HK40070084B - Pyridine derivative as fgfr and vegfr dual inhibitors - Google Patents

Description

Pyridine derivatives as dual inhibitors of FGFR and VEGFR

This application claims the following priority:

CN201910684252.3, application date 2019-07-26;

CN201911266249.6, application date 2019-12-11;

CN202010230493.3, application date 2020-03-27.

Technical Field

This invention relates to a dual inhibitor of FGFR and VEGFR, specifically to a compound or pharmaceutically acceptable salt of formula (I).

Background Technology

Fibroblast growth factor receptors (FGFRs) are a class of receptor proteins that specifically bind to fibroblast growth factor (FGF). The FGFR family includes the following types: FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, and FGFR4. FGFRs are bioactive substances with functions such as transducing biological signals, regulating cell growth, and participating in tissue repair. Clinically, high expression, mutations, or fusions of FGFRs have been found to induce tumor development and progression, for example, in diseases such as liver cancer, bladder cancer, lung cancer, and breast cancer. The binding of FGFRs to their ligand FGF leads to the autophosphorylation of multiple intracellular tyrosine residues, resulting in downstream signal transduction, including MEK/MAPK, PLCy/PKC, PI3K/AKT, and STATS. Therefore, FGFRs are considered important anti-tumor targets.

The VEGFR family includes three specific tyrosine kinase receptors: VEGFR-1, VEGFR-2 (KDR), and VEGFR-3. VEGFR-2 is a crucial regulator of VEGF signaling, inducing endothelial cell proliferation, increasing vascular permeability, and promoting angiogenesis. Furthermore, VEGFR-2 has a greater affinity for VEGF than VEGFR-1. Studies have shown that endothelial cells express only VEGFR-2, and activation of VEGFR-2 efficiently stimulates angiogenesis. Therefore, VEGFR-2 is a primary target for anti-angiogenic drug development.

The VEGFR and FGFR pathways work together to activate and generate endothelial cells in angiogenesis. Sometimes, VEGF requires the presence of FGF to exert its pro-angiogenic effect. The synergistic effect of the FGFR and VEGFR pathways can also inhibit tumor immune escape and improve tumor suppression.

Summary of the Invention

This invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

in,

_R1 is selected from H and _C1-3 alkyl groups optionally substituted with 1, 2 or 3 _Ra ;

_R2 and _R3 are independently selected from H, F, Cl, Br, I, OH and _NH2, respectively;

_R4 is selected from H, _C1-6 alkyl and _C3-5 cycloalkyl, wherein the _C1-6 alkyl and _C3-5 cycloalkyl are optionally substituted by 1, 2 or 3 _Rb ;

L is selected from -N( _R5 )C(=O)-, -N( _R5 )S(=O) _2- , -N( _R5 )C(=O)N( _R5 )- and -N( _R5 )-;

_R5 is independently selected from H and _C1-3 alkyl groups;

Cycle B is selected from 5-6 member heteroaryl groups;

_Ra and _Rb are independently selected from H, F, Cl, Br, I, OH, _NH2 , CN and _CH3 , respectively;

The 5-6 membered heteroaryl group comprises 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from -NH-, -O-, -S- and -N-.

In some embodiments of the present invention, _R1 is selected from H, _CH3 and _CH2CH3 , wherein _CH3 and _CH2CH3 are optionally replaced by 1 _, 2 or 3 _{Ra ,} and other variables are as defined in the present invention.

In some embodiments of _the present invention, _R1 is selected from H, _CH3 , _CH2OH , _{CH2CH2OH and CH2CH3} , and other variables are as defined in the present invention.

In some embodiments of the present invention, the aforementioned _R4 is selected from H, cyclopropane, _CH3 , _CH2CH3 , CH( _CH3 ) ₂ , C( _CH3 ) _{3 ,} and _CH2CH2CH3 , wherein the cyclopropane, _CH3 , _CH2CH3 , CH( _CH3 ) ₂ , C( _CH3 ) _{3 ,} and _CH2CH2CH3 are optionally substituted by ₁ , ₂ , or _{3 Rb} , _and other variables are as defined in the present invention.

In some embodiments of the present invention, _R4 is selected _from H, _CH3 , _CH2CH3 , CH( _CH3 ) ₂ , C( _CH3 ) ₃ and _{CH2CH2CH3 ,} and other variables are as _defined in the present invention.

In some embodiments of the present invention, _R5 is independently selected from H, _CH3 and _CH2CH3 , and other variables are as defined in _the present invention.

In some embodiments of the present invention, the above L is selected from -NHC(=O)-, -NHC(=O)NH-, -NHS(=O) _2- and -NH-, and other variables are as defined in the present invention.

In some embodiments of the present invention, -LR ₄ is selected from other variables as defined in the present invention.

In some embodiments of the present invention, the ring B is selected from imidazole, pyrazol, piperidinyl, morpholinyl, and tetrahydropyranyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, the ring B is selected from imidazole and pyrazolyl groups, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above-mentioned structural units are selected from other variables as defined in the present invention.

In some embodiments of the present invention, the above-mentioned structural units are selected from other variables as defined in the present invention.

This invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

in,

_R1 is selected from H and _C1-3 alkyl groups optionally substituted with 1, 2 or 3 _Ra ;

_R2 and _R3 are independently selected from H, F, Cl, Br, I, OH, _NH2 and _CH3 , respectively;

_R4 is selected from H, _C1-6 alkyl, _C1-3 alkoxy, _C3-5 cycloalkyl, tetrahydropyranyl and 1,3-dioxolanecycloyl, wherein the _C1-6 alkyl, _C1-3 alkoxy, _C3-5 cycloalkyl, tetrahydropyranyl and 1,3-dioxolanecycloyl are optionally substituted by 1, 2 or 3 _Rb ;

L is selected from -N( _R5 )C(=O)-, -N( _R5 )S(=O) _2- , -N( _R5 )C(=O)N( _R5 )-, -N( _R5 ) _CH2- and -N( _R5 )-;

_R5 is independently selected from H and _C1-3 alkyl groups;

Ring B is selected from pyrazolyl and imidazoleyl groups, wherein the pyrazolyl and imidazoleyl groups are optionally substituted by one or two R6 _groups ;

_R6 is selected from H and _C1-3 alkyl groups;

_Ra and _Rb are independently selected from H, F, Cl, Br, I, OH, _NH2 , CN and _CH3 , respectively.

In some embodiments of the present invention, _R1 is selected from H, _CH3 and _CH2CH3 , wherein _CH3 and _CH2CH3 are optionally replaced by 1 _, 2 or 3 _{Ra ,} and other variables are as defined in the present invention.

