 4R5; wherein R is hydrogen, or C 1-6 alkyl, R 4 and R 5 are each independently selected from: hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene, C 2-6 hydroxyalkylene, C 2-6 aminoalkylene, C 2-6 carboxyalkylene, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-6 alkylene (3-6 membered heterocyclyl), and, A C 3-6 heteroaryl, C 1-6 alkylsulfonyl, C 3-6 cycloalkylsulfonyl, or C 2-6 heterocycloalkylsulfonyl; r 4 and R 5 are connected with each other or form a 3-8 membered heterocyclic group or heterocyclic aryl group containing 1-3 hetero atoms;
Each of G 4 and G 5 is independently selected from: hydrogen;
R 1 is selected from: hydrogen;
R 2 is selected from: hydrogen;
Each R 3 is independently selected from: c 3-6 cycloalkyl;
x 1、X2 and X 3 are each independently selected from: halogen;
X 4 is selected from: hydrogen.
In some embodiments, the compounds of formula IIIb according to the present invention are selected from the following structures, and are characterized by including but not limited to any of the following structures:
in a second aspect, the present invention provides a process for producing a compound of formula IIIb, characterized in that: it can be prepared by either of the following two methods:
the first method comprises the following five steps, and the reaction equation is as follows:
The second method comprises the following three steps, and the reaction equation is as follows:
wherein,
R 4 and R 5 are each independently selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 2-6 hydroxyalkylene, C 2-6 aminoalkylene, C 2-6 carboxyalkylene, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclylalkylene, C 6-12 aryl, C 3-10 heterocyclylaryl, C 1-6 alkylsulfonyl, C 3-6 cycloalkylsulfonyl, or C 2-6 heterocyclylalkylsulfonyl, or 3-8 membered heterocyclyl or heterocyclylaryl having 1 to 3 heteroatoms, each of R 4 and R 5 being attached to each other.
R 6 is selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene, C 2-6 hydroxyalkylene, C 2-6 aminoalkylene, C 3-6 aminocycloalkylene, C 2-6 carboxyalkylene, C 3-6 cycloalkyl, C 3-6 aminocycloalkylene, C 1-6 amino (C 3-6 cycloalkyl) alkylene, 3-6 membered heterocyclyl, or 3-6 membered heterocyclylalkylene.
In another aspect of the present invention, there is further provided a process for the synthetic preparation of the following intermediate compound RM1 b-01:
In a further aspect the invention further provides a process for the synthetic preparation of the following compound SM2-01 and its use in the synthetic preparation of a compound of formula IIIb:
Reaction one:
reaction II:
in another aspect, the invention provides a compound of formula IIIb or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent and/or excipient.
In another aspect, the invention provides the use of a compound of formula IIIb or a composition thereof in the manufacture of a medicament for the prevention or treatment of a hematological disorder.
In another aspect, the present invention provides the use of a compound of formula IIIb or a composition thereof in the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from: pancreatic cancer, lung cancer, renal cancer, liver cancer, gastric cancer, cervical cancer, leukemia and other various cancer diseases.
Another aspect of the invention provides a combination product comprising a compound according to any one of formula IIIb or a compound according to claim 6, and an additional pharmaceutically active agent selected from the group consisting of: (1) an immunomodulator; (2) PD-1; (3) PD-L1; or (4) other compounds not belonging to the above-mentioned (1) to (3).
In a preferred embodiment, the additional pharmaceutically active agent is selected from the group consisting of: (1) an immunomodulator; (2) PD-1; (3) PD-L1; or (4) other compounds not belonging to the above-mentioned (1) to (3).
In the combination product of the present invention, the immunomodulator includes, but is not limited to, car-T or other immunomodulators.
In the above combination product of the present invention, the PD-1 comprises an active agent that is marketed or under clinical trials, including, but not limited to: opdivo, keytruda, JS001, SHR-1210, BGB-A317, ICI308, BAT1306, terlipressin Li Shan, or Xindi Li Shan.
In the above combination product of the invention, the PD-L1 comprises an active agent that is marketed or under clinical trials, including, but not limited to: recombinant fully human anti-PD-L1 monoclonal antibody injection, TECENTRIQ, BAVENCIO, LICTAYO, IMFINZI or an aclacindine soft capsule.
In preferred embodiments, the compounds or compositions of the invention are particularly useful in the treatment of cancer or related angiogenesis inhibition, prevention and treatment of hematological disorders. Meanwhile, compared with three similar control medicines, the compound provided by the invention has better multi-target selectivity and inhibition activity.
The above-described embodiments and other aspects of the invention will be apparent from the following detailed description. For this reason, various references are set forth herein that describe in more detail certain background information, processes, compounds, and/or compositions, and are each incorporated by reference in their entirety.
Detailed Description
In the following description, certain specific details are set forth in order to provide a thorough understanding of embodiments of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these details. Throughout the specification and claims of this specification, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to be open-ended, i.e. to be "including but not limited to", unless the context requires otherwise.
Reference in the specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
I. Definition of the definition
In the present invention, when not specifically specified, the term "alkyl" means a branched, straight-chain, monocyclic and polycyclic saturated alkane group containing 1 to 20 carbon atoms, which is composed of only carbon and hydrogen atoms. In a preferred embodiment, the alkyl group has one to twelve carbon atoms (C1C 12 alkyl), one to eight carbon atoms (C1C 8 alkyl) or one to six carbon atoms (C1C 6 alkyl) and is attached to the remainder of the molecule by a single bond. The alkyl group may be unsubstituted or substituted with one or more substituents. In some embodiments, the alkyl group comprises 1 to 9 carbon atoms (e.g., 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms). Exemplary alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, and various isomers thereof, and the like. The alkyl group, including one or more carbons thereof, may optionally be attached to one or more groups including, but not limited to: deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, amino (NH 2), amino, alkylamino, aminocarbonyl, alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkoxycarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkenyl, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclyl, alkylureido, aryl, aryloxy, heteroaryl, heterocycloaryloxy, fused ring aryl, fused ring heteroaryl, fused ring oxy, fused ring aryloxy, fused ring heterocycloaryloxy, arylureido, or heterocycloarylureido.
As used herein, "cycloalkyl" refers to a ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyl groups may include multiple fused rings. Carbocyclyl groups may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The carbocyclyl group may be unsubstituted or substituted with one or more substituents. In some embodiments, a carbocyclyl group contains 3 to 10 carbon atoms, for example 3 to 6 carbon atoms.
In the present invention, unless otherwise specified, "aryl" refers to any stable monocyclic, bicyclic, tricyclic, or tetracyclic ring that may contain up to 7 carbon atoms per ring, wherein at least one ring is an aromatic hydrocarbon ring system. Exemplary aryl groups are hydrocarbon ring system groups containing hydrogen and 6 to 9 carbon atoms and at least one aromatic ring; hydrocarbon ring system groups comprising hydrogen and 9-12 carbon atoms and at least one aromatic ring; hydrocarbon ring system groups comprising hydrogen and 12-15 carbon atoms and at least one aromatic ring; or a hydrocarbon ring system group comprising hydrogen and 15 to 18 carbon atoms and at least one aromatic ring. For the purposes of the present invention, aryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from the following constitution: benzene, biphenyl, anthracene, azulene, fluorene, indane, indene, naphthalene, phenanthrene, pyrene, and the like.
In the present invention, unless otherwise specified, the "heterocyclic group" is an aromatic or non-aromatic heterocyclic ring having 3 to 16 ring atoms, containing 1 to 3 (if monocyclic), 1 to 6 (if bicyclic), or 1 to 9 (if tricyclic or polycyclic) heteroatoms selected from one or more of O, N and S, or containing 0 to 3 carbon-carbon double bonds, and includes bicyclic and tricyclic fused ring groups. The "heterocyclic" moiety may contain 3 to 14 carbon atoms, for example 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "heterocycle" encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties, and heteroaromatic moieties. For example, the heterocyclic group may be ethylene oxide, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran. Thus, "heterocyclyl" includes the above-described heteroaryl groups, as well as dihydro or tetrahydro analogs thereof, and includes, but is not limited to, the following "heterocyclyl": benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazole, benzothiazolyl, benzothienyl, benzoxazolyl, isobenzofuranyl, pyridopyridyl, and heterocyclic groups may be linked to other small organic molecule groups through carbon or heteroatoms to form novel pharmaceutically effective compounds.
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
II Compounds of the invention
1) The invention firstly designs and introduces a novel polysubstituted arylamine and alkylamine functional group, and synthesizes a polysubstituted anilino urea compound which can more effectively treat diseases such as various tumors with abnormal proliferation of angiogenesis.
2) The present invention relates generally to compounds encompassed by formula IIIb, and cis-, trans-, enantiomer-, diastereomer-, racemate-, tautomer-, or pharmaceutically acceptable salts or hydrates thereof, as well as deuterated or other isotopically substituted compounds:
Wherein the definition of the compound ,E、G1、G2、G3、G4、G5、R1、R2、R3、X1、X2、X3、X4 of formula IIIb and the like is as defined in the claims and the specification. Specific embodiments of the compounds of formula IIIb are also described below.
3) The compounds of the present invention may exist in a variety of isomeric forms, as well as in one or more tautomeric forms, including two single tautomers, and mixtures of tautomers. The term "isomer" is intended to encompass all isomeric forms of the compounds of the present invention, including tautomeric forms of the compounds.
In this specification, a "pharmaceutically acceptable salt" is a pharmaceutically acceptable, organic or inorganic acid or base salt of a compound of the invention. Wherein a typical pharmaceutically acceptable salt is selected from, but not limited to, any one of the following acids or bases: the inorganic acid salt is mainly selected from hydrochloride, bromate, iodate, phosphate, sulfate, bicarbonate, bisulfate, borate or nitrate; the organic acid salt is mainly selected from acetate, benzoate, methanesulfonate, toluenesulfonate or valerate.
The compounds of the invention may be isotopically labeled in which one or more atoms are replaced by atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of formula IIIb include: isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, or chlorine. Examples of such isotopes are ：2H(D)、3H、11C、13C、14C、13N、15N、15O、17O、18O、18F、36Cl. these radiolabeled compounds, respectively, can be used to detect biodistribution, tissue concentration, and kinetics of transport and excretion from biological tissue, including subjects administered the labeled compounds. Labeled compounds are also useful in determining the effect, site or pattern of action of a treatment, as well as the binding affinity of a candidate therapeutic to a pharmacologically important target. Thus, certain radiolabeled compounds of formula IIIb are useful in drug and/or tissue distribution studies. The radioactive isotopes tritium, 3 H, and carbon-14, 14 C, are particularly useful for this purpose because they are easy to incorporate and detection means are readily available.
Substitution with heavy isotopes such as deuterium (D), i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life of deuterium-containing compounds). Substitution of deuterium for hydrogen energy reduces the dosage required to achieve therapeutic effects and thus may be preferred for use in a discovery or clinical setting.
Substitution of positron emitting isotopes (e.g., 11C,18F,15 O and 13 N) can afford labeled analogs of the compounds of the invention useful in Positron Emission Tomography (PET) studies, for example, for detecting substance receptor occupancy. Isotopically-labeled compounds of formula IIIb can be prepared generally by conventional techniques known to those skilled in the art or by analogous to those described in the preparations and examples section below, using suitable isotopically-labeling reagents.
