WO2019001460A1 - Polycyclic compound serving as irak4 inhibitor - Google Patents

Abstract

The invention relates to a polycyclic compound serving as IRAK4 inhibitor and uses thereof in preparing a drug treating IRAK4-associated diseases. More specifically, the invention relates to said compound represented by formula (I) and a pharmaceutically acceptable salt thereof.

Description

Fused ring compound as IRAK4 inhibitor

Reference to related application

This application claims the following priority:

CN201710501838.2, application date 2017-06-27.

Technical field

The present invention relates to a class of IRAK4 inhibitors and their use in the manufacture of a medicament for the treatment of diseases associated with IRAK4. Specifically, it relates to a compound of the formula (I) and a pharmaceutically acceptable salt thereof.

Background technique

Interleukin-1 receptor kinase 4 (IRAK4) is a serine/threonine-specific protein kinase belonging to the tyrosine-like kinase (TLK) family of interleukin-1, 18, 33 receptors and Toll-like receptors. The key node in the innate immune response involved in the body. When the extracellular signal molecule binds to the interleukin receptor or Toll-like receptor, it recruits to form the MyD88:IRAK4:IRAK1/2 polyprotein complex, which leads to phosphorylation of IRAK1/2, mediating a series of downstream signaling, thereby activating p38 and JNK. And the NF-kB signaling pathway ultimately leads to the expression of pro-inflammatory cytokines. Clinical pathology studies have shown that individuals with IRAK4 mutations have protective effects against chronic lung disease and inflammatory bowel disease. The IRAK4 defect itself is not lethal, individuals can survive to adulthood, and the risk of infection decreases with age. Therefore, IRAK4 has become an important therapeutic target and has attracted a wide range of research and development interests.

Therefore, there is a need for new compounds and methods for inhibiting IRAK4 for the treatment of autoimmune diseases. The present invention provides a series of 4-fused ring compounds having higher inhibitory activity and better selectivity.

Summary of the invention

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

among them,

m is selected from: 0, 1, 2 or 3;

Ring A is selected from a 5- to 6-membered heteroaryl ring;

Ring B is selected from the group consisting of C _3-7 cycloalkyl, 4-6 heterocycloalkyl;

L is selected from: O or NH;

R _{1 is} selected from H or is selected from C _{1 - 3} alkyl, C _1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;

R _{2 is} selected from OH, NH ₂ , CN, halogen, or selected from the group consisting of 1, 2 or 3 R: C _1-3 alkyl, C _1-3 heteroalkyl, 4 to 6-membered heterocyclic ring alkyl;

R is selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , CN, Me, Et, CF ₃ .

The "hetero" of the C _1-3 heteroalkyl group, the 4-6 membered heterocycloalkyl group or the 5- to 6-membered heterocycloalkenyl group is independently selected from: N, O, S, NH, -C (=O) NH-; the number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.

In some embodiments of the invention, the ring A is selected from the group consisting of pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thienyl.

In some aspects of the invention, the structural unit

From:

R _{1 is} as defined in the present invention.

In some embodiments of the invention, the above R _{1 is} selected from H or is selected from the group consisting of: 1, 2 or 3 R: Me, Et,

R is as defined by the present invention.

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

In some aspects of the invention, the structural unit

From:

R _{1 is} as defined in the present invention.

In some embodiments of the invention, the ring B is selected from the group consisting of a cyclopentyl group, a cyclohexane group, and a tetrahydrofuranyl group.

In some aspects of the invention, the structural unit

From:

R _{2 is} as defined in the present invention.

In some aspects of the invention, the structural unit

From:

R _{2 is} as defined in the present invention.

In some embodiments of the invention, the above R _{2 is} selected from the group consisting of OH, NH ₂ , CN, halogen, or selected from the group consisting of 1, 2 or 3 R: Me, Et,

Morpholinyl, R is as defined in the invention.

In some aspects of the invention, the above R _{2 is} selected from the group consisting of OH, NH ₂ , CN, F, Cl, Br, I, Me, Et,

In some aspects of the invention, the structural unit

From:

R _{1 is} as defined in the present invention.

In some embodiments of the invention, the above ring A is selected from the group consisting of pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thienyl, and other variables are as defined above.

In some aspects of the invention, the structural unit

From:

Other variables are as defined above.

In some embodiments of the invention, the above R _{1 is} selected from H or is selected from the group consisting of: 1, 2 or 3 R: Me, Et,

Other variables are as defined above.

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

Other variables are as defined above.

In some aspects of the invention, the structural unit

From:

Other variables are as defined above.

In some embodiments of the invention, the ring B is selected from the group consisting of: cyclopentyl, cyclohexane, tetrahydrofuran, and other variables are as defined above.

In some aspects of the invention, the structural unit

From:

Other variables are as defined above.

In some aspects of the invention, the structural unit

From:

Other variables are as defined above.

