Novel pyrimidine derivatives with Bruton's tyrosine kinase inhibitory activity

Abstract

The present invention relates to novel pyrimidine derivatives, solvates, stereoisomers, or pharmaceutically acceptable salts thereof, which have Bruton's tyrosine kinase inhibitory activity and are represented by the following chemical formula I, and pharmaceutical compositions containing the same as active ingredients. The novel pyrimidine derivatives of the present invention effectively inhibit the enzymatic activity of Bruton's tyrosine kinase (BTK), and can therefore be useful as active ingredients in pharmaceutical compositions for the prevention or treatment of BTK-mediated diseases such as autoimmune diseases or cancer: Chemical I JPEG2025534514000040.jpg4163.

Description

[Technical Field]

[0001] The present invention relates to novel pyrimidine derivatives having Bruton's tyrosine kinase inhibitory activity, and pharmaceutical compositions containing the same as an active ingredient. [Background technology]

[0002] Bruton's tyrosine kinase (BTK) is a member of the Tec family of tyrosine kinases. It plays a central role in the signaling cascades of receptors such as the B-cell receptor (BCR), Fc receptors, chemokine receptors, Toll-like receptors (TLRs), and CD40, and functions as a regulator of not only early B-cell development but also mature B-cell activation, signaling, and survival.

[0003] B cells are activated into mature antibody-producing cells by signals transmitted by B-cell receptors (BCRs), which recognize antigens on the surface of antigen-presenting cells. However, abnormal signaling by BCRs can lead to abnormal proliferation of B cells and the formation of pathological autoantibodies, which can lead to cancer, autoimmune diseases, and / or inflammatory diseases.

[0004] Therefore, inhibiting BTK in abnormal B cell proliferation blocks BCR signaling, preventing B cell-mediated diseases. The use of BTK inhibitors is a useful approach for treating B cell-mediated diseases such as various cancers, tumors, and autoimmune diseases.

[0005] Against this technological background, active and multifaceted research has been conducted to develop BTK inhibitors that can effectively inhibit BTK activity (International Patent Publication WO2008 / 039218). However, the BTK inhibitors developed to date have problems: they do not exhibit sufficiently selective inhibitory activity against BTK, or they exhibit side effects such as drug resistance or toxicity to normal cells, preventing their effective use in the treatment of various cancers, tumors, and autoimmune diseases.

[0006] Therefore, the present inventors have conducted research into novel compounds and have identified novel pyrimidine derivative compounds that have excellent selective inhibitory activity as BTK inhibitors, thereby completing the present invention. Summary of the Invention [Problem to be solved by the invention]

[0007] One aspect of the present invention provides novel pyrimidine derivatives that exhibit inhibitory activity against Bruton's tyrosine kinase (BTK).

[0008] In another aspect, there is provided a pharmaceutical composition for preventing or treating a Bruton's tyrosine kinase (BTK)-mediated disease, comprising the pyrimidine derivative as an active ingredient.

[0009] Yet another aspect provides a use of the pyrimidine derivative for the manufacture of a medicament for the prevention or treatment of a Bruton's tyrosine kinase (BTK)-mediated disease.

[0010] Yet another embodiment provides a method for preventing or treating a Bruton's tyrosine kinase (BTK)-mediated disease, comprising administering the pyrimidine derivative to an individual in need thereof. [Means for solving the problem]

[0011] One aspect of the present invention provides a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof of Formula I:

[0012] Chemical I [ka]

[0013] In the above formula I, W is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, or a substituted or unsubstituted C3-C 10 is a heterocycloalkyl group,

[0014] R1, R2 and R3 are each independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C 10 a cycloalkyl group, or R1 is linked to one of R2 or R3 to form a 4- to 7-membered heterocycle together with the atoms to which they are attached;

[0015] R6 and R7 are each independently hydrogen, halogen, or a substituted or unsubstituted C1-C6 alkyl group, or are joined together to form an unsaturated or partially saturated 5- to 7-membered heteroaryl ring together with the atoms to which they are attached, wherein the heteroaryl ring contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S;

[0016] R4, R5, R8 and R9 are each independently hydrogen, halogen, cyano, hydroxyl, thiol, nitro, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl group, or a substituted or unsubstituted C3-C6 heterocycloalkyl group; and

[0017] The term "substituted or unsubstituted" as used herein includes halogen, cyano, hydroxyl, thiol, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl groups, C3-C 10 Heterocycloalkyl groups, C3-C 10 Aryl groups and C1-C 10 It is substituted with a substituent selected from heteroaryl groups or does not have any substituents.

[0018] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating a Bruton's tyrosine kinase (BTK)-mediated disease, comprising as an active ingredient a compound of Formula I, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the BTK-mediated disease is an autoimmune disease or cancer.

[0019] Yet another aspect of the present invention provides a method for preventing or treating a Bruton's tyrosine kinase (BTK)-mediated disease, comprising administering to an individual a compound of Formula I, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the BTK-mediated disease is an autoimmune disease or cancer. [Effects of the Invention]

[0020] The compound of Formula I, solvates, stereoisomers, or pharmaceutically acceptable salts thereof according to one embodiment can be useful as an active ingredient in a pharmaceutical composition for preventing or treating BTK-mediated diseases, such as autoimmune diseases or cancer, by effectively inhibiting the enzymatic activity of Bruton's tyrosine kinase (BTK). DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention will now be described in further detail.

[0022] Unless otherwise defined, all technical terms used herein have the meanings commonly understood by those of ordinary skill in the art related to the present invention. Although preferred methods and samples are described herein, similar or equivalent methods and samples are also included within the scope of the present invention. Numerical values ​​described herein are considered to include the meaning of "about" even if not explicitly stated. The contents of all publications referenced herein are incorporated herein by reference in their entirety.

[0023] One aspect of the invention provides a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof of Formula I:

[0024] Chemical I [ka]

[0025] In the above formula I, W is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, or a substituted or unsubstituted C3-C 10 is a heterocycloalkyl group,

[0026] R1, R2 and R3 are each independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C 10 a cycloalkyl group, or R1 is linked to one of R2 or R3 to form a 4- to 7-membered heterocycle together with the atoms to which they are attached;

[0027] R6 and R7 are each independently hydrogen, halogen, or a substituted or unsubstituted C1-C6 alkyl group, or are joined together to form an unsaturated or partially saturated 5- to 7-membered heteroaryl ring together with the atoms to which they are attached, wherein the heteroaryl ring contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S;

[0028] R4, R5, R8 and R9 are each independently hydrogen, halogen, cyano, hydroxyl, thiol, nitro, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl group, or a substituted or unsubstituted C3-C6 heterocycloalkyl group; and

[0029] The term "substituted or unsubstituted" as used herein includes halogen, cyano, hydroxyl, thiol, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl groups, C3-C 10 Heterocycloalkyl groups, C3-C 10 Aryl groups and C1-C 10 It is substituted with a substituent selected from heteroaryl groups or does not have any substituents.

[0030] As used herein, the term "halogen" can be F, Cl, Br, or I.

[0031] As used herein, the term "alkyl" means, unless otherwise specified, a substituted or unsubstituted, straight-chain or branched hydrocarbon residue. The alkyl group may include, without limitation, methyl, ethyl, propyl, butyl, pentyl, or all possible isomers thereof, such as isopropyl, isobutyl, and t-butyl.

[0032] As used herein, unless otherwise specified, the term "alkoxy" refers to a substituted or unsubstituted, straight-chain or branched hydrocarbon residue linked with oxygen. The alkoxy may include, without limitation, all possible isomers thereof, such as methoxy, ethoxy, propoxy, and butoxy, or isopropoxy, isobutoxy, and t-butoxy.

[0033] As used herein, the term "alkenyl" refers to unsaturated aliphatic groups analogous in length and substitution to the alkyls described above, but which contain one or more carbon-carbon double bonds. For example, it may include, without limitation, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and branched-chain alkenyl groups, or all of their (E) or (Z) isomers.

[0034] As used herein, the term "alkynyl" refers to unsaturated aliphatic groups analogous in length and substitution to the alkyls described above, but which contain one or more carbon-carbon triple bonds. Examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and branched-chain alkynyl groups.

[0035] The term "cycloalkyl," as used herein, unless otherwise specified, refers to substituted or unsubstituted saturated monocyclic and polycyclic hydrocarbon rings, generally having the specified number of carbon atoms comprising the ring. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0036] As used herein, unless otherwise specified, the term "heterocycloalkyl" refers to a monocyclic, bicyclic, or tricyclic or higher substituted or unsubstituted cyclic alkyl containing one or more, e.g., 1 to 4, or 1 to 3, heteroatoms selected from the group consisting of N, O, and S, and is also referred to as a "heterocycle." Examples of monocyclic heterocycloalkyls include, but are not limited to, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, piperazinyl, and similar groups. Examples of bicyclic heterocycloalkyls include, but are not limited to, diazabicyclo[2.2.1]heptyl, hexahydropyrrolo[3,4-c]pyrrolo, and similar groups.

[0037] As used herein, the term "azacycle" refers to a saturated monocyclic hydrocarbon group of the specified number of carbon atoms, as defined for "cycloalkyl," where one carbon atom is replaced by a nitrogen atom. This is also referred to as an "azacycloalkyl" or "azahydrocarbon." Unless otherwise specified, azacycloalkyl refers to a cyclic azahydrocarbon group having 2 to 6 ring carbon atoms and 1 nitrogen atom, 2 to 5 ring carbon atoms and 1 nitrogen atom, or 4 to 5 ring carbon atoms and 1 nitrogen atom. Exemplary azacycle groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, dihydroazepinyl, and the like.

