Method for producing modified BTK inhibitor

Abstract

This specification provides a BTK inhibitor containing piperidine modified at the 3-position. Furthermore, methods for preparing and using the BTK inhibitor are disclosed.

Description

Technical Field

[0001] The present disclosure relates to BTK inhibitors and methods of preparing and using them. The BTK inhibitor has a piperidine ring substituted at the 3-position. For example, the BTK inhibitor can be a compound of formulas (1)-(9):

Chemical formula

Background Art

[0002] The enzyme BTK is a member of the Tec family of non-receptor tyrosine kinases. BTK is expressed in most hematopoietic cells, including B cells, mast cells, and macrophages. BTK plays a role in the development and activation of B cells. BTK activity is involved in the etiology of several disorders and conditions, including B cell-related blood cancers (such as non-Hodgkin lymphoma and B cell chronic lymphocytic leukemia) and autoimmune diseases (such as multiple sclerosis, rheumatoid arthritis, lupus, immune thrombocytopenia (ITP), rheumatoid arthritis, Sjögren's syndrome, pemphigus, inflammatory bowel disease (IBD), lupus nephritis, atopic dermatitis, warm autoimmune hemolytic anemia, asthma and other acute respiratory distress, and chronic idiopathic urticaria, etc.).

[0003] Therefore, a pharmaceutical composition containing a therapeutically effective amount of a BTK inhibitor can be useful for the treatment of certain cancers and autoimmune diseases.

[0004] When treating certain cancers and autoimmune diseases with BTK inhibitors, it is also desirable that the BTK inhibitors can be readily absorbed by the body and administered in a storage-stable form. The pharmaceutically active substance used to prepare the therapeutic agent should be as pure as possible, and its stability in long-term storage should be ensured under various environmental conditions. These properties are useful for preventing the appearance of unintended degradation products in the pharmaceutical composition, which may potentially be toxic or simply reduce the efficacy of the composition.

[0005] One factor in the suitability of an inhibitor compound as a therapeutic agent is its ability to interact with a binding site on a protein target that allows for at least one of more selective, specific, and stronger binding. The metabolism of piperidine-containing BTK inhibitors has the potential to cause ring-opening of the piperidine, which may reduce its binding affinity for C481 sulfhydryl, and as a result, the overall drug efficacy is reduced. Therefore, structural modifications of BTK inhibitors that can prevent or modify this ring-opening process are focused on, for example, certain substitutions at the 3-position of the piperidine moiety. Without being bound by theory, it is believed that by providing a substitution at the 3-position of the piperidine, this substitution provides stability and / or rigidity to the ring structure that can prevent metabolism and / or degradation of the ring structure.

Summary of the Invention

Means for Solving the Problems

[0006] Accordingly, the present disclosure relates to BTK inhibitors and methods for preparing and using them, where the BTK inhibitor has a piperidine ring substituted at the 3-position. For example, the BTK inhibitor is a compound of formulas (1)-(9):

Chemical formula

[0007] Further objects and advantages will be in part described in the following description, be in part understood from this description, or be recognized by practice. The objects and advantages will be realized and achieved by the elements and combinations specifically recited in the appended claims.

[0008] It should be understood that both the foregoing general description and the following detailed description are merely exemplary and explanatory and are not restrictive of the claims.

[0009] The accompanying drawings incorporated herein and constituting a part of this specification illustrate one (some) embodiments and together with the specification serve to explain the principles described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0010] Definitions Unless otherwise specified, the following terms used in this specification and the claims are defined for the purposes of this disclosure and have the following meanings:

[0011] As used herein, "BTK inhibitor", "BTK inhibitor compound", "compounds of formulas (1)-(9)", and "compounds (1)-(9)" have the following structures:

CHEMICAL

[0012] As used herein, the terms "comprising" and "including" may be used interchangeably. The terms "comprising" and "including" should be construed as indicating the presence of the features or components described as such, but not precluding the presence or addition of one or more features, or components, or groups thereof. In addition, the terms "comprising" and "including" are intended to include examples subsumed by the term "consisting of". Accordingly, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0013] The term "consisting of" means that the subject has at least 90%, 95%, 97%, 98% or 99% of the described features or components of which it consists. In another embodiment, the term "consisting of" excludes any other features or components from any subsequent listing of scope, except for those that are not essential to the technical effect to be achieved.