In some embodiments of the invention, the above R _{2 is} selected from OH, NH ₂ , CN, halogen, or selected from the group consisting of 1, 2 or 3 R: Me, Et,

Morpholinyl, other variables are as defined above.

In some aspects of the invention, the above R _{2 is} selected from the group consisting of OH, NH ₂ , CN, F, Cl, Br, I, Me, Et,

Other variables are as defined above.

In some aspects of the invention, the structural unit

From:

Other variables are as defined above.

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

among them,

R ₁ , R ₂ and L are as defined above.

Still other aspects of the invention are arbitrarily combined by the above variables.

The present invention also provides a compound of the formula: or a pharmaceutically acceptable salt thereof:

In some embodiments of the invention, the above compound or a pharmaceutically acceptable salt thereof:

The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a medicament for treating IRAK4.

Related definition

Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound 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 invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat 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, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.

Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.

As used herein, a "pharmaceutically acceptable salt" is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturaldehyde, propionic acid, salicylic acid, stearic acid, acrylic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, Tartaric acid and p-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.

Unless otherwise indicated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of one another.

Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.

Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.

Wedge solid key unless otherwise stated

And wedge-shaped dashed keys

Represents the absolute configuration of a solid center with straight solid keys

And straight dashed keys

Indicates the relative configuration of the stereocenter, using wavy lines

Indicates a wedge solid key

Or wedge-shaped dotted key

Or with wavy lines

Represents a straight solid key

And straight dashed keys

The compounds of the invention may be present in particular. Unless otherwise indicated, the terms "tautomer" or "tautomeric form" mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization. The valence tautomer includes the mutual transformation of some of the bonding electrons. 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 indicated, the terms "enriched in one isomer", "isomer enriched", "enriched in one enantiomer" or "enantiomeric enriched" refer to one of the isomers or pairs The content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.

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

The optically active (R)- and (S)-isomers as well as the 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 invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, and then by conventional methods well known in the art. The diastereomers are resolved and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate). The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) or ^C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

"Optional" or "optionally" means that the subsequently described event or condition may, but is not necessarily, to occur, and that the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of. When the substituent is oxygen (ie, =0), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.

When any variable (eg, R) occurs 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 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

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

When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit.

It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene. When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group. When the listed linking group does not indicate its direction of attachment, its connection direction is arbitrary, for example,

The medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B.

It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right.

Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring" means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms. Thus, "5- to 7-membered ring" includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term "5- to 7-membered heterocycloalkyl ring" includes pyridyl and piperidinyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a hetero atom which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites. The nitrogen atom in the heterocycle is optionally quaternized. A preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one. The term "aromatic heterocyclic group" or "heteroaryl" as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one. Bridged rings are also included in the definition of heterocycles. A bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.

Examples of heterocyclic compounds include, but are not limited to, acridinyl, anthracycline, benzimidazolyl, benzofuranyl, benzofurylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl, indanyl, mesoindolyl, fluorenyl, 3H-indole Mercapto, isobenzofuranyl, isodecyl, isoindoline, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl , octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, hydroxymethyl, pyrimidinyl, phenanthryl, phenanthroline, phenazine, phenothiazine , benzoxanthyl, phenoloxazinyl, pyridazinyl, piperazinyl, piperidinyl, piperidinone, 4-piperidinone, piperonyl, pteridinyl, fluorenyl, pyranyl, Pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl , pyrrolyl, quinazolinyl, quinolyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, tetrazolyl, 6H -1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4 -thiadiazolyl, thiazolidine, thiazolyl, isothiazolylthiophenyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1H-1, 2,3- Triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl and xanthene. Also included are fused ring and spiro compounds.

Unless otherwise specified, the term "hydrocarbyl" or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic. The hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C ₁ -C ₁₂ represents 1 to 12 carbons) , C _{1-12 is} selected from 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 ; C _{3-12 is} selected from C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ .). "Hydrocarbyl" includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members. An aromatic hydrocarbon group such as benzene, naphthalene or the like. In some embodiments, the term "hydrocarbyl" means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl). A homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl. The unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.

Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. The hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively. Examples include, but are not limited to, -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S -CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ ,- CH ₂ -CH=N-OCH ₃ and -CH=CH-N(CH ₃ )-CH ₃ . Up to two heteroatoms may be consecutive, for example, -CH ₂ -NH-OCH _3.

Unless otherwise specified, the term "cycloalkyl", "heterocycloalkyl" or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl) A heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized "hydrocarbyl group" or "heterohydrocarbyl group", respectively. Further, in the case of a heterohydrocarbyl group or a heterocycloalkyl group (such as a heteroalkyl group or a heterocycloalkyl group), a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.

Unless otherwise specified, the term "alkyl" is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH ₂ F) or polysubstituted (eg, -CF ₃ ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of the alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.

Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term "haloalkyl" is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C ₁ -C ₄ )alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait. Unless otherwise specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

The above-described alkyl groups having the specified number of carbon atoms, "alkoxy" represents attached through an oxygen bridge, unless otherwise specified, C _1-6 alkoxy groups include _{C 1, C 2, C 3} , C 4, C 5 , and C ₆ alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.

Unless otherwise specified, the term "aryl" denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, fluorenyl, 2-benzimidazolyl, 5-indenyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quina Porphyrin group, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

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 set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.

The solvent used in the present invention is commercially available. The present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for t-butoxycarbonyl 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 chloride Sulfone; CS ₂ represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n-Bu ₄ NF stands for fluorinated four Butylammonium; iPrOH stands for 2-propanol; mp stands for melting point; LDA stands for diisopropylamino lithium.

Compound by hand or

Software naming, commercially available compounds using the supplier catalog name.

Technical effect:

The invention obtains a series of 4 fused ring compounds with greatly improved permeability and improved metabolic stability, and has better drug properties and higher kinase selectivity.

Detailed ways

The invention is described in detail below by the examples, but is not intended to limit the invention. The present invention has been described in detail herein, the embodiments of the present invention are disclosed herein, and various modifications and changes may be made to the embodiments of the present invention without departing from the spirit and scope of the invention. It will be obvious.

Intermediate A1:

synthetic route:

Step 1: Synthesis of Compound A1-1

Ethyl bromoacetate (500 g, 2.99 mol, 331.13 mL, 1.00 eq) was added to a solution of dimethyl sulfide (215.79 g, 3.47 mol, 253.87 mL, 1.16 eq) in acetone (1000 mL) and stirred for 48 hours. After that, a large amount of a white solid was precipitated, filtered, and the filter cake was washed with acetone (2000 mL) to give Compound A1-1. ¹ H NMR (400 MHz, deuterated methanol) δ: 4.58 - 4.51 (m, 2H), 4.36 - 4.31 ( m, 2H), 3.07–3.01 (m, 6H), 1.36–1.32 (m, 3H).

Step 2: Synthesis of Compound A1-2

Addition of 1.8-diazabicyclo[5.4.0]undec-7-ene (166.10 g, 1.09 mol, 164.46 mL, 1.00 eq) to compound A1-1 (250 g, 1.09 mol) at 15 °C After stirring for 30 minutes in a solution of 1.00 eq. of dichloromethane (2000 mL), 2-cyclopentenone (89.58 g, 1.09 mol, 91.40 mL, 1.00 eq) was added to the reaction mixture, and the reaction was stirred for 16 hours. After that, the reaction is over. The reaction solution was diluted with water (1000 mL), the pH was adjusted to 4 with dilute hydrochloric acid (2M), and the organic layer was separated. The aqueous layer was extracted with dichloromethane (800 mL×3), and the organic phase was combined. 2) Wash twice, dry over anhydrous sodium sulfate, and after filtration, the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate=50/1-8/1) to afford compound A1-2. ¹ H NMR (400 MHz, deuterated chloroform) δ=4.19-4.07 (m, 2H), 2.51–2.47 (m, 1H), 2.31-2.16 (m, 2H), 2.16-2.05 (m, 2H), 2.04-1.96 (m, 2H), 1.29-1.20 (m, 3H).

Step 3: Synthesis of Compound A1-3

Compound A1-2 (123.5 g, 734.29 mmol, 1.00 eq), ethyl cyanoacetate (99.67 g, 881.15 mmol, 94.03 mL, 1.20 eq), diethylamine (64.45 g, 881.15 mmol, 90.77 mL, 1.20 eq) and a solution of sublimed sulfur (28.26 g, 881.15 mmol, 1.20 eq) in ethanol (2000 mL) was stirred for 12 h. After the reaction was completed, the reaction mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjj The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 50/1 - 5 / 1) to give compound A1-3. ¹ H NMR (400 MHz, deuterated chloroform) δ = 5.85 (s, 2H) , 4.31-4.23 (m, 2H), 4.17 - 4.12 (m, 2H), 3.09 - 3.05 (m, 1H), 3.02 - 2.97 (m, 1H), 2.90 - 2.81 (m, 1H), 2.51 - 2.49 ( m, 1H), 1.40 - 1.34 (m, 1H), 1.33-1.30 (m, 3H), 1.28 - 1.25 (t, J = 7.2 Hz, 3H).