Embodiments of the invention described herein are also intended to encompass in vivo metabolites of the compounds of formula IIIb. These products may originate, for example, from processes of oxidation, reduction, hydrolysis, amidation, esterification, etc., which are mainly due to the enzymatic activity of the compounds of the present invention after administration.
The invention also provides pharmaceutically acceptable salt forms of the compounds of formula IIIb. The scope of the present invention encompasses acid addition salts formed by contacting a pharmaceutically suitable acid with a compound of the present invention.
"Pharmaceutically acceptable acid addition salt" means: those salts that retain the properties of the bioavailable and free base, are not biologically or otherwise undesirable, and their formation employs mineral acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, and the like; and organic acids such as, but not limited to, acetic acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid, or valeric acid, and the like.
Crystallization generally yields solvates of the compounds of the present invention. The term "solvate" as used herein refers to: an aggregate comprising one or more molecules of a compound of the invention and one or more molecules of a solvent. The solvent may be water, in which case the solvate may be a hydrate. Or the solvent may be an organic solvent. Thus, the compounds of the present invention may exist in hydrated forms, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvate forms. The compounds of the invention may be true solvates, while in other cases the compounds of the invention may retain only adventitious water or a mixture of water plus some adventitious solvent.
III pharmaceutical composition
In one embodiment, the compound of formula IIIb is formulated in the form of a pharmaceutically acceptable composition comprising an amount of the compound of formula IIIb effective to treat the particular disease or condition of interest after administration of the pharmaceutical composition to a mammal. The pharmaceutical compositions of the present invention may comprise a compound of formula IIIb in combination with a pharmaceutically acceptable carrier, diluent or excipient.
Therapeutic application
The compounds of the invention, or pharmaceutically acceptable salts thereof, may also be administered prior to, concurrently with, or after the administration of one or more other therapeutic agents. Such combination therapies include the administration of a single pharmaceutical dosage formulation comprising a compound of the invention and one or more other active agents, as well as the administration of the compound of the invention and each active agent in separate pharmaceutical dosage formulations.
The invention has the positive progress effects that:
1) The invention optimizes and synthesizes some novel urea compounds of formula IIIb of tyrosine kinase (RTK) inhibitor from urea anticancer medicine structure, and for several important RTK targets (such as: VEGFR1, VEGFR2 (KDR), VEGFR3, FGFR2, RET, etc.) have better inhibitory effect.
2) Some novel IIIb urea compounds of the invention are useful for a variety of tumor cell lines [ e.g.: pancreatic cancer (BXPC 3), lung cancer (A549), kidney cancer (Caki-1), liver cancer (Hep 3B 2.1-7), gastric cancer (SNU 16), cervical cancer (Hela), leukemia (K562) and the like) have better inhibition effect, can be used as a targeting drug for effectively treating some tumors or related cancers generated by the mediation of RTK kinase, and has better RTK targeting selectivity and safety.
3) Some novel formula IIIb ureas of the present invention have better safety, for example: the compounds IIIb-08, IIIb-09, IIIb-45, IIIb-50, IIIb-55, IIIb-56, IIIb-57, IIIb-58, IIIb-60, IIIb-61, IIIb-65 not only have a MTD toxic dose (QD) of greater than 150mg/kg, but also have a potassium channel safety parameter hERG >30uM (the MTD toxic dose of rats with lenvartinib is 40mg/kg, hERG=11.9 uM).
Detailed Description
The English abbreviations and notes of chemical reagents and solvents in the process of synthesizing novel polysubstituted aniline serving as an innovation key point are summarized in the instrument and raw material description part in the examples.
All the raw materials (e.g., SM1, SM2, SM3, SM 4), reagents, solvents, etc., used in the present invention can be commercially available or ordered.
In the present invention, the synthetic reaction routes, methods and conditions involved in preparing each new compound of formula IIIb are all conventionally known in the art, and according to the synthetic preparation methods disclosed in the present invention, those skilled in the art can prepare each specific compound involved in each compound of formula according to the same principles and methods as those described in the present invention.
The invention will be described in further detail by way of examples, which are not intended to limit the scope of the invention. The experimental procedures, which are not specifically identified in the examples below, were carried out according to conventional well-known methods and conditions, or according to the commercial specifications.
In the present invention, the synthetic reaction routes, methods and conditions involved in preparing each new compound of formula IIIb are all conventional routes, methods and conditions in the art, and according to the synthetic preparation methods disclosed in the present invention described below, those skilled in the art can use the same principle and method as the above to prepare each specific compound involved in each compound of formula IIIb in the present invention (see compounds IIIb-01 to IIIb-65 in the structural formula series of formula IIIb in table 6 in detail below) by selecting different reagents such as SM1 (table 1), SM2 (table 2), SM3 (table 4 a), SM4 (table 4 b) and the like, respectively, according to the conventional synthetic methods shown in the following synthetic reaction scheme 1.
English abbreviations and comments of chemical reagents and solvents in the process of synthesizing the novel polysubstituted aryl urea compounds are summarized in the instrument and raw material description parts in the examples.
The invention optimizes the following three methods for synthesizing the compounds of the formula IIIb series through researches on reaction conditions related to synthesis.
The synthesis method 1 comprises the following steps: synthesis of Compounds of formula IIIb
In the above synthetic method 1, R 4、R5 and R 6 are each as defined for R 4、R5 and R 6 in claims 1 to 5, respectively; r 4 and R 5 are connected with each other or form a 3-8 membered heterocyclic group or heterocyclic aryl group containing 1-3 hetero atoms; the specific synthetic reaction implementation steps are as follows:
1.1, synthesis of intermediate RM 1:
To a 50mL single-necked flask, SM1 (1.0 eq), SM2 (13 mmol), potassium tert-butoxide (1.0-1.5 eq) and DMSO (7-10X) were added, and the mixture was reacted at 85℃under nitrogen atmosphere, after which the reaction mixture was worked up by HPLC, purified by column chromatography and dried to give intermediate RM1.
1.2, Synthesis of intermediate RM 2:
to a 100mL three-necked flask, intermediate RM1 (1.0 eq), DMF (5 x) and pyridine (5.0 x) were added, the ice-water bath was controlled at not more than 10 ℃, phenyl chloroformate (5.0 eq) was added dropwise, the reaction was carried out at room temperature after the completion of the dropwise addition, and after the completion of the HPLC display reaction, the reaction solution was worked up, purified by column chromatography and dried to obtain intermediate RM2.
1.3 Synthesis of intermediate RM 3:
intermediate RM2 (1.0 eq) and reagent SM3 (1.0-5.0 eq) are added into a round bottom reaction bottle, pyridine (1.0-5.0 eq) is dissolved in DMF (5-10 x), and the mixture reacts at 20-80 ℃ until HPLC shows that the reaction is finished, and then the intermediate RM3 is obtained after the conventional operations of post-treatment, column chromatography purification, drying and the like.
1.4 Synthesis of intermediate RM 4:
Intermediate RM3 (1.0 eq) and THF (2-10×), meOH (2-10×) and sodium hydroxide (2.0-10.0 eq) were added to a round bottom reaction flask and reacted at 20-80 ℃ until HPLC showed the end of the reaction, after adjusting the pH to about 6 with 3N-HCl, a solid product precipitated, and intermediate RM4 was obtained by conventional procedures such as filtration, purification, drying, and the like.
1.5, Synthesis of a target product IIIb:
Intermediate RM4-02 (1.0 eq), DMF (2-10 x), HATU (1.0-2.0 eq) and reagent SM4 (1.0-2.0 eq) are added into a round bottom reaction bottle, DIEA (1.0-2.0 eq) is dripped into the bottle at 20-40 ℃, and after the reaction is finished, the HPLC shows that the target product of the formula IIIb is obtained through the conventional operations of post-treatment, column chromatography purification, drying and the like.
The synthesis method 2 comprises the following steps: synthesis of Compounds of formula IIIb
In the above synthetic method 2, R 4、R5 and R 6 are each as defined for R 4、R5 and R 6 in claims 1 to 5, respectively; r 4 and R 5 are connected with each other or form a 3-8 membered heterocyclic group or heterocyclic aryl group containing 1-3 hetero atoms; the specific synthetic reaction implementation steps are as follows:
2.1 synthesis of intermediate RM 1b:
2.1-1, SM2 and pyridine (4 eq) obtained above were added to DMF (5 x) solvent in a round bottom flask, phenyl chloroformate (3.0 eq) was added dropwise at a temperature below 10℃and reacted at room temperature after the addition was completed. HPLC shows that after the reaction is finished, the RM2b intermediate is obtained after the conventional operations of post-treatment, column chromatography purification, drying and the like.
2.1-2, Dissolving the obtained intermediate RM2b, a reagent SM3 (3 eq) and pyridine (3 eq) in MeCN (20 x) in a round bottom reaction bottle, reacting at 60-80 ℃, waiting until the reaction is finished by HPLC, and obtaining an RM1b product after the conventional operations of post-treatment, column chromatography purification, drying and the like.
2.2, Synthesizing a target product IIIb:
RM1b (1.0 eq) and SM1 (1-1.5 eq) obtained above, potassium tert-butoxide (1.5 eq) were added to DMSO (10X) in a round bottom flask and reacted at 80-100 ℃. After the reaction is finished, the HPLC shows that the target product of the formula IIIb is obtained through post-treatment, column chromatography purification and drying.
TABLE 1 raw material SM1 Structure
TABLE 2 Structure of raw Material SM2
TABLE 3A structural formula of the first substituted etherification reaction product "RM1" series in Synthesis method one
TABLE 3b structural formula of the second coupling reaction product "RM2" series in Synthesis method one
TABLE 3c reaction product "RM3" series of structural formulas
TABLE 3d fourth step ester hydrolysis reaction product of Synthesis method one "RM4" series of structural formulas
TABLE 3e structural formula of the first step of the Synthesis method III to give the urea reaction product "RM1b" series
TABLE 4 raw materials SM3 series Structure
TABLE 4 raw materials SM4 series Structure
TABLE 5 formula IIIb polysubstituted aryl urea compounds
In addition to the compounds IIIb-01 to IIIb-65 prepared in the corresponding examples 1 to 65, some deuterated reagents in which one or more hydrogens of SM1 (Table 1), SM2 (Table 2), SM3 (Table 4 a) and SM4 (Table 4 b) are replaced by deuterium isotopes can be synthesized according to the above synthesis methods, and some compounds in which some "H" of the compounds in the following Table 5a are replaced by deuterium (D) isotopes (e.g., ：IIIb-66、IIIb-67、IIIb-68、IIIb-69、IIIb-70、IIIb-71、IIIb-72、IIIb-73、IIIb-74、IIIb-75、IIIb-76、IIIb-77、IIIb-78、IIIb-79、IIIb-80、IIIb-81、IIIb-82、IIIb-83、IIIb-84、IIIb-85、IIIb-86、IIIb-87、IIIb-88、IIIb-89) or compounds in which some or all hydrogens (H) of the compounds in the formula IIIb are replaced by deuterium (D) isotopes) can be synthesized under the protection of a safety device.
TABLE 5 Structure of deuterated isotopic Compounds of the polysubstituted aryl ureas of formula IIIb
Specifically, the synthesis and analysis results of each novel structural compound of formula IIIb are shown in the final examples of the present invention, and the structural characterization of each compound is determined by LC-MS and/or nuclear magnetic resonance (1 H-NMR, and/or 19 F-NMR) analysis, respectively.
