Process for preparing modified BTK inhibitors

Abstract

Provided herein are BTK inhibitors containing piperidine modified at position 3. Further disclosed herein are methods of making and using the BTK inhibitors.

Description

Technical Field

[0001] The present disclosure relates to BTK inhibitors and methods for preparing and using BTK inhibitors, wherein the BTK inhibitor has a piperidine ring substituted at the 3-position, for example, the BTK inhibitor can be selected from compounds of formula (1)-(9):

[0002]

[0003] wherein X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is C1-C4 alkyl optionally substituted with 1 to 3 halogens. The compounds of formula (1)-(9) are Bruton's tyrosine kinase (BTK) inhibitors and thus can be used to treat diseases or disorders caused by excessive BTK signaling, such as diseases selected from autoimmune diseases, inflammatory diseases or cancer. Prior art

[0004] Enzyme BTK is a member of Tec family non-receptor tyrosine kinase. 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 has been involved in the pathogenesis of some disorders and conditions, including B cell-related blood cancers (such as non-Hodgkin's 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 antibody autoimmune hemolytic anemia, asthma and other acute respiratory distress, and chronic spontaneous urticaria).

[0005] Therefore, pharmaceutical compositions comprising a therapeutically effective amount of a BTK inhibitor may be used to treat certain cancers and autoimmune diseases.

[0006] When treating certain cancers and autoimmune diseases with BTK inhibitors, it is also desirable that the treatment can be administered in a form that is easily absorbed by the body and also stable for storage. The pharmaceutical active substance used to prepare the treatment should be as pure as possible and should be stable for long-term storage under various environmental conditions. These characteristics help prevent the appearance of unexpected degradation products in the pharmaceutical composition, which may be potentially toxic or simply result in a reduction in the efficacy of the composition.

[0007] One factor in the suitability of an inhibitor compound as a therapeutic agent is its ability to interact with the targeted binding site of a protein, thereby allowing at least one of more selectivity, specificity, and stronger binding. The metabolism of piperidine-containing BTK inhibitors can cause the piperidine to undergo ring opening, which may reduce the binding affinity of the piperidine to the C481 sulfhydryl group, thereby resulting in a decrease in overall efficacy. Therefore, it is of interest to structural modifications to BTK inhibitors that can prevent or modify this ring opening process, such as certain substitutions at the 3-position of the piperidine moiety. Although not being bound by theory, it is believed that by providing a substitution at the 3-position of the piperidine, this substituent provides stability and / or rigidity to the ring structure, thereby preventing metabolism and / or degradation of the ring structure. Summary of the invention

[0008] Thus, the present disclosure relates to BTK inhibitors and methods for preparing and using BTK inhibitors, wherein the BTK inhibitor has a piperidine ring substituted at the 3-position, for example, the BTK inhibitor can be selected from compounds of formula (1)-(9):

[0009]

[0010] wherein X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is a C1-C4 alkyl optionally substituted with 1 to 3 halogens; and methods for preparing the compounds. The present disclosure also relates to compositions comprising a pharmaceutically acceptable excipient and at least one compound selected from those disclosed herein. The present disclosure still further relates to methods for treating diseases or disorders mediated by BTK, the methods comprising administering to a patient in need thereof an effective amount of a compound selected from those disclosed herein.

[0011] Additional objects and advantages will be set forth in part in the following description and in part will be understood from the description or may be learned by practice. Said objects and advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0012] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claims.

[0013] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate one (several) embodiments and, together with the description, serve to explain the principles described herein. DETAILED DESCRIPTION

[0014] definition

[0015] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings:

[0016] As used herein, "BTK inhibitor", "BTK inhibitor compound", "compounds of formula (1)-(9)" and "compounds (1)-(9)" refer to BTK inhibitors having the following structure:

[0017]

[0018]

[0019] wherein X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is C1-C4 alkyl optionally substituted with 1 to 3 halogens.

[0020] As used herein, the terms "comprising" and "including" can be used interchangeably. The terms "comprising" and "including" are interpreted as specifying the presence of the features or components mentioned, but do not exclude 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 covered by the term "consisting of". Therefore, the term "consisting of" can be used to replace the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0021] The term "consisting of" means that the subject matter has at least 90%, 95%, 97%, 98% or 99% of the features or components that constitute it. In another embodiment, the term "consisting of" excludes any other features or components from the scope of any subsequent statement, except for features or components that are not essential to the technical effect to be achieved.

[0022] As used herein, the term "or" is interpreted 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 will only occur if a combination of elements, functions, steps or acts are inherently mutually exclusive to some extent.

[0023] As used herein, "the 3-position of piperidine" and "the piperidine ring substituted at the 3-position" means the position represented by "3" as shown below:

[0024]

[0025] "Alkyl" is a saturated, partially saturated or unsaturated straight or branched chain non-cyclic hydrocarbon having 1 to 10 carbon atoms (C1-C 10The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. The alkyl group is a saturated alkyl group. In certain embodiments, when an alkyl group described herein is referred to as "substituted," the alkyl group described herein may be substituted with any one or more substituents such as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; amide; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; nitrogen oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2 or O(alkyl)aminocarbonyl.

[0026] "Halogen" or "halo" is fluoro, chloro, bromo or iodo.

[0027] A "hydroxy" group is -OH.

[0028] An "alkoxy" group is an -O-(alkyl) group wherein alkyl is as defined above.

[0029] Embodiments of the present disclosure are intended to encompass stereoisomers of the compounds provided herein, such as compounds of formula (9).

[0030] As used herein and unless otherwise indicated, the term "stereoisomer" or "pure stereoisomer" means one stereoisomer of a particular compound that is substantially free of other stereoisomers of the compound. For example, a pure stereoisomer compound having one chiral center will be substantially free of the relative enantiomer of the compound. A pure stereoisomer compound having two chiral centers will be substantially free of other diastereomers of the compound. Typical pure stereoisomer compounds contain 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 may have chiral centers and may exist as racemates, individual enantiomers or diastereomers and mixtures thereof. All such isomeric forms (including mixtures thereof) are included in the embodiments disclosed herein.