Step 4: Synthesis of Compound A1-4

An aqueous solution (70 mL) of sodium cyanate (8.80 g, 135.43 mmol, 2 eq) was added to a solution of the compound A1-3 (20 g, 67.72 mmol, 1 eq) in EtOAc (150 mL). . The reaction mixture was filtered, and the filter cake was washed with water, and then dried to give a crude product. The crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 10/1 - 1 / 1). ¹ H NMR (400MHz, deuterochloroform) δ: 10.30 (s, 1H ), 4.86 (s, 2H), 4.37-4.27 (m, 2H), 4.20-4.11 (m, 2H), 3.20-3.12 (m, 1H), 3.06–3.01 (m, 1H), 2.99-2.92 (m, 1H), 2.58–2.51 (m, 1H), 1.36 (t, J=7.2 Hz, 3H), 1.33-1.29 (m, 1H) , 1.29-1.25 (m, 3H).

Step 5: Synthesis of Compound A1-5

Potassium carbonate (6.15 g, 44.47 mmol, 3 eq) was added to a solution of compound A-4 (5.76 g, 14.82 mmol, 1 eq) in ethanol (200 mL). The reaction was slowly heated to 80 ° C, and after stirring for 5 hours, a solid precipitated. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ethanol, dissolved in water (150 mL), diluted with hydrochloric acid (2M) to adjust pH to 3, and a gray solid was precipitated, filtered, and then washed with water to obtain compound A1 -5. ¹ H NMR (400MHz, deuterated methanol) δ: 4.14 (q, J = 7.2Hz, 2H), 3.25-3.15 (m, 1H), 3.07-2.98 (m, 2H), 2.65-2.58 (m, 1H) , 1.37.1-33 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H).

Step 6: Synthesis of Compound A1

N,N-dimethylaniline (1.99 g) was slowly added to a mixture of compound A1-5 (3.35 g, 10.97 mmol, 1 eq) and phosphorus oxychloride (50.46 g, 329.10 mmol, 30.58 mL, 30 eq). 16.45 mmol, 2.09 mL, 1.5 eq), the reaction mixture was slowly warmed to 100 ° C and stirred for 5 hours. After the reaction was completed, the reaction mixture was evaporated to dryness EtOAcjjjjjjjjjj (20 mL × 3), the organic phase was combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate Agent: petroleum ether / ethyl acetate = 50/1 - 20/1) gave compound A1. ¹ H NMR (400MHz, deuterochloroform) δ: 4.20 (q, J = 7.2Hz, 2H), 3.49-3.38 (m, 1H), 3.35-3.28 (m, 1H), 3.27-3.19 (m, 1H) , 2.81-2.70 (m, 1H), 1.49-1.44 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H).

Intermediate B1:

CAS: 103023-50-3

Intermediate B2:

CAS: 1063734-49-5

Intermediate B3:

CAS: 177906-48-8

Intermediate B4:

CAS: 177906-46-6

Intermediate B5:

CAS: 84976-47-6

Intermediate B6:

CAS: 24340-76-9

Example 1: Synthesis of Compound WX001

synthetic route:

Step 1: Synthesis of Compound WX001-1

Sodium hydride (135.94 mg, 3.40 mmol, purity 60%, 4 eq) was added to a solution of Compound B1 (121.69 mg, 849.60 μmol, 1 eq) in THF (15 mL), and stirred for 30 min. A solution of Compound A1 (300 mg, 849.60 μmol, 1 eq) in tetrahydrofuran (10 mL) was stirred at 60 ° C for 2 hr. Quenched with water (10 mL), EtOAc (EtOAc (EtOAc)EtOAc. WX001-1. LCMS (ESI) m/z: 436 [M+H] ⁺

Step 2: Synthesis of Compound WX001-2

Compound WX001-2 (60 mg, 137.63 μmol, 1 eq), Compound B2 (26.73 mg, 275.25 μmol, 2 eq), tris(dibenzylideneacetone) dipalladium (12.60 mg, 13.76 μmol, 0.1 eq), 4,5 a solution of bis(diphenylphosphino)-9,9-dimethyloxaxan (7.96 mg, 13.76 μmol, 0.1 eq) and sodium tert-butoxide (26.45 mg, 275.25 μmol, 2 eq) in dioxane ( 10 mL) was stirred in an oil bath at 100 ° C for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. after filtration, the filtrate was removed by rotary evaporation under reduced pressure to give the solvent WX001-2.LCMS (ESI) m / z: 497 [m + H] +.

Step 3: Synthesis of Compound WX001-3

To a mixed solution of the compound WX001-2 (50 mg, 100.68 μmol, 1 eq) in methanol (3 mL) and water (1 mL), water and lithium hydroxide (25.35 mg, 604.08 μmol, 6 eq), and stirred at 15 ° C 2 hours. After completion of the reaction, the reaction mixture was diluted with water (10 mL), and the mixture was adjusted to pH 3 with dilute hydrochloric acid (2M), and the solvent was removed by evaporation under reduced pressure to give compound WX001-3. LCMS (ESI) m/z: 469 [M+H ] ⁺ .