In some embodiments of _the present invention, _R1 is selected from H, _CH3 , _CH2OH , _{CH2CH2OH and CH2CH3} , and other variables are as defined in the present invention.

In some embodiments of the present invention, the aforementioned _R4 is selected from H, cyclopropane, _CH3 , _CH2CH3 , CH( _CH3 ) ₂ , C(CH3) ₃ , _CH2CH2CH3 , CH2CH( _CH3 ) _{2 , OCH3} , _OCH2CH3 , _{tetrahydropyranyl} , and _{1,3 - dioxolanecycloyl} , wherein the cyclopropane, _CH3 , _CH2CH3 , CH( _CH3 ) ₂ , C( _CH3 ) ₃ , _CH2CH2CH3 , CH2CH _{( CH3} ) ₂ , _OCH3 , _OCH2CH3 , _{tetrahydropyranyl} , _{and 1,3} - _{dioxolanecycloyl} are optionally substituted by 1, ₂ , or 3 _Rb , and other variables are as defined in the present invention.

In some _embodiments of the present invention, _R4 is selected _from H, _CH3 , _CH2CH3 , _CH ( _CH3 ) ₂ , C( _CH3 ) ₃ , _CH2CH2CH3 , _OCH2CH3 , _and other variables as defined in the present invention.

In some embodiments of the present invention, _R5 is independently selected from H, _CH3 and _CH2CH3 , and other variables are as defined in _the present invention.

In some embodiments of the present invention, L is selected from -NHC(=O)-, -NHC(=O)NH-, -NHS(=O) _2- , _-NHCH2- and -NH-, and other variables are as defined in the present invention.

In some embodiments of the present invention, -LR ₄ is selected from other variables as defined in the present invention.

In some embodiments of the present invention, the aforementioned ring B is selected from those optionally replaced by one or two R _6s , and other variables are as defined in the present invention.

In some embodiments of the present invention, the ring B is selected from other variables as defined in the present invention.

In some embodiments of the present invention, the above-mentioned structural units are selected from other variables as defined in the present invention.

In some embodiments of the present invention, the above-mentioned structural units are selected from other variables as defined in the present invention.

This invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

in,

_R1 is selected from H and _C1-3 alkyl groups optionally substituted with 1, 2 or 3 _Ra ;

_R2 and _R3 are independently selected from H, F, Cl, Br, I, OH, _NH2 and _CH3 , respectively;

_R4 is selected from H, _C1-6 alkyl, _C1-3 alkoxy, _C3-5 cycloalkyl, tetrahydropyranyl and 1,3-dioxolanecycloyl, wherein the _C1-6 alkyl, _C1-3 alkoxy, _C3-5 cycloalkyl, tetrahydropyranyl and 1,3-dioxolanecycloyl are optionally substituted by 1, 2 or 3 _Rb ;

L is selected from -N( _R5 )C(=O)-, -N( _R5 )S(=O) _2- , -N( _R5 )C(=O)N( _R5 )-, -N( _R5 ) _CH2- and -N( _R5 )-;

_R5 is independently selected from H and _C1-3 alkyl groups;

Ring B is selected from pyrazolyl and imidazoleyl groups, wherein the pyrazolyl and imidazoleyl groups are optionally substituted by one or two R6 _groups ;

_R6 is selected from H and _C1-3 alkyl groups;

_Ra and _Rb are independently selected from H, F, Cl, Br, I, OH, _NH2 , CN and _CH3 , respectively.

In some embodiments of the present invention, _R1 is selected from H, _CH3 and _CH2CH3 , wherein _CH3 and _CH2CH3 are optionally replaced by 1 _, 2 or 3 _{Ra ,} and other variables are as defined in the present invention.

In some embodiments of _the present invention, _R1 is selected from H, _CH3 , _CH2OH , _{CH2CH2OH and CH2CH3} , and other variables are as defined in the present invention.

In some embodiments of the present invention, the aforementioned _R4 is selected from H, cyclopropane, _CH3 , _CH2CH3 , CH( _CH3 ) ₂ , C(CH3) ₃ , _CH2CH2CH3 , CH2CH( _CH3 ) _{2 , OCH3} , _OCH2CH3 , _{tetrahydropyranyl} , and _{1,3 - dioxolanecycloyl} , wherein the cyclopropane, _CH3 , _CH2CH3 , CH( _CH3 ) ₂ , C( _CH3 ) ₃ , _CH2CH2CH3 , CH2CH _{( CH3} ) ₂ , _OCH3 , _OCH2CH3 , _{tetrahydropyranyl} , _{and 1,3} - _{dioxolanecycloyl} are optionally substituted by 1, ₂ , or 3 _Rb , and other variables are as defined in the present invention.

In some _embodiments of the present invention, _R4 is selected _from H, _CH3 , _CH2CH3 , _CH ( _CH3 ) ₂ , C( _CH3 ) ₃ , _CH2CH2CH3 , _OCH2CH3 , _and other variables as defined in the present invention.

In some embodiments of the present invention, _R5 is independently selected from H, _CH3 and _CH2CH3 , and other variables are as defined in _the present invention.

In some embodiments of the present invention, L is selected from -NHC(=O)-, -NHC(=O)NH-, -NHS(=O) _2- , _-NHCH2- and -NH-, and other variables are as defined in the present invention.

In some embodiments of the present invention, -LR ₄ is selected from other variables as defined in the present invention.

In some embodiments of the present invention, the aforementioned ring B is selected from those optionally replaced by one or two R _6s , and other variables are as defined in the present invention.

In some embodiments of the present invention, the ring B is selected from other variables as defined in the present invention.

In some embodiments of the present invention, the above-mentioned structural units are selected from other variables as defined in the present invention.

In some embodiments of the present invention, the above-mentioned structural units are selected from other variables as defined in the present invention.

The present invention also includes some solutions derived from arbitrary combinations of the above variables.

In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from...

in,

_R1 , _R2 , _R3 , L and _R4 are as defined in this invention.

In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from...

in,

_R1 , _R2 , _R3 and _R4 are as defined in this invention.

The present invention also provides compounds of the following formula or pharmaceutically acceptable salts thereof.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above-described compound or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

The present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts thereof or the above-described pharmaceutical compositions in the preparation of drugs related to dual inhibitors of FGFR and VEGFR.

In some embodiments of the present invention, the above-described application, wherein the FGFR and VEGFR dual inhibitor-related drug is a drug for solid tumors.

Definitions and Explanations

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

Some compounds of this invention may exist in non-solventized or solvated forms, including hydrated forms. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of this invention.

Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide a pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography with a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates). The compounds of the present invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium ( ^3H ), iodine-125 ( ^125I ), or C-14 ( ^14C ). As another example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared to undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations in the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and/or their variants are only permitted if such combinations produce a stable compound.

When the number of a linking group is 0, such as -(CRR) _0- , it indicates that the linking group is a single bond.

When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.

When a substituent is vacant, it indicates that the substituent is not present. For example, in A-X, if X is vacant, the structure is actually A. When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridinium group as a substituent can be attached to the substituted group via any carbon atom on the pyridine ring. When the listed linking group does not specify its direction of attachment, the direction is arbitrary. For example, if the linking group L is -M-W-, then -M-W- can be attached to rings A and B in the same direction as the left-to-right reading order or in the opposite direction. Combinations of linking groups, substituents, and/or their variants are only permitted if such combinations produce a stable compound.

Unless otherwise specified, the term " _C1-6 alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The _C1-6 alkyl group includes _C1-5 , _C1-4 , _C1-3 , C1-2, _C2-6 , _C2-4 , _C6 , and _C5 alkyl groups, etc.; it can be monovalent (e.g., methyl), divalent (e.g. _, methylene), or polyvalent (e.g., methine). Examples of _C1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, and t-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), hexyl, etc.

Unless otherwise specified, the term " _C1-3 alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of one to three carbon atoms. The _C1-3 alkyl group includes _C1-2 and _C2-3 alkyl groups, etc.; it can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). Examples of _C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

Unless otherwise specified, the term " _C1-3 alkoxy" refers to alkyl groups comprising one to three carbon atoms that are attached to the remainder of a molecule by an oxygen atom. _C1-3 alkoxy groups include _C1-2 , _C2-3 , _C3 , and _C2 alkoxy groups, etc. Examples of _C1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

Unless otherwise specified, "C _3-5 cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic system. The C _3-5 cycloalkyl group includes C _3-4 and C _4-5 cycloalkyl groups, etc.; it can be monovalent, divalent, or polyvalent. Examples of _{C 3-5} cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.

Unless otherwise specified, the terms "5-6-membered heteroaryl" and "5-6-membered heteroaryl" are used interchangeably in this invention. The term "5-6-membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O) _p , where p is 1 or 2). The 5-6-membered heteroaryl can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6-membered heteroaryl includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl). (and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (such as affinity substitution). For example, representative leaving groups include trifluoromethanesulfonates; chlorine, bromine, and iodine; sulfonate groups, such as methanesulfonates, toluenesulfonates, p-bromobenzenesulfonates, p-toluenesulfonates, etc.; acyloxy groups, such as acetoxy groups, trifluoroacetoxy groups, etc.

The term "protecting group" includes, but is not limited to, "amino protecting group," "hydroxy protecting group," or "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4′-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanolyl groups (e.g., acetyl); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc.

The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

The solvent used in this invention is commercially available. The following abbreviations are used in this invention: aq represents aqueous solution; eq represents equivalent or equal amount; DCM represents dichloromethane; PE represents PE; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, an amine protecting group; BOC represents tert-butyloxycarbonyl, an amine protecting group; HOAc represents acetic acid; rt represents room temperature; O/N represents overnight; THF represents tetrahydrofuran; Boc _2O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; iPrOH represents 2-propanol; mp represents melting point; Xantphos represents 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene; Pd(dppf)Cl ₂ represents [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride; DIEA represents N,N′-diisopropylethylamine; NIS represents N-iodosuccinimide.

Compounds are named according to conventional naming principles in the field or using software; commercially available compounds are named according to the supplier's catalog.

Technical effect

The compounds of this invention exhibit excellent FGFRs and VEGFR2 kinase activities. The introduction of the nitrogen heteroatom in the intermediate aromatic ring of the compounds of this invention unexpectedly revealed that this change can significantly improve the metabolic stability of the compounds in vivo, greatly increase the oral absorption and drug exposure, and is very likely to demonstrate better therapeutic effects in clinical practice. The compounds of this invention have demonstrated excellent tumor treatment effects.

Instruction manual illustrations

Figure 1: Tumor volume growth curves in each group during drug administration;

Figure 2: Body weight change curves of animals in each group during drug administration.

Detailed Implementation

The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof.

Compare with Example 1

Step 1

3,5-dinitrobromobenzene (10 g, 40.49 mmol) and (2,4-difluoro)phenylboronic acid (6.39 g, 40.49 mmol) were dissolved in water (2 mL) and acetonitrile (120 mL). Palladium acetate (454.46 mg, 2.02 mmol) and triethylamine (12.29 g, 121.46 mmol, 16.91 mL) were added. The mixture was stirred at 85 °C for 16 hours. The reaction solution was directly evaporated to dryness to obtain a crude solid product. The crude product was purified by column chromatography with PE:EA = 5:1 to obtain compound a.

¹ H NMR (400MHz, CDCl ₃ ) δ 9.06 (t, J=2.00Hz, 1H), 8.72 (dd, J=1.92, 1.10Hz, 2H), 7.54 (td, J=8.74, 6.32Hz, 1H), 7.00-7.15 (m, 2H).

Step Two

Compound a (6.5 g, 23.20 mmol) was dissolved in a 65 mL EtOAc hydrogenation flask, and Pd/C (1 g, 23.20 mmol, 10% purity) was added. The mixture was then placed in a 50 Psi hydrogen cylinder (46.77 mg, 23.20 mmol, 1 eq) and stirred at 45 °C for 16 hours. The reaction mixture was filtered, and the filtrate was evaporated to dryness to obtain compound b.

LCMS(ESI)m/z: 220.9[M+1] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ,) δ7.36-7.45 (m, 1H), 7.20-7.30 (m, 1H), 7.10 (td, J=8.52, 2.44Hz, 1H), 5.92 (d, J=1.52Hz, 2H), 5.86 (d, J=1.82Hz, 1H), 4.84 (s, 4H).

Step 3

To a DMSO (15 mL) solution of compound b (2.37 g, 10.76 mmol), DIEA (417.28 mg, 3.23 mmol, 562.37 μL), ethoxytrimethylsilane (2.29 g, 19.37 mmol), and 4-bromo-1-fluoro-2-nitrobenzene (2.37 g, 10.76 mmol, 1.32 mL) were added, and the mixture was stirred at 100 °C for 16 hours. The reaction mixture was then added to 100 mL of water and stirred, resulting in the precipitation of a large amount of solid. The solid was collected by vacuum filtration, and 20 mL of anhydrous toluene was added to the filter cake. The mixture was then evaporated to dryness to obtain compound c.