[0031] Embodiments disclosed herein encompass the use of pure stereoisomeric forms of compounds disclosed herein, as well as the use of mixtures of those forms. For example, mixtures of stereoisomers comprising the same or different amounts of a particular compound can be used in the methods and compositions disclosed herein. These isomers can be synthesized or separated asymmetrically using standard techniques (such as chiral columns or chiral separating agents). See, for example, Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions page 268 (EL Eliel editor, Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., SeparationOf Enantiomers: Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and PracticalMethods (Springer Science&Business Media, 2007); Subramanian, G. Chiral Separation Techniques: Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0032] It should 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 compounds are separated into E or Z isomers. In other embodiments, the compounds are mixtures of E or Z isomers.

[0033] It should be noted that if there is an inconsistency between the depicted structure and the name of the structure, more weight is given to the depicted structure.

[0034] Compound

[0035] In some embodiments, the present disclosure relates to compounds of formula (1):

[0036]

[0037] or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is a C1-C4 alkyl optionally substituted with 1 to 3 halogens. In some embodiments, Y is selected from methyl, ethyl, CH(halogen)2 and C(halogen)3. In some embodiments, halogen is F.

[0038] In some embodiments, the present disclosure relates to compounds of formula (2):

[0039]

[0040] or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is a C1-C4 alkyl optionally substituted with 1 to 3 halogens. In some embodiments, Y is selected from methyl, ethyl, CH(halogen)2 and C(halogen)3. In some embodiments, halogen is F.

[0041] In some embodiments, the present disclosure relates to compounds of formula (3):

[0042]

[0043] or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is a C1-C4 alkyl optionally substituted with 1 to 3 halogens. In some embodiments, Y is selected from methyl, ethyl, CH(halogen)2 and C(halogen)3. In some embodiments, halogen is F.

[0044] In some embodiments, the present disclosure relates to compounds of formula (4):

[0045]

[0046] or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is a C1-C4 alkyl optionally substituted with 1 to 3 halogens. In some embodiments, Y is selected from methyl, ethyl, CH(halogen)2 and C(halogen)3. In some embodiments, halogen is F.

[0047] In some embodiments, the present disclosure relates to compounds of formula (5):

[0048]

[0049] or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is a C1-C4 alkyl optionally substituted with 1 to 3 halogens. In some embodiments, Y is selected from methyl, ethyl, CH(halogen)2 and C(halogen)3. In some embodiments, halogen is F.

[0050] In some embodiments, the present disclosure relates to compounds of formula (6):

[0051]

[0052] or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is a C1-C4 alkyl optionally substituted with 1 to 3 halogens. In some embodiments, Y is selected from methyl, ethyl, CH(halogen)2 and C(halogen)3. In some embodiments, halogen is F.

[0053] In some embodiments, the present disclosure relates to compounds of formula (7):

[0054]

[0055] or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is a C1-C4 alkyl optionally substituted with 1 to 3 halogens. In some embodiments, Y is selected from methyl, ethyl, CH(halogen)2 and C(halogen)3. In some embodiments, halogen is F.

[0056] In some embodiments, the present disclosure relates to compounds of formula (8):

[0057]

[0058] or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is a C1-C4 alkyl optionally substituted with 1 to 3 halogens. In some embodiments, Y is selected from methyl, ethyl, CH(halogen)2 and C(halogen)3. In some embodiments, halogen is F.

[0059] In some embodiments, the present disclosure relates to compounds of formula (9):

[0060]

[0061] or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is a C1-C4 alkyl optionally substituted with 1 to 3 halogens. In some embodiments, Y is selected from methyl, ethyl, CH(halogen)2 and C(halogen)3. In some embodiments, halogen is F.

[0062] In some embodiments, the present disclosure relates to a compound selected from Table 1 or a pharmaceutically acceptable salt thereof. Although certain compounds described in the present disclosure (including Table 1) are presented in specific stereoisomers and / or non-stereochemical forms, it should be understood that any or all stereochemical forms (including any enantiomeric or diastereomeric forms) and any tautomeric or other forms of any compound of the present disclosure (including Table 1) are described herein.

[0063] Table 1.

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073] or a pharmaceutically acceptable salt thereof.

[0074] It is to be understood that throughout this specification, combinations of substituents and / or variables of the depicted formulae are permissible only if such contributions result in stable compounds.

[0075] In addition, all compounds of formula (1)-(9) that exist in free base or acid form can be converted into their pharmaceutically acceptable salts by methods known to those skilled in the art by treatment with appropriate inorganic or organic bases or acids. Salts of compounds of formula (1)-(9) can be converted into their free base or acid form by standard techniques.

[0076] 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.

[0077] In some embodiments, the disclosure relates to methods 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 the compounds described herein, or administering a composition as described herein.

[0078] The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or methods provided herein. It should be noted that one skilled in the art would know how to modify the procedures described in the illustrative schemes and examples to obtain the desired products.

[0079] Example

[0080] The following examples are presented by way of illustration and not limitation. Compounds are named using the automatic name generation tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures and supports the Cahn-Ingold-Prelog rule for stereochemistry. Those skilled in the art may modify the procedures described in the exemplary embodiments to obtain the desired products.

[0081] Salts of compounds described herein can be prepared by standard methods, such as including an acid (eg, TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or stirring the product with a solution of an acid (eg, aqueous HCl) following chromatographic purification.

[0082] The following abbreviations may be relevant to the application.

[0083] abbreviation

[0084] Boc: tert-Butyloxycarbonyl

[0085] DAST: Diethylaminosulfur trifluoride

[0086] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0087] DEAD: Diethyl azodicarboxylate

[0088] DIPEA: diisopropylethylamine

[0089] DMF: dimethylformamide

[0090] DMSO: dimethyl sulfoxide

[0091] EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0092] EtOH: ethanol

[0093] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, azabenzotriazole tetramethyluronium hexafluorophosphate

[0094] HOBt: Hydroxybenzotriazole

[0095] i-PrOH: isopropanol

[0096] mCPBA: meta-chloroperbenzoic acid

[0097] MeOH: Methanol

[0098] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride

[0099] SFC: Supercritical Fluid Chromatography

[0100] TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate

[0101] TEA: triethylamine

[0102] TEMPO: (2,2,6,6-tetramethylpiperidin-1-yl)oxy

[0103] TFA: trifluoroacetic acid

[0104] THF: Tetrahydrofuran

[0105] tol: toluene

[0106] 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)

[0107]

[0108] To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-a) in toluene and water, (4-phenoxyphenyl)boronic acid (1-b), Pd(dppf)Cl2 and K3PO4 are added. The reaction solution is stirred at 90°C to 100°C to obtain 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-c). 1-c is dissolved in THF and cooled to 0°C, and (3S,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-ol (1-d), diethyl azodicarboxylate and triphenylphosphine are added thereto. The reaction solution was stirred at room temperature to give 1-((3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-e). 1-e was dissolved in ethyl acetate and hydrogenated with H2 and Pd / C to give 1-((3R,5R)-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-f). 1-f is reacted with acryloyl chloride (1-g) in dichloromethane in the presence of N,N-diisopropylethylamine base to give 1-((3R,5R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)prop-2-en-1-one (1-h). The tert-butyldimethylsilyl protected alcohol of 1-h is deprotected under acidic conditions to give 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).

