Ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) modulators and uses thereof

Abstract

To provide small-molecule modulators of ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1).SOLUTION: Provided is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: SELECTED DRAWING: None

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Patent Application No. 62 / 953,066, filed December 23, 2019, which is incorporated herein by reference in its entirety.

[0002] Described herein are ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) modulators, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders in which ENPP1 is implicated. Summary of the Invention

[0003] Described herein are compounds and compositions as modulators of ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) and for treating disorders associated with ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1), such as pseudogout, and methods of using these compounds and compositions.

[0004] In one aspect, provided herein is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: [ka] During the ceremony, Ring B is aryl or 5- or 6-membered heteroaryl; n is 0, 1, 2, or 3; m is 1 or 2, p is 0, 1, 2, or 3; Y 1 Ha-NR 4 - or -O-, L 1 -Y 2 -L 2 -or- Y 2 -L 2 -L3 - and Y 2 is a bond or -C(=O)-, L 2 is a bond or optionally substituted C-C alkylene, C-C heteroalkylene, C-C alkenylene, C-C alkynylene, or C-C cycloalkylene, each optionally containing one, two, or three R 7 is replaced by L 3 is one, two or three R 7 is a C3-C6 cycloalkylene optionally substituted with R 1 is H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 8 optionally replaced by R 2 is H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -NR 1A S(=O)2(C1,-C4 alkyl), -S(=O)2N(R 1A )2, -OC(=O)(C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), -C(=O)N(R 1A )2, -NR 1A C(=O)(C1-C4 alkyl), -NR 1A C(=O)O(C1-C4 alkyl), -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A)2, -S(C1-C4 alkyl), -S(=O)(C1-C4 alkyl), -S(=O)2(C1-C4 alkyl), C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, -C 1-6 Alkyl-OH, -C 1-6 Heteroalkyl-OH, C 1-6 Alkyl-C(=O)OH, -C 1-6 heteroalkyl-C(=O)OH, monocyclic C2-C6 heterocycloalkyl, phenyl, or monocyclic 5-6 membered heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 9 optionally replaced by R 3 is H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 9 optionally replaced by R 4 is H, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 5 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -S(=O)R 1B , -NO2, -N(R 1A )2, -S(=O)2R 1B , -NHS(=O)2R 1B , -S(=O)2N(R 1A )2, -C(=O)R 1B , -OC(=O)R 1B , -C(=O)OR 1A , -OC(=O)OR 1A , -C(=O)N(R 1A )2, -OC(=O)N(R1A )2, -NR 1A C(=O)N(R 1A )2, -NR 1A C(=O)R 1B , -NR 1A C(=O)OR 1A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl or cycloalkyl; Each R 6 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , N(R 1A )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy or C1-C4 heteroalkyl; Each R 7 , R 8 and R 9 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -N(R 1A )2, -C(=O)OR 1A , oxo(=O), C1-C4 alkyl or C1-C4 fluoroalkyl; Each R 1A are independently hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and Each R 1B are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0005] In some embodiments presented herein, the compound of formula (I) has the structure of formula (II), or a pharmaceutically acceptable salt or solvate thereof: [ka]

[0006] In some embodiments provided herein, the compound of Formula (I) has the structure of Formula (III): [ka] X 3 , X 4 , and X 5 are each independently CH or N.

[0007] In some embodiments presented herein, the compound of formula (I) has the structure of formula (IV), or a pharmaceutically acceptable salt or solvate thereof: [ka]

[0008] In another aspect, provided herein is a compound having the structure of formula (V), or a pharmaceutically acceptable salt or solvate thereof: [ka] During the ceremony, Ring D is phenyl or a 5- or 6-membered heteroaryl; q is 0, 1, 2, or 3; L 5 is an optionally substituted C1-C3 alkylene, and one, two, or three R 26 optionally replaced by R 20 is H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 27 optionally replaced by R 21is H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, and alkyl, alkenyl, alkynyl, aryl, and heteroaryl each represent one, two, or three R 28 optionally replaced by R 22 H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -NR 1A S(=O)2(C1-C4 alkyl), -S(=O)2N(R 1A )2, -OC(=O)(C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), -C(=O)N(R 1A )2, -NR 1A C(=O)(C1-C4 alkyl), -NR 1A C(=O)O(C1-C4 alkyl), -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -S(C1-C4 alkyl), -S(=O)(C1-C4 alkyl), -S(=O)2(C1-C4 alkyl), C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, -C 1-6 Alkyl-OH, -C 1-6 Heteroalkyl-OH, C 1-6 Alkyl-C(=O)OH, -C 1-6 heteroalkyl-C(=O)OH, monocyclic C2-C6 heterocycloalkyl, phenyl, or monocyclic 5-6 membered heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 29 optionally replaced by R 23 H, halogen, -CN, -OH, -OR 1B , -SH, -SR1B , -S(=O)R 1B , -NO2, -N(R 1A )2, -S(=O)2R 1B , -NHS(=O)2R 1B , -S(=O)2N(R 1A )2, -C(=O)R 1B , -OC(=O)R 1B , -C(=O)OR 1A , -OC(=O)OR 1A , -C(=O)N(R 1A )2, -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -NR 1A C(=O)R 1B , -NR 1A C(=O)OR 1A , C1-C6 alkyl, C2-C4 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl or cycloalkyl; Each R 24 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -S(=O)R 1B , -NO2, -N(R 1A )2, -S(=O)2R 1B , -NHS(=O)2R 1B , -S(=O)2N(R 1A )2, -C(=O)R 1B , -OC(=O)R 1B , -C(=O)OR 1A , -OC(=O)OR 1A , -C(=O)N(R 1A )2, -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -NR 1A C(=O)R 1B , -NR 1A C(=O)OR 1A , C1-C6 alkyl, C2-C4 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl or cycloalkyl; R25 is H, C1-6 alkyl or C1-C6 cycloalkyl; Each R 26 is halogen or C1-C6 alkyl, Each R 27 , R 28 and R 29 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -N(R 1A )2, -C(=O)OR 1A , oxo(=O), C1-C4 alkyl, or C1-C4 fluoroalkyl; Each R 1A are independently hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, benzyl, or heteroaryl, and Each R 1B are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0009] In some embodiments provided herein, the compound of Formula (V) has the structure of Formula (VI): [ka] Each R 26 are independently H, halogen, or C1-C4 alkyl.

[0010] In some embodiments presented herein, the compound of formula (V) has the structure of formula (VII), or a pharmaceutically acceptable salt or solvate thereof: [ka]

[0011] In some embodiments provided herein, the compound of Formula (V) has the structure of Formula (VIII): [ka] Y 3 is O or S, and Y 4 is CH.

[0012] In another aspect, provided herein is a compound having the structure of formula (IX), or a pharmaceutically acceptable salt or solvate thereof: [ka] During the ceremony, Y a is CH or N, Ring E is phenyl or a 5- or 6-membered heteroaryl; w is 0, 1, 2, or 3; L 6 is an optionally substituted C1-C3 alkylene, and one, two, or three R 36 optionally replaced by R 30 is -C1-C6 alkyl, -C3-C6 cycloalkyl, -C3-C6 heterocycloalkyl, phenyl, or monocyclic heteroaryl, and alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 37 optionally replaced by R 31 is H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, and alkyl, alkenyl, alkynyl, aryl, and heteroaryl each represent one, two, or three R 38 optionally replaced by R 32 H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A)2, -NR 1A S(=O)2(C1-C4 alkyl), -S(=O)2N(R 1A )2, -OC(=O)(C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), -C(=O)N(R 1A )2, -NR 1A C(=O)(C1-C4 alkyl), -NR 1A C(=O)O(C1-C4 alkyl), -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -S(C1-C4 alkyl), -S(=O)(C1-C4 alkyl), -S(=O)2(C1-C4 alkyl), C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, -C 1-6 Alkyl-OH, -C 1-6 Heteroalkyl-OH, C 1-6 Alkyl-C(=O)OH, -C 1-6 heteroalkyl-C(=O)OH, monocyclic C2-C6 heterocycloalkyl, phenyl, or monocyclic 5-6 membered heteroaryl, and alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 39 optionally replaced by R 33 is H, C1-C6 alkyl, or C1-C6 cycloalkyl; R 34 H, halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -S(=O)R 1B , -NO2, -N(R 1A )2, -S(=O)2R 1B , -NHS(=O)2R 1B , -S(=O)2N(R 1A )2, -C(=O)R 1B , -OC(=O)R 1B , -C(=O)OR 1A , -OC(=O)OR 1A , -C(=O)N(R 1A )2, -OC(=O)N(R 1A )2, -NR1A C(=O)N(R 1A )2, -NR 1A C(=O)R 1B , -NR 1A C(=O)OR 1A , C1-C6 alkyl, C2-C4 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl or cycloalkyl; Each R 35 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -S(=O)R 1B , -NO2, -N(R 1A )2, -S(=O)2R 1B , -NHS(=O)2R 1B , -S(=O)2N(R 1A )2, -C(=O)R 1B , -OC(=O)R 1B , -C(=O)OR 1A , -OC(=O)OR 1A , -C(=O)N(R 1A )2, -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -NR 1A C(=O)R 1B , -NR 1A C(=O)OR 1A , C1-C6 alkyl, C2-C4 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl or cycloalkyl; Each R 36 is halogen or C1-C6 alkyl, Each R 37 , R 38 and R 39 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -N(R 1A )2, -C(=O)OR 1A , oxo(=O), C1-C4 alkyl or C1-C4 fluoroalkyl; Each R 1Aare independently hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, benzyl, or heteroaryl, and Each R 1B are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0013] In some embodiments provided herein, the compound of formula (IX) has the structure of formula (X): [ka] Each R 36 are independently H, halogen, or C1-C4 alkyl.

[0014] In some embodiments provided herein, the compound of formula (IX) has the structure of formula (XI), or a pharmaceutically acceptable salt or solvate thereof: [ka]

[0015] In some embodiments provided herein, the compound of formula (IX) has the structure of formula (XII): [ka] Y 3 is O or S, and Y 4 is CH.

[0016] In another aspect, provided herein is a pharmaceutical composition comprising a compound having the structure of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0017] In another aspect, provided herein are methods of treating a disease or condition through modulation of ENPP1 in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is pseudogout.

[0018] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from the detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0019] Pseudogout (or "false gout") is a form of arthritis caused by the deposition of calcium pyrophosphate crystals and is sometimes known as calcium pyrophosphate dihydrate crystal deposition disease (CPPD). CPPD is a form of arthritis that causes pain, stiffness, tenderness, redness, warmth, and swelling (inflammation) in some joints. It usually affects one joint at a time, but can affect several joints at once. Symptoms are similar to those of other diseases, particularly gout (which is why this form of arthritis had the old name pseudogout—"false gout"). Some symptoms of CPPD may be thought of as symptoms of rheumatoid arthritis or osteoarthritis. CPPD commonly affects the knees or wrists. Less frequently, it can involve the hips, shoulders, elbows, knuckles, toes, or ankles. Symptoms include sudden, severe joint pain, swollen joints that are warm and tender to the touch, and red skin, including the affected joint. Less frequently, CPPD can cause persistent swelling, heat, and pain in some joints, even mimicking rheumatoid arthritis. This condition results from the abnormal formation of calcium pyrophosphate dihydrate (CPPD) crystals in cartilage or synovial fluid, which can lead to sudden attacks of arthritis similar to gout. The cause of abnormal CPPD crystal deposition in cartilage is often unknown. CPPD crystals can be seen in association with several underlying disorders, such as joint injury, hyperparathyroidism, hypomagnesemia, hypophosphatasia, hypothyroidism, and hemochromatosis. Abnormal CPPD crystal formation may also be a genetic trait.

[0020] CPPD affects both men and women. It occurs more frequently in people with aging and generally affects people over the age of 60. People with thyroid conditions, kidney failure, or disorders affecting calcium, phosphate, or iron metabolism are at increased risk of CPPD. This condition is also commonly present in people with osteoarthritis. Osteoarthritis "flares" associated with joint pain, swelling, and redness may actually be due to CPPD in some cases. CPPD is rare in younger patients.

[0021] Treatment of CPPD is similar to that of acute gout attacks with anti-inflammatory drugs. Anti-inflammatory drugs are usually continued until the CPPD attack is completely resolved. Otherwise, colchicine is usually prescribed for CPPD attacks. Low doses can be prescribed for longer periods to reduce the risk of recurrent CPPD attacks. Nonsteroidal anti-inflammatory drugs (NSAIDS) are used to treat CPPD attacks, especially when colchicine cannot be prescribed. Certain patients, such as those with poor kidney function, bleeding disorders, heart disease, and certain other health complications, cannot take these medications. Corticosteroids can be prescribed for those who cannot take NSAIDs or colchicine.

[0022] Ectonucleotide pyrophosphatase / phosphodiesterase family member 1 is an enzyme encoded by the ENPP1 gene in humans. This gene is a member of the ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family. The encoded protein is a type II transmembrane glycoprotein containing two identical disulfide-linked subunits. This protein has broad specificity and cleaves a variety of substrates, including nucleotides and phosphodiester bonds in the nucleotide sugar. This protein can function to hydrolyze nucleoside 5' triphosphates to their corresponding monophosphates and can also hydrolyze diadenosine polyphosphates. Mutations in this gene are associated with generalized arterial calcification in infancy, ossification of the posterior longitudinal ligament of the spine (OPLL), autosomal recessive hypophosphatemic rickets 2 (ARHR2), and insulin resistance.

[0023] The ENPP1 gene provides the instructions for making a protein called ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1). The ENPP1 protein helps break down a molecule called adenosine triphosphate (ATP), especially when it is found outside the cell (extracellular). Extracellular ATP is quickly broken down into adenosine monophosphate (AMP) and another molecule called pyrophosphate. Pyrophosphate is important in preventing the buildup of abnormal deposits of calcium (calcification) and other minerals (mineralization) in the body.

[0024] In some embodiments, the compounds described herein are modulators of ENPP1. In some embodiments, the compounds described herein are used to treat an ENPP1-related disorder. In some embodiments, the ENPP1-mediated disorder is pseudogout or calcium pyrophosphate dihydrate crystal deposition disease (CPPD).

[0025] In another aspect, the present disclosure provides a method of treating pseudogout by administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII), or a pharmaceutically acceptable salt or solvate thereof.

[0026] compound In one aspect, provided herein is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: [ka] During the ceremony, Ring B is aryl or 5- or 6-membered heteroaryl; n is 0, 1, 2, or 3; m is 1 or 2, p is 0, 1, 2, or 3; Y 1 Ha-NR4 - or -O-, L 1 -Y 2 -L 2 -or- Y 2 -L 2 -L 3 - and Y 2 is a bond or -C(=O)-, L 2 is a bond or optionally substituted C-C alkylene, C-C heteroalkylene, C-C alkenylene, C-C alkenylene, or C-C cycloalkylene, each optionally containing one, two, or three R 7 is replaced by L 3 is one, two or three R 7 is a C3-C6 cycloalkylene optionally substituted with R 1 is H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 8 optionally replaced by R 2 is H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -NR 1A S(=O)2(C1,-C4 alkyl), -S(=O)2N(R 1A )2, -OC(=O)(C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), -C(=O)N(R 1A )2, -NR 1A C(=O)(C1-C4 alkyl), -NR 1A C(=O)O(C1-C4 alkyl), -OC(=O)N(R 1A)2, -NR 1A C(=O)N(R 1A )2, -S(C1-C4 alkyl), -S(=O)(C1-C4 alkyl), -S(=O)2(C1-C4 alkyl), C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, -C 1-6 Alkyl-OH, -C 1-6 Heteroalkyl-OH, C 1-6 Alkyl-C(=O)OH, -C 1-6 heteroalkyl-C(=O)OH, monocyclic C2-C6 heterocycloalkyl, phenyl, or monocyclic 5-6 membered heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 9 optionally replaced by R 3 is H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 9 optionally replaced by R 4 is H, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 5 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -S(=O)R 1B , -NO2, -N(R 1A )2, -S(=O)2R 1B , -NHS(=O)2R 1B , -S(=O)2N(R 1A )2, -C(=O)R 1B , -OC(=O)R 1B , -C(=O)OR 1A , -OC(=O)OR 1A, -C(=O)N(R 1A )2, -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -NR 1A C(=O)R 1B , -NR 1A C(=O)OR 1A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl or cycloalkyl; Each R 6 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , N(R 1A )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy or C1-C4 heteroalkyl; Each R 7 , R 8 and R 9 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -N(R 1A )2, -C(=O)OR 1A , oxo(=O), C1-C4 alkyl or C1-C4 fluoroalkyl; Each R 1A are independently hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, benzyl, or heteroaryl, and Each R 1B are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0027] In some embodiments of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, R 1 is halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A)2, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 8 In some embodiments, R 1 is halogen, —C1-C6 alkyl, C2-C6 alkenyl, phenyl, or monocyclic heteroaryl. In some embodiments, R 1 is phenyl. In some embodiments, R 1 is monocyclic heteroaryl. In some embodiments, R 1 is halogen or -C1-C6 alkyl. In some embodiments, R 1 is -Br, -Cl, -I, or -F. In some embodiments, R 1 is -Br. In some embodiments, R 1 is —Cl. In some embodiments, R 1 is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R 1 is —CH3. In some embodiments, R 1 is H.

[0028] In some embodiments of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, R 3 is H, halogen, -C1-C6 alkyl, -C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, and alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 9 In some embodiments, R 3 is phenyl. In some embodiments, R 3 is halogen. In some embodiments, R3 is -Cl, -Br, -I, or -F. In some embodiments, R 3 is —Cl. In some embodiments, R 3 is -Br. In some embodiments, R 3 is -I. In some embodiments, R 3 is -C1-C6 alkyl. In some embodiments, R 3 is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R 3 is —CH3. In some embodiments, R 3 is H.

[0029] In some embodiments of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, R 3 is hydrogen and R 1 is halogen, C1-C6 alkyl, or phenyl. In some embodiments, R 3 is hydrogen and R 1 is -Br, -Cl, or -I. In some embodiments, R 3 is hydrogen and R 1 is —CH3. In some embodiments, R 3 is hydrogen and R 1 is phenyl.

[0030] In some embodiments of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, R 4 is H or C1-C6 alkyl. In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is —CH3. In some embodiments, R 4 is H.

[0031] In some embodiments of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, each R 6 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR1B , N(R 1A )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, or C1-C4 heteroalkoxy. In some embodiments, each R 6 is independently halogen or C-C alkyl. In some embodiments, each R 6 is independently -Cl, -Br, -F, -I, -CH or -CHCH. In some embodiments, each R 6 are independently -CH3.

[0032] In some embodiments of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, p is 1, 2, or 3. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 0.

[0033] In some embodiments of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, m is 1. In some embodiments, m is 2.

[0034] In some embodiments presented herein, the compound of formula (I) has the structure of formula (II), or a pharmaceutically acceptable salt or solvate thereof: [ka]

[0035] In some embodiments of Formula (I) or (II) or a pharmaceutically acceptable salt or solvate thereof, Y 1 Ha-NR 4 - and R 4 is H or C1-C4 alkyl. In some embodiments, R 4 is H. In some embodiments, R 4 is C1-C4 alkyl. In some embodiments, R 4 In some embodiments of formula (I) or (II), Y1 is -NH-.

[0036] In some embodiments, ring B is aryl. In some embodiments, ring B is monocyclic or bicyclic aryl. In some embodiments, aryl is phenyl. In some embodiments of Formula (I) or (II) or a pharmaceutically acceptable salt or solvate thereof, ring B is phenyl.

[0037] In some embodiments of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, ring B is a 6-membered heteroaryl. In some embodiments, ring B is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, ring B is pyridinyl.

[0038] In some embodiments of Formula (I) or (II) or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] and In the formula, X 3 , X 4 and X 5 are each independently CH or N.

[0039] In some embodiments of Formula (I) or (II) or a pharmaceutically acceptable salt or solvate thereof, X 3 is N and X 4 and X 5 are each CH. In some embodiments, X 3 and X 4 is N and X 5 is CH. In some embodiments, X 3 is CH and X 4 and X 5 are each N. In some embodiments, X3 and X 5 are N and X 4 is CH. In some embodiments, X 3 , X 4 and X 5 are each CH. In some embodiments, X 3 , X 4 and X 5 are N respectively.

[0040] In some embodiments, the compound of formula (I) has the structure of formula (III): or a pharmaceutically acceptable salt or solvate thereof. [ka]

[0041] In some embodiments of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, L 1 is Y 2 -L 2 and Y 2 is a bond or -C(=O)-, and L 2 is one, two or three R 7 C-C alkylene, C-C alkenylene, or C-C heteroalkylene optionally substituted with R 7 is C1-C6 alkyl. In some embodiments, Y 2 is a bond. In some embodiments, Y 2 is —C(═O)—. In some embodiments, L 2 is a C1-C6 heteroalkylene optionally substituted with 1 or 2 -CH3. In some embodiments, L 2 is a C2-C6 alkynylene optionally substituted with 1 or 2 -CH3. In some embodiments, L 2 is a C2-C5 alkylene or C2-C6 alkenylene optionally substituted with 1 or 2 -CH3. In some embodiments, L 2is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2(CH2)2CH2-, -CH2(CH2)3CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH=CH-, or -CH(CH3)CH=CH-. In some embodiments, L 2 is -CH2CH2-, -CH2CH2CH2-, -CH2(CH2)2CH2-, or -CH2CH=CH-. In some embodiments, L 2 is —C(CH3)2CH2CH2— or —CH(CH3)CH2CH2—. In some embodiments, L 2 is -CH2CH2CH2-. In some embodiments, L 2 is —CH(CH)CH—. In some embodiments, L 2 is -CHCH=CH-. In some embodiments, L 2 is -CH(CH 3) CH=CH-.

[0042] In some embodiments of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, L 1 is Y 2 -L 2 and Y 2 is a bond or -C(=O)-, and L 2 is cyclopropylene. In some embodiments, Y 2 is -C(=O)-, and L 2 is cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene. 2 is cyclopropylene.

[0043] In some embodiments of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, L 1 Ha-Y 2 -L 2 -L 3 - and Y2 is a bond or -C(=O)-, and L 2 is a C2-C5 alkylene or C2-C6 heteroalkylene optionally substituted with one or two -CH3; 3 is C3-C6 cyclopropylene. In some embodiments, L 1 Ha-Y 2 -L 2 -L 3 - and Y 2 is a bond or -C(=O)-, and L 2 is a C2-C5 alkylene optionally substituted with one or two -CH3, and L 3 is C3-C6 cyclopropylene. In some embodiments, L 1 Ha-Y 2 -L 2 -L 3 - and Y 2 is a bond or -C(=O)-, and L 2 is -CH2-, and L 3 is C3-C6 cyclopropylene. In some embodiments, L 1 Ha-Y 2 -L 2 -L 3 - and Y 2 is a bond or -C(=O)-, and L 2 is -CH2-, and L 3 is cyclopropylene.

[0044] In some embodiments of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, Y 2 is a bond. In some embodiments, Y 2 is -C(=O)-.

[0045] In some embodiments, the compound of formula (I) has the structure of formula (IV), or a pharmaceutically acceptable salt or solvate thereof. [ka]

[0046] In some embodiments of Formula (IV) or a pharmaceutically acceptable salt or solvate thereof, X 3 is N and X 4 and X 5 are each CH. In some embodiments, X 4 is N and X 3 and X 5 are each CH. In some embodiments, X 5 is N and X 3 and X 4 are each CH. In some embodiments, X 3 , X 4 and X 5 are each CH. In some embodiments, X 3 , X 4 and X 5 are N respectively.

[0047] In some embodiments of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, each R 5 are independently halogen, -CN, OR 1B , -C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 heteroalkyl. In some embodiments, each R 5 is independently -Br, -Cl, -F, -CN, -CF, -CH, or -OCH. In some embodiments, each R 5 is independently -Br, -Cl, -F, or -I. In some embodiments, each R 5 is independently -Cl or -F. In some embodiments, each R 5 is independently -I. In some embodiments, each R 5 is independently -F. In some embodiments, each R 5 is independently —CN, —CF, —CH, or —OCH. In some embodiments, each R 5 is independently —CN. In some embodiments, each R 5is independently —CF. In some embodiments, each R 5 is independently —CH. In some embodiments, each R 5 are independently -OCH3.

[0048] In some embodiments of Formula (I), (II), (III), or (VI), or a pharmaceutically acceptable salt or solvate thereof, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 0.

[0049] In some embodiments of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] is.

[0050] In some embodiments, [ka] teeth, [ka] is.

[0051] In some embodiments, [ka] teeth [ka] is.

[0052] In some embodiments, [ka] teeth [ka] is.

[0053] In some embodiments, [ka] teeth [ka] is.

[0054] In some embodiments of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, R 2 is halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -NR 1A S(=O)2(C1, -C4 alkyl), -S(=O)2N(R 1A )2, -OC(=O)(C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), -C(=O)N(R 1A )2, -NR 1A C(=O)(C1-C4 alkyl), -NR 1A C(=O)O(C1-C4 alkyl), -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -S(C1-C4 alkyl), -S(=O)(C1-C4 alkyl), -S(=O)2(C1-C4 alkyl), C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, -C 1-6 Alkyl-OH, -C 1-6 heteroalkyl-OH, monocyclic C2-C6 heterocycloalkyl, phenyl, or monocyclic 5-6 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 9 and each R 9are independently halogen, -OH, -OR 1B , -SH, -SR 1B , -N(R 1A )2, C1-C4 alkyl, or C1-C4 fluoroalkyl.

[0055] In some embodiments of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, R 2 is halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -C1-C6 alkyl, C1-C4 fluoroalkyl, -C 1-6 Alkyl-OH or -C 1-6 In some embodiments, R 2 is -Br, -Cl, -F, -CN, -NH, -NHCH, -NHCHCH, -N(CH), -OCH, -CF, -CH, -CHCH, or -NH(CH)OH. 2 is -Br, -Cl, -F, or -CN. In some embodiments, R 2 is -NH, -NHCH, -NHCHCH, -N(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -CH(CH), or -NH(CH)OH. 2 is —NH(CH)OH. In some embodiments, R 2 is —NH(C-C cycloalkyl). In some embodiments, R 2 is -NH-cyclopropyl, -NH-cyclobutyl, or -NH-cyclohexyl. 2 is -NH-benzyl. In some embodiments, R 2 is -SH, -SCH, or -SCHCH. In some embodiments, R 2is -OH, -OCH or -OCHCH, -OCHCHCH, -OCHCHCH(CH). In some embodiments, R 2 is -OCH3, -CF3, -CH3 or -CH2CH3.

[0056] In some embodiments of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, R 2 is one, two or three R 9 In some embodiments, R 2 is piperazine, piperidine, or morpholino. In some embodiments, R 2 is piperazine. In some embodiments, R 2 is piperidine. In some embodiments, R 2 is morpholine.

[0057] In some embodiments of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, R 2 is H.

[0058] In some embodiments of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, R 2 is one, two or three R 9 and each R is phenyl or monocyclic heteroaryl optionally substituted with 9 are independently halogen, -OH, OR 1B , -SH, -SR 1B , -N(R 1A )2, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R 2 is phenyl. In some embodiments, R 2is a monocyclic heteroaryl. In some embodiments, the monocyclic heteroaryl is 2-pyridyl, 3-pyridyl, or 4-pyridyl. In some embodiments, the monocyclic heteroaryl is 2-pyridyl. In some embodiments, the monocyclic heteroaryl is 3-pyridyl. In some embodiments, the monocyclic heteroaryl is 4-pyridyl.

[0059] In another aspect, provided herein is a compound having the structure of Formula (V), or a pharmaceutically acceptable salt or solvate thereof: [ka] During the ceremony, Ring D is phenyl or a 5- or 6-membered heteroaryl; q is 0, 1, 2, or 3; L 5 is an optionally substituted C1-C3 alkylene, and one, two, or three R 26 optionally replaced by R 20 is H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 27 optionally replaced by R 21 is H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 28 optionally replaced by R 22 H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -NR 1A S(=O)2(C1-C4 alkyl), -S(=O)2N(R 1A )2, -OC(=O)(C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), -C(=O)N(R 1A )2, -NR 1A C(=O)(C1-C4 alkyl), -NR 1A C(=O)O(C1-C4 alkyl), -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -S(C1-C4 alkyl), -S(=O)(C1-C4 alkyl), -S(=O)2(C1-C4 alkyl), C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, -C 1-6 Alkyl-OH, -C 1-6 Heteroalkyl-OH, C 1-6 Alkyl-C(=O)OH, -C 1-6 heteroalkyl-C(=O)OH, monocyclic C2-C6 heterocycloalkyl, phenyl, or monocyclic 5-6 membered heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 29 optionally replaced by R 23 H, halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -S(=O)R 1B , -NO2, -N(R 1A )2, -S(=O)2R1B , -NHS(=O)2R 1B , -S(=O)2N(R 1A )2, -C(=O)R 1B , -OC(=O)R 1B , -C(=O)OR 1A , -OC(=O)OR 1A , -C(=O)N(R 1A )2, -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -NR 1A C(=O)R 1B , -NR 1A C(=O)OR 1A , C1-C6 alkyl, C2-C4 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, or cycloalkyl; Each R 24 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -S(=O)R 1B , -NO2, -N(R 1A )2, -S(=O)2R 1B , -NHS(=O)2R 1B , -S(=O)2N(R 1A )2, -C(=O)R 1B , -OC(=O)R 1B , -C(=O)OR 1A , -OC(=O)OR 1A , -C(=O)N(R 1A )2, -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -NR 1A C(=O)R 1B , -NR 1A C(=O)OR 1A , C1-C6 alkyl, C2-C4 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl or cycloalkyl; R 25 is H, C1-6 alkyl or C1-C6 cycloalkyl; Each R 26are independently H, halogen, or C1-C6 alkyl; Each R 27 , R 28 and R 29 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -N(R 1A )2, -C(=O)OR 1A , oxo(=O), C1-C4 alkyl or C1-C4 fluoroalkyl; Each R 1A are independently hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, benzyl, or heteroaryl, and Each R 1B are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0060] In some embodiments of Formula (V) or a pharmaceutically acceptable salt or solvate thereof, R 21 is halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 28 In some embodiments, R 21 is -C1-C6 alkyl, -C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, and alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 28 In some embodiments, R 21is —C1-C6 alkyl, phenyl, or monocyclic heteroaryl, each optionally substituted with 1, 2, or 3 halogens. In some embodiments, R 21 is phenyl optionally substituted with 1, 2, or 3 -Cl, -Br, or -F. In some embodiments, R 21 is a monocyclic heteroaryl. In some embodiments, the monocyclic heteroaryl is 2-pyridyl, 3-pyridyl, or 4-pyridyl. In some embodiments, R 21 is unsubstituted phenyl. In some embodiments, R 21 is unsubstituted 2-pyridyl, 3-pyridyl, or 4-pyridyl. In some embodiments, R 21 is halogen or -C1-C6 alkyl. In some embodiments, R 21 is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R 21 is —CH3. In some embodiments, R 21 is -Cl, -Br, -I, or -F. In some embodiments, R 21 is H.

[0061] In some embodiments of Formula (V) or a pharmaceutically acceptable salt or solvate thereof, R 25 is H or C1-C6 alkyl. In some embodiments, R 25 is C1-C6 alkyl. In some embodiments, R 25 is -CH3 or -CH2CH3. In some embodiments, R 25 is H.

[0062] In some embodiments of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, R 21 is H and R 25 is H.