Step 4: Synthesis of Compound WX001

O-(7-azabenzotriazole-1-) was added to a solution of compound WX001-3 (90 mg, 192.07 μmol, 1 eq) in N,N-dimethylformamide (2 mL) at 15 °C -N,N,N',N'-tetramethylurea hexafluorophosphate (94.94 mg, 249.70 μmol, 1.3 eq), N,N-diisopropylethylamine (32.27 mg, 249.70 μmol, 43.49 μL, 1.3 eq) and aqueous ammonia (29.17 mg, 249.70 μmol, 32.05 μL, 1.3 eq), stirred for 1 hour. After the reaction was completed, 10 mL of water was added to the reaction mixture, and extracted with ethyl acetate (10 mL×3). The phase was dried over anhydrous sodium sulfate. After filtration, the solvent was obtained by rotary evaporation under reduced pressure. The crude product was purified by high-performance liquid chromatography (column: Phenomenex Gemini 150*25 mm*10 μm; mobile phase: [water (10 mM NH ₄ HCO _{3 )} )-ACN]; B%: 20%-50%, 3 min), the compound WX001 was obtained. LCMS (ESI) m/z: 468 [M+H] ⁺ . ¹ H NMR (400 MHz, deuterated methanol) δ = 7.89 (s, 1H), 7.58 (s, 1H), 5.23 - 5.13 (m, 1H) , 3.88(s,3H), 3.24–3.21(m,1H), 3.07–3.01(m,1H), 2.94-2.90(m,1H),2.91(s,1H),2.83–2.74(m,1H) , 2.59 (s, 6H), 2.56-2.52 (m, 1H), 2.45-2.36 (m, 2H), 2.15 - 2.08 (m, 2H), 1.69-1.55 (m, 4H), 1.39 - 1.30 (m, 1H).

Implementation of columns 2 and 3: Synthesis of compounds WX002A and WX002B

synthetic route:

Step 1: Synthesis of Compound WX002-1

Potassium carbonate (629.73 mg, 4.56 mmol, 3 eq) and compound B3 (500 mg, 1.52 mmol, 1 eq) were added to a solution of compound A1 (455.69 mg, 2.13 mmol, 1.4 eq) in EtOAc (15 mL). The solution was slowly warmed to 70 ° C and stirred for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and water (20 mL) was added to the mixture. The mixture was filtered, and the filtrate was evaporated under reduced pressure to give the compound WX002-1. ¹ H NMR (400 MHz, deuterated methanol) δ = 4.21-4.14 (m, 2H), 3.42-3.33 (m, 3H), 3.17-3.10 (m, 1H), 2.73 - 2.67 (m, 1H), 2.14 1.94 (m, 4H), 1.63 - 1.52 (m, 2H), 1.44-1.43 (m, 1H), 1.45 (s, 9H), 1.39-1.37 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H).

Step 2: Synthesis of Compound WX002-2

Hydrochloric acid / dioxane (4M, 15 mL, 43.77 eq) was added to a solution of Compound A2-1 (710 mg, 1.37 mmol, 1 eq) in dioxane (15 mL) and stirred for 12 hr. After completion of the reaction, the reaction mixture was concentrated by rotary evaporation under reduced pressure to give compound WX002-2. LCMS (ESI) m/z: 407 [M+H] ⁺

Step 3: Synthesis of Compound WX002-3

Potassium carbonate (187.03 mg, 1.35 mmol, 3 eq) was added to a solution of compound WX002-2 (0.2 g, 451.07 μmol, 1.00 eq, HCl) in acetonitrile (10 mL), and stirred for 10 min. 2-Dibromoethyl ether (125.53 mg, 541.28 μmol, 67.85 μL, 1.20 eq), the reaction mixture was slowly warmed to 70 ° C and stirred for 12 hours. After completion of the reaction, the reaction solution was slowly cooled to room temperature, filtered, and the filter cake was washed with methanol, and the filtrate was evaporated to dryness under reduced pressure to give compound WX002-3. LCMS (ESI) m / z: 477 [M + 1] +.

Step 4-7: Synthesis of Compounds WX002A and WX002B

The compound WX002 (34 mg, 71.04 μmol, 1 eq) was synthesized by SFC according to the synthesis method in the first step of Example 1, and was separated by SFC (column: OD (250 mm * 30 mm, 10 um); mobile phase: [0.1% ammonia methanol]; B%: 55%-55%, 3.1min; 100min)), respectively obtained compounds WX002A and WX002B