[0109] 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)

[0110]

[0111] To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-a) in toluene and water, (4-phenoxyphenyl)boronic acid (1-b), Pd(dppf)Cl2 and K3PO4 are added. The reaction solution is stirred at 90°C to 100°C to obtain 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-c). 1-c is dissolved in THF and cooled to 0°C, and tert-butyl (3S,5R)-3-hydroxy-5-methoxypiperidine-1-carboxylate (1-i), diethyl azodicarboxylate and triphenylphosphine are added thereto. The reaction solution was 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). The Boc protected amine of 1-j is deprotected under acidic conditions to give 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 give 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).

[0112] 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)

[0113]

[0114] To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-a) in toluene and water, (4-phenoxyphenyl)boronic acid (1-b), Pd(dppf)Cl2 and K3PO4 are added. The reaction solution is stirred at 90°C-100°C to obtain 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-c). 1-c is dissolved in THF and cooled to 0°C, and (S)-5-hydroxy-3,3-dimethylpiperidine-1-carboxylic acid tert-butyl ester (1-l), diethyl azodicarboxylate and triphenylphosphine are added thereto. The reaction solution is stirred at room temperature to obtain (R)-5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-dimethylpiperidine-1-carboxylic acid tert-butyl ester (1-m). The Boc protected amine of 1-m is deprotected under acidic conditions to give (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 give (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).

[0115] 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)

[0116]

[0117] To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-a) in toluene and water, (4-phenoxyphenyl)boronic acid (1-b), Pd(dppf)Cl2 and K3PO4 are added. The reaction solution is stirred at 90°C-100°C to obtain 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-c). 1-c is dissolved in THF and cooled to 0°C, to which (S)-tert-butyl 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 (R)-tert-butyl 5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-difluoropiperidine-1-carboxylate (1-p). The Boc protected amine of 1-p is deprotected under acidic conditions to give (R)-1-(5,5-difluoropiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1-q), which is then reacted with acryloyl chloride (1-g) in dichloromethane in the presence of N,N-diisopropylethylamine base to give (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).

[0118] 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)

[0119]

[0120] To a solution of 2,4-dichloro-3-nitropyridine (2-a) and triethylamine in DMF is added (3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-amine (2-b). The reaction solution is stirred at room temperature to give N-((3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-2-chloro-3-nitropyridine-4-amine (2-c), which is dissolved in DMF and reacted with potassium phthalimide (2-d) to give 2-(4-(((3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)amino)-3-nitropyridine-2-yl)isoindoline-1,3-dione (2-e). 2-e was 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 was subjected to a cross-coupling reaction with (4-phenoxyphenyl)boronic acid (1-b) in the presence of Cu(OAc), TEMPO and triethylamine in dichloromethane to afford 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). The phthalimide protected amine of 2-h was deprotected by reaction with hydrazine in ethanol to give 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), and the remaining benzyl protected amine was deprotected by reaction of 2-i with H2 and Pd / C in MeOH to give 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 2-fluoroacryloyl chloride (2-k) in the presence of triethylamine base in dichloromethane to give 4-amino-1-((3S,5R)-5-((tert-butyldimethylsilyl)oxy)-1-(2-fluoroacryloyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2-1).The tert-butyldimethylsilyl protected alcohol of 2-1 was deprotected under acidic conditions to give 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).

[0121] 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)

[0122]

[0123] To a solution of 2,4-dichloro-3-nitropyridine (2-a) and triethylamine in DMF was added tert-butyl (3R,5R)-3-amino-5-methoxypiperidine-1-carboxylate (2-m). The reaction solution was stirred at room temperature to give tert-butyl (3R,5R)-3-((2-chloro-3-nitropyridin-4-yl)amino)-5-methoxypiperidine-1-carboxylate (2-n), which was reacted with bis(4-methoxybenzyl)amine (2-o) in the presence of triethylamine base in isopropanol to give 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 was reacted with Fe in AcOH / MeOH to reduce its nitro group, followed by reaction 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 was subjected to a cross-coupling reaction with (4-phenoxyphenyl)boronic acid (1-b) in the presence of Cu(OAc), TEMPO and triethylamine in dichloromethane to afford 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 was deprotected under acidic conditions to give 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 was reacted with 2-fluoroacryloyl chloride (2-k) in the presence of triethylamine base in dichloromethane to give 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).

[0124] 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]pyridin-2-one (2-C)

[0125]

[0126] The alcohol of (S)-tert-butyl 5-hydroxy-3,3-dimethylpiperidine-1-carboxylate (2-t) was initiated with methanesulfonyl chloride in the presence of triethylamine base in dichloromethane and then converted to the amine by subsequent reaction with NaN3 in DMF and triphenylphosphine in THF / H2O to give (R)-tert-butyl 5-amino-3,3-dimethylpiperidine-1-carboxylate (2-u). 2-u is added to a solution of 2,4-dichloro-3-nitropyridine (2-a) and triethylamine in DMF and stirred at room temperature to give (R)-tert-butyl 5-((2-chloro-3-nitropyridin-4-yl)amino)-3,3-difluoropiperidine-1-carboxylate (2-v), which is reacted with bis(4-methoxybenzyl)amine (2-o) in the presence of triethylamine base in isopropanol to give (R)-tert-butyl 5-((2-((4-methoxybenzyl)(4-methylbenzyl)amino)-3-nitropyridin-4-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (2-w). 2-w was reacted with Fe in AcOH / MeOH to reduce its nitro group and then reacted with carbonyldiimidazole in acetonitrile to form (S)-tert-butyl 5-(4-(bis(4-methoxybenzyl)amino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (2-x). 2-x was subjected to a cross-coupling reaction with (4-phenoxyphenyl)boronic acid (1-b) in the presence of Cu(OAc), TEMPO and triethylamine in dichloromethane to afford (S)-tert-butyl 5-(4-(bis(4-methoxybenzyl)amino)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (2-y). The Boc protected amine of 2-y is deprotected under acidic conditions to give (S)-4-amino-1-(5,5-dimethylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2-z), and the free amine of 2-z is reacted with 2-fluoroacryloyl chloride (2-k) in the presence of triethylamine base in dichloromethane to give (S)-4-amino-1-(1-(2-fluoroacryloyl)-5,5-dimethylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2-c).

