WO2020094084A1 - Tricyclic derivative as ret inhibitor - Google Patents

Abstract

A compound having a tricyclic structure and an application of the compound in preparation of an RET kinase inhibitor. Specifically disclosed are a compound represented by formula (II), isomers or pharmaceutically acceptable salts of the compound.

Description

Tricyclic derivatives as RET inhibitors

This application claims the following priority

CN201811322015.4, application date 2018.11.07.

CN201910186910.6, application date 2019.03.12.

Technical field

The invention relates to a series of compounds with triple ring structure and their application in the preparation of RET kinase inhibitors. Specifically, it relates to a compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

Background technique

RET protein is a receptor tyrosine kinase RTK and a transmembrane glycoprotein. It is expressed by the proto-oncogene RET (REarranged during Transfection) on chromosome 10, and it develops in the embryonic kidney and enteric nervous system Plays an important role in addition to homeostasis in a variety of tissues, such as neurons, neuroendocrine, hematopoietic tissues, and male germ cells. Unlike other RTKs, RET does not directly bind to ligand molecules: such as artemin, glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (neurturin, persephin), these are all GNDF Family ligands (GFLs). These ligands GFLs usually bind to the GDNF family receptor α (GFRα), and the formed GFLs-GFRα complex mediates the self-dimerization of the RET protein, causing trans autophosphorylation of tyrosine on the intracellular domain , Recruit relevant linker proteins, activate cell proliferation and other signaling cascades, and related signaling pathways include MAPK, PI3K, JAK-STAT, PKA, PKC, etc.

There are two main mechanisms of RET carcinogenic activation: one is that the rearrangement of chromosomes produces new fusion proteins, usually the fusion of the kinase domain of RET and the protein containing the self-dimerization domain; the second is that the RET mutations are directly or indirectly The kinase activity of RET is activated. These changes in somatic or germ cell levels are involved in the pathogenesis of various cancers. 5% -10% of patients with papillary thyroid cancer have RET chromosome rearrangements; and 60% of medullary medullary thyroid cancers have RET point mutations; of all NSCLC patients, about 1-2% have Among RET fusion proteins, KIF5B-RET is the most common.

In conclusion, abnormal RET expression or activation is found in various tumors and gastrointestinal disorders such as allergic bowel syndrome. Therefore, RET inhibitors have potential clinical value in tumor or intestinal disorders.

Summary of the invention

The present invention provides a compound represented by formula (II), an isomer thereof or a pharmaceutically acceptable salt thereof,

among them,

R _{1 is} selected from H, F, Cl, Br, I, C _1-6 alkyl, C _1-6 alkoxy, 5-6 membered heteroaryl, and 5-10 membered heterocycloalkenyl, the C _{1 -6} alkyl, C _{1- 6} alkoxy group, a 5 to 6 membered heteroaryl and 5 to 10-membered heterocycloalkenyl group is optionally substituted with 1, 2 or 3 substituents R _a;

R _{1 is} selected from H, F, Cl, Br, I, C _1-6 alkyl, C _1-6 alkoxy, pyrazolyl and 3,6-dihydropyranyl, the C _1-6 alkyl group, C _1-6 alkoxy, 3,6-dihydro-pyrazolyl, and pyranyl optionally substituted with 1, 2 or 3 substituents R _a;

R _{2 is} selected from H, F, Cl, Br, I, CN, and C _1-6 alkyl, the C _1-6 alkyl is optionally substituted with 1, 2, or 3 R _b ;

R _{3 is} selected from H, F, Cl, Br, I, C _1-6 alkyl and C _1-6 alkoxy, the C _1-6 alkyl and C _1-6 alkoxy are optionally substituted by 1, 2 or 3 R _c substitutions;

n is selected from 0, 1, 2, 3 and 4;

Ring A is selected from phenyl and 5-8 membered heteroaryl;

Ring A is selected from phenyl and pyridyl;

L _{1 is} selected from

-C (= O) -C _1-3 alkyl- and C _1-3 alkyl, the -C (= O) -C _1-3 alkyl- and C _1-3 alkyl are optionally substituted by 1, 2 or 3 _Rd substitutions;

R _{a is} selected from H, F, Cl, Br, I, NH ₂ , CN and C _1-3 alkyl groups, the C _1-3 alkyl groups are optionally substituted with 1, 2 or 3 R;

R _{b is} selected from H, F, Cl, Br, I, NH ₂ and CN;

R _{c is} selected from H, F, Cl, Br and I;

R _{d is} selected from H, F, Cl, Br, I, OH, NH ₂ and CN;

R is selected from H, F, Cl, Br, I, OH, NH ₂ and CN;

The carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.

The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

among them,

R ₁ is selected H, F, Cl, Br, I , and C _1-6 alkoxy, a C _1-6 alkoxy group optionally substituted with 1, 2 or 3 R _a;

R _{2 is} selected from H, F, Cl, Br, I, CN, and C _1-6 alkyl, the C _1-6 alkyl is optionally substituted with 1, 2, or 3 R _b ;

R _{3 is} selected from H, F, Cl, Br, I, and C _1-3 alkyl, the C _1-3 alkyl is optionally substituted with 1, 2, or 3 R _c ;

L _{1 is} selected from

And -C (= O) -C _1-3 alkyl-, the -C (= O) -C _1-3 alkyl- is optionally substituted with 1, 2 or 3 _Rd ;

R _{a is} selected from H, F, Cl, Br and I;

R _{b is} selected from H, F, Cl, Br, I, NH ₂ and CN;

R _{c is} selected from H, F, Cl, Br and I;

R _{d is} selected from H, F, Cl, Br, I, OH, NH ₂ and CN;

The carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.

In some embodiments of the present invention, the above R _{1 is} selected from H, F, Cl, Br, I, C _1-3 alkyl, C _1-3 alkoxy, pyrazolyl, imidazolyl and 3,6-di Hydrogen-2H-pyranyl, the C _1-3 alkyl, C _1-3 alkoxy, pyrazolyl, imidazolyl and 3,6-dihydro-2H-pyranyl are optionally 1, 2 Or 3 _Ra substitutions, other variables are as defined in the present invention.

In some embodiments of the present invention, the above R _{1 is} selected from H, F, Cl, Br, I, C _1-3 alkyl, C _1-3 alkoxy,

The C _1-3 alkyl group, C _1-3 alkoxy group,

Optionally substituted with 1,2 or 3 substituents R _a, the other variables are as defined in the present invention.

In some aspects of the invention, the above R _{1 is} selected from H,

Other variables are as defined in the present invention.

In some aspects of the present invention, the above-described R ₁ is selected from H and a C _1-3 alkoxy group, a C _1-3 alkoxy said alkoxy optionally substituted with 1, 2 or 3 R _a, of the present invention other variables are as As defined.

In some aspects of the invention, the above R _{1 is} selected from H,

Other variables are as defined in the present invention.

In some aspects of the invention, the above R _{1 is} selected from

Other variables are as defined in the present invention.

In some embodiments of the present invention, the above R _{2 is} selected from H, F, Cl, Br, I, CN and C _1-3 alkyl, the C _1-3 alkyl is optionally substituted by 1, 2 or 3 R _b instead, other variables are as defined in the present invention.

In some embodiments of the present invention, the above R _{2 is} selected from H, F, Cl, Br, I, CN, CH ₂ NH ₂ , CH ₂ CN and

Other variables are as defined in the present invention.

In some aspects of the invention, the above R _{2 is} selected from CN, and other variables are as defined in the invention.

In some embodiments of the present invention, the above R _{3 is} selected from H, F, Cl, Br, I, C _1-3 alkyl and C _1-3 alkoxy, the C _1-3 alkyl and C _{1- The 3} alkoxy groups are optionally substituted with 1, 2 or 3 R _c , and other variables are as defined in the present invention.