Example 2 is WX002A, (17.68 mg, 33.03 μmol, yield 50.16%). LCMS (ESI) m/z: 509 [M+H] ⁺ . ¹ H NMR (400 MHz, deuterated methanol) δ = 7.83 (s) , 1H), 7.57 (s, 1H), 4.22–4.05 (m, 1H), 3.87 (s, 3H), 3.80–3.71 (m, 4H), 3.27–3.19 (m, 1H), 3.02–2.96 (m) , 1H), 2.81 - 2.71 (m, 4H), 2.61-2.54 (m, 1H), 2.53 - 2.42 (m, 1H), 2.33 - 2.26 (m, 1H), 2.25 - 2.18 (s, 1H), 2.16 –2.08 (m, 2H), 1.53-1.44 (m, 4H), 1.37-1.34 (m, 1H), 1.30–1.27 (m, 1H). SFC (OD-3S_3_40_3ML column: Chiralcel OD-3 100×4.6mm ID, 3um mobile phase: 40% methanol (0.05% diethylamine)-CO ₂ ; flow rate: 3 mL / min; detection wavelength: 220 nm, RT = 1.847 min, 88.6% ee).

Example 3 is WX002B, (13.86 mg, 26.02 μmol, yield 39.52%). LCMS (ESI) m/z: 509 [M+H] ⁺ . ¹ H NMR (400 MHz, deuterated methanol) δ = 7.84 (s) , 1H), 7.56 (s, 1H), 4.13 - 4.03 (m, 1H), 3.87 (s, 3H), 3.76-3.72 (m, 4H), 3.28 - 3.19 (m, 1H), 3.02 - 2.98 (m , 1H), 2.72–2.64 (m, 4H), 2.60–2.55 (m, 1H), 2.43–2.34 (m, 1H), 2.32–2.26 (m, 1H), 2.23–2.19 (m, 1H), 2.14 –2.05 (m, 2H), 1.51–1.42 (m, 4H), 1.37-1.33 (m, 1H), 1.30–1.26 (m, 1H). SFC (OD-3S_3_40_3ML column: Chiralcel OD-3 100×4.6mm ID, 3um mobile phase: 40% methanol (0.05% diethylamine)-CO ₂ ; flow rate: 3 mL / min; detection wavelength: 220 nm, RT = 2.525 min, 100% ee).

Implementation column 4:

synthetic route:

The compounds A1 and B4 were used as starting materials, and synthesized in the same manner as in the synthesis method of Example 1.

WX003: LCMS (ESI) m / z:. 454 [M + H] + 1 H NMR (400MHz, deuterated methanol) δ = 7.86 (s, 1H ), 7.54 (s, 1H), 4.27-4.20 (m, 1H), 3.87 (s, 3H), 3.29–3.22 (m, 1H), 3.06-2.99 (m, 2H), 2.62–2.57 (m, 1H), 2.17-1.98 (m, 2H), 1.76-1.61 ( m, 6H), 1.38–1.36 (m, 1H), 1.30 (s, 3H).

Example 5:

synthetic route:

Step 1: Synthesis of Compound WX004-1

Sodium tert-butoxide (32.66 mg, 339.84 μmol, 1.2) was added to a solution of compound A1 (100 mg, 283.20 μmol, 1 eq) and compound B5 (29.94 mg, 339.84 μmol, 1.2 eq) in dioxane (5 mL). Eq), then the reaction was stirred at 75 ° C for 6 hours. After the reaction was completed, the reaction solution was added to a saturated aqueous solution of 15 mL of sodium chloride, and ethyl acetate (10 mL × 3), and the organic phase was combined, and the organic phase was dried over anhydrous sodium sulfate. crude, the crude product was purified by preparative thin layer chromatography (developing solvent: petroleum ether: ethyl acetate = 3: 1) to give compound WX004-1.LCMS (ESI) m / z: 381 [m + H] +.

Step 2: Synthesis of Compound WX004-2

Compound WX004-1 (80 mg, 210.06 μmol, 1 eq), Compound B6 (94.92 mg, 630.18 μmol, 3 eq), tris(dibenzylideneacetone) dipalladium (19.24 mg, 21.01 μmol, 0.1 eq), 4,5 - bis(diphenylphosphino)-9,9-dimethyloxaxan (12.15 mg, 21.01 μmol, 0.1 eq) and cesium carbonate (205.32 mg, 630.18 μmol, 3 eq) in dioxane solution at 100 The reaction was stirred at ° C for 3 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness to afford crude crystals of crude material (yield: petroleum ether: ethyl acetate = 1:1) to afford compound WX004- 2. LCMS (ESI) m/z: 459 [M+H] ⁺ .

