Pyrazolo[3,4-d]pyrimidin-6-yl-sulfonamide derivatives for the inhibition of sgk-1

Abstract

Compounds of Formula I and their pharmaceutically acceptable salts are provided as inhibitors of SGK-1, for example, for the treatment of conditions such as long QT syndrome, heart failure, arrhythmia, ischemic injury, ischemic infarction, cardiac fibrosis, angiogenesis, restenosis, dilated cardiomyopathy, stent failure, prostate cancer, epilepsy, colorectal cancer, breast cancer, Parkinson's disease, and Lafra disease.

Description

Technical Field

[0001] This technical field relates to pyrazolo[3,4-d]pyrimidine-6-yl sulfonamide derivatives and pharmaceutical compositions that inhibit SGK-1, and more specifically to pyrazolo[3,4-d]pyrimidine-6-yl sulfonamide derivatives and pharmaceutical compositions for treating heart diseases such as long QT syndrome that can be treated by SGK-1 inhibition. Background Technology

[0002] Long QT syndrome (LQTS) is a condition of the heart's electrical system in which the repolarization of the heart is affected after a heartbeat. LQTS increases the risk of arrhythmias, which can lead to fainting, drowning, or even sudden death. Several genetic causes of LQTS have been identified, and most mutations occur in genes encoding the three major cardiac ion channels (KCNQ1, KCNH2, and SCN5a).

[0003] Several existing treatment options exist for LQTS, such as using beta-blockers to slow the heart rate by reducing the effect of adrenaline on the heart, surgery on the nerves regulating the heartbeat, and / or the use of implantable cardioverter-defibrillators. However, none of the existing treatment options address the underlying mechanistic problem.

[0004] Serine / threonine protein kinase 1 (SGK-1) (also known as serum / glucocorticoid-regulated kinase 1) is a protein kinase that plays a role in cellular stress responses. SGK-1 activates certain potassium, sodium, and chloride channels. For example, SGK-1 is known to regulate inositol transporters during osmotic stress. The use of SGK-1 inhibitors for the treatment of LQTS has been reported in WO 2015048531. However, several challenges remain in developing SGK-1 inhibitors for the treatment of heart diseases such as LQTS. Summary of the Invention

[0005] In one aspect, a compound of formula I is provided: Formula I Or its pharmaceutically acceptable salt. in: Z is selected from the following groups: direct bond, O, S, CH(R9), and N(R). 10 ); R1 is selected from the following groups: H, -N(R) 11 )R 12 -N(R) 13 )-C(O)-R 14 , -NR 13 -S(O)2-R 15-NR 13 -C(O)-NH-R 16 -(C1-C4)-alkyl, –(C1-C4)-alkyl-OR 17 and –(C1-C4)-alkyl-N(R 18 )R 19 ; R3 is selected from the group consisting of: H, (C1-C8)-alkyl, R 30 and (C1-C4)-alkyl-R 30 Wherein the (C1-C8)-alkyl group is unsubstituted or is substituent by one or more identical or different substituents R 31 replace; R 30 It is a 3- to 12-membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic cyclic group comprising 0, 1, 2, or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the group is unsubstituted or substituented by one or more identical or different substituents R. 32 replace; R 31 Choose from the following groups: halogen, -OH, -CF3, -O-(C1-C4)-alkyl, -N(R 33 )-R 34 and -CN; R 32 Choose from the group consisting of: halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, -(C1-C4)-alkyl-(C3-C7)-cycloalkyl, -(C1-C4)-alkyl-OR 37 -(C1-C4)-alkyl-N(R) 38 )-R 39 -(C1-C4)-alkyl-CN, -C(O)-(C1-C4)-alkyl, -CN, -OH, =O, -O-(C1-C4)-alkyl, -N(R 40 )-R 41 -C(O)-O-(C1-C4)-alkyl and -C(O)-N(R 42 )-R 43 ; A is a direct bond or -CH2-; Y is selected from the group consisting of carbocyclic and heterocyclic groups, wherein the group is unsubstituted or substituted by one or more identical or different substituents R5; R5 is selected from the group consisting of: halogens, (C1-C4)-alkyl, -O-(C1-C4)-alkyl, and -CN; When Y is not 1,4-phenylene, or when Y is 1,4-phenylene and R1 is -(C1-C4)-alkyl-N(R18 )R 19 When: R2 is selected from the group consisting of (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl, phenyl, and 5- or 6-membered monocyclic, saturated, partially unsaturated, or aromatic heterocyclic groups, wherein the heterocyclic group comprises 1, 2, or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is bonded via a cyclic carbon atom or a cyclic nitrogen atom, wherein R2 is unsubstituted or substituented by one or more identical or different substituents R 20 replace; When Y is 1,4-phenylene and R1 is H,-N(R 11 )R 12 -N(R) 13 )-C(O)-R 14 -NR 13 -S(O)2-R 15 -NR 13 -C(O)-NH-R 16 -(C1-C4)-alkyl or -(C1-C4)-alkyl-OR 17 When: R2 is selected from the group consisting of (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl, and 5- or 6-membered monocyclic, saturated or partially unsaturated heterocyclic groups, said heterocyclic group comprising 1, 2 or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and bonded via cyclic carbon atoms or cyclic nitrogen atoms, wherein R2 is unsubstituted or substituted by one or more identical or different substituents R 20 replace; R 20 Choose from the following groups: halogen, -CF3, (C1-C4)-alkyl, -OR 21 -N(R) 22 )R 23 (C1-C4)-alkyl-OR 24 (C1-C4)-alkyl-N(R) 25 )R 26 and -CN; R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 21 R 22 R 23 R24 R 25 R 26 R 37 R 38 R 39 R 40 R 41 R 42 and R 43 Each is independently selected from the group consisting of H and (C1-C4)-alkyl groups; R 33 and R 34 The following groups are chosen independently of each other: H, -CH=O, (C1-C4)-alkyl and (C3-C7)-cycloalkyl, wherein the (C1-C4)-alkyl and (C3-C7)-cycloalkyl are unsubstituted or substituents R of the same or different groups. 50 Replace; and R 50 Choose from the following groups: halogen, -OH, -O-(C1-C4)-alkyl, -CF3, and -CN.

[0006] In one aspect, a compound of formula II is provided: Formula II Or its pharmaceutically acceptable salt. in: Z is selected from the following groups: O, CH2, S, and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 Select Free - (CH2) p -N(R 33 )R 34 The group formed; p is 1, 2, 3 or 4; R2 is selected from the group consisting of: a 5- or 6-membered monocyclic, aromatic, or heteroaromatic group containing 1, 2, or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein R2 is unsubstituted or substituented by one or more identical or different substituents R 20 replace; R 20 Choose from the following groups: halogen, -CF3, (C1-C4)-alkyl, -OR 21 , -N(R 22 )R 23 (C1-C4)-alkyl-OR 24 (C1-C4)-alkyl-N(R) 25 )R 26 and -CN; R 21 R 22 R 23 R 24 R 25 and R 26 Each is independently selected from the group consisting of H and (C1-C4)-alkyl groups; R 33 and R 34 The following groups are selected independently of each other: -CH=O, (C1-C4)-alkyl, and (C3-C7)-cycloalkyl, wherein the (C1-C4)-alkyl and (C3-C7)-cycloalkyl are each unsubstituted or substituented by one or more of the same or different substituents R. 50 Replace; and R 50 Choose from the following groups: halogens, -OH, -O-(C1-C4)-alkyl, CF3, and -CN.

[0007] On the other hand, a compound of formula II is provided: Formula II Or its pharmaceutically acceptable salt. in: Z is selected from the following groups: direct bond, O, S, CH(R9), and N(R). 10 ); R1 is selected from the following groups: H, -N(R) 11 )R 12 -N(R) 13 )-C(O)-R 14 -NR 13 -S(O)2-R 15 -NR 13 -C(O)-NH-R 16 -(C1-C4)-alkyl, –(C1-C4)-alkyl-OR 17 and –(C1-C4)-alkyl-N(R 18 )R 19 ; R3 is selected from the group consisting of: H, (C1-C8)-alkyl, R 30 and (C1-C4)-alkyl-R 30 Wherein the (C1-C8)-alkyl group is unsubstituted or is substituent by one or more identical or different substituents R 31 replace; R 30It is a 3- to 12-membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic cyclic group comprising 0, 1, 2, or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the group is unsubstituted or substituented by one or more identical or different substituents R. 32 replace; R 31 Choose from the following groups: halogen, -OH, -CF3, -O-(C1-C4)-alkyl, -N(R 33 )-R 34 and -CN; R 32 Choose from the group consisting of: halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, -(C1-C4)-alkyl-(C3-C7)-cycloalkyl, -(C1-C4)-alkyl-OR 37 -(C1-C4)-alkyl-N(R) 38 )-R 39 -(C1-C4)-alkyl-CN, -C(O)-(C1-C4)-alkyl, -CN, -OH, =O, -O-(C1-C4)-alkyl, -N(R 40 )-R 41 -C(O)-O-(C1-C4)-alkyl and -C(O)-N(R 42 )-R 43 ; R2 is a 6-membered monocyclic heteroaromatic group containing one or two nitrogen atoms, wherein R2 is unsubstituted or substituented by one or more identical or different substituents R. 20 replace; R 20 Choose from the following groups: halogen, -CF3, (C1-C4)-alkyl, -OR 21 -N(R) 22 )R 23 (C1-C4)-alkyl-OR 24 (C1-C4)-alkyl-N(R) 25 )R 26 and -CN; R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 21 R 22 R 23 R 24R 25 R 26 R 37 R 38 R 39 R 40 R 41 R 42 and R 43 Each is independently selected from the group consisting of H and (C1-C4)-alkyl groups; R 33 and R 34 The following groups are chosen independently of each other: H, -CH=O, (C1-C4)-alkyl and (C3-C7)-cycloalkyl, wherein the (C1-C4)-alkyl and (C3-C7)-cycloalkyl are unsubstituted or substituents R of the same or different groups. 50 Replace; and R 50 Choose from the following groups: halogen, -OH, -O-(C1-C4)-alkyl, -CF3, and -CN.

[0008] In another aspect, a compound of formula II is provided: Formula II Or its pharmaceutically acceptable salt. in: Z is selected from the following groups: O, CH2, S, and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 Select Free - (CH2) p -N(R 33 )R 34 The group formed; p is 1, 2, 3 or 4; R2 is a 6-membered monocyclic heteroaromatic group containing one or two nitrogen atoms, wherein R2 is unsubstituted or substituented by one or more identical or different substituents R. 20 replace; R 20 Choose from the following groups: halogen, -CF3, (C1-C4)-alkyl, -OR 21 -N(R) 22 )R 23 (C1-C4)-alkyl-OR 24 (C1-C4)-alkyl-N(R) 25 )R 26 and -CN; R 21 R 22 R 23 R24 R 25 and R 26 Each is independently selected from the group consisting of H and (C1-C4)-alkyl groups; R 33 and R 34 The following groups are selected independently of each other: -CH=O, (C1-C4)-alkyl, and (C3-C7)-cycloalkyl, wherein the (C1-C4)-alkyl and (C3-C7)-cycloalkyl are each unsubstituted or substituented by one or more of the same or different substituents R. 50 Replace; and R 50 Choose from the following groups: halogens, -OH, -O-(C1-C4)-alkyl, CF3, and -CN.

[0009] On the other hand, a compound of formula III is provided: Formula III Or its pharmaceutically acceptable salt. in: Z is selected from the following groups: O, CH2, S, and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 Select Free - (CH2) p -N(R 33 )R 34 The group that makes up the group, in which the group -(CH2) p - The zero, one, or two hydrogen atoms are independently replaced by F; p is 1, 2, 3 or 4; R2 is selected from the group consisting of: a 5- or 6-membered monocyclic, aromatic, or heteroaromatic group containing 1, 2, or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein R2 is unsubstituted or substituented by one or more identical or different substituents R 20 replace; R 20 Choose from the following groups: halogen, -CF3, (C1-C4)-alkyl, -OR 21 -N(R) 22 )R 23 (C1-C4)-alkyl-OR 24 (C1-C4)-alkyl-N(R) 25 )R 26 and -CN; R 21 R 22 R 23 R 24 R25 and R 26 Each is independently selected from the group consisting of H and (C1-C4)-alkyl groups; R 33 and R 34 The following groups are selected independently of each other: -CH=O, (C1-C4)-alkyl, and (C3-C7)-cycloalkyl, wherein the (C1-C4)-alkyl and (C3-C7)-cycloalkyl are each unsubstituted or substituented by one or more of the same or different substituents R. 50 replace; R 50 Choose from the following groups: halogen, -OR 27 -O-(C1-C4)-alkyl, -CF3, and -CN; R 27 Choose from the group consisting of: H, -C(=O)-(C1-C4)-alkyl, natural amino acids bound by an α-carboxyl group, or P(=O)(OH)2; and W1, W2, W3, and W4 are independently selected from the following groups: H, halogen, -OR 21 -CF3, (C1-C4)-alkyl and -CN.

[0010] On the other hand, a compound of formula III is provided: Formula III Or its pharmaceutically acceptable salt. in: Z is selected from the group composed of O and NH; R1 is selected from the group consisting of H and (C1-C4)-alkyl groups; R3 is -(CH2) p -N(R 33 )R 34 ; p is 2, 3, or 4; R2 is ; Z1 and Z2 are independently selected from the following groups: Cl, F, -OMe, and -CN; R 33 and R 34 Each is independently (C1-C4)-alkyl; and W1, W2, W3, and W4 are independently selected from the following groups: H, halogen, -OR 21 -CF3, (C1-C4)-alkyl and -CN, R 21 Choose from the group consisting of H and (C1-C4)-alkyl groups.

[0011] On the other hand, a compound of formula III is provided: Formula III Or its pharmaceutically acceptable salt. in: Z is selected from the group composed of O and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 is a nitrogen-containing heterocycle selected from the following groups: , , , and In which zero, one, or two hydrogens on any of the -CH2- groups of the nitrogen-containing heterocycle are substituted with halogen, -OH, -CN, -CF3, or (C1-C4)-alkyl; R 35 H or unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; and R 50 Choose from the following groups: halogens, -OH, -O-(C1-C4)-alkyl, CF3, and -CN; R2 is ; Z1 and Z2 are independently selected from the following groups: Cl, F, -OMe, and -CN; W1 is either F or OMe; W2 is either H or F; W3 is H; and W4 is H.

[0012] On the other hand, a compound of formula III is provided: Formula III Or its pharmaceutically acceptable salt. in: Z is selected from the group composed of O and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 is a nitrogen-containing heterocycle selected from the following groups: , , , , , and In which zero, one, or two hydrogens on any of the -CH2- groups of the nitrogen-containing heterocycle are substituted with halogen, -OH, -CN, -CF3, or (C1-C4)-alkyl; R 35 H or unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; and R 50 Choose from the following groups: halogens, -OH, -O-(C1-C4)-alkyl, CF3, and -CN; R2 is ; Z1 and Z2 are independently selected from the following groups: Cl, F, -OMe, and -CN; W1, W2, W3, and W4 are independently selected from the following groups: H, halogen, -OR 21 -CF3, (C1-C4)-alkyl and -CN, R 21 Choose from the group consisting of H and (C1-C4)-alkyl groups.

[0013] On the other hand, a compound of formula III is provided: Formula III Or its pharmaceutically acceptable salt. in: Z is selected from the group composed of O and NH; R1 is a (C1-C4)-alkyl group; R3 can be selected from the following groups: -(CH2) p -N(R 33 )R 34 , and ; p is 2, 3, or 4; R 33 R 34 and R 35 Independent of each other, either unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; R 50 Choose from the following groups: halogen, -OR 27 -O-(C1-C4)-alkyl, -CF3, and -CN; R 27 Choose from the following groups: H, -C(=O)-(C1-C4)alkyl, natural amino acids bound by α-carboxyl groups, or P(=O)(OH)2; R2 is ; Z1 and Z2 are independently selected from the following groups: Cl, F, -OMe, and -CN; W1 is either F or OMe; W2 is H; W3 is H; and W4 is H.

[0014] In another aspect, a compound of formula IV is provided: Formula IV Or its pharmaceutically acceptable salt. in: Z is selected from the group composed of O and NH; R3 can be selected from the following groups: -(CH2) p -N(R 33 )R 34 , , , and , p is 2, 3, or 4; R 33 and R 34 Independent of each other, either unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; R 35 H or unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; R 50 Choose from the following groups: halogen, -OR 27 -O-(C1-C4)-alkyl -CF3 and -CN; R 27 Choose from the following groups: H, -C(=O)-(C1-C4)alkyl, natural amino acids bound by α-carboxyl groups, and P(=O)(OH)2; R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogens, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; and W1 is a halogen.

[0015] On the other hand, a compound of formula IV is provided: Formula IV Or its pharmaceutically acceptable salt. in: Z-R3 can be selected from the following groups: , and ; R 27 Choose from the following groups: H, , , , , , , and ; R2 can be selected from the following groups: , , , , , and ;and W1 is selected from the group consisting of Cl and F.

[0016] On the other hand, a compound of formula V is provided: Formula V Or its pharmaceutically acceptable salt. in: R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; W1 is selected from the group consisting of free hydrogen and halogens; R 33 -CH3 or -(CH2)-(CH2)-OR 27 ;and R 27 Choose from the following groups: H, -C(=O)-(C1-C4)alkyl, natural amino acids bound by α-carboxyl groups, and -P(=O)(OH)2.

[0017] In one aspect, a compound of formula Vb is provided: Vb Or its pharmaceutically acceptable salt. in: R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogens, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; and W1 is selected from the group consisting of free hydrogen and halogens.

[0018] On the other hand, a compound of formula VI is provided: Style VI Or its pharmaceutically acceptable salt. in: Y1 is either H or F; q is 0 or 1; R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; W1 is selected from the group consisting of free hydrogen and halogens; R 35 H or unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; R 50 Choose from the following groups: halogen, -OR 27 -O-(C1-C4)-alkyl, -CF3, and -CN; R 27 Choose from the following groups: H, -C(=O)-(C1-C4)alkyl, natural amino acids bound by α-carboxyl groups, and P(=O)(OH)2.

[0019] In another aspect, a pharmaceutical composition is provided comprising a compound as defined herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0020] In another aspect, the use of compounds as defined herein or pharmaceutically acceptable salts thereof as SGK-1 inhibitors is provided. For example, compounds as defined herein or pharmaceutically acceptable salts thereof may be used to treat prostate cancer or epilepsy. For example, compounds as defined herein or pharmaceutically acceptable salts thereof may be used to treat cardiovascular diseases selected from the group consisting of long QT syndrome, heart failure, arrhythmia, ischemic injury, ischemic infarction, cardiac fibrosis, angiogenesis, restenosis, dilated cardiomyopathy, and stent failure. More specifically, compounds as defined herein or pharmaceutically acceptable salts thereof may be used to treat long QT syndrome.

[0021] On the other hand, the use of compounds as defined herein or pharmaceutically acceptable salts thereof for the manufacture of a drug that inhibits SGK-1 in a subject is provided. For example, the drug may be used to treat prostate cancer. For example, the drug may be used to treat epilepsy. For example, the drug may be used to treat cardiovascular diseases selected from the group consisting of long QT syndrome, heart failure, arrhythmia, ischemic injury, ischemic infarction, cardiac fibrosis, angiogenesis, restenosis, dilated cardiomyopathy, and stent failure. More specifically, the drug may be used to treat long QT syndrome.

[0022] On the other hand, methods are provided for treating other conditions related to SGK-1-mediated mechanisms. Such conditions may include, but are not limited to, at least one of prostate cancer, colorectal cancer, breast cancer (e.g., drug-resistant breast cancer), Parkinson's disease, and Lafora disease.

[0023] On the other hand, a method for treating prostate cancer is provided. This method includes administering to a subject a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0024] On the other hand, methods for treating cardiovascular diseases are provided. These methods involve administering to a subject a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof. Cardiovascular diseases are selected from the group consisting of long QT syndrome, heart failure, arrhythmias, ischemic injury, ischemic infarction, cardiac fibrosis, angiogenesis, restenosis, dilated cardiomyopathy, and stent failure.

[0025] On the other hand, methods for treating long QT syndrome are provided. These methods involve administering to a subject a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof. Detailed Implementation

[0026] This specification relates to compounds of formula I or pharmaceutically acceptable salts thereof. Formula I Compounds of Formula I and their pharmaceutically acceptable salts are pharmacologically active compounds that regulate protein kinase activity, particularly the activity of serum and glucocorticoid-regulated kinase isoform 1 (SGK-1). Compounds of Formula I or their pharmaceutically acceptable salts may be suitable for treating diseases in which SGK-1 activity is inappropriate. Non-limiting examples of such conditions may include long QT syndrome, heart failure, arrhythmias, ischemic injury, ischemic infarction, cardiac fibrosis, angiogenesis, restenosis, dilated cardiomyopathy, stent failure, prostate cancer, and epilepsy. Compounds of Formula I and their pharmaceutically acceptable salts are described in more detail herein.

[0027] definition Unless otherwise stated, the following terms and phrases as used herein have the following meanings. The fact that a particular term or phrase is not specifically defined should not be associated with uncertainty or lack of clarity, but rather the term is used in its ordinary meaning herein. When a trade name is used herein, it is intended to independently include the trade name product and the active pharmaceutical ingredient of the trade name product.

[0028] "Alkyl" refers to a hydrocarbon containing primary, secondary, or tertiary carbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C2). 20Alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl) or 1 to 4 carbon atoms (i.e., C1-C4 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)2), and 2-butyl (s-Bu, sec-butyl, -CH(CH3)2). 3) CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH 2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(C) H3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3) and octyl (-(CH2)7CH3).

[0029] "Alkoxy" refers to a group having the formula -O-alkyl, wherein the alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of the alkoxy group can have 1 to 20 carbon atoms (i.e., C1-C2). 20 alkoxy group), 1 to 12 carbon atoms (i.e., C1-C) 12 Alkoxy groups (or alkoxy groups with 1 to 4 carbon atoms, i.e., C1-C4 alkoxy groups). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), tert-butoxy (-OC(CH3)3 or -OtBu), etc.

[0030] "Haloalkyl" refers to an alkyl group as defined above, wherein one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. The alkyl portion of a haloalkyl group may have 1 to 20 carbon atoms (i.e., C1-C2). 20 Halogenated alkyl groups), 1 to 12 carbon atoms (i.e., C1-C1), 12 (Halogenated alkyl) or 1 to 4 carbon atoms (i.e., C1-C4 haloalkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, etc.

[0031] “Cycloalkyl” refers to a monocyclic or bicyclic carbocyclic functional group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, and bicyclic [5.2.0]nonyl. Cycloalkyl groups may have 3 to 12 carbon atoms (i.e., C3-C4). 12 Cycloalkyl groups, with 3 to 7 carbon atoms (i.e., C3-C7 cycloalkyl) or 3 to 6 carbon atoms (i.e., C3-C6 cycloalkyl). Unless otherwise specified, the term "(C3-C7)cycloalkyl" refers to a cycloalkyl group containing 3 to 8 carbon atoms. Therefore, the term "(C3-C7)cycloalkyl" includes monocyclic cycloalkyl groups containing 3 to 7 carbon atoms and bicyclic cycloalkyl groups containing 6 to 7 carbon atoms.

[0032] "Alkenyl" refers to a hydrocarbon containing primary, secondary, or tertiary carbon atoms and having at least one unsaturated site (i.e., carbon-carbon, sp2 double bond). For example, an alkenyl group can have 2 to 20 carbon atoms (i.e., C2-C). 20 alkenyl), 2 to 12 carbon atoms (i.e., C2-C) 12 Alkenyl groups (2 to 6 carbon atoms, i.e., C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene, vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0033] "Alkyne" refers to a hydrocarbon containing primary, secondary, or tertiary carbon atoms and having at least one unsaturated site (i.e., a carbon-carbon, sp triple bond). For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., C2-C). 20 alkynyl group), 2 to 12 carbon atoms (i.e., C2-C) 12 Alkyne groups consist of 2 to 6 carbon atoms (i.e., C2-C6 alkynyl groups). Examples of suitable alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynylate (-CH2C=CH), etc.

[0034] "Alkylene" refers to a saturated, branched, or straight-chain hydrocarbon group with two monovalent groups, derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, alkylene groups can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylene (-CH2CH2CH2CH2-).

[0035] "Alkenyl" refers to an unsaturated, branched, or straight-chain hydrocarbon group with two monovalent centers, derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent olefin. For example, alkenyl groups can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkenyl groups include, but are not limited to, 1,2-ethylene (-CH=CH-).

[0036] "Imyynyl" refers to an unsaturated, branched, or straight-chain hydrocarbon group with two monovalent groups, derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. For example, an ynylyl group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical ynylyl groups include, but are not limited to, ethynyl (-C≡C-), propynyl (-CH2C=C-), and 4-pentynyl (-CH2CH2CH2C=C-).

[0037] "Aryl" refers to a monovalent aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom in a parent aromatic ring system. For example, aryl groups can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalenes, anthracene, biphenyls, etc.

[0038] "Arylene" refers to an aryl group as defined above, which is derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent aryl group and has two monovalent group centers. Typical arylenes include, but are not limited to, phenylene, such as 1,4-phenylene.

[0039] "Arylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (usually the terminal or sp3 carbon atom) is replaced by an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethyl-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, naphthobenzyl, 2-naphthophenylethyl-1-yl, etc. Arylalkyl groups can contain 6 to 20 carbon atoms; for example, the alkyl moiety may have 1 to 6 carbon atoms and the aryl moiety may have 6 to 14 carbon atoms.

[0040] "Arylalkenyl" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom (usually a terminal or sp3 carbon atom, and also an sp2 carbon atom) is replaced by an aryl group. The aryl moiety of an arylalkenyl group may include any aryl group disclosed herein, and the alkenyl moiety of an arylalkenyl group may include any alkenyl group disclosed herein. The arylalkenyl group may contain 6 to 20 carbon atoms, for example, the alkenyl moiety may be 1 to 6 carbon atoms and the aryl moiety may be 6 to 14 carbon atoms.

[0041] "Arylynyl" refers to an acyclic ynyl group in which one of the hydrogen atoms bonded to a carbon atom (usually a terminal or sp3 carbon atom, and sometimes an sp carbon atom) is replaced by an aryl group. The aryl moiety of an arylynyl group may include any aryl group disclosed herein, and the ynyl moiety of an arylynyl group may include any ynyl group disclosed herein. The arylynyl group may contain 6 to 20 carbon atoms; for example, the ynyl moiety may be 1 to 6 carbon atoms and the aryl moiety may be 6 to 14 carbon atoms.

[0042] As used in this article, "halogen" refers to F, Cl, Br, or I.

[0043] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein that is substituted with at least one halogen. Examples of branched or straight-chain "haloalkyl" as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and tert-butyl groups that are independently substituted with one or more halogens (e.g., fluorine, chlorine, bromine, and iodine). The term "haloalkyl" should be interpreted to include substituents such as perfluoroalkyl groups, such as -CF3.

[0044] The term “substituted” in relation to alkyl, aryl, arylalkyl, carbocyclic, heterocyclic and other groups used herein, such as “substituted alkyl,” “substituted cycloalkyl,” “substituted aryl,” “substituted arylalkyl,” “substituted heterocyclic” and “substituted carbocyclic,” respectively means a group in which one or more hydrogen atoms are independently substituted by a non-hydrogen substituent. Typical substituents include, but are not limited to, -X, -R, -O-, =O, -OR, -SR, -S-, -NR2, -N(+)R3, =NR, -CX3, -CRX2, -CR2X, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N2, -N3, -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C(=O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O)2OR, -S(=O)2R, -OS(=O)2OR, -S(=O)2NR, -S =O)R, -NRS(=O)2R, -NRS(=O)2NRR, -NRS(=O)2OR, -OP(=O)(OR)2, -P(=O)(OR)2, -P(O)(OR)(O)R, -C(=O)R, -C(=S)R, -C(=O)OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR)NRR, -NRC(=NR)NRR, wherein each X is independently a halogen: F, Cl, Br or I; and each R is independently H, alkyl, cycloalkyl, aryl, arylalkyl, heterocyclic or protecting group or prodrug moiety. Divalent groups may also be similarly substituted.

[0045] Those skilled in the art will recognize that when a portion such as “alkyl,” “aryl,” “heterocyclic,” etc., is substituted by one or more substituents, that portion is alternatively referred to as the “alkylene,” “aryene,” “heterocyclic,” etc. portion (i.e., indicating that at least one of the hydrogen atoms in the parent “alkyl,” “aryl,” “heterocyclic” portion has been substituted by the indicated substituent). When a portion such as “alkyl,” “aryl,” “heterocyclic,” etc., is referred to herein as “substituted” or is graphically shown as substituted (or optionally substituted, for example, when the number of substituents is in the range of zero to positive integers), the terms “alkyl,” “aryl,” “heterocyclic,” etc., should be understood to be interchangeable with “alkylene,” “aryene,” “heterocyclic,” etc.

[0046] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by heteroatoms such as O, N, or S. For example, if the carbon atom of an alkyl group attached to the parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkoxy group (e.g., -OCH3, etc.), an amine (e.g., -NHCH3, -N(CH3)2, etc.), or a thioalkyl group (e.g., -SCH3). If the non-terminal carbon atom of an alkyl group not attached to the parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkyl ether (e.g., -CH2CH2-O-CH3, etc.), an alkylamine (e.g., -CH2NHCH3, -CH2N(CH3)2, etc.), or a thioalkyl ether (e.g., -CH2-S-CH3). If the terminal carbon atom of an alkyl group is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is a hydroxyalkyl group (e.g., -CH2CH2-OH), an aminoalkyl group (e.g., -CH2NH2), or an alkylthiol group (e.g., -CH2CH2-SH). The heteroalkyl group may have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. C1-C6 heteroalkyl groups refer to heteroalkyl groups having 1 to 6 carbon atoms.

[0047] As used herein, “heterocyclic” or “heterocyclic group” includes, for example, but not limited to, Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry. (WA Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950–present), especially Volumes 13, 14, 16, 19, and 28; and those heterocycles described in J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment of the invention, “heterocycle” includes “carbon ring” as defined herein, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms have been substituted with heteroatoms (e.g., O, N, P, or S). The term “heterocycle” or “heterocyclic group” includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings). Heterocycles include aromatic and non-aromatic monocyclic, bicyclic, and polycyclic rings, whether fused, bridging, or spirocyclic. As used herein, the term “heterocycle” includes, but is not limited to, “heteroaryl.”

[0048] Examples of heterocyclic compounds include, but are not limited to, pyridinyl, dihydropyridinyl, tetrahydropyridinyl (piperidinyl), thiazolyl, tetrahydrothiophene, sulfur-oxidized tetrahydrothiophene, pyrimidinyl, furanyl, thiophene, pyrroleyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indoleyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, and 4-piperidinoneyl. Pyrrolyl, azacyclic butyl, 2-pyrrolidone, pyrrololinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azaocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thiophene, thiaanthryl, pyranyl, isobenzofuranyl, benzopyranyl, xanthonyl, phenthiaxyl (p henoxathinyl), 2H-pyrroloyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indazinyl, isoydinolyl, 3H-indolyl, 1H-indazolyl, purine, 4H-quinazinyl, phthalazinyl, naphthidyl, quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, 4aH-carbazoleyl, carbazoleyl, β-carbolinyl, phenanthridineyl, acridineyl, pyrimidineyl , phenanthrolinyl, phenazinyl, phenthiazinyl, furazinyl, phenoxazinyl, isochromyl, chromanyl, imidazoalkyl, imidazolinyl, pyrazolyl, pyrazolyl, piperazinyl, dihydroindolyl, isodihydroindolyl, quininecycloyl, morpholinyl, oxazolyl, benzotriazolyl, benzoisooxazolyl, oxoindolyl, benzooxazolinyl, and isatinoyl.

[0049] As an example and not a limitation, the heterocyclic carbon bonded to the carbon atom is at positions 2, 3, 4, 5, or 6 of pyridine; positions 3, 4, 5, or 6 of pyridazine; positions 2, 4, 5, or 6 of pyrimidine; positions 2, 3, 5, or 6 of pyrazine; positions 2, 3, 4, or 5 of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole; positions 2, 4, or 5 of oxazole, imidazole, or thiazole; positions 3, 4, or 5 of isoxazole, pyrazole, or isothiazole; positions 2 or 3 of aziridine; positions 2, 3, or 4 of aziridine; positions 2, 3, or 4 of aziridine; positions 2, 3, 4, 5, 6, 7, or 8 of quinoline or positions 1, 3, 4, 5, 6, 7, or 8 of isoquinoline. More typically, the heterocycles of the bonded carbon include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

[0050] By way of example and not limitation, the nitrogen-bonded heterocycle is bonded at the 1-position of aziridinium, aziridine, pyrrole, pyrrolidine, 2-pyrrololine, 3-pyrroleline, imidazole, imidazoline, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, dihydroindole, and 1H-indazole; at the 2-position of isoindole or isoindoline; at the 4-position of morpholine; and at the 9-position of carbazole or β-carbline. More typically, the nitrogen-bonded heterocycle includes 1-aziridinyl, 1-aziridine, 1-pyrroleyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0051] "Hypo-heterocyclic group" refers to a heterocyclic group as defined herein, derived by substituting a carbon atom or a hydrogen atom from a heterocyclic group with an open valence. Similarly, "heteroaryl group" refers to an aromatic hypo-heterocyclic group.

[0052] "Heterocyclic alkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (usually a terminal or sp3 carbon atom) is replaced by a heterocyclic group (i.e., the heterocyclic-alkylene moiety). Typical heterocyclic alkyl groups include, but are not limited to, heterocyclic-CH2-, 2-(heterocyclic)ethyl-1-yl, etc., wherein the "heterocyclic" moiety includes any of the aforementioned heterocyclic groups, including those described in the Principles of Modern Heterocyclic Chemistry. Those skilled in the art will also understand that a heterocyclic group can be attached to the alkyl moiety of a heterocyclic alkyl group via carbon-carbon or carbon-heteroatom bonds, provided that the resulting group is chemically stable. Heterocyclic alkyl groups contain 2 to 20 carbon atoms; for example, the alkyl moiety of an arylalkyl group contains 1 to 6 carbon atoms and the heterocyclic moiety contains 1 to 14 carbon atoms. Examples of heterocyclic alkyl groups include, but are not limited to, 5-membered heterocycles containing sulfur, oxygen and / or nitrogen, such as thiazolylmethyl, 2-thiazolylethyl-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc.; and 6-membered heterocycles containing sulfur, oxygen and / or nitrogen, such as piperidinylmethyl, piperazinemethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidinylmethyl, pyrazinemethyl, etc.

[0053] "Heterocyclic alkenyl" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom (usually a terminal or sp3 carbon atom, and also an sp2 carbon atom) is replaced by a heterocyclic group (i.e., a heterocyclic-alkenyl-part). The heterocyclic moiety of a heterocyclic alkenyl group includes any heterocyclic group described herein, including those described in the Principles of Modern Heterocyclic Chemistry, and the alkenyl moiety of a heterocyclic alkenyl group includes any alkenyl group disclosed herein. Those skilled in the art will also understand that a heterocyclic group can be attached to the alkenyl moiety of a heterocyclic alkenyl group via carbon-carbon or carbon-heteroatom bonds, provided that the resulting group is chemically stable. Heterocyclic alkenyl groups contain 2 to 20 carbon atoms; for example, the alkenyl moiety of a heterocyclic alkenyl group contains 1 to 6 carbon atoms and the heterocyclic moiety contains 1 to 14 carbon atoms.

[0054] "Heteroaryl" refers to a monovalent aromatic heterocyclic group having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that may be included in an aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all those listed in the definition of "heterocyclic group," including pyridinyl, pyrroloyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thiophenyl, benzofuranyl, benzothiophenyl, carbazoyl, imidazoyl, thiazoyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc.

[0055] A "carbocyclic ring" or "carbocyclic group" refers to a saturated, partially unsaturated, or aromatic ring having 3 to 7 carbon atoms as a monocyclic ring, 7 to 12 carbon atoms as a bicyclic ring, and up to about 20 carbon atoms as a polycyclic ring. Monocyclic carbocyclic rings have 3 to 6 ring atoms, and more commonly 5 or 6 ring atoms. Bicyclic carbocyclic rings have 7 to 12 ring atoms, for example, arranged in bicyclic (4,5), (5,5), (5,6), or (6,6) systems, or have 9 or 10 ring atoms arranged in bicyclic (5,6) or (6,6) systems. Carbocyclic rings include aromatic and non-aromatic monocyclic, bicyclic, and polycyclic rings, whether fused, bridging, or spirocyclic. Non-limiting examples of monocyclic carbocyclic rings include cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, or aryl groups such as phenyl. Therefore, as used herein, "carbocyclic ring" includes, but is not limited to, "aryl," "phenyl," and "biphenyl."

[0056] "Carbocyclic group" refers to a carbocyclic group or carbocyclic ring as defined above, derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent carbocyclic group, and having two monovalent group centers. Typical carbocyclic groups include, but are not limited to, phenylene. Therefore, as used herein, "carbocyclic group" includes, but is not limited to, "aryl".

[0057] "Carbocycloalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (usually the terminal or sp3 carbon atom) is replaced by a carbocycloyl group as defined above. Typical carbocycloalkyl groups include, but are not limited to, arylalkyl groups such as benzyl, 2-phenylethyl-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, naphthobenzyl, 2-naphthophenylethyl-1-yl, or cycloalkylalkyl groups such as cyclopropylmethyl, cyclobutylethyl, cyclohexylmethyl, etc. Arylalkyl groups may contain 6 to 20 carbon atoms, for example, the alkyl moiety has 1 to 6 carbon atoms and the aryl moiety has 6 to 14 carbon atoms. Cycloalkylalkyl groups may contain 4 to 20 carbon atoms, for example, the alkyl moiety has 1 to 6 carbon atoms and the cycloalkyl group has 3 to 14 carbon atoms.

[0058] "Arylhexaalkyl" refers to a heteroalkyl group as defined herein, in which a hydrogen atom that may be attached to a carbon atom or heteroatom is replaced by an aryl group as defined herein. The aryl group may be bonded to a carbon atom of the heteroalkyl group or to a heteroatom of the heteroalkyl group, provided that the resulting arylhexaalkyl group provides a chemically stable moiety. For example, arylhexaalkyl groups may have the general formulas -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, etc. Furthermore, any alkylene moiety in the above general formulas may be further substituted by any substituents defined or illustrated herein.

[0059] "Heteroarylalkyl" refers to an alkyl group as defined herein, in which a hydrogen atom is replaced by a heteroaryl group as defined herein. Non-limiting examples of heteroarylalkyl groups include -CH2-pyridinyl, -CH2-pyrroloyl, -CH2-oxazolyl, -CH2-indolyl, -CH2-isoindolyl, -CH2-purinyl, -CH2-furanyl, -CH2-thienyl, -CH2-benzofuranyl, -CH2-benzothienyl, -CH2-carbazoyl, -CH2-imidazoyl, -CH2-thiazoyl, -CH2-isooxazolyl, -CH2-pyrazolyl, -CH2-isothiazoyl, -CH2-quinolinyl, -CH2-isoquinolinyl, -CH2-pyridinyl, -CH2-pyrazinyl, -CH(CH3)-pyridinyl, -CH(CH3)-pyrroloyl, -CH(CH3)- Oxazolyl, -CH(CH3)-indolyl, -CH(CH3)-isoindolyl, -CH(CH3)-purine, -CH(CH3)-furanyl, -CH(CH3)-thiophenyl, -CH(CH3)-benzofuranyl, -CH(CH3)-benzothiophenyl, -CH(CH3)-carbazoyl, -CH(CH3)-imidazoyl, -CH(CH3)-thiazoyl, -CH(CH3)-isooxazolyl, -CH(CH3)-pyrazolyl, -CH(CH3)-isothiazoyl, -CH(CH3)-quinolinyl, -CH(CH3)-isoquinolinyl, -CH(CH3)-pyridazinyl, -CH(CH3)-pyrimidinyl, -CH(CH3)-pyrazinyl, etc.

[0060] Regarding specific portions of the compounds of the formulas of the present invention, such as optionally substituted aryl groups, the term "optionally substituted" refers to portions having 0, 1, or more substituents.

[0061] As used herein, the term "prodrug" refers to any compound that, when administered to a biological system, produces a medicinal substance (i.e., the active ingredient) through spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and / or metabolic chemical reactions. Therefore, a prodrug is a covalently modified analogue or potential form of a therapeutically active compound.

[0062] Those skilled in the art will recognize that the substituents and other portions of the compounds described herein should be selected to provide sufficiently stable compounds that are pharmaceutically useful for formulation into acceptable and stable pharmaceutical compositions.