The synthesis and effect of various intermediates and compounds of the present invention are illustrated by the following examples.
The instruments and raw materials involved in the examples are described below:
nuclear magnetic resonance (hydrogen spectrum and fluorine spectrum) is analyzed by an Assetnd 400m nuclear magnetic resonance apparatus manufactured by Bruker company. Chemical shifts were recorded using tetramethylsilane as an internal standard, and were expressed in ppm using deuterated DMSO, meOH, and other solvents for nuclear magnetic analysis (CDCl 3: δ=7.26 ppm). The recorded data information is as follows: chemical shift, fragmentation and coupling constants (s: singlet; d: doublet; t: triplet; q: quartet; br: broad; m: multiplet).
Mass spectral data was analyzed using a liquid phase 1260 produced by Agilent corporation in combination with mass spectrum 6120. The molecular weight of the compounds of formula IIIb in the present invention is predominantly in cationic mode ESI-MS [ (M+H) + ].
In the present invention, the specific raw materials and intermediates involved are provided by custom processing by Shanghai Zan nan technology Co., ltd, and all other chemical reagents are purchased from reagent suppliers such as Shanghai reagent company, aldrich company, acros company, etc. If the intermediates or products required for the reaction in the synthesis are not sufficient for the next step or the like, the synthesis is repeated a plurality of times until a sufficient number. The activity test and pharmacological and toxicological tests of the compound prepared by the invention are completed by CRO service companies in Shanghai, beijing and other places according to industry regulations.
The English abbreviations related to the chemical raw materials, reagents and solvents in the present invention and examples thereof are as follows:
Boc t-Butoxycarbonyl group
(Boc) 2 O: di-tert-butyl dicarbonate
CDI: n, N' -carbonyldiimidazole
DBU:1, 8-diazabicyclo [5.4.0] undec-7-ene
EDCI: N-ethyl-N' -3-dimethylaminopropyl) carbodiimide hydrochloride
HATU:2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate
NBS: n-bromosuccinimide
NCS: n-chlorosuccinimide
SOCl 2: thionyl chloride
Pd/C: palladium carbon
DIEA: n, N-diisopropylethylamine
DMAP: 4-dimethylaminopyridine
HMTA: hexamethylene tetramine
Py: pyridine compound
HBr: hydrobromic acid
HCl: hydrochloric acid
HOAc: glacial acetic acid
TFA: trifluoroacetic acid
MsOH: methanesulfonic acid
TsOH: para-toluene sulfonic acid
Cs 2CO3 cesium carbonate
TBuOK potassium tert-butoxide
KOH potassium hydroxide
NaOH: sodium hydroxide
LiOH: lithium hydroxide
ACN/MeCN: acetonitrile
DCM: dichloromethane (dichloromethane)
DCE: dichloroethane (dichloroethane)
DMF: n, N-dimethylformamide
DMSO: dimethyl sulfoxide
Et 2 O: diethyl ether
EA: acetic acid ethyl ester
PE: petroleum ether
THF: tetrahydrofuran (THF)
TBME: methyl tert-butyl ether
Me methyl radical
Et: ethyl group
Pr-propyl radical
IPr isopropyl group
CPr cyclopropyl
Ph phenyl group
According to the above-described related synthetic methods, the key trihaloaminophenol compounds SM2-01 and the series of compounds IIIb-01 to IIIb-65 of the present invention are synthesized, respectively:
Example 1
Synthesis of compound SM 2-01:
the synthesis method of SM2-01 comprises the following steps:
Preparation of diazonium salt of sulfanilic acid: to a 1L three-necked flask, sulfanilic acid (60 g,1.00 eq), water (500 mL) and Na2CO3 (20.0 g) were added, stirred until the mixture became clear, a solution of NaNO2 (25.0 g) in water (75 mL) was added dropwise at an internal temperature of 0℃and, after the completion of the dropwise addition, concentrated hydrochloric acid (86 mL) was added dropwise at an internal temperature of <5℃and stirred for 40 minutes (refrigerated standby).
3-Chloro-2, 6-difluorophenol (44.2 g), water (516.0 g), aqueous NaOH (5 mol/L,70 mL) and Na2CO3 (27.6 g) are added into a 1L three-port reaction bottle, when the ice water bath is cooled to 0-5 ℃, a diazonium salt solution of sulfanilic acid is dripped into the bottle, after the dripping is finished, concentrated hydrochloric acid is added to adjust the PH to 5.0 after the reaction is finished, ammonium formate (108.0 g) is added, zn powder (65.0 g) is added, and the mixture is reacted at room temperature. To the end of the reaction, EA (1.0L) was added, stirred, filtered, the filtrate extracted with EA (500 m×2), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, dichloromethane (120 mL) was added, stirred, filtered, dried to give the product 4-amino-3-chloro-2, 6-difluorophenol (SM 2-01, 40.0 g), yield: 83%.
NMR analysis confirmed that nuclear magnetic resonance hydrogen spectrum data of product SM2-01 hydrochloride: 1H NMR (400 MHz, d 4CD3 OD) δ:7.30/7.273 (m, 1H).
Nuclear magnetic resonance carbon spectrum data of product SM2-01 hydrochloride: 13C-NMR (100 MHz, d4CD3 OD) δ:153.51 (m), 151.95 (m), 137.45 (m), 120.98 (m), 113.68 (m), 109.00 (m).
Nuclear magnetic resonance fluorine spectrum data of product SM2-01 hydrochloride: 19F-NMR (377MHz, d4CD3 OD) δ: -132.36/-132.40/-133.09/-133.13.
The ESI-MS [ (M+H) + ] of the product SM2-01 is confirmed by mass spectrometry: theoretical m/z value: 180.0, found: 180.1.
The synthesis method of SM2-01 is as follows:
3-chloro-2, 6-difluorophenol (1000 g) and DCM (4L) are added into a 10.0L three-port reaction bottle, stirred and dissolved in an ice water bath, cooled to 0 ℃, concentrated nitric acid (600 g) is added dropwise, the temperature is controlled to be less than 10 ℃, the dropwise addition is completed, the stirring is completed, water (2.0L) is added, the stirring is carried out for 0.5 hour, liquid separation is carried out, filtrate is coarsely removed by DCM (2.0L multiplied by 2), organic phases are combined, water washing and concentration are carried out, and 1.35kg of 3-chloro-2, 6-difluoro-4-nitrophenol is obtained.
To a 10.0L three-necked flask, 3-chloro-2, 6-difluoro-4-nitrophenol (665 g) and water (5.0L) were added, and the mixture was heated to 85℃and iron powder (500.0 g) was slowly added thereto, and concentrated hydrochloric acid (100 mL) was added dropwise while controlling the internal temperature to not higher than 95 ℃. After completion of the dropwise addition of iron powder (40.0 g) was added and cooled to below 40 ℃, EA (2.5L) was added, stirred and filtered, the filtrate was extracted with EA, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, DCM (600 mL) was added, stirred, filtered and dried to give the product 4-amino-3-chloro-2, 6-difluorophenol (SM 2-01, 393 g), two steps total yield: 72%.
NMR analysis confirmed that nuclear magnetic resonance hydrogen spectrum data of product SM 2-01: 1H NMR (400 MHz, d4CD3 OD) δ:7.30/7.273 (m, 1H).
The ESI-MS [ (M+H) + ] of the product SM2-01 is confirmed by mass spectrometry: theoretical m/z value: 180.0, found: 180.1.
Nuclear magnetic resonance and mass spectrometry analysis confirm that the two synthesis methods can reliably obtain the key trihalogenated amino phenol compound SM2-01 in the innovation of the invention.
Example 2
Synthesis of Compound IIIb-01:
according to the method shown in the synthesis method I
The first step:
to a 50mL single-necked flask, SM1-01 (2.52 g,10 mmol), SM2-01 (2.34 g,13 mmol), potassium tert-butoxide (1.46 g,13 mmol) and DMSO (20 mL) were added, and the mixture was reacted at 85℃under nitrogen protection, after the reaction was completed, the reaction mixture was cooled to room temperature and slowly poured into 100mL of ice water to precipitate a solid, and the solid was filtered, washed with water and dried sufficiently to obtain intermediate RM1-23 (3.28 g), yield: 83%;
and a second step of:
To a 100mL three-necked flask, adding intermediate RM1-23 (3.95 g,10 mmol), DMF (20 mL) and pyridine (30 mmol), controlling ice-water bath at not more than 10 ℃, dropping phenyl chloroformate (30 mmol) at room temperature, after dropping, reacting at room temperature, after HPLC showing the end of the reaction, cooling the reaction liquid slowly into 100mL water, precipitating solid, filtering, washing the filter cake with water, drying, purifying by column chromatography to obtain intermediate RM2-23 (3.45 g), yield: 67%;
and a third step of:
To a 100mL single-necked flask, intermediate RM2-23 (5.15 g,10 mmol), meCN (50 mL) and SM3-01 (30 mmol) were added, and the reaction was carried out at 60℃to give a solid product RM3-01 (2.91 g) after the completion of the reaction, which was obtained by separating out a solid by HPLC, filtering, washing and drying, and purifying by column chromatography, yield: 61%.
Fourth step:
to a 100mL single-necked flask, intermediate RM3-01 (4.78 g,10 mmol), THF (10 mL), meOH (10 mL), and sodium hydroxide (30 mmol) were added and reacted at 40℃to give a solid product RM4-01 (3.94 g) after the reaction was completed and the pH was adjusted to about 6 by 3N-hydrochloric acid, followed by precipitation, filtration, washing and drying, yield: 85%.
Fifth step:
To a 100mL single-necked flask, intermediate RM4-01 (460 mg,1.0 mmol), DMF (5 mL), HATU (1.3 mmol) and SM4-01 (1.5 mmol) were added dropwise, DIEA (3.0 mmol) was added dropwise, the reaction was carried out at 20℃and after the completion of the reaction, water was added to precipitate a solid, which was filtered, washed and dried, and then purified by column chromatography to give a solid product IIIb-01 (386 mg), yield: 81%.
Analysis confirmed that 1H NMR of Compound IIIb-01 (400 MHz, DMSO+1.0eq methanesulfonic acid )δ：9.06-9.05(d,1H),8.68(s,1H),8.54(m,1H),8.43(s,1H),8.36-8.32(dd,1H),7.69(s,1H),7.48(d,1H),7.33-7.31(d,1H),4.09(s,3H),2.85-2.84(d,3H),2.61(m,1H),2.39(s,3H),0.70-0.69(m,2H),0.46(m,2H).
ESI-MS [ (M+H) + ] of Compound IIIb-01, confirmed by mass spectrometry: theoretical m/z value: 477.1, found: 477.2.