[0014] As used herein, the term "or" should be construed as an inclusive "or" meaning any one or any combination. Thus, "A, B or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B and C". An exception to this definition occurs only when the combination of elements, functions, steps or acts are mutually exclusive in some way.

[0015] As used herein, "the 3-position of piperidine" and "a piperidine ring substituted at the 3-position" mean the position denoted by "3" as shown below: [Chemical formula]

[0016] An "alkyl" group has 1 to 10 carbon atoms (C1-C 10alkyl), typically having 1 to 8 carbon atoms (C1-C8 alkyl), or in some embodiments, 1 to 6 (C1-C6 alkyl), 1 to 3 (C1-C3 alkyl), or 2 to 6 (C2-C6 alkyl) carbon atoms, which is a saturated, partially saturated, or unsaturated straight-chain or branched acyclic hydrocarbon. In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl, while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. In some embodiments, the alkyl group is an unsaturated alkyl group, also referred to as an alkenyl group or an alkynyl group. A small alkyl group refers to an alkyl group having 1 to 4 carbons. In certain embodiments, when the alkyl groups described herein are said to be "substituted", they are any substituents as found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or can be substituted with O(alkyl)aminocarbonyl.

[0017] "Halogen" or "halo" is fluorine, chlorine, bromine, or iodine.

[0018] The "hydroxy" group is -OH.

[0019] An "alkoxy" group is -O-(alkyl), where alkyl is defined above.

[0020] Embodiments of the present disclosure are intended to encompass stereoisomers of the compounds provided herein, such as the compounds of formula (9).

[0021] As used herein, unless otherwise indicated, the terms "stereoisomer" or "stereoisomerically pure" mean one stereoisomer of a particular compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomer of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomer of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomer of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound. The compounds disclosed herein can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the embodiments disclosed herein.

[0022] The use of stereoisomerically pure forms of the compounds disclosed herein, as well as the use of mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers: Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0023] It should also be noted that the compounds disclosed herein may include E and Z isomers, or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In certain embodiments, the compound is isolated as either the E or Z isomer. In other embodiments, the compound is a mixture of the E and Z isomers.

[0024] If there is a conflict between the illustrated structure and the name of that structure, the illustrated structure shall be given more weight.

[0025] Compound In some embodiments, the present disclosure relates to a compound of formula (1): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein X is selected from -OH, -OY, -Y2, and -(halo)2, and Y is C1-C4 alkyl optionally substituted with 1-3 halos. In some embodiments, Y is selected from methyl, ethyl, CH(halo)2, and C(halo)3. In some embodiments, halo is F.

[0026] In some embodiments, the present disclosure relates to a compound of formula (2): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein X is selected from -OH, -OY, -Y2, and -(halo)2, and Y is C1-C4 alkyl optionally substituted with 1-3 halos. In some embodiments, Y is selected from methyl, ethyl, CH(halo)2, and C(halo)3. In some embodiments, halo is F.

[0027] In some embodiments, the present disclosure relates to a compound of formula (3): [Chemical formula] Regarding or its pharmaceutically acceptable salt, in the formula, X is selected from -OH, -OY, -Y2, and -(halo)2, and Y is C1-C4 alkyl optionally substituted with 1 to 3 halos. In some embodiments, Y is selected from methyl, ethyl, CH(halo)2, and C(halo)3. In some embodiments, halo is F.

[0028] In some embodiments, the present disclosure relates to a compound of formula (4):

Chemical formula

[0029] In some embodiments, the present disclosure relates to a compound of formula (5):

Chemical formula

[0030] In some embodiments, the present disclosure relates to a compound of formula (6):

Chemical formula

[0031] In some embodiments, the present disclosure relates to a compound of formula (7):

Chemical formula

[0032] In some embodiments, the present disclosure relates to a compound of formula (8):

Chemical formula

[0033] In some embodiments, the present disclosure relates to a compound of formula (9):

Chemical formula

[0034] In some embodiments, the present disclosure relates to compounds selected from Table 1 or their pharmaceutically acceptable salts. Certain compounds described in the present disclosure including Table 1 are presented as specific stereoisomers and / or in non-stereochemical forms, but it is understood that any and all stereochemical forms including any enantiomeric or diastereomeric forms, and any tautomeric or other forms of any of the compounds of the present disclosure including Table 1 are described herein.