[0063] In some embodiments of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, L5 is an optionally substituted C1-C3 alkylene, and one, two, or three R 26 and each R 26 is independently halogen or C1-C6 alkyl. In some embodiments, L 5 is unsubstituted C1-C3 alkylene. In some embodiments, L 5 is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, L 5 is -CH2-.

[0064] In some embodiments, the compound of Formula (V) has the structure of Formula (VI): [ka] Each R 26 are independently H, halogen, or C1-C4 alkyl.

[0065] In some embodiments of Formula (VI) or a pharmaceutically acceptable salt or solvate thereof, R 26 is independently halogen or C-C alkyl. In some embodiments, each R 26 is independently H or C1-C4 alkyl. In some embodiments, each R 26 is independently H, CH, -CHCH, or -CH(CH). In some embodiments, each R 26 is independently H or -CH. In some embodiments, each R 26 is H.

[0066] In some embodiments of Formula (V) or (VI) or a pharmaceutically acceptable salt or solvate thereof, R 20 is halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A)2, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 27 In some embodiments, R 20 is one, two or three R 27 phenyl or monocyclic heteroaryl optionally substituted with R 27 is halogen or C1-C4 alkyl. In some embodiments, the monocyclic heteroaryl is 2-pyridyl, 3-pyridyl, or 4-pyridyl. In some embodiments, R 20 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl optionally substituted with 1, 2, or 3 -Cl, -Br, or -F. In some embodiments, R 20 is phenyl. In some embodiments, R 20 is 2-pyridyl. In some embodiments, R 20 is halogen or -C1-C6 alkyl. In some embodiments, R 20 is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R 20 is —CH3. In some embodiments, R 20 is -Cl, -Br, -I, or -F. In some embodiments, R 21 is H.

[0067] In some embodiments of Formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, R 20 is unsubstituted phenyl.

[0068] In some embodiments of Formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, Ring D is phenyl. In some embodiments, Ring D is a 6-membered heteroaryl. In some embodiments, Ring D is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ring D is pyridinyl.

[0069] In some embodiments of Formula (V) or (VI) or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] and In the formula, X 6 , X 7 and X 8 are each independently CH or N.

[0070] In some embodiments of Formula (V) or (VI) or a pharmaceutically acceptable salt thereof, X 6 is N and X 7 and X 8 are each independently CH. In some embodiments, X 6 and X 7 are independently N and X 8 is CH. In some embodiments, X 6 is CH and X 7 and X 8 are each independently N.

[0071] In some embodiments of Formula (V) or (VI) or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] is.

[0072] In some embodiments of Formula (V) or (VI) or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] is.

[0073] In some embodiments, the compound of formula (V) has the structure of formula (VII), or a pharmaceutically acceptable salt or solvate thereof. [ka]

[0074] In some embodiments of Formula (V), (VI) or (VII) or a pharmaceutically acceptable salt or solvate thereof, R 23 is halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -S(=O)R 1B , -NO2, -N(R 1A )2, -S(=O)2R 1B , -S(=O)2N(R 1A )2, -C(=O)R 1B , -C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R 23 is halogen, C-C alkyl, or C-C haloalkyl. 23 is -Cl, -F, -Br, -CN, -CH, -CF, -SH, -NH, or -OCH. In some embodiments, R 23 is -F. In some embodiments, R 23 is —Cl. In some embodiments, R 23 is -Br. In some embodiments, R 23 is —CF. In some embodiments, R23 is —CH3. In some embodiments, R 23 is -OCH3.

[0075] In some embodiments of Formula (V), (VI) or (VII) or a pharmaceutically acceptable salt or solvate thereof, R 23 is -S(=O)2N(R 1A )2, and each R 1A is independently H or -C1-C3 alkyl. In some embodiments, R 23 is -S(=O)2NH2.

[0076] In some embodiments of Formula (V), (VI) or (VII) or a pharmaceutically acceptable salt or solvate thereof, R 24 is halogen, -CN, -OH, -OR 1B , -NO2, -N(R 1A )2, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments, R 23 are -Br, -Cl, -F, -CN, -CF3, -CH 3、 or -OCH3. In some embodiments, R 23 is -Br, -Cl, or -F. In some embodiments, R 23 is -CH3 or -OCH3.

[0077] In some embodiments of Formula (V), (VI) or (VII) or a pharmaceutically acceptable salt or solvate thereof, each R 24 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -S(=O)R 1B , -NO2, -N(R 1A )2, -S(=O)2R 1B , -S(=O)2N(R 1A )2, -C(=O)R 1B , -C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R 24is independently halogen, C-C alkyl, or C-C haloalkyl. 24 is independently -Cl, -F, -Br, -CN, -CH, -CF, -SH, -NH, or -OCH. In some embodiments, each R 24 is -F. In some embodiments, each R 24 is —Cl. In some embodiments, each R 24 is -Br. In some embodiments, each R 24 is —CF. In some embodiments, each R 24 is —CH. In some embodiments, each R 24 is -OCH3.

[0078] In some embodiments of Formula (V), (VI), or (VII), or a pharmaceutically acceptable salt or solvate thereof, q is 1 and R 24 is -S(=O)2N(R 1A )2, and each R 1A is independently H or -C1-C3 alkyl. In some embodiments, q is 1 and R 24 is -S(=O)2NH2.

[0079] In some embodiments of Formula (V), (VI) or (VII) or a pharmaceutically acceptable salt or solvate thereof, each R 24 are independently halogen, -CN, -OH, -NO2, -N(R 1A )2, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments, each R 24 is independently -Br, -Cl, -F, -CN, -CF, -CH, or -OCH. In some embodiments, each R 24 is independently -Br, -Cl, or -F. In some embodiments, each R 24 are independently -CH3 or -OCH3.

[0080] In some embodiments of Formula (V), (VI), or (VII), or a pharmaceutically acceptable salt or solvate thereof, q is 1 or 2. In some embodiments, q is 1. In some embodiments, q is 0.

[0081] In some embodiments of Formula (V), (VI) or (VII) or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth, [ka] is.

[0082] In some embodiments of Formula (V), (VI) or (VII) or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] is.

[0083] In some embodiments of Formula (V), (VI) or (VII) or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] is.

[0084] In some embodiments of Formula (V), (VI), or (VII), or a pharmaceutically acceptable salt or solvate thereof, Ring D is a 5-membered heteroaryl. In some embodiments, Ring D is oxazole, thiazole, pyrrole, furan, or thiophene. In some embodiments, Ring D is furan or thiophene. In some embodiments, Ring D is furan. In some embodiments, Ring D is thiophene.

[0085] In some embodiments of Formula (V) or (VI) or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] and Y 5 is O, S or NR 1C and Y 6 is O, S, N or CH, and R 1C is H or C1-C6 alkyl.

[0086] In some embodiments of Formula (V) or (VI) or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] is. In some embodiments, Y 5 is O and Y 6 is CH. In some embodiments, Y 5 is S and Y 6 is CH. In some embodiments, Y 5 is NR 1C and Y 6 is CH and R 1C is H or -CH3. In some embodiments, Y5 is NR 1C and Y 6 is N and R 1C is H or -CH3. In some embodiments, Y 5 is NR 1C and Y 6 is O and R 1C is H or -CH3. In some embodiments, Y 5 is NR 1C and Y 6 is S and R 1C is H or -CH3.

[0087] In some embodiments of Formula (V) or (VI) or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] is. In some embodiments, Y 5 is O and Y 6 is CH. In some embodiments, Y 5 is S and Y 6 is CH. In some embodiments, Y 5 is NR 1C and Y 6 is CH and R 1C is H or -CH3. In some embodiments, Y 5 is NR 1C and Y 6 is N and R 1C is H or -CH3. In some embodiments, Y 5 is NR 1C and Y 6 is O and R 1C is H or -CH3. In some embodiments, Y 5 is NR 1C and Y 6 is S and R 1C is H or -CH3.

[0088] In some embodiments, the compound of Formula (V) has the structure of Formula (VIII): [ka] During the ceremony, Y 5 is O or S, and Y 6 is CH.

[0089] In some embodiments of Formula (VIII) or a pharmaceutically acceptable salt or solvate thereof, Y 5 is S. In some embodiments, Y 5 is O.

[0090] In some embodiments of Formula (VIII) or a pharmaceutically acceptable salt or solvate thereof, each R 24 are independently halogen, -CN, -OR 1B , -S(=O)2N(R 1A )2, -C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R 24 are independently -Cl, -F, -Br, -CN, -CH3, -CF3, or -OCH3.

[0091] In some embodiments of Formula (VIII) or a pharmaceutically acceptable salt or solvate thereof, each R 24 are independently -S(=O)2N(R 1A )2 and R 1A is H or -C1-C3 alkyl. In some embodiments, each R 24 are independently -S(=O)2NH2.

[0092] In some embodiments of Formula (VIII) or a pharmaceutically acceptable salt or solvate thereof, q is 1. In some embodiments, q is 0.

[0093] In some embodiments of Formula (V), (VI), (VII) or (VIII) or a pharmaceutically acceptable salt or solvate thereof, R 22 is halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -NR 1A S(=O)2(C1-C4 alkyl), -S(=O)2N(R 1A )2, -OC(=O)(C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), -C(=O)N(R 1A )2, -NR 1A C(=O)(C1-C4 alkyl), -NR 1A C(=O)O(C1-C4 alkyl), -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -S(C1-C4 alkyl), -S(=O)(C1-C4 alkyl), -S(=O)2(C1-C4 alkyl), C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, -C 1- C6 alkyl-OH, -C 1- C6 heteroalkyl-OH, monocyclic C2-C6 heterocycloalkyl, phenyl, or monocyclic 5-6 membered heteroaryl, and alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 29 and each R 29 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , N(R 1A )2, C1-C4 alkyl, or C1-C4 fluoroalkyl.

[0094] In some embodiments of Formula (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt or solvate thereof, R 22 is halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A)2, -C1-C6 alkyl, C1-C4 fluoroalkyl, -C 1-6 Alkyl-OH or -C 1-6 In some embodiments, R 22 is -Br, -Cl, -F, -CN, -NH, -NHCH, -NHCHCH, -N(CH), -OCH, -CF, -CH, -CHCH, or -NH(CH)OH. 22 is -Br, -Cl, -F, or -CN. In some embodiments, R 22 is -NH, -NHCH, -NHCHCH, -N(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -CH(CH), or -NH(CH)OH. 22 is —NH(CH)OH. In some embodiments, R 22 is —NH(C-C cycloalkyl). In some embodiments, R 22 is -NH-cyclopropyl, -NH-cyclobutyl, or -NH-cyclohexyl. 22 is -NH-benzyl. In some embodiments, R 22 is -SH, -SCH, or -SCHCH. In some embodiments, R 22 is -OH, -OCH or -OCHCH, -OCHCHCH, -OCHCHCH(CH). In some embodiments, R 22 is -OCH3, -CF3, -CH3 or -CH2CH3.

[0095] In some embodiments of Formula (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt or solvate thereof, R 22 is halogen, -CN, -OH, -OR 1B , -N(R 1A )2, -C1-C6 alkyl, C1-C4 fluoroalkyl, -C 1-C6 alkyl-OH, or -C 1- C heteroalkyl-OH. In some embodiments, R 32 HA-OR 1B , -N(R 1A )2, -C1-C6 alkyl or -C 1- C alkyl-OH. In some embodiments, R 22 is -NH, -NHCH, -NHCHCH, -N(CH), -OCH, -CH, -CHCH, or -NH(CH)OH. 22 is —NH(CH)OH. In some embodiments, R 22 is H. In some embodiments, R 22 is Br or -Cl.

[0096] In some embodiments of Formula (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt or solvate thereof, R 22 is one, two or three R 29 In some embodiments, R 22 is piperazine, piperidine, or morpholino. In some embodiments, R 22 is piperazine. In some embodiments, R 22 is piperidine. In some embodiments, R 22 is morpholine.

[0097] In some embodiments of Formula (V), (VI), (VII) or (VIII), or a pharmaceutically acceptable salt or solvate thereof, R 22 is benzyl, phenyl, or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 R 29 Each R is replaced by 29 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , N(R 1A)2, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R 22 is phenyl. In some embodiments, R 22 is a 6-membered heteroaryl. In some embodiments, the 6-membered heteroaryl is 2-pyridyl, 3-pyridyl, or 4-pyridyl. In some embodiments, R 22 is heteroaryl and is 2-pyridyl. In some embodiments, R 22 is heteroaryl and is 3-pyridyl. In some embodiments, R 22 is heteroaryl and is 4-pyridyl.

[0098] In another aspect, provided herein is a compound having the structure of formula (IX), or a pharmaceutically acceptable salt or solvate thereof: [ka] During the ceremony, Y a is CH or N, Ring E is phenyl or a 5- or 6-membered heteroaryl; w is 0, 1, 2, or 3; L 6 is an optionally substituted C1-C3 alkylene, and one, two, or three R 36 optionally replaced by R 30 is -C1-C6 alkyl, -C3-C6 cycloalkyl, -C3-C6 heterocycloalkyl, phenyl, or monocyclic heteroaryl, and alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 37 optionally replaced by R 31 is H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, and alkyl, alkenyl, alkynyl, aryl, and heteroaryl each represent one, two, or three R 38 optionally replaced by R 32 H, halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -NR 1A S(=O)2(C1-C4 alkyl), -S(=O)2N(R 1A )2, -OC(=O)(C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), -C(=O)N(R 1A )2, -NR 1A C(=O)(C1-C4 alkyl), -NR 1A C(=O)O(C1-C4 alkyl), -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -S(C1-C4 alkyl), -S(=O)(C1-C4 alkyl), -S(=O)2(C1-C4 alkyl), C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, -C 1-6 Alkyl-OH, -C 1-6 Heteroalkyl-OH, C 1-6 Alkyl-C(=O)OH, -C 1-6 heteroalkyl-C(=O)OH, monocyclic C2-C6 heterocycloalkyl, phenyl, or monocyclic 5-6 membered heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 39 optionally replaced by R 33 is H, C1-C6 alkyl, or C1-C6 cycloalkyl; R 34 H, halogen, -CN, -OH, -OR 1B , -SH, -SR 1B, -S(=O)R 1B , -NO2, -N(R 1A )2, -S(=O)2R 1B , -NHS(=O)2R 1B , -S(=O)2N(R 1A )2, -C(=O)R 1B , -OC(=O)R 1B , -C(=O)OR 1A , -OC(=O)OR 1A , -C(=O)N(R 1A )2, -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -NR 1A C(=O)R 1B , -NR 1A C(=O)OR 1A , C1-C6 alkyl, C2-C4 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl or cycloalkyl; Each R 36 are independently H, halogen, or C1-C6 alkyl; Each R 35 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -S(=O)R 1B , -NO2, -N(R 1A )2, -S(=O)2R 1B , -NHS(=O)2R 1B , -S(=O)2N(R 1A )2, -C(=O)R 1B , -OC(=O)R 1B , -C(=O)OR 1A , -OC(=O)OR 1A , -C(=O)N(R 1A )2, -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -NR 1A C(=O)R 1B , -NR 1A C(=O)OR 1A, C1-C6 alkyl, C2-C4 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl or cycloalkyl; Each R 37 , R 38 and R 39 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -N(R 1A )2, -C(=O)OR 1A , oxo(=O), C1-C4 alkyl or C1-C4 fluoroalkyl; Each R 1A are independently hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, benzyl, or heteroaryl, and Each R 1B are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0099] In some embodiments of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, R 30 are each possibly containing one, two or three R 37 In some embodiments, R is —C1-C6 alkyl, —C3-C6 cycloalkyl, or —C3-C6 heterocycloalkyl substituted with 30 is one, two or three R 37 In some embodiments, R is phenyl or monocyclic heteroaryl optionally substituted with 30 is C-C cycloalkyl or -C-C heterocycloalkyl. In some embodiments, R 30 is cyclopropyl, cyclopentyl, cyclohexyl, or pipedyl. In some embodiments, R 30 is phenyl. In some embodiments, R 30 is C1-C6 alkyl. In some embodiments, R 30is -CH, -CH-CH, or -CH(CH). In some embodiments, R 30 is -CH3.

[0100] In some embodiments of Formula (IX) or a pharmaceutically acceptable salt or solvate thereof, R 31 is halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, where alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 38 In some embodiments, R 31 is -C1-C6 alkyl, -C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C6 heteroalkyl, phenyl, or monocyclic heteroaryl, each of which is optionally substituted with 1, 2, or 3 halogen or C1-C6 alkyl. 31 is one, two or three R 38 In some embodiments, R is phenyl or monocyclic heteroaryl optionally substituted with 31 is C-C cycloalkyl or -C-C heterocycloalkyl. In some embodiments, R 31 is cyclopropyl, cyclopentyl, cyclohexyl, or pipedyl. In some embodiments, R 31 is phenyl. In some embodiments, R 31 is halogen or C1-C6 alkyl. In some embodiments, R 31 is -Br, -Cl, -I, or -F. In some embodiments, R 31 is -Br or -Cl. In some embodiments, R 31is -CH, -CH-CH, or -CH(CH). In some embodiments, R 31 is —CH3. In some embodiments, R 31 is H.

[0101] In some embodiments of Formula (IX) or a pharmaceutically acceptable salt or solvate thereof, R 33 is H or C1-C6 alkyl. In some embodiments, R 33 is —CH3. In some embodiments, R 33 is H.

[0102] In some embodiments of Formula (IX) or a pharmaceutically acceptable salt or solvate thereof, R 31 is H and R 33 is H.

[0103] In some embodiments of Formula (IX) or a pharmaceutically acceptable salt or solvate thereof, R 30 is -C1-C6 alkyl, and R 31 and R 33 is H. In some embodiments, R 30 is -CH3 and R 31 and R 33 is H.

[0104] In some embodiments of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, L 6 is an optionally substituted C1-C3 alkylene, and one, two, or three R 36 and each R 36 is independently halogen or C alkyl. In some embodiments, L 6 is unsubstituted C1-C3 alkylene. In some embodiments, L 6 is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, L 6 is -CH2-.

[0105] In some embodiments, the compound of Formula (IX) has the structure of Formula (X): [ka] Each R 36 are independently H, halogen, or C1-C4 alkyl.

[0106] In some embodiments of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, R 36 is independently halogen or C-C alkyl. In some embodiments, each R 36 is independently H or C1-C4 alkyl. In some embodiments, each R 36 is independently H, CH, -CHCH, or -CH(CH). In some embodiments, each R 36 is independently H or -CH. In some embodiments, each R 36 is H.

[0107] In some embodiments of Formula (IX) or (X), or a pharmaceutically acceptable salt or solvate thereof, ring E is phenyl. In some embodiments, ring E is a 6-membered heteroaryl. In some embodiments, the 6-membered heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, the 6-membered heteroaryl is pyridinyl.

[0108] In some embodiments of Formula (IX) or (X), or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] and In the formula, X 9 ,X 10 and X 11are each independently CH or N.

[0109] In some embodiments of formula (IX) or (X), or a pharmaceutically acceptable salt or solvate thereof, X 11 is N and X 9 and X 10 are each independently CH. In some embodiments, X 11 and X 9 are each independently N, and X 10 is CH. In some embodiments, X 11 is CH and X 9 and X 10 are each independently N.

[0110] In some embodiments of Formula (IX) or (X), or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] is.

[0111] In some embodiments of Formula (IX) or (X), or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] is.

[0112] In some embodiments, the compound of formula (IX) has the structure of formula (XI), or a pharmaceutically acceptable salt or solvate thereof. [ka]

[0113] In some embodiments of Formula (XI), or a pharmaceutically acceptable salt or solvate thereof, R 34 is halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -S(=O)R 1B , -NO2, -N(R 1A )2, -S(=O)2R 1B , -S(=O)2N(R 1A )2, -C(=O)R 1B , -C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R 34 -CN,-OR 1B , halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R 34 is -Cl, -F, -Br, -CN, -CH, -CF, -SH, -NH, or -OCH. In some embodiments, R 34 is -F. In some embodiments, R 34 is —Cl. In some embodiments, R 34 is -Br. In some embodiments, R 34 is —CF. In some embodiments, R 34 is —CH3. In some embodiments, R 34 is -OCH3.

[0114] In some embodiments of Formula (XI), or a pharmaceutically acceptable salt or solvate thereof, R 34 is -S(=O)2N(R 1A )2, and each R 1A is independently H or -C1-C3 alkyl. In some embodiments, R 34 is -S(=O)2NH2.

[0115] In some embodiments of Formula (XI), or a pharmaceutically acceptable salt or solvate thereof, each R 34 are independently halogen, -CN, -OH, -OR 1B , -NO2, -N(R 1A)2, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments, each R 35 is independently -Br, -Cl, -F, -CN, -CF, -CH, or -OCH. In some embodiments, each R 35 is independently -Br, -Cl, or -F. In some embodiments, each R 35 are independently -CH3 or -OCH3.

[0116] In some embodiments of Formula (XI) or a pharmaceutically acceptable salt or solvate thereof, w is 1 or 2. In some embodiments, w is 1. In some embodiments, w is 0.

[0117] In some embodiments of Formula (XI) or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] is.

[0118] In some embodiments of Formula (XI) or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] is.

[0119] In some embodiments of Formula (XI) or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] is.

[0120] In some embodiments of Formula (IX) or (X), or a pharmaceutically acceptable salt or solvate thereof, Ring E is a 5-membered heteroaryl. In some embodiments, the 5-membered heteroaryl is oxazole, thiazole, pyrrole, furan, or thiophene. In some embodiments, the 5-membered heteroaryl is furan or thiophene. In some embodiments, the 5-membered heteroaryl is furan. In some embodiments, the 5-membered heteroaryl is thiophene.

[0121] In some embodiments of Formula (IX) or (X), or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] and Y 3 is O, S or NR 1C and Y 4 is O, S, N or CH, and R 1C is hydrogen or C1-C6 alkyl.

[0122] In some embodiments of Formula (IX) or (X), or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] is. In some embodiments, Y 3 is O and Y 4 is CH. In some embodiments, Y 3 is S and Y 4 is CH. In some embodiments, Y 3 is NR1C and Y 4 is CH and R 1C is H or -CH3. In some embodiments, Y 3 is NR 1C and Y 4 is N and R 1C is H or -CH3. In some embodiments, Y 3 is NR 1C and Y 4 is O and R 1C is H or -CH3. In some embodiments, Y 3 is NR 1C and Y 4 is S and R 1C is H or -CH3.

[0123] In some embodiments of Formula (IX) or (X), or a pharmaceutically acceptable salt or solvate thereof, [ka] teeth [ka] In some embodiments, Y 3 is O and Y 4 is CH. In some embodiments, Y 3 is S and Y 4 is CH. In some embodiments, Y 3 is NR 1C and Y 4 is CH and R 1C is H or -CH3. In some embodiments, Y 3 is NR 1C and Y 4 is N and R 1C is H or -CH3. In some embodiments, Y 3 is NR 1C and Y 4 is O and R 1C is H or -CH3. In some embodiments, Y 3is NR 1C and Y 4 is S and R 1C is H or -CH3.

[0124] In some embodiments, the compound of Formula (IX) has the structure of Formula (XII): [ka] Y 3 is O or S, and Y 4 is CH.

[0125] In some embodiments of Formula (XII) or a pharmaceutically acceptable salt or solvate thereof, Y 3 is S. In some embodiments, Y 3 is O.

[0126] In some embodiments of Formula (XII) or a pharmaceutically acceptable salt or solvate thereof, each R 35 are independently halogen, -CN, -S(=O)2N(R 1A )2, -C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R 35 is -Cl, -F, -Br, -CN, -CH3, -CF3 or -OCH3.

[0127] In some embodiments of Formula (XII) or a pharmaceutically acceptable salt or solvate thereof, each R 35 are independently -S(=O)2N(R 1A )2 and R 1A is H or -C1-C3 alkyl. In some embodiments, each R 35 are independently -S(=O)2NH2.

[0128] In some embodiments of Formula (XII) or a pharmaceutically acceptable salt or solvate thereof, w is 0. In some embodiments, w is 1.

[0129] In some embodiments of Formula (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt or solvate thereof, R 32 is halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A )2, -NR 1A S(=O)2(C1, -C4 alkyl), -S(=O)2N(R 1A )2, -OC(=O)(C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), -C(=O)N(R 1A )2, -NR 1A C(=O)(C1-C4 alkyl), -NR 1A C(=O)O(C1-C4 alkyl), -OC(=O)N(R 1A )2, -NR 1A C(=O)N(R 1A )2, -S(C1-C4 alkyl), -S(=O)(C1-C4 alkyl), -S(=O)2(C1-C4 alkyl), C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, -C 1-6 Alkyl-OH, -C 1-6 heteroalkyl-OH, monocyclic C2-C6 heterocycloalkyl, phenyl, or monocyclic 5-6 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R 39 and each R 39 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -N(R 1A )2, C1-C4 alkyl or C1-C4 fluoroalkyl.

[0130] In some embodiments of Formula (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt or solvate thereof, R 32 is halogen, -CN, -OH, -OR 1B , -SR 1B , -N(R 1A)2, -C1-C6 alkyl, C1-C4 fluoroalkyl, -C 1-6 Alkyl-OH or -C 1-6 In some embodiments, R 32 -Br, -Cl, -F, -CN, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -OCH 3、 In some embodiments, R 32 is -Br, -Cl, -F, or -CN. In some embodiments, R 32 is -NH, -NHCH, -NHCHCH, -N(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -NH(CH), -CH(CH), or -NH(CH)OH. 32 is —NH(CH)OH. In some embodiments, R 32 is —NH(C-C cycloalkyl). In some embodiments, R 32 is -NH-cyclopropyl, -NH-cyclobutyl, or -NH-cyclohexyl. 32 is -NH-benzyl. In some embodiments, R 32 is -SH, -SCH, or -SCHCH. In some embodiments, R 32 is -OH, -OCH, or -OCHCH, -OCHCHCH, -OCHCHCH(CH). In some embodiments, R 32 Ha-OCH 3、 -CF3, -CH3, or -CH2CH3.

[0131] In some embodiments of Formula (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt or solvate thereof, R 32 is halogen, -CN, -OH, -OR 1B , -N(R 1A)2, -C1-C6 alkyl, C1-C4 fluoroalkyl, -C 1-6 Alkyl-OH or -C 1-6 In some embodiments, R 32 HA-OR 1B , -N(R 1A )2, -C1-C6 alkyl or -C 1-6 In some embodiments, R 32 is -NH, -NHCH, -NHCHCH, -N(CH), -OCH, -CH, -CHCH, or -NH(CH)OH. 32 is —NH(CH)OH. In some embodiments, R 32 is H. In some embodiments, R 32 is Br or -Cl.

[0132] In some embodiments of Formula (IX), (X), (XI), or (XII) or a pharmaceutically acceptable salt or solvate thereof, R 32 is one, two or three R 39 In some embodiments, R 32 is piperazine, piperidine, or morpholino. In some embodiments, R2 is piperazine. In some embodiments, R 32 is piperidine. In some embodiments, R 32 is morpholine.

[0133] In some embodiments of Formula (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt or solvate thereof, R 32 is phenyl or 6-membered heteroaryl, each of which is optionally substituted by one, two, or three R 39 Each R is replaced by 39 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , N(R 1A)2, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R 32 is phenyl. In some embodiments, R 32 is a 6-membered heteroaryl. In some embodiments, the 6-membered heteroaryl is 2-pyridyl, 3-pyridyl, or 4-pyridyl. In some embodiments, R 32 is heteroaryl and is 2-pyridyl.

[0134] In some embodiments of Formula (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt or solvate thereof, Y a is N.

[0135] In some embodiments of Formula (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt or solvate thereof, Y a is CH.

[0136] In some embodiments, each R 26 and R 36 is independently H, halogen, or -C1-C4 alkyl. In some embodiments, each R 26 and R 36 is independently halogen or -C1-C4 alkyl. In some embodiments, each R 26 and R 36 is independently H or halogen. In some embodiments, each R 26 and R 36 is independently H, -Br, -Cl, -I, or -F. In some embodiments, each R 26 and R 36 is independently H or -C1-C4 alkyl. In some embodiments, each R 26 and R 36 are independently H.

[0137] In some embodiments, each R 7 , R 8 , R 9 , R 27 , R28 , R 29 , R 37 , R 38 and R 39 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -N(R 1A )2, -C(=O)OR 1A , oxo(=O), C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, each R 7 , R 8 , R 9 , R 27 , R 28 , R 29 , R 37 , R 38 and R 39 are independently halogen, -CN, -OH, -OR 1B , -SH, -SR 1B , -N(R 1A )2, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, each R 7 , R 8 , R 9 , R 27 , R 28 , R 29 , R 37 , R 38 and R 39 is independently -Cl, -Br, -I, or -F. In some embodiments, each R 7 , R 8 , R 9 , R 27 , R 28 , R 29 , R 37 , R 38 and R 39 is independently -Cl or -Br. In some embodiments, each R 7 , R 8 , R 9 , R 27 , R 28 , R 29 , R 37 , R 38 and R 39 are independently -CN, -OH, -OR 1B , -SH, -SR1B and R 1B is C1-C6 alkyl, or C2-C6 alkenyl. In some embodiments, each R 7 , R 8 , R 9 , R 27 , R 28 , R 29 , R 37 , R 38 and R 39 is independently -CN, -OH, -OCH, -SH, or -SCH. In some embodiments, each R 7 , R 8 , R 9 , R 27 , R 28 , R 29 , R 37 , R 38 and R 39 is N(R 1A )2 and R 1A is H or C1-C6 alkyl. In some embodiments, each R 7 , R 8 , R 9 , R 27 , R 28 , R 29 , R 37 , R 38 and R 39 is independently —NH. In some embodiments, each R 7 , R 8 , R 9 , R 27 , R 28 , R 29 , R 37 , R 38 and R 39 is independently C1-C4 alkyl or C1-C4 fluoroalkyl.

[0138] In some embodiments, R 1A is independently hydrogen, C-C alkyl, cycloalkyl, heterocycloalkyl, aryl, benzyl, or heteroaryl. 1A is independently H or C1-C6 alkyl. 1Ais independently C1-C6 alkyl. 1A is independently -CH, -CHCH, or -CH(CH). In some embodiments, each R 1A is independently H. In some embodiments, each R 1A is independently cycloalkyl or heterocycloalkyl. In some embodiments, cycloalkyl is cyclopentyl, cyclobutyl, cyclohexyl, or cycloheptyl.

[0139] In some embodiments, each R 1B is independently H, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 1B is independently C1-C6 alkyl. In some embodiments, each R 1B is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, each R 1B is independently C1-C6 heteroalkyl. In some embodiments, each R 1B is independently aryl. In some embodiments, each R 1B is independently phenyl. In some embodiments, each R 1B is independently cycloalkyl or heterocycloalkyl. In some embodiments, cycloalkyl is cyclopentyl, cyclobutyl, cyclohexyl, or cycloheptyl.

[0140] In some embodiments of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) or a pharmaceutically acceptable salt or solvate thereof, non-limiting examples of compounds described herein are shown in Tables 1-3. [Table 1-1] [Table 1-2] Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 [Table 3-10] [Table 3-11] [Table 3-12]

[0141] Further forms of the compound In another aspect, compounds having the structure of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) contain one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric, and epimeric forms, as well as appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entegegene (E), and zusammen (Z) isomers, as well as appropriate mixtures thereof. In certain embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is accomplished by chromatography, or by formation of diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley and Sons, Inc., 1981. In one aspect, stereoisomers are obtained by stereoselective synthesis.