Example 3
Synthesis of Compound IIIb-02:
the method is carried out according to a method shown in a first synthesis method:
the first step: to a 50mL single-necked flask, SM1-01 (2.52 g,10 mmol), SM2-01 (2.12 g,13 mmol), potassium tert-butoxide (1.46 g,13 mmol) and DMSO (20 mL) were added, and the mixture was reacted at 85℃under nitrogen protection, after the reaction was completed, the reaction mixture was cooled to room temperature and slowly poured into 100mL of ice water to precipitate a solid, and the solid was filtered, washed with water and dried sufficiently to obtain intermediate RM1-24 (2.95 g), yield: 78%;
And a second step of: to a 100mL three-necked flask, adding intermediate RM1-24 (3.78 g,10 mmol), DMF (20 mL) and pyridine (30 mmol), controlling ice-water bath at not more than 10 ℃, dropping phenyl chloroformate (30 mmol) at room temperature, after dropping, reacting at room temperature, after HPLC showing the end of the reaction, cooling the reaction liquid slowly into 100mL water, precipitating solid, filtering, washing the filter cake with water, drying, purifying by column chromatography to obtain intermediate RM2-24 (3.64 g), yield: 73%;
And a third step of: to a 100mL single-necked flask, intermediate RM2-24 (4.98 g,10 mmol), meCN (50 mL) and SM3-01 (30 mmol) were added, and the reaction was carried out at 60℃to give a solid product RM3-02 (2.63 g) after the completion of the reaction, which was obtained by separating out a solid by HPLC, filtering, washing and drying, and purifying by column chromatography, yield: 57%.
Fourth step: to a 100mL single-necked flask, intermediate RM3-02 (4.61 g,10 mmol), THF (10 mL), meOH (10 mL), and sodium hydroxide (30 mmol) were added to react at 40℃and after the reaction was completed, HPLC showed that a solid was precipitated after adjusting the pH to about 6 with a dilute acid, filtered, washed and dried to give a solid product RM4-02 (3.53 g), yield: 79%.
Fifth step: to a 100mL single-necked flask, intermediate RM4-02 (447 mg,1.0 mmol), DMF (5 mL), HATU (1.3 mmol) and SM4-01 (1.5 mmol) were added dropwise to react at 20℃with DIEA (3.0 mmol), and after HPLC showed the completion of the reaction, water was added to precipitate a solid, which was filtered, washed and dried to give a solid product IIIb-02 (308 mg) which was purified by column chromatography in the yield: 67%.
ESI-MS [ (M+H) + ] of Compound IIIb-02, confirmed by mass spectrometry: theoretical m/z value: 461.1, found: 461.2.
Example 4
Synthesis of Compound IIIb-03:
the method is carried out according to a method shown in a first synthesis method:
the synthesis procedure for the preparation of compound IIIb-03 was the same as in example 2, wherein compound SM4-02 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-03 (329 mg), yield: 67%.
ESI-MS [ (M+H) + ] of Compound II1-03, confirmed by mass spectrometry: theoretical m/z value: 491.1, found: 491.1.
Example 5
Synthesis of Compound IIIb-04:
the method is carried out according to a method shown in a first synthesis method:
The synthetic method for preparing compound IIIb-04 was the same as in example 2, wherein compound SM4-03 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up, and purified by column chromatography to give solid product IIIb-04 (345 mg), yield: 68%.
ESI-MS [ (M+H) + ] of Compound IIIb-04, confirmed by mass spectrometry: theoretical m/z value: 505.1, found: 505.0.
Example 6
Synthesis of Compound IIIb-05
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-05 was the same as in example 2, wherein compound SM4-11 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up, and purified by column chromatography to give solid product IIIb-05 (401 mg), yield: 77%.
Analysis confirmed that 1H NMR of Compound IIIb-05 (400 MHz, DMSO+1.0eq methanesulfonic acid )δ：8.97(m,1H),8.78-8.75(t,1H),8.63(s,1H),8.41(s,1H),8.36-8.32(dd,1H),7.63(s,1H),7.46-7.45(d,1H),7.19(m,1H),4.65-4.63(t,1H),4.54-4.51(t,1H),4.07(s,3H),3.68-3.64(t,1H),3.62-3.58(t,1H),2.61(m,1H),2.33(m,3H),0.72-0.67(m,2H),0.45(m,2H).
Analysis confirmed that 19F NMR (377MHz, DMSO+1.0eq methanesulfonic acid) of compound IIIb-05, δ: -126.67(s), -127.72(s).
ESI-MS [ (M+H) + ] of Compound IIIb-05, confirmed by mass spectrometry: theoretical m/z value: 521.1, found: 521.2.
Example 7
Synthesis of Compound IIIb-06
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-06 is the same as in example 2, wherein compound SM4-04 (1.5 mmol) is used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which is dried by the same work-up, and purified by column chromatography to give solid product IIIb-06 (407 mg), yield: 80%.
ESI-MS [ (M+H) + ] of Compound IIIb-06, confirmed by mass spectrometry: theoretical m/z value: 509.1, found: 509.1.
Example 8
Synthesis of Compound IIIb-07
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-07 was the same as in example 3, wherein compound SM4-05 (1.5 mmol) was used in the fifth reaction step to react with intermediate RM4-02 to form an amide bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-07 (424 mg), yield: 83%.
Analysis confirmed that 1H NMR of Compound IIIb-07 (400 MHz, DMSO+1.0eq methanesulfonic acid )δ：9.12-9.10(d,1H),8.98-8.95(t,1H),8.85(s,1H),8.67(s,1H),8.25-8.22(m,1H),7.72(s,1H),7.39-7.37(d,1H),7.03(m,1H),6.33-6.05(m,1H),4.09(s,3H),3.79-3.70(m,2H),2.61(m,1H),2.39(s,3H),0.68-0.65(m,2H),0.46-0.42(m,2H).
Analysis confirmed that 19F NMR of compound IIIb-07 (377MHz, DMSO+1.0eq methanesulfonic acid) δ: -121.56(s), -132.15(s), -132.18(s), -150.58(s), -150.64(s).
ESI-MS [ (M+H) + ] of Compound IIIb-07 as confirmed by mass spectrometry: theoretical m/z value: 511.1, found: 511.1.
Example 9
Synthesis of Compound IIIb-08
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-08 was the same as in example 2, wherein compound SM4-05 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up, and purified by column chromatography to give solid product IIIb-08 (453 mg), yield: 86%.
Analysis shows that the compound IIIb-08 1H NMR(400MHz,DMSO)δ：8.82-8.79(t,J＝6.0Hz,1H),8.72-8.71(d,J＝5.3Hz,1H),8.60(s,1H),8.36(s,1H),8.32-8.28(dd,1H),7.59(s,1H),7.43-7.42(d,1H),6.78-6.77(d,J＝5.3Hz,1H),6.33-6.05(tt,1H),4.04(s,3H),3.79-3.70(m,2H),2.61(m,1H),0.70-0.67(m,2H),0.45(m,2H).
Analysis confirmed that 19F NMR (377MHz, DMSO). Delta.) of compound IIIb-08: -121.62(s), -127.11 (m), -127.88(s).
ESI-MS [ (M+H) + ] of Compound IIIb-08, confirmed by mass spectrometry: theoretical m/z value: 527.1, found: 527.1.
Example 10
Synthesis of Compound IIIb-09
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-09 was the same as in example 2, wherein compound SM4-06 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up, and purified by column chromatography to give solid product IIIb-09 (441 mg), yield: 81%.
Analysis shows that the compound IIIb-09 1H NMR(400MHz,DMSO)δ：9.04-9.01(t,1H),8.73-8.72(d,J＝5.2Hz,1H),8.53(s,1H),8.35(s,1H),8.32-8.28(dd,1H),7.60(s,1H),7.43(d,1H),6.79-6.77(d,J＝5.2Hz,1H),4.18-4.13(m,2H),4.03(s,3H),2.61(m,1H),0.70-0.68(m,2H),0.45(m,2H).
Analysis confirmed that 19F NMR (377MHz, DMSO). Delta.) of compound IIIb-09: -70.29(s), -127.07/-127.08 (d), -127.84(s).
ESI-MS [ (M+H) + ] of Compound IIIb-09, confirmed by mass spectrometry: theoretical m/z value: 545.1, found: 545.1.
Example 11
Synthesis of Compound IIIb-10
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-10 is the same as in example 2, wherein compound SM4-07 (1.5 mmol) is used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, and after the same post-treatment drying, the solid product IIIb-10 (368 mg) is purified by column chromatography to obtain the yield: 69%.
ESI-MS [ (M+H) + ] of Compound IIIb-10, confirmed by mass spectrometry: theoretical m/z value: 534.2, found: 534.1.
Example 12
Synthesis of Compound IIIb-11
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-11 is the same as in example 3, wherein compound SM4-08 (1.5 mmol) is used in the fifth reaction to react with intermediate RM4-02 to form an amide bond product, which is dried by the same work-up, and purified by column chromatography to give solid product IIIb-11 (424 mg), yield: 87%.
ESI-MS [ (M+H) + ] of Compound IIIb-11, confirmed by mass spectrometry: theoretical m/z value: 487.2, found: 487.2.
Example 13
Synthesis of Compound IIIb-12
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-12 is the same as in example 2, wherein compound SM4-08 (1.5 mmol) is used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which is dried by the same work-up, and purified by column chromatography to give solid product IIIb-12 (392 mg), yield: 78%.
ESI-MS [ (M+H) + ] of Compound IIIb-12, confirmed by mass spectrometry: theoretical m/z value: 503.1, found: 503.1.
Example 14
Synthesis of Compound IIIb-13
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-13 was the same as in example 2, wherein compound SM4-09 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up, and purified by column chromatography to give solid product IIIb-13 (402 mg), yield: 74%.
ESI-MS [ (M+H) + ] of Compound IIIb-13, confirmed by mass spectrometry: theoretical m/z value: 543.2, found: 543.0.
Example 15
Synthesis of Compound IIIb-14
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-14 was the same as in example 2, wherein compound SM4-10 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up, and purified by column chromatography to give solid product IIIb-14 (317 mg), yield: 63%.
ESI-MS [ (M+H) + ] of Compound IIIb-14, confirmed by mass spectrometry: theoretical m/z value: 503.1, found: 503.0.
Example 16
Synthesis of Compound IIIb-15
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-15 is the same as in example 3, wherein compound SM4-12 (1.5 mmol) is used in the fifth reaction to react with intermediate RM4-02 to form an amide bond product, which is dried by the same work-up, and purified by column chromatography to give solid product IIIb-15 (236 mg), yield: 48%.
ESI-MS [ (M+H) + ] of Compound IIIb-15, confirmed by mass spectrometry: theoretical m/z value: 491.1, found: 491.3.
Example 17
Synthesis of Compound IIIb-16
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-16 was the same as in example 2, wherein compound SM4-12 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide-bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-16 (294 mg), yield: 58%.
ESI-MS [ (M+H) + ] of Compound IIIb-16, confirmed by mass spectrometry: theoretical m/z value: 507.1, found: 507.1.
Example 18
Synthesis of Compound IIIb-17
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-17 is the same as in example 2, wherein compound SM4-13 (1.5 mmol) is used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, and after drying by the same work-up, the solid product IIIb-17 (245 mg) is purified by column chromatography to give the yield: 47%.
ESI-MS [ (M+H) + ] of Compound IIIb-17, confirmed by mass spectrometry: theoretical m/z value: 521.1, found: 521.2.
Example 19
Synthesis of Compound IIIb-18
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-18 is the same as in example 2, wherein compound SM4-14 (1.5 mmol) is used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which is dried by the same work-up, and purified by column chromatography to give solid product IIIb-18 (422 mg), yield: 81%.
Analysis shows that the compound IIIb-18 1H NMR(400MHz,DMSO)δ：8.71-8.69(d,J＝5.2Hz,1H),8.57(s,1H),8.35(s,1H),8.32-8.28(dd,1H),8.26-8.24(d,1H),7.56(s,1H),7.43-7.42(d,1H),6.76-6.75(d,J＝5.2Hz,1H),4.85(m,1H),4.03(m,4H),3.45(m,1H),3.42(m,1H),2.60(m,1H),1.18-1.16(d,J＝6.6Hz,3H),0.70(m,2H),0.45(m,2H).
