CN115215799A - Urea multi-target tyrosine kinase inhibitor and various medical applications thereof - Google Patents

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

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CN115215799A
CN115215799A CN202210968135.1A CN202210968135A CN115215799A CN 115215799 A CN115215799 A CN 115215799A CN 202210968135 A CN202210968135 A CN 202210968135A CN 115215799 A CN115215799 A CN 115215799A
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詹正云
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AB Pharma Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups

Abstract

The invention discloses a compound shown in a formula IIIb, a cis-trans isomer, a racemate, a deutero-or pharmaceutically acceptable salt thereof or a mixture of the cis-trans isomer, the racemate, the deutero-or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, an important target inhibitor of a plurality of tyrosine kinases (RTK) and application of the compound in treating diseases such as a plurality of tumors accompanied with angiogenesis and the like. The compound can be used as an RTK targeted multi-antibody medicament with better inhibitory activity to be used 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 and G 1 、G 2 、G 3 、G 4 、G 5 、R 1 、R 2 、R 3 、X 1 、X 2 、X 3 、X 4 And possible isotopic substitution of each element in the compound is as defined herein.

Description

Urea multi-target tyrosine kinase inhibitor and various medical applications thereof
Technical Field
The invention relates to a novel urea compound formed by polysubstituted arylamine and alkylamine. More particularly, the invention relates to polysubstituted arylamino urea compounds which can be used as multi-target tyrosine kinase inhibitors and various medical applications thereof.
Background
Protein Tyrosine Kinases (PTKs) are the largest known protein superfamily, and are important pivotal junctions for extracellular signal transmission into cells. The tyrosine kinase plays an important role in regulating the proliferation and differentiation of cells, and abnormal expression of PTK can activate a series of downstream signal pathways to cause cascade reaction, so that the cell proliferation regulation is disordered, and finally, tumors are formed. Tyrosine kinases can be classified into Receptor type tyrosine kinases (RTKs) and non-Receptor type tyrosine kinases (nrks), wherein the Receptor type tyrosine kinases (RTKs) include Vascular Endothelial Growth Factor Receptors (VEGFR), fibroblast Growth Factor Receptors (FGFR), epidermal Growth Factor receptors (Epidermal Growth Factor Receptor), which are members of the Epidermal Growth Factor Receptor (HER) family, tyrosine kinase membrane receptors (c-Met), platelet-derived Growth Factor Receptor (PDGFR α), RET and the like, and these RTKs are closely related to tumor diseases and target therapy thereof.
To date, more than 80% of kinases have been targeted for therapeutic drug development, and reports indicate that pathological increase of vascular endothelialization is related to onset or development of various diseases, and proliferation of solid tumors depends on angiogenesis, so that drugs effective in inhibiting tyrosine kinase (RTK) targets such as the tyrosine kinases VEGFR1-3, FGFR1-4, EGFR, RET, c-MET, etc., have become the main targeted therapeutic approaches for refractory solid tumors. Most of the molecular targeted antitumor drugs on the market at present are protein Tyrosine Kinase Inhibitors (TKIs) taking PTKs as targets.
At present, most molecular targeted antitumor drugs on the market at home and abroad are protein Tyrosine Kinase Inhibitors (TKI) taking PTK as targets, for example, sorafenib (Sorafenib, ref-1), regorafenib (Ref-2) and Ranatinib (Lenvatinib, levatinib, ref-3) which have better inhibition effects on tyrosine kinases VEGFR1-3 and FGFR1-4 are small molecular urea compounds anticancer drugs which have better inhibition effects on tyrosine kinases VEGFR1-3 and are clinically used for treating liver cancer, and the protein targeted antitumor drugs have better antitumor effects in clinical treatment.
The invention aims to develop a novel multi-target Tyrosine Kinase Inhibitor (TKI) with higher tyrosine kinase inhibition activity and lower toxic side effect through the innovative design of a small molecular structure and a functional group thereof, and the TKI can be 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 thereof.
The invention relates to a type IIIb polysubstituted anilinourea compound containing a novel polysubstituted aniline group as an innovation key point, which is used as a multi-target Tyrosine Kinase Inhibitor (TKI), can not only effectively inhibit vascular endothelial growth factor receptors (VEGFR 1, VEGFR2 and VEGFR 3) and fibroblast growth factor receptors (FGFR 1-4), but also effectively inhibit a plurality of important Receptor Tyrosine Kinases (RTKs) which can cause angiogenesis and tumor growth diseases except for normal cell functions, such as tyrosine kinases including but not limited to EGFR, RET, PDGFR alpha and the like, so that a stronger angiogenesis inhibiting effect can be generated, and the compound has better application in more effectively preventing and treating various tumors and other diseases accompanied with abnormal proliferation of angiogenesis.
The structure of the urea compound containing the polysubstituted aniline group is characterized in that according to the structural characteristics of tyrosine kinase targets, structural modification innovation and optimization are carried out by introducing multiple substituent groups into aniline, so that a multi-target Tyrosine Kinase Inhibitor (TKI) with a better inhibition effect is developed, and various tumors can be effectively treated.
Disclosure of Invention
The invention solves the core problem of developing a novel urea compound containing polysubstituted aniline as an innovative characteristic, which has better inhibition effect on various tumor cell strains such as pancreatic cancer (BXPC 3), lung cancer (A549), kidney cancer (Caki-1), liver cancer (Hep3B2.1-7), stomach cancer (SNU 16), cervical cancer (Hela), leukemia (K562) and the like and kinase targets such as VEGFR1-3, FGFR1-4, EGFR, RET and the like, and the result shows that the inhibition effect is better, the application prospect is better and the safety is better.
In a first aspect, the present invention provides a compound represented by formula IIIb, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a tautomer, or a pharmaceutically acceptable salt or hydrate thereof, and a deuterated or isotopically substituted compound:
Figure BDA0003795483320000031
wherein, the first and the second end of the pipe are connected with each other,
e is nitrogen (N), or CH;
G 1 is hydrogen, deuterium (D), halogen, -CN, C 1-20 Alkyl radical, C 1-20 Alkoxy, or C 1-20 An alkylamino group;
G 2 is halogen, -CN, C 1-20 Alkylamino radical, C 1-20 Hydroxyalkyleneamino group, C 1-20 Cyanoalkyleneamino group, C 1-20 Amino alkylene amino group, C 3-20 Amino cycloalkylamino radical, C 1-20 Carboxyalkyleneamino group, C 3-20 A carboxycycloalkylamino group, a 3-to 6-membered heterocyclylamino group, OR-OR 6 (ii) a Wherein R is 6 Selected from: hydrogen, deuterium, C 1-20 Alkyl radical, C 1-20 Haloalkyl, C 1-20 Cyanoalkylene group, C 3-20 Cyanocycloalkylene radical, C 2-20 Hydroxyalkylene, C 2-20 Aminoalkylene group, C 3-20 Amino cycloalkylene radical, C 2-20 Carboxyalkylene group, C 3-20 Carboxy cycloalkylene radical, C 3-6 A cycloalkyl group, a,C 3-6 Amino cycloalkylene radical, C 1-20 Amino group (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 、C 1-20 Alkoxy radical, C 1-20 Alkylamino, or-C (O) NR 4 R 5 (ii) a Wherein R is hydrogen, or C 1-20 Alkyl radical, R 4 And R 5 Each independently selected from: hydrogen, deuterium, C 1-20 Alkyl radical, C 1-20 Haloalkyl, C 1-20 Cyanoalkylene group, C 3-20 Cyanocycloalkylene radical, C 2-20 Hydroxyalkylene group, C 3-20 Hydroxy cycloalkylene radical, C 2-20 Aminoalkylene group, C 3-20 Amino cycloalkylene radical, C 2-20 Carboxyalkylene group, C 3-20 Carboxy cycloalkylene radical, C 3-20 Cycloalkenyl radical, C 3-20 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclylalkylene, C 6-20 Aryl radical, C 3-20 Heterocyclic aryl radicals, C 1-20 Alkylsulfonyl radical, C 3-20 Cycloalkylsulfonyl, or C 2-20 A heterocycloalkylsulfonyl group; r 4 And R 5 A 3-to 8-membered heterocyclic or heterocyclic aryl group containing 1 to 3 heteroatoms bonded to each other;
G 4 and G 5 Each independently selected from: hydrogen, deuterium (D), halogen, -CN, C 1-20 Alkyl radical, C 1-20 Alkoxy, or C 1-20 An alkylamino group;
R 1 selected from: hydrogen, deuterium, C 1-20 Alkyl radical, C 3-20 Cycloalkyl, or C 3-20 A deuterated cycloalkyl group;
R 2 and R 3 Each independently selected from: hydrogen, deuterium, C 1-20 Alkyl radical, C 3-20 Cycloalkyl radical, C 3-20 Deuterated cycloalkyl, or 3-6 membered heterocyclyl;
X 1 、X 2 and X 3 Each independently selected from: halogen, -CN, -NH 2 、C 1-20 Alkoxy, or C 1-20 An alkylamino group;
X 4 selected from: hydrogen and deuteriumHalogen, -CN, -NH 2 、C 1-20 Alkoxy, or C 1-20 An alkylamino group.
In some of the preferred embodiments of the present invention,
e is nitrogen (N), or CH;
G 1 is hydrogen, deuterium (D), halogen, -CN, C 1-6 Alkyl radical, C 1-6 Alkoxy, or C 1-6 An alkylamino group;
G 2 is halogen, -CN, C 1-6 Alkylamino radical, C 1-6 Hydroxyalkyleneamino group, C 1-6 Cyanoalkyleneamino group, C 1-6 Amino alkylene amino group, C 3-6 Amino cycloalkylamino radical, C 1-6 Carboxyalkyleneamino group, C 3-6 A carboxy cycloalkylamino group, a 3-to 6-membered heterocyclylamino group, OR-OR 6 (ii) a Wherein R is 6 Selected from: hydrogen, deuterium, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Cyanoalkylene group, C 3-6 Cyanocycloalkylene radical, C 2-6 Hydroxyalkylene group, C 2-6 Aminoalkylene group, C 3-6 Amino cycloalkylene radical, C 2-6 Carboxyalkylene group, C 3-6 Carboxy cycloalkylene radical, C 3-6 Cycloalkyl radical, C 3-6 Amino cycloalkylene radical, C 1-6 Amino group (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 、C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, or-C (O) NR 4 R 5 (ii) a Wherein R is hydrogen, or C 1-6 Alkyl radical, R 4 And R 5 Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Cyanoalkylene group, C 3-6 Cyanocycloalkylene radical, C 2-6 Hydroxyalkylene group, C 3-6 Hydroxy cycloalkylene radical, C 2-6 Aminoalkylene group, C 3-6 Amino cycloalkylene radical, C 2-6 Carboxyalkylene group, C 3-6 Carboxy cycloalkylene radical, C 3-6 Cycloalkenyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclylalkylene, and,C 6-10 Aryl radical, C 3-10 Heterocyclic aryl radicals, C 1-6 Alkylsulfonyl radical, C 3-6 Cycloalkylsulfonyl, or C 2-6 A heterocycloalkylsulfonyl group; r 4 And R 5 A 3-to 8-membered heterocyclic or heterocyclic aryl group containing 1 to 3 heteroatoms bonded to each other;
G 4 and G 5 Each independently selected from: hydrogen, deuterium (D), halogen, -CN, C 1-6 Alkyl radical, C 1-6 Alkoxy, or C 1-6 An alkylamino group;
R 1 selected from: hydrogen, deuterium, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, or C 3-6 A deuterated cycloalkyl group;
R 2 and R 3 Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Deuterated cycloalkyl, or 3-6 membered heterocyclyl;
X 1 、X 2 and X 3 Each independently selected from: halogen, -CN, -NH 2 、C 1-6 Alkoxy, or C 1-6 An alkylamino group;
X 4 selected from: hydrogen, deuterium, halogen, -CN, -NH 2 、C 1-6 Alkoxy, or C 1-6 An alkylamino group.
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 is 6 Selected from: hydrogen, deuterium, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Cyanoalkylene group, C 3-6 Cyanocycloalkylene radical, C 2-6 Hydroxyalkylene, C 2-6 Aminoalkylene group, C 3-6 Amino cycloalkylene radical, C 2-6 Carboxyalkylene group, C 3-6 Cycloalkyl radical, C 3-6 Amino cycloalkylene radical, C 1-6 Amino group (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 4 R 5 (ii) a Wherein R is hydrogen, or C 1-6 Alkyl radical, R 4 And R 5 Each independently selected from: hydrogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Cyanoalkylene group, C 3-6 Cyanocycloalkylene radical, C 2-6 Hydroxyalkylene group, C 2-6 Aminoalkylene group, C 2-6 Carboxyalkylene group, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 1-6 Alkylene (3-to 6-membered heterocyclic group), C 3-6 Heterocyclic aryl radicals, C 1-6 Alkylsulfonyl radical, C 3-6 Cycloalkylsulfonyl, or C 2-6 A heterocycloalkylsulfonyl group; r 4 And R 5 A 3-to 8-membered heterocyclic or heterocyclic aryl group containing 1 to 3 heteroatoms bonded to each other;
G 4 and G 5 Each independently selected from: hydrogen;
R 1 selected from: hydrogen;
R 2 selected from: hydrogen;
R 3 each independently selected from: c 3-6 A cycloalkyl group;
X 1 、X 2 and X 3 Each independently selected from: halogen;
X 4 selected from: and (3) hydrogen.