[0038] As used herein, unless otherwise specified, the term "aryl" refers to a substituted or unsubstituted aromatic group, such as a C-C 30 Aryl, C6-C 20 Aryl, or C6-C 10 Aryl includes alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms, and may include, without limitation, for example, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, or all possible isomers thereof.

[0039] As used herein, unless otherwise specified, the term "heteroaryl" refers to a monocyclic, bicyclic or higher substituted or unsubstituted aromatic group containing one or more, for example, 1 to 4, or 1 to 3, heteroatoms selected from the group consisting of N, O, and S, and is also referred to as a "heteroaryl ring." Examples of monocyclic heteroaryls include, but are not limited to, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups. Examples of bicyclic heteroaryls include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, oxoisoquinolinyl, purinyl, furopyridinyl, oxochromene, dioxoisoindoline, pyrazolopyridinyl, pyrazolo[1,5-a]pyridinyl, and similar groups.

[0040] As used herein, the term "partially saturated" refers to the presence of at least one site of saturation, i.e., at least one single bond, within the aryl or heteroaryl ring as defined above. As used herein, the term "unsaturated" refers to the absence of any site of saturation, i.e., no single bond, within the aryl or heteroaryl ring as defined above.

[0041] As used herein, unless otherwise specified, the term "substituted" means that at least one hydrogen atom has been replaced with a non-hydrogen group, such as a halogen, a cyano group, a hydroxyl group, a thiol group, a nitro group, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C3-C6 10 Cycloalkyl groups, C3-C 10 Heterocycloalkyl groups, C3-C 10 Aryl groups and C1-C 10It may be substituted with a substituent selected from heteroaryl groups.

[0042] In this specification, a numerical range expressed using the term "to" refers to a range that includes the numerical values ​​stated before and after the term "to" as the lower and upper limits, respectively.

[0043] As used herein, the term "solvate" may include a molecular complex comprising a compound and one or more pharmaceutically acceptable solvent molecules, such as ethanol or water. A complex where the solvent molecule is water is also referred to as a "hydrate."

[0044] As used herein, the term "stereoisomer" means a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is optically or sterically different, specifically a partial stereoisomer, enantiomer, geometric isomer, or conformational isomer.

[0045] As used herein, the term "derivative" refers to a compound obtained by substituting a part of the structure of the above compound with a different atom or atomic group.

[0046] The compounds may also be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, such as those derived from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid.

[0047] The pharmaceutically acceptable salts of the compounds can be prepared by dissolving the compound of Formula I in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, adding an excess amount of an organic acid or an aqueous solution of an inorganic acid, followed by precipitation or crystallization. The solvent or excess acid can then be evaporated from the mixture, followed by drying to obtain the addition salt, or by filtering the precipitated salt with suction.

[0048] In one embodiment, W is a substituted or unsubstituted C2-C6 alkenyl group; R1, R2, and R3 are, independently of one another, hydrogen or a substituted or unsubstituted C1-C6 alkyl group, or R1 is connected to one of R2 or R3 to form a 4- to 7-membered heterocyclic ring together with the atoms to which they are attached; R6 and R7 are, independently of one another, hydrogen, halogen, or a substituted or unsubstituted C1-C6 alkyl group, or are connected to one another to form an unsaturated or partially saturated 6-membered heteroaryl ring together with the atoms to which they are attached, wherein the heteroaryl ring contains 1 to 3 nitrogen atoms; and R4, R5, R8, and R9 are, independently of one another, hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C6 cycloalkyl group.

[0049] In one embodiment, W is a substituted or unsubstituted C2-C6 alkenyl group; R1, R2, and R3 are, independently of one another, hydrogen or a substituted or unsubstituted C1-C3 alkyl group, or R1 is connected to one of R2 or R3 to form a 4- to 7-membered azacycle with the atom to which they are attached; R4 and R5 are, independently of one another, hydrogen, halogen, or a substituted or unsubstituted C1-C3 alkyl group; R6 and R7 are, independently of one another, hydrogen, halogen, or a substituted or unsubstituted C1-C3 alkyl group, or connected to one another to form, together with the atom to which they are attached, an unsaturated or partially saturated 6-membered heteroaryl ring, wherein the heteroaryl ring contains 1 to 3 nitrogen atoms; R8 is hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C6 cycloalkyl group; and R9 is hydrogen, halogen, or a substituted or unsubstituted C1-C3 alkyl group.

[0050] In one embodiment, R8 and R9 may be located at the meta position relative to R7. For example, the compound of formula I may have the same positional relationship between R8 and R9 as in formula I-1 below:

[0051] Chemical formula I-1 [ka]

[0052] In the above chemical formula I-1, W, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined in Formula I above.

[0053] In one embodiment, W is [ka] and;R x , R y and R zare each independently hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl group, a cyano group, or -(CH2) n -NR 10 R 11 n is an integer from 0 to 6; and R 10 and R 11 are each independently a substituted or unsubstituted C1-C6 alkyl group, or can be linked together to form a 4- to 7-membered azacycle together with the nitrogen atom to which they are attached.

[0054] In one embodiment, W is [ka] and;R x is hydrogen, halogen, or a substituted or unsubstituted C1-C3 alkyl group; R y is hydrogen, halogen, a substituted or unsubstituted C1-C3 alkyl group, or -(CH2) n -NR 10 R 11 and;R z is hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl group, or a cyano group; n is an integer of 0 or 1; and R 10 and R 11 are each independently a substituted or unsubstituted C1-C3 alkyl group, or can be linked together to form a 4- to 7-membered azacycle together with the nitrogen atom to which they are attached.

[0055] In one example of the compound of Formula I, the compound is of Formula Ia: Chemical formula Ia [ka]

[0056] In the above formula Ia, W, R1, R2, R3, R4, R5, R6, R8, and R9 are as defined in Formula I above.

[0057] In one example of the compound of Formula I, the compound is of Formula Ib: Chemical formula Ib [ka]

[0058] In the above formula Ib, X1 and X2 are each independently -C(R 12 )2-, -CR 12 -, or -N-; [ka] is a single or double bond; R 12 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl group; and W, R1, R2, R3, R4, R5, R8, and R9 are as defined in Formula I above.

[0059] In one embodiment, the compound of formula I may be selected from the group consisting of the following compounds 1) to 23):

[0060] 1) N-(3-(6-amino-5-(3-N-methylacrylamido)prop-1-yn-1-yl)pyrimidin-4-yl)5-fluoro-2-methylphenyl)-2-fluoro-4-isopropylbenzamide;

[0061] 2) N-(3-(6-amino-5-(3-N-methylacrylamido)prop-1-yn-1-yl)pyrimidin-4-yl)5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;

[0062] 3) N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide;

[0063] 4) N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide;

[0064] 5) N-(3-(4-amino-6-(3-(6-cyclo-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide;

[0065] 6) N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide;

[0066] 7) N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-2,5-difluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide;

[0067] 8) N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-2,5-dimethylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide;

[0068] 9) N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)acrylamide;

[0069] 10) N-(3-(4-amino-6-(3-(6-(tert-butyl)-8-fluoro-1-oxophthalazin-2-(1H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide;

[0070] 11) N-(3-(4-amino-6-(3-(6-cyclopropyl-1-oxophthalazin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide;

[0071] 12) N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide;

[0072] 13) N-(3-(4-amino-6-(3-(6-(tert-butyl)-8-fluoro-1-oxophthalazin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide;

[0073] 14) N-(3-(4-amino-6-(3-(6-tert-butyl)-1-oxophthalazin-2-(1H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide;

[0074] 15) N-(3-(4-amino-6-(3-(7-cyclopropyl-5-fluoro-4-oxoquinazolin-3(4H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide;

[0075] 16) (R)-2-(3-(5-((1-acryloylpyrrolidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one;

[0076] 17) (S)-2-(3-(5-((1-acryloylpyrrolidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one;

[0077] 18) (S)-2-(3-(5-((1-acryloylpyrrolidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-8-fluoro-6-isoquinolin-1-(2H)-one;

[0078] 19) (S)-2-(3-(6-amino-5-((1-(2-fluoroacryloyl)pyrrolidin-2-yl)ethynyl)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one;

[0079] 20) (S)-2-(3-(6-amino-5-((1-(2-chloroacryloyl)pyrrolidin-2-yl)ethynyl)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one;

[0080] 21) (S)—N-(3-(5-((1-acryloylpyrrolidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;

[0081] 22) 2-(3-(5-((1-acryloylpiperidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-isoquinolin-1(2H)-one; and

[0082] 23) (S)-2-(3-(5-((1-acryloylpiperidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-8-fluoro-6-isopropylisoquinolin-1(2H)-one.

[0083] Compounds of Formula I having a triple bond attached to the aminopyrimidine backbone according to one embodiment can effectively inhibit BTK activity.

[0084] Another embodiment provides a pharmaceutical composition for preventing or treating a Bruton's tyrosine kinase (BTK)-mediated disease, comprising the compound of Formula I, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the BTK-mediated disease is an autoimmune disease or cancer.