Analysis confirmed that 19F NMR (377MHz, DMSO). Delta.) of compound IIIb-18: -127.09/127.10 (d), -127.84(s).
ESI-MS [ (M+H) + ] of Compound IIIb-18, confirmed by mass spectrometry: theoretical m/z value: 521.1, found: 521.2.
Example 20
Synthesis of Compound IIIb-19
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-19 was the same as in example 2, wherein compound SM4-15 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide-bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-19 (305 mg), yield: 57%.
ESI-MS [ (M+H) + ] of Compound IIIb-19, confirmed by mass spectrometry: theoretical m/z value: 535.1, found: 535.2.
Example 21
Synthesis of Compound IIIb-20
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-20 was the same as in example 2, wherein compound SM4-16 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up, and purified by column chromatography to give solid product IIIb-20 (242 mg), yield: 45%.
ESI-MS [ (M+H) + ] of Compound IIIb-20, confirmed by mass spectrometry: theoretical m/z value: 537.1, found: 537.2.
Example 22
Synthesis of Compound IIIb-21
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-21 was the same as in example 2, wherein compound SM4-17 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up, and purified by column chromatography to give solid product IIIb-21 (295 mg), yield: 55%.
Analysis shows that the compound IIIb-21 1H NMR(400MHz,DMSO)δ：8.72-8.70(d,J＝5.2Hz,1H),8.69(s,1H),8.51(t,1H),8.35(s,1H),8.32-8.28(dd,1H),7.59(s,1H),7.46(d,1H),6.77(d,J＝5.2Hz,1H),4.95(d,1H),4.68(t,1H),4.05(s,3H),3.67-3.66(m,1H),3.48(m,1H),3.42-3.37(m,2H),3.31-3.28(m,2H),2.61(m,1H),0.70-0.68(m,2H),0.45(m,2H).
The mass spectrometry confirmed that 19F NMR (377MHz, DMSO). Delta.) of compound IIIb-21: -127.10/127.11 (d), -127.86(s).
Analysis confirmed that ESI-MS [ (M+H) + ] of Compound IIIb-21: theoretical m/z value: 537.1, found: 537.2.
Example 23
Synthesis of Compound IIIb-22
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-22 was the same as in example 2, wherein compound SM4-18 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up, and purified by column chromatography to give solid product IIIb-22 (258 mg), yield: 48%.
As confirmed by mass spectrometry, compound IIIb-22 1H NMR(400MHz,DMSO)δ：8.72-8.71(d,J＝5.3Hz,1H),8.69(s,1H),8.51(t,1H),8.36(s,1H),8.32-8.28(dd,1H),7.59(s,1H),7.46(d,1H),6.77-6.76(d,J＝5.3Hz,1H),4.95(d,1H),4.68(t,1H),4.05(s,3H),3.67-3.66(m,1H),3.48(m,1H),3.42-3.37(m,2H),3.31-3.28(m,2H),2.61(m,1H),0.70-0.68(m,2H),0.45(m,2H).
The mass spectrometry confirmed that 19F NMR (377MHz, DMSO). Delta.) of compound IIIb-22: -127.10/127.11 (d), -127.86(s).
ESI-MS [ (M+H) + ] of Compound IIIb-22, confirmed by mass spectrometry: theoretical m/z value: 537.1, found: 537.2.
Example 24
Synthesis of Compound IIIb-23
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-23 is the same as in example 2, wherein compound SM4-19 (1.5 mmol) is used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which is dried by the same work-up, and purified by column chromatography to give solid product IIIb-23 (219 mg), yield: 41%.
ESI-MS [ (M+H) + ] of Compound IIIb-23, confirmed by mass spectrometry: theoretical m/z value: 533.1, found: 533.2.
Example 25
Synthesis of Compound IIIb-24
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-24 was the same as in example 2, wherein compound SM4-20 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up, and purified by column chromatography to give solid product IIIb-24 (296 mg), yield: 57%.
ESI-MS [ (M+H) + ] of Compound IIIb-24, confirmed by mass spectrometry: theoretical m/z value: 519.1, found: 519.2.
Example 26
Synthesis of Compound IIIb-25
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-25 was the same as in example 2, wherein compound SM4-21 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up, and purified by column chromatography to give solid product IIIb-25 (277 mg), yield: 52%.
ESI-MS [ (M+H) + ] of Compound IIIb-25, confirmed by mass spectrometry: theoretical m/z value: 533.1, found: 533.2.
Example 27
Synthesis of Compound IIIb-26
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-26 is the same as in example 2, wherein compound SM4-22 (1.5 mmol) is used in the fifth reaction to react with intermediate RM4-01 to form an amide-bond product, which is dried by the same work-up, and purified by column chromatography to give solid product IIIb-26 (314 mg), yield: 59%.
ESI-MS [ (M+H) + ] of Compound IIIb-26, confirmed by mass spectrometry: theoretical m/z value: 533.1, found: 533.0.
Example 28
Synthesis of Compound IIIb-27
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-27 was the same as in example 2, wherein compound SM4-23 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide-bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-27 (300 mg), yield: 55%.
ESI-MS [ (M+H) + ] of Compound IIIb-27, confirmed by mass spectrometry: theoretical m/z value: 546.2, found: 546.0.
Example 29
Synthesis of Compound IIIb-28
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-28 was the same as in example 2, wherein compound SM4-24 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-28 (465 mg), yield: 83%.
ESI-MS [ (M+H) + ] of Compound IIIb-28, as confirmed by mass spectrometry: theoretical m/z value: 560.2, found: 560.0.
Example 30
Synthesis of Compound IIIb-29
According to the method shown in the second synthesis method
The first step:
To a 50mL single-necked flask, SM1-12 (2.19 g,10 mmol), SM2-01 (2.34 g,13 mmol), potassium tert-butoxide (1.46 g,13 mmol) and DMSO (20 mL) were added, and the mixture was reacted at 85℃under nitrogen protection, after the reaction was completed, the reaction mixture was cooled to room temperature and slowly poured into 100mL of ice water to precipitate a solid, filtered, and the cake was washed with water and dried sufficiently to obtain intermediate RM1-25 (2.10 g), yield: 58%;
and a second step of:
To a 100mL three-necked flask, adding intermediate RM1-25 (3.62 g,10 mmol), DMF (20 mL) and pyridine (30 mmol), controlling ice-water bath at not more than 10 ℃, dropping phenyl chloroformate (30 mmol) at room temperature, after dropping, reacting at room temperature, after HPLC showing the end of the reaction, cooling the reaction liquid slowly into 100mL water, precipitating solid, filtering, washing the filter cake with water, drying, purifying by column chromatography to obtain intermediate RM2-25 (4.10 g), yield: 85%;
and a third step of:
To a 50mL single-necked flask, intermediate RM2-25 (480 mg,1 mmol), meCN (10 mL) and SM3-01 (3 mmol) were added, and the mixture was reacted at 60℃to give a solid product IIIb-29 (280 mg) after the completion of the reaction, filtration, washing and drying and purification by column chromatography, yield: 63%.
ESI-MS [ (M+H) + ] of Compound IIIb-29, confirmed by mass spectrometry: theoretical m/z value: 445.1, found: 444.8.
Example 31
Synthesis of Compound IIIb-30
According to the method shown in the second synthesis method
The first step:
To a 50mL single-necked flask, SM1-12 (2.19 g,10 mmol), SM2-11 (2.49 g,13 mmol), potassium tert-butoxide (1.46 g,13 mmol) and DMSO (20 mL) were added, and the mixture was reacted at 85℃under nitrogen protection, after the completion of the reaction, the reaction solution was cooled to room temperature and slowly poured into 100mL of ice water to precipitate a solid, filtered, and the cake was washed with water and dried sufficiently to give intermediate RM1-26 (2.43 g), yield: 65%;
and a second step of:
To a 100mL three-necked flask, adding intermediate RM1-26 (3.74 g,10 mmol), DMF (20 mL) and pyridine (30 mmol), controlling ice-water bath at not more than 10 ℃, dropping phenyl chloroformate (30 mmol) at room temperature, after dropping, reacting at room temperature, after HPLC showing the end of the reaction, pouring the reaction liquid into 100mL water slowly, precipitating solid, filtering, washing the filter cake with water, drying, purifying by column chromatography to obtain intermediate RM2-26 (3.95 g), yield: 80%;
and a third step of:
To a 50mL single port flask, intermediate RM2-26 (494 mg,1 mmol), meCN (10 mL), pyridine (3 mmol) and SM3-01 (3 mmol) were added, and after the reaction was completed at 60℃HPLC showed that a solid precipitated, filtered, washed and dried, and purified by column chromatography to give solid product IIIb-30 (274 mg), yield: 60%.
ESI-MS [ (M+H) + ] of Compound IIIb-30, confirmed by mass spectrometry: theoretical m/z value: 457.1, found: 457.0.
Example 32
Synthesis of Compound IIIb-31
According to the method shown in the synthesis method I
The synthesis method for preparing the compound IIIb-31 is the same as in example 2, wherein in the fifth step, compound SM4-25 (1.5 mmol) is used to react with intermediate RM4-01 to form an amide bond product, and after the same post-treatment, the solid is purified by column chromatography.
The resulting solid was subjected to alkaline hydrolysis with THF/MeOH system, pH was adjusted to about 6 after the reaction was completed, the solid was precipitated, filtered, washed, and dried to give solid product IIIb-31 (290 mg), yield: 53%.
ESI-MS [ (M+H) + ] of Compound IIIb-31, confirmed by mass spectrometry: theoretical m/z value: 547.1, found: 547.2.
Example 33
Synthesis of Compound IIIb-32
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-32 was the same as in example 2, wherein compound SM4-26 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide-bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-32 (259 mg), yield: 48%.
ESI-MS [ (M+H) + ] of Compound IIIb-32, confirmed by mass spectrometry: theoretical m/z value: 539.1, found: 538.9.
Example 34
Synthesis of Compound IIIb-33
The synthesis of the preparation of compound IIIb-33 is the same as in the first four steps of example 1.
Fifth step:
to a 50mL single-necked flask, intermediate RM4-01 (178 mg,1.0 mmol), DMF (5 mL) and CDI (1.5 mmol) were added dropwise to DIEA (3.0 mmol), and after completion of the reaction, SM4-27 (3.0 mmol) was added to the flask after completion of the reaction as shown by HPLC, and after completion of the reaction, water was added to precipitate a solid, which was filtered, washed and dried, and purified by column chromatography to give a solid product IIIb-33 (151 mg), yield: 28%.
ESI-MS [ (M+H) + ] of Compound IIIb-33, confirmed by mass spectrometry: theoretical m/z value: 541.1, found: 540.9.
Example 35
Synthesis of Compound IIIb-34
The synthesis procedure for the preparation of compound IIIb-34 was identical to the first four steps of example 1.
Fifth step:
To a 50mL single-necked flask, intermediate RM4-01 (178 mg,1.0 mmol), DMF (5 mL) and CDI (1.5 mmol) were added dropwise to DIEA (3.0 mmol), and after completion of the reaction, SM4-28 (3.0 mmol) was added to the flask after completion of the reaction as shown by HPLC, and after completion of the reaction, water was added to precipitate a solid, which was filtered, washed and dried, and purified by column chromatography to give a solid product IIIb-34 (130 mg), yield: 23%.