In some aspects of the invention, the above R _{3 is} selected from H, F, Cl, Br, I, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ and -OCH ₃ , and other variables are as defined in the invention.

In some aspects of the present invention, the above R _{3 is} selected from H, F, Cl, Br, I, and CH ₃ , the CH _{3 is} optionally substituted with 1, 2, or 3 R _c , and other variables are as defined in the present invention .

In some embodiments of the present invention, the above R _{3 is} selected from H, F, Cl, Br, I, CH ₃ , CH ₂ F, CHF ₂ and CF ₃ , and other variables are as defined in the present invention.

In some aspects of the invention, the above R _{3 is} selected from H, F, Cl, Br, and I, and other variables are as defined in the invention.

In some embodiments of the present invention, the A ring is selected from phenyl and pyridyl, and other variables are as defined in the present invention.

In some aspects of the invention, the above structural unit

Select from

Other variables are as defined in the present invention.

In some aspects of the invention, the above structural unit

Select from

Other variables are as defined in the present invention.

In some aspects of the invention, the above L _{1 is} selected from

Said

It can be optionally substituted with 1, 2 or 3 _Rd , and other variables are as defined in the present invention.

In some aspects of the invention, the above L _{1 is} selected from

Other variables are as defined in the present invention.

In some aspects of the invention, the above L _{1 is} selected from

Other variables are as defined in the present invention.

In some aspects of the present invention, wherein L _{1 is} selected from

And -CH _2- , described

And -CH ₂ -are optionally substituted with 1, 2, or 3 _Rd , and other variables are as defined in the present invention.

In some aspects of the invention, the above L _{1 is} selected from

And -CH _2- , other variables are as defined in the present invention.

In some aspects of the invention, the above structural unit

Select from

Other variables are as defined in the present invention.

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

Among them, R ₁ , R ₂ and R _{3 are} as defined in the present invention.

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

Among them, R ₁ , R ₂ , L ₁ and R _{3 are} as defined in the present invention.

There are still some solutions of the present invention that are derived from any combination of the above variables.

The present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

The present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

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

The invention also provides the application of the above compound, its isomer or pharmaceutically acceptable salt thereof in the preparation of RET kinase inhibitor.

The invention also provides the application of the above composition in the preparation of RET kinase inhibitors.

Definition and description

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding trade product or its active ingredient.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds 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 the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds 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 including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Bisulfate, 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, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also includes salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups and can be converted to any base or acid addition salt.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound 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 the appropriate base or acid in water or an organic solvent or a mixture of both.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S) -enantiomers, diastereomers Isomers, (D) -isomers, (L) -isomers, and their racemic mixtures and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this Within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl. All these isomers and mixtures thereof are included in the scope of the present invention.

Unless otherwise stated, the term "enantiomer" or "optical isomer" refers to stereoisomers in a mirror image relationship with each other.

Unless otherwise stated, the term "cis-trans isomer" or "geometric isomer" is caused by the fact that double bonds or single bonds of ring-forming carbon atoms cannot rotate freely.

Unless otherwise stated, the term "diastereomers" refers to stereoisomers in which molecules have two or more chiral centers and are in a non-mirror relationship.

Unless otherwise stated, "(+)" means right-handed, "(-)" means left-handed, "(DL)" or "(±)" means racemic.

Unless otherwise stated, use a solid wedge key

And wedge-shaped dotted keys

Represents the absolute configuration of a three-dimensional center, using straight solid line keys

And straight dotted keys

Represents the relative configuration of the three-dimensional center, with wavy lines

Represents a solid wedge key

Or wedge-shaped dotted key

Or with wavy lines

Represents straight solid line keys

And straight dotted keys

Unless otherwise stated, when a double bond structure exists in a compound, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (including nitrogen atoms In the double bond of, a lone pair of electrons on the nitrogen atom is regarded as a substituent to which it is connected), if the compound on the double bond in the compound is wavy

Linked means the (Z) isomer, (E) isomer or a mixture of two isomers of the compound. For example, the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or (A-2) or as two isomers of formula (A-1) and formula (A-2) Exists in the form of a mixture; the following formula (B) indicates that the compound exists as a single isomer of formula (B-1) or formula (B-2) or as both formula (B-1) and formula (B-2) There is a mixture of isomers. The following formula (C) indicates that the compound exists as a single isomer of formula (C-1) or formula (C-2) or as two isomers of formula (C-1) and formula (C-2) In the form of a mixture.

The compounds of the present invention may be present in specific. Unless otherwise stated, the term "tautomer" or "tautomeric form" means that at room temperature, isomers of different functional groups are in dynamic equilibrium and can quickly convert to each other. If tautomers are possible (as in solution), the chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversion through proton migration, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomer (valence tautomer) includes some recombination of bond-forming electrons for mutual conversion. A specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

Unless otherwise stated, the terms "rich in one isomer", "isomer enriched", "rich in one enantiomer" or "enantiomerically enriched" refer to one of the isomers or pairs The content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal to 99.9%.

Unless otherwise stated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the excess of isomer or enantiomer (ee value) is 80% .

The optically active (R)-and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary groups are cleaved to provide pure The 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 a diastereomer is formed with an appropriate optically active acid or base, and then by conventional methods known in the art The diastereomers are resolved and the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually done by using chromatography, which uses a chiral stationary phase, and is optionally combined with chemical derivatization methods (for example, the formation of amino groups from amines) Formate). The compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). For another example, the hydrogen can be replaced by heavy hydrogen to form a deuterated drug. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced toxic and side effects and increased drug stability. , Strengthen efficacy, prolong the biological half-life of drugs and other advantages. The conversion of all isotopic compositions of the compounds of the present invention, whether radioactive or not, is included in the scope of the present invention. "Optional" or "optionally" means that the subsequently described events or conditions may, but need not necessarily occur, and that the description includes situations in which the events or conditions occur and situations in which the 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 may include heavy hydrogen and hydrogen variants, as long as the valence state of the particular atom is normal and the compound after substitution is stable of. When the substituent is oxygen (ie = O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis that they are chemically achievable.

When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group can optionally be substituted with up to two Rs, and R in each case has independent options. In addition, combinations of substituents and / or variants thereof are only allowed if such combinations will produce stable compounds.

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

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

When a substituent is vacant, it means that the substituent does not exist. For example, when X is vacant in A-X, it means that the structure is actually A. When the substituents listed do not indicate through which atom they are connected to the substituted group, such substituents can be bonded through any of their atoms, for example, pyridyl as a substituent can be through any one of the pyridine rings The carbon atom is attached to the substituted group.

When the listed linking group does not indicate the connection direction, the connection direction is arbitrary, for example,

The linking group L in the middle is -MW-, then -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right

It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right

Combinations of the linking groups, substituents, and / or variants thereof are only allowed if such combinations will produce stable compounds.

Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group may be connected to other groups by chemical bonds. The chemical bond connecting the site with other groups can be a straight solid bond

Straight dotted key

Or wavy lines

Said. For example, the straight solid line bond in-℃ H ₃ indicates that the oxygen atom in the group is connected to other groups;

The straight dashed bond in means that the two ends of the nitrogen atom in the group are connected to other groups;

The wavy line in indicates that it is connected to other groups through the carbon atoms at the 1 and 2 positions of the phenyl group.

Unless otherwise specified, the term "C _1-6 alkyl" is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms. The C _1-6 alkyl group includes C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ and C ₅ alkyl groups; etc .; Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C _1-6 alkyl 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 and so on.

Unless otherwise specified, the term "C _1-3 alkyl" is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms. The C _1-3 alkyl group includes C _1-2 and C _2-3 alkyl groups, etc .; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine) . Example C _{1- 3} alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like. Unless otherwise specified, "C _2-8 alkenyl" is used to denote a linear or branched hydrocarbon group consisting of at least one carbon-carbon double bond consisting of 2 to 8 carbon atoms, a carbon-carbon double bond It can be located anywhere on the group. The C _2-8 alkenyl group includes C _2-6 , C _2-4 , C _2-3 , C ₄ , C ₃ and C ₂ alkenyl groups; it may be monovalent, divalent or multivalent. Examples of C _2-8 alkenyl include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, hexadienyl, and the like.