[0063] Some compounds in this specification and their pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs. As used herein, crystal polymorphism refers to the ability of a crystalline compound to exist in different crystal structures. Polymorphism can typically occur as a response to changes in temperature, pressure, or both. Polymorphism can also be caused by changes in the crystallization process.

[0064] Polymorphs can be distinguished by various physical properties known in the art, such as X-ray diffraction patterns, solubility, and melting point. Crystalline polymorphism may be due to differences in crystal packing (packing polymorphism) or differences in packing between different conformational isomers of the same molecule (conformational polymorphism). As used herein, pseudopolymorphism refers to the ability of a compound's hydrates or solvates to exist in different crystal structures. Some pseudopolymorphism in the compounds described in this specification may be due to differences in crystal packing (packing pseudopolymorphism) or differences in packing between different conformational isomers of the same molecule (conformational pseudopolymorphism). It should be understood that all polymorphs and pseudopolymorphs of the compounds described herein and their pharmaceutically acceptable salts are included within the scope of this specification.

[0065] The compounds and their pharmaceutically acceptable salts described herein may exist in the form of amorphous solids. As used herein, an amorphous solid is a solid in which the atoms are not in long-range ordered positions within the solid. This definition also applies when the crystal size is two nanometers or less. Additives (including solvents) may be used to produce the amorphous forms of the compounds described herein.

[0066] Some of the compounds described herein contain one or more chiral centers, or can exist in multiple stereoisomers. The scope of this specification includes mixtures of stereoisomers and purified enantiomers or enantiomer / diastereomer-enriched mixtures. The scope of this specification also includes individual isomers of the compounds described herein, and any fully or partially balanced mixtures thereof. The compounds of this specification and their pharmaceutically acceptable salts also include individual isomers of compounds represented by the above formula as mixtures of isomers with one or more chiral centers reversed.

[0067] The compounds described in this specification may exist in both solvated (e.g., hydrated) and non-solvated forms. Generally, but not absolutely, the salts of the compounds described in this specification are pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a non-toxic salt of the compounds described in this specification.

[0068] Examples of suitable pharmaceutically acceptable salts include inorganic acid addition salts, such as chlorides, bromides, sulfates, phosphates, and nitrates; organic acid addition salts, such as acetates, galactobionates, propions, succinates, lactates, glycolates, malates, tartrates, citrates, maleates, fumarates, methanesulfonates, p-toluenesulfonates, and ascorbic acid salts; salts with acidic amino acids, such as aspartate and glutamate; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as magnesium and calcium salts; ammonium salts; organic basic salts, such as trimethylamine, triethylamine, pyridine, methylpyridine, dicyclohexylamine, and N,N'-dibenzylethylenediamine; and salts with basic amino acids, such as lysine and arginine. In some cases, the salt may be a hydrate or an ethanol solvate.

[0069] This document describes and illustrates, by way of example, the definitions of various genera and subgenera and the substituents of the compounds of this invention. Those skilled in the art will understand that any combination of the above definitions and substituents should not produce an inoperable substance or compound. An "inoperable substance or compound" refers to a compound structure that violates relevant scientific principles (e.g., carbon atoms linked by more than four covalent bonds) or is too unstable to be isolated and formulated into a pharmaceutically acceptable dosage form.

[0070] Pharmaceutical Composition The compounds described in this specification may be formulated with conventional carriers and excipients, which will be selected according to conventional practice. Tablets will contain excipients, flow aids, fillers, binders, etc. Aqueous formulations are prepared aseptically and are generally isotonic when intended for delivery by a route other than oral administration. All formulations will optionally contain excipients, such as those described in the Handbook of Pharmaceutical Excipients (1986), the entire text of which is incorporated herein by reference. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. The pH of the formulation is in the range of about 3 to about 11, but is generally about 7 to 10.

[0071] While the active ingredient can be applied alone, it is preferred that the active ingredient be in the form of a pharmaceutical formulation. Formulations of the present invention intended for veterinary and human use comprise at least one active ingredient, as well as one or more acceptable carriers and optional other therapeutic ingredients.

[0072] The carrier must be "acceptable," meaning it is compatible with other components of the formulation and physiologically harmless to its recipient.

[0073] Formulations include those suitable for the routes of administration described above. Formulations are readily available in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. Techniques and formulations are typically discussed in Remington's Pharmaceutical Sciences. The document was found in (Mack Publishing Co., Easton, Pa.), and the full text is incorporated herein by reference. Such methods involve steps of binding an active ingredient to a carrier constituting one or more auxiliary ingredients. Generally, formulations are prepared by uniformly and tightly binding the active ingredient to a liquid carrier or a finely fragmented solid carrier, or both, and then shaping the product if necessary.

[0074] The formulations of the present invention suitable for oral administration can be in the form of discrete units, such as capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient; in the form of powders or granules; in the form of solutions or suspensions in aqueous or non-aqueous liquids; or in the form of oil-in-water or water-in-oil liquid emulsions. The active ingredient can also be administered in the form of pellets, syrups, or pastes.

[0075] Tablets are prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by compressing the active ingredient, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in a suitable machine in a free-flowing form such as powder or granules.

[0076] Molded tablets can be prepared by molding a mixture of powdered active ingredients wetted with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored, and may optionally be formulated to provide slow or controlled release of the active ingredient.

[0077] Pharmaceutical formulations according to this specification include one or more compounds, one or more pharmaceutically acceptable carriers or excipients, and optional other therapeutic agents. Pharmaceutical formulations containing an active ingredient can be in any form suitable for the intended method of administration. When intended for oral use, they can be prepared as, for example, tablets, lozenges, sugar tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more pharmaceutical agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation.

[0078] Tablets containing an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for tablet manufacturing are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated using known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with waxes.

[0079] Oral formulations may also exist as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium such as peanut oil, liquid paraffin, or olive oil.

[0080] The aqueous suspension of the present invention contains an active substance mixed with excipients suitable for manufacturing aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic, and dispersing or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkyl esters and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanethoxycetyl alcohol), and condensation products of ethylene oxide and esters derived from fatty acids and hexadiene anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

[0081] Oil suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oils such as liquid paraffin. Oral suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those described herein) and flavoring agents may be added to provide a palatable oral formulation. These compositions may be preserved by adding antioxidants such as ascorbic acid.

[0082] The dispersible powders and granules of the present invention, suitable for preparing aqueous suspensions by adding water, provide an active ingredient that can be mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0083] Pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oil phase can be vegetable oils such as olive oil or peanut oil, mineral oils such as liquid paraffin, or mixtures thereof. Suitable emulsifiers include naturally occurring gums, such as gum arabic and gum tragali; naturally occurring phospholipids, such as soybean lecithin; esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate; and condensation products of these metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and elixirs can be formulated with sweeteners such as glycerin, sorbitol, or sucrose. Such formulations may also contain modifiers, preservatives, flavoring agents, or coloring agents.

[0084] The pharmaceutical compositions of the present invention can be in the form of sterile injectable formulations, such as sterile injectable aqueous suspensions or oil suspensions. The suspensions can be formulated using suitable dispersants or wetting agents and suspending agents mentioned herein, according to known techniques. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, non-enteric-acceptable diluents or solvents, such as solutions in 1,3-butanediol, or prepared as lyophilized powders. Acceptable media and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils can conventionally be used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injections.

[0085] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific administration modality. For example, a timed-release formulation intended for oral administration to humans may contain about 1 mg to 1000 mg of the active substance mixed with a suitable and convenient amount of carrier material, which may comprise about 5% to about 95% (by weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable dosage amounts. For example, an aqueous solution intended for intravenous infusion may contain about 3 µg to 500 µg of active ingredient per mL of solution to allow for the infusion of a suitable volume at a rate of about 30 mL / hour.

[0086] Formulations for rectal administration may be available in suppository form with a suitable matrix, including, for example, cocoa butter or salicylates.

[0087] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners.

[0088] The formulation is present in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Temporary injectable solutions and suspensions are prepared from the aforementioned types of sterile powders, granules, and tablets. Preferred single-dose formulations are those containing the active ingredient at a daily dose or a sub-daily dose, or an appropriate portion thereof, as described above.

[0089] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations of the present invention may also include other conventional reagents in the art for the types of formulations discussed, such as flavoring agents for those suitable for oral administration.

[0090] The compounds described herein can also be formulated to provide controlled release of the active ingredient, thereby allowing for less frequent dosing or improving the pharmacokinetic or toxicological characteristics of the active ingredient. Therefore, compositions comprising one or more of the compounds described herein formulated for sustained or controlled release are also provided.

[0091] The effective dose of the active ingredient depends at least on the nature of the condition being treated, its toxicity, whether the compound is for prevention (lower dose) or for combating the active disease or condition, the method of delivery, and the pharmaceutical formulation, and will be determined by clinicians using routine dose-escalation studies. Effective doses are expected to be from about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, typically from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, more typically from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, and even more typically from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day. For example, a candidate daily dose for an adult weighing about 70 kg would be in the range of about 0.05 mg to about 100 mg, or about 0.1 mg to about 25 mg, or about 0.4 mg to about 4 mg, and may be in the form of a single dose or multiple doses.

[0092] SGK-1 and related symptoms This specification relates to compounds or pharmaceutically acceptable salts thereof for the treatment of various conditions that can be treated by inhibiting SGK-1. For example, the condition may be long QT syndrome (LQTS), such as hereditary or acquired LQTS, or other cardiovascular diseases that can be treated by inhibiting SGK-1 (e.g., dilated cardiomyopathy—hereditary or acquired). Without being bound by theory, it is believed that inhibition of SGK-1 in vivo has a protective effect and can alleviate symptoms associated with LQTS; it may reduce and alleviate symptoms associated with heart failure, arrhythmias, ischemic injury, ischemic infarction, cardiac fibrosis, angiogenesis, restenosis, hereditary or acquired dilated cardiomyopathy, hypertrophic cardiomyopathy, and stent failure.

[0093] Long QT syndrome (LQTS) can be hereditary (e.g., caused by mutations in the KCNQ1, KCNH2, or SCN5a genes). Alternatively, LQT syndrome can be acquired without genetic mutations due to exposure to external stimuli. For example, acquired LQT syndrome may be a side effect of medications such as erythromycin or haloperidol. Acquired LQT syndrome is also associated with other heart conditions such as myocardial ischemia.

[0094] This specification also relates to compounds or pharmaceutically acceptable salts thereof for the treatment of other conditions associated with SGK-1-mediated mechanisms, such as prostate cancer, colorectal cancer, breast cancer (e.g., drug-resistant breast cancer), Parkinson's disease, and Lafra disease.

[0095] Serine / threonine protein kinase (SGK-1) (also known as serum / glucocorticoid-regulated kinase 1) is a protein kinase that plays a role in cellular stress responses. In vivo, SGK-1 activates certain potassium, sodium, and chloride channels. For example, this protein is known to regulate inositol transporters during osmotic stress. As used herein, the term "SGK-1 inhibitor" refers to any compound that can block, inhibit, interfere with, or reduce the biological activity of SGK-1.

[0096] In some embodiments, the compounds of this specification can be used to increase fetal hemoglobin (HbF) in red blood cells. In some embodiments, the compounds of this specification can be used to treat β-hemoglobinopathies. In some embodiments, the compounds of this specification can be used to treat sickle cell disease.

[0097] In some embodiments, the compounds of this specification can be used to treat prostate cancer. In other embodiments, the compounds of this specification can be used to treat epilepsy.

[0098] SGK-1 inhibitors The compounds and pharmaceutically acceptable salts thereof described herein are pharmacologically active compounds that regulate protein kinase activity, particularly the activity of serum and glucocorticoid-regulated kinase isoform 1 (SGK-1). The compounds and pharmaceutically acceptable salts thereof may be indicated for the treatment of conditions in which SGK-1 activity is inadequate. Non-limiting examples of such conditions may include long QT syndrome, heart failure, arrhythmias, ischemic injury, ischemic infarction, cardiac fibrosis, angiogenesis, restenosis, dilated cardiomyopathy, stent failure, prostate cancer, and epilepsy. Other non-limiting examples of such conditions include β-hemoglobinopathies, such as sickle cell disease.

[0099] In one respect, compounds of formula I or pharmaceutically acceptable salts thereof are provided. Formula I In some implementations, Z is selected from the group consisting of: direct bond, -O-, -S-, -CH(R9), and -N(R). 10 )-, where R9 and R 10 Z is independently selected from the group consisting of H and (C1-C4)-alkyl groups. In some embodiments, Z is selected from the group consisting of: direct bond, -O-, -S-, -CH2-, and -NH-. In some embodiments, Z is a direct bond. In some embodiments, Z is selected from the group consisting of -O- and -NH-.

[0100] In some embodiments, R3 is selected from the group consisting of: H, (C1-C8)-alkyl, R 30 and (C1-C4)-alkyl-R 30 Wherein the (C1-C8)-alkyl group is unsubstituted or is substituent by one or more identical or different substituents R 31 Replace. R 30 It is a 3- to 12-membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic cyclic group comprising 0, 1, 2, or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the group is unsubstituted or substituented by one or more identical or different substituents R. 32 Replace. R 31 Choose from the following groups: halogen, -OH, -CF3, -O-(C1-C4)-alkyl, -N(R 33 )-R 34 and -CN. R 32 Choose from the group consisting of: halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, -(C1-C4)-alkyl-(C3-C7)-cycloalkyl, -(C1-C4)-alkyl-OR 37 -(C1-C4)-alkyl-N(R) 38 )-R 39 -(C1-C4)-alkyl-CN, -C(O)-(C1-C4)-alkyl, -CN, -OH, =O, -O-(C1-C4)-alkyl, -N(R 40 )-R 41 -C(O)-O-(C1-C4)-alkyl and -C(O)-N(R 42 )-R 43 .

[0101] In some implementation schemes, R 33 and R 34The groups selected independently from the following composition: H, (C1-C4)-alkyl, and (C3-C7)-cycloalkyl, wherein the (C1-C4)-alkyl and (C3-C7)-cycloalkyl are unsubstituted or substituents R of one or more identical or different substituents. 50 Replace, where R 50 The group selected is from the following: halogen, -OH, -O-(C1-C4)-alkyl, -CF3, and -CN. In some embodiments, R 37 R 38 R 39 R 40 R 41 R 42 and R 43 They are selected independently from the group consisting of H and (C1-C4)-alkyl groups.

[0102] In some implementations, R3 is selected from the group consisting of: H, -CH2OH, -CH3、 , , , , , , , , , , , , and .

[0103] In some embodiments, Z is a direct bond and R3 is selected from the group consisting of H, -CH2OH, and -CH3. In other embodiments, Z is selected from the group consisting of -O- and -NH- and R3 is selected from the group consisting of: , , , , , , , , , , , , and .

[0104] In some implementations, R1 is selected from the group consisting of: H, -N(R) 11 )R 12 -N(R)13 )-C(O)-R 14 -NR 13 -S(O)2-R 15 -NR 13 -C(O)-NH-R 16 -(C1-C4)-alkyl, -(C1-C4)-alkyl-OR 17 and -(C1-C4)-alkyl-N(R) 18 )R 19 , where R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 and R 19 They are selected independently from the group consisting of H and (C1-C4)-alkyl groups.

[0105] In some embodiments, R1 is selected from -(C1-C4)-alkyl and -(C1-C4)-alkyl-N(R 18 )R 19 The group to which it is composed. In some embodiments, R1 is selected from the group consisting of: -CH3, -CH2N(CH3)2 and -CH2-CH2-N(CH3)2.

[0106] In some embodiments, Y is selected from the group consisting of carbocyclic and heterocyclic groups, wherein the group is unsubstituted or substituted with one or more identical or different substituents R5, wherein R5 is selected from the group consisting of halogens, (C1-C4)-alkyl, -O-(C1-C4)-alkyl, and -CN. In some embodiments, Y is selected from the group consisting of aryl and heteroaryl groups, wherein the group is unsubstituted or substituted with one or more identical or different substituents R5.

[0107] In some implementations, Y is selected from the group consisting of: , , , , , , , and .

[0108] It should be understood that when listing two symmetrical Y groups, such as and ,or and This means there are two options: including and ,or and .

[0109] In some embodiments, A is selected from the group consisting of a direct bond or -CH2-. When A is a direct bond, -Y- is directly attached to the nitrogen of the sulfonamide group.

[0110] In some embodiments, R2 is selected from the group consisting of (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl, phenyl, and 5- or 6-membered monocyclic, saturated, partially unsaturated, or aromatic heterocyclic groups, wherein the heterocyclic group comprises 1, 2, or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is bonded via a cyclic carbon atom or a cyclic nitrogen atom, wherein R2 is unsubstituted or substituted with one or more identical or different substituents R 20 Replace, where R 20 Choose from the following groups: halogens, -CF3, (C1-C4)-alkyl, -OR 21 -N(R) 22 )R 23 (C1-C4)-alkyl-OR 24 (C1-C4)-alkyl-N(R) 25 )R 26 and -CN, and where R 21 R 22 R 23 R 24 R 25 and R 26 They are selected independently from the group consisting of H and (C1-C4)-alkyl groups.

[0111] In some embodiments, when Y is not 1,4-phenylene, or when Y is 1,4-phenylene and R1 is -(C1-C4)-alkyl-N(R 18 )R 19 When: R2 is selected from the group consisting of (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl, phenyl, and 5- or 6-membered monocyclic, saturated, partially unsaturated, or aromatic heterocyclic groups, wherein the heterocyclic group comprises 1, 2, or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is bonded via a cyclic carbon atom or a cyclic nitrogen atom, wherein R2 is unsubstituted or substituented by one or more identical or different substituents R 20 Replace, where R 20 Choose from the following groups: halogens, -CF3, (C1-C4)-alkyl, -OR21 -N(R) 22 )R 23 (C1-C4)-alkyl-OR 24 (C1-C4)-alkyl-N(R) 25 )R 26 and -CN, and where R 21 R 22 R 23 R 24 R 25 and R 26 They are selected independently from the group consisting of H and (C1-C4)-alkyl groups.

[0112] In other embodiments, when Y is 1,4-phenylene and R1 is H,-N(R 11 )R 12 , -N(R 13 )-C(O)-R 14 -NR 13 -S(O)2-R 15 -NR 13 -C(O)-NH-R 16 -(C1-C4)-alkyl or –(C1-C4)-alkyl-OR 17 In this case, R2 is selected from the group consisting of (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl, and 5- or 6-membered monocyclic, saturated or partially unsaturated heterocyclic groups, wherein the heterocyclic group comprises 1, 2 or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and is bonded via a cyclic carbon atom or a cyclic nitrogen atom, wherein R2 is unsubstituted or substituted by one or more identical or different substituents R 20 Replace, where R 20 Choose from the following groups: halogens, -CF3, (C1-C4)-alkyl, -OR 21 -N(R) 22 )R 23 (C1-C4)-alkyl-OR 24 (C1-C4)-alkyl-N(R) 25 )R 26 and -CN, and where R 21 R 22 R 23 R 24 R 25 and R 26 They are selected independently from the group consisting of H and (C1-C4)-alkyl groups.

[0113] In some implementations, R2 is selected from the group consisting of: -CH3、 , , , , , , , , , , , , , , , , , , , , , and .

[0114] In some embodiments, Y is 1,4-phenylene and R2 is selected from the group consisting of: -CH3, , , and .

[0115] In some embodiments, the compounds of formula I are selected from the group consisting of: , , , , , , and , Or its pharmaceutically acceptable salt.

[0116] In some embodiments, the compounds of formula I are selected from the group consisting of: , , , , , , , , , , , and Or, or a pharmaceutically acceptable salt thereof.

[0117] On the other hand, compounds of formula II or pharmaceutically acceptable salts thereof are provided: Formula II in: Z is selected from the following groups: O, CH2, S, and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 Select Free - (CH2) p -N(R 33 )R 34 The group formed; p is 1, 2, 3 or 4; R2 is selected from the group consisting of: a 5- or 6-membered monocyclic, aromatic, or heteroaromatic group containing 1, 2, or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein R2 is unsubstituted or substituented by one or more identical or different substituents R 20 replace; R 20 Choose from the following groups: halogen, -CF3, (C1-C4)-alkyl, -OR 21 , -N(R 22 )R 23 (C1-C4)-alkyl-OR 24 (C1-C4)-alkyl-N(R) 25 )R 26 and -CN; R 21 R 22 R 23 R 24 R 25 and R 26 Each is independently selected from the group consisting of H and (C1-C4)-alkyl groups; R 33 and R 34 The following groups are selected independently of each other: -CH=O, (C1-C4)-alkyl, and (C3-C7)-cycloalkyl, wherein the (C1-C4)-alkyl and (C3-C7)-cycloalkyl are each unsubstituted or substituented by one or more of the same or different substituents R. 50 Replace; and R 50 Choose from the following groups: halogens, -OH, -O-(C1-C4)-alkyl, CF3, and -CN.

[0118] In some embodiments, Z is NH. In other embodiments, Z is O. In some embodiments, R1 is methyl. In some embodiments, p is 2, 3, or 4.

[0119] In some implementations, R2 is selected from the group consisting of: , , , , , , , , , , , , , , and .

[0120] In some implementation schemes, R 33 It is methyl. In some embodiments, R 34 It is a methyl group.

[0121] In some implementations, R3 is selected from the following groups: , , , , and .

[0122] In some embodiments, the compound of formula II is selected from the group consisting of: , , , , , , , , , , and , Or its pharmaceutically acceptable salt.

[0123] In another aspect, compounds of formula II or pharmaceutically acceptable salts thereof are provided: Formula II in: Z is selected from the following groups: direct bond, O, S, CH(R9), and N(R). 10 ); R1 is selected from the following groups: H, -N(R) 11 )R 12 -N(R) 13 )-C(O)-R 14 , -NR 13 -S(O)2-R 15 -NR 13 -C(O)-NH-R 16 -(C1-C4)-alkyl, –(C1-C4)-alkyl-OR 17 and –(C1-C4)-alkyl-N(R) 18 )R 19 ; R3 is selected from the group consisting of: H, (C1-C8)-alkyl, R 30 and (C1-C4)-alkyl-R 30 Wherein the (C1-C8)-alkyl group is unsubstituted or is substituent by one or more identical or different substituents R 31 replace; R 30 It is a 3- to 12-membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic cyclic group comprising 0, 1, 2, or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the group is unsubstituted or substituented by one or more identical or different substituents R. 32 replace; R 31 Choose from the following groups: halogens, -OH, -CF3, -O-(C1-C4)-alkyl, -N(R 33 )-R 34 and -CN; R 32 Choose from the group consisting of: halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, -(C1-C4)-alkyl-(C3-C7)-cycloalkyl, -(C1-C4)-alkyl-OR 37 -(C1-C4)-alkyl-N(R) 38 )-R 39 -(C1-C4)-alkyl-CN, -C(O)-(C1-C4)-alkyl, -CN, -OH, =O, -O-(C1-C4)-alkyl, -N(R 40 )-R 41 -C(O)-O-(C1-C4)-alkyl and -C(O)-N(R42 )-R 43 ; R2 is a 6-membered monocyclic heteroaromatic group containing one or two nitrogen atoms, wherein R2 is unsubstituted or substituented by one or more identical or different substituents R. 20 replace; R 20 Choose from the following groups: halogen, -CF3, (C1-C4)-alkyl, -OR 21 , -N(R 22 )R 23 (C1-C4)-alkyl-OR 24 (C1-C4)-alkyl-N(R) 25 )R 26 and -CN; R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 21 R 22 R 23 R 24 R 25 R 26 R 37 R 38 R 39 R 40 R 41 R 42 and R 43 Each is independently selected from the group consisting of H and (C1-C4)-alkyl groups; R 33 and R 34 The groups selected independently from the following composition: H, (C1-C4)-alkyl, and (C3-C7)-cycloalkyl, wherein the (C1-C4)-alkyl and (C3-C7)-cycloalkyl are unsubstituted or substituents R of one or more identical or different substituents. 50 Replace; and R 50 Choose from the following groups: halogen, -OH, -O-(C1-C4)-alkyl, -CF3, and -CN.

[0124] In some embodiments, R1 is selected from -(C1-C4)-alkyl and -(C1-C4)-alkyl-N(R 18 )R 19The group to which it is composed. For example, in some embodiments, R1 is selected from the group consisting of: -CH3, -CH2N(CH3)2 and -CH2-CH2-N(CH3)2.

[0125] In some embodiments, Z is selected from the group consisting of -O- and -NH-. In some embodiments, R3 is selected from the group consisting of: , , , , , , , , , , , , and .

[0126] In some implementations, Z is a direct bond. In some implementations, R3 is selected from the group consisting of H, -CH2OH, and -CH3.

[0127] In some implementations, R2 is selected from the group consisting of: , , , , , , , , , , and , , , , and .

[0128] In some embodiments, the compound of formula II is selected from the group consisting of: , , , , , , and , Or its pharmaceutically acceptable salt.

[0129] In another aspect, a compound of formula III is provided: Formula III Or its pharmaceutically acceptable salt. in: Z is selected from the following groups: O, CH2, S, and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 Select Free - (CH2) p -N(R 33 )R 34 The group that makes up the group, in which the group -(CH2) p - The zero, one, or two hydrogen atoms are independently replaced by F; p is 1, 2, 3 or 4; R2 is selected from the group consisting of: a 5- or 6-membered monocyclic, aromatic, or heteroaromatic group containing 1, 2, or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein R2 is unsubstituted or substituented by one or more identical or different substituents R 20 replace; R 20 Choose from the following groups: halogen, -CF3, (C1-C4)-alkyl, -OR 21 -N(R) 22 )R 23 (C1-C4)-alkyl-OR 24 (C1-C4)-alkyl-N(R) 25 )R 26 and -CN; R 21 R 22 R 23 R 24 R 25 and R 26 Each is independently selected from the group consisting of H and (C1-C4)-alkyl groups; R 33 and R 34 The following groups are selected independently of each other: -CH=O, (C1-C4)-alkyl, and (C3-C7)-cycloalkyl, wherein the (C1-C4)-alkyl and (C3-C7)-cycloalkyl are each unsubstituted or substituented by one or more of the same or different substituents R. 50 replace; R 50 Choose from the following groups: halogen, -OR 27 -O-(C1-C4)-alkyl, -CF3, and -CN; R 27Choose from the group consisting of: H, -C(=O)-(C1-C4)-alkyl, natural amino acids bound by an α-carboxyl group, or P(=O)(OH)2; and W1, W2, W3, and W4 are independently selected from the following groups: H, halogen, -OR 21 -CF3, (C1-C4)-alkyl and -CN.

[0130] In some embodiments, Z is NH. In other embodiments, Z is O. In some embodiments, R1 is methyl. In some embodiments, p is 2, 3, or 4.

[0131] In some implementations, R2 is or Z1 and Z2 are independently selected from the group consisting of Cl, F, -OMe and -CN, and Z3 is selected from the group consisting of H, halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN.

[0132] In some implementations, R2 is selected from the group consisting of: , , , , , , ,and .

[0133] In some implementations, R2 is selected from the group consisting of: , , , , , and .

[0134] In some implementations, R2 is or In some implementations, R2 is... .

[0135] In some implementation schemes, R 33 =Methyl. In some embodiments, R 34 =Methyl.

[0136] In some implementations, R3 is selected from the following groups: , , , and , where R 51 It is (C1-C4)-alkyl.

[0137] In some implementation schemes: W1, W2, W3, and W4 are each H; W1 is F or Cl, and W2, W3, and W4 are each H; or W1 and W2 are each labeled F, and W3 and W4 are each labeled H.

[0138] In some embodiments, W1 is F or Cl, W2 is H, W3 is H, and W4 is H. In some embodiments, W1 is F, W2 is H, W3 is H, and W4 is H. In some embodiments, W1 is Cl, W2 is H, W3 is H, and W4 is H.

[0139] In another aspect, a compound of formula III is provided: Formula III Or its pharmaceutically acceptable salt. in: Z is selected from the group composed of O and NH; R1 is selected from the group consisting of H and (C1-C4)-alkyl groups; R3 Select Free - (CH2) p -N(R 33 )R 34 The group formed; p is 2, 3, or 4; R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; R 33 and R 34 Each is independently (C1-C4)-alkyl; W1, W2, W3, and W4 are independently selected from the following groups: H, halogen, -OR 21 -CF3, (C1-C4)-alkyl and -CN; and R 21 Choose from the group consisting of H and (C1-C4)-alkyl groups.

[0140] In some implementations, R1 is methyl.

[0141] In some implementations, R3 is selected from the following groups: , and .

[0142] In some implementations, R3 is .

[0143] In some implementations, R2 is selected from the group consisting of: , , , , , and .

[0144] In some implementations, R2 is or .

[0145] In some implementation schemes, W1, W2, W3, and W4 are each H; W1 is F, and W2, W3, and W4 are each H; or W1 and W2 are each labeled F, and W3 and W4 are each labeled H.

[0146] In some implementations, W1 is F, and W2, W3 and W4 are each H.

[0147] In some implementations, Z is NH.

[0148] In some implementations, compounds selected from the group consisting of: and Or, or a pharmaceutically acceptable salt thereof.

[0149] In another aspect, a compound of formula III is provided: Formula III Or its pharmaceutically acceptable salt. in: Z is selected from the group composed of O and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 is a nitrogen-containing heterocycle selected from the following groups: , , , , , , , , , , and In which zero, one, or two hydrogens on the -CH2- group of the nitrogen-containing heterocycle are substituted with halogen, -OH, -CN, -CF3, or (C1-C4)-alkyl; R 35 H or unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; and R 50 Choose from the following groups: halogens, -OH, -O-(C1-C4)-alkyl, CF3, and -CN; R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; W1 is F; W2 is either H or F; W3 is H; and W4 is H.

[0150] In some implementations, Z is O.

[0151] In some implementations, R2 is selected from the group consisting of: , , , , , , ,and .

[0152] In some implementations, R2 is selected from the group consisting of: , , , , , and .

[0153] In some implementations, R1 is methyl.

[0154] In some implementations, R3 is .

[0155] In some implementation schemes, R 35 It is methyl or isopropyl.

[0156] In some implementations, W2 is H.

[0157] In another aspect, a compound of formula III is provided: Formula III Or its pharmaceutically acceptable salt. in: Z is selected from the group composed of O and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 is a nitrogen-containing heterocycle selected from the following groups: , , , and In which zero, one, or two hydrogens on any of the -CH2- groups of the nitrogen-containing heterocycle are substituted with halogen, -OH, -CN, -CF3, or (C1-C4)-alkyl; R 35 H or unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; and R 50 Choose from the following groups: halogens, -OH, -O-(C1-C4)-alkyl, CF3, and -CN; R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; W1 is F, Cl, or OMe; W2 is either H or F; W3 is H; and W4 is H.

[0158] In some implementations, Z is O.

[0159] In some implementations, R1 is methyl.

[0160] In some implementations, R3 is .

[0161] In some implementation schemes, R 35 It is methyl or isopropyl.

[0162] In some implementations, W2 is H.

[0163] In some implementations, R2 is selected from the group consisting of: , , , , , and In some implementations, R2 is: or .

[0164] In some implementations, compounds selected from the group consisting of: and Or, or a pharmaceutically acceptable salt thereof.

[0165] In another aspect, a compound of formula III is provided: Formula III Or its pharmaceutically acceptable salt. in: Z is selected from the group composed of O and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 is a nitrogen-containing heterocycle selected from the following groups: , , , , , and In which zero, one, or two hydrogens on any of the -CH2- groups of the nitrogen-containing heterocycle are substituted with halogen, -OH, -CN, -CF3, or (C1-C4)-alkyl; R 35 H or unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; and R 50 Choose from the following groups: halogens, -OH, -O-(C1-C4)-alkyl, CF3, and -CN; R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; W1, W2, W3, and W4 are independently selected from the following groups: H, halogen, -OR 21 -CF3, (C1-C4)-alkyl and -CN, R 21 Choose from the group consisting of H and (C1-C4)-alkyl groups.

[0166] In some implementations, Z is O.

[0167] In some implementations, R1 is methyl.

[0168] In some implementations, R3 is or .

[0169] In some implementation schemes, R 35 It is methyl or isopropyl.

[0170] In some implementation schemes, W1 is H, F, Cl, or OMe; W2 is either H or F; W3 is H; and W4 is H.

[0171] In some implementations, W1 is F, W2 is H, W3 is H, and W4 is H. In some implementations, W1 is Cl, W2 is H, W3 is H, and W4 is H.

[0172] In some implementations, R2 is selected from the group consisting of: , , , , , and .

[0173] In some implementations, R2 is or .

[0174] In some implementations, compounds selected from the group consisting of: and , Or its pharmaceutically acceptable salt.

[0175] In another aspect, a compound of formula IV is provided: Formula IV Or its pharmaceutically acceptable salt. in: Z is selected from the group composed of O and NH; R3 can be selected from the following groups: -(CH2) p -N(R 33 )R 34 , , , and , p is 2, 3, or 4; R 33 and R 34 Independent of each other, either unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; R 35 H or unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; R 50 Choose from the following groups: halogen, -OR 27 -O-(C1-C4)-alkyl, -CF3, and -CN; R 27 Choose from the following groups: H, -C(=O)-(C1-C4)alkyl, natural amino acids bound by α-carboxyl groups, and P(=O)(OH)2; R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogens, (C1-C4) alkyl groups, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; and W1 is a halogen.

[0176] In some implementations, Z is O. In other implementations, Z is NH.

[0177] In some implementation schemes, R 27 Choose H or The group consists of -C(=O)-(C1-C4) alkyl groups.

[0178] In some implementations, R3 is -(CH2). p -N(R 33 )R 34 In some implementations, p = 2. In some implementations, R... 33 It is a methyl group.

[0179] In some implementation schemes, R 34 It is methyl. In other embodiments, R 34 It is -(CH2)2-OH or -(CH2)2-OC(=O)-(C1-C4)alkyl.

[0180] In some implementations, R3 is In some implementations, R 35 It is methyl or isopropyl.

[0181] In some implementations, R3 is In some implementations, R 35 For H.

[0182] In some implementations, Z-R3 is selected from the group consisting of: , , , and .

[0183] In some implementations, the Z-R3 is selected freely. and A group that is formed.

[0184] In some implementations, the Z-R3 is selected freely. and A group that is formed.

[0185] In some implementations, Z-R3 is .

[0186] In some implementations, W1 is F. In other implementations, W1 is Cl.

[0187] In some implementations, R2 is Z1 and Z2 can be independently selected from Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe.

[0188] In some implementations, R2 is or In some implementations, R2 is... .

[0189] In some implementations, R2 is Z3 can be selected from the group consisting of H, Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe, or the group consisting of H, -CH3, -CF3, -OCH(CH3)2 and -OMe, or the group consisting of -CH3, -OCH(CH3)2 and -OMe.

[0190] In some embodiments, the compound of formula IV is a compound of formula IVa: , Or its pharmaceutically acceptable salt. in: R2 can be selected from the following groups: , , , , , and ; W1 selects the group composed of Cl and F; and R 27 Choose from the following groups: H, , , , , , , and .

[0191] In some embodiments, the compound of formula IV is a compound of formula IVb: Or its pharmaceutically acceptable salt. in: R2 can be selected from the following groups: , , , , , and ;and W1 is selected from the group consisting of Cl and F.

[0192] In some embodiments, the compound of formula IV is a compound of formula IVc: , Or its pharmaceutically acceptable salt. in: R2 can be selected from the following groups: , , , , , and ; W1 selects the group composed of Cl and F; and R 35 Select from the group consisting of methyl and isopropyl groups.

[0193] In some embodiments, the compound of formula IV is a compound of formula IVd: , Or its pharmaceutically acceptable salt. in: R2 can be selected from the following groups: , , , , , and ;and W1 is selected from the group consisting of Cl and F.

[0194] In some embodiments, the compounds of formula IV are selected from the group consisting of: compounds numbered in Table A below: 28, 38, 78, 79, 84, 85, 99, 100, 101, 102, 103, 104, 105, 107, 106, 108, 109, 110, 111, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 12 6, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 155, 156, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173 and 174, or pharmaceutically acceptable salts thereof.

[0195] On the other hand, a compound of formula IV is provided: Formula IV Or its pharmaceutically acceptable salt. in: Z-R3 can be selected from the following groups: , and ; R27 Choose from the following groups: H, , , , , , , and ; R2 can be selected from the following groups: , , , , , and ;and W1 is selected from the group consisting of Cl and F.

[0196] In some implementations, W1 is Cl. In other implementations, W1 is F. In some implementations, R2 is... In some implementations, R 27 It is H. In some implementations, Z-R3 is H.

[0197] On the other hand, a compound of formula V is provided: Formula V Or its pharmaceutically acceptable salt. in: R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; W1 is selected from the group consisting of free hydrogen and halogens; R 33 -CH3 or -(CH2)-(CH2)-OR 27 ;and R 27 Choose from the following groups: H, -C(=O)-(C1-C4)alkyl, natural amino acids bound by α-carboxyl groups, and -P(=O)(OH)2.

[0198] In some implementations, W1 is F. In some implementations, W1 is Cl.

[0199] In some implementations, R2 is Z1 and Z2 can be independently selected from Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe.

[0200] In some implementations, R2 is or In some implementations, R2 is... .

[0201] In some implementations, R2 is Z3 can be selected from the group consisting of H, Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe, or the group consisting of H, -CH3, -CF3, -OCH(CH3)2 and -OMe, or the group consisting of -CH3, -OCH(CH3)2 and -OMe.

[0202] In some implementation schemes, R 33 For -CH3. In other implementations, R 33 -(CH2)-(CH2)-OR 27 In some implementations, R 27 Choose from the group consisting of H and -C(=O)-(C1-C4)alkyl groups.

[0203] In some embodiments, the compound of formula V is a compound of formula Va: , Or its pharmaceutically acceptable salt. in: R2 can be selected from the following groups: , , , , , and ; W1 selects the group composed of H, Cl, and F; and R 27 Choose from the following groups: H, , , , , , , and .

[0204] In some embodiments, the compound of formula V is a compound of formula Vb: Or its pharmaceutically acceptable salt. in: R2 can be selected from the following groups: , , , , , and ;and W1 is selected from the group consisting of H, Cl, and F.

[0205] In some embodiments, the compounds of formula V are selected from the group consisting of compounds numbered in Table A below: 9, 20, 22, 24, 27, 30, 38, 45, 72, 73, 78, 84, 85, 99, 100, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 150, 151, 152 and 153, or pharmaceutically acceptable salts thereof.

[0206] In one aspect, a compound of formula Vb is provided: Vb Or its pharmaceutically acceptable salt. in: R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogens, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; and W1 is selected from the group consisting of free hydrogen and halogens.

[0207] In some implementations, W1 is F. In other implementations, W1 is Cl.

[0208] In some implementations, R2 is Z1 and Z2 can be independently selected from Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe.

[0209] In some implementations, R2 is .

[0210] In some implementations, R2 is Z3 can be selected from the group consisting of H, Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe, or the group consisting of H, -CH3, -CF3, -OCH(CH3)2 and -OMe, or the group consisting of -CH3, -OCH(CH3)2 and -OMe.

[0211] In some embodiments, the compound of formula Vb is selected from compounds numbered 9, 38, 45, 84, 85 and 111 in Table A below, or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the compounds of formula Vb are selected from the group consisting of compounds 24, 27, 30, 73, 100, 103, 104, 105, 106, 107, 108, 109, 110, 113 and 112 numbered in Table A below, or pharmaceutically acceptable salts thereof.

[0213] On the other hand, a compound of formula VI is provided: Style VI Or its pharmaceutically acceptable salt. in: Y1 is either H or F; q is 0 or 1; R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; W1 is selected from the group consisting of free hydrogen and halogens; R 35 H or unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; R 50 Choose from the following groups: halogen, -OR 27 -O-(C1-C4)-alkyl -CF3 and -CN; R 27 Choose from the following groups: H, -C(=O)-(C1-C4)alkyl, natural amino acids bound by α-carboxyl groups, and P(=O)(OH)2.

[0214] In some implementations, Y1 is H.

[0215] In some embodiments, the compound of formula VI is selected from the group consisting of: , , Style VIa Style VIb and , Vic and Vid Or its pharmaceutically acceptable salt.

[0216] In some embodiments, the compound of formula VI is a compound of formula VIa: Or, or a pharmaceutically acceptable salt thereof.

[0217] In some implementations, q = 1.

[0218] In some implementations, W1 is F. In other implementations, W1 is Cl.

[0219] In some implementations, R2 is Z1 and Z2 can be independently selected from Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe.

[0220] In some implementations, R2 is .

[0221] In some implementations, R2 is Z3 can be selected from the group consisting of H, Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe, or the group consisting of H, -CH3, -CF3, -OCH(CH3)2 and -OMe, or the group consisting of -CH3, -OCH(CH3)2 and -OMe.