[0035]

Table 1

[0036]

Table 2

[0037]

Table 3

[0038]

Table 4

[0039]

Table 5

[0040]

Table 6

[0041]

Table 7

[0042]

Table 8

[0043]

Table 9

[0044] or a pharmaceutically acceptable salt thereof.

[0045] It is understood herein that combinations of substituents and / or variables of the indicated formulas are only permitted if such combinations result in stable compounds.

[0046] Furthermore, all compounds of Formulas (1)-(9) that exist in the free base or acid form can be converted into their pharmaceutically acceptable salts by treatment with a suitable inorganic or organic base or acid by methods known to those skilled in the art. The salts of the compounds of Formulas (1)-(9) can be converted into their free base or acid forms by standard techniques.

[0047] In some embodiments, the present disclosure relates to a composition comprising a pharmaceutically acceptable excipient and at least one compound selected from any one of the compounds described herein.

[0048] In some embodiments, the present disclosure relates to a method of treating a disease or disorder mediated by BTK, the method comprising administering to a patient in need thereof an effective amount of a compound selected from any one of the compounds described herein, or administering a composition as described herein.

[0049] The compounds described in this specification can be prepared using conventional organic compounds and commercially available starting materials, or the methods provided in this specification. It should be noted that those skilled in the art know the procedures described in the exemplary schemes and examples for reaching the desired products.

Examples

[0050] The following examples are presented for illustrative purposes only, not by way of limitation. In naming the compounds, an automated name generation tool provided by ChemBiodraw Ultra (Cambridgesoft) is used, which aids in the Cahn-Ingold-Prelog rules of stereochemistry to generate systematic names for chemical structures. Those skilled in the art can modify the procedures described in the illustrative examples to reach the desired products.

[0051] The salts of the compounds described in this specification can be prepared by standard methods such as the inclusion of an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or by stirring the product in an acid solution (e.g., aqueous HCl) after chromatographic purification.

[0052] The following abbreviations may be relevant to this application. Abbreviations Boc: tert-butyloxycarbonyl DAST: diethylaminosulfur trifluoride DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DEAD: diethyl azodicarboxylate DIPEA: diisopropylethylamine DMF: dimethylformamide DMSO: dimethyl sulfoxide EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOH: ethanol HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, hexafluorophosphate azabenzotriazolium tetramethyluronium HOBt: Hydroxybenzotriazole i-PrOH: Isopropyl alcohol mCPBA: Meta-chloroperbenzoic acid MeOH: Methanol Pd(dppf)Cl2: [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride SFC: Supercritical fluid chromatography TBTU: 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate TEA: Triethylamine TEMPO: (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl TFA: Trifluoroacetic acid THF: Tetrahydrofuran tol: Toluene

[0053] Example S1. 1-((3R,5R)-3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-hydroxypiperidin-1-yl)prop-2-en-1-one (1-A)

Chem.

[0054] Example S2. 1-((3R,5R)-3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-methoxypiperidin-1-yl)prop-2-en-1-one (1-B) [Chemical formula] In toluene and water, to a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-a), (4-phenoxyphenyl)boronic acid (1-b), Pd(dppf)Cl2, and K3PO4 are added. By stirring the reaction solution at 90 - 100 °C, 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-c) is obtained. 1-c is dissolved in THF and cooled to 0 °C, where tert-butyl (3S,5R)-3-hydroxy-5-methoxypiperidine-1-carboxylate (1-i), diethyl azodicarboxylate, and triphenylphosphine are added. The reaction solution is stirred at room temperature to obtain tert-butyl (3R,5R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-methoxypiperidine-1-carboxylate (1-j). Deprotection of the Boc-protected amine of 1-j under acidic conditions gives 1-((3R,5R)-5-methoxypiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-k), which is then reacted with acryloyl chloride (1-g) in dichloromethane in the presence of N,N-diisopropylethylamine base to obtain 1-((3R,5R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-methoxypiperidin-1-yl)prop-2-en-1-one (1-B).