Unless otherwise specified, the term "C _1-6 alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through one oxygen atom. The C _1-6 alkoxy group includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ and C ₃ alkoxy groups, etc. . Examples of C _1-6 alkoxy include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy Oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, etc.

Unless otherwise specified, the term "C _1-3 alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through one oxygen atom. The C _1-3 alkoxy group includes C _1-2 , C _2-3 , C ₃ and C ₂ alkoxy groups and the like. Examples of C _1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

Unless otherwise specified, the term "halogen" or "halogen" itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

Unless otherwise specified, C _{n-n + m} or C _n -C _{n + m} includes any specific case of n to n + m carbons, for example, C _1-12 includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , and C ₁₂ , and also includes any range from n to n + m, for example, C _1-12 includes C _{1- 3} , C _1-6 , C _1-9 , C _3-6 , C _3-9 , C _3-12 , C _6-9 , C _6-12 , and C _9-12, etc .; similarly, n yuan to n + m member means that the number of atoms in the ring is n to n + m, for example, 3-12 member ring includes 3 member ring, 4 member ring, 5 member ring, 6 member ring, 7 member ring, 8 member ring, 9 member ring , 10-membered ring, 11-membered ring, and 12-membered ring, also including any range from n to n + m, for example, 3-12 membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring Rings, 5-7 member rings, 6-7 member rings, 6-8 member rings, 6-10 member rings, etc.

Unless otherwise specified, the terms "5-8 membered heteroaryl ring" and "5-8 membered heteroaryl group" of the present invention may be used interchangeably. The term "5-8 membered heteroaryl group" means from 5 to 8 ring atoms The cyclic group composed of a conjugated π electron system has 1, 2, 3, or 4 ring atoms as heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. It can be a monocyclic ring or a fused bicyclic ring system, where each ring is aromatic. Where nitrogen atoms are optionally quaternized, nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S (O) _p , p is 1 or 2). The 5-8 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or carbon atom. The 5-8 membered heteroaryl group includes 5-7 membered, 5-6 membered, 5 membered, and 6 membered heteroaryl groups. Examples of the 5-8 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyryl Oxazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5- Oxazolyl, etc.), 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-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (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-pyrimidyl and 4-pyrimidyl, etc.).

Unless otherwise specified, the terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl group" of the present invention can be used interchangeably, and the term "5-6 membered heteroaryl group" means from 5 to 6 ring atoms The monocyclic group with a conjugated π electron system consists of 1, 2, 3, or 4 ring atoms that are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. Where nitrogen atoms are optionally quaternized, nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S (O) _p , p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or carbon atom. The 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyryl Oxazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5- Oxazolyl, etc.), 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-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (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-pyrimidyl and 4-pyrimidyl, etc.).

Unless otherwise specified, the term "5-10 membered heterocyclenyl" by itself or in combination with other terms means a partially unsaturated cyclic group consisting of 5 to 10 ring atoms containing at least one carbon-carbon double bond , Whose 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally Oxidation (ie NO and S (O) _p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic systems, in which the bicyclic and tricyclic systems include spiro, bicyclic and bridged rings, any ring of this system is non-aromatic. In addition, as far as the "5-10 membered heterocyclic alkenyl group" is concerned, the hetero atom may occupy the connection position of the heterocyclic alkenyl group with the rest of the molecule. The 5-10 membered heterocyclic alkenyl group includes 5-8 membered, 5-6 membered, 4-5 membered, 4 membered, 5 membered, and 6 membered heterocyclic alkenyls. Examples of 5-10 membered heterocyclic alkenyl groups include, but are not limited to

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination with other chemical synthesis methods, and well known to those skilled in the art Equivalently, preferred embodiments include but are not limited to the embodiments of the present invention.

The compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with Bruker D8 venture diffractometer to diffract the intensity data, the light source is CuKα radiation, scanning mode:

After scanning and collecting the relevant data, the crystal structure can be further analyzed by the direct method (Shelxs97) to confirm the absolute configuration.

The solvent used in the present invention is commercially available. The following abbreviations are used in the present invention: aq stands for water; HATU stands for O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate ; EDC stands for N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent and equivalent; CDI stands for Carbonyldiimidazole; DCM for methylene chloride; PE for petroleum ether; DIAD for diisopropyl azodicarboxylate; DMF for N, N-dimethylformamide; DMSO for dimethylsulfoxide; EtOAc for ethyl acetate Ester; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, which is an amine protecting group; Boc for tert-butoxycarbonyl, which is an amine protecting group; HOAc for acetic acid; NaCNBH ₃ for sodium cyanoborohydride ; Rt stands for room temperature; O / N stands for overnight; THF stands for tetrahydrofuran; Boc ₂ O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl ₂ stands for subchloride Sulfone; CS ₂ stands for carbon disulfide; TsOH stands for p-toluenesulfonic acid; NFSI stands for N-fluoro-N- (benzenesulfonyl) benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n-Bu ₄ NF stands for fluorine Tetrabutylammonium; iPrOH represents 2-propanol; mp Representative mp; LDA lithium diisopropylamide Representative; H for hour; min for minutes; MgCl ₂ Representative chloride; Na ₃ VO ₄ represents a sodium vanadium.

Compounds are used according to conventional naming principles in the art or used

The software is named, and the commercially available compounds adopt the supplier catalog name.

Technical effect

The compounds of the present invention exhibit good inhibitory activity against wild-type and V804M mutant RET.

detailed description

The following describes the present invention in detail through examples, but it does not mean any adverse limitation of the present invention. The present invention has been described in detail herein, and the specific embodiments thereof are also disclosed. For those skilled in the art, various changes and improvements are made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention Will be obvious.

Examples 1 and 2:

Step 1: Synthesis of intermediate 001-3

Add compound 001-1 (2g, 12.49mmol, 1eq) and compound 001-2 (3.24g, 14.99mmol, 1.2eq) to a 100mL three-necked flask, add acetonitrile (3mL), add N, N-diiso with magnetic stirring Propylethylamine (4.84g, 37.48mmol, 6.53mL, 3eq) was reacted at 25 ° C for 2 hours. The reaction solution was dissolved in 30 mL of water and 30 mL of ethyl acetate, the layers were extracted, and the aqueous phase was extracted three times with ethyl acetate (3 × 30 mL). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), and finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain intermediate 001-3.

LCMS: MS (ESI) m / z: 301 [M-tBu + 1] ⁺

Step 2: Synthesis of intermediate 001-4

Add intermediate 001-3 (3.0g, 8.42mmol, 1eq) to a 100mL single-necked bottle, add N, N-dimethylformamide (3mL), and add sodium hydrogen (1.01g, 25.26mmol, 0 ° C under magnetic stirring) 60% content, 3eq), after the addition is completed, the temperature is raised to 25 ° C for 0.5h, and then the temperature is raised to 90 ° C for 0.5h. The reaction solution was cooled to 25 ° C, 50 mL of water was added to the reaction solution, filtered, and the filter cake was dissolved in 40 mL of water to be slurried, filtered and dried in vacuo to obtain intermediate 001-4.

LCMS: MS (ESI) m / z: 281 [M-tBu + 1] ⁺

Step 3: Synthesis of intermediate 001-5

Raney nickel (76.42 mg, 891.95 μmol, 0.2 eq) was added to a stainless steel hydrogenation flask, followed by methanol (80 mL) and tetrahydrofuran (80 mL), followed by intermediate 001-4 (1.5 g, 4.46 mmol, 1 eq). Under a pressure of 30 psi of hydrogen (8.99 mg, 4.46 mmol, 1 eq), the reaction was performed at 25 ° C. for 24 h. The reaction solution was cooled to 25 ° C, filtered and concentrated with celite to obtain intermediate 001-5.