[0127] 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)

[0128]

[0129] To a solution of 2,4-dichloro-3-nitropyridine (2-a) and triethylamine in DMF was added (R)-tert-butyl 5-amino-3,3-difluoropiperidine-1-carboxylate (2-a'). The reaction solution was stirred at room temperature to give tert-butyl (R)-5-((2-chloro-3-nitropyridin-4-yl)amino)-3,3-difluoropiperidine-1-carboxylate (2-b'), which was reacted with bis(4-methoxybenzyl)amine (2-o) in the presence of triethylamine base in isopropanol to give tert-butyl (R)-3,3-difluoro-5-((2-((4-methoxybenzyl)(4-methylbenzyl)amino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (2-c'). 2-c' was reacted with Fe in AcOH / MeOH to reduce its nitro group, followed by reaction with carbonyldiimidazole in acetonitrile to form (S)-tert-butyl 5-(4-(bis(4-methoxybenzyl)amino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-3,3-difluoropiperidine-1-carboxylate (2-d'). 2-d′ was subjected to a cross-coupling reaction with (4-phenoxyphenyl)boronic acid (1-b) in the presence of Cu(OAc), TEMPO, and triethylamine in dichloromethane to afford (S)-tert-butyl 5-(4-(bis(4-methoxybenzyl)amino)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-3,3-difluoropiperidine-1-carboxylate (2-e′). The Boc protected amine of 2-e' is deprotected under acidic conditions to give (S)-4-amino-1-(5,5-difluoropiperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2-f'), and the free amine of 2-f' is reacted with 2-fluoroacryloyl chloride (2-k) in the presence of triethylamine base in dichloromethane to give (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).

[0130] 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)

[0131]

[0132] To a solution of 2,4-dichloro-3-nitropyridine (2-a) and triethylamine in DMF is added (3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-amine (2-b). The reaction solution is stirred at room temperature to give N-((3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-2-chloro-3-nitropyridine-4-amine (2-c), which is dissolved in DMF and reacted with potassium phthalimide (2-d) to give 2-(4-(((3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)amino)-3-nitropyridine-2-yl)isoindoline-1,3-dione (2-e). 2-e was 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 was subjected to a cross-coupling reaction with (4-phenoxyphenyl)boronic acid (1-b) in the presence of Cu(OAc), TEMPO and triethylamine in dichloromethane to afford 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). The phthalimide protected amine of 2-h was deprotected by reaction with hydrazine in ethanol to give 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), and the remaining benzyl protected amine was deprotected by reaction of 2-i with H2 and Pd / C in MeOH to give 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 was reacted with acryloyl chloride (1-g) in the presence of triethylamine base in dichloromethane to give 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 was deprotected under acidic conditions to give 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).

[0133] 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)

[0134]

[0135] To a solution of 2,4-dichloro-3-nitropyridine (2-a) and triethylamine in DMF was added tert-butyl (3R,5R)-3-amino-5-methoxypiperidine-1-carboxylate (2-m). The reaction solution was stirred at room temperature to give tert-butyl (3R,5R)-3-((2-chloro-3-nitropyridin-4-yl)amino)-5-methoxypiperidine-1-carboxylate (2-n), which was reacted with bis(4-methoxybenzyl)amine (2-o) in the presence of triethylamine base in isopropanol to give 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 was reacted with Fe in AcOH / MeOH to reduce its nitro group, followed by reaction 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 was subjected to a cross-coupling reaction with (4-phenoxyphenyl)boronic acid (1-b) in the presence of Cu(OAc), TEMPO and triethylamine in dichloromethane to afford 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 was deprotected under acidic conditions to give 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 was reacted with acryloyl chloride (1-g) in the presence of triethylamine base in dichloromethane to give 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).

[0136] 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]pyridin-2-one (3-C)

[0137]

[0138] The alcohol of (S)-tert-butyl 5-hydroxy-3,3-dimethylpiperidine-1-carboxylate (2-t) was initiated with methanesulfonyl chloride in the presence of triethylamine base in dichloromethane and then converted to the amine by subsequent reaction with NaN3 in DMF and triphenylphosphine in THF / H2O to give (R)-tert-butyl 5-amino-3,3-dimethylpiperidine-1-carboxylate (2-u). 2-u is added to a solution of 2,4-dichloro-3-nitropyridine (2-a) and triethylamine in DMF and stirred at room temperature to give (R)-tert-butyl 5-((2-chloro-3-nitropyridin-4-yl)amino)-3,3-difluoropiperidine-1-carboxylate (2-v), which is reacted with bis(4-methoxybenzyl)amine (2-o) in the presence of triethylamine base in isopropanol to give (R)-tert-butyl 5-((2-((4-methoxybenzyl)(4-methylbenzyl)amino)-3-nitropyridin-4-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (2-w). 2-w was reacted with Fe in AcOH / MeOH to reduce its nitro group and then reacted with carbonyldiimidazole in acetonitrile to form (S)-tert-butyl 5-(4-(bis(4-methoxybenzyl)amino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (2-x). 2-x was subjected to a cross-coupling reaction with (4-phenoxyphenyl)boronic acid (1-b) in the presence of Cu(OAc), TEMPO and triethylamine in dichloromethane to afford (S)-tert-butyl 5-(4-(bis(4-methoxybenzyl)amino)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (2-y). The Boc protected amine of 2-y is deprotected under acidic conditions to give (S)-4-amino-1-(5,5-dimethylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2-z), and the free amine of 2-z is reacted with acryloyl chloride (1-g) in the presence of triethylamine base in dichloromethane to give (S)-4-amino-1-(1-(2-fluoroacryloyl)-5,5-dimethylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (3-c).