[0055] Example S3. (R)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-dimethylpiperidin-1-yl)prop-2-en-1-one (1-C) [Chemical formula] To a solution of toluene and 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-a) in water, (4-phenoxyphenyl)boronic acid (1-b), Pd(dppf)Cl2, and K3PO4 are added. By stirring the reaction solution at 90 - 100 °C, 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-c) is obtained. 1-c is dissolved in THF and cooled to 0 °C, where tert-butyl (S)-5-hydroxy-3,3-dimethylpiperidine-1-carboxylate (1-l), diethyl azodicarboxylate, and triphenylphosphine are added. The reaction solution is stirred at room temperature to obtain tert-butyl (R)-5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (1-m). Deprotection of the Boc-protected amine of 1-m under acidic conditions gives (R)-1-(5,5-dimethylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-n), which is then reacted with acryloyl chloride (1-g) in dichloromethane in the presence of N,N-diisopropylethylamine base to obtain (R)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-dimethylpiperidin-1-yl)prop-2-en-1-one (1-C).

[0056] Example S4. (R)-1-(5-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-difluoropiperidin-1-yl)prop-2-en-1-one (1-D)

Chemical formula

[0057] Example S5. 4-Amino-1-((3S,5R)-1-(2-fluoroacryloyl)-5-hydroxypiperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2-A)

Chemical Structure

[0058] Example S6. 4-Amino-1-((3S,5R)-1-(2-fluoroacryloyl)-5-methoxypiperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2-B) [Chemical formula] To a solution of 2,4-dichloro-3-nitropyridine (2-a) and triethylamine in DMF, tert-butyl (3R,5R)-3-amino-5-methoxypyridine-1-carboxylate (2-m) is added. The reaction solution is stirred at room temperature to obtain tert-butyl (3R,5R)-3-((2-chloro-3-nitropyridin-4-yl)amino)-5-methoxypiperidine-1-carboxylate (2-n), which is reacted with bis(4-methoxybenzyl)amine (2-o) and a triethylamine base in isopropyl alcohol to obtain tert-butyl (3R,5R)-3-methoxy-5-((2-((4-methoxybenzyl)(4-methylbenzyl)amino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (2-p). 2-p is reacted with Fe in AcOH / MeOH to reduce its nitro group, and then reacted with carbonyldiimidazole in acetonitrile to form tert-butyl (3S,5R)-3-(4-(bis(4-methoxybenzyl)amino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-5-methoxypiperidine-1-carboxylate (2-q). 2-q undergoes a cross-coupling reaction with (4-phenoxyphenyl)boronic acid (1-b), Cu(OAc)2, TEMPO, and triethylamine in dichloromethane to obtain tert-butyl (3S,5R)-3-(4-(bis(4-methoxybenzyl)amino)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-5-methoxypiperidine-1-carboxylate (2-r).The Boc-protected amine of 2-r is deprotected under acidic conditions to obtain 4-amino-1-((3S,5R)-5-methoxypiperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2-s), and the free amine of 2-s is reacted with 2-fluoroacryloyl chloride (2-k) in dichloromethane in the presence of triethylamine base to obtain 4-amino-1-((3S,5R)-1-(2-fluoroacryloyl)-5-methoxypiperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2-B).

[0059] Example S7. (S)-4-Amino-1-(1-(2-fluoroacryloyl)-5,5-dimethylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]piperidin-2-one (2-C)

Chemical formula

[0060] Example S8. (S)-4-Amino-1-(5,5-difluoro-1-(2-fluoroacryloyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2-D)

Chemical formula

[0061] Example S9. 1-((3S,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (3-A) [Chemical Structure] To a solution of 2,4-dichloro-3-nitropyridine (2-a) in DMF, (3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-amine (2-b) is added. The reaction solution is stirred at room temperature to obtain N-((3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-2-chloro-3-nitropyridin-4-amine (2-c), which is dissolved in DMF and reacted with 1,3-dioxoisoindoline-2-idocarboxylic acid potassium salt (2-d) to obtain 2-(4-(((3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)amino)-3-nitropyridin-2-yl)isoindoline-1,3-dione (2-e). 2-e is reacted with zinc and NH4Cl in THF / H2O to reduce its nitro group, and then reacted with carbonyldiimidazole in acetonitrile to form 2-(1-((3S,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-4-yl)isoindoline-1,3-dione (2-f). 2-f undergoes a cross-coupling reaction with (4-phenoxyphenyl)boronic acid (1-b), Cu(OAc)2, TEMPO, and triethylamine in dichloromethane to obtain 2-(1-((3S,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-4-yl)isoindoline-1,3-dione (2-h).By reacting with hydrazine in ethanol, the 2-h phthalimide-protected amine is deprotected to obtain 4-amino-1-((3S,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2-i). By reacting 2-i with H2 and Pd / C in MeOH, the remaining benzyl-protected amine is deprotected to obtain 4-amino-1-((3S,5R)-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2-j). 2-j is reacted with acryloyl chloride (1-g) in the presence of triethylamine in dichloromethane to obtain 1-((3S,5R)-1-acryloyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (3-b). The tert-butyldimethylsilyl-protected alcohol of 3-b is deprotected under acidic conditions to obtain 1-((3S,5R)-1-acryloyl-5-hydroxypiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (3-A).