LCMS(ESI)m/z: 419.9[M+1] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ )δ9.40 (s, 1H), 8.33 (d, J=2.26Hz, 1H), 7.33-7.46 (m, 2H), 7.21-7.25 (m, 2H), 7.11-7.19 (m, 1 H), 6.86-6.97 (m, 2H), 6.76 (d, J=1.52Hz, 1H), 6.68 (d, J=1.76Hz, 1H), 6.56 (t, J=2.02Hz, 1H).

Step Four

Under nitrogen protection, cyclopropylsulfonyl chloride (1.66 g, 11.78 mmol) was added to a pyridine (30 mL) suspension of compound c (4.5 g, 10.71 mmol), and the mixture was stirred at 20 °C for 2 hours. Acetic acid (34.6 mL) was added to the reaction mixture, followed by water (250 mL). Ethyl acetate (150 mL * 2) was added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, then concentrated under reduced pressure to give compound d.

LCMS(ESI)m/z: 525.8[M+1] ⁺ .

Step 5

Triphenylphosphine (1.40 g, 5.34 mmol), palladium acetate (359.67 mg, 1.60 mmol), and potassium carbonate (3.84 g, 27.77 mmol) were added to a dimethyl sulfoxide (110 mL)/water (30 mL) solution of compound d (5.6 g, 10.68 mmol) and 1-methyl-4-pyrazoloniate (2.78 g, 13.35 mmol). The mixture was stirred at 100 °C for 16 hours under nitrogen protection. While stirring, water (200 mL) was added to the reaction mixture, resulting in the precipitation of a solid. The filter cake was collected by vacuum filtration, transferred to a single-necked flask via dichloromethane, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (fast silica gel column chromatography) with petroleum ether/ethyl acetate = 0/1 to obtain compound e.

LCMS(ESI)m/z: 526.4[M+3] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ )δ9.45 (s, 1H), 8.29 (d, J=2.02Hz, 1H), 7.73 (s, 1H), 7.62 (s, 1H), 7.53-7.58 (m, 1H), 7.37-7.48 (m, 2H), 7.16-7. 24 (m, 3H), 6.90-7.01 (m, 2H), 6.71 (s, 1H), 3.96 (s, 3H), 2.52-2.65 (m, 1H), 1.22-1.26 (m, 2H), 0.98-1.11 (m, 2H).

Step Six

Pd/C (1 g, 5.33 mmol, 1 eq) was added to a formic acid (30 mL) solution of compound e (2.8 g, 5.33 mmol, 10% purity), and the mixture was stirred at 30 °C under a hydrogen balloon (15 psi) atmosphere for 16 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to high performance liquid chromatography (HPLC) (column: YMC-Triart Prep C18 150*40 mm*7 μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 35%-50%, 10 min) to obtain the trifluoroacetate of compound A. The trifluoroacetate of compound A was added to a sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound A.

LCMS(ESI)m/z: 506.0[M+1] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.25 (br s, 1H), 8.65 (s, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.94 (s, 1H), 7.71-7.81 ( m, 1H), 7.64-7.70 (m, 1H), 7.55-7.63 (m, 3H), 7.40-7.51 (m, 2H), 7.27 (br t, J=7.53Hz, 1H), 3.88 (s, 3H), 2.81-2.93 (m, 1H), 0.98-1.08 (m, 4H).

Compare with Example 2

Compound B

The synthesis method was the same as in Control Example 1, except that methanesulfonamide was substituted for cyclopropylsulfonamide to obtain the trifluoroacetate of compound B. The trifluoroacetate of compound B was added to a sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound B.

LCMS(ESI)m/z: 480.1[M+1] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.35 (s, 1H), 9.17 (s, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.68-7.78 (m, 3H), 7.61 (br d, J=8.53Hz, 2H), 7.49 (s, 1H), 7.38-7.47 (m, 1H), 7.27 (dt, J=2.13, 8.47Hz, 1H), 3.88 (s, 3H), 3.18 (s, 3H).

Compare with Example 3

Step 1

To a solution of 2,6-dichloro-4-aminopyridine (10 g, 61.35 mmol) and (2,4-difluorobenzene)boronic acid (11.62 _g , 73.62 mmol) in dioxane (100 mL)/water (30 mL), Pd(dppf) _Cl₂ (4.49 g, 6.13 mmol) and _K₃PO₄ (26.04 g, 122.70 mmol) were added, and the mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was separated, and the organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (fast silica gel column chromatography) with a petroleum ether/ethyl acetate ratio of 5/1 to obtain compound k.

LCMS(ESI)m/z: 240.9[M+1] ⁺ .

Step Two

To a pyridine (10 mL) solution of compound k (1 g, 4.16 mmol), methanesulfonyl chloride (1.90 g, 16.62 mmol, 1.29 mL) was added, and the mixture was stirred at 30 °C for 1 hour. Water (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (rapid silica gel column chromatography) with a petroleum ether/ethyl acetate ratio of 3/1 to obtain compound m.

LCMS(ESI)m/z: 318.9[M+1] ⁺ .

Step 3

Compound 1c (0.1 g, 308.53 μmol) was dissolved in DMF (3 mL). Under nitrogen protection, hexabutyldistin (268.47 mg, 462.79 μmol, 231.44 μL) and compound m (157.34 mg, 493.64 μmol) were added, followed by Pd ₍ dppf) _{Cl₂.CH₂Cl₂} (125.98 _mg , 154.26 μmol). The mixture was stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was completed and cooled to room temperature, the reaction solution was added and quenched with potassium fluoride aqueous solution. The mixture was extracted with ethyl acetate, and the combined organic phases were concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B (acetonitrile)%: 15%-45%, 8.5 min) to obtain the formate of compound C. The formate of compound C was added to sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound C.

LCMS(ESI)m/z: 481.1[M+1] ⁺ ;

¹ H NMR (400MHz, METHANOL-d4) δ9.97 (br d, J=7.28Hz, 1H), 8.37 (br s, 1H), 8.26 (s, 1H), 8.01-8.13 (m, 2H), 7.69-7.84 (m, 1H), 7.65 (s, 1H), 7.50-7.57 (m, 2H), 7.05-7.22 (m, 2H), 3.98 (s, 3H), 3.23 (s, 3H).

Example 1

Step 1

Chloroacetaldehyde (8.51 g, 43.35 mmol, 6.97 mL) was added dropwise to EtOH (60 mL) containing 5 g of 4-bromo-2-aminopyridine (60 mL), and the mixture was stirred at 80 °C for 16 hours. The reaction solution was evaporated to dryness under reduced pressure to give crude compound 1a.

LCMS(ESI)m/z: 197.0[M+1] ⁺ , 199.0[M+3] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.89-8.96 (m, 1H), 8.40-8.45 (m, 1H), 8.30 (d, J=1.52Hz, 1H), 8.19 (d, J=2.02Hz, 1H), 7.70 (dd, J=1.76, 7.28Hz, 1H).

Step Two

Compound 1a (10 g, 50.75 mmol) and 1-methyl-4-pyrazolone ester (11.62 g, 55.83 mmol) were dissolved in dioxane (155 mL) and _H₂O (75 mL). Pd(dppf) _Cl₂ (3.71 g, 5.08 mmol) and potassium phosphate (21.55 g, 101.51 mmol) were added, and the mixture was stirred at 100 °C for 16 hours. The reaction mixture was extracted with water (150 mL) and ethyl acetate (150 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (fast silica gel column chromatography) with a petroleum ether/ethyl acetate ratio of 3/1 to obtain compound 1b.

LCMS(ESI)m/z: 198.8[M+1] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ 8.11 (br d, J=7.04Hz, 1H), 7.79 (s, 1H), 7.54-7.71 (m, 3H), 7.37 (br s, 1H), 6.90 (d, J=6.78Hz, 1H), 3.96 (s, 3H).

Step 3

Iodosuccinimide (32.69 g, 145.29 mmol) was added to a dichloromethane (240 mL) solution of compound 1b (24 g, 121.08 mmol), and the mixture was stirred at 30 °C for 16 hours. The reaction solution was filtered to obtain a filtrate, which was then diluted with water (400 mL) and extracted with dichloromethane (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (rapid silica gel column chromatography) with a dichloromethane/methanol ratio of 10/1 to obtain compound 1c.

LCMS(ESI)m/z: 325.0[M+1] ⁺ .

Step Four

To a mixed solution of compound 1c (1 g, 3.09 mmol), (2,6-dichloro-4-pyridine)boronic acid (650.96 mg, 3.39 mmol) in dioxane (10 mL) and water (3 mL), Pd(dppf) _Cl₂ (225.75 mg, 308.53 μmol) and potassium phosphate (1.31 g, 6.17 mmol) were added. The mixture was stirred at 120 °C for 1 hour under nitrogen protection in a microwave reactor. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (rapid silica gel column chromatography) with dichloromethane/methanol = 10/1 to obtain compound 1d. LCMS (ESI) m/z: 343.9 [M+1] ^⁺ .

Step 5

To a solution of compound 1d (150 mg, 435.80 μmol), cyclopropanesulfonamide (52.80 mg, 435.80 μmol), and dioxane (4 mL), palladium acetate (9.78 mg, 43.58 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (25.22 mg, 43.58 μmol), and cesium carbonate (425.97 mg, 1.31 mmol) were added to a microwave reactor under nitrogen protection and stirred at 120 °C for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (rapid silica gel column chromatography) with a dichloromethane/methanol ratio of 10/1 to obtain compound 1e.

LCMS(ESI)m/z: 429.0[M+1] ⁺ .

Step Six

To a solution of compound 1e (150 mg, 349.74 μmol), 2,4-difluorophenylboronic acid (90.00 mg, 569.94 μmol), and dioxane (3 mL)/water (1 mL), Pd(dppf) _Cl₂ (25.59 mg, 34.97 μmol) and potassium phosphate (222.71 mg, 1.05 mmol) were added, and the mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (HPLC) (column: Boston Green ODS 150 mm * 30 mm * 5 μm; mobile phase: [water (0.075% trifluoroacetic acid) - acetonitrile]; B (acetonitrile) %: 32%-52%, 12 min) to obtain the trifluoroacetate of compound 1. Compound 1 was obtained by adding the trifluoroacetate of compound 1 to a sodium bicarbonate solution, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure.

LCMS(ESI)m/z: 507.0[M+1] ⁺ ;

¹ H NMR (400MHz, MeOD) δ8.78 (d, J=7.28Hz, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.17-8.26 (m, 1H), 8.16 (s, 1H), 8.05 (s, 1H), 7.83 (s, 1H), 7. 78 (dd, J=1.52, 7.28Hz, 1H), 7.39 (s, 1H), 7.10-7.20 (m, 2H), 4.00 (s, 3H), 3.08-3.20 (m, 1H), 1.20-1.32 (m, 2H), 1.04-1.14 (m, 2H).

The preparation of compound 2 in Table 1 follows the same route as compound 1, except that in step six, the raw material used is replaced by raw material B in the table below to obtain the trifluoroacetate of the corresponding compound. The obtained trifluoroacetate of the compound is added to a sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the corresponding compound.

Table 1

Example 3

Step 1

To a solution of compound 1d (0.5 g, 1.45 mmol), ethyl carbamate (110.01 mg, 1.23 mmol), and 1,4-dioxane (15 mL), palladium acetate (32.61 mg, 145.27 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (168.11 mg, 290.53 μmol), and cesium carbonate (1.42 g, 4.36 mmol) were added. The mixture was stirred at 120 °C for 20 minutes under nitrogen protection in a microwave reactor. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain compound 3a.

LCMS(ESI)m/z: 397.1[M+1] ⁺ .

Step Two

To a solution of compound 3a (150 mg, 378.00 μmol), 2,4-difluorophenylboronic acid (71.63 mg, 453.60 μmol) in THF (1.5 mL) and _H₂O (0.5 mL), Pd(dppf) _Cl₂ (27.66 mg, 37.80 μmol) and potassium phosphate (160.47 mg, 755.99 μmol) were added. The mixture was stirred at 100 °C for 30 minutes under nitrogen protection using a microwave. The reaction mixture was separated, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was then separated by preparative high-performance liquid chromatography (HPLC) (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 25%-55%, 8 min) to obtain the trifluoroacetate of compound 3. The trifluoroacetate of compound 3 was added to a sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 3.

LCMS(ESI)m/z: 475.1[M+1] ⁺ ;

¹ H NMR (400MHz, CD ₃ OD) δ8.81 (d, J=7.28Hz, 1H), 8.37 (s, 1H), 8.24-8.31 (m, 2H), 8.12-8.21 (m, 2H), 8.03 (s, 1H), 7. 71-7.81 (m, 2H), 7.05-7.19 (m, 2H), 4.27 (q, J=7.04Hz, 2H), 4.00 (s, 3H), 1.35 (t, J=7.16Hz, 3H).

The preparation of compound 4 in Table 2 follows the same route as compound 3, except that the raw material used in step 2 is replaced by raw material B in the table below to obtain the trifluoroacetate of the corresponding compound. The trifluoroacetate of the obtained compound is added to sodium bicarbonate solution, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the corresponding compound.

Table 2

Example 6

Step 1

Compound 1d (200 mg, 581.06 μmol) and ethylsulfonamide (114.16 mg, 1.05 mmol) were dissolved in 1,4-dioxane (5 mL), and palladium acetate (13.05 mg, 58.11 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (67.24 mg, 116.21 μmol), and cesium carbonate (567.96 mg, 1.74 mmol) were added. The mixture was stirred in a microwave at 120 °C for 1 hour under nitrogen protection. The reaction solution was directly filtered, and the filter cake was washed with DCM/MeOH = 10/1. The filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (DCM/MeOH = 10/1) to obtain compound 6a.

LCMS(ESI)m/z: 417.3[M+1] ⁺ .

Step Two

Compound 6a (0.2 g, 479.75 μmol) and 2,4-difluorophenylboronic acid (113.64 mg, 719.62 μmol) were dissolved in 1,4-dioxane (6 mL) and _H₂O (3 mL). Potassium phosphate (305.51 mg, 1.44 mmol) and Pd(dppf) _Cl₂ (35.10 mg, 47.97 μmol) were added, and the mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction solution was filtered, evaporated to dryness to obtain crude product, and purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%-50%, 7 min) to obtain the trifluoroacetate of compound 6. Compound 6 was obtained by adding the trifluoroacetate of compound 6 to a sodium bicarbonate solution, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure.

LCMS(ESI)m/z: 495.0[M+1] ⁺ ;

¹ H NMR (400MHz, CD ₃ OD) δ8.80 (br d, J=7.34Hz, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 8.13-8.23 (m, 2H), 8.10 (s, 1H), 7.76-788 ( m, 2H), 7.33 (s, 1H), 7.08-7.22 (m, 2H), 4.02 (s, 3H), 3.61 (q, J=7.36Hz, 2H), 1.43ppm (br t, J=7.36Hz, 3H).

The preparation of the compounds in Table 3 follows the same route as compound 6, except that the raw material used in step one is replaced by raw material B in the table below to obtain the free state or trifluoroacetate of the corresponding compound. The trifluoroacetate of the obtained compound is added to sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase is dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the corresponding compound.

Table 3

Example 12

Step 1

To a solution of compound 1a (5 g, 25.38 mmol), 1,5-dimethyl-1H-pyrazole-4-boronic acid linalool ester (6.20 g, 27.91 mmol), and dioxane (45 mL)/water (15 mL), Pd(dppf) _Cl₂ (1.86 g, 2.54 mmol) and potassium phosphate (10.77 g, 50.75 mmol) were added. The mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction solution was filtered, and water (100 mL) was added. The mixture was then extracted with dichloromethane (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (rapid silica gel column chromatography) with a dichloromethane/methanol ratio of 10/1 to obtain compound 12a.

LCMS(ESI)m/z: 212.9[M+1] ⁺ .

Step Two

NIS (152.64 mg, 678.45 μmol) was added to a dichloromethane (5 mL) solution of compound 12a (0.12 g, 565.37 μmol), and the mixture was stirred at 25 °C for 16 hours. Water (10 mL) was added to the reaction solution, followed by extraction with dichloromethane (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate, then concentrated under reduced pressure to give compound 12b.

LCMS(ESI)m/z: 338.9[M+1] ⁺ .

Step 3

Pd(dppf) _Cl₂ (865.55 mg, 1.18 mmol) and potassium phosphate (5.02 g, 23.66 mmol) were added to a solution of 12b (2.72 g, 14.20 mmol) in dioxane (45 mL)/water (15 mL), and the mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction solution was filtered directly, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (fast silica gel column chromatography) in dichloromethane/methanol = 10/1 to obtain compound 12c.

LCMS(ESI)m/z: 358.1[M+1] ⁺ .

Step Four

To a solution of 12c (0.15 g, 418.73 μmol), ethyl carbamate (32 mg, 359.18 μmol), and dioxane (15 mL), palladium acetate (9.40 mg, 41.87 μmol), cesium carbonate (409.29 mg, 1.26 mmol), and Xantphos (48.46 mg, 83.75 μmol) were added. The mixture was stirred at 120 °C for 20 minutes under nitrogen protection in a microwave reactor. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparing thin-layer chromatography silica gel plates (DCM:MeOH = 15:1) to obtain compound 12d.

LCMS(ESI)m/z: 411.1[M+1] ⁺ .

Step 5

Pd(dppf) _Cl₂ (5.34 mg, 7.30 μmol) and _K₃PO₄ (31.00 mg, 146.04 μmol) were added to a tetrahydrofuran (1.5 mL)/water (0.5 mL) solution of 12d (30 mg, 73.02 μmol), _2,4 -difluorophenylboronic acid (13.84 mg, 87.62 μmol), and the mixture was stirred at 100 °C for 30 min under nitrogen protection and microwave. The reaction mixture separated into layers, and the organic phase was collected and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high performance liquid chromatography (column: Welch Xtimate C18 100*25 mm*3 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%-50%, 8 min) to obtain the trifluoroacetate of compound 12. The trifluoroacetate of compound 12 was added to a sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 12.

LCMS(ESI)m/z: 489.2[M+1] ⁺ ;

¹ H NMR (400MHz, MeOD-d ₄ )δ8.85 (d, J=7.28Hz, 1H), 8.28 (s, 2H), 8.11-8.22 (m, 1H), 7.85-7.97 (m, 2H), 7.79 (s, 1H), 7.65 (d, J=7. 54Hz, 1H), 7.04-7.19 (m, 2H), 4.27 (q, J=7.04Hz, 2H), 3.91 (s, 3H), 2.60 (s, 3H), 1.35 (t, J=7.04Hz, 3H).

Example 13

Step 1

To a solution of 12c (0.25 g, 697.89 μmol), methanesulfonamide (132.77 mg, 1.40 mmol), and dioxane (5 mL), palladium acetate (15.67 mg, 69.79 μmol), Xantphos (80.76 mg, 139.58 μmol), and cesium carbonate (682.16 mg, 2.09 mmol) were added. The mixture was stirred at 120 °C for 1 hour under nitrogen protection in a microwave reactor. The reaction solution was directly filtered to obtain the filtrate, which was then concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative TLC (DCM:MeOH = 10:1) to obtain compound 13a.

LCMS(ESI)m/z: 417.0[M+1] ⁺ .

Step Two

To a solution of 13a (200 mg, 479.75 μmol), 2,4-difluorophenylboronic acid (90.91 mg, 575.70 μmol) in tetrahydrofuran (1.5 mL)/water (0.5 mL), Pd(dppf) _Cl₂ (35.10 mg, 47.97 μmol) and potassium phosphate (203.67 mg, 959.50 μmol) were added. The mixture was stirred at 100 °C for 45 minutes under nitrogen protection in a microwave reactor. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative thin-layer chromatography on silica gel plates (DCM:MeOH = 10:1) to obtain the crude product. The crude product was then separated by preparative high-performance liquid chromatography (HPLC) (column: BostonGreen ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 23%-53%, 8 min) to obtain the trifluoroacetate of compound 13. The trifluoroacetate of compound 13 was added to sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 13.

LCMS(ESI)m/z: 495.0[M+1] ⁺ ;

¹ H NMR (400MHz, CD ₃ OD-d ₄ )δ8.83 (d, J=7.28Hz, 1H), 8.35 (s, 1H), 8.19 (dt, J=6.90, 8.85Hz, 1H), 7.90-7.98 (m, 2H), 7.84 (s, 1H) , 7.68-7.77 (m, 1H), 7.31 (d, J=1.00Hz, 1H), 7.09-7.21 (m, 2H), 3.92 (s, 3H), 3.41 (s, 3H), 2.61 (s, 3H).

Biological test data:

Experimental Example 1: In vitro enzyme activity test of the compounds of the present invention

The _IC50 values of the test compounds against human FGFR1, FGFR2, and VEGFR2 were determined using the ^33P isotope-labeled kinase activity assay (Reaction Biology Corp).

Buffer conditions: 20 mM Hepes (pH 7.5), ₁₀ mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 _{mM Na3VO4} , 2 mM DTT, 1% DMSO.

Test Procedure: At room temperature, dissolve the test compound in DMSO to prepare a 10 mM solution. Dissolve the substrate in freshly prepared buffer solution, add the test kinase, and mix thoroughly. Using an acoustic device (Echo 550), add the DMSO solution containing the test compound to the above-mixed reaction solution. The compound concentrations in the reaction solution are 10 μM, 2.50 μM, 0.62 μM, 0.156 μM, 39.1 nM, 9.8 nM, 2.4 nM, 0.61 nM, 0.15 nM, 0.038 nM or 3 μM, 1 μM, 0.333 μM, 0.111 μM, 37.0 nM, 12.3 nM, 4.12 nM, 1.37 nM, 0.457 nM, 0.152 nM. After 15 minutes of incubation, ³³ p-ATP (activity 0.01 μCi/μL, corresponding concentrations listed in Table 4) was added to initiate the reaction. Information on FGFR1, FGFR2, KDR, and their concentrations in the reaction solution is listed in Table 4. After the reaction proceeded at room temperature for 120 minutes, the reaction solution was spotted onto P81 ion-exchange filter paper (Whatman #3698-915). After repeatedly washing the filter paper with 0.75% phosphoric acid solution, the radioactivity of the residual phosphorylated substrate on the filter paper was measured. Kinase activity data are expressed as a comparison between the kinase activity containing the test compound and the kinase activity of the blank group (containing only DMSO). _IC50 values were obtained by curve fitting using Prism4 software (GraphPad), and the experimental results are shown in Table 5.

Table 4: Information on kinases, substrates and ATP in in vitro assays.

Table 5. _IC50 test results of the kinase activity of the compounds of this invention.

Note: N/A indicates not tested.

Conclusion: The compounds of this invention exhibit excellent FGFRs and VEGFR2 kinase activities. Compared with the trifluoroacetate salts of control compounds A and B, the imidazopyridine core compounds of this invention show nearly 4-10 times higher FGFR1 or FGFR2 kinase activity and nearly 1-13 times higher VEGFR2 kinase activity, which is highly likely to demonstrate superior therapeutic effects at lower doses in clinical applications. Compared with the formate salt of control compound C, the different sites of nitrogen atom introduction on the central aromatic ring of the compounds of this invention have a significant impact on activity. It was found that the heteroatom N introduced at position 2 of the benzene ring sulfonamide of this invention has significantly higher activity than that at position 4, with a 1000-fold increase in VEGFR2 activity.

Experimental Example 2: Pharmacokinetic Evaluation of the Compounds of the Invention

Experimental procedure: A clear solution of the test compound in 0.1 mg/mL 5% DMSO/10% solution and 85% water was injected into female Balb/c mice via the tail vein (after overnight fasting, 7-9 weeks of age). The dosage was 0.2 mg/kg. Female Balb/c mice (7-9 weeks old, fasted overnight) were administered a 0.1 mg/mL solution of the test compound in a 90% (25% HP-β-CD/10% polyoxyethylene castor oil (pH 4-5)) clear solution via gavage. Approximately 30 μL of blood was collected from the jugular vein at 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 h post-administration, and from the tail vein at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 h post-administration. The plasma was then separated by centrifugation. Plasma concentrations were determined by LC-MS/MS. Relevant pharmacokinetic parameters were calculated using the non-compartmental linear logarithmic trapezoidal method with WinNonlin ^™ Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software.

Experimental data analysis:

Table 6 Summary of Pharmacokinetic Data

Note: -- indicates that this parameter cannot be calculated; _C0 represents the initial concentration; _Cmax represents the peak concentration; _Tmax represents the time to peak concentration; T1 _/2 represents the elimination half-life; _Vdss represents the steady-state apparent volume of distribution; Cl represents the total clearance; _Tlast represents the time point of the last quantifiable drug; _AUC0-last represents the area under the plasma concentration-time curve from time 0 to the last quantifiable time point; AUC0 _-inf represents the area under the plasma concentration-time curve from time 0 to infinity; MRT0 _-las represents the mean residence time from time 0 to the last quantifiable time point; F(%) represents bioavailability.

Compared with the trifluoroacetate of control compound A, the plasma clearance rate of the trifluoroacetate of compound 1 of the present invention is reduced by nearly half, the intravenous drug exposure AUC is increased by two times, and the oral absorption drug exposure is increased by nearly two times.

Experimental conclusion: The introduction of the nitrogen heteroatom in the middle aromatic ring of the compound of this invention significantly improves the metabolic stability of the compound in vivo, greatly increases the oral absorption of the drug, and will demonstrate better pharmacokinetic oral absorption and better therapeutic effects in clinical practice.

Experiment Example 3: Antitumor Activity Test in In Vivo Animal Tumor Models

Experimental objective:

This study investigates the tumor-suppressing effect of the compound of the present invention in a mouse model of human gastric cancer SNU-16 subcutaneous xenograft tumor.

Experimental methods:

1) Tumor tissue preparation

Tumor tissue preparation: SNU-16 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum under standard conditions of 5% _CO2 , 37°C, and saturated humidity. Depending on cell growth, cells were passaged or replenished with medium 1 to 2 times per week, with a passage ratio of 1:3 to 1:4.

2) Organize vaccination and grouping

SNU-16 cells in logarithmic growth phase were collected, counted, and resuspended in 50% serum-free RPMI-1640 medium and 50% Matrigel, adjusting the cell concentration to 4 × ^10⁷ cells/mL. The cells were placed in an ice box, and the cell suspension was aspirated with a 1 mL syringe and injected subcutaneously into the right anterior axilla of nude mice. Each animal received 200 μL (8 × ^10⁶ cells/mouse) to establish a SNU-16 xenograft model. Animal condition was regularly observed, tumor diameter was measured using electronic calipers, and the data were entered into an Excel spreadsheet to calculate tumor volume and monitor tumor growth. Once the tumor volume reached 100–300 ^mm³ , 60 healthy tumor-bearing mice with similar tumor volumes (104–179 ^mm³ ) were selected and randomly divided into 10 groups (n=6), with an average tumor volume of approximately 143 ^mm³ per group.

3) Measure the tumor diameter twice a week, calculate the tumor volume, and weigh and record the animal's weight.

The formula for calculating tumor volume (TV) is as follows: TV (mm ³ )＝l×w ² /2 where l represents the long diameter of the tumor (mm); w represents the short diameter of the tumor (mm).

The antitumor efficacy of the compounds was evaluated using TGI (%) or relative tumor proliferation rate (T/C) (%). Relative tumor proliferation rate (T/C) (%) = _TRTV / _CRTV × 100% ( _TRTV : mean RTV in the treatment group; _CRTV : mean RTV in the negative control group). Relative tumor volume (RTV) was calculated based on tumor measurements using the formula RTV = _Vt / _V0 , where _V0 is the tumor volume measured at the time of administration (D0), and _Vt is the tumor volume at a specific measurement in the corresponding mouse. _TRTV and _CRTV data were taken from the same day.

TGI (%) reflects the tumor growth inhibition rate. TGI (%) = [(1 - (mean tumor volume at the end of treatment - mean tumor volume at the start of treatment)) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100%.

Experimental results:

In a mouse SNU-16 gastric cancer model, after continuous administration for 28 days, the compounds of this invention exhibited significant antitumor activity compared to the solvent group, with a tumor growth inhibition rate (%TGI) of 69% and a relative tumor proliferation rate (%T/C) of 31%. Specific results are shown in Table 7, Figure 1, and Figure 2 (in the figures, QD indicates once-daily administration).

Table 7 Summary of SNU-16 Tumor Growth Inhibition Rate and Relative Tumor Proliferation Rate

*In all treatment groups, the dosage was changed to 20 mg/kg/day on day 8 and to 40 mg/kg/day on day 17.

Experimental conclusion: The compounds of this invention exhibit significant antitumor activity.

Claims (18)

1. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, _R1 is selected from H and _C1-3 alkyl groups optionally substituted with 1, 2 or 3 _Ra ; _R2 and _R3 are independently selected from H, F, Cl, Br, I, OH, _NH2 and _CH3 , respectively; _R4 is selected from H, _C1-6 alkyl, _C1-3 alkoxy, _C3-5 cycloalkyl, tetrahydropyranyl, and 1,3-dioxolanecycloyl, wherein the _C1-6 alkyl, _C1-3 alkoxy, _C3-5 cycloalkyl, tetrahydropyranyl, and 1,3-dioxolanecycloyl are optionally substituted by 1, 2, or 3 _Rb . L is selected from -N( _R5 )C(=O)-, -N( _R5 )S(=O) _2- , -N( _R5 ) _CH2- and -N( _R5 )-; _R5 is independently selected from H and _C1-3 alkyl groups; Ring B is a pyrazol group, which may optionally be substituted by one or two R6 _groups ; _R6 is selected from H and _C1-3 alkyl groups; _Ra and _Rb are independently selected from H, F, Cl, Br, I, OH, _NH2 , CN and _CH3 , respectively. 2. The compound of claim 1 or _a pharmaceutically acceptable salt thereof, wherein _R1 is selected from H, _CH3 and _CH2CH3 , wherein the _CH3 and _CH2CH3 are optionally substituted by 1 _, 2 or 3 _Ra . 3. _The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein _R1 is selected from H, _CH3 , _CH2OH , _{CH2CH2OH and CH2CH3} . 4. _The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein _R4 is selected from H, cyclopropane, _CH3 , _CH2CH3 , CH( _CH3 ) ₂ , C _{( CH3} ) ₃ , _CH2CH2CH3 , _CH2CH ( _CH3 ) ₂ , _OCH3 , _OCH2CH3 , tetrahydropyranyl, and _1,3 -dioxolanecycloyl, wherein the cyclopropane, _{CH3 , CH2CH3} , CH( _CH3 ) ₂ , C( _CH3 ) ₃ , _CH2CH2CH3 , _CH2CH ( _CH3 ) ₂ , _OCH3 , _OCH2CH3 , tetrahydropyranyl _, and 1,3 _- dioxolanecycloyl are optionally substituted _by 1 _, 2, or 3 _Rb . 5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein _R4 is selected from _H , _CH3 , _CH2CH3 , CH( _CH3 ) ₂ , C( _CH3 ) _{3 , CH2CH2CH3 , OCH2CH3 ,} 6. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein _R5 is independently selected from H, _CH3 and _{CH2CH3 ,} respectively. 7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein L is selected from -NHC(=O)-, -NHS(=O) _2- , _-NHCH2- and -NH-. 8. The compound according to claim 5 or 7, or a pharmaceutically acceptable salt thereof, wherein -LR ₄ is selected from... 9. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group optionally substituted with one or two R ₆ . 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein ring B is selected from... 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the structural units are selected from... 12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein the structural units are selected from... 13. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from... in, _R1 , _R2 , _R3 , L and _R4 are as defined in any one of claims 1 to 3. 14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, selected from... in, _R1 , _R2 , _R3 and _R4 are as defined in claim 13. 15. The compound shown in the following formula, or a pharmaceutically acceptable salt thereof, 16. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier. 17. The use of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or the composition according to claim 16 in the preparation of a medicament related to dual inhibitors of FGFR and VEGFR. 18. The application according to claim 17, wherein the FGFR and VEGFR dual inhibitor-related drug is a drug for solid tumors.