[0139] 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)

[0140]

[0141] To a solution of 2,4-dichloro-3-nitropyridine (2-a) and triethylamine in DMF was added (R)-tert-butyl 5-amino-3,3-difluoropiperidine-1-carboxylate (2-a'). The reaction solution was stirred at room temperature to give tert-butyl (R)-5-((2-chloro-3-nitropyridin-4-yl)amino)-3,3-difluoropiperidine-1-carboxylate (2-b'), which was reacted with bis(4-methoxybenzyl)amine (2-o) in the presence of triethylamine base in isopropanol to give tert-butyl (R)-3,3-difluoro-5-((2-((4-methoxybenzyl)(4-methylbenzyl)amino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (2-c'). 2-c' was reacted with Fe in AcOH / MeOH to reduce its nitro group, followed by reaction with carbonyldiimidazole in acetonitrile to form (S)-tert-butyl 5-(4-(bis(4-methoxybenzyl)amino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-3,3-difluoropiperidine-1-carboxylate (2-d'). 2-d′ was subjected to a cross-coupling reaction with (4-phenoxyphenyl)boronic acid (1-b) in the presence of Cu(OAc), TEMPO, and triethylamine in dichloromethane to afford (S)-tert-butyl 5-(4-(bis(4-methoxybenzyl)amino)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-3,3-difluoropiperidine-1-carboxylate (2-e′). The Boc protected amine of 2-e' is deprotected under acidic conditions to give (S)-4-amino-1-(5,5-difluoropiperidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2-f'), and the free amine of 2-f' is reacted with acryloyl chloride (1-g) in the presence of triethylamine base in dichloromethane to give (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).

[0142] Example S13. (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-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile (4-A)

[0143]

[0144] 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°C to 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, and (3S,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-ol (1-d), diethyl azodicarboxylate and triphenylphosphine are added thereto. The reaction solution was stirred at room temperature to give 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 was dissolved in ethyl acetate and hydrogenated with H2 and Pd / C to give 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 was reacted with (E)-2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoic acid (4-f) in DMF in the presence of HATU and diisopropylethylamine base to give (E)-2-((3R,5R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-((tert-butyldimethylsilyl)oxy)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile (4-g). The tert-butyldimethylsilyl protected alcohol of 4-g was deprotected with tetrabutylammonium fluoride in THF to give (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-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile (4-A).

[0145] Example S14. (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-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile (4-B)

[0146]

[0147] 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°C-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, and tert-butyl (3S,5R)-3-hydroxy-5-methoxypiperidine-1-carboxylate (1-i), diethyl azodicarboxylate and triphenylphosphine are added thereto. The reaction solution was stirred at room temperature to give tert-butyl (3R,5R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-methoxypiperidine-1-carboxylate (4-h). The Boc-protected amine of 4-h was deprotected under acidic conditions to give 3-(2-fluoro-4-phenoxyphenyl)-1-((3R,5R)-5-methoxypiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-i), and the free amine of 4-i was reacted with (E)-2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pentan-2-yl in DMF. -enoic acid (4-f) was reacted in the presence of HATU and diisopropylethylamine base to give (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-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile (4-B).

[0148] 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)pent-2-enenitrile (4-C)

[0149]

[0150] 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 were added. The reaction solution was stirred at 90°C-100°C to obtain 3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-b). 4-b was dissolved in THF and cooled to 0°C, and (S)-5-hydroxy-3,3-dimethylpiperidine-1-carboxylic acid tert-butyl ester (1-l), diethyl azodicarboxylate and triphenylphosphine were added thereto. The reaction solution was stirred at room temperature to give (R)-5-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-dimethylpiperidine-1-carboxylic acid tert-butyl ester (4-j). The Boc-protected amine of 4-j was deprotected under acidic conditions to give (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 was reacted with (E)-2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pentyl-2-nitropropene in DMF. The 2-enoic acid (4-f) was reacted in the presence of HATU and diisopropylethylamine base to give (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)pent-2-enenitrile (4-c).

[0151] 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)pent-2-enenitrile (4-D)

[0152]

[0153] 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 were added. The reaction solution was stirred at 90°C-100°C to obtain 3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-b). 4-b was dissolved in THF and cooled to 0°C, and (S)-tert-butyl 3,3-difluoro-5-hydroxypiperidine-1-carboxylate (1-o), diethyl azodicarboxylate and triphenylphosphine were added thereto. The reaction solution was stirred at room temperature to give (R)-5-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester (4-1). The Boc-protected amine of 4-1 was deprotected under acidic conditions to give (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 was reacted with (E)-2-cyano-4-methyl-4-(4-(oxetane-3-yl)piperazin-1-yl)pentyl-2-nitropropene in DMF. The 2-enoic acid (4-f) was reacted in the presence of HATU and diisopropylethylamine base to give (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)pent-2-enenitrile (4-D).

[0154] 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)

[0155]

[0156] 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°C to 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, and (3S,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-ol (1-d), diethyl azodicarboxylate and triphenylphosphine are added thereto. The reaction solution was stirred at room temperature to give 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 was dissolved in ethyl acetate and hydrogenated with H2 and Pd / C to give 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 was 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 afford (E)-2-((3R,5R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-((tert-butyldimethylsilyl)oxy)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (5-b). The tert-butyldimethylsilyl protected alcohol of 5-b was deprotected under acidic conditions to give (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).

[0157] 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)

[0158]

[0159] 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°C-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, and tert-butyl (3S,5R)-3-hydroxy-5-methoxypiperidine-1-carboxylate (1-i), diethyl azodicarboxylate and triphenylphosphine are added thereto. The reaction solution was stirred at room temperature to obtain tert-butyl (3R,5R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-methoxypiperidine-1-carboxylate (4-h). The Boc protected amine of 4-h was deprotected under acidic conditions to give 3-(2-fluoro-4-phenoxyphenyl)-1-((3R,5R)-5-methoxypiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-i), and the free amine of 4-i was 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 give (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).