[0062] Example S10. 1-((3S,5R)-1-Acryloyl-5-methoxypiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (3-B)

Chemical Structure

[0063] Example S11. (S)-4-Amino-1-(1-(2-fluoroacryloyl)-5,5-dimethylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]piperidin-2-one (3-C)

Chemical formula

[0064] Example S12. (S)-4-Amino-1-(5,5-difluoro-1-(2-fluoroacryloyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (3-D)

Chemical formula

[0065] Example S13. (E)-2-((3R,5R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyridin-1-yl)-5-hydroxypiperidin-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)penta-2-enenitrile (4-A) [Chemical formula] To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-a) in toluene and water, (2-fluoro-4-phenoxyphenyl)boronic acid (4-a), Pd(dppf)Cl2, and K3PO4 are added. The reaction solution is stirred at 90 - 100 °C to obtain 3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-b). 4-b is dissolved in THF and cooled to 0 °C, where (3S,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-ol (1-d), diethyl azodicarboxylate, and triphenylphosphine are added. The reaction solution is stirred at room temperature to obtain 1-((3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-d). 4-d is dissolved in ethyl acetate and hydrogenated with H2 and Pd / C to obtain 1-((3R,5R)-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-e). 4-e is reacted with (E)-2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)penta-2-enoic acid (4-f) in DMF in the presence of HATU and diisopropylethylamine base to obtain (E)-2-((3R,5R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-((tert-butyldimethylsilyl)oxy)piperidin-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)penta-2-enenitrile (4-g).Deprotection of the 4-g tert-butyldimethylsilyl-protected alcohol with tetrabutylammonium fluoride in THF gives (E)-2-((3R,5R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyridin-1-yl)-5-hydroxypiperidin-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)penta-2-enenitrile (4-A).

[0066] Example S14. (E)-2-((3R,5R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-methoxypiperidin-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)penta-2-enenitrile (4-B)

Chemical Structure

[0067] Example S15. (R,E)-2-(5-(4-Amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-dimethylpiperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)penta-2-enenitrile (4-C) [Chemical formula] To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-a) in toluene and water, (2-fluoro-4-phenoxyphenyl)boronic acid (4-a), Pd(dppf)Cl2, and K3PO4 are added. The reaction solution is stirred at 90 - 100 °C to obtain 3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-b). 4-b is dissolved in THF, cooled to 0 °C, and here, tert-butyl (S)-5-hydroxy-3,3-dimethylpiperidine-1-carboxylate (1-l), diethyl azodicarboxylate, and triphenylphosphine are added. The reaction solution is stirred at room temperature to obtain tert-butyl (R)-5-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (4-j). The Boc-protected amine of 4-j is deprotected under acidic conditions to obtain (R)-1-(5,5-dimethylpiperidin-3-yl)-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-k), and the free amine of 4-k is reacted with (E)-2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)penta-2-enoic acid (4-f) in DMF in the presence of HATU and diisopropylethylamine base to obtain (R,E)-2-(5-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-dimethylpiperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)penta-2-enenitrile (4-C).

[0068] Example S16. (R,E)-2-(5-(4-Amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)penta-2-enenitrile (4-D) [Chemical formula] To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-a) in toluene and water, (2-fluoro-4-phenoxyphenyl)boronic acid (4-a), Pd(dppf)Cl2, and K3PO4 are added. The reaction solution is stirred at 90 - 100 °C to obtain 3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-b). 4-b is dissolved in THF and cooled to 0 °C, where tert-butyl (S)-3,3-difluoro-5-hydroxypiperidine-1-carboxylate (1-o), diethyl azodicarboxylate, and triphenylphosphine are added. The reaction solution is stirred at room temperature to obtain tert-butyl (R)-5-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-difluoropiperidine-1-carboxylate (4-l). The Boc-protected amine of 4-l is deprotected under acidic conditions to obtain (R)-1-(5,5-difluoropiperidin-3-yl)-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-m), and the free amine of 4-m is reacted with (E)-2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)penta-2-enoic acid (4-f) in DMF in the presence of HATU and diisopropylethylamine base to obtain (R,E)-2-(5-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)penta-2-enenitrile (4-D).