[0222] In some implementation schemes, R 27 Choose from the group consisting of H and -C(=O)-(C1-C4)alkyl groups.

[0223] In some implementation schemes, R 35 It is H, (C1-C4)-alkyl, or unsubstituted (C1-C4)-alkyl. In some embodiments, R 35 For H.

[0224] In some embodiments, the compound of formula VI is a compound of formula VIa: , Or its pharmaceutically acceptable salt. in: R2 can be selected from the following groups: , , , , , and ;and W1 is selected from the group consisting of H, Cl, and F.

[0225] In some embodiments, the compound of formula VI is selected from the group consisting of: compounds numbered in Table A below, 29, 41, 42, 44, 46, 47, 49, 50, 53, 54, 56, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67, 69, 70, 71, 92, 155 and 156, or pharmaceutically acceptable salts thereof.

[0226] For all embodiments relating to Formula VI described herein, the compound of Formula VI is preferably not a racemic form of Formula VIa: VIA Or its pharmaceutically acceptable salt. in: Y2 is either H or F; and R 52 Choose from the following groups: , , , , , , and .

[0227] Example Some abbreviations and acronyms are used in the description of the following experimental procedures and embodiments. Although most of these abbreviations and acronyms will be understood by those skilled in the art.

[0228] Preparation of compounds Use ACS-grade solvents and reagents without further purification.

[0229] Prepared compounds are typically characterized by spectroscopic and chromatographic data, particularly mass spectrometry (MS) and / or nuclear magnetic resonance (NMR) spectra. ¹H-NMR spectra are typically recorded at 600 MHz. In NMR characterization, the chemical shift δ (in ppm), number of hydrogen atoms (H), coupling constant J (in Hz), and peak multiplicity are given (s: singlet, d: doublet, dd: doublet, t: triplet, dt: doublett, m: multiplet; br: broad peak). In MS characterization, the mass number (m / z) of the peak of the molecular ion (M) or related ions such as ion [M+1], i.e., the protonated molecular ion [M+H] or ion [M-1], is given, depending on the ionization method used. Typically, the ionization method is electrospray ionization (ES+ or ES-).

[0230] Compound 1 N -(4-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1 H -pyrazolo[3,4- d ]pyrethrum (Pyridine-6-yl)phenyl)ethylenesulfonamide (i) 4,6-Dichloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine Commercially available 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (1.00 g, 5.29 mmol, 1.00 equivalent) was dissolved in THF (13.3 mL, 0.4 M) in a reaction vessel with a magnetic stir bar. Then, 3,4-dihydro-2H-pyran (2.42 mL, 26.5 mmol, 5.00 equivalent) and pyridinium 4-toluenesulfonate (66.3 mg, 0.264 mmol, 0.05 equivalent) were added at room temperature. The colorless reaction mixture was heated to 60 °C for 3 h (the solution turned pale yellow), cooled, and the evaporation was evaporated. The residue was dissolved in ethyl acetate (20 mL) and washed with saturated sodium bicarbonate aqueous solution (3 × 20 mL), dried over sodium sulfate, filtered, and evaporated to give the desired product (1.28 g, 94% yield) as a pale yellow solid.

[0231] (ii) 6-Chloro-4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine Under an argon atmosphere, 1-isopropylpiperidin-4-ol (498 mg, 3.30 mmol, 4.74 equivalents) was dissolved in anhydrous THF (5.00 mL) in a reaction vessel with a magnetic stir bar, and the mixture was cooled on an ice bath. Sodium hydride (26.5 mg, 60% suspension in mineral oil) was then added, and the mixture was stirred on an ice bath for approximately 30 min. 4,6-Dichloro-3-methyl-1-(tetrahydro-pyran-2-yl)1H-pyrazolo-3,4-pyrimidine (200 mg, 0.70 mmol, 1.00 equivalents) dissolved in THF (2.00 mL) was added. The ice bath was removed, and the mixture was stirred at room temperature until complete conversion of the starting material was observed by TLC (AcOEt / hexane). The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over sodium sulfate, filtered, and evaporated. The crude product was purified by silica gel rapid chromatography using a mixture of ethyl acetate and hexane as the eluent. Evaporation yielded the desired product (241 mg, 88% yield) as a colorless oil. LCMS (ESI, m / z): 394.5 [M+H]+.

[0232] (iii) N -(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)ethylenesulfonamide Ethylenesulfonyl chloride (217 µL, 2.28 mmol, 1.00 equivalent) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)aniline (500 mg, 2.28 mmol, 1.00 equivalent) were added to a reaction vessel containing a magnetic stir bar, followed by 9.58 mL of anhydrous DCM and 196 µL of pyridine. The reaction mixture was stirred at room temperature. After 20 h, the reaction mixture was cooled in an ice bath and quenched with 1 M aqueous sodium hydroxide solution (forming a yellow solution). The organic phase was separated, and the aqueous phase was acidified with 2 M aqueous hydrochloric acid solution (forming a white precipitate) and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and evaporated to give the crude product. Purification was performed by silica gel rapid chromatography using a mixture of ethyl acetate and hexane as the eluent to give the desired product as a white solid (234 mg, 33% yield). LCMS (ESI, m / z): 309.2 [M+H]+.

[0233] (iv) N -(4-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1 H -pyrazolo[3,4- d Pyrimidine-6- phenyl sulfonamide Will N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)ethanesulfonamide (60.0 mg, 1.00 equivalent) was added together with MK0016 (76.4 mg, 1.00 equivalent) to a reaction vessel containing a magnetic stir bar. BDFP (11.3 mg) and cesium carbonate (196 mg, 2.2 equivalent), followed by 1.94 mL of dioxane and 324 µL of water, were added, and the mixture was heated to 100 °C with stirring. The reaction was monitored by LC-MS. After 3 h, the reaction mixture was cooled to room temperature and quenched with a saturated aqueous solution of sodium bicarbonate (10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined aqueous phases were dried over sodium sulfate, filtered, and evaporated to give a crude product as a brown oil.

[0234] The crude product was dissolved in a mixture of 4M HCl in Diox (1 mL) and iPrOH (1 mL) and stirred at room temperature for 2 h, then the solvent was evaporated. The reaction was monitored by LC-MS. The crude product was purified by elution with a water / MeCN gradient containing 0.1% TFA through a C18 reversed-phase column. The fraction containing the product was lyophilized to give the desired pure product (18 mg, 20% yield) as a grayish-white TFA salt. LCMS (ESI, m / z): 457.7 [M+H]+. 1 H NMR (600MHz, DMSO- d 6) δ 13.49(brs, 1H), 10.40 (d, J=12.75Hz, 1 H), 9.41 (br s, 1 H), 8.37 (dd, J=18.80,8.99Hz, 2 H), 7.29 (dd, J=8.57, 4.81Hz, 2 H), 6.20 (dd, J= 17.61, 5.14Hz,1H), 6.13 - 6.00 (m, 2H), 5.93-5.57 (m, 1H), 3.65 - 3.11 (m, 7H), 2.59 (s,3H), 2.38 - 2.17 (m, 2H), 2.00 (t, J=13.57, 1 H), 1.32 (d, J = 6.88Hz, 6H).

[0235] Compound 2 N -(4-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1 H -pyrazolo[3,4- d ]pyrethrum (Pyridine-6-yl)phenyl)pyrrolidine-1-sulfonamide The compound was prepared according to the procedure described in Example 1. The desired product (5.6 mg, 8% yield) was obtained as a grayish-white TFA salt. LCMS (ESI, m / z): 500.7 [M+H]+. 1H NMR (600MHz, DMSO- d 6) δ 13.47(brs, 1H), 10.21 (d, J=14.67Hz, 1 H), 9.39 (br s, 1 H), 8.37 (dd, J=18.66,9.03Hz, 2 H), 7.33 (br t, J=8.76Hz, 2 H) , 5.87-5.66 (m,1H), 3.58 - 3.36 (m,10H), 2.59 (s, 3H), 2.40-2.16 (m, 2H), 2.11-1.93 (m, 1H),1.76-1.69 (m, 4H) ,1.46 -1.41 (m, 1H), 1.32 (d, J = 6.9Hz, 6H).

[0236] Compound 3,4-cyano- N -(4-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1 H -pyrazolo[3, 4- d ]pyrimidin-6-yl)phenyl)benzenesulfonamide The compound was prepared according to the procedure described in Example 1. The desired product (103 mg, 75% yield) was obtained as a grayish-white TFA salt. LCMS (ESI, m / z): 532.4 [M+H]+. 1 H NMR (600MHz, DMSO- d 6) δ 13.51(br s, 1H), 10.95-10.93 (m, 1H), 9.43 (br d, 1H), 8.41 - 8.30 (m, 2H), 8.08 -7.96 (m, 4H), 7.27 - 7.25 (m, 2H), 5.83 - 5.62 (m, 1H), 3.58 - 3.18 (m, 9H),2.58 - 2.50 (m, 1H), 2.58 (s, 3H), 2.33 - 2.18 (m, 2H), 2.01-1.96(m, 1H),1.30 (d, J = 6.6Hz, 6H).

[0237] Compound 4 4-(aminomethyl)- N -(4-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1 H -Pyrazole and [3,4- d ]pyrimidin-6-yl)phenyl)benzenesulfonamide A solution of compound 3 (33.5 mg, 0.07 mmol, 1.00 equivalent) in methanol (630 µL, 0.1 M) was treated at 0 °C with cobalt(II) chloride (16.4 mg, 0.13 mmol, 2.00 equivalent), and the resulting mixture was stirred for 5 min before the addition of sodium borohydride (23.8 mg, 0.63 mmol, 10.0 equivalent). The resulting suspension was gradually warmed to room temperature. After 16 hours, 10 mL of 3N hydrochloric acid solution was added and the mixture was stirred for 10 min, followed by the addition of 1 mL of 880 ammonia solution. The crude product was purified by elution using a C18 reversed-phase column with a water / MeCN gradient containing 0.1% TFA. The fraction containing the product was lyophilized to give the desired pure product (15.7 mg, 47% yield) as a grayish-white TFA salt. LCMS (ESI, m / z): 536.7 [M+H]+. 1 H NMR(400MHz, CDCl3): δ 13.45 (br s, 1H), 10.91-10.65 (m, 1H), 9.43-9.17 (br d1H), 8.29 (d, J= 8.6Hz, 2H), 8.19 (br, s, 2H), 7.87 (dd, J=8.21, 3.91Hz, 2H),7.60 (d, J=8.60, 2H), 7.25 (dd, J=8.79, 4.10Hz, 2H), 5.92-5.47 (m, 1H),3.70-3.05 (m, 10H), 2.55 (s, 3H), 2.38 - 2.10 (m, 2H), 2.02-1.89(m, 1H),1.28(d, J = 6.6Hz, 6H).

[0238] Compound 5 N -(4-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1 H -pyrazolo[3,4- d ]pyrethrum (Pyridine-6-yl)phenyl)propane-2-sulfonamide The compound was prepared according to the procedure described in Example 1. The desired product (82.7 mg, 67% yield) was obtained as a grayish-white TFA salt. LCMS (ESI, m / z): 473.5 [M+H]+. 1 H NMR (600MHz, DMSO- d6) δ13.45 (br s, 1H), 10.14-10.12 (m, 1H), 9.31 (br s, 1H), 8.41 - 8.36 (m, 2H), 7.39 - 7.36 (m, 1H), 5.86 - 5.55 (m, 1H), 3.57 - 3.18 (m, 5H), 2.58 (s, 3H), 2.30 - 2.21 (m, 2H), 1.99 -1.97 (m, 1H), 1.47-1.41 (m, 2H), 1.30 (d, J =6.6Hz, 6H).

[0239] Compound 6 N -(4-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1 H -pyrazolo[3,4- d ]pyrethrum (Pyridine-6-yl)phenyl)piperidine-1-sulfonamide The compound was prepared according to the procedure described in Example 1. The desired product (11.9 mg, 14% yield) was obtained as a grayish-white TFA salt. LCMS (ESI, m / z): 514.6 [M+H]+. 1 H NMR (600MHz, CDCl3): δ13.46 (br, s, 1H), 10.32-10.17(m, 1H), 9.24(br,d, 1H), 8.35 (dd, J=12.5,8.99Hz, 2H), 7.42 - 7.15 (m, 2H), 5.85 (m, 1H), 3.39 - 2.89 (m, 10H), 2.58 (s, 3H), 2.38 - 2.12 (m, 3H), 2.01-1.89 (m, 1H), 1.41-1.38 (m, 6H), 1.29 (d,J = 6.64Hz, 6H).

[0240] Compound 7 N -(4-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1 H -pyrazolo[3,4- d ]pyrethrum (Pyridine-6-yl)phenyl)pyridine-2-sulfonamide The compound was prepared according to the procedure described in Example 1. The desired product (113 mg, 79% yield) was obtained as a grayish-white TFA salt. LCMS (ESI, m / z): 508.6 [M+H]+. 1 H NMR (600MHz, DMSO- d6) δ 13.49(br s, 1H), 10.91-10.89 (m, 1H), 9.41 (br s, 1H), 8.96 - 8.90 (m, 1H), 8.80 -8.78 (m, 1H), 8.36 - 8.19 (m, 3H), 7.63 -7.60 (m, 1H), 7.27 - 7.25 (m, 2H),5.83 - 5.61 (m, 1H), 3.57 - 3.18 (m, 5H), 2.58 (s, 3H), 2.30 - 2.21 (m, 2H),1.99 -1.97 (m, 1H), 1.47-1.41 (m, 2H), 1.30 (d, J = 6.6Hz, 6H).

[0241] Compound 8, 5-chloro- N -(4-(4-(2-(dimethylamino)ethoxy)-3-methyl-1 H -pyrazolo[3,4- d ]pyrethrum (Pyridine-6-yl)phenyl)-2-fluorobenzenesulfonamide (i) 5-Chloro-2-Fluoro- N -[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl]benzene sulfonamide Under N2 conditions, 5-chloro-2-fluorobenzenesulfonyl chloride (1.00 g, 4.36 mmol, 1.00 equivalent), dichloromethane (10 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)aniline (0.956 g, 4.36 mmol, 1.00 equivalent), and pyridine (0.345 g, 4.36 mmol, 1.00 equivalent) were charged into a 50-mL three-necked round-bottom flask. The reaction mixture was stirred overnight at room temperature and diluted with dichloromethane (50 mL). The resulting mixture was washed with water (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate / hexane (1 / 3) elution to give the desired product, 5-chloro-2-fluoro-2-yl, as a pale yellow solid. N -[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]benzenesulfonamide (1.03 g, 57% yield). LCMS (ESI, m / z): 412 [M+H]+.

[0242] (ii) 2-[[6-chloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-yl]oxy]eth dimethylamine To a 20-mL vial, add 4,6-dichloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidine (75.0 mg, 0.261 mmol, 1.00 equivalent), dimethylaminoethanol (23.8 mg, 0.261 mmol, 1.00 equivalent), potassium carbonate (72.2 mg, 0.522 mmol, 2.00 equivalent), and acetonitrile (3 mL). Stir the resulting solution overnight at room temperature. Filter off the solid and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography with elution of dichloromethane / methanol (95 / 5) to give the desired product (65.0 mg, 73% yield) as a grayish-white solid. LCMS (ESI, m / z): 340 [M+H]+.

[0243] (iii) 5-Chloro- N -(4-(4-(2-(dimethylamino)ethoxy)-3-methyl-1 H -pyrazolo[3,4- d ]pyrethrum (Pyridine-6-yl)phenyl)-2-fluorobenzenesulfonamide Under N2 atmosphere, 5-chloro-2-fluoro- N-[ 4-(4,4,5,5-Tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]benzenesulfonamide (87.3 mg, 0.212 mmol, 1.20 equivalents), (2-[[6-chloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-yl]oxy]ethyl)dimethylamine (60.0 mg, 0.177 mmol, 1.00 equivalents), 1,4-dioxane (2 mL), water (0.2 mL), cesium carbonate (115 mg, 0.353 mmol, 2.00 equivalents), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (14.4 mg, 0.0180 mmol, 0.10 equivalents). The resulting solution was stirred overnight at 100 °C. The solid was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase column chromatography under the following conditions (column: Agela C18 column, 120 g; mobile phase A: water (0.05% TFA); mobile phase B: ACN; flow rate: 40 mL / min; gradient: 0% B to 45% B over 45 min; detector: 220 nm) to obtain the desired product 5-chloro- N-( 4-[4-[2-(dimethylamino)ethoxy]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl]phenyl)-2-fluorobenzenesulfonamide (50.0 mg, 40% yield). LCMS (ESI, m / z): 589 [M+H]+.

[0244] Add 5-chloro- to a 25-mL two-necked round-bottom flask N-(4-[4-[2-(dimethylamino)ethoxy]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl]phenyl)-2-fluorobenzenesulfonamide (54.0 mg, 0.092 mmol, 1.00 equivalent), isopropanol (2.6 mL), and 1,4-dioxane (1.5 mL) in 2 M hydrochloric acid (gas). The resulting solution was stirred at room temperature for 3 h and concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: Xselect CSH OBD column 30 × 50 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18% B to 38% B over 7 min; detector: 220 nm) to give the desired product 5-chloro- N -(4-(4-(2-(dimethylamino)ethoxy)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-2-fluorobenzenesulfonamide (12.7 mg, 27% yield). LCMS (ESI, m / z): 505 [M+H]+. 1 H NMR (400MHz, DMSO-) d 6) δ 13.42 (s, 1H), 10.82 (s, 1H), 8.35 - 8.21 (m, 2H), 7.86 - 7.84 (m,1H), 7.74 - 7.72 (m, 1H), 7.47 (t, J = 8.0Hz, 1H), 7.26 - 7.17 (m, 2H), 4.75 (t, J = 4.0Hz, 2H), 2.89 (t, J = 6.0Hz, 2H), 2.50 (s, 3H), 2.36 (s, 6H).

[0245] Compound 9 5-chloro- N -(4-(4-((2-(dimethylamino)ethyl)amino)-3-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)phenyl)-2-fluorobenzenesulfonamide (i) 6-Chloro- N -[2-(dimethylamino)ethyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d] Pyrimidine-4-amine To an 8-mL vial, add 4,6-dichloro-3-methyl-1-(tetrahydropyran-2-yl)-2H,3H-pyrazolo[3,4-d]pyrimidine (74.3 mg, 0.259 mmol, 1.00 equivalent), (2-aminoethyl)dimethylamine (22.8 mg, 0.259 mmol, 1.00 equivalent), dichloromethane (3.0 mL), and triethylamine (57.7 mg, 0.571 mmol, 2.20 equivalent). Stir the resulting solution overnight at room temperature and concentrate under reduced pressure. Purify the residue by silica gel column chromatography with dichloromethane / methanol (95 / 5) elution to give the desired product, 6-chloro-, as a colorless solid. N -[2-(dimethylamino)ethyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidine-4-amine (55.0 mg, 62% yield). LCMS (ESI, m / z): 339 [M+H]+.

[0246] (ii) 5-Chloro- N -(4-(4-((2-(dimethylamino)ethyl)amino)-3-methyl-1 H -pyrazolo[3,4- d ] Pyrimidin-6-yl)phenyl)-2-fluorobenzenesulfonamide Add 5-chloro-2-fluoro- to an 8-mL vial N -[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]benzenesulfonamide (69.2 mg, 0.168 mmol, 1.00 equivalent), 6-chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidine-4-amine (similar to the procedure described in Example 8, derived from 6-chloro-3-methyl Preparation of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (57.0 mg, 0.168 mmol, 1.00 equivalent), 1,4-dioxane (2.9 mL), water (0.3 mL), cesium carbonate (109 mg, 0.336 mmol, 2.00 equivalent), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (13.7 mg, 0.0170 mmol, 0.10 equivalent). The resulting solution was stirred overnight at 100 °C. The solid was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase column chromatography under the following conditions (column: Agela C18 column, 120 g; mobile phase A: water (0.05% TFA); mobile phase B: ACN; flow rate: 40 mL / min; gradient: 0% B to 55% B over 45 min; detector: 220 nm) to obtain the desired product 5-chloro- N -[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide (50.0 mg, 51% yield). LCMS (ESI, m / z): 588 [M+H]+.

[0247] Add 5-chloro- to a 25-mL two-necked round-bottom flask N -[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide (55.0 mg, 0.094 mmol, 1.00 equivalent), isopropanol (3 mL), and 1 mL of 1,4-dioxane solution in 2 M hydrochloric acid (gas). The resulting solution was stirred at room temperature for 3 h and concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: Xselect CSH OBD column 30 × 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18% B to 38% B over 7 min; detector: 220 nm) to give the desired product 5-chloro- N -[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide (13.6 mg, 29% yield). LCMS (ESI, m / z): 504 [M+H]+. 1 H NMR (400MHz, DMSO-) d 6 ): δ 12.95 (s, 1H), 10.69 (s, 1H), 8.27 - 8.20 (m, 2H), 7.83(dd, J = 6.0, 2.7Hz, 1H), 7.73 (dt, J = 8.6, 3.4Hz, 1H), 7.46 (t, J = 9.2Hz,1H), 7.16 (d, J = 8.5Hz, 2H), 7.02 (d, J = 6.2Hz, 1H), 3.79 - 3.71 (m, 2H), 2.74 (s, 2H), 2.51 (s, 3H), 2.38 (s, 6H).

[0248] Compound 10 5-chloro- N -(4-(4-(4-(dimethylamino)butoxy)-3-methyl-1 H -pyrazolo[3,4- d ] Pyrimidin-6-yl)phenyl)-2-fluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 8. The desired product (18.4 mg, 39% yield) was obtained as a grayish-white solid. LCMS (ESI, m / z): 519 [M+H]+. 1 H NMR (300MHz, DMSO-d 6) δ 13.39(s, 1H), 8.33 - 8.17 (m, 2H), 7.84 - 7.81 (m, 1H), 7.71 - 7.69 (m, 1H), 7.43(t, J = 9.0Hz, 1H), 7.31 - 7.10 (m, 2H), 4.65 (t, J = 6.0Hz, 2H), 2.67 (t, J= 6.0Hz, 2H), 2.50 (s, 3H), 2.36 (s, 6H), 2.08 - 1.99 (m, 2H).

[0249] Compound 11 5-chloro- N -(4-(4-((4-(dimethylamino)butyl)amino)-3-methyl-1 H -pyrazolo[3, 4- d ]pyrimidin-6-yl)phenyl)-2-fluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 9. The desired product (17.3 mg, 40% yield) was obtained as a grayish-white solid. LCMS (ESI, m / z): 518 [M+H]+. 1H NMR (400MHz, DMSO- d 6): δ12.90 (s, 1H), 8.21 (d, J = 8.5Hz, 2H), 7.82 (dd, J = 6.0, 2.7Hz, 1H), 7.69(s, 1H), 7.44 (t, J = 9.0Hz, 2H), 7.13 (d, J = 8.5Hz, 2H), 3.69 - 3.62 (m,2H), 2.57 (s, 2H), 2.51 (s, 3H), 2.32 (s, 6H), 1.90 - 1.82 (m, 2H).

[0250] Compound 12, 5-chloro-2-fluoro- N -(5-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1 H -pyrazol [3,4- d Pyrimidin-6-yl)pyrimidin-2-yl)benzenesulfonamide (i) N -(5-bromopyrimidin-2-yl)-5-chloro-2-fluorobenzenesulfonamide At -40 °C under N2, lithium hexamethyldisilamide (9.00 mL, 9.00 mmol, 1.05 equivalent, 1 M solution in THF) was added dropwise to a solution of 5-bromopyrimidin-2-amine (1.50 g, 8.62 mmol, 1.00 equivalent) in tetrahydrofuran (60 mL). The resulting mixture was stirred at -40 °C for 0.5 h and then at room temperature for 1 h. A solution of 5-chloro-2-fluorobenzenesulfonyl chloride (2.40 g, 10.5 mmol, 1.20 equivalent) in tetrahydrofuran (5 mL) was then added dropwise at -40 °C. The resulting mixture was stirred at -40 °C for 1 h and then at room temperature for 16 h. The reaction mixture was quenched at 0 °C with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0-15% ethyl acetate / petroleum ether, to give the desired product (750 mg, 24% yield) as a yellow solid. LCMS (ESI, m / z): 366 [M+H]+.

[0251] (ii) 5-Chloro-2-Fluoro- N -[5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)pyrimidine-2- [Benzenesulfonamide] Will N A mixture of 5-bromopyrimidin-2-yl)-5-chloro-2-fluorobenzenesulfonamide (700 mg, 1.53 mol, 1.00 equivalent), bis(pinacolyl)diboron (900 mg, 3.54 mmol, 2.30 equivalent), potassium acetate (380 mg, 3.87 mmol, 2.50 equivalent), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (112 mg, 0.150 mmol, 0.10 equivalent) in 1,4-dioxane (30 mL) was stirred at 85 °C under N2 for 16 hours and diluted with water (100 mL). The mixture was extracted with ethyl acetate (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography under the following conditions (column: Agela C18 column; mobile phase A: water; mobile phase B: ACN; flow rate: 40 mL / min; gradient: 0% B to 80% B over 7 min; detector: 220 nm) to obtain the desired product (140 mg, 18% yield) as a pale yellow solid. LCMS (ESI, m / z): 332 [M+H-82]+ (iii) 5-Chloro-2-Fluoro- N -(5-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1-(tetrahydro-2H-) pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidin-2-yl)benzenesulfonamide 5-chloro-2-fluoro N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrimidin-2-yl]benzenesulfonamide (90.0 mg, 0.220 mmol, 1.20 equivalents), 4-[[6-chloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-yl]oxy]-1-isopropylpiperidine (prepared from 6-chloro-3-methyl-1H-pyrazolo3,4-dipyrimidin using a procedure similar to that described in Example 1). The mixture of sodium bicarbonate (75.0 mg, 0.190 mmol, 1.00 equivalent), sodium bicarbonate (31 mg, 0.370 mmol, 2.00 equivalent), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichlorochloride (16.00 mg, 0.022 mmol, 0.10 equivalent) in 1,4-dioxane (3.5 mL) / ethanol (1.5 mL) / water (2.0 mL) was stirred at 80 °C under N2 for 2 h and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography under the following conditions (column: Agela C18 column, 120 g; mobile phase A: water (0.05% TFA); mobile phase B: ACN; flow rate: 40 mL / min; gradient: 30% B to 80% B over 7 min; detector: 220 nm) to give the desired product (30.0 mg, 25% yield) as a pale yellow solid. LCMS (ESI, m / z): 645 [M+H]+.

[0252] (iv) 5-Chloro-2-Fluoro- N -(5-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1 H -pyrazolo[3, 4- d Pyrimidin-6-yl)pyrimidin-2-yl)benzenesulfonamide At 0°C, 5-chloro-2-fluoro- N -(5-[4-[(1-isopropylpiperidin-4-yl)methyl]-3-methyl-1-(tetrahydropyran-2-yl)-2H,3H-pyrazolo[3,4-d]pyrimidin-6-yl]pyrimidin-2-yl)benzenesulfonamide (30.0 mg, 0.046 mmol, 1.00 equivalent) was added to a solution of 1,4-dioxane in 4 M HCl (gas) in 2 mL of methanol. The resulting mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: XSelect CSH preparative C18 OBD column, 19 × 250 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 54% B to 74% B over 8 min; detector: 254 nm) to obtain the desired product (8.4 mg, 32% yield) as a white solid. LCMS (ESI, m / z): 561 [M+H]+. 1 H NMR (300MHz, DMSO- d6) δ 13.62 (brs, 1H), 9.36 - 9.10 (m, 2H), 7.99 - 7.82 (m, 1H), 7.82 - 7.79(m, 1H), 7.50 (t, J = 8.7Hz, 1H), 5.91 - 5.71 (m, 1H), 3.57 - 3.06 (m, 9H), 2.58 - 2.50 (m, 1H), 2.31 - 1.82 (m, 3H), 1.30 (d, J = 6.6Hz, 6H).

[0253] Compound 13 5-chloro-2-fluoro- N -(4-(3-methyl-4-((pyridin-4-ylmethyl)amino)-1 H -pyrazolo[3, 4- d ]pyrimidin-6-yl)phenyl)benzenesulfonamide (i) 6-Chloro-3-methyl-1-(tetrahydropyran-2-yl)- N -(pyridin-4-ylmethyl)pyrazolo[3,4-d]pyrimidine- 4-amine To a 20-mL vial, add 4,6-dichloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidine (150 mg, 0.522 mmol, 1.00 equivalent), dichloromethane (3 mL), 4-pyridinemethylamine (62.1 mg, 0.575 mmol, 1.10 equivalent), and trimethylamine (58.2 mg, 0.575 mmol, 1.10 equivalent). Stir the resulting solution overnight at room temperature and quench with water (10 mL). Extract the mixture with dichloromethane (3 × 10 mL), combine the organic layers, wash with water (3 × 10 mL), dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by reversed-phase column chromatography under the following conditions (column: Agela C18 column, 120 g; mobile phase A: water; mobile phase B: ACN; flow rate: 40 mL / min; gradient: 5% B to 95% B over 35 min; detector: 220 nm) to obtain the desired product (120 mg, 64% yield) as a grayish-white solid. LCMS (ESI, m / z): 359 [M+H]+.

[0254] (ii) 5-Chloro-2-Fluoro- N -(4-(3-methyl-4-((pyridin-4-ylmethyl)amino)-1 H -pyrazolo[3,4- d ] Pyrimidin-6-yl)phenyl)benzenesulfonamide The desired product (20.0 mg, 51% yield) in beige solid form was obtained following the general procedure described in Example 1. LCMS (ESI, m / z): 524 [M+H]+. 1 H NMR (300MHz, DMSO- d6): δ 13.03 (s, 1H), 11.00(s, 1H), 8.52 - 8.44 (m, 2H), 8.17 - 8.08 (m, 2H), 7.84 (dd, J = 6.0, 2.7Hz,2H), 7.76 (ddd, J = 8.8, 4.1, 2.7Hz, 1H), 7.54 - 7.42 (m, 1H), 7.46 - 7.38(m, 2H), 7.21 - 7.10 (m, 2H), 4.83 (d, J = 5.7Hz, 2H), 2.61 (s, 3H).

[0255] Compound 14 5-Chloro-2-Fluoride N -((5-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1H-pyrazole [3,4-d]pyrimidin-6-yl)furan-2-yl)methyl)benzenesulfonamide-2,2,2-trifluoroacetaldehyde (i) 5-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyran Azo[3,4-d]pyrimidin-6-yl)furan-2-carbaldehyde A mixture of 4-[[6-chloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-yl]oxy]-1-isopropylpiperidine (prepared from 6-chloro-3-methyl-1H-pyrazolo3,4-dipyrimidine using a procedure similar to that described in Example 1) (500 mg, 1.27 mmol, 1.00 equivalent) and 5-formylfuran-2-ylboronic acid (300 mg, 2.14 mmol, 1.69 equivalent), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (103 mg, 0.140 mmol, 0.11 equivalent) and cesium carbonate (799 mg, 2.45 mmol, 1.93 equivalent) in 1,4-dioxane (12 mL) and water (2 mL) was stirred at 100 °C under N2 for 4 hours and quenched with water (50 mL). The mixture was extracted with ethyl acetate (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with 0-100% ethyl acetate / petroleum ether to give 5-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)furan-2-carboxaldehyde (450 mg, 78% yield) as a pale brown solid. LCMS (ESI, m / z): 454 [M+H]+.

[0256] (ii) (E)-5-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)furan-2-carboxaldehyde oxime A mixture of 5-[4-[(1-isopropylpiperidin-4-yl)oxy]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl]furan-2-carboxaldehyde (430 mg, 0.95 mmol, 1.00 equivalent), sodium acetate (172 mg, 2.10 mmol, 2.20 equivalent), and hydroxylamine hydrochloride (86.0 mg, 1.24 mmol, 1.30 equivalent) in ethanol (20 mL) was stirred at 50 °C for 1 h and concentrated under reduced pressure. The residue was diluted with water (50 mL). The mixture was extracted with ethyl acetate (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give (E)-5-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)furan-2-carboxaldehyde oxime (350 mg, crude product), which was used in the next step without any further purification. LCMS (ESI, m / z): 469 [M+H]+.

[0257] (iii) (5-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)furan-2-yl)methylamine To (E)- N -[(5-[4-[(1-isopropylpiperidin-4-yl)oxy]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl]furan-2-yl)methylene]hydroxylamine (300 mg, 0.64 mmol, 1.00 equivalent) was added to a solution of acetic acid (10 mL) with zinc powder (419 mg, 6.39 mmol, 10.0 equivalent). The resulting mixture was stirred at 50 °C for 2 h. The solid was filtered off, and the filter cake was washed with acetic acid (2 × 10 mL). The combined filtrates were concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography under the following conditions (column: Agela C18 column, 120 g; mobile phase A: water (0.05% TFA); mobile phase B: ACN; flow rate: 40 mL / min; gradient: 50% B to 80% B over 10 min; detector: 254 nm) to give (5-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)furan-2-yl)methylamine (50.0 mg, 17% yield) as a light brown solid. LCMS (ESI, m / z): 455 [M+H]+.

[0258] 5-Chloro-2-Fluoro- N -((5-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)furan-2-yl)methyl)benzenesulfonamide At 0 °C under N2, 5-chloro-2-fluorobenzenesulfonyl chloride (27.0 mg, 0.110 mmol, 1.00 equivalent) was added to a solution of 1-(5-[4-[(1-isopropylpiperidin-4-yl)oxy]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl]furan-2-yl)methylamine (50.0 mg, 0.110 mmol, 1.00 equivalent) and trimethylamine (17.0 mg, 0.160 mmol, 1.50 equivalent) in dichloromethane (3 mL). The resulting mixture was stirred at room temperature for 3 hours and quenched with water (20 mL). The mixture was extracted with dichloromethane (3 × 50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 5-chloro-2-fluorobenzenesulfonyl chloride as a brown oil. N -((5-(4-(((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)furan-2-yl)methyl)benzenesulfonamide (15.0 mg, crude product), which was used in the next step without any further purification. LCMS (ESI, m / z): 647 [M+H]+.

[0259] (iv) 5-Chloro-2-Fluoro- N -((5-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1H-pyrazolo[3, [4-d]pyrimidin-6-yl)furan-2-yl)methyl)benzenesulfonamide-2,2,2-trifluoroacetaldehyde At 0°C, 5-chloro-2-fluoro- N -((5-(4-(((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)furan-2-yl)methyl)benzenesulfonamide (15.0 mg, 0.023 mmol, 1.00 equivalent) was added to a mixture of methanol (2 mL) and 1,4-dioxane solution (0.2 mL) in 4 M HCl (gas). The resulting mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: XBridge preparative OBD C18 column, 19 × 250 mm, 5 µm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 23% B to 42% B over 7 min; detector: 254 nm) to obtain 5-chloro-2-fluoro- N -((5-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)furan-2-yl)methyl)benzenesulfonamide-2,2,2-trifluoroacetaldehyde (6.5 mg, 42% yield). LCMS (ESI, m / z): 563 [M+H-CF3COOH]+. 1H NMR (400MHz, DMSO- d 6) δ 13.48 (brs, 1H), 8.86 - 8.83 (m, 1H), 7.60 - 7.53 (m, 2H), 7.33 - 6.99 (m, 3H), 6.41 (d, J = 3.9Hz, 1H), 5.74 - 5.51 (m, 1H), 4.30 (d, J = 5.2Hz, 2H), 3.58 - 3.20 (m, 7H), 2.70 -2.58 (m, 2H), 2.31 - 1.96 (m, 3H), 1.40 - 1.20 (m, 6H).

[0260] Compound 15 N -[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidine [Pyridine-6-yl)phenyl]-3-fluoropyridine-4-sulfonamide (i) 4-(benzylthio)-3-fluoropyridine Potassium carbonate (4.20 g, 30.4 mmol, 2.00 equivalent) was added to an acetonitrile solution (7.5 mL) of 4-chloro-3-fluoropyridine (2.00 g, 15.2 mmol, 1.00 equivalent), followed by an acetonitrile solution (15 mL) of benzylthiol (1.89 g, 0.0150 mmol, 1.00 equivalent) at 0 °C. The mixture was then stirred at room temperature and concentrated under reduced pressure. The reaction mixture was quenched with water at room temperature. The resulting mixture was extracted with dichloromethane (2 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography with ethyl acetate / hexane (1 / 3) elution to give the target product, 4-(benzylthio)-3-fluoropyridine (2.5 g, 72% yield), as a brownish-yellow oil. LCMS (ESI, m / z): 220 [M+H]+.

[0261] (ii) 3-Fluoropyridine-4-sulfonyl chloride NaClO (10 mL) and 4-(benzylthio)-3-fluoropyridine (800 mg, 3.65 mmol, 1.00 equivalent) were added to a stirred solution of hydrochloric acid (12 mL) in dichloromethane (8 mL) at -5 °C under air. The resulting mixture was stirred at -5 °C under air for 1 h. Dichloromethane was added to the reaction mixture at room temperature. The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product, 3-fluoropyridine-4-sulfonyl chloride, was used directly in the next step without further purification. LCMS (ESI, m / z): 196 [M+H]+ .

[0262] (iii) 4,6-Dichloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidine Under N2 conditions, 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (750 mg, 3.69 mmol, 1.00 equivalent), tetrahydrofuran (20 mL), dihydropyran (2.25 mL, 26.7 mmol, 7.10 equivalent), and p-toluenesulfonic acid pyridinium (50.0 mg, 0.199 mmol, 0.05 equivalent) were added to a 50 mL three-necked round-bottom flask. The resulting solution was stirred at 60 °C for 3 h and concentrated under reduced pressure. The mixture was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution in ethyl acetate / hexane (3 / 7) to give the desired product, 4,6-dichloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidine (750 mg, 71% yield), as a grayish-white solid. LCMS (ESI, m / z): 287 [M+H]+.

[0263] (iv) 6-Chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4- d]pyrimidine-4-amine To an 8-mL vial, add 4,6-dichloro-3-methyl-1-(tetrahydropyran-2-yl)-2H,3H-pyrazolo[3,4-d]pyrimidine (74.3 mg, 0.259 mmol, 1.00 equivalent), (2-aminoethyl)dimethylamine (22.8 mg, 0.259 mmol, 1.00 equivalent), dichloromethane (3.0 mL), and triethylamine (57.7 mg, 0.571 mmol, 2.20 equivalent). Stir the resulting solution overnight at room temperature and concentrate under reduced pressure. The residue was purified by silica gel column chromatography with elution of dichloromethane / methanol (95 / 5) to give the desired product, 6-chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidine-4-amine, as a colorless solid (55.0 mg, 62% yield). LCMS (ESI, m / z): 339 [M+H]+.

[0264] (v) 6-(4-aminophenyl)-N-[2-(dimethylamino)ethyl]-3-methyl-1-(tetrahydropyran-2-yl)pyridine Azo[3,4-d]pyrimidin-4-amine At room temperature under a nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (32.4 mg, 0.0440 mmol, 0.150 equivalent), cesium carbonate (192 mg, 0.590 mmol, 2.00 equivalent), and water (0.3 mL) were added partically to a stirred solution of 6-chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.295 mmol, 1.00 equivalent) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)aniline (77.6 mg, 0.354 mmol, 1.20 equivalent) in dioxane (2 mL). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column: Agela C18 column, 120 g; mobile phase A: water (0.05% trifluoroacetic acid); mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 0% B to 55% B over 45 min; detector: 220 nm) to give 6-(4-aminophenyl)-N-[2-(dimethylamino)ethyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidine-4-amine (89 mg, 76% yield) as a brownish-yellow solid. LCMS (ESI, m / z): 396 [M+H]+.

[0265] (vi) N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1-(tetrahydropyran-2-yl)pyrazole [3,4-d]pyrimidin-6-yl)phenyl]-3-fluoropyridine-4-sulfonamide Pyridine (50.0 mg, 0.632 mmol, 5.00 equivalent) was added to a stirred solution of 6-(4-aminophenyl)-N-[2-(dimethylamino)ethyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-amine (50.0 mg, 0.126 mmol, 1.00 equivalent) and 3-fluoropyridine-4-sulfonyl chloride (123 mg, 0.632 mmol, 5.00 equivalent) in dichloromethane (8 mL). The resulting mixture was stirred overnight at room temperature under air. The reaction mixture was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column: Agela C18 column, 120 g; mobile phase A: water (0.05% trifluoroacetic acid); mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 0% B to 55% B over 45 min; detector: 220 nm) to give N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-3-fluoropyridine-4-sulfonamide (60.0 mg, 42% yield) as a brownish-yellow solid. LCMS (ESI, m / z): 555 [M+H]+.