[0160] 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)

[0161]

[0162] 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 were added. The reaction solution was stirred at 90°C-100°C to obtain 3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-b). 4-b was dissolved in THF and cooled to 0°C, and (S)-5-hydroxy-3,3-dimethylpiperidine-1-carboxylic acid tert-butyl ester (1-l), diethyl azodicarboxylate and triphenylphosphine were added thereto. The reaction solution was stirred at room temperature to obtain (R)-tert-butyl 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 was deprotected under acidic conditions to give (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 was 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 give (R,E)-2-(5-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-dimethylpiperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (5-c).

[0163] 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)

[0164]

[0165] 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 were added. The reaction solution was stirred at 90°C-100°C to obtain 3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4-b). 4-b was dissolved in THF and cooled to 0°C, and (S)-tert-butyl 3,3-difluoro-5-hydroxypiperidine-1-carboxylate (1-o), diethyl azodicarboxylate and triphenylphosphine were added thereto. The reaction solution was stirred at room temperature to obtain (R)-tert-butyl 5-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,3-difluoropiperidine-1-carboxylate (4-1). The Boc protected amine of 4-1 is deprotected under acidic conditions to give (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 give (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).

[0166] 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)

[0167]

[0168] 2,4-Dichloro-3-nitropyridine (2-a) and benzyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (6-a) were coupled in the presence of DBU in DMF to give benzyl 4-(((6-amino-5-chloropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (6-b), which was subsequently subjected to a cross-coupling reaction with (4-phenoxyphenyl)boronic acid (1-b) in the presence of Cu(OAc)2, TEMPO and triethylamine in dichloromethane to give benzyl 4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (6-c). 6-C was dissolved in methanol and hydrogenated with H2 and Pd / C to give 4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-3-ol (6-d). 6-d was coupled with acryloyl chloride (1-g) in the presence of sodium bicarbonate in THF / H2O to give 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-one (6-A).

[0169] 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)

[0170]

[0171] 2,4-Dichloro-3-nitropyridine (2-a) and 4-(aminomethyl)-3-methoxypiperidine-1-carboxylic acid (6-e) were coupled in the presence of DBU in DMF to give tert-butyl 4-(((6-amino-5-chloropyrimidin-4-yl)amino)methyl)-3-methoxypiperidine-1-carboxylate (6-f), which was subsequently subjected to a cross-coupling reaction with (4-phenoxyphenyl)boronic acid (1-b) in the presence of Cu(OAc)2, TEMPO and triethylamine in dichloromethane to give tert-butyl 4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-methoxypiperidine-1-carboxylate (6-g). The Boc protected amine of 6-g was deprotected under acidic conditions to give N4-((3-methoxypiperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (6-h), and the free amine of 6-h was coupled with acryloyl chloride (1-g) in the presence of sodium bicarbonate in THF / H2O to give 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-methoxypiperidin-1-yl)prop-2-en-1-one (6-B).

[0172] 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)

[0173]

[0174] 2,4-Dichloro-3-nitropyridine (2-a) and tert-butyl 4-(aminomethyl)-3,3-dimethylpiperidine-1-carboxylate (6-i) were coupled in the presence of DBU in DMF to give tert-butyl 4-(((6-amino-5-chloropyrimidin-4-yl)amino)methyl)-3,3-dimethylpiperidine-1-carboxylate (6-i), which was subsequently subjected to a cross-coupling reaction with (4-phenoxyphenyl)boronic acid (1-b) in the presence of Cu(OAc)2, TEMPO and triethylamine in dichloromethane to give tert-butyl 4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3,3-dimethylpiperidine-1-carboxylate (6-k). The Boc protected amine of 6-k was deprotected under acidic conditions to give N4-((3,3-dimethylpiperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (6-1), and the free amine of 6-1 was coupled with acryloyl chloride (1-g) in the presence of sodium bicarbonate in THF / H2O to give 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3,3-dimethylpiperidin-1-yl)prop-2-en-1-one (6-c).

[0175] 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)

[0176]

[0177] 2,4-Dichloro-3-nitropyridine (2-a) and tert-butyl 4-(aminomethyl)-3,3-difluoropiperidine-1-carboxylate (6-m) were coupled in the presence of DBU in DMF to give tert-butyl 4-(((6-amino-5-chloropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidine-1-carboxylate (6-n), which was subsequently subjected to a cross-coupling reaction with (4-phenoxyphenyl)boronic acid (1-b) in the presence of Cu(OAc)2, TEMPO and triethylamine in dichloromethane to give tert-butyl 4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidine-1-carboxylate (6-o). The Boc protected amine of 6-o was deprotected under acidic conditions to give N4-((3,3-difluoropiperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (6-p), and the free amine of 6-p was coupled with acryloyl chloride (1-g) in the presence of sodium bicarbonate in THF / H2O to give 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)prop-2-en-1-one (6-D).

[0178] Example S25. 4-((3S,5S)-3-(but-2-ynamido)-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-A)

[0179]

[0180] 4-Bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid (7-a) and tert-butyl ((3S,5S)-5-hydroxypiperidin-3-yl)carbamate (7-b) in THF were coupled in the presence of allylpalladium(II) chloride dimer, silver trifluoromethanesulfonate, t-Bu-XPhos and sodium tert-butoxide base to give 4-((3S,5S)-3-((tert-butoxycarbonyl)amino)-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid (7-c). The formic acid of 7-c was converted to the amide by reaction with NH3 in the presence of EDCI and HOBt in DMF to give tert-butyl ((3S,5S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-hydroxypiperidin-3-yl)carbamate (7-d). The Boc protected amine of 7-d was deprotected under acidic conditions to give 4-((3S,5S)-3-amino-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-e), and the free amine of 7-e was coupled with but-2-ynoic acid (7-f) in the presence of TBTU and triethylamine base in DMF to give 4-((3S,5S)-3-(but-2-ynamido)-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-A).

[0181] Example S26. 4-((3S,5S)-3-(but-2-ynamido)-5-methoxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-B)

[0182]

[0183] The phenyl ester of 7-g was converted to the methoxy group by reacting benzyl (3S,5S)-3-(benzoyloxy)-5-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (7-g) with LiOH.H2O in THF / H2O and MeI and Ag2O in DMF / ACN. The benzylcarbonyl protected amine was subsequently deprotected with H2 and Pd / C in MeOH to give tert-butyl ((3S,5S)-5-methoxypiperidin-3-yl)carbamate (7-h). 4-Bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid (7-a) and 7-h in THF were coupled in the presence of allylpalladium(II) chloride dimer, silver trifluoromethanesulfonate, t-Bu-XPhos and sodium tert-butoxide base to give 4-((3S,5S)-3-((tert-butoxycarbonyl)amino)-5-methoxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid (7-i). The formic acid of 7-i was converted to the amide by reaction with NH3 in the presence of EDCI and HOBt in DMF to give tert-butyl ((3S,5S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-methoxypiperidin-3-yl)carbamate (7-j). The Boc protected amine of 7-j was deprotected under acid conditions to give 4-((3S,5S)-3-amino-5-methoxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-k), and the free amine of 7-k was coupled with but-2-ynoic acid (7-f) in the presence of TBTU and triethylamine base in DMF to give 4-((3S,5S)-3-(but-2-ynamido)-5-methoxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-B).