LCMS: MS (ESI) m / z: 307 [M + 1] ⁺

Step 4: Synthesis of intermediate 001-6

One-necked bottle 1: Dissolve intermediate 001-5 (200mg, 652.83μmol, 1eq) in acetic acid (1mL), dropwise add 48% hydrobromic acid (1mL), then react at 70 ° C for 0.5h, then move to room temperature After stirring for 1 h, the reaction was cooled to 0 ° C., and an aqueous solution (0.5 ml of water) of sodium nitrite (54.05 mg, 783.39 μmol, 1.2 eq) was added dropwise to react for 0.5 h.

Single-necked bottle 2: Dissolve cuprous bromide (140.47mg, 979.24μmol, 29.82μL, 1.5eq) in 48% hydrobromic acid (1mL), stir at 70 ° C, and add the reaction solution in single-necked bottle 1 dropwise , Continue to react at 70 ℃ for 1h. The reaction was cooled to room temperature, adjusted to pH-9 with 1M sodium bicarbonate solution (50 mL), followed by extraction with ethyl acetate and concentration to obtain intermediate 001-6.

LCMS: MS (ESI) m / z: 270 [M + 1] ⁺

Step 5: Synthesis of intermediate 001-8

Intermediate 001-6 (225 mg, 832.95 μmol, 1 eq) was dissolved in dichloromethane (3 mL), triethylamine (168.57 mg, 1.67 mmol, 231.87 L, 2 eq) and 001-7 (129.21) were added at 25 ° C mg, 832.95μmol, 1eq), and finally add O- (7-azabenzotriazole-1-YL) -N, N, N, N-tetramethylurea hexafluorophosphine salt (475.07mg, 1.25mmol , 1.5eq), react at 25 ° C for 1h. Water (30 mL) was added to the reaction solution, followed by dichloromethane extraction (2 × 50 mL), washed with saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography (ethyl acetate: petroleum ether = 0 ~ 0.7: 1) to obtain intermediate 001-8.

LCMS: MS (ESI) m / z: 406.9 [M + 1] ⁺

Step 6: Synthesis of intermediate 001-10

Intermediate 001-8 (130mg, 319.22μmol, 1eq), 001-9 (121.59mg, 478.84μmol, 1.5eq), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride Dichloromethane complex (26.07mg, 31.92μmol, 0.1eq), and potassium acetate (62.66mg, 638.45μmol, 2eq) were dissolved in dioxane (5mL) and reacted at 85 ° C for 2h. The reaction solution was cooled to room temperature, ethyl acetate (100 mL) was added, and filtered through celite. The mother liquor was washed with water (100 mL), saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated. After preparation and thin layer separation and purification (ethyl acetate / petroleum ether = 2.5 / 1), intermediate 001-10 was obtained.

LCMS: MS (ESI) m / z: 455 [M + 1] ⁺

Step 7: Synthesis of 001/002

Intermediate 001-10 (69 mg, 151.88 μmol, 1 eq), 001-11 (57.43 mg, 227.82 μmol, 1.5 eq), tetrakis (triphenylphosphine) palladium (17.55 mg, 15.19 μmol, 0.1 eq) and sodium carbonate The solution (2M, 0.5mL, 6.58eq) was dissolved in dioxane (2mL), replaced by nitrogen and protected by nitrogen, and reacted at 90 ° C for 2h. The reaction solution was cooled to room temperature, filtered through celite, added with water (20 mL), extracted with ethyl acetate (2 × 30 mL), combined organic layers, washed with saturated sodium chloride solution, and concentrated. The crude product was dissolved in DMSO (3mL) and separated by high performance liquid chromatography (column: Xtimate C18 150 × 25mm × 5μm; mobile phase: [water (0.225% formic acid-acetonitrile); acetonitrile%: 44% -64%, 7min) Then, the chiral separation column: DAICEL CHIRALCEL OJ-H (250mm × 30mm, 5μm); mobile phase: [0.1% ammonia methanol]; carbon dioxide%: 30% -30%, min) to separate compounds 001 and 002.

LCMS: MS (ESI) m / z: 500.2 [M + 1] ⁺

Compound 001, SFC peak position 3.88min

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.53 (br t, J = 12.30 Hz, 0.5H), 2.66-3.04 (m, 2H), 3.24-3.36 (m, 1H), 3.41 (br dd, J = 10.67 , 8.16Hz, 0.5H), 3.90 (s, 3H), 3.95 (br d, J = 11.04Hz, 1H), 3.99-4.08 (m, 2H), 4.23-4.37 (m, 2H), 4.62-4.77 ( m, 2H), 7.09 (s, 1H), 7.13-7.20 (m, 1H), 7.36-7.44 (m, 2H), 7.96 (d, J = 1.51 Hz, 1H), 8.13 (d, J = 1.51 Hz , 1H), 8.19 (s, 1H), 8.40 (br s, 1H).

Compound 002, SFC peak position 4.25min

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.53 (br t, J = 12.30 Hz, 0.5H), 2.66-3.04 (m, 2H), 3.24-3.36 (m, 1H), 3.41 (br dd, J = 10.67 , 8.16Hz, 0.5H), 3.90 (s, 3H), 3.95 (br d, J = 11.04Hz, 1H), 3.99-4.08 (m, 2H), 4.23-4.37 (m, 2H), 4.62-4.77 ( m, 2H), 7.09 (s, 1H), 7.13-7.20 (m, 1H), 7.36-7.44 (m, 2H), 7.96 (d, J = 1.51 Hz, 1H), 8.13 (d, J = 1.51 Hz , 1H), 8.19 (s, 1H), 8.40 (br s, 1H)

Examples 3 and 4:

Step 1: Synthesis of intermediate 001-12

Intermediate 001-6 (4.45g, 16.47mmol, 1eq) was dissolved in dichloromethane (50mL), followed by the addition of di-tert-butyl dicarbonate (4.31g, 19.77mmol, 4.54mL, 1.2eq) at 20 ° C With 4-dimethylaminopyridine (201.26mg, 1.65mmol, 0.1eq), react at 20 ° C for 0.5h. The reaction solution was washed with water (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography (40g flash silica gel column, ethyl acetate in petroleum ether = 0-20%) to obtain intermediate 001-12.

LCMS: MS (ESI) m / z: 313.7 [M + 1-tBu] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.49 (s, 9H), 2.60 (br s, 1H), 2.75 (td, J = 12.55, 3.26 Hz, 1H), 2.94 (s, 1H), 3.32 (ddt, J = 11.23, 8.09, 3.26, 3.26 Hz, 1H), 3.94 (dd, J = 11.04, 8.28 Hz, 1H), 4.12 (m, 2H), 4.25 (dd, J = 10.92, 3.14 Hz, 1H), 4.46 (br d, J = 12.05 Hz, 1H), 7.09 (d, J = 2.01 Hz, 1H), 7.82 (d, J = 2.26 Hz, 1H)

Step 2: Synthesis of intermediate 001-13

Intermediate 001-12 (4.25g, 11.48mmol, 1eq), 001-9 (3.79g, 14.92mmol, 1.3eq), [1,1'-bis (diphenylphosphino) ferrocene] dichloride Palladium dichloromethane complex (468.71 mg, 573.95 μmol, 0.05 eq) and potassium acetate (2.25 g, 22.96 mmol, 2 eq) were dissolved in dioxane (50 mL) and reacted at 90 ° C. for 2.5 h. The reaction solution was filtered while hot, washed with water (100 mL), and concentrated. The crude product was subjected to silica gel column chromatography (20g flash silica gel column, ethyl acetate in petroleum ether: 0-15%) to isolate intermediate 001-13.