[0085] As used herein, the term "treating" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting pathology or symptoms of the disease, condition, or disorder, i.e., preventing further occurrence of the pathology and / or symptoms, or ameliorating a disease, e.g., ameliorating a disease, condition, or disorder in an individual experiencing or exhibiting pathology or symptoms of the disease, condition, or disorder, i.e., reversing the pathology and / or symptoms, e.g., reducing disease severity.

[0086] As used herein, the term "preventing" or "prevention" refers to preventing a disease, for example, preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder, but who has not yet experienced or exhibited pathology or symptoms of the disease.

[0087] As used herein, the term "individual" or "patient" refers to any animal, including mammals, e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and humans.

[0088] As used herein, the term "BTK-mediated disease" refers to a condition or disease that develops as a result of excessive signal transduction due to overactivity of BTK, and that can be prevented, improved, or treated by inhibiting BTK activity. The BTK-mediated disease includes autoimmune diseases and cancer. The term "autoimmune disease" as used herein refers to any group of diseases in which tissue damage is associated with a humoral or cell-mediated response to the body's own components. Examples of autoimmune diseases include rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, myasthenia gravis, Hashimoto's thyroiditis, iodothyroiditis, Graves' disease, Sjögren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, nystagmus-clonic syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, and idiopathic encephalomyelitis. These conditions include, but are not limited to, thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, autonomic dysfunction, asthma, chronic spontaneous urticaria, pemphigus, systemic lupus erythematosus, hidradenitis, skin rot, immunoglobulin G4-related disease, endometriosis, interstitial cystitis, neuromyotonia, or vulvodynia.

[0089] As used herein, "cancer" refers to a physiological condition in mammals that is typically characterized by unregulated cell growth. In the present invention, cancer includes carcinoma, lymphoma, blastoma, sarcoma, leukemia, or malignant lymphoma. More specific examples of cancer include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer, e.g., small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinoma and lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric or abdominal cancer, e.g., gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular adenoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary carcinoma, kidney or renal cell carcinoma, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer.

[0090] In the present invention, cancer may also be a B-cell malignant tumor, such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), B-cell prolymphocytic leukemia, diffuse large B-cell lymphoma (DLBCL), splenic marginal zone lymphoma (SMZL), Burkitt's lymphoma, B-cell non-Hodgkin's lymphoma, follicular lymphoma, primary central nervous system lymphoma (PCNSL), or nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL), hairy cell leukemia, splenic lymphoma, lymphoplasmacytic lymphoma, etc. The present invention relates to a method for treating Bruton's tyrosine kinase (BTK)-mediated diseases, such as cutaneous lymphoma, cutaneous follicle center lymphoma, cutaneous ...

[0091] In one embodiment, the pharmaceutical composition may contain a conventional pharmaceutically acceptable carrier, excipient, or additive, and may be formulated by a conventional method into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, and microemulsions, or parenteral dosage forms such as intramuscular, intravenous, or subcutaneous administration.

[0092] When the pharmaceutical composition is prepared in the form of an oral preparation, examples of the excipient or carrier used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents, diluents, etc. When the pharmaceutical composition is prepared in the form of an injection, examples of the excipient or carrier include water, saline, aqueous glucose solution, aqueous sugar solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, surfactant, suspending agent, emulsifying agent, etc.

[0093] The dosage of the pharmaceutical composition is an amount effective for the treatment or prevention of an individual or patient and can be administered orally or parenterally depending on the purpose. For oral administration, the active ingredient is administered in an amount of 0.01 to 1000 mg, more specifically 0.1 to 300 mg per kg of body weight per day. For parenteral administration, the active ingredient is administered in an amount of 0.01 to 100 mg, more specifically 0.1 to 50 mg per kg of body weight per day. The dosage for a particular individual or patient must be determined in light of various relevant factors, such as the patient's weight, age, sex, health condition, diet, administration time, administration method, and disease severity, and may be adjusted appropriately by a specialist. The dosages described above are not intended to limit the scope of the present invention in any way. A physician or veterinarian of ordinary skill in the relevant art can easily determine and prescribe the required effective amount of the pharmaceutical composition. For example, a physician or veterinarian may start a dosage of a compound of the invention used in a pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0094] In one embodiment, the pharmaceutical compositions encompass pharmaceutical compositions containing a therapeutically effective amount of at least one compound according to one embodiment as an active ingredient, alone or in combination with a pharmaceutical carrier. Optionally, a compound according to one embodiment may be administered alone, in combination with a compound according to another embodiment, or co-administered with one or more other therapeutic agents or other pharmaceutically active substances, either simultaneously, separately, or sequentially. Other combination therapies involving BTK inhibitors, as known in the art, are also within the scope of the present invention.

[0095] Another embodiment provides a method for preventing or treating a Bruton's tyrosine kinase (BTK)-mediated disease, comprising administering to an individual in need thereof the compound of Formula I, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same, wherein the BTK-mediated disease is an autoimmune disease or cancer.

[0096] For details of the method of prevention or treatment, the above explanation regarding the pharmaceutical composition according to one aspect of the present invention is applicable.

[0097] Furthermore, the dosage used in the method for prevention or treatment is an amount effective for treatment or prevention of an individual or patient, and the same explanation as for the dosage of the pharmaceutical composition applies thereto.

[0098] Another embodiment provides a pharmaceutical use of the compound of Formula I, solvate, stereoisomer, or pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a Bruton's tyrosine kinase (BTK)-mediated disease, wherein the BTK-mediated disease is an autoimmune disease or cancer.

[0099] The details of the medicinal use are the same as those of the pharmaceutical composition according to one aspect of the present invention.

[0100] The method for preparing the compound of Formula I will now be described in detail.

[0101] The compound of Formula I can be prepared by, but is not limited to, the method shown in the following Reaction Scheme 1. Those skilled in the art of organic compounds can also prepare the compound by other synthetic methods different from those specifically shown in the following examples by appropriately adjusting the specific reaction route, reaction conditions, reaction amounts, etc.

[0102] [Reaction Scheme 1] [ka]

[0103] To explain this in more detail with reference to Reaction Scheme 1, The compounds of Chemical Formula 5 and Chemical Formula 7 can be prepared from commercially available compounds using common knowledge in the field of organic chemistry.

[0104] In Reaction Scheme 1, R1, R2, R3, R4, R5, R6, R7, R8, R9 and W are as defined in Chemical Formula I above.

[0105] The compound of Chemical Formula 4 can be produced by Sonogashira coupling of the compound of Chemical Formula 5 with the compound of Chemical Formula 6 using an appropriate palladium catalyst, such as bis(triphenylphosphine)palladium(II) dichloride. The solvent used in the reaction can be any solvent that does not inhibit the reaction. Examples of the solvent used in the reaction include polar aprotic solvents such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, and tetrahydrofuran; polar protic solvents such as methanol, ethanol, 2-propanol, 2-isopropanol, and 2-butanol; and nonpolar aprotic solvents such as toluene and 1,4-dioxane. A specific example is N,N-dimethylformamide. The reaction temperature is 0°C to 150°C, preferably 100°C.

[0106] The compound of Chemical Formula 4 and the boronate ester compound of Chemical Formula 7 are subjected to Suzuki coupling to prepare the compound of Chemical Formula 3. The solvent used in the reaction is diethylene glycol dimethyl ether:water=7:1, and the preferred reaction temperature is 100°C.

[0107] The compound of Formula 3 was reacted with an organic acid such as trifluoroacetic acid or an inorganic acid such as concentrated hydrochloric acid in an organic solvent such as dichloromethane to deprotect the t-butoxycarbonyl group, thereby preparing the compound of Formula 2. The reaction temperature is 0°C to room temperature, preferably room temperature.

[0108] The compound of Formula 2 can be reacted with various acids using an appropriate coupling reagent, such as T3P, and an appropriate base, such as N,N-diisopropylamine, to prepare the compound of Formula 1. The solvent used in the reaction can be any solvent that does not inhibit the reaction. Examples of the solvent used in the reaction include polar aprotic solvents such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, and tetrahydrofuran; polar protic solvents such as methanol, ethanol, 2-propanol, 2-isopropanol, and 2-butanol; and nonpolar aprotic solvents such as toluene and 1,4-dioxane. A specific example is N,N-dimethylformamide. The reaction temperature is 0°C to room temperature, preferably 0°C.

[0109] Pharmaceutical compositions containing the compound of Formula I, solvates, stereoisomers, and pharmaceutically acceptable salts thereof synthesized by such a production method as an active ingredient can be used to treat BTK-mediated diseases, such as autoimmune diseases or cancer, by effectively inhibiting the enzymatic activity of Bruton's tyrosine kinase (BTK). [Example]

[0110] The present invention will be described in detail below with reference to examples, but the following examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention.

[0111] Example 1: Preparation of N-(3-(6-amino-5-(3-N-methylacrylamido)prop-1-yn-1-yl)pyrimidin-4-yl)5-fluoro-2-methylphenyl)-2-fluoro-4-isopropylbenzamide

[0112] [ka]

[0113] Step 1) Preparation of methyl 2-fluoro-4-isopropylbenzoate Methyl 4-bromo-2-fluorobenzoate (10.0 g, 42.9 mmol), 2-isopropyl boronic acid pinacol ester (12.5 mL, 64.4 mmol), palladium(II) dichloride dichloromethane complex (3.6 g, 4.3 mmol), and calcium carbonate (17.9 g, 128.7 mmol) were diluted with 200 mL of 1,4-dioxane:water (4:1) and stirred at 80°C for 4 hours. After completion of the reaction, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and evaporated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate:hexane (1:50, volume ratio)) to afford the title compound (8.17 g, 98% yield).