[0266] (vii) N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidine- [6-yl)phenyl]-3-fluoropyridine-4-sulfonamide Trifluoroacetic acid (1 mL) was added to a stirred solution of N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-3-fluoropyridine-4-sulfonamide (35.0 mg, 0.0630 mmol, 1.00 equivalent) in isopropanol (1 mL). The resulting mixture was stirred at room temperature in air for 3 h. The resulting mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column: YMC-Actus Triart C18 30*250, 5µm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7% B to 32% B over 7 min; 254 nm; Rt: 6.47 min; detector: UV 254 nm). This yielded N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-3-fluoropyridine-4-sulfonamide (5.9 mg, 19% yield) as a grayish-white solid. LCMS (ESI, m / z): 471 [M+H]+. 1 H NMR (400MHz, DMSO- d 6): δ 12.90 (s, 1H), 10.51 (s, 1H), 8.69 (s, 1H), 8.54 (d, J = 8.0Hz, 1H), 8.16 - 8.14 (m, 2H), 7.75 (t, J = 8.0Hz, 1H), 7.06 - 6.98 (m, 3H), 3.80 - 3.75 (m, 2H), 2.89 -2.83 (m, 2H), 2.52 (s, 3H), 2.44 (s, 6H).

[0267] Compound 16, 6-amino-N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazol] [3,4-d]pyrimidin-6-yl)phenyl]pyridine-3-sulfonamide (i) 6-Chloro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]pyridine-3- sulfonamide At 0 °C under air, pyridine (85.8 mg, 1.085 mmol, 1.15 equivalent) was added dropwise to a stirred solution of 6-chloropyridine-3-sulfonyl chloride (200 mg, 0.943 mmol, 1.00 equivalent) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)aniline (206 mg, 0.943 mmol, 1.00 equivalent) in dichloromethane (10 mL). The resulting mixture was stirred overnight at room temperature under air. The reaction mixture was quenched with water at room temperature. The resulting mixture was extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of ethyl acetate / hexane (1 / 1) to give the desired product, 6-chloro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]pyridine-3-sulfonamide (270 mg, 72% yield), as a yellow solid. LCMS (ESI, m / z): 361 [M+H] + .

[0268] (ii) 6-[[(4-methoxyphenyl)methyl]amino]-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane] Cyclopentan-2-yl)phenyl]pyridine-3-sulfonamide At room temperature under air, 4-methoxy-benzylamine (52.1 mg, 0.380 mmol, 1.50 equivalent) was added dropwise to a stirred solution of 6-chloro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-ylphenyl]pyridine-3-sulfonamide (100 mg, 0.253 mmol, 1.00 equivalent) in 1-methyl-2-pyrrolidone (7.5 mL). The resulting mixture was stirred overnight at 60 °C under air. The reaction mixture was quenched with water at room temperature. The resulting mixture was then rinsed with ethyl acetate. Extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with ethyl acetate / hexane (1 / 1) to give the desired product. This yielded 6-[[(4-methoxyphenyl)methyl]amino]-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]pyridine-3-sulfonamide (90.0 mg, 71% yield) as a brownish-yellow solid. LCMS (ESI, m / z): 496 [M+H] + .

[0269] (iii) 4,6-Dichloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidine Under N2 conditions, 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (750 mg, 3.69 mmol, 1.00 equivalent), tetrahydrofuran (20 mL), dihydropyran (2.25 mL, 26.7 mmol, 7.10 equivalent), and p-toluenesulfonic acid pyridinium (50.0 mg, 0.199 mmol, 0.05 equivalent) were added to a 50 mL three-necked round-bottom flask. The resulting solution was stirred at 60 °C for 3 h and concentrated under reduced pressure. The mixture was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution in ethyl acetate / hexane (3 / 7) to give the desired product, 4,6-dichloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidine, as a grayish-white solid (750 mg, 71% yield). LCMS (ESI, m / z): 287 [M+H] + .

[0270] (iv) 6-Chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4- d]pyrimidine-4-amine To an 8-mL vial, add 4,6-dichloro-3-methyl-1-(tetrahydropyran-2-yl)-2H,3H-pyrazolo[3,4-d]pyrimidine (74.3 mg, 0.259 mmol, 1.00 equivalent), (2-aminoethyl)dimethylamine (22.8 mg, 0.259 mmol, 1.00 equivalent), dichloromethane (3.0 mL), and triethylamine (57.7 mg, 0.571 mmol, 2.20 equivalent). Stir the resulting solution overnight at room temperature and concentrate under reduced pressure. The residue was purified by silica gel column chromatography with elution of dichloromethane / methanol (95 / 5) to give the desired product, 6-chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-amine, as a colorless solid (55.0 mg, 62% yield). LCMS (ESI, m / z): 339 [M+H] + .

[0271] (v) N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1-(tetrahydropyran-2-yl)pyrazol] [3,4-d]pyrimidin-6-yl)phenyl]-6-[[(4-methoxyphenyl)methyl]amino]pyridine-3-sulfonamide At room temperature under a nitrogen atmosphere, 6-[[(4-methoxyphenyl)methyl]amino]-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]pyridine-3-sulfonamide (90.0 mg, 0.182 mmol, 1.00 equivalent) and 6-chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1-(tetrahydropyran-2-yl)pyridine-3-sulfonamide (90.0 mg, 0.182 mmol, 1.00 equivalent) and 6-chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1-(tetrahydropyran-2-yl)pyridine-3-sulfonamide (90.0 mg, 0.182 mmol, 1.00 equivalent) were reacted with nitrogen at a nitrogen atmosphere. Azo[3,4-d]pyrimidin-4-amine (61.5 mg, 0.182 mmol, 1.00 equivalent) was added to a stirred solution of dioxane (2 mL) along with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (19.9 mg, 0.0270 mmol, 0.150 equivalent), cesium carbonate (118 mg, 0.363 mmol, 2.00 equivalent), and water (0.3 mL). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. The crude product was purified by reversed-phase column chromatography under the following conditions (column: Agela C18 column, 120 g; mobile phase A: water (0.05% trifluoroacetic acid); mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 0% B to 55% B over 45 min; detector: 220 nm) to obtain N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-6-[[(4-methoxyphenyl)methyl]amino]pyridine-3-sulfonamide (62.0 mg, 50% yield) as a brownish-yellow solid. LCMS (ESI, m / z): 672 [M+H] + .

[0272] (vi) 6-Amino-N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)phenyl]pyridine-3-sulfonamide Trifluoroacetic acid (2 mL) was added to a stirred solution of N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-6-[[(4-methoxyphenyl)methyl]amino]pyridine-3-sulfonamide (30.0 mg, 0.0450 mmol, 1.00 equivalent) under air at 0 °C. The resulting mixture was stirred overnight under air at 25 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column: XSelect CSH preparative C18 OBD column, 5µm, 19*150mm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 10 B to 30 B over 7 min; 220 nm; RT1: 5.93; RT2; injection volume: ml; number of runs; detector: UV 254 nm) to give 6-amino-N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]pyridine-3-sulfonamide (1.9 mg, 9% yield) as a grayish-white solid. LCMS (ESI, m / z): 468 [M+H] + . 1 H NMR (400MHz, DMSO-) d 6): δ 12.93 (s, 1H), 11.03 (s, 1H), 8.26 - 8.22 (m, 2H), 7.63- 7.60 (m, 1H), 7.18 - 7.15 (m, 2H), 7.01 - 6.98 (m, 1H), 6.87 (s, 3H), 6.43- 6.40 (m, 1H), 3.70 - 3.68 (m, 2H), 2.50 - 2.48 (m, 2H), 2.47 (s, 3H), 2.25 (s, 6H).

[0273] Compound 17 5-Chloro-2-fluoro-N-(4-[4-[(1-isopropylazacyclobutane-3-yl)oxy]-3-methyl-1H- Pyrazolo[3,4-d]pyrimidin-6-yl]phenyl)benzenesulfonamide This compound was prepared according to the procedure described in Example 1. The desired product was a grayish-white solid (35.0 mg, 50%). LCMS (ESI, m / z): 531 [M+H] + . 1 H NMR (300MHz, DMSO- d6) δ 13.45 (s, 1H), 8.24 –8.21 (d, J = 9.0Hz 2H), 7.84 – 7.81 (m, 1H), 7.74 – 7.69 (m, 1H), 7.48-7.42(t, J = 9.0Hz, 1H), 5.46-5.38 (m, 1H), 3.96-3.91(t, J = 9.0Hz, 1H), 3.37-3.32(m, 3H), 2.49 (s, 3H), 0.99-0.97 (d, J = 6.0Hz 6H).

[0274] Compound 18 N -[2-([6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3,4-] d]pyrimidin-4-yl]amino)ethyl]-N-methylformamide (i) N-(2-[[6-chloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-yl]amino] ethyl(N-methylcarbamate) tert-butyl Trimethylamine (70.9 mg, 0.697 mmol, 2.00 equivalent) was added dropwise to a stirred solution of 4,6-dichloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidine (100 mg, 0.348 mmol, 1.00 equivalent) and N-(2-aminoethyl)-N-methylcarbamate tert-butyl ester (91.0 mg, 0.522 mmol, 1.50 equivalent) in dichloromethane (4 mL). The resulting mixture was stirred overnight at room temperature under air. The resulting solution was diluted with 20 mL of dichloromethane. The resulting mixture was washed with 2 × 10 mL of water. The resulting mixture was concentrated under vacuum. This yielded 130 mg (83%) of N-(2-[[6-chloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-yl]amino]ethyl)-N-methylcarbamate tert-butyl ester as a pale yellow solid. LCMS29 (ESI, m / z): 425 [M+H]+.

[0275] (ii) N-[2-([6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1-(tetrahydropyran-2-yl)] Pyrazolo[3,4-d]pyrimidin-4-yl]amino)ethyl]-N-methylcarbamate tert-butyl ester At room temperature under a nitrogen atmosphere, 5-chloro-2-fluoro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]benzenesulfonamide (151 mg, 0.367 mmol, 1.20 equivalents) and N-(2-[[6-chloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-yl]amino]ethyl)-N-methyl Tert-butyl carbamate (130 mg, 0.306 mmol, 1.00 equivalent) was added to a stirred solution of dioxane (2 mL) with cesium carbonate (199 mg, 0.612 mmol, 2.00 equivalent) and water (0.30 mL), followed by the addition of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloro(II) (38.5 mg, 0.0470 mmol, 0.180 equivalent). The resulting mixture was stirred at 100 °C under a N2 atmosphere for 3 h. The reaction mixture was cooled. The solid was filtered off. The crude product was purified by preparative HPLC under the following conditions (IntelFlash-1) (column, C18 silica gel; mobile phase, ACN / water = 5 / 95, increased to ACN / water = 56 / 44 in 30 steps; detector, 220 nm). This yielded 140 mg (64%) of N-[2-([6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-yl]amino)ethyl]-N-methylcarbamate tert-butyl ester as a light brown solid. LCMS (ESI, m / z): 674 [M+H] + .

[0276] (iii) 5-Chloro-2-fluoro-N-(4-(3-methyl-4-((2-(methylamino)ethyl)amino)-1H-pyrazolo[3, 4-d]pyrimidin-6-yl)phenyl)benzenesulfonamide Trifluoroacetic acid (1 mL) was added to a stirred solution of N-[2-([6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-yl]amino)ethyl]-N-methylcarbamate tert-butyl ester (140 mg) in dichloromethane (2 mL). The resulting mixture was stirred at room temperature in air for 3 h. The resulting mixture was concentrated under reduced pressure. The residue of 70.0 mg 5-chloro-2-fluoro-N-(4-(3-methyl-4-((2-(methylamino)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)benzenesulfonamide was used directly. LCMS (ESI, m / z): 490 [M+H] + .

[0277] (iv) N -[2-([6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidine [Pyridine-4-yl]amino)ethyl]-N-methylformamide At room temperature and under an air atmosphere, 1,1,3-trioxo-1λ6,2-benzothiazol-2-carboxaldehyde (34.5 mg, 0.163 mmol, 1.00 equivalent) was added to a stirred solution of 5-chloro-2-fluoro-N-[4-(3-methyl-4-[[2-(methylamino)ethyl]amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide (70.00 mg, 0.163 mmol, 1.00 equivalent) in NMP (2 mL). The resulting mixture was stirred at room temperature under a N2 atmosphere for 1 h. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge preparative C18 OBD column, 19*150 mm 5 µm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 18 B to 38 B over 7 min; detector: 220 nm). This yielded 23.2 mg (29%) of N-[2-([6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino)ethyl]-N-methylformamide as a solid. LCMS (ESI, m / z): 518 [M+H] + . 1 H NMR (400MHz, DMSO- d 6) δ 12.99 (s, 1H), 11.02(s, 1H), 11.13(s, 1H), 8.32 – 8.25 (m, 2H), 8.01– 7.84 (m, 3H), 7.77 – 7.76 (m, 1H), 7.52-7.48 (m, 2H), 7.32 – 7.20 (s, 1H), 3.79-3.73(m, 2H), 3.57-3.53(m, 2H), 2.98-2.80(m, 3H), 2.67 (s, 3H).

[0278] Compound 19 N-(4-(4-(2-(dimethylamino)ethylamino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (Pyridine-6-yl)phenyl)-4-methoxypyridine-3-sulfonamide (i) 4-chloro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)pyridine-3- sulfonamide Add 4-chloropyridine-3-sulfonyl chloride (900.00 mg, 4.244 mmol, 1.00 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)aniline (929.92 mg, 4.244 mmol, 1.00 equivalent), DCM (15.00 mL), and pyridine (671.48 mg, 8.488 mmol, 2.00 equivalent) to a 50 mL round-bottom flask. Stir the resulting solution overnight at room temperature. Dilute the resulting solution with 50 mL of DCM. Wash the resulting mixture with 2 × 30 mL of brine and 1 × 30 mL of water. Dry the mixture over anhydrous sodium sulfate and concentrate. Pour the residue onto a silica gel column containing ethyl acetate / petroleum ether (0:100 to 20:80). Combine the collected fractions and concentrate. This yielded 700 mg (37.61%) of 4-chloro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]pyridine-3-sulfonamide as a grayish-white solid. LCMS (ESI, m / z): 395 [M+H] + .

[0279] (ii) 4-(4-methoxypyridine-3-sulfonylamino)phenylboronic acid Add 4-chloro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]pyridine-3-sulfonamide (650.00 mg, 1.647 mmol, 1.00 equivalent), MeOH (3.00 mL, 0.094 mmol, 0.06 equivalent), and CH3ONa (1.00 mL) to a 25 mL round-bottom flask. Stir the resulting solution overnight in an oil bath at 70 °C. Concentrate the resulting mixture. Dilute the resulting solution with 10 mL of H2O. Wash the resulting mixture with 2 × 10 mL of DCM. Adjust the pH of the solution to 2–3 with HCl (2 mol / L). Wash the resulting mixture with 2 × 10 mL of EA. Concentrate the aqueous layer. This yields 350 mg (crude product) of 4-(4-methoxypyridine-3-sulfonylamino)phenylboronic acid as a pale yellow oil. LCMS (ESI, m / z): 309 [M+H]+.

[0280] (iii) N-(4-(4-(2-(dimethylamino)ethylamino)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-4-methoxypyridine-3-sulfonamide To a 50-mL three-necked round-bottom flask purged and maintained under an inert N2 atmosphere, add 4-(4-methoxypyridine-3-sulfonylamino)phenylboronic acid (NaN mg, 0.649 mmol, 2.75 equivalents, 60%), 6-chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-amine (80.00 mg, 0.236 mmol, 1.00 equivalents), dioxane (4.00 mL), Cs₂CO₃ (230.78 mg, 0.708 mmol, 3.00 equivalents), water (1.00 mL), and Pd(dppf)Cl₂ (17.28 mg, 0.024 mmol, 0.10 equivalents). Stir the resulting solution in an oil bath at 100 °C for 40 hours. Cool the reaction mixture in a water bath. The resulting solution and E08786-007 were diluted with 20 mL of water. The resulting mixture was washed with 2 × 20 mL of DCM. The resulting mixture was concentrated. The residue was applied to a C18 gel with H2O (0.5% NH4HCO3) / ACN (90:10 to 10:90) over 45 minutes. The collected fractions were combined and concentrated. This yielded 50 mg (33.63%) of N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-4-methoxypyridine-3-sulfonamide as a pale yellow oil. LCMS (ESI, m / z): 567 [M+H] + (iv) N-(4-(4-(2-(dimethylamino)ethylamino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 4-(4-methoxypyridine-3-sulfonamide) Add to a 50 mL round-bottom flask N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-4-methoxypyridine-3-sulfonamide (50.00 mg, 0.088 mmol, 1.00 equivalent), IPA (5.00 mL), and HCl (gas) in 1,4-dioxane (5.00 mL, 0.073 mmol, 0.83 equivalent). Stir the resulting solution at room temperature for 3 hours. Concentrate the resulting mixture. Purify the crude product by preparative HPLC. Column: Xselect CSH OBD column, 30*150mm*5µm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O); mobile phase B: ACN; flow rate: 60 ml / min; gradient: 13% B to 38% B over 7 min; 254 / 220 nm; Rt: 5.13 min (detected and collected by LCMS). The combined fractions were lyophilized to obtain 14.1 mg of the desired product as a white solid. LCMS (ESI, m / z): 483 [M+H] + . 1 H NMR (400MHz, DMSO- d 6) δ 8.81 (s, 1H), 8.55 (d,J = 6.0Hz, 1H), 8.27 – 8.30 (m, 2H), 7.21 – 7.24 (m, 3H), 4.63 (s, 1H), 4.06(s, 3H), 3.88 (t, J = 6.7Hz, 2H), 2.75 (t, J = 6.7Hz, 2H), 2.62 (s, 3H), 2.40(s, 7H).

[0281] Compound 20 N-[4-[4-([2-[(2-hydroxyethyl)(methyl)amino]ethyl]amino]amino)-5-methyl-7-(tetrahydro] pyran-2-yl)pyrrolo[2,3-d]pyrimidin-2-yl]phenyl]pyridine-2-sulfonamide This compound was prepared according to the procedure described in Example 9. The desired product was a grayish-white solid (13.9 mg). LCMS (ESI, m / z): 482 [M+H] + . 1H NMR (300MHz, CD3OD) δ 8.66-8.64 (m, 1H), 8.27-8.22(m, 2H), 8.01 – 7.96 (m, 2H), 7.57 – 7.52(m, 1H), 7.25-7.21 (m, 2H), 3.85-3.81 (t, J= 6.6Hz 2H), 3.69-3.65 (t, J= 6.0Hz 2H), 2.83-2.78 (t, J= 6.0Hz2H), 2.68-2.64 (t, J= 6.0Hz 2H), 2.58 (s, 3H), 2.43 (s, 3H).

[0282] Compound 21 N -[4-[4-([2-[(2-hydroxyethyl)(methyl)amino]ethyl]amino)-3-methyl-1H-pyrazole [3,4-d]pyrimidin-6-yl]phenyl]pyridine-3-sulfonamide This compound was prepared according to the procedure described in Example 9. The desired product was a grayish-white solid (41.2 mg, 60% yield). LCMS (ESI, m / z): 483 [M+H] + . 1 H NMR (400MHz, DMSO- d 6): δ 12.95 (s, 1H), 10.64 (s, 1H), 8.93 (s, 1H), 8.77 - 8.75 (m, 1H), 8.25 - 8.23 ​​(m, 2H), 8.17 -8.14 (m, 1H), 7.61 - 7.58 (m, 1H), 7.19 - 7.17 (m, 2H), 7.00 - 6.97 (m, 1H), 4.45 (s, 1H), 3.72 - 3.67 (m, 2H), 3.50 (t, J = 8.0Hz, 2H), 2.71 - 2.69 (m,2H), 2.55 - 2.52 (m, 2H), 2.50 (s, 3H), 2.33 (s, 3H).

[0283] Compound 22, 5-chloro-2-fluoro-N-[4-[4-([2-[(2-hydroxyethyl)(methyl)amino]ethyl]amino]amino)-3-methyl [1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl]benzenesulfonamide] This compound was prepared according to the procedure described in Example 9. The desired product was a grayish-white solid (28.8 mg, 29%). LCMS (ESI, m / z): 534 [M+H] + . 1 H NMR (400MHz, DMSO-d 6) δ 12.94 (s, 1H), 13.00(s, 1H), 10.82 (s, 1H), 8.24 – 8.22 (d, J =8.0Hz, 2H), 7.84 – 7.82 (m, 1H),7.75 – 7.72 (m, 1H), 7.48-7.44 (t, J = 8.0Hz, 1H), 7.17 – 7.15 (d, J =8.0Hz, 2H), 7.01-6.98 (d, J =8.0Hz, 1H), 4.50 (s, 1H), 3.74 – 3.71 (t, J =4.0Hz, 2H),3.53 – 3.50 (t, J =4.0Hz, 2H), 2.77 – 2.74 (t, J =6.0Hz, 2H), 2.67 (s, 3H), 2.33 (s, 3H).

[0284] Compound 23 N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidine [Pyridine-6-yl]phenyl]pyridine-3-sulfonamide This compound was prepared according to the procedure described in Example 9. The desired product was a grayish-white solid (26.9 mg, 31% yield). LCMS (ESI, m / z): 453 [M+H] + . 1 H NMR (400MHz, DMSO- d 6): δ 12.95 (s, 1H), 11.15 (s, 1H), 8.93 (s, 1H), 8.77 - 8.75 (m, 1H), 8.25 - 8.23 ​​(d, J = 8.0Hz,2H), 8.17 - 8.14 (m, 1H), 7.61 - 7.58 (m, 1H), 7.19 - 7.17 (m, 2H), 7.01 (t, J = 4.0Hz, 1H), 3.74 - 3.69 (m, 2H), 2.62 (t, J = 8.0Hz, 2H), 2.52 (s, 3H), 2.29 (s, 6H).

[0285] Compound 24 N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidine [Pyridine-6-yl]phenyl]pyridine-2-sulfonamide This compound was prepared according to the procedure described in Example 9. The desired product was a grayish-white solid (14.9 mg, 17.67%). LCMS29 (ESI, m / z): 453 [M+H] + . 1 H NMR (400MHz, DMSO- d 6) δ 12.93 (s,1H), 10.77 (s, 1H), 8.72 – 8.70 (m, 1H), 8.22 – 8.01 (m, 2H), 8.07 – 8.01 (m,3H), 7.65 – 7.62 (m, 1H), 7.23-7.21 (d, J = 8.0Hz, 2H), 7.00 – 6.98 (t, J =4.0Hz, 1H), 3.72-3.67(m, 2H), 2.58-2.55 (t, J = 8.0Hz, 3H), 2.52 (s, 2H), 2.25(s, 6H).

[0286] Compound 25 5-Chloro-2-fluoro-N-(4-(4-(((1-isopropylazacyclobutane-3-yl)amino)-3-methyl-1H- Pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (i) 3-Methyl-6-(4-nitrophenyl)-1,3a,7,7a-tetrahydro-4H-pyrazolo[3,4-d]pyrimidin-4-one At room temperature, 4-nitrobenzaldehyde (2.15 g, 14.29 mmol, 2.0 equivalent) and I2 (3.63 g, 14.290 mmol, 2.0 equivalent) were added to a stirred mixture of 3-amino-5-methyl-2H-pyrazol-4-carboxamide (1 g, 7.143 mmol, 1.0 equivalent) in 20 mL of ACN. The resulting mixture was stirred at 90 °C for 4 hours. The mixture was cooled at room temperature and filtered. The filter cake was washed with 2 × 100 mL of ACN and dried under an IR lamp to give 3-methyl-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (900 mg, crude product) as a pink solid. LCMS (ESI, m / z): 272 [M+H] + (ii) 4-Chloro-3-methyl-6-(4-nitrophenyl)-3a,4,7,7a-tetrahydro-1H-pyrazolo[3,4-d]pyrimidine At room temperature, DMF (0.536 g, 7.35 mmol, 1.0 equivalent) was added to a stirred mixture of 3-methyl-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (2 g, 7.35 mmol, 1.0 equivalent) and SOCl2 (17.50 g, 147 mmol, 20.0 equivalent). The resulting mixture was stirred at 80 °C for 4 hours. The mixture was cooled and quenched with water (100 mL) at room temperature, filtered, and the filter cake was washed with Et2O (2 × 100 mL) and dried under an IR lamp to give 4-chloro-3-methyl-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin (1.6 g, 88% purity, 75.05% yield) as a yellow solid. LCMS (ESI, m / z): 290 [M+H] + .

[0287] (iii) N-(1-isopropylazacyclobutane-3-yl)-3-methyl-6-(4-nitrophenyl)-1H-pyrazolo[3, [4-d]pyrimidin-4-amine At room temperature, DIEA (668.5 mg, 5.172 mmol, 5.0 equivalent) and 1-isopropylazacyclobutane-3-amine (235 mg, 2.068 mmol, 2.0 equivalent) were added to a stirred mixture of 4-chloro-3-methyl-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]azacyclobutane-3-amine (300 mg, 1.034 mmol, 1.0 equivalent) in DMF (5 mL). The resulting mixture was stirred at 50 °C for 2 hours. The mixture was then diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated, and purified by column chromatography to give 160 mg (93% purity, white solid) of 1-isopropyl-N-[3-methyl-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]azacyclobutane-3-amine in 46% yield. LCMS (ESI, m / z): 368 [M+H] + .

[0288] (iv) 6-(4-aminophenyl)-N-(1-isopropylazacyclobutane-3-yl)-3-methyl-1H-pyrazolo[3,4- d]pyrimidine-4-amine 1-Isopropyl-N-[3-methyl-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]azacyclobutane-3-amine (160 mg, 0.435 mmol, 1.0 equivalent) and 20% Pd / C (230 mg, 0.217 mmol, 0.5 equivalent) were dissolved in DMF (5 mL) under a H2 (5 bar) atmosphere. The mixture was stirred at 25 °C for 18 hours. The resulting mixture was filtered, and the filtrate was removed under reduced pressure to give N-[6-(4-aminophenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-1-isopropylazacyclobutane-3-amine, a white solid crude product (130 mg, 86.4% purity, 88.4% yield, white solid). LCMS (ESI, m / z): 338 [M+H] + (v) 5-Chloro-2-fluoro-N-(4-(4-(((1-isopropylazacyclobutane-3-yl)amino)-3-methyl-1H-pyrazole [3,4-d]pyrimidin-6-yl)phenyl)benzenesulfonamide A solution of N-[6-(4-aminophenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-1-isopropylazacyclobutane-3-amine (130 mg, 0.385 mmol, 1.0 equivalent) and pyridine (30.8 mg, 0.385 mmol, 1.0 equivalent) in anhydrous DMF (1 mL) was stirred with chloro(5-chloro-2-fluorophenyl)methylene-λ6-sulfonone (87.3 mg, 0.385 mmol, 1.0 equivalent) at room temperature for 24 hours. The organic layer was treated with HCl aqueous solution (5%, 10 mL) and DCM (10 mL), dried over anhydrous Na2SO4, evaporated under vacuum, and purified by HPLC (column: XBridge Shield RP18 OBD column, 19*250 mm, 10 µm; mobile phase A: water (10 MMOL / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 18 B to 48 B, 220 nm over 10 min; RT1: 9.60) to give 5-chloro-2-fluoro-N-(4-[4-[(1-isopropylazacyclobutane-3-yl)amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl)benzenesulfonamide (17.8 mg, 95.7% purity, 8.73% yield, yellow solid). LCMS (ESI, m / z): 530.2 [M+H] + . 1 H NMR (300MHz, DMSO- d6) δ 12.99(s, 1H), 8.20 (d, J = 8.5Hz, 2H), 7.82 (dd, J = 6.0, 2.7Hz, 1H), 7.70 (dt, J= 8.8, 3.4Hz, 1H), 7.44 (dd, J = 10.9, 7.5Hz, 0.96 (d, J = 6.2Hz, 6H).

[0289] Compound 26 5-chloro-2-fluoro-N-(4-(3-methyl-4-((2-morpholinoethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)phenyl)benzenesulfonamide (i) 6-Chloro-3-methyl-N-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine Add 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (150.00 mg, 0.739 mmol, 1.00 equivalent), DCM (15.00 mL), DIEA (286.46 mg, 2.216 mmol, 3 equivalent), and N-aminoethylmorpholine (115.42 mg, 0.887 mmol, 1.20 equivalent) to a 50 mL round-bottom flask. Stir the resulting solution at room temperature for 16 hours. Extract the solution with 2 × 30 mL of ethyl acetate, dry to anhydrous sodium sulfate, and concentrate. This yields 200 mg (82.10%) of 6-chloro-3-methyl-N-[2-(morpholin-4-yl)ethyl]-1H-pyrazolo[3,4-d]pyrimidine-4-amine as a yellow solid. LCMS (ES. m / z): 297 [M+H] + .

[0290] (ii) 5-Chloro-2-fluoro-N-(4-(3-methyl-4-((2-morpholinoethyl)amino)-1H-pyrazolo[3,4-d]pyrimidine (Pyridine-6-yl)phenyl)benzenesulfonamide Add 6-chloro-3-methyl-N-[2-(morpholin-4-yl)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200.00 mg, 0.674 mmol, 1.00 equivalent), dioxane (16.00 mL), H2O (4.00 mL), 5-chloro-2-fluoro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]benzenesulfonamide (305.19 mg, 0.741 mmol, 1.10 equivalent), Cs2CO3 (658.75 mg, 2.022 mmol, 3 equivalent), and Pd(dppf)Cl2 (49.31 mg, 0.067 mmol, 0.1 equivalent) to a 50-mL round-bottom flask. Stir the resulting solution at 100 °C for 3 hours. The resulting solution was extracted with 3 × 50 mL of ethyl acetate, dried under reduced pressure in an oven, and concentrated. The crude product was purified by rapid preparative HPLC under the following conditions (column, silica gel C18 (210 g); mobile phase A: water-10 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 55 B to 60 B; 254 nm);). The solution was concentrated. The solid was washed with CH3CN (3 mL × 2). The solid was collected by filtration. This yielded 65.3 mg (17.05%) of 5-chloro-2-fluoro-N-[4-(3-methyl-4-[[2-(morpholin-4-yl)ethyl]amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide as a pale brown solid. 1 H-NMR (CD3OD, 300MHz) δ (ppm):8.29 (d, J = 9.0Hz, 2H), 7.86-7.89 (m, 1H), 7.60-7.64 (m, 1H), 7.21-7.32(m,3H), 3.85-3.91 (m, 2H), 3.70-3.73 (m, 4H), 2.71-2.80 (m, 2H), 2.67 (s, 7H). LCMS(ES. m / z): 546 [M+H] + .

[0291] Compound 27 N-(4-(4-((2-(dimethylamino)ethyl)amino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (Pyridine-6-yl)phenyl)-4-methoxypyridine-2-sulfonamide This compound was prepared according to the procedure described in Example 9. The desired product was a grayish-white solid (21.9 mg, 11.6% yield). LCMS (ESI, m / z): 483.3 [M+H] + . 1 H NMR (300MHz, DMSO- d6) δ 12.95 (s, 1H), 8.52 (d, J = 5.6Hz, 1H), 8.27 – 8.18 (m, 2H), 7.51 (d, J = 2.5Hz, 1H), 7.29 –7.17 (m, 3H), 7.02 (t, J = 5.7Hz, 1H), 3.90 (s, 3H), 3.72 (q, J = 6.5Hz, 2H), 2.62 (t, J = 6.8Hz, 2H), 2.52 (s, 3H). 2.29 (s, 6H).

[0292] Compound 28 5-chloro-2-fluoro-N-(4-(4-(((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1H-pyrazolo [3,4-d]pyrimidin-6-yl)phenyl)benzenesulfonamide The compound was prepared according to the procedure described in Example 9. The desired product was a white solid (37.6 mg, 32.16%). 1 H-NMR (DMSO- d 6, 300MHz) δ (ppm): 13.6 (s, 1H), 7.89-7.96 (m, 2H), 7.69-7.23 (m, 1H), 7.53-7.57 (m, 1H), 7.25-7.34 (m, 2H), 5.70 (s, 1H), 3.61(s, 1H), 3.22 (s, 4H), 2.48 (s, 3H), 1.97-2.27 (m, 4H), 1.25 (d, J = 6.6Hz, 6H). LCMS (ES. m / z): 577 [M+H] + .

[0293] Compound 29 5-Chloro-2-Fluoride N -(4-(4-(((3 S 4 R )-3-Fluoroperidin-4-yl)oxy)-3-methyl-1 H -pyr Azo[3,4-] d ]pyrimidin-6-yl)phenyl)benzenesulfonamide (i) (3 S 4 R )-4-((6-chloro-3-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-4-yl)oxy)-3-fluoropiperidine- 1-Tert-butyl formate Add 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (100.00 mg, 0.493 mmol, 1.00 equivalent), (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (118.79 mg, 0.542 mmol, 1.10 equivalent), and THF (10.00 mL) to a 50 mL round-bottom flask. Stir the resulting solution at room temperature for 20 min. Then add NaH (59.10 mg, 2.463 mmol, 5 equivalent) at 0 °C. Stir the resulting solution at room temperature for 2 h. Then quench the reaction mixture by adding water. Extract the resulting solution with 2 × 50 mL ethyl acetate, dry to anhydrous sodium sulfate, and concentrate. Wash the resulting mixture with EtOAc. Collect the solid by filtration. This yielded 110 mg (52.10%) of (3S,4R)-4-([6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester as a pale yellow solid. LCMS (ES. m / z): 386 [M+H] + .

[0294] (ii) (3 S 4 R )-4-((6-(4-((5-chloro-2-fluorophenyl)sulfonylamino)phenyl)-3-methyl-1 H -pyrazol [3,4- d tert-butyl pyrimidin-4-yl)oxy)-3-fluoropiperidine-1-carboxylate Add (3S,4R)-4-([6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy)-3-fluoropiperidin-1-carboxylic acid tert-butyl ester (100.00 mg, 0.259 mmol, 1.00 equivalent), dioxane (8.00 mL), H2O (2.00 mL), and 5-chloro-2-fluoro -N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]benzenesulfonamide (106.70 mg, 0.259 mmol, 1.00 equivalent), Cs₂CO₃ (126.67 mg, 0.389 mmol, 1.5 equivalent), Pd(dppf)Cl₂ (37.93 mg, 0.052 mmol, 0.2 equivalent). The resulting solution was stirred at 100 °C for 16 hours. The resulting mixture was concentrated. The residue was purified by preparative TLC (DCM:MeOH = 20:1). This yielded 150 mg (72.90%) of (3S,4R)-4-([6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester as a yellow solid. LCMS (ES. m / z): 635 [M+H] + .

[0295] (iii) 5-Chloro-2-Fluoro- N -(4-(4-(((3 S 4 R )-3-Fluoroperidin-4-yl)oxy)-3-methyl-1 H -Pyrazole and [3,4- d ]pyrimidin-6-yl)phenyl)benzenesulfonamide Add (3S,4R)-4-([6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (130.00 mg, 0.205 mmol, 1.00 equivalent), DCM (5.00 mL), and HCl (4 M in 1,4-dioxane) (5.00 mL, 87.587 mmol, 427.88 equivalent) to a 50-mL round-bottom flask. Stir the resulting solution at room temperature for 2 hours. Concentrate the resulting mixture. The solid was analyzed by preparative HPLC (column: YMC-ActusTriart C18, 30 mm × 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25 B to 45 B, 254 nm over 7 min; RT1: 6.73; RT2: injection volume: ml; number of runs;). This yielded 20.7 mg (18.18%) of 5-chloro-2-fluoro-N-[4-(4-[[(3S,4R)-3-fluoropiperidin-4-yl]oxy]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide as a white solid. 1 H-NMR (CD3OD,300MHz) δ (ppm): 8.32 (d, J = 9Hz, 2H), 7.86-7.89 (m, 1H), 7.57-7.62 (m, 1H), 7.22-7.30 (m, 3H), 5.68-5.89 (m, 1H), 5.08 (s, 1H), 3.06-3.21 (m, 2H), 2.79-3.02 (m, 2H), 2.59 (s, 3H), 2.04-3.01 (m, 2H).LCMS(ES. m / z): 535 [M+H] + .

[0296] Compound 30 N-(4-(4-((2-(dimethylamino)ethyl)amino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (Pyridine-6-yl)phenyl)-4-(trifluoromethyl)pyridine-2-sulfonamide The compound was prepared according to the procedure described in Example 9. The desired product was a white solid (41.6 mg). 1 H NMR (300MHz, DMSO-) d 6) δ 12.91 (s, 1H), 8.98 (d, J= 5.0Hz, 1H), 8.24 – 8.15 (m,3H), 8.10 – 7.99 (m, 1H), 7.19 (d, J = 8.7Hz, 2H), 6.99 (t, J = 5.6Hz, 1H), 3.72 (d, J = 6.3Hz, 2H), 2.66 (t, J = 6.7Hz, 2H), 2.50 (s, 3H), 2.31 (s, 6H). LCMS (ES, m / z): 521 [M+H] + .

[0297] Compound 31 N -(4-(4-((2-(dimethylamino)ethyl)amino)-3-methyl-1 H -pyrazolo[3,4- d ]pyrethrum (Pyridine-6-yl)phenyl)-5-(trifluoromethyl)pyridine-2-sulfonamide The compound was prepared according to the procedure described in Example 9. The desired product was a white solid (17.8 mg). 1 H NMR (300MHz, DMSO-) d 6) δ 12.94 (s, 1H), 9.14 (s, 1H), 8.48 (dd, J = 8.3, 2.3Hz, 1H), 8.20 (dd, J = 8.3, 5.1Hz, 3H), 7.20 (d, J = 8.5Hz, 2H), 7.02 (s, 1H), 3.72 (d, J = 6.2Hz, 2H), 2.70 (s, 2H), 2.50 (s, 3H), 2.34 (s, 6H). LCMS (ES,m / z): 521 [M+H] + .

[0298] Compound 32 N -(4-(4-((2-(diethylamino)ethyl)amino)-3-methyl-1 H -pyrazolo[3,4- d ]pyrethrum (Pyridine-6-yl)phenyl)-2,5-difluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 28. The desired product was a grayish-white solid (39.1 mg, 16.4%). 1 H-NMR (DMSO- d 6, 300MHz) δ (ppm): 12.95 (s, 1H), 10.63 (s, 1H), 8.22(d, J= 8.7Hz, 2H), 7.69-7.63 (m, 1H), 7.57 (d, J = 3.6Hz, 2H), 7.15 (d, J =8.7Hz, 2H), 7.03-6.99 (m, 1H), 3.71 (d, J = 5.7Hz, 2H), 2.82-2.78 (m, 2H), 2.72-2.61 (m, 4H), 2.53 (s, 3H), 1.08 (s, 6H). LCMS (ES. m / z): 516 [M+H] + .

[0299] Compound 33 2,5-difluoro- N -(4-(3-methyl-4-((2-(pyrrolid-1-yl)ethyl)amino)-1 H -Pyrazole and [3,4- d ]pyrimidin-6-yl)phenyl)benzenesulfonamide The compound was prepared according to the procedure described in Example 28. The desired product was a white solid (60.0 mg, 99.4% purity). LCMS (ESI, m / z): 514.4 [M+H]+. 1 H NMR (300MHz, DMSO- d 6) δ 12.94 (s, 1H),8.29 – 8.13 (m, 2H), 7.65 (ddd, J = 8.0, 5.4, 3.1Hz, 1H), 7.56 – 7.38 (m,2H), 7.21 – 7.00 (m, 3H), 3.77 (q, J = 6.4Hz, 2H), 2.89 (t, J = 6.7Hz, 2H), 2.75 (d, J = 6.3Hz, 4H), 2.53 (s, 3H), 1.74 (h, J = 3.0Hz, 4H).

[0300] Compound 34 2,5-difluoro- N -(4-(3-methyl-4-((1-methylazacyclobutane-3-yl)oxy)-1 H -pyr Azo[3,4-] d ]pyrimidin-6-yl)phenyl)benzenesulfonamide The compound was prepared according to the procedure described in Example 8. The desired product was a white solid, yielding the desired product (9.1 mg, 99.1% purity) in the form of a TFA salt. 1 H NMR (300MHz, DMSO- d6) δ 13.62 (s, 1H), 11.18(s, 1H), 8.28 (d, J = 8.5Hz, 2H), 7.79 – 7.69 (m, 1H), 7.56 (dtd, J = 18.3,9.0, 8.6, 4.2Hz, 2H), 7.32 – 7.23 (m, 2H), 5.71 (s, 1H), 4.71 (s, 2H), 4.41(s, 2H), 2.97 (s, 3H), 2.58 (s, 3H), 1.24 (s, 1H).). LCMS (ESI, m / z): 487.1 [M+H] + .