LCMS: MS (ESI) m / z: 335.9 [M + 1-C ₆ H ₁₀ ] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.32 (s, 12H), 1.49 (s, 9H), 2.63 (br s, 1H), 2.80 (td, J = 12.61, 3.14 Hz, 1H), 2.95 (br s , 1H), 3.36-3.44 (m, 1H), 3.92 (dd, J = 11.04, 8.03Hz, 1H), 4.12-4.18 (m, 2H), 4.21-4.25 (m, 1H), 4.65 (br d, J = 12.55 Hz, 1H), 7.29 (d, J = 1.51 Hz, 1H), 8.17 (d, J = 1.51 Hz, 1H).

Step 3: Synthesis of intermediate 001-14

Intermediate 001-13 (300mg, 718.90μmol, 1eq), 001-11 (271.82mg, 1.08mmol, 1.5eq), tetrakis (triphenylphosphine) palladium (83.07mg, 71.89μmol, 0.1eq) and sodium carbonate (2M, 1mL, 2.78eq) was dissolved in dioxane (4mL) and reacted at 90 ° C for 3h. The reaction solution was filtered on a hot pad of celite, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography (12g flash silica gel, ethyl acetate in petroleum ether: 0-50%) to obtain intermediate 001-14.

LCMS: MS (ESI) m / z: 463.0 [M + 1] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.43 (s, 9H), 2.67 (br d, J = 1.76 Hz, 1 H), 2.76 (td, J = 12.55, 3.26 Hz, 1 H), 2.92 (br s , 1H), 3.36-3.45 (m, 1H), 3.86 (s, 1H), 3.89 (s, 3H), 3.94–3.98 (m, 1H), 4.03–4.05 (m, 1H), 4.42 (dd, J = 11.17, 3.14 Hz, 1H), 4.50 (br d, J = 12.30 Hz, 1H), 7.26 (d, J = 2.01 Hz, 1H), 7.30 (d, J = 2.01 Hz, 1H), 7.96 (d, J = 2.26 Hz, 1H), 8.57 (s, 1H), 8.67 (d, J = 2.01 Hz, 1H)

Step 4: Synthesis of Intermediate 001-15

Intermediate 001-14 (250 mg, 540.54 μmol, 1 eq) was dissolved in dichloromethane (6 mL), followed by addition of trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 24.99 eq), and reacted at 20 ° C. for 0.5 h. The reaction solution was concentrated, ethyl acetate (50 mL) was dissolved, and washed with water (2 × 30 mL). The product is in the water phase and the impurities are in the organic phase. Potassium carbonate (5g) and ethyl acetate (30mL) were added to the aqueous phase and stirred for 0.5h. It was then extracted with ethyl acetate (2 × 30 mL), dried over anhydrous sodium sulfate, and concentrated. Without further purification, intermediate 001-15 was obtained.

LCMS: MS (ESI) m / z: 362.8 [M + 1] ⁺

Step 5: Synthesis of 003/004

Intermediate 001-15 (40mg, 110.38μmol, 1eq) and 001-16 (19.68mg, 143.49μmol, 1.3eq) were dissolved in dichloromethane (3mL), followed by the addition of sodium triacetoxyborohydride (70.18mg , 331.14μmol, 3eq), react at 20 ℃ for 1h. The reaction solution was concentrated to dryness. The crude product was separated by high performance liquid chromatography (chromatographic column: Xtimate C18 150 * 25mm * 5μm; mobile phase: [water (0.225% formic acid) -acetonitrile]; acetonitrile%: 22% -52%, 8min), and then chiral separation ( Chromatographic column: DAICEL CHIRALCEL OJ-H (250mm * 30mm, 5μm); mobile phase: [0.1% ammonia ethanol]; carbon dioxide%: 30% -30%, min) Compounds 003 and 004 were separated.

LCMS: MS (ESI) m / z: 484.0 [M + 1] ⁺

Compound 003, SFC peak position 3.62min

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.16 (br t, J = 10.67 Hz, 1H), 2.43 (br t, J = 10.54 Hz, 1 H), 3.04 (br d, J = 10.79 Hz, 1 H), 3.08 -3.17 (m, 2H), 3.65-3.79 (m, 3H), 3.91 (s, 3H), 3.95 (s, 3H), 4.05 (br dd, J = 10.92, 7.40 Hz, 1H), 4.28 (dd, J = 11.04, 2.51 Hz, 1H), 4.67 (br d, J = 13.05 Hz, 1H), 6.78 (d, J = 8.53 Hz, 1H), 7.12 (dd, J = 11.17, 1.63 Hz, 2H), 7.71 (br d, J = 8.53 Hz, 1H), 7.96 (d, J = 1.76 Hz, 1H), 8.12 (br d, J = 10.79 Hz, 2H), 8.19 (s, 1H). Compound 004, SFC peak Location 3.99min

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.91 (br s, 1H), 2.29 (br s, 1H), 2.85 (br s, 1H), 3.01 (br d, J = 9.29 Hz, 2H), 3.45-3.65 (m, 3H), 3.91 (s, 3H), 3.95 (s, 3H), 3.98-4.04 (m, 1H), 4.23 (br d, J = 8.53 Hz, 1H), 4.59 (br d, J = 13.05 Hz, 1H), 6.77 (d, J = 8.28 Hz, 1H), 7.10 (d, J = 2.01 Hz, 1H), 7.14 (d, J = 2.01 Hz, 1H), 7.64 (br s, 1H), 7.95 (d, J = 2.01 Hz, 1H), 8.09 (d, J = 1.51 Hz, 1H), 8.12 (d, J = 2.01 Hz, 1H), 8.19 (s, 1H)

Examples 5, 6:

Step 1: Synthesis of 005/006

Dissolve intermediates 001-15 (40 mg, 110.38 μmol, 1 eq), 001-17 (20.39 mg, 143.49 μmol, 15.45 μL, 1.3 eq) in dichloromethane (3 mL), then add sodium triacetoxyborohydride (70.18mg, 331.14μmol, 3eq), react at 20 ℃ for 1h. The crude product was separated by high performance liquid chromatography (chromatographic column: Xtimate C18 150 * 25mm * 5μm; mobile phase: [water (0.225% formic acid) -acetonitrile]; acetonitrile%: 22% -52%, 8min), and then chiral separation ( Chromatography column: YMC CHIRAL Amylose-C (250mm * 30mm, 10μm; mobile phase: [0.1% ammonia ethanol]; carbon dioxide%: 40% -40%, min) to separate compounds 005 and 006.

LCMS: MS (ESI) m / z: 489.0 [M + 1] ⁺

Compound 005, SFC peak position 0.95min

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.98 (br t, J = 10.67 Hz, 1H), 2.27-2.39 (m, 1H), 2.87-3.06 (m, 3H), 3.50-3.61 (m, 1H), 3.74-3.84 (m, 2H), 3.90 (s, 3H), 3.99 (t, J = 10.79Hz, 1H), 4.24 (dd, J = 10.79, 2.76Hz, 1H), 4.57 (br d, J = 12.30 Hz, 1H), 6.92 (br t, J = 7.65 Hz, 2H), 7.08 (d, J = 1.76 Hz, 1H), 7.13 (d, J = 1.76 Hz, 1H), 7.27-7.32 (m, 1H) , 7.94 (d, J = 1.51 Hz, 1H), 8.11 (d, J = 1.76 Hz, 1H), 8.19 (s, 1H)

Compound 006, SFC peak position 1.18min

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.98 (t, J = 10.67 Hz, 1H), 2.29-2.39 (m, 1H), 2.87-3.06 (m, 3H), 3.50-3.60 (m, 1H), 3.73 -3.84 (m, 2H), 3.90 (s, 3H), 3.99 (dd, J = 10.79, 8.78 Hz, 1H), 4.24 (dd, J = 10.79, 3.26 Hz, 1H), 4.57 (br d, J = 11.80Hz, 1H), 6.92 (t, J = 7.65Hz, 2H), 7.08 (d, J = 2.01Hz, 1H), 7.13 (d, J = 2.01Hz, 1H), 7.27-7.32 (m, 1H) , 7.94 (d, J = 2.01 Hz, 1H), 8.11 (d, J = 2.01 Hz, 1H), 8.19 (s, 1H)

Examples 7, 8:

Step 1: Synthesis of intermediate 001-19

Intermediate 001-13 (1g, 2.40mmol, 1eq), 001-18 (901.43mg, 2.40mmol, 1eq), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride The methyl chloride complex (195.69mg, 239.63μmol, 0.1eq) and sodium carbonate solution (2M, 4mL, 3.34eq) were dissolved in dioxane (15mL) and reacted at 60 ° C for 3h. The reaction solution was filtered while hot, the filter cake was washed with ethyl acetate (50 mL), the filtrate was washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography (ethyl acetate in petroleum ether: 0-30%) to obtain intermediate 001-19.