In some embodiments, the compounds of formula IIIb of the present invention are selected from the following structures, which are characterized by including, but not limited to, any of the following structures:
Figure BDA0003795483320000051
Figure BDA0003795483320000061
in a second aspect, the present invention provides a process for the preparation of a compound of formula IIIb, characterized in that: it can be prepared by any one of the following two methods:
the first method comprises the following five steps, and the reaction equation is as follows:
Figure BDA0003795483320000071
the second method comprises the following three steps, and the reaction equation is as follows:
Figure BDA0003795483320000072
wherein the content of the first and second substances,
R 4 and R 5 Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Cyanoalkylene group, C 2-6 Hydroxyalkylene group, C 2-6 Aminoalkylene group, C 2-6 Carboxyalkylene group, C 2-6 Alkenyl radical, C 3-6 Cycloalkenyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclylalkylene, C 6-12 Aryl radical, C 3-10 Heterocyclic aryl radicals, C 1-6 Alkylsulfonyl radical, C 3-6 Cycloalkylsulfonyl, or C 2-6 Heterocycloalkylsulfonyl, or R 4 And R 5 Are connected with each other to form a 3-8 membered heterocyclic group or heterocyclic aryl group containing 1-3 heteroatoms.
R 6 Selected from: hydrogen, deuterium, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Cyanoalkylene group, C 3-6 Cyanocycloalkylene radical, C 2-6 Hydroxyalkylene group, C 2-6 Aminoalkylene group, C 3-6 Amino cycloalkylene radical, C 2-6 Carboxyalkylene group, C 3-6 Cycloalkyl, C 3-6 Amino cycloalkylene radical, C 1-6 Amino group (C) 3-6 Cycloalkyl) alkylene, 3-6 membered heterocyclyl, or 3-6 membered heterocyclylalkylene.
In another aspect, the invention further provides a method for preparing the following intermediate compound RM1b-01:
Figure BDA0003795483320000081
in a further aspect the present invention provides a process for the synthetic preparation of the following compounds SM2-01 and their use in the synthetic preparation of compounds of formula IIIb:
reaction I:
Figure BDA0003795483320000082
and (2) reaction II:
Figure BDA0003795483320000083
in another aspect of the present invention, there is provided a compound of formula IIIb or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent and/or excipient.
In another aspect of the present invention, there is provided a use of a compound represented by formula IIIb or a composition thereof for the preparation of a medicament for the prevention or treatment of a hematological disease.
In another aspect of the present invention, there is provided a use of a compound represented by formula IIIb or a composition thereof for the preparation of a medicament for treating cancer, wherein the cancer is selected from: pancreatic cancer, lung cancer, renal cancer, liver cancer, gastric cancer, cervical cancer, leukemia, and other 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 a further pharmaceutically active agent selected from: (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: (1) an immunomodulator; (2) PD-1; (3) PD-L1; or (4) other compounds not belonging to the above-mentioned (1) to (3).
In the above-mentioned combination drug product of the present invention, the immunomodulator includes, but is not limited to, car-T or other immunomodulators.
In the above combination drug product of the present invention, the PD-1 contains active agents that are marketed or in clinical trials, including but not limited to: opdivo, keytruda, JS001, SHR-1210, BGB-A317, ICI308, BAT1306, terepril mab, or Cedilizumab.
In the above combination drug product of the present invention, the PD-L1 comprises active agents that are marketed or in clinical trials, including but not limited to: recombinant human anti-PD-L1 monoclonal antibody injection, tecntriq, bavencio, IIIctayo, imfinzi or alcaladine soft capsule.
In a preferred embodiment, the compounds or compositions of the invention are particularly useful in the treatment of cancer or related angiogenesis inhibiting, preventing and treating hematological disorders. Meanwhile, compared with three similar control drugs, the compound provided by the invention has better multi-target selectivity and inhibitory activity.
The above-described embodiments and other aspects of the present invention will become apparent in the following detailed description. To this end, various references are set forth herein that describe in more detail certain background information, procedures, compounds and/or compositions, and are each incorporated by reference herein in its 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 specific details. Throughout the description and claims of this specification, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", for example, "comprising" and "including" are to be understood as open, inclusive (i.e., "including, but not limited to").
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
In the present invention, when not particularly specified, "alkyl" means a branched, straight-chain, monocyclic and polycyclic saturated alkyl group including 1 to 20 carbon atoms, which is composed of only carbon and hydrogen atoms. In a preferred embodiment, the alkyl group has from one to twelve carbon atoms (C1C 12 alkyl), from one to eight carbon atoms (C1C 8 alkyl), or from one to six carbon atoms (C1C 6 alkyl), and is attached to the remainder of the molecule by a single bond. An alkyl group may be unsubstituted or substituted with one or more substituents. In some embodiments, the alkyl group contains 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, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, and their various isomers, 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, the group consisting of: deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, amino (NH) 2 ) An amino group, an alkylamino group, an aminocarbonyl group, an alkyl group, an alkoxy group, an alkoxycarbonyl group, an alkylcarbonylamino group, an alkoxycarbonylamino group, an alkylaminocarbonyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkoxy group, a cycloalkoxycarbonyl group, a cycloalkyl amino group, a cycloalkyl aminocarbonyl group, a cycloalkenyl group, a cyclic ether group, a heterocyclic group, an alkylureido group, an aryl group, an aryloxy group, a heterocyclic aryl group, a heterocyclic aryloxy group, a condensed-ring aryl group, a condensed-ring heterocyclic aryl group, a condensed-ring oxy group, a condensed-ring aryloxy group, a condensed-ring heterocyclic aryloxy group, an arylureido group, or a heterocyclic arylureido group.
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. The carbocyclyl group may include multiple fused rings. The carbocyclyl group may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Carbocyclyl groups may be unsubstituted or substituted with one or more substituents. In some embodiments, carbocyclyl groups contain 3 to 10 carbon atoms, for example 3 to 6 carbon atoms.
In the present invention, when not specifically defined, the "aryl" refers to any stable hydrocarbon ring system group that may contain up to 7 carbon atoms per ring, monocyclic, bicyclic, tricyclic, or tetracyclic, wherein at least one ring is aromatic. Exemplary aryl groups are hydrocarbon ring systems containing hydrogen and 6 to 9 carbon atoms and at least one aromatic ring; a hydrocarbon ring system group containing hydrogen and 9 to 12 carbon atoms and at least one aromatic ring; a hydrocarbon ring system group containing hydrogen and 12 to 15 carbon atoms and at least one aromatic ring; or a hydrocarbon ring system group containing hydrogen and 15 to 18 carbon atoms and at least one aromatic ring. For the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from the following structure: benzene, biphenyl, anthracene, azulene, fluorene, indane, indene, naphthalene, phenanthrene, pyrene and the like.
In the present invention, when not particularly 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 ring system and 7 to 14 carbon atoms in a polycyclic ring system. "heterocycle" encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties, and heteroaromatic moieties. For example, a heterocyclyl group can 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-mentioned heterocyclic aryl groups as well as dihydro or tetrahydro analogs thereof, and includes, but is not limited to, the following "heterocyclyl": benzimidazolyl, benzofuranyl, benzpyrazolyl, benzotriazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, isobenzofuranyl, pyridopyridyl, heterocyclyl can be connected with other organic small molecule groups through carbon atoms or hetero atoms to form a novel compound with medicinal effect.
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
Compounds of the invention
1) The invention firstly designs and introduces a functional group containing novel polysubstituted arylamine and alkylamine, and synthesizes polysubstituted anilinourea compounds which can more effectively treat diseases such as a plurality of tumors accompanied with abnormal proliferation of angiogenesis and the like.
2) The present invention relates generally to compounds encompassed by formula IIIb, and cis, trans isomers, enantiomers, diastereomers, racemates, tautomers, or pharmaceutically acceptable salts or hydrates thereof, as well as deuterated or other isotopically substituted compounds:
Figure BDA0003795483320000111
wherein, the compound of formula IIIb, E, G 1 、G 2 、G 3 、G 4 、G 5 、R 1 、R 2 、R 3 、X 1 、X 2 、X 3 、X 4 Etc. are defined as set forth in the claims and the specification. Specific embodiments of the compounds of formula IIIb are also described below.
3) The compounds of the invention may exist in a variety of isomeric forms, as well as 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 the present specification, a "pharmaceutically acceptable salt" is a pharmaceutically acceptable, organic or inorganic acid or base salt of a compound of the present invention. Wherein, typical pharmaceutically acceptable salts are selected from any one of the following acids or bases: the inorganic acid salt is selected from hydrochloride, bromate, iodate, phosphate, sulfate, bicarbonate, bisulfate, borate, or nitrate; the organic acid salt is selected from acetate, benzoate, methanesulfonate, toluenesulfonate or valerate.
The compounds of the present 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: 2 H(D)、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 18 F、 36 and (4) Cl. These radiolabeled compounds are useful for detecting biodistribution, tissue concentration, and kinetics of transport and excretion from biological tissues, including the subject to which the labeled compound is administered. Labeled compounds are also useful for determining therapeutic effect, site or mode of action, and binding affinity of candidate therapeutics to pharmacologically important targets. Thus, certain radioactive substance labeled compounds of formula IIIb can be used for drug and/or tissue distribution studies. Radioisotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose because they are easy to incorporate and detection means are readily available.
With heavy isotopes such as deuterium (D) i.e 2 H substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life of deuterium-containing compounds). Substitution of deuterium for hydrogen can reduce the dosage required to obtain a therapeutic effect and can therefore be preferred for use in a discovery or clinical setting.
Positron emitting isotopes (e.g. of the type 11 C， 18 F， 15 O and 13 n) can provide labeled analogs of the compounds of the invention that are useful in Positron Emission Tomography (PET) studies, e.g., for detecting substance receptor occupancy. Isotopically-labeled compounds of formula IIIb can generally be prepared by conventional techniques known to those skilled in the art or by procedures otherwise described in the preparations and examples section belowIn a similar manner to those described above, using a suitable isotopically labelled reagent.
The embodiments of the invention described herein are also intended to encompass in vivo metabolites of the formula IIIb compounds. These products may originate, for example, from processes of oxidation, reduction, hydrolysis, amidation, esterification and the like, which are mainly attributed to the enzymatic activity following administration of the compounds of the invention.
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 salts" means: those salts that retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and whose formation employs inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, carbonic, and the like; and organic acids such as, but not limited to, acetic acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid, valeric acid, or the like.
Crystallization typically yields solvates of the compounds of the invention. The term "solvate" as used herein means: 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. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist in the form of hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as corresponding solvate forms. The compounds of the present invention may be true solvates, while in other cases the compounds of the present invention may retain only adventitious water or a mixture of water plus some adventitious solvent.
Pharmaceutical composition
In one embodiment, the compound of formula IIIb is formulated in a pharmaceutically acceptable composition comprising an amount of the compound of formula IIIb effective to treat the particular disease or condition of interest following 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 applications
The compounds of the present invention, or pharmaceutically acceptable salts thereof, may also be administered prior to, concurrently with, or subsequent to the administration of one or more other therapeutic agents. Such combination therapy includes the administration of a single pharmaceutical dosage formulation comprising a compound of the present invention and one or more other active agents, as well as the administration of the compound of the present invention and each active agent in separate pharmaceutical dosage formulations.
The positive progress effects of the invention are as follows:
1) The invention structurally optimizes and synthesizes a plurality of novel tyrosine kinase (RTK) inhibitor urea compounds with a formula IIIb from urea anti-cancer drugs, and the compounds have obvious curative effect on several important RTK targets (such as: VEGFR1, VEGFR2 (KDR), VEGFR3, FGFR2, RET, etc.) have better inhibitory effects.
2) Some novel IIIb urea compounds of the invention are useful in 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), stomach cancer (SNU 16), cervical cancer (Hela), leukemia (K562) and the like ] have better inhibition effects, can be used as a targeted drug to effectively treat some tumors or related cancers generated by RTK kinase mediation, and have better RTK targeting selectivity and safety.
3) Some of the novel urea compounds of formula IIIb of the present invention have better safety properties, for example: 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 gave MTD toxic doses (QD) in rats of greater than 150mg/kg, but also gave parameters hERG >30uM for potassium channel safety (MTD toxic dose in rats of ranvatinib of 40mg/kg, hERG =11.9 uM).
Detailed Description
The English abbreviation comments of chemical reagents and solvents in the process of synthesizing the novel polysubstituted aniline as the innovative key aryl urea compound are all summarized in the instrument and raw material description part in the examples.
All of the raw materials (e.g., SM1, SM2, SM3, and SM 4), reagents, and solvents used in the present invention are commercially available or commercially available.
In the present invention, the synthetic reaction routes, methods and conditions involved in the preparation of each new compound of formula IIIb are all conventionally known in the art, and according to the synthetic preparation methods disclosed below, those skilled in the art can prepare each specific compound involved in each compound of formula in the present invention by using the same principle and method.
The present invention is further described in detail below by way of examples, but the present invention is not limited thereby within the scope of the examples described. The following examples were carried out in accordance with conventional methods and conditions known to those skilled in the art, or according to the instructions for commercial products.
According to the synthetic preparation method disclosed in the invention, the technical personnel can adopt the same principle and method, and can respectively select different reagents such as SM1 (table 1), SM2 (table 2), SM3 (table 4 a), SM4 (table 4 b) and the like according to the conventional synthetic method shown in the following synthetic reaction scheme 1 to respectively prepare the specific compounds related to the general compounds in the invention (for details, see the compounds IIIb-01 to IIIb-65 in the formula series of the IIIb in the table 6 below).
The English abbreviation comments of chemical reagents and solvents in the process of synthesizing the novel polysubstituted aryl urea compound are all summarized in the instrument and raw material description part in the examples.
The invention optimizes the following three methods for synthesizing the compound of the formula IIIb series through the research of reaction conditions related to the synthesis.