[0142] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. A prodrug may be, for example, bioavailable by oral administration, whereas the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the design of a prodrug increases effective water solubility. A non-limiting example of a prodrug is a compound described herein that is administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is detrimental to motility, but is then metabolically hydrolyzed to the active carboxylic acid once inside cells, where water solubility is beneficial. A further example of a prodrug may be a short peptide (polyamino acid) linked to an acid group, where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0143] In one aspect, prodrugs are designed to alter the metabolic stability or transport properties of a drug, mask side effects or toxicity, improve the taste of the drug, or alter other characteristics or properties of the drug. Once a drug-active compound is known, knowledge of in vivo pharmacokinetic and pharmacodynamic processes and drug metabolism makes it possible to design prodrugs of that compound. (See, e.g., Nogrady (1985) Medicinal Chemistry: A Biochemical Approach, Oxford University Press, New York, pp. 388-392; Silverman (1992) "The Organic Chemistry of Drug Design and Drug Action," Academic Press, Inc., San Diego, pp. 352-401; Rooseboom et al., "Pharmacological Reviews," 56:53-102, 2004; Aesop Cho, "Recent Advances in Oral Prodrug Discovery," Annual Reports in Medicinal Chemistry, Vol. 41, pp. 395-407, 2006; T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," the ACS Symposium Series, Vol. 14).

[0144] In some cases, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0145] In some embodiments, the aromatic ring moieties of the compounds described herein are susceptible to various metabolic reactions, and the incorporation of appropriate substituents on the aromatic ring structure reduces, minimizes, or eliminates this metabolic pathway. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogens or alkyl groups.

[0146] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0147] The compounds described herein include isotopically labeled compounds, which are identical to those listed in the various formulas and structures presented herein, but are included by virtue of the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F and 36 In one embodiment, the isotopically labeled compounds described herein, e.g., 3 H and 14 Incorporation of radioactive isotopes such as C is useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium offers certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0148] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism that needs to produce a metabolic product that is used to bring about a desired effect, including a desired therapeutic effect.

[0149] As used herein, "pharmaceutically acceptable" refers to a material, e.g., a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., that may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0150] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) with an acid. A pharmaceutically acceptable salt can also be obtained by reacting a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) with a base to form a salt.

[0151] The compounds described herein can be formed as and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to, (1) salts obtained by converting the free base form of the compound to a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, or an organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2 (2) acid addition salts formed by reacting an acidic proton present in the parent compound with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, or potassium), an alkaline earth ion (e.g., magnesium or calcium), or an aluminum ion. In some cases, the compounds described herein may coordinate with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein may form salts with amino acids such as, but not limited to, arginine and lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0152] It should be understood that a reference to a pharmaceutically acceptable salt includes solvent addition forms, particularly solvates. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and can be formed during the crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvate is water, or alcoholates are formed when the solvate is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein can exist in unsolvated and solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0153] Compound synthesis In some embodiments, synthesis of the compounds described herein is achieved using means described in the chemical literature, using methods described herein, or by a combination thereof. Additionally, solvents, temperatures, and other reaction conditions presented herein may be varied.

[0154] In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fisher Scientific (Fisher Chemicals), and Acros Organics.

[0155] In further embodiments, the compounds described herein, and other related compounds with different substituents, can be synthesized using techniques and materials described herein, as well as other methods and methods described in, for example, Fieser and Fieser, "Reagents for Organic Synthesis," Vols. 1-17 (John Wiley and Sons, 1991); Rodd, "Chemistry of Carbon Compounds," Vols. 1-5 and supplements (Elsevier Science Publishers, 1989); "Organic Reactions," Vols. 1-40 (John Wiley and Sons, 1991); Larock, "Comprehensive Organic Transformations" (VCH Publishers Inc., 1989); March, "Advanced Organic Chemistry," 4th Edition (Wiley 1992); Carey and Sundberg, "Advanced Organic The compounds may be synthesized using art-recognized methods such as those described in "Protective Groups in Organic Synthesis," 4th Edition, Volumes A and B (Plenum 2000, 2001), and Green and Wuts, "Protective Groups in Organic Synthesis," 3rd Edition (Wiley, 1999), all of which are incorporated by reference for such disclosures. General methods for preparing the compounds disclosed herein may be derived from reactions which may be modified by the use of appropriate reagents and conditions to introduce the various moieties found in the formulas provided herein. As a guide, the following synthetic methods may be utilized.

[0156] In the reactions described, it may be necessary to protect reactive functional groups, such as hydroxy, amino, imino, thio, or carboxy groups, which may be desirable in the final product to prevent their undesired participation in the reaction. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in Greene and Wuts, "Protective Groups in Organic Synthesis," 3rd Edition, John Wiley & Sons, New York, NY, 1999, and Kocienski, "Protective Groups," Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosures.

[0157] It will be understood that the reactions shown above are exemplary.

[0158] In one aspect, the compounds are synthesized as described in the Examples section.

[0159] definition In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, throughout the specification and the following claims, the word "comprises" and variations thereof, such as "includes" and "comprising," should be interpreted in an open and inclusive sense, i.e., "including but not limited to." Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0160] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Also, it should be noted that the term "or" is generally used in its sense including "and / or" unless the content clearly dictates otherwise.

[0161] As used herein, the following terms have the following meanings unless otherwise indicated.

[0162] "Oxo" refers to the =O substituent.

[0163] "Thioxo" refers to the =S substituent.

[0164] "Alkyl" refers to a straight or branched hydrocarbon chain radical having from 1 to 20 carbon atoms and attached to the rest of the molecule by a single bond. Alkyl containing up to 10 carbon atoms is C1-C 10 Similarly, when referred to as alkyl, for example, an alkyl containing up to 6 carbon atoms is a C1-C6 alkyl. Alkyl groups containing other numbers of carbon atoms (and other moieties defined herein) are similarly represented. Alkyl groups include, but are not limited to, C1-C 10Examples of alkyl include alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl, and C4-C8 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethylpropyl, and the like. In some embodiments, alkyl is methyl, ethyl, s-butyl, or 1-ethylpropyl. Unless specifically stated otherwise in the specification, alkyl groups can be optionally substituted as described below. "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the remainder of the molecule to a radical group. In some embodiments, alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, alkylene is -CH2-. In some embodiments, alkylene is -CH2CH2-. In some embodiments, alkylene is -CH2CH2CH2-. In some embodiments, alkylene is -CH2CH2CH2-.

[0165] The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions, such as ethenylene [(-CH=CH-), (-C::C-)]. Examples of suitable alkenyl groups include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, and the like. Unless otherwise specified, the term "alkenyl" can include "alkenylene" groups.

[0166] The term "alkynyl," as used herein, alone or in combination, refers to a straight- or branched-chain hydrocarbon radical having one or more triple bonds and containing 2 to 20 carbon atoms. In certain embodiments, alkynyl contains 2 to 6 carbon atoms. In further embodiments, alkynyl contains 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions, such as ethynylene (-C:::C-, -C≡C-). Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term "alkynyl" can include "alkynylene" groups.

[0167] "Alkoxy" refers to a radical of the formula -OR, where R is an alkyl group as defined herein. Unless specifically stated otherwise in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and pentoxy. In some embodiments, an alkoxy is methoxy. In some embodiments, an alkoxy is ethoxy.

[0168] "Heteroalkylene" refers to an alkyl radical as defined above in which one or more carbon atoms of the alkyl have been replaced with an O, N, or S atom. "Heteroalkylene" or "heteroalkylene chain" refers to a straight or branched divalent heteroalkyl chain connecting the remainder of the molecule to the radical group. Unless specifically stated otherwise in the specification, a heteroalkyl or heteroalkylene group can be optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to, -OCHOMe, -OCHCHOMe, or -OCHCHOCHCHNH. Representative heteroalkylene groups include, but are not limited to, -OCHCHO-, -OCHCHOCHCHO-, or -OCHCHOCHCHOCHCHO-.

[0169] "Alkylamino" refers to a radical of the formula -NHR or -NRR, where each R is independently an alkyl radical as defined above. Unless specifically stated otherwise in the specification, an alkylamino group may be optionally substituted as described below.

[0170] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where n is an integer. An aromatic may be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0171] "Aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthalenyl. In some embodiments, an aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless specifically stated otherwise in this specification, the term "aryl" or the prefix "ar-" (e.g., "aralkyl") is meant to include aryl radicals that are optionally substituted.

[0172] "Carboxy" refers to -COH. In some embodiments, the carboxy moiety may be replaced with a "carboxylic acid bioisostere," which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties as a carboxylic acid group. A compound having a carboxylic acid moiety can exchange the carboxylic acid moiety for a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to a carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere ionizes at physiological pH to approximately the same extent as a carboxylic acid group. Examples of carboxylic acid bioisosteres include, but are not limited to, the following: [ka] etc.

[0173] "Cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. Cycloalkyls can be saturated or partially unsaturated. Cycloalkyls can be fused to an aromatic ring (in which case the cycloalkyl is attached via a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, cycloalkyls are C3-C6 cycloalkyls. In some embodiments, cycloalkyls are 3-6 membered cycloalkyls. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3-10 carbon atoms, 3-8 carbon atoms, 3-6 carbon atoms, or 3-5 carbon atoms. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, and 3,4-dihydronaphthalen-1(2H)-one. Unless stated otherwise specifically in the specification, cycloalkyl groups may be optionally substituted.

[0174] "Fused" refers to any ring structure described herein that is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, a carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or fused heteroaryl ring can be replaced with a nitrogen atom.

[0175] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0176] "Haloalkyl" refers to an alkyl radical, as defined above, substituted with one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless specifically stated otherwise in the specification, a haloalkyl group may be optionally substituted.

[0177] "Haloalkoxy" refers to an alkoxy radical, as defined above, substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, etc. Unless specifically stated otherwise in the specification, a haloalkoxy group may be optionally substituted.

[0178] "Heterocycloalkyl" or "heterocyclyl" or "heterocyclic ring" refers to a stable 3- to 14-membered non-aromatic ring radical containing from 2 to 13 carbon atoms and from 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl is a C2-C7 heterocycloalkyl. In some embodiments, a heterocycloalkyl is a C2-C6 heterocycloalkyl. In some embodiments, a heterocycloalkyl is a C2-C5 heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 5-membered heterocycloalkyl. Unless specifically stated otherwise in the specification, a heterocycloalkyl radical can be a monocyclic or bicyclic ring system, which can include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical may be partially or fully saturated. Examples of such heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl.The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have 2 to 8 carbons in the ring. In some embodiments, heterocycloalkyls have 2 to 8 carbons and 1 or 2 N atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless specifically stated otherwise in this specification, heterocycloalkyl groups may be optionally substituted.

[0179] "Heteroaryl" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl is monocyclic or bicyclic. In some embodiments, heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, heteroaryl is a 5-membered heteroaryl. In some embodiments, heteroaryl is a 6-membered heteroaryl. Specific examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Specific examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Specific examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, heteroaryls contain 0 to 4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.

[0180] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional groups individually and independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C-C alkylalkyne, halogen, acyl, acyloxy, -COH, -COalkyl, nitro, and amino, including mono- and di-substituted amino groups (e.g., -NH, -NHR, -N(R)). In some embodiments, the optional substituents are independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, and COalkyl. In some embodiments, optional substituents are independently selected from fluoro, chloro, bromo, iodo, -CH, -CHCH, -CF, -OCH, and OCF. In some embodiments, optional substituents are independently selected from fluoro, chloro, -CH, -CF, -OCH, and OCF. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic, saturated or unsaturated carbon atom, excluding aromatic carbon atoms) include oxo (=O).

[0181] As used herein, "co-administration" and like terms are meant to encompass the administration of selected therapeutic agents to a single patient and are intended to include therapeutic regimens in which agents are administered by the same or different routes of administration, or at the same or different times.

[0182] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient quantity of an agent or compound being administered to relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case can be determined using techniques such as a dose escalation study.

[0183] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combining of two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), and a co-agent are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), and a co-agent are administered to a patient simultaneously, concurrently, or sequentially as separate entities without any specific intervening time limit, such that such administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0184] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human.

[0185] As used herein, the terms "treat," "treating," or "treatment" include alleviating, attenuating, or ameliorating at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, e.g., halting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating conditions caused by a disease or condition, or prophylactically and / or therapeutically arresting symptoms of a disease or condition.

[0186] "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom accompanied by switching of a single bond and an adjacent double bond. In bonding configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include the following: [ka]

[0187] Administration and Pharmaceutical Compositions In some embodiments, the compound described herein is formulated into pharmaceutical composition.The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients, which facilitates the processing of active compound into the preparation that can be used pharmaceutically.The appropriate formulation depends on the selected route of administration. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington, The Science and Practice of Pharmacy, 19th Edition (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins, 1999), which are incorporated herein by reference for such disclosures.

[0188] As used herein, a pharmaceutical composition refers to a mixture of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. The pharmaceutical composition facilitates administration of the compound to an organism.

[0189] The pharmaceutical formulations described herein can be administered to a subject in a variety of ways by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, buccal, topical, or transdermal routes of administration. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast-dissolve formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and combined immediate and controlled release formulations.

[0190] In some embodiments, the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) is administered orally.

[0191] In some embodiments, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) is administered topically. In such embodiments, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) is formulated into various topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, gums, smears, medicated sticks, medicated bandages, balms, creams, or ointments. In one aspect, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) is administered topically to the skin.

[0192] In another embodiment, the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) is administered by inhalation.

[0193] In another embodiment, the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) are formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, and the like.

[0194] In another embodiment, the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) is formulated as eye drops.

[0195] In any of the foregoing aspects, there are further embodiments in which an effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by inhalation to a mammal, and / or (e) administered by nasal administration to a mammal, and / or (f) administered by injection to a mammal, and / or (g) administered topically to a mammal, and / or (h) administered by ophthalmic administration, and / or (i) administered rectally to a mammal, and / or (j) administered non-systemically or topically to a mammal.

[0196] In any of the foregoing aspects, there are further embodiments comprising a single administration of an effective amount of the compound, including further embodiments in which (i) the compound is administered once, (ii) the compound is administered to the mammal multiple times over a daily period, (iii) continuously, or (iv) continuously.

[0197] In any of the foregoing aspects, there are further embodiments comprising multiple administrations of an effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently as a single dose, (ii) the time between multiple administrations is every 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the mammal every 12 hours, or (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday during which administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced, at the end of which administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from two days to one year.

[0198] In certain embodiments, the compounds described herein are administered locally rather than systemically.

[0199] In some embodiments, the compounds described herein are administered locally. In some embodiments, the compounds described herein are administered systemically.

[0200] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, the pharmaceutical formulation of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) is in the form of a capsule.

[0201] In one aspect, the liquid pharmaceutical dosage form for oral administration is in the form of an aqueous suspension or solution selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[0202] For administration by inhalation, the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) are formulated for use as an aerosol, mist or powder.

[0203] For buccal or sublingual administration, the compositions can take the form of tablets, lozenges, or gels formulated in conventional manner.

[0204] In some embodiments, the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) is prepared as a transdermal dosage form.

[0205] In one embodiment, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) is formulated into a pharmaceutical composition that is suitable for intramuscular, subcutaneous or intravenous injection.

[0206] In some embodiments, the compounds described herein may be administered topically and may be formulated into a variety of topically administrable compositions such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments.

[0207] In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) are formulated into a rectal composition such as an enema, rectal gel, rectal foam, rectal aerosol, suppository, jelly suppository or retention enema.

[0208] Administration Methods and Treatment Regimen In one embodiment, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) is used in the preparation of a medicament for treating a disease or condition described herein. Additionally, a method of treating any of the diseases or conditions described herein in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt, active metabolite, prodrug, or solvate thereof.

[0209] In certain embodiments, compositions containing the compounds described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one symptom of the disease or condition. The amount effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. Therapeutically effective amounts can optionally be determined by methods including, but not limited to, dose escalation clinical trials.

[0210] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.

[0211] In certain embodiments, the dose of the administered drug may be temporarily reduced or temporarily suspended for a period of time (ie, a "drug holiday").

[0212] Doses used for adult human treatment typically range from 0.01 mg to 5000 mg per day, or from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently provided in a single dose or in divided doses.

[0213] Combination treatment In certain cases, it will be appropriate to administer at least one compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) in combination with another therapeutic agent.

[0214] In a specific embodiment, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) is co-administered with a second therapeutic agent, wherein the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0215] In the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, etc. In further embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with the one or more other therapeutic agents.

[0216] When administration is simultaneous, the multiple therapeutic agents may be provided in a single, unified form or in multiple forms, by way of example only. [Example]

[0217] The following examples are intended to illustrate, but not limit, the disclosed embodiments.

[0218] All reactions were carried out in oven-dried glassware under an argon atmosphere with magnetic stirring. All solvents and chemicals were purchased from Sigma-Aldrich or Acros and used as received without further purification. Compound purity was established by liquid chromatography-mass spectrometry (HPLC-MS) and was >95% for all compounds tested. Silica gel column chromatography was performed using pre-packed silica cartridges from RediSep (ISCO Ltd.) and eluted using an Isco Companion system. 1 H- and 13 C-NMR spectra were obtained on a Jeol 400 spectrometer at 400 MHz and 100 MHz, respectively. Chemical shifts are reported in δ (ppm) relative to the residual solvent peak or TMS as the internal standard. Coupling constants are reported in Hz. High-resolution ESI-TOF mass spectra were obtained from the Mass Spectrometry Core at Sanford-Burnham Medical Research Institute (Orlando, FL). HPLC-MS analyses were performed on a Shimadzu 2010 EV LCMS using the following conditions: a Kromisil C18 column (reverse-phase, 4.6 mm × 50 mm); a linear gradient from 10% acetonitrile and 90% water to 95% acetonitrile and 5% water over 4.5 min; a flow rate of 1 mL / min; and UV photodiode array detection from 200 nm to 300 nm. Example 1 [ka]

[0219] 5-phenyl-2-(pyridin-2-yl)-N-(pyridin-4-ylmethyl)thieno[2,3-d]pyrimidin-4-amine

[0220] Step 1: To a solution of acetophenone (1.20 g, 10.0 mmol) and ethyl 2-cyanoacetate (2.48 g, 22.0 mmol) in toluene (40 mL) was added morpholine (1.31 g, 15.0 mmol) and AcOH (1.20 g, 20.0 mmol). The resulting mixture was stirred at 125 °C for 24 h using a Dean-Stark apparatus. The mixture was then concentrated in vacuo to give a residue, which was dissolved in EtOH (40 mL). Sulfur powder (480 mg, 15.0 mmol) and diethylamine (730 mg, 10.0 mmol) were then added to the reaction mixture, which was heated to 50 °C for 3 h. The reaction was monitored by LCMS. The hot solution was filtered to remove sulfur powder, concentrated in vacuo, and purified by silica gel column (PE / EA=100 / 1 to 20 / 1) to give ethyl 2-amino-4-phenylthiophene-3-carboxylate (2.12 g, yield: 86%) as a white solid.

[0221] Step 2: To a solution of ethyl 2-amino-4-phenylthiophene-3-carboxylate (247 mg, 1.0 mmol) and picolinonitrile (208 mg, 2.0 mmol) in dioxane (10 mL) was added HCl / dioxane (10 mL, >2 M). The resulting mixture was stirred at 100 °C overnight. The reaction was monitored by LCMS. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by reverse-phase column chromatography (5–95% ACN in HO, 40 min) to give 5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-ol (238 mg, 78% yield) as a yellow solid.

number

[0222] Step 3: A mixture of 5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-ol (238 mg, 0.78 mmol) in POCl (5 mL) was stirred at 110 °C overnight. The reaction was monitored by LCMS and TLC. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column (DCM / MeOH = 100 / 1 to 20 / 1) to give 4-chloro-5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidine (126 mg, yield: 50%) as a yellow solid.

[0223] Step 4: To a solution of 4-chloro-5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidine (100 mg, 0.31 mmol) in ACN (20 mL) was added phenylmethanamine (66.8 mg, 0.62 mmol), followed by K2CO3 (128 mg, 0.93 mmol). The resulting mixture was stirred at 80 °C for 3 h. The reaction was monitored by LCMS. Then, K2CO3 was filtered off, and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC using NH4OH as an additive to give 5-phenyl-2-(pyridin-2-yl)-N-(pyridin-4-ylmethyl)thieno[2,3-d]pyrimidin-4-amine (48.6 mg, yield: 40%) as a yellow solid.

number

[0224] 5-Phenyl-2-(pyridin-2-yl)-N-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-4-amine: The title compound was prepared using the general procedure for 5-phenyl-2-(pyridin-2-yl)-N-(pyridin-4-ylmethyl)thieno[2,3-d]pyrimidin-4-amine (Example 1).

number

[0225] (5-Phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine: The title compound was prepared using the general procedure for (4-methyl-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine (Example 1.7).

number

[0226] N-(4-Methoxybenzyl)-5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-amine: The title compound was prepared using the general procedure for 5-phenyl-2-(pyridin-2-yl)-N-(pyridin-4-ylmethyl)thieno[2,3-d]pyrimidin-4-amine (Example 1).

number

[0227] N-(4-Fluorobenzyl)-5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-amine: The title compound was prepared using the general procedure for 5-phenyl-2-(pyridin-2-yl)-N-(pyridin-4-ylmethyl)thieno[2,3-d]pyrimidin-4-amine (Example 1).

number

[0228] N-Benzyl-5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-amine: The title compound was prepared using the general procedure for 5-phenyl-2-(pyridin-2-yl)-N-(pyridin-4-ylmethyl)thieno[2,3-d]pyrimidin-4-amine (Example 1).

number

[0229] 4-(((5-Phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide: The title compound was prepared using the general procedure for 5-phenyl-2-(pyridin-2-yl)-N-(pyridin-4-ylmethyl)thieno[2,3-d]pyrimidin-4-amine (Example 1).

number

[0230] (4-Methyl-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine

[0231] Step 1: To a solution of 1-phenyl-ethanone (12 g, 100 mmol) in toluene, cyano-acetic acid ethyl ester (24.8 g, 220 mmol), morpholine (13.05 g, 150 mmol), and acetic acid (12.0 g, 200 mmol) were added. Using a Dean start apparatus, the reaction mixture was refluxed for 24 h. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with EA (300 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was dissolved in EtOH (50 mL). Then, sulfur powder (4.8 g, 150 mmol) and diethylamine (7.3 g, 100 mmol) were added to the solution, which was heated to 50 °C for 3 h. The hot solution was filtered to remove unreacted sulfur, and the filtrate was concentrated in vacuo to give a residue, which was purified by silica gel column (PE / EA=10 / 1) to give 2-amino-4-phenyl-thiophene-3-carboxylic acid ethyl ester (19.7 g, yield: 79.8%) as a yellow solid.

number

[0232] Step 2: To a solution of 2-amino-4-phenyl-thiophene-3-carboxylic acid ethyl ester (4.0 g, 16.19 mmol) in HCl / dioxane (50 mL) was added pyridine-2-carbonitrile (2.02 g, 19.43 mmol). The mixture was stirred at 100 °C overnight. The reaction was monitored by TLC and LCMS. The mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column (PE / EA = 1 / 1) to give 5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-ol (4.0 g, yield: 81.6%) as a yellow solid.

number

[0233] Step 3: A solution of 5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-ol (4.0 g, 13.11 mmol) in POCl (20 mL) was stirred at 110 °C overnight. Residual phosphorus oxychloride was removed in vacuo, and the residue was diluted with DCM (100 mL). The mixture was washed with saturated aqueous NaHCO (50 mL), brine (50 mL), dried over NaSO, and concentrated to dryness in vacuo. The residue was purified by silica gel column (PE / EA = 1 / 1) to give 4-chloro-5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidine (2.0 g, yield: 47.3%) as a yellow solid.

[0234] Step 4: To a solution of 4-chloro-5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidine (100 mg, 0.31 mmol) in ACN (30 mL) was added 4-methyl-benzylamine (74.64 mg, 0.62 mmol) and K2CO3 (127.7 mg, 0.93 mmol). The mixture was stirred at 80 °C for 3 h. The reaction was monitored by LCMS, and then the mixture was concentrated in vacuo to give a residue that was purified by preparative HPLC to give (4-methyl-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine (70.2 mg, yield: 57%) as a yellow solid.

number

[0235] (2-Fluoro-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl): The title compound was prepared using the general procedure for (4-methyl-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine (Example 1.7).

number

[0236] (3-Fluoro-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl): The title compound was prepared using the general procedure for (4-methyl-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine (Example 1.7).

number

[0237] (4-Chloro-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl): The title compound was prepared using the general procedure for (4-methyl-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine (Example 1.7).

number

[0238] 4-[(5-Phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-methyl]-benzonitrile: The title compound was prepared using the general procedure for (4-methyl-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine (Example 1.7).

number

[0239] 3-[(5-Phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-methyl]-benzenesulfonamide: The title compound was prepared using the general procedure for (4-methyl-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine (Example 1.7).

number

[0240] 2-Fluoro-4-(((5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide: The title compound was prepared using the general procedure for 2-chloro-4-(((5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 1.18).

number

[0241] 4-(((5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)-2-(trifluoromethyl)benzenesulfonamide: The title compound was prepared using the general procedure for 3-methyl-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.2).

number

[0242] 3-Methyl-4-(((5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 3-methyl-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.2).

number

[0243] 2-Methoxy-4-(((5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide: The title compound was prepared using the general procedure for 3-methyl-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.2).

number

[0244] 3-Methoxy-4-(((5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: To a solution of 4-chloro-5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidine (113 mg, 0.35 mmol) and 4-(aminomethyl)-3-methoxybenzenesulfonamide (100 mg, 0.46 mmol) in DMF (2 mL) was added TEA (106 mg, 1.05 mmol). The reaction was stirred at 100° C. for 3 h. The DMF was removed under reduced pressure. The residue was purified by preparative HPLC to give 3-methoxy-4-(((5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (7.5 mg, yield: 2.8%) as a white solid.

number

[0245] 2-Chloro-4-(((5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: A solution of 4-(aminomethyl)-2-chlorobenzenesulfonamide (60 mg, 0.27 mmol), TEA (46 mg, 0.46 mmol), and 4-chloro-5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidine (73 mg, 0.23 mmol) in DMF (3 mL) was stirred at 80 °C overnight. DMF was removed under reduced pressure. The residue was purified by preparative HPLC (NHHCO) to give 2-chloro-4-(((5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (7.1 mg, 6.1% yield) as a yellow solid.

number

[0246] 2-Methyl-4-(((5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 2-chloro-4-(((5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 1.18).

number

[0247] 4-(((2-(pyridin-2-yl)-5-(pyridin-4-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide

[0248] Step 1: A solution of ethyl 2-amino-4-(pyridin-4-yl)thiophene-3-carboxylate (500 mg, 2 mmol) and picolinonitrile (315 mg, 3 mmol) in HCl / dioxane (15 mL) was stirred at 90° C. for 2 days. The reaction mixture was filtered and the pad dried to give 2-(pyridin-2-yl)-5-(pyridin-4-yl)thieno[2,3-d]pyrimidin-4-ol (200 mg, 32.4% yield) as a gray solid. MS: m / z 307.3 (M+H) + ).

[0249] Step 2: A solution of 2-(pyridin-2-yl)-5-(pyridin-4-yl)thieno[2,3-d]pyrimidin-4-ol (150 mg, 0.49 mmol) in POCl (3 mL) was stirred at 120 °C for 2 h. POCl was removed under reduced pressure. The residue was washed with saturated aqueous NaHCO (80 mL) and the aqueous phase was extracted with EA (100 mL). The organic layer was dried over NaSO and concentrated to give 4-chloro-2-(pyridin-2-yl)-5-(pyridin-4-yl)thieno[2,3-d]pyrimidine (200 mg, crude) as a gray solid. MS: m / z 325.2 (M+H) + ).

[0250] Step 3: A solution of 4-chloro-2-(pyridin-2-yl)-5-(pyridin-4-yl)thieno[2,3-d]pyrimidine (150 mg, 0.46 mmol), 4-(aminomethyl)benzenesulfonamide (103 mg, 0.46 mmol), and TEA (140 mg, 1.38 mmol) in DMF (5 mL) was stirred at 80 °C overnight. DMF was removed under reduced pressure. The residue was purified by preparative HPLC (NH4HCO3) to give 4-(((2-(pyridin-2-yl)-5-(pyridin-4-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (0.7 mg, yield: 0.3%) as a brown solid.

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[0251] 3-Chloro-4-(((5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 2-chloro-4-(((5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 1.18).

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[0252] 4-(((2-(Pyridin-2-yl)-5-(pyridin-3-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((2-(pyridin-2-yl)-5-(pyridin-4-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 1.20).

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[0253] 4-(((2,5-di(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide

[0254] Step 1: To a solution of 1-(pyridin-2-yl)ethanone (1.2 g, 10 mmol) in DMF (40 mL) was added ethyl 2-cyanoacetate (2.33 mL, 22 mmol), morpholine (1.3 mL, 5.7 mmol), and S powder (480 mg, 15 mmol). The mixture was stirred overnight at 60 °C under a N atmosphere. The reaction mixture was concentrated, and the residue was purified using a silica gel column (PE / EA = 7 / 1) to give ethyl 2-amino-4-(pyridin-2-yl)thiophene-3-carboxylate (1.8 g, yield: 73%) as a brown oil.

[0255] Step 2: To a solution of ethyl 2-amino-4-(pyridin-2-yl)thiophene-3-carboxylate (100 mg, 0.28 mmol) in dioxane (5 mL), picolinonitrile (35 mg, 0.34 mmol) and HCl / dioxane (5 mL) were added. The reaction mixture was stirred at 100° C. overnight. The mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column (DCM / MeOH=10 / 1) to give 4-chloro-2,5-di(pyridin-2-yl)thieno[2,3-d]pyrimidine (20 mg, yield: 23%) as a yellow solid.

[0256] Step 3: A solution of 4-chloro-2,5-di(pyridin-2-yl)thieno[2,3-d]pyrimidine (100 mg, 0.31 mmol), 4-(aminomethyl)benzenesulfonamide (76 mg, 0.33 mmol), and DIEA (80 mg, 0.62 mmol) in DMSO (10 mL) was stirred overnight at 100° C. The mixture was purified by preparative HPLC to give 4-(((2,5-di(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (6.8 mg, yield: 4.6%) as a yellow solid.

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[0257] 4-(((2,5-Diphenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide: The title compound was prepared using the general procedure for 5-(((5-methyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide (Example 1.37).

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[0258] 4-(((2-(4-Methylpiperazin-1-yl)-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((2-morpholino-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 1.38).

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[0259] 4-(((2-(Chloropropylamino)-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((2-morpholino-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 1.38).

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[0260] 5-(((2,5-diphenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide

[0261] The title compound was prepared using the general procedure for 5-(((5-methyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide (Example 1.37).

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[0262] 5-(((5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide

[0263] Step 1: A mixture of ethyl 2-amino-4-phenylthiophene-3-carboxylate (500 mg, 2.02 mmol) in formamide (4 mL) was stirred at 200 °C under microwave irradiation for 2 h. The reaction was monitored by LCMS. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by reverse-phase column chromatography (5 to 95% ACN in HO, 40 min) to give 5-phenylthieno[2,3-d]pyrimidin-4(3H)-one (408 mg, 88% yield) as a white solid.

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[0264] Step 2: A mixture of 5-phenylthieno[2,3-d]pyrimidin-4(3H)-one (408 mg, 1.79 mmol) in POCl3 (10 mL) was stirred at 110 °C overnight. The reaction was monitored by LCMS. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column (DCM / MeOH = 100 / 1 to 30 / 1) to give 4-chloro-5-phenylthieno[2,3-d]pyrimidine (186 mg, yield: 42%) as a yellow solid.