LCMS: MS (ESI) m / z: 511.1 [M + 1] ⁺

¹ H NMR (400MHz, CDCl ₃ ) δppm 1.50 (s, 9H), 1.65 (br s, 1H), 2.66 (br s, 1H), 2.83-2.93 (m, 1H), 2.99 (br s, 1H), 3.43-3.53 (m, 1H), 4.02 (dd, J = 10.92, 8.16 Hz, 1H), 4.16 (br d, J = 6.78 Hz, 1H), 4.32 (dd, J = 11.04, 3.01 Hz, 1H), 4.65 (br d, J = 12.05 Hz, 1H), 7.15 (d, J = 2.01 Hz, 1H), 7.39 (d, J = 1.51 Hz, 1H), 7.97 (d, J = 2.01 Hz, 1H), 8.26 (s, 1H), 8.69 (d, J = 1.76 Hz, 1H).

Step 2: Synthesis of intermediate 001-21

Intermediate 001-19 (708 mg, 1.38 mmol, 1 eq), 001-20 (374.49 mg, 1.80 mmol, 1.3 eq), tetrakis (triphenylphosphine) palladium (119.99 mg, 103.84 μmol, 0.075 eq) and potassium carbonate (382.70mg, 2.77mmol, 2eq) was dissolved in dioxane (10mL) and water (2mL), replaced with nitrogen and protected with nitrogen, and reacted at 90 ° C for 2h. The reaction solution pad was filtered through Celite, washed with water (50 mL), and concentrated. The crude product was subjected to silica gel column chromatography (12g flash silica gel column, ethyl acetate in petroleum ether: 0-70%) to obtain intermediate 001-21.

LCMS: MS (ESI) m / z: 513.1 [M + 1] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.51 (s, 9H), 2.68 (br s, 1H), 2.86-2.95 (m, 1H), 3.02 (br s, 1H), 3.49 (br dd, J = 11.29 , 8.03Hz, 1H), 4.00 (s, 3H), 4.02-4.08 (m, 1H), 4.16 (br s, 2H), 4.34 (dd, J = 11.04, 3.26Hz, 1H), 4.68 (br d, J = 11.80 Hz, 1H), 7.22 (d, J = 2.01 Hz, 1H), 7.41 (d, J = 1.51 Hz, 1H), 7.69 (s, 1H), 7.79 (s, 1H), 8.02 (d, J = 2.01 Hz, 1H), 8.26 (s, 1H), 8.65 (d, J = 1.25 Hz, 1H).

Step 3: Synthesis of intermediate 001-22

Intermediate 001-21 (740 mg, 1.30 mmol, 1 eq) was dissolved in dichloromethane (5 mL), followed by addition of trifluoroacetic acid (1.39 g, 12.16 mmol, 900.00 μL, 9.35 eq), and reacted at 20 ° C. for 2 h. To the reaction solution, ethyl acetate (50 mL) and water (50 mL) were added to separate the organic phase, impurities were in the organic phase, potassium carbonate (3 eq) was added to the aqueous phase, stirred for 0.5 hours, and extracted with ethyl acetate (2 × 50 mL) . Without further purification, intermediate 001-22 was obtained.

LCMS: MS (ESI) m / z: 413.0 [M + 1] ⁺

Step 4: Synthesis of 007/008

Intermediate 001-22 (70 mg, 169.72 μmol, 1 eq) was dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (34.35 mg, 339.44 μmol, 47.25 μL, 2 eq) and O- (7-azabenzene Benzotriazole-1-YL) -N, N, N, N-tetramethylurea hexafluorophosphine salt (77.44mg, 203.66μmol, 1.2eq), and finally added intermediate 001-7 (31.59mg, 203.66μmol , 1.2eq), and react at 20 ° C for 0.5 hour. The reaction solution was concentrated to dryness. The crude product was separated by high performance liquid chromatography (chromatographic column: Xtimate C18 150 * 25mm * 5μm; mobile phase: [water (0.225% formic acid) -acetonitrile]; acetonitrile%: 28% -58%, 8min), and then chiral resolution (Chromatography column: DAICEL CHIRALCEL OJ-H (250mm * 30mm, 5μm); mobile phase: [0.1% ammonia ethanol]; carbon dioxide%: 40% -40%, min) Compounds 007 and 008 were separated.

LCMS: MS (ESI) m / z: 550.1 [M + 1] ⁺

Compound 007, SFC peak position 3.89min.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.41-2.96 (m, 2H), 3.18-3.34 (m, 1H), 3.91-3.92 (m, 6H), 4.22 (br s, 2H), 4.60 (br s, 2H), 5.23 (br d, J = 3.76 Hz, 1H), 7.04-7.41 (m, 4H), 7.61 (br s, 1H), 7.71 (br s, 1H), 7.92 (br s, 1H), 8.18 (br s, 1H), 8.32 (br s, 1H), 8.56 (br s, 1H).

Compound 008, SFC peak position 4.31min.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.38-2.92 (m, 2H), 3.16-3.31 (m, 1H), 3.76-3.97 (m, 6H), 4.08-4.29 (m, 2H), 4.48-4.66 ( m, 2H), 5.17 (d, J = 3.76 Hz, 1H), 7.02-7.34 (m, 4H), 7.56 (br d, J = 3.01 Hz, 1H), 7.66 (br d, J = 3.01 Hz, 1H ), 7.88 (br s, 1H), 8.13 (br d, J = 3.76 Hz, 1H), 8.27 (br s, 1H), 8.52 (br d, J = 2.26 Hz, 1H).

Examples 9, 10:

Step 1: Synthesis of 009/010

The intermediates 001-22 (110 mg, 266.70 μmol, 1 eq) and 001-16 (45.72 mg, 333.38 μmol, 1.25 eq) were dissolved in dichloromethane (15 mL), followed by the addition of sodium triacetoxyborohydride (169.57 mg , 800.10μmol, 3eq), react at 20 ℃ for 2h. Water (50 mL) was added to the reaction solution, followed by extraction with dichloromethane (2 × 50 mL), dried over anhydrous sodium sulfate, and concentration. The crude product was separated by high performance liquid chromatography (chromatographic column: Xtimate C18 150 * 25mm * 5μm; mobile phase: [water (0.225% formic acid) -acetonitrile]; acetonitrile%: 20% -50%, 8min) and then chiral separation Column: DAICEL CHIRALCEL OJ (250mm * 30mm, 10μm); mobile phase: [0.1% ammonia ethanol]; carbon dioxide%: 40% -40%, min) Compounds 009 and 010 were separated.