Figure BDA0003795483320000151
The synthesis method 1 comprises the following steps: synthesis of Compounds of formula IIIb
In the above-described synthesis method 1,R 4 、R 5 and R 6 Each of which is as defined in claims 1 to 5 4 、R 5 And R 6 The same; r is 4 And R 5 Connected with each other to form a 3-8 membered heterocyclic or heterocyclic aryl group containing 1-3 heteroatoms; the specific synthetic reaction implementation steps are as follows:
1.1, synthesis of intermediate RM1:
adding SM1 (1.0 eq), SM2 (13 mmol), potassium tert-butoxide (1.0-1.5 eq) and DMSO (7-10 x) into a 50mL single-neck bottle, reacting under the protection of nitrogen at 85 ℃, after the reaction is finished by HPLC, post-treating the reaction solution, purifying by column chromatography, and drying to obtain an intermediate RM1.
1.2, synthesis of intermediate RM 2:
adding the intermediate RM1 (1.0 eq), DMF (5 x) and pyridine (5.0 x) into a 100mL three-necked bottle, controlling the temperature in an ice-water bath to be less than or equal to 10 ℃, dropwise adding phenyl chloroformate (5.0 eq), reacting at room temperature after dropwise adding, after HPLC (high performance liquid chromatography) shows that the reaction is finished, post-treating the reaction liquid, purifying by column chromatography and drying to obtain the intermediate RM2.
1.3, synthesis of an intermediate RM 3:
adding an intermediate RM2 (1.0 eq) and a reagent SM3 (1.0-5.0 eq) into a round bottom reaction bottle, dissolving pyridine (1.0-5.0 eq) into DMF (5-10 x), reacting at 20-80 ℃, and performing conventional operations such as aftertreatment, column chromatography purification, drying and the like to obtain the intermediate RM3 after HPLC shows that the reaction is finished.
1.4, synthesis of intermediate RM 4:
adding intermediate RM3 (1.0 eq) and THF (2-10 x), meOH (2-10 x) and sodium hydroxide (2.0-10.0 eq) into a round bottom reaction flask, reacting at 20-80 ℃, adjusting the pH to about 6 by 3N-HCl after HPLC shows that the reaction is finished, precipitating a solid product, and then carrying out conventional operations such as filtration, purification, drying and the like to obtain intermediate RM4.
1.5, synthesizing a target product IIIb:
adding an intermediate RM4-02 (1.0 eq), DMF (2-10 x), HATU (1.0-2.0 eq) and a reagent SM4 (1.0-2.0 eq) into a round bottom reaction bottle, dripping DIEA (1.0-2.0 eq) at 20-40 ℃, and performing conventional operations such as aftertreatment, column chromatography purification, drying and the like after HPLC (high performance liquid chromatography) shows that the reaction is finished to obtain the target product of the formula IIIb.
Figure BDA0003795483320000161
The synthesis method 2 comprises the following steps: synthesis of Compounds of formula IIIb
In the above Synthesis method 2, R 4 、R 5 And R 6 Each of which is as defined in claims 1 to 5 4 、R 5 And R 6 The same; r 4 And R 5 A 3-to 8-membered heterocyclic or heterocyclic aryl group containing 1 to 3 heteroatoms bonded to each other; the specific synthetic reaction implementation steps are as follows:
2.1, synthesis of intermediate RM1 b:
2.1-1, respectively adding the obtained SM2 and pyridine (4 eq) into a DMF (5 x) solvent in a round bottom reaction bottle, dropwise adding phenyl chloroformate (3.0 eq) at the temperature of lower than 10 ℃, and reacting at room temperature after dropwise adding. After HPLC shows that the reaction is finished, the RM2b intermediate is obtained after conventional operations such as post-treatment, column chromatography purification, drying and the like.
And 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 ℃, and obtaining an RM1b product after the HPLC shows that the reaction is finished and the conventional operations such as aftertreatment, column chromatography purification, drying and the like are carried out.
2.2, synthesizing a target product IIIb:
RM1b (1.0 eq) and SM1 (1-1.5 eq), potassium tert-butoxide (1.5 eq) obtained above were added to DMSO (10X) in a round-bottom reaction flask and reacted at 80-100 ℃. After HPLC shows that the reaction is finished, the target product of the formula IIIb is obtained after post-treatment, column chromatography purification and drying.
TABLE 1 structural formula of SM1 raw material
Figure BDA0003795483320000171
Figure BDA0003795483320000181
TABLE 2 Structure of starting Material SM2
Figure BDA0003795483320000182
Figure BDA0003795483320000191
TABLE 3a structural formula of the first step substitution etherification reaction product "RM1" series in Synthesis method one
Figure BDA0003795483320000192
Figure BDA0003795483320000201
TABLE 3b structural formula of the second step coupling reaction product "RM2" series in Synthesis method one
Figure BDA0003795483320000211
Figure BDA0003795483320000221
Figure BDA0003795483320000231
TABLE 3c structural formula of reaction product "RM3" series
Figure BDA0003795483320000232
TABLE 3d structural formula of the ester hydrolysis product "RM4" of the fourth step in the first Synthesis procedure
Figure BDA0003795483320000233
TABLE 3e structural formulas of the first step urea-forming reaction product "RM1b" series in Synthesis method III
Figure BDA0003795483320000241
TABLE 4a raw material SM3 series structural formula
Figure BDA0003795483320000242
Figure BDA0003795483320000251
TABLE 4b raw material SM4 series structural formula
Figure BDA0003795483320000252
Figure BDA0003795483320000261
TABLE 5 structural formula of polysubstituted aryl ureas of formula IIIb
Figure BDA0003795483320000262
Figure BDA0003795483320000271
Figure BDA0003795483320000281
Figure BDA0003795483320000291
Figure BDA0003795483320000301
Figure BDA0003795483320000311
Figure BDA0003795483320000321
In addition to synthesizing the corresponding compounds IIIb-01 to IIIb-65 according to the present invention by the above-mentioned reactions, not only compounds IIIb-01 to IIIb-65 according to the present invention can be synthesized, but also compounds in the following table 5a in which a part "H" of the compounds as described in claims 1 to 5 is replaced with deuterium (D) isotope (such as: 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 of formula IIIb in which part or all of the hydrogens (H) in the compound are replaced with deuterium (D) isotopes.
TABLE 5a structural formula of deuterated isotopic compounds of polysubstituted aryl ureas of formula IIIb
Figure BDA0003795483320000322
Figure BDA0003795483320000331
Figure BDA0003795483320000341
With particular reference to the results of the synthesis and analysis of each of the novel structural compounds of formula IIIb, detailed in the last example of the invention, the structural characterization of each compound is respectively by LC-MS and/or NMR: ( 1 H-NMR, and/or 19 F-NMR), and the like.
The synthesis and effect of various intermediates and compounds of the present invention are illustrated by the following examples.
The instruments and materials involved in the examples are described below:
the NMR spectra (hydrogen and fluorine) were obtained by analysis with an Ascend 400m NMR spectrometer from Bruker. Chemical shifts are reported in ppm (CDCl) using tetramethylsilane as an internal standard and deuterated solvents such as DMSO and MeOH for nuclear magnetic resonance analysis 3 : δ =7.26 ppm). The data information recorded is as follows: chemical shifts and their splitting and coupling constants (s: singlet; d: doublet; t: triplet; q: quartet; br: broad; m: multiplet).
The mass spectrum data was analyzed by using a combination of a liquid phase 1260 and a mass spectrum 6120, which are manufactured by Agilent. The molecular weight of the compound of formula IIIb in the invention is mainly cation mode ESI-MS [ (M + H) + ]。
The specific materials and intermediates involved in the present invention were provided by custom-made processing of shanghai zanan technologies ltd, and all other chemical reagents were purchased from reagent suppliers such as shanghai reagent company, aldrich company, acros company, and the like. If the intermediates or products required by the reaction in the synthesis process are not enough for the next step and other experiments, the synthesis is repeated for a plurality of times until the intermediates or products are enough. The activity test and the tests of pharmacology, toxicology and the like of the compound prepared by the invention are finished by CRO service companies in Shanghai and Beijing and the like according to the industrial regulations.
The English abbreviations used in the present invention and in the examples thereof for the chemical raw materials, reagents and solvents are as follows:
boc tert-butoxycarbonyl
(Boc) 2 O: di-tert-butyl dicarbonate
CDI: n, N' -carbonyldiimidazole
And (3) 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: hexamethylenetetramine
Py: pyridine compound
HBr: hydrobromic acid
HCl: hydrochloric acid
HOAc: glacial acetic acid
TFA: trifluoroacetic acid
MsOH: methanesulfonic acid (methanesulfonic acid)
TsOH: para toluene sulfonic acid
Cs 2 CO 3 Cesium carbonate
tBuOK potassium tert-butoxide
KOH potassium hydroxide
NaOH: sodium hydroxide (NaOH)
LiOH: lithium hydroxide
ACN/MeCN: acetonitrile
DCM: methylene dichloride
DCE: dichloroethane
DMF: n, N-dimethylformamide
DMSO (dimethylsulfoxide): dimethyl sulfoxide
Et 2 O: diethyl ether
EA: ethyl acetate
PE: petroleum ether
THF: tetrahydrofuran (THF)
TBME: methyl tert-butyl ether
Me is methyl
Et: ethyl radical
Pr of propyl group
iPr-isopropyl group
cPr cyclopropyl
Ph is phenyl
According to the above-described synthesis methods, the key trihaloaminophenol compound SM2-01 and the series of compounds IIIb-01 to IIIb-65 of formula IIIb of the present invention were synthesized, respectively:
example 1
Synthesis of Compound SM 2-01:
the first synthesis method of SM2-01 comprises the following steps:
Figure BDA0003795483320000371
preparation of diazonium salt of sulfanilic acid: p-aminobenzenesulfonic acid (60g, 1.00eq), water (500 mL) and Na2CO3 (20.0 g) are added into a 1L three-necked bottle, stirred until the mixture is clear, the internal temperature is controlled to be 0 ℃, a NaNO2 (25.0 g) water (75 mL) solution is dripped in, after dripping, concentrated hydrochloric acid (86 mL) is dripped in, the internal temperature is controlled to be less than 5 ℃, and then stirred for 40 minutes (refrigerated for standby).
Adding 44.2g of 3-chloro-2, 6-difluorophenol, 516.0g of water, 5mol/L of NaOH (70 mL) aqueous solution and 27.6g of Na2CO3 into a 1L three-mouth reaction flask, dripping a diazonium salt solution of sulfanilic acid when cooling in an ice water bath to 0-5 ℃, stirring until the reaction is finished, adding concentrated hydrochloric acid to adjust the pH to 5.0, then adding 108.0g of ammonium formate, adding 65.0g of Zn powder, and reacting at room temperature. To the end of the reaction, EA (1.0L) was added, stirred, filtered, the filtrate EA extracted (500 mx 2), the organic phases combined, washed with water, dried over anhydrous sodium sulfate, concentrated, added dichloromethane (120 mL), stirred, filtered, dried to give the product 4-amino-3-chloro-2, 6-difluorophenol (SM 2-01, 40.0 g), yield: 83 percent.
NMR analysis confirmed that the product SM2-01 hydrochloride had hydrogen nuclear magnetic resonance spectra data: 1H NMR (400MHz, d) 4 CD 3 OD)δ：7.30/7.273(m,1H)。
Nuclear magnetic resonance carbon spectrum data of product SM2-01 hydrochloride: 13C-NMR (100MHz, d4CD3OD) delta: 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, d4CD3OD) delta: -132.36/-132.40/-133.09/-133.13.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of product SM 2-01: theoretical value of m/z: 180.0, found: 180.1.
and a second synthesis method of SM 2-01:
Figure BDA0003795483320000381
adding 3-chloro-2, 6-difluorophenol (1000 g) and DCM (4L) into a 10.0L three-mouth reaction bottle, stirring and dissolving in ice-water bath, cooling to 0 ℃ in ice-water bath, dropwise adding concentrated nitric acid (600 g), controlling the temperature to be less than 10 ℃, completing dripping, stirring until the reaction is finished, adding water (2.0L), stirring for 0.5 hour, separating liquid, roughly removing filtrate through DCM (2.0L multiplied by 2), combining organic phases, washing with water, and concentrating to obtain 1.35kg of 3-chloro-2, 6-difluoro-4-nitrophenol.
3-chloro-2, 6-difluoro-4-nitrophenol (665 g) and water (5.0L) were charged into a 10.0L three-necked flask, heated to 85 ℃ and iron powder (500.0 g) was slowly added thereto while controlling the internal temperature to not higher than 95 ℃ and concentrated hydrochloric acid (100 mL) was added dropwise. Stirring for reaction for minutes after dripping, supplementing iron powder (40.0 g) until the reaction is finished, cooling to a temperature lower than 40 ℃, adding EA (2.5L), stirring and filtering, extracting the filtrate by EA, combining organic phases, washing, drying by anhydrous sodium sulfate, concentrating, adding DCM (600 mL), stirring, filtering, drying to obtain a product 4-amino-3-chloro-2, 6-difluorophenol (SM 2-01, 393 g), and the total yield of the two steps: and 72 percent.
NMR analysis confirmed that the product SM2-01 has hydrogen nuclear magnetic resonance spectrum data: 1H NMR (400MHz, d4CD3OD) delta: 7.30/7.273 (m, 1H).
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of product SM 2-01: theoretical value of m/z: 180.0, found: 180.1.
the nuclear magnetic resonance and mass spectrometry prove that the trihaloaminophenol compound SM2-01 which is the key in the innovation can be reliably obtained by the two synthesis methods.