[0114] 1 H-NMR (300MHz, CDCl3): δ7.90~7.84 (t, 1H), 7.28~7.24 (m, 1H), 7.20~7.16 (m, 1H), 5.47 (s, 1H), 5.21 (s, 1H), 3.91 (s, 3H), 2.12 (s, 3H).

[0115] Step 2) Preparation of methyl 2-fluoro-4-isopropylbenzoate 8.17 g (42.1 mmol) of the compound prepared in step 1 was dissolved in 140 mL of methanol, and 2.0 g (8.4 mmol) of platinum(IV) oxide was added. The reaction mixture was degassed and stirred under hydrogen for 10 minutes, and then stirred under hydrogen for 18 hours at 25°C. After the reaction was completed, the resulting reaction mixture was filtered under reduced pressure through a filter filled with Celite, and the filtrate was distilled under reduced pressure to obtain 8.16 g (yield: 99%) of the title compound.

[0116] 1H-NMR (300MHz, DMSO-d6): δ7.82~7.76 (m, 1H), 7.23~7.17 (m, 2H), 3.82 (s, 3H), 3.01~2.88 (s, 1H), 1.20~1.17 (d, 6H).

[0117] Step 3) Preparation of 2-fluoro-4-isopropylbenzoic acid 8.16 g (41.6 mmol) of the compound prepared in step 2 was diluted with 100 mL of tetrahydrofuran:methanol:water (3:3:1) and cooled to 0°C. 5.5 g (124.8 mmol) of lithium hydroxide monohydrate was added, and the reaction mixture was stirred at 25°C for 4 hours. After the reaction was completed, the resulting reaction mixture was distilled under reduced pressure. The resulting residue was acidified (pH 3-4) with 1N hydrochloric acid to produce a solid. The resulting solid was filtered and washed twice with 100 mL of water. The resulting solid was dried in a drying oven at 50°C to obtain 6.1 g of the title compound (yield: 81%).

[0118] 1 H-NMR (300MHz, DMSO-d6): δ 13.02 (brs, 1H), 7.80~7.75 (m, 1H) 7.18~7.14 (m, 2H), 2.98~2.87 (m, 1H), 1.20~1.18 (d, 6H).

[0119] Step 4) Preparation of 2-(5-fluoro-2-methyl-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 30 g (124.4 mmol) of 2-bromo-4-fluoro-6-nitrotoluene was dissolved in 1.0 L of 1,4-dioxane, followed by the addition of 48.3 g (186.5 mmol) of bis(pinacolato)diboron, 44 g (435.2 mmol) of potassium acetate, and 5.2 g (6.2 mmol) of palladium(II) dichloride dichloromethane complex. The reaction mixture was refluxed and stirred at 100°C for 2 hours. After the reaction was completed, the resulting reaction mixture was cooled to room temperature, filtered under reduced pressure through a filter filled with Celite, and distilled. The resulting residue was purified by column chromatography (ethyl acetate:hexane = 1:50 (volume ratio)) to obtain 34.2 g (yield: 98%) of the title compound.

[0120] 1 H-NMR (300MHz, CDCl3): δ 7.67~7.64 (m, 1H), 7.54~7.50 (m, 1H), 2.61 (s, 3H), 1.33 (s, 12H).

[0121] Step 5) Preparation of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 34.1 g (121.3 mmol) of the compound obtained in step 4 was diluted with 340 mL of ethyl acetate, and 3.4 g (30.4 mmol) of 10% palladium on activated carbon was added. The reaction mixture was degassed and stirred under hydrogen for 10 minutes, and then stirred under hydrogen for 18 hours at 25°C. After the reaction was completed, the resulting reaction mixture was filtered under reduced pressure through a filter filled with Celite, and the filtrate was distilled under reduced pressure to obtain 28.7 g (yield: 94%) of the title compound.

[0122] 1 H-NMR (300MHz, CDCl3): δ 6.90~6.87 (m, 1H), 6.48~6.45 (m, 1H), 3.69 (brs, 2H), 2.32 (s, 3H), 1.35 (s, 12H).

[0123] Step 6) Preparation of 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide 7.89 g (31.4 mmol) of the compound obtained in step 5) and 5.72 g (31.4 mmol) of the compound obtained in step 3) were diluted with 100 mL of N,N-dimethylformamide, and 24.4 g (62.8 mmol) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate and 16.6 mL (94.3 mmol) of N,N-diisopropylethyleneamine were added. The reaction mixture was stirred at 50°C for 14 hours. After the reaction was completed, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and evaporated under reduced pressure. The resulting residue was separated by column chromatography (ethyl acetate:hexane = 1:20 (volume ratio)) to obtain 8.3 g (yield: 64%) of the title compound.

[0124] Step 7) Preparation of 6-chloro-5-iodo-pyrimidin-4-amine 60 g (463.1 mmol) of 6-chloropyrimidin-4-amine was diluted with 360 mL of N,N-dimethylformamide, and 108.6 g (463.1 mmol) of N-iodosuccinimide was added. The reaction mixture was stirred at 100 °C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium thiosulfate. The resulting solid was filtered and washed twice with 500 mL of distilled water. The resulting solid was dried in a drying oven at 50 °C to give 48.8 g (41% yield) of the title compound.

[0125] Step 8) Preparation of tert-butyl methyl(prop-2-yn-1-yl)carbamate 50 g (322.2 mmol) of tert-butyl prop-2-yn-1-ylcarbamate was diluted with 500 mL of N,N-dimethylformamide and cooled to 0°C. 14.2 g (354.4 mmol) of sodium hydride was added in portions at 0°C, and the reaction mixture was stirred for 30 minutes. 26.4 mL (418.8 mmol) of iodine was added, and the reaction mixture was stirred at 50°C for 3 hours. After the reaction was completed, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 49.2 g of the title compound (yield: 90%).

[0126] 1 H-NMR (300MHz, CDCl3): δ 4.03 (bs, 2H), 2.90 (s, 3H), 2.21 (s, 1H), 1.46 (s, 9H).

[0127] Step 9) Preparation of tert-butyl (3-(4-amino-6-chloropyrimidin-5-yl)prop-2-yn-1-yl)(methyl)carbamate 17.8 g (69.7 mmol) of the compound prepared in step 7 was diluted with 90 mL of N,N-dimethylformamide, and 2.5 g (3.5 mmol) of bis(triphenylphosphine)palladium(II) dichloride and 677 mg (3.5 mmol) of copper iodide were added under nitrogen. A solution of 17.7 g (104.5 mmol) of tert-butylmethyl(prop-2-yn-1-yl)carbamate diluted with 45 mL of N,N-dimethylformamide and a solution of 19.6 mL (139.4 mmol) of triethylamine diluted with 45 mL of N,N-dimethylformamide were added at 25°C, and the reaction mixture was stirred at 35°C for 18 hours under nitrogen. After the reaction was completed, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water and aqueous sodium bicarbonate solution. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the residue obtained by vacuum distillation was separated by column chromatography (ethyl acetate:hexane = 1:5 (volume ratio)) to obtain 7.1 g (yield: 34%) of the title compound.

[0128] 1 H-NMR (300MHz, DMSO-d6): δ 8.17 (s, 1H), 4.30 (bs, 2H), 2.87 (s, 3H), 1.40 (s, 9H).

[0129] Step 10) Preparation of tert-butyl (3-(4-amino-6-(5-fluoro-3-(2-fluoro-4-isopropylbenzamido)-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)(methyl)carbamate 1 g (3.4 mmol) of the compound prepared in step 9) and 1.7 g (4.0 mmol) of the compound prepared in step 6) were diluted with 40 mL of dimethoxyethane:distilled water (7:1), and 10.2 mL (10.2 mmol) of 1 M sodium bicarbonate was added. The reaction mixture was degassed and stirred under nitrogen for 10 minutes, and then 193 mg (0.3 mmol) of bis(triphenylphosphine)palladium(II) dichloride was added. The reaction mixture was stirred at 100°C for 5 hours. After the reaction was completed, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water and aqueous sodium bicarbonate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and evaporated under reduced pressure. The resulting residue was separated by column chromatography (ethyl acetate:hexane (1:1 (volume ratio)) to obtain 525 mg (yield: 28%) of the title compound.

[0130] 1 H-NMR (300MHz, CDCl3): δ 8.60~8.54 (m, 2H), 8.20~8.09 (m, 2H), 7.25~7.17 (m, 2H), 7.05~7.00 (m, 1H), 6.92~6.88 (m, 1H), 5.70 (brs, 2H), 4.09 (s, 2H), 3.01~2.92 (m, 1H), 2.74 (s, 3H), 2.15 (s, 3H), 1.41 (s, 9H), 1.28~1.25 (d, 6H).

[0131] Step 11) Preparation of N-(3-(6-amino-5-(3-(methylamino)prop-1-yn-1-yl)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-isopropylbenzamide 515 mg (0.94 mmol) of the compound prepared in Step 10) was diluted with 10 mL of dichloromethane, and 1.4 mL (18.7 mmol) of trifluoroacetic acid was added slowly at 25° C. The reaction mixture was stirred at 25° C. for 1 hour. After the reaction was completed, the reaction mixture was distilled under reduced pressure to obtain 421 mg (99%) of the title compound.