LCMS: MS (ESI) m / z: 534.3 [M + 1] ⁺

Compound 009, SFC peak position 4.89min

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.87 (br t, J = 10.79 Hz, 1H), 2.18-2.31 (m, 1H), 2.82 (br d, J = 10.29 Hz, 1H), 2.92-3.03 (m , 2H), 3.41-3.60 (m, 3H), 3.97 (d, J = 15.56 Hz, 7H), 4.22 (dd, J = 10.79, 3.01 Hz, 1H), 4.52-4.62 (m, 1H), 6.76 ( d, J = 8.53 Hz, 1H), 7.16 (d, J = 2.01 Hz, 1H), 7.39 (s, 1H), 7.61 (dd, J = 8.53, 2.26 Hz, 1H), 7.68 (s, 1H), 7.78 (s, 1H), 7.99 (d, J = 1.76Hz, 1H), 8.07 (s, 1H), 8.25 (s, 1H), 8.62 (s, 1H)

Compound 010, SFC peak position 5.94min

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.88 (br t, J = 10.54 Hz, 1H), 2.25 (br t, J = 10.42 Hz, 1 H), 2.83 (br d, J = 10.54 Hz, 1 H), 2.92 -3.04 (m, 2H), 3.40-3.59 (m, 3H), 3.90-4.06 (m, 7H), 4.22 (br d, J = 10.54 Hz, 1H), 4.56 (br d, J = 13.55 Hz, 1H ), 6.75 (br d, J = 8.28 Hz, 1H), 7.16 (s, 1H), 7.39 (s, 1H), 7.62 (br d, J = 8.53 Hz, 1H), 7.68 (s, 1H), 7.78 (s, 1H), 7.99 (s, 1H), 8.08 (br s, 1H), 8.25 (s, 1H), 8.62 (s, 1H)

Examples 11, 12:

Step 1: Synthesis of 011/012

Dissolve intermediates 001-22 (90 mg, 218.21 μmol, 1 eq) and 001-17 (37.21 mg, 261.85 μmol, 28.19 μL, 1.2 eq) in dichloromethane (1 mL), then add sodium triacetoxyborohydride (138.74mg, 654.63μmol, 3eq), react at 20 ° C for 2h. Water (50 mL) was added to the reaction solution, extracted with dichloromethane (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by high-performance liquid chromatography (chromatographic column: Boston Green ODS 150 * 30mm 5μm; mobile phase: [water (0.075% trifluoroacetic acid) -acetonitrile]; acetonitrile%: 25% -55%, 7min) and then separated by chiral separation (Chromatographic column: DAICEL CHIRALCEL OJ-H (250mm * 30mm, 5μm); mobile phase: [0.1% ammonia ethanol]; carbon dioxide%: 40% -40%, min) separated 011 and 012.

LCMS: MS (ESI) m / z: 539.1 [M + 1] +

Compound 011, SFC peak position 2.93min

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.05 (br s, 1H), 2.37 (br s, 1H), 2.87-3.15 (m, 3H), 3.60 (br s, 1H), 3.83-4.16 (m, 6H ), 4.26 (br d, J = 10.79 Hz, 1H), 4.59 (br d, J = 10.79 Hz, 1H), 6.93 (br s, 2H), 7.15 (br s, 1H), 7.28-7.34 (m, 1H), 7.39 (br s, 1H), 7.68 (br s, 1H), 7.78 (br s, 1H), 7.98 (br s, 1H), 8.24 (br s, 1H), 8.62 (br s, 1H) Compound 012, SFC peak position 3.33min

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.21 (br t, J = 10.29 Hz, 1H), 2.44-2.56 (m, 1H), 3.05-3.28 (m, 3H), 3.71-3.75 (mz, 1H), 3.95 (br s, 2H), 3.99 (s, 3H), 4.03 (dd, J = 11.04, 7.78 Hz, 1H), 4.29 (dd, J = 11.04, 2.76 Hz, 1H), 4.67 (br d, J = 13.05Hz, 1H), 6.88-6.99 (m, 2H), 7.16 (d, J = 2.01Hz, 1H), 7.30-7.38 (m, 1H), 7.40 (d, J = 1.25Hz, 1H), 7.68 ( s, 1H), 7.78 (s, 1H), 7.98 (d, J = 2.01Hz, 1H), 8.24 (s, 1H), 8.63 (d, J = 1.00Hz, 1H).

Examples 13, 14:

Step 1: Synthesis of intermediate 001-24

Intermediate 001-19 (708 mg, 1.38 mmol, 1 eq), 001-23 (378.11 mg, 1.80 mmol, 1.3 eq), tetrakis (triphenylphosphine) palladium (159.99 mg, 138.45 μmol, 0.1 eq) and potassium carbonate (382.70mg, 2.77mmol, 2eq) was dissolved in dioxane (10mL) and water (2mL), and reacted at 90 ° C for 2h. The reaction solution was filtered through Celite, washed with water (30 mL), and concentrated. The crude product was separated by silica gel column chromatography (12g flash silica gel column, ethyl acetate in petroleum ether: 0-50%) to obtain intermediate 001-24.

LCMS: MS (ESI) m / z: 515.0 [M + 1] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.51 (s, 9H), 2.55 (br d, J = 1.51 Hz, 2H), 2.66 (br s, 1H), 2.82-2.91 (m, 1H), 2.99 (br s, 1H), 3.42-3.53 (m, 1H), 3.97-4.05 (m, 3H), 4.12-4.25 (m, 2H), 4.32 (dd, J = 10.92, 3.14 Hz, 1H), 4.37 (q, J = 2.51 Hz, 2H), 4.65 (br d, J = 11.80 Hz, 1H), 6.31 (br s, 1H), 7.18 (d, J = 2.01 Hz, 1H), 7.42 (d, J = 1.25 Hz, 1H), 7.99 (d, J = 2.01 Hz, 1H), 8.26 (s, 1H), 8.49 (s, 1H)

Step 2: Synthesis of intermediate 001-25

Intermediate 001-24 (490 mg, 952.24 μmol, 1 eq) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 14.18 eq) was added at 20 ° C. for 1 h. The reaction solution was concentrated to dryness, ethyl acetate (50 mL) and water (50 mL) were added and stirred for 10 minutes, and then the organic phase was separated. Potassium carbonate (5eq) was added to the aqueous phase, stirred at 20 ° C for 0.5h, extracted with ethyl acetate (2 × 50mL), dried over anhydrous sodium sulfate, and concentrated. Without further purification, intermediate 001-25 was obtained.

LCMS: MS (ESI) m / z: 414.9 [M + 1] ⁺

Step 3: Synthesis of 013/014

The intermediates 001-25 (130 mg, 313.66 μmol, 1 eq) and 001-16 (51.62 mg, 376.39 μmol, 1.2 eq) were dissolved in dichloromethane (15 mL), followed by the addition of sodium triacetoxyborohydride (199.43 mg , 940.99μmol, 3eq), reacted at 20 ℃ for 3h. The reaction solution was filtered to remove insoluble materials, and the filtrate was concentrated and then chirally resolved (chromatographic column: YMC CHIRAL, Amylose-C (250mm * 30mm, 10μm; mobile phase: [0.1% ammonia isopropanol]; carbon dioxide%: 50% -50%, min) isolated compounds 013 and 014.