[0301] Compound 35 5-chloro-2-fluoro- N -(4-(4-((2-((2-hydroxyethyl)(methyl)amino)ethyl)(methyl)amino 3-methyl-1-yl H -pyrazolo[3,4- d ]pyrimidin-6-yl)phenyl)benzenesulfonamide (i) (2-((2-hydroxyethyl)(methyl)amino)ethyl)(methyl)carbamate tert-butyl ester A mixture of 2-(methylamino)ethanol-1-ol (1.10 g, 14.67 mmol), tert-butyl (2-(methylamino)ethyl)carbamate (2.54 g, 14.67 mmol), sodium triacetoxyborohydride (6.22 g, 29.34 mmol), and AcOH (0.1 mL) in CHCl3 (40 mL) was stirred at room temperature for 16 hours. The reaction mixture was washed with saturated aqueous NaHCO3 solution (20 mL), followed by brine (20 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum. This yielded tert-butyl (2-((2-hydroxyethyl)(methyl)amino)ethyl)(methyl)carbamate (720 mg, Y = 23%) as a pale yellow oil, which was used directly in the next step without any further purification. LCMS (ES, m / z): 233 [M+H] + .

[0302] (ii) 2-(methyl(2-(methylamino)ethyl)amino)ethanol-1-ol TFA (4 mL) was added to a solution of tert-butyl (2-((2-hydroxyethyl)(methyl)amino)ethyl)(methyl)carbamate (720 mg, 3.09 mmol) in DCM (12 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum. This yielded 2-(methyl(2-(methylamino)ethyl)amino)ethanol-1-ol (530 mg crude product, TFA salt form), a pale brown oil, which could be used directly in the next step without any further purification. LCMS (ES, m / z): 133 [M+H] + .

[0303] (iii) 2-((2-((6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl) (methyl)amino)ethanol-1-ol A mixture of 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 0.99 mmol), 2-(methyl(2-(methylamino)ethyl)amino)ethanol-1-ol (530 mg crude product, TFA salt form), and DIPEA (1.67 mL, 9.99 mmol) in DCM (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum. The residue was purified by reversed-phase chromatography under the following conditions (column: Agela C18 column, 120 g; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 0 B to 100% B over 20 min; 254 nm). This yielded a pale yellow solid of 2-((2-((6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)(methyl)amino)ethane-1-ol (280 mg, Y = 95%). LCMS (ES, m / z): 299 [M+H] + .

[0304] (iv) 5-Chloro-2-Fluoro- N -(4-(4-((2-((2-hydroxyethyl)(methyl)amino)ethyl)(methyl)amino)-3- Methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)benzenesulfonamide trifluoroacetate A mixture of 2-((2-((6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)(methyl)amino)ethyl-1-ol (100 mg, 0.33 mmol), 5-chloro-2-fluoro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)benzenesulfonamide (204 mg, 0.50 mmol), cesium carbonate (196 mg, 0.60 mmol), and Pd(dppf)Cl2 (22 mg, 0.03 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was degassed and refilled three times with N2, then stirred at 100 °C under N2 for 3 hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18, 30 mm × 150 mm, 5 µm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B over 7 min; 254 nm; RT: 5.12). This yielded 5-chloro-2-fluoro- N -(4-(4-((2-((2-hydroxyethyl)(methyl)amino)ethyl)(methyl)amino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)benzenesulfonamide trifluoroacetate (11.9 mg).1 H NMR (400MHz, DMSO-) d 6) δ 13.27 (brs, 1H), 11.08 (s, 1H), 9.36 (s, 1H), 8.32 – 8.24(m, 2H), 7.86 (dd, J = 6.1, 2.7Hz, 1H), 7.80 (ddd, J = 8.8, 4.2, 2.7Hz, 1H),7.52 (t, J = 9.3Hz, 1H), 7.29 – 7.20 (m, 2H), 4.27 – 4.16 (m, 2H), 3.80 –3.50 (m, 4H), 3.50 – 3.30 (m, 4H), 3.20 (dd, J = 13.1, 5.7Hz, 1H), 2.89 (d, J = 4.3Hz, 3H), 2.61 (s, 3H). LCMS (ES, m / z): 548 [M+H] + -114.

[0305] Compound 36 2,5-difluoro- N -(3-Methyl-4-(3-Methyl-4-((2-(pyrrolid-1-yl)ethyl)amino)- 1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)phenyl)benzenesulfonamide The compound was prepared according to the procedure described in Example 9. The desired product (40.6 mg, 99.6% purity) was obtained in the form of a white TFA salt. 1 H NMR (300MHz, DMSO- d 6) δ 10.96 (s, 1H), 9.56 (s, 1H), 7.77 – 7.67 (m, 2H), 7.58 (dtt, J = 18.3, 9.1, 4.8Hz, 2H), 7.41 (s, 1H), 7.11– 7.00 (m, 2H), 3.84 (d, J = 5.8Hz, 2H), 3.61 (s, 2H), 3.41 (t, J = 5.7Hz,2H), 3.01 (s, 2H), 2.59 (s, 3H), 2.44 (s, 3H), 1.90 (s, 2H), 1.66 (s, 2H). LCMS (ESI, m / z): 528 [M+H] + .

[0306] Compound 37 5-Chloro-2-Fluoride N -(4-(3-methyl-4-((2-(pyrrolid-1-yl)ethyl)amino)-1 H -Pyrazole and [3,4- d ]pyrimidin-6-yl)phenyl)benzenesulfonamide The compound was prepared according to the procedure described in Example 9. The desired product (14.3 mg, 99.6% purity) was obtained as a white TFA salt solid. 1 H NMR (300MHz, DMSO- d 6) δ 11.09 (s, 1H), 9.58 (s, 1H), 8.34 – 8.24 (m, 2H), 7.90 – 7.75 (m, 2H), 7.53 (t, J = 9.3Hz, 1H), 7.39 –7.19 (m, 3H), 3.95 (d, J = 6.0Hz, 2H), 3.73 – 3.59 (m, 2H), 3.54 – 3.40 (m,2H), 3.11 (d, J = 9.6Hz, 2H), 2.57 (s, 3H), 2.00 (s, 2H), 1.90 – 1.73 (m,2H). LCMS (ESI, m / z): 530 [M+H] + .

[0307] Compound 38 5-chloro- N -(4-(4-((2-(dimethylamino)ethyl)amino)-3-methyl-1 H -pyrazolo[3, 4- d ]pyrimidin-6-yl)-2-fluorophenyl)-2-fluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 9. The desired product (28.6 mg, 19%) was obtained as a white TFA salt solid. LCMS (ES. m / z): 522 [M+H] + . 1 H-NMR (CD3OD, 300MHz) δ (ppm): 8.19-8.10 (m, 1H), 8.09-8.06 (m, 1H), 7.81-7.78 (m, 1H), 7.68-7.53 (m, 2H), 7.35-7.29 (m, 1H), 4.16-4.12 (m, 2H), 3.57-3.53 (m, 2H), 2.98 (s, 6H), 2.65 (s, 3H).

[0308] Compound 39 N -(4-(4-((2-(dimethylamino)ethyl)amino)-3-ethyl-1 H -pyrazolo[3,4- d ]pyrethrum (Pyridine-6-yl)phenyl)-2,5-difluorobenzenesulfonamide (i) 6-Chloro-N-[2-(dimethylamino)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine At 0 °C, DIEA (1.12 g, 10.5 mmol, 1.0 equivalent) was added to a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (2.0 g, 10.5 mmol, 1.0 equivalent) and (2-aminoethyl)dimethylamine (2.72 g, 21.1 mmol, 1.0 equivalent) in anhydrous THF (20 mL), and the mixture was stirred at room temperature for 4 h. The organic layer was treated with H2O (20 mL), extracted with DCM (30 mL), dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product of the desired product (1.3 g, 93% purity, pale yellow solid).

[0309] (ii) N-[4-(4-[[2-(dimethylamino)ethyl]amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzene 2,5-Difluorobenzenesulfonamide Under a nitrogen atmosphere at room temperature, 2,5-difluoro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]benzenesulfonamide (2.34 g, 5.93 mmol, 1.1 equivalent) was added to a solution of 6-chloro-N-[2-(dimethylamino)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.3 g, 5.39 mmol, 1.0 equivalent), Pd(dppf)Cl2 (788.6 mg, 1.08 mmol, 0.2 equivalent), and Cs2CO3 (2.64 mg, 8.09 mmol, 1.5 equivalent) in 1,4-dioxane (24 mL) and H2O (6 mL). The reaction mixture was purged with nitrogen three times and stirred at 100 °C under nitrogen for 12 hours. The reactants were cooled to room temperature and neutralized to pH 7-8 with saturated 1N HCl aqueous solution, followed by washing with DCM (3 x 100 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by HPLC to obtain the desired product (350.0 mg, 90% purity, grayish-white solid).

[0310] (iii) N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-iodo-1H-pyrazolo[3,4-d]pyrimidine-6- [2,5-difluorobenzenesulfonamide](phenyl)-2,5-difluorobenzenesulfonamide NIS (143 mg, 0.634 mol, 1.0 equivalent) was added to a stirred solution of N-[4-(4-[[2-(dimethylamino)ethyl]amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-2,5-difluorobenzenesulfonamide (300.0 mg, 0.634 mmol, 1.0 equivalent) in HOAc (10 mL), and the resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure and diluted with water (100 mL). The residue was acidified to pH 7 with aqueous NaOH solution (1 M). The mixture was extracted with DCM. The organic layer was dried over Na2SO4, concentrated, and purified by column chromatography to give the desired product (peak A: 90 mg, 70% purity, grayish-white solid; peak B: 120 mg, 55% purity, grayish-white solid).

[0311] (iv) N-[4-(4-[[2-(dimethylamino)ethyl]amino]-5-vinyl-7H-pyrrolo[2,3-d]pyrimidine [Pyridine-2-yl)phenyl]-2,5-difluorobenzenesulfonamide Under a nitrogen atmosphere at room temperature, 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxoborane (93 mg, 0.6 mmol, 3 equivalents) was added to a solution of N-[4-(4-[[2-(dimethylamino)ethyl]amino]-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl]-2,5-difluorobenzenesulfonamide (120 mg, 0.2 mmol, 1.0 equivalent), Pd(dppf)Cl2 (43.9 mg, 0.06 mmol, 0.3 equivalent), and K2CO3 (55.2 mg, 0.4 mmol, 2 equivalent) in dioxane (4 mL) and H2O (1 mL). The reaction mixture was purged with nitrogen three times and stirred at 100 °C under nitrogen for 18 h. The reactants were cooled to room temperature and neutralized to pH 7-8 with saturated 1N HCl aqueous solution, followed by washing with DCM (3 x 5 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by reversed-phase chromatography (10 mmol / L NH₄HCO₃ / ACN) to obtain the desired product (75 mg, 50% purity, grayish-white solid).

[0312] (v) N -[4-(4-[[2-(dimethylamino)ethyl]amino]-5-ethyl-7H-pyrrolo[2,3-d]pyrimidine-2- [2,5-difluorobenzenesulfonamide](phenyl)-2,5-difluorobenzenesulfonamide Pd / C (32 mg, 0.03 mmol, 0.2 equivalent) was added to a solution of N-[4-(4-[[2-(dimethylamino)ethyl]amino]-5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl]-2,5-difluorobenzenesulfonamide (75 mg, 0.15 mmol, 1.0 equivalent) in CH3OH (5 mL) and DMF (5 mL) at room temperature under a H2 atmosphere. The reaction mixture was purged three times with nitrogen and stirred at 25 °C for 20 h. The combined organic phases were filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by reversed-phase chromatography (column: Xselect CSH OBD column 30*150mm 5µm, n; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 9% B to 39% B, 39% B over 9 min; wavelength: 254 nm; RT1 (min): 7.58; number of runs: 0) to obtain the desired product (24 mg, 96.5% purity, white solid) in the form of TFA salt. LCMS (ESI, m / z): 502 [M-2TFA+H] + . 1 H NMR (300MHz, DMSO- d 6) δ 11.10 (s, 1H), 9.49 (s, 1H), 8.33-8.24 (m, 2H), 7.76-7.49 (m, 3H), 7.29-7.18 (m, 3H), 3.97(d, J = 5.7Hz, 2H), 3.41 (d, J = 5.7Hz, 2H), 2.98 (q, J = 7.5Hz, 2H), 2.88 (d, J = 4.7Hz, 6H), 1.28 (t, J = 7.5Hz, 3H).

[0313] Compound 40 N -(2-((6-(4-((5-chloro-2-fluorophenyl)sulfonylamino)-2-methylphenyl)-3-methyl-1 H - Pyrazolo[3,4- d ]pyrimidin-4-yl)amino)ethyl)- N -Methylformamide (i) (2-(N-methylformamido)ethyl)tert-butyl carbamate A suspension of N-[2-(methylamino)ethyl]carbamate tert-butyl ester (2.00 g, 11.478 mmol) in ethyl formate (6 mL, 72.87 mmol) was stirred at 60 °C for 3 hours. The resulting mixture was cooled and concentrated under vacuum. The residue was applied to a silica gel column containing 0–3% MeOH / DCM. This yielded N-[2-(N-methylformamido)ethyl]carbamate tert-butyl ester (2.12 g, Y = 82%) as a yellow oil. LCMS (ESI, m / z): 203 [M+H]+ .

[0314] (ii) N -(2-aminoethyl)-N-methylformamide TFA (10 mL) was added to a solution of (2-(N-methylformamido)ethyl)carbamate (2.12 g, 10.50 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum. This yielded N-(2-aminoethyl)-N-methylformamide (2.00 g crude product, TFA salt form), a pale brown oil, which could be used directly in the next step without any further purification. LCMS (ES, m / z): 103 [M+H]+ (iii) N-(2-((6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)ethyl)-N-methyl formamide A mixture of 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (1.97 g, 9.54 mmol), N-(2-aminoethyl)-N-methylformamide (2.00 mg crude product, TFA salt form) and DIPEA (15.7 mL, 95.4 mmol) in DCM (30 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum. The residue was purified by reversed-phase chromatography under the following conditions (column: Agela C18 column, 330 g; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 0% B to 100% B over 20 min; 254 nm). This yielded N-(2-((6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)ethyl)-N-methylformamide (2.05 g, Y = 73%), a pale yellow solid. LCMS (ES, m / z): 269 [M+H] + .

[0315] (iv) 5-Chloro-2-fluoro-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl) Phenylbenzenesulfonamide A mixture of 5-chloro-2-fluorobenzenesulfonyl chloride (97 mg, 0.429 mmol), pyridine (101 mg, 1.28 mmol), and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexicyclopentan-2-yl)aniline (100 mg, 0.429 mmol) in DCM (5 mL) was stirred at room temperature for 16 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1 / 3). This yielded 5-chloro-2-fluoro-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexicyclopentan-2-yl)phenyl)benzenesulfonamide (148 mg, Y = 81%) as a white solid. LCMS (ESI, m / z): 424 [M-1] - .

[0316] (v) N-(2-((6-(4-(((5-chloro-2-fluorophenyl)sulfonylamino)-2-methylphenyl)-3-methyl-1H-pyrazole) [3,4-d]pyrimidin-4-yl)amino)ethyl)-N-methylformamide A mixture of 5-chloro-2-fluoro-N-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]benzenesulfonamide (80 mg, 0.194 mmol), N-[2-([6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino)ethyl]-N-methylformamide (50 mg, 0.194 mmol), Pd(dppf)Cl2.CH2Cl2 (15.83 mg, 0.019 mmol), and Cs2CO3 (126.63 mg, 0.389 mmol) in dioxane (2 mL) and water (0.5 mL) was stirred at 100 °C under nitrogen for 3 hours. The reaction mixture was cooled and concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions (column: Xselect CSH OBD column 30*150mm 5µm, n; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 50% B over 13 min; 254 nm; RT: 7.55). This yielded N-[2-([6-[4-(5-chloro-2-fluorobenzenesulfonylamino)-2-methylphenyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino)ethyl]-N-methylformamide (14.9 mg) as a white solid in the form of a TFA salt. 1 H NMR (400MHz, DMSO- d6) δ 11.04(brs, 1H), 7.92 - 7.80 (m, 3H), 7.75 - 7.73 (m, 1H), 7.55 - 7.49 (m, 1H), 7.11 - 7.04 (m, 2H), 3.76 - 3.65 (m, 3H), 3.64 - 3.59 (m, 2H), 2.94 - 2.71 (m, 3H), 2.67 - 2.58 (m, 2H), 2.51 - 2.42 (m, 3H). LCMS (ES, m / z): 532 [M+H] + -114.

[0317] Compound 41 5-Chloro-2-Fluoride N -(4-(4-(((3 S 4 R )-3-fluoro-1-isopropylpiperidin-4-yl)oxy)-3- Methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)phenyl)benzenesulfonamide (i) 5-Chloro-2-fluoro-N-[4-(4-[[(3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl]oxy]-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide Pd(dppf)Cl2.CH2Cl2 (13 mg, 0.015 mmol) and Cs2CO3 (100 mg, 0.306 mmol) were added to a stirred mixture of (3S,4R)-4-([6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy)-3-fluoro-1-isopropylpiperidine (50 mg, 0.153 mmol) in 1,4-dioxane (3.0 mL) and H2O (1.0 mL). The flask was evacuated and rinsed three times with nitrogen. The resulting mixture was stirred at 100 °C for 3 hours under nitrogen. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18, 30 mm × 150 mm, 5 µm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B over 7 min; 254 nm; RT: 5.12). This yielded 5-chloro-2-fluoro-N-[4-(4-[[(3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl]oxy]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide trifluoroacetic acid (11.3 mg, Y = 11%, a mixture of two enantiomers) as a white solid. 1 H NMR (400MHz, DMSO-) d6) δ 13.57 (s, 1H), 11.18 (s, 1H), 9.50 - 9.30 (m, 1H), 8.40 -8.35 (m, 2H), 7.88- 7.86 (m, 2H), 7.55 - 7.51 (m, 1H), 7.29 -7.27 (m, 2H),5.85 - 5.45 (m, 2H),3.82 - 3.47 (m, 4H), 2.68 -2.66 (m, 2H), 2.52 - 2.50 (m,3H),2.33 - 2.32 (m, 1H), 1.32 (d, J = 6.24Hz, 6H). LCMS (ES, m / z): 577 [M+H] + -114.

[0318] Compound 42 5-chloro-2-fluoro- N -(4-(4-(((3 R 4 S )-4-Fluoropyrrolidine-3-yl)oxy)-3-methyl-1 H - Pyrazolo[3,4- d ]pyrimidin-6-yl)phenyl)benzenesulfonamide The compound was prepared according to the procedure described in Example 29. The desired product (40.2 mg, 99.5% purity) was obtained as a white TFA salt. LCMS (ESI, m / z): 521 [M-TFA+H] + . 1 H NMR (300MHz, DMSO- d 6) δ13.63 (s, 1H), 11.21 (s, 1H), 9.57 (d, J = 112.0Hz, 2H), 8.41-8.32 (m, 2H), 7.92-7.77 (m, 2H), 7.53 (t, J = 9.3Hz, 1H), 7.33-7.24 (m, 2H), 5.97 (dtd, J =20.4, 7.9, 3.7Hz, 1H), 5.82-5.56 (m, 1H), 3.98 (s, 2H), 3.76 (s, 2H), 3.68(s, 1H), 3.43 (t, J = 10.1Hz, 1H), 2.53 (s, 3H).

[0319] Compound 43 5-chloro-2-fluoro- N -(4-(4-(((3 S 4 R )-3-Fluoroperidin-4-yl)oxy)-3-methyl-1 H -pyr Azo[3,4-] d pyrimidin-6-yl)-3-methylphenyl)benzenesulfonamide The compound was prepared according to the procedure described in Example 29. The desired product (30.8 mg, 23%) was obtained in the form of a white TFA salt. 1H-NMR (CD3OD, 300MHz) δ (ppm): 7.87-7.81 (m, 2H), 7.65-7.60 (m,1H), 7.33-7.27 (m, 1H), 7.14-7.07 (m, 2H), 5.84-5.71 (m, 1H), 5.43-5.27 (m,1H), 3.81-3.73 (m, 1H), 3.62-3.46 (m, 2H), 3.31-3.39 (m, 1H), 2.59 (s, 6H), 2.39 (m, 2H). LCMS (ES. m / z): 549 [M+H] + .

[0320] Compound 44 ( R )-5-chloro- N -(4-(4-((3,3-difluoropiperidin-4-yl)oxy)-3-methyl-1 H -pyrazol [3,4- d ]pyrimidin-6-yl)phenyl)-2-fluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 29. The desired product (4.8 mg, 5%) was obtained in the form of a white TFA salt. 1 H-NMR (CD3OD, 400MHz) δ (ppm): 8.33 (d, J = 8.7Hz, 2H), 7.89-7.87(m, 1H), 7.61-7.57 (m, 1H), 7.29-7.22 (m, 3H), 5.99-5.96 (m, 1H), 3.28-2.85(m, 4H), 2.59 (s, 3H), 2.39-2.01 (m, 2H). LCMS (ES. m / z): 553 [M+H] + .

[0321] Compound 45 N -(4-(4-((2-(dimethylamino)ethyl)amino)-3-methyl-1 H -pyrazolo[3,4- d ]pyrethrum (Pyridine-6-yl)phenyl)-2,5-difluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 9. The desired product (21.5 mg, 22%) was obtained in the form of a white TFA salt. 1 H NMR (400MHz, DMSO- d 6): δ 13.15 (s, 1H), 11.1 (s, 1H), 9.41-9.25 (m, 1H), 8.26 (d, J=8.60Hz, 2H), 7.66-7.72 (m, 1H), 7.62-7.55 (m, 1H),7.54-7.47 (m, 1H), 7.22 (d, J = 8.60Hz, 2H), 3.42 - 3.32 (m, 2H), 3.42-3.32(m, 2H), 2.54 (s, 3H), 1.10 (s, 6H). LCMS (ES. m / z): 488.5 [M+H] + .

[0322] Compound 46 5-Chloro-2-fluoro-N-(4-(4-((((3R,4S)-3-fluoropiperidin-4-yl)oxy)-3-methyl-1H-pyridine Azo[3,4-d]pyrimidin-6-yl)phenyl)benzenesulfonamide At 0 °C, NaH (60 mg, 1.476 mmol) was added to a solution of 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 0.984 mmol) and (3R,4S)-3-fluoro-4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (218 mg, 0.984 mmol) in anhydrous DMF (2 mL), and the mixture was stirred at room temperature for 2 hours. The organic layer was treated with H2O (10 mL), extracted with DCM (15 mL), dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product (3R,4S)-4-((6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluoropiperidin-1-carboxylic acid tert-butyl ester (160 mg, 85% purity, white solid). LCMS (ESI, m / z): 386 [M+H]+.

[0323] (i) (3R,4S)-4-((6-(4-((5-chloro-2-fluorophenyl)sulfonylamino)phenyl)-3-methyl-1H-pyrazol [3,4-d]pyrimidin-4-yl)oxy)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere at room temperature, tert-butyl 3-(3R,4S)-4-((6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluoropiperidine-1-carboxylate (160 mg, 0.43 mmol, 1.0 equivalent), Pd(dppf)Cl2 (63.4 mg, 0.09 mmol, 0.2 equivalent), and Cs2CO3 (212 mg, 0.65 mmol, 1.5 equivalent) in a solution of 1,4-dioxane (12 mL) and H2O (3 mL) was added to a solution of 5-chloro-2-fluoro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)benzenesulfonamide (196 mg, 0.48 mmol, 1.1 equivalent). The reaction mixture was purged three times with nitrogen and stirred at 100°C for 16 hours under nitrogen. The reaction mixture was cooled to room temperature and neutralized to pH 7–8 with 1N HCl aqueous solution, followed by washing with DCM (3 x 20 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by reversed-phase chromatography (C18 column; mobile phase, MeCN / water, 10% to 36% gradient over 18 min; detector, UV 254 nm) to obtain the desired product (130 mg, 48% purity, pale brown solid). LCMS (ESI, m / z): 635 [M+H]⁺ (ii) 5-Chloro-2-fluoro-N-(4-(4-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-3-methyl-1H-pyrazolo [3,4-d]pyrimidin-6-yl)phenyl)benzenesulfonamide trifluoroacetic acid At 25 °C, CF-3COOH (2 mL) was added to a solution of (3R,4S)-4-((6-(4-(((5-chloro-2-fluorophenyl)sulfonylamino)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.204 mmol) in 2 mL of ACN, and the mixture was stirred at room temperature for 10 hours. The mixture was concentrated under reduced pressure to give the crude product. The crude product was then purified by reversed-phase chromatography (column: XBridge Shield RP18 OBD column, 19*150mm, 5µm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25mL / min; gradient: 20% B to 50% B, 50% B over 9 min; wavelength: 254nm; RT1 (min): 7.38; runs: 0) to give 5-chloro-2-fluoro-N-(4-(4-((((3R,4S)-3-fluoropiperidin-4-yl)oxy)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)benzenesulfonamide trifluoroacetic acid (55.8 mg, 99.5% purity, white solid). LCMS (ESI, m / z): 535 [M-TFA+H]+. 1H NMR (300MHz, DMSO-d6) δ 13.56 (s, 1H), 9.11 (s, 1H), 8.44 – 8.31 (m, 2H), 7.93 – 7.72 (m,2H), 7.53 (t, J = 9.3Hz, 1H), 7.32 – 7.23 (m, 2H), 6.07 – 5.71 (m, 1H), 5.38(d, J = 48.2Hz, 1H), 3.71 – 3.47 (m, 2H), 3.35 – 3.23 (m, 4H), 2.58(s, 3H), 2.26 (td, J = 15.9, 15.0, 4.8Hz, 2H).

[0324] Compound 47 5-Chloro-2-fluoro-N-(4-(4-((((3S,4S)-3-fluoropiperidin-4-yl)oxy)-3-methyl-1H-pyridine Azo[3,4-d]pyrimidin-6-yl)phenyl)benzenesulfonamide The compound was prepared according to the procedure described in Example 46. The desired product (66.5 mg, 95.8% purity) was obtained in the form of a pale pink TFA salt. LCMS (ESI, m / z): 535 [M-TFA+H]+. 1 H NMR (300MHz, DMSO- d 6)δ 13.56 (s, 1H), 8.39 – 8.28 (m, 2H), 7.89 (dd, J = 6.0, 2.7Hz, 1H), 7.80(ddd, J = 8.8, 4.2, 2.7Hz, 1H), 7.53 (t, J = 9.3Hz, 1H), 7.35 – 7.23 (m, 2H), 5.95 – 5.82 (m, 1H), 5.30 – 5.02 (m, 1H), 3.69 – 3.49 (m, 2H), 3.27 (d, J =11.7Hz, 4H), 2.55 (s, 3H), 2.39 (s, 1H), 2.17 – 2.06 (m, 1H).

[0325] Compound 48 5-chloro-2-fluoro-N-(4-{3-methyl-4-[(3S)-pyrrolidine-3-yloxy]-1H-pyrazolo[3, 4-d]pyrimidin-6-yl}phenyl)benzenesulfonamide The compound was prepared according to the procedure described in Example 47. The desired product (19.5 mg, Y = 21%) was obtained as a white TFA salt. LCMS (ES. m / z): 503 [M+H]+. 1H-NMR (CD3OD, 300MHz) δ (ppm):8.37 (d, J = 8.7Hz, 2H), 7.88-7.86 (m, 1H), 7.64-7.59 (m, 1H), 7.32-7.25 (m,3H), 6.11(d, J = 3.0Hz,1H), 3.83-3.71 (m, 2H), 3.59-3.55 (m, 2H), 2.59-2.49 (m, 5H).

[0326] Compound 49 5-chloro-N-(4-{4-[(4,4-difluoropyrrolidine-3-yl)oxy]-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-6-yl}phenyl)-2-fluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 47. The desired product (12.2 mg, 98.4% purity) was obtained as a grayish-white TFA salt. LCMS (ESI, m / z): 539 [M-TFA+H]+. 1 H NMR (300MHz, DMSO- d 6) δ13.67 (s, 1H), 11.17 (s, 1H), 10.08 (s, 1H), 8.47 – 8.31 (m, 2H), 7.98 – 7.73(m, 2H), 7.53 (t, J = 9.3Hz, 1H), 7.29 (dd, J = 9.8, 3.0Hz, 2H), 6.34 – 6.07(m, 1H), 4.15 – 3.87 (m, 3H), 3.78 (dt, J = 13.5, 2.8Hz, 1H), 2.56 (s, 3H).

[0327] Compound 50 5-chloro-2-fluoro-N-[4-(4-{[(3S,4R)-3-fluoro-1-(2-hydroxyethyl)piperidin-4-yl]oxy [3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide (i) 2-[(3S,4R)-4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-3-fluoropiperazine [Pyr-1-yl]ethanol DIEA (257 mg, 1.996 mmol, 4.0 equivalent) was added to a solution of (3S,4R)-4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-3-fluoropiperidine (150 mg, 0.499 mmol, 1.0 equivalent) and 2-bromoethanol (311 mg, 2.495 mmol, 5.0 equivalent) in anhydrous DMF (2 mL), and the mixture was stirred at room temperature for 2 h. The organic layer was treated with H2O (20 mL), extracted with DCM (20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, silica gel; mobile phase, MeCN / water, 10% to 35% gradient over 18 min; detector, UV 254 nm) to give the purified product (120 mg, 93% purity, white solid). LCMS (ESI, m / z): 330[M+H]+.

[0328] (ii) 5-Chloro-2-fluoro-N-[4-(4-{[(3S,4R)-3-fluoro-1-(2-hydroxyethyl)piperidin-4-yl]oxy}-3- Methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide Under a nitrogen atmosphere at room temperature, 5-chloro-2-fluoro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-4-yl)phenyl)benzenesulfonamide (170 mg, 0.37 mmol, 1.1 equivalent) was added to a solution of 2-[(3S,4R)-4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-3-fluoropiperidin-1-yl]ethanol (120 mg, 0.338 mmol, 1.0 equivalent), Pd(dppf)Cl2 (49.5 mg, 0.068 mmol, 0.2 equivalent) and Cs2CO3 (165 mg, 0.51 mmol, 1.5 equivalent) in 1,4-dioxane (8 mL) and H2O (2 mL). The reaction mixture was purged three times with nitrogen and stirred at 100°C for 16 hours under nitrogen. The reaction mixture was cooled to room temperature and neutralized to pH 7-8 with saturated 1N HCl aqueous solution, followed by washing with DCM (3 x 20 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure to give the crude product. The crude product was then purified by reversed-phase chromatography (column: Xselect CSH OBD column 30*150mm 5µm, n; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18% B to 28% B, 28% B over 13 min; wavelength: 254 nm; RT1 (min): 11.52; number of runs: 0) to obtain 5-chloro-2-fluoro-N-[4-(4-{[(3S,4R)-3-fluoro-1-(2-hydroxyethyl)piperidin-4-yl]oxy}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide; trifluoroacetic acid (34.6 mg, 99.5% purity, yellow solid). LCMS (ESI, m / z): 579 [M-TFA+H]+. 1 ¹H NMR (300MHz, methanol-d⁴) δ 8.46 –8.34 (m, 2H), 7.91 (dd, J = 6.1, 2.7Hz, 1H), 7.65 (ddd, J = 8.9, 4.2, 2.7Hz, 1H), 7.41 – 7.26 (m, 3H), 5.97 (dt, J = 27.9, 7.9Hz, 1H), 5.50 (d, J = 48.0Hz, 1H), 4.22 – 3.40 (m, 8H), 2.65 (s, 3H), 2.54 (d, J = 7.7Hz, 2H).

[0329] Compound 51 5-Chloro-2-fluoro-N-[4-(4-{[1-(2-hydroxyethyl)piperidin-4-yl]oxy}-3-methyl-1H-pyridine Azo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide (i ) tert-Butoxy[4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)piperidin-1-yl] methanol At 0 °C, NaH (84.22 mg, 2.106 mmol, 3.0 equivalent) was added to a solution of 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 1.404 mmol, 1.0 equivalent) and tert-butyl 4-hydroxypiperidin-1-carboxylate (339 mg, 1.685 mmol, 1.2 equivalent) in anhydrous DMF (2 mL), and the mixture was stirred at room temperature for 2 hours. The organic layer was treated with H2O (10 mL), extracted with DCM (15 mL), dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product tert-butoxy[4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)piperidin-1-yl]methanol (230 mg, 75% purity, orange oil). LCMS(ESI, m / z): 368 [M+H]+.

[0330] (ii) 4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)piperidine To a solution of tert-butyl 4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)piperidine-1-carboxylate (230 mg, 0.470 mmol, 1.0 equivalent) in ACN (3 mL), CF3COOH (3 mL) was added and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to give a crude product. The crude product was then purified by reversed-phase chromatography under the following conditions (C18 column; mobile phase, MeCN / water, 10% to 35% gradient over 15 min; detector, UV 254 nm) to give the desired product (150 mg, 90% purity, white solid). LCMS (ESI, m / z): 268 [M+H]+.

[0331] (iii) 2-[4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)piperidin-1-yl]ethyl alcohol DIEA (260 mg, 2.016 mmol, 4.0 equivalent) was added to a solution of 4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)piperidine (150 mg, 0.504 mmol, 1.0 equivalent) and 2-bromoethanol (315 mg, 2.520 mmol, 5.0 equivalent) in anhydrous DMF (2 mL), and the mixture was stirred at room temperature for 16 h. The organic layer was treated with H2O (20 mL), extracted with DCM (20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, silica gel; mobile phase, MeCN / water, 10% to 37% gradient over 15 min; detector, UV 254 nm) to give the purified product (130 mg, 94% purity, white solid). LCMS (ESI, m / z): 312 [M+H]+.

[0332] (iv) 5-Chloro-2-fluoro-N-[4-(4-{[1-(2-hydroxyethyl)piperidin-4-yl]oxy}-3-methyl-1H-pyrazolo [3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide Boric acid (233 mg, 0.51 mmol, 1.3 equivalents) was added to a solution of 2-[4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)piperidin-1-yl]ethanol (130 mg, 0.392 mmol), Pd(dppf)Cl2 (57.3 mg, 0.078 mmol), and Cs2CO3 (127.7 mg, 0.392 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was purged three times with nitrogen and stirred at 100 °C for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, neutralized to pH 7–8 with 1N HCl aqueous solution, and washed with DCM (3 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was then purified by reversed-phase chromatography (column: YMC-Actus Triart C18 ExRS, 30*150mm, 5µm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60mL / min; gradient: 20% B to 25% B, 25% B over 16 min; wavelength: 254nm; RT1 (min): 12.55) to obtain the desired product (39.9mg, 99.9% purity, white solid). LCMS (ESI, m / z): 561 [M+H]+. 1H NMR (300MHz, methanol-d4) δ 8.43 – 8.32 (m, 2H), 7.89 (dd, J = 6.1, 2.6Hz, 1H), 7.68 –7.58 (m, 1H), 7.30 (dd, J = 14.3, 8.8Hz, 3H), 5.98 – 5.57 (m, 1H), 3.95 (dd,J = 6.3, 4.0Hz, 2H), 3.74 (dd, J = 43.1, 12.8Hz, 2H), 3.38 (t, J = 5.3Hz,4H), 2.70 – 2.12 (m, 7H).

[0333] Compound 52 5-Chloro-2-fluoro-N-[4-(4-{[1-(2-hydroxyethyl)pyrrolidine-3-yl]oxy}-3-methyl-1H- Pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide The compound was prepared according to the procedure described in Example 51. The desired product (9.1 mg, 99.3% purity, white solid) was obtained as a white free base. LCMS (ESI, m / z): 547 [M+H]+. 1 H NMR (300MHz, DMSO- d6) δ 13.42 (s, 1H), 8.34 – 8.21 (m, 2H), 7.85 (dd, J = 6.0, 2.7Hz, 1H), 7.77– 7.68 (m, 1H), 7.46 (t, J = 9.3Hz, 1H), 7.25 – 7.15 (m, 2H), 5.73 (td, J =6.8, 3.3Hz, 1H), 4.58 (s, 1H), 3.52 (d, J = 7.0Hz, 2H), 3.16 (dd, J = 11.3,6.3Hz, 1H), 2.98 – 2.85 (m, 2H), 2.64 (t, J = 6.1Hz, 3H), 2.47 – 2.35 (m,4H), 2.09 – 1.92 (m,1H).

[0334] Compound 53 5-Chloro-2-fluoro-N-[4-(4-{[(3R,4R)-3-fluoropiperidin-4-yl]oxy}-3-methyl-1H-pyridine Azo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide The compound was prepared according to the procedure described in Example 47. The desired product (16.8 mg, 54%) was obtained as a white TFA salt. LCMS (ES. m / z): 535 [M+H]+. 1 H-NMR (DMSO- d 6, 300MHz) δ (ppm):13.55 (s, 1H), 9.28 (s, 1H), 8.33 (d, J = 8.7Hz, 2H), 7.89-7.78(m, 2H), 7.55-7.49 (m, 1H), 7.28 (d, J = 8.7Hz, 2H), 5.87 (s, 1H), 5.26-5.09 (m, 1H), 3.70-3.27 (m, 4H), 3.62 (s, 3H), 2.27 (s, 2H), 2.14-2.08 (m, 1H).

[0335] Compound 54 5-Chloro-N-[4-(4-{[(3S,4R)-1-ethyl-3-fluoropiperidin-4-yl]oxy}-3-methyl-1H- Pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide (i) (3S,4R)-4-([6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy)-3-fluoropiperidine- 1-Tert-butyl formate Add 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (300.00 mg, 1.478 mmol, 1.00 equivalent), THF (15.00 mL), and (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (323.98 mg, 1.478 mmol, 1.00 equivalent) to a 50 mL round-bottom flask. Stir the resulting solution at room temperature for 30 min. Then add NaH (177.30 mg, 4.433 mmol, 3 equivalent, 60%) at 0 °C. Stir the resulting solution at room temperature for 2 h. Concentrate the resulting mixture. Wash the solid with ethyl ether. Collect the solid by filtration. This yielded 280 mg (44.20%) of (3S,4R)-4-([6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester as a yellow solid. LCMS (ES.m / z): 386 [M+H]+.

[0336] (ii) (3S,4R)-4-([6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy)-3-fluoropiperidine hydrochloride To a 50-mL round-bottom flask, add tert-butyl (3S,4R)-4-([6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy)-3-fluoropiperidine-1-carboxylic acid (280.00 mg, 0.726 mmol, 1.00 equivalent), DCM (6.00 mL), and HCl (4 M in 1,4-dioxane) (6.00 mL, 105.105 mmol, 115.86 equivalent). Stir the resulting solution at room temperature for 2 hours. Concentrate the resulting mixture. This yields 200 mg (76.99%) of the desired compound as a white solid. LCMS (ES. m / z): 286 [M+H]+.

[0337] (iii) (3S,4R)-4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-1-ethyl- 3-Fluoroperidine A solution of (3S,4R)-4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-3-fluoropiperidine hydrochloride (180 mg, 0.559 mmol, 1.00 equivalent), MeOH (6 mL, 148.193 mmol, 265.24 equivalent), acetaldehyde (49.23 mg, 1.118 mmol, 2 equivalent), AcOH (33.55 mg, 0.559 mmol, 1.00 equivalent), and H₂O (0.5 mL, 27.754 mmol, 49.68 equivalent) was stirred at room temperature for 30 min. NaBH₃CN (70.22 mg, 1.118 mmol, 2 equivalent) was added, and the mixture was stirred at 60 °C for 3 h. The added NaBH3CN (70.22 mg, 1.118 mmol, 2 equivalents) was then stirred at 60 °C for 16 h. The mixture was cooled to room temperature. The reaction mixture was quenched with water. The resulting mixture was extracted with EtOAc (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 15:1) to give the desired product (100 mg, 51.34%) as a yellow oil. LCMS (ES. m / z): 314 [M+H]+.