[0132] Step 12) Preparation of N-(3-(6-amino-5-(3-N-methylacrylamido)prop-1-yn-1-yl)pyrimidin-4-yl)5-fluoro-2-methylphenyl)-2-fluoro-4-isopropylbenzamide 0.1 mL (1.4 mmol) of acrylic acid and 0.66 mL (3.7 mmol) of N,N-diisopropylethylamine were diluted with 4 mL of N,N-dimethylformamide, and 0.36 mL (1.2 mmol) of propylphosphonic anhydride (50% by weight) was added. The reaction mixture was stirred at 25° C. for 30 minutes.

[0133] 421 mg (0.94 mmol) of the compound prepared in step 11 was diluted with 4 mL of N,N-dimethylformamide and cooled to 0°C. 0.5 mL (2.8 mmol) of N,N-diisopropylethylamine was added and stirred at the same temperature for 30 minutes. The reaction mixture prepared above was slowly added dropwise and stirred at 0°C for 4 hours. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with distilled water. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The residue obtained was separated by column chromatography (dichloromethane:methanol = 8:1 (volume ratio)) to obtain 100 mg (yield: 21%) of the title compound.

[0134] 1H-NMR (300MHz, DMSO-d6): δ 9.78 (bs, 1H), 8.40 (s, 1J), 7.71~7.66 (t, 1H), 7.55~7.51 (d, 1H), 7.26~7.16 (m, 2H), 6.99~6.97 (m, 1H), 6.68~6.56 (m, 1H), 6.09~5.99 (m, 1H), 5.65~5.56 (m, 1H), 4.33 (s, 2H), 3.02~2.93 (m, 1H), 2.80~2.73 (m, 3H), 2.02 (s, 3H), 1.23~1.21 (d, 6H).

[0135] MS (ESI + ): m / z = 504.21 [M+H] + .

[0136] Example 2: Preparation of N-(3-(6-amino-5-(3-N-methylacrylamido)prop-1-yn-1-yl)pyrimidin-4-yl)5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide

[0137] [ka]

[0138] In step 10 of Example 1, 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 4-cyclopropyl-2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide. The same procedure as in Example 1 was carried out to prepare 213 mg of this compound (yield: 38%).

[0139] 1H-NMR (300MHz, DMSO-d6) δ 9.71 (bs, 1H), 8.39 (s, 1H), 7.66~7.61 (t, 1H), 7.53~7.50 (m, 1H), 7.07~7.02 (m, 2H), 6.98~6.96 (m, 1H), 6.66~6.55 (m, 1H), 6.09~5.98 (m, 1H), 5.64~5.55 (m, 1H), 4.33 (s, 2H), 2.79~2.72 (m, 3H), 2.05~1.96 (m, 4H), 1.06~1.00 (m, 1H), 0.80~0.76 (m, 1H).

[0140] MS (ESI + ): m / z = 502.20 [M+H] + .

[0141] Example 3: Preparation of N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide

[0142] [ka]

[0143] In step 10 of Example 1, 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-cyclopropyl-8-fluoro-2-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-3,4-dihydroisoquinolin-1(2H)-one. The same method as in Example 1 was carried out to prepare 64 mg of this compound (yield: 12%).

[0144] 1H-NMR (300MHz, DMSO-d6) δ 8.42 (s, 1H), 7.83 (m, 1H), 7.61 (m, 1H), 7.43 (d, 1H), 6.92 (s, 1H), 6.90 (d, 1H), 6.83 (m, 1H), 6.11 (d, 1H), 5.62 (m, 1H), 4.55 (d, 2H), 3.93 (m, 2H), 3.09 (m, 1H), 3.07 (s, 3H), 2.88 (s, 1H), 2.00 (m, 1H), 1.05 (m, 2H), 0.82 (m, 2H).

[0145] MS (ESI + ): m / z = 514.20 [M+H] + .

[0146] Example 4: Preparation of N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide

[0147] [ka]

[0148] In step 10) of Example 1, 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-cyclopropyl-8-fluoro-2-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one. The same method as in Example 1 was carried out to prepare 10 mg of this compound (yield: 11%).

[0149] 1H-NMR (300MHz, DMSO-d6) δ 8.41 (s, 1H), 7.34 (m, 1H), 7.13 (m, 1H), 6.94 (s, 1H), 6.86 (d, 1H), 6.74 (m, 1H), 6.13 (d, 1H), 5.61 (m, 1H), 4.36 (d, 2H), 3.87 (m, 1H), 3.61 (m, 1H), 3.08 (s, 3H), 2.83 (s, 1H), 2.77 (s, 1H), 2.01 (m, 1H), 1.95 (s, 3H), 1.05 (m, 2H), 0.83 (m, 2H).

[0150] MS (ESI + ): m / z = 528.21 [M+H] + .

[0151] Example 5: Preparation of N-(3-(4-amino-6-(3-(6-cyclo-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide

[0152] [ka]

[0153] In step 10) of Example 1, 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-cyclopropyl-8-fluoro-2-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoquinolin-1(2H)-one. The same method as in Example 1 was carried out to prepare 103 mg of this compound (yield: 28%).

[0154] 1H-NMR (300MHz, DMSO-d6) δ 8.43 (s, 1H), 7.89~7.84 (m, 2H), 7.59~7.57 (m, 1H), 7.56~7.48 (m, 1H), 7.02~6.97 (d, 1H), 6.65~6.61 (d, 1H), 6.11~6.05 (dd, 1H), 5.63~5.59 (dd, 1H), 4.55~4.48 (d, 2H), 3.01 (s, 2H), 2.85 (s, 1H), 2.10~2.04 (m, 1H), 1.13~1.06 (m, 2H), 0.90~0.86 (m, 2H).

[0155] MS (ESI + ): m / z = 512.18 [M+H] + .

[0156] Example 6: Preparation of N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide

[0157] [ka]

[0158] In step 10 of Example 1, 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-cyclopropyl-8-fluoro-2-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoquinolin-1(2H)-one. The same method as in Example 1 was carried out to prepare 87 mg of this compound (yield: 17%).

[0159] 1H-NMR (300MHz, DMSO-d6) δ 8.40 (s, 1H), 7.38~7.35 (m, 1H), 7.27~7.21 (m, 3H), 7.01~6.96 (m, 1H), 6.74~6.60 (m, 2H), 6.13~6.07 (m, 1H), 5.66~5.56 (m, 1H), 4.39~4.35 (m, 2H), 2.89~2.79 (m, 3H), 2.09~2.01 (m, 1H), 1.80 (s, 3H), 1.11~1.04 (m, 2H), 0.87~0.85 (m, 2H).

[0160] MS (ESI + ): m / z = 526.20 [M+H] + .

[0161] Example 7: Preparation of N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-2,5-difluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide

[0162] [ka]

[0163] In step 10 of Example 1, 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-cyclopropyl-2-(2,5-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoroisoquinolin-1(2H)-one. The same method as in Example 1 was carried out to prepare 3 mg of this compound (yield: 5%).

[0164] 1H-NMR (300MHz, DMSO-d6) δ 8.43 (s, 1H), 7.69 (m, 1H), 7.51 (m, 1H), 7.42 (m, 1H), 7.26 (s, 1H), 7.02 (m, 1H), 6.71 (m, 1H), 6.06 (d, 1H), 5.64 (m, 1H), 4.46 (d, 2H), 3.35 (m, 2H), 3.30 (s, 3H), 2.92 (s, 1H), 2.80 (s, 1H), 2.06 (m, 1H), 1.10 (m, 2H), 0.85 (m, 2H).

[0165] MS (ESI + ): m / z = 530.17 [M+H] + .

[0166] Example 8: Preparation of N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-2,5-dimethylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide

[0167] [ka]

[0168] In step 10) of Example 1, 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-cyclopropyl-2-(2,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoroisoquinolin-1(2H)-one. The same method as in Example 1 was carried out to prepare 18 mg of this compound (yield: 11%).

[0169] 1H-NMR (300MHz, DMSO-d6) δ 8.40 (s, 1H), 7.26~7.16 (m, 4H), 7.00~6.96 (d, 1H), 6.76~6.60 (m, 2H), 6.28~5.91 (m, 1H), 5.72~5.57 (dd, 1H), 4.40~4.21 (d, 2H), 2.88~2.78 (d, 3H), 2.32 (s, 3H), 2.09~2.04 (m, 1H), 1.81 (s, 3H), 1.12~1.06 (m, 2H), 0.89~0.84 (m, 2H).

[0170] MS (ESI + ): m / z = 522.22 [M+H] + .

[0171] Example 9: Preparation of N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)acrylamide

[0172] [ka]

[0173] In step 10 of Example 1, tert-butyl (3-(4-amino-6-chloropyrimidin-5-yl)prop-2-yn-1-yl) (methyl)carbamate was used instead of tert-butyl (3-(4-amino-6-chloropyrimidin-5-yl)prop-2-yn-1-yl)carbamate, and 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was used instead of 6-cyclopropyl-8-fluoro-2-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoquinolin-1(2H)-one. The same method as in Example 1 was carried out to prepare 30 mg of this compound (yield: 6%).