[0069] Example S17. (E)-2-((3R,5R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-hydroxypiperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (5-A) [Chemical formula] To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-a) in toluene and water, (2-fluoro-4-phenoxyphenyl)boronic acid (4-a), Pd(dppf)Cl2, and K3PO4 are added. The reaction solution is stirred at 90 - 100 °C to obtain 3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-b). 4-b is dissolved in THF, cooled to 0 °C, and here, (3S,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-ol (1-d), diethyl azodicarboxylate, and triphenylphosphine are added. The reaction solution is stirred at room temperature to obtain 1-((3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-d). 4-d is dissolved in ethyl acetate and hydrogenated with H2 and Pd / C to obtain 1-((3R,5R)-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-e). 4-e is coupled with (E)-2-cyano-4,4-dimethylpent-2-enoic acid (5-a) in dichloromethane in the presence of EDCI, HOBt, and triethylamine base to obtain (E)-2-((3R,5R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-((tert-butyldimethylsilyl)oxy)piperidin-1-carbonyl)-4,4-dimethylpent-2-enenitrile (5-b). Deprotection of the tert-butyldimethylsilyl-protected alcohol of 5-b under acidic conditions gives (E)-2-((3R,5R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-hydroxypiperidin-1-carbonyl)-4,4-dimethylpent-2-enenitrile (5-A).

[0070] Example S18. (E)-2-((3R,5R)-3-(4-Amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-methoxypiperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (5-B)

Chemical formula

[0071] Example S19. (E)-2-((3R,5R)-3-(4-Amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-methoxypiperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (5-C)

Chemical formula

[0072] Example S20. (R,E)-2-(5-(4-Amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (5-D) [Chemical formula] To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-a) in toluene and water, (2-fluoro-4-phenoxyphenyl)boronic acid (4-a), Pd(dppf)Cl2, and K3PO4 are added. The reaction solution is stirred at 90 - 100 °C to obtain 3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-b). 4-b is dissolved in THF and cooled to 0 °C, where tert-butyl (S)-3,3-difluoro-5-hydroxypiperidine-1-carboxylate (1-o), diethyl azodicarboxylate, and triphenylphosphine are added. The reaction solution is stirred at room temperature to obtain tert-butyl (R)-5-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-difluoropiperidine-1-carboxylate (4-l). The Boc-protected amine of 4-l is deprotected under acidic conditions to obtain (R)-1-(5,5-difluoropiperidin-3-yl)-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-m), and the free amine of 4-m is reacted with (E)-2-cyano-4,4-dimethylpent-2-enoic acid (5-a) in dichloromethane in the presence of EDCI, HOBt, and triethylamine base to obtain (R,E)-2-(5-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (5-D).

[0073] Example S21.1 - (4 - ((((6 - Amino - 5 - (4 - phenoxyphenyl)pyrimidin - 4 - yl)amino)methyl) - 3 - hydroxypiperidin - 1 - yl)prop - 2 - en - 1 - one (6 - A))

Chemical Structure

[0074] Example S22.1 - (4 - ((((6 - Amino - 5 - (4 - phenoxyphenyl)pyrimidin - 4 - yl)amino)methyl) - 3 - methoxypiperidin - 1 - yl)prop - 2 - en - 1 - one (6 - B))

Chemical Structure

[0075] Example S23. 1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3,3-dimethylpiperidin-1-yl)prop-2-en-1-one (6-C)

Chemical Structure

[0076] Example S24. 1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3,3-dimethylpiperidin-1-yl)prop-2-en-1-one (6-D)

Chemical formula

[0077] Example S25. 4-((3S,5S)-3-(but-2-ynamido)-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-A)

Chemical Structure

[0078] Example S26. 4-((3S,5S)-3-(but-2-ynamido)-5-methoxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-B)

Chemical Structure

[0079] Example S27. (S)-4-(5-(but-2-ynamido)-3,3-dimethylpiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-C)

Chem.

[0080] Example S28. (S)-4-(5-(but-2-ynamido)-3,3-difluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-D)

Chem.