[0338] (iv) 5-Chloro-N-[4-(4-{[(3S,4R)-1-ethyl-3-fluoropiperidin-4-yl]oxy}-3-methyl-1H-pyrazole [3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide The following were added: (3S,4R)-4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-1-ethyl-3-fluoropiperidine (100 mg, 0.319 mmol, 1.00 equivalent), 5-chloro-2-fluoro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]benzenesulfonamide (144.33 mg, 0.351 mmol, 1.1 equivalent), Pd(dppf)Cl2 A solution of Cs₂CO₃ (46.64 mg, 0.064 mmol, 0.2 equivalents), Cs₂CO₃ (155.77 mg, 0.479 mmol, 1.5 equivalents), and Cs₂CO₃ (155.77 mg, 0.479 mmol, 1.5 equivalents) in dioxane (4 mL, 47.216 mmol, 148.15 equivalents) and H₂O (1 mL, 55.508 mmol, 174.16 equivalents) was stirred at 100 °C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The solid was purified by flash evaporation under the following conditions (column, C18 (40 g); mobile phase A: water-10 mM NH₄HCO₃, mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient 60 B to 65 B; 254 nm). The crude product was then purified by preparative HPLC under the following conditions (column: Xselect CSH OBD column 30×150mm 5µm, n; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 35% B, 35% B over 9 min; wavelength: 254 nm; RT1 (min): 7.48);) to obtain the desired product (19.3 mg, 8.91%) as a white solid. LCMS (ES. m / z): 563 [M+H]+. 1 H-NMR (CD3OD, 300MHz) δ (ppm): 7.58 (d, J = 8.7Hz, 2H), 7.09-7.06 (m,1H), 6.85-6.82 (m, 1H), 6.23-6.46 (m, 3H), 4.92-5.13 (m, 1H), 4.76-4.60 (m,1H), 3.21 (d, J = 9.3Hz, 1H), 2.26-3.02 (m, 5H), 1.79-1.64 (m, 5H), 0.66-0.61(m, 3H).

[0339] Compound 55 5-chloro-2-fluoro-N-{4-[3-methyl-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine [Pyridine-6-yl]phenyl}benzenesulfonamide The compound was prepared according to the procedure described in Example 47. The desired product (3.4 mg, 8.29%) was obtained as a white TFA salt. LCMS (ES. m / z): 517 [M+H]+. 1 H-NMR (300MHz, DMSO- d 6) δ (ppm):13.49 (s, 1H), 11.16 (s, 1H), 8.67-8.41 (m, 2H), 8.33 (d, J = 9.0Hz, 2H), 7.82-7.78 (m, 2H), 7.56-7.49 (m, 1H), 7.27 (d, J = 8.7Hz, 2H), 5.74-5.71 (m,1H), 3.58-3.48 (m, 4H), 2.59 (s, 3H), 2.13-2.25 (m, 2H), 1.96-2.05 (m, 2H).

[0340] Compound 56 5-chloro-N-[4-(4-{[(3R,4S)-1-ethyl-4-fluoropyrrolidine-3-yl]oxy}-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 47. The desired product (20.9 mg, 9.41%) was obtained as a grayish-white TFA salt. LCMS (ES. m / z): 549 [M+H]+. 1 H-NMR (CD3OD, 300MHz) δ (ppm):8.40-8.37 (m, 2H), 7.88-7.85 (m, 1H), 7.64-7.59 (m, 1H), 7.32-7.26 (m, 3H),6.16-6.10 (m, 1H), 5.85-5.68 (m, 1H), 3.65-4.23 (m, 4H), 3.48-3.41 (m, 2H), 2.61 (s, 3H), 1.44-1.39 (m, 3H).

[0341] Compound 57 5-Chloro-2-fluoro-N-[4-(4-{[(3R,4S)-4-fluoro-1-isopropylpyrrolidine-3-yl]oxy}- 3-Methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide (i) (3R,4S)-3-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-4-fluoro-1-iso Propylpyrrolidine Acetone (376.97 mg, 6.490 mmol, 1.00 equivalent) was added to a solution of (3R,4S)-3-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-4-fluoropyrrolidine hydrochloride (200 mg, 0.649 mmol, 1.00 equivalent) in MeOH (10.00 mL, 246.97 mmol, 380.54 equivalent), and the mixture was stirred for 30 min. NaBH3CN (81.58 mg, 1.298 mmol, 2 equivalent) was added, and the mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by flash evaporation under the following conditions (column, C18 (80 g); mobile phase A: water-10 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient 48 B to 60 B; 254 nm) to obtain the desired product (120 mg, 53.03%) as a yellow oil. LCMS (ES. m / z): 314 [M+H]+.

[0342] (ii) 5-Chloro-2-fluoro-N-[4-(4-{[(3R,4S)-4-fluoro-1-isopropylpyrrolidine-3-yl]oxy}-3-methyl [1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide (3R,4S)-3-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-4-fluoro-1-isopropylpyrrolidine (120 mg, 0.382 mmol, 1.00 equivalent), 5-chloro-2-fluoro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]benzenesulfonamide (173.20 mg, 0.420 mmol, 1.1 mmol) A solution of Pd(dppf)Cl2 (55.97 mg, 0.076 mmol, 0.2 equivalents) and Cs2CO3 (186.92 mg, 0.573 mmol, 1.5 equivalents) in dioxane (2.40 mL, 28.295 mmol, 74.07 equivalents) and H2O (0.60 mL, 33.265 mmol, 87.08 equivalents) was stirred at 100 °C for 16 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The solid was purified by flash evaporation under the following conditions (column, C18 (80 g); mobile phase A: water-10 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient 65 B to 72 B; 254 nm). The crude product was purified by preparative HPLC under the following conditions (column: Kinetex EVO C18 column, 30 × 150, 5 µm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 40% B, 40% B over 9 min; wavelength: 254 nm; RT1 (min): 6.78; number of runs: 0) to obtain a grayish-white solid (26.1 mg, 10.00%). LCMS (ES. m / z): 563 [M+H]+. 1 H-NMR (CD3OD, 300MHz) δ (ppm):8.37 (d, J = 8.7Hz, 2H), 7.88-7.85 (m, 1H), 7.64-7.58 (m, 1H), 7.31-7.25 (m,3H), 6.13-6.08 (m, 1H), 5.84-5.66 (m, 1H), 4.07-3.59 (m, 5H), 2.59 (s, 3H), 1.47-1.44 (m, 6H).

[0343] Compound 58 5-Chloro-2-fluoro-N-[4-(4-{[(3R,4S)-4-fluoro-1-methylpyrrolidine-3-yl]oxy}-3- Methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide The compound was prepared according to the procedure described in Example 57. The desired product (14.3 mg, Y = 6.95%) was obtained as a grayish-white TFA salt. LCMS (ES. m / z): 535 [M+H]+.1 H-NMR (CD3OD, 300MHz) δ (ppm):8.38 (d, J = 8.7Hz, 2H), 7.88-7.85 (m, 1H), 7.65-7.59 (m, 1H), 7.32-7.26 (m,3H), 6.18-6.08 (m, 1H), 5.86-5.68 (m, 1H), 4.13-3.52 (m, 4H), 3.07 (s, 3H), 2.61 (s, 3H).

[0344] Compound 59 5-chloro-N-[4-(4-{[(4R)-1-ethyl-3,3-difluoropiperidin-4-yl]oxy}-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 57. The desired product (29.9 mg, Y = 10.92%) was obtained as a white TFA salt with LCMS (ES. m / z): 581 [M+H]+. 1 H-NMR (CD3OD, 300MHz) δ (ppm):8.38 (d, J = 8.7Hz, 2H), 7.89-7.86 (m, 1H), 7.64-7.59 (m, 1H), 7.31-7.25 (m,3H), 6.22-6.15 (m, 1H), 3.94 (s, 2H), 3.54-3.36 (m, 4H), 2.62-2.51 (m, 5H), 1.46-1.41 (m, 3H).

[0345] Compound 60 5-chloro-N-[4-(4-{[(4R)-3,3-difluoro-1-methylpiperidin-4-yl]oxy}-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 57. The desired product (16.3 mg, 12.55%) was obtained as a white TFA salt. LCMS (ES. m / z): 567 [M+H]+. 1 H-NMR (CD3OD, 300MHz) δ (ppm):8.39-8.36 (m, 2H), 7.89-7.86 (m, 1H), 7.64-7.60 (m, 1H), 7.31-7.25 (m, 3H),6.19-6.12 (m, 1H), 3.97-3.89 (m, 2H), 3.53 (s, 2H), 3.06 (s, 3H), 2.62-2.52 (m, 5H).

[0346] Compound 61 5-Chloro-2-fluoro-N-[4-(4-{[(3R,4S)-4-fluoro-1-(2-hydroxyethyl)pyrrolidine-3-yl]oxy [3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide The compound was prepared according to the procedure described in Example 50. The desired product (12.7 mg, 7.22%) was obtained as a white TFA salt. LCMS (ES. m / z): 565 [M+H]+. 1 H-NMR (CD3OD, 400MHz) δ (ppm): 8.38(d, J = 8.8Hz, 2H), 7.88-7.86 (m, 1H), 7.64-7.60 (m, 1H), 7.31-7.26 (m, 3H), 6.13-6.08 (m, 1H), 5.82-5.69 (m, 1H), 4.15-4.07 (m, 2H), 3.93-3.78 (m, 4H), 3.55-3.50 (m, 2H), 2.61 (s, 3H).

[0347] Compound 62 N -[4-(4-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]oxy}-3-methyl-1H-pyrazole [3,4-d]pyrimidin-6-yl)phenyl]-4-methoxypyridine-2-sulfonamide The compound was prepared according to the procedure described in Example 57. The desired product (52.2 mg, 26.58%) was obtained as a white solid and a TFA salt. 1 H-NMR (DMSO- d 6, 300MHz) δ (ppm): 10.92 (s, 1H), 9.94 (s,1H), 8.52 (d, J = 5.7Hz, 1H), 8.30 (d, J = 9.0Hz, 2H), 7.53 (d, J = 2.4Hz,1H), 7.32-7.21 (m, 3H), 5.67-5.94 (m, 1H), 5.53-5.37 (m, 1H), 3.91 (s, 3H), 3.76-3.42 (m, 4H), 2.87 (s, 3H), 2.58 (s, 3H), 2.48-2.19 (m, 2H). LCMS (ES. m / z): 528 [M+H]+.

[0348] Compound 63 N -[4-(4-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]oxy}-3-methyl-1H-pyrazole [3,4-d]pyrimidin-6-yl)phenyl]-4-(trifluoromethyl)pyridine-2-sulfonamide The compound was prepared according to the procedure described in Example 57. The desired product (34.1 mg, 16.5%) was obtained as a white solid and a TFA salt. ¹H-NMR (DMSO- d6, 300MHz) δ (ppm): 13.56 (s, 1H), 11.15 (s,1H), 9.95 (s, 1H), 9.03 (d, J = 4.8Hz, 2H), 8.34-8.12 (m, 4H), 7.33 (d, J =8.7Hz, 1H), 5.62-5.97 (m, 1H), 5.53-5.29 (m, 1H), 3.92-3.43 (m, 4H), 2.95 (s, 3H), 2.59 (s, 3H), 2.47-2.23 (m, 2H). LCMS (ES. m / z): 566 [M+H]+.

[0349] Compound 64 5-chloro-N-[4-(4-{[(3S,4R)-1-(2,2-difluoroethyl)-3-fluoropiperidin-4-yl]oxy}- 3-Methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide (i) (3 S 4 R 3-Fluoroperidine-4-ol hydrochloride To (3) S 4 R 3-Fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.00 g, 4.561 mmol, 1.00 equivalent) was added to a solution of DCM (15 mL, 235.951 mmol, 51.73 equivalent) with HCl (4 M in 1,4-dioxane) (15 mL, 416.667 mmol, 91.36 equivalent) and stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. This gave a yellow solid (3-... S 4 R 3-Fluoroperidol-4-ol hydrochloride (700 mg, 88.77%). LCMS (ES. m / z): 120 [M+H-HCl]+.

[0350] (ii) (3 S 4 R )-1-(2,2-difluoroethyl)-3-fluoropiperidine-4-ol (3) S 4 R A solution of 3-fluoropiperidine-4-ol hydrochloride (680.94 mg, 4.376 mmol, 1.4 equivalents), 1,1-difluoro-2-iodoethane (600 mg, 3.126 mmol, 1.00 equivalents), and NaHCO3 (787.8 mg, 9.378 mmol, 3.00 equivalents) in EtOH (20 mL, 344.271 mmol, 110.1 equivalents) was stirred at 80 °C for 36 h. The solution was collected by filtration. The resulting mixture was concentrated under reduced pressure. The crude product was recrystallized from DCM / MeOH (98% / 2%) to give a yellow oily substance (3... S 4 R1-(2,2-difluoroethyl)-3-fluoropiperidine-4-ol (30 mg, 4.72%). LCMS (ES. m / z): 184 [M+H]+.

[0351] (iii) (3 S 4 R )-4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-1-(2,2- (difluoroethyl)-3-fluoropiperidine At 0℃, towards (3) S 4 R 1-(2,2-difluoroethyl)-3-fluoropiperidin-4-ol (30.0 mg, 0.164 mmol, 1.00 equivalent) was added to a solution of THF (4.00 mL, 51.7 mmol, 315.6 equivalents) with NaH (26.20 mg, 0.66 mmol, 4.00 equivalents). The mixture was stirred for 30 min. 4,6-Dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (36.58 mg, 0.180 mmol, 1.10 equivalents) was added, and the mixture was warmed to room temperature and stirred at room temperature for 16 h. The reaction mixture was quenched with water. The resulting mixture was extracted with EtOAc (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The solid was purified by rapid preparative HPLC under the following conditions (column, C18 spherical, 20µm-35µm, 100A (40g); mobile phase A: water-10mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 35mL / min; gradient: 56B to 67B; 254nm) to obtain a white solid (3 S 4 R )-4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-1-(2,2-difluoroethyl)-3-fluoropiperidine (20 mg, 31.42%). LCMS (ES. m / z): 350 [M+H]+.

[0352] (iv) 5-Chloro-N-[4-(4-{[(3 S 4 R )-1-(2,2-difluoroethyl)-3-fluoropiperidin-4-yl]oxy}-3-methyl [1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide (3) S 4 R4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-1-(2,2-difluoroethyl)-3-fluoropiperidine (30 mg, 0.086 mmol, 1.00 equivalent), 5-chloro-2-fluoro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]benzenesulfonamide (38.84 mg, 0.095 mmol, 1.10 equivalent) Pd(dppf)Cl2 (12.55 mg, 0.017 mmol, 0.2 equivalents) and Cs2CO3 (41.92 mg, 0.129 mmol, 1.5 equivalents) were stirred at 100 °C for 16 h under a nitrogen atmosphere with a mixture of 1,4-dioxane (3.00 mL, 34.05 mmol, 397.0 equivalents) and H2O (0.75 mL, 41.63 mmol, 485.34 equivalents). The resulting mixture was concentrated under reduced pressure. The solid was purified by rapid preparative HPLC under the following conditions (column, C18 spherical 20 µm–35 µm 100A (40 g); mobile phase A: water–10 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 35 mL / min; gradient: 60 B to 68 B; 254 nm). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 µm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 34% B to 55% B, 55% B over 7 min; wavelength: 254 nm; RT1 (min): 6.58); to obtain a grayish-white solid 5-chloro-N-[4-(4-{[(3 S 4 R 1-(2,2-difluoroethyl)-3-fluoropiperidin-4-yl]oxy}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide; trifluoroacetic acid (8.6 mg, 13.71%). 1 H-NMR (DMSO- d6, 300MHz) δ (ppm): 11.14 (s, 1H), 8.31 (d, J = 8.4Hz, 2H), 7.89-7.77 (m, 2H), 7.46-7.58 (m, 1H), 7.27 (d, J =8.7Hz, 2H), 6.03-6.49 (m, 1H), 5.83-5.75 (m, 1H), 5.14-4.92(m, 1H), 3.25-2.73(m, 6H), 2.59 (s, 3H), 2.12-2.05 (m, 2H). LCMS (ES. m / z): 599 [M+H]+.

[0353] Compound 65 5-chloro-2-fluoro-N-(4-(4-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)oxy)- 3-Methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (i) 6-Chloro-4-(((3 S 4 R )-3-fluoro-1-(methyl- d 3)piperidin-4-yl)oxy)-3-methyl-1 H -pyrazolo[3,4- d Pyrimidine (3) S 4 R A solution of 3-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-3-fluoropiperidine hydrochloride (300 mg, 0.931 mmol, 1.00 equivalent), CD3I (134.98 mg, 0.931 mmol, 1 equivalent), and DIEA (361 mg, 2.79 mmol, 3.00 equivalent) in DMF (8.00 mL, 103.4 mmol, 111.0 equivalent) was stirred at room temperature for 16 h. The resulting mixture was extracted with EtOAc (3 × 40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The solid was purified by rapid preparative HPLC under the following conditions (column, C18 spherical 20µm-35µm 100A (120g); mobile phase A: water-10mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 50mL / min; gradient: 49B to 68B; 254nm) to give 6-chloro-4-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)oxy)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (120mg, 38.31%) as a yellow solid. LCMS (ES. m / z): 303 [M+H]+.

[0354] (ii) 5-Chloro-2-fluoro-N-(4-(4-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)oxy)-3-methyl 1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (3) S 4 R A mixture of 4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-3-fluoro-1-(2H3)methylpiperidine (120 mg, 0.396 mmol, 1.00 equivalent), 5-chloro-2-fluoro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]benzenesulfonamide (179.5 mg, 0.436 mmol, 1.10 equivalent), Pd(dppf)Cl2 (58.00 mg, 0.079 mmol, 0.2 equivalent), and Cs2CO3 (193.7 mg, 0.59 mmol, 1.50 equivalent) in 1,4-dioxane (4 mL) and water (1 mL) was stirred at 100 °C under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure. The solid was purified by rapid preparative HPLC under the following conditions (column, C18 spherical 20µm-35µm 100A (80g); mobile phase A: water-10mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 40mL / min; gradient: 40B to 51B; 254nm). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 µm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 23% B to 43% B, 43% B over 7 min; wavelength: 254 nm; RT1 (min): 4.93) to obtain a grayish-white solid 5-chloro-2-fluoro-N-[4-(4-{[(3S,4R)-3-fluoro-1-(2H3)methylpiperidin-4-yl]oxy}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide; trifluoroacetic acid (21.4 mg, 7.79%). 1 H-NMR (DMSO- d6, 300MHz)δ (ppm): 11.18 (s, 1H), 10.02 (s, 1H), 8.35 (d, J = 8.7Hz, 2H), 7.95-7.78 (m,2H), 7.56-7.50 (m, 1H), 7.28 (d, J = 8.7Hz, 2H), 5.82-5.70 (m, 1H), 5.53-5.28 (m, 1H), 3.92-3.43 (m, 4H), 2.59 (s, 3H), 2.45-2.19 (m, 2H). LCMS(ES. m / z):552 [M+H]+.

[0355] Compound 66 N -[4-(4-{[(3 S 4 R 3-Fluoro-1-methylpiperidin-4-yl]oxy-3-methyl-1H-pyrazole [3,4-d]pyrimidin-6-yl)phenyl]pyridine-2-sulfonamide The compound was prepared according to the procedure described in Example 57. The desired product (4.6 mg, 9.10%) was obtained as a white solid and a free base. 1 H NMR (300MHz, DMSO- d 6) δ 13.54 (s, 1H), 10.95 (s, 1H), 9.96 (s, 1H), 8.72 (dt, J = 4.7, 1.4Hz, 1H), 8.33 – 8.22 (m, 2H), 8.20 – 7.96(m, 2H), 7.67 (ddd, J = 7.2, 4.7, 1.6Hz, 1H), 7.46 – 7.28 (m, 3H), 7.04 (d, J= 51.1Hz, 1H), 5.81 (s, 1H), 5.40 (d, J = 48.0Hz, 1H), 3.51 (s, 3H), 2.84 (s,3H), 2.52 (s,3H), 2.36 – 2.15 (m, 2H). LCMS (ESI, m / z): 498[M+H]+, Compound 67 N -[4-(4-{[(3 S 4 R 3-Fluoro-1-methylpiperidin-4-yl]oxy-3-methyl-1H-pyrazole [3,4-d]pyrimidin-6-yl)phenyl]pyridine-2-sulfonamide The compound was prepared according to the procedure described in Example 57. The desired product (4.6 mg, 9.10%) was obtained as a white solid and a TFA salt. 1 H NMR (300MHz, DMSO- d6) δ 13.54 (s, 1H), 10.95 (s, 1H), 9.96 (s, 1H), 8.72 (dt, J = 4.7, 1.4Hz, 1H), 8.33 – 8.22 (m, 2H), 8.20 – 7.96(m, 2H), 7.67 (ddd, J = 7.2, 4.7, 1.6Hz, 1H), 7.46 – 7.28 (m, 3H), 7.04 (d, J= 51.1Hz, 1H), 5.81 (s, 1H), 5.40 (d, J = 48.0Hz, 1H), 3.51 (s, 3H), 2.84 (s,3H), 2.52 (s,3H), 2.36 – 2.15 (m, 2H). LCMS (ESI, m / z): 498[M+H]+.

[0356] Compound 67 N -[4-(4-{[(3 R 4 S )-4-fluoro-1-methylpyrrolidone-3-yl]oxy-3-methyl-1H-pyrrolidone [3,4-d]pyrimidin-6-yl]phenyl]-4-(trifluoromethyl)pyridine-2-sulfonamide The compound was prepared according to the procedure described in Example 57. The desired product (47.7 mg, 20.44%) was obtained as a white solid and a TFA salt. 1 H-NMR (CD3OD, 300MHz) δ (ppm): 8.92 (d, J = 4.8Hz, 1H), 8.37 (d, J = 8.7Hz, 2H), 8.23 ​​(s, 1H), 7.90 (d, J = 4.8Hz, 1H), 7.34 (d, J =8.7Hz, 2H), 6.17-6.09 (m, 1H), 5.85-5.68 (m, 1H), 4.11-3.97 (m, 4H), 3.07 (s, 3H), 2.60 (s, 3H). LCMS (ES. m / z): 552 [M+H]+.

[0357] Compound 68 5-Chloro-2-Fluoro- N -[4-(4-{[(3 S 4 R )-3-fluoro-1-methylpiperidin-4-yl]oxy}-3-methyl [1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-methylphenyl]benzenesulfonamide The compound was prepared according to the procedure described in Example 57. The desired product (24.4 mg, 10.78%) was obtained as a white solid and a TFA salt. 1H-NMR (CD3OD, 300MHz) δ (ppm): 7.87-7.81 (m, 2H), 7.66-7.61 (m, 1H), 7.33-7.27 (m, 1H), 7.13-7.07 (m, 2H), 5.85-5.64 (m, 1H), 5.48-5.22 (m, 1H), 3.67 (s, 1H), 3.69-3.48 (m, 2H), 3.42-3.35 (m, 1H), 2.96 (s,3H), 2.60 (s, 6H), 2.53-2.38 (m, 2H). LCMS (ES. m / z): 563 [M+H]+.

[0358] Compound 69 5-Chloro-2-Fluoride N -[2-Fluoro-4-(4-{[(3 S 4 R )-3-fluoro-1-methylpiperidin-4-yl]oxy}- 3-Methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide The compound was prepared according to the procedure described in Example 57. The desired product (23.5 mg, 17.17%) was obtained as a grayish-white solid and a TFA salt. 1 H-NMR (CD3OD, 300MHz) δ (ppm): 8.26(d, J=8.4Hz, 1h),8.16-8.12(dd, J=1.8&11.7Hz, 1H), 7.81-7.78 (dd, J=2.7&6Hz, 1H), 7.67-7.62 (m,1H), 7.59-7.54 (t, J=8.1Hz, 1H), 7.35-7.29 (t, J=9.3Hz, 1H), 5.95-5.78(m,1H), 5.43(d, J=47.7Hz, 1H), 3.77 (s, 1H), 3.79-3.59 (m, 2H), 3.49-3.46 (m,1H), 3.00 (s, 3H), 2.65 (s, 3H), 2.53-2.42 (m, 2H). LCMS (ES. m / z): 567 [M+H]+.

[0359] Compound 70 N -[4-(4-{[(3 R )-4,4-difluoro-1-methylpyrrolidone-3-yl]oxy-3-methyl-1H-pyrrolidone [3,4-d]pyrimidin-6-yl]phenyl]-4-(trifluoromethyl)pyridine-2-sulfonamide The compound was prepared according to the procedure described in Example 57. The desired product (6.3 mg, 5.49%) was obtained as a white solid and a TFA salt. 1H NMR (CD3OD ,400MHz) δ 8.91 (d, J = 4.8Hz, 1H), 8.37 (d, J= 8.4Hz, 2H), 8.23 ​​(s, 1H), 7.90 – 7.89 (m, 1H), 7.33 – 7.31 (m, 2H), 6.19(d, J = 10.4Hz, 1H), 4.12(m, 1H), 3.87 – 3.84 (m, 3H), 2.94 (s, 3H), 2.63 (s, 3H). LCMS (ESI, m / z): 570[M+H]+.

[0360] Compound 71 5-chloro-N-[4-(4-{[(4R)-3,3-difluoro-1-(2-hydroxyethyl)piperidin-4-yl]oxy}-3- Methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 51. The desired product (18.7 mg, 21.5%) was obtained as a white solid and as a white solid TFA salt. 1 H-NMR (DMSO- d 6 , 300MHz) δ (ppm): 8.34 (d, J =8.4Hz, 2H), 7.92-7.74 (m, 2H), 7.51-7.40 (m, 1H), 7.23 (d, J = 8.7Hz, 2H), 5.98-5.95 (m, 1H), 4.85-4.81 (m, 1H), 4.40-4.27 (m, 2H), 3.84-3.71 (m, 2H), 3.24-2.77 (m, 4H), 2.68 (s, 3H), 2.23-2.19 (m, 1H), 1.95-1.79 (m, 1H). LCMS (ES. m / z): 597 [M+H]+.

[0361] Compound 72 N -{4-[4-({2-[(2-hydroxyethyl)(methyl)amino]ethyl}amino)-3-methyl-1H-pyrazole [3,4-d]pyrimidin-6-yl]phenyl}-4-(trifluoromethyl)pyridine-2-sulfonamide The compound was prepared according to the procedure described in Example 51. The desired product (34.5 mg, 17.58%) was obtained as a grayish-white solid in the form of a TFA salt. 1 H-NMR (DMSO- d 6, 300MHz) δ (ppm): 12.95 (s, 1H), 9.01(d, J = 4.8Hz, 1H), 8.23 ​​(d, J = 8.7Hz, 3H), 8.07 (d, J = 4.8Hz, 1H), 7.23(d, J = 8.7Hz, 2H), 7.03-6.99 (m, 1H), 4.50 (s, 1H), 3.74-3.71 (m, 2H), 3.57-3.49 (m, 2H), 2.76-2.72 (m, 2H), 2.68-2.59 (m, 2H), 2.48 (s, 3H), 2.39(s,3H). LCMS (ES. m / z): 551 [M+H]+.

[0362] Compound 73 N -[4-(4-{[2-(dimethylamino)ethyl]amino}-3-methyl-1H-pyrazolo[3,4-d]pyrimidine [Pyridine-6-yl)phenyl]-4-isopropoxypyridine-2-sulfonamide (i)4-Isopropoxy-2-methylpyridine 2-Iodopropane (8.86 g, 52.11 mmol, 1.50 equivalent) was added dropwise to a stirred mixture of 2-chloropyridin-4-ol (4.5 g, 34.738 mmol, 1.00 equivalent) and K₂CO₃ (9.60 g, 69.48 mmol, 2.00 equivalent) in DMF (90 mL, 1163 mmol, 33.5 equivalent) and stirred at 60 °C for 16 h. The resulting mixture was extracted with EA (100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, silica gel; mobile phase, EA / PE, 0% to 50% gradient over 30 min; detector, UV 254 nm). This yielded 4-isopropoxy-2-methylpyridine (5 g, 95.19%) as a yellow oil. LCMS (ESI, m / z): 172 [M+H]⁺.

[0363] (ii) 2-(benzylthio)-4-isopropoxypyridine KF (1.69 g, 29.14 mmol, 1.00 equivalent) and benzylthiol (7.24 g, 58.27 mmol, 2.00 equivalent) were added in portions to a stirred mixture of 4-isopropoxy-2-methylpyridine (5.00 g, 33.1 mmol, 1.00 equivalent) and Cs₂CO₃ (18.98 g, 58.27 mmol, 2.00 equivalent) in DMF (100 mL), and the mixture was stirred at 60 °C for 16 h. The resulting mixture was extracted with EA (500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, C18 silica gel; mobile phase, ACN / water, 10% to 50% gradient over 30 min; detector, UV 254 nm). This yielded 2-(benzylthio)-4-isopropoxypyridine as a yellow oil. LCMS (ESI, m / z): 260[M+H]+ (iii) Bis(4-isopropoxypyridine-2-sulfonyl chloride) At room temperature, HCl (20 mL) and NaClO2 (20 mL) were added in portions to a stirred mixture of 4 g of 2-(benzylthio)-4-isopropoxypyridine in DCM (10 mL). After stirring for 2 hours, the resulting mixture was concentrated under reduced pressure. The desired product could be detected by LCMS. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 236 [M+H]+.

[0364] (iv) 4-Isopropoxy-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]pyridine-2-sulfonamide At room temperature, 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)aniline (1.53 g, 7.00 mmol, 1.00 equivalent) and pyridine (0.55 g, 7.00 mmol, 1.00 equivalent) were added in portions to a stirred mixture of bis(4-isopropoxypyridine-2-sulfonyl chloride) (3.3 g, 7.00 mmol, 1.00 equivalent) in DCM (10 mL), and the mixture was stirred for 4 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN / water, 10% to 90% gradient over 30 min; detector, UV 254 nm. This yielded a grayish-white solid, 4-isopropoxy-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)phenyl]pyridine-2-sulfonamide (4.2 g, 86.05%). LCMS (ESI, m / z): 419[M+H]+.

[0365] (v)N-[4-(4-{[2-(dimethylamino)ethyl]amino}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-4-isopropoxypyridine-2-sulfonamide To 4-isopropoxy- N [4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]pyridine-2-sulfonamide (180.6 mg, 0.43 mmol, 1.10 equivalents) and 6-chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.393 mmol, 1.00 equivalents) were added to a solution of 1,4-dioxane (4 mL, 1.179 mmol) and H2O (1 mL) along with Cs2CO3 (191.87 mg, 0.590 mmol, 1.5 equivalents) and Pd(dppf)Cl2 (57.45 mg, 0.079 mmol, 0.2 equivalents). After stirring at 100 °C for 16 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, C18 silica gel; mobile phase, ACN / water, 10% to 90% gradient over 30 min; 40 ml / min; detector, UV 254 nm). The residue was purified by preparative TLC (column: YMC-Actus Triart C18, 30*150mm, 5µm; mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3.H2O), mobile phase B: ACN; flow rate: 60mL / min; gradient: 25% B to 52% B, 52% B over 7 min; wavelength: 254nm; RT1 (min): 6.17) to obtain N-[4-(4-{[2-(dimethylamino)ethyl]amino}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-4-isopropoxypyridine-2-sulfonamide (23.7mg, 11.78%) as a white solid. 1 H NMR (300MHz, DMSO- d 6) δ 12.94 (s, 1H), 10.74 (s, 1H), 8.47 (d, J =5.7Hz, 1H), 8.23 ​​– 8.20 (m, 2H), 7.43 (d, J = 2.4Hz, 1H), 7.23 (d, J = 8.7Hz,2H), 7.16 (dd, J = 5.7, 2.4Hz, 1H), 7.01 (t, J = 5.6Hz, 1H), 4.84 (p, J =6.2Hz, 1H), 3.70 (q, J = 6.4Hz, 2H), 2.56 (t, J = 6.9Hz, 2H), 2.51-2.50(m,3H),2.24 (s, 6H), 1.27 (d, J = 6Hz, 6H). LCMS (ESI, m / z): 511.15[M+H]+.

[0366] Compound 74 N -[4-(4-{[3-(dimethylamino)-2,2-difluoropropyl]amino}-3-methyl-1H-pyrazol [3,4-d]pyrimidin-6-yl)phenyl]-4-(trifluoromethyl)pyridine-2-sulfonamide (i) N 1-{6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}-2,2-difluoropropane-1,3-diamine At room temperature, 2,2-difluoropropane-1,3-diamine dihydrochloride (450.7 mg, 2.46 mmol, 1.00 equivalent) was added dropwise to a stirred mixture of 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 2.46 mmol, 1.00 equivalent) and DIEA (1910 mg, 14.78 mmol, 6.00 equivalent) in DCM (50 mL), and the mixture was stirred for 48 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, C18 silica gel; mobile phase, ACN / water, 50 mL / min, 10% to 90% gradient over 30 min; detector, UV 254 nm). This yielded N1-{6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}-2,2-difluoropropane-1,3-diamine (400 mg, 58.70%) as a brownish-yellow solid. LCMS (ESI, m / z): 277[M+H]+.

[0367] (ii)6-Chloro- N -[3-(dimethylamino)-2,2-difluoropropyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine At room temperature, CH3I (161.98 mg, 1.14 mmol, 2.00 equivalent) was added dropwise to a stirred mixture of N1-{6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}-2,2-difluoropropane-1,3-diamine; bis(trifluoroacetic acid) (288 mg, 0.571 mmol, 1.00 equivalent) and DIEA (368.7 mg, 2.85 mmol, 5.00 equivalent) in DMF (30 mL), and the mixture was stirred for 16 h. The aqueous layer was extracted with EA (300 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, C18 silica gel; mobile phase, ACN / water, 50 mL / min, 10% to 90% gradient over 30 min; detector, UV 254 nm). This yielded 6-chloro-N-[3-(dimethylamino)-2,2-difluoropropyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-amine (60 mg, 34.51%) as a grayish-white solid. LCMS (ESI, m / z): 305 [M+H]+.

[0368] (iii) N -[4-(4-{[3-(dimethylamino)-2,2-difluoropropyl]amino}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-4-(trifluoromethyl)pyridine-2-sulfonamide Add Cs2CO3 (48.11 mg, 0.147 mmol, 1.50 equivalent) and Pd(dppf)Cl2 (14.41 mg, 0.020 mmol, 0.20 equivalent) to a solution of 6-chloro-N-[3-(dimethylamino)-2,2-difluoropropyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.098 mmol, 1.00 equivalent) and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]-4-(trifluoromethyl)pyridine-2-sulfonamide (46.37 mg, 0.108 mmol, 1.10 equivalent) in 1,4-dioxane (1.5 mL) and H2O (0.37 mL). After stirring at 100°C for 16 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, C18 silica gel; mobile phase, ACN / water, 40 ml / min, 10% to 90% gradient over 10 min; detector, UV 254 nm). The residue was purified by preparative TLC (column: XBridge Shield RP18 OBD column, 30*150mm, 5µm; mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3.H2O), mobile phase B: ACN; flow rate: 60mL / min; gradient: 22% B to 42% B, 42% B over 7 min; wavelength: 254nm; RT1 (min): 5.43) to obtain N-[4-(4-{[3-(dimethylamino)-2,2-difluoropropyl]amino}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-4-(trifluoromethyl)pyridine-2-sulfonamide (5.1mg, 8.94%) as a white solid. 1 H NMR (300MHz, DMSO- d 6 ) δ 12.95 (s, 1H), 8.92 (s, 1H), 8.25-8.13 (m, 3H), 7.92 (s, 1H), 7.22-7.08 (m, 3H), 4.29-4.17 (m, 2H), 2.82 (t, J= 13.5Hz, 2H), 2.53 (s, 3H), 2.29 (s, 6H). LCMS (ESI, m / z): 571.10 [M+H]+.

[0369] Compound 75 5-chloro-N-[4-(4-{[3-(dimethylamino)-2,2-difluoropropyl]amino}-3-methyl-1H- Pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 51. The desired product (4.5 mg, 8.10%) was obtained as a grayish-white solid. 1 H NMR (300MHz, methanol-) d 4 ) δ 8.29 (d, J = 8.7Hz, 2H), 7.89 (dd, J =6.0, 2.7Hz, 1H), 7.65-7.60 (m, 1H), 7.53-7.26 (m, 3H), 4.36-4.32 (m, 2H), 3.96-3.86 (m, 2H), 2.89 (s, 6H), 2.66 (s, 3H), 1.37 (s, 1H). LCMS (ESI, m / z):554.10[M+H-TFA]+.

[0370] Compound 76 5-Chloro-2-Fluoro-N-{4-[4-({2-[(2-hydroxy-2-methylpropyl)(methyl)amino]ethyl}amino] 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenylbenzenesulfonamide (i) N 2-[(2-hydroxy-2-methylpropyl)(methyl)amino]ethyl} tert-butyl carbamate At room temperature, towards N 1,2-[2-(methylamino)ethyl]carbamate tert-butyl ester (1.50 g, 8.61 mmol, 1.00 equivalent) and K₂CO₃ (3.57 g, 25.83 mmol, 3.00 equivalent) were added dropwise to a stirred mixture in ACN (20 mL), followed by 2,2-dimethylethylene oxide (0.93 g, 12.91 mmol, 1.50 equivalent), and the mixture was stirred under reflux for 16 hours. The resulting mixture was filtered, and the filter cake was washed with ACN (100 mL). The filtrate was concentrated under reduced pressure. The desired product was detected by LCMS. LCMS (ESI, m / z): 247 [M+H]⁺.

[0371] (ii) 1-[(2-aminoethyl)(methyl)amino]-2-methylprop-2-ol At room temperature, a 1,4-dioxane solution (10 mL) of HCl (gas) was added dropwise to a stirred solution of N-{2-[(2-hydroxy-2-methylpropyl)(methyl)amino]ethyl}carbamate (1.40 g, 1.00 equivalent) in dioxane (10 mL), and the mixture was stirred for 6 hours. The resulting mixture was concentrated under reduced pressure. The desired product was detected by LCMS. LCMS (ESI, m / z): 147 [M+H]+.

[0372] (iii) 1-{[2-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)ethyl](methyl)amino}-2-methylprop-2-ol At room temperature, 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (208.3 mg, 1.03 mmol, 1.00 equivalent) was added fractionally to a stirred solution of 1-[(2-aminoethyl)(methyl)amino]-2-methylprop-2-ol (150 mg, 1.03 mmol, 1.00 equivalent) and DIEA (397.7 mg, 3.08 mmol, 3.00 equivalent) in 2 mL of THF, and the mixture was stirred for 3 hours. The resulting mixture was concentrated under reduced pressure. The desired product was detected by LCMS. LCMS (ESI, m / z): 313 [M+H]+ (iv) 5-Chloro-2-fluoro-N-{4-[4-({2-[(2-hydroxy-2-methylpropyl)(methyl)amino]ethyl}amino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}benzenesulfonamide Add Pd(dppf)Cl2 (46.78 mg, 0.064 mmol, 0.20 equivalent) and Cs2CO3 (156.2 mg, 0.480 mmol, 1.50 equivalent) to a solution of 1-{[2-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)ethyl](methyl)amino}-2-methylprop-2-ol (100 mg, 0.320 mmol, 1.00 equivalent) and 5-chloro-2-fluoro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)phenyl]benzenesulfonamide (197.4 mg, 0.48 mmol, 1.50 equivalent) in 1,4-dioxane (4 mL) and H2O (1.00 mL). After stirring at 100°C for 16 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, C18 silica gel; mobile phase, ACN / water, 10% to 90% gradient over 30 min; detector, UV 254 nm, 40 ml / min). The residue was purified by preparative TLC (column: XSelect CSH preparative C18 OBD column, 19*150mm, 5µm; mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3.H2O), mobile phase B: ACN; flow rate: 25mL / min; gradient: 23% B to 53% B, 53% B over 7 min; wavelength: 254nm; RT1 (min): 6.8); to obtain 5-chloro-2-fluoro-N-{4-[4-({2-[(2-hydroxy-2-methylpropyl)(methyl)amino]ethyl}amino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}benzenesulfonamide (3.9mg, 2.09%) as a grayish-white solid. 1 H NMR (400MHz, methanol-) d 4 ) δ 8.28 – 8.25 (m, 2H), 7.86-7.84 (m,1H), 7.61-7.57 (m, 1H), 7.29 – 7.24 (m, 1H), 7.24 – 7.16 (m, 2H), 3.82 (t, J= 6.4Hz, 2H), 2.85-2.81 (m, 2H), 2.65 (s, 3H), 2.48 (s, 5H), 1.17 (s, 6H). LCMS (ESI, m / z): 562.15 [M+H]+.

[0373] Compound 77 2-Fluoro-N-{4-[4-({2-[(2-hydroxyethyl)(methyl)amino]ethyl}amino)-3-methyl-1H- Pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}-5-methoxybenzenesulfonamide The compound was prepared according to the procedure described in Example 51. The desired product (20.6 mg, 8.96%) was obtained as a white solid. 1 H NMR (300MHz, DMSO- d 6) δ 10.93 (s,1H), 9.34 (s,1H), 8.27 (d, J=8.7Hz,2H), 7.39 – 7.20 (m, 6H), 4.00(s,2H), 3.78-3.69 (m,5H), 3.53-3.17 (m, 4H), 2.90 (d, J = 4.8Hz, 3H), 2.55 (s, 3H). LCMS (ESI, m / z): 530.20 [M+H]+.