Example 2
Synthesis of Compound IIIb-01:
according to the method shown in the first synthesis method
The first step is as follows:
to a 50mL single-neck flask, the starting materials SM1-01 (2.52g, 10mmol), SM2-01 (2.34g, 13mmol), potassium tert-butoxide (1.46g, 13mmol) and DMSO (20 mL) were added, the mixture was reacted at 85 ℃ under nitrogen protection, after the reaction was completed by HPLC, the reaction mixture was cooled to room temperature, poured slowly into 100mL of ice water, a solid precipitated, filtered, the cake washed with water, and dried sufficiently to obtain intermediate RM1-23 (3.28 g), yield: 83 percent;
the second step:
adding the intermediate RM1-23 (3.95g, 10mmol), DMF (20 mL) and pyridine (30 mmol) into a 100mL three-necked flask, controlling the temperature of an ice-water bath to be not more than 10 ℃, dropwise adding phenyl chloroformate (30 mmol), reacting at room temperature after dropwise addition, cooling the reaction liquid after HPLC (high performance liquid chromatography) shows that the reaction is finished, slowly pouring the reaction liquid into 100mL water, separating out a solid, filtering, washing a filter cake with water, drying, and purifying by column chromatography to obtain the intermediate RM2-23 (3.45 g), wherein the yield is as follows: 67%;
the third step:
adding the intermediate RM2-23 (5.15g, 10mmol), meCN (50 mL) and SM3-01 (30 mmol) into a 100mL single-neck bottle, reacting at 60 ℃, and after HPLC (high performance liquid chromatography) shows that a solid is separated out after the reaction is finished, filtering, washing and drying, and purifying by column chromatography to obtain a solid product RM3-01 (2.91 g) with the yield: 61 percent.
The fourth step:
to a 100mL single vial, intermediate RM3-01 (4.78g, 10 mmol), THF (10 mL), meOH (10 mL), and sodium hydroxide (30 mmol) were added, and the reaction was carried out at 40 deg.C, after completion of the reaction as shown by HPLC, after adjusting the pH to about 6 with 3N-hydrochloric acid, a solid precipitated, filtered, washed and dried to give solid product RM4-01 (3.94 g) in yield: 85 percent.
The fifth step:
adding intermediate RM4-01 (464mg, 1.0mmol), DMF (5 mL), HATU (1.3 mmol) and SM4-01 (1.5 mmol) into a 100mL single-neck flask, dropwise adding DIEA (3.0 mmol), reacting at 20 ℃, adding water to precipitate a solid after HPLC (high performance liquid chromatography) shows that the reaction is finished, filtering, washing, drying, and purifying by column chromatography to obtain a solid product IIIb-01 (386 mg) with yield: 81 percent.
Analysis confirmed 1H NMR (400MHz, DMSO +1.0eq methanesulfonic acid) delta for compound IIIb-01: 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).
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-01: theoretical value of m/z: 477.1, found: 477.2.
example 3
Synthesis of Compound IIIb-02:
the method comprises the following steps:
the first step is as follows: adding raw materials SM1-01 (2.52g, 10mmol), SM2-01 (2.12g, 13mmol), potassium tert-butoxide (1.46g, 13mmol) and DMSO (20 mL) into a 50mL single-neck flask, reacting at 85 ℃, cooling the reaction solution to room temperature after HPLC (high performance liquid chromatography) shows that the reaction is finished, slowly pouring the reaction solution into 100mL of ice water, precipitating a solid, filtering, washing a filter cake with water, and fully drying to obtain an intermediate RM1-24 (2.95 g), wherein the yield is as follows: 78 percent;
the second step is that: adding intermediate RM1-24 (3.78g, 10mmol), DMF (20 mL) and pyridine (30 mmol) into a 100mL three-necked bottle, controlling the temperature in an ice water bath to be not more than 10 ℃, dropwise adding phenyl chloroformate (30 mmol), reacting at room temperature after dropwise addition, cooling the reaction liquid after HPLC (high performance liquid chromatography) shows that the reaction is finished, slowly pouring the reaction liquid into 100mL of water, separating out a solid, filtering, washing a filter cake with water, drying, and purifying by column chromatography to obtain intermediate RM2-24 (3.64 g), wherein the yield is: 73 percent;
the third step: adding the intermediate RM2-24 (4.98g, 10mmol), meCN (50 mL) and SM3-01 (30 mmol) into a 100mL single-neck bottle, reacting at 60 ℃, and after HPLC (high performance liquid chromatography) shows that a solid is separated out after the reaction is finished, filtering, washing and drying, and purifying by column chromatography to obtain a solid product RM3-02 (2.63 g) with yield: 57 percent.
The fourth step: to a 100mL single vial, intermediate RM3-02 (4.61g, 10mmol), THF (10 mL), meOH (10 mL), and sodium hydroxide (30 mmol) were added, and the reaction was carried out at 40 ℃, after completion of the reaction as shown by HPLC, after adjusting to pH of about 6 with a dilute acid, a solid precipitated, filtered, washed, and dried to give solid product RM4-02 (3.53 g), yield: 79 percent.
The fifth step: adding intermediate RM4-02 (447mg, 1.0mmol), DMF (5 mL), HATU (1.3 mmol) and SM4-01 (1.5 mmol) into a 100mL single-neck flask, dropwise adding DIEA (3.0 mmol), reacting at 20 ℃, adding water to precipitate a solid after HPLC (high performance liquid chromatography) shows that the reaction is finished, filtering, washing, drying, and purifying by column chromatography to obtain a solid product IIIb-02 (308 mg), wherein the yield is as follows: 67%.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-02: theoretical value of m/z: 461.1, found: 461.2.
example 4
Synthesis of Compound IIIb-03:
the method comprises the following steps:
the synthetic 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 step to react with intermediate RM4-01 to form an amide bond product, which was dried by the same post-treatment and purified by column chromatography to give solid product IIIb-03 (329 mg) with yield: 67%.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compounds II 1-03: theoretical value of m/z: 491.1, found: 491.1.
example 5
Synthesis of Compound IIIb-04:
the method comprises the following steps:
the synthetic procedure for the preparation of compound IIIb-04 was the same as in example 2, wherein compound SM4-03 (1.5 mmol) was reacted with intermediate RM4-01 in the fifth reaction step to form amide bond product, which was dried by the same post-treatment and purified by column chromatography to obtain solid product IIIb-04 (345 mg) with yield: 68 percent.
ESI-MS [ (M + H) + ], confirmed by mass spectrometry, of the compound IIIb-04: theoretical value of m/z: 505.1, found: 505.0.
example 6
Synthesis of Compound IIIb-05
According to the method shown in the first synthesis method
The synthesis procedure for the preparation of compound IIIb-05 is the same as in example 2, wherein compound SM4-11 (1.5 mmol) is used in the fifth reaction step to react with intermediate RM4-01 to form an amide bond product, which is dried by the same post-treatment and purified by column chromatography to give solid product IIIb-05 (401 mg) in yield: 77 percent.
Analysis confirmed 1H NMR (400MHz, DMSO +1.0eq methanesulfonic acid) delta for compound IIIb-05: 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 the 19F NMR (377MHz, DMSO +1.0eq methanesulfonic acid) delta for compound IIIb-05: -126.67(s), -127.72(s).
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-05: theoretical value of m/z: 521.1, found: 521.2.
example 7
Synthesis of Compound IIIb-06
According to the method shown in the first synthesis method
The synthetic method for preparing the compound IIIb-06 is the same as that of example 2, wherein in the fifth step, the compound SM4-04 (1.5 mmol) is adopted to react with the intermediate RM4-01 to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-06 (407 mg) is obtained by column chromatography purification, and the yield is as follows: 80 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-06: theoretical value of m/z: 509.1, found: 509.1.
example 8
Synthesis of Compound IIIb-07
According to the method shown in the first synthesis method
The synthetic method for preparing the compound IIIb-07 is the same as that of example 3, wherein the compound SM4-05 (1.5 mmol) is adopted to react with the intermediate RM4-02 in the fifth step reaction to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-07 (424 mg) is obtained through column chromatography purification, and the yield is as follows: 83 percent.
Analysis confirmed 1H NMR (400MHz, DMSO +1.0eq methanesulfonic acid) delta for compound IIIb-07: 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 the 19F NMR (377MHz, DMSO +1.0eq methanesulfonic acid) delta for compound IIIb-07: -121.56(s), -132.15(s), -132.18(s), -150.58(s), -150.64(s).
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-07: theoretical value of m/z: 511.1, found: 511.1.
example 9
Synthesis of Compound IIIb-08
According to the method shown in the first synthesis method
The synthetic method for preparing the compound IIIb-08 is the same as that of example 2, wherein the compound SM4-05 (1.5 mmol) is adopted to react with the intermediate RM4-01 in the fifth step reaction to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-08 (453 mg) is obtained through column chromatography purification, and the yield is as follows: 86 percent.
Analysis confirmed the 1H NMR (400MHz, DMSO). Delta. For compound IIIb-08: 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 the 19F NMR (377MHz, DMSO). Delta.for compound IIIb-08: -121.62(s), -127.11 (m), -127.88(s).
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-08: theoretical value of m/z: 527.1, found: 527.1.
example 10
Synthesis of Compound IIIb-09
According to the method shown in the first synthesis method
The synthetic procedure for the preparation of compound IIIb-09 was the same as in example 2, wherein compound SM4-06 (1.5 mmol) was reacted with intermediate RM4-01 in the fifth reaction step to form amide bond product, which was dried by the same post-treatment and purified by column chromatography to obtain solid product IIIb-09 (441 mg), yield: 81 percent.
Analysis confirmed the 1H NMR (400MHz, DMSO) delta of compound IIIb-09: 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 the 19F NMR (377 MHz, DMSO). Delta.: -70.29(s), -127.07/-127.08 (d), -127.84(s).
Mass spectrometry confirmed ESI-MS [ (M + H) + ] of compound IIIb-09: theoretical value of m/z: 545.1, found: 545.1.
example 11
Synthesis of Compound IIIb-10
According to the method shown in the first synthesis method
The synthesis method for preparing the compound IIIb-10 is the same as that of example 2, wherein in the fifth step, the compound SM4-07 (1.5 mmol) is adopted to react with the intermediate RM4-01 to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-10 (368 mg) is obtained by column chromatography purification, and the yield: and 69 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-10: theoretical value of m/z: 534.2, found: 534.1.
example 12
Synthesis of Compound IIIb-11
According to the method shown in the synthesis method I
The synthetic procedure for the preparation of compound IIIb-11 is the same as in example 3, wherein compound SM4-08 (1.5 mmol) is used in the fifth reaction step to react with intermediate RM4-02 to form an amide bond product, which is dried by the same post-treatment and purified by column chromatography to give solid product IIIb-11 (424 mg), yield: 87 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-11: theoretical value of m/z: 487.2, found: 487.2.
example 13
Synthesis of Compound IIIb-12
According to the method shown in the first synthesis method
The synthesis procedure for the preparation of compound IIIb-12 is the same as in example 2, in which compound SM4-08 (1.5 mmol) is used in the fifth reaction step to react with intermediate RM4-01 to form an amide bond product, which is dried by the same post-treatment and purified by column chromatography to give solid product IIIb-12 (392 mg), yield: and 78 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-12: theoretical value of m/z: 503.1, found: 503.1.
example 14
Synthesis of Compound IIIb-13
According to the method shown in the first synthesis method
The synthesis procedure for the preparation of compound IIIb-13 is the same as in example 2, wherein compound SM4-09 (1.5 mmol) is used in the fifth reaction step to react with intermediate RM4-01 to form an amide bond product, which is dried by the same post-treatment and purified by column chromatography to give solid product IIIb-13 (402 mg), yield: 74 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-13: theoretical value of m/z: 543.2, found: 543.0.
example 15
Synthesis of Compound IIIb-14
According to the method shown in the synthesis method I
The synthetic procedure for the preparation of compound IIIb-14 is the same as in example 2, wherein compound SM4-10 (1.5 mmol) is reacted with intermediate RM4-01 in the fifth reaction step to form an amide bond product, which is dried by the same workup and purified by column chromatography to give solid product IIIb-14 (317 mg) in yield: and 63 percent.
ESI-MS [ (M + H) + ], confirmed by mass spectrometry, of the compound IIIb-14: theoretical value of m/z: 503.1, found: 503.0.
example 16
Synthesis of Compound IIIb-15
According to the method shown in the synthesis method I
The synthetic procedure for the preparation of compound IIIb-15 was the same as in example 3, wherein compound SM4-12 (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 workup and purified by column chromatography to give solid product IIIb-15 (236 mg) with yield: 48 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-15: theoretical value of m/z: 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 is the same as in example 2, in which compound SM4-12 (1.5 mmol) is used in the fifth reaction step to react with intermediate RM4-01 to form an amide bond product, which is dried by the same post-treatment and purified by column chromatography to give solid product IIIb-16 (294 mg), yield: 58 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-16: theoretical value of m/z: 507.1, found: 507.1.
example 18
Synthesis of Compound IIIb-17
According to the method shown in the first synthesis method
The synthetic procedure for the preparation of compound IIIb-17 was the same as in example 2, wherein compound SM4-13 (1.5 mmol) was used in the fifth reaction step to react with intermediate RM4-01 to form amide bond product, which was dried by the same post-treatment and purified by column chromatography to obtain solid product IIIb-17 (245 mg), yield: and 47 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-17: theoretical value of m/z: 521.1, found: 521.2.
example 19
Synthesis of Compound IIIb-18
According to the method shown in the synthesis method I
The synthetic procedure for the preparation of compound IIIb-18 was the same as in example 2, wherein compound SM4-14 (1.5 mmol) was used in the fifth reaction step to react with intermediate RM4-01 to form amide bond product, which was dried by the same post-treatment and purified by column chromatography to obtain solid product IIIb-18 (422 mg), yield: 81 percent.
The 1H NMR (400MHz, DMSO). Delta. Of compound IIIb-18 was confirmed by analysis: 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 the 19F NMR (377 MHz, DMSO). Delta.for compounds IIIb-18: 127.09/127.10 (d), -127.84(s).
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-18: theoretical value of m/z: 521.1, found: 521.2.
example 20
Synthesis of Compounds IIIb-19
According to the method shown in the first synthesis method
The synthetic procedure for the preparation of compounds IIIb-19 is the same as in example 2, wherein compound SM4-15 (1.5 mmol) is used in the fifth reaction step to react with intermediate RM4-01 to form an amide bond product, which is dried by the same workup and purified by column chromatography to give solid product IIIb-19 (305 mg) with yield: 57 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-19: theoretical value of m/z: 535.1, found: 535.2.
example 21
Synthesis of Compound IIIb-20
According to the method shown in the first synthesis method
The synthetic method for preparing the compound IIIb-20 is the same as that of example 2, wherein the compound SM4-16 (1.5 mmol) is adopted to react with the intermediate RM4-01 in the fifth step reaction to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-20 (242 mg) is obtained through column chromatography purification, and the yield is as follows: 45 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-20: theoretical value of m/z: 537.1, found: 537.2.
example 22
Synthesis of Compound IIIb-21
According to the method shown in the first synthesis method
The synthesis procedure for the preparation of compound IIIb-21 is the same as in example 2, in which compound SM4-17 (1.5 mmol) is used in the fifth reaction step to react with intermediate RM4-01 to form an amide bond product, which is dried by the same post-treatment and purified by column chromatography to give solid product IIIb-21 (295 mg), yield: and 55 percent.
Analysis confirmed the 1H NMR (400MHz, DMSO). Delta. For compound IIIb-21: 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).
Mass spectrometry confirmed the 19F NMR (377MHz, DMSO) delta of compounds IIIb-21: -127.10/127.11 (d), -127.86(s).
Analysis confirmed that ESI-MS [ (M + H) + ], for compound IIIb-21: theoretical value of m/z: 537.1, found: 537.2.
example 23
Synthesis of Compound IIIb-22
According to the method shown in the first synthesis method
The synthetic procedure for the preparation of compound IIIb-22 was the same as in example 2, wherein compound SM4-18 (1.5 mmol) was used in the fifth reaction step to react with intermediate RM4-01 to form an amide bond product, which was dried by the same workup and purified by column chromatography to give solid product IIIb-22 (258 mg), with yield: and 48 percent.
Mass spectroscopy confirmed the 1H NMR (400MHz, DMSO). Delta. For compound IIIb-22: 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).
Mass spectrometry confirmed the 19F NMR (377MHz, DMSO). Delta. For compound IIIb-22: -127.10/127.11 (d), -127.86(s).
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-22: theoretical value of m/z: 537.1, found: 537.2.
example 24
Synthesis of Compound IIIb-23
According to the method shown in the first synthesis method
The synthesis procedure for the preparation of compound IIIb-23 is the same as in example 2, wherein compound SM4-19 (1.5 mmol) is used in the fifth reaction step to react with intermediate RM4-01 to form an amide bond product, which is dried by the same post-treatment and purified by column chromatography to give solid product IIIb-23 (219 mg) with yield: 41 percent.
ESI-MS [ (M + H) + ], confirmed by mass spectrometry, of the compound IIIb-23: theoretical value of m/z: 533.1, found: 533.2.
example 25
Synthesis of Compound IIIb-24
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-24 is the same as in example 2, wherein compound SM4-20 (1.5 mmol) is used in the fifth reaction step to react with intermediate RM4-01 to form an amide bond product, which is dried by the same post-treatment and purified by column chromatography to give solid product IIIb-24 (296 mg), yield: 57 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-24: theoretical value of m/z: 519.1, found: 519.2.
example 26
Synthesis of Compound IIIb-25
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-25 is the same as in example 2, in which compound SM4-21 (1.5 mmol) is used in the fifth reaction step 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-25 (277 mg) in yield: 52 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-25: theoretical value of m/z: 533.1, found: 533.2.
example 27
Synthesis of Compound IIIb-26
According to the method shown in the first synthesis method
The synthesis procedure for the preparation of compound IIIb-26 is the same as in example 2, in which compound SM4-22 (1.5 mmol) is used in the fifth reaction step to react with intermediate RM4-01 to form an amide bond product, which is dried by the same post-treatment and purified by column chromatography to give solid product IIIb-26 (314 mg), yield: 59 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-26: theoretical value of m/z: 533.1, found: 533.0.
example 28
Synthesis of Compound IIIb-27
According to the method shown in the synthesis method I
The synthesis method for preparing the compound IIIb-27 is the same as that of example 2, wherein the compound SM4-23 (1.5 mmol) is adopted to react with the intermediate RM4-01 in the fifth step reaction to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-27 (300 mg) is obtained through column chromatography purification, and the yield is as follows: and 55 percent.
ESI-MS [ (M + H) + ], confirmed by mass spectrometry, of the compound IIIb-27: theoretical value of m/z: 546.2, found: 546.0.
example 29
Synthesis of Compound IIIb-28
According to the method shown in the first synthesis method
The synthetic method for preparing the compound IIIb-28 is the same as that of the example 2, wherein in the fifth step, the compound SM4-24 (1.5 mmol) is adopted to react with the intermediate RM4-01 to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-28 (465 mg) is obtained through column chromatography purification, and the yield is as follows: 83 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-28: theoretical value of m/z: 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 is as follows:
to a 50mL single-neck flask, the starting materials SM1-12 (2.19g, 10mmol), SM2-01 (2.34g, 13mmol), potassium tert-butoxide (1.46g, 13mmol) and DMSO (20 mL) were added, the mixture was reacted at 85 ℃ under nitrogen protection, after the reaction was completed by HPLC, the reaction mixture was cooled to room temperature, poured slowly into 100mL of ice water, a solid precipitated, filtered, the cake washed with water, and dried sufficiently to obtain intermediate RM1-25 (2.10 g), yield: 58 percent;
the second step is that:
adding intermediate RM1-25 (3.62g, 10mmol), DMF (20 mL) and pyridine (30 mmol) into a 100mL three-necked bottle, controlling the temperature in an ice-water bath to be not more than 10 ℃, dropwise adding phenyl chloroformate (30 mmol), reacting at room temperature after dropwise addition, cooling the reaction liquid after HPLC (high performance liquid chromatography) shows that the reaction is finished, slowly pouring the reaction liquid into 100mL of water, separating out a solid, filtering, washing a filter cake with water, drying, and purifying by column chromatography to obtain intermediate RM2-25 (4.10 g), wherein the yield is as follows: 85 percent;
the third step:
adding the intermediate RM2-25 (482mg, 1mmol), meCN (10 mL) and SM3-01 (3 mmol) into a 50mL single-neck flask, reacting at 60 ℃, and after HPLC shows that the reaction is finished, separating out a solid, filtering, washing, drying, and purifying by column chromatography to obtain a solid product IIIb-29 (280 mg) with yield: and 63 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-29: theoretical value of m/z: 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 is as follows:
to a 50mL single-neck flask, the raw materials SM1-12 (2.19g, 10mmol), SM2-11 (2.49g, 13mmol), potassium tert-butoxide (1.46g, 13mmol) and DMSO (20 mL) were added, the mixture was reacted at 85 ℃ under nitrogen protection, after HPLC showed that the reaction was completed, the reaction solution was cooled to room temperature, slowly poured into 100mL of ice water, a solid precipitated, filtered, washed with water, and sufficiently dried to obtain an intermediate RM1-26 (2.43 g), and the yield: 65 percent;
the second step:
adding the intermediate RM1-26 (3.74g, 10mmol), DMF (20 mL) and pyridine (30 mmol) into a 100mL three-necked flask, controlling the temperature of an ice-water bath to be not more than 10 ℃, dropwise adding phenyl chloroformate (30 mmol), reacting at room temperature after dropwise addition, cooling the reaction liquid after HPLC (high performance liquid chromatography) shows that the reaction is finished, slowly pouring the reaction liquid into 100mL water, precipitating a solid, filtering, washing a filter cake with water, drying, and purifying by column chromatography to obtain the intermediate RM2-26 (3.95 g), wherein the yield is as follows: 80 percent;
the third step:
adding the intermediate RM2-26 (494mg, 1mmol), meCN (10 mL), pyridine (3 mmol) and SM3-01 (3 mmol) into a 50mL single-neck bottle, reacting at 60 ℃, and after HPLC (high performance liquid chromatography) shows that a solid precipitates after the reaction is finished, filtering, washing and drying, and purifying by column chromatography to obtain a solid product IIIb-30 (274 mg), wherein the yield is as follows: 60 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-30: theoretical value of m/z: 457.1, found: 457.0.
example 32
Synthesis of Compound IIIb-31
According to the method shown in the first synthesis method
The synthetic method for preparing the compound IIIb-31 is the same as that of the example 2, wherein in the fifth step, the compound SM4-25 (1.5 mmol) is adopted to react with the intermediate RM4-01 to form an amido bond product, and after the same post-treatment, the solid is obtained by column chromatography purification.
The solid obtained was hydrolyzed with THF/MeOH system, after the reaction was completed, the pH was adjusted to about 6, and a solid precipitated, which was filtered, washed, and dried to obtain the solid product IIIb-31 (290 mg), yield: 53 percent.
ESI-MS [ (M + H) + ], confirmed by mass spectrometry, of the compound IIIb-31: theoretical value of m/z: 547.1, found: 547.2.
example 33
Synthesis of Compounds IIIb-32
According to the method shown in the synthesis method I
The synthesis method for preparing the compound IIIb-32 is the same as that of example 2, wherein the compound SM4-26 (1.5 mmol) is adopted to react with the intermediate RM4-01 in the fifth step reaction to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-32 (259 mg) is obtained through column chromatography purification, and the yield is as follows: 48 percent.
ESI-MS [ (M + H) + ], confirmed by mass spectrometry, of the compounds IIIb-32: theoretical value of m/z: 539.1, found: 538.9.
example 34
Synthesis of Compounds IIIb-33
Preparation of Compounds IIIb-33 the synthesis was identical to the first four steps of example 1.
The fifth step:
adding intermediate RM4-01 (478mg, 1.0mmol), DMF (5 mL) and CDI (1.5 mmol) into a 50mL single-neck bottle, dropwise adding DIEA (3.0 mmol), reacting at 20 ℃, after the reaction for converting into the intermediate is finished, adding SM4-27 (3.0 mmol), after the reaction is finished, adding water to precipitate a solid, filtering, washing, drying, and purifying by column chromatography to obtain a solid product IIIb-33 (151 mg), wherein the yield is as follows: 28 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-33: theoretical value of m/z: 541.1, found: 540.9.
example 35
Synthesis of Compound IIIb-34
Preparation of Compounds IIIb-34 the synthesis was the same as for the first four steps of example 1.
The fifth step:
adding intermediate RM4-01 (478mg, 1.0mmol), DMF (5 mL) and CDI (1.5 mmol) into a 50mL single-neck flask, dropwise adding DIEA (3.0 mmol), reacting at 20 ℃, adding SM4-28 (3.0 mmol) after the reaction for converting into the intermediate is finished by HPLC (high performance liquid chromatography), adding water to precipitate a solid after the reaction is finished by HPLC, filtering, washing, drying, and purifying by column chromatography to obtain a solid product IIIb-34 (130 mg), wherein the yield is as follows: 23 percent.
ESI-MS [ (M + H) + ], confirmed by mass spectrometry, of the compound IIIb-34: theoretical value of m/z: 567.1, found: 567.0.
example 36
Synthesis of Compounds IIIb-35
According to the method shown in the synthesis method I
Preparation of compound IIIb-35 the synthesis was the same as in example 2, wherein compound SM4-29 (1.5 mmol) was used in the fifth reaction step to react with intermediate RM4-01 to form amide bond product, which was dried by the same post-treatment and purified by column chromatography to obtain solid product IIIb-35 (409 mg) with yield: 73 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-35: theoretical value of m/z: 560.1, found: 559.8.
example 37
Synthesis of Compound IIIb-36
According to the method shown in the first synthesis method
The synthesis method for preparing the compound IIIb-36 is the same as that of example 2, wherein in the fifth step, the compound SM4-30 (1.5 mmol) is adopted to react with the intermediate RM4-01 to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-36 (387 mg) is obtained by column chromatography purification, and the yield is as follows: and 69 percent.
ESI-MS [ (M + H) + ], confirmed by mass spectrometry, of the compound IIIb-36: theoretical value of m/z: 560.1, found: 559.8.
example 38
Synthesis of Compound IIIb-37
According to the method shown in the synthesis method I
The synthesis method for preparing the compound IIIb-37 is the same as that of example 2, wherein the compound SM4-31 (1.5 mmol) is adopted to react with the intermediate RM4-01 in the fifth step reaction to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-37 (178 mg) is obtained through column chromatography purification, and the yield is as follows: 31 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-37: theoretical value of m/z: 573.1, found: 573.0.
example 39
Synthesis of Compound IIIb-38
According to the method shown in the synthesis method I
The synthesis method for preparing the compound IIIb-38 is the same as that of example 2, wherein the compound SM4-32 (1.5 mmol) is adopted to react with the intermediate RM4-01 in the fifth step reaction to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-38 (167 mg) is obtained through column chromatography purification, and the yield is as follows: 29 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-38: theoretical value of m/z: 575.1, found: 575.2.
example 40
Synthesis of Compound IIIb-39
According to the method shown in the synthesis method I
Preparation of compound IIIb-39 the synthesis was the same as in example 2, wherein compound SM4-33 (1.5 mmol) was used in the fifth reaction step to react with intermediate RM4-01 to form amide bond product, which was dried by the same post-treatment and purified by column chromatography to obtain solid product IIIb-39 (408 mg), yield: 73 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-39: theoretical value of m/z: 559.1, found: 558.9.
EXAMPLE 41
Synthesis of Compound IIIb-40
According to the method shown in the synthesis method I
The synthetic method for preparing the compound IIIb-40 is the same as that of the example 2, wherein the compound SM4-34 (1.5 mmol) is adopted to react with the intermediate RM4-01 in the fifth step reaction to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-40 (400 mg) is obtained through column chromatography purification, and the yield is as follows: 70 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-40: theoretical value of m/z: 573.1, found: 572.9.
example 42
Synthesis of Compound IIIb-41
According to the method shown in the synthesis method I
The synthetic method for preparing the compound IIIb-41 is the same as that of the example 2, wherein in the fifth step, the compound SM4-35 (1.5 mmol) is adopted to react with the intermediate RM4-01 to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-41 (383 mg) is obtained through column chromatography purification, and the yield is as follows: 67%.
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-41: theoretical value of m/z: 571.1, found: 570.9.
example 43
Synthesis of Compound IIIb-42
According to the method shown in the synthesis method I
Preparation of compound IIIb-42 the synthesis procedure was the same as in example 2, wherein compound SM4-36 (1.5 mmol) was used in the fifth reaction step to react with intermediate RM4-01 to form amide bond product, which was dried by the same post-treatment and purified by column chromatography to obtain solid product IIIb-42 (334 mg), yield: 58 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-42: theoretical value of m/z: 575.1, found: 574.9.
example 44
Synthesis of Compounds IIIb-43
According to the method shown in the synthesis method I
The synthesis procedure for the preparation of compound IIIb-43 is the same as in example 2, wherein compound SM4-37 (1.5 mmol) is used in the fifth reaction step to react with intermediate RM4-01 to form an amide bond product, which is dried by the same post-treatment and purified by column chromatography to give solid product IIIb-43 (224 mg), yield: 39 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-43: theoretical value of m/z: 575.1, found: 575.2.
example 45
Synthesis of Compounds IIIb-44
According to the method shown in the synthesis method I
Preparation of compound IIIb-44 the synthesis was the same as in example 2, wherein compound SM4-38 (1.5 mmol) was used in the fifth reaction step to react with intermediate RM4-01 to form amide bond product, which was dried by the same post-treatment and purified by column chromatography to obtain solid product IIIb-44 (132 mg), yield: 27 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compounds IIIb-44: theoretical value of m/z: 488.1, found: 487.8.
example 46
Synthesis of Compounds IIIb-45
According to the method shown in the synthesis method I
The synthetic method for preparing the compound IIIb-45 is the same as that of example 2, wherein the compound SM4-39 (1.5 mmol) is adopted to react with the intermediate RM4-01 in the fifth step reaction to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-45 (236 mg) is obtained through column chromatography purification, and the yield is as follows: and 47 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-45: theoretical value of m/z: 502.1, found: 501.9.
example 47
Synthesis of Compound IIIb-46
According to the method shown in the synthesis method I
The synthesis method for preparing the compound IIIb-46 is the same as that of example 2, wherein the compound SM4-40 (1.5 mmol) is adopted to react with the intermediate RM4-01 in the fifth step reaction to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-46 (289 mg) is obtained through column chromatography purification, and the yield is as follows: 56 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-46: theoretical value of m/z: 516.1, found: 515.9.
example 48
Synthesis of Compounds IIIb-47
According to the method shown in the synthesis method I
The synthesis method for preparing the compound IIIb-47 is the same as that of example 2, wherein the compound SM4-41 (1.5 mmol) is adopted to react with the intermediate RM4-01 in the fifth step reaction to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-47 (419 mg) is obtained through column chromatography purification, and the yield is as follows: 79 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-47: theoretical value of m/z: 530.1, found: 529.9.
example 49
Synthesis of Compounds IIIb-48
According to the method shown in the synthesis method I
The synthetic method for preparing the compound IIIb-48 is the same as that of the example 2, wherein the compound SM4-42 (1.5 mmol) is adopted to react with the intermediate RM4-01 in the fifth step reaction to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-48 (322 mg) is obtained through column chromatography purification, and the yield is as follows: 61 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-48: theoretical value of m/z: 528.1, found: 527.9.
example 50
Synthesis of Compounds IIIb-49
According to the method shown in the first synthesis method
Preparation of compound IIIb-49 the synthesis procedure was the same as in example 2, wherein compound SM4-43 (1.5 mmol) was used in the fifth reaction step to react with intermediate RM4-01 to form amide bond product, which was dried by the same post-treatment and purified by column chromatography to obtain solid product IIIb-49 (396 mg), yield: 73 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-49: theoretical value of m/z: 542.1, found: 541.9.
example 51
Synthesis of Compounds IIIb-50
According to the method shown in the synthesis method I
The synthesis method for preparing the compound IIIb-50 is the same as that of example 2, wherein the compound SM4-44 (1.5 mmol) is adopted to react with the intermediate RM4-01 in the fifth step reaction to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-50 (356 mg) is obtained through column chromatography purification, and the yield is as follows: and 69 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ] of compound IIIb-50: theoretical value of m/z: 516.1, found: 515.9.
example 52
Synthesis of Compound IIIb-51
The synthetic procedure for the preparation of compound IIIb-51 is the same as in the first four steps of example 1, wherein compound SM4-45 (1.5 mmol) is reacted with intermediate RM4-01 in the fifth reaction step to form an amide bond product, which is subjected to the same post-treatment and then purified by column chromatography to obtain a solid.
The obtained solid is subjected to acid amino protecting group removal through a THF/MeOH system, after the reaction is finished, the pH is adjusted to about 10, a solid is precipitated, filtered, washed and dried to obtain a solid product IIIb-51 (172 mg), and the yield: 34 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-51: theoretical value of m/z: 506.1, found: 505.9.
example 53
Synthesis of Compound IIIb-52
The synthesis method for preparing the compound IIIb-52 is the same as that of example 2, wherein the compound SM4-46 (1.5 mmol) is adopted to react with the intermediate RM4-01 in the fifth step reaction to form an amido bond product, and after the same post-treatment and drying, the solid product IIIb-52 (228 mg) is obtained through column chromatography purification, and the yield is as follows: and 43 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-52: theoretical value of m/z: 529.1, found: 528.8.
example 54
Synthesis of Compound IIIb-53
Preparation of compound IIIb-53 the synthesis procedure was the same as in example 2, wherein compound SM4-47 (1.5 mmol) was used in the fifth reaction step to react with intermediate RM4-01 to form amide bond product, which was dried by the same post-treatment and purified by column chromatography to obtain solid product IIIb-53 (337 mg), yield: 62 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-53: theoretical value of m/z: 543.1, found: 543.0.
example 55
Synthesis of Compounds IIIb-54
Preparation of compound IIIb-54 the synthesis procedure was the same as in example 2, wherein compound SM4-48 (1.5 mmol) was used in the fifth reaction step to react with intermediate RM4-01 to form amide bond product, which was dried by the same post-treatment and purified by column chromatography to obtain solid product IIIb-54 (358 mg), yield: 66 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ] of compound IIIb-54: theoretical value of m/z: 543.1, found: 543.0.
example 56
Synthesis of Compounds IIIb-55:
according to the method shown in the third synthesis method
Figure BDA0003795483320000601
Preparation of phenyl 2-chloro-3, 5-difluoro-4-hydroxybenzenecarbamate:
Figure BDA0003795483320000602
adding SM2-01 (100g, 0.56mol), pyridine (58g, 0.73mol) and DMF (1L) into a 5L three-necked bottle, stirring, cooling in an ice-water bath at the temperature of not more than 10 ℃, dropwise adding phenyl chloroformate (96g, 0.61mol), sampling and detecting after 15 minutes of addition until SM2-01 conversion is finished, and directly carrying out the next step.
The analysis confirms that the intermediate: nuclear magnetic resonance hydrogen spectrum of phenyl 2-chloro-3, 5-difluoro-4-hydroxybenzenecarbamate, 1H-NMR (400mhz, dmso) δ:10.71 (s, 1H), 9.78 (s, 1H), 7.44-7.36 (m, 3H), 7.27-7.19 (m, 3H); NMR spectrum of the intermediate, 19F NMR (377MHz, DMSO). Delta.: -131.38/-131.42 (d), -132.79/-132.81 (d).
And (3) dropwise adding cyclopropylamine (127g, 2.24mol) at the temperature of not higher than 10 ℃, stirring for half an hour, after the detection of conversion is finished, adding acetonitrile (2L), stirring for half an hour, filtering, leaching with ethyl acetate (300 mL), and drying to obtain 1- (2-chloro-3, 5-difluoro-4-hydroxyphenyl) -3-cyclopropylurea cyclopropylammonium salt (143 g).
The intermediate is prepared by reacting: 1- (2-chloro-3, 5-difluoro-4-hydroxyphenyl) -3-cyclopropylurea cyclopropylammonium salt (143 g) was added to a 5L three-necked flask, added to methanol (600 mL), stirred well, 6N-hydrochloric acid (80 mL) was added dropwise, stirred to complete dissolution, water (3L) was added, stirred for about 1 hour, filtered, washed with water (1.0L), dried to give RM1b-01 (117 g) in 80% yield.
The analysis confirms that the nuclear magnetic resonance hydrogen spectrum of the intermediate RM1b-01, 1H-NMR (400MHz, DMSO) delta: 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); nuclear magnetic resonance carbon spectrum of intermediate RM1b-01, 13C-NMR (100MHz, DMSO). Delta.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); NMR fluorine spectrum of intermediate RM1b-01, 19F-NMR (377MHz, DMSO). Delta.: 132.09 (m). Mass spectrometry confirmed ESI-MS [ (M + H) + ] of compound RM1b-01: theoretical value of m/z: 263.0, found: 263.1.
adding SM1-02 (269mg, 1.0mmol), RM1b-01 (342mg, 1.3mol), potassium tert-butoxide (146mg, 1.3mmol) and dimethyl sulfoxide (3 mL) into a 50mL single-mouth bottle, heating to 65 ℃ for reaction, after the reaction is finished, cooling, dropping into ice water (30 mL), fully stirring, filtering, washing with water, and purifying by column chromatography to obtain a target compound IIIb-55:312mg, yield 63%.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-55: theoretical value of m/z: 495.1, found: 494.9.
example 57
Synthesis of Compounds IIIb-56
The synthesis of the compound IIIb-56 was carried out in the same manner as in example 55, wherein compound SM1-03 (1.0 mmol) was reacted with intermediate RM1b-01 (1.3 mmol) in the third reaction step, and the same work-up was carried out followed by column chromatography to purify the compound IIIb-56 (323 mg), yielding: 60 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-56: theoretical value of m/z: 513.1, found: 512.8.
example 58
Synthesis of Compounds IIIb-57
Preparation of compound IIIb-57 the synthesis was the same as in example 55, using compound SM1-04 (1.0 mmol) in the third reaction step to react with intermediate RM1b-01 (1.3 mmol), and purification by column chromatography after the same work-up gave product IIIb-57 (276 mg), yield: 52 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-57: theoretical value of m/z: 531.1, found: 530.8.
example 59
Synthesis of Compound IIIb-58
The synthesis procedure for the preparation of the compounds IIIb-58 is the same as in example 55, except that in the third step reaction compound SM1-05 (1.0 mmol) is used to react with intermediate RM1b-01 (1.3 mmol), which after the same work-up is purified by column chromatography to give the product IIIb-58 (259 mg) in yield: and 53 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-58: theoretical value of m/z: 488.1, found: 487.8.
example 60
Synthesis of Compound IIIb-59
The synthesis procedure for the preparation of compound IIIb-59 is the same as in example 55, except that in the third step reaction compound SM1-06 (1.0 mmol) is used to react with intermediate RM1b-01 (1.3 mmol), and after the same work-up column chromatography purification the product IIIb-59 (354 mg) is obtained, yield: 68 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-59: theoretical value of m/z: 520.1, found: 519.9.
example 61
Synthesis of Compound IIIb-60
The synthesis procedure for the preparation of compound IIIb-60 is the same as in example 55, except that in the third step, compound SM1-07 (1.0 mmol) is reacted with intermediate RM1b-01 (1.3 mmol), and the same work-up is followed by column chromatography purification to give the solid product.
Removing the silyl ether protecting group of hydroxyl from the obtained solid by a MeOH system and adding tetrabutylammonium bromide, removing THF by desolventizing after the reaction is finished, adding water to precipitate a solid, filtering, washing, and drying to obtain a solid product IIIb-60 (192 mg), wherein the yield is as follows: 38 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-60: theoretical value of m/z: 493.1, found: 492.9.
example 62
Synthesis of Compound IIIb-61
The synthesis procedure for the preparation of compound IIIb-61 is the same as in example 55, except that in the third step, compound SM1-08 (1.0 mmol) is reacted with intermediate RM1b-01 (1.3 mmol), and the same work-up is followed by column chromatography purification to give the solid product.
And (3) removing the amino protecting group of the obtained solid through THF/MeOH system, adjusting pH to about 10 after the reaction is finished, precipitating the solid, filtering, washing, and drying to obtain a solid product IIIb-61 (233 mg), wherein the yield is as follows: 45 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-61: theoretical value of m/z: 518.1, found: 517.9.
example 63
Synthesis of Compounds IIIb-62:
the synthesis procedure for the preparation of compound IIIb-62 is the same as in example 55, except that in the third step reaction compound SM1-09 (1.0 mmol) is used to react with intermediate RM1b-01 (1.3 mmol), which is purified by column chromatography after the same work-up to give product IIIb-62 (305 mg) in yield: 59 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-62: theoretical value of m/z: 517.1, found: 516.9.
example 64
Synthesis of Compounds IIIb-63
The synthesis procedure for the preparation of the compounds IIIb-63 is the same as in example 55, except that in the third step reaction compound SM1-09 (1.0 mmol) is used to react with intermediate RM1b-01 (1.3 mmol), which is purified by column chromatography after the same work-up to give the product IIIb-63 (274 mg) in yield: and 53 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ], for compound IIIb-63: theoretical value of m/z: 517.1, found: 516.9.
example 65
Synthesis of Compounds IIIb-64
The synthesis procedure for the preparation of the compounds IIIb-64 was the same as in example 55, except that in the third step reaction, the compound SM1-11 (1.0 mmol) was used to react with intermediate RM1b-01 (1.3 mmol), and the same work-up was followed by column chromatography purification to give the product IIIb-64 (331 mg) in yield: and 64 percent.
Mass spectrometry confirmed that ESI-MS [ (M + H) + ] of compound IIIb-64: theoretical value of m/z: 517.1, found: 516.9.
example 66
Synthesis of Compounds IIIb-65
The synthesis procedure for the preparation of compounds IIIb-65 was the same as in example 55, except that in the third step reaction, compounds SM1-16 (1.0 mmol) were used to react with intermediate RM1b-01 (1.3 mmol), and the same work-up followed by column chromatography purification gave the product IIIb-65 (286 mg), yield: 57 percent.
Mass spectrometry confirmed ESI-MS [ (M + H) + ] of compound IIIb-65: theoretical value of m/z: 502.1, found: 501.9.
example 67
And (2) a second synthesis method of the compound IIIb-08:
Figure BDA0003795483320000641
A1.0L three-necked flask was charged with SM1-13 (10.0 g, 33mmol), RM1b-01 (11.3g, 43mmol), potassium tert-butoxide (4.8g, 43mmol) and dimethyl sulfoxide (100 mL), and the mixture was heated to 65 ℃ for reaction, after the reaction was completed, cold-cut and dropwise added with ice water (1L), stirred, filtered, washed with an appropriate amount of water, and dried to obtain IIIb-08 (13.0 g) in yield: 75 percent.
Example 68
The second synthesis method of the compound IIIb-50 comprises the following steps:
or according to the method shown in the third synthesis method
Figure BDA0003795483320000642
1.0L three-necked bottle containing SM1-14 (10.0g, 35mmol), RM1b-01 (11.8g, 45mmol), potassium tert-butoxide (5.0g, 45mmol) and dimethyl sulfoxide (100 mL) was heated to 65 ℃ for reaction, after the reaction was completed, ice water (1L) was added thereto after cold cutting, and after stirring, filtration, washing with an appropriate amount of water and drying, IIIb-50 (12.8 g) was obtained in a yield: 71 percent.
Example 69: in vitro inhibitory Activity drug Effect test
The compound prepared by the invention can preliminarily determine and screen the effect of inhibiting 7 tumor cell line targets such as 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) and leukemia (K562) by the following in-vitro inhibition activity test experiments, and further screen better new anti-cancer drugs by determining the inhibition activity of various RTK targets such as VEGFR1, VEGFR2 (KDR), VEGFR3, FGFR2 and RET, and finally confirm the curative effect of the new drugs by clinical experiments. Other methods will be apparent to those of ordinary skill in the art.
This example investigated the proliferation inhibitory effect of compounds (IIIb-01 to IIIb-65) on various tumor cells.
1. The cell plating experiment was performed on the first day by uniformly plating 100ul of cells containing 5000 cells per well (for example, 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) and the like) on a 96-well cell culture plate (Corning 3917 plate), and then placing the cell plate in a cell culture chamber.
2. The compound dosing experiment was performed the following day, compounds were prepared, 10 concentration points were prepared for each test compound and positive reference drug, diluted in culture medium with a concentration gradient of 1.5 ul of test compound or positive reference drug is added into the cell plate, the final concentration of the test compound is 10uM at most, the final concentration of the positive reference drug is 3uM at most, the DMSO concentration is controlled below 0.2%, and then the cell plate is placed in a cell culture box for culture for 72 hours.
3. On the fifth day, after 72 hours of treatment, a CTG reagent (Promega G7573) was prepared according to the reagent instructions, and the prepared CTG reagent and the cell plate were simultaneously placed in a room temperature environment for 30 minutes for thermal equilibrium. Then 50ul of CTG reagent is added into the hole of each cell plate, the cell plates are evenly mixed by low speed oscillation and then are placed at room temperature for 20 minutes, and the cell plates are preserved in dark. Then placing the cell culture plate in a plate reader (Envision or Viewlux) to record data and analyzing and calculating the proliferation inhibition rate, wherein the compound concentration corresponding to 50% inhibition rate in the curve is the IC of the proliferation inhibition effect of the compound on the tumor cell line 50 。
Five kinase inhibitory Activity (IC) 50 ) Evaluation experiments:
in the experiment, the inhibition effect of the small molecular compound inhibitor on 17 kinases is detected by using a fluorescence microfluidics Mobility detection technology (Mobility-Shift Assay).
1. Buffer solution preparation: 50mM HEPES, pH 7.5,0.00015% Brij-35.
2. The compounds were formulated into a concentration gradient in 100% DMSO, diluted to 10% DMSO with buffer, and added to a 384 well plate. The starting concentration of the compound was 500nM, 25. Mu.M was prepared by 100% DMSO, and diluted 10-fold with a gradient, 10-fold diluted with buffer solution, 10-th DMSO-containing compound intermediate dilution was prepared, and 5. Mu.l to 384-well plates were transferred.
3. The kinase was diluted to optimal concentration with the following buffer: 50mM HEPES, pH 7.5,0.00015% Brij-35,2mM DTT (final enzyme reaction concentration: VEGFR-1 (FLT 1): 2nM VEGFR-2 (KDR): 1.2nM VEGFR-3 (FLT 4): 1.5nM FGFR1: 2FGFR3: 8nM FGFR4: 3.5nM. Transfer 10 μ l to 384 well plates and incubate with compound for 10 min.
4. The substrate was diluted to optimal concentration with the following buffers: 50mM HEPES, pH 7.5,0.00015% Brij-35. Wherein the final reaction concentration is as follows:
VEGFR1(FLT1)：3μM Peptide30(5-FAM-KKKKEEIYFFFCONH 2 ),278μM ATP,10mM MgCl 2 ；
VEGFR2(KDR)：3μM Peptide22(5-FAM-EEPLYWSFPAKKKCONH 2 ),92μM ATP,10mM MgCl 2 ；
VEGFR3(FLT4)：3μM Peptide30(5-FAM-KKKKEEIYFFFCONH 2 ),84μM ATP,10mM MgCl 2 ；
FGFR2：3μM Peptide22(5-FAM-EEPLYWSFPAKKKCONH 2 ),1.9μM ATP,10mM MgCl 2 ；
RET：3μM Peptide22(5-FAM-EEPLYWSFPAKKKCONH 2 ),23μM ATP,10mM MgCl 2
5. reading the conversion rate by using a Caliper Reader, calculating the conversion rate as inhibition, and calculating the formula Percent inhicon = (maxConversion)/(max-min) × 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 channel) is an important parameter related to compound safety in the research process of new drugs, and potassium ion (K) + ) The channel is highly expressed in the heart and is the rapid repolarization of the myocardial action potential in three phasesThe main component of the current (IKr). Loss of function due to hERG mutations is often associated with some inherited long QT syndrome (LQTS) and increases the risk of developing severe ventricular arrhythmias, the torsionally imposed tachycardia. Potassium ion (K) + ) The side effects caused by the inhibition of the channel are one of the main reasons for the failure of new drug research and marketing in recent years if the in vitro inhibitory effect IC of hERG of a compound 50 <30uM, the compound may present the above mentioned risks and risks. Thus the in vitro inhibitory Effect (IC) of the hERG channel of the drug 50 ) Evaluations have been recommended by the international conference on drug registration coordination as part of preclinical safety evaluation efforts (ICHS 7B Expert Working Group,' 02).
In vitro inhibitory Effect (IC) of hERG 50 ) Evaluation experiment:
the stably transformed cells were dropped on a round slide and placed in a petri dish at a cell density of less than 50% and incubated overnight. The experimental cells were transferred to an approximately 1ml bath embedded in an inverted microscope platform and perfused with extracellular fluid at a perfusion rate of 2.7 ml/min. The experiment was started after 5 minutes of stabilization. Membrane currents were recorded using a HEKA EPC-10 patch clamp amplifier and PATCHMASTER acquisition system (HEKA Instruments Inc., D-67466 Lambrrecht, pfalz, germany). All experiments were done at room temperature (22-24 ℃). A P-97 microelectrode drawing machine (Sun Instrument Company, one Digital Drive, novato, CA 94949) was used to straighten the electrodes (BF 150-110-10) during the experiments. The inner diameter of the electrode is 1-1.5mm, and the water inlet resistance after the electrode is filled with the internal liquid is 2-4 MOmega. The electrophysiological stimulation protocol for the hERG potassium channel was to first clamp the membrane voltage at-80 mV, give the cells a 2s, +20mV voltage stimulation, activate the hERG potassium channel, repolarize to-50 mV for 5s, generate an outward tail current, and stimulate the frequency once every 15 s. The current value is the peak value of the tail current.
Channel currents were recorded in the experiment using a whole-cell recording mode. Extracellular fluid (approximately 2 ml per minute) was first perfused and continuously recorded, and the current was waited for stabilization (current decay (Run-Down) less than 5% in 5 minutes) at which time the tail current peak was the control current value. And then perfusing the extracellular fluid containing the drug to be detected and continuously recording until the inhibition effect of the drug on the hERG current reaches a stable state, wherein the tail current peak value is the current value after the drug is added. The steady state criterion is determined by whether the nearest consecutive 3 current traces coincide. After reaching a stable state, if the hERG current returns to or approaches the level before dosing after perfusion washing with extracellular fluid, perfusion testing can continue for other concentrations or drugs. 30 μ M Quinidine (Quinidine) was used in the experiment as a positive control to ensure that the cell response used was normal.
Partially preferred compounds of formula IIIb (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) inhibit various tumor cell lines [ e.g.: the results of activity tests on 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 (PC-3), leukemia (K562), etc. ] and tyrosine kinases (e.g., VEGFR1, VEGFR2 (KDR), VEGFR3, FGFR2, RET) are shown in tables 6, 7 and 8 below, respectively.
The range of activity effect (IC) of each compound in inhibiting pancreatic cancer cell line (BXPC 3) 50 ) In that<5.0uM is designated "A", an activity range of 5.0-10.0uM is designated "B", and an activity range>10.0uM is designated "C";
the activity range (IC) of each compound for inhibiting lung cancer cell strain (A549) 50 ) In that<2.5uM is designated "A", the activity range is 2.5-5.0uM is designated "B", the activity range is>5.0uM is designated "C";
the range of activity (IC) of each compound inhibiting renal cancer cell line (Caki-1) 50 ) In that<2.5uM is designated "A", an activity range of 2.5-5.0uM is designated "B", and an activity range>5.0uM is designated "C";
the activity range (IC) of each compound for inhibiting liver cancer cell lines (Hep 3B 2.1-7) 50 ) In that<2.5uM is designated "A", an activity range of 2.5-5.0uM is designated "B", and an activity range>5.0uM is designated "C";
the range of activity (IC) of each compound inhibiting gastric cancer cell line (SNU 16) 50 ) In that<5.0uM designated "A", activity rangeIn the range of 5.0-10.0uM, denoted as "B", activity range>10.0uM designated "C";
the activity range (IC) of each compound for inhibiting cervical cancer cell line (Hela) 50 ) In that<5.0uM is designated "A", an activity range of 5.0-10uM is designated "B", and an activity range>10uM is denoted "C";
the range of the Effect (IC) of each Compound on inhibiting the Activity of leukemia cell lines (K562) 50 ) In that<5.0uM is designated "A", an activity range of 5.0-10uM is designated "B", and an activity range>10uM is denoted "C";
the activity effect range (IC) of each compound for inhibiting prostate cancer cell strain (PC-3) 50 ) In that<5.0uM is designated "A", an activity range of 5.0-10uM is designated "B", and an activity range>10uM is designated "C".
Table 6: results of three cell line inhibitory Activity assays for some Compounds of formula IIIb
Figure BDA0003795483320000681
Figure BDA0003795483320000691
Figure BDA0003795483320000701
Table 7: the activity results of some preferred compounds shown in formula IIIb in inhibiting four cell strains of liver cancer, gastric cancer, cervical cancer and leukemia
Figure BDA0003795483320000702
Figure BDA0003795483320000711
Some preferred compounds of formula IIIbThe activity results of the compounds respectively used for inhibiting RTK targets such as VEGFR1-3, FGFR2, RET and the like are respectively listed in the following table 8; wherein each compound inhibits the activity range (IC) of various tyrosine kinases VEGFR1, KDR (VEGFR 2) and VEGFR3 50 ) In that<5nM is designated "A", the activity range is 5-10nM is designated "B", the activity range is>10nM is denoted "C"; the range of effects (IC) of each compound on the inhibition of the activity of various tyrosine kinases FGFR2 50 ) In that<50nM is designated "A", the activity range is 50-100nM is designated "B", the activity range is>100nM is denoted "C"; the range of effects (IC) of each compound on inhibiting the activity of various tyrosine kinases RET 50 ) In that<5nM is designated "A", the activity range is 5-10nM is designated "B", the activity range is>10nM is indicated as "C".
Table 8: results of inhibition of the Activity of three tyrosine kinases by certain preferred Compounds of formula IIIb
Figure BDA0003795483320000712
Figure BDA0003795483320000721
Table 9: results of hERG inhibition Effect assays for some preferred Compounds
Figure BDA0003795483320000722
Figure BDA0003795483320000731
Figure BDA0003795483320000741
Figure BDA0003795483320000751
From the results of the tests 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 inhibitory effects on various tumor cell lines and tyrosine kinases, and the inhibitory activity and the safety parameters of hERG >30uM are obviously better than those of the 3 urea control drugs of ranvatinib, regorafenib and sorafenib which are 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 and IIIb-65" with higher activity in the above tables 7 to 9, the present invention separately performed MTD toxicity test (150 mg/kg, QD) in rats, and no abnormal condition such as death occurred after the continuous administration for 14 days. The anatomical results of rats do not show any abnormal change in various internal organs such as heart, liver, lung, kidney, stomach, intestine and the like in vivo, and the tested compound is generally considered to be safe and nontoxic within a proper dosage.
At present, the preferable 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 respectively used for carrying out in vivo inhibition tests on tumors such as nude mouse subcutaneous transplantation pancreatic cancer cell strains (BXPC 3), gastric cancer cell strains (SNU 16), liver cancer cell strains (Hep 3B 2.1-7) and the like, and good tumor inhibition effect is observed, the tumor inhibition rate of nude mouse subcutaneous tumors within 3-4 weeks can reach 80-110%, and the results show that the preferable compounds have good anti-tumor activity efficacy. Therefore, the designed and synthesized 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 have better inhibitory activity effect, better safety and medicament forming property and application value of further carrying out preclinical research and clinical test such as medicament 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 antitumor innovative drugs have better inhibitory activity effects, and the MTD toxicity test (150 mg/kg and QD) of rats does not cause death and other abnormal conditions after being continuously taken for 14 days, has better safety (the MTD reported by the method is 40mg/kg better than that of the control drug Ranatinib, and the related inhibitory activity and safety results are better than those of the currently known same control drugs such as Ranatinib.
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 a full range of equivalents to the claims. Accordingly, the claims are not limited by the disclosure.

Claims (13)

1. A compound of formula IIIb, and its cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, or pharmaceutically acceptable salts or hydrates, and deuterated or other isotopically substituted compounds:
Figure FDA0003795483310000011
wherein, the first and the second end of the pipe are connected with each other,
e is nitrogen (N), or CH;
G 1 is hydrogen, deuterium (D), halogen, -CN, C 1-20 Alkyl radical, C 1-20 Alkoxy, or C 1-20 An alkylamino group;
G 2 is halogen, -CN, C 1-20 Alkylamino radical, C 1-20 Hydroxyalkyleneamino group, C 1-20 Cyanoalkyleneamino group, C 1-20 Amino alkylene amino group, C 3-20 Amino cycloalkylamino radical, C 1-20 Carboxyalkyleneamino group, C 3-20 A carboxycycloalkylamino group, a 3-to 6-membered heterocyclylamino group, OR-OR 6 (ii) a Wherein R is 6 Selected from: hydrogen and deuterium、C 1-20 Alkyl radical, C 1-20 Haloalkyl, C 1-20 Cyanoalkylene group, C 3-20 Cyanocycloalkylene radical, C 2-20 Hydroxyalkylene group, C 2-20 Aminoalkylene group, C 3-20 Amino cycloalkylene radical, C 2-20 Carboxyalkylene group, C 3-20 Carboxy cycloalkylene radical, C 3-6 Cycloalkyl radical, C 3-6 Amino cycloalkylene radical, C 1-20 Amino group (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 、C 1-20 Alkoxy radical, C 1-20 Alkylamino, or-C (O) NR 4 R 5 (ii) a Wherein R is hydrogen, or C 1-20 Alkyl radical, R 4 And R 5 Each independently selected from: hydrogen, deuterium, C 1-20 Alkyl radical, C 1-20 Haloalkyl, C 1-20 Cyanoalkylene group, C 3-20 Cyanocycloalkylene radical, C 2-20 Hydroxyalkylene group, C 3-20 Hydroxy cycloalkylene radical, C 2-20 Aminoalkylene group, C 3-20 Amino cycloalkylene radical, C 2-20 Carboxyalkylene group, C 3-20 Carboxy cycloalkylene radical, C 3-20 Cycloalkenyl radical, C 3-20 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclylalkylene, C 6-20 Aryl radical, C 3-20 Heterocyclic aryl radicals, C 1-20 Alkylsulfonyl radical, C 3-20 Cycloalkylsulfonyl, or C 2-20 A heterocycloalkylsulfonyl group; r 4 And R 5 A 3-to 8-membered heterocyclic or heterocyclic aryl group containing 1 to 3 heteroatoms bonded to each other;
G 4 and G 5 Each independently selected from: hydrogen, deuterium (D), halogen, -CN, C 1-20 Alkyl radical, C 1-20 Alkoxy, or C 1-20 An alkylamino group;
R 1 selected from: hydrogen, deuterium, C 1-20 Alkyl radical, C 3-20 Cycloalkyl, or C 3-20 A deuterated cycloalkyl group;
R 2 and R 3 Each independently selected from: hydrogen, deuterium, C 1-20 Alkyl radical, C 3-20 A cycloalkyl group, a,C 3-20 Deuterated cycloalkyl, or 3-6 membered heterocyclyl;
X 1 、X 2 and X 3 Each independently selected from: halogen, -CN, -NH 2 、C 1-20 Alkoxy, or C 1-20 An alkylamino group;
X 4 selected from the group consisting of: hydrogen, deuterium, halogen, -CN, -NH 2 、C 1-20 Alkoxy, or C 1-20 An alkylamino group.
2. The compound of claim 1,
e is nitrogen (N), or CH;
G 1 is hydrogen, deuterium (D), halogen, -CN, C 1-6 Alkyl radical, C 1-6 Alkoxy, or C 1-6 An alkylamino group;
G 2 is halogen, -CN, C 1-6 Alkylamino radical, C 1-6 Hydroxyalkyleneamino group, C 1-6 Cyanoalkyleneamino group, C 1-6 Amino alkyleneamino, C 3-6 Amino cycloalkylamino radical, C 1-6 Carboxy alkylene amino group, C 3-6 A carboxycycloalkylamino group, a 3-to 6-membered heterocyclylamino group, OR-OR 6 (ii) a Wherein R is 6 Selected from the group consisting of: hydrogen, deuterium, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Cyanoalkylene group, C 3-6 Cyanocycloalkylene radical, C 2-6 Hydroxyalkylene group, C 2-6 Aminoalkylene group, C 3-6 Amino cycloalkylene radical, C 2-6 Carboxyalkylene group, C 3-6 Carboxy cycloalkylene radical, C 3-6 Cycloalkyl radical, C 3-6 Amino cycloalkylene radical, C 1-6 Amino group (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 、C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, or-C (O) NR 4 R 5 (ii) a Wherein R is hydrogen, or C 1-6 Alkyl radical, R 4 And R 5 Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl radical, C 1-6 Halogenated alkyl radical、C 1-6 Cyanoalkylene group, C 3-6 Cyanocycloalkylene radical, C 2-6 Hydroxyalkylene, C 3-6 Hydroxy cycloalkylene radical, C 2-6 Aminoalkylene group, C 3-6 Amino cycloalkylene radical, C 2-6 Carboxyalkylene group, C 3-6 Carboxy cycloalkylene radical, C 3-6 Cycloalkenyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclylalkylene, C 6-10 Aryl radical, C 3-10 Heterocyclic aryl radicals, C 1-6 Alkylsulfonyl radical, C 3-6 Cycloalkylsulfonyl, or C 2-6 A heterocycloalkylsulfonyl group; r 4 And R 5 Connected with each other to form a 3-8 membered heterocyclic or heterocyclic aryl group containing 1-3 heteroatoms;
G 4 and G 5 Each independently selected from: hydrogen, deuterium (D), halogen, -CN, C 1-6 Alkyl radical, C 1-6 Alkoxy, or C 1-6 An alkylamino group;
R 1 selected from: hydrogen, deuterium, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, or C 3-6 A deuterated cycloalkyl group;
R 2 and R 3 Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 A deuterated cycloalkyl, or 3-6 membered heterocyclyl;
X 1 、X 2 and X 3 Each independently selected from: halogen, -CN, -NH 2 、C 1-6 Alkoxy, or C 1-6 An alkylamino group;
X 4 selected from: hydrogen, deuterium, halogen, -CN, -NH 2 、C 1-6 Alkoxy, or C 1-6 An alkylamino group.
3. The compound of claim 2,
e is CH;
G 1 is hydrogen;
G 2 is-OR 6 Wherein R is 6 Selected from: hydrogen, deuterium, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Cyanoalkylene group, C 3-6 CyanocycloalkylenesBase, C 2-6 Hydroxyalkylene group, C 2-6 Aminoalkylene group, C 3-6 Amino cycloalkylene radical, C 2-6 Carboxyalkylene group, C 3-6 Cycloalkyl radical, C 3-6 Amino cycloalkylene radical, C 1-6 Amino group (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 4 R 5 (ii) a Wherein R is hydrogen, or C 1-6 Alkyl radical, R 4 And R 5 Each independently selected from: hydrogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Cyanoalkylene group, C 3-6 Cyanocycloalkylene radical, C 2-6 Hydroxyalkylene group, C 2-6 Aminoalkylene group, C 2-6 Carboxyalkylene group, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 1-6 Alkylene (3-to 6-membered heterocyclic group), C 3-6 Heterocyclic aryl radicals, C 1-6 Alkylsulfonyl radical, C 3-6 Cycloalkylsulfonyl, or C 2-6 A heterocycloalkylsulfonyl group; r 4 And R 5 Connected with each other to form a 3-8 membered heterocyclic or heterocyclic aryl group containing 1-3 heteroatoms;
G 4 and G 5 Each independently selected from: hydrogen;
R 1 selected from: hydrogen;
R 2 selected from: hydrogen;
R 3 each independently selected from: c 3-6 A cycloalkyl group;
X 1 、X 2 and X 3 Each independently selected from: halogen;
X 4 selected from the group consisting of: and (3) hydrogen.
4. The compound of claims 1-3, wherein the compound of formula IIIb is selected from the following structures:
Figure FDA0003795483310000041
Figure FDA0003795483310000051
5. a process for the preparation of a compound of formula IIIb according to any one of claims 1 to 4,
wherein, the first and the second end of the pipe are connected with each other,
e is CH;
G 1 、G 4 and G 5 Each is hydrogen;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is C 3 A cycloalkyl group;
X 1 is F;
X 2 is Cl;
X 3 is F;
X 4 is hydrogen;
G 2 is-OR 6 Wherein R is 6 Selected from the group consisting of: hydrogen, deuterium, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Cyanoalkylene group, C 3-6 Cyanocycloalkylene radical, C 2-6 Hydroxyalkylene group, C 2-6 Aminoalkylene group, C 3-6 Amino cycloalkylene radical, C 2-6 Carboxyalkylene group, C 3-6 Cycloalkyl radical, C 3-6 Amino cycloalkylene radical, C 1-6 Amino group (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 4 R 5 (ii) a Wherein R is hydrogen, or C 1-6 Alkyl radical, R 4 And R 5 Each independently selected from: hydrogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Cyanoalkylene group, C 3-6 Cyanocycloalkylene radical, C 2-6 Hydroxyalkylene group, C 2-6 Aminoalkylene group, C 2-6 Carboxyalkylene group, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 1-6 Alkylene (3-to 6-membered heterocyclic group), C 3-6 Heterocyclic aryl radicals, C 1-6 An alkylsulfonyl group,C 3-6 Cycloalkylsulfonyl, or C 2-6 A heterocycloalkylsulfonyl group; r is 4 And R 5 A 3-to 8-membered heterocyclic or heterocyclic aryl group containing 1 to 3 heteroatoms bonded to each other;
the method is characterized in that: is prepared by any one of the following two methods:
the first method comprises the following five steps, and the reaction equation is as follows:
Figure FDA0003795483310000061
the second method comprises the following three steps, and the reaction equation is as follows:
Figure FDA0003795483310000062
6. a process for the preparation of a compound of formula IIIb according to claim 5, wherein: the first reaction step in process one gives the following intermediate compound RM1:
Figure FDA0003795483310000071
7. a process for the preparation of a compound of formula IIIb according to claim 5, wherein: the first reaction in method two gives the following intermediate compound RM1b-01:
Figure FDA0003795483310000072
8. the process according to claims 5 to 7, characterized in that the key polysubstituted compound SM2-01 can be prepared by either of the following two reactions:
firstly, reacting:
Figure FDA0003795483310000073
and (2) reaction II:
Figure FDA0003795483310000074
9. a composition comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent and/or excipient.
10. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the prophylaxis or treatment of a disease of the hematological system.
11. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of cancer.
12. The use of claim 11, wherein the cancer is selected from: pancreatic cancer, lung cancer, kidney cancer, liver cancer, stomach cancer, cervical cancer and leukemia.
13. A combination pharmaceutical product comprising a compound according to any one of claims 1 to 4, and a further pharmaceutically active agent selected from: (1) an immunomodulator; (2) PD-1; (3) PD-L1; or (4) other compounds not belonging to the above-mentioned (1) to (3).
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