ESI-MS [ (M+H) + ] of Compound IIIb-34, confirmed by mass spectrometry: theoretical m/z value: 567.1, found: 567.0.
Example 36
Synthesis of Compound IIIb-35
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-35 was the same as in example 2, wherein compound SM4-29 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide-bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-35 (409 mg), yield: 73%.
ESI-MS [ (M+H) + ] of Compound IIIb-35, confirmed by mass spectrometry: theoretical m/z value: 560.1, found: 559.8.
Example 37
Synthesis of Compound IIIb-36
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-36 was the same as in example 2, wherein compound SM4-30 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide-bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-36 (387 mg), yield: 69%.
ESI-MS [ (M+H) + ] of Compound IIIb-36, confirmed by mass spectrometry: theoretical m/z value: 560.1, found: 559.8.
Example 38
Synthesis of Compound IIIb-37
According to the method shown in the synthesis method I
The synthesis of the preparation of compound IIIb-37 was carried out in the same manner as in example 2, wherein compound SM4-31 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-37 (178 mg), yield: 31%.
ESI-MS [ (M+H) + ] of Compound IIIb-37, confirmed by mass spectrometry: theoretical m/z value: 573.1, found: 573.0.
Example 39
Synthesis of Compound IIIb-38
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-38 was the same as in example 2, wherein compound SM4-32 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide-bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-38 (167 mg), yield: 29%.
ESI-MS [ (M+H) + ] of Compound IIIb-38, confirmed by mass spectrometry: theoretical m/z value: 575.1, found: 575.2.
Example 40
Synthesis of Compound IIIb-39
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-39 was the same as in example 2, wherein compound SM4-33 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide-bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-39 (408 mg), yield: 73%.
ESI-MS [ (M+H) + ] of Compound IIIb-39, confirmed by mass spectrometry: theoretical m/z value: 559.1, found: 558.9.
Example 41
Synthesis of Compound IIIb-40
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-40 was the same as in example 2, wherein compound SM4-34 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide-bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-40 (400 mg), yield: 70%.
ESI-MS [ (M+H) + ] of Compound IIIb-40, confirmed by mass spectrometry: theoretical m/z value: 573.1, found: 572.9.
Example 42
Synthesis of Compound IIIb-41
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-41 was the same as in example 2, wherein compound SM4-35 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-41 (383 mg), yield: 67%.
ESI-MS [ (M+H) + ] of Compound IIIb-41, confirmed by mass spectrometry: theoretical m/z value: 571.1, found: 570.9.
Example 43
Synthesis of Compound IIIb-42
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-42 was the same as in example 2, wherein compound SM4-36 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide-bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-42 (334 mg), yield: 58%.
ESI-MS [ (M+H) + ] of Compound IIIb-42, confirmed by mass spectrometry: theoretical m/z value: 575.1, found: 574.9.
Example 44
Synthesis of Compound IIIb-43
According to the method shown in the synthesis method I
The synthetic method for preparing compound IIIb-43 is the same as in example 2, wherein compound SM4-37 (1.5 mmol) is used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, and after drying by the same work-up, the solid product IIIb-43 (224 mg) is purified by column chromatography to give the yield: 39%.
ESI-MS [ (M+H) + ] of Compound IIIb-43, confirmed by mass spectrometry: theoretical m/z value: 575.1, found: 575.2.
Example 45
Synthesis of Compound IIIb-44
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-44 was the same as in example 2, wherein compound SM4-38 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide-bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-44 (132 mg), yield: 27%.
ESI-MS [ (M+H) + ] of Compound IIIb-44 as confirmed by mass spectrometry: theoretical m/z value: 488.1, found: 487.8.
Example 46
Synthesis of Compound IIIb-45
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-45 was the same as in example 2, wherein compound SM4-39 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-45 (236 mg), yield: 47%.
ESI-MS [ (M+H) + ] of Compound IIIb-45, confirmed by mass spectrometry: theoretical m/z value: 502.1, found: 501.9.
Example 47
Synthesis of Compound IIIb-46
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-46 was the same as in example 2, wherein compound SM4-40 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-46 (289 mg), yield: 56%.
ESI-MS [ (M+H) + ] of Compound IIIb-46, confirmed by mass spectrometry: theoretical m/z value: 516.1, found: 515.9.
Example 48
Synthesis of Compound IIIb-47
According to the method shown in the synthesis method I
The synthesis of the preparation of compound IIIb-47 was carried out in the same manner as in example 2, wherein compound SM4-41 (1.5 mmol) was used in the fifth reaction with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-47 (419 mg), yield: 79%.
ESI-MS [ (M+H) + ] of Compound IIIb-47, confirmed by mass spectrometry: theoretical m/z value: 530.1, found: 529.9.
Example 49
Synthesis of Compound IIIb-48
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-48 was the same as in example 2, wherein compound SM4-42 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide-bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-48 (322 mg), yield: 61%.
ESI-MS [ (M+H) + ] of Compound IIIb-48, confirmed by mass spectrometry: theoretical m/z value: 528.1, found: 527.9.
Example 50
Synthesis of Compound IIIb-49
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-49 was the same as in example 2, wherein compound SM4-43 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-49 (396 mg), yield: 73%.
ESI-MS [ (M+H) + ] of Compound IIIb-49, confirmed by mass spectrometry: theoretical m/z value: 542.1, found: 541.9.
Example 51
Synthesis of Compound IIIb-50
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-50 was the same as in example 2, wherein compound SM4-44 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-50 (356 mg), yield: 69%.
ESI-MS [ (M+H) + ] of Compound IIIb-50, confirmed by mass spectrometry: theoretical m/z value: 516.1, found: 515.9.
Example 52
Synthesis of Compound IIIb-51
The synthesis procedure for the preparation of compound IIIb-51 was the same as in the previous four steps of example 1, wherein compound SM4-45 (1.5 mmol) was used in the fifth step to react with intermediate RM4-01 to form an amide-bond product, which was worked up identically and purified by column chromatography to give a solid.
The obtained solid is subjected to acidic removal of amino protecting groups through a THF/MeOH system, the pH is regulated to about 10 after the reaction is finished, the solid is separated out, filtered, washed and dried to obtain a solid product IIIb-51 (172 mg), and the yield is: 34%.
ESI-MS [ (M+H) + ] of Compound IIIb-51, confirmed by mass spectrometry: theoretical m/z value: 506.1, found: 505.9.
Example 53
Synthesis of Compound IIIb-52
The synthesis procedure for the preparation of compound IIIb-52 was the same as in example 2, wherein compound SM4-46 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide-bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-52 (228 mg), yield: 43%.
ESI-MS [ (M+H) + ] of Compound IIIb-52, confirmed by mass spectrometry: theoretical m/z value: 529.1, found: 528.8.
Example 54
Synthesis of Compound IIIb-53
The synthesis of the preparation of compound IIIb-53 was carried out in the same manner as in example 2, wherein compound SM4-47 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form an amide bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-53 (337 mg), yield: 62%.
ESI-MS [ (M+H) + ] of Compound IIIb-53, confirmed by mass spectrometry: theoretical m/z value: 543.1, found: 543.0.
Example 55
Synthesis of Compound IIIb-54
The synthesis procedure for the preparation of compound IIIb-54 was the same as in example 2, wherein compound SM4-48 (1.5 mmol) was used in the fifth reaction to react with intermediate RM4-01 to form the amide-bond product, which was dried by the same work-up and purified by column chromatography to give solid product IIIb-54 (358 mg), yield: 66%.
ESI-MS [ (M+H) + ] of Compound IIIb-54, confirmed by mass spectrometry: theoretical m/z value: 543.1, found: 543.0.
Example 56
Synthesis of Compound IIIb-55:
According to the method shown in the third synthesis method
Preparation of phenyl 2-chloro-3, 5-difluoro-4-hydroxybenzoate:
SM2-01 (100 g,0.56 mol), pyridine (58 g,0.73 mol) and DMF (1L) are added into a 5L three-port bottle, stirred, cooled by ice water bath, and phenyl chloroformate (96 g,0.61 mol) is dripped into the bottle, and after 15 minutes of addition, sampling is carried out until the conversion of SM2-01 is finished, the bottle directly enters the next step.
Analysis confirmed that this intermediate: nuclear magnetic resonance hydrogen spectrum of phenyl 2-chloro-3, 5-difluoro-4-hydroxybenzoate, 1H-NMR (400 mhz, dmso) δ:10.71 (s, 1H), 9.78 (s, 1H), 7.44-7.36 (m, 3H), 7.27-7.19 (m, 3H); nuclear magnetic resonance fluorine spectrum of the intermediate, 19F NMR (377MHz, DMSO) delta: -131.38/-131.42 (d), -132.79/-132.81 (d).
Cyclopropylamine (127 g,2.24 mol) was added dropwise at a controlled temperature of not higher than 10℃and stirred for half an hour, after completion of detection of conversion, acetonitrile (2L) was added and stirred for half an hour, followed by filtration, rinsing with ethyl acetate (300 mL) and drying to give 1- (2-chloro-3, 5-difluoro-4-hydroxyphenyl) -3-cyclopropylurea cyclopropylammonium salt (143 g).
This intermediate was taken: 1- (2-chloro-3, 5-difluoro-4-hydroxyphenyl) -3-cyclopropylurea cyclopropylammonium salt (143 g) was added to a 5L three-necked flask, methanol (600 mL) was added, and the mixture was stirred uniformly, 6N-hydrochloric acid (80 mL) was added dropwise, stirred until it was completely dissolved, water (3L) was added, stirred for about 1 hour, filtered, washed with water (1.0L), and dried to give RM1b-01 (117 g) in 80% yield.
Analysis shows that nuclear magnetic resonance hydrogen spectrum ,1H-NMR(400MHz,DMSO)δ：10.13(s,1H),7.90(s,1H),7.86-7.82(dd,1H),7.11(d,1H),2.56(m,1H),0.67-0.62(m,2H),0.43-0.39(m,2H); of intermediate RM1b-01 and nuclear magnetic resonance carbon spectrum ,13C-NMR(100MHz,DMSO)δ:155.47(s),151.82(m),149.74(m),129.04(m),128.87-128.67(m),105.54(m),103.54(m),22.27(s),6.19(s); of intermediate RM1b-01, and nuclear magnetic resonance fluorine spectrum 19F-NMR (377MHz, DMSO) delta: -132.09 (m). ESI-MS [ (M+H) + ] of Compound RM1b-01, confirmed by mass spectrometry: theoretical m/z value: 263.0, found: 263.1.
SM1-02 (268 mg,1.0 mmol), RM1b-01 (349mg, 1.3 mmol), potassium tert-butoxide (146 mg,1.3 mmol) and dimethyl sulfoxide (3 mL) are added into a 50mL single-port bottle, the temperature is raised to 65 ℃ for reaction, after the reaction is finished, ice water (30 mL) is dripped into the bottle after cold cutting, and the mixture is fully stirred, filtered, washed with water and purified by column chromatography to obtain the target compound IIIb-55:312mg, yield 63%.
ESI-MS [ (M+H) + ] of Compound IIIb-55, confirmed by mass spectrometry: theoretical m/z value: 495.1, found: 494.9.