[0374] Compound 78 5-chloro-2-fluoro-N-{2-fluoro-4-[4-({2-[(2-hydroxyethyl)(methyl)amino]ethyl}amino)- 3-Methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}benzenesulfonamide The compound was prepared according to the procedure described in Example 51. The desired product (19.5 mg, 14.80%) was obtained as a white solid. 1 H NMR (400MHz, DMSO- d 6 ) δ 12.96 (s, 1H), 7.95 – 7.90 (m, 2H), 7.71-7.69 (m, 1H), 7.57 (d, J = 8Hz, 1H), 7.35-7.21 (m, 2H), 7.09 (t, J = 5.2Hz,1H), 3.86 (d, J = 5.6Hz, 2H), 3.62 (s, 2H), 3.11 (s, 2H), 2.95 (s, 2H), 2.65 (s, 3H), 2.53 (s, 3H). LCMS (ESI, m / z): 552.05 [M+H]+.

[0375] Compound 79 5-Chloro-2-fluoro-N-(2-fluoro-4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1H-pyridine Azo[3,4-d]pyrimidin-6-yl}phenyl)benzenesulfonamide The compound was prepared according to the procedure described in Example 57. The desired product (10.8 mg, 8.37%) was obtained as a grayish-white solid. 1 H NMR (300MHz, DMSO- d 6) δ 13.37 (s, 1H), 7.95 – 7.88 (m, 2H), 7.73-7.70 (m, 1H), 7.58-7.53 (m, 1H), 7.35-7.25 (m, 2H), 5.63(s,1H), 3.12 (s,4H), 2.69 (s, 3H), 2.53 (s, 3H), 2.20 (s, 2H), 2.07 (s, 3H). LCMS (ESI, m / z):549.10 [M+H]+.

[0376] Compound 80 N -(4-{4-[(1-isopropylpiperidin-4-yl)oxy]-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (Pyridine-6-yl)phenyl-4-methoxypyridine-2-sulfonamide The compound was prepared according to the procedure described in Example 57. The desired product (12.7 mg, 7.30%) was obtained as a white solid. 1 H NMR (400MHz, DMSO- d 6 ) δ 13.38 (s, 1H), 8.50 (d, J = 5.6Hz, 1H), 8.23– 8.21 (m, 2H), 7.51 (d, J = 2.4Hz, 1H), 7.28 – 7.24 (m, 2H), 7.19 (dd, J =5.6, 2.5Hz, 1H), 5.50 (tt, J = 7.3, 3.6Hz, 1H), 3.89 (s, 3H), 2.78-2.67 (m,3H), 2.08-2.03 (m, 2H), 1.83 – 1.80 (m, 2H), 1.02 (d, J = 6.8Hz, 6H). LCMS (ESI, m / z): 538.25[M+H]+.

[0377] Compound 81 (i)2-((2-(6-chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)ethyl)(methyl)amino)ethanol Add 4,6-dichloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidine (450.00 mg, 1.57 mmol, 1.00 equivalent), 2-[(2-aminoethyl)(methyl)amino]ethanol (277.8 mg, 2.35 mmol, 1.50 equivalent), DCM (10.0 mL), and TEA (317.2 mg, 3.13 mmol, 2.00 equivalent) to a 50 mL round-bottom flask. Stir the resulting solution overnight at room temperature. Concentrate the resulting mixture. Apply the residue to a silica gel column containing dichloromethane / methanol (100:0 to 85:15). Combine the collected fractions and concentrate. This yielded 500 mg (77.84%) of a colorless oily substance, 2-[2-[[[6-chloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-yl]amino]ethyl)(methyl)amino]ethanol. LCMS (ESI, m / z): 369 [M+H]+.

[0378] (ii)4-( N -(5-chloro-2-fluorophenyl)aminosulfonyl)phenylboronic acid Add the following to a 50-mL three-necked round-bottom flask purged with nitrogen and kept under an inert atmosphere: 2-[(2-[[6-chloro-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-yl]amino]ethyl)(methyl)amino]ethanol (300.00 mg, 0.813 mmol, 1.00 equivalent), 4-(5-chloro-2-fluorobenzenesulfonylamino)phenylboronic acid (219.76 mg, 0.667 mmol, 0.82 equivalent), dioxane (8.00 mL), H2O (2.00 mL, 0.111 mmol, 0.14 equivalent), Cs2CO3 (529.98 mg, 1.627 mmol, 2.0 equivalent), and Pd(dppf)Cl2 (119.02 mg, 0.163 mmol, 0.2 equivalent). The resulting solution was stirred overnight in an oil bath at 90°C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The resulting solution was diluted with 50 mL of DCM. The resulting mixture was washed with 2 × 30 mL of brine and 1 × 30 mL of water. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column containing dichloromethane / methanol (100:0 to 10:90). The collected fractions were combined and concentrated. This gave 90 mg (16.11%) of 5-chloro-2-fluoro-N-[4-[4-([2-[(2-hydroxyethyl)(methyl)amino]ethyl]amino]amino)-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl]phenyl]benzenesulfonamide as a colorless oil. LCMS (ESI, m / z): 618 [M+H]+.

[0379] (iii) (2S)-2-((2-(6-(4-(5-chloro-2-fluorophenylsulfonylamino)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)ethyl)(methyl)amino)ethyl 2-(tert-butoxycarbonylamino)-3-methylbutyrate Add 5-chloro-2-fluoro-N-[4-[4-([2-[(2-hydroxyethyl)(methyl)amino]ethyl]amino]amino)-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl]phenyl]benzenesulfonamide (80.00 mg, 0.129 mmol, 1.00 equivalent), (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid (30.93 mg, 0.142 mmol, 1.10 equivalent), DCM (8.00 mL), DCC (53.4 mg, 0.258 mmol, 2.00 equivalent), and DMAP (15.81 mg, 0.129 mmol, 1.00 equivalent) to a 50-mL round-bottom flask. Stir the resulting solution at room temperature for 4 hours. Concentrate the resulting mixture. The crude product (150 mg) was purified by rapid preparative HPLC under the following conditions (CombiFlash-1) (column, C18 silica gel; mobile phase, water (NH4HCO3 0.05%) / ACN = 80:20, increased to water (NH4HCO3 0.05%) / ACN = 30:70 over 45 min; detector, 220 nm). This yielded 15 mg (12.76%) of 2-[[2-([6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-yl]amino)ethyl](methyl)amino]ethyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyrate as a grayish-white solid. LCMS (ESI, m / z): 817 [M+H]+.

[0380] (iv)(S)-2-((2-(6-(4-(5-chloro-2-fluorophenylsulfonylamino)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)ethyl)(methyl)amino)ethyl2-amino-3-methylbutyrate Add 2-[[2-([6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1-(tetrahydropyran-2-yl)pyrazolo[3,4-d]pyrimidin-4-yl]amino)ethyl](methyl)amino]ethyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyrate (15.00 mg, 0.018 mmol, 1.00 equivalent), HCl (gas) in 1,4-dioxane solution (2.00 mL), and IPA (2.0 mL) to a 25 mL round-bottom flask. Stir the resulting solution at room temperature for 4 hours. Concentrate the resulting mixture. Purify the crude product (30 mg) by HPLC. Column: XBridge preparative C18 OBD column, 19*250mm*5µm; mobile phase A: water (0.05% TFA); mobile phase B: ACN; flow rate: 25ml / min; gradient: 30% B to 50% B over 7 min; 254 / 220nm; Rt: 4.75min (detected and collected by lcms). 13.6 mg of a grayish-white solid was obtained. 1 H NMR (400MHz, DMSO- d 6) δ10.62 (s, 1H), 8.57 – 8.49 (m, 4H), 7.86 (d, J = 8.5Hz, 2H), 7.49 (s, 1H), 7.40 – 7.15 (m, 4H), 4.72 – 4.44 (m, 2H), 4.07 (s, 2H), 3.90 (s, 2H), 3.82 –3.30 (m, 3H), 2.98 (s, 3H), 2.59 (d, J = 1.5Hz, 3H), 0.89 (d, J = 6.0Hz, 6H). LCMS (ESI, m / z): 633 [M+H-CF3COOH]+.

[0381] Compound 82 2-{[2-({6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-4-yl}amino)ethyl](methyl)amino}ethyl 2,2-dimethylpropionate At 40 °C, trimethylacetic anhydride (69.76 mg, 0.374 mmol, 2.0 equivalent) was added dropwise to a stirred mixture of 5-chloro-2-fluoro-N-{4-[4-({2-[(2-hydroxyethyl)(methyl)amino]ethyl}amino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}benzenesulfonamide (100 mg, 0.187 mmol, 1 equivalent) and stirred at 120 °C for 6 h. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, C18 silica gel; mobile phase, which can be in water, in a 10% to 50% gradient over 30 min; detector, UV 254 nm, 40 mL / min). The crude product was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 30*150mm, 5µm; mobile phase A: water (0.05% TFA), mobile phase: canACN; flow rate: 60mL / min; gradient: 27% B to 47% B, 47% B over 7 min; wavelength: 254nm; RT1 (min): 4; number of runs: 0) to obtain 2-{2-({6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)ethyl](methyl)amino}ethyl 2,2-dimethylpropionate (21.2 mg, 17.93%) as a white solid). ¹H NMR (400MHz, methanol-) d 4 ) δ 8.24 – 8.21 (m, 2H), 7.91-7.89(m, 1H), 7.65-7.61 (m, 1H), 7.33 – 7.27 (m, 3H), 4.33 (t, J = 4.9Hz, 2H), 4.22 (d, J = 6.1Hz, 2H), 3.64 (s, 4H), 3.06 (d, J = 1.6Hz, 3H), 2.70 – 2.65(m, 3H), 1.10 (s, 9H). LCMS (ESI, m / z): 618.15[M+H]+.

[0382] Compound 83 2-{[2-({6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-4-yl}amino)ethyl](methyl)amino}ethyl 3-methylbutyrate At 0 °C, neopentanoyl chloride (24.84 mg, 0.206 mmol, 1.10 equivalent) was added dropwise to a stirred solution of 5-chloro-2-fluoro-N-{4-[4-({2-[(2-hydroxyethyl)(methyl)amino]ethyl}amino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}benzenesulfonamide (100 mg, 0.187 mmol, 1.00 equivalent) in DMF (3 mL) and Et3N (37.90 mg, 0.374 mmol, 2.00 equivalent). The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was quenched by adding water. The resulting mixture was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column 30*150mm, 5µm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 ml / min, gradient: 25% B to 45% over 7 min, wavelength: 254 nm; RT: 4.57 min) to obtain a white solid 2-{[2-({6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)ethyl](methyl)amino}ethyl 3-methylbutyrate TFA salt (21.3 mg), purity: 98.2%). ¹H NMR (300 MHz, DMSO-) d 6 ) δ 11.09 (s, 1H), 9.71 (s, 1H), 8.42 – 8.16 (m, 2H), 8.05 – 7.68 (m, 2H), 7.52 (t, J = 9.3Hz, 1H), 7.39 –7.18 (m, 3H), 4.31 (t, J = 5.1Hz, 2H), 4.00 (s, 2H), 3.65-3.51 (m, 2H), 2.95(s, 3H), 2.57 (s, 3H), 2.06 (d, J = 7.1Hz, 2H), 1.87 (dt, J = 13.5, 6.7Hz,1H), 0.78 (d, J = 6.6Hz, 5H). LCMS (ESI, m / z): 618 [M+H-CF3COOH]+.

[0383] Compound 84 N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidine [Pyridine-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 38. The desired product was a white solid (23.6 mg, 7.84%). LCMS (ES. m / z): 522 [M-TFA+H]+. 1H-NMR (CD3OD, 300MHz) δ (ppm): 8.19-8.16 (m, 1H), 8.10-8.06 (dd, J = 1.8 &12Hz, 1H), 7.81-7.78 (m, 1H), 7.68-7.63(m, 2H), 7.57 (t, J = 8.2Hz, 1H), 7.35-7.29 (t, J = 9.3Hz, 1H), 4.16-4.13 (t,J = 5.7Hz, 2H), 3.56-3.53 (t, J = 5.7Hz, 2H), 2.98 (s, 6H), 2.65 (s, 3H).

[0384] Compound 85 N -(2-chloro-4-(4-((2-(dimethylamino)ethyl)amino)-3-methyl-1 H -pyrazolo[3, 4- d ]pyrimidin-6-yl)phenyl)-2,5-difluorobenzenesulfonamide This compound was prepared according to the procedure described in Example 38. The desired product was a white solid (4.56 mg, 46%). LCMS: (ES, m / z): [M+H]+ = 522, 1 H NMR (300MHz, DMSO- d 6) δ 12.97 (s, 1H), 9.75(s, 1H), 8.23 ​​(d, J = 2.1Hz, 1H), 8.94 – 7.08 (m, 1H), 7.44 – 7.53 (m, 1H),7.32 (q, J = 8.7, 6.8Hz, 3H), 7.18 (t, J = 5.8Hz, 1H), 5.76 (s, 2H), 3.94 (d,J = 6.2Hz, 2H), 3.17 (s, 1H), 2.81 (d, J = 5.8Hz, 6H), 2.55 (d, J = 7.2Hz,3H).

[0385] Compound 86 5-chloro-2-fluoro-N-[4-(4-{2-[(2-hydroxyethyl)(methyl)amino]ethoxy}-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide The compound was prepared according to the procedure described in Example 9. The desired product was a grayish-white solid (516.3 mg, 30% yield). LCMS (ESI, m / z): 535 [M+H]+. 1 H NMR (300MHz, DMSO- d6) δ 13.43 (s, 1H),8.33 – 8.23 ​​(m, 2H), 7.86 (dd, J = 6.1, 2.7Hz, 1H), 7.75 (ddd, J = 8.8, 4.1,2.7Hz, 1H), 7.48 (t, J = 9.3Hz, 1H), 7.27 – 7.16 (m, 2H), 4.73 (t, J = 5.6Hz,2H), 4.46 (s, 1H), 3.51 (t, J = 6.2Hz, 2H), 3.39 (s, 3H), 2.97 (t, J = 5.5Hz,2H), 2.63 (t, J = 6.2Hz, 2H), 2.49 (s, 3H), 2.39 (s, 3H).

[0386] Compound 87 2-[[2-([6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-4-yl]amino)ethyl](methyl)amino]ethyl acetate The compound was prepared according to the procedure described in Example 83. The desired product was a white solid (50.3 mg, 95.1% purity). LCMS (ESI, m / z): 576+H+. 1 H NMR (300MHz, DMSO- d 6) δ 12.96 (s, 1H), 10.98(s, 1H), 8.26 (d, J = 8.4Hz, 2H), 7.89 – 7.68 (m, 2H), 7.49 (t, J = 9.3Hz,1H), 7.20 (d, J = 8.4Hz, 2H), 6.98 (t, J = 5.6Hz, 1H), 4.09 (t, J = 5.9Hz,2H), 3.69 (q, J = 6.4Hz, 2H), 2.69 (dt, J = 8.4, 4.6Hz, 4H), 2.55 (s, 3H), 2.33 (s, 3H), 1.94 (s, 3H).

[0387] Compound 88 2-{[2-({6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-4-yl}amino)ethyl](methyl)amino}ethoxyphosphonic acid At room temperature, 5-chloro-2-fluoro-N-{4-[4-({2-[(2-hydroxyethyl)(methyl)amino]ethyl}amino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}benzenesulfonamide (200 mg, 0.375 mmol, 1.00 equivalent) was added dropwise to the mixture at -40 °C. The resulting mixture was then stirred at -40 °C for 1 hour. The residue was alkalized to pH 8 with NaHCO3. The residue was acidified with AcOH. The residue was purified by preparative HPLC (column: XBridge Shield RP18OBD column, 19*250mm, 10µm; mobile phase A: water (10mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 25mL / min; gradient: 12% B to 28% B, 28% B over 5 min; wavelength: 220nm; RT1 (min): 4.58) to obtain 2-{[2-({6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)ethyl](methyl)amino}ethoxyphosphonic acid (98.3mg, 41.12%) as a white solid. LCMS (ESI, m / z): 614.1 [M+H]+. 1 H NMR (300MHz, DMSO- d 6) δ 13.05 (s, 1H), 11.07 (s, 1H), 8.30 – 8.27(m, 2H), 7.87-7.77 (m, 2H), 7.55-7.48 (m, 1H), 7.29-7.22 (m, 3H), 4.15-4.12 (m, 2H), 4.00-3.98 (m, 2H), 3.47 (s, 4H), 2.93 (s, 3H), 2.56 (s, 3H).

[0388] Compound 89 2-{[2-({6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3, [4-d]pyrimidin-4-yl}amino)ethyl](methyl)amino}ethyl 2-methylpropionate trifluoroacetic acid Isobutyric anhydride (0.62 g, 3.933 mmol, 1.5 equivalent) was added fractionally to a stirred solution of isobutyric acid (15 mL, 170.249 mmol, 64.94 equivalent) and stirred at 120 °C for 16 h. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN / water (0.05% TFA), gradient from 10% to 50% over 60 min; detector, UV 254 nm, 50 mL / min. This yields a white solid, 2-{[2-({6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)ethyl](methyl)amino}ethyl 2-methylpropionate trifluoroacetic acid (1.0438 g, 54.39%). LCMS (ESI, m / z): 604.15 [M+H]+. 1 H NMR (400MHz, DMSO- d 6) δ 11.11 (s, 1H), 9.89 (s, 1H), 8.30 – 8.28 (m, 2H), 7.87-7.85 (m, 1H), 7.82 – 7.78 (m, 1H), 7.54 –7.50 (m, 1H), 7.37 (s, 1H), 7.25 – 7.23 (m, 2H), 4.31 (t, J = 5.1Hz, 2H), 4.01 (s, 2H), 3.58 -3.44 (m,4H), 2.96 (s, 3H), 2.57 (s, 3H), 2.48-2.39 (m,1H), 1.00 (d, J = 6.8Hz, 6H).

[0389] Compound 90 2-{[2-({6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-4-yl}amino)ethyl](methyl)amino}ethylpropionate; bis(trifluoroacetic acid) Propionic anhydride (97.56 mg, 2.00 equivalent) was added to a 3 mL solution of bis(5-chloro-2-fluoro-N-{4-[4-({2-[(2-hydroxyethyl)(methyl)amino]ethyl}amino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}benzenesulfonamide (200 mg, 0.187 mmol, 1.00 equivalent). The mixture was stirred at 100 °C for 4 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with DMF (3 mL). The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 gel; mobile phase, MeCN / water (TFA 0.05%), 10% to 90% gradient over 40 min; detector, UV 254 nm and 220 nm. This yields the desired product, 2-{[2-({6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)ethyl](methyl)amino}ethyl propionate, as a white solid; bis(trifluoroacetic acid) (114.2 mg, 85.43%). LCMS (ESI, m / z): 590 [M+H]+. 1 H NMR (400MHz, DMSO-) d 6) δ 11.12 (s, 1H), 9.83 (s, 1H), 8.30 – 8.28 (m, 2H), 7.87(dd, J = 6.1, 2.7Hz, 1H), 7.80 (m, 1H), 7.52 (t, J = 9.3Hz, 1H), 7.40 (s,1H), 7.28 – 7.22 (m, 2H), 4.31 (t, J = 5.1Hz, 2H), 4.01 (m, 2H), 3.58-3.44(m,4H), 2.95 (s, 3H), 2.57 (s, 3H), 2.22 (q, J = 7.5Hz, 2H), 0.93 (t, J = 7.5Hz, 3H).

[0390] Compound 91 2-{[2-({6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3, [4-d]pyrimidin-4-yl}amino)ethyl](methyl)amino}ethyl butyrate trifluoroacetic acid At room temperature, 5-chloro-2-fluoro-N-{4-[4-({2-[(2-hydroxyethyl)(methyl)amino]ethyl}amino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}benzenesulfonamide (200 mg, 0.375 mmol, 1.00 equivalent) was added dropwise to a stirred solution of butyric acid (3 mL) and stirred at 120 °C for 6 h. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN / water (0.05% TFA), 10% to 50% gradient over 30 min; detector, UV 254 nm. This yielded a white solid, 2-{[2-({6-[4-(5-chloro-2-fluorobenzenesulfonylamino)phenyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)ethyl](methyl)amino}ethyl butyrate trifluoroacetic acid (176.6 mg, 63.04%). LCMS (ESI, m / z): 604.20 [M+H]+. 1 H NMR (300MHz, DMSO-) d 6) δ 11.09 (s, 1H), 9.75 (s,1H), 8.30 – 8.27 (m, 2H), 7.87-7.79 (m, 2H), 7.52 (t, J = 9.3Hz, 1H), 7.36 – 7.22 (m, 3H), 4.32 (t, J =5.1Hz, 2H), 3.99 (s, 2H), 2.93 – 2.85 (m, 3H), 2.73 (s, 1H), 2.57 (s, 3H),2.15 (t, J = 7.4Hz, 2H), 1.48-1.35 (m, 2H), 0.78 (t, J = 7.4Hz, 3H).

[0391] Compound 92 5-chloro-2-fluoro-N-[4-(4-{[(3S,4R)-3-fluoro-1-(2-hydroxy-2-methylpropyl)piperidine- 4-yl]oxy}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide (i) 1-[(3S,4R)-4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-3-fluoropiperidin-1-yl]-2-methylprop-2-ol A solution of (3S,4R)-4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-3-fluoropiperidine hydrochloride (200 mg, 0.621 mmol, 1.00 equivalent) and Cs₂CO₃ (257.39 mg, 1.863 mmol, 3 equivalent) in DMF (10 mL) was stirred at 60 °C for 16 h. The solution was collected by filtration. The solid was purified by rapid preparative HPLC under the following conditions (column, C18 spherical 20 µm–35 µm 100A (120 g); mobile phase A: water–10 mM NH₄HCO₃, mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient 41 B to 48 B; 254 nm). This yielded a yellow oily substance, 1-[(3S,4R)-4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-3-fluoropiperidin-1-yl]-2-methylprop-2-ol (30 mg, 10.80%). LCMS (ES. m / z): 358 [M+H]+.

[0392] (ii) 5-Chloro-2-fluoro-N-[4-(4-{[(3S,4R)-3-fluoro-1-(2-hydroxy-2-methylpropyl)piperidin-4-yl]oxy}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide 1-[(3S,4R)-4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-3-fluoropiperidin-1-yl]-2-methylprop-2-ol (30 mg, 0.084 mmol, 1 equivalent), 5-chloro-2-fluoro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]benzenesulfonamide ( A solution of 34.52 mg (0.084 mmol, 1.00 equivalent) of Pd(dppf)Cl2 (12.27 mg, 0.017 mmol, 0.20 equivalent) and Cs2CO3 (40.98 mg, 0.126 mmol, 1.50 equivalent) in 1,4-dioxane (3 mL) and H2O (0.75 mL) was stirred at 100 °C under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure. The solid was purified by rapid preparative HPLC under the following conditions (column, C18 spherical 20 µm–35 µm 100A (800 g); mobile phase A: water–10 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient 50 B to 58 B; 254 nm). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge preparative OBDC18 column, 30 × 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 50% B, 50% B over 9 min; wavelength: 254 nm; RT1 (min): 5.85). This yielded 5-chloro-2-fluoro-N-[4-(4-{[(3S,4R)-3-fluoro-1-(2-hydroxy-2-methylpropyl)piperidin-4-yl]oxy}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]benzenesulfonamide (4.5 mg, 8.69%) as a white solid. LCMS (ES. m / z): 607 [M+H]+. 1 H-NMR (DMSO- d6, 300MHz) δ (ppm): 8.28-8.16 (m, 2H),7.81-7.88 (m, 1H), 7.68-7.65 (m, 1H), 7.43-7.38 (m, 1H), 7.18-7.06 (m, 2H),5.82-5.74 (m, 1H), 5.09-4.86 (m, 1H), 4.81 (s, 1H), 4.18 (s, 2H), 3.13-2.91(m, 2H), 2.75 (s, 3H), 2.39 (s, 2H), 2.08-1.91 (m, 2H), 1.16 (s, 6H).

[0393] Compound 93 5-chloro-2-fluoro-N-{4-[4-({2-[(2-hydroxyethyl)(isopropyl)amino]ethyl}amino)-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}benzenesulfonamide (i)N-{2-[(2-hydroxyethyl)(isopropyl)amino]ethyl}carbamate K₂CO₃ (534.1 mg, 3.86 mmol, 2.00 equivalent) was added in portions to a stirred mixture of N-(2-bromoethyl)carbamate (433 mg, 1.93 mmol, 1.00 equivalent) and 2-(isopropylamino)ethanol (199.3 mg, 1.93 mmol, 1.00 equivalent) in 15 mL of ACN, and the mixture was stirred at 60 °C for 16 h. The residue was purified by rapid chromatography under the following conditions (column, silica gel; mobile phase, DCM / MeOH, 0% to 10% gradient over 30 min; detector, UV 254 nm). This yielded N-{2-[(2-hydroxyethyl)(isopropylamino]ethyl}carbamate (100 mg, 21.01%) as a grayish-white solid. LCMS (ESI, m / z): 247 [M+H]+.

[0394] (ii) 2-[(2-aminoethyl)(isopropyl)amino]ethanol hydrochloride At room temperature, a solution of 1,4-dioxane containing HCl (gaseous) (3 mL, 98.74 mmol, 243.2 equivalents) was added dropwise to a stirred solution of N-{2-[(2-hydroxyethyl)(isopropyl)amino]ethyl}carbamate (100 mg, 0.406 mmol, 1.00 equivalents) in DCM (3 mL), and the mixture was stirred for 2 hours. The resulting mixture was concentrated under reduced pressure. This yielded 2-((2-aminoethyl)(isopropyl)amino)ethanol-1-ol dihydrochloride (80 mg, 100%) as a grayish-white solid. LCMS (ESI, m / z): 147 [M-2HCl+H]+.

[0395] (iii) 5-Chloro-2-fluoro-N-{4-[4-({2-[(2-hydroxyethyl)(isopropyl)amino]ethyl}amino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}benzenesulfonamide The compound was prepared according to the procedure described in Example 9. The desired product was a white solid (50.3 mg, 95.1% purity (3.2 mg, 11.78%)). LCMS (ESI, m / z): 562.10 [M+H]+. 1 H NMR (300MHz, DMSO-) d 6) δ 12.94 (s, 1H), 8.24 (d, J = 8.3Hz, 2H), 7.83-7.67 (m, 2H), 7.47(t, J = 9.2Hz, 1H), 7.16 (d, J = 8.4Hz, 2H), 7.02 (m, 1H), 4.45 (s, 1H), 3.63(q, J = 6.7, 6.2Hz, 2H), 3.45 (m, 2H), 3.07 – 2.96 (m, 1H), 2.70 (t, J =6.9Hz, 2H), 2.55 (m, 4H), 0.96 (d, J = 6.5Hz, 6H) Compound 94 5-chloro-N-{4-[4-({2-[ethyl(2-hydroxyethyl)amino]ethyl}amino)-3-methyl-1H-pyridine Azo[3,4-d]pyrimidin-6-yl]phenyl}-2-fluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 93. The desired product was a white solid (22.1 mg, 19.64%). LCMS (ES. m / z): 548 [M+H]+. 1 H-NMR (DMSO- d 6, 300MHz) δ (ppm): 12.93 (s,1H), 11.11 (s, 1H), 8.23 ​​(d, J = 8.7Hz, 2H), 7.84-7.70 (m, 2H), 7.49-7.43 (m,1H), 7.17-6.99 (m, 3H), 4.48 (s, 1H), 3.69-3.61 (m, 2H), 3.51-3.47 (m, 2H), 2.98-2.61 (m, 6H), 2.53 (s, 3H), 1.02-0.97 (m, 3H).

[0396] Compound 95 5-Chloro-2-fluoro-N-{4-[4-({3-[(2-hydroxyethyl)(methyl)amino]propyl}amino)-3-methyl 1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}benzenesulfonamide The compound was prepared according to the procedure described in Example 9. The desired product was a white solid (3.7 mg, 3.88%). LCMS (ES. m / z): 548 [M+H]+. 1 H-NMR (DMSO- d 6, 300MHz) δ (ppm): 12.86 (s, 1H), 8.17 (d, J = 8.4Hz, 2H), 7.81-7.74 (m, 1H), 7.67-7.64 (m, 1H), 7.49-7.29 (m, 2H), 7.07 (d, J = 8.4Hz, 2H), 4.52 (s, 1H), 3.72-3.56 (m, 4H), 2.68-2.59 (m,4H), 2.48 (s, 3H), 2.25 (s, 3H), 1.92-1.79 (m, 2H).

[0397] Compound 96 N-[4-(4-{[2-(dimethylamino)ethyl]amino}-3-methyl-1H-pyrazolo[3,4-d]pyrimidine [Pyridine-6-yl)-2-methoxyphenyl]-2,5-difluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 9. The desired product was a grayish-white solid (120.7 mg, 19.76%). LCMS (ESI, m / z): 518.2 [M+H]+. 1 H NMR (300MHz, DMSO- d 6) δ 13.01 (s,1H), 7.94 – 7.82 (m, 2H), 7.73-7.51 (m, 3H), 7.29 (d, J = 8.2Hz, 1H), 7.09(t, J = 5.7Hz, 1H), 3.77-3.71 (m, 2H), 3.62 (s, 3H), 2.65 (t, J = 6.8Hz, 2H), 2.53-2.50 (s, 3H), 2.30 – 2.14 (m, 6H).

[0398] Compound 99 5-chloro-N-{2-chloro-4-[4-({2-[(2-hydroxyethyl)(methyl)amino]ethyl}amino)-3-methyl 1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}-2-fluorobenzenesulfonamide (i) 5-Chloro-N-[2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]-2-fluorobenzenesulfonamide At room temperature, a DCM solution (10 mL) of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)aniline (1 g, 3.944 mmol, 1 equivalent) and pyridine (467.99 mg, 5.916 mmol, 1.5 equivalent) was added to a 50-mL round-bottom flask. The resulting mixture was stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (10:1) elution to give 5-chloro-N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]-2-fluorobenzenesulfonamide (1 g, 56.83%) as a grayish-white solid. LCMS: (ES, m / z): [MH]+ = 446 (ii) 2-[[2-([6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino)ethyl](methyl)amino]ethanol Add 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (240.00 mg, 1.182 mmol, 1.00 equivalent), DCM (10.00 mL), DIEA (458.33 mg, 3.546 mmol, 3 equivalent), and 2-[(2-aminoethyl)(methyl)amino]ethanol (209.55 mg, 1.773 mmol, 1.50 equivalent) to a 50 mL round-bottom flask. Stir the resulting solution at room temperature for 16 hours. Concentrate the resulting mixture. Wash the solid with EA and MeOH (10 / 1). Collect the solid by filtration. This yields 220 mg (60.78%) of 2-[[2-([6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino)ethyl](methyl)amino]ethanol as a white solid. LCMS: (ES, m / z): [M+H]+ = 285 (iii) 5-Chloro-N-{2-chloro-4-[4-({2-[(2-hydroxyethyl)(methyl)amino]ethyl}amino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}-2-fluorobenzenesulfonamide A solution of 5-chloro-N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]-2-fluorobenzenesulfonamide (300 mg, 0.672 mmol, 1 equivalent), Cs₂CO₃ (328.65 mg, 1.008 mmol, 1.5 equivalent), Pd(dppf)Cl₂ (98.41 mg, 0.134 mmol, 0.2 equivalent) in H₂O (30.00 mL, 1664.127 mmol, 2476.38 equivalent) and dioxane (9.00 mL, 106.163 mmol, 157.98 equivalent) was treated at room temperature under a nitrogen atmosphere for 10 min. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The mixture was then cooled to room temperature. The residue was purified by silica gel column chromatography with elution of CH2Cl2 / MeOH (10:1) to obtain the desired product (138.8 mg, 35.37%) as a grayish-white solid. LCMS: (ES, m / z): [M+H]+ = 568 1H NMR (400MHz, DMSO-d6) δ 12.95 (s, 1H), 9.59(s, 1H), 8.23 ​​(s, 1H), 8.02 (d, J = 8.6Hz, 1H), 7.70 (d, J = 4.8Hz, 1H), 7.54(d, J = 8.7Hz, 1H), 7.35 – 7.27 (m, 2H), 7.13 (d, J = 5.7Hz, 1H), 5.13 (s,1H), 3.93 (q, J = 6.1Hz, 2H), 3.68 (s, 6H), 3.15 (d, J = 11.7Hz, 2H), 2.80 (s, 3H), 2.54 (s, 3H).

[0399] Compound 100 N-[2-chloro-4-(4-{[2-(dimethylamino)ethyl]amino}-3-methyl-1H-pyrazolo[3, [4-d]pyrimidin-6-yl)phenyl]-4-isopropoxypyridine-2-sulfonamide (i)4-Isopropoxypyridine-2-sulfonyl chloride At room temperature, a DCM solution (20 mL, 314.612 mmol) of 2-(benzylthio)-4-isopropoxypyridine (1 g, 3.855 mmol, 1 equivalent), HCl (5 mL, 164.564 mmol), and NaClO2 (15 mL, 8%) was added to a 100 mL round-bottom flask. The resulting mixture was stirred at room temperature for 4 h. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 4-Isopropoxypyridine-2-sulfonyl chloride (1 g, 93.54%) was given as a yellow oil. LCMS: (ES, m / z): [MH]+ = 236 (ii) N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl]-4-isopropoxypyridine-2-sulfonamide At room temperature, a DCM solution (15 mL, 235.959 mmol, 1 equivalent) of 4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-1-methylpiperidine (1 g, 3.549 mmol, 1 equivalent), 5-chloro-N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]-2-fluorobenzenesulfonamide (1.58 g, 3.542 mmol, 1.00 equivalent) and pyridine (0.42 g, 5.324 mmol, 1.5 equivalent) was added to a 50 mL round-bottom flask. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (10:1) elution to give N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]-4-isopropoxypyridine-2-sulfonamide (600 mg, 26.55%) as a yellow solid. CMS: (ES, m / z): [M+H]+ = 453 (iii) 6-Chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine Add 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (1.00 g, 4.925 mmol, 1.00 equivalent), DCM (30.00 mL), (2-aminoethyl)dimethylamine (521.03 mg, 5.910 mmol, 1.2 equivalent), and DIEA (1.90 g, 14.701 mmol, 2.98 equivalent) to a 100 mL round-bottom flask. Stir the resulting solution at room temperature for 3 hours. Concentrate the resulting mixture. Wash the solid with diethyl ether. Collect the solid by filtration. This gives 1.2 g (86.08%) of 6-chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-amine as a white solid. LCMS: (ES, m / z): [M+H]+ = 255 (iv)N-[2-chloro-4-(4-{[2-(dimethylamino)ethyl]amino}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-4-isopropoxypyridine-2-sulfonamide A solution of 6-chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.963 mmol, 1 equivalent), N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]-4-isopropoxypyridine-2-sulfonamide (888.74 mg, 1.963 mmol, 1 equivalent), Pd(dppf)Cl2 (287.26 mg, 0.393 mmol, 0.2 equivalent), and Cs2CO3 (959.34 mg, 2.945 mmol, 1.5 equivalent) in dioxane (10 mL) and H2O (3 mL) was treated at room temperature under a nitrogen atmosphere for 10 min. The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. Cool the mixture to room temperature. Concentrate the resulting mixture under reduced pressure. Purify the residue by silica gel column chromatography with CH2Cl2 / MeOH (10:1) to give the desired product (129.9 mg, 11.44%) as a brown solid. LCMS: (ES, m / z): [M+H]+ = 5451H NMR (400MHz, DMSO-d6) δ 13.04 (s, 1H), 11.18 (s,1H), 8.13-8.43 (d, J = 5.6Hz, 3H), 7.25-7.47 (d, J = 8.6Hz, 3H), 7.11 (dd, J= 5.7, 2.5Hz, 1H), 4.79 (p, J = 6.0Hz, 1H), 3.91 (q, J = 6.1Hz, 2H), 3.18 (t,J = 6.4Hz, 2H), 2.70 (s, 4H), 2.57 (s, 2H), 1.92 (s, 4H), 1.26 (dd, J = 14.0,6.5Hz, 6H), 0.90 (t, J = 7.0Hz, 1H).

[0400] Compound 101 5-chloro-N-(2-chloro-4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1H-pyrazolo [3,4-d]pyrimidin-6-yl}phenyl)-2-fluorobenzenesulfonamide (i) 4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-1-methylpiperidine At 0 °C, a THF solution (10 mL) of 4,6-dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 2.463 mmol, 1 equivalent) and 1-methyl-4-piperidinol (0.28 g, 2.463 mmol, 1 equivalent) was added to a 50 mL round-bottom flask, followed by the addition of NaH (0.09 g, 3.695 mmol, 1.5 equivalent). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was quenched by adding water (10 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (5:1) elution to give 4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-1-methylpiperidine (300 mg, 43.24%) as a white solid. LCMS: (ES, m / z): [MH]+ = 282 (ii) 5-Chloro-N-(2-Chloro-4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)-2-fluorobenzenesulfonamide A solution of 4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-1-methylpiperidine (400 mg, 1.420 mmol, 1 equivalent), 5-chloro-N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]-2-fluorobenzenesulfonamide (633.38 mg, 1.420 mmol, 1 equivalent), Pd(dppf)Cl2 (207.77 mg, 0.284 mmol, 0.2 equivalent), and Cs2CO3 (693.87 mg, 2.130 mmol, 1.5 equivalent) in H2O (3 mL) and dioxane (12 mL) was treated at room temperature under a nitrogen atmosphere for 10 min. The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with CH2Cl2 / MeOH (10:1) to give the desired product (113.4 mg, 14.05%) as a white solid. LCMS: (ES, m / z): [M+H]+ =565, 1H NMR (300MHz, DMSO-d6) δ 13.33 (s, 1H), 9.56 (s, 1H), 8.21 (d, J =2.1Hz, 1H), 8.01 (dd, J = 8.7, 2.2Hz, 1H), 7.71 (dd, J = 6.0, 2.8Hz, 1H), 7.52 (dt, J = 8.7, 3.4Hz, 1H), 7.23 – 7.35 (m, 2H), 5.64 (s, 1H), 3.39 (s,4H), 3.17 (d, J = 4.0Hz, 3H), 2.79 (s, 3H), 2.53 (s, 3H), 2.26 (s, 2H), 2.12 (s, 2H).

[0401] Compound 102 N-(2-chloro-4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1H-pyrazolo[3,4- d]pyrimidin-6-yl}phenyl)-2,5-difluorobenzenesulfonamide Cs₂CO₃ (0.87 g, 2.662 mmol, 1.5 equivalent) and Pd(dppf)cl₂ (0.26 g, 0.355 mmol, 0.2 equivalent) were added in portions to a stirred mixture of 4-({6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}oxy)-1-methylpiperidine (0.5 g, 1.775 mmol, 1 equivalent) and N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]-2,5-difluorobenzenesulfonamide (0.84 g, 1.953 mmol, 1.1 equivalent) in 1,4-dioxane (8 mL) and H₂O (2 mL) for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, silica gel; mobile phase, MeOH / DCM, 0% to 15% gradient over 30 min; detector, UV 254 nm). This yielded N-(2-chloro-4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)-2,5-difluorobenzenesulfonamide (0.2104 g, 21.23%) as a grayish-white solid. LCMS (ESI, m / z): 549 [M+H]+. 1H NMR (300MHz, DMSO-d6) δ 13.33 (s, 1H), 9.60 (s,1H), 8.21 (d, J = 2.2Hz, 1H), 8.00 (dd, J = 8.7, 2.2Hz, 1H), 7.49 (ddd, J =8.1, 5.4, 2.9Hz, 1H), 7.29 (dq, J = 8.1, 2.9, 1.7Hz, 3H), 5.63 (s, 1H), 3.21(s, 4H), 2.76 (s, 3H), 2.53 (s, 3H), 2.16 (d, J = 48.7Hz, 4H).

[0402] Compound 103 N-[2-chloro-4-(4-{[2-(dimethylamino)ethyl]amino}-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-6-yl)phenyl]pyridine-2-sulfonamide (i) Pyridine-2-sulfonyl chloride At 0 °C, HCl (10 mL, 329.128 mmol, 73.17 equivalents) and NaOCl (10 mL, 147.770 mmol, 32.85 equivalents) were added in portions to a stirred mixture of 2-pyridinethiol (0.5 g, 4.498 mmol, 1 equivalent) in DCM (5 mL, 78.653 mmol, 17.49 equivalents). The aqueous layer was extracted with H₂O (10 mL × 3) and DCM (10 mL × 3). The resulting mixture was concentrated under reduced pressure. This yielded pyridine-2-sulfonyl chloride (0.4 g, 30.04%) as a yellow oil. LCMS (ESI, m / z): 178 [M+H]⁺.