[0174] 1 H-NMR (300MHz, DMSO-d6) δ 8.43~8.41 (m, 2H), 7.40~7.32 (m, 2H), 7.27~7.22 (m, 2H), 7.02~6.97 (m, 1H), 6.65~6.62 (m, 1H), 6.25~6.06 (m, 2H), 5.63 (5.59 (m, 1H), 4.20~4.10 (m, 2H), 2.09~2.03 (m, 1H), 1.82 (s, 3H), 1.12~1.05 (m, 2H), 0.88~0.83 (m, 2H).

[0175] MS (ESI + ): m / z = 512.18 [M+H] + .

[0176] Example 10: Preparation of N-(3-(4-amino-6-(3-(6-(tert-butyl)-8-fluoro-1-oxophthalazin-2-(1H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide

[0177] [ka]

[0178] In step 10 of Example 1, 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-(tert-butyl)-8-fluoro-2-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phthalazin-1(2H)-one. The same method as in Example 1 was carried out to prepare 89 mg of this compound (yield: 23%).

[0179] 1 H-NMR (300MHz, DMSO-d6) δ 8.56 (s, 1H), 8.44 (s, 1H), 8.14~8.11 (m, 1H), 7.87~7.86 (d, 1H), 7.83~7.74 (m, 2H), 7.68~7.63 (td, 1H), 6.84~6.57 (m, 1H), 6.06~6.00 (td, 1H), 5.61~5.57 (d, 1H), 4.55~4.48 (d, 2H), 3.05~2.85 (d, 3H), 1.38 (s, 9H).

[0180] MS (ESI + ): m / z = 515.19 [M+H] + .

[0181] Example 11: Preparation of N-(3-(4-amino-6-(3-(6-cyclopropyl-1-oxophthalazin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide

[0182] [ka]

[0183] In step 10 of Example 1, 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-cyclopropyl-2-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phthalazin-1(2H)-one. The same procedure as in Example 1 was carried out to prepare 63 mg of this compound (yield: 15%).

[0184] 1 H-NMR (300MHz, DMSO-d6) δ 8.45 (s, 1H), 8.40 (s, 1H), 8.18~8.15 (m, 1H), 7.69~7.61 (m, 1H), 7.41~7.38 (m, 1H), 7.28~7.23 (m, 1H), 6.73~6.64 (m, 1H), 6.12~6.01 (m, 1H), 5.69~5.58 (m, 1H), 4.38 (s, 2H), 2.87~2.79 (m, 3H), 2.22~2.13 (m, 1H), 1.81 (s, 3H), 1.17~1.10 (m, 2H), 0.90~0.87 (m, 2H).

[0185] MS (ESI + ): m / z = 509.20 [M+H] + .

[0186] Example 12: Preparation of N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide

[0187] [ka]

[0188] In step 10 of Example 1, 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-cyclopropyl-8-fluoro-2-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phthalazin-1(2H)-one. The same method as in Example 1 was carried out to prepare 32 mg of this compound (yield: 22%).

[0189] 1 H-NMR (300MHz, DMSO-d6) δ 8.42~8.41 (m, 2H), 7.55 (s, 1H), 7.44~7.38 (m, 2H), 7.28~7.23 (m, 1H), 6.73~6.62 (m, 1H), 6.11~6.01 (m, 1H), 5.68~5.58 (m, 1H), 4.38 (s, 2H), 2.87~2.84 (m, 3H), 2.20~2.11 (m, 1H), 1.82 (s, 3H), 1.18~1.11 (m, 2H), 0.94~0.88 (m, 2H).

[0190] MS (ESI + ): m / z = 527.19 [M+H] + .

[0191] Example 13: Preparation of N-(3-(4-amino-6-(3-(6-(tert-butyl)-8-fluoro-1-oxophthalazin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide

[0192] [ka]

[0193] In step 10 of Example 1, 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-(tert-butyl)-8-fluoro-2-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phthalazin-1(2H)-one. The same method as in Example 1 was carried out to prepare 18 mg of this compound (yield: 22%).

[0194] 1 H-NMR (300MHz, DMSO-d6) δ 8.54~8.53 (m, 1H), 8.42 (s, 1H), 7.88 (s, 1H), 7.78~7.73 (m, 1H), 7.42~7.39 (m, 1H), 7.29~7.25 (m, 1), 6.75~6.64 (m, 1H), 6.12~6.03 (m, 1H), 5.70~5.60 (m, 1H), 4.39 (s, 2H), 2.87~2.81 (m, 3H), 1.85 (s, 3H), 1.37 (s, 9H).

[0195] MS (ESI + ): m / z = 543.22 [M+H] + .

[0196] Example 14: Preparation of N-(3-(4-amino-6-(3-(6-tert-butyl)-1-oxophthalazin-2-(1H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide

[0197] [ka]

[0198] In step 10 of Example 1, 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-(tert-butyl)-2-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phthalazin-1(2H)-one. The same method as in Example 1 was carried out to prepare 50 mg of this compound (yield: 20%).

[0199] 1 H-NMR (300MHz, DMSO-d6) δ 8.51 (s, 1H), 8.44 (s, 1H), 8.22-8.19 (d, 1H), 8.16 (s, 1H), 7.82-7.76 (t, 1H), 7.70-7.63 (m, 3H), 6.74-6.54 (m, 1H), 6.07-6.01 (dd, 1H), 5.61-5.56 (dd, 1H), 4.54-4.49 (d, 2H), 3.00-2.83 (d, 3H), 2.27-2.17 (m, 1H), 1.19-1.13 (m, 2H), 0.93-0.89 (m, 2H).

[0200] MS (ESI + ): m / z = 511.22 [M+H] + .

[0201] Example 15: Preparation of N-(3-(4-amino-6-(3-(7-cyclopropyl-5-fluoro-4-oxoquinazolin-3(4H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide

[0202] [ka]

[0203] In step 10 of Example 1, 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 7-cyclopropyl-5-fluoro-3-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one. The same method as in Example 1 was carried out to prepare 26 mg of this compound (yield: 14%).

[0204] 1 H-NMR (300MHz, DMSO-d6) δ 8.53 (s, 1H), 8.48 (s, 1H), 8.42-8.39 (m, 1H), 8.17 (s, 1H), 7.80-7.73 (m, 1H), 7.71-7.66 (m, 3H), 6.70-5.83 (m, 2H), 5.65-5.51 (d, 1H), 4.52-4.46 (d, 2H), 3.01-2.83 (d, 3H), 2.26-2.15 (m, 1H), 1.18-1.13 (m, 2H), 0.93-0.90 (m, 2H).

[0205] MS (ESI + ): m / z = 513.18 [M+H] + .

[0206] Example 16: Preparation of (R)-2-(3-(5-((1-acryloylpyrrolidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinolin-1-(2H)-one

[0207] [ka]

[0208] In step 10 of Example 1, tert-butyl (3-(4-amino-6-chloropyrimidin-5-yl)prop-2-yn-1-yl) (methyl)carbamate was replaced with tert-butyl (R)-2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyrrolidine-1-carboxylate, and 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-cyclopropyl-8-fluoro-2-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoquinolin-1(2H)-one. The same method as in Example 1 was carried out to prepare 40 mg of this compound (yield: 21%).

[0209] 1 H-NMR (300MHz, DMSO-d6) δ 8.42 (s, 1H), 7.41~7.24 (m, 4H), 7.02~6.98 (d, 1H), 6.66~6.64 (m, 1H), 6.54~6.51 (m, 1H), 6.18~6.07 (m, 1H), 5.68~5.48 (m, 1H), 4.96~4.95 (m, 1H), 4.77~4.75 (m, 1H), 3.45~3.32 (m, 2H), 2.13~2.03 (m, 3H), 1.90-1.89 (m, 2H), 1.13~1.06 (m, 2H), 0.89~0.86 (m, 2H).

[0210] MS (ESI + ): m / z = 552.21 [M+H] + .

[0211] Example 17: Preparation of (S)-2-(3-(5-((1-acryloylpyrrolidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinolin-1-(2H)-one

[0212] [ka]

[0213] In step 10 of Example 1, tert-butyl (3-(4-amino-6-chloropyrimidin-5-yl)prop-2-yn-1-yl) (methyl)carbamate was replaced with tert-butyl (S)-2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyrrolidine-1-carboxylate, and 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-cyclopropyl-8-fluoro-2-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoquinolin-1(2H)-one. The same method as in Example 1 was carried out to prepare 42 mg of this compound (yield: 25%).

[0214] 1 H-NMR (300MHz, DMSO-d6) δ 8.42 (s, 1H), 7.41~7.24 (m, 4H), 7.02~6.98 (d, 1H), 6.66~6.64 (m, 1H), 6.54~6.51 (m, 1H), 6.18~6.07 (m, 1H), 5.68~5.48 (m, 1H), 4.96~4.95 (m, 1H), 4.77~4.75 (m, 1H), 3.45~3.32 (m, 2H), 2.13~2.03 (m, 3H), 1.90~1.89 (m, 2H), 1.13~1.06 (m, 2H), 0.89~0.86 (m, 2H).

[0215] MS (ESI + ): m / z = 552.21 [M+H] + .

[0216] Example 18: Preparation of (S)-2-(3-(5-((1-acryloylpyrrolidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-8-fluoro-6-isoquinolin-1-(2H)-one

[0217] [ka]

[0218] In Example 12, 6-cyclopropyl-8-fluoro-2-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)phthalazin-1(2H)-one was replaced with 8-fluoro-2-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)-6-isopropylisoquinolin-1(2H)-one. The same method as in Example 12 was carried out, except that 16 mg of this compound (yield: 22%) was prepared.