[0081] Example S29. 6-(1-Acryloyl-3-hydroxypiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-A)

Chemical Structure

[0082] Example S30. 6-(1-Acryloyl-3-methoxypiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-B)

Chemical formula

[0083] Example S31. 6-(1-Acryloyl-3,3-dimethylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-C) [Chem.] To a solution of 6-chloro-2-(4-phenoxyphenyl)nicotinamide (8-a) in dioxane and water are added (1-(tert-butoxycarbonyl)-3,3-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (8-n), Pd(dppf)Cl2, and Na2CO3. By stirring the reaction solution at 90 - 100 °C, tert-butyl 5-carbamoyl-3',3'-dimethyl-6-(4-phenoxyphenyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (8-o) is obtained. 8-o undergoes reaction with H2 and Pd / C in MeOH to give tert-butyl 4-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)-3,3-dimethylpiperidine-1-carboxylate (8-p). 8-p is deprotected with TFA in dichloromethane to give 6-(3,3-dimethylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-q). 8-q is then reacted with acryloyl chloride (1-g) in the presence of sodium bicarbonate base in THF / H2O to give 6-(1-acryloyl-3,3-dimethylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-C).

[0084] Example S32. 6-(1-Acryloyl-3,3-difluoropiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-D) [Chem.] To a solution of dioxane and 6-chloro-2-(4-phenoxyphenyl)nicotinamide (8-a) in water, (1-(tert-butoxycarbonyl)-3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (8-r), Pd(dppf)Cl2, and Na2CO3 are added. By stirring the reaction solution at 90 - 100 °C, tert-butyl 5-carbamoyl-3’,3’-difluoro-6-(4-phenoxyphenyl)-3’,6’-dihydro-[2,4’-bipyridine]-1’(2’H)-carboxylate (8-s) is obtained. 8-s is reacted with H2 and Pd / C in MeOH to obtain tert-butyl 4-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)-3,3-difluoropiperidine-1-carboxylate (8-t). 8-t is deprotected with TFA in dichloromethane to obtain 6-(3,3-difluoropiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-u). 8-u is then reacted with acryloyl chloride (1-g) in THF / H2O in the presence of sodium bicarbonate base to obtain 6-(1-acryloyl-3,3-difluoropiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-D).

[0085] Example S33. (S)-7-((3R,4R)-1-acryloyl-3-hydroxypiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)-7-((3R,4S)-1-acryloyl-3-hydroxypiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (9-A and 9-A’)

Chemical formula

[0086] Example S34. ((7S)-7-(1-Acryloyl-3,3-dimethylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (9-B) [Chemical Structure] In dichloromethane, in the presence of HATU and triethylamine, 1-(tert-butoxycarbonyl)-3,3-dimethylpiperidine-4-carboxylic acid (9-k) is reacted with N,O-dimethylhydroxylamine hydrochloride (9-l) to obtain tert-butyl 4-(methoxy(methyl)carbamoyl)-3,3-dimethylpiperidine-1-carboxylate (9-m), which is then converted to tert-butyl 4-acetyl-3,3-dimethylpiperidine-1-carboxylate (9-n) by reacting with MeMgBr in THF. 9-n is reacted with N,N-dimethylformamide dimethyl acetal in DMF to obtain tert-butyl (E)-4-(3-(dimethylamino)acryloyl)-3,3-dimethylpiperidine-1-carboxylate (9-o). The coupling of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (9-a) and 9-o in acetic acid gives tert-butyl 4-(3-carbamoyl-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)-3,3-dimethylpiperidine-1-carboxylate (9-p), which is reduced with sodium borohydride in ethanol to obtain tert-butyl 4-(3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)-3,3-dimethylpiperidine-1-carboxylate (9-q). The Boc-protected amine of 9-q is deprotected under acidic conditions to obtain 7-(3,3-dimethylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (9-r), where the enantiomers are separated by supercritical fluid chromatography to give (7S)-7-(3,3-dimethylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (9-s).9-s was then reacted with acryloyl (1-g) in acetonitrile / H2O in the presence of sodium bicarbonate base to afford (7S)-7-(1-acryloyl-3,3-dimethylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (9-B).

[0087] Example S35. (7S)-7-(1-Acryloyl-3,3-difluoropiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (9-C)

Chemical formula

Claims

1. The compound of formula (1): [Chemical Formula 1] or a pharmaceutically acceptable salt thereof, wherein X is -OH, -OY, -Y ２ , and -(halo) ２ selected from, and Y is C optionally substituted with 1 to 3 halo １ ~C ４ alkyl, a compound.