[0184] Example S27. (S)-4-(5-(But-2-ynamido)-3,3-dimethylpiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-C)

[0185]

[0186] 4-Bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid (7-a) and (S)-tert-butyl(5,5-dimethylpiperidin-3-yl)carbamate (7-l) in THF were coupled in the presence of allylpalladium(II) chloride dimer, silver trifluoromethanesulfonate, t-Bu-XPhos and sodium tert-butoxide base to give (S)-4-(5-((tert-butoxycarbonyl)amino)-3,3-dimethylpiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid (7-m). The formic acid of 7-m was converted to the amide by reaction with NH3 in the presence of EDCI and HOBt in DMF to give tert-butyl (S)-(1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5,5-dimethylpiperidin-3-yl)carbamate (7-n). The Boc protected amine of 7-n was deprotected under acidic conditions to give (S)-4-(5-amino-3,3-dimethylpiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-o), and the free amine of 7-o was coupled with but-2-ynoic acid (7-f) in the presence of TBTU and triethylamine base in DMF to give (S)-4-(5-(but-2-ynamido)-3,3-dimethylpiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-c).

[0187] Example S28. (S)-4-(5-(But-2-ynylamido)-3,3-difluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-D)

[0188]

[0189] 4-Bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid (7-a) and (S)-tert-butyl(5,5-difluoropiperidin-3-yl)carbamate (7-p) in THF were coupled in the presence of allylpalladium(II) chloride dimer, silver trifluoromethanesulfonate, t-Bu-XPhos and sodium tert-butoxide base to give (S)-4-(5-((tert-butoxycarbonyl)amino)-3,3-difluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid (7-q). The formic acid of 7-q was converted to the amide by reaction with NH3 in the presence of EDCI and HOBt in DMF to give tert-butyl (S)-(1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5,5-difluoropiperidin-3-yl)carbamate (7-r). The Boc protected amine of 7-r was deprotected under acidic conditions to give (S)-4-(5-amino-3,3-difluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-s), and the free amine of 7-s was coupled with but-2-ynoic acid (7-f) in the presence of TBTU and triethylamine base in DMF to give (S)-4-(5-(but-2-ynamido)-3,3-difluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (7-D).

[0190] Example S29. 6-(1-Acryloyl-3-hydroxypiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-A)

[0191]

[0192] To a solution of 6-chloro-2-(4-phenoxyphenyl)nicotinamide (8-a) in dioxane and water, (1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (8-b), Pd(dppf)Cl2, and Na2CO3 were added. The reaction solution was stirred at 90°C-100°C to give benzyl 5-carbamoyl-6-(4-phenoxyphenyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (8-c). 8-c was then reacted with mCPBA in dichloromethane, followed by Zn and NH4Cl in THF / H2O to give alcohol-substituted benzyl 4-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)-3-hydroxypiperidine-1-carboxylate (8-d). Deprotection of the amine of 8-d with H2 and Pd / C in MeOH afforded 6-(3-hydroxypiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-e), which was subsequently reacted with acryloyl chloride (1-g) in the presence of sodium bicarbonate base in THF / H2O to afford 6-(1-acryloyl-3-hydroxypiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-a).

[0193] Example S30.6-(1-Acryloyl-3-methoxypiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-B)

[0194]

[0195] To a solution of methyl 6-amino-2-chloronicotinate (8-f) in dioxane and water, (4-phenoxyphenyl)boronic acid (1-b), Pd(dppf)Cl2 and Na2CO3 are added. The reaction solution is stirred at 90°C-100°C to give 6-amino-2-(4-phenoxyphenyl)nicotinic acid (8-h). The amine of 8-h is converted to chlorine by reacting it with isoamyl nitrite and CuCl2 in acetonitrile to give methyl 6-chloro-2-(4-phenoxyphenyl)nicotinate (8-i). 8-I was coupled with (1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (8-b) by reaction with Pd(dppf)Cl2 and Na2CO3 in dioxane and water to give 1'-benzyl 5-methyl 6-(4-phenoxyphenyl)-3',6'-dihydro-[2,4'-bipyridyl]-1',5(2'H)-dicarboxylate (8-j). 8-j was subsequently reacted with mCPBA in dichloromethane followed by Zn and NH4Cl in THF / H2O to give alcohol substituted 6-(1-((benzyloxy)carbonyl)-3-hydroxypiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinate (8-k). 8-k is then reacted with MeI and Ag2O in DMF / ACN and NH3 in MeOH to give benzyl 4-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)-3-methoxypiperidine-1-carboxylate (8-1). Deprotection of the amine of 8-1 with H2 and Pd / C in MeOH gives 6-(3-methoxypiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-m), which is then reacted with acryloyl chloride (1-g) in the presence of sodium bicarbonate base in THF / H2O to give 6-(1-acryloyl-3-methoxypiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-B).

[0196] Example S31.6-(1-Acryloyl-3,3-dimethylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-C)

[0197]

[0198] To a solution of 6-chloro-2-(4-phenoxyphenyl)nicotinamide (8-a) in dioxane and water, (1-(tert-butoxycarbonyl)-3,3-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (8-n), Pd(dppf)Cl2 and Na2CO3 were added. The reaction solution was stirred at 90°C-100°C to give tert-butyl 5-carbamoyl-3',3'-dimethyl-6-(4-phenoxyphenyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (8-o). 8-o was subjected to 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).