[0219] 1 H-NMR (300MHz, DMSO-d6) δ 8.43 (s, 1H), 7.44~7.20 (m, 5H), 6.73~6.53 (m, 2H), 6.20~6.02 (m, 1H), 5.76~5.69 (m, 1H), 4.96~4.76 (m, 1H), 3.15~3.01 (m, 1H), 2.25~1.75 (m, 6H), 1.35~1.20 (d, 6H).

[0220] MS (ESI + ): m / z = 554.23 [M+H] + .

[0221] Example 19: Preparation of (S)-2-(3-(6-amino-5-((1-(2-fluoroacryloyl)pyrrolidin-2-yl)ethynyl)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one

[0222] [ka]

[0223] The same procedure as in Example 12 was carried out, except that 2-fluoroacrylic acid was used instead of acrylic acid, to prepare 19 mg of this compound (yield: 5%).

[0224] 1 H-NMR (300MHz, DMSO-d6) δ8.41 (s, 1H), 7.40~7.23 (m, 4H), 7.00~6.96 (m, 1H), 6.64~6.60 (m, 1H), 5.46~5.28 (m, 2H), 4.77 (m, 1H), 4.43~4.33 (m, 1H), 3.57~3.41 (m, 2H), 2.09~2.01 (m, 2H), 1.85~1.82 (m, 6H), 1.11~1.04 (m, 2H), 0.87~0.82 (m, 2H).

[0225] MS (ESI + ): m / z = 570.20 [M+H] + .

[0226] Example 20: Preparation of (S)-2-(3-(6-amino-5-((1-(2-chloroacryloyl)pyrrolidin-2-yl)ethynyl)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one

[0227] [ka]

[0228] The same procedure as in Example 12 was carried out, except that 2-chloroacrylic acid was used instead of acrylic acid, to prepare 45 mg of this compound (yield: 11%).

[0229] 1 H-NMR (300MHz, DMSO-d6) δ 8.42 (s, 1H), 7.42~7.26 (m, 4H), 7.01~6.96 (m, 1H), 6.64~6.60 (m, 1H), 5.83~5.74 (m, 2H), 4.75 (m, 1H), 4.43~4.34 (m, 1H), 3.51~3.42 (m, 2H), 2.13~2.01 (m, 2H), 1.97~1.82 (m, 6H), 1.11~1.05 (m, 2H), 0.88~0.83 (m, 2H).

[0230] MS (ESI + ): m / z = 586.17 [M+H] + .

[0231] Example 21: Preparation of (S)—N-(3-(5-((1-acryloylpyrrolidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide

[0232] [ka]

[0233] In Example 17, 6-cyclopropyl-8-fluoro-2-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoquinolin-1(2H)-one was replaced with 4-cyclopropyl-2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide. The same procedure as in Example 17 was carried out to prepare 225 mg of this compound (yield: 31%).

[0234] 1H-NMR (300MHz, DMSO-d6) δ 9.70-9.68 (m, 1H), 8.39-8.38 (d, 2H), 7.65-7.64 (m, 1H), 7.61-7.51 (m, 1H), 7.08-7.03 (m, 2H), 6.95-6.94 (m, 1H), 6.52-6.43 (m, 1H), 6.13-6.04 (m, 1H), 5.64-5.53 (m, 1H), 4.87-4.68 (m, 1H), 3.79-3.76 (m, 1H), 2.04-1.95 (m, 3H), 1.79-1.72 (m, 4H), 1.07-1.00 (m, 2H), 0.80-0.75 (m, 2H).

[0235] MS (ESI + ): m / z = 527.22 [M+H] + .

[0236] Example 22: Preparation of 2-(3-(5-((1-acryloylpiperidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-isoquinolin-1(2H)-one

[0237] [ka]

[0238] In step 10 of Example 1, tert-butyl (3-(4-amino-6-chloropyrimidin-5-yl)prop-2-yn-1-yl) (methyl)carbamate was replaced with tert-butyl 2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)piperidine-1-carboxylate, and 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-cyclopropyl-8-fluoro-2-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoquinolin-1(2H)-one. The same method as in Example 1 was carried out to prepare 25 mg of this compound (yield: 13%).

[0239] 1 H-NMR (300MHz, DMSO-d6) δ 8.42 (s, 1H), 7.43~7.39 (m, 2H), 7.35 (s, 1H), 7.34~7.19 (m, 1H), 7.02~6.98 (d, 1H), 6.80~6.71 (q, 1H), 6.65~6.63 (m, 1H), 6.11~6.04 (d, 1H), 5.70~5.62 (t, 1H), 3.80~3.73 (m, 1H), 2.85~2.70 (m, 1H), 2.10~2.03 (m, 1H), 1.80~1.74 (m, 3H), 1.58~1.52 (m, 4H) 1.11~1.06 (t, 2H), 0.88~0.85 (m, 2H).

[0240] MS (ESI + ): m / z = 566.23 [M+H] + .

[0241] Example 23: Preparation of (S)-2-(3-(5-((1-acryloylpiperidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-8-fluoro-6-isopropylisoquinolin-1(2H)-one

[0242] [ka]

[0243] In step 10 of Example 1, tert-butyl (3-(4-amino-6-chloropyrimidin-5-yl)prop-2-yn-1-yl) (methyl)carbamate was replaced with tert-butyl (S)-2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)piperidine-1-carboxylate, and 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylbenzamide was replaced with 6-cyclopropyl-8-fluoro-2-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoquinolin-1(2H)-one. The same method as in Example 1 was carried out to prepare 55 mg of this compound (yield: 16%).

[0244] 1 H-NMR (300MHz, DMSO-d6) δ 8.42 (s, 1H), 7.42~7.30 (m, 2H), 7.27 (s, 1H), 7.22~7.18 (m, 1H), 7.02~6.97 (m, 1H), 6.79~6.70 (m, 1H), 6.65~6.62 (m, 1H), 6.10~6.04 (m, 1H), 5.69~5.62 (m, 1H), 4.45~4.38 (m, 3H), 2.11~2.02 (m, 1H), 1.80~1.73 (m, 3H), 1.55~1.51 (m, 3H), 1.11~1.06 (m, 2H), 0.87~0.86 (m, 2H).

[0245] MS (ESI + ): m / z = 566.23 [M+H] + .

[0246] [Test example] Test Example 1: Confirmation of the inhibitory effect on Bruton's tyrosine kinase (BTK) To determine whether the compounds obtained in the above examples exhibit inhibitory activity against the BTK enzyme, kinase activity inhibition was evaluated. To this end, a Z'-Lyte kinase assay was performed using Thermo Fisher Scientific's SelectScreen profiling service. The test method is summarized as follows:

[0247] The compounds prepared in the above examples were dissolved in DMSO to prepare 10 mM solutions and sent to Thermo Fisher Scientific. According to Thermo Fisher Scientific's protocol, each compound solution was diluted in 100% DMSO to a 100X concentration ranging from 1,000 nM to 0.32 nM (dilution factor 1 / 5). BTK enzyme was then diluted in kinase buffer (50 mM HEPES (pH 7.5), 10 mM MgCl, 1 mM EGTA, 0.01% BRIJ-35) to a concentration of ~10 ng / assay. Assays were performed in low-volume 384-well plates (NBS, black 384-well plates). First, 100 nL of diluted compound solution was added, followed by 2.4 μL of kinase buffer, 5 μL of a 2X concentration mixture of peptide substrate and kinase (as specified in the protocol), and 2.5 μL of 140 μM ATP solution. The mixture was stirred for 30 seconds and then incubated at room temperature for 60 minutes. 5 μL of color-developing solution was then added and stirred for 30 seconds, after which the peptide substrate fluorescence was detected for 60 minutes. After the incubation, fluorescence values ​​(400 nm excitation filter, 445 / 520 nm emission filter) were measured using a fluorescence plate reader. The inhibitory activity of the compound against the kinase reaction was calculated using the Z'-Lyte kinase assay protocol as a phosphorylation inhibition rate of 0-100% relative to the control group, and the concentration at which 50% activity was inhibited was determined as the 50% inhibitory concentration (IC). 50 ) values ​​were calculated. Analysis of results and IC 50The values ​​were calculated using GraphPad Prism, and the results are shown in Table 1 below.

[0248] [Table 1]

[0249] As shown in Table 1 above, the compounds of Examples 1 to 23 exhibited excellent inhibitory activity against the BTK enzyme.