LCMS: MS (ESI) m / z: 536.1 [M + 1] ⁺

Compound 013, SFC peak position 1.35min

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.88 (br t, J = 10.79 Hz, 1H), 2.19-2.32 (m, 1H), 2.54 (br s, 2H), 2.83 (br d, J = 10.29 Hz, 1H), 2.92-3.05 (m, 2H), 3.40-3.60 (m, 3H), 3.90-4.06 (m, 6H), 4.22 (br dd, J = 10.67, 2.64 Hz, 1H), 4.37 (br d, J = 2.01 Hz, 2H), 4.57 (br d, J = 13.05 Hz, 1H), 6.30 (br s, 1H), 6.76 (d, J = 8.28 Hz, 1H), 7.15 (s, 1H), 7.42 ( s, 1H), 7.62 (br d, J = 8.28 Hz, 1H), 7.97 (s, 1H), 8.08 (s, 1H), 8.26 (s, 1H), 8.48 (s, 1H)

Compound 014, SFC peak position 1.87min

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.88 (br t, J = 10.79 Hz, 1H), 2.19-2.32 (m, 1H), 2.54 (br s, 2H), 2.83 (br d, J = 10.29 Hz, 1H), 2.92-3.05 (m, 2H), 3.40-3.60 (m, 3H), 3.90-4.06 (m, 6H), 4.22 (br dd, J = 10.67, 2.64 Hz, 1H), 4.37 (br d, J = 2.01 Hz, 2H), 4.57 (br d, J = 13.05 Hz, 1H), 6.30 (br s, 1H), 6.76 (d, J = 8.28 Hz, 1H), 7.15 (s, 1H), 7.42 ( s, 1H), 7.62 (br d, J = 8.28 Hz, 1H), 7.97 (s, 1H), 8.08 (s, 1H), 8.26 (s, 1H), 8.48 (s, 1H)

Biological test data:

Experimental Example 1: Evaluation of the inhibitory activity of wild-type and V804M mutant kinases in vitro

³³ P isotope-labeled kinase activity test (Reaction Biology Corp) was used to determine the IC ₅₀ value to evaluate the test compound's ability to inhibit human wild-type, V804M mutant RET.

Buffer conditions: 20 mM hydroxyethylpiperazine ethanesulfonic acid (Hepes) (pH 7.5), 10 mM MgCl ₂ , 1 mM ethylene glycol diaminoethyl ether tetraacetic acid (EGTA), 0.02% polyoxyethylene dodecyl ether ( Brij35), 0.02 mg / mL bovine serum albumin, 0.1 mM Na ₃ VO ₄ , 2 mM dithiothreitol (DTT), 1% DMSO.

Compound treatment: The test compound was dissolved in 100% DMSO and serially diluted by Integra Viaflo Assist with DMSO to a specific concentration.

Test procedure: Dissolve the substrate in the newly prepared buffer solution, add the tested kinase to it and mix gently. Using acoustic technology (Echo 550), the DMSO solution in which the test compound is dissolved is added to the above-mentioned mixed reaction solution, and incubated at room temperature for 20 minutes. The compound concentration in the reaction solution was 3μM, 1μM, 0.333μM, 0.1μM, 0.0370μM, 0.0123μM, 4.12nM, 1.37nM, 0.457nM, 0.152nM. After incubating for 15 minutes, ³³ P-ATP (activity 0.01 μCi / μL, Mie constant concentration) was added to start the reaction. After the reaction was performed at room temperature for 120 minutes, the radioactivity was detected by the filter binding method. The kinase activity data is expressed by comparing the kinase activity of the test compound with the kinase activity of the blank group (containing only DMSO), and the IC ₅₀ value is obtained by curve fitting using Prism4 software (GraphPad).

Table 1: Results of in vitro screening tests for compounds of the present invention

Conclusion: The compounds of the present invention exhibit good inhibitory activity against wild-type and V804M mutant RET.

Claims (19)

1. The compound represented by formula (II), its isomer or a pharmaceutically acceptable salt thereof,

   

   among them,

   R _{1 is} selected from H, F, Cl, Br, I, C _1-6 alkyl, C _1-6 alkoxy, pyrazolyl and 3,6-dihydropyranyl, the C _1-6 alkyl group, C _1-6 alkoxy, 3,6-dihydro-pyrazolyl, and pyranyl optionally substituted with 1, 2 or 3 substituents R _a;

   R _{2 is} selected from H, F, Cl, Br, I, CN, and C _1-6 alkyl, the C _1-6 alkyl is optionally substituted with 1, 2, or 3 R _b ;

   R _{3 is} selected from H, F, Cl, Br, I, C _1-6 alkyl and C _1-6 alkoxy, the C _1-6 alkyl and C _1-6 alkoxy are optionally substituted by 1, 2 or 3 R _c substitutions;

   n is selected from 0, 1, 2, 3 and 4;

   Ring A is selected from phenyl and pyridyl;

   L _{1 is} selected from

   

   -C (= O) -C _1-3 alkyl- and C _1-3 alkyl, the -C (= O) -C _1-3 alkyl- and C _1-3 alkyl are optionally substituted by 1, 2 or 3 _Rd substitutions;

   R _{a is} selected from H, F, Cl, Br, I, NH ₂ , CN and C _1-3 alkyl groups, the C _1-3 alkyl groups are optionally substituted with 1, 2 or 3 R;

   R _{b is} selected from H, F, Cl, Br, I, NH ₂ and CN;

   R _{c is} selected from H, F, Cl, Br and I;

   R _{d is} selected from H, F, Cl, Br, I, OH, NH ₂ and CN;

   R is selected from H, F, Cl, Br, I, OH, NH ₂ and CN;

   The carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
2. The compound according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from H, F, Cl, Br, I, C _1-3 alkyl, C _1-3 alkoxy Group, pyrazolyl, imidazolyl and 3,6-dihydro-2H-pyranyl, the C _1-3 alkyl, C _1-3 alkoxy, pyrazolyl, imidazolyl and 3,6- dihydro -2H- pyran group optionally substituted with 1, 2 or 3 R _a.
3. The compound according to claim 2, its isomer or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from H, F, Cl, Br, I, C _1-3 alkyl, C _1-3 alkoxy base,

   

   The C _1-3 alkyl group, C _1-3 alkoxy group,

   

   Optionally substituted with 1,2 or 3 substituents R _a.
4. The compound according to claim 3, its isomer or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from H,

   

   
5. The compound according to any one of claims 1 to 4, its isomer, or a pharmaceutically acceptable salt thereof, wherein R _{2 is} selected from H, F, Cl, Br, I, CN, and C _1-3 alkyl , The C _1-3 alkyl group is optionally substituted with 1, 2, or 3 R _b .
6. The compound according to claim 5, its isomer or a pharmaceutically acceptable salt thereof, wherein R _{2 is} selected from H, F, Cl, Br, I, CN, CH ₂ NH ₂ , CH ₂ CN and

   
7. The compound according to any one of claims 1 to 4, its isomer or a pharmaceutically acceptable salt thereof, wherein R _{3 is} selected from H, F, Cl, Br, I, C _1-3 alkyl and C _1-3 alkoxy, the C _1-3 alkyl and C _1-3 alkoxy are optionally substituted with 1, 2 or 3 R _c .
8. The compound according to claim 7, its isomer or a pharmaceutically acceptable salt thereof, wherein R _{3 is} selected from H, F, Cl, Br, I, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ and -OCH ₃ .
9. The compound according to claim 1 or 8, its isomer or a pharmaceutically acceptable salt thereof, wherein the structural unit

   

   Select from

   
10. The compound according to claim 9, its isomer or a pharmaceutically acceptable salt thereof, wherein the structural unit

    

    Select from

    

    
11. The compound, isomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein L _{1 is} selected from

    

    

    And -CH _2- , described

    

    And -CH ₂ -are optionally substituted with 1, 2, or 3 _Rd .
12. The compound according to claim 11, its isomer or a pharmaceutically acceptable salt thereof, wherein L _{1 is} selected from

    

    

    And -CH _2- .
13. The compound according to claim 12, its isomer or a pharmaceutically acceptable salt thereof, wherein the structural unit

    

    Select from

    
14. The compound according to any one of claims 1 to 13, its isomer or a pharmaceutically acceptable salt thereof, which is selected from

    

    However, R ₁ , L ₁ and R _{3 are} as defined in any one of claims 1 to 13.
15. The compound represented by the following formula, its isomer or a pharmaceutically acceptable salt thereof, is selected from

    
16. The compound according to claim 15, its isomer or a pharmaceutically acceptable salt thereof, which is selected from

    

    
17. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 16, an isomer or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
18. Use of the compound according to any one of claims 1 to 16, its isomer, or a pharmaceutically acceptable salt thereof in the preparation of a RET kinase inhibitor.
19. Use of the composition according to claim 18 in the preparation of RET kinase inhibitors.