Example 57
Synthesis of Compound IIIb-56
The synthesis of the preparation of compound IIIb-56 was carried out in the same manner as in example 55, using compound SM1-03 (1.0 mmol) and intermediate RM1b-01 (1.3 mmol) in the third reaction step, and purifying by column chromatography after the same work-up gave IIIb-56 (323 mg), yield: 60%.
ESI-MS [ (M+H) + ] of Compound IIIb-56, confirmed by mass spectrometry: theoretical m/z value: 513.1, found: 512.8.
Example 58
Synthesis of Compound IIIb-57
The synthesis of the preparation of compound IIIb-57 was carried out in the same manner as in example 55, using compound SM1-04 (1.0 mmol) and intermediate RM1b-01 (1.3 mmol) in the third reaction step, and purifying by column chromatography after the same work-up gave product IIIb-57 (276 mg), yield: 52%.
ESI-MS [ (M+H) + ] of Compound IIIb-57 as confirmed by mass spectrometry: theoretical m/z value: 531.1, found: 530.8.
Example 59
Synthesis of Compound IIIb-58
The synthesis procedure for the preparation of compound IIIb-58 was the same as in example 55, using compound SM1-05 (1.0 mmol) in the third reaction step with intermediate RM1b-01 (1.3 mmol) and purification by column chromatography after the same work-up gave product IIIb-58 (259 mg), yield: 53%.
ESI-MS [ (M+H) + ] of Compound IIIb-58 as confirmed by mass spectrometry: theoretical m/z value: 488.1, found: 487.8.
Example 60
Synthesis of Compound IIIb-59
The synthesis procedure for the preparation of compound IIIb-59 was the same as in example 55, using compound SM1-06 (1.0 mmol) in the third reaction step with intermediate RM1b-01 (1.3 mmol) and purification by column chromatography after the same work-up gave product IIIb-59 (354 mg), yield: 68%.
ESI-MS [ (M+H) + ] of Compound IIIb-59 as confirmed by mass spectrometry: theoretical m/z value: 520.1, found: 519.9.
Example 61
Synthesis of Compound IIIb-60
The synthesis method for preparing the compound IIIb-60 was the same as in example 55, wherein in the third reaction step, the compound SM1-07 (1.0 mmol) was reacted with the intermediate RM1b-01 (1.3 mmol), followed by the same post-treatment and purification by column chromatography to obtain a solid product.
The obtained solid is treated by a/MeOH system, tetrabutylammonium bromide is added to remove the silyl ether protecting group of the hydroxyl, THF is removed by desolventizing after the reaction is finished, water is added to separate out the solid, and the solid product IIIb-60 (192 mg) is obtained after filtration, washing and drying, and the yield is obtained: 38%.
ESI-MS [ (M+H) + ] of Compound IIIb-60, confirmed by mass spectrometry: theoretical m/z value: 493.1, found: 492.9.
Example 62
Synthesis of Compound IIIb-61
The synthesis method for preparing the compound IIIb-61 was the same as in example 55, wherein in the third reaction step, the compound SM1-08 (1.0 mmol) was reacted with the intermediate RM1b-01 (1.3 mmol) and purified by column chromatography after the same work-up to give a solid product.
The obtained solid is subjected to acidic removal of amino protecting groups through a THF/MeOH system, the pH is regulated to about 10 after the reaction is finished, the solid is separated out, filtered, washed and dried to obtain a solid product IIIb-61 (233 mg), and the yield is: 45%.
ESI-MS [ (M+H) + ] of Compound IIIb-61, confirmed by mass spectrometry: theoretical m/z value: 518.1, found: 517.9.
Example 63
Synthesis of Compound IIIb-62:
the synthesis procedure for the preparation of compound IIIb-62 was the same as in example 55, using compound SM1-09 (1.0 mmol) in the third reaction step with intermediate RM1b-01 (1.3 mmol) and purification by column chromatography after the same work-up gave product IIIb-62 (305 mg), yield: 59%.
ESI-MS [ (M+H) + ] of Compound IIIb-62, confirmed by mass spectrometry: theoretical m/z value: 517.1, found: 516.9.
Example 64
Synthesis of Compound IIIb-63
The synthesis procedure for the preparation of compound IIIb-63 was the same as in example 55, using compound SM1-09 (1.0 mmol) in the third reaction step with intermediate RM1b-01 (1.3 mmol) and purification by column chromatography after the same work-up gave product IIIb-63 (274 mg), yield: 53%.
ESI-MS [ (M+H) + ] of Compound IIIb-63, as confirmed by mass spectrometry: theoretical m/z value: 517.1, found: 516.9.
Example 65
Synthesis of Compound IIIb-64
The synthesis procedure for the preparation of compound IIIb-64 was the same as in example 55, using compound SM1-11 (1.0 mmol) in the third reaction with intermediate RM1b-01 (1.3 mmol) and purification by column chromatography after the same work-up gave product IIIb-64 (331 mg), yield: 64%.
ESI-MS [ (M+H) + ] of Compound IIIb-64, confirmed by mass spectrometry: theoretical m/z value: 517.1, found: 516.9.
Example 66
Synthesis of Compound IIIb-65
The synthesis procedure for the preparation of compound IIIb-65 was the same as in example 55, using compound SM1-16 (1.0 mmol) in the third reaction step with intermediate RM1b-01 (1.3 mmol) and purification by column chromatography after the same work-up gave product IIIb-65 (286 mg), yield: 57%.
ESI-MS [ (M+H) + ] of Compound IIIb-65, confirmed by mass spectrometry: theoretical m/z value: 502.1, found: 501.9.
Example 67
The synthesis method of the compound IIIb-08 is as follows:
SM1-13 (10.0 g,33 mmol), RM1b-01 (11.3 g,43 mmol), potassium tert-butoxide (4.8 g,43 mmol) and dimethyl sulfoxide (100 mL) are added into a 1.0L three-necked flask, the temperature is raised to 65 ℃ for reaction, after the reaction is finished, ice water (1L) is dripped into the flask after cold cutting, stirring, filtering, washing with a proper amount of water, and drying to obtain IIIb-08 (13.0 g), yield: 75%.
Example 68
The synthesis method of the compound IIIb-50 comprises the following steps:
or according to the method shown in the third synthetic method
SM1-14 (10.0 g,35 mmol), RM1b-01 (11.8 g,45 mmol), potassium tert-butoxide (5.0 g,45 mmol) and dimethyl sulfoxide (100 mL) in a 1.0L three-necked flask are heated to 65 ℃ for reaction, ice water (1L) is dripped after cold cutting after the reaction is finished, stirring, filtering, washing with a proper amount of water, and drying to obtain IIIb-50 (12.8 g), yield: 71%.
Example 69: in vitro inhibitory Activity potency experiment
The compound prepared by the invention can be used for preliminarily determining and screening the effect of inhibiting 7 tumor cell lines targets such as pancreatic cancer (BXPC 3), lung cancer (A549), kidney cancer (Caki-1), liver cancer (Hep 3B 2.1-7), gastric cancer (SNU 16), cervical cancer (Hela), leukemia (K562) and the like by the following preclinical in vitro inhibition activity test experiment, and further screening better anticancer new drugs by determining the inhibition activity of a plurality of RTK targets such as VEGFR1, VEGFR2 (KDR), VEGFR3, FGFR2, RET and the like, and finally confirming the curative effect of the new drugs by clinical test. Other methods will be apparent to those of ordinary skill in the art.
This example describes the proliferation inhibition effect of the compounds (IIIb-01 to IIIb-65) on various tumor cells.
1. Cell plating experiments were performed on the first day, and 100ul of cells containing 5000 cells [ e.g., pancreatic cancer (BXPC 3), lung cancer (A549), kidney cancer (Caki-1), liver cancer (Hep 3B 2.1-7), stomach cancer (SNU 16), cervical cancer (Hela), prostate cancer cell line (PC-3), leukemia (K562), etc. ] were uniformly plated on a 96-well cell culture plate (Corning 3917 plate), and then the cell plates were placed in a cell culture box.
2. Compound dosing experiments are carried out the next day, compounds are prepared, 10 concentration points are prepared for each compound to be tested and positive reference drugs, the compound to be tested and the positive reference drugs are diluted in culture solution in a concentration gradient of 1:3, and holes are formed. 5ul of the compound to be tested or the positive reference drug is added into the cell plate, the final concentration of the compound to be tested is 10uM at the maximum, the final concentration of the positive reference drug is 3uM at the maximum, the DMSO concentration is controlled below 0.2%, and then the cell plate is placed in a cell incubator for culturing for 72 hours.
3. On the fifth day, after 72 hours of treatment, CTG reagent (Promega G7573) was prepared according to the reagent instructions, and the prepared CTG reagent and cell plates were simultaneously placed in a room temperature environment for 30 minutes to perform thermal equilibration. Then 50ul of CTG reagent is added into the hole of each cell plate, and the cell plates are stirred evenly at a low speed and then are placed at room temperature for 20 minutes for preservation in a dark place. The cell culture plates were then placed on a plate reader (Envision or Viewlux) to record data and analyzed to calculate proliferation inhibition, and the compound concentration corresponding to 50% inhibition in the curve was IC 50 for the compound proliferation inhibition on the tumor cell line.
Experiment for evaluation of five kinase inhibitory activities (IC 50):
The inhibition of 17 kinases by small molecule inhibitors was tested by using fluorescence microfluidic Mobility detection technology (Mobility-SHIFT ASSAY).
1. Buffer solution preparation: 50mM HEPES,pH 7.5,0.00015%Brij-35.
2. Compounds were formulated as concentration gradients in 100% dmso and diluted with buffer to 10% dmso and added to 384 well plates. Initial compound concentration was 500nM, 25. Mu.M was made up with 100% DMSO, diluted 10 times in gradient, diluted 10 times with buffer, made up as an intermediate compound dilution with 10% DMSO, and transferred to a 5. Mu.l to 384 well plate.
3. Kinase was diluted to optimal concentration with the following buffers: 50mM HEPES,pH 7.5,0.00015%Brij-35,2mM DTT (final enzyme reaction concentration ：VEGFR-1(FLT1)：2nM;VEGFR-2(KDR)：1.2nM;VEGFR-3(FLT4)：1.5nM;FGFR1：2nM;FGFR2：9nM;FGFR3：8nM;FGFR4：10nM;PDGFRα：3.5nM;c-MET：10nM;RET：7nM;EGFR：6nM). was transferred to 10. Mu.l in 384 well plates and incubated with compound for 10 min.
4. The substrate was diluted to optimal concentration with the following buffer: 50mM HEPES,pH 7.5,0.00015%Brij-35. Wherein the final concentration of the reaction is as follows:
VEGFR1(FLT1)：3μM Peptide30(5-FAM-KKKKEEIYFFFCONH2),278μM ATP,10mM MgCl2；
VEGFR2(KDR)：3μM Peptide22(5-FAM-EEPLYWSFPAKKKCONH2),92μM ATP,10mM MgCl2；
VEGFR3(FLT4)：3μM Peptide30(5-FAM-KKKKEEIYFFFCONH2),84μM ATP,10mM MgCl2；
FGFR2：3μM Peptide22(5-FAM-EEPLYWSFPAKKKCONH2),1.9μM ATP,10mM MgCl2；
RET：3μM Peptide22(5-FAM-EEPLYWSFPAKKKCONH2),23μM ATP,10mM MgCl2
5. Conversion was read with CALIPER READER and calculated as inhibition, formula Percent inhIcition = (maxConversion)/(max-min) x 100.