Claims

1. A compound of Formula I, a solvate, stereoisomer, or a pharmaceutically acceptable salt thereof: Chemical I 【Chemical 1】 In the above formula I, W is a substituted or unsubstituted C １ -C ６ alkyl group, substituted or unsubstituted C ２ -C ６ Alkenyl group, substituted or unsubstituted C ２ -C ６ Alkynyl group, substituted or unsubstituted C １ -C ６ an alkoxy group, or a substituted or unsubstituted C ３ -C １０ is a heterocycloalkyl group, R １ , R ２ and R ３ are each independently hydrogen, substituted or unsubstituted C １ -C ６ an alkyl group, or a substituted or unsubstituted C ３ -C １０ is a cycloalkyl group, or R １ is R ２ or R ３ to form a 4- to 7-membered heterocycle together with the atoms to which they are attached, R ６ and R ７ are each independently hydrogen, halogen, or substituted or unsubstituted C １ -C ６ are alkyl groups or are joined together to form, together with the atoms to which they are attached, an unsaturated or partially saturated 5- to 7-membered heteroaryl ring, wherein said heteroaryl ring contains 1 to 3 heteroatoms selected from the group consisting of N, O and S; R ４ , R ５ , R ８ and R ９ are each independently hydrogen, halogen, a cyano group, a hydroxyl group, a thiol group, a nitro group, a substituted or unsubstituted C １ -C ６ alkyl group, substituted or unsubstituted C ２ -C ６ Alkenyl group, substituted or unsubstituted C ２ -C ６ Alkynyl group, substituted or unsubstituted C １ -C ６ Alkoxy group, substituted or unsubstituted C ３ -C ６ a cycloalkyl group, or a substituted or unsubstituted C ３ -C ６ is a heterocycloalkyl group, and The term "substituted or unsubstituted" refers to a halogen, a cyano group, a hydroxyl group, a thiol group, a nitro group, a C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ３ -C １０ Cycloalkyl group, C ３ -C １０ Heterocycloalkyl group, C ３ -C １０ aryl groups, and C １ -C １０ It is substituted with a substituent selected from heteroaryl groups or does not have any substituents.

2. W is a substituted or unsubstituted C ２ -C ６ is an alkenyl group, R １ , R ２ and R ３ are each independently hydrogen or substituted or unsubstituted C １ -C ６ alkyl group or R １ is R ２ or R ３ to form a 4- to 7-membered heterocycle together with the atoms to which they are attached, R ６ and R ７ are each independently hydrogen, halogen, or substituted or unsubstituted C １ -C ６ are alkyl groups or are joined together to form, together with the atoms to which they are attached, an unsaturated or partially saturated 6-membered heteroaryl ring, wherein said heteroaryl ring contains 1 to 3 nitrogen atoms; and R ４ , R ５ , R ８ and R ９ are each independently hydrogen, halogen, substituted or unsubstituted C １ -C ６ an alkyl group, or a substituted or unsubstituted C ３ -C ６ 2. The compound of formula I according to claim 1, a solvate, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein: R is a cycloalkyl group.

3. W is a substituted or unsubstituted C ２ -C ６ is an alkenyl group, R １ , R ２ and R ３ are each independently hydrogen or substituted or unsubstituted C １ -C ３ alkyl group or R １ is R ２ or R ３ to form a 4- to 7-membered azacyclic ring together with the atom to which they are attached; R ４ and R ５ are each independently hydrogen, halogen, or substituted or unsubstituted C １ -C ３ is an alkyl group, R ６ and R ７ are each independently hydrogen, halogen, or substituted or unsubstituted C １ -C ３ are alkyl groups or are joined together to form, together with the atom to which they are attached, an unsaturated or partially saturated 6-membered heteroaryl ring, wherein said heteroaryl ring contains 1 to 3 nitrogen atoms; R ８ is hydrogen, halogen, substituted or unsubstituted C １ -C ６ an alkyl group, or a substituted or unsubstituted C ３ -C ６ is a cycloalkyl group, and R ９ is hydrogen, halogen, or substituted or unsubstituted C １ -C ３ 2. The compound of formula I according to claim 1, a solvate, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group.

4. W is 【Chemistry 2】 and R ｘ , R ｙ and R ｚ are each independently hydrogen, halogen, substituted or unsubstituted C １ -C ６ an alkyl group, a cyano group, or -(CH ２ ) ｎ -NR １０ R １１ and n is an integer from 0 to 6, and R １０ and R １１ are each independently a substituted or unsubstituted C １ -C ６ 2. The compound of formula I according to claim 1, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the alkyl groups are alkyl groups or are linked together to form a 4- to 7-membered azacyclic ring together with the nitrogen atom to which they are attached.

5. R ｘ is hydrogen, halogen, or substituted or unsubstituted C １ -C ３ is an alkyl group, R ｙ is hydrogen, halogen, substituted or unsubstituted C １ -C ３ Alkyl group, or -(CH ２ ) ｎ -NR １０ R １１ and R ｚ is hydrogen, halogen, substituted or unsubstituted C １ -C ６ an alkyl group or a cyano group, n is an integer of 0 or 1, and R １０ and R １１ are each independently a substituted or unsubstituted C １ -C ３ 5. The compound of formula I according to claim 4, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the alkyl groups are alkyl groups or are linked together to form a 4- to 7-membered azacyclic ring together with the nitrogen atom to which they are attached.

6. 2. The compound of formula I of claim 1, wherein the compound of formula I is a compound of formula Ia: Chemical formula Ia 【Chemistry 3】 In the above formula Ia, W, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ８ and R ９ is as defined in claim 1.

7. 2. The compound of formula I of claim 1, a solvate, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula Ib: Chemical Ib 【Chemistry 4】 In the above formula Ib, X １ and X ２ are each independently -C(R １２ ) ２ -, -CR １２ - or -N-; 【Chemistry 5】 is a single or double bond, R １２ is hydrogen or substituted or unsubstituted C １ -C ６ is an alkyl group, and W.R. １ , R ２ , R ３ , R ４ , R ５ , R ８ and R ９ is as defined in claim 1.

8. The compound of formula I according to claim 1, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from the group consisting of the following compounds 1) to 23): 1) N-(3-(6-amino-5-(3-N-methylacrylamido)prop-1-yn-1-yl)pyrimidin-4-yl)5-fluoro-2-methylphenyl)-2-fluoro-4-isopropylbenzamide; 2) N-(3-(6-amino-5-(3-N-methylacrylamido)prop-1-yn-1-yl)pyrimidin-4-yl)5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; 3) N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide; 4) N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide; 5) N-(3-(4-amino-6-(3-(6-cyclo-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide; 6) N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide; 7) N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-2,5-difluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide; 8) N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-2,5-dimethylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide; 9) N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)acrylamide; 10) N-(3-(4-amino-6-(3-(6-(tert-butyl)-8-fluoro-1-oxophthalazin-2-(1H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide; 11) N-(3-(4-amino-6-(3-(6-cyclopropyl-1-oxophthalazin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide; 12) N-(3-(4-amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide; 13) N-(3-(4-amino-6-(3-(6-(tert-butyl)-8-fluoro-1-oxophthalazin-2(1H)-yl)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide; 14) N-(3-(4-amino-6-(3-(6-tert-butyl)-1-oxophthalazin-2-(1H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide; 15) N-(3-(4-amino-6-(3-(7-cyclopropyl-5-fluoro-4-oxoquinazolin-3(4H)-yl)-5-fluorophenyl)pyrimidin-5-yl)prop-2-yn-1-yl)-N-methylacrylamide; 16) (R)-2-(3-(5-((1-acryloylpyrrolidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one; 17) (S)-2-(3-(5-((1-acryloylpyrrolidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one; 18) (S)-2-(3-(5-((1-acryloylpyrrolidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-8-fluoro-6-isoquinolin-1-(2H)-one; 19) (S)-2-(3-(6-amino-5-((1-(2-fluoroacryloyl)pyrrolidin-2-yl)ethynyl)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one; 20) (S)-2-(3-(6-amino-5-((1-(2-chloroacryloyl)pyrrolidin-2-yl)ethynyl)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one; 21) (S)—N-(3-(5-((1-acryloylpyrrolidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; 22) 2-(3-(5-((1-acryloylpiperidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6-cyclopropyl-8-isoquinolin-1(2H)-one; and 23) (S)-2-(3-(5-((1-acryloylpiperidin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-8-fluoro-6-isopropylisoquinolin-1(2H)-one.

9. A pharmaceutical composition for preventing or treating a Bruton's tyrosine kinase (BTK)-mediated disease, comprising the compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 as an active ingredient, The pharmaceutical composition, wherein the BTK-mediated disease is an autoimmune disease or cancer.

10. 10. The pharmaceutical composition of claim 9, wherein the composition exhibits inhibitory activity against Bruton's tyrosine kinase (BTK).

11. The autoimmune diseases include rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, myasthenia gravis, Hashimoto's thyroiditis, iodothyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, nystagmus-clonic syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, ophthalmopathy, and ophthalmopathy.

10. The pharmaceutical composition of claim 9, wherein the disease is any one selected from the group consisting of neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, autonomic nervous system dysfunction, asthma, chronic spontaneous urticaria, pemphigus, systemic lupus erythematosus, hidradenitis, skin rot, immunoglobulin G4-related disease, endometriosis, interstitial cystitis, neuromyotonia, and vulvodynia.

12. 10. The pharmaceutical composition of claim 9, wherein the cancer is a B-cell malignancy.

13. 10. The pharmaceutical composition of claim 9, wherein the composition is formulated in the form of a tablet, pill, powder, capsule, syrup, emulsion, or microemulsion.

14. 10. A method for preventing or treating a Bruton's tyrosine kinase (BTK)-mediated disease, comprising administering to an individual in need thereof a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, The method, wherein the BTK-mediated disease is an autoimmune disease or cancer.

15. 10. Use of a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 for the manufacture of a medicament for the prevention or treatment of a Bruton's tyrosine kinase (BTK)-mediated disease, comprising: The BTK-mediated disease is an autoimmune disease or cancer.

Images