Step 3: Synthesis of Compound WX004-3

Water and lithium hydroxide (54.90 mg, 1.31 mmol, 6 eq) were added to a solution of the compound WX004-2 (100 mg, 218.08 μmol, 1 eq) in methanol (3 mL) and water (1 eq) and stirred for 3 hr. After completion of the reaction, 5 mL of water was added to the reaction mixture, and the reaction liquid was diluted. To the reaction was added dropwise dilute hydrochloric acid (2M) to adjust the pH to 3, and the mixture was evaporated under reduced pressure to give compound WX004-3. LCMS (ESI) m/z: 437 [M+H] ⁺

Step 4: Synthesis of Compound WX004

O-(7-azabenzotriazol-1-yl) was added to a solution of compound WX004-3 (400 mg, 929.15 μmol, 1.74 eq) in N,N-dimethylformamide (6 mL). -N,N,N',N'-tetramethylurea hexafluorophosphate (264.23 mg, 694.93 μmol, 1.3 eq), N,N-diisopropylethylamine (89.81 mg, 694.93 μmol, 121.04 μL, 1.3 eq) and aqueous ammonia (81.18 mg, 694.93 μmol, 89.21 μL, 1.3 eq) were stirred for 10 hours. After the completion of the reaction, 10 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (10 mL × 4), and the organic phase was combined. The crude product was purified by two highly efficient preparative liquid phases (column: Phenomenex Synergi C18 150 mm*25 mm*10 μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; B%: 15%-45%, 11 min) and Column: Phenomenex Synergi C18 150 mm * 25 mm * 10 μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; B%: 12% - 42%, 11 min) afforded compound WX004. LCMS (ESI) m/z: 430[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ=7.52 (br s, 1H), 6.89 (br s, 1H), 6.68 (s, 1H), 5.40–5.22 (m, 1H), 4.12–4.01 (m, 1H), 3.99-3.79 (m, 3H), 3.11–3.01 (m, 1H), 2.29 (s, 3H), 2.03-1.94 (m, 2H), 1.51–1.41 ( m, 1H), 1.31-1.28 (m, 1H), 1.24–1.22 (m, 2H), 0.87-0.82 (m, 1H).

NMR and MS data for each example

Test Example 1: In vitro evaluation

³³ P-isotope labeled using kinase activity test (Reaction Biology Corp) was measured to evaluate the IC ₅₀ values of test compounds to human's ability to inhibit IRAK4.

Buffer conditions: 20 mM Hepes (pH 7.5), 10 mM MgCl ₂ , 1 mM EGTA, 0.02% Brij 35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO.

Test procedure: The test compound was dissolved in DMSO at room temperature to prepare a 10 mM solution for use. The substrate is dissolved in a freshly prepared buffer, and the kinase to be tested is added thereto and mixed well. A DMSO solution in which the test compound was dissolved was added to the above mixed reaction solution by an acoustic technique (Echo 550). The concentration of the compound in the reaction mixture was 10 μM, 3.33 μM, 1.11 μM, 0.370 μM, 0.123 μM, 41.2 nM, 13.7 nM, 4.57 nM, 1.52 nM, 0.508 nM. After 15 minutes of incubation, ³³ P-ATP (activity 0.01 μCi/μl, corresponding concentrations listed in Table 1) was added to initiate the reaction. The supplier's article number, lot number, and concentration information in the reaction solution of IRAK4 and its substrate are listed in Table 1. After the reaction was allowed to proceed at room temperature for 120 minutes, the reaction solution was spotted on a P81 ion exchange filter paper (Whatman #3698-915). After repeatedly washing the filter paper with a 0.75% phosphoric acid solution, the radioactivity of the phosphorylated substrate remaining on the filter paper was measured. The kinase activity data was expressed as an alignment of the kinase activity of the test compound and the kinase activity of the blank group (DMSO only), and the IC50 value was obtained by curve fitting by Prism4 software (GraphPad), and the experimental results are shown in Table 2.

Table 1: Information on kinases, substrates and ATP in in vitro assays.

Kinase	supplier	Cat#	Lot#	Kinase concentration (nM) in the reaction solution	ATP concentration (μM)
IRAK4	Invitrogen	PV3362	404828G	3	20

Substrate	supplier	Cat#	Lot#	Substrate concentration in the reaction solution (μM)
MBP	Active Motif	102641	04811001	20

Table 2: In vitro screening test results of the compounds of the present invention

Conclusion: The compounds of the invention exhibit good inhibitory activity against IRAK4.

Test Example 2: Evaluation of in vitro plasma stability

The biomatrix in this experiment is cryopreserved plasma of animals or humans. These plasmas were purchased from Bioreclamation, NY, USA, and the plasma of cynomolgus monkeys was purchased from Suzhou Xishan Zhongke Experimental Animal Co., Ltd. (Suzhou, China) or other qualified supplier. All plasma was stored in a -80 ° C refrigerator.

The test and control materials were incubated with animal and human plasma for a period of up to 120 minutes at 37 ° C, the final concentration of the compound and the control was 2 μM, and the final concentration of the organic solvent DMSO should be ≤ 1%. Samples were taken at the indicated time points (0, 10, 30, 60 and 120 minutes) and quenched with acetonitrile or methanol containing the internal standard. After centrifugation, the resulting supernatant was detected by LC/MS/MS method. The control should be metabolized at a rate in the test system and the accompanying controls are required for each experiment.