2. The compound of formula (2): 【Chemical Formula 2】 or a pharmaceutically acceptable salt thereof, wherein X is -OH, -OY, -Y ２ , and -(halo) ２ selected from, and Y is C optionally substituted with 1 to 3 halos １ ~C ４ alkyl, a compound.

3. The compound of formula (3): [Chemical Formula 3] or a pharmaceutically acceptable salt thereof, wherein X is -OH, -OY, -Y ２ , and -(halo) ２ selected from, and Y is C optionally substituted with 1 to 3 halos １ ~C ４ alkyl, a compound.

4. The compound of formula (4): [Chemical Formula 4] or a pharmaceutically acceptable salt thereof, wherein X is -OH, -OY, -Y ２ , and -(halo) ２ selected from, and Y is C optionally substituted with 1 to 3 halos １ ~C ４ alkyl, a compound.

5. The compound of formula (5): 【Chemical Formula 5】 or a pharmaceutically acceptable salt thereof, wherein X is selected from -OH, -OY, -Y ２ , and -(halo) ２ , and Y is C １ -C ４ alkyl optionally substituted with 1 to 3 halo atoms, a compound.

6. The compound of formula (6): 【Chemical Formula 6】 or a pharmaceutically acceptable salt thereof, wherein X is selected from -OH, -OY, -Y ２ , and -(halo) ２ , and Y is C １ ~C ４ alkyl optionally substituted with 1 to 3 halos, a compound.

7. The compound of formula (7): 【Chemical Formula 7】 or a pharmaceutically acceptable salt thereof, wherein X is -OH, -OY, -Y ２ , and -(halo) ２ selected from, and Y is C optionally substituted with 1 to 3 halos １ ~C ４ alkyl, a compound.

8. The compound of formula (8): 【Chemical 8】 or a pharmaceutically acceptable salt thereof, wherein X is -OH, -OY, -Y ２ , and -(halo) ２ selected from, and Y is C optionally substituted with 1 to 3 halos １ ~C ４ alkyl, a compound.

9. The compound of formula (9): 【Chemical Formula 9】 or a pharmaceutically acceptable salt thereof, wherein X is selected from -OH, -OY, -Y ２ , and -(halo) ２ , and Y is C optionally substituted with 1 to 3 halo １ ~C ４ alkyl, a compound

10. Y is methyl, ethyl, CH(halo) ２ , and C(halo) ３ and is selected from the group consisting of: a compound according to any one of claims 1 to 9

11. The compound according to any one of claims 1 to 10, wherein halo is F.

12. The following: 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 The compound according to any one of claims 1 to 11, selected from or a pharmaceutically acceptable salt thereof.

13. A composition comprising a pharmaceutically acceptable excipient and at least one compound selected from any one of claims 1 to 12.

14. A method of treating a disease or disorder mediated by BTK, comprising administering to a patient in need thereof an effective amount of a compound selected from any one of claims 1 to 12, or the composition according to claim 13.

15. A method for preparing a compound of formula (3-A), comprising 【Chemical 10】 (a) combining a compound of formula (2-a): 【Chemical Formula 11】 with a compound of formula (2-b): 【Chemical Formula 12】 to provide a compound of formula (2-c): 【Chemical 13】 ; (b) combining the compound of formula (2-c) with a compound of formula (2-d): 【Chemical Formula 14】 to provide a compound of formula (2-e): 【Chemical Formula 15】 ; (c) subjecting the compound of formula (2-e) to a ring-forming reaction to provide a compound of formula (2-f): 【Chemical 16】 ; (d) reacting the compound of formula (2-f) with a compound of formula (1-b): 【Chemical 17】 to provide a compound of formula (2-h): 【Chemical 18】 ; (e) deprotecting the nitrogen substituted on the pyridine of the compound of formula (2-h) to provide a compound of formula (2-i): 【Chemical Formula 19】 ; (f) deprotecting the piperidine nitrogen of the compound of formula (2-i) to provide a compound of formula (2-j): 【Chemical 20】 ; (g) combining the compound of formula (2-j) with a compound of formula (1-g): 【Chemical 21】 to provide a compound of formula (3-b): 【Chemical 22】 to provide, (h) deprotecting the oxygen of the compound of formula (3-b) to provide a compound of formula (3-A), and a method comprising the same.

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