[0199] Example S32.6-(1-Acryloyl-3,3-difluoropiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-D)

[0200]

[0201] To a solution of 6-chloro-2-(4-phenoxyphenyl)nicotinamide (8-a) in dioxane and water was added (1-(tert-butoxycarbonyl)-3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (8-r), Pd(dppf)Cl2 and Na2CO3. The reaction solution was stirred at 90°C-100°C to give tert-butyl 5-carbamoyl-3',3'-difluoro-6-(4-phenoxyphenyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (8-s). 8-s was reacted with H2 and Pd / C in MeOH to give 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 give 6-(3,3-difluoropiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-u). 8-u 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-difluoropiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (8-D).

[0202] 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')

[0203]

[0204] Tert-butyl 4-acetyl-3,6-dihydropyridine-1(2H)-carboxylate (9-b) was reacted with N,N-dimethylformamide dimethyl acetal in DMF to give (E)-tert-butyl 4-(3-(dimethylamino)acryloyl)-3,6-dihydropyridine-1(2H)-carboxylate (9-c). Coupling of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (9-a) and 9-c in acetic acid afforded tert-butyl 4-(3-carbamoyl-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (9-d), which was reduced with sodium borohydride in ethanol to afford tert-butyl 4-(3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (9-e). The enantiomers of 9-e were separated using supercritical fluid chromatography to give (S)-tert-butyl 4-(3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (9-f). 9-f was subjected to hydroxylation with AD-Mixα and methanesulfonamide in tert-butyl alcohol and water to give tert-butyl (3S,4S)-4-((S)-3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)-3,4-dihydroxypiperidine-1-carboxylate (9-g) (alternatively, reaction with AD-Mixβ results in the addition of a hydroxyl group with the opposite stereochemistry). The hydroxy substituent of 9-g was reduced with triethylsilane and trifluoroacetic acid in dichloromethane to give tert-butyl (3R)-4-((S)-3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)-3-hydroxypiperidine-1-carboxylate (9-h), wherein the enantiomers were separated by supercritical fluid chromatography to give (3R,4R)-4-((S) -3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (9-i) and (3R,4S)-4-((S)-3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (9-j).The amines of both isomers were each deprotected and reacted with acryloyl chloride (1-g) in the presence of sodium bicarbonate in THF / H2O to give (S)-7-((3R,4R)-1-acryloyl-3-hydroxypiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (9-A) 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').

[0205] 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)

[0206]

[0207] 1-(tert-Butoxycarbonyl)-3,3-dimethylpiperidine-4-carboxylic acid (9-k) was reacted with N,O-dimethylhydroxylamine hydrochloride (9-1) in the presence of HATU and triethylamine in dichloromethane to give 4-(methoxy(methyl)carbamoyl)-3,3-dimethylpiperidine-1-carboxylic acid (9-m), which was subsequently converted to tert-butyl 4-acetyl-3,3-dimethylpiperidine-1-carboxylate (9-n) by reaction with MeMgBr in THF. 9-n was reacted with N,N-dimethylformamide dimethyl acetal in DMF to give tert-butyl (E)-4-(3-(dimethylamino)acryloyl)-3,3-dimethylpiperidine-1-carboxylate (9-o). 5-Amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (9-a) and 9-o in acetic acid were coupled to give tert-butyl 4-(3-carbamoyl-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)-3,3-dimethylpiperidine-1-carboxylate (9-p), which was reduced with sodium borohydride in ethanol to give 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 was deprotected under acidic conditions to give 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 were 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 chloride (1-g) in the presence of sodium bicarbonate base in acetonitrile / H2O to give (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).

[0208] 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)

[0209]

[0210] The alcohol of tert-butyl (3R)-4-((S)-3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)-3-hydroxypiperidine-1-carboxylate (9-h) was oxidized by reaction with oxalyl chloride followed by triethylamine in DMSO to give tert-butyl 4-((S)-3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)-3-oxopiperidine-1-carboxylate (9-t). 9-t was reacted with diethylaminosulfur trifluoride in dichloromethane to give tert-butyl 4-((S)-3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)-3,3-difluoropiperidine-1-carboxylate (9-u), and the Boc-protected amine of 9-u was subsequently deprotected under acidic conditions to give (7S)-7-(3,3-difluoropiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (9-v). 9-v was reacted with acryloyl chloride (1-g) in the presence of sodium bicarbonate base in acetonitrile / H2O to give (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).

Claims

1. A compound of formula (1): or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is C1-C4 alkyl optionally substituted with 1 to 3 halogens.

2. A compound of formula (2): or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is C1-C4 alkyl optionally substituted with 1 to 3 halogens.

3. A compound of formula (3): or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is C1-C4 alkyl optionally substituted with 1 to 3 halogens.

4. A compound of formula (4): or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is C1-C4 alkyl optionally substituted with 1 to 3 halogens.

5. A compound of formula (5): or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is C1-C4 alkyl optionally substituted with 1 to 3 halogens.

6. A compound of formula (6): or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is C1-C4 alkyl optionally substituted with 1 to 3 halogens.

7. A compound of formula (7): or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is C1-C4 alkyl optionally substituted with 1 to 3 halogens.

8. A compound of formula (8): or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is C1-C4 alkyl optionally substituted with 1 to 3 halogens.

9. A compound of formula (9): or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OH, -OY, -Y2 and -(halogen)2, and Y is C1-C4 alkyl optionally substituted with 1 to 3 halogens.

10. The compound of any one of claims 1 to 9, wherein Y is selected from methyl, ethyl, CH(halogen)2 and C(halogen)3.

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

12. 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 for 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 claims 1 to 12 or a composition according to claim 13.

15. A method for preparing a compound of formula (3-A): The method comprises: (a) making a compound of formula (2-a): Coupling with a compound of formula (2-b): To provide a compound of formula (2-c): (b) coupling a compound of formula (2-c) with a compound of formula (2-d): To provide a compound of formula (2-e): (c) undergoing a ring-forming reaction in a compound of formula (2-e) to provide a compound of formula (2-f): (d) coupling a compound of formula (2-f) with a compound of formula (1-b): To provide a compound of formula (2-h): (e) deprotecting the nitrogen substituted on the pyridine of the compound of formula (2-h) to provide a compound of formula (2-i): (f) deprotecting the piperidine nitrogen of the compound of formula (2-i) to provide a compound of formula (2-j): (g) coupling a compound of formula (2-j) with a compound of formula (1-g): To provide a compound of formula (3-b): (h) Deprotecting the oxygen of the compound of formula (3-b) to provide a compound of formula (3-A).

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