[0403] (ii) N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl]pyridine-2-sulfonamide At room temperature, pyridine (0.53 g, 6.756 mmol, 3 equivalents) was added fractionally to a stirred mixture of pyridine-2-sulfonyl chloride (0.4 g, 2.252 mmol, 1 equivalent) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)aniline (0.57 g, 2.252 mmol, 1 equivalent) in DCM (4 mL, 62.922 mmol, 27.94 equivalents). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, silica gel; mobile phase, PE / EA, 0% to 50% gradient over 30 min; detector, UV 254 nm. This yielded N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)phenyl]pyridine-2-sulfonamide (0.2 g, 15.34%) as a grayish-white solid. LCMS (ESI, m / z): 395 [M+H]+.

[0404] (iii) N-[2-chloro-4-(4-{[2-(dimethylamino)ethyl]amino}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]pyridine-2-sulfonamide Under a nitrogen atmosphere at 100 °C, Cs₂CO₃ (0.29 g, 0.883 mmol, 1.5 equivalent) and Pd(dppf)Cl₂ (0.09 g, 0.118 mmol, 0.2 equivalent) were added in portions to a stirred mixture of 6-chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.15 g, 0.589 mmol, 1 equivalent) and N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]pyridine-2-sulfonamide (0.26 g, 0.648 mmol, 1.1 equivalent) in 1,4-dioxane (8 mL) and H₂O (2 mL) and added in portions overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column, silica gel; mobile phase, MeOH / DCM, 0% to 15% gradient over 30 min; detector, UV 254 nm). This yielded the desired product (0.0389 g, 13.28%) as a grayish-white solid. LCMS (ESI, m / z):553 [M+H]+1H NMR (300MHz, DMSO-d6) δ 12.98 (s, 1H), 9.86 (s, 1H), 8.63 (d, J= 4.4Hz, 1H), 8.25 (d, J = 2.0Hz, 1H), 8.10 – 7.77 (m, 3H), 7.59 – 7.40 (m,2H), 7.14 (t, J = 5.7Hz, 1H), 3.84 (q, J = 6.2Hz, 2H), 3.02 (t, J = 6.5Hz,2H), 2.57 (d, J = 15.7Hz, 9H).

[0405] Compound 107 N-[2-chloro-4-(4-{[2-(dimethylamino)ethyl]amino}-3-methyl-1H-pyrazolo[3, [4-d]pyrimidin-6-yl)phenyl]-4-methoxypyridine-2-sulfonamide; trifluoroacetic acid The compound was prepared according to a procedure similar to that used for the synthesis of compound 84. The desired product (51.4 mg, 16.59%) was obtained as a grayish-white solid. LCMS: (ES, m / z): [M+H]+ = 517.1H NMR (400MHz, DMSO-d6) δ13.20 (s, 1H), 10.34 (s, 1H), 9.56 (s, 1H), 8.56 (d, J = 5.6Hz, 1H), 8.35 (d,J = 1.9Hz, 1H), 8.28 (dd, J = 8.5, 2.0Hz, 1H), 7.51 (d, J = 8.5Hz, 1H), 7.44(d, J = 2.4Hz, 1H), 7.38 (q, J = 5.7Hz, 1H), 7.27 (dd, J = 5.6, 2.5Hz, 1H),3.99 (q, J = 5.9Hz, 2H), 3.91 (s, 2H), 2.89 (d, J = 4.4Hz, 6H), 2.58 (s, 3H).

[0406] Compound 111 5-Chloro-N-[2-Chloro-4-(4-{[2-(dimethylamino)ethyl]amino}-3-methyl-1H-pyrazole [3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide This compound was prepared according to a procedure similar to that used in the synthesis of compound 84. The desired product (0.0328 g, 12.83%) was obtained as a white solid. LCMS (ESI, m / z): 538 [M+H]+.1H NMR (300MHz, DMSO-d6) δ 12.94 (s, 1H), 8.21 (d, J = 2.1Hz, 1H), 7.98 (d, J = 8.7Hz, 1H), 7.76 – 7.45 (m, 2H), 7.32 – 7.02 (m, 3H), 3.91 (d, J = 5.9Hz, 2H), 2.85 – 2.67 (m, 6H), 2.54 (s, 5H).

[0407] Compound 112 N-[2-chloro-4-(4-{[2-(dimethylamino)ethyl]amino}-3-methyl-1H-pyrazolo[3, [4-d]pyrimidin-6-yl)phenyl]-4-methylpyridine-2-sulfonamide; trifluoroacetic acid The compound was prepared according to a procedure similar to that used for the synthesis of compound 84. The desired product (32.2 mg, 10.62%) was obtained as a grayish-white solid. LCMS: (ES, m / z): [M+H]+ = 5011H NMR (400MHz, DMSO-d6) δ 13.17(s, 1H), 10.28 (s, 1H), 9.47 (s, 1H), 8.58 (d, J = 2.1Hz, 1H), 8.33 (d, J =2.0Hz, 1H), 8.27 (dd, J = 8.4, 2.0Hz, 1H), 7.90 (dd, J = 8.2, 2.2Hz, 1H), 7.84 (d, J = 8.0Hz, 1H), 7.50 (d, J = 8.5Hz, 1H), 7.36 (p, J = 5.5, 4.9Hz,1H), 3.98 (q, J = 5.9Hz, 2H), 3.42 (q, J = 5.7Hz, 2H), 2.89 (d, J = 4.2Hz, 6H), 2.58 (s, 3H), 2.41 (s, 3H).

[0408] Compound 126 2,5-Difluoro-N-(2-fluoro-4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1H-pyridine Azo[3,4-d]pyrimidin-6-yl}phenyl)benzenesulfonamide This compound was prepared according to a procedure similar to that used in the synthesis of compound 102. The desired product (0.4049 g, 42.11%) was obtained as a yellow solid. LCMS (ESI, m / z): 533 [M+H]+. 1 H NMR (300MHz, DMSO-d6) δ 13.41(s, 1H), 9.95 (s, 1H), 8.10 – 7.61 (m, 2H), 7.65 – 7.04 (m, 5H), 5.71 (d, J =36.7Hz, 1H), 3.21 – 3.09 (m, 4H), 2.73 (s, 3H), 2.42 (s, 3H), 2.16 (d, J =44.1Hz, 4H).

[0409] Compound 154 5-chloro- N -(4-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-methyl-1 H -pyr Azo[3,4-] d ]pyrimidin-6-yl)phenyl)-2-fluorobenzenesulfonamide The compound was prepared according to the procedure described in Example 9. The desired product (5 mg, 4.9%) was obtained as a grayish-white solid. LCMS (ESI, m / z): 519.8 [M+H]+. 1H NMR (400MHz, DMSO- d 6 ): δ 11.05 (s, 1H), 8.26 (d, J = 8.60, 2H), 7.87-7.73 (m, 2H), 7.50 (s, 1H), 7.23 (d J = 8.79Hz, 2H), 4.19 (m, 2H), 3.46 - 3.40 (m, 2H), 3.38 (s, 3H), 2.85 (d, J =4.49Hz, 6H), 2.59 (s, 3H).

[0410] Compound 156 N-[2-chloro-4-(4-{[(3S,4R)-3-fluoropiperidin-4-yl]oxy}-3-methyl-1H-pyrazolo] [3,4-d]pyrimidin-6-yl)phenyl]-2,5-difluorobenzenesulfonamide hydrochloride This compound was prepared according to a procedure similar to that used in the synthesis of compound 29. The desired product (0.2211 g, 77.66%) was obtained as a grayish-white solid. LCMS (ESI, m / z): 553 [M+H]+, 1 H NMR (300MHz, DMSO-d6) δ 13.67(s, 1H), 10.81 (s, 1H), 9.30 (s, 1H), 8.78 (s, 1H), 8.46 – 8.27 (m, 2H), 7.72– 7.44 (m, 4H), 5.90 (dd, J = 26.8, 9.3Hz, 1H), 5.46 (s, 1H), 3.67 (s, 4H), 2.56 (s, 3H) 2.21 (s, 2H).

[0411] Compounds 127-155 and 157-174 were prepared according to a procedure similar to the other procedures described herein.

[0412] Table A. List of compounds Bioactivity ●SGK1 determination The ability of the synthesized compounds to inhibit SGK-1 was assessed in enzyme assays by measuring their effect on the ability of isolated SGK1 enzymes to catalyze the transfer of phosphate from ATP to labeled substrate peptide serine / threonine residues, and in cell assays by using the NanoBRET target binding assay kit.

[0413] Enzyme activity assay. The SGK-1 activity of the compound was tested by measuring its ability to inhibit the transfer of phosphate from ATP to the fluorescein-labeled substrate peptide FLPeptide 6 (PerkinElmer, Waltham, USA, catalog number: 760350). The enzymatic reaction was initiated by adding 15 µL of solution 1 containing (mM) 10 MgCl2, 0.010% Brij-35, 2 DTT, 0.05% BSA, 1 EGTA, 50 HEPES (pH 7.5), and 0.665 nM SGK to 5 µL of solution 2 containing 10 MgCl2, 0.010% Brij-35, 2 DTT, 0.05% BSA, 1 EGTA, 50 HEPES (pH 7.5), 6 µM FLPeptide, and 80 µM ATP. After incubating the plate at room temperature for 90 min, 75 µL of stop buffer (containing 0.5 M EDTA) was added to terminate the reaction. Samples were analyzed using an EZ reader. To determine the dose-response relationship of the compounds, stock solutions of the compounds prepared in DMSO were diluted and tested in duplicate in a 10-point, ternary dilution series, starting from a final concentration of 10 µM.

[0414] Cellular enzyme activity assay. SGK1 NanoBRET was used. ™The Target-Binding (TE) Intracellular Kinase Assay Kit was used to measure cellular SGK1-kinase activity. The BRET method relies on the emission of a light signal, which depends on the spatial proximity of the luciferase-conjugated target protein and the fluorescently labeled tracer molecule. Therefore, the substitution of the tracer by a competitive inhibitor attenuates the significant BRET signal. HEK293 cells cultured in Dulbecco modified Eagle medium (DMEM) were transfected with 9 µg / mL vector DNA and 1 µg / mL SGK1-NanoLuc fusion vector, and the liplid:DNA complex was mixed with a 1:20 (v:v) cell suspension. Transfected cells were seeded at 2000 cells / 100 µL / well in 96-well plates and incubated overnight. After overnight incubation, 5 µL of 20× NanoBRET tracer (final 0.5 µM) was added to each well, followed by 10 µL of 10× cpd solution, and incubated at 37 °C and 5% CO2 for 2 hours. Then, 50 µL of 3× complete substrate solution was added to each well, and the plate was equilibrated at room temperature for 15-30 min before the luminescence signal was read using a Synergy 4 plate reader.

[0415] Table B. IC50 inhibitors of SGK-1 activity 50 value ●Solubility The buffer solution for preparing FeSSIF was prepared by dissolving 4.040 g NaOH, 8.650 g glacial acetic acid, and 11.874 g NaCl in approximately 900 mL of ultrapure water, and adjusting the pH of the solution to 5.0 with 1 N NaOH or 1 N HCl. The solution was then diluted to 1000 mL with ultrapure water at room temperature. 11.200 g of FaSSIF, FeSSIF, and FaSSGF powder was added to approximately 500 mL of the buffer solution. The mixture was stirred until the powder was completely dissolved. The solution was then diluted to 1000 mL with the buffer solution at room temperature. The solution is ready for use within 48 hours at room temperature and within 24 hours at 37°C.

[0416] Stock solutions were prepared in DMSO at a concentration of 10 mM for both the test compound and the control compound progesterone.

[0417] The procedure for solubility determination involved sequentially placing 30 µL of stock solution (10 mM) of each sample into its appropriate 96-well holder, and adding 970 µL of FeSSIF or pH 7.4 PBS to each vial of an open solubility sample plate. This determination was repeated twice. A stir bar was added to each vial, and the plates were sealed with molded PTFE / silicone stoppers. The solubility sample plates were then transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 1100 RPM for 2 hours at 25 °C. After 2 hours, the stoppers were removed, and the stir bar was removed using a large magnet, transferring the samples from the solubility sample plates to a filter plate. All samples were filtered using a Vacuum Manifold. A 5 µL aliquot was taken from the filtrate, followed by the addition of 5 µL of DMSO and a mixture of 490 µL of H₂O and acetonitrile. The dilution factor was adjusted based on the solubility values ​​and the LC-MS signal response.

[0418] Preparation of the 3µM standard (STD): 15µL was transferred from the 10mM DMSO STD plate to the remaining empty plate, and then 485µL of DMSO was added to the plate to achieve an STD concentration of 300µM. 5µL of DMSO STD was transferred from the 300µM DMSO STD plate to the remaining empty plate, and then 5µL of FeSSIF or PBS pH 7.4 and a mixture of 490µL H2O and acetonitrile were added to the plate to achieve a final STD concentration of 3µM. The concentration of the standard was varied based on the LC-MS signal response.

[0419] The sample analysis procedure involved placing the plate in the autosampler. The sample was evaluated by LC-MS / MS analysis (LC system: Shimadzu, MS analysis: Triple Quad™ 5500 instrument from AB Inc (Canada) with ESI interface; method: temperature 40°C, injection volume: 1 µL or 2 µL, column: XSelect Hss T3 2.5 µm (2.1 × 50 mm) column XP; mobile phase: 0.1% formic acid / water (A) and 0.1% formic acid / acetonitrile (B) and elution rate: 1.0 mL / min).

[0420] Data analysis was performed using Microsoft Excel for all calculations. LC, combined with mass spectrometry peak identification and quantification, was used to analyze and quantify the filtrate relative to a standard of known concentration. Solubility values ​​for the test and control compounds were calculated as follows: Exclude any values ​​of compounds that are not within the specified limits and repeat the experiment.

[0421] Table C. Solubility of Compounds ●Kinetic selectivity Using KinaseSeeker ™ The following compounds were profiled using a 10 µM 50-kinase mixture assay.

[0422] Mixed kinases : AKT1, AKT2, AKT3, PDK1 / PDPK1, PKA / PRKACA, PKC-ε / PRKCE, PKG1 / PRKG1, PKX / PRKX, RPS6KA3 / RSK2, RPS6KA4 / MSK2, YA NK2, AMPK-α1 / AMPK, CAMK1D, CAMK2D, DAPK3, MARK1, MARK2, PIM1, SNF1LK / SIK1, SNF1LK2 / SIK2 / QIK, CLK2, CDK5, p38-α / MAPK14, AAK1, AURKA, AURKB, AURKC, PLK4, SLK, TAOK1, YSK1, ABL1, DDR1, EPHA5, EPHB2, FLT1 / VEGFR1, FLT3, HCK, IGF 1R, ITK, KIT, MUSK, PDGFRB, PTK2B / PYK2, SRC, TNK1, VEGFR2 / KDR / FLK1, ACVR2A / ACVR2, MLK2 / MAP3K10, MLK3 / MAP3K11.

[0423] Measurement Design Kinase Seeker is a competitive binding assay in which the substitution of an active site-dependent probe by an inhibitor is measured by changes in the luminescence signal. The luminescence reading translates into a highly sensitive and robust assay with low background and minimal interference from the test compound.

[0424] The assay involved diluting a 10 mM stock solution of the compound to a concentration of 250 µM in DMSO. False positives for luciferase were assessed before co-occurrence of the compounds. The compound was then screened in duplicate for each kinase. For the kinase assay, each Cfluc-kinase was translated with Fos-Nfluc for 90 min at 30 °C using a cell-free system (cell lysate). Aliquots of 24 µL of lysate containing either 1 µL of DMSO (inhibitor-free control) or a solution of the compound in DMSO (10 µM final concentration) were incubated at room temperature for 2 h in the presence of the kinase-specific probe. 80 µL of luciferase assay reagent was added to each solution, and luminescence was immediately measured on a photometer. The profile analysis data of all kinases were plotted against each profiled kinase with an inhibition percentage. A heatmap representing the effects of compounds on the kinases was also generated.

[0425] Table D. Kinase selectivity of compounds ●hERG The HEK 293 cell line (catalog number K1236), stably expressing hERG, was purchased from Invitrogen. Cells were cultured in 85% DMEM, 10% dialyzed FBS, 0.1 mM NEAA, 25 mM HEPES, 100 U / mL penicillin-streptomycin, and 5 µg / mL blastcinin and 400 µg / mL genicin. TrypLE was used. ™ Express cells divide approximately three times per week and maintain 40% to 80% confluence. Prior to assay, cells were transferred to coverslips at 5 × 10⁵ cells / 6 cm cell culture dish and induced with 1 µg / mL doxycycline for 48 hours.

[0426] Solution preparations: Extracellular solution (mM): 132 NaCl, 4 KCl, 3 CaCl2, 0.5 MgCl2, 11.1 Glucose, and 10 HEPES (pH adjusted to 7.35 with NaOH). Intercellular solution (mM): 140 KCl, 2 MgCl2, 10 EGTA, 10 HEPES, and 5 MgATP (pH adjusted to 7.35 with KOH). Working solutions for the test compounds were prepared according to SOP-ADMET-MAN-007. Initially, the test compounds were prepared as stock solutions in DMSO at a final concentration of 10 mM. The stock solutions of each compound were then serially diluted with DMSO at a 1:3 ratio to prepare three additional intermediate solutions: 3.33 mM, 1.11 mM, and 0.37 mM. Prior to hERG assays, working solutions were prepared by diluting the 10 mM, 3.33 mM, 1.11 mM, and 0.37 mM intermediate solutions 1000-fold using extracellular solutions, resulting in final concentrations of 10 mM, 3.33 mM, 1.11 mM, and 0.37 mM. A 30 µM working solution was also prepared by diluting the 10 mM DMSO stock solution 333.333-fold. The final DMSO concentration in the working solutions was maintained in the range of 0.1%–0.3% (v / v). hERG current was measured for IC50 determination in the presence of five doses, including 30µM, 10µM, 3.33µM, 1.11µM and 0.37µM.

[0427] The data analysis uses the following equation to calculate the current suppression percentage.

[0428] Graphpad Prism 8....

Claims

1. A compound of formula Vb: Vb Or its pharmaceutically acceptable salt. in: R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogens, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; and W1 is selected from the group consisting of free H and halogens.

2. The compound according to claim 1, wherein W1 is F.

3. The compound according to claim 1, wherein W1 is Cl.

4. The compound according to any one of claims 1 to 3, wherein R2 is .

5. The compound according to claim 1, wherein Z1 and Z2 are independently selected from the group consisting of: Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe.

6. The compound according to claim 1, wherein R2 is or .

7. The compound according to claim 1, wherein R2 is .

8. The compound according to claim 1, wherein R2 is .

9. The compound according to claim 8, wherein Z3 is selected from the group consisting of H, Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe.

10. The compound according to claim 8, wherein Z3 is selected from the group consisting of H, -CH3, -CF3, -OCH(CH3)2 and -OMe.

11. The compound according to claim 8, wherein Z3 is selected from the group consisting of -CH3, -OCH(CH3)2 and -OMe.

12. The compound according to claim 1, wherein the compound is: 、 、 、 、 、 、 Or its pharmaceutically acceptable salt.

13. The compound according to claim 1, wherein the compound is: 、 、 、 、 、 、 、 、 ， Or its pharmaceutically acceptable salt.

14. A compound of formula V: Formula V Or its pharmaceutically acceptable salt. in: R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; W1 is selected from the group consisting of free hydrogen and halogens; R 33 -CH3 or -(CH2)-(CH2)-OR 27 ;and R 27 Choose from the following groups: H, -C(=O)-(C1-C4)alkyl, natural amino acids bound by α-carboxyl groups, and -P(=O)(OH)2.

15. The compound according to claim 14, wherein W1 is F.

16. The compound according to claim 14, wherein W1 is Cl.

17. The compound according to claim 14, wherein R2 is .

18. The compound according to claim 14, wherein Z1 and Z2 are independently selected from the group consisting of: Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe.

19. The compound according to claim 14, wherein R2 is or .

20. The compound according to claim 14, wherein R2 is .

21. The compound according to claim 14, wherein R2 is .

22. The compound according to claim 21, wherein Z3 is selected from the group consisting of H, Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe.

23. The compound according to claim 21, wherein Z3 is selected from the group consisting of H, -CH3, -CF3, -OCH(CH3)2 and -OMe.

24. The compound according to claim 21, wherein Z3 is selected from the group consisting of -CH3, -OCH(CH3)2 and -OMe.

25. The compound according to claim 14, wherein R 33 It is -CH3.

26. The compound according to claim 14, wherein R 33 -(CH2)-(CH2)-OR 27 .

27. The compound according to claim 26, wherein R 27 Choose from the group consisting of H and -C(=O)-(C1-C4)alkyl groups.

28. The compound according to claim 14, wherein the compound is: ， Or its pharmaceutically acceptable salt. in: R2 can be selected from the following groups: , , , , , and ; W1 selects the group composed of H, Cl, and F; and R 27 Choose from the following groups: H, , , , , , , and .

29. The compound according to claim 14, wherein the compound is: Or its pharmaceutically acceptable salt. in: R2 can be selected from the following groups: , , , , , and ;and W1 is selected from the group consisting of H, Cl, and F.

30. The compound according to claim 14, wherein the compound is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， Or its pharmaceutically acceptable salt.

31. A compound of formula VI: Style VI Or its pharmaceutically acceptable salt. in: Y1 is either H or F; q is 0 or 1; R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogens, (C1-C4) alkyl groups, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; W1 is a halogen; R 35 H or unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; R 50 Choose from the following groups: halogen, -OR 27 -O-(C1-C4)-alkyl, -CF3, and -CN; R 27 Choose from the following groups: H, -C(=O)-(C1-C4)alkyl, natural amino acids bound by α-carboxyl groups, and P(=O)(OH)2.

32. The compound according to claim 31, wherein Y1 is H.

33. The compound according to claim 31, wherein the compound is selected from the group consisting of: 、 、 and , Or its pharmaceutically acceptable salt.

34. The compound according to claim 31, wherein the compound is: Or, or a pharmaceutically acceptable salt thereof.

35. The compound according to claim 31, wherein q is 1.

36. The compound according to claim 31, wherein W1 is F.

37. The compound according to claim 31, wherein W1 is Cl.

38. The compound according to claim 31, wherein R2 is .

39. The compound according to claim 31, wherein Z1 and Z2 are independently selected from the group consisting of: Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe.

40. The compound according to claim 31, wherein R2 is or .

41. The compound according to claim 31, wherein R2 is .

42. The compound according to claim 31, wherein R2 is .

43. The compound according to claim 42, wherein Z3 is selected from the group consisting of H, Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe.

44. The compound according to claim 42, wherein Z3 is selected from the group consisting of H, -CH3, -CF3, -OCH(CH3)2 and -OMe.

45. The compound according to claim 42, wherein Z3 is selected from the group consisting of -CH3, -OCH(CH3)2 and -OMe.

46. ​​The compound according to claim 31, wherein R 27 Choose from the group consisting of H and -C(=O)-(C1-C4)alkyl groups.

47. The compound according to claim 31, wherein R 35 It is H, a substituted (C1-C4)-alkyl, or an unsubstituted (C1-C4)-alkyl.

48. The compound according to claim 31, wherein R 35 For H.

49. The compound according to claim 31, wherein the compound is: ， Or its pharmaceutically acceptable salt. in: R2 can be selected from the following groups: , , , , , and ;and W1 is either Cl or F.

50. The compound according to claim 31, wherein the compound is: 、 、 ， Or its pharmaceutically acceptable salt.

51. A compound of formula IV: Formula IV Or its pharmaceutically acceptable salt. in: Z is either O or NH; R3 can be selected from the following groups: -(CH2) p -N(R 33 )R 34 , , , and , p is 2, 3, or 4; R 33 and R 34 Independent of each other, either unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; R 35 H or unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; R 50 Choose from the following groups: halogen, -OR 27 -O-(C1-C4)-alkyl, -CF3, and -CN; R 27 Choose from the following groups: H, -C(=O)-(C1-C4)alkyl, natural amino acids bound by α-carboxyl groups, and P(=O)(OH)2; R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogens, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; and W1 is a halogen.

52. The compound according to claim 51, wherein Z is O.

53. The compound according to claim 51, wherein Z is NH.

54. The compound according to claim 51, wherein R 27 Choose from the group consisting of H or -C(=O)-(C1-C4) alkyl groups.

55. The compound according to claim 51, wherein R3 is -(CH2). p -N(R 33 )R 34 .

56. The compound according to claim 55, wherein p = 2.

57. The compound according to claim 55, wherein R 33 It is a methyl group.

58. The compound according to claim 55, wherein R 34 It is a methyl group.

59. The compound according to claim 55, wherein R 34 It is -(CH2)2-OH or -(CH2)2-OC(=O)-(C1-C4)alkyl.

60. The compound according to claim 51, wherein R3 is .

61. The compound according to claim 60, wherein R 35 It is methyl or isopropyl.

62. The compound according to claim 51, wherein R3 is .

63. The compound according to claim 62, wherein R 35 For H.

64. The compound according to claim 51, wherein Z-R3 is selected from the group consisting of: , , , and .

65. The compound according to claim 64, wherein Z-R3 is selected from... and A group that is formed.

66. The compound according to claim 64, wherein R 27 Choose from the group consisting of H and -C(=O)-(C1-C4)alkyl groups.

67. The compound according to claim 66, wherein R 27 For H.

68. The compound according to claim 64, wherein Z-R3 is or .

69. The compound according to claim 64, wherein Z-R3 is .

70. The compound according to claim 51, wherein W1 is F.

71. The compound according to claim 51, wherein W1 is Cl.

72. The compound according to claim 51, wherein R2 is .

73. The compound according to claim 72, wherein Z1 and Z2 are independently selected from the group consisting of: Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe.

74. The compound according to claim 72, wherein R2 is or .

75. The compound according to claim 72, wherein R2 is .

76. The compound according to claim 51, wherein R2 is .

77. The compound according to claim 76, wherein Z3 is selected from the group consisting of H, Cl, F, -CH3, -CN, -OCH(CH3)2 and -OMe.

78. The compound according to claim 76, wherein Z3 is selected from the group consisting of H, -CH3, -CF3, -OCH(CH3)2 and -OMe.

79. The compound according to claim 76, wherein Z3 is selected from the group consisting of -CH3, -OCH(CH3)2 and -OMe.

80. The compound according to claim 51, wherein the compound is: ， Or its pharmaceutically acceptable salt. in: R2 can be selected from the following groups: , , , , , and ; W1 is either Cl or F; and R 27 Choose from the following groups: H, , , , , , , and .

81. The compound according to claim 51, wherein the compound is: Or its pharmaceutically acceptable salt. in: R2 can be selected from the following groups: , , , , , and ;and W1 is either Cl or F.

82. The compound according to claim 51, wherein the compound is: ， Or its pharmaceutically acceptable salt. in: R2 can be selected from the following groups: , , , , , and ; W1 is either Cl or F; and R 35 It is methyl or isopropyl.

83. The compound according to claim 51, wherein the compound is: ， Or its pharmaceutically acceptable salt. in: R2 can be selected from the following groups: , , , , , and ;and W1 is either Cl or F.

84. The compound according to claim 51, wherein the compound is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or its pharmaceutically acceptable salt.

85. A compound of formula IV: Formula IV Or its pharmaceutically acceptable salt. in: Z-R3 can be selected from the following groups: , and ; R 27 Choose from the following groups: H, , , , , , , and ; R2 can be selected from the following groups: , , , , , and ;and W1 is either Cl or F.

86. The compound according to claim 85, wherein W1 is Cl.

87. The compound according to claim 85, wherein W1 is F.

88. The compound according to claim 85, wherein R2 is .

89. The compound according to claim 85, wherein R 27 For H.

90. The compound according to claim 85, wherein Z-R3 is .

91. A compound of formula II: Formula II Or its pharmaceutically acceptable salt. in: Z is selected from the following groups: O, CH2, S, and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 Select Free - (CH2) p -N(R 33 )R 34 The group formed; p is 1, 2, 3 or 4; R2 is selected from the group consisting of: 5-membered non-aromatic monocyclic rings, 6-membered non-aromatic monocyclic rings, 6-membered aromatic groups, and 6-membered heteroaromatic groups containing 1, 2, or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein R2 is unsubstituted or substituented by one or more identical or different substituents R 20 replace; R 20 Choose from the following groups: halogen, -CF3, (C1-C4)-alkyl, -OR 21 -N(R) 22 )R 23 (C1-C4)-alkyl-OR 24 (C1-C4)-alkyl-N(R) 25 )R 26 and -CN; R 21 R 22 R 23 R 24 R 25 and R 26 Each is independently selected from the group consisting of H and (C1-C4)-alkyl groups; R 33 and R 34 The following groups are selected independently of each other: -CH=O, (C1-C4)-alkyl, and (C3-C7)-cycloalkyl, wherein the (C1-C4)-alkyl and (C3-C7)-cycloalkyl are each unsubstituted or substituented by one or more of the same or different substituents R. 50 Replace; and R 50 Choose from the following groups: halogens, -OH, -O-(C1-C4)-alkyl, CF3, and -CN.

92. The compound of claim 91 or a pharmaceutically acceptable salt thereof, wherein Z is NH.

93. The compound of claim 91 or a pharmaceutically acceptable salt thereof, wherein Z is O.

94. The compound of claim 91 or a pharmaceutically acceptable salt thereof, wherein R1 is methyl.

95. The compound of claim 91 or a pharmaceutically acceptable salt thereof, wherein p is 2, 3 or 4.

96. The compound of claim 91 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of: , , , , , , , , , , , , , , and .

97. The compound of claim 91 or a pharmaceutically acceptable salt thereof, wherein R2 is... , , , , , and .

98. The compound of claim 91 or a pharmaceutically acceptable salt thereof, wherein R 33 =Methyl.

99. The compound of claim 91 or a pharmaceutically acceptable salt thereof, wherein R 34 =Methyl.

100. The compound according to claim 91, wherein R3 is selected from the group consisting of: , , , , and .

101. A compound, said compound being selected from the group consisting of: , , , , , , , , , , , and , Or its pharmaceutically acceptable salt.

102. A compound, said compound being selected from the group consisting of: 、 、 、 、 、 、 and , Or its pharmaceutically acceptable salt.

103. A compound, said compound being selected from the group consisting of: 、 、 、 、 、 、 and , Or its pharmaceutically acceptable salt.

104. A compound, said compound being selected from the group consisting of: , , , , , , , , , , , and , Or its pharmaceutically acceptable salt.

105. A compound of formula II: Formula II Or its pharmaceutically acceptable salt. in: Z is selected from the following groups: O, CH2, S, and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 Select Free - (CH2) p -N(R 33 )R 34 The group formed; p is 1, 2, 3 or 4; R2 is a 6-membered monocyclic or 6-membered heteroaromatic group, wherein the monocyclic or heteroaromatic group contains one or two nitrogen atoms, and R2 is unsubstituted or substituented by one or more identical or different substituents R. 20 replace; R 20 Choose from the following groups: halogen, -CF3, (C1-C4)-alkyl, -OR 21 -N(R) 22 )R 23 (C1-C4)-alkyl-OR 24 (C1-C4)-alkyl-N(R) 25 )R 26 and -CN; R 21 R 22 R 23 R 24 R 25 and R 26 Each is independently selected from the group consisting of H and (C1-C4)-alkyl groups; R 33 and R 34 The following groups are selected independently of each other: -CH=O, (C1-C4)-alkyl, and (C3-C7)-cycloalkyl, wherein the (C1-C4)-alkyl and (C3-C7)-cycloalkyl are each unsubstituted or substituented by one or more of the same or different substituents R. 50 Replace; and R 50 Choose from the following groups: halogens, -OH, -O-(C1-C4)-alkyl, CF3, and -CN.

106. The compound of claim 105 or a pharmaceutically acceptable salt thereof, wherein Z is NH.

107. The compound of claim 105 or a pharmaceutically acceptable salt thereof, wherein Z is O.

108. The compound of claim 105 or a pharmaceutically acceptable salt thereof, wherein R1 is methyl.

109. The compound of claim 105 or a pharmaceutically acceptable salt thereof, wherein p is 2, 3 or 4.

110. The compound of claim 105 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of: , , , , , , , , , , , , , , , and .

111. The compound of claim 105 or a pharmaceutically acceptable salt thereof, wherein R 33 =Methyl.

112. The compound of claim 105 or a pharmaceutically acceptable salt thereof, wherein R 34 =Methyl.

113. The compound according to claim 105, wherein R3 is selected from the group consisting of: , , , , and .

114. A compound of formula III: Formula III Or its pharmaceutically acceptable salt. in: Z is selected from the following groups: O, CH2, S, and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 Select Free - (CH2) p -N(R 33 )R 34 The group consists of the group -(CH2). p - The zero, one, or two hydrogen atoms are independently replaced by F; p is 1, 2, 3 or 4; R2 is selected from the group consisting of: 5-6 membered non-aromatic monocyclic rings, 6 membered aromatic groups, and 6 membered heteroaromatic groups containing 1, 2, or 3 identical or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein R2 is unsubstituted or substituented by one or more identical or different substituents R 20 replace; R 20 Choose from the following groups: halogen, -CF3, (C1-C4)-alkyl, -OR 21 , -N(R 22 )R 23 (C1-C4)-alkyl-OR 24 (C1-C4)-alkyl-N(R) 25 )R 26 and -CN; R 21 R 22 R 23 R 24 R 25 and R 26 Each is independently selected from the group consisting of H and (C1-C4)-alkyl groups; R 33 and R 34 The following groups are selected independently of each other: -CH=O, (C1-C4)-alkyl, and (C3-C7)-cycloalkyl, wherein the (C1-C4)-alkyl and (C3-C7)-cycloalkyl are each unsubstituted or substituented by one or more of the same or different substituents R. 50 replace; R 50 Choose from the following groups: halogen, -OR 27 -O-(C1-C4)-alkyl, -CF3, and -CN; R 27 Choose from the following groups: H, -C(=O)-(C1-C4)-alkyl, native amino acids linked by an α-carboxyl group, or P(=O)(OH)2; and W1, W2, W3, and W4 are independently selected from the following groups: H, halogen, -OR 21 -SH, -CF3, (C1-C4)-alkyl and -CN.

115. The compound of claim 114 or a pharmaceutically acceptable salt thereof, wherein Z is NH.

116. The compound of claim 114 or a pharmaceutically acceptable salt thereof, wherein Z is O.

117. The compound of claim 114 or a pharmaceutically acceptable salt thereof, wherein R1 is methyl.

118. The compound of claim 114 or a pharmaceutically acceptable salt thereof, wherein p is 2, 3 or 4.

119. The compound of claim 114 or a pharmaceutically acceptable salt thereof, wherein: R2 is or ; Z1 and Z2 are independently selected from the group consisting of: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; and Z3 is selected from the group consisting of: H, halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN.

120. The compound of claim 114 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of: , , , , , and .

121. The compound of claim 114 or a pharmaceutically acceptable salt thereof, wherein R 33 =Methyl.

122. The compound of claim 114 or a pharmaceutically acceptable salt thereof, wherein R 34 =Methyl.

123. The compound according to claim 114, wherein R3 is selected from the group consisting of: , , , and , where R 51 It is (C1-C4)-alkyl.

124. The compound according to claim 114, wherein: W1, W2, W3, and W4 are each H; W1 is F or Cl, and W2, W3, and W4 are each H; or W1 and W2 are each labeled F, and W3 and W4 are each labeled H.

125. The compound according to claim 114, wherein W1 is F or Cl, W2 is H, W3 is H and W4 is H.

126. A compound of formula III: Formula III Or its pharmaceutically acceptable salt. in: Z is selected from the group composed of O and NH; R1 is selected from the group consisting of H and (C1-C4)-alkyl groups; R3 is -(CH2) p -N(R 33 )R 34 ; p is 2, 3, or 4; R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; R 33 and R 34 Each is independently (C1-C4)-alkyl; and W1, W2, W3, and W4 are independently selected from the following groups: H, halogen, -OR 21 -CF3, (C1-C4)-alkyl and -CN, R 21 Choose from the group consisting of H and (C1-C4)-alkyl groups.

127. The compound according to claim 126, wherein R1 is methyl.

128. The compound according to claim 126, wherein R3 is selected from the group consisting of: , and .

129. The compound according to claim 128, wherein R3 is .

130. The compound according to claim 126, wherein R2 is selected from the group consisting of: , , , , , and .

131. The compound according to claim 126, wherein: W1, W2, W3, and W4 are each H; W1 is F or Cl, and W2, W3, and W4 are each H; or W1 and W2 are each labeled F, and W3 and W4 are each labeled H.

132. The compound according to claim 126, wherein W1 is F or Cl, and W2, W3 and W4 are each H.

133. The compound according to claim 126, wherein Z is NH.

134. A compound, wherein the compound is selected from the group consisting of: and Or, or a pharmaceutically acceptable salt thereof.

135. A compound of formula III: Formula III Or its pharmaceutically acceptable salt. in: Z is selected from the group composed of O and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 is a nitrogen-containing heterocycle selected from the following groups: , , , and In which zero, one, or two hydrogens on any of the -CH2- groups of the nitrogen-containing heterocycle are substituted with halogen, -OH, -CN, -CF3, or (C1-C4)-alkyl; R 35 H or unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; and R 50 Choose from the following groups: halogens, -OH, -O-(C1-C4)-alkyl, CF3, and -CN; R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; W1 is F, OMe, or Cl; W2 is either H or F; W3 is H; and W4 is H.

136. The compound according to claim 135, wherein Z is O.

137. The compound according to claim 135, wherein R1 is methyl.

138. The compound according to claim 135, wherein R3 is .

139. The compound according to claim 135, wherein R 35 It is methyl or isopropyl.

140. The compound according to claim 135, wherein W2 is H.

141. The compound according to claim 135, wherein R2 is selected from the group consisting of: , , , , , and .

142. A compound selected from the group consisting of: and Or, or a pharmaceutically acceptable salt thereof.

143. A compound of formula III: Formula III Or its pharmaceutically acceptable salt. in: Z is selected from the group composed of O and NH; R1 is selected from the group consisting of H and -(C1-C4)-alkyl groups; R3 is a nitrogen-containing heterocycle selected from the following groups: , , , , , and In which zero, one, or two hydrogens on any of the -CH2- groups of the nitrogen-containing heterocycle are substituted with halogen, -OH, -CN, -CF3, or (C1-C4)-alkyl; R 35 H or unsubstituted or with one or more identical or different substituents R 50 Substituted (C1-C4)-alkyl; and R 50 Choose from the following groups: halogens, -OH, -O-(C1-C4)-alkyl, CF3, and -CN; R2 is or ; Z1 and Z2 are independently selected from the following groups: halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3 and -CN; Z3 is selected from the group consisting of: H, halogen, (C1-C4)alkyl, -OH, -O-(C1-C4)alkyl, -CF3, and -CN; W1, W2, W3, and W4 are independently selected from the following groups: H, halogen, -OR 21 -CF3, (C1-C4)-alkyl and -CN, R 21 Choose from the group consisting of H and (C1-C4)-alkyl groups.

144. The compound according to claim 143, wherein Z is O.

145. The compound according to claim 143, wherein R1 is methyl.

146. The compound according to claim 143, wherein R3 is or .

147. The compound according to claim 143, wherein R 35 It is methyl or isopropyl.

148. The compound according to claim 143, wherein... W1 is H, F, OMe, or Cl; W2 is either H or F; W3 is H; and W4 is H.

149. The compound according to claim 143, wherein W1 is F, W2 is H, W3 is H and W4 is H.

150. The compound according to claim 143, wherein R2 is selected from the group consisting of: , , , , , and .

151. A compound, said compound being selected from the group consisting of: and , Or its pharmaceutically acceptable salt.

152. A pharmaceutical composition comprising a compound according to any one of claims 1 to 151 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

153. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 151 for the manufacture of a medicament that inhibits SGK-1 in a subject.

154. Use of the compound according to any one of claims 1 to 151 for the manufacture of a medicament for the treatment of prostate cancer, colorectal cancer, breast cancer, Parkinson's disease, or Lafra disease.

155. Use of the compound according to any one of claims 1 to 151 for the manufacture of a medicament for the treatment of epilepsy.

156. Use of any compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 151 for the manufacture of a medicament for the treatment of cardiovascular diseases selected from the group consisting of: long QT syndrome, heart failure, arrhythmia, ischemic injury, ischemic infarction, cardiac fibrosis, angiogenesis, restenosis, dilated cardiomyopathy, and stent failure.

157. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 151 for the manufacture of a medicament for the treatment of long QT syndrome.

158. The use according to claim 157, wherein the long QT syndrome is hereditary long QT syndrome.

159. The use according to claim 157, wherein the long QT syndrome is acquired long QT syndrome.

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