6. The IC50 formula Y=bottom+ (Top-Bottom)/(1+ (IC 50/X) ≡ HillSlope) was calculated by fitting with XL-fit5.4.0.8 software.
HERG (potassium ion channel) is an important parameter involved in compound safety in the research process of new drugs, potassium ion (K +) channel is highly expressed in heart, and is a main component of myocardial action potential three-phase rapid repolarization current (IKr). Loss of function due to hERG mutations is often accompanied by some inherited long QTs syndrome (LQTS) and increases the risk of developing severe ventricular arrhythmias, torsionally effectuating tachycardia. Side effects caused by inhibition of potassium (K +) channels are one of the main reasons for failure and marketing of new drug studies in recent years, and if the in vitro inhibitory effect IC 50 <30uM of hERG of a compound, the compound may present the above-described risks and risks. Thus the in vitro inhibition effect (IC 50) assessment of the hERG channel of drugs has been recommended by the international drug registration coordination conference as part of the preclinical safety assessment effort (ICHS 7B Expert Working Group,' 02).
Experiment for evaluation of in vitro inhibition effect (IC 50) of hERG:
The stably-rotated cells were dropped onto a round slide and placed in a petri dish with a cell density of less than 50% and cultured overnight. The experimental cells were transferred to a bath of about 1ml embedded in an inverted microscope platform, and the extracellular fluid was perfused at a perfusion rate of 2.7 ml/min. After 5 minutes of stabilization, the experiment was started. Membrane current was recorded using a HEKA EPC-10 patch clamp amplifier and PATCHMASTER acquisition system (HEKA Instruments inc., D-67466lambrecht, pfalz, germany). All experiments were performed at room temperature (22-24 ℃). A P-97 microelectrode drawing instrument (Sutter Instrument Company, one DIGITAL DRIVE, novato, CA 94949) was used in the experiments to straighten the electrodes (BF 150-110-10). The inner diameter of the electrode is 1-1.5mm, and the water inlet resistance after being filled with the internal liquid is 2-4MΩ. The electrophysiological stimulation scheme of hERG potassium channel is that first, the membrane voltage is clamped at-80 mV, the cell is stimulated for 2s, +20mV voltage, the hERG potassium channel is activated, and then repolarized to-50 mV for 5s, so as to generate outward tail current, and the stimulation frequency is once every 15 s. The current value is the peak value of the tail current.
The channel current was recorded using a whole cell recording mode in the experiment. Extracellular fluid (approximately 2ml per minute) was first perfused and recorded continuously, and current stabilization was awaited (current decay (Run-Down) less than 5% in 5 minutes), at which point the tail current peak was the control current value. And then, the extracellular fluid containing the drug to be detected is perfused and continuously recorded until the inhibition effect of the drug on hERG current reaches a stable state, and at the moment, the tail current peak value is the current value after drug addition. The steady state criteria is determined by whether the nearest 3 consecutive current traces overlap. After reaching the steady state, if hERG current reverts to or approaches the magnitude prior to drug administration after rinsing with extracellular fluid perfusion, then perfusion testing may continue for other concentrations or drugs. 30 μ M Quinidine (quinidine) was used in the experiment as a positive control to ensure that the cells used responded normally.
Some preferred test results for the activity of compounds of formula IIIb and the like (e.g., ：IIIb-06、IIIb-08、IIIb-09、IIIb-21、IIIb-45、IIIb-50、IIIb-55、IIIb-56、IIIb-57、IIIb-58、IIIb-60、IIIb-61、IIIb-65) to inhibit various tumor cell lines [ e.g., pancreatic cancer (BXPC 3), lung cancer (A549), renal cancer (Caki-1), liver cancer (Hep 3B 2.1-7), gastric cancer (SNU 16), cervical cancer (Hela), prostate cancer (PC-3), leukemia (K562), and the like ] and tyrosine kinases (e.g., VEGFR1, VEGFR2 (KDR), VEGFR3, FGFR2, RET) are shown in tables 6, 7 and 8, respectively.
The range of activity effect (IC 50) of each compound against pancreatic cancer cell line (BXPC 3) is indicated as "a" at <5.0uM, the range of activity is indicated as "B" at 5.0-10.0uM, and the range of activity >10.0uM is indicated as "C";
The range of activity effect (IC 50) of each compound against lung cancer cell line (a 549) is indicated as "a" at <2.5uM, the range of activity is indicated as "B" at 2.5-5.0uM, and the range of activity >5.0uM is indicated as "C";
The range of activity effect (IC 50) of each compound against the kidney cancer cell line (Caki-1) is labeled "a" at <2.5uM, the range of activity is labeled "B" at 2.5-5.0uM, and the range of activity >5.0uM is labeled "C";
The range of the activity effect (IC 50) of each compound for inhibiting liver cancer cell lines (Hep 3B 2.1-7) is marked as "A" in <2.5uM, the range of activity is marked as "B" in 2.5-5.0uM, and the range of activity >5.0uM is marked as "C";
The range of activity effect (IC 50) of each compound against gastric cancer cell line (SNU 16) is indicated as "a" at <5.0uM, the range of activity is indicated as "B" at 5.0-10.0uM, and the range of activity >10.0uM is indicated as "C";
the range of activity effect (IC 50) of each compound against cervical cancer cell line (Hela) is indicated as "a" at <5.0uM, the range of activity is indicated as "B" at 5.0-10uM, and the range of activity >10uM is indicated as "C";
The range of activity (IC 50) of each compound inhibiting leukemia cell line (K562) is indicated as "a" for <5.0uM, as "B" for the range of activity between 5.0 and 10uM, as "C" for the range of activity >10 uM;
The range of activity (IC 50) of each compound inhibiting prostate cancer cell line (PC-3) is indicated as "A" at <5.0uM, the range of activity is indicated as "B" at 5.0-10uM, and the range of activity >10uM is indicated as "C".
Table 6: results of inhibition Activity test of three cell lines of some Compounds of formula IIIb
Table 7: results of inhibiting the Activity of four cell lines of liver cancer, gastric cancer, cervical cancer and leukemia by some preferred Compounds of formula IIIb
The results of some preferred compounds of formula IIIb for inhibiting the activity of RTK targets such as VEGFR1-3, FGFR2, RET, respectively, are shown in Table 8 below; wherein each compound inhibits the activity effect range (IC 50) of various tyrosine kinases VEGFR1, KDR (VEGFR 2), VEGFR3, denoted as "a" at <5nM, denoted as "B" at 5-10nM, denoted as "C" at >10 nM; the range of activity of each compound to inhibit various tyrosine kinases FGFR2 (IC 50) is denoted "a" at <50nM, the range of activity is denoted "B" at 50-100nM, and the range of activity >100nM is denoted "C"; the range of activity of each compound to inhibit various tyrosine kinases RET (IC 50) is indicated as "a" at <5nM, the range of activity is indicated as "B" at 5-10nM, and the range of activity >10nM is indicated as "C".
Table 8: results of inhibition of the Activity of three tyrosine kinases by some preferred Compounds of formula IIIb
Table 9: hERG inhibition assay of some preferred Compounds
From the various test results in the above tables 6, 7, 8 and 9, it can be found that the compounds "IIIb-08, IIIb-09, IIIb-45, IIIb-50, IIIb-55, IIIb-56, IIIb-57, IIIb-58, IIIb-60, IIIb-61 and IIIb-65" listed in the above tables have better inhibition effect on various tumor cell lines and tyrosine kinase, and the inhibition activity and safety parameters such as hERG >30uM are obviously better than those of 3 urea control drugs of lenvatinib, regorafenib and sorafenib which are already clinically marketed.
Example 70: compound toxicity screening assay
In order to test the toxicity of the novel compounds "IIIb-08, IIIb-09, IIIb-45, IIIb-50, IIIb-55, IIIb-56, IIIb-57, IIIb-58, IIIb-60, IIIb-61, IIIb-65" having high activity in the above-mentioned tables 7 to 9, the present invention conducted MTD toxicity tests (150 mg/kg, QD) in rats, respectively, and no abnormal cases such as death occurred in the oral administration for 14 consecutive days. The rat anatomy results also showed no abnormal changes in various organs such as heart, liver, lung, kidney, stomach, intestine, etc., and the tested compounds were generally considered safe and nontoxic within the appropriate dose.
At present, the preferred compounds (such as IIIb-08, IIIb-09, IIIb-45, IIIb-50, IIIb-56, IIIb-57, IIIb-58, IIIb-60, IIIb-61 and IIIb-65) are used for respectively carrying out in vivo inhibition tests on tumors such as pancreatic cancer cell strain (BXPC 3), gastric cancer cell strain (SNU 16), liver cancer cell strain (Hep 3B 2.1-7) and the like transplanted under the skin of nude mice, and have the advantages that the tumor inhibition rate of the subcutaneous tumors of the nude mice can reach 80-110% within 3-4 weeks, so that the preferred compounds have better antitumor activity efficacy. Therefore, the preferred compounds 'IIIb-08, IIIb-09, IIIb-45, IIIb-50, IIIb-55, IIIb-56, IIIb-57, IIIb-58, IIIb-60, IIIb-61 and IIIb-65' designed and synthesized in the invention have better inhibitory activity effect, better safety and pharmacy, and have application value for further carrying out preclinical researches and clinical experiments such as medicine toxicology and the like.
In conclusion, the compounds 'IIIb-08, IIIb-09, IIIb-45, IIIb-50, IIIb-55, IIIb-56, IIIb-57, IIIb-58, IIIb-60, IIIb-61 and IIIb-65' found in the research of the multi-target anti-tumor innovative medicaments not only have better inhibitory activity, but also have MTD toxicity test (150 mg/kg, QD) of rats, no death and other abnormal conditions occur in the continuous 14-day oral administration, and better safety (40 mg/kg MTD reported by the publication of the comparison medicament 'lenvatinib') is better than that of the currently known equivalent comparison medicaments of the same class of the lenvatinib.
In general, the terms used in the claims should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments and other chemically reasonable variations that follow the full scope of equivalents to which the claims are entitled. Accordingly, the claims are not limited by the present disclosure.

Claims (8)

1. A compound selected from the following structures:
2. A process for the preparation of a compound as claimed in claim 1, wherein: is prepared by either of the following two methods:
the first method comprises the following five steps, and the reaction equation is as follows:
The second method comprises the following three steps, and the reaction equation is as follows:
Wherein:
R is hydrogen or C 1-6 alkyl,
R 4、R5 and R 6 are defined as groups at the corresponding positions of the compounds of claim 1.
3. The method of claim 2, wherein: the first reaction step in method one gives the following intermediate compound RM1:
4. The method of claim 2, wherein: the first reaction step in method two gives the following intermediate compound RM1b:
5. The method of any one of claims 2-4, wherein the key polysubstituted compound SM2-01 is prepared by either of the following two reactions:
Reaction one:
reaction II:
6. a composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent and/or excipient.
7. Use of a compound of claim 1 in the manufacture of a medicament for the treatment of a cancer selected from the group consisting of: pancreatic cancer, lung cancer, kidney cancer, liver cancer, stomach cancer, cervical cancer or leukemia.
8. Use of a compound according to claim 1 in the manufacture of a medicament for inhibiting the activity of a tyrosine kinase selected from the group consisting of: VEGFR1, KDR, VEGFR3, FGFR2, or RET.
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