[0265] Step 3: To a solution of 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine (93 mg, 0.38 mmol) in ACN (20 mL) was added 5-(aminomethyl)thiophene-2-sulfonamide (172 mg, 0.76 mmol), followed by K2CO3 (157 mg, 1.14 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction was monitored by LCMS. Then, K2CO3 was filtered off, and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC using NH4HCO3 as an additive to give 5-(((5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide (15.0 mg, yield: 10%) as a white solid.

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[0266] 5-(((5-phenyl-2-(pyridin-4-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide

[0267] Step 1: To a solution of ethyl 2-amino-4-phenylthiophene-3-carboxylate (1.0 g, 4.04 mmol) and isonicotinonitrile (842 mg, 8.08 mmol) in dioxane (10 mL) was added HCl / dioxane (10 mL). The resulting mixture was stirred at 100 °C overnight. The reaction was monitored by LCMS. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column (DCM / MeOH = 30 / 1) to give 5-phenyl-2-(pyridin-4-yl)thieno[2,3-d]pyrimidin-4(3H)-one (882 mg, yield: 72%) as a yellow solid.

[0268] Step 2: A mixture of 5-phenyl-2-(pyridin-4-yl)thieno[2,3-d]pyrimidin-4(3H)-one (882 mg, 2.89 mmol) in POCl (6 mL) was stirred at 110 °C overnight. The reaction was monitored by LCMS. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column (DCM / MeOH = 100 / 1 to 30 / 1) to give 4-chloro-5-phenyl-2-(pyridin-4-yl)thieno[2,3-d]pyrimidine (706 mg, yield: 75%) as a yellow solid.

[0269] Step 3: To a solution of 4-chloro-5-phenyl-2-(pyridin-4-yl)thieno[2,3-d]pyrimidine (100 mg, 0.31 mmol) in ACN (20 mL) was added 5-(aminomethyl)thiophene-2-sulfonamide (106 mg, 0.46 mmol), followed by K2CO3 (128 mg, 0.93 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction was monitored by LCMS. The K2CO3 was then filtered off, and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC using NH4HCO3 as an additive to give 5-(((5-phenyl-2-(pyridin-4-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide (12.4 mg, yield: 8%) as a yellow solid.

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[0270] 5-(((5-Phenyl-2-(pyridin-3-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide: The title compound was prepared using the general procedure for 5-(((5-methyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide (Example 1.37).

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[0271] 5-(((5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide: The title compound was prepared using the general procedure for 5-phenyl-2-(pyridin-2-yl)-N-(pyridin-4-ylmethyl)thieno[2,3-d]pyrimidin-4-amine (Example 1).

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[0272] N-((5-Methylfuran-2-yl)methyl)-5-phenyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-amine: The title compound was prepared using the general procedure for (4-methyl-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine (Example 1.7).

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[0273] (5-Phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-thiophen-2-ylmethyl-amine: The title compound was prepared using the general procedure for (4-methyl-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine (Example 1.7).

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[0274] (5-Amino-1-methyl-1H-pyrazol-4-ylmethyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine: The title compound was prepared using the general procedure for (4-methyl-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine (Example 1.7).

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[0275] Furan-2-ylmethyl-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine: The title compound was prepared using the general procedure for (4-methyl-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine (Example 1.7).

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[0276] Cyclopentyl-methyl-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine: The title compound was prepared using the general procedure for (4-methyl-benzyl)-(5-phenyl-2-pyridin-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine (Example 1.7).

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[0277] 5-(((5-methyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide

[0278] Step 1 and Step 2: To a solution of picolinic acid (1.23 g, 10.0 mmol) in (COCl) (10 mL), two drops of DMF were added. The resulting mixture was stirred at room temperature for 0.5 h. The mixture was then concentrated in vacuo to give picolinoyl chloride as a white solid, which was dissolved in dry DCM (40 mL). Methyl 2-amino-4-methylthiophene-3-carboxylate (2.05 g, 12.0 mmol) was then added, followed by TEA (3.03 g, 30.0 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS and TLC. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (DMC) to give methyl 4-methyl-2-(picolinamido)thiophene-3-carboxylate (2.54 g, yield: 92%) as a brown solid.

[0279] Step 3: To a mixture of methyl 4-methyl-2-(picolinamido)thiophene-3-carboxylate (1.38 g, 5.0 mmol) and triphenylphosphine (3.93 g, 15.0 mmol) in ACN (30 mL) was added CCl (2.31 g, 15.0 mmol). The resulting mixture was stirred at room temperature for 48 h. The reaction was then treated with NHAc (excess) and heated in a sealed tube vial at 110 °C overnight. The reaction was monitored by LCMS. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by reverse-phase column chromatography (5–95% ACN in HO, 60 min) to give 5-methyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4(3H)-one (924 mg, 76% yield) as a yellow solid.

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[0280] Step 4: A mixture of 5-methyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4(3H)-one (924 mg, 3.80 mmol) in POCl (8 mL) was stirred at 110 °C overnight. The reaction was monitored by LCMS and TLC. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column (DCM / MeOH = 30 / 1) to give 4-chloro-5-methyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidine (910 mg, yield: 92%) as a brown solid.

[0281] Step 5: To a solution of 4-chloro-5-methyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidine (200 mg, 0.76 mmol) in ACN (20 mL) was added 5-(aminomethyl)thiophene-2-sulfonamide (262 mg, 1.15 mmol), followed by K2CO3 (309 mg, 2.24 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction was monitored by LCMS. The K2CO3 was then filtered off, and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC using NH4OH as an additive to give 5-(((5-methyl-2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide (23.0 mg, yield: 7%) as a yellow solid.

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[0282] 4-(((2-morpholino-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide

[0283] Step 1: To a solution of ethyl 2-amino-4-phenylthiophene-3-carboxylate (494 mg, 2.0 mmol) in acetic acid (10 mL) was added an aqueous solution of sodium cyanate (260 mg, 4.0 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS and TLC. The reaction mixture was then concentrated in vacuo to give a residue, which was purified using a silica gel column (DCM / MeOH=30 / 1) to give ethyl 4-phenyl-2-ureidothiophene-3-carboxylate (312 mg, yield: 54%) as a white solid.

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[0284] Step 2: To a solution of ethyl 4-phenyl-2-ureidothiophene-3-carboxylate (312 mg, 1.07 mmol) in ethanol (30 mL) was added KOH (180 mg, 3.21 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction was monitored by LCMS. The white solid that precipitated from the mixture was then filtered and dried in air to give 5-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (204 mg, yield: 78%) as a white solid.

[0285] Step 3: A mixture of 5-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (400 mg, 1.64 mmol) in POCl (10 mL) was stirred at 110 °C overnight. The reaction was monitored by LCMS. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column (DCM) to give 2,4-dichloro-5-phenylthieno[2,3-d]pyrimidine (404 mg, yield: 70%) as a colorless oil.

[0286] Step 4: To a solution of 2,4-dichloro-5-phenylthieno[2,3-d]pyrimidine (340 mg, 1.21 mmol) in ACN (20 mL) was added 4-(aminomethyl)benzenesulfonamide (538 mg, 2.42 mmol), followed by DIEA (626 mg, 4.84 mmol). The resulting mixture was then stirred at room temperature overnight. The reaction was monitored by LCMS. The solid that precipitated from the mixture was then filtered, washed with ACN (30 mL), and dried in air to give 4-(((2-chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (420 mg, 81% yield) as a white solid.

[0287] Step 5: To a solution of 4-(((2-chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (50 mg, 0.12 mmol) and morpholine (21 mg, 0.24 mmol) in DMSO (5 mL) was added K2CO3 (50 mg, 0.36 mmol). The resulting mixture was then stirred at room temperature overnight. The reaction was monitored by LCMS. Then, K2CO3 was filtered off, and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC using NH4HCO3 as an additive to give 4-(((2-morpholino-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (15.2 mg, yield: 27%) as a white solid.

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[0288] 4-(((5-Phenyl-2-(piperidin-1-yl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((2-morpholino-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 1.38).

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[0289] 4-(((2-(Chlorohexylamino)-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((2-morpholino-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 1.38).

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[0290] 4-(((2-(Benzylamino)-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((2-morpholino-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 1.38).

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[0291] 4-(((2-(Methylamino)-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((2-morpholino-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 1.38).

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[0292] 4-(((2-(Dimethylamino)-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((2-morpholino-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 1.38).

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[0293] 4-(((2-methyl-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide

[0294] Step 1: To a solution of ethyl 2-amino-4-phenylthiophene-3-carboxylate (1.0 g, 4.04 mmol) and acetonitrile (332 mg, 8.08 mmol) in dioxane (5 mL) was added HCl / dioxane (10 mL). The resulting mixture was stirred at 100 °C overnight. The reaction was monitored by LCMS. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by reverse-phase column chromatography (10–80% ACN in HO, 60 min) to give 2-methyl-5-phenylthieno[2,3-d]pyrimidin-4(3H)-one (542 mg, 55% yield) as a yellow solid.

[0295] Step 2: A mixture of 2-methyl-5-phenylthieno[2,3-d]pyrimidin-4(3H)-one (542 mg, 2.24 mmol) in POCl3 (8 mL) was stirred at 110 °C overnight. The reaction was monitored by LCMS. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column (DCM / MeOH = 100 / 1 to 30 / 1) to give 4-chloro-2-methyl-5-phenylthieno[2,3-d]pyrimidine (446 mg, yield: 77%) as a yellow solid.

[0296] Step 3: To a solution of 4-chloro-2-methyl-5-phenylthieno[2,3-d]pyrimidine (100 mg, 0.38 mmol) in ACN (20 mL) was added 4-(aminomethyl)benzenesulfonamide (171 mg, 0.77 mmol), followed by K2CO3 (159 mg, 1.15 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction was monitored by LCMS. Then, K2CO3 was filtered off, and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC using NH4OH as an additive to give 4-(((2-methyl-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (41.6 mg, yield: 26%) as a white solid.

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[0297] 5-(((2-Methyl-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide: The title compound was prepared using the general procedure for 4-(((2-methyl-5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 1.44).

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[0298] 4-(((5-Phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide: The title compound was prepared using the general procedure for 5-(((5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide (Example 1.28).

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[0299] 4-(((3-phenyl-6-(pyridin-2-yl)thieno[2,3-b]pyridin-4-yl)amino)methyl)benzenesulfonamide

[0300] Step 1: To a solution of acetophenone (12 g, 100 mmol) and ethyl 2-cyanoacetate (24.8 g, 220 mmol) in toluene (200 mL) was added morpholine (13.1 g, 150 mmol) and AcOH (12 g, 200 mmol). The resulting mixture was stirred at 130 °C for 24 h using a Dean-Stark apparatus. The mixture was then concentrated to give a residue, which was dissolved in EtOH (200 mL). S (4.8 g, 150 mmol) and diethylamine (3.3 g) were added to the mixture. The mixture was stirred at 50 °C for 3 h. The resulting solution was purified on a silica gel column (PE / EA = 20 / 1) to give ethyl 2-amino-4-phenylthiophene-3-carboxylate (11.3 g, yield: 46%) as a yellow solid.

[0301] Step 2: To a solution of ethyl 2-amino-4-phenylthiophene-3-carboxylate (2 g, 8.1 mmol) in DCM (100 mL) was added methyl 3-chloro-3-oxopropanoate (1.32 g, 9.7 mmol) and TEA (1 mL). The mixture was stirred at room temperature for 10 minutes. The resulting solution was purified using a silica gel column (DCM) to give ethyl 2-(3-methoxy-3-oxopropanamido)-4-phenylthiophene-3-carboxylate (2.8 g, 100% yield) as a yellow oil.

[0302] Step 3: To a solution of ethyl 2-(3-methoxy-3-oxopropanamido)-4-phenylthiophene-3-carboxylate (2.8 g, 8.1 mmol) in DMF (20 mL) was added NaH (1.1 g, 48.6 mmol) at 0 °C. The mixture was stirred at room temperature overnight. HO (100 mL) was added to the resulting solution and acidified to pH = 1 with HCl. The suspension was filtered. The cake was dried to give methyl 4,6-dihydroxy-3-phenylthieno[2,3-b]pyridine-5-carboxylate (2.0 g, yield: 87%) as a yellow solid.

[0303] Step 4: A solution of methyl 4,6-dihydroxy-3-phenylthieno[2,3-b]pyridine-5-carboxylate (2.0 g, 6.9 mmol) in KOH solution (100 mL, 2 M) was stirred at 120 °C overnight. The resulting solution was acidified to pH = 5 with HCl (100 mL). The suspension was filtered and rinsed with HO (1 mL) to give 3-phenylthieno[2,3-b]pyridine-4,6-diol (1.7 g, crude) as a yellow solid.

[0304] Step 5: A solution of 3-phenylthieno[2,3-b]pyridine-4,6-diol (1.0 g, 4.1 mmol) in phenylphosphonic acid dichloride (15 mL) was stirred at 180 °C for 3 h. DCM (100 mL) was added to the resulting solution, which was quenched with saturated aqueous NaHCO and extracted with DCM (60 mL × 3). The combined organic layer was concentrated, and the residue was purified by silica gel column chromatography (DCM) to give 4,6-dichloro-3-phenylthieno[2,3-b]pyridine (430 mg, yield: 39%) as a brown solid.

[0305] Step 6: To a solution of 4,6-dichloro-3-phenylthieno[2,3-b]pyridine (150 mg, 0.5 mmol) in dioxane (5 mL) was added 2-(tributylstannyl)pyridine (276 mg, 0.75 mmol) and Pd(PPh3)4 (57 mg, 0.05 mmol). The mixture was stirred at 140 °C for 1.5 h. Saturated aqueous KF solution was added to the resulting solution and stirred for 30 min. The solution was extracted with EA (60 mL × 3). The combined organic layer was concentrated to give 4-chloro-3-phenyl-6-(pyridin-2-yl)thieno[2,3-b]pyridine (67 mg, yield: 42%) as a yellow solid.

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[0306] Step 7: To a solution of 4-chloro-3-phenyl-6-(pyridin-2-yl)thieno[2,3-b]pyridine (67 mg, 0.2 mmol) in NMP (5 mL) was added 4-(aminomethyl)benzenesulfonamide (154 mg, 0.8 mmol) and t-BuOK (1.3 mg, 0.12 mmol). The mixture was stirred at 200° C. for 4 hours. The resulting solution was concentrated and purified by preparative HPLC to give 4-(((3-phenyl-6-(pyridin-2-yl)thieno[2,3-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (3.5 mg, yield: 4%) as a yellow solid.

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[0307] 4-((2-Chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: To a suspension of 2,4-dichloro-5-phenylthieno[2,3-d]pyrimidine (136 mg) and homosulfamine hydrochloride (130 mg) in 2-propanol (5 mL) was added N,N-diisopropylethylamine (0.2 mL) at room temperature. The resulting mixture was stirred at 90° C. for 3 hours and then cooled to room temperature. The precipitate was collected, washed with methanol, and then dried under reduced pressure to give the title compound as a pale yellow solid (200 mg, 96% yield).

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[0308] 4-((5-Bromothieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 1.48 using 5-bromo-4-chlorothieno[2,3-d]pyrimidine and homosulfamine hydrochloride.

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[0309] 4-((2-(2-Hydroxyethylamino)-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: To a mixture of 4-((2-chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide (40 mg) obtained in Example 1.48 in n-butanol (1.5 mL) was added 2-aminoethanol (0.02 mL). After stirring at 200° C. in a microwave for 3 hours, the resulting mixture was concentrated under reduced pressure. The residue was purified by automated flash chromatography using 1-5% methanol in dichloromethane as the eluent to give the title compound as a colorless solid (37 mg, 88% yield).

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[0310] 4-((2-(3-hydroxypropyl)amino-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 1.50 using 4-((2-chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 1.48 and 3-amino-1-propanol.

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[0311] 4-((2-(N-ethyl-N-(2-hydroxyethyl)amino)-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared following the general procedure of Example 1.50 using 4-((2-chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 1.48 and 2-(ethylamino)ethanol.

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[0312] 4-((2-(N-ethyl-N-(1-hydroxy-2-methylpropan-2-yl)amino)-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 1.50 using 4-((2-chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 1.48 and 1-ethylamino-2-methyl-2-propanol.

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[0313] 4-((2-(2-Methoxyethyl)amino-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 1.50 using 4-((2-chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide obtained in Example 1.48 and 2-methoxyethylamine.

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[0314] 4-((2-(N-methyl-N-(2-methoxyethyl)amino)-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 1.50 using 4-((2-chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide obtained in Example 1.48 and N-(2-methoxyethyl)methylamine.

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[0315] 4-((2-(3-Methoxypropyl)amino-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 1.50 using 4-((2-chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide obtained in Example 1.48 and 3-methoxypropylamine.

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[0316] 4-((2-amino-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 1.50 using 4-((2-chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 1.48 and 10% ammonia solution.

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[0317] 4-((2-((N-2-(dimethylamino)ethyl)-N-methylamino)-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 1.50 using 4-((2-chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide obtained in Example 1.48 and N,N,N'-trimethylethylenediamine.

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[0318] 4-((2-(3-Dimethylaminopropyl)amino-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 1.50 using 4-((2-chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide obtained in Example 1.48 and N,N-dimethyl-1,3-propanediamine.

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[0319] 4-((2-(2-Dimethylamino)ethylamino-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 1.50 using 4-((2-chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide obtained in Example 1.48 and N,N-dimethylethylenediamine.

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[0320] 4-((2-(2-Butoxycarbonyl)ethylamino-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 1.50 using 4-((2-chloro-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide obtained in Example 1.48, tert-butyl 3-aminopropanoate hydrochloride, and N,N-diisopropylethylamine in n-butanol. MS: m / z 540.2 (M+H + ). Example 1.62 [ka]

[0321] 4-((2-(2-Carboxy)ethylamino-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: To a solution of 4-((2-(2-butoxycarbonyl)ethylamino-5-phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide (12 mg) obtained in Example 1.61 in tetrahydrofuran (0.8 mL) was added 1 mol / L sodium hydroxide solution (0.4 mL) at room temperature. After stirring overnight, 1 mol / L hydrochloric acid (0.4 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried under reduced pressure. The residue was washed twice with methanol to give the title compound as a pale yellow solid (6 mg, yield 56%).

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[0322] 4-((6-methylthieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide

[0323] The title compound was prepared according to the general procedure of Example 1.48 using 4-chloro-6-methylthieno[2,3-d]pyrimidine and homosulfamine hydrochloride.

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[0324] 4-((2-Methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 1.48 using 4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine and homosulfamine hydrochloride.

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[0325] 4-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)aminoethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 1.48 using 4-chloro-5-phenylthieno[2,3-d]pyrimidine and 4-(1-aminoethyl)benzenesulfonamide. MS: m / z 411 (M+H + ). Example 1.66 [ka]

[0326] 4-(5-Phenylthieno[2,3-d]pyrimidin-4-yl)aminomethyl-1-piperidinesulfonamide: The title compound was prepared according to the general procedure of Example 1.48 using 4-chloro-5-phenylthieno[2,3-d]pyrimidine and 4-aminomethyl-1-piperidinesulfonamide hydrochloride. MS: m / z 404 (M+H + ). Example 1.67 [ka]

[0327] 4-((5-Phenyl-2-(2-pyridyl)thieno[2,3-d]pyrimidin-4-yl)aminomethyl)-1-piperidinesulfonamide: The title compound was prepared according to the general procedure of Example 1.48 using 4-chloro-5-phenyl-2-(2-pyridyl)thieno[2,3-d]pyrimidine and 4-aminomethyl-1-piperidinesulfonamide hydrochloride.

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[0328] N-(2-(1-(5-phenyl-2-(2-pyridyl)thieno[2,3-d]pyrimidin-4-yl)-4-piperidyl)ethyl)sulfamide: The title compound was prepared according to the general procedure of Example 1.48 using 4-chloro-5-phenyl-2-(2-pyridyl)thieno[2,3-d]pyrimidine and N-(2-(4-piperidyl)ethyl)sulfamide hydrochloride.

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[0329] 4-((5-(1-Cyclohexenyl)thieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: To a mixture of 4-((5-bromothieno[2,3-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide from Example 1.49 (150 mg), 2-(1-cyclohexenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (94 mg), and tripotassium phosphate (160 mg) in 1,4-dioxane (1.5 mL) and water (0.4 mL) was added chloro-(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (28 mg). After stirring at 120 °C for 3 h in a microwave oven, the resulting mixture was diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by automated flash chromatography (NH-modified silica gel) using 0-15% methanol in dichloromethane as the eluent, followed by automated flash chromatography (diol-modified silica gel) using 0-2% methanol in dichloromethane as the eluent to afford the title compound as a pale yellow amorphous solid (125 mg, 83% yield).

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[0330] 4-((5-Phenylthieno[2,3-d]pyrimidin-4-yl)oxymethyl)benzenesulfonamide: To a solution of 4-(hydroxymethyl)benzenesulfonamide (67.1 mg) in N,N-dimethylformamide (1 mL) was added sodium hydride (60%, dispersion in paraffin liquid, 31.4 mg) at 0° C. After stirring for 30 minutes at 0° C., 4-chloro-5-phenylthieno[2,3-d]pyrimidine (88.2 mg) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 3 hours and quenched by adding saturated ammonium chloride solution and ethyl acetate. The organic phase was washed with water and brine and dried over anhydrous sodium sulfate. The resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was washed with 80% ethyl acetate in hexane and then dried under reduced pressure to give the title compound as a beige solid (39.3 mg, 28% yield).

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[0331] 4-(((1-methyl-6-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide

[0332] Step 1: To a solution of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 1 mmol) in ACN (30 mL) was added 4-(aminomethyl)benzenesulfonamide (2.4 g, 10.8 mmol) and DIEA (258 mg, 2 mmol). The mixture was stirred at room temperature for 3 hours. The resulting solution was filtered. The cake was washed with ACN to give 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (240 mg, 68% yield) as a yellow solid.

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[0333] Step 2: A mixture of 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (100 mg, 0.28 mmol), KCO (97 mg, 0.7 mmol), and Pd(dppf)Cl (22 mg, 0.03 mmol) in dioxane / HO (24 mL / 6 mL) was stirred at 100 °C under a N atmosphere (balloon) overnight. The mixture was concentrated and purified by preparative HPLC to give 4-(((1-methyl-6-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (14 mg, 13% yield) as a white solid.

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[0334] 2-Fluoro-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 2-chloro-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.4).

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[0335] 3-Methyl-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide

[0336] Step 1: To a solution of 4-fluoro-2-methylbenzonitrile (1 g, 7.4 mmol) in DMF (5 mL) was added BnSH (1.01 g, 8.1 mmol) and K2CO3 (2.0 g, 14.8 mmol). The mixture was stirred at 100 °C overnight. Then, the reaction mixture was diluted with EA (40 mL). The organic layer was washed with water (100 mL × 2), brine (100 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column (EA / PE = 1 / 10) to give 4-(benzylthio)-2-methylbenzonitrile (1.6 g, yield: 90.3%) as a white solid.

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[0337] Step 2: To a solution of NCS (3.3 g, 25.1 mmol) and 2 M HCl (1.67 mL) in ACN (20 mL) was added 4-(benzylthio)-2-methylbenzonitrile (1.5 g, 6.2 mmol). The mixture was stirred at 0 °C for 1 h. Then, the reaction mixture was concentrated, and the residue was partitioned between EA (20 mL) and water (20 mL). The organic layer was dried over Na SO and concentrated to give 4-cyano-3-methylbenzene-1-sulfonyl chloride (1.1 g, yield: 82%) as a white solid.

[0338] Step 3: To a solution of 4-cyano-3-methylbenzene-1-sulfonyl chloride (1.1 g, 5.1 mmol) in THF (10 mL) was added NH3HO (0.5 mL). The mixture was stirred at 0 °C for 30 min. The reaction mixture was then concentrated, and the residue was purified by silica gel column (EA / PE = 1 / 1) to give 4-cyano-3-methylbenzenesulfonamide (800 mg, yield: 80%) as a white solid.

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[0339] Step 4: To a solution of 4-cyano-3-methylbenzenesulfonamide (700 mg, 3.58 mmol) in MeOH (10 mL) was added Raney Ni (140 mg). The mixture was stirred at room temperature under a H atmosphere (balloon) for 3 hours. The reaction mixture was then filtered, and the filtrate was concentrated to give 4-(aminomethyl)-3-methylbenzenesulfonamide (420 mg, 69% yield) as a white solid.

[0340] Step 5: To a solution of 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.29 mmol) in DMF (2 mL) was added 4-(aminomethyl)-3-methylbenzenesulfonamide (71 mg, 0.35 mmol) and EtN (53 mg, 0.53 mmol). The mixture was stirred at 80 °C for 3 h. The reaction mixture was then concentrated, and the residue was purified by preparative HPLC to give 3-methyl-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (25 mg, yield: 25.3%) as a white solid.

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[0341] 3-Methoxy-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 3-methyl-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.2).

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[0342] 2-Chloro-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 3-methyl-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.2).

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[0343] 1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)propyl)piperidin-4-amine

[0344] Step 1: To a mixture of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (768 mg, 3.78 mmol) in ACN (40 mL), tert-butyl piperidin-4-ylcarbamate (758 mg, 3.78 mmol) was added, followed by DIEA (1.47 g, 11.34 mmol). The resulting mixture was stirred at room temperature overnight. The solid that precipitated from the mixture was collected by filtration. The cake was dried in air to give tert-butyl (1-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (1.31 g, yield: 94%) as a yellow solid.

[0345] Step 2: To a mixture of tert-butyl (1-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (100 mg, 0.27 mmol) in MeOH (10 mL) was added Pd / C (20 mg, 20% by weight). The resulting mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. Then, Pd / C was removed by filtration. The filtrate was concentrated in vacuo to give tert-butyl (1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (86.8 mg, yield: 96%) as a white solid.

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[0346] Step 3: To a mixture of tert-butyl (1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (86.8 mg, 0.26 mmol) in dioxane (10 mL) was added HCl / dioxane (5 mL, >4 M). The resulting mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. The mixture was concentrated in vacuo to give 1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-amine (70.2 mg, yield: 100%) as a white solid.

[0347] Step 4: To a mixture of 1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-amine (70.2 mg, 0.26 mmol) in MeOH (10 mL) was added 3-(pyridin-4-yl)propanal (42 mg, 0.31 mmol). The resulting mixture was stirred at room temperature overnight. Then, NaBH(OAc) (165 mg, 0.78 mmol) was added, and the mixture was stirred at room temperature for another 1 hour. The reaction was monitored by LCMS. The mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC using NHHCO as an additive to give 1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)propyl)piperidin-4-amine (10.6 mg, yield: 12%) as a yellow solid.

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[0348] 1-(1-methyl-6-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)propyl)piperidin-4-amine

[0349] Step 1: To a solution of tert-butyl (1-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (183 mg, 0.50 mmol) and 1-methylpiperazine (150 mg, 1.50 mmol) in DMSO (5 mL) was added KCO (207 mg, 1.50 mmol). The resulting mixture was then stirred at 100° C. overnight. The reaction was monitored by LCMS. Then the K2CO3 was filtered off, and the filtrate was concentrated in vacuo to give a residue, which was purified by silica gel column (DCM / MeOH=100 / 1 to 30 / 1) to give tert-butyl (1-(1-methyl-6-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (174 mg, yield: 81%) as a yellow solid.

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[0350] Step 2: To a solution of tert-butyl (1-(1-methyl-6-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (174 mg, 0.40 mmol) in EA (10 mL) was added HCl / dioxane (10 mL). The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. Then, the mixture was concentrated in vacuo to give 1-(1-methyl-6-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-amine (132 mg, yield: 89%) as a yellow solid.

[0351] Step 3: To a solution of 1-(1-methyl-6-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-amine (132 mg, 0.36 mmol) in MeOH (10 mL) was added 3-(pyridin-4-yl)propanal (58 mg, 0.43 mmol). The resulting mixture was stirred at room temperature overnight. Then, NaBHCN (68 mg, 1.08 mmol) was added to the mixture, and the mixture was stirred for another 1 hour. The reaction was monitored by LCMS. The mixture was then concentrated in vacuo to give a residue, which was purified by preparative HPLC using TFA as an additive to give 1-(1-methyl-6-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)propyl)piperidin-4-amine (21.1 mg, yield: 13%) as a yellow solid.

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[0352] 1-(1-Methyl-6-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)propyl)piperidin-4-amine: The title compound was prepared using the general procedure for 1-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)propyl)piperidin-4-amine (Example 2.51).

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[0353] 4-(((9-Methyl-9H-purin-6-yl)amino)methyl)benzenesulfonamide: The title compound was prepared using the general procedure for 5-(((5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide (Example 1.28).

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[0354] N-Benzyl-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0355] Step 1 and Step 2: To a solution of picolinic acid (246 mg, 2.0 mmol) in (COCl) (3 mL) was added one drop of DMF. The resulting mixture was stirred at room temperature for 0.5 h. The mixture was then concentrated in vacuo to give picolinoyl chloride as a white solid, which was dissolved in dry DCM (20 mL). Ethyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate (676 mg, 4.0 mmol) was then added, followed by TEA (607 mg, 6.0 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS and TLC. The reaction mixture was then concentrated in vacuo to give a residue, which was purified using a silica gel column (DMC / MeOH = 100 / 1 to 50 / 1) to give ethyl 1-methyl-5-(picolinamido)-1H-pyrazole-4-carboxylate (482 mg, yield: 88%) as a white solid.

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[0356] Step 3: To a mixture of ethyl 1-methyl-5-(picolinamido)-1H-pyrazole-4-carboxylate (274 mg, 1.0 mmol) and triphenylphosphine (787 mg, 3.0 mmol) in ACN (20 mL) was added CCl (462 mg, 3.0 mmol). The resulting mixture was stirred at room temperature for 48 h. The reaction was then treated with NHAc (excess) and heated in a sealed tube vial at 110 °C overnight. The reaction was monitored by LCMS. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by reverse-phase column chromatography (5–95% ACN in HO, 60 min) to give 1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (82 mg, 36% yield) as a white solid.

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[0357] Step 4: A mixture of 1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (1.12 g, 4.93 mmol) in POCl (10 mL) was stirred at 110 °C overnight. The reaction was monitored by LCMS and TLC. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column (DCM / MeOH = 20 / 1) to give 4-chloro-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.11 g, yield: 92%) as a yellow solid.

[0358] Step 5: To a solution of 4-chloro-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.41 mmol) in ACN (20 mL) was added phenylmethanamine (52.3 mg, 0.49 mmol), followed by K2CO3 (168 mg, 1.22 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction was monitored by LCMS. The K2CO3 was then filtered off, and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC using NH4OH as an additive to give N-benzyl-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (60.0 mg, yield: 47%) as a yellow solid.

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[0359] 4-(((1-Methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for N-benzyl-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 2.9).

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[0360] N-(4-Methoxybenzyl)-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: The title compound was prepared using the general procedure for N-benzyl-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 2.9).

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[0361] N-(3-Fluorobenzyl)-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: The title compound was prepared using the general procedure for N-benzyl-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 2.9).

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[0362] N-(4-Chlorobenzyl)-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: The title compound was prepared using the general procedure for N-benzyl-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 2.9).

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[0363] 4-(((1-Methyl-6-(piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: A solution of 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (130 mg, 0.36 mmol) and piperidine (62 mg, 0.73 mol) in DMF (2 mL) was stirred at 110° C. for 3 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give 4-(((1-methyl-6-(piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (35 mg, yield: 23.5%) as a white solid.

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[0364] 4-(((1-Methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: A mixture of 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (100 mg, 0.28 mmol), pyridin-3-ylboronic acid (107 mg, 0.84 mmol), KCO (120 mg, 0.8 mmol), Pd(dppf)Cl (44 mg, 0.05 mmol), and Pd(PPh) (47 mg, 0.05 mmol) in dioxane / HO (24 mL / 6 mL) was stirred at 90 °C overnight under a N atmosphere (balloon). The reaction solution was concentrated, and the residue was purified by preparative HPLC to give 4-(((1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (66.9 mg, yield: 61%) as a white solid.

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[0365] 4-(((1-Methyl-6-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound (40 mg, yield: 28%, yellow solid) was prepared using the general procedure for 4-(((1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide.

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[0366] 1-Methyl-6-(pyridin-2-yl)-N-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: The title compound was prepared using the general procedure for N-benzyl-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 2.9).

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[0367] 1-Methyl-6-(pyridin-2-yl)-N-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: The title compound was prepared using the general procedure for N-benzyl-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 2.9).

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[0368] 1-Methyl-6-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: The title compound was prepared using the general procedure for N-benzyl-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 2.9).

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[0369] 1-(1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)propyl)piperidin-4-amine

[0370] Step 1 and Step 2: To a solution of picolinic acid (1.23 g, 10.0 mmol) in (COCl) (10 mL), two drops of DMF were added. The resulting mixture was stirred at room temperature for 0.5 h. The mixture was then concentrated in vacuo to give picolinoyl chloride as a white solid, which was dissolved in dry DCM (20 mL). Ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (3.38 g, 20.0 mmol) was then added, followed by TEA (3.03 g, 30.0 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS and TLC. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column (DCM / MeOH=50 / 1) to give ethyl 1-methyl-5-(picolinamido)-1H-pyrazole-4-carboxylate (2.36 g, yield: 86%) as a white solid.

[0371] Step 3: To a mixture of ethyl 1-methyl-5-(picolinamido)-1H-pyrazole-4-carboxylate (2.36 g, 8.60 mmol) and triphenylphosphine (6.77 g, 25.8 mmol) in ACN (40 mL) was added CCl (3.97 g, 25.8 mmol). The resulting mixture was stirred at room temperature for 48 h. The reaction was then treated with NHAc (excess) and heated in a sealed tube vial at 110 °C overnight. The reaction was monitored by LCMS. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by reverse-phase column chromatography (5 to 95% ACN in HO, 60 min) to give 1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (946 mg, 48% yield) as a white solid.

[0372] Step 4: A mixture of 1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (946 mg, 4.16 mmol) in POCl (10 mL) was stirred at 110 °C overnight. The reaction was monitored by LCMS and TLC. The reaction mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column (DCM / MeOH = 50 / 1) to give 4-chloro-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (824 mg, yield: 81%) as a yellow solid.

[0373] Step 5: To a solution of 4-chloro-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (491 mg, 2.0 mmol) in ACN (30 mL) was added tert-butyl piperidin-4-ylcarbamate (801 mg, 4.0 mmol), followed by DIEA (774 mg, 6.0 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column (DCM / MeOH=50 / 1) to give tert-butyl (1-(1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (455 mg, yield: 56%) as a yellow solid.

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[0374] Step 6: To a mixture of tert-butyl (1-(1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (455 mg, 1.10 mmol) in dioxane (20 mL) was added HCl / dioxane (10 mL, >4 M). The resulting mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. The mixture was concentrated in vacuo to give 1-(1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-amine (quantitative) as a yellow solid.

[0375] Step 7: To a mixture of 1-(1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-amine (100 mg, 0.29 mmol) in MeOH (10 mL) was added 3-(pyridin-4-yl)propanal (78 mg, 0.58 mmol). The resulting mixture was stirred at room temperature overnight. Then, NaBCNH3 (55 mg, 0.87 mmol) was added, and the mixture was stirred at room temperature for another 1 hour. The reaction was monitored by LCMS. The mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC using NH4HCO3 as an additive to give 1-(1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)propyl)piperidin-4-amine (22.8 mg, yield: 18%) as a yellow solid.

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[0376] 1-Methyl-6-(pyridin-2-yl)-N-(thiophen-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: The title compound was prepared using the general procedure for N-benzyl-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 2.9).

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[0377] 1-Methyl-N-((5-methylfuran-2-yl)methyl)-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: The title compound was prepared using the general procedure for N-benzyl-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 2.9).

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[0378] N-(furan-2-ylmethyl)-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: The title compound was prepared using the general procedure for N-benzyl-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 2.9).

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[0379] 5-(((1-Methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide: The title compound was prepared using the general procedure for N-benzyl-1-methyl-6-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 2.9).

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[0380] 4-(((1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide: A mixture of 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (50 mg, 0.14 mmol) and Pd / C (15 mg, 0.1 mmol) in MeOH (50 mL) was stirred at room temperature under a H atmosphere (balloon) for 30 minutes. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give 4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (4.4 mg, 10% yield) as a white solid.

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[0381] 4-(((1,6-Dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide: The title compound (200 mg, 43% yield, white solid) was prepared using the general procedure for 4-(((1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.15).

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[0382] 4-(((1-methyl-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide (Example 2.27) and 4-(((6-(dimethylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide (Example 2.28)

[0383] Step 1: To a solution of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (2 g, 9.9 mmol) in ACN (100 mL) was added 4-(aminomethyl)benzenesulfonamide (2.4 g, 10.8 mmol) and DIEA (2.5 g, 19.4 mmol). The mixture was stirred at room temperature for 2 hours. The resulting solution was filtered. The cake was washed with ACN to give 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (2.3 g, 66% yield) as a yellow solid.

[0384] Step 2: A mixture of 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (100 mg, 0.28 mmol), KCO (77.3 mg, 0.56 mmol), and methanamine (22.8 mg, 0.34 mmol) in DMF (15 mL) was stirred at 100° C. overnight. The resulting solution was concentrated, and the residue was purified by preparative HPLC to give 4-(((1-methyl-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (2.4 mg) and 4-(((6-(dimethylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (30.6 mg), both as white solids.

[0385]

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[0386] 4-(((1-Methyl-6-morpholino-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound (63.4 mg, 57% yield, white solid) was prepared using the general procedure for 4-(((1-methyl-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.27).

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[0387] 4-(((6-(Cyclohexylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound (32.2 mg, yield: 28%, yellow solid) was prepared using the general procedure for 4-(((1-methyl-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide (Example 2.27).

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[0388] 4-(((6-(Ethyl(methyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound (66.2 mg, yield: 63%, white solid) was prepared using the general procedure for 4-(((1-methyl-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.27).

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[0389] 4-(((6-(Benzyl(methyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound (79.9 mg, yield: 66%, white solid) was prepared using the general procedure for 4-(((1-methyl-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.27).

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[0390] 4-(((1-Methyl-6-(piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound (38.9 mg, yield: 35%, yellow solid) was prepared using the general procedure for 4-(((1-methyl-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.27).

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[0391] 4-(((1-Methyl-6-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound (71.5 mg, yield: 62%, yellow solid) was prepared using the general procedure for 4-(((1-methyl-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.27).

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[0392] 4-(((6-(Cyclopropylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound (36.2 mg, 35% yield, white solid) was prepared using the general procedure for 4-(((1-methyl-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.27).

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[0393] 4-(((1-Methyl-6-(methyl(phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: To a mixture of 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (100 mg, 0.28 mmol) in N-methylaniline (6 mL) was added CuI (106 mg, 0.56 mmol). The mixture was stirred at 120° C. overnight. The resulting solution was concentrated, and the residue was purified by preparative HPLC to give 4-(((1-methyl-6-(methyl(phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (12.5 mg, 11% yield) as a purple solid.

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[0394] 4-(((6-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide

[0395] Steps 1 and 2: Steps 1 and 2 were prepared using the general procedure for 4-(((6-(cyclopropylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.35).

[0396] Step 3: A mixture of 4-(((6-(tert-butylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (62 mg, 0.16 mmol) and TFA (0.5 ml) in DCM / HO (10 mL / 0.5 mL) was stirred at 100° C. for 1 day. The resulting solution was concentrated, and the residue was purified by preparative HPLC to give 4-(((6-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (4.8 mg, yield: 9%) as a white solid.

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[0397] 4-(((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide

[0398] Step 1: A solution of phenylhydrazine hydrochloride (1 g, 6.9 mmol), 2-(ethoxymethylene)malononitrile (0.8 g, 6.9 mmol), and TEA (2 g, 20.7 mmol) in EtOH (15 mL) was stirred at 50° C. for 5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column (PE / EA=10 / 1) to give 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile (1 g, yield: 78.7%) as a yellow solid. MS: m / z 185.4 (M+H + ).

[0399] Step 2: A solution of 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile (1 g, 5.4 mmol) in formic acid (10 mL) was stirred at 100° C. overnight. The reaction was concentrated, and the residue was purified by slurry with DCM to give 1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol (0.8 g, 72% yield) as a yellow solid. MS: m / z 213.3 (M+H + ).

[0400] Step 3: A solution of 1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol (200 mg, 0.9 mmol) in POCl (5 mL) was stirred at 120 °C for 3 h. POCl was removed under reduced pressure. The mixture was quenched with hot water and neutralized with saturated aqueous NaHCO (100 mL). The aqueous phase was extracted with EA (100 mL × 3). The combined organic layers were dried and concentrated. The residue was purified by silica gel column (PE / EA = 10 / 1) to give 4-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (0.11 g, yield: 51%) as a white solid.

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[0401] Step 4: A solution of 4-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.4 mmol), 4-(aminomethyl)benzenesulfonamide (145.2 mg, 0.6 mmol), and K2CO3 (180 mg, 1.3 mmol) in ACN (5 mL) was stirred at 80 °C overnight. The reaction mixture was neutralized to pH = 7 and filtered. The filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to give 4-(((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (89.3 mg, yield: 54%) as a white solid.

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[0402] 4-(((1-methyl-6-vinyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.39) and 4-(((6-ethyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.40)

[0403] Step 1: A solution of 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (300 mg, 0.85 mmol), potassium vinyltrifluoroborate (228 mg, 1.70 mmol), KCO (352 mg, 2.55 mmol), and Pd(dppf)Cl (62 mg, 0.08 mmol) in dioxane / HO (3 mL / 0.5 mL) was stirred at 100 °C overnight. The reaction was then concentrated, and the residue was purified by preparative HPLC to give 4-(((1-methyl-6-vinyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (114 mg, 38.9% yield) as a white solid.

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[0404] Step 2: A solution of 4-(((1-methyl-6-vinyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (110 mg, 0.319 mmol) and Pd / C (11 mg) in MeOH (10 mL) was stirred at room temperature for 3 h. Then the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give 4-(((6-ethyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (22 mg, yield: 20%) as a white solid.

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[0405] 4-(((1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-2-(trifluoromethyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 3-methyl-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.2).

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[0406] 2-Methoxy-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 3-methyl-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.2).

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[0407] 4-(((1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide

[0408] Step 1: To a solution of benzyl 4-oxopiperidine-1-carboxylate (2.0 g, 8.6 mmol) in MeOH (10 mL) was added tert-butyl hydrazine carboxylate (1.14 g, 8.6 mmol) and HOAc (1.04 g, 17.2 mmol). The mixture was stirred at room temperature for 1 hour. Then, NaBHCN (1.08 g, 17.2 mmol) was added to the mixture. The new mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with DCM (10 mL x 3). The combined organic layers were concentrated in vacuo to give benzyl 4-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1-carboxylate (2.6 g, 86.7% yield) as a yellow oil. MS: m / z 350.5 (M+H) + ).

[0409] Step 2: To a solution of benzyl 4-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1-carboxylate (2.60 g, 7.4 mmol) in DCM (40 mL) was added TFA (10 mL) dropwise. The reaction mixture was stirred at room temperature overnight. The reaction was evaporated to remove the solvent to give benzyl 4-hydrazinylpiperidine-1-carboxylate (2.19 g, 70.4% yield) as a yellow oil. MS: m / z 250.4 (M+H + ).

[0410] Step 3: To a solution of benzyl 4-hydrazinylpiperidine-1-carboxylate (2.19 g, 6.04 mmol) in EtOH (20 mL) was added 2-(ethoxymethylene)malononitrile (670 mg, 5.49 mmol) and TEA (1.67 g, 16.47 mmol). The mixture was heated to 85 °C and stirred overnight. The reaction mixture was evaporated to remove the solvent. The residue was purified by silica flash column chromatography (EA / PE = 0-40%) to give benzyl 4-(5-amino-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.52 g, yield: 77.6%) as a yellow oil.

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[0411] Step 4: A solution of benzyl 4-(5-amino-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate (500 mg, 1.54 mmol) in formic acid (20 mL) was stirred at 100° C. overnight. The reaction mixture was evaporated to remove the solvent. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give 1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (302 mg, yield: 89.6%) as a white solid. MS: m / z 220.1 (M+H + ).

[0412] Step 5: A solution of 1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (300 mg, 1.37 mmol) in formaldehyde (20 mL) was stirred at room temperature for 1 hour. Then, NaBHCN (173 mg, 2.74 mmol) was added to the above mixture and stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with DCM (10 mL x 3). The combined organic layers were concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give 1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (57 mg, yield: 18.0%) as a white solid.

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[0413] Step 6: To a solution of 4-(aminomethyl)benzenesulfonamide (65 mg, 0.29 mmol) in ACN (5 mL) was added BOP (128 mg, 0.29 mmol) and DBU (38 mg, 0.25 mmol) under a N atmosphere (balloon). The reaction mixture was stirred at room temperature for 1 hour. Next, 1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (45 mg, 0.19 mmol) was added to the mixture, and the new mixture was stirred overnight. The reaction mixture was evaporated to remove the solvent. The residue was poured into HO (10 mL) and extracted with DCM (10 mL × 3). The combined organic layers were concentrated in vacuo. The residue was purified by preparative HPLC to give 4-(((1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (10.6 mg, yield: 13.8%) as a colorless oil.

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[0414] 4-(((1-methyl-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide

[0415] Step 1: A mixture of 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(3aH)-one (500 mg, 0.33 mmol) in Br / HO (10 mL / 3 mL) was stirred at room temperature for 2 days. The mixture was concentrated to give 3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(3aH)-one (650 mg, 80% yield) as a yellow solid. MS: m / z 228.0 (M+H + ).

[0416] Step 2: A mixture of 3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(3aH)-one (600 mg, 2.6 mmol), phenylboronic acid (470 mg, 3.9 mmol), KCO (1.07 g, 7.8 mmol), and Pd(dppf)Cl (190 mg, 0.03 mmol) in dioxane / HO was stirred at 95 °C overnight under a N atmosphere (balloon). The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica flash column (PE / EA = 0 / 1) to give 1-methyl-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(3aH)-one (170 mg, yield: 28.9%) as a brown solid. MS: m / z 227.0 (M+H + ).

[0417] Step 3: A mixture of 1-methyl-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(3aH)-one (129 mg, 0.57 mmol) in POCl (5 mL) was stirred at 100° C. for 4 h. The mixture was concentrated to give 4-chloro-1-methyl-3-phenyl-3a,4-dihydro-1H-pyrazolo[3,4-d]pyrimidine (85 mg, 61% yield) as a yellow solid. MS: m / z 247.0 (M+H). + ).

[0418] Step 4: To a mixture of 4-chloro-1-methyl-3-phenyl-3a,4-dihydro-1H-pyrazolo[3,4-d]pyrimidine (85 mg, 0.35 mmol) and K2CO3 (241 mg, 1.75 mmol) in ACN (5 mL) was added 4-(aminomethyl)benzenesulfonamide (231 mg, 1.04 mmol). The mixture was stirred at 80 °C overnight. The mixture was filtered, and the filtrate was purified by preparative HPLC to give 4-(((1-methyl-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (3 mg) as a white solid.

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[0419] 4-(((1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide

[0420] Step 1: A mixture of 5-amino-1,3-dimethyl-1H-pyrazole-4-carboxamide (400 mg, 2.5 mmol) in triethoxymethane (20 mL) was stirred at 140° C. for 2 days. The mixture was concentrated to give 1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol (300 mg, 73% yield) as a yellow solid. MS: m / z 165.0 (M+H + ).

[0421] Step 2: A mixture of 1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol (200 mg, 1.2 mmol) in POCl (5 mL) was stirred at 95 °C for 4 h. The mixture was concentrated to give 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 89% yield) as a yellow solid. MS: m / z 182.9 (M+H). + ).

[0422] Step 3: A mixture of 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 1.09 mmol), KCO (451 mg, 3.27 mmol), and 4-(aminomethyl)benzenesulfonamide (489 mg, 2.19 mmol) in ACN (10 mL) was stirred overnight at 80° C. The mixture was filtered, and the filtrate was purified by preparative HPLC to give 4-(((1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide (2.1 mg) as a white solid.

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[0423] 2-Methyl-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide

[0424] Step 1: A solution of 4-bromo-3-methylbenzonitrile (2 g, 10.2 mmol), CsCO (6.6 g, 20.4 mmol), Pd(dba) (467 mg, 0.51 mmol), Xantphos (295 mg, 0.51 mmol), and phenylmethanethiol (1.5 g, 12.24 mmol) in dioxane (20 mL) was stirred overnight at 100 °C under a N atmosphere (balloon). The dioxane was removed under reduced pressure. The residue was purified using a silica gel column (PE / EA = 1 / 1) to give 4-(benzylthio)-3-methylbenzonitrile (1 g, 36% yield) as a yellow solid.

[0425] Steps 2-5: The title compound was prepared using the general procedure for 2-chloro-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.4).

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[0426] 3-Chloro-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 2-chloro-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.4).

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[0427] 4-(((6-(benzylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide

[0428] Step 1: To a solution of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 2.46 mmol) in ACN (40 mL) was added 4-(aminomethyl)benzenesulfonamide (604 mg, 2.7 mmol) and DIEA (635 mg, 4.92 mmol). The mixture was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to afford 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (735 mg, 85% yield) as a yellow solid.

[0429] Step 2: To a solution of 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (50 mg, 0.14 mmol) in DMF (3 mL) was added phenylmethanamine (76 mg, 0.71 mmol) and potassium carbonate (39 mg, 0.28 mmol). After stirring at 100° C. for 2 h by microwave, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give 4-(((6-(benzylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (5.6 mg, yield: 9.5%) as a white solid.

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[0430] 4-(((6-(Ethylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide: A solution of 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (50 mg, 0.14 mmol), ethanamine (25.2 mg, 0.56 mmol), and potassium carbonate (39 mg, 0.28 mmol) in DMSO (5 mL) was stirred at 100° C. for 2 h under a sealed tube, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give 4-(((6-(ethylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (9.8 mg, yield: 19.2%) as a white solid.

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[0431] 4-(((1-methyl-6-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-benzenesulfonamide

[0432] Step 1: A solution of 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (50 mg, 0.14 mmol) in aniline (3 mL) was stirred at 120° C. overnight. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give 4-(((1-methyl-6-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (2.0 mg, yield: 0.9%) as a white solid.

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[0433] 1-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)propyl)piperidin-4-amine

[0434] Step 1: To a solution of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (768 mg, 1.21 mmol) in ACN (40 mL) was added tert-butyl piperidin-4-ylcarbamate (758 mg, 3.78 mmol), followed by DIEA (1.47 g, 11.34 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The solid that precipitated from the mixture was then filtered and dried in air to give tert-butyl (1-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (1.31 g, yield: 94%) as a yellow solid.

[0435] Step 2: To a solution of tert-butyl (1-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (366 mg, 1.0 mmol) and methylboronic acid (600 mg, 10.0 mmol) in dioxane / HO (30 mL / 10 mL) was added KCO (414 mg, 3.0 mmol), followed by Pd(dppf)Cl (73 mg, 0.1 mmol). The resulting mixture was then stirred at 80 °C under a N atmosphere (balloon) overnight. The reaction was monitored by LCMS and TLC. The mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column (DCM / MeOH=100 / 1 to 30 / 1) to give tert-butyl (1-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (186 mg, yield: 54%) as a yellow solid.

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[0436] Step 3: To a solution of tert-butyl (1-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (186 mg, 0.53 mmol) in EA (10 mL) was added HCl / dioxane (6 mL). The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. Then, the mixture was concentrated in vacuo to give 1-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-amine (118 mg, yield: 89%) as a brown solid.

[0437] Step 4: To a solution of 1-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-amine (118 mg, 0.42 mmol) in MeOH (10 mL) was added 3-(pyridin-4-yl)propanal (57 mg, 0.42 mmol). The resulting mixture was stirred at room temperature overnight. Then, NaBHCN (80 mg, 1.26 mmol) was added to the mixture, and the mixture was stirred for another 1 hour. The reaction was monitored by LCMS. The mixture was then concentrated in vacuo to give a residue, which was purified by preparative HPLC using NHHCO as an additive to give 1-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)propyl)piperidin-4-amine (27.2 mg, yield: 18%) as a yellow solid.

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[0438] 5-(((1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)pyridine-2-sulfonamide: The title compound was prepared using the general procedure for 3-methyl-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.2).

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[0439] 6-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)pyridine-3-sulfonamide

[0440] The title compound was prepared using the general procedure for 3-methyl-4-(((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.2).

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[0441] 4-[(1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-ylamino)-methyl]-benzenesulfonamide

[0442] Step 1: A solution of 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1 g, 5.92 mmol) in formamide (10 mL) was stirred at 180 °C for 3 h. After cooling to room temperature, the reaction mixture was filtered and the pad was rinsed with THF to give 1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol (500 mg, 56% yield) as a white solid. MS: m / z 151.1 (M+H) + ).

[0443] Step 2: A mixture of 1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol (500 mg, 3.33 mmol) in POCl (8 mL) was stirred at 120 °C for 16 h. POCl was removed under reduced pressure. The residue was neutralized with saturated aqueous NaHCO (100 mL) and extracted with EA (100 mL x 3). The combined organic layers were dried over NaSO and concentrated to give 7-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine (600 mg, crude) as a yellow solid.

[0444] Step 3: A mixture of 7-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine (220 mg, 1.31 mmol), 4-(aminomethyl)benzenesulfonamide (366 mg, 1.96 mmol), and K2CO3 (728 mg, 5.24 mmol) in ACN (30 mL) was stirred at 80 °C overnight. The mixture was acidified to pH = 7 with 2 M HCl. The suspension was then filtered, and the pad was purified by preparative HPLC (NH4HCO3) to give 4-[(1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-ylamino)-methyl]-benzenesulfonamide (86 mg, yield: 21%) as a white solid.

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[0445] 4-(((1-methyl-1H-pyrazolo[3,4-c]pyridazin-4-yl)amino)methyl)benzenesulfonamide

[0446] Step 1: To a suspension of 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (1.0 g, 8.19 mmol) in THF (20 mL) was added MeMgBr (27 mL, 81.9 mmol) dropwise at 0 °C. The mixture was then stirred at 70 °C for 2 h. The reaction mixture was poured into saturated aqueous NH4Cl (100 mL) and extracted with EA (50 mL x 3). The organic layer was washed with brine (100 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column (PE / EA = 3 / 1 to 1 / 1) to give 1-(5-amino-1-methyl-1H-pyrazol-4-yl)ethanone (591 mg, yield: 52%) as a yellow solid.

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[0447] Step 2: To a suspension of 4,7-dibromobenzo[c][1,2,5]thiadiazole (129 mg, 0.93 mmol) in HO (1 mL) and concentrated HCl (4 mL) was added a solution of NaNO (128 mg, 1.86 mmol) in HO (0.5 mL) dropwise at 0 °C. The mixture was stirred at −5 °C for 20 min. The mixture was then warmed to room temperature and stirred for 10 min. The mixture was stirred at 65 °C for 30 min. The reaction mixture was cooled in an ice bath and then filtered. The filtrate was lyophilized to afford 1-methyl-1H-pyrazolo[3,4-c]pyridazin-4-ol (198 mg, crude) as a yellow solid.

[0448] Step 3: A suspension of 1-methyl-1H-pyrazolo[3,4-c]pyridazin-4-ol (198 mg, crude) and POCl3 (8 mL) in DCM (4 mL) was stirred at 65 °C for 2.5 h. LCMS showed that 1-methyl-1H-pyrazolo[3,4-c]pyridazin-4-ol had reacted completely. The mixture was concentrated. The residue was neutralized with saturated aqueous NaHCO3 (10 mL) and extracted with EA (30 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column (PE / EA = 8 / 1 to 6 / 1) to give 4-chloro-1-methyl-1H-pyrazolo[3,4-c]pyridazine (40 mg, yield: 18%) as a white solid. MS: m / z 168.9 (M+H) + )

[0449] Step 4: A suspension of 4-chloro-1-methyl-1H-pyrazolo[3,4-c]pyridazine (40 mg, 0.24 mmol), 4-(aminomethyl)benzenesulfonamide (177 mg, 0.95 mmol), and t-BuOK (1.6 mg, 0.014 mmol) in NMP (15 mL) was stirred at 180 °C for 4 h by microwave. The reaction mixture was concentrated to remove NMP. The residue was purified by preparative HPLC to give 4-(((1-methyl-1H-pyrazolo[3,4-c]pyridazin-4-yl)amino)methyl)benzenesulfonamide (36 mg, yield: 48%) as a yellow solid.

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[0450] 4-(((1-methyl-1H-pyrazolo[3,4-d]pyridazin-4-yl)amino)methyl)benzenesulfonamide

[0451] Step 1: A suspension of sodium (Z)-1,4-diethoxy-1,4-dioxobut-2-en-2-olate (4.2 g, 20 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (5.4 mL, 40 mmol) in EtOH (10 mL) was stirred at room temperature for 30 minutes. AcOH (2.4 mL, 40 mmol) was added to the mixture. The new mixture was stirred at room temperature for 24 hours. The mixture was concentrated. The residue was purified by silica gel column (PE / EA=1 / 1) to give (Z)-diethyl 2-((dimethylamino)methylene)-3-oxosuccinate (2.4 g, yield: 49%) as a yellow oil. MS: m / z 244.1 (M+H + ).

[0452] Step 2: To a suspension of (Z)-diethyl 2-((dimethylamino)methylene)-3-oxosuccinate (930 mg, 3.8 mmol) in EA (20 mL) was added tert-butyl 1-methylhydrazinecarboxylate (788 mg, 5.4 mmol) at −5° C. The mixture was stirred at −5° C. for 2 hours. The mixture was concentrated. The residue was purified by silica gel column (PE / EA=2 / 1) to give (Z)-diethyl 2-((2-(tert-butoxycarbonyl)-2-methylhydrazinyl)methylene)-3-oxosuccinate (980 mg, yield: 75%) as a white solid. MS: m / z 345.2 (M+H + ).

[0453] Step 3: To a suspension of (Z)-diethyl 2-((2-(tert-butoxycarbonyl)-2-methylhydrazinyl)methylene)-3-oxosuccinate (300 mg, 0.87 mmol) in EtOH (8 mL) was added HCl / EA (8 mL). The mixture was stirred at room temperature for 16 h. The mixture was concentrated to give diethyl 1-methyl-1H-pyrazole-4,5-dicarboxylate (280 mg, crude) as a yellow solid. MS: m / z 227.1 (M+H + ).

[0454] Step 4: To a suspension of diethyl 1-methyl-1H-pyrazole-4,5-dicarboxylate (280 mg, 1.2 mmol) in EtOH (50 mL) was added NHNH 2· HO (10 mL) was added. The mixture was stirred at 90° C. for 16 hours. The mixture was concentrated. The residue was purified by reverse phase column chromatography to give 1-methyl-5,6-dihydro-1H-pyrazolo[3,4-d]pyridazine-4,7-dione (350 mg, crude) as a yellow solid. MS: m / z 167.1 (M+H + ).

[0455] Step 5: To a suspension of 1-methyl-5,6-dihydro-1H-pyrazolo[3,4-d]pyridazine-4,7-dione (161 mg, crude) was added POCl (5 mL). The mixture was stirred at 100 °C for 1 h. The mixture was concentrated. The residue was neutralized with saturated aqueous NaHCO (20 mL) and extracted with EA (20 mL). The organic layer was dried over NaSO and concentrated. The residue was purified by reverse-phase column chromatography to give 4,7-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyridazine (23 mg, yield: 11%) as a yellow solid. MS: m / z 203.2 (M+H) + ).

[0456] Step 6: A suspension of 4,7-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyridazine (23 mg, 0.11 mmol), KCO (47 mg, 0.34 mmol), and 4-(aminomethyl)benzenesulfonamide (76 mg, 0.34 mmol) in NMP (2 mL) was stirred at 130° C. for 2 h. The mixture was purified by preparative HPLC to give 4-(((7-chloro-1-methyl-1H-pyrazolo[3,4-d]pyridazin-4-yl)amino)methyl)benzenesulfonamide (5 mg, yield: 12%) as a yellow solid.

[0457] Step 7: A suspension of 4-(((7-chloro-1-methyl-1H-pyrazolo[3,4-d]pyridazin-4-yl)amino)methyl)benzenesulfonamide (5 mg, 0.0142 mmol) and Pd / C (3 mg) in MeOH (3 mL) was stirred at room temperature under an H atmosphere (balloon) for 16 h. The mixture was filtered. The filtrate was purified by preparative HPLC to give 4-(((1-methyl-1H-pyrazolo[3,4-d]pyridazin-4-yl)amino)methyl)benzenesulfonamide (3.3 mg, yield: 73%) as a white solid.

[0458]

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[0459] N-(3-(4-Fluorophenyl)propyl)-1-(3-methylisoxazolo[5,4-d]pyrimidin-4-yl)piperidin-4-amine: The title compound was prepared using the general procedure for 1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)propyl)piperidin-4-amine (Example 2.5).

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[0460] 4-(((3-Methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)amino)methyl)benzenesulfonamide: The title compound was prepared using the general procedure for 5-(((5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide (Example 1.28).

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[0461] 4-(((3-Methylisoxazolo[5,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide: The title compound was prepared using the general procedure for 5-(((5-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methyl)thiophene-2-sulfonamide (Example 1.28).

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[0462] 4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide

[0463] Step 1: A solution of 2,4-dichloronicotinaldehyde (1.0 g, 5.7 mmol), ethane-1,2-diol (709 mg, 11.4 mmol), and TsOH (980 mg, 5.7 mmol) in toluene (30 mL) was stirred overnight at 130° C. After completion, the reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (PE / EA=2 / 1) to give 2,4-dichloro-3-(1,3-dioxolan-2-yl)pyridine (1.1 g, yield: 88%) as a yellow oil.

[0464] Step 2: To a solution of 2,4-dichloro-3-(1,3-dioxolan-2-yl)pyridine (150 mg, 0.86 mmol) in ACN (15 mL) was added 4-(aminomethyl)benzenesulfonamide (573 mg, 2.57 mmol) and DIEA (332 mg, 2.57 mmol). The reaction mixture was stirred at 100° C. overnight. The mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column (DCM / MeOH=10 / 1) to give 4-(((2-chloro-3-(1,3-dioxolan-2-yl)pyridin-4-yl)amino)methyl)benzenesulfonamide (70 mg, yield: 22%) as a yellow solid.

[0465] Step 3: To a solution of 4-(((2-chloro-3-(1,3-dioxolan-2-yl)pyridin-4-yl)amino)methyl)benzenesulfonamide (50 mg, 0.14 mmol) in THF (10 mL) was added 5% HCl (1 mL). The mixture was stirred at room temperature overnight. The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL × 3). The combined EA layers were dried over Na2SO4, filtered, and concentrated. The residue was then dissolved in DMSO (5 mL), and methylhydrazine and DIEA (55 mg, 0.42 mmol) were added. The mixture was stirred at 120 °C overnight. The mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give 4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (9.0 mg, yield: 20%) as a white solid.

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[0466] 3-chloro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide

[0467] Step 1: A solution of 2-chloro-4-fluorobenzonitrile (3 g, 19 mmol), BnSH (2.3 mL, 19.7 mmol), and KCO (5.3 g, 38.4 mmol) in DMF (35 mL) was stirred at 110 °C overnight. The reaction mixture was poured into HO (150 mL) and extracted with EA (150 mL). The EA layer was washed with brine (150 mL × 2), dried over NaSO, and concentrated to dryness in vacuo. The residue was purified by silica gel column (PE / EA = 20 / 1) and silica flash column (2% EA in PE) to give 4-(benzylthio)-2-chlorobenzonitrile (1.5 g, yield: 30%) as a yellow solid.

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[0468] Step 2: A solution of NCS (206 mg, 1.54 mmol) and HCl (0.3 mL, 3.6 mmol) in MeCN (4 mL) was stirred at room temperature for 30 min. Then, a solution of 4-(benzylthio)-2-chlorobenzonitrile (100 mg, 0.39 mmol) in MeCN (3 mL) was added to the reaction mixture. The new mixture was stirred at room temperature for 2 h. The reaction mixture was poured into HO (40 mL) and extracted with EA (40 mL). The EA layer was washed with brine (40 mL), dried over NaSO, and concentrated to give 3-chloro-4-cyanobenzene-1-sulfonyl chloride (150 mg, yield: crude) as a colorless oil.

[0469] Step 3: To a solution of 3-chloro-4-cyanobenzene-1-sulfonyl chloride (150 mg, 0.6 mmol) in THF (3 mL) was added NH3.HO (1.5 mL) at room temperature. The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated, and the residue was purified by silica flash column (25% EA in PE) to give 3-chloro-4-cyanobenzenesulfonamide (65 mg, yield: 50%) as a white solid.

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[0470] Step 4: A solution of 3-chloro-4-cyanobenzenesulfonamide (300 mg, 1.4 mmol), Raney Ni, and NHOH (1.5 mL) in MeOH (10 mL) was stirred under a H atmosphere (balloon) at room temperature for 3.5 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness in vacuo. The residue was purified by reverse-phase column chromatography (22% MeCN in H2O) to afford 4-(aminomethyl)-3-chlorobenzenesulfonamide (165 mg, 54% yield) as a white solid.

[0471] Step 5: A solution of 4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (30 mg, 0.18 mmol), 4-(aminomethyl)-3-chlorobenzenesulfonamide (160 mg, 0.73 mmol), and t-BuOK (1.2 mg, 0.01 mmol) in NMP (2 mL) was stirred at 180° C. for 4 hours under microwave conditions. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (NH4CO3) to give 3-chloro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (4.5 mg, 7% yield) as a yellow solid.

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[0472] 4-(((1-Methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-2-(trifluoromethyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 3-chloro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.61).

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[0473] 3-Methoxy-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide: The title compound was prepared using the general procedure for 3-chloro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.61).

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[0474] 3-Fluoro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide

[0475] Step 1: To a solution of 4-amino-2-fluorobenzonitrile (4 g, 29.4 mmol) in MeCN (100 mL) was added BnS and t-BuONO (2.1 g) at room temperature. The mixture was then stirred at 60 °C for 2 h. The reaction mixture was poured into saturated aqueous NaHCO (300 mL) and extracted with EA (250 mL). The EA layer was washed with brine (200 mL), dried over NaSO, and concentrated to dryness in vacuo. The residue was purified using a silica gel column (PE / EA = 100 / 1) to give 4-(benzylthio)-2-fluorobenzonitrile (2.7 g, yield: 38%) as a yellow solid.

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[0476] Step 2: A solution of NCS (440 mg, 3.3 mmol) and HCl (0.7 mL, 8.4 mmol) in MeCN (3 mL) was stirred at room temperature for 30 min. Then, a solution of 4-(benzylthio)-2-fluorobenzonitrile (200 mg, 0.8 mmol) in MeCN (2 mL) was added to the reaction mixture. The new mixture was stirred at room temperature for 2 h. The reaction mixture was poured into HO (50 mL) and extracted with EA (50 mL). The EA layer was washed with brine (50 mL), dried over NaSO, and concentrated to give 4-cyano-3-fluorobenzene-1-sulfonyl chloride (180 mg, yield: crude) as a colorless oil.

[0477] Step 3: To a solution of 4-cyano-3-fluorobenzene-1-sulfonyl chloride (180 mg, 0.8 mmol) in THF (3 mL) was added NH3.HO (2 mL) at room temperature. The mixture was stirred at 60 °C for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica flash column (28% EA in PE) to give 4-cyano-3-fluorobenzenesulfonamide (150 mg, yield: 91%) as a white solid.

[0478] Step 4: A solution of 4-cyano-3-fluorobenzenesulfonamide (550 mg, 2.75 mmol), Raney Ni, and NHOH (4 mL) in MeOH (35 mL) was stirred under a H atmosphere (balloon) at room temperature for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness in vacuo. The residue was purified by reverse-phase column chromatography (14% MeCN in H2O) to afford 4-(aminomethyl)-3-fluorobenzenesulfonamide (370 mg, 66% yield) as a yellow solid.

[0479] Step 5: A solution of 4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (75 mg, 0.45 mmol), 4-(aminomethyl)-3-fluorobenzenesulfonamide (370 mg, 1.81 mmol), and t-BuOK (3 mg, 0.03 mmol) in NMP (4 mL) was stirred at 180° C. for 4 hours under a microwave atmosphere. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (NH4CO3) to give 3-fluoro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (22.8 mg, 15% yield) as a white solid.

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[0480] 2-Methoxy-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 3-chloro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.61).

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[0481] 4-(((1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)benzenesulfonamide

[0482] Step 1: To a solution of 2,4-dichloronicotinaldehyde (100 mg, 0.57 mmol) in MeOH (20 mL) was added methylhydrazine (29 mg, 0.63 mmol) and TEA (0.5 mL). The mixture was stirred at room temperature for 2 hours. The resulting solution was filtered. The cake was purified by preparative TLC (DCM / MeOH = 30 / 1) to give 4-chloro-1-methyl-1H-pyrazolo[4,3-c]pyridine (80 mg, yield: 83%) as a white solid.

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[0483] Step 2: The title compound (13.8 mg, 15% yield, white solid) was prepared using the general procedure for 4-(((1-methyl-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzenesulfonamide (Example 2.27).

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[0484] 2-Fluoro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide

[0485] Step 1: A solution of 3,4-difluorobenzonitrile (5 g, 35.97 mmol), phenylmethanethiol (4.2 mL, 35.97 mmol), and K2CO3 (10 g, 71.94 mmol) in DMSO (20 mL) was stirred at 110 °C overnight. The reaction mixture was diluted with water (120 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column (PE / EA = 20 / 1) to give 4-(benzylthio)-3-fluorobenzonitrile (5.89 g, yield: 67%) as a white solid.

[0486] Step 2: A solution of 4-(benzylthio)-3-fluorobenzonitrile (5.89 g, 24.24 mmol) and NCS (13 g, 96.95 mmol) in AcOH (20 mL) was stirred at 0° C. for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with brine (200 mL), dried over NaSO, and concentrated to give 4-cyano-2-fluorobenzene-1-sulfonyl chloride (5 g, crude) as a colorless oil.

[0487] Step 3: 4-cyano-2-fluorobenzene-1-sulfonyl chloride (5 g, 22.83 mmol) and NH3 in THF (10 mL) . The solution of HO (2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (PE / EA=2 / 1) to give 4-cyano-2-fluorobenzenesulfonamide (2.5 g, yield: 54%) as a white solid.

[0488] Step 4: 4-cyano-2-fluorobenzenesulfonamide (500 mg, 2.5 mmol), Raney Ni (500 mg, 2.5 mmol) and NH3 in MeOH (5 mL) . HO (1 mL) was stirred under an H atmosphere (balloon) at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by reverse-phase column chromatography to give 4-(aminomethyl)-2-fluorobenzenesulfonamide (300 g, yield: 59%) as a white solid.

[0489] Step 5: A solution of 4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (30 mg, 0.18 mmol), 4-(aminomethyl)-2-fluorobenzenesulfonamide (146 mg, 0.718 mmol), and t-BuOK (1.2 mg, 0.01 mmol) in NMP (2 mL) was stirred at 180° C. for 4 hours by microwave irradiation. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give 2-fluoro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (8 mg, yield: 13%) as a white solid.

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[0490] 2-Chloro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 2-fluoro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.67).

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[0491] 3-Methyl-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 2-fluoro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.67).

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[0492] 2-Methyl-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 2-fluoro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.67).

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[0493] 6-(((1-Methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)pyridine-3-sulfonamide: The title compound was prepared using the general procedure for 2-fluoro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.67).

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[0494] 5-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)pyridine-2-sulfonamide

[0495] The title compound was prepared using the general procedure for 2-fluoro-4-(((1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.67).

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[0496] 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide

[0497] Step 1: Na (7 g, 304 mmol) was added to EtOH at room temperature, and the mixture was stirred under a N atmosphere (balloon) for 1 hour. Next, ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (12 g, 71 mmol) was added to the mixture. The new mixture was stirred at room temperature for 0.5 hours, after which dimethyl malonate was added dropwise to the reaction mixture. The new reaction mixture was stirred overnight at 85 °C under a N atmosphere (balloon). The reaction mixture was concentrated, and the residue was dissolved in HO (approximately 200 mL). The suspension was filtered, and the pad was dissolved in HO (120 mL). The solution was acidified to pH = 3.0 with concentrated HCl. The new suspension was filtered, and the pad was dried to give a portion of ethyl 4-hydroxy-1-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. The filtrate was then acidified again with concentrated HCl. The suspension was filtered and the pad was triturated with EA / HO (60 mL / 15 mL) to give another portion of ethyl 4-hydroxy-1-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. The combined target material was approximately 18 g of a pale yellow solid.

[0498] Step 2: A solution of ethyl 4-hydroxy-1-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (5.8 g, 24.5 mmol) and NaOH (7 g) in HO (40 mL) was stirred at 100° C. overnight. The reaction mixture was acidified with concentrated HCl to pH=3.0. The suspension was filtered and rinsed with HO and EA to give 4-hydroxy-1-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (1.5 g, 37% yield) as a white solid.

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[0499] Step 3: A solution of 4-hydroxy-1-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7.6 g, 46 mmol) in PhPOCl (38 mL) was stirred at 170° C. for 8 h. The reaction mixture was cooled to room temperature, and hot water (150 mL, ca. 50° C.) was added. The mixture was then slowly neutralized with NaHCO. The HO phase was extracted with EA (150 mL). The EA phase was washed with brine (150 mL), dried, and concentrated to give 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (8.2 g, yield: 89%) as a gray solid.

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[0500] Step 4: A solution of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (4 g, 20 mmol), 4-(aminomethyl)benzenesulfonamide (4 g, 21.5 mmol), and K2CO3 (6.8 g, 49 mmol) in DMF (30 mL) was stirred at 100 °C overnight. The reaction mixture was poured into HO (100 mL) and extracted with EA (160 mL). The suspension was filtered, and the pad was rinsed with HO and EA to give 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (2.49 g, 36% yield) as an off-white solid.

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[0501] 4-(((6-(Isopropylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide: A solution of 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (60 mg, 0.17 mmol) and iPr-NH (2 mL) in NMP (0.5 mL) was stirred at 200° C. for 16 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (NHCO) to give 4-(((6-(isopropylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (5 mg, yield: 8%) as a white solid.

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[0502] 4-(((6-(Ethylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((6-(isopropylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.74).

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[0503] 4-(((1-Methyl-6-(methylamino)-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((6-(isopropylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.74).

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[0504] 4-(((1-Methyl-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((6-(isopropylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.74).

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[0505] 4-(((6-Amino-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((6-(isopropylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.74).

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[0506] 4-(((6-(Diethylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((6-(isopropylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.74).

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[0507] 4-(((6-(Butylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((6-(isopropylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.74).

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[0508] 4-(((6-((2-hydroxyethyl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((6-(isopropylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.74).

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[0509] 4-(((1-Methyl-6-morpholino-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-benzenesulfonamide: The title compound was prepared using the general procedure for 4-(((6-(isopropylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.74).

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[0510] 4-((6-Chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: To a suspension of 2,4,6-trichloro-5-pyrimidinecarboxaldehyde (3.12 g) in ethanol (30 mL) was added dropwise ethylhydrazine (1.09 mL) and triethylamine (6.2 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 hour and then at room temperature for 3 hours. Homosulfamine hydrochloride (3.64 g) and triethylamine (4.2 mL) were added, and the mixture was stirred at 80° C. for 4 hours. After the reaction, the reaction mixture was evaporated under reduced pressure. Ethyl acetate and saturated ammonium chloride solution were added to the residue, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected, washed successively with water, ethyl acetate, and 2-propanol, and then dried under reduced pressure to give the title compound as a yellow solid (2.37 g, 44% yield).

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[0511] 4-((6-chloro-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.83 using cyclopropylhydrazine hydrochloride.

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[0512] 5-((6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)thiophene-2-sulfonamide: To a suspension of 4,6-dichloro-1-methylpyrazolo[3,4-d]pyrimidine (77.4 mg) and 5-(aminomethyl)thiophene-2-sulfonamide (88.0 mg) in 2-propanol (2 mL) was added N,N-diisopropylethylamine (0.146 mL) at room temperature. The resulting mixture was stirred at 85° C. for 7 hours and evaporated under reduced pressure. Ethyl acetate and saturated ammonium chloride solution were added to the residue, and the mixture was stirred at room temperature. The precipitate was collected, washed successively with water and ethyl acetate, and then dried under reduced pressure to give the title compound as a yellow solid (60.0 mg, 44% yield).

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[0513] 4-((6-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide

[0514] Step 1: To a suspension of 2,4,6-trichloro-5-pyrimidinecarboxaldehyde (797 mg) in ethanol (12 mL) was added dropwise 2,2,2-trifluoroethylhydrazine (70% by weight in water, 612 mg) and triethylamine (1.60 mL) at −78°C. The resulting mixture was stirred at −78°C for 30 minutes and then from 0°C to room temperature for 1.5 hours. The reaction mixture was evaporated under reduced pressure. Ethyl acetate was added to the residue, which was washed successively with saturated ammonium chloride solution and brine, and then dried over anhydrous sodium sulfate. The resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by automated flash chromatography using 0 to 25% ethyl acetate in hexane to give 4,6-dichloro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidine as a colorless solid (260 mg, 25% yield). MS: m / z 271.0 (M+H + ).

[0515] Step 2: The title compound was prepared according to the general procedure of Example 2.85 using the above obtained 4,6-dichloro-1-(2,2,2 trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidine and homosulfamine hydrochloride.

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[0516] 4-((3-bromo-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide

[0517] Step 1: To a solution of 3-bromo-4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (50.6 mg), triphenylphosphine (98.2 mg) in methanol (0.2 mL) and tetrahydrofuran (2.0 mL) was added 1,1'-(azodicarbonyl)dipiperidine (94.8 mg) at room temperature. The reaction mixture was stirred at room temperature for 6 hours, then quenched by adding water and extracted with ethyl acetate. The combined organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by automated flash chromatography using 10–75% ethyl acetate in dichloromethane followed by 9% methanol in dichloromethane as eluent to give 3-bromo-4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine as a colorless solid (31.5 mg, 59.2% yield).

[0518] Step 2: The title compound was prepared according to the general procedure in Example 2.85 using the above obtained 3-bromo-4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine and homosulfamine hydrochloride.

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[0519] 4-((3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.85 using 3-bromo-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine and homosulfamine hydrochloride. MS: m / z 397 (M+H + ). Example 2.89 [ka]

[0520] 4-((3-Bromo-1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.85 using 3-bromo-4-chloro-1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidine and homosulfamine hydrochloride.

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[0521] 4-((3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide

[0522] Step 1: To a suspension of 3,4-dichloro-1H-pyrazolo[3,4-d]pyrimidine (66.8 mg) and potassium carbonate (111 mg) in N,N-dimethylformamide (2.0 mL) was added iodomethane (0.048 mL). The mixture was stirred overnight at room temperature, then quenched by adding water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by automated flash chromatography using 0 to 60% ethyl acetate in dichloromethane as the eluent to give 3,4-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine as a colorless solid (55.1 mg, 76.8% yield).

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[0523] Step 2: The title compound was prepared according to the general procedure of Example 2.85 using the above obtained 3,4-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine and homosulfamine hydrochloride.

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[0524] 4-((6-Ethoxy-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: 4-((6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide (40.9 mg) obtained in Example 2.83 was added to 20% sodium ethoxyethanol solution (1 mL) and stirred at 80° C. for 6 hours. The resulting mixture was diluted with DMSO and water and purified by preparative HPLC using 0.1 volume / volume percent (v / v%) formic acid in distilled water and 0.1 v / v% formic acid-acetonitrile as eluents to obtain the title compound as a colorless amorphous substance (22.4 mg, yield 53%).

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[0525] 4-((6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.85 using 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine and homosulfamine hydrochloride. MS: m / z 353.0 (M+H + ). Example 2.93 [ka]

[0526] 4-((6-Ethoxy-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.91 using the 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained above.

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[0527] 4-((6-Methoxy-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.92 using 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.91 and 1 mol / l sodium methoxide solution.

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[0528] 5-((6-Methoxy-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)thiophene-2-sulfonamide: The title compound was prepared according to the general procedure of Example 2.91 using 5-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)thiophene-2-sulfonamide obtained in Example 2.85 and 1 mol / l sodium methoxide solution.

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[0529] 4-((3-Bromo-6-methoxy-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.91 using 4-((3-bromo-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.87 and 1 mol / l sodium methoxide solution.

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[0530] 4-((3-Bromo-6-ethoxy-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.91 using 4-((3-bromo-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.87.

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[0531] 4-((1-Ethyl-6-(3-methoxy-3-methylbutoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: Potassium tert-butoxide (147 mg) was added to 3-methoxy-3-methylbutanol (1 mL) at room temperature. After stirring at the same temperature for 20 minutes, 4-((6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide (109 mg) obtained in Example 2.83 was added. The resulting mixture was stirred at 70°C for 10 hours, diluted with dimethyl sulfoxide, and purified by preparative HPLC using 0.1 v / v% formic acid in distilled water and 0.1 v / v% formic acid in acetonitrile as eluents to obtain the title compound as a colorless solid (102 mg, yield 76%).

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[0532] 4-((6-(2,2,2-Trifluoroethoxy)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.98 using 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.92 and 2,2,2-trifluoroethanol in dimethyl sulfoxide.

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[0533] 4-((6-Butoxy-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.98 using 4-((6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.83 and 1-butanol.

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[0534] 4-((1-Methyl-6-(3-methylbutoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared following the general procedure of Example 2.98 using 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.92 and 3-methyl-1-butanol.

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[0535] 4-((1-Ethyl-6-(3-methylbutoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.98 using 4-((6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.83 and 3-methyl-1-butanol.

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[0536] 4-((6-(2-Hydroxyethoxy)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.98 using 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.92, 2-(tert-butyldimethylsilyloxy)ethanol and sodium tert-butoxide.

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[0537] 4-((1-Ethyl-6-(2-hydroxyethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared following the general procedure of Example 2.98 using 4-((6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.83 and ethylene glycol.

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[0538] 4-((6-(3-Hydroxypropoxy)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.98 using 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.92, 1,3-propanediol, and sodium tert-butoxide.

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[0539] 4-((6-(3-Hydroxy-3-methylbutoxy)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.98 using 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.92 and 3-methyl-1,3-butanediol.

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[0540] 4-((1-Methyl-6-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: To a mixture of 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.92 (30.2 mg) in dimethyl sulfoxide (1 mL) was added sodium thiomethoxide (11.0 mg) and stirred at 80° C. for 11 hours. The resulting mixture was quenched by adding ethyl acetate and saturated ammonium chloride. The organic layer was separated, washed successively with water and brine, and then dried over anhydrous sodium sulfate. The resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using 0.1 v / v % formic acid in distilled water and 0.1 v / v % formic acid-acetonitrile as eluents to give the title compound as a colorless solid (11.5 mg, 37% yield).

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[0541] 4-((6-(Ethylsulfanyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.107 using 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.92 and sodium ethanethiolate.

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[0542] 4-((1-Ethyl-6-(ethylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.107 using 4-((6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.83 and sodium ethanethiolate.

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[0543] 4-((3-Bromo-6-(ethylsulfanyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.107 using 4-((3-bromo-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.85 and sodium ethanethiolate.

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[0544] 4-((1-Methyl-6-(propylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.107 using 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.92 and sodium 1-propanethiolate.

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[0545] 4-((6-Methoxycarbonylmethylthio-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.107 using 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.92, methyl thioglycolate, and potassium tert-butoxide.

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[0546] 4-((6-Carboxymethylthio-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: To a solution of 4-((6-methoxycarbonylmethylthio-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide (43.4 mg) obtained in Example 2.112 in tetrahydrofuran (1 mL) and methanol (1 mL) was added 1 mol / L sodium hydroxide solution (1 mL) at room temperature. The mixture was stirred at room temperature overnight, and then 1 mol / L hydrochloric acid solution (1 mL) was added. The resulting mixture was evaporated under reduced pressure. The residue was washed with water and dried under reduced pressure to give the title compound as a colorless solid (31.1 mg, yield 74%).

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[0547] 4-((6-(2-tert-butoxycarbonylaminoethylthio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.107 using 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.92, tert-butyl (2-sulfanylethyl)carbamate, and potassium tert-butoxide.

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[0548] 4-((6-(2-aminoethylthio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide hydrochloride: To a mixture of 4-((6-(2-tert-butoxycarbonylamino)ethylthio-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.114 (28.3 mg) in methanol (1 mL) was added 4 M hydrogen chloride in dioxane (1 mL) at room temperature. The resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was evaporated under reduced pressure and then dried under reduced pressure to give the title compound as a yellow solid (23.0 mg, yield 93%).

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[0549] 4-((6-(2-tert-Butoxycarbonylaminoethoxy)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.98 using 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.92, tert-butyl (2-hydroxyethyl)carbamate, and sodium tert-butoxide. Example 2.117 [ka]

[0550] 4-((6-(2-aminoethoxy)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.115 using the 4-((6-(2-tert-butoxycarbonylaminoethoxy)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained above. MS: m / z 378.1 (M+H + ). Example 2.118 [ka]

[0551] 4-((6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: To a mixture of 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide obtained in Example 2.92 (42.8 mg) in isopropanol (0.6 mL) was added 28% ammonia solution (0.6 mL). The mixture was stirred at 120 to 140° C. under microwave irradiation until the starting material disappeared (approximately 18 hours). The reaction mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate and then purified by automated flash chromatography using 0-12% methanol in dichloromethane as the eluent to give the title compound as a colorless solid (21.0 mg, 51.9% yield).

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[0552] 4-((6-chloro-1-methyl-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: To a mixture of 4-((3-bromo-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide (251 mg) obtained in Step 2 of Example 2.87, phenylboronic acid (72.0 mg), and tripotassium phosphate (187 mg) in 1,4-dioxane (6.0 mL) and water (1.5 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (49.8 mg). After stirring at 100° C. under microwave irradiation for 1 hour, the resulting mixture was quenched by adding water and extracted with ethyl acetate. The combined organic layer was washed successively with water and brine and dried over anhydrous sodium sulfate. The resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using 0.1% v / v formic acid in distilled water and 0.1% v / v formic acid in acetonitrile as eluents to give the title compound as a light brown solid (118 mg, yield 47.3%).

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[0553] 4-((6-Chloro-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.119 using 4-((3-bromo-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Step 2 of Example 2.87 and trimethylboroxine (3.5 M solution in THF).

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[0554] 4-((3-(Cyclopropylethynyl)-1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: To a mixture of 4-((3-bromo-1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzene-1-sulfonamide (50.7 mg) obtained in Example 2.89, N,N-diisopropylethylamine (0.11 mL), copper(I) iodide (8.7 mg), and cyclopropylacetylene (0.030 mL) in N,N-dimethylformamide (1.25 mL) was added bis(triphenylphosphine)palladium(II) dichloride (49.8 mg) under a nitrogen atmosphere. After stirring at 100° C. in a microwave oven for 2.5 hours, the mixture was diluted with ethyl acetate and water and filtered through a pad of Celite. The organic layer was separated from the aqueous layer, washed with brine, and dried over anhydrous sodium sulfate. The resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by automated flash chromatography using 20-100% ethyl acetate in dichloromethane as the eluent, followed by preparative HPLC using 0.1% v / v formic acid in distilled water and 0.1% v / v formic acid in acetonitrile as the eluents, to give the title compound as a light brown solid (24.7 mg, 50.5% yield).

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[0555] 4-((1-ethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)aminomethyl)benzenesulfonamide

[0556] Step 1: To a mixture of 4-chloro-1H-pyrazolo[3,4-b]pyridine (5 g) and potassium carbonate (5.40 g) in acetonitrile (20 mL) was added iodoethane (5.08 g). After stirring at 80 °C for 8 hours, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and then dried over anhydrous sodium sulfate. The resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 5-17% ethyl acetate in petroleum ether as the eluent to give 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine as a colorless oil (2.4 g, 40.6% yield).

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[0557] Step 2: To a mixture of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine (2.2 g) obtained above and diphenylmethanimine (2.20 g) in 1,4-dioxane (20 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (701 mg), cesium carbonate (4.34 g), and bis(dibenzylideneacetone)palladium(0) (697 mg). The reaction mixture was stirred at 120°C under a nitrogen atmosphere for 16 hours. The resulting mixture was quenched with water and extracted with ethyl acetate. 4M aqueous HCl (12.11 mL) was added to the organic layer, and the mixture was stirred at 20°C for 3 hours. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate. The resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 17-33% ethyl acetate in petroleum ether as eluent and 2-5% methanol in dichloromethane as eluent to give 4-amino-1-ethyl-1H-pyrazolo[3,4-b]pyridine as a colorless oil (850 mg, 43.3% yield).

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[0558] Step 3: To a mixture of the above-obtained 4-amino-1-ethyl-1H-pyrazolo[3,4-b]pyridine (202 mg) and 4-formylbenzenesulfonamide (254 mg) in tetrahydrofuran (4 mL) was added sodium triacetoxyborohydride (530 mg). After stirring at room temperature for 24 hours and then at 40°C for 2 hours, sodium triacetoxyborohydride (263 mg) was added. After stirring at 40°C for 1 hour, 4-formylbenzenesulfonamide (219 mg) was added to the reaction mixture. The resulting mixture was stirred at 40°C for 2.5 hours, and sodium triacetoxyborohydride (535 mg) was added. After stirring at 40°C overnight, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with methanol and dichloromethane. The combined organic layers were dried over sodium sulfate. The resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 17-33% ethyl acetate in petroleum ether as eluent and 0-10% methanol in dichloromethane as eluent to give the title compound as a colorless oil (70.7 mg, 17% yield).

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[0559] 4-((1-Methyl-3,6-diphenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.119 using 4-((3-bromo-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Step 2 of Example 2.87, phenylboronic acid, and tetrakis(triphenylphosphine)palladium(0).

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[0560] 4-((6-Chloro-1-methyl-3-(2-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.119 using 4-((3-bromo-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Step 2 of Example 2.87, copper(I) iodide, (2-pyridine) cyclic triol borate lithium salt, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in DMF.

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[0561] 4-((6-Chloro-1-methyl-3-(3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.119 using 4-((3-bromo-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Step 2 of Example 2.87 and 3-pyridylboronic acid.

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[0562] 4-((6-Chloro-1-methyl-3-(4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.119 using 4-((3-bromo-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Step 2 of Example 2.87 and 4-pyridylboronic acid.

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[0563] 4-((3-(1-Cyclopenten-1-yl)-1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.119 using 4-((3-bromo-1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.89, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II), and 2-(1-cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

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[0564] 4-((6-chloro-3-(3-chlorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.119 using 4-((3-bromo-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Step 2 of Example 2.87 and 3-chlorophenylboronic acid.

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[0565] 4-((6-chloro-3-(4-chlorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.119 using 4-((3-bromo-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Step 2 of Example 2.87 and 4-chlorophenylboronic acid.

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[0566] 4-((6-chloro-3-(2-chlorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.119 using 4-((3-bromo-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Step 2 of Example 2.87 and 2-chlorophenylboronic acid.

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[0567] 4-((3-Bromo-1-methyl-6-piperidino-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.118 using 4-((3-bromo-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Step 2 of Example 2.87, piperidine, and potassium carbonate in dimethyl sulfoxide.

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[0568] 4-((1-Methyl-3-phenyl-6-piperidino-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.118 using 4-((6-chloro-1-methyl-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide obtained in Example 2.119, piperidine, and potassium carbonate in dimethyl sulfoxide.

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[0569] 4-((1-methyl-6-trifluoromethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide

[0570] Step 1: Sodium hydride (428 mg) was added to a solution of 5-amino-1-methyl-1H-pyrazole-4-carboxamide (0.5 g) in ethanol (10 mL). The mixture was stirred at 10° C. for 0.5 hours. Then, ethyl 2,2,2-trifluoroacetate (760 mg) was added to the mixture. The resulting mixture was stirred at 80° C. for 8 hours. After removing the ethanol, the mixture was quenched by the addition of saturated aqueous ammonium chloride solution (30 mL) and then extracted three times with ethyl acetate. The combined organic layers were washed three times with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-methyl-6-trifluoromethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol as a yellow solid (0.5 g, 64% yield). MS: m / z 219.0 (M+H + ).

[0571] Step 2: A solution of 1-methyl-6-trifluoromethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol (1.7 g) obtained above in POCl3 (13.0 mL) was stirred at 110 °C for 5 h. After concentration under reduced pressure, 50 mL of dichloromethane was added to the mixture, which was quenched by the addition of saturated aqueous sodium bicarbonate (60 mL) at 0 °C and then extracted with dichloromethane (30 mL, 3 times). The combined organic layers were washed with brine (30 mL, 3 times), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography using 2 to 10% ethyl acetate in petroleum ether to give 4-chloro-1-methyl-6-trifluoromethyl-1H-pyrazolo[3,4-d]pyrimidine as a colorless solid (1.02 g, 55% yield).

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[0572] Step 3: The title compound was prepared according to the general procedure of Example 2.85 using the above obtained 4-chloro-1-methyl-6-trifluoromethyl-1H-pyrazolo[3,4-d]pyrimidine and homosulfamine hydrochloride.

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[0573] 4-((6-cyclopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)aminomethyl)-benzenesulfonamide

[0574] Step 1: A mixture of 5-amino-1-methylpyrazole (1 g) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (1.90 g) in toluene (20 mL) was stirred at 70° C. under a nitrogen atmosphere for 5 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography using 25% ethyl acetate in petroleum ether to give ethyl 6-cyclopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate as a colorless solid (900 mg, 36% yield).

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[0575] Step 2: To a mixture of water (2 mL) and tetrahydrofuran (8 mL) containing ethyl 6-cyclopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (900 mg) obtained above, lithium hydroxide monohydrate (770 mg) was added at 20° C. The mixture was stirred at 20° C. for 12 hours. The reaction mixture was poured into water (10 mL) and acidified to pH 6 with 2 M hydrochloric acid. The mixture was then filtered, and the filter cake was concentrated in vacuo to afford cyclopropyl-1-methyl-pyrazolo[3,4-b]pyridine-4-carboxylic acid as a colorless solid (600 mg, 75% yield).

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[0576] Step 3: Using the 4-amino-6-cyclopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine obtained above, the title compound was prepared according to the general procedure of Example 2.122. MS: m / z 358 (M+H + ). Example 2.135 [ka]

[0577] 4-((3-Cyclopentyl-1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide: A mixture of 4-((3-(1-cyclopenten-1-yl)-1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)benzenesulfonamide (33.5 mg) obtained in Example 2.127 and 5% Pd—C(W) (31.2 mg) in methanol (2.5 mL) was stirred under a hydrogen atmosphere at room temperature for 6 hours using a balloon. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using 0.1% by volume formic acid in distilled water and 0.1% by volume formic acid in acetonitrile as eluents to give the title compound as a colorless solid (21.8 mg, yield 65%).

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[0578] 4-(N-Methyl-N-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)aminomethyl)-benzenesulfonamide: The title compound was prepared according to the general procedure of Example 2.85 using 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine and 4-(methylaminomethyl)-benzenesulfonamide.

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[0579] 4-((1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)oxymethyl)benzenesulfonamide: To a solution of 4-(hydroxymethyl)benzenesulfonamide (50.6 mg) in N,N-dimethylformamide (1 mL) was added sodium hydride (60%, dispersion in paraffin liquid, 30.7 mg) at 0° C. After stirring at 0° C. for 40 minutes, 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (59.3 mg) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 5 hours and quenched by adding saturated ammonium chloride solution and ethyl acetate. The organic phase was washed with water and brine and then dried over anhydrous sodium sulfate. The resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by automated flash chromatography using 0-80% ethyl acetate in hexanes as eluent to give the title compound as a colorless solid (32.8 mg, 29.5% yield).

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[0580] 6-(((6-(ethylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)pyridine-3-sulfonamide (Example 2.139)

[0581] Step 1: A solution of 5-fluoropicolinonitrile (3 g, 25 mmol), BnSH (3.7 g, 30 mmol), and KCO (6.9 g, 50 mmol) in DMF (50 mL) was stirred at 80 °C overnight. The reaction mixture was poured into HO (150 mL) and extracted with EA (150 mL). The EA layer was washed with brine (150 mL × 2), dried over NaSO, concentrated under reduced pressure, and dried in vacuo. The residue was purified by silica gel column (PE / EA = 10 / 1) to give 5-(benzylthio)picolinonitrile (4.35 g, yield: 77%) as a yellow solid.

[0582] Step 2: To a solution of 5-(benzylthio)picolinonitrile (1.5 g, 6.6 mmol) in DCM / HO (45 mL / 22.5 mL) was added HCl (9 mL) and NaClO (45 mL) slowly at 0 °C. The mixture was stirred at room temperature for 4 h. The reaction mixture was poured into HO (40 mL) and extracted with EA (40 mL). The EA layer was washed with brine (40 mL), dried over NaSO, and concentrated under reduced pressure to give 6-cyanopyridine-3-sulfonyl chloride (crude) as a yellow oil.

[0583] Step 3: To a solution of 6-cyanopyridine-3-sulfonyl chloride (1.3 g, 6.4 mmol) in THF (50 mL) was added NH3.HO (10 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography to give 6-cyanopyridine-3-sulfonamide (690 mg, yield: 63%) as a white solid.

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[0584] Step 4: A solution of 6-cyanopyridine-3-sulfonamide (690 mg, 3.8 mmol), Raney Ni, and NHOH (1.5 mL) in MeOH (50 mL) was stirred under a H atmosphere (balloon) at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude 6-(aminomethyl)pyridine-3-sulfonamide as a white solid.

[0585] Step 5: A solution of 6-(aminomethyl)pyridine-3-sulfonamide (690 mg, 3.7 mmol), 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (751 mg, 3.7 mmol), and DIEA (0.5 mL) in ACN (30 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 6-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)pyridine-3-sulfonamide (136 mg, 10% yield) as a white solid.

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[0586] Step 6: A solution of 6-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)pyridine-3-sulfonamide (60 mg, 0.17 mmol), ethanamine (9 mg, 0.2 mmol), and KCO (70 mg, 0.51 mmol) in DMSO (5 mL) was stirred at 100° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 6-(((6-(ethylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)pyridine-3-sulfonamide (136 mg, 10% yield) as a white solid.

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[0587] 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-3-fluorobenzenesulfonamide (Example 2.140) and 4-(((6-(ethylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-3-fluorobenzenesulfonamide (Example 2.141)

[0588] Step 1: A solution of 4-amino-2-fluorobenzonitrile (5 g, 37 mmol), 1,2-dibenzyldisulfane (7.2 g, 29 mmol), and t-BuONO (2.7 g, 26 mmol) in ACN (100 mL) was stirred for 2 hours at 60° C. The reaction mixture was concentrated, and the residue was purified by silica gel column (PE / EA=100 / 5) to give 4-(benzylthio)-2-fluorobenzonitrile (4.0 g, yield: 45%) as a white solid.

[0589] Step 2: To a solution of 4-(benzylthio)-2-fluorobenzonitrile (4.0 g, 16.5 mmol) in ACN (200 mL) was added NCS (8.8 g, 65.8 mmol) and HCl (4.1 mL). The mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into HO (40 mL) and extracted with EA (40 mL). The EA layer was washed with brine (40 mL), dried over NaSO, and concentrated under reduced pressure to give 4-cyano-3-fluorobenzene-1-sulfonyl chloride (crude) as a yellow solid.

[0590] Step 3: To a solution of 4-cyano-3-fluorobenzene-1-sulfonyl chloride (3.6 g, 16.5 mmol) in THF (50 mL) was added NH3.HO (10 mL). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography to give 4-cyano-3-fluorobenzenesulfonamide (2.8 g, 85% yield) as a brown solid.

[0591] Step 4: A solution of 4-cyano-3-fluorobenzenesulfonamide (500 mg, 2.5 mmol) and BHMeS (2 mL) in THF (30 mL) was stirred at 45 °C for 4 h. Then, MeOH (10 mL) and HCl (5 mL) were added. The solution was stirred at 45 °C for 1 h and purified by silica flash column chromatography to give 4-(aminomethyl)-3-fluorobenzenesulfonamide (480 mg, 94% yield) as a white solid.

[0592] Step 5: A solution of 4-(aminomethyl)-3-fluorobenzenesulfonamide (100 mg, 0.49 mmol), 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.49 mmol), and DIEA (0.5 mL) in ACN (20 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-3-fluorobenzenesulfonamide (60 mg, 33% yield) as a white solid.

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[0593] Step 6: A solution of 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-3-fluorobenzenesulfonamide (30 mg, 0.08 mmol) and ethanamine (2 mL) in DMSO (5 mL) was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 4-(((6-(ethylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-3-fluorobenzenesulfonamide (11.3 mg, 38% yield) as a white solid.

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[0594] 6-(((6-Chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)pyridine-3-sulfonamide: The title compound was prepared using the general procedure for 6-(((6-(ethylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)pyridine-3-sulfonamide.

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[0595] 4-(((6-Chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-3-fluorobenzenesulfonamide: A solution of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (200 mg, 0.99 mmol), 4-(aminomethyl)-3-fluorobenzenesulfonamide (210 mg, 1.03 mmol), and KCO (560 mg, 4.06 mmol) in NMP (4 mL) was stirred at 100 °C overnight. The reaction mixture was poured into HO (30 mL) and extracted with EA (30 mL). The EA phase was concentrated, and the residue was purified by reverse phase column chromatography to give 4-(((6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-3-fluorobenzenesulfonamide (28 mg, yield: 8%) as a yellow solid.

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[0596] 4-(((6-(Ethylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)-3-fluorobenzenesulfonamide: The title compound was prepared using the general procedure for 4-(((6-(isopropylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)benzenesulfonamide (Example 2.74).

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[0597] N-Benzyl-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine

[0598] Step 1: A solution of methyl 3-amino-4-methylthiophene-2-carboxylate (3 g, 17.5 mmol) in formamide (20 mL) was stirred at 200 °C for 8 h. The reaction was cooled to room temperature and filtered. The pad was rinsed with THF to give 7-methylthieno[3,2-d]pyrimidin-4-ol (2 g, 68.9% yield) as a gray solid.

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[0599] Step 2: A solution of 7-methylthieno[3,2-d]pyrimidin-4-ol (500 mg, 3.0 mmol) in POCl (5 mL) was stirred at 120 °C for 2 h. POCl was removed under reduced pressure. The residue was neutralized with saturated aqueous NaHCO (100 mL) and extracted with EA (200 mL × 3). The combined organic layers were dried over NaSO and concentrated to give 4-chloro-7-methylthieno[3,2-d]pyrimidine (0.66 g, crude) as a yellow solid.

[0600] Step 3: A solution of 4-chloro-7-methylthieno[3,2-d]pyrimidine (560 mg, 3.0 mmol), TEA (0.6 g, 6.0 mmol), and tert-butyl piperidin-4-ylcarbamate (1.2 g, 6.0 mmol) in DMF (5 mL) was stirred at 80° C. for 4 hours. DMF was removed under reduced pressure. The residue was purified using a silica gel column (PE / EA=1 / 1) to give tert-butyl (1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (0.75 g, yield: 71%) as a white solid. MS: m / z 349.2 (M+H + ).

[0601] Step 4: A solution of tert-butyl (1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (0.75 g, 2.1 mmol) and TFA (2 mL) in DCM (10 mL) was stirred at room temperature for 4 hours. DCM and TFA were removed under reduced pressure. The residue was washed with saturated aqueous NaHCO3 and concentrated. The residue was dissolved in MeOH and filtered. The filtrate was concentrated to give 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (740 mg, crude) as a colorless oil.

[0602] Step 5: A solution of 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (100 mg, 0.4 mmol), (chloromethyl)benzene (40 mg, 0.3 mmol), K2CO3 (110 mg, 0.8 mmol), and KI (2 mg) in DMF (3 mL) was stirred at 110 °C for 5 h. DMF was removed under reduced pressure. The residue was purified by preparative HPLC (NH4HCO3) to give N-benzyl-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (14.8 mg, 11.6% yield) as a colorless oil.

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[0603] 1-(7-Methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)propyl)piperidin-4-amine: The title compound was prepared using the general procedure for 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-2-yl)propyl)piperidin-4-amine (Example 3.3).

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[0604] 1-(7-Methylthieno[3,2-d]pyrimidin-4-yl)-N-(pyridin-4-ylmethyl)piperidin-4-amine: The title compound was prepared using the general procedure for N-benzyl-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (Example 3).

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[0605] 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-2-yl)propyl)piperidin-4-amine

[0606] Step 1: To a solution of (COCl) (370 mg, 2.9 mmol) in DCM (10 mL), DMSO (456 mg, 5.8 mmol) was added dropwise (balloon) under a N atmosphere. The mixture was stirred at −78° C. for 1 h. Next, 3-(pyridin-2-yl)propan-1-ol (200 mg, 1.4 mmol) was slowly added to the mixture, and the new mixture was stirred at −78° C. for another 1 h. Next, DIEA (1.1 g, 8.8 mmol) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column (DCM / MeOH=10 / 1) to give 3-(pyridin-2-yl)propanal (166 mg, yield: 84%) as a yellow solid.

[0607] Step 2: A solution of 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (277 mg, 1.1 mmol) and 3-(pyridin-2-yl)propanal (166 mg, 1.2 mmol) in ACN (10 mL) was stirred at room temperature for 0.5 h. Then, the mixture was cooled to 0 °C, and NaBHCN (232 mg, 3.7 mmol) was added. The reaction mixture was stirred at room temperature overnight. ACN was removed under reduced pressure. The residue was purified by preparative HPLC (NHHCO) to give 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-2-yl)propyl)piperidin-4-amine (25.8 mg, yield: 5%) as a white solid.

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[0608] 1-(7-Methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(p-tolyl)propyl)piperidin-4-amine: The title compound was prepared using the general procedure for 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-2-yl)propyl)piperidin-4-amine (Example 3.3).

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[0609] N-(3-(4-Fluorophenyl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine: The title compound was prepared using the general procedure for 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-2-yl)propyl)piperidin-4-amine (Example 3.3).

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[0610] 4-(3-((1-(7-Methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)amino)propyl)benzonitrile: The title compound was prepared using the general procedure for 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-2-yl)propyl)piperidin-4-amine (Example 3.3).

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[0611] 7-Methyl-4-(4-(4-(pyridin-4-yl)butyl)piperazin-1-yl)thieno[3,2-d]pyrimidine

[0612] Step 1: Step 1 was the same as step 1 of 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-2-yl)propyl)piperidin-4-amine (Example 3.3).

[0613] Step 2: Step 2 was the same as step 3 of N-benzyl-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (Example 3.0).

[0614] Step 3: Step 3 was the same as step 2 of 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-2-yl)propyl)piperidin-4-amine (Example 3.3).

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[0615] 3-(2-Methoxypyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propenamide: The title compound was prepared using the general procedure for 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (Example 3.38).

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[0616] 3-(2-Bromopyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propenamide: The title compound was prepared using the general procedure for 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (Example 3.38).

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[0617] 3-(3-Chloropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propenamide: The title compound was prepared using the general procedure for 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (Example 3.38).

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[0618] (E)-3-(3-chloropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)acrylamide: The title compound was prepared using the general procedure for 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (Example 3.38).

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[0619] 1-(7-Methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(3-(trifluoromethyl)phenyl)propyl)piperidin-4-amine: The title compound was prepared using the general procedure for 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-2-yl)propyl)piperidin-4-amine (Example 3.3).

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[0620] N-(3-(3-chloropyridin-4-yl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine: To a solution of 3-(3-chloropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (150 mg, 0.36 mmol) in THF (3 mL) was added DIBAL-H (1.5 M, 4 mL) at −78° C. The mixture was stirred under H atmosphere (balloon) at −78° C. for 6 h. It was then slowly quenched with HO at −65° C. The mixture was concentrated and purified by preparative HPLC (NH4HCO3) to give N-(3-(3-chloropyridin-4-yl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (13.5 mg, yield: 9.3%) as a yellow oil.

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[0621] N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)-3-(o-tolyl)propanamide: The title compound was prepared using the general procedure for 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (Example 3.38).

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[0622] N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)-3-(m-tolyl)propanamide: The title compound was prepared using the general procedure for 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (Example 3.38).

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[0623] 1-(7-Methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(o-tolyl)propyl)piperidin-4-amine: The title compound was prepared using the general procedure for N-(3-(3-fluoropyridin-4-yl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (Example 3.40).

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[0624] 1-(7-Methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(m-tolyl)propyl)piperidin-4-amine: The title compound was prepared using the general procedure for N-(3-(3-fluoropyridin-4-yl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (Example 3.40).

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[0625] 3-(3-Chlorophenyl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide: The title compound was prepared using the general procedure for 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (Example 3.38).

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[0626] N-(3-(3-chlorophenyl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine: The title compound was prepared using the general procedure for N-(3-(3-fluoropyridin-4-yl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (Example 3.40).

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[0627] 3-(4-Fluorophenyl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide: The title compound was prepared using the general procedure for 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (Example 3.38).

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[0628] N-(3-(4-Fluorophenyl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine: The title compound was prepared using the general procedure for N-(3-(3-fluoropyridin-4-yl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (Example 3.40).

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[0629] 2-(4-Fluorophenoxy)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)acetamide

[0630] Step 1: A solution of 4-fluorophenol (2 g, 17.8 mmol) and K2CO3 (7.4 g, 53.5 mmol) in acetone (20 mL) was stirred at room temperature for 2 hours. Then, methyl 2-bromoacetate (5.4 g, 35.6 mmol) was added to the solution. The mixture was stirred at room temperature for 0.5 hours and at 60 °C overnight. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column (PE / EA = 10 / 1) to give methyl 2-(4-fluorophenoxy)acetate (3.2 g, yield: 96.7%) as a white solid.

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[0631] Step 2: A solution of methyl 2-(4-fluorophenoxy)acetate (1 g, 5.4 mmol) and LiOH (0.4 g, 10.8 mmol) in MeOH / water (9 mL / 3 mL) was stirred at room temperature for 2 hours. MeOH was removed under reduced pressure. The aqueous phase was acidified with 1 N HCl. The solid formed was collected by filtration to give 2-(4-fluorophenoxy)acetic acid (700 mg, yield: 75.8%) as a white solid.

[0632] Step 3: A solution of 2-(4-fluorophenoxy)acetic acid (100 mg, 0.6 mmol), HATU (268.2 mg, 0.7 mmol), and DIEA (227.6 mg, 1.8 mmol) in DCM (5 mL) was stirred at room temperature for 10 minutes. Next, 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (167.3 mg, 0.6 mmol) was added, and the new mixture was stirred at room temperature overnight. DCM was removed under reduced pressure. The residue was purified by slurry in DMF to give 2-(4-fluorophenoxy)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)acetamide (28.3 mg, 12% yield) as a white solid.

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[0633] N-(2-(4-Fluorophenoxy)ethyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine: The title compound was prepared using the general procedure for N-(3-(3-fluoropyridin-4-yl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (Example 3.40).

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[0634] N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)pyridin-4-amine

[0635] The title compound was prepared using the general procedure from Step 1 to Step 4: 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-3-yl)propyl)piperidin-4-amine (Example 3.26).

[0636] Step 5: A solution of 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (200 mg, 0.81 mmol), 4-chloropyridine (133 mg, 0.89 mmol), t-BuONa (432 mg, 3.22 mmol), Pd(OAc) (18 mg, 0.08 mmol), and TTBP (23 mg, 0.08 mmol) in dioxane (10 mL) was stirred at 100 °C under a N atmosphere (balloon) overnight. The reaction mixture was filtered. The filtrate was concentrated, and the residue was purified by preparative HPLC (NH OAc) to give N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)pyridin-4-amine (3.5 mg, yield: 1.3%) as a white solid.

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[0637] 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(2-(pyridin-4-yl)ethyl)piperidin-4-amine

[0638] Step 1: To a solution of 2-(pyridin-4-yl)ethanol (200 mg, 1.6 mmol) and TEA (323 mg, 3.2 mmol) in DCM (15 mL) was added MsCl (217 mg, 1.9 mmol) at 0 °C. The mixture was stirred under a N atmosphere (balloon) at 0 °C for 1 h. The mixture was washed with saturated aqueous NaHCO (15 mL), dried over NaSO, and concentrated to give 2-(pyridin-4-yl)ethyl methanesulfonate (321 mg, 100% yield) as a yellow oil.

[0639] Step 2: A solution of 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (360 mg, 1.45 mmol), 2-(pyridin-4-yl)ethyl methanesulfonate (321 mg, 1.6 mmol), and K2CO3 (600 mg, 4.35 mmol) in DMF (10 mL) was stirred at 60 °C overnight. DMF was removed under reduced pressure. The residue was purified by preparative HPLC (NH4HCO3) to give 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(2-(pyridin-4-yl)ethyl)piperidin-4-amine (1.1 mg, yield: 0.2%) as a yellow oil.

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[0640] 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-3-yl)propyl)piperidin-4-amine

[0641] Step 1: A solution of methyl 3-amino-4-methylthiophene-2-carboxylate (10 g, 0.058 mol) in formamide (100 mL) was stirred at 200 °C for 8 h. The reaction was cooled to room temperature and filtered. The pad was rinsed with THF to give 7-methylthieno[3,2-d]pyrimidin-4-ol (5.3 g, 55% yield) as a gray solid.

[0642] Step 2: A solution of 7-methylthieno[3,2-d]pyrimidin-4-ol (4.8 g, 0.03 mol) in POCl (40 mL) was stirred at 120 °C for 2 h. POCl was removed under reduced pressure. The residue was neutralized with saturated aqueous NaHCO (150 mL) and extracted with EA (200 mL × 3). The combined organic layers were dried over NaSO and concentrated. The residue was purified by silica gel column (PE / EA = 10 / 1) to give 4-chloro-7-methylthieno[3,2-d]pyrimidine (4.3 g, yield: 81%) as a white solid.

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[0643] Step 3: To a solution of 4-chloro-7-methylthieno[3,2-d]pyrimidine (3.5 g, 19 mmol) and tert-butyl piperidin-4-ylcarbamate (7.6 g, 38 mmol) in DMF (50 mL) was added TEA (3.8 g, 38 mmol). The mixture was stirred at 80° C. for 2 hours. DMF was removed under reduced pressure. The residue was purified by silica gel column (PE / EA=10 / 1) to give tert-butyl (1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (5.8 g, yield: 87.9%) as a white solid. MS: m / z 349.5 (M+H + ).

[0644] Step 4: A solution of tert-butyl (1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (2 g, 5.7 mmol) and TFA (4 mL) in DCM (20 mL) was stirred at room temperature overnight. DCM and TFA were removed under reduced pressure. The residue was treated with saturated aqueous NaHCO3 and concentrated. The residue was dissolved in MeOH and the mixture was filtered. The filtrate was concentrated to give 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (2 g, crude) as a yellow oil. MS: m / z 249.4 (M+H + ).

[0645] Step 5: Step 5 was the same as step 1 of 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-2-yl)propyl)piperidin-4-amine (Example 3.3).

[0646] Step 6: A solution of 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (330 mg, 1.35 mmol) and 3-(pyridin-3-yl)propanal (200 mg, 1.48 mmol) in ACN (15 mL) was stirred at room temperature for 0.5 h. The reaction was then cooled to 0 °C, and NaBHCN (254 mg, 4.05 mmol) was added. The reaction was stirred at room temperature overnight. The ACN was removed under reduced pressure. The residue was purified by preparative HPLC (NHHCO) to afford 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-3-yl)propyl)piperidin-4-amine (88.4 mg, yield: 17.8%) as a yellow oil.

number

[0647] 1-(7-Methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-phenylpropyl)piperidin-4-amine: The title compound was prepared using the general procedure for 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-3-yl)propyl)piperidin-4-amine (Example 3.26).

number

[0648] N-(3-(4-chlorophenyl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine: The title compound was prepared using the general procedure for 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-3-yl)propyl)piperidin-4-amine (Example 3.26).

number

[0649] 1-(7-Methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)propyl)pyrrolidin-3-amine: The title compound was prepared using the general procedure for 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-3-yl)propyl)piperidin-4-amine (Example 3.26).

number

[0650] N-(3-(2-methylpyridin-4-yl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine

[0651] The title compound was prepared using the general procedure from Step 1 to Step 2: 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (Example 3.38).

[0652] Step 3: To a solution of ethyl 3-(2-methylpyridin-4-yl)propanoate (340 mg, 1.76 mmol) in THF (10 mL) was added LiAlH (200 mg, 5.28 mmol) slowly at 0 °C. The mixture was stirred at 0 °C for 0.5 h. To the reaction mixture was added 1 mL of water, 1 mL of NaOH (aqueous, 15%), and 3 mL of water slowly at 0 °C. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (PE / EA=5 / 1) to give 3-(2-methylpyridin-4-yl)propan-1-ol (220 mg, yield: 83%) as a colorless oil.

[0653] Step 4 to Step 5: The title compound was prepared using the general procedure for 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-3-yl)propyl)piperidin-4-amine (Example 3.26).

number

[0654] 3-(4-Methoxyphenyl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide: The title compound was prepared using the general procedure for 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (Example 3.38).

number

[0655] N-(3-(4-Methoxyphenyl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine: The title compound was prepared using the general procedure for N-(3-(3-fluoropyridin-4-yl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (Example 3.40).

number

[0656] N-(3-(2-fluorophenyl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine: The title compound was prepared using the general procedure for 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N-(3-(pyridin-3-yl)propyl)piperidin-4-amine (Example 3.26).

number

[0657] 3-(3-methylpyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide

[0658] Step 1: To a solution of 3-bromoisonicotinaldehyde (2 g, 10.7 mmol) in DCM (30 mL) was added a solution of ethyl 2-(triphenylphosphoranylidene)acetate (3.7 g, 10.7 mmol) in DCM (20 mL). The mixture was stirred at room temperature under a N2 atmosphere for 2 hours. The DCM was removed under reduced pressure. The residue was purified using a silica gel column (PE / EA=1 / 1) to give (E)-ethyl 3-(3-bromopyridin-4-yl)acrylate (2.3 g, yield: 85%) as a yellow oil. MS: m / z 258.2 (M+H + ).

[0659] Step 2: A solution of (E)-ethyl 3-(3-bromopyridin-4-yl)acrylate (1.5 g, 5.88 mmol), methylboronic acid (704 mg, 11.76 mol), K2CO3 (2.4 g, 17.64 mmol), and Pd(dppf)Cl2 (430 mg, 0.588 mmol) in dioxane / water (40 mL / 8 mL) was stirred at 100 °C overnight under a N2 atmosphere (balloon). Dioxane and water were removed under reduced pressure. The residue was purified by silica gel column (PE / EA = 1 / 1) to give (E)-ethyl 3-(3-methylpyridin-4-yl)acrylate (600 mg, yield: 54.5%) as a yellow oil.

number

[0660] The title compound was prepared using the general procedure from Step 3 to Step 5: 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (Example 3.38).

number

[0661] N-(3-(3-Methylpyridin-4-yl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine: The title compound was prepared using the general procedure for N-(3-(3-fluoropyridin-4-yl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (Example 3.40).

number

[0662] 3-(2-Fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide: The title compound was prepared using the general procedure for 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (Example 3.38).

number

[0663] N-(3-(2-Fluoropyridin-4-yl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine: The title compound was prepared using the general procedure for N-(3-(3-fluoropyridin-4-yl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (Example 3.40).

number

[0664] 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide

[0665] Step 1: To a solution of 3-fluoroisonicotinaldehyde (500 mg, 4 mmol) in DCM (20 mL) was added a solution of ethyl 2-(triphenylphosphoranylidene)acetate (1.39 g, 4 mmol) in DCM (10 mL). The mixture was stirred at room temperature under a N2 atmosphere (balloon) for 2 hours. The DCM was removed under reduced pressure. The residue was purified using a silica gel column (PE / EA=1 / 1) to give (E)-ethyl 3-(3-fluoropyridin-4-yl)acrylate (700 mg, yield: 89.7%) as a yellow oil. MS: m / z 196.3 (M+H + ).

[0666] Step 2: A solution of (E)-ethyl 3-(3-fluoropyridin-4-yl)acrylate (650 mg, 3.3 mmol) and Pd / C (130 mg) in MeOH (20 mL) was stirred overnight at room temperature under an H atmosphere (balloon). The reaction mixture was filtered, and the filtrate was concentrated to give ethyl 3-(3-fluoropyridin-4-yl)propanoate (600 mg, 91.5% yield) as a colorless oil. MS: m / z 198.3 (M+H + ).

[0667] Step 3: A solution of ethyl 3-(3-fluoropyridin-4-yl)propanoate (500 mg, 2.54 mmol) and LiOH (120 mg, 5 mmol) in MeOH / water (9 mL / 3 mL) was stirred at room temperature for 1 hour. The MeOH was removed under reduced pressure. The aqueous layer was acidified with 1 N hydrochloric acid. The suspension was filtered, and the pad was rinsed with water to give 3-(3-fluoropyridin-4-yl)propanoic acid (280 mg, yield: 65.3%) as a white solid.

[0668] Step 4: A solution of 3-(3-fluoropyridin-4-yl)propanoic acid (560 mg, 3.3 mmol), HATU (1.5 g, 3.96 mmol), and DIEA (638 mg, 4.95 mmol) in DMF (10 mL) was stirred at room temperature for 10 minutes. Next, 1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine (821 mg, 3.3 mmol) was added, and the mixture was stirred at room temperature overnight. DMF was removed under reduced pressure. The residue was purified by silica gel column (DCM / MeOH=10 / 1) to give 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (650 mg, yield: 50%) as a white solid.

number

[0669] 3-(3-Fluorophenyl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide: The title compound was prepared using the general procedure for 3-(3-fluoropyridin-4-yl)-N-(1-(7-methylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)propanamide (Example 3.38).

number

[0670] N-(3-(3-Fluoropyridin-4-yl)propyl)-1-(7-methylthieno[3,2-d]pyrimidin-4-yl...

Claims

1. A compound having the structure of formula (I), or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 1】 During the ceremony, Ring B is aryl or 5- or 6-membered heteroaryl; n is 0, 1, 2, or 3; m is 1 or 2; p is 0, 1, 2, or 3; Y １ Ga-NR ４ - or O-, L １ But, -Y ２ -L ２ - or Y ２ -L ２ -L ３ - and Y ２ is a bond or C(═O)—, L ２ is a bond or an optionally substituted C １ -C ６ Alkylene, C １ -C ６ Heteroalkylene, C ２ -C ６ Alkenylene, C ２ -C ６ Alkynylene or C ３ -C ６ cycloalkylene, each optionally containing one, two or three R ７ is replaced by L ３ , 1, 2 or 3 R ７ C optionally substituted with ３ -C ６ is cycloalkylene, R １ is H, halogen, -CN, -OH, -OR １Ｂ , -SR １Ｂ , -N(R １Ａ ) ２ , -C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, C １ -C ６ heteroalkyl, phenyl, or monocyclic heteroaryl, wherein alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R ８ optionally replaced by R ２ is H, halogen, -CN, -OH, -OR １Ｂ , -SR １Ｂ , -N(R １Ａ ) ２ , -NR １Ａ S (= O) ２ (C １ , -C ４ alkyl), -S(=O) ２ N (R １Ａ ) ２ , -OC(=O)(C １ -C ４ alkyl), —CO ２ H, -CO ２ (C １ -C ４ alkyl), —C(═O)N(R １Ａ ) ２ , -NR １Ａ C(=O)(C １ -C ４ alkyl), -NR １Ａ C(=O)O(C １ -C ４ alkyl), —OC(═O)N(R １Ａ ) ２ , -NR １Ａ C(=O)N(R １Ａ ) ２ , -S(C １ -C ４ alkyl), -S(=O)(C １ -C ４ alkyl), -S(=O) ２ (C １ -C ４ alkyl), C １ -C ６ Alkyl, C ２ -C ４ Alkenyl, C ２ -C ４ Alkynyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, —C １－６ Alkyl-OH, -C １－６ Heteroalkyl-OH, C １－６ Alkyl-C(=O)OH, -C １－６ Heteroalkyl-C(=O)OH, monocyclic C ２ -C ６ heterocycloalkyl, phenyl, or monocyclic 5-6 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R ９ optionally replaced by R ３ is H, halogen, -CN, -OH, -OR １Ｂ , -SR １Ｂ , -N(R １Ａ ) ２ , -C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, C １ -C ６ heteroalkyl, phenyl, or monocyclic heteroaryl, wherein alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R ９ optionally replaced by R ４ H, C １ -C ６ Alkyl, or C ３ -C ６ is cycloalkyl, Each R ５ are independently halogen, —CN, —OH, —OR １Ｂ , -SH, -SR １Ｂ , -S(=O)R １Ｂ , -NO ２ , -N(R １Ａ ) ２ , -S(=O) ２ R １Ｂ , -NHS(=O) ２ R １Ｂ , -S(=O) ２ N (R １Ａ ) ２ , -C(=O)R １Ｂ , —OC(═O)R １Ｂ , -C(=O)OR １Ａ , -OC(=O)OR １Ａ , -C(=O)N(R １Ａ ) ２ , -OC(=O)N(R １Ａ ) ２ , -NR １Ａ C(=O)N(R １Ａ ) ２ , -NR １Ａ C(=O)R １Ｂ , -NR １Ａ C(=O)OR １Ａ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ is heteroalkyl or cycloalkyl; Each R ６ are independently halogen, —CN, —OH, —OR １Ｂ , -SH, -SR １Ｂ , N(R １Ａ ) ２ , C １ -C ４ Alkyl, C ２ -C ４ Alkenyl, C ２ -C ４ Alkynyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy or C １ -C ４ is heteroalkyl, Each R ７ , R ８ and R ９ are independently halogen, —CN, —OH, —OR １Ｂ , -SH, -SR １Ｂ , -N(R １Ａ ) ２ , -C(=O)OR １Ａ , oxo (=O), C １ -C ４ Alkyl or C １ -C ４ is a fluoroalkyl; Each R １Ａ are independently hydrogen, C １ -C ６ alkyl, cycloalkyl, heterocycloalkyl, aryl, benzyl, or heteroaryl, and Each R １Ｂ are independently hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ The compound, or a pharmaceutically acceptable salt or solvate thereof, which is heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2.

3. R ３ is H, R １ is halogen or C １ -C ６ is alkyl, 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

4. R １ is —Br, —Cl, or I; 4. The compound of claim 3, or a pharmaceutically acceptable salt or solvate thereof.

5. R １ Ga-CH ３ That is, 4. The compound of claim 3, or a pharmaceutically acceptable salt or solvate thereof.

6. 6. The compound of any one of claims 1 to 5, wherein the compound of formula (I) has the structure of formula (II), or a pharmaceutically acceptable salt or solvate thereof. 【Chemistry 2】

7. Y １ Ga-NR ４ - and R ４ is H or C １ -C ４ is alkyl, 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof.

8. Y １ is —NH—; 8. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof.

9. Ring B is phenyl; 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof.

10. Ring B is a 6-membered heteroaryl; 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof.

11. Ring B is a 6-membered heteroaryl which is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; 11. The compound of claim 10, or a pharmaceutically acceptable salt or solvate thereof.

12. Ring B is a 6-membered heteroaryl which is pyridinyl; 12. A compound according to claim 10 or 11, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 13】 【Chemistry 3】 but 【Chemistry 4】 and X ３ , X ４ , and X ５ are each independently CH or N; 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

14. X ３ is N, and X ４ and X ５ are CH, 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof.

15. 15. The compound of any one of claims 1 to 14, wherein the compound of formula (I) has the structure of formula (III): or a pharmaceutically acceptable salt or solvate thereof. 【Transformation 5】

16. p is 0; 16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof.

17. R ２ is H, halogen, -CN, -OH, -OR １Ｂ , -N(R １Ａ ) ２ , -C １ -C ６ Alkyl, C １ -C ４ Fluoroalkyl, —C １－６ Alkyl-OH, or C １－６ heteroalkyl-OH; 17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof.

18. R ２ is H, —Br, —Cl, —F, —CN, —NH ２ , -NHCH ３ , -NHCH ２ CH ３ , -N(CH ３ ) ２ , -OCH ３、 -CF ３ , -CH ３ , -CH ２ CH ３ or NH(CH ２ ) ２ OH, 18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof.

19. R ２ is H, 19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof.

20. L １ Y ２ -L ２ and Y ２ is a bond or C(═O)—, and L ２ , 1, 2 or 3 R ７ C optionally substituted with ２ -C ５ Alkylene or C ２ -C ５ alkenylene, and R ７ is C １ -C ６ is alkyl, 20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

21. L ２ Ga-CH ２ CH ２ -, -CH ２ CH ２ CH ２ -, -CH ２ (CH ２ ) ２ CH ２ - or CH ２ CH═CH—; 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof.

22. L ２ Ga-CH ２ CH ２ CH ２ -is, 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof.

23. L １ Y ２ -L ２ and Y ２ is a bond or C(═O)—, and L ２ is cyclopropylene; 20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

24. L １ Ga-Y ２ -L ２ -L ３ - and Y ２ is a bond or C(═O)—, L ２ is C ２ -C ５ alkylene, and L ３ is C ３ -C ６ is cyclopropylene, 20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

25. L １ Ga-Y ２ -L ２ -L ３ - and Y ２ is a bond or C(═O)—, L ２ Ga-CH ２ - and L ３ is cyclopropylene; 25. The compound of claim 24, or a pharmaceutically acceptable salt thereof.

26. Y ２ is a bond, 26. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof.

27. Y ２ is —C(═O)—; 26. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof.

28. 28. The compound of any one of claims 1 to 13 or claims 15 to 27, wherein the compound of formula (I) has the structure of formula (IV), or a pharmaceutically acceptable salt or solvate thereof. 【Transformation 6】

29. X ３ is N, and X ４ and X ５ are CH, 29. The compound of claim 28, or a pharmaceutically acceptable salt thereof.

30. X ４ is N, and X ３ and X ５ are CH, 29. The compound of claim 28, or a pharmaceutically acceptable salt thereof.

31. X ５ is N, and X ３ and X ４ are CH, 29. The compound of claim 28, or a pharmaceutically acceptable salt thereof.

32. X ３ , X ４ and X ５ are CH, 29. The compound of claim 28, or a pharmaceutically acceptable salt thereof.

33. Each R ５ are independently halogen, —CN, —OR １Ｂ , -C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl or C １ -C ６ is heteroalkyl, 33. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof.

34. Each R ５ are independently —Br, —Cl, —F, —CN, or —CF ３ , -CH ３ or OCH ３ That is, 34. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof.

35. Each R ５ Ga-CH ３ That is, 35. The compound of claim 34, or a pharmaceutically acceptable salt thereof.

36. Each R ５ Ga-OCH ３ That is, 35. The compound of claim 34, or a pharmaceutically acceptable salt thereof.

37. Each R ５ are independently —Cl or F; 35. The compound of claim 34, or a pharmaceutically acceptable salt thereof.

38. n is 1; 38. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof.

39. n is 0; 38. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof. 【Request Item 40】 【Chemistry 7】 but 【Transformation 8】 That is, 35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof. 【Request Item 41】 【Chemistry 9】 but 【Chemistry 10】 That is, 41. The compound of claim 40, or a pharmaceutically acceptable salt thereof. 【Request Item 42】 【Chemistry 11】 but 【Chemistry 12】 That is, 41. The compound of claim 40, or a pharmaceutically acceptable salt thereof.

43. 10. The compound of claim 1, wherein the compound has one of the following structures: 【Chemistry 13-1】 【Chemistry 13-2】 【Chemistry 13-3】 [Chemistry 13-4] 【Chemistry 13-5】 【Chemistry 13-6】 【Chemistry 13-7】 【Chemistry 13-8】 【Chemistry 13-9】

44. A compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has one of the following structures: 【Chemistry 14】

45. A compound having the structure of formula (V), or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 15】 During the ceremony, Ring D is phenyl or 5- or 6-membered heteroaryl; q is 0, 1, 2, or 3; L ５ is optionally substituted C １ -C ３ alkylene, and one, two, or three R ２６ optionally replaced by R ２０ is H, halogen, -CN, -OH, -OR １Ｂ , -SR １Ｂ , -N(R １Ａ ) ２ , -C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, C １ -C ６ heteroalkyl, phenyl, or monocyclic heteroaryl, wherein alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R ２７ optionally replaced by R ２１ is H, halogen, -CN, -OH, -OR １Ｂ , -SR １Ｂ , -N(R １Ａ ) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, C １ -C ６ heteroalkyl, phenyl, or monocyclic heteroaryl, wherein alkyl, alkenyl, alkynyl, aryl, and heteroaryl each represent one, two, or three R ２８ optionally replaced by R ２２ is H, halogen, -CN, -OH, -OR １Ｂ , -SR １Ｂ , -N(R １Ａ ) ２ , -NR １Ａ S (= O) ２ (C １ -C ４ alkyl), -S(=O) ２ N (R １Ａ ) ２ , -OC(=O)(C １ -C ４ alkyl), —CO ２ H, -CO ２ (C １ -C ４ alkyl), —C(═O)N(R １Ａ ) ２ , -NR １Ａ C(=O)(C １ -C ４ alkyl), -NR １Ａ C(=O)O(C １ -C ４ alkyl), —OC(═O)N(R １Ａ ) ２ , -NR １Ａ C(=O)N(R １Ａ ) ２ , -S(C １ -C ４ alkyl), -S(=O)(C １ -C ４ alkyl), -S(=O) ２ (C １ -C ４ alkyl), C １ -C ６ Alkyl, C ２ -C ４ Alkenyl, C ２ -C ４ Alkynyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, —C １－６ Alkyl-OH, -C １－６ Heteroalkyl-OH, C １－６ Alkyl-C(=O)OH, -C １－６ Heteroalkyl-C(=O)OH, monocyclic C ２ -C ６ heterocycloalkyl, phenyl, or monocyclic 5-6 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, aryl, and heteroaryl each represent one, two, or three R ２９ optionally replaced by R ２３ is H, halogen, -CN, -OH, -OR １Ｂ , -SH, -SR １Ｂ , -S(=O)R １Ｂ , -NO ２ , -N(R １Ａ ) ２ , -S(=O) ２ R １Ｂ , -NHS(=O) ２ R １Ｂ , -S(=O) ２ N (R １Ａ ) ２ , -C(=O)R １Ｂ , —OC(═O)R １Ｂ , -C(=O)OR １Ａ , -OC(=O)OR １Ａ , -C(=O)N(R １Ａ ) ２ , -OC(=O)N(R １Ａ ) ２ , -NR １Ａ C(=O)N(R １Ａ ) ２ , -NR １Ａ C(=O)R １Ｂ , -NR １Ａ C(=O)OR １Ａ , C １ -C ６ Alkyl, C ２ -C ４ Alkynyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ is heteroalkyl or cycloalkyl; Each R ２４ are independently halogen, —CN, —OH, —OR １Ｂ , -SH, -SR １Ｂ , -S(=O)R １Ｂ , -NO ２ , -N(R １Ａ ) ２ , -S(=O) ２ R １Ｂ , -NHS(=O) ２ R １Ｂ , -S(=O) ２ N (R １Ａ ) ２ , -C(=O)R １Ｂ , —OC(═O)R １Ｂ , -C(=O)OR １Ａ , -OC(=O)OR １Ａ , -C(=O)N(R １Ａ ) ２ , -OC(=O)N(R １Ａ ) ２ , -NR １Ａ C(=O)N(R １Ａ ) ２ , -NR １Ａ C(=O)R １Ｂ , -NR １Ａ C(=O)OR １Ａ , C １ -C ６ Alkyl, C ２ -C ４ Alkynyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ is heteroalkyl or cycloalkyl; R ２５ H, C １ - ６ Alkyl or C １ -C ６ is cycloalkyl, Each R ２６ are independently H, halogen or C １ -C ６ is alkyl, Each R ２７ , R ２８ and R ２９ are independently halogen, —CN, —OH, —OR １Ｂ , -SH, -SR １Ｂ , -N(R １Ａ ) ２ , oxo (=O), C １ -C ４ Alkyl, or C １ -C ４ is a fluoroalkyl; Each R １Ａ are independently hydrogen, C １ -C ６ alkyl, cycloalkyl, heterocycloalkyl, aryl, benzyl, or heteroaryl; and Each R １Ｂ are independent and H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ The compound, or a pharmaceutically acceptable salt or solvate thereof, which is heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

46. R ２１ is H and R ２５ is H, 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt thereof.

47. L ５ is unsubstituted C １ -C ３ is alkylene, 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

48. L ５ Ga-CH ２ -is, 48. The compound of claim 47, or a pharmaceutically acceptable salt thereof.

49. The compound of formula (V) has the structure of formula (VI): 【Chemistry 16】 Each R ２６ are independently H, halogen or C １ -C ４ is alkyl, 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt or solvate thereof.

50. R ２０ is unsubstituted phenyl or monocyclic heteroaryl; 50. The compound according to any one of claims 45 to 49, or a pharmaceutically acceptable salt thereof.

51. R ２０ is unsubstituted phenyl; 51. The compound according to any one of claims 45 to 50, or a pharmaceutically acceptable salt thereof.

52. Ring D is phenyl; 51. The compound according to any one of claims 45 to 50, or a pharmaceutically acceptable salt thereof.

53. Ring D is a 6-membered heteroaryl; 51. The compound according to any one of claims 45 to 50, or a pharmaceutically acceptable salt thereof.

54. 6-membered heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; 54. The compound of claim 53, or a pharmaceutically acceptable salt or solvate thereof.

55. the 6-membered heteroaryl is pyridinyl; 55. A compound according to claim 53 or 54, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 56】 【Chemistry 17】 but [Chemistry 18] and X ６ , X ７ , and X ８ are each independently CH or N; 50. The compound according to any one of claims 45 to 49, or a pharmaceutically acceptable salt thereof.

57. X ６ is N and X ７ and X ８ are each independently CH; 57. The compound of claim 56, or a pharmaceutically acceptable salt thereof. 【Request Item 58】 【Chemistry 19】 but 【Chemistry 20】 That is, 52. The compound according to any one of claims 45 to 51, or a pharmaceutically acceptable salt thereof.

59. 59. The compound of any one of claims 45-52 or claim 58, wherein the compound of formula (V) has the structure of formula (VII), or a pharmaceutically acceptable salt or solvate thereof. 【Chemistry 21】

60. R ２３ is halogen, -CN, -OH, -OR １Ｂ , -SH, -SR １Ｂ , -S(=O)R １Ｂ , -NO ２ , -N(R １Ａ ) ２ , -S(=O) ２ R １Ｂ , -S(=O) ２ N (R １Ａ ) ２ , -C(=O)R １Ｂ , -C １ -C ６ Alkyl or C １ -C ６ haloalkyl, 60. The compound of any one of claims 45 to 59, or a pharmaceutically acceptable salt or solvate thereof.

61. R ２３ -Cl, -F, -Br, -CN, -CH ３ , -CF ３ , -SH, -NH ２ , or OCH ３ That is, 61. The compound of claim 60, or a pharmaceutically acceptable salt or solvate thereof.

62. R ２３ is -S (=O) ２ N (R １Ａ ) ２ and each R １Ａ are independently H or C １ -C ３ is alkyl, 61. The compound of claim 60, or a pharmaceutically acceptable salt or solvate thereof.

63. R ２３ is -S (=O) ２ NH ２ That is, 63. A compound according to any one of claims 45 to 60 or claim 62, or a pharmaceutically acceptable salt or solvate thereof.

64. Each R ２４ are independently halogen, —CN, —OH, —OR １Ｂ , -NO ２ , -N(R １Ａ ) ２ , -C １ -C ６ Alkyl, or C １ -C ６ Haloalkyl, C １ -C ６ is hydroxyalkyl, 64. The compound according to any one of claims 45 to 63, or a pharmaceutically acceptable salt or solvate thereof.

65. Each R ２４ are independently —Br, —Cl, —F, —CN, or —CF ３ , -CH ３ or OCH ３ That is, 65. The compound of claim 64, or a pharmaceutically acceptable salt or solvate thereof.

66. q is 1 or 2; 66. The compound according to any one of claims 45 to 65, or a pharmaceutically acceptable salt or solvate thereof.

67. q is 0; 66. The compound according to any one of claims 45 to 65, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 68】 【Chemistry 22】 but 【Chemistry 23】 That is, 50. The compound according to any one of claims 45 to 49, or a pharmaceutically acceptable salt thereof.

69. Ring D is a 5-membered heteroaryl; 51. The compound according to any one of claims 45 to 50, or a pharmaceutically acceptable salt thereof.

70. Ring D is a 5-membered heteroaryl which is oxazole, thiazole, pyrrole, furan, or thiophene; 70. The compound of claim 69, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 71】 【Chemistry 24】 but 【Chemistry 25】 and Y ５ is O, S or NR １Ｃ and Y ６ is O, S, N or CH, and R １Ｃ is hydrogen or C １ -C ６ is alkyl, 51. The compound according to any one of claims 45 to 50, or a pharmaceutically acceptable salt thereof.

72. The compound has the structure of formula (VIII): 【Chemistry 26】 72. The compound of claim 71.

73. Y ５ is S or O; 73. The compound of claim 72, or a pharmaceutically acceptable salt thereof.

74. Each R ２４ are independently halogen, —CN, —OR １Ｂ , -S(=O) ２ N (R １Ａ ) ２ , -C １ -C ６ Alkyl, or C １ -C ６ haloalkyl, 74. The compound of any one of claims 69 to 73, or a pharmaceutically acceptable salt or solvate thereof.

75. Each R ２４ are independently —Cl, —F, —Br, —CN, or —CH ３ , -CF ３ or OCH ３ That is, 75. The compound of claim 74, or a pharmaceutically acceptable salt or solvate thereof.

76. q is 1; 76. The compound of any one of claims 69 to 75, or a pharmaceutically acceptable salt or solvate thereof.

77. q is 0; 76. The compound of any one of claims 69 to 75, or a pharmaceutically acceptable salt or solvate thereof.

78. R ２４ is -S (=O) ２ N (R １Ａ ) ２ and each R １Ａ are independently H or C １ -C ３ is alkyl, 77. The compound of claim 76, or a pharmaceutically acceptable salt or solvate thereof.

79. R ２４ is -S (=O) ２ NH ２ That is, 77. The compound of claim 76, or a pharmaceutically acceptable salt or solvate thereof.

80. R ２２ is H, halogen, -CN, -OH, -OR １Ｂ , -N(R １Ａ ) ２ , -C １ -C ６ Alkyl, C １ -C ４ Fluoroalkyl, —C １－６ Alkyl-OH, or C １－６ heteroalkyl-OH; 80. The compound of any one of claims 45 to 79, or a pharmaceutically acceptable salt or solvate thereof.

81. R ２２ Ga-NH ２ , -NHCH ３ , -NHCH ２ CH ３ , -N(CH ３ ) ２ , -OCH ３ , -CH ３ , -CH ２ CH ３ or NH(CH ２ ) ２ OH, 81. The compound of claim 80, or a pharmaceutically acceptable salt or solvate thereof.

82. R ２２ 80. The compound of any one of claims 45 to 79, or a pharmaceutically acceptable salt or solvate thereof, wherein is phenyl or 6-membered heteroaryl.

83. R ２２ is a 6-membered heteroaryl; 83. The compound of claim 82, or a pharmaceutically acceptable salt or solvate thereof.

84. the 6-membered heteroaryl is 2-pyridyl, 3-pyridyl, or 4-pyridyl; 84. The compound of claim 83, or a pharmaceutically acceptable salt or solvate thereof.

85. 46. ​​The compound of claim 45, wherein the compound has one of the following structures: or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 27-1】 【Chemistry 27-2】 【Chemistry 27-3】 【Chemistry 27-4】 【Chemistry 27-5】

86. A compound having one of the following structures: 【Chemistry 28】

87. A compound having the structure of formula (IX), or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 29】 During the ceremony, Y ａ is CH or N, Ring E is phenyl or a 5- or 6-membered heteroaryl; w is 0, 1, 2, or 3; L ６ optionally substituted C １ -C ３ alkylene, and one, two, or three R ３６ optionally replaced by R ３０ Ga-C １ -C ６ Alkyl, —C ３ -C ６ Cycloalkyl, —C ３ -C ６ heterocycloalkyl, phenyl, or monocyclic heteroaryl, wherein alkyl, alkenyl, alkynyl, aryl, and heteroaryl each have one, two, or three R ３７ optionally replaced by R ３１ is H, halogen, -CN, -OH, -OR １Ｂ , -SR １Ｂ , -N(R １Ａ ) ２ , -C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, C １ -C ６ heteroalkyl, phenyl, or monocyclic heteroaryl, wherein alkyl, alkenyl, alkynyl, aryl, and heteroaryl each represent one, two, or three R ３８ optionally replaced by R ３２ is H, halogen, -CN, -OH, -OR １Ｂ , -SR １Ｂ , -N(R １Ａ ) ２ , -NR １Ａ S (= O) ２ (C １ -C ４ alkyl), -S(=O) ２ N (R １Ａ ) ２ , -OC(=O)(C １ -C ４ alkyl), —CO ２ H, -CO ２ (C １ -C ４ alkyl), —C(═O)N(R １Ａ ) ２ , -NR １Ａ C(=O)(C １ -C ４ alkyl), -NR １Ａ C(=O)O(C １ -C ４ alkyl), —OC(═O)N(R １Ａ ) ２ , -NR １Ａ C(=O)N(R １Ａ ) ２ , -S(C １ -C ４ alkyl), -S(=O)(C １ -C ４ alkyl), -S(=O) ２ (C １ -C ４ alkyl), C １ -C ６ Alkyl, C ２ -C ４ Alkenyl, C ２ -C ４ Alkynyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, —C １－６ Alkyl-OH, -C １－６ Heteroalkyl-OH, C １－６ Alkyl-C(=O)OH, -C １－６ Heteroalkyl-C(=O)OH, monocyclic C ２ -C ６ heterocycloalkyl, phenyl, or monocyclic 5-6 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, aryl, and heteroaryl each represent one, two, or three R ３９ optionally replaced by R ３３ H, C １ -C ６ Alkyl, or C １ -C ６ is cycloalkyl, R ３４ is H, halogen, -CN, -OH, -OR １Ｂ , -SH, -SR １Ｂ , -S(=O)R １Ｂ , -NO ２ , -N(R １Ａ ) ２ , -S(=O) ２ R １Ｂ , -NHS(=O) ２ R １Ｂ , -S(=O) ２ N (R １Ａ ) ２ , -C(=O)R １Ｂ , —OC(═O)R １Ｂ , -C(=O)OR １Ａ , -OC(=O)OR １Ａ , -C(=O)N(R １Ａ ) ２ , -OC(=O)N(R １Ａ ) ２ , -NR １Ａ C(=O)N(R １Ａ ) ２ , -NR １Ａ C(=O)R １Ｂ , -NR １Ａ C(=O)OR １Ａ , C １ -C ６ Alkyl, C ２ -C ４ Alkynyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ is heteroalkyl or cycloalkyl; Each R ３５ are independently halogen, —CN, —OH, —OR １Ｂ , -SH, -SR １Ｂ , -S(=O)R １Ｂ , -NO ２ , -N(R １Ａ ) ２ , -S(=O) ２ R １Ｂ , -NHS(=O) ２ R １Ｂ , -S(=O) ２ N (R １Ａ ) ２ , -C(=O)R １Ｂ , —OC(═O)R １Ｂ , -C(=O)OR １Ａ , -OC(=O)OR １Ａ , -C(=O)N(R １Ａ ) ２ , -OC(=O)N(R １Ａ ) ２ , -NR １Ａ C(=O)N(R １Ａ ) ２ , -NR １Ａ C(=O)R １Ｂ , -NR １Ａ C(=O)OR １Ａ , C １ -C ６ Alkyl, C ２ -C ４ Alkynyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ is heteroalkyl or cycloalkyl; Each R ３６ are independently H, halogen or C １ -C ６ is alkyl, Each R ３７ , R ３８ and R ３９ are independently halogen, —CN, —OH, —OR １Ｂ , -SH, -SR １Ｂ , -N(R １Ａ ) ２ , -C(=O)OR １Ａ , oxo (=O), C １ -C ４ Alkyl or C １ -C ４ is a fluoroalkyl; Each R １Ａ are independently hydrogen, C １ -C ６ alkyl, cycloalkyl, heterocycloalkyl, aryl, benzyl, or heteroaryl; and Each R １Ｂ are independently hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ The compound, or a pharmaceutically acceptable salt or solvate thereof, which is heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

88. R ３１ is H and R ３３ is H, 88. The compound of claim 87, or a pharmaceutically acceptable salt thereof.

89. R ３０ is C １ -C ６ is alkyl, 89. The compound of claim 87 or 88, or a pharmaceutically acceptable salt thereof.

90. R ３０ Ga-CH ３ That is, 90. The compound of claim 89, or a pharmaceutically acceptable salt thereof.

91. L ６ is unsubstituted C １ -C ３ is alkylene, 91. The compound according to any one of claims 87 to 90, or a pharmaceutically acceptable salt thereof.

92. L ６ Ga-CH ２ -is, 92. The compound of claim 91, or a pharmaceutically acceptable salt thereof.

93. The compound of formula (IX) has the structure of formula (X): 【Transformation 30】 During the ceremony, Each R ３６ are independently H or C １ -C ４ 88. The compound of claim 87, or a pharmaceutically acceptable salt or solvate thereof, wherein:

94. Ring E is phenyl; 94. The compound according to any one of claims 87 to 93, or a pharmaceutically acceptable salt thereof.

95. Ring E is a 6-membered heteroaryl; 94. The compound according to any one of claims 87 to 93, or a pharmaceutically acceptable salt thereof.

96. Ring E is a 6-membered heteroaryl which is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; 96. The compound of claim 95, or a pharmaceutically acceptable salt or solvate thereof.

97. Ring E is a 6-membered heteroaryl which is pyridinyl; 97. A compound according to claim 95 or 96, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 98】 【Chemistry 31】 but 【Chemistry 32】 and X ９ , X １０ , and X １１ are each independently CH or N; 94. The compound according to any one of claims 87 to 93, or a pharmaceutically acceptable salt thereof.

99. X １１ is N and X ９ and X １０ are CH, 99. The compound of claim 98, or a pharmaceutically acceptable salt thereof. 【Request Item 100】 【Chemistry 33】 but 【Transformation 34】 That is, 95. The compound according to any one of claims 87 to 94, or a pharmaceutically acceptable salt thereof.

101. 101. The compound of any one of claims 87-94 or claim 100, wherein the compound of formula (IX) has the structure of formula (XI), or a pharmaceutically acceptable salt or solvate thereof. 【Chemistry 35】

102. R ３４ is halogen, -CN, -OH, -OR １Ｂ , -SH, -SR １Ｂ , -S(=O)R １Ｂ , -NO ２ , -N(R １Ａ ) ２ , -S(=O) ２ R １Ｂ , -S(=O) ２ N (R １Ａ ) ２ , -C(=O)R １Ｂ , -C １ -C ６ Alkyl or C １ -C ６ haloalkyl, 102. The compound according to any one of claims 87 to 101, or a pharmaceutically acceptable salt or solvate thereof.

103. R ３４ -Cl, -F, -Br, -CN, -CH ３ , -CF ３ , -SH, -NH ２ , or OCH ３ That is, 103. The compound of claim 102, or a pharmaceutically acceptable salt or solvate thereof.

104. R ３４ is -S (=O) ２ N (R １Ａ ) ２ and each R １Ａ are independently H or C １ -C ３ is alkyl, 103. The compound of claim 102, or a pharmaceutically acceptable salt or solvate thereof.

105. R ３４ is -S (=O) ２ NH ２ That is, 105. The compound of claim 104, or a pharmaceutically acceptable salt or solvate thereof.

106. Each R ３５ are independently halogen, —CN, —OH, —OR １Ｂ , -NO ２ , -N(R １Ａ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl or C １ -C ６ is hydroxyalkyl, 106. The compound according to any one of claims 87 to 105, or a pharmaceutically acceptable salt or solvate thereof.

107. Each R ３５ are independently —Br, —Cl, —F, —CN, or —CF ３ , -CH ３ or OCH ３ That is, 107. The compound of claim 106, or a pharmaceutically acceptable salt or solvate thereof.

108. w is 1 or 2; 108. The compound according to any one of claims 87 to 107, or a pharmaceutically acceptable salt or solvate thereof.

109. w is 0, 106. The compound according to any one of claims 87 to 105, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 110】 【Chemistry 36】 but 【Chemistry 37】 That is, 94. The compound according to any one of claims 87 to 93, or a pharmaceutically acceptable salt thereof.

111. Ring E is a 5-membered heteroaryl; 94. The compound according to any one of claims 87 to 93, or a pharmaceutically acceptable salt thereof.

112. Ring E is a 5-membered heteroaryl which is oxazole, thiazole, pyrrole, furan, or thiophene; 112. The compound of claim 111, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 113】 【Chemistry 38】 but 【Chemistry 39】 and Y ３ is O, S or NR １Ｃ and Y ４ is O, S, N or CH, and R １Ｃ is hydrogen or C １ -C ６ is alkyl, 112. The compound of claim 111, or a pharmaceutically acceptable salt thereof.

114. The compound has the structure of formula (XII): 【Chemistry 40】 114. The compound of claim 113, or a pharmaceutically acceptable salt or solvate thereof.

115. Y ３ is S or O; 115. The compound of claim 114, or a pharmaceutically acceptable salt thereof.

116. Each R ３５ are independently halogen, -CN, -S(=O) ２ N (R １Ａ ) ２ , -C １ -C ６ Alkyl or C １ -C ６ is haloalkyl, Each R １Ａ are independently hydrogen or C １ -C ６ is alkyl, 116. The compound of any one of claims 111 to 115, or a pharmaceutically acceptable salt or solvate thereof.

117. w is 1, 117. The compound of any one of claims 111 to 116, or a pharmaceutically acceptable salt or solvate thereof.

118. w is 0, 116. The compound of any one of claims 111 to 115, or a pharmaceutically acceptable salt or solvate thereof.

119. R ３５ is -S (=O) ２ NH ２ That is, The compound of claim 117.

120. R ３２ is H, halogen, -CN, -OH, -OR １Ｂ , -N(R １Ａ ) ２ , -C １ -C ６ Alkyl, C １ -C ４ Fluoroalkyl, —C １－６ Alkyl-OH, or C １－６ heteroalkyl-OH; 120. The compound of any one of claims 87 to 119, or a pharmaceutically acceptable salt or solvate thereof.

121. R ３２ Ga-NH ２ , -NHCH ３ , -NHCH ２ CH ３ , -N(CH ３ ) ２ , -OCH ３ , -CH ３ , -CH ２ CH ３ or NH(CH ２ ) ２ OH, 121. The compound of claim 120, or a pharmaceutically acceptable salt or solvate thereof.

122. R ３２ is phenyl or 6-membered heteroaryl; 120. The compound of any one of claims 87 to 119, or a pharmaceutically acceptable salt or solvate thereof.

123. R ３２ is a 6-membered heteroaryl which is 2-pyridyl, 3-pyridyl, or 4-pyridyl; 123. The compound of claim 122, or a pharmaceutically acceptable salt or solvate thereof.

124. Y ａ is N, 124. The compound of any one of claims 87 to 123, or a pharmaceutically acceptable salt or solvate thereof.

125. Y ａ is CH, 124. The compound of any one of claims 87 to 123, or a pharmaceutically acceptable salt or solvate thereof.

126. 88. The compound of claim 87, wherein the compound has one of the following structures: 【Chemistry 41-1】 【Chemistry 41-2】 【Chemistry 41-3】 【Chemistry 41-4】 【Chemistry 41-5】

127. A compound having one of the following structures: 【Chemistry 42】

128. 128. A pharmaceutical composition comprising a compound according to any one of claims 1 to 127, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

129. 129. The pharmaceutical composition of claim 128, wherein the pharmaceutical composition is formulated for administration to a mammal by intravenous, subcutaneous, oral, inhalation, nasal, transdermal, or ocular administration.

130. 129. The pharmaceutical composition of claim 128, wherein the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

131. 128. A method for treating or preventing arthritis in a mammal, comprising administering to the mammal a compound according to any one of claims 1 to 127, or a pharmaceutically acceptable salt or solvate thereof.

132. 132. The method of claim 131, wherein the arthritis is pseudogout.

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