The test compound ID and the control substance (bisaptodine, enalapril and prubensin) powder were separately prepared into a 10 mM stock solution with DMSO or other organic solvent, and then further diluted to 100 μM by selecting an appropriate organic solvent. Working fluid.

The stop solution is formulated with acetonitrile or other organic solvent containing an internal standard (tolbutamide or other suitable compound). The prepared stop solution is stored in a refrigerator at 2-8 °C.

The frozen animal plasma and human plasma were taken out from a -80 ° C refrigerator and preheated in a 37 ° C water bath for 10-20 minutes. Then, centrifuge at 5200 xg for 5 minutes to remove debris. Finally, the pH was adjusted to 7.4 ± 0.1 using 1% phosphoric acid or 1 N sodium hydroxide.

Incubation will be done in a 96-well plate (or other suitable container). First, a certain volume of blank plasma was added to the incubation plate, and then the test solution and the control working solution were separately added, and the reaction time points were 0, 10, 30, 60, and 120 minutes, respectively. There were 2 parallel samples per compound at each time point and the incubation was done in a water bath at 37 °C. In the test system, the final concentration of the compound ID and the control was 2 μM. Among them, probufen was used as a reference substance for CD-1 mice, cynomolgus monkeys and human plasma, enalapril was used as a reference substance for SD rat plasma, and bisacodyl was used as a reference substance for beagle dog plasma.

At the end of each time point incubation, the corresponding sample was taken and the stop solution (acetonitrile or methanol) containing the internal standard was added in proportion to terminate the reaction.

Immediately after sealing all the sample plates, shake them on a shaker and centrifuge at 3220 x g for 20 minutes. The supernatant is diluted with ultrapure water or other dilutions in a certain ratio. After mixing, the sample is analyzed by LC/MS/MS.

All samples were analyzed and determined by liquid chromatography tandem mass spectrometry (LC/MS/MS).

For routine items, semi-quantitative analysis of the content of the test and control in the sample is expressed as the peak area ratio (PAR) of the compound/internal standard.

The conventional project will calculate the remaining amount of the test compound by converting the ratio of the compound to the peak area of the internal standard in the following formula to the remaining percentage:

As shown in Table 3 below:

Table 3: Results of in vitro screening test (plasma stability test) of the compound of the present invention

Compound	Remaining amount (rat plasma)
Example 3	117%

Conclusion: The compounds of the invention exhibit better stability in rat plasma.

Claims (15)

1. a compound of formula (I) or a pharmaceutically acceptable salt thereof,

   

   among them,

   m is selected from: 0, 1, 2 or 3;

   Ring A is selected from a 5- to 6-membered heteroaryl ring;

   Ring B is selected from the group consisting of C _3-7 cycloalkyl, 4-6 heterocycloalkyl;

   L is selected from: O or NH;

   R _{1 is} selected from H or is selected from C _{1 - 3} alkyl, C _1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;

   R _{2 is} selected from OH, NH ₂ , CN, halogen, or selected from the group consisting of 1, 2 or 3 R: C _1-3 alkyl, C _1-3 heteroalkyl, 4 to 6-membered heterocyclic ring alkyl;

   R is selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , CN, Me, Et, CF ₃ ;

   The "hetero" of the C _1-3 heteroalkyl group, the 4-6 membered heterocycloalkyl group or the 5- to 6-membered heterocycloalkenyl group is independently selected from: N, O, S, NH, -C (=O) NH-; the number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
2. The compound according to claim 1, wherein the ring A is selected from the group consisting of pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thienyl, or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit

   

   From:

   

   
4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from H or is selected from the group consisting of 1, 2 or 3 R: Me, Et,

   
5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from the group consisting of H, Me, Et,

   
6. The compound according to claim 3 or 5, or a pharmaceutically acceptable salt thereof, wherein the structural unit

   

   From:

   
7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of cyclopentyl, cyclohexane, and tetrahydrofuranyl.
8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein the structural unit

   

   From:

   

   
9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the structural unit

   

   From:

   

   
10. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R _{2 is} selected from OH, NH ₂ , CN, halogen, or selected from the group consisting of 1, 2 or 3 R: Me, Et ,

    

    Morpholinyl.
11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R _{2 is} selected from the group consisting of OH, NH ₂ , CN, F, Cl, Br, I, Me, Et,

    
12. The compound according to claim 9 or 11, or a pharmaceutically acceptable salt thereof, wherein the structural unit

    

    From:

    
13. The compound according to any one of claims 1, 4, 5, 10 and 11, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

    

    

    among them,

    R ₁ , R ₂ , L are as defined in claims ₁ , ₄ , ₅ , ₁₀ and 11.
14. A compound of the formula: or a pharmaceutically acceptable salt thereof:

    
15. A compound according to claim 14 or a pharmaceutically acceptable salt thereof: