Adenosine receptor antagonist compounds

Abstract

The present disclosure provides adenosine receptor (e.g., A2A and / or A1 receptor) antagonist compounds and compositions comprising the compounds. The present disclosure also provides methods of using the compounds and compositions to modulate (e.g., inhibit or antagonize) A2A and / or A1 receptors in biological systems. The compounds and compositions are used in a variety of therapeutic applications, including the treatment of cancer and immuno-oncology. The compounds and compositions are used in a variety of therapeutic applications, including the treatment of central nervous system or neurodegenerative disorders such as Parkinson's disease.

Description

[Technical field]

[0001] Cross-reference to related application This application claims the benefit of priority from Korean Application No. 10-2019-0149117, filed November 19, 2019, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Prologue Adenosine carries out many biological functions through specific cellular receptors and is associated with a variety of biological activities, including immune function and inflammation.

[0003] There are four types of adenosine receptors (A1, A2A, A2B, and A3), which are coupled to heteromeric G proteins. A2A and A2B receptors are each connected to the Gs subtype of Gα protein. When these receptors are stimulated, the receptor format changes, and such changes induce the shedding of activated Gs subunits by Gβρ dimers, which hydrolyzes intracellular adenosine triphosphate (ATP) and generates cyclic adenosine monophosphate (cAMP). cAMP synthesis activates protein kinase A (PKA) and phosphorylation of other proteins. In T cells, mainly type I PKA isoforms are present around the T cell receptor (TCR), and increased activation of PKA due to increased cAMP levels inhibits the TCR signaling process, contributing to the development of various diseases.

[0004] Cancer cells produce significantly more adenosine than normal cells. In cancer cells, high-density adenosine induces the activation of A2A receptors, thereby inhibiting the immune system and protecting the cells. In the tumor microenvironment, the concentration of adenosine is 50 μM, which is increased compared to normal cells, and may lead to immune suppression of T cell function and activation. A2A receptor antagonists can be used to regulate the inhibition of the immune system by cancer cells and induce anti-cancer effects.

[0005] A2A receptor antagonists are under development for immuno-oncology therapy. A2A receptor antagonists can enhance antitumor immunity. A2A receptors are widely produced in leukocytes. Activation of A2A receptors on T cells reduces TCR-mediated cytotoxicity and cytokine production, inhibits T cell proliferation, and induces Treg cell proliferation. In immuno-oncology, immune checkpoint inhibitors (e.g., antibody inhibitors) of PD-1 or PD-L1 are widely used. However, statistically only 20% to 30% of patients produce PD-1 / PD-L1, so there are many patients who do not benefit from the efficacy of such inhibitors. Treatments involving immune checkpoint inhibitors in combination with A2A receptor antagonists are of interest.

[0006] The regulation of adenosine receptors is important for the treatment of various indications. The modulation activity of adenosine A1 receptors is important for the treatment of nervous system disorders, asthma, heart failure, renal failure, etc.; antagonizing adenosine A2A receptors is important for the treatment of Parkinson's disease, etc.; modulating the activity of adenosine A2B receptors is important for the treatment of chronic lung disorders such as asthma, cancer, immuno-oncology, etc.; modulating adenosine A3 receptors is important for the treatment of asthma and chronic obstructive pulmonary disorder, glaucoma, cancer, cerebral apoplexy, etc. Summary of the Invention

[0007] overview The present disclosure provides adenosine receptor (e.g., A2A and / or A1 receptor) antagonist compounds and compositions comprising said compounds. The present disclosure also provides methods of using said compounds and compositions to modulate (e.g., inhibit or antagonize) A2A and / or A1 receptors in biological systems. The compounds and compositions are used in a variety of therapeutic applications, including the treatment of cancer, and immuno-oncology applications. The compounds and compositions are used in a variety of therapeutic applications, including the treatment of central nervous system or neurodegenerative diseases, such as Parkinson's disease.

[0008] In a first aspect, the disclosure provides an A2A and / or A1 antagonist compound of formula (I) or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000001.tif2849(I) Here, Z 1 and Z 2 is independently selected from CR and N; Z 1 and Z 2 at least one of is N; R is H, (C 1 -C 3 ) alkyl, or substituted (C 1 -C 3 ) alkyl; Y 1 Or Y 4 is an independent CR 10 and N, and at least two of Y1 to Y4 are independently selected from CR 10 and; R 10 are independently H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO2 NH 2 , substituted sulfonamide, and thiol; R a and R b are independently H, F, (C 1 -C 3 ) alkyl, and substituted (C 1 -C 3 ) alkyl, or R a and R b are attached to a ring and together with the carbon atoms to which they are attached form a cyclopropyl, or substituted cyclopropyl; A is phenyl, substituted phenyl, pyridyl, or substituted pyridyl.

[0009] In a second aspect, the disclosure provides a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt thereof (e.g., a compound of Formula (I)-(XVIb)), and a pharma- ceutically acceptable excipient.

[0010] In a third aspect, the disclosure provides a method of modulating (e.g., inhibiting or antagonizing) adenosine A2A and / or A1 receptors, comprising contacting a sample or a cell or a biological system with an effective amount of a compound described herein (e.g., a compound of Formula (I)-(XVIb) or a pharma- ceutically acceptable salt thereof).

[0011] Also provided are methods of treating cancer, comprising administering a therapeutically effective amount of an A2A and / or A1 receptor antagonist compound (e.g., as described herein) to a subject having cancer. In some embodiments, the method further comprises co-administering an additional active agent, such as an immune checkpoint inhibitor, to the subject. Also provided are methods of treating central nervous system or neurodegenerative disease, comprising administering a therapeutically effective amount of an A2A and / or A1 receptor antagonist compound (e.g., a compound of Formula (I)-(XVIb), or a pharma- ceutical acceptable salt thereof, as described herein) to a subject having or at risk of having a central nervous system or neurodegenerative disease.

[0012] Detailed Description Adenosine receptor antagonist compounds As summarized above, the present disclosure provides A2A and / or A1 receptor antagonist compounds and compositions. These compounds can modulate adenosine A2A and / or A1 receptors in cells and biological systems of interest. These compounds are used in a variety of therapeutic applications, including the treatment of cancer and immuno-oncology, and the treatment of central nervous system and neurodegenerative diseases such as Parkinson's disease.

[0013] The compounds of the present disclosure can be described as cyano-substituted fused pyrimidine compounds that include a core structure having a 2-amino-pyrimidine ring fused to a 5-membered heterocycle. The core structure itself can be further substituted with a benzonitrile substituent (e.g., 3-cyano-phenyl) or a derivative thereof (e.g., cyano-pyridyl substituent). The fused 5-membered heterocycle can be further substituted with an optionally substituted benzyl group. In some cases, the compounds have a 9H-purin-2-amine or 1H-pyrazolo[3,4-d]pyrimidin-6-amine core structure that is further substituted as described herein.

[0014] In some embodiments, the compound is, for example, a benzonitrile-substituted fused pyrimidine compound of the formula: TIFF0007681616000002.tif2841 or a derivative thereof (e.g., a derivative compound in which the 3-benzonitrile group is replaced with a cyano-pyridyl group), where Cy is a fused 5-membered heterocycle (e.g., a heteroaryl or heterocycloalkyl ring) containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. R is an optionally substituted phenyl group. R 10 is one or more optional substituents. In some embodiments, R is a halogen, a hydroxyl group, a thiol group, a carbonyl group, an amide group, a nitro group, an amino group, a substituted or unsubstituted (C 1 -C 5 ) alkyl group, substituted or unsubstituted (C 2 -C 5 ) alkenyl groups, substituted or unsubstituted (C 2 -C 5 ) alkynyl groups, substituted or unsubstituted (C 1 -C 3 ) haloalkyl groups, and substituted or unsubstituted (C 1 -C 3 ) aminoalkyl group or substituted or unsubstituted (C 1 -C 5 ) R independently selected from an alkoxy group; 11 , R 12 , and / or R 13 phenyl substituted by a group, and R 10 is a hydrogen, halogen, hydroxyl group, thiol group, substituted or unsubstituted (C 1 -C 5 ) alkyl group, substituted or unsubstituted (C 2 -C 5 ) alkenyl groups, substituted or unsubstituted (C 2 -C 5 ) alkynyl groups, substituted or unsubstituted (C 1 -C 3 ) haloalkyl groups, substituted or unsubstituted (C 1 -C 5 ) an alkoxy group, or a cyano group.

[0015] In some embodiments, the aforementioned R 11 and R 13 are independently hydrogen, halogen, (C 1 -C 5 ) alkyl group, or (C 1 -C 3 ) haloalkyl group, as defined above for R 12 is hydrogen or an amino group, and each of the R 10 are independently hydrogen, halogen, (C 1 -C 5 ) an alkyl group, or a cyano group. Further embodiments of the above formula are described herein.

[0016] Embodiments of the disclosure include A2A and / or A1 antagonist compounds of formula (I) or solvates, hydrates, prodrugs, and / or stereoisomers thereof, or pharma- ceutically acceptable salts thereof: TIFF0007681616000003.tif2849(I) Where: Z 1 and Z 2 is independently selected from CR and N; Z 1 and Z 2 at least one of is N; R is H, (C 1 -C 3 ) alkyl, or substituted (C 1 -C 3 ) alkyl; Y 1 Or Y 4 is an independent CR 10 and N are selected, Y 1 Or Y 4 At least two of the following were independently CR 10 and; R 10 are independently H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 NH 2 , substituted sulfonamide, and thiol; R a and R b are independently H, F, (C 1 -C 3 ) alkyl, and substituted (C 1 -C 3 ) alkyl, or R a and R b are attached to a ring and together with the carbon atoms to which they are attached form a cyclopropyl, or substituted cyclopropyl; A is phenyl, substituted phenyl, pyridyl, or substituted pyridyl.

[0017] In some embodiments of Formula (I), Y 1 Or Y 4 CR 10 and N, where Y 1 Or Y 4 At least three of the studies were independently 10 It is.

[0018] In some embodiments of Formula (I), Z is a group such that the compound is a compound of Formula (Ia), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. 1 is CR and Z 2 is N. TIFF0007681616000004.tif3351(Ia)

[0019] In some embodiments of Formula (Ia), R is (C 1 -C 3 ) alkyl. In some embodiments of Formula (Ia), R is H.

[0020] In some embodiments of Formula (I), Z is a compound of Formula (Ib), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. 1 is CR and Z2 is N. TIFF0007681616000005.tif3354(Ib)

[0021] In some embodiments of Formula (Ib), R is (C 1 -C 3 ) alkyl. In some embodiments of Formula (Ib), R is H.

[0022] In some embodiments of Formula (I)-(Ib), A is phenyl. In some embodiments of Formula (I)-(Ib), A is substituted phenyl. In some embodiments of Formula (I)-(Ib), A is phenyl or one, two, or three R 20 groups, each R 20 is (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2-C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 NH 2 , substituted sulfonamide, and thiol.

[0023] In some embodiments of Formula (I)-(Ib), A is pyridyl. In some embodiments of Formula (I)-(Ib), A is substituted pyridyl. A can be an optionally substituted pyridyl that is 2-pyridyl, 3-pyridyl, or 4-pyridyl. In some embodiments of Formula (I)-(Ib), A is pyridyl or one, two, or three R 20 R is a pyridyl substituted with a 20 is (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )Alkoxy, -CONH 2 , substituted amide, -NH2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 NH 2 , substituted sulfonamide, and thiol.

[0024] In some embodiments of Formulas (I)-(Ib), R a and R b are H, respectively.

[0025] In some embodiments of Formula (Ia)-(Ib), Y 1 Or Y 4 CR 10 and N, where Y 1 Or Y 4 At least three of the studies were independently 10 It is.

[0026] In some embodiments of Formula (Ia)-(Ib), the compound includes compounds of Formula (IIa) or (IIb), or solvates, hydrates, prodrugs, and / or stereoisomers thereof, or pharma- ceutically acceptable salts thereof: TIFF0007681616000006.tif42170 where R 1 Or R 9 are independently H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C1 -C 8 )Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 NH 2 , substituted sulfonamide, and thiol.

[0027] In some embodiments of Formula (IIa)-(IIb), R 1 Or R 9 are independently H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) Alkoxy, -NH 2 , substituted amino, halogen, and hydroxyl. In some embodiments of Formula (IIa)-(IIb), R 1 Or R 9 are independently H, NH 2 , F, C.H. 3 , and C.F. 3 is selected from.

[0028] In some embodiments of Formula (IIa)-(IIb), the compound includes the compound of Formula (IIIa) or (IIIb), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000007.tif46170, where R 21 and R 22 are independently H, (C 1 -C 8 ) alkyl, substituted (C 1 -C8 ) Alkyl, SO 2 R 30 , and C.O.R. 30 Selected from R 30 is (C 1 -C 8 ) alkyl, or substituted (C 1 -C 8 ) alkyl.

[0029] In some embodiments of Formulas (IIIa)-(IIIb), R 21 and R 22 are H, respectively.

[0030] In some embodiments of Formula (IIIa)-(IIIb), R 5 , R 6 , R 8 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) alkoxy, halogen, and hydroxyl. In some embodiments of Formula (IIIa)-(IIIb), R 5 , R 6 , R 8 and R 9 But, H, F, CH 3 , and C.F. 3 In some embodiments of Formula (IIIa)-(IIIb), R 5 , R 6 , R 8 and R 9 are H, respectively.

[0031] In some embodiments of Formula (IIIa)-(IIIb), R 2 Or R 4 are H and R 1 is H, (C1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 In some embodiments of Formulae (IIIa)-(IIIb), R 1 H, F, CH 3 , and C.F. 3 is selected from.

[0032] In some embodiments of Formula (IIIa)-(IIIb), the compound is selected from the following: or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000008.tif106170

[0033] In some embodiments of Formula (IIIa)-(IIIb), the compound is of Formula (IVa) or (IVb), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000009.tif41170

[0034] In some embodiments of Formula (IVa)-(IVb), R 6 But (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5In some embodiments of formula (IVa)-(IVb), R is selected from alkoxy, halogen, and hydroxyl. 6 However, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, and (C 1 -C 3 In some embodiments of formula (IVa)-(IVb), R 6 CH 3 or CF 3 It is.

[0035] In some embodiments of Formula (IVa)-(IVb), R 2 Or R 4 are H and R 1 is H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 In some embodiments of formula (IVa)-(IVb), R is selected from alkoxy, halogen, and hydroxyl. 1 H, F, CH 3 , and C.F. 3 is selected from.

[0036] In some embodiments of Formula (IVa)-(IVb), the compound is selected from the following: or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000010.tif143170

[0037] In some embodiments of Formula (IIIa)-(IIIb), the compound is of Formula (Va) or (Vb), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000011.tif41170

[0038] In some embodiments of Formulas (Va)-(Vb), R 5 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) alkoxy, halogen, and hydroxyl. In some embodiments of Formula (Va)-(Vb), R 5 and R 9 is independently selected from H and halogen. In some embodiments of Formula (Va)-(Vb), R 5 is F. In some embodiments of Formula (Va)-(Vb), R 9 is F. In some embodiments of Formula (Va)-(Vb), R 5 and R 9 are each F. In some embodiments of Formula (Va)-(Vb), R 5 is H and R 9 is F.

[0039] In some embodiments of Formula (Va)-(Vb), the compound is selected from the following: or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000012.tif144170

[0040] In some embodiments of Formula (IIa)-(IIb), the compound is of Formula (VIa) or (VIb), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000013.tif41170

[0041] In some embodiments of Formulas (VIa)-(VIb), R 5 , R 6 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) Alkoxy, -NH 2 , substituted amino, halogen, and hydroxyl. In some embodiments of Formula (VIa)-(VIb), R 6 H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, and (C 1 -C 3 In some embodiments of formula (VIa)-(VIb), R 6 CH 3 or CF 3 In some embodiments of formula (VIa)-(VIb), R 6 is H.

[0042] In some embodiments of Formulas (VIa)-(VIb), R 5 and R 9 is independently selected from H and halogen. In some embodiments of Formula (VIa)-(VIb), R 5 is F. In some embodiments of Formula (VIa)-(VIb), R9 is F. In some embodiments of Formula (VIa)-(VIb), R 5 and R 9 are each F. In some embodiments of Formula (VIa)-(VIb), R 5 is H and R 9 is F.

[0043] In some embodiments of Formula (VIa)-(VIb), the compound is selected from the following: or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000014.tif94170

[0044] In some embodiments of Formulas (IIa)-(VIb), R 1 Or R 4 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) Alkoxy, -NH 2 In some embodiments of Formula (IIa)-(VIb), R is independently selected from substituted amino, halogen, and hydroxyl. 1 Or R 4 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) independently selected from haloalkyl and halogen.

[0045] In some embodiments of Formulas (IIa)-(VIb), R 1 is H. In some embodiments of Formula (IIa)-(VIb), R 1 But (C1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 In some embodiments of Formulae (IIa)-(VIb), R 1 F, CH 3 or CF 3 In some embodiments of Formula (IIa)-(VIb), R 2 , R 3 or R 4 is (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 In some embodiments of formulas (IIa)-(VIb), R 2 , R 3 and R 4 are H, respectively.

[0046] In some embodiments of Formula (Ia)-(Ib), the compound is of Formula (VIIa) or (VIIb), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. TIFF0007681616000015.tif42170, where Y 1 Or Y 4 is CR 10 and N are independently selected, Y 1 Or Y 4 At least three of the following were independently CR 10 and; R 5 Or R 9 and each R 10 is H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2-C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 NH 2 , substituted sulfonamide, and thiol.

[0047] In some embodiments of Formula (VIIa)-(VIIb), Y 1 Or Y 4 One of them is N.

[0048] In some embodiments of Formulas (VIIa)-(VIIb), R 5 Or R 9 and each R 10 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) Alkoxy, -NH 2 , substituted amino, halogen, and hydroxyl. In some embodiments of Formula (VIIa)-(VIIb), R 5 Or R 9 and each R 10 But, H, NH 2 , F, C.H. 3, and C.F. 3 are independently selected from

[0049] In some embodiments of Formula (VIIa)-(VIIb), the compound is of Formula (VIIIa) or (VIIIb), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000016.tif46170, where Y 1 Or Y 4 One of them is N; R 21 and R 22 is H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) Alkyl, SO 2 R 30 , and C.O.R. 30 are independently selected from R 30 is (C 1 -C 8 ) alkyl, or substituted (C 1 -C 8 ) alkyl.

[0050] In some embodiments of Formulas (VIIIa)-(VIIIb), R 21 and R 22 are H, respectively.

[0051] In some embodiments of Formulae (VIIIa)-(VIIIb), R 5 , R 6 , R 8 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5) alkoxy, halogen, and hydroxyl. In some embodiments of Formula (VIIIa)-(VIIIb), R 5 , R 6 , R 8 and R 9 But, H, F, CH 3 , and C.F. 3 In some embodiments of Formula (VIIIa)-(VIIIb), R 5 , R 6 , R 8 and R 9 are H, respectively.

[0052] In some embodiments of Formula (VIIIa)-(VIIIb), the compound is selected from the following: or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000017.tif143170

[0053] In some embodiments of Formula (VIIIa)-(VIIIb), the compound is of Formula (IXa) or (IXb), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000018.tif41170

[0054] In some embodiments of Formulae (IXa)-(IXb), R 6 But (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 In some embodiments of Formulae (IXa)-(IXb), R 6 However, (C1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, and (C 1 -C 3 In some embodiments of formula (IXa)-(IXb), R 6 CH 3 or CF 3 It is.

[0055] In some embodiments of Formula (IXa)-(IXb), the compound is selected from the following: or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000019.tif219170 TIFF0007681616000020.tif73170

[0056] In some embodiments of Formula (VIIIa)-(VIIIb), is of Formula (Xa) or (Xb), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. TIFF0007681616000021.tif41170

[0057] In some embodiments of Formulae (Xa)-(Xb), R 5 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) alkoxy, halogen, and hydroxyl. In some embodiments of Formula (Xa)-(Xb), R 5 and R 9is independently selected from H and halogen. In some embodiments of Formula (Xa)-(Xb), R 5 is F. In some embodiments of Formula (Xa)-(Xb), R 9 is F. In some embodiments of Formula (Xa)-(Xb), R 5 and R 9 are each F. In some embodiments of Formula (Xa)-(Xb), R 5 is H and R 9 is F.

[0058] In some embodiments of Formula (Xa)-(Xb), the compound is selected from the following: or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000022.tif213170 TIFF0007681616000023.tif72170

[0059] In some embodiments of Formula (VIIa)-(VIIb), the compound is of Formula (XIa) or (XIb), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. TIFF0007681616000024.tif41170

[0060] In some embodiments of Formulas (XIa)-(XIb), R 5 , R 6 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) Alkoxy, -NH 2, substituted amino, halogen, and hydroxyl. In some embodiments of Formula (XIa)-(XIb), R 6 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, and (C 1 -C 3 In some embodiments of formula (XIa)-(XIb), R 6 CH 3 or CF 3 In some embodiments of formula (XIa)-(XIb), R 6 is H.

[0061] In some embodiments of Formulas (XIa)-(XIb), R 5 and R 9 is independently selected from H and halogen. In some embodiments of Formula (XIa)-(XIb), R 5 is F. In some embodiments of Formula (XIa)-(XIb), R 9 is F. In some embodiments of Formula (XIa)-(XIb), R 5 and R 9 are each F. In some embodiments of Formula (XIa)-(XIb), R 5 is F and R 9 is H.

[0062] In some embodiments of Formula (XIa)-(XIb), the compound is selected from the following: or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000025.tif124170

[0063] In some embodiments of Formula (VIIa)-(VIIb), the compound is of Formula (XIVa) or (XIVb), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. TIFF0007681616000026.tif46170, where Y 4 is CR 4 or N; R 1 Or R 4 is H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 NH 2 , a substituted sulfonamide, and a thiol; R 21 and R 22 is H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) Alkyl, SO 2 R 30 , and C.O.R. 30 are independently selected from R 30 is (C 1 -C 8 ) alkyl, and substituted (C 1 -C 8 ) alkyl.

[0064] In some embodiments of Formulae (XIVa)-(XIVb), R 5 , R 6 , R 8 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) independently selected from alkoxy, halogen, and hydroxyl.

[0065] In some embodiments of Formulas (XIVa)-(XIVb), R 21 and R 22 are H, respectively.

[0066] In some embodiments of Formulas (XIVa)-(XIVb), R 2 Or R 4 are H and R 1 is H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 In some embodiments of Formula (XIVa)-(XIVb), R is selected from alkoxy, halogen, and hydroxyl. 1 H, F, CH 3 , and C.F. 3 is selected from.

[0067] In some embodiments of Formula (XIVa)-(XIVb), the compound is of Formula (XVa) or (XVb), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. TIFF0007681616000027.tif41170

[0068] In some embodiments of Formulae (XVa)-(XVb), R 5 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) alkoxy, halogen, and hydroxyl. In some embodiments of Formula (XVa)-(XVb), R 5 and R 9 is independently selected from H and halogen. In some embodiments of Formula (XVa)-(XVb), R 5 is F. In some embodiments of Formula (XVa)-(XVb), R 9 is F. In some embodiments of Formula (XVa)-(XVb), R 5 and R 9 are each F. In some embodiments of Formula (XVa)-(XVb), R 5 is H and R 9 is F.

[0069] In some embodiments of Formulae (XVa)-(XVb), R 1 teeth, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 In some embodiments of Formula (XVa)-(XVb), R1 H, F, CH 3 , and C.F. 3 is selected from.

[0070] In some embodiments of Formula (XVa)-(XVb), Y 4 In some embodiments of formula (XVa)-(XVb), Y 4 is N.

[0071] In some embodiments of Formula (XVIa)-(XVIb), the compound is selected from the following: or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000028.tif72170

[0072] In some embodiments of Formula (XIVa)-(XIVb), the compound is of Formula (XVIa) or (XVIb), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. TIFF0007681616000029.tif41170

[0073] In some embodiments of Formulae (XVIa)-(XVIb), R 6 But (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 In some embodiments of Formulae (XVIa)-(XVIb), R 6 However, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, and (C 1 -C3 In some embodiments of Formula (XVIa)-(XVIb), R 6 CH 3 or CF 3 It is.

[0074] In some embodiments of Formulae (XVIa)-(XVIb), R 1 H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 In some embodiments of Formulae (XVIa)-(XVIb), R 1 H, F, CH 3 , and C.F. 3 is selected from.

[0075] In some embodiments of Formula (XVIa)-(XVIb), Y 4 In some embodiments of Formula (XVIa)-(XVIb), Y 4 is N.

[0076] In some embodiments of Formula (XVIa)-(XVIb), the compound is selected from the following, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF0007681616000030.tif75170

[0077] In some embodiments of Formula (I)-(Ib), the compound is of Formula (XIIa) or (XIIb). TIFF0007681616000031.tif44170, where Y 5 Or Y 7 are each independently CR 20or N and Y 5 Or Y 7 One of the is N;R 1 Or R 4 , R 8 , R 9 and each R 20 is H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 NH 2 , substituted sulfonamide, and thiol.

[0078] In some embodiments of Formula (XIIa)-(XIIb), Y 5 is N. In some embodiments of Formula (XIIa)-(XIIb), Y 6 is N. In some embodiments of Formula (XIIa)-(XIIb), Y 7 is N.

[0079] In some embodiments of Formulas (XIIa)-(XIIb), R 8 , R 9 and each R 20 is H, (C 1 -C 5) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) Alkoxy, -NH 2 , substituted amino, halogen, and hydroxyl.

[0080] In some embodiments of Formulas (XIIa)-(XIIb), R 8 , R 9 and each R 20 H, NH 2 , F, C.H. 3 , and C.F. 3 are independently selected from

[0081] In some embodiments of Formulas (XIIa)-(XIIb), R 1 Or R 4 is H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) Alkoxy, -NH 2 , substituted amino, halogen, and hydroxyl. In some embodiments of Formula (XIIa)-(XIIb), R 1 Or R 4 is H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, and halogen.

[0082] In some embodiments of Formula (I)-(Ib), the compound is of Formula (XIIIa) or (XIIIb). TIFF0007681616000032.tif39170, where Y 5 From Y 7 are each independently CR 20 or N and Y 5 From Y 7 One of them is N; R 8 , R 9 , each R 10 , and each R 20 is H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 NH 2 , substituted sulfonamide, and thiol.

[0083] In some embodiments of Formula (XIIIa)-(XIIIb), Y 5 is N. In some embodiments of Formula (XIIIa)-(XIIIb), Y 6 is N. In some embodiments of Formula (XIIIa)-(XIIIb), Y 7is N.

[0084] In some embodiments of Formulae (XIIIa)-(XIIIb), R 8 , R 9 and each R 20 is H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) Alkoxy, -NH 2 In some embodiments of Formula (XIIIa)-(XIIIb), R is independently selected from substituted amino, halogen, and hydroxyl. 8 , R 9 and each R 20 are H, F, and CH 3 , and C.F. 3 In some embodiments of Formula (XIIIa)-(XIIIb), each R 10 is H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) Alkoxy, -NH 2 , substituted amino, halogen, and hydroxyl.

[0085] In some embodiments of Formula (XIIIa)-(XIIIb), Y 1 is CR 10 It is.

[0086] In some embodiments of Formulas (XIIIa)-(XIIIb), R 10is H. In some embodiments of Formula (XIIIa)-(XIIIb), R 10 is (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 In some embodiments of Formula (XIIIa)-(XIIIb), R 10 are H, F, and CH 3 , and C.F. 3 It is.

[0087] In some embodiments of Formula (XIIIa)-(XIIIb), Y 1 Or Y 4 are CR 10 It is.

[0088] In some embodiments of Formula (XIIIa)-(XIIIb), each R 10 is (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, and halogen.

[0089] In some embodiments of Formula (XIIIa)-(XIIIb), Y 1 Or Y 4 In some embodiments of Formula (XIIIa)-(XIIIb), Y 1 Or Y 4 and n is 0 or 1. In some embodiments of Formula (XIIIa)-(XIIIb), Y 1 is N. In some embodiments of Formula (XIIIa)-(XIIIb), Y 2 is N. In some embodiments of Formula (XIIIa)-(XIIIb), Y 3 is N. In some embodiments of Formula (XIIIa)-(XIIIb), Y 4 is N.

[0090] In some of the above embodiments, the compound is of formula (Ia) to (XVIa) (e.g., a purine compound), or a salt thereof (e.g., a pharma- ceutically acceptable salt). In some of the above embodiments, the compound is of formula (Ib) to (XVIb) (e.g., a pyrazolopyrimidine compound), or a salt thereof (e.g., a pharma- ceutically acceptable salt).

[0091] In some embodiments of Formula (I), the compound is selected from: 3-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo-[3,4-d]-pyrimidin-4-yl)-benzonitrile; 3-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo-[3,4-d]-pyrimidin-4-yl)-2-methylbenzonitrile; 3-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo-[3,4-d]-pyrimidin-4-yl)-2-fluorobenzonitrile; 3-(2-amino-9-(4-aminobenzyl)-9H-purin-6-yl)-benzonitrile; 3-(2-amino-9-(4-aminobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile; 3-(2-amino-9-(4-aminobenzyl)-9H-purin-6-yl)-2-methylbenzonitrile; 3-(2-amino-9-(4-amino-2,6-difluorobenzyl)-9H-purin-6-yl)-benzonitrile; 3-(2-amino-9-(4-amino-2,6-difluorobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile; 3-(2-amino-9-(4-amino-2-fluorobenzyl)-9H-purin-6-yl)-benzonitrile; 3-(2-amino-9-(4-amino-2-fluorobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile; 3-(2-amino-9-(4-amino-3-methylbenzyl)-9H-purin-6-yl)-benzonitrile; 3-(2-amino-9-(4-amino-3-methylbenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile; 3-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)benzonitrile; 3-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile; and 3-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-2-methylbenzonitrile.

[0092] All salts, and / or solvates, hydrates, prodrugs, and / or stereoisomers of the compounds described herein, e.g., compounds of Formula (I)-(XVIb), or compounds shown in Table 1, are included in the present disclosure. Thus, any of the compounds described herein may be referred to as a compound of Formula (I)-(XVIb), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0093] In some embodiments, the compound is represented by the structure of one of the compounds in Table 1, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a salt thereof (e.g., a pharma- ceutically acceptable salt). In some embodiments, the compound is represented by the structure of one of the compounds in Table 1 that is of formula (Ia) (e.g., a purine compound) or a salt thereof (e.g., a pharma- ceutically acceptable salt). In some embodiments, the compound is represented by the structure of one of the compounds in Table 1 that is of formula (Ib) (e.g., a pyrazolo-pyrimidine compound) or a salt thereof (e.g., a pharma- ceutically acceptable salt). The present disclosure is meant to include any one of the compounds in Table 1, or a salt thereof, and / or a solvate, hydrate, prodrug thereof, single stereoisomer, mixture of stereoisomers, and / or isotopically labeled forms thereof. For example, solvates, hydrates, prodrugs and / or salts of stereoisomeric forms of any of the compounds described herein (e.g., of Formulas (I)-(XVIb)) or shown in Table 1 are meant to be included in the disclosure herein. TIFF0007681616000033.tif250165 TIFF0007681616000034.tif251167 TIFF0007681616000035.tif245170 TIFF0007681616000036.tif244170 TIFF0007681616000037.tif225170 TIFF0007681616000038.tif81170Isotope-labeled analogues

[0094] The present disclosure also includes isotopically labeled compounds identical to the compounds described herein except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature ("isotopologues"). Compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. Examples of isotopes that can be incorporated into the compounds described herein include:2 H("D"), 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Included are isotopes of each of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as Cl. For example, the compounds described herein may have one or more H atoms replaced with deuterium.

[0095] In general, a reference or depiction of a particular element, such as hydrogen or H, is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Thus, tritium, 14 C. 32 P and 35 Within the scope of the present technology are compounds that contain radioisotopes such as S. Procedures for incorporating such labels into the compounds of the present technology will be readily apparent to those of skill in the art based on the disclosure herein.

[0096] Unless otherwise stated, the compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having the present structures except for the replacement of a carbon with a C-rich carbon are within the scope of this disclosure.

[0097] In some embodiments, 3 H and 14 Certain isotopically labeled compounds, such as those labeled with C, may be useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14C) Isotopes may be particularly preferred because they are easy to prepare and detect. Furthermore, substitution with heavier isotopes, such as deuterium, may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced required dosage, and may therefore be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by procedures similar to those disclosed herein, for example in the Examples section, by replacing isotopically labeled reagents with nonisotopically labeled reagents.

[0098] In some embodiments, the compounds disclosed in the present disclosure are deuterated analogs of any of the compounds or salts thereof as described herein. Deuterated analogs of compounds of formula (I)-(XVIb) are compounds in which one or more hydrogen atoms are replaced with deuterium. In some embodiments, deuterated analogs are deuterated R, R a , R b , or R 1 Or R 20 A compound of formula (I) comprising a group.

[0099] Deuterium substituted compounds are synthesized using a variety of methods as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000;6(10)] 2000, 110 pp; George W.; Varma, Rajender S. Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of Radiolabeled Compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0100] Deuterated starting materials are readily available and are provided by the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Many deuterium-containing reagents and building blocks are commercially available from chemical vendors such as Aldrich Chemical Co. Fluorinated Analogues

[0101] In some embodiments, the compounds disclosed in the present disclosure are fluorinated analogs of any compound or salt thereof as described herein. Fluorinated analogs of compounds of formula (I)-(XVIb) are compounds in which one or more hydrogen atoms or substituents are replaced with fluorine atoms. In some embodiments, fluorinated analogs are fluorinated R, R a , R b , or R 1 Or R 20 In some embodiments of the fluorinated analogs of the compounds of formula (I), a hydrogen atom of the aliphatic or aromatic C-H bond is replaced by a fluorine atom. In some embodiments of the fluorinated analogs of the compounds of formula (I), at least one hydrogen of the optionally substituted aryl (e.g., phenyl) or the optionally substituted heteroaryl (e.g., pyridyl) is replaced by a fluorine atom. In some embodiments of the fluorinated analogs of the compounds of formula (I), a hydroxyl substituent (-OH) or an amino substituent (-NH 2 In some embodiments of the fluorinated analogs of the compounds, the compounds are -F, -CF 3 , -CF 2 CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , and -OCF 2 CF 3 The compound includes one or more substituents independently selected from: Isomers

[0102] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.

[0103] The compounds described herein may have asymmetric centers, geometric centers (e.g., double bonds), or both. All chiral, diastereomeric, racemic forms, and all geometric isomeric forms of a structure are intended unless a particular stereochemistry or isomeric form is specifically indicated. In some embodiments, the compounds described herein have one or more chiral centers. When the absolute stereochemistry is not explicitly indicated, it is understood that each chiral center may be independently in the R or S configuration or a mixture thereof. Thus, the compounds described herein include optical isomers enriched or resolved at any or all asymmetric atoms, as is clear from the depiction. Racemic mixtures of R- and S-enantiomers, and enantio-enriched stereoisomeric mixtures including R- and S-enantiomers, as well as individual optical isomers, may be isolated or synthesized to be substantially free of their enantiomeric or diastereomeric partners, and all of these stereoisomers are within the scope of the present technology.

[0104] Compounds of the present disclosure containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or by use of chiral auxiliaries.

[0105] Geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a cycloalkyl or heterocycle can also exist in the compounds of the present disclosure. Geometric isomers of olefins, C=N double bonds, or other types of double bonds can exist in the compounds described herein, and all such stable isomers are included in the present disclosure. Specifically, cis and trans geometric isomers of the compounds of the present disclosure can also exist and can be isolated as a mixture of isomers or as separated isomeric forms.

[0106] The compounds of the present disclosure also include tautomeric forms. Tautomers result from the exchange of a single bond with an adjacent double bond with the concomitant transfer of a proton. Tautomers include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of protic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactimum pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution. Salts and other forms

[0107] In some embodiments, the compounds described herein are present in the form of a salt. In some embodiments, the compounds are provided in the form of a pharma- ceutically acceptable salt.

[0108] Compounds contained in the present compositions that are basic in nature can form a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharma- ceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts with pharmacologically acceptable anions, including, but not limited to, chlorides.

[0109] Compounds containing amine functional groups or nitrogen-containing heteroaryl groups may be basic in nature and may react with various inorganic and organic acids to form corresponding salts.The compounds may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.In some embodiments, the pharmaceutically acceptable salts may be salts derived from hydrochloric acid (i.e., the hydrochloride salts of the compounds described herein), and the like.

[0110] Pharmaceutically acceptable salts of the compounds of the present disclosure can be produced by dissolving the compound in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, adding an excess of an organic or inorganic acid in water, and precipitating or crystallizing. Additional salts can then be obtained by evaporating the solvent or excess acid from the mixture and drying it, or by filtering the extracted salt to produce the salt.

[0111] Other examples of salts include the anion of the disclosed compound combined with a suitable cation. For therapeutic use, the salt of the disclosed compound may be pharmaceutically acceptable. However, non-pharmaceutically acceptable acid and base salts may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0112] Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts.

[0113] Compounds containing a basic or acidic moiety can also form pharma- ceutically acceptable salts with various amino acids. Compounds of the present disclosure can contain both acidic and basic groups, for example, one amino group and one carboxylic acid group. In such cases, the compounds can exist as acid addition salts, zwitterions, or base salts.

[0114] The compounds described herein may exist in various forms, including crystalline, powdered and amorphous forms of the compounds, such as pharma- ceutically acceptable salts, including polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.It is understood that any one of the salt forms of the subject compounds may exist in crystalline, powdered, or amorphous form.

[0115] The compounds described herein may exist as solvates, particularly hydrates, and all such solvates and hydrates are intended unless otherwise stated. The term "solvate" can refer to a compound of the present disclosure that includes stoichiometric or non-stoichiometric solvents combined by non-covalent intermolecular forces or salts thereof. Hydrates may form during the preparation of the compound or compositions that include the compound, or hydrates may form over time due to the hygroscopic nature of the compound. Compounds of the present technology may also exist as organic solvates, including dimethylformamide (DMF), ether, and alcohol solvates, among others. Identification and preparation of specific solvates are within the skill of one of ordinary skill in the art of synthetic organic or medicinal chemistry.

[0116] In some embodiments, the compounds described herein exist in the form of a solvate. In some embodiments, the compounds described herein exist in the form of a hydrate when the solvent component of the solvate is water. Prodrug

[0117] In some embodiments, the compounds described herein exist in the form of prodrugs.Any convenient prodrug form of the subject compound can be prepared according to the strategies and methods described, for example, by Rauchio et al. ("Prodrugs: Design and Clinical Applications", Nature Reviews Drug Discovery 7, 255-270 (February 2008)). compound synthesis

[0118] The compounds of the present disclosure can be synthesized according to standard methods known in the art [see, for example, "Organic Chemistry" by Morrison and Boyd, 6th Edition, Prentice Hall (1992)]. Some compounds and / or intermediates of the present disclosure are commercially available, known in the literature, or readily available by those of skill in the art using standard procedures. Some compounds of the present disclosure can be synthesized using the schemes, examples, or intermediates described herein. In cases where the synthesis of a compound, its intermediates, or variants is not fully described, one of skill in the art can recognize that reaction times, number of equivalents of reagents, and / or temperatures can be varied from the reactions described herein to prepare the compound or intermediates presented, or variants thereof, and that different work-up and / or purification techniques may be necessary or desirable to prepare such compounds, intermediates, or variants.

[0119] The synthesized compounds may be verified for proper structure by methods known to those skilled in the art, for example, by nuclear magnetic resonance (NMR) spectroscopy and / or mass spectrometry. Pharmaceutical Compositions

[0120] The compounds of the present disclosure can be formulated into pharmaceutical compositions. The pharmaceutical compositions can include one or more exemplary A2A and / or A1 receptor antagonist compounds (e.g., as described herein) and at least one excipient (e.g., a pharma- ceutically acceptable excipient).

[0121] The compounds described herein may find use in pharmaceutical compositions for administration to subjects in need thereof in a variety of therapeutic applications in which inhibition or antagonism of the activity of the A2A and / or A1 receptors is desirable.

[0122] Thus, in a second aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound described herein, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and at least one pharma- ceutically acceptable excipient. The phrase "pharma- ceutically acceptable excipient" refers to any ingredient other than the compound of the present invention described herein (e.g., a vehicle capable of suspending or dissolving an active compound, or any other convenient pharma- ceutically acceptable carrier, excipient, or additive), which is substantially non-toxic and non-inflammatory in a patient. Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (gliding agents), lubricants, preservatives, printing inks, adsorbents, dispensing or dispersing agents, sweeteners, and water of hydration. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound described herein, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0123] The pharmaceutical compositions can be formulated according to any convenient method and can be prepared in a variety of forms for oral administration, such as tablets, pills, powders, nanoparticles, capsules, syrups, suspensions, emulsions and microemulsions, or in forms for parenteral administration, such as preparations for intramuscular, intravenous or subcutaneous administration.

[0124] In certain examples, the pharmaceutical composition may include a pharma- ceutical carrier, excipient, or additive. The pharmaceutical composition may be prepared as a pharmaceutical product by conventional methods, and may be prepared as various oral pharmaceutical products such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, etc., or may be prepared as parenteral drugs such as intramuscular injections, intravenous injections, subcutaneous injections, etc.

[0125] When the pharmaceutical composition is prepared in the form of an oral drug, examples of additives or carriers used may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspensions, emulsifiers, diluents, etc. When the pharmaceutical composition of the present disclosure is prepared in the form of an injection, additives or carriers may include water, saline, aqueous glucose solution, similar sugar-soluble solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, surfactant, suspension, emulsifier, etc.

[0126] In some embodiments, the pharmaceutical composition is formulated for parenteral administration to a subject in need thereof. In some parenteral embodiments, the pharmaceutical composition is formulated for intravenous administration to a subject in need thereof. In some parenteral embodiments, the pharmaceutical composition is formulated for subcutaneous administration to a subject in need thereof. Methods for modulating the A2A and / or A1 receptors

[0127] Aspects of the present disclosure include a method for modulating the activity of A2A and / or A1 receptor in a biological system or sample. In some embodiments, modulating the activity of A2A and / or A1 receptor refers to inhibiting A2A and / or A1 receptor in a sample. In some embodiments, modulating the activity of A2A and / or A1 receptor refers to antagonizing the activity of A2A and / or A1 receptor in a cell or biological system.

[0128] In some embodiments, the method includes contacting the sample with a compound of the present disclosure capable of modulating A2A and / or A1 receptor activity. In some embodiments, the method includes contacting a cell or biological system with a compound of the present disclosure capable of modulating A2A and / or A1 receptor activity.

[0129] The present disclosure provides compounds having A2A and / or A1 receptor modulating activity, e.g., A2A and / or A1 receptor inhibiting and / or antagonistic activity. In some embodiments, the compounds have A2A receptor inhibiting and / or antagonistic activity. In some embodiments, the compounds have A2A and A1 receptor inhibiting and / or antagonistic activity. In some embodiments, the compounds have A1 receptor inhibiting and / or antagonistic activity. The ability of the compounds to modulate A2A and / or A1 receptor activity can be characterized using various assays, e.g., A2A and / or A1 receptor binding assays and / or A2A receptor functional assays. For example, the experimental section describes an A2A receptor binding assay. Exemplary compounds of the present disclosure were evaluated to determine K i IC values ​​were determined to demonstrate that compounds of the present disclosure can provide specific binding to human A2A receptors in an assay system. Additionally, the experimental section describes an A2A functional assay that involves monitoring cAMP signals generated in a human recombinant A2A receptor stable cell line. Exemplary compounds of the present disclosure were evaluated and IC 50 values ​​were obtained, indicating that the compounds are capable of antagonizing the human A2A receptor in the assay system.

[0130] Aspects of the present disclosure include methods of modulating (e.g., inhibiting or antagonizing) A2A and / or A1 receptors using compounds described herein. Such methods may include modulating A2A and / or A1 receptors in biological systems by contacting such systems with a compound (e.g., a compound having a structure according to Formula (I)-(XVIb) or a compound in Table 1). Biological systems may include, but are not limited to, cells, tissues, organs, bodily fluids, organisms, non-mammalian subjects, and mammalian subjects (e.g., humans). Biological systems may include subjects (e.g., human subjects).

[0131] In some embodiments, a method of inhibiting or antagonizing an A2A and / or A1 receptor comprises contacting a biological system or sample comprising the A2A and / or A1 receptor with an effective amount of any of the compounds described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein for inhibiting or antagonizing an A2A and / or A1 receptor. In certain embodiments, the biological system or sample is in vitro. In another embodiment, the biological system or sample is in vivo. In some embodiments, the sample is a cell sample. In some embodiments, the A2A and / or A1 receptor is membrane-bound.

[0132] The compounds of the present disclosure can antagonize the A2A receptor, for example, as evaluated by a human A2A functional assay as described in Example 3. An A2A receptor antagonist compound by such a method has an IC 50 value (e.g., as evaluated by the cAMP assay of Example 3) of 10 μM or less, such as 2 μM or less, 1 μM or less, 500 nM or less, 300 nM or less, 100 nM or less, 30 nM or less, or 10 nM or less. The biological system may include a subject (e.g., a human subject). An A2A receptor antagonist compound by such a method has a K i value (e.g., as evaluated by the binding assay of Example 2) of 1 μM or less, such as 500 nM or less, 300 nM or less, 100 nM or less, 30 nM or less, 10 nM or less, 3 nM or less, or 1 nM or less.

[0133] In some embodiments, the compound is an A2A receptor antagonist that exhibits a desired level of inhibitory activity at the A1 receptor. In some embodiments, the compound is a dual antagonist of the A2A and A1 receptors. In some embodiments, the desired level of A1 receptor inhibitory activity is the K iIt refers to compounds whose value is 1 mM or less, for example 300 μM or less, 100 μM or less, 30 μM or less, 10 μM or less, 3 μM or less, or 1 μM or less. In some embodiments, the compounds of the present disclosure show inhibitory activity against A2A receptors and A1 receptors. Example 4, Table 5 in the experimental section provides A2A and A1 receptor inhibition data showing that the compounds of the present disclosure can have strong activity as dual antagonists. In such cases, the compounds can be used to treat CNS and neurodegenerative diseases (e.g., compounds of formula (Ib) to (XVIb)). Treatment indications

[0134] Aspects of the present disclosure include methods of treating a subject for a therapeutic indication of interest using the compounds and / or compositions disclosed herein. The term "therapeutic indication" refers to a symptom, condition, disorder, or disease that may be alleviated, stabilized, ameliorated, cured, or otherwise addressed in a subject by some form of treatment or other therapeutic intervention (e.g., administration of an A2A and / or A1 receptor antagonist). Therapeutic indications related to the modulation of A2A and / or A1 receptor biological activity and / or dysfunction are referred to herein as "adenosine receptor-related indications." In some embodiments, the methods of the present disclosure may include treating an adenosine receptor-related indication by administering an effective amount of the compounds and / or compositions disclosed herein (e.g., A2A and / or A1 receptor antagonist compounds) to a subject.

[0135] The terms "treating" or "treatment" refer to inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in a subject experiencing the pathology or symptoms of the disease, condition, or disorder, i.e., preventing further recurrence of the pathology and / or symptoms, or ameliorating the disease, e.g., ameliorating a disease, condition, or disorder in a subject experiencing the pathology or symptoms of the disease, condition, or disorder, i.e., reversing the pathology and / or symptoms, e.g., reducing the severity of the disease. In the context of the present disclosure, insofar as related to any of the other conditions listed below, the terms "treating", "treatment", etc. mean alleviating or reducing at least one symptom related to such condition, or slowing or reversing the progression or expected progression of such condition.

[0136] The terms "prevent" or "preventing" mean preventing a disease, e.g., preventing a disease in a subject that has not experienced or exhibited the pathology or symptoms of the disease, e.g., preventing a disease, condition, or disorder, even though the entity may potentially have a tendency for the disease, condition, or disorder.

[0137] The terms "individual", "patient", "subject", and "entity" are used interchangeably and refer to a human or non-human animal in need of treatment for a disease. More specifically, it refers to mammals such as humans, non-human primates, mice, dogs, cats, horses, cows, rabbits, rats, or other mammals. Cancer and Immuno-Oncology

[0138] The present disclosure provides methods of treating or preventing cancer in a subject using a subject compound as a therapeutic agent, and compositions comprising the compound. Any cancer for which an A2A receptor antagonist is considered useful by those skilled in the art is contemplated as a cancer treatable by this embodiment, either as a monotherapy or in combination with any of the other therapeutic agents discussed below.

[0139] "Cancer", which is a disease to be prevented or treated by the aforementioned pharmaceutical composition, is a collective term for diseases caused by cells that have aggressive properties, such as the cells dividing and growing despite normal growth limits, invasive properties, such that the cells invade surrounding tissues, and metastatic properties, such that the cells spread to other areas of the body. In some embodiments, the cancer is a solid tumor cancer. Cancers to be prevented or treated using the compounds and pharmaceutical compositions of the present disclosure include lung cancer, breast cancer, prostate cancer, ovarian cancer, solenoma, cervical cancer, bladder cancer, head and neck cancer, renal cell carcinoma, esophageal cancer, pancreatic cancer, brain cancer, liver cancer, leukemia, lymphoma, melanoma, multiple myeloma, Ewing's sarcoma, osteosarcoma, colorectal neoplasm, cholangiocarcinoma, choriocarcinoma These include, but are not limited to, oral cancer, neuroblastoma, skin cancer, testicular cancer, stromal tumors, germ cell tumors, and thyroid cancer.

[0140] In some embodiments, the cancer is kidney, breast, lung, or liver cancer. In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the liver cancer is hepatocellular carcinoma (HCC). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is a solid tumor cancer.

[0141] In some embodiments, the method further comprises identifying a subject as suffering from or having cancer.

[0142] The disclosed compound can be administered alone or in combination with one or more additional agents described herein.Accordingly, the method embodiment includes co-administering to a subject an effective amount of the disclosed compound or composition and an effective amount of an additional active agent.The compound and the additional active agent can be administered simultaneously or sequentially.

[0143] In some embodiments of the method, the additional active agent is an anti-cancer agent selected from an anti-angiogenic agent, an anti-inflammatory agent, an immune checkpoint inhibitor, a poly ADP-ribose polymerase (PARP) inhibitor, a chemotherapeutic agent, and an immunological anti-cancer agent.

[0144] Given the immunosuppressive role of adenosine, administration of an A2A receptor antagonist of the present disclosure (e.g., a compound of Formula (Ia) to (XVIa)) can enhance the efficacy of immunotherapy, such as immune checkpoint inhibitor therapy. In some embodiments, the additional active agent is an immune checkpoint inhibitor selected from a CTLA-4 inhibitor, a PD-1 inhibitor, and a PD-L1 inhibitor.

[0145] In some embodiments, the immune checkpoint inhibitor is an antibody or antibody fragment. In some embodiments, the additional therapeutic agent is an anti-PD-1 antibody. In another embodiment, the additional therapeutic agent is an anti-PD-L1 antibody. In some embodiments, the additional therapeutic agent is selected from pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab. inflammatory diseases

[0146] The present disclosure provides a method for treating or preventing inflammatory diseases in a subject using the subject compounds as therapeutic agents, and compositions containing the compounds. Any inflammatory disease for which an A2A receptor antagonist is considered useful by those skilled in the art is contemplated as a disease treatable using the compounds of the present disclosure, either as monotherapy or in combination with other therapeutic agents (e.g., as described herein).

[0147] In some embodiments, the method includes administering to a subject having an inflammatory disease a therapeutically effective amount of an A2A and / or A1 receptor antagonist compound (e.g., as described herein). In some embodiments, the inflammatory disease is a chronic inflammatory disease, such as rheumatoid arthritis (RA). In some embodiments, the inflammatory disease is an acute inflammatory disease.

[0148] In some embodiments, the method further comprises identifying a subject suffering from or at risk for an inflammatory disease.

[0149] In some embodiments, the method further comprises identifying an underlying disease associated with the inflammatory disease or a condition associated with the inflammatory disease. CNS and Neurodegenerative Diseases

[0150] The present disclosure provides a method for treating or preventing central nervous system (CNS) or neurodegenerative diseases or disorders in a subject using the compounds of the present disclosure as therapeutic agents or pharmaceutical compositions comprising the compounds. In some embodiments, the CNS disease is referred to as a neurodegenerative disease or disorder of the CNS. The CNS and neurodegenerative diseases that can be prevented or treated using the compounds and pharmaceutical compositions of the present disclosure include, but are not limited to, Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis, Huntington's disease (HD), depression, schizophrenia, and epilepsy.

[0151] In some embodiments, the method is a method for treating or preventing Parkinson's disease, comprising administering to a subject having or at risk of Parkinson's disease an effective amount of a compound of the present disclosure. In some cases, the compound has dual inhibitory activity at both the A2A receptor and the A1 receptor (e.g., compounds of formulas (Ib to XVIb)).

[0152] In some embodiments, the method further comprises identifying a subject suffering from or at risk for a CNS or neurodegenerative disease.

[0153] In some embodiments, the method further comprises identifying an underlying disease or condition associated with the CNS or neurodegenerative disease.

[0154] The amount of the aforementioned pharmaceutical composition to be administered is an amount effective for treating or preventing the disease of the entity or patient, and can be administered orally or parenterally depending on the purpose. For oral administration, the amount to be administered based on the active ingredient is 0.01-1,000 mg per kg of body weight, more specifically 0.1-300 mg per kg. For parenteral administration, 0.01-100 mg based on the active ingredient is administered per kg of body weight per day, more specifically 0.1-50 mg once or several times. The amount to be administered to a particular entity or patient can be determined based on many relevant factors, including the patient's weight, age, sex, health condition, diet, administration time, administration method, severity of disease, etc. It is understood that the dosage can be appropriately increased or decreased by the expert, and the aforementioned dosage amount is in no way intended to limit the scope of the present disclosure. A physician or veterinarian having ordinary level of knowledge in the relevant technical field can determine and formulate the effective amount of the pharmaceutical composition. For example, a physician or veterinarian may start with an amount of a compound used in a pharmaceutical composition under the present disclosure that is less than the amount required to achieve the desired therapeutic effect, and gradually increase the amount administered until the desired effect is achieved.

[0155] The compounds and compositions of the present disclosure can be administered alone, in combination with a compound according to another example of the present disclosure, or in simultaneous, separate or sequential co-administration with at least one other therapeutic agent, such as another active pharmaceutical ingredient described herein.

[0156] In certain examples, pharmaceutical compositions of the present disclosure include within their scope pharmaceutical compositions that contain an effective therapeutic amount of at least one of the compounds according to the specific examples as an active ingredient, or in combination with a pharmaceutical carrier. Optionally, the compounds according to the embodiments of the present disclosure can be administered independently, in combination with another compound according to the specific examples, or simultaneously with one or more other therapeutic agents, such as an anti-cancer agent (e.g., as described herein), or simultaneously, separately, or sequentially in combination with an active pharmaceutical ingredient. definition

[0157] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0158] It is understood that the definitions provided herein are not intended to be mutually exclusive, and thus, some chemical moieties may be included in more than one definition of a term.

[0159] "C x -C y The term "alkyl," when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, is meant to include groups containing x to y carbons in the chain. For example, "C 1 -C 6 The term "alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight chain alkyl and branched chain alkyl groups containing 1-6 carbons. In some embodiments, "(C x -C y The term "(C )alkylene" refers to a substituted or unsubstituted alkylene chain having x to y carbons in the alkylene chain. For example, "(C x -C y ) Alkylene may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0160] The term "alkyl" refers to an unbranched or branched saturated hydrocarbon chain. In some embodiments, alkyl as used herein refers to an alkyl group having 1 to 20 carbon atoms (C 1 -C 20 ) alkyl), 1 to 10 carbon atoms ((C 1 -C 10 ) alkyl), 1 to 8 carbon atoms ((C 1 -C 8 ) alkyl), 1-6 carbon atoms ((C 1 -C 6 ) alkyl), 1-5 carbon atoms ((C 1 -C 5 ) alkyl) or 1-3 carbon atoms ((C 1-C 3 ) alkyl). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons can be included. For example, "butyl" can include n-butyl, sec-butyl, isobutyl, and t-butyl, and "propyl" can include n-propyl and isopropyl. Unless otherwise stated herein, alkyl chains are optionally substituted with one or more substituents, such as those described herein.

[0161] The term "alkoxy" refers to an unbranched or branched alkyl group attached to an oxygen atom (alkyl-O-). In some embodiments, alkoxy as used herein refers to an alkyl group having 1 to 20 carbon atoms (C 1 -C 20 )alkoxy), 1 to 10 carbon atoms ((C 1 -C 10 )alkoxy), 1 to 8 carbon atoms ((C 1 -C 8 )alkoxy), 1-6 carbon atoms ((C 1 -C 6 )alkoxy), 1-5 carbon atoms ((C 1 -C 5 )alkoxy) or 1-3 carbon atoms ((C 1 -C 5 ) alkoxy). Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, and butoxy. When an alkoxy residue having a specific number of carbons is named, all geometric isomers having that number of carbons can be included, such as isopropoxy, isobutoxy, and t-butoxy. Unless otherwise stated herein, the alkoxy chain is optionally substituted with one or more substituents, such as those described herein.

[0162] The term "alkylene" refers to an alkyl group consisting of only carbon and hydrogen, no unsaturation, and preferably of 1 to 20 carbon atoms (C 1 -C 20 ) alkylene), 1-10 carbon atoms ((C 1 -C 10 ) alkylene), 1-6 carbon atoms ((C 1 -C 6 ) alkylene), or 1-5 carbon atoms ((C 1 -C 5 ) alkylene) refers to a linear divalent hydrocarbon chain attached to a radical group having a cyclic group. Examples include, but are not limited to, methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively. Unless stated otherwise in the specification, the alkylene chain is optionally substituted with one or more substituents, such as those described herein. Examples include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), 2-methylpropylene (-CH 2 -CH(CH 3 )-CH 2 -), hexylene (-(CH 2 ) 6 -), etc.

[0163] The term "alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic alkenyl groups. In some embodiments, an alkenyl group is an alkyl group having 2-10 carbon atoms (C 2 - 10 In another embodiment, the alkenyl group has 2 to 4 carbon atoms in the chain (C 2 - 4alkenyl). Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, 3-methylbut-1-enyl, n-pentenyl, heptenyl, octenyl, cyclohexyl-butenyl, decenyl, and the like, and isomers thereof. An alkylalkenyl is an alkyl group, as defined herein, attached to an alkenyl group, as defined herein. An alkenyl group can be unsubstituted or substituted through available carbon atoms with one or more groups, as defined above for alkyl.

[0164] The term "alkynyl" refers to linear or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms, preferably from 2 to 3 carbon atoms, and having at least one, and preferably one or two, sites of acetylenic (C≡C-) unsaturation. Examples of such alkynyl groups include acetylenyl (C≡CH), propargyl (CH 2 C≡CH), 1-propynyl, 1-butynyl, and 1-pentynyl.

[0165] The term "aminoalkyl" refers to a group formed by combining an alkyl and an amino group. Examples include -NHCH 3 , -NHCH 2 CH 3 -NHCHCH 3 ) 2 , -N(CH3) 2 , -NCH 3 (CH 2 CH 3 )-NCH 3 (CH(CH 3 ) 2 ) and similar groups.

[0166] The term "aryl" refers to a monocyclic or polycyclic group having at least one hydrocarbon aromatic ring, where the ring atoms of at least one hydrocarbon aromatic ring are all carbon. Aryl can include groups having a single aromatic ring (e.g., phenyl) and multiple fused aromatic rings (e.g., naphthyl, anthryl). Aryl can further include groups having one or more aromatic hydrocarbon rings fused to one or more non-aromatic hydrocarbon rings (e.g., fluorene; 2,3-dihydro-1H-indene; 1,2,3,4-tetrahydronaphthalene). In certain embodiments, aryl includes groups having an aromatic hydrocarbon ring fused to a non-aromatic ring, where the non-aromatic ring contains at least one ring heteroatom independently selected from the group consisting of N, O, and S. For example, in some embodiments, aryl includes groups having a phenyl ring fused to a non-aromatic ring, where the non-aromatic ring contains at least one ring heteroatom independently selected from the group consisting of N, O, and S (e.g., chroman; thiochroman; 2,3-dihydrobenzofuran; indoline). In some embodiments, aryl, as used herein, is an alkyl group having 6 to 14 carbon atoms (C 6 -C 14 )aryl), or 6 to 10 carbon atoms ((C 6 -C 10 ) aryl). If the aryl contains a fused ring, the aryl can be attached to one or more substituents or moieties of the formulae described herein through any atom of the fused ring, if valence allows.

[0167] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated hydrocarbon. In some embodiments, a cycloalkyl is a cyclic ring system having 3 to 20 carbon atoms (C 3 -C 20 )cycloalkyl), 3 to 8 carbon atoms ((C 3 -C 8 )cycloalkyl), 3 to 6 carbon atoms ((C 3 -C 6 )cycloalkyl), or 3 to 5 carbon atoms ((C 3 -C 5) cycloalkyl). In some embodiments, cycloalkyl has 3 to 8 carbon atoms with single or multiple cyclic rings, including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, octahydropentalenyl, octahydro-1H-indene, decahydronaphthalene, cubane, bicyclo[3.1.0]hexane, and bicyclo[1.1.1]pentane, and the like.

[0168] The term "carbocycle" refers to a saturated, unsaturated, or aromatic ring system in which each atom of the ring system is carbon. Carbocycles include 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 6-12 membered bridged rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Bicyclic carbocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings, as valences permit. Bicyclic carbocycles include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl.

[0169] The term "haloalkyl" refers to a monohaloalkyl or polyhaloalkyl group which may be further substituted or unsubstituted. The terms halogen and alkyl are as defined herein.

[0170] The term "heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 6-12 membered bridged rings. Bicyclic heterocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings, as valences permit. In exemplary embodiments, an aromatic ring, such as pyridyl, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, morpholine, piperidine, or cyclohexene. Bicyclic heterocycles include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems.

[0171] The term "heteroaryl" refers to a monocyclic or bicyclic or higher aromatic group that may be substituted or unsubstituted containing at least one heteroatom (e.g., a heteroatom selected from B, N, O, S, P(=O), Si, and P). In some embodiments, the term refers to an aromatic group of 4 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. Such heteroaryl groups may have a single ring (i.e., pyridinyl or furyl) or multiple fused rings (i.e., indolizinyl or benzothienyl), where the fused ring may or may not be aromatic and / or contain a heteroatom if the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Examples of monocyclic heteroaryls include, but are not limited to, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, thiophenyl, furanyl, imidazolyl, isoxazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, and similar groups. Examples of bicyclic heteroaryls include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothiadiazole, benzotriazolyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl, oxochromene, dioxoisoindoline, pyrazolopyridinyl, pyrazolo[1,5-a]pyridinyl, and similar groups. Preferred heteroaryls include 5- or 6-membered heteroaryls such as pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

[0172] The term "heterocycloalkyl" refers to a substituted or unsubstituted monocyclic alkyl containing one or more heteroatoms selected from B, N, O, S, P(=O), Si, and P. Examples include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, thiomorpholinyl, imidazolidinyl, tetrahydrofurfuryl, and similar groups.

[0173] The term "heteroalkyl" refers to an alkyl substituent in which one or more carbon atoms and any associated hydrogen atoms are independently replaced with the same or different heteroatom groups. For example, one, two, or three carbon atoms can be independently replaced with the same or different heteroatom substituents.

[0174] The term "substituted" refers to one or more carbon or heteroatoms of a compound that can be substituted, e.g., NH or NH 2 "Substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the allowed valences of the substituted atom and substituent, and it will be understood that the substitution results in a stable compound. For example, stable compounds include, but are not limited to, compounds that do not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. In certain embodiments, substituted refers to a moiety having a substituent replacing two hydrogen atoms on the same carbon atom, such as, for example, replacing two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group. The term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0175] Those skilled in the art will understand that the substituents themselves can be substituted if necessary.Unless specifically stated as "unsubstituted", reference to a chemical moiety herein is understood to include substituted and unsubstituted variants.For example, reference to a "heteroaryl" group or moiety, unless otherwise specified, implicitly includes both substituted and unsubstituted variants.

[0176] When referring to a feature of a compound, the phrase "optionally substituted" may be used interchangeably with the phrase "unsubstituted or substituted," and non-hydrogen substituents may or may not be present on a given atom or group, and thus the description includes structures in which non-hydrogen substituents are present and structures in which non-hydrogen substituents are absent. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. With respect to any group that contains one or more substituents, it is understood by those of skill in the art that such groups are not intended to introduce substitutions or substitution patterns that are sterically impractical, synthetically impractical, and / or inherently unstable.

[0177] It will also be understood by those of skill in the art that when "optionally substituted" is used, any portion of the following term can be substituted.

[0178] The terms "linker," "bond," and "linking group" are used interchangeably and refer to a linking moiety that covalently bonds two or more substituents. A linking moiety may connect two groups where the linker may be linear, branched, cyclic, or a single atom. In some embodiments, the linker is divalent. In some embodiments, the linker is a branched linker. In some embodiments, the two or more substituents covalently bonded by the linking moiety are optionally substituted alkyl or alkoxy groups. In some embodiments, the linker is -CO 2 is selected from -, -O-, -°C0-, -CONH-, -NHCO-, and -NH-.

[0179] In some embodiments, a substituent may be any of the substituents described herein, for example, halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO 2 ), imino (= NH), oximo (= N-OH), hydrazino (= N-NH 2 ), -R b -OR a , -R b -℃(O)-R a , -R b -℃(O)-OR a , -R b -℃(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(Ra)C(O)OR a , -R b -N(R a )C(O)R a , -R b N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a ) 2(t can be 1 or 2). In another exemplary embodiment, the substituents include alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which can be selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, imino, oximo, hydrazine, -R b -OR a , -R b -℃(O)-R a , -R b -℃(O)-OR a , -R b -℃(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(Ra)C(O)OR a , -R b -N(R a )C(O)R a , -R b N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a ) 2(t is 1 or 2) can be substituted arbitrarily. Here, each R a , R b , and R c is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, where valences permit, each R a , R b , and R c is an alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, imino, oximo, hydrazine, -R b -OR a , -R b -℃(O)-R a , -R b -℃(O)-OR a , -R b -℃(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(Ra)C(O)OR a , -R b -N(R a )C(O)R a , -R b N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -Rb -S(O) t N(R a ) 2 (t is 1 or 2) Optional substitutions can be made.

[0180] The term "isomer" or "three-dimensional isomer" refers to two or more compounds that contain the same number and type of atoms, groups, or components, but differ in the structural arrangement of the atoms and in the connectivity of the atoms. The term can refer to compounds that are identical in terms of chemical equations or molecular equations, but differ optically or three-dimensionally, or salts thereof, and can be, in particular, partially three-dimensional isomers, enantiomers, geometric isomers, or shape isomers.

[0181] The term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0182] "Stereoisomers" refer to compounds composed of the same atoms linked by the same bonds, but with different, incompatible three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0183] Individual enantiomers and diastereomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or stereocenters, or by preparation of racemic mixtures followed by resolution methods well known to those skilled in the art. These separation methods are exemplified by (1) attachment of the mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and liberation of the optically pure product from the auxiliary, (2) salt formation using an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers in a chiral liquid chromatography column, or (4) kinetic separation using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their respective enantiomers by well-known methods such as chiral phase gas chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, chemical or enzymatic reactions in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or the transformation of an existing stereocenter, is well known in the art. Stereoselective synthesis includes both enantioselective and diastereoselective transformations. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0184] The symbol = denotes a bond that may be a single bond, double bond, or triple bond, as described herein. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds include both the "E" and "Z" isomers.

[0185] Alternatively, substituents around a carbon-carbon double bond may be referred to as "cis" or "trans", where "cis" represents substituents on the same side of the double bond and "trans" represents substituents on the opposite side of the double bond. The configuration of substituents around a carbon ring can also be specified as "cis" or "trans". The term "cis" represents substituents on the same side of the plane of the ring, and the term "trans" represents substituents on the opposite side of the plane of the ring. A mixture of compounds in which substituents are arranged on both the same and opposite sides of the plane of the ring is called "cis / trans".

[0186] Singular articles such as "one", "a", "the", and similar referents in the context of describing elements are to be construed as covering both the singular and plural forms unless otherwise indicated in this document or clearly contradicted by the context. The listing of a range of values herein is merely intended to serve as a simplified method of referring individually to each individual value within the range, including the upper and lower limits of the range, unless otherwise stated herein, and each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated in this document or clearly contradicted by the context. The use of any examples, or exemplary language (i.e., "such as") provided herein is merely intended to better clarify the embodiments and is not limiting of the claims unless otherwise specifically stated.

[0187] In some embodiments, when the term "about" is used in front of a quantitative value, the present disclosure includes the specific quantitative value itself unless otherwise specified. As used herein, the term "about" refers to a variation of ±10% from the nominal value unless otherwise indicated or inferred. When percentages are provided with respect to the amount of a component or material in a composition, unless otherwise specified or understood from the context, the percentages are to be understood as weight-based percentages.

[0188] If a molecular weight is provided and is not, for example, an absolute value of a polymer, and is not otherwise specified or understood from the context, the molecular weight should be understood to be the average molecular weight.

[0189] It should be understood that the order of steps or the order for performing particular actions is not important as long as the present disclosure continues to function. Further, two or more steps or actions can be performed simultaneously.

[0190] A dash ("-") symbol not between two letters or symbols indicates the point of attachment or point of connection of a substituent. For example, -NH 2 is attached via a nitrogen atom.

[0191] The term "pharmaceutically acceptable salt" refers to salts that are acceptable for administration to a subject. Such salts, including the counterions, are understood to have mammalian safety acceptable for a given dosing regimen. Such salts can also be derived from pharmaceutically acceptable inorganic or organic bases, and pharmaceutically acceptable inorganic or organic acids, and can include organic and inorganic counterions. The neutral form of the compounds described herein can be converted to the corresponding salt form by contacting the compound with a base or acid and isolating the resulting salt.

[0192] The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable diluent", "pharmaceutically acceptable carrier", and "pharmaceutically acceptable adjuvant" are used interchangeably and refer to excipients, diluents, carriers, or adjuvants useful in preparing a pharmaceutical composition, which are generally safe, non-toxic, and neither biologically nor otherwise undesirable. Also included are excipients, diluents, carriers, and adjuvants that can be used in veterinary and human pharmaceuticals. The phrase "pharmaceutically acceptable excipient" includes both one and more than one of such excipients, diluents, carriers, and / or adjuvants.

[0193] The term "pharmaceutical composition" is meant to encompass compositions suitable for administration to a subject, such as a mammal, particularly a human. Generally, a "pharmaceutical composition" is sterile and preferably free of contaminants that may elicit an undesirable response in a subject (i.e., the compounds in the pharmaceutical composition are of pharmaceutical grade). Pharmaceutical compositions can be designed to be administered to a subject or patient in need thereof via a number of different routes of administration, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, subcutaneous, and the like. Exemplary embodiments

[0194] As described herein, the text refers to various embodiments of the compounds, compositions and methods of the present invention.The various embodiments described are intended to provide various illustrative examples and should not be interpreted as descriptions of alternative species.Rather, it should be noted that the descriptions of the various embodiments provided herein may be of overlapping scope.The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present technology.

[0195] Regardless of the scope of the claims appended hereto, aspects of the present disclosure are illustrated by the following passages.

[0196] Item 1. A compound of formula (Ia) or formula (Ib), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. TIFF0007681616000039.tif39170, where R is H, (C 1 -C 3 ) alkyl, or substituted (C 1 -C 3 ) alkyl; Y 1 Or Y 4 is an independent CR 10 and N are selected, Y 1 Or Y 4 At least two of the following were independently CR 10 and; R10 are independently H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 NH 2 , substituted sulfonamide, and thiol; R a and R b are independently H, F, (C 1 -C 3 ) alkyl, and substituted (C 1 -C 3 ) alkyl, or R a and R b are attached to a ring and together with the carbon atoms to which they are attached form a cyclopropyl, or substituted cyclopropyl; A is phenyl, substituted phenyl, pyridyl, or substituted pyridyl.

[0197] Item 2. A is phenyl or one, two, or three R 20 groups, each R 20 is (C 1 -C 8) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 NH 2 , a substituted sulfonamide, and a thiol.

[0198] Item 3. A is pyridyl or one, two, or three R 20 R is a pyridyl substituted with a 20 is (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )Alkoxy, -CONH2 , substituted amide, -NH 2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 NH 2 , a substituted sulfonamide, and a thiol.

[0199] Item 4. The compound according to any one of items 1-3, wherein R is H.

[0200] Item 5. R a and R b and each is H.

[0201] Item 6. The compound according to item 2, wherein the compound is of formula (IIa) or (IIb): TIFF0007681616000040.tif41170, where R 1 Or R 9 are independently H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO3 H, -SO 2 NH 2 , substituted sulfonamide, and thiol.

[0202] Item 7. R 1 Or R 9 are independently H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) Alkoxy, -NH 2 7. The compound according to claim 6, wherein the aryl group is selected from the group consisting of substituted amino, halogen, and hydroxyl.

[0203] Item 8. R 1 Or R 9 are independently H, NH 2 , F, C.H. 3 , and C.F. 3 Item 8. The compound according to item 7, selected from:

[0204] Item 9. The compound according to item 6, wherein the compound is of formula (IIIa) or (IIIb): TIFF0007681616000041.tif47170, where R 21 and R 22 are independently H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) Alkyl, SO 2 R 30 , and C.O.R. 30 Selected from R 30 is (C 1 -C 8 ) alkyl, or substituted (C 1 -C 8 ) alkyl.

[0205] Item 10. R 21 and R 22 and each is H.

[0206] Item 11. R 5 , R 6 , R 8 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 11. The compound according to claim 9 or 10, wherein each of the groups is independently selected from alkoxy, halogen, and hydroxyl.

[0207] Item 12. R 5 , R 6 , R 8 and R 9 But, H, F, CH 3 , and C.F. 3 Item 12. The compound according to item 11, independently selected from:

[0208] Item 13. R 5 , R 6 , R 8 and R 9 and each is H.

[0209] Item 14. A compound according to any one of items 9 to 13 described below: R 2 Or R 4 are H and R 1 is H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C1 -C 5 ) is selected from alkoxy, halogen, and hydroxyl.

[0210] Item 15. R 1 is H, F, CH 3 , and CF 3 and is the compound according to Item 14.

[0211] Item 16. The compound according to Item 15, wherein the compound is selected from the following: TIFF0007681616000042.tif108170

[0212] Item 17. The compound according to Item 9, wherein the compound is of formula (IVa) or (IVb): TIFF0007681616000043.tif41170

[0213] Item 18. R 6 is (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 ) alkoxy, substituted (C 1 -C 5 ) alkoxy, halogen, and hydroxyl, and is the compound according to Item 17.

[0214] Item 19. R 6 is (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, and (C 1 -C 3 ) haloalkyl, and is the compound according to Item 18.

[0215] Item 20. R 6 is CH 3 or CF 3 and is the compound according to Item 19.

[0216] Item 21. A compound according to any one of items 17 to 20 described below. R 2 Or R 4 are H and R 1 is H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) alkoxy, halogen, and hydroxyl.

[0217] Item 22. R 1 H, F, CH 3 , and C.F. 3 22. The compound according to item 21, selected from:

[0218] Item 23. The compound according to any one of items 17 to 22, wherein the compound is selected from the following: TIFF0007681616000044.tif143170

[0219] Item 24. The compound according to item 9, wherein the compound is of formula (Va) or (Vb): TIFF0007681616000045.tif41170

[0220] Item 25. R 5 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 525. The compound according to claim 24, wherein each of the groups is independently selected from alkoxy, halogen, and hydroxyl.

[0221] Item 26. R 5 and R 9 is independently selected from H and halogen.

[0222] Item 27. R 5 27. The compound according to item 26, wherein is F.

[0223] Item 28. R 9 28. The compound according to item 26 or 27, wherein is F.

[0224] Item 29. The compound according to item 26, wherein the compound is selected from the following: TIFF0007681616000046.tif149170

[0225] Item 30. The compound according to item 6, wherein the compound is of formula (VIa) or (VIb): TIFF0007681616000047.tif41170

[0226] Item 31. R 5 , R 6 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) Alkoxy, -NH 2 31. The compound according to item 30, wherein each of the groups is independently selected from substituted amino, halogen, and hydroxyl.

[0227] Item 32. R 6 H, (C 1 -C 5 ) alkyl, substituted (C1 -C 5 ) alkyl, and (C 1 -C 3 32. The compound according to claim 30 or 31, wherein said compound is selected from haloalkyl.

[0228] Item 33. R 6 CH 3 or CF 3 33. The compound according to item 32, wherein

[0229] Item 34. R 6 33. The compound according to item 32, wherein

[0230] Item 35. R 5 and R 9 is independently selected from H and halogen.

[0231] Item 36. R 5 The compound according to item 35, wherein is F.

[0232] Item 37. R 9 The compound according to claim 35 or 36, wherein

[0233] Item 38. The compound according to item 35, wherein the compound is selected from the following: TIFF0007681616000048.tif85170

[0234] Item 39. Each R 10 or R 1 Or R 4 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) Alkoxy, -NH 239. The compound according to any one of items 1 to 38, wherein each of the groups is independently selected from substituted amino, halogen, and hydroxyl.

[0235] Item 40. Each R 10 or R 1 Or R 4 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 40. The compound according to claim 39, wherein:

[0236] Item 41. R 1 The compound according to any one of items 6 to 40, wherein

[0237] Item 42. R 1 But (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 41. The compound according to any one of items 6 to 40, wherein the alkyl group is selected from haloalkyl and halogen.

[0238] Item 43. R 1 F, CH 3 or CF 3 43. The compound according to item 42, wherein

[0239] Item 44. R 2 Or R 4 and each is H.

[0240] Item 45. The compound according to item 1 or 2, wherein the compound is of formula (VIIa) or (VIIb): TIFF0007681616000049.tif42170 where R 5 Or R 9 and each R 10 is H, (C1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO2NH 2 , substituted sulfonamide, and thiol.

[0241] Item 46. Y 1 Or Y 4 Item 46. The compound according to item 45, wherein one of

[0242] Item 47. R 5 Or R 9 and each R 10 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) Alkoxy, -NH 2 47. The compound according to claim 46, wherein each of the groups is independently selected from substituted amino, halogen, and hydroxyl.

[0243] Item 48. R 5 or R 9 and each R 10 is independently selected from H, NH 2 , F, CH 3 , and CF 3 and is the compound according to item 47.

[0244] Item 49. The compound according to item 46, wherein the compound is of formula (VIIIa) or (VIIIb): TIFF0007681616000050.tif46170 Here, R 21 and R 22 are independently selected from H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, SO 2 R 30 , and COR 30 , and R 30 is (C 1 -C 8 ) alkyl or substituted (C 1 -C 8 ) alkyl.

[0245] Item 50. The compound according to item 49, wherein R 21 and R 22 are each H.

[0246] Item 51. R 5 , R 6 , R 8 and R 9 are independently selected from H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 ) alkoxy, substituted (C 1 -C 5 ) alkoxy, halogen, and hydroxyl, and is the compound according to item 49 or 50.

[0247] Item 52. R 5 , R 6 , R 8 and R 9 But, H, F, CH 3 , and C.F. 3 52. The compound according to item 51, independently selected from:

[0248] Item 53. R 5 , R 6 , R 8 and R 9 and each is H.

[0249] Item 54. The compound according to item 53, wherein the compound is selected from the following: TIFF0007681616000051.tif143170

[0250] Item 55. The compound according to item 49, wherein the compound is of formula (IXa) or (IXb): TIFF0007681616000052.tif41170

[0251] Item 56. R 6 But (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 56. The compound according to claim 55, wherein said aryl group is selected from alkoxy, halogen, and hydroxyl.

[0252] Item 57. R 6 However, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, and (C 1 -C 357. The compound according to item 56, wherein said alkyl is selected from haloalkyl.

[0253] Item 58. R 6 CH 3 or CF 3 58. The compound according to item 57, wherein

[0254] Item 59. The compound according to item 58, wherein the compound is selected from the following: TIFF0007681616000053.tif219170 TIFF0007681616000054.tif73170

[0255] Item 60. The compound according to item 49, wherein the compound is of formula (Xa) or (Xb): TIFF0007681616000055.tif41170

[0256] Item 61. R 5 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 61. The compound according to claim 60, wherein each of the groups is independently selected from alkoxy, halogen, and hydroxyl.

[0257] Item 62. R 5 and R 9 is independently selected from H and halogen.

[0258] Item 63. R 5 63. The compound according to item 62, wherein

[0259] Item 64. R 9 The compound according to item 62 or 63, wherein is F.

[0260] Item 65. The compound according to item 62, wherein the compound is selected from the following: TIFF0007681616000056.tif212170 TIFF0007681616000057.tif72170

[0261] Item 66. The compound according to item 46, wherein the compound is of formula (XIa) or (XIb): TIFF0007681616000058.tif41170

[0262] Item 67. R 5 , R 6 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) Alkoxy, -NH 2 67. The compound according to item 66, wherein each of the groups is independently selected from substituted amino, halogen, and hydroxyl.

[0263] Item 68. R 6 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, and (C 1 -C 3 68. The compound according to claim 66 or 67, wherein said compound is selected from haloalkyl.

[0264] Item 69. R 6 CH 3 or CF 3 69. The compound according to item 68, wherein

[0265] Item 70. R 669. The compound according to item 68, wherein

[0266] Item 71. R 5 and R 9 is independently selected from H and halogen.

[0267] Item 72. R 5 72. The compound according to item 71, wherein is F.

[0268] Item 73. R 9 73. The compound according to claim 71 or 72, wherein

[0269] Item 74. The compound according to item 71, wherein the compound is selected from the following: TIFF0007681616000059.tif122170

[0270] Item 75. The compound according to item 45, wherein the compound is of formula (XIVa) or (XIVb): TIFF0007681616000060.tif47170, where Y 4 is CR 4 or N; R 1 Or R 4 is H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )Alkoxy, -CONH 2, substituted amide, -NH 2 , substituted amino, -CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 NH 2 , a substituted sulfonamide, and a thiol; R 21 and R 22 is H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) Alkyl, SO 2 R 30 , and C.O.R. 30 are independently selected from R 30 is (C 1 -C 8 ) alkyl, and substituted (C 1 -C 8 ) alkyl.

[0271] Item 76. R 5 , R 6 , R 8 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 76. The compound according to item 75, wherein each of the groups is independently selected from alkoxy, halogen, and hydroxyl.

[0272] Item 77. R 21 and R 22 and each is H.

[0273] Item 78. A compound according to any one of items 75 to 77, comprising: R 2Or R 4 are H and R 1 is H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 ) alkoxy, halogen, and hydroxyl.

[0274] Item 79. R 1 H, F, CH 3 , and C.F. 3 79. The compound according to item 78, selected from:

[0275] Item 80. The compound according to item 75, wherein the compound is of formula (XVa) or (XVb): TIFF0007681616000061.tif41170

[0276] Item 81. R 5 and R 9 But, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 81. The compound according to item 80, wherein each of the groups is independently selected from alkoxy, halogen, and hydroxyl.

[0277] Item 82. R 5 and R 9 82. The compound according to item 81, wherein is independently selected from H and halogen.

[0278] Item 83. R 5 83. The compound according to item 82, wherein

[0279] Item 84. R 9 The compound according to item 82 or 83, wherein is F.

[0280] Item 85. The compound according to item 75, wherein the compound is of formula (XVIa) or (XVIb): TIFF0007681616000062.tif41170

[0281] Item 86. R 6 But (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 86. The compound according to claim 85, wherein said aryl group is selected from alkoxy, halogen, and hydroxyl.

[0282] Item 87. R 6 However, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, and (C 1 -C 3 87. The compound according to item 86, wherein said alkyl is selected from haloalkyl.

[0283] Item 88. R 6 CH 3 or CF 3 88. The compound according to item 87, wherein

[0284] Item 89. R 1 H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C5 )alkoxy, substituted (C 1 -C 5 89. The compound according to any one of items 80 to 88, wherein the aryl group is selected from alkoxy, halogen, and hydroxyl.

[0285] Item 90. R 1 H, F, CH 3 , and C.F. 3 89. The compound according to claim 89, selected from:

[0286] Item 91. Y 4 The compound according to any one of items 75 to 90, wherein is CH.

[0287] Item 92. Y 4 The compound according to any one of items 75 to 90, wherein is N.

[0288] Item 93. The compound according to items 75, 80 or 85, wherein the compound is selected from the following: TIFF0007681616000063.tif146170

[0289] Item 94. The compound according to item 1, wherein the compound is a compound of Table 1, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0290] Item 95. A pharmaceutical composition comprising the compound according to any one of items 1 to 94, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0291] Item 96. A compound for use in inhibiting or antagonizing adenosine A2A and / or A1 receptors, the compound being a compound according to any one of items 1-94, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0292] Item 97. A pharmaceutical composition for use in inhibiting or antagonizing adenosine A2A and / or A1 receptors, the pharmaceutical composition being as described in item 95.

[0293] Item 98. A method for inhibiting adenosine A2A and / or A1 receptors, comprising: contacting a sample containing adenosine A2A and / or A1 receptors with an effective amount of a compound according to any one of items 1-94, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, to inhibit adenosine A2A and / or A1 receptors.

[0294] Item 99. The method of item 98, wherein the sample is in vitro.

[0295] Item 100. A method for antagonizing adenosine A2A and / or A1 receptors, comprising: A cell containing an adenosine A2A and / or A1 receptor is contacted with an effective amount of a compound according to any one of paragraphs 1-94, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, to antagonize the adenosine A2A and / or A1 receptor.

[0296] Item 101. The method of item 100, wherein the cells are contained in a sample of cells in vitro.

[0297] Item 102. The method of item 100, wherein the cell is contained in a biological system in vivo.

[0298] Item 103. A method of treating cancer comprising administering to a subject having cancer a therapeutically effective amount of an A2A and / or A1 receptor antagonist compound according to any one of items 1-94, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0299] Item 104. The method of item 103, wherein the cancer is a solid tumor cancer.

[0300] Item 105. Cancer is lung cancer, breast cancer, prostate cancer, ovarian cancer, solenoma, cervical cancer, bladder cancer, head and neck cancer, renal cell carcinoma, esophageal cancer, pancreatic cancer, brain cancer, liver cancer, leukemia, lymphoma, melanoma, multiple myeloma, Ewing's sarcoma, osteosarcoma, colorectal tumor, bile duct cancer, choriocarcinoma , oral cancer, neuroblastoma, skin cancer, testicular cancer, stromal tumors, germ cell tumors, and thyroid cancer.

[0301] Item 106. The method of item 105, wherein the cancer is a liver cancer that is hepatocellular carcinoma (HCC).

[0302] Item 107. The method of item 105, wherein the cancer is a lung cancer that is non-small cell lung cancer (NSCLC).

[0303] Item 108. The method of any one of items 103 to 107, further comprising co-administering to the subject an additional active agent.

[0304] Item 109. The method of item 108, wherein the additional active agent is selected from an anti-angiogenic agent, an anti-inflammatory agent, an immune checkpoint inhibitor, a PARP inhibitor, a chemotherapeutic agent, and an immune anti-cancer agent.

[0305] Item 110. The method of item 109, wherein the additional active agent is an immune checkpoint inhibitor selected from a CTLA-4 inhibitor, a PD-1 inhibitor, and a PD-L1 inhibitor.

[0306] Item 111. The method of item 110, wherein the immune checkpoint inhibitor is an antibody or antibody fragment.

[0307] Item 112. A method for treating an inflammatory disease, comprising administering to a subject having an inflammatory disease a therapeutically effective amount of an A2A and / or A1 receptor antagonist compound according to any one of items 1-94, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0308] Item 113. The method of item 112, wherein the inflammatory disease is a chronic inflammatory disease.

[0309] Item 114. The method of item 112, wherein the inflammatory disease is an acute inflammatory disease.

[0310] Item 115. A method for treating a central nervous system disorder, comprising administering to a subject having or at risk for a central nervous system disorder a therapeutically effective amount of an A2A and / or A1 receptor antagonist compound according to any one of items 1-94, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0311] Item 116. The method of item 115, wherein the central nervous system disease is selected from Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, depression, schizophrenia, and epilepsy.

[0312] Item 117. The method of item 116, wherein the central nervous system disease is Parkinson's disease.

[0313] Item 118. The compound according to any one of items 1 to 94, or the pharmaceutical composition according to item 95, for use in treating a disease selected from cancer, an inflammatory disease, and a central nervous system disease.

[0314] Item 119. Use of a compound according to any one of items 1 to 94 or a pharmaceutical composition according to item 95 in the manufacture of a medicament for treating a disease selected from cancer, an inflammatory disease and a central nervous system disease.

[0315] Item 120. Compound of the formula: TIFF0007681616000064.tif2842 or a solvate, three-dimensional isomer, or pharma- ceutically acceptable salt thereof; wherein Cy is a fused 5-membered heterocycle (e.g., a heteroaryl or heterocycloalkyl ring) containing at least one heteroatom selected from nitrogen, oxygen, and sulfur; R is R 11 , R 12 , and / or R 13 is a phenyl group substituted with; R 11 , R 12 , and / or R 13 are each independently a halogen, a hydroxyl group, a thiol group, a carbonyl group, an amide group, a nitro group, an amino group, a substituted or unsubstituted (C 1 -C 5 ) alkyl group, substituted or unsubstituted (C 2 -C 5 ) alkenyl groups, substituted or unsubstituted (C 2 -C 5 ) alkynyl groups, substituted or unsubstituted (C 1 -C 3 ) haloalkyl groups, and substituted or unsubstituted (C 1 -C 3 ) aminoalkyl group or substituted or unsubstituted (C 1 -C 5 ) an alkoxy group, and R 10 is a hydrogen, halogen, hydroxyl group, thiol group, substituted or unsubstituted (C 1 -C 5 ) alkyl group, substituted or unsubstituted (C 2 -C 5 ) alkenyl groups, substituted or unsubstituted (C 2 -C 5 ) alkynyl groups, substituted or unsubstituted (C 1 -C 3 ) haloalkyl groups, substituted or unsubstituted (C 1 -C 5) an alkoxy group, or a cyano group.

[0316] Item 121. Cy contains at least one heteroatom selected from nitrogen, oxygen, and sulfur to form a 5-membered heteroaryl ring fused with an atom of the pyrimidine ring, and R is each a hydrogen, a halogen, an amino group, a hydroxyl group, a thiol group, (C 1 -C 5 ) alkyl group, (C 2 -C 5 ) alkenyl group, (C 2 -C 5 ) alkynyl group, (C 1 -C 3 ) haloalkyl group, (C 1 -C 3 ) aminoalkyl group, or (C 1 -C 5 ) R independently selected from alkoxy groups; 11 , R 12 , and / or R 13 Each R10 is a hydrogen, halogen, a hydroxyl group, a thiol group, (C 1 -C 5 ) alkyl group, (C 2 -C 5 ) alkenyl group, (C 2 -C 5 ) alkynyl group, (C 1 -C 3 ) haloalkyl group, (C 1 -C 5 121. The compound or solvate, trimeric isomer or pharma- ceutically acceptable salt of item 120, wherein each of the compounds is independently selected from: alkoxy;

[0317] Item 122. Cy contains at least one nitrogen atom and forms a 5-membered heteroaryl ring fused to an atom of the pyrimidine ring, and R has the structure TIFF0007681616000065.tif2323, which is bonded to the nitrogen atom of the Cy ring, and R 11 , R 12 , and / or R 13 are hydrogen, halogen, amino group, (C1 -C 5 ) alkyl group, (C 2 -C 5 ) alkenyl group, (C 2 -C 5 ) alkynyl group, (C 1 -C 3 ) haloalkyl group, (C 1 -C 3 ) aminoalkyl group, or (C 1 -C 5 ) an alkoxy group, and each R 10 is hydrogen, halogen, hydroxyl group, thiol group, (C 1 -C 5 ) alkyl group, (C 2 -C 5 ) alkenyl group, (C 2 -C 5 ) alkynyl group, (C 1 -C 3 ) haloalkyl group, (C 1 -C 5 121. The compound or solvate, trimeric isomer or pharma- ceutically acceptable salt of item 120, wherein each of the compounds is independently selected from: alkoxy;

[0318] Item 123. Cy contains at least one nitrogen atom and forms a 5-membered heteroaryl ring with the atoms of the pyrimidine ring, and R is TIFF0007681616000066.tif2323, which is bonded to the nitrogen atom of the Cy ring. R 11 and R 13 are hydrogen, halogen, and (C 1 -C 5 ) alkyl group, (C 2 -C 5 ) alkenyl group, (C 2 -C 5 ) alkynyl group, (C 1 -C 3 ) haloalkyl group, or (C 1 -C 5 ) an alkoxy group, R 12 teeth hydrogen or an amino group, and each R 10 are hydrogen, halogen, (C 1-C 5 ) alkyl group, (C 2 -C 5 ) alkenyl group, (C 2 -C 5 ) alkynyl group, (C 1 -C 3 ) haloalkyl group, (C 1 -C 5 121. The compound or solvate, trimeric isomer or pharma- ceutically acceptable salt of item 120, wherein each of the compounds is independently selected from: alkoxy;

[0319] Item 124. R 11 and R 13 are hydrogen, halogen, and (C 1 -C 5 ) alkyl group, (C 2 -C 5 ) alkenyl group, (C 2 -C 5 ) alkynyl group, (C 1 -C 3 ) haloalkyl group, or (C 1 -C 5 ) an alkoxy group, R 12 is hydrogen or an amino group, R 10 are hydrogen, halogen, (C 1 -C 5 ) alkyl group, (C 2 -C 5 ) alkenyl group, (C 2 -C 5 ) alkynyl group, (C 1 -C 3 ) haloalkyl group, or (C 1 -C 5 124. The compound or solvate, trimeric isomer or pharma- ceutically acceptable salt of item 123, wherein: R is an alkoxy group; R is an alkoxy group; or R is an alkoxy group;

[0320] Item 125. R 11 and R 13 are hydrogen, halogen, and C 1 -C 5 Alkyl group, or C 1 -C 3 is a haloalkyl group, R 12is hydrogen or an amino group, and R 10 are hydrogen, halogen, C 1 -C 5 125. The compound or solvate, trimeric isomer or pharma- ceutically acceptable salt of item 124, wherein: R is independently selected from an alkyl group, an alkyl group, or a cyano group.

[0321] Item 126. Cy is a pyrimidine bonded to Cy. and forming a pyrazolopyrimidine or purine, R is TIFF0007681616000067.tif2828, and is bonded to the nitrogen atom of Cy, R 11 and R 13 are hydrogen, halogen, and C 1 -C 5 Alkyl group, C 2 -C 5 Alkenyl group, C 2 -C 5 Alkynyl group, C 1 -C 3 Haloalkyl group, or C 1 -C 5 is an alkoxy group, R 2 is hydrogen or an amino group, R 10 is hydrogen, halogen, C 1 -C 5 Alkyl group, C 2 -C 5 Alkenyl group, C 2 -C 5 Alkynyl group, C 1 -C 3 Haloalkyl group, C 1 -C 5 121. The compound or solvate, trimeric form or pharma- ceutically acceptable salt of item 120, wherein R is an alkoxy group, or a cyano group.

[0322] Item 127. R 11 and R 13 are hydrogen, halogen, and C 1 -C 5 Alkyl group, C 2 -C 5 Alkenyl group, C2 -C 5 Alkynyl group, C 1 -C 3 Haloalkyl group, or C 1 -C 5 is an alkoxy group, R 2 is hydrogen or an amino group, R 10 is hydrogen, halogen, C 1 -C 5 Alkyl group, C 2 -C 5 Alkenyl, C 2 -C 5 Alkynyl, C 1 -C 3 Haloalkyl group, C 1 -C 5 127. The compound of claim 126, or a solvate, trimeric isomer or pharma- ceutically acceptable salt thereof, which is alkoxy or cyano.

[0323] Item 128. The compound of item 120, or a solvate, a three-dimensional isomer or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 3-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo-[3,4-d]-pyrimidin-4-yl)-benzonitrile; 3-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo-[3,4-d]-pyrimidin-4-yl)-2-methylbenzonitrile; 3-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo-[3,4-d]-pyrimidin-4-yl)-2-fluorobenzonitrile; 3-(2-amino-9-(4-aminobenzyl)-9H-purin-6-yl)-benzonitrile; 3-(2-amino-9-(4-aminobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile; 3-(2-amino-9-(4-aminobenzyl)-9H-purin-6-yl)-2-methylbenzonitrile; 3-(2-amino-9-(4-amino-2,6-difluorobenzyl)-9H-purin-6-yl)-benzonitrile; 3-(2-amino-9-(4-amino-2,6-difluorobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile; 3-(2-amino-9-(4-amino-2-fluorobenzyl)-9H-purin-6-yl)-benzonitrile; 3-(2-amino-9-(4-amino-2-fluorobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile; 3-(2-amino-9-(4-amino-3-methylbenzyl)-9H-purin-6-yl)-benzonitrile; 3-(2-amino-9-(4-amino-3-methylbenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile; 3-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-benzonitrile; 3-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile; and 3-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-2-methylbenzonitrile.

[0324] Item 129. A pharmaceutical composition for preventing or treating cancer, comprising an effective amount of a compound according to any one of items 119 to 127, or a solvate, a three-dimensional isomer, or a pharma- ceutically acceptable salt thereof.

[0325] Item 130. The pharmaceutical composition according to item 129, wherein the composition has an antagonistic effect on the adenosine A2A receptor.

[0326] Item 131. Cancer is lung cancer, breast cancer, prostate cancer, ovarian cancer, solenoma, cervical cancer, bladder cancer, head and neck cancer, renal cell carcinoma, esophageal cancer, pancreatic cancer, brain cancer, liver cancer, leukemia, lymphoma, melanoma, multiple myeloma, Ewing's sarcoma, osteosarcoma, colorectal tumor, bile duct cancer, choriocarcinoma , oral cancer, neuroblastoma, skin cancer, testicular cancer, stromal tumor, germ cell tumor, or thyroid cancer.

[0327] Item 132. The pharmaceutical composition according to item 129, wherein the composition is administered simultaneously, separately or sequentially with another anticancer agent.

[0328] Item 133. The pharmaceutical composition according to item 129, wherein the composition is prepared in a pharma- ceutically acceptable form, which is a tablet, pill, powder, capsule, syrup, emulsion, or microemulsion. EXAMPLES

[0329] The following examples are provided to illustrate the present disclosure and should not be interpreted as limiting the scope of the present technology in any way. Any method that is functionally equivalent is within the scope of the present technology. In addition to those described herein, various modifications of the present technology will be apparent to those skilled in the art from the above description. Such modifications are included within the scope of the appended claims.

[0330] All temperatures are in degrees Celsius unless otherwise noted. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be allowed for.

[0331] If an abbreviation is not defined, it has its generally accepted meaning. General synthesis method

[0332] The final compound was confirmed by high performance liquid chromatography / mass spectrometry (HPLC / MS) analysis and was determined to be greater than 90% by weight pure. 1 H nuclear magnetic resonance (NMR) spectra were obtained using CDCl 3 (Residual internal standard CHCl 3 = δ 7.26), dimethyl sulfoxide (DMSO)-d 6 (Residual internal standard CD 3 S℃D 2 H=δ2.50), methanol-d 4 (Residual internal standard CD 2 HOD=δ3.30), or acetone-d 6 (Residual internal standard CD 3 C℃D2 The electron transfer coefficients were recorded at 100 MHz (H = δ 2.05). Reported chemical shifts (δ) are given in parts per million (ppm) and coupling constants (J) are given in Hertz (Hz). Spin multiplicities are: s = singlet, bs = broad singlet, bm = broad multiplet, d = doublet, t = triplet, q = quartet, p = quintet, dd = doublet of doublets, ddd = doublet of doublets of doublets, dt = doublet of triplets, td = triplet of doublets, tt = triplet of triplets, m = multiplet.

[0333] HPLC-MS analysis was performed using gradient elution. Medium pressure liquid chromatography (MPLC) was performed using both normal and reverse phase silica gel columns. Example 1: Preparation of Compounds

[0334] The compounds of the present disclosure are produced by adapting well-known chemical transformations according to the methods depicted in Schemes 1 or 2 below. The synthesis of some exemplary compounds in Table 1 is described below in Examples 1.1 to 1.69. Several other compounds in Table 1 were prepared by adapting the methods described herein and evaluated according to the biological assays described in Examples 2-4.

[0335] General scheme 1 An exemplary synthetic method of TIFF0007681616000068.tif79161 is described in detail below.

[0336] To explain in more detail with reference to the above scheme 1, the first step is to dissolve the A-2 compound in tetrahydrofuran and water solvents, and to produce the compound of scheme A-3 by chain reaction of the solution with hydrazine monohydrate at 25°C to 60°C for 24 hours; the second step is to dissolve the A-3 compound in N,N-dimethylformamide solvent, and then to react the solution with the compound of scheme A-4 by nucleophilic substitution at 25°C to 60°C for 24 hours under conditions of potassium carbonate or cesium carbonate to produce the compound of scheme A-5. It is possible to prepare the compound shown by the above scheme 1 through a series of processes including; and a third step of dissolving the A-5 compound in 1,4-dioxane and distilled water, reacting the solution with the compound of scheme A-6 in a Suzuki coupling reaction at 100° C. to 115° C. for 2 to 24 hours under conditions in which 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile and its derivatives, and tetrakis(triphenylphosphine)palladium and sodium carbonate are provided, or the solution undergoes a Suzuki coupling reaction under the same conditions, dissolving the solution in an ethanol solvent, and the solution undergoing a reduction reaction under conditions of tin(II) chloride dihydrate and acid to produce the A compound. Here, R in the above scheme 1 is a1 , R a2 , R a3 , R a4 , and R a5 is a substituent of the formulae described herein, for example, R of formula (IIb) 1 Or R 9 and a cyano group.

[0337] General scheme 2 An exemplary synthetic method of TIFF0007681616000069.tif74161 is described in detail below.

[0338] It is possible to produce the compounds shown by the above scheme through a series of processes including: a first step of dissolving the B-1 compound in N,N-dimethylformamide solvent, reacting the solution with the compound of scheme A-4 in a nucleophilic substitution reaction at 25°C to 60°C for 24 hours under conditions of providing potassium carbonate or cesium carbonate to produce the B-2 compound; and a second step of dissolving the B-2 compound in 1,4-dioxane and distilled water solvent, reacting the solution with the compound of scheme A-6 in a Suzuki coupling reaction at 100°C to 115°C for 2 hours to 24 hours under conditions of providing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile and its derivatives, tetrakis(triphenylphosphine)palladium, and sodium carbonate, or the solution undergoes a Suzuki coupling reaction under the same conditions, dissolving the solution in ethanol solvent, and reducing the solution with tin(II) chloride dihydrate and acid conditions to produce the B compound. Here, R in the above scheme 2 is a1 , R a2 , R a3 , R a4 , and R a5 represents a substituent of the formulae described herein, for example, R of formula (IIa) 1 Or R 9 and a cyano group.

[0339] Example 1.1: Preparation of 3-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile (Compound 201)

[0340] 1.1.1. Preparation of 4-chloro-(4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine TIFF0007681616000070.tif36130Reagents and conditions: (a) Hydrazine, TEA, THF:H 2 O (3:1), room temperature to 50 °C, 3 h, quant; (b) 4-nitrobenzyl bromide, K 2 CO 3, DMF, 0°C to room temperature, 12 hours, 58%.

[0341] Step 1: Preparation of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine

[0342] 2-Amino-4,6-dichloropyrimidine-5-carbaldehyde (S1, 4 g, 20.83 mmol) was dissolved in tetrahydrofuran (THF) and H 2 The reaction mixture was then heated to 50° C., stirred for 3 hours, and concentrated. The concentrate was then washed with distilled water. Washing As a result, the intermediate compound (S2, 3.45 g, 100%) was obtained. 1 H-NMR (DMSO-d 6 , 400MHz): δ13.25(s, 1H), 8.02(s, 1H), 7.14(s, 2H).

[0343] Step 2: Preparation of 4-chloro-1-(4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

[0344] The intermediate compound (S2, 3.0 g, 18.12 mmol) produced in step 1 above was dissolved in dimethylformamide (DMF) and 4-nitrobenzyl bromide (3.92 g, 18.12 mmol), and potassium carbonate (K 2 CO 3 , 3.75g, 27.18mmol) was added to it. Then, it was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate (EA) and washed by distillation. It was then dried over magnesium sulfate, filtered and concentrated. The concentrate was then purified by silica gel chromatography to obtain the desired compound (S3, 3.2g, 58%). 1 H-NMR (DMSO-d 6 , 400MHz): δ8.19(d, 2H), 8.09(s, 1H), 7.40-7.38(m, 4H), 5.56(s, 2H).

[0345] 1.1.2. Preparation of 3-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile (Compound 201). TIFF0007681616000071.tif36161Reagents and conditions: (c) 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile, Pd(PPh 3 ) 4 , Na 2 CO 3 , dioxane:H 2 HO (8:1), room temperature to 105 °C, 12 h, 70%; (d) SnCl 2 .2H 2 O, concentrated HCl, EtOH, room temperature to 50°C, 3 h, 45%.

[0346] Step 1: Preparation of 3-(6-amino-1-(4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile

[0347] The compound of Example 1-1 above (S3, 1.0 g, 3.28 mmol) was dissolved in 1,4-dioxane and H 2 2,4-dimethylphenylphosphine (DPPh) (1.2 g, 4.2 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaneboron-2-yl)benzonitrile (1.12 g, 4.92 mmol), tetrakis(triphenylphosphine)palladium ((0)(Pd(PPh 3 ) 4 , 758 mg, 0.65 mmol), and sodium carbonate (Na 2 CO 3 , 695mg, 6.56mmol) was added to it. The reaction mixture was then stirred at 105°C for 12 hours in a sealed tube, then diluted with dichloromethane (DCM), which was then washed with distilled water. It was then dried over magnesium sulfate, then filtered and concentrated, and the concentrate was washed with ethyl acetate / hexane (EA / Hex) to obtain intermediate compound (S4, 852mg, 70%). 1 H-NMR (DMSO-d 6, 400MHz): δ8.54(s, 1H), 8.51-8.49(m, 2H), 8.08(dd, 1H), 7.80(t, 1H), 7.42(d, 2H), 7.15(s, 2H), 5.62(s, 2H).

[0348] Step 2: Preparation of 3-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile

[0349] The intermediate compound (S4, 400 mg, 1.07 mmol) produced in step 1 above was dissolved in ethanol (EtOH) and then added with tin(II) chloride dihydrate (SnCl 2 2H 2 201, 161 mg, 45%. The concentrate was then purified by silica gel chromatography to give the desired compound (201, 161 mg, 45%). The reaction mixture was then stirred at 50° C. for 3 hours, then diluted with dichloromethane (DCM) and washed with distilled water. It was then dried over magnesium sulfate, then dried, filtered, and concentrated. The concentrate was then purified by silica gel chromatography to give the desired compound (201, 161 mg, 45%). 1 H-NMR (DMSO-d 6 , 400MHz): δ8.50(s, 1H), 8.48-8.45(m, 1H), 8.35(s, 1H), 8.07-8.04(m, 1H), 7 .79(t, 1H), 7.07(s, 2H), 6.95(d, 2H), 6.47(d, 2H), 5.23(s, 2H), 5.04(s, 2H).

[0350] Example 1.2: Preparation of 3-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-methylbenzonitrile (Compound 205) TIFF0007681616000072.tif36161Reagents and conditions: (a) 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile, Pd(PPh 3 ) 4 , Na 2 CO 3 , dioxane:H2 O(8:1), room temperature to 105 °C, 12 h, 81%; (b) SnCl 2 .2H 2 O, concentrated HCl, EtOH, room temperature to 50 °C, 3 h, 74%.

[0351] Step 1: Preparation of 3-(6-amino-1-(4-nitrobenzyl[3,4-d]pyrimidin-4-yl)-2-methylbenzonitrile

[0352] Using the same process as in Step 1 of the above Example 1.1.2, except using 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxyboron-2-yl)benzonitrile (120 mg, 0.49 mmol) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.12 g, 4.92 mmol) in Step 1 of the above Example 1.1.2, intermediate compound (S5, 103 mg, 81%) was obtained. 1 H-NMR (DMSO-d 6 , 400MHz): δ8.21(d, 2H), 7.97(d, 1H), 7.90(s, 1H), 7.82(d, 1H), 7.56(t, 1H), 7.46(d, 2H), 7.13(s, 2H), 5.59(s, 2H), 2.52(s, 3H)

[0353] Step 2: Preparation of 3-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-methylbenzonitrile

[0354] In step 2 of Example 1.2 above, tin(II) chloride dihydrate (SnCl 2 .2H 2 The same process as in Step 2 of Example 1.1.2 above was carried out on the intermediate compound from Step 1 above (S5, 103 mg, 0.26 mmol), except for changing the amounts of (S4, 180 mg, 0.80 mmol) and concentrated HCl (aq) (0.45 ml, 5.34 mmol), to give the desired compound (205, 71 mg, 74%). 1 H-NMR (DMSO-d 6, 400MHz): δ7.95(d, 1H), 7.79(d, 1H), 7.77(s, 1H), 7.54(t, 1H), 7.05(s , 2H), 6.98(d, 2H), 6.48(d, 2H), 5.21(s, 2H), 5.04(s, 2H), 2.49(s, 3H).

[0355] Example 1.3: Preparation of 3-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile (Compound 202) TIFF0007681616000073.tif36161Reagents and conditions: (a) 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile, Pd(PPh 3 ) 4 , Na 2 CO 3 , dioxane:H 2 HO (8:1), room temperature to 105 °C, 12 h, 90%; (b) SnCl 2 .2H 2 O, concentrated HCl, EtOH, room temperature to 50°C, 3 h, 92%.

[0356] Step 1: Preparation of 3-(6-amino-1-(4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile The procedure was repeated in step 1 of Example 1.1.2 above, except that 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.21 g, 4.92 mmol) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.12 g, 4.92 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 ,758mg, 0.65mmol) and sodium carbonate (Na 2 CO 3The same process as in Step 1 of Example 1.1.2 above was carried out, except for changing the amount of dimethylformamide (DMSO) (695 mg, 6.56 mmol), to give an intermediate compound (S6, 1.15 g, 90%). 1 H-NMR (DMSO-d 6 , 400MHz): δ8.22-8.15(m, 4H), 8.10(d, 1H), 7.61(t, 1H), 7.43(d, 2H), 7.21(s, 2H), 5.60(s, 2H).

[0357] Step 2: Preparation of 3-(6-amino-1-4(4-aminobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile

[0358] In step 2 of Example 1.1.2 above, tin(II) chloride dihydrate (SnCl 2 .2H 2 O, 250 mg, 1.11 m The same process as in Step 2 of Example 1.1.2 above was carried out on the intermediate compound in Step 1 above (S6, 144 mg, 0.37 mmol) except for changing the amounts of 1,2-dichlorophenyl ether (0.51 ml, 7.5 mmol) and concentrated HCl(aq) (0.62 ml, 7.40 mmol) to give the desired compound (202, 131 mg, 92%). 1 H-NMR (DMSO-d 6 , 400MHz): δ8.14(t, 2H) 7.96(d, 1H), 7.11(s, 2H), 6.96(d, 2H), 6.48(d, 2H), 5.22(s, 2H), 5.04(s, 2H).

[0359] Example 1.4: Preparation of 3-(2-amino-9-(4-aminobenzyl)-9H-purin-6-yl)benzonitrile (Compound 101)

[0360] 1.4.1. Preparation of 6-chloro-9(4-nitrobenzyl)-9H-purin-2-amine TIFF0007681616000074.tif3687Reagents and conditions: (a) 4-nitrobenzyl bromide, K 2 CO 3 , DMF, rt.

[0361] 6-Chloro-9H-purin-2-amine (S12, 3 g, 18.12 mmol) was dissolved in N,N-dimethylformamide (DMF) and 4-nitrobenzyl bromide (4.1 g, 19.30 mmol) and potassium carbonate (K 2 CO 3 , 3.76 g, 27.18 mmol) was added. The mixture was then stirred at room temperature. The reaction mixture was then diluted with dichloromethane (DCM) and washed with distilled water. It was then dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to obtain intermediate compound (S8, 395 mg, 42%). 1 H-NMR (DMSO-d 6 , 400MHz): δ8.27(s, 1H), 8.22-8.20(m, 2H), 7.47-7.45(m, 2H), 6.96(s, 2H), 5.46(s, 2H).

[0362] 1.4.2. Preparation of 3-(2-amino-9-(4-aminobenzyl)-9H-purin-6-yl)benzonitrile TIFF0007681616000075.tif28170 Reagents and conditions: (a) H 2 Pd(PPh) in 1,4-dioxane 3 ) 4 , Na 2 CO 3 , microwave, 105°C, 30 min. (b) SnCl 2 2H 2 O, concentrated HCl(aq), EtOH, 55°C, 4 hours.

[0363] Step 1: Preparation of 3-(2-amino-9-(4-nitrobenzyl)-9H-purin-6-yl)benzonitrile

[0364] The intermediate compound (S8, 200 mg, 0.652 mmol) was dissolved in 1,4-dioxane and treated with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (224 mg, 0.978 mmol) and tetrakis(triphenylphosphine)palladium(0) ((Pd(PPh 3 ) 4 , 151 mg, 0.131 mmol), and sodium carbonate (Na 2 CO 3 , 139 mg, 1.304 mmol) was added, and then the solution was heated at 105° C. using a microwave apparatus and stirred for 30 minutes. The reaction mixture was then diluted with dichloromethane (DCM) and washed with distilled water. It was then dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to give the intermediate compound (S9, 395 mg, 54%). 1 H-NMR (DMSO-d 6 , 400MHz): δ9.10-9.08(m, 1H), 9.05-9.02(m, 1H), 8.39(s, 1H), 8.22(d, 2H), 8.03-8.01(m, 1H), 7.80(t, 1H), 7.51-7.49(m, 2H), 6.73(s, 2H), 5.53(s, 2H).

[0365] Step 2: Preparation of 3-(2-amino-9-(4-aminobenzyl)-9H-purin-6-yl)benzonitrile

[0366] The intermediate compound (S9, 244 mg, 0.624 mmol) produced in step 1 above was dissolved in ethanol (EtOH) and tin(II) chloride dihydrate (SnCl 2 .2H 2 2H2O, 423 mg, 1.872 mmol) and concentrated HCl (aq) (1.1 mL, 12.48 mmol) were added and the solution was stirred at 55° C. for 4 h. The reaction mixture was then diluted with dichloromethane (DCM) and then washed with distilled water. The solution was then dried over magnesium sulfate, filtered, concentrated, and the concentrate was purified by silica gel chromatography to give the desired compound (101, 41 mg, 38%). 1H-NMR (DMSO-d 6 , 400MHz): δ9.07(s, 1H), 9.02(d, 1H), 8.24(s, 1H), 8.00(d, 1H), 7.78(t, 1H), 7.05-7.03(m, 2H), 6.69(br, 2H), 6.52-6.50(m, 2H), 5.11(d, 4H).

[0367] Example 1.5: Preparation of 3-(2-amino-9-(4-aminobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile (Compound 102) TIFF0007681616000076.tif28161Reagents and conditions: (a) H 2 Pd(PPh) in 1,4-dioxane 3 ) 4 , Na 2 CO 3 , microwave, 105°C, 1 hour. (b) SnCl 2 .2H 2 O, concentrated HCl(aq), EtOH, 55°C, 4 hours.

[0368] Step 1: Preparation of 3-(2-amino-9-(4-nitrobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile

[0369] The same process as in Step 1 of Example 1.1 above was carried out, except that in Step 1 of Example 1.1 above, 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (224 mg, 0.978 mmol) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (224 mg, 0.978 mmol), to obtain intermediate compound (S10, 395 mg, 54%). 1 H-NMR (DMSO-d 6 , 400MHz): δ8.29(s, 1H), 8.27-8.17(m, 2H), 8.13-8.07(m, 1H), 7.65-7.50(m, 4H), 6.78(d, 2H), 5.51(d, 2H).

[0370] Step 2: Preparation of 3-(2-amino-9-(4-aminobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile

[0371] The same process as Step 2 of Example 1.1 above was carried out on the intermediate compound of Step 1 above (S10, 244 mg, 0.624 mmol) to give the desired compound (102, 52 mg, 48%). 1 H-NMR (DMSO-d 6 , 400MHz): δ8.22-8.13(m, 2H), 8.13-8.07(m, 1H), 7.57(t, 1H), 7.05(d, 2H), 6.73(s, 2H), 6.51(d, 2H), 5.11(d, 4H).

[0372] Example 1.6: Preparation of 3-(2-amino-9-(4-aminobenzyl)-9H-purin-6-yl)-2-methylbenzonitrile (Compound 105) TIFF0007681616000077.tif28161Reagents and conditions: (a) H 2 Pd(PPh) in 1,4-dioxane 3 ) 4 , Na 2 CO 3 , microwave, T = 105 °C, 1 hour. (b) SnCl 2 .2H 2 O, concentrated HCl(aq), EtOH, 55°C, 4 hours.

[0373] Step 1: Preparation of 3-(2-amino-9-(4-nitrobenzyl)-9H-purin-6-yl)-2-methylbenzonitrile

[0374] The same process as in Step 1 of Example 1.1 above was carried out, except that in Step 1 of Example 1.1 above, 2-methyl-3-(4,4,5,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (224 mg, 0.978 mmol) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (224 mg, 0.978 mmol) to obtain intermediate compound (S11, 395 mg, 54%).1 H-NMR (DMSO-d 6 , 400MHz): δ8.27-8.22(m, 2H), 7.83(d, 1H), 7.88(d, 1H), 7.65-7.52(m, 4H), 6.71(s, 2H), 5.50(s, 2H).

[0375] Step 2: Preparation of 3-(2-amino-9-(4-aminobenzyl)-9H-purin-6-yl)-2-methylbenzonitrile

[0376] The same process as Step 2 of Example 1.1 above was carried out on the intermediate compound of Step 1 above (S11, 244 mg, 0.624 mmol) to give the desired compound (105, 52 mg, 48%). 1 H-NMR (DMSO-d 6 , 400MHz): δ8.10(d, 1H), 7.91(d, 1H), 7.83(d, 1H), 7.51(t, 1H), 7.06(d, 2H), 6.66(s, 2H), 6.55-6.46(m, 2H), 5.10(d, 4H), 3.32(s, 3H).

[0377] Example 1.7: Preparation of 3-(2-amino-9-(4-amino-2,6-difluorobenzyl)-9H-purin-6-yl)benzonitrile (Compound 107) TIFF0007681616000078.tif36117 TIFF0007681616000079.tif36117Reagents and conditions: (a) 2-(bromomethyl)-1,3-difluoro-5-nitrobenzene, K 2 CO 3 , DMF, room temperature, overnight; (b) Pd(PPh 3 ) 4 , K 2 CO 3 , 1,4-dioxane, H 2 O, 115℃, 4 hours; (c)SnCl 2 .2H 2 O, concentrated HCl(aq), EtOH, 55°C, 4 hours.

[0378] Step 1: Preparation of 6-chloro-9-(2,6-difluoro-4-nitrobenzyl)-9H-purin-2-amine

[0379] 6-Chloro-9H-purin-2-amine (S12, 500 mg, 2.95 mmol) was dissolved in dimethylformamide (DMF) and 2-(bromomethyl)-1,3-difluoro-5-nitrobenzene (817.4 mg, 3.24 mmol) and potassium carbonate (K 2 CO 3 , 611.6 mg, 4.43 mmol) was added and the solution was stirred at room temperature for 1 day. The reaction mixture was then diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, concentrated, and the concentrate was purified by silica gel chromatography to give the intermediate compound (S13, 300 mg, 33%). 1 H-NMR (DMSO-d 6 , 400MHz): δ8.68(s, 1H), 7.55(d, 2H), 6.93(s, 2H), 4.99(s, 2H).

[0380] Step 2: Preparation of 3-(2-amino-9-(2,6-difluoro-4-nitrobenzyl)-9H-purin-6-yl)benzonitrile

[0381] The intermediate compound (S13, 150 mg, 0.44 mmol) produced in step 1 above was dissolved in 1,4-dioxane, and the solution was mixed with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (151 mg, 0.66 mmol), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 , 25.4 mg, 0.022 mmol), and potassium carbonate (K 2 CO 3 , 121.6 mg, 0.88 mmol) was added, heated at 115° C., and stirred for 4 hours. The reaction mixture was then diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to obtain the intermediate compound (S14, 95.5 mg, 53.3%).1 H-NMR (methanol-d 4 , 400MHz): δ8.98(s, 1H), 8.93(dd, 1H), 8.18(s, 1H), 8.01-7.96(m, 2H), 7.86(dd, 1H), 7.70(t, 1H), 5.56(s, 2H).

[0382] Step 3: Preparation of 3-(2-amino-9-(4-amino-2,6-difluorobenzyl)-9H-purin-6-yl)benzonitrile

[0383] The intermediate compound (S14, 95.1 mg, 0.23 mmol) produced in step 2 above was dissolved in ethanol (EtOH) and tin(II) chloride dihydrate (SnCl 2 .2H 2 O, 263.4 mg, 1.17 mmol) was added and the solution was stirred at 55° C. for 4 hours. The reaction mixture was then diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to give the desired compound (107, 38.7 mg, 44.6%). 1 H-NMR (DMSO-d 6 , 400MHz): δ9.06(s, 1H), 8.99(dd, 1H), 8.05(s, 1H), 7.98(dd, 1H), 7.78(t, 1H), 6.67(s, 2H), 6.25-6.18(m, 2H), 5.89(s, 2H), 5.17(s, 2H).

[0384] Example 1.8: Preparation of 3-(2-amino-9-(4-amino-2,6-difluorobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile (Compound 108) TIFF0007681616000080.tif28161 Reagents and conditions: (a) Pd(PPh 3 ) 4 , K 2 CO 3 1,4-Dioxane, H 2 O, 115°C, overnight; (b) SnCl 2 .2H 2O, concentrated HCl(aq), EtOH, 55°C, 3 hours.

[0385] Step 1: Preparation of 3-(2-amino-9-(2,6-difluoro-4-nitrobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile

[0386] The same process as in Step 2 of Example 1.4 above was carried out, except that in Step 2 of Example 1.4 above, 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (130.5 mg, 0.53) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (151 mg, 0.66 mmol), to obtain intermediate compound (S15, 100 mg, 53.4%). 1 H-NMR (CDCl 3 , 400MHz): δ8.15-8.13(m, 1H), 7.90-7.87(m, 3H), 7.75-7.74(m, 1H), 7.40(t, 1H), 5.54(s, 2H), 5.12(s, 2H).

[0387] Step 2: Preparation of 3-(2-amino-9-(4-amino-2,6-difluorobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile

[0388] The intermediate compound (S15, 100 mg, 0.24 mmol) produced in step 1 above was dissolved in ethanol (EtOH) and tin(II) chloride dihydrate (SnCl 2 .2H 2 O, 265 mg, 1.18 mmol) was added to the solution, and the solution was stirred at 50° C. for 3 hours. The reaction mixture was then diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to give the desired compound (108, 32.9 mg, 34.7%). 1 H-NMR (methanol-d 4, 400MHz): δ8.12-8.08(m, 1H), 7.96-7.91(m, 2H), 7.53(t, 1H), 6.26(d, 2H), 5.29(s, 2H).

[0389] Example 1.9: Preparation of 3-(2-amino-9-(4-amino-2-fluorobenzyl)-9H-purin-6-yl)benzonitrile (Compound 109) TIFF0007681616000081.tif36115 TIFF0007681616000082.tif33110Reagents and conditions: (a) 1-(bromomethyl)-2-fluoro-4-nitrobenzene, K 2 CO 3 , DMF, room temperature, overnight; (b) Pd(PPh 3 ) 4 , K 2 CO 3 , 1,4-dioxane, H 2 O, 115℃, 5 hours; (c) SnCl 2 .2H 2 O, EtOH, 50°C, 1 hour.

[0390] Step 1: Preparation of 6-chloro-9-(2-fluoro-4-nitrobenzyl)-9H-purin-2-amine

[0391] 6-Chloro-9H-purin-2-amine (S12, 500 mg, 2.95 mmol) was dissolved in dimethylformamide (DMF) and 1-(bromomethyl)-2-fluoro-4-nitrobenzene (758.2 mg, 3.24 mmol) and potassium carbonate (K 2 CO 3 , 611.6 mg, 4.43 mmol) was added to the solution, and the solution was stirred for 1 day. After that, the reaction mixture was diluted with dichloromethane (DCM), then washed with distilled water, dried over magnesium sulfate, dried, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to obtain intermediate compound (S16, 742 mg, 77%). 1 H-NMR (DMSO-d 6, 400MHz): δ8.23(s, 1H), 8.18(dd, 1H), 8.03(dd, 1H), 7.30(t, 1H), 6.97(s, 2H), 5.49(s, 2H).

[0392] Step 2: Preparation of 3-(2-amino-9-(2-fluoro-4-nitrobenzyl)-9H-purin-6-yl)-benzonitrile

[0393] The intermediate compound (S16, 300 mg, 0.93 mmol) produced in step 1 above was dissolved in 1,4-dioxane and H 2 O, and the solution was added with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzonitrile (318.4 mg, 1.39 mmol) and tetrakis(triphenylphosphine)palladium ((0)Pd(PPh 3 ) 4 , 53.7 mg, 0.05 mmol), and potassium carbonate (K 2 CO 3 , 257 mg, 1.86 mmol) was added to the solution, and the solution was heated to 115° C. and stirred for 5 hours. The reaction mixture was then diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound (S17, 162 mg, 44.8%). 1 H-NMR (DMSO-d 6 , 400MHz): δ9.09(s, 1H), 9.02(dd, 1H), 8.35(s, 1H), 8.19(dd, 1H), 8.06-8.01(m, 2H), 7.81(t, 1H), 7.31(t, 1H), 6.75(s, 2H), 5.55(s, 2H).

[0394] Step 3: Preparation of 3-(2-amino-9-(4-amino-2-fluorobenzyl)-9H-purin-6-yl)benzonitrile

[0395] The intermediate compound (S17, 89 mg, 0.23 mmol) produced in the second step described above was dissolved in ethanol (EtOH) and then added with tin(II) chloride dihydrate (SnCl2 .2H 2 O, 257 mg, 1.14 mmol) was added to the solution, and the solution was stirred at 50° C. for 1 hour. The reaction mixture was then diluted with dichloromethane (DCM), then washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to give the desired compound (109, 19 mg, 23%). 1 H-NMR (DMSO-d 6 , 400MHz): δ9.06(s, 1H), 9.01(d, 1H), 8.14(s, 1H), 8.00(d, 1H), 7.79(t , 1H), 6.98(t, 1H), 6.69(s, 2H), 6.32(d, 2H), 5.48(s, 2H), 5.16(s, 2H).

[0396] Example 1.10: Preparation of 3-(2-amino-9-(4-amino-2-fluorobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile (Compound 103) TIFF0007681616000083.tif28161Reagents and conditions: (a) Pd(PPh 3 ) 4 , K 2 CO 3 1,4-Dioxane, H 2 O, 115°C, overnight; (b) SnCl 2 .2H 2 O, EtOH, 50°C, 3 hours.

[0397] Step 1: Preparation of 3-(2-amino-9-(2-fluoro-4-nitrobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile

[0398] In step 2 of Example 1.6 above, the same process as in step 2 of Example 1.6 above was carried out, except that 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (138 mg, 0.56 mmol) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (318 mg, 1.39 mmol), and the intermediate compound (S18, 80 mg, 42.7%) was obtained. 1 H-NMR (methanol-d 4 , 400 MHz): δ 8.21 (s, 1H), 8.15 - 8.07 (m, 3H), 7.98 - 7.93 (m, 1H), 7.59 - 7.52 (m, 2H), 5.60 (s, 2H).

[0399] Step 2: Preparation of 3-(2-amino-9-(4-amino-2-fluorobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile

[0400] In step 3 of Example 1.6 above, only the amount of tin(II) chloride dihydrate (SnCl 2 .2H 2 O, 180 mg, 0.80 mmol) was changed, and the same process as in step 3 of Example 1.6 above was carried out on the intermediate compound (S18, 65 mg, 0.16 mmol) of step 1 above to obtain the target compound (103, 14.4 mg, 24%). 1 H-NMR (DMSO-d 6 , 400 MHz): δ 8.17 (t, 1H), 8.10 (t, 1H), 8.05 (s, 1H), 7.58 (t, 1H), 7.01 (t, 1H), 6.74 (s, 2H), 6.36 - 6.32 (m, 2H), 5.50 (s, 2H), 5.15 (s, 2H).

[0401] Example 1.11: Preparation of 3-(2-amino-9-(4-amino-3-methylbenzyl)-9H-purin-6-yl)benzonitrile (Compound 104) TIFF0007681616000084.tif36115 TIFF0007681616000085.tif33110Reagents and conditions: (a) 4-(bromomethyl)-2-methyl-1-nitrobenzene, K 2 CO 3 , DMF, room temperature, overnight; (b) Pd(PPh 3 ) 4 , K 2 CO 3 , 1,4-dioxane, H 2 O, 115℃, 2 hours; (c)SnCl 2 .2H 2 HO, EtOH, 55 °C, overnight.

[0402] Step 1: Preparation of 6-chloro-9-(3-methyl-4-nitrobenzyl)-9H-purin-2-amine

[0403] 6-Chloro-9H-purin-2-amine (S12, 846 mg, 4.99 mmol) was dissolved in N,N-dimethylformamide (DMF) and 4-(bromomethyl)-2-methyl-1-nitrobenzene (1.263 g, 5.49 mmol) and potassium carbonate (K 2 CO 3 , 1.03 g, 7.49 mmol) was added to the solution, and then the solution was stirred at room temperature for 1 day. After that, the reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, concentrated, and the concentrate was purified by silica gel chromatography to obtain intermediate compound (S19, 1.28 g, 80.5%). 1 H-NMR (CDCl 3 , 400MHz): δ7.97(d, 1H), 7.77(s, 1H), 7.22-7.18(m, 2H), 5.30(s, 2H), 2.59(s, 3H).

[0404] Step 2: Preparation of 3-(2-amino-9-(3-methyl-4-nitrobenzyl)-9H-purin-6-yl)benzonitrile

[0405] The intermediate compound (S19, 278 mg, 0.87 mmol) produced in step 1 above was dissolved in 1,4-dioxane and H 2Dissolve 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzonitrile (300 mg, 1.31 mmol) and tetrakis(triphenylphosphine)palladium(0) ((Pd(PPh 3 ) 4 , 50.3 mg, 0.043 mmol), and potassium carbonate (K 2 CO 3 , 240.4 mg, 1.74 mmol) was added to the solution, and the solution was heated to 105° C. and stirred for 2 hours. The reaction mixture was then diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to obtain the intermediate compound (S20, 143 mg, 42.7%). 1 H-NMR (CDCl 3 , 400MHz): δ9.07(s, 1H), 9.02(d, 1H), 7.98(d, 1H), 7.84(s, 1H), 7.78(d, 1H), 7.59-7.51(m, 1H), 7.50-7.44(m, 2H), 5.36(s, 2H), 5.08(s, 2H), 2.59(s, 3H).

[0406] Step 3: Preparation of 3-(2-amino-9-(4-amino-3-methylbenzyl)-9H-purin-6-yl)benzonitrile

[0407] The intermediate compound (S20, 143 mg, 0.37 mmol) produced in step 2 above was dissolved in ethanol (EtOH) and tin(II) chloride dihydrate (SnCl 2 .2H 2 O, 418.6 mg, 1.86 mmol) was added and the solution was stirred at 55° C. for 1 day. The reaction mixture was then diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, concentrated, and the concentrate was purified by silica gel chromatography to give the desired compound (104, 23.6 mg, 18%). 1 H-NMR (DMSO-d 6, 400MHz): δ9.08(s, 1H), 9.02(d, 1H), 8.23(s, 1H), 7.99(d, 1H), 7.79(t, 1H), 6.96(s , 1H), 6.91(d, 1H), 6.86(s, 2H), 6.55(d, 1H), 5.11(s, 2H), 4.87(s, 2H), 2.01(s, 3H).

[0408] Example 1.12: Preparation of 3-(2-amino-9-(4-amino-3-methylbenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile (Compound 106) TIFF0007681616000086.tif28158Reagents and conditions: (a) Pd(PPh 3 ) 4 , K 2 CO 3 , 1,4-dioxane, H 2 O, 115℃, 2 hours; (c)SnCl 2 .2H 2 HO, EtOH, 55 °C, overnight

[0409] Step 1: Preparation of 3-(2-amino-9-(3-methyl-4-nitrobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile

[0410] The intermediate compound (S19, 300 mg, 0.94 mmol) was dissolved in 1,4-dioxane and H 2 2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (349 mg, 1.41 mmol) and tetrakis(triphenylphosphine)palladium(0) ((Pd(PPh 3 ) 4 , 54.3 mg, 0.05 mmol), and potassium carbonate (K 2 CO 3, 260 mg, 1.88 mmol) was added to the solution, and the solution was heated to 115° C. and stirred for 2 hours. The reaction mixture was then diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound (S21, 298.2 mg, 78.6%). 1 H-NMR (CDCl 3 , 400MHz): δ8.22-8.16(m, 1H), 7.99(d, 1H), 7.83(s, 1H), 7.79(t, 1H), 7.70-7.64(m, 1H), 7.43(t, 1H), 7.25(s, 1H), 5.13(s, 2H), 2.60(s, 3H).

[0411] Step 2: Preparation of 3-(2-amino-9-(4-amino-3-methylbenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile

[0412] The intermediate compound (S21, 298.2 mg, 0.74 mmol) produced in step 1 above was dissolved in ethanol (EtOH) and then added with tin(II) chloride dihydrate (SnCl 2 .2H 2 O, 835 mg, 3.7 mmol) was added to the solution, and the solution was stirred at 55° C. for 1 day. The reaction mixture was then diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to give the desired compound (106, 98 mg, 35.5%). 1 H-NMR (DMSO-d 6 , 400MHz): δ8.19-8.14(m, 2H), 8.10-8.07(m, 1H), 7.57(t, 1H), 6.97(s, 1H), 6 .92(d, 1H), 6.73(s, 2H), 6.55(d, 1H), 5.09(s, 2H), 4.88(s, 2H), 2.01(s, 3H).

[0413] Example 1.13: Preparation of 3-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)benzonitrile (Compound 112) TIFF0007681616000087.tif30153 Reagents and conditions: (a) 2,6-difluorobenzyl bromide, K 2 CO 3 , DMF, room temperature, 4 h; (b) Pd(PPh 3 ) 4 , K 2 CO 3 , 1,4-dioxane, H 2 O, 115°C, overnight.

[0414] Step 1: Preparation of 6-chloro-9-(2,6-difluorobenzyl)-9H-purin-2-amine

[0415] 6-Chloro-9H-purin-2-amine (S12, 800 mg, 4.72 mmol) was dissolved in dimethylformamide (DMF) and 2,6-difluorobenzyl bromide (1.46 g, 7.08 mmol) and potassium carbonate (K 2 CO 3 , 1.95 g, 14.16 mmol) was added to the solution and the solution was stirred at room temperature for 4 hours. The reaction mixture was then filtered through a pad of Celite and the remaining liquid was diluted with ethyl acetate (EA). The solution was then washed with distilled water, then dried over sodium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to give the intermediate compound (S22, 850 mg, 58%). 1 H-NMR (DMSO-d 6 , 400MHz): δ8.10(s, 1H), 7.49-7.46(m, 1H), 7.15(t, 2H), 6.68(s, 2H), 5.35(s, 2H).

[0416] Step 2: Preparation of 3-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)benzonitrile

[0417] The intermediate compound (S22, 100 mg, 0.31 mmol) produced in step 1 above was dissolved in 1,4-dioxane and H 2Dissolve 3-(4,4,5,5-tetramethyl-1,3,2)-dioxaborolan-2-yl)benzonitrile (85.2 mg, 0.37 mmol) and tetrakis(triphenylphosphine)palladium(0) ((Pd(PPh 3 ) 4 , 18 mg, 0.02 mmol), and potassium carbonate (K 2 CO 3 , 85.7 mg, 0.62 mmol) solution, and the solution was heated to 115° C. and stirred for 1 day. The reaction mixture was then diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to give the desired compound (112, 81 mg, 89%). 1 H-NMR (CDCl 3 , 400MHz): δ9.02(s, 1H), 8.98(dd, 1H), 7.87(s, 1H), 7.75(dd, 1H), 7.61(t, 1H), 7.39-7.32(m, 1H), 6.97(t, 2H), 5.39(s, 2H), 5.07(s, 2H).

[0418] Example 1.14: Preparation of 3-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-2-fluorobenzonitrile (Compound 113) TIFF0007681616000088.tif36137 Reagents and conditions: (a) Pd(PPh 3 ) 4 , K 2 CO 3 , 1,4-dioxane, H 2 O, 115°C, overnight.

[0419] The above-mentioned embodiment 1.13 The intermediate compound (S22, 50 mg, 0.17 mmol) produced in step 1 was dissolved in 1,4-dioxane and H 2Dissolve 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneboron-2-yl)benzonitrile (49.4 mg, 0.20 mmol) and tetrakis(triphenylphosphine)palladium(0) ((Pd(PPh 3 ) 4 , 8.7 mg, 0.008 mmol), and potassium carbonate (K 2 CO 3 , 47 mg, 0.34 mmol) was added to the solution, and the solution was heated to 115° C. and stirred for 1 day. The reaction mixture was then diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to give the desired compound (113, 45 mg, 70%). 1 H-NMR (DMSO-d 6 , 400MHz): δ8.18-8.11(m, 1H), 8.10-8.08(m, 2H), 7.57(t, 1H), 7.51-7.46(m, 1H), 7.16(t, 2H), 6.73(s, 2H), 5.39(s, 2H).

[0420] Example 1.15: Preparation of 3-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-2-methylbenzonitrile (Compound 114) TIFF0007681616000089.tif36140Reagents and conditions: (a) Pd(PPh 3 ) 4 , K 2 CO 3 , 1,4-dioxane, H 2 O, 115°C, 4 hr.

[0421] The above-mentioned embodiment 1.13 The intermediate compound (S22, 50 mg, 0.17 mmol) produced in step 1 was dissolved in 1,4-dioxane and H 2 Dissolve 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneboron-2-yl)benzonitrile (48.6 mg, 0.20 mmol) and tetrakis(triphenylphosphine)palladium(0) ((Pd(PPh 3) 4 , 8.7 mg, 0.008 mmol), and potassium carbonate (K 2 CO 3 , 47 mg, 0.34 mmol) was added, and the solution was heated to 115° C. and stirred for 4 h. The reaction mixture was then diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to give the desired compound (114, 47.6 mg, 74%). 1 H-NMR (methanol-d 4 , 400MHz): δ8.07(s, 1H), 7.83(dd, 1H), 7.77(dd, 1H), 7.54-7.46(m, 2H), 7.07(t, 2H), 5.50(s, 2H), 2.51(s, 3H).

[0422] Example 1.16: Preparation of 3-[2-amino-9-[[4-amino-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]benzonitrile (Compound 110) TIFF0007681616000090.tif69150Reagents and conditions: (a) K 2 CO 3 , DMAc, 25°C, 3 hours. (b)Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 110℃, 15 hours; (c) Fe, NH 4 Cl, EtOH / H 2 O, 80 °C, 2 hr.

[0423] Step 1: Preparation of 6-chloro-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-2-amine.

[0424] To a solution of 4-(bromomethyl)-1-nitro-2-(trifluoromethyl)benzene (3 g, 10.56 mmol) in DMAc (50 mL) was added intermediate S12, 6-chloro-9H-purin-2-amine (1.79 g, 10.56 mmol) and K 2 CO 3(2.92 g, 21.12 mmol) was added. The mixture was then stirred at 25° C. for 3 hours. After that, water (80 mL) was added to the mixture and extracted with ethyl acetate (80 mL×3). The combined organic phase was washed with brine (150 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (80 g Sepa Flash® silica flash column, eluent of 20-100% ethyl acetate / petroleum ether gradient @ 60 mL / min). Compound S23, 6-chloro-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-2-amine (2.5 g, 6.62 mmol, 63% yield, 98.7% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ8.27(s, 1H), 8.12(d, J=8.3Hz, 1H), 8.05(s, 1H), 7.67(dd, J=8.3Hz, 1H), 6.97(s, 2H), 5.50(s, 2H). MS: m / z=373.0 (M+1, ESI+).

[0425] Step 2: Preparation of 3-[2-amino-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]benzonitrile

[0426] To a solution of compound S23, 6-chloro-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-2-amine (2.5 g, 6.71 mmol, 1 equiv.), (3-cyanophenyl)boronic acid (1.97 g, 13.42 mmol, 2 equiv.), Pd(dppf)Cl in dioxane (40 mL) and water (10 mL) was added. 2 (490 mg, 670.80 μmol, 0.1 equiv.) and K 2 CO 3(1.85 g, 13.42 mmol, 2 equiv.) was added. The mixture was then stirred at 110° C. for 15 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (40 g Sepa Flash® silica flash column, eluent of 20-60% ethyl acetate / petroleum ether gradient @ 50 mL / min). Compound S24, 3-[2-amino-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]benzonitrile (2.3 g, 4.56 mmol, 68% yield, 87% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ9.08(t, J=1.5Hz, 1H), 9.02(td, J=1.4, 8.0Hz, 1H), 8.38(s, 1H), 8.13(d, J=8.4Hz, 1H), 8.08(d, J=1.2Hz, 1 H), 8.01(td, J=1.3, 7.8Hz, 1H), 7.79(t, J=7.8Hz, 1H), 7.71(dd, J=1.5, 8.4Hz, 1H), 6.73(s, 2H), 5.56(s, 2H). MS: m / z=440.0 (M+1, ESI+).

[0427] Step 3: Preparation of 3-[2-amino-9-[[4-amino-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]benzonitrile A solution of 3-[2-amino-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]benzonitrile (2.3 g, 4.55 mmol, 87% purity, 1 equiv.) in ethanol (30 mL) and water (6 mL) was diluted with iron powder (1.27 g, 22.77 mmol, 5 equiv.) and NH 4Cl (1.95 g, 36.44 mmol, 8 equiv.) was added. The mixture was then stirred at 80° C. for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum. Water (80 mL) was added to the mixture and extracted with ethyl acetate (80 mL×3). The combined organic phase was filtered and concentrated in vacuum to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250*70*10 μm; mobile phase: [hexane-EtOH (0.1% ammonium hydroxide)]; B%: 30%-70%, 15 min) to give the product. The product was purified by recrystallization from THF (20 mL) at 70° C. to give the crude product. The crude product was purified by preparative HPLC (column: Welch Ultimate XB-SiOH 250*50*10um; mobile phase: [Hexane-EtOH (0.1% ammonium hydroxide)]; B%: 5%-45%, 15 min). Compound 110 or 3-[2-amino-9-[[4-amino-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]benzonitrile (602.34 mg, 1.44 mmol, 32% yield, 97.62% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.07(s, 1H), 9.01(brd, J=7.9Hz, 1H), 8.30(s, 1H), 8.00(brd, J=7.7Hz, 1H), 7.78(t, J=7.9Hz, 1H) , 7.41(s, 1H), 7.29(brd, J=8.6Hz, 1H), 6.79(d, J=8.6Hz, 1H), 6.71(s, 2H), 5.65(s, 2H), 5.19(s, 2H). HRMS-TOF:410.1347

[0428] Example 1.17: Preparation of 3-[2-amino-9-[[4-amino-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]2-fluorobenzonitrile (Compound 111) TIFF0007681616000091.tif44154 Reagents and conditions: (a) Pd(PPh 3 ) 4 , K 2 CO 3 , dioxane / H 2 O, 110℃, 15 hours; (b) Fe, NH4 Cl, EtOH / H 2 O, 60 °C, 1 hr.

[0429] Step 1: Preparation of 3-[2-amino-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]-2-fluorobenzonitrile

[0430] (3-cyano-2-fluorophenyl)boronic acid (265 mg, 1.61 mmol, 1.5 equiv.), intermediate compound S23 or 6-chloro-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-2-amine (400 mg, 1.07 mmol), Pd(PPh 3 ) 4 (124 mg, 107.00 μmol) and K 2 CO 3 A mixture of (296 mg, 2.14 mmol) was degassed and purged with nitrogen three times, then the mixture was stirred at 100° C. under nitrogen atmosphere for 15 h. The reaction mixture was concentrated under reduced pressure to remove dioxane and water to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 35 mL / min). The intermediate compound 3-[2-amino-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]-2-fluorobenzonitrile (200 mg, 437.31 μmol, 41% yield) was obtained as a yellow solid. MS: m / z=440.3 (M+1, ESI+).

[0431] Step 2: Preparation of 3-[2-amino-9-[[4-amino-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]2-fluorobenzonitrile.

[0432] A solution of 3-[2-amino-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]-2-fluorobenzonitrile (300 mg, 655.97 μmol, 1 equiv.) in ethanol (15 mL) and water (5 mL) was added with NH 4 Cl (292 mg, 5.25 mmol, 8 equiv.) and iron powder (183 mg, 3.28 mmol, 5 equiv.) were added. The mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure to remove ethanol to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%, 10 min). Compound 111 or 3-[2-amino-9-[[4-amino-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]benzonitrile (75.32 mg, 175.81 μmol, 27% yield, 99.75% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ8.21(s, 1H), 8.17(t, 1H), 8.09(t, 1H), 7.57(t, 1H), 7.41(s, 1H), 7.30(brd, 1H), 6.80(d, 1H), 6.75(s, 2H), 5.65(s, 2H), 5.17(s, 2H). HRMS-TOF:428.1244.

[0433] Example 1.18: Preparation of 6-[2-amino-9-[(4-aminophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (Compound 115) TIFF0007681616000092.tif39153Reagents and conditions: (a) XPhos-Pd-G3, THF, 90 °C, 15 h. (b) Fe, NH 4 Cl, THF / H 2 O, 80 °C, 2 hr.

[0434] Step 1: Preparation of 6-[2-amino-9-[(4-nitrophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile

[0435] To a solution of intermediate compound S8, 6-chloro-9-[(4-nitrophenyl)methyl]purin-2-amine (800 mg, 2.63 mmol, 1 equiv.) in THF (20 mL) was added 6-tributylstannylpyridine-2-carbonitrile (2.06 g, 5.25 mmol, 2 equiv.) and XPhos-Pd-G3 (222 mg, 262.56 μmol, 0.1 equiv.). The mixture was then stirred at 90° C. for 15 h. Water (30 mL) was added to the mixture and extracted with ethyl acetate (30 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 35 mL / min). The compound 6-[2-amino-9-[(4-nitrophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (167 mg, 372.27 μmol, 14% yield, 83% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ):δ8.91(dd, J=0.9, 8.1Hz, 1H), 8.37(s, 1H), 8.31-8.25(m, 1H), 8.22(d, J=8.7Hz, 2 H), 8.18(dd, J=0.9, 7.6Hz, 1H), 7.50(d, J=8.7Hz, 2H), 6.85(brs, 1H), 5.53(s, 2H). MS: m / z=373.1 (M+1, ESI+).

[0436] Step 2: Preparation of 6-[2-amino-9-[(4-aminophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile

[0437] To a solution of 6-[2-amino-9-[(4-nitrophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (160 mg, 429.72 μmol, 1 equiv) in water (3 mL) and THF (9 mL) was added NH 4 Cl (184 mg, 3.44 mmol, 8 equiv.) and iron powder (120 mg, 2.15 mmol, 5 equiv.) were added. The mixture was then stirred at 80° C. for 2 h. The reaction mixture was filtered and the filtrate was diluted with saturated NaHCO3 Solution (30 mL) was added and extracted with ethyl acetate (80 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50 mm*10 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 5%-41%, 10 min) to give compound 115 or 6-[2-amino-9-[(4-aminophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (18.59 mg, 53.55 μmol, 12% yield, 95.94% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.92(brd, J=7.9Hz, 1H), 8.34-8.22(m, 2H), 8.16(brd, J=7.5Hz, 1H), 7.05(br d, J=8.0Hz, 2H), 6.81(brs, 2H), 6.52(brd, J=8.0Hz, 2H), 5.13(brd, J=7.3Hz, 4H). HRMS-TOF:343.1415.

[0438] Example 1.19: Preparation of 6-[2-amino-9-[(4-amino-2-fluorophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (Compound 119) TIFF0007681616000093.tif38153Reagents and conditions: (a) XPhos-Pd-G3, THF, 90 °C, 15 h. (b) Fe, NH 4 Cl, THF / H 2 O, 80°C, 1.5 hr.

[0439] Step 1: Preparation of 6-[2-amino-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile.

[0440] To a mixture of intermediate compound S16 or 6-chloro-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-2-amine (0.8 g, 2.48 mmol, 1 equiv.) in THF (10 mL) was added 6-tributylstannylpyridine-2-carbonitrile (1.8 g, 4.58 mmol, 1.85 equiv.) and XPhos-Pd-G3 (210 mg, 247.92 μmol, 0.1 equiv.). The mixture was then stirred at 90° C. for 15 h. Saturated aqueous potassium fluoride solution (30 mL) was added to the mixture and extracted with ethyl acetate (30 mL×3). The organic phases were combined and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (25 g SepaFlash® silica flash column, eluent with 0-100% ethyl acetate / petroleum ether gradient 50 mL / min). The compound 6-[2-amino-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (260 mg, 652.78 μmol, 26% yield, 98.0% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.90(d, J=7.9Hz, 1H), 8.33(s, 1H), 8.28(t, J=7.9Hz, 1H), 8.21-8.15(m, 2H) , 8.05(dd, J=1.8, 8.5Hz, 1H), 7.33(t, J=8.1Hz, 1H), 6.84(brs, 2H), 5.55(s, 2H). MS: m / z=391.0 (M+1, ESI+).

[0441] Step 2: Preparation of 6-[2-amino-9-[(4-amino-2-fluorophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile

[0442] A solution of 6-[2-amino-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (150 mg, 384.29 μmol, 1 equiv.) in water (1.5 mL) and THF (6 mL) was treated with iron powder (107 mg, 1.92 mmol, 5 equiv.) and NH 4Cl (164 mg, 3.07 mmol, 8 equiv.) was added. The mixture was then stirred at 80° C. for 1.5 h. The reaction mixture was filtered. The filtrate was diluted with saturated NaHCO 3 The combined organic phase was washed with anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (column: Phenomenex Gemini NX-C18 (75*30mm*3μm); mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 13%-40%, 7 min). Compound 119 or 6-[2-amino-9-[(4-amino-2-fluoro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (21.61mg, 58.63μmol, 15% yield, 98.70% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.91(dd, J=1.0, 8.0Hz, 1H), 8.30-8.24(m, 1H), 8.16(d, J=7.8Hz, 1H), 8.14(s, 1H) ), 6.99(t, J=8.5Hz, 1H), 6.81(s, 2H), 6.41-6.28(m, 2H), 5.49(brs, 2H), 5.18(s, 2H). HRMS-TOF:361.1321.

[0443] Example 1.20: Preparation of 6-[2-amino-9-[(4-amino-2,6-difluoro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (Compound 123) TIFF0007681616000094.tif38158Reagents and conditions: (a) XPhos-Pd-G3, THF, 90 °C, 15 h. (b) Fe, NH 4 Cl, THF / H 2 O, 80°C, 1.5 hr.

[0444] Step 1: Preparation of 6-[2-amino-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile

[0445] A mixture of intermediate compound S13 or 6-chloro-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-2-amine (1 g, 2.94 mmol, 1 equiv), 6-tributylstannylpyridine-2-carbonitrile (2.31 g, 5.87 mmol, 2 equiv) and XPhos-Pd-G3 (250 mg, 293.54 μmol, 0.1 equiv) in THF (15 mL) was degassed with nitrogen and heated at 90 °C for 15 h. Water (30 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1 to 0 / 1). Compound 6-[2-amino-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (500 mg, 1.05 mmol, 36% yield, 85% purity) was obtained as a yellow solid. 1 1H NMR (400 MHz, DMSO-d 6 ) δ = 8.86 (d, J = 8.0 Hz, 1H), 8.31 - 8.23 (m, 2H), 8.15 (d, J = 7.6 Hz, 1H), 8.09 (d, J = 7.4 Hz, 2H), 6.76 (brs, 2H), 5.52 (s, 2H) MS: m / z = 409.1 (M+1, ESI+).

[0446] Step 2: Preparation of 6-[2-amino-9-[(4-amino-2,6-difluoro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile

[0447] To a solution of 6-[2-amino-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (200 mg, 489.81 μmol, 1 equiv) in THF (8 mL) and water (2 mL) were added iron powder (137 mg, 2.45 mmol, 5 equiv) and NH 4 Cl (210 mg, 3.92 mmol, 8 equiv). Next, the mixture was stirred at 80 °C for 1.5 h. The reaction mixture was filtered, and saturated NaHCO 3Aqueous solution (30 mL) was added and extracted with ethyl acetate (80 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 18%-38%, 9 min). Compound 123 or 6-[2-amino-9-[(4-amino-2,6-difluoro-phenyl)methyl]purine-6-yl]pyridine-2-carbonitrile (31.07 mg, 79.80 μmol, 16% yield, 99.33% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.88(dd, J=1.1, 8.1Hz, 1H), 8.29-8.22(m, 1H), 8.15(dd, J=1.0, 7.8Hz, 1H) ), 8.03(s, 1H), 6.77(s, 2H), 6.22(d, J=10.5Hz, 2H), 5.88(s, 2H), 5.17(s, 2H). HRMS-TOF:379.1235.

[0448] Example 1.21: Preparation of 6-[2-amino-9-[(2,6-difluorophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (Compound 131) TIFF0007681616000095.tif36146Reagents and conditions: (a) XPhos-Pd-G3, THF, 90°C, 15 hours.

[0449] To a solution of intermediate compound S22 or 6-chloro-9-[(2,6-difluorophenyl)methyl]purin-2-amine (200 mg, 676.42 μmol, 1 equiv.) and 6-tributylstannylpyridine-2-carbonitrile (266 mg, 676.42 μmol, 1 equiv.) in THF (10 mL) was added XPhos-Pd-G3 (57.26 mg, 67.64 μmol, 0.1 equiv.). The mixture was then stirred at 90° C. for 15 h. Aqueous potassium fluoride solution (30 mL) was added to the mixture and extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with anhydrous Na 2 SO4 The mixture was dried at 40° C., filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, 0-100% ethyl acetate / petroleum ether gradient @ 35 mL / min eluent). Compound 133 or 6-[2-amino-9-[(2,6-difluorophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (40.26 mg, 110.81 μmol, 16% yield, 96.84% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.87(dd, J=1.0, 8.1Hz, 1H), 8.29-8.22(m, 1H), 8.18(s, 1H), 8.15(dd, J=1.0 , 7.7Hz, 1H), 7.58-7.39(m, 1H), 7.16(t, J=8.1Hz, 2H), 6.77(s, 2H), 5.42(s, 2H). HRMS-TOF:364.1121.

[0450] Example 1.22: Preparation of 6-[2-amino-9-[(4-amino-3-methyl-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (Compound 127) TIFF0007681616000096.tif38155Reagents and conditions: (a) XPhos-Pd-G3, THF, 90 °C, 15 h. (b) Fe, NH 4 Cl, THF / H 2 O, 80 °C, 1 hr.

[0451] Step 1: Preparation of 6-[2-amino-9-[(3-methyl-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile

[0452] A mixture of intermediate compound S19 or 6-chloro-9-[(3-methyl-4-nitro-phenyl)methyl]purin-2-amine (0.8 g, 2.51 mmol, 1 equiv.), 6-tributylstannylpyridine-2-carbonitrile (1.80 g, 4.58 mmol, 1.82 equiv.) and XPhos-Pd-G3 (212 mg, 251.01 μmol, 0.1 equiv.) in THF (10 mL) was degassed and heated to 90° C. under nitrogen for 15 h. The mixture was added with saturated aqueous potassium fluoride solution (30 mL) and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (25 g SepaFlash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 50 mL / min). Compound 6-[2-amino-9-[(3-methyl-4-nitro-phenyl)methyl]purine-6-yl]pyridine-2-carbonitrile (350 mg, 900.89 μmol, 35% yield, 99.45% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.91(dd, J=0.8, 8.0Hz, 1H), 8.36(s, 1H), 8.32-8.24(m, 1H), 8.17(dd, J=0.9, 7.7Hz, 1 H), 7.98(d, J=8.4Hz, 1H), 7.41(s, 1H), 7.28(brd, J=8.4Hz, 1H), 6.83(s, 2H), 5.45(s, 2H). MS: m / z=387.1 (M+1, ESI+).

[0453] Step 2: Preparation of 6-[2-amino-9-[(4-amino-3-methyl-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile

[0454] A solution of 6-[2-amino-9-[(3-methyl-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (150 mg, 388.23 μmol, 1 equiv.) in water (1 mL) and THF (4 mL) was diluted with iron powder (108 mg, 1.94 mmol, 5 equiv.) and NH4 Cl (166 mg, 3.11 mmol, 8 equiv.) was added. The mixture was then stirred at 80° C. for 1 h. The reaction mixture was filtered. The filtrate was diluted with saturated NaHCO 3 The combined organic phase was diluted with anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (column: Phenomenex Gemini NX-C18 75*30mm*3μm; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B%: 10%-40%, 8 min) to give compound 127 or 6-[2-amino-9-[(4-amino-3-methyl-phenyl)methyl]purine-6-yl]pyridine-2-carbonitrile (37.55 mg, 101.86 μmol, 26% yield, >99% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.90(dd, J=1.0, 8.1Hz, 1H), 8.28-8.23(m, 1H), 8.22(s, 1H), 8.15(dd, J=1.1, 7.7Hz, 1H), 6.95(s, 1H), 6 .91(dd, J=1.9, 8.1Hz, 1H), 6.79(s, 2H), 6.55(d, J=8.1Hz, 1H), 5.11(s, 2H), 4.89-4.83(m, 2H), 2.01(s, 3H). HRMS-TOF:357.1571.

[0455] Example 1.23: Preparation of 2-[2-amino-9-[(4-aminophenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (Compound 116) TIFF0007681616000097.tif69153Reagents and conditions: (a) CuI, DMSO, 110°C, 15 hours; (b) NaOMe, MeOH, 25°C, 0.5 hours; (c) Pd(OAc) 2 , Cy 3 P.K. 2 CO 3 , dioxane, 130 °C, 10 h, MW; (d) Fe, NH 4 Cl, EtOH / H 2O, 60 °C, 1 hr.

[0456] Step 1: Preparation of methyl 3-((4-cyanopyridin-2-yl)sulfonyl)propanoate

[0457] A mixture of 2-bromopyridine-4-carbonitrile (4.4 g, 24.04 mmol, 1 equiv.), sodium 3-methoxy-3-oxo-propane-1-sulfinate (5.02 g, 28.85 mmol, 1.2 equiv.), CuI (5.49 g, 28.85 mmol, 1.2 equiv.) in DMSO (50 mL) was degassed and purged with nitrogen three times, then the mixture was stirred at 110° C. under nitrogen atmosphere for 15 h. The mixture was then cooled to room temperature, diluted with ethyl acetate (50 mL), and filtered through a pad of silica. The filtrate was washed with water (2×20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered through a pad of silica, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 35 mL / min). The compound methyl 3-[(4-cyano-2-pyridyl)sulfonyl]propanoate (3 g, 11.80 mmol, 49% yield) was obtained as a white solid. MS: m / z=254.9 (M+1, ESI+).

[0458] Step 2: Preparation of (4-cyano-2-pyridyl)sulfinyloxysodium

[0459] To a solution of methyl 3-[(4-cyano-2-pyridyl)sulfonyl]propanoate (1.1 g, 4.33 mmol, 1 equiv.) in methanol (10 mL) was added sodium methoxide (233 mg, 4.33 mmol, 1 equiv.). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove methanol to give a residue. The crude product of intermediate compound S25 or (4-cyano-2-pyridyl)sulfinyloxysodium (700 mg, crude) was obtained as a yellow solid and used in the next step without further purification. MS: m / z=167.0 (M+1, ESI+).

[0460] Step 3: Preparation of 2-[2-amino-9-[(4-nitrophenyl)methyl]purin-6-yl]pyridine-4-carbonitrile

[0461] Intermediate compound S25 or (4-cyano-2-pyridyl)sulfinyloxysodium (374 mg, 1.97 mmol, 1.2 equiv.), intermediate compound S8 or 6-chloro-9-[(4-nitrophenyl)methyl]purin-2-amine (500 mg, 1.64 mmol, 1 equiv.), tricyclohexylphosphine (92 mg, 328.20 μmol, 0.2 equiv.), K 2 CO 3 (453 mg, 3.28 mmol, 2 equiv.) and Pd(OAc) 2 A mixture of (36 mg, 164.10 μmol, 0.1 equiv) in dioxane (2 mL) was taken in a microwave tube. The sealed tube was heated at 130° C. under microwave for 10 h. The reaction mixture was concentrated under reduced pressure to remove dioxane to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 40 mL / min). Compound 2-[2-amino-9-[(4-nitrophenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (360 mg, 734.81 μmol, 45% yield, 76% purity) was obtained as a yellow solid. MS: m / z=373.1 (M+1, ESI+).

[0462] Step 4: Preparation of 2-[2-amino-9-[(4-aminophenyl)methyl]purin-6-yl]pyridine-4-carbonitrile

[0463] Intermediate compound S26 or 2-[2-amino-9-[(4-nitrophenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (150 mg, 402.86 μmol, 1 equiv.) and NH 4To a solution of Cl (172 mg, 3.22 mmol, 8 equiv.) was added iron powder (112 mg, 2.01 mmol, 5 equiv.). The mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure to remove ethanol and water to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 5%-25%, 10 min). Compound 116 or 2-[2-amino-9-[(4-aminophenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (22.85 mg, 64.35 μmol, 16% yield, 96.90% purity, 0.2 FA) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.01(dd, 1H), 8.94(s, 1H), 8.22(s, 1H), 7.98(dd, 1H), 7.04(d, 2H), 6.74(s, 2H), 6.51(d, 2H), 5.13(s.4H). HRMS-TOF:343.1415.

[0464] Example 1.24: Preparation of 2-[2-amino-9-[(4-amino-2-fluoro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (Compound 120) TIFF0007681616000098.tif38154Reagents and conditions: (a) Pd(OAc) 2 , Cy 3 P.K. 2 CO 3 , dioxane, 130 °C, 10 h, MW; (b) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 1 hr.

[0465] Step 1: Preparation of 2-[2-amino-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile.

[0466] Intermediate compound S25 or (4-cyano-2-pyridyl)sulfinyloxy sodium (424 mg, 2.23 mmol, 1.2 equiv.), intermediate compound S16 or 6-chloro-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-2-amine (600 mg, 1.86 mmol, 1 equiv.), tricyclohexylphosphine (104 mg, 371.88 μmol, 0.2 equiv.), K 2 CO 3 A mixture of (513 mg, 3.72 mmol, 2 equiv.) and palladium acetate (42 mg, 185.94 μmol, 0.1 equiv.) in dioxane (4 mL) was taken in a microwave tube. The sealed tube was heated at 130° C. under microwave for 10 h. The reaction mixture was concentrated under reduced pressure to remove dioxane to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 35 mL / min). The compound 2-[2-amino-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (300 mg, 768.58 μmol, 41% yield) was obtained as a white solid. MS: m / z=391.1 (M+1, ESI+).

[0467] Step 2: Preparation of 2-[2-amino-9-[(4-amino-2-fluoro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile

[0468] Dissolve 2-[2-amino-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (150 mg, 230.57 μmol, 1 equiv.) in ethanol (15 mL) and water (5 mL) with NH 4 To a solution of Cl (98 mg, 1.84 mmol, 8 equiv.) was added iron powder (64 mg, 1.15 mmol, 5 equiv.). The mixture was stirred at 60° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (10 mM NH 4 HCO3 The product was then purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [water (10mMNH 4 HCO 3 B%: 8%-38%, 10 min). Finally, compound 120 or 2-[2-amino-9-[(4-amino-2-fluoro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (9.83 mg, 26.40 μmol, 11% yield, 97.25% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.02(d, 1H), 8.89(s, 1H), 8.13(s, 1H), 7.99(d, 1H), 6.98(t, 1H), 6.75(s, 2H), 6.33(d, 2H), 5.48(s, 2H), 5.17(s2H). HRMS-TOF:361.1319.

[0469] Example 1.25: 2 Preparation of -[2-amino-9-[(4-amino-2,6-difluoro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (Compound 124) TIFF0007681616000099.tif38154Reagents and conditions: (a) Pd(OAc) 2 , Cy 3 P.K. 2 CO 3 , dioxane, 130 °C, 10 h, MW; (b) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 1 hr. Step 1: 2-[2-amino-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (4-Cyano-2-pyridyl)sulfinyloxysodium (419 mg, 2.20 mmol, 1.5 equiv.), 6-chloro-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-2-amine (500 mg, 1.47 mmol, 1 equiv.), tricyclohexylphosphine (123 mg, 440.31 μmol, 0.3 equiv.), K 2 CO 3 (405mg, 2.94mmol, 2eq) and palladium acetate (50mg, 223.09μmol, 0.15eq) were taken in a microwave tube in dioxane (10mL). The sealed tube was heated under microwave at 130℃ for 10h. The reaction mixture was concentrated under reduced pressure to remove dioxane and obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (0.225%FA)-ACN]; B%: 23%-53%, 10min). Compound 2-[2-amino-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (120mg, 293.89μmol, 20% yield) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.02(d, 1H), 8.85(s, 1H), 8.28(s, 1H), 8.11-8.07(m, 2H), 7.99(d, 1H), 6.72(s, 2H), 5.52(s, 2H). MS:m / z=409.1(M+1, ESI+) Step 2: 2-[2-amino-9-[(4-amino-2,6-difluoro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile 2-[2-amino-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (100 mg, 244.91 μmol, 1 equiv.) and NH 4To a solution of Cl (104 mg, 1.96 mmol, 8 equiv.) was added iron powder (68 mg, 1.22 mmol, 5 equiv.). The mixture was stirred at 60° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 13%-43%, 10 min) to give the product with 90% purity. A second preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 22%-52%, 9 min). The compound 2-[2-amino-9-[(4-amino-2,6-difluoro-phenyl)methyl]purine-6-yl]pyridine-4-carbonitrile (34.57 mg, 89.87 μmol, 37% yield, 97.96% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.01(dd, 1H), 8.87(s, 1H), 8.03(s, 1H), 7.99(dd, 1H), 6.72(s, 2H), 6.22(d, 2H), 5.88(s, 2H), 5.17(s, 2H). HRMS(TOF):379.1229

[0470] Example 1.26: Preparation of 2-[2-amino-9-[(4-amino-2,6-difluoro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (Compound 132) TIFF0007681616000100.tif39158Reagents and conditions: (a) Pd(OAc) 2 , Cy 3 P.K. 2 CO 3 , dioxane, 130°C, 10 h, MW.

[0471] Intermediate compound S25 or (4-cyano-2-pyridyl)sulfinyloxysodium (231 mg, 1.22 mmol, 1.2 equiv), intermediate compound S22 or 6-chloro-9-[(2,6-difluorophenyl)methyl]purin-2-amine (300 mg, 1.01 mmol, 1 equiv), palladium acetate (22 mg, 101.46 μmol, 0.1 equiv), tricyclohexylphosphine (56 mg, 202.93 μmol, 0.2 equiv) and K in dioxane (6 mL). 2 CO 3 After the mixture of (280mg, 2.03mmol, 2eq) was degassed and purged with nitrogen three times, the mixture was stirred at 130°C for 10 hours under microwave conditions. The mixture was concentrated under reduced pressure to remove dioxane to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 15%-45%, 7min). Compound 132 or 2-[2-amino-9-[(2,6-difluorophenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (49.39mg, 130.41μmol, 13% yield, 93.37% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.01(dd, 1H), 8.87(s, 1H), 8.18(s, 1H), 7.99(dd, 1H), 7.54-7.43(m, 1H), 7.21-7.12(m, 2H), 6.73(s, 2H), 5.41(s, 2H). HRMS-TOF:364.1121.

[0472] Example 1.27: Preparation of 2-[2-amino-9-[(4-amino-3-methyl-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (Compound 128) TIFF0007681616000101.tif38155Reagents and conditions: (a) Pd(OAc) 2 , Cy 3 P.K. 2 CO 3 , dioxane, 130 °C, 10 h, MW; (b) Fe, NH 4Cl, EtOH / H 2 O, 60 °C, 1 hr.

[0473] Step 1: Preparation of 2-[2-amino-9-[(3-methyl-4-nitro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile

[0474] Intermediate compound S25 or sodium 4-cyanopyridine-2-sulfinate (357 mg, 1.88 mmol, 1.2 equiv.), intermediate compound S19 or 6-chloro-9-[(3-methyl-4-nitro-phenyl)methyl]purin-2-amine (500 mg, 1.57 mmol, 1 equiv.), palladium acetate (35 mg, 157.00 μmol, 0.1 equiv.), tricyclohexylphosphine (87 mg, 314.00 μmol, 0.2 equiv.) and K in dioxane (2 mL). 2 CO 3 After the mixture of (433 mg, 3.14 mmol, 2 eq) was degassed and purged with nitrogen three times, the mixture was stirred at 130° C. for 10 h under microwave conditions. The reaction mixture was concentrated under reduced pressure to remove dioxane to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® silica flash column, eluent of 0-10% ethyl acetate / petroleum ether gradient @ 30 mL / min). The compound 2-[2-amino-9-[(3-methyl-4-nitro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (300 mg, 535.76 μmol, 34% yield, 69% purity) was obtained as a yellow solid. MS: m / z=387.3 (M+1, ESI+).

[0475] Step 2: Preparation of 2-[2-amino-9-[(4-amino-3-methyl-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile 2-[2-amino-9-[(3-methyl-4-nitro-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (150 mg, 388.23 μmol, 1 equiv.) and NH in water (5 mL) and ethanol (15 mL). 4To a solution of Cl (7M, 444 μL, 8 equiv.) was added iron powder (108 mg, 1.94 mmol, 5 equiv.). The mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure to remove ethanol and water to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 8%-28%, 9 min.). Compound 128 or 2-[2-amino-9-[(4-amino-3-methyl-phenyl)methyl]purin-6-yl]pyridine-4-carbonitrile (21.82 mg, 58.15 μmol, 15% yield, 96.70% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.02(d, 1H), 8.90(s, 1H), 8.23(s, 1H), 7.99(d, 1H), 6.95(s, 1H), 6.93-6 .90(m, 1H), 6.75(s, 2H), 6.55(d, 1H), 5.12(s, 2H), 4.87(s, 2H), 2.06(s, 3H). HRMS-TOF:357.1569.

[0476] Example 1.28: Preparation of 2-[2-amino-9-[[4-amino-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]pyridine-4-carbonitrile (Compound 135) TIFF0007681616000102.tif42155Reagents and conditions: (a) Pd(OAc) 2 , Cy 3 P.K. 2 CO 3 , dioxane, 130 °C, 10 h, MW; (b) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 1 hr.

[0477] Step 1: Preparation of 2-[2-amino-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]pyridine-4-carbonitrile.

[0478] Intermediate compound S25 or sodium 4-cyanopyridine-2-sulfinate (230 mg, 1.21 mmol, 1.5 equiv.), intermediate compound S23 or 6-chloro-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-2-amine (300 mg, 804.96 μmol, 1 equiv.), potassium carbonate (222 mg, 1.61 mmol, 2 equiv.) and Cy in dioxane (5 mL). 3 A mixture of P-Pd-G3 (52 mg, 80.50 μmol, 0.1 equiv.) was degassed and purged with nitrogen three times, and then the mixture was stirred under nitrogen atmosphere at 120° C. for 16 h. The reaction mixture was concentrated under reduced pressure to remove dioxane to give a residue. The residue was purified by preparative HPLC (column: Sympac C18 150*25*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 34%-54%, 10 min). Compound 135 or 2-[2-amino-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]pyridine-4-carbonitrile (300 mg, 647.23 μmol, 80% yield, 95% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.04(dd, J=0.7, 4.9Hz, 1H), 8.90(s, 1H), 8.37(s, 1H), 8.13(s, 1H), 8.08(s, 1H) , 8.01(dd, J=1.5, 5.0Hz, 1H), 7.71(dd, J=1.2, 8.4Hz, 1H), 6.80(s, 2H), 5.57(s, 2H).

[0479] Step 2: Preparation of 2-[2-amino-9-[[4-amino-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]pyridine-4-carbonitrile.

[0480] A solution of 2-[2-amino-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purine-6-yl]pyridine-4-carbonitrile (300 mg, 681.29 μmol, 1 equiv.) in ethanol (15 mL) and water (5 mL) was treated with iron powder (190 mg, 3.41 mmol, 5 equiv.) and NH 4Cl (292 mg, 5.45 mmol, 8 equiv.) was added. The mixture was stirred at 60° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Sympac C18 150*25*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 17%-47%, 10 min). Compound 135 or 2-[2-amino-9-[[4-amino-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]pyridine-4-carbonitrile (40.01 mg, 96.51 μmol, 14% yield, 98.98% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.02(d, 1H), 8.89(s, 1H), 8.29(s, 1H), 7.99(dd, 1H), 7.40(d, 1H), 7.29 (dd, 1H), 6.82-6.74(m, 3H), 5.64(s, 2H), 5.20(s, 2H)HRMS-TOF:411.1281.

[0481] Example 1.29: Preparation of 5-[2-amino-9-[(4-aminophenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (Compound 117) TIFF0007681616000103.tif42158Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 110℃, 15 hours. (b) Fe, NH 4 Cl, EtOH / H 2 O, 80 °C, 1 hr.

[0482] Step 1: Preparation of 5-[2-amino-9-[(4-nitrophenyl)methyl]purin-6-yl]pyridine-3-carbonitrile.

[0483] Intermediate compound S8 or 6-chloro-9-[(4-nitrophenyl)methyl]purin-2-amine (200 mg, 656.40 μmol, 1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (181 mg, 787.68 μmol, 1.2 equiv.), Pd(dppf)Cl in dioxane (10 mL) and water (0.5 mL). 2 (48 mg, 65.64 μmol, 0.1 equiv.) and K 2 CO 3 A mixture of (181 mg, 1.31 mmol, 2 equiv) was degassed and then heated to 110° C. under nitrogen for 15 h. Water (130 mL) was added to the mixture and extracted with ethyl acetate (130 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was analyzed by preparative TLC (SiO 2 , PE:EA=1:1). The compound 5-[2-amino-9-[(4-nitrophenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (150 mg, 330.34 μmol, 50% yield, 82% purity) was obtained as a yellow solid. MS: m / z=373 (M+1, ESI+).

[0484] Step 2: Preparation of 5-[2-amino-9-[(4-aminophenyl)methyl]purin-6-yl]pyridine-3-carbonitrile

[0485] A solution of 5-[2-amino-9-[(4-nitrophenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (150 mg, 330.34 μmol, 1 equiv.) in ethanol (9 mL) and water (3 mL) was treated with iron powder (92 mg, 1.65 mmol, 5 equiv.) and NH 4Cl (141 mg, 2.64 mmol, 8 equiv.) was added. The mixture was then stirred at 80° C. for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum. Then, water (50 mL) was added to the mixture and extracted with ethyl acetate (80 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to obtain a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 14%-44%, 10 min). Compound 117 or 5-[2-amino-9-[(4-aminophenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (20.59 mg, 58.88 μmol, 18% yield, 98.45% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=10.01(d, J=1.8Hz, 1H), 9.30(s, 1H), 9.16(d, J=1.8Hz, 1H), 8.29(s, 1H), 7.05 (brd, J=8.3Hz, 2H), 6.77(s, 2H), 6.52(d, J=8.3Hz, 2H), 5.14(s, 2H), 5.11(s, 2H). HRMS-TOF:343.1410.

[0486] Example 1.30: Preparation of 5-[2-amino-9-[(4-amino-2-fluoro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (Compound 121) TIFF0007681616000104.tif39158Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 110℃, 15 hours. (b) Fe, NH 4 Cl, EtOH / H 2 O, 80 °C, 1 hr.

[0487] Step 1: Preparation of 5-[2-amino-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile.

[0488] Intermediate compound S16 or 6-chloro-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-2-amine (300 mg, 929.71 μmol, 1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (320 mg, 1.39 mmol, 1.5 equiv.), K 2 CO 3 (257 mg, 1.86 mmol, 2 equiv.) and Pd(dppf)Cl 2 A mixture of (68 mg, 92.97 μmol, 0.1 equiv) was degassed and heated to 110° C. under nitrogen for 15 h. Water (30 mL) was added to the mixture, which was then extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with brine (50 mL×2) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 70° C., filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent 0-80% ethyl acetate / petroleum ether gradient @ 35 mL / min). Compound 121 or 5-[2-amino-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (200 mg, 502.14 μmol, 54% yield, 98% purity) was obtained as a yellow solid. MS: m / z=391.2 (M+1, ESI+).

[0489] Step 2: Preparation of 5-[2-amino-9-[(4-amino-2-fluoro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile.

[0490] 5-[2-amino-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (200 mg, 512.39 μmol, 1 equiv.) and NH 4To a solution of Cl (220 mg, 4.10 mmol, 8 equiv.) was added iron powder (143 mg, 2.56 mmol, 5 equiv.). The mixture was then stirred at 80° C. for 1 h. The mixture was concentrated in vacuo to give a residue. To the residue was added water (30 mL) and extracted with ethyl acetate (30 mL×3). The organic phases were combined and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo to give a residue. The crude product was triturated with methanol (10 mL) and THF (1 mL) at 60° C. for 30 minutes. Compound 121 or 5-[2-amino-9-[(4-amino-2-fluoro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (60 mg, 166.51 μmol, 32% yield, 95.08% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=10.01(d, J=2.0Hz, 1H), 9.30(t, J=2.1Hz, 1H), 9.17(d, J=2.0Hz, 1H), 8.20(s, 1H) ), 6.99(t, J=8.4Hz, 1H), 6.79(s, 2H), 6.44-6.28(m, 2H), 5.50(s, 2H), 5.18(s, 2H). HRMS-TOF:361.1319.

[0491] Example 1.31: Preparation of 5-[2-amino-9-[(4-amino-2,6-difluoro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (Compound 125) TIFF0007681616000105.tif39158Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 110℃, 2 hours; (b) Fe, NH 4 Cl, EtOH / H 2 O, 80 °C, 1 hr.

[0492] Step 1: Preparation of 5-[2-amino-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile.

[0493] Intermediate compound S13 or 6-chloro-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-2-amine (200 mg, 587.07 μmol, 1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (270 mg, 1.17 mmol, 2 equiv.), Pd(dppf)Cl 2 (43 mg, 58.71 μmol, 0.1 equiv.) and K 2 CO 3 A mixture of (162 mg, 1.17 mmol, 2 equiv.) was taken in dioxane (10 mL) and water (2 mL) in a microwave tube. The sealed tube was heated at 110 °C for 2 h under microwave conditions. Water (130 mL) was then added to the mixture and extracted with ethyl acetate (130 mL x 2). The organic phases were combined and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @ 40 mL / min). Compound 125 or 5-[2-amino-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (200 mg, 426.14 μmol, 72% yield, 87% purity) was obtained as a yellow solid. MS: m / z=408.9 (M+1, ESI+).

[0494] Step 2: Preparation of 5-[2-amino-9-[(4-amino-2,6-difluoro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile.

[0495] To a solution of 5-[2-amino-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (200 mg, 489.81 μmol, 1 equiv.) in ethanol (8 mL) and water (2 mL) was added iron powder (137 mg, 2.45 mmol, 5 equiv.) and NH 4Cl (210 mg, 3.92 mmol, 8 equiv.) was added. The mixture was then stirred at 80° C. for 1 h. The reaction mixture was then filtered, the filtrate was concentrated in vacuo, and the residue was then added with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (column: Waters Vinridis Silica 2-EP OBD 50*150mm*5μm; mobile phase: [heptane-EtOH (0.1%NH 3 H 2 O)]; B%: 5%-45%, 10 min). Compound 125 or 5-[2-amino-9-[(4-amino-2,6-difluoro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (16.22 mg, 40.31 μmol, 8% yield, 96.64% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.99(d, J=2.0Hz, 1H), 9.28(t, J=2.1Hz, 1H), 9.15(d, J=2.1Hz, 1H), 8. 09(s, 1H), 6.74(s, 2H), 6.22(d, J=10.4Hz, 2H), 5.88(s, 2H), 5.17(s, 2H). HRMS-TOF:379.1229.

[0496] Example 1.32: Preparation of 5-[2-amino-9-[(2,6-difluorophenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (Compound 133) TIFF0007681616000106.tif38150Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 110°C, 15 hr.

[0497] Intermediate compound S22 or 6-chloro-9-[(2,6-difluorophenyl)methyl]purin-2-amine (150 mg, 507.31 μmol, 1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (140 mg, 608.78 μmol, 1.2 equiv.), Pd(dppf)Cl in dioxane (10 mL) and water (1 mL). 2 (37 mg, 50.73 μmol, 0.1 equiv.) and K 2 CO 3 A mixture of (140mg, 1.01mmol, 2eq) was degassed and heated to 110°C under nitrogen for 15h. The mixture was concentrated in vacuum to give a residue. The residue was purified by preparative HPLC (column: XtimateC18 150*40mm*10μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 30%-60%, 10min). Compound 133 or 5-[2-amino-9-[(2,6-difluorophenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (60.03mg, 161.42μmol, 32% yield, 96.75% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.98(d, J=1.7Hz, 1H), 9.27(s, 1H), 9.16(d, J=1.7Hz, 1H), 8.24(s, 1H), 7.55-7.42(m, 1H), 7.16(t, J=8.1Hz, 2H), 6.74(s, 2H), 5.42(s, 2H). HRMS-TOF:364.1121.

[0498] Example 1.33: Preparation of 5-[2-amino-9-[(4-amino-3-methyl-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (Compound 129) TIFF0007681616000107.tif39158Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 110℃, 15 hours. (b) Fe, NH 4 Cl, EtOH / H 2O, 80 °C, 1 hr.

[0499] Step 1: Preparation of 5-[2-amino-9-[(3-methyl-4-nitro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile

[0500] Intermediate compound S19 or 6-chloro-9-[(3-methyl-4-nitro-phenyl)methyl]purin-2-amine (300 mg, 941.27 μmol, 1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (325 mg, 1.41 mmol, 1.5 equiv.), Pd(dppf)Cl in dioxane (10 mL) and water (0.5 mL). 2 (69 mg, 94.13 μmol, 0.1 equiv.) and K 2 CO 3 (260 mg, 1.88 mmol, 2 equiv.) was degassed and heated to 110° C. under nitrogen for 15 h. After that, water (80 mL) was added to the mixture and extracted with ethyl acetate (80 mL×3). The organic phases were combined and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent 0-80% ethyl acetate / petroleum ether gradient @ 30 mL / min). The compound 5-[2-amino-9-[(3-methyl-4-nitro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (300 mg, 750.84 μmol, 79% yield, 96.7% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=10.02(d, J=2.0Hz, 1H), 9.31(t, J=2.1Hz, 1H), 9.17(d, J=2.0Hz, 1H), 8.41(s, 1H), 7.97(d, J =8.4Hz, 1H), 7.41(s, 1H), 7.28(dd, J=1.5, 8.4Hz, 1H), 6.80(s, 2H), 5.45(s, 2H), 2.49(brs, 3H). MS: m / z=387 (M+1, ESI+).

[0501] Step 2: Preparation of 5-[2-amino-9-[(4-amino-3-methyl-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile

[0502] A solution of 5-[2-amino-9-[(3-methyl-4-nitro-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (300 mg, 722.1 μmol, 1 equiv.) in ethanol (9 mL) and water (3 mL) was diluted with iron powder (202 mg, 3.61 mmol, 5 equiv.) and NH 4 Cl (310 mg, 5.78 mmol, 8 equiv.) was added. The mixture was then stirred at 80° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was then added with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with anhydrous Na 2 SO 4 The crude product was triturated with methanol (8 mL) at 25° C. for 30 minutes, then filtered, and the solid was dried under reduced pressure. Compound 129 or 5-[2-amino-9-[(4-amino-3-methyl-phenyl)methyl]purin-6-yl]pyridine-3-carbonitrile (36.5 mg, 99.14 μmol, 13% yield, 96.26% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=10.01(d, J=2.0Hz, 1H), 9.29(t, J=2.0Hz, 1H), 9.15(d, J=2.0Hz, 1H), 8.28(s, 1H), 6.96(s, 1H), 6.92(dd, J=1.7, 8.1Hz, 1H), 6.76(s, 2H), 6.56(d, J=8.1Hz, 1H), 5.12(s, 2H), 2.01(s, 3H). HRMS-TOF:357.1555.

[0503] Example 1.34: Preparation of 4-[2-amino-9-[(4-aminophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (Compound 118) TIFF0007681616000108.tif39158Reagents and conditions: (a) Pd(dppf)Cl2 , K 2 CO 3 , dioxane / H 2 O, 110°C, 2 hours, MW. (b) Fe, NH 4 Cl, EtOH / H 2 O, 80 °C, 1 hr.

[0504] Step 1: Preparation of 4-[2-amino-9-[(4-nitrophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile.

[0505] Intermediate compound S8 or 6-chloro-9-[(4-nitrophenyl)methyl]purin-2-amine (200 mg, 656.40 μmol, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (755 mg, 3.28 mmol, 5 equiv.), K 2 CO 3 (181 mg, 1.31 mmol, 2 equiv.) and Pd(dppf)Cl 2 A mixture of (48 mg, 65.64 μmol, 0.1 equiv) in dioxane (10 mL) and water (2 mL) was taken in a microwave tube. The sealed tube was heated at 110° C. for 2 h under microwave conditions. Then water (130 mL) was added to the mixture and extracted with ethyl acetate (130 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent of 0-80% ethyl acetate / petroleum ether gradient @ 35 mL / min). Compound 4-[2-amino-9-[(4-nitrophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (200 mg, 504.92 μmol, 77% yield, 94% purity) was obtained as a yellow solid. MS: m / z=373.1 (M+1, ESI+).

[0506] Step 2: Preparation of 4-[2-amino-9-[(4-aminophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile

[0507] Dissolve 4-[2-amino-9-[(4-nitrophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (200 mg, 537.14 μmol, 1 equiv.) and NH in ethanol (8 mL) and water (2 mL). 4 To a solution of Cl (230 mg, 4.30 mmol, 8 equiv.) was added iron powder (150 mg, 2.69 mmol, 5 equiv.). The mixture was then stirred at 80° C. for 1 h. The reaction mixture was filtered, the filtrate was concentrated in vacuum, and then water (50 mL) was added to the residue and extracted with ethyl acetate (50 mL×3). The combined organic phase was concentrated in vacuum to give the residue. The residue was purified by preparative HPLC (column: Waters Vinridis Silica 2-EP OBD 50*150 mm*5 μm; mobile phase: [Heptane-EtOH (0.1% NH 3 H 2 O)]; B%: 5%-45%, 10 min) to give compound 118 or 4-[2-amino-9-[(4-aminophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (38.42 mg, 107.37 μmol, 20% yield, 92.28% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.05(s, 1H), 8.98(d, J=5.3Hz, 1H), 8.89(dd, J=1.4, 5.2Hz, 1H), 8.33(s, 1H), 7. 05(brd, J=8.3Hz, 2H), 6.82(s, 2H), 6.52(d, J=8.4Hz, 2H), 5.14(s, 2H), 5.11(s, 2H). HRMS-TOF:343.1413.

[0508] Example 1.35: Preparation of 4-[2-amino-9-[(4-amino-2-fluoro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (Compound 122) TIFF0007681616000109.tif39158Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 110°C, 2 hours, MW. (b) Fe, NH4 Cl, THF / H 2 O, 80 °C, 1 hr.

[0509] Step 1: Preparation of 4-[2-amino-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile

[0510] Intermediate compound S16 or 6-chloro-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-2-amine (300 mg, 929.71 μmol, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (428 mg, 1.86 mmol, 2 equiv.), K 2 CO 3 (257 mg, 1.86 mmol, 2 equiv.) and Pd(dppf)Cl 2 A mixture of (68 mg, 92.97 μmol, 0.1 equiv) in dioxane (8 mL) and water (2 mL) was placed in a microwave tube. The sealed tube was heated at 110° C. for 2 h under microwave conditions. The mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient @ 60 mL / min). Compound 4-[2-amino-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (200 mg, 478.83 μmol, 52% yield, 93.45% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.04(s, 1H), 8.99(d, J=4.6Hz, 1H), 8.88(dd, J=1.5, 5.1Hz, 1H), 8.41(s, 1H), 8.18(dd, J= 2.1, 9.9Hz, 1H), 8.04(dd, J=1.9, 8.6Hz, 1H), 7.35(t, J=8.0Hz, 1H), 6.86(s, 2H), 5.56(s, 2H). MS: m / z=391.1 (M+1, ESI+).

[0511] Step 2: Preparation of 4-[2-amino-9-[(4-amino-2-fluoro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile

[0512] A solution of 4-[2-amino-9-[(2-fluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (200 mg, 512.39 μmol, 1 equiv.) in ethanol (9 mL) and water (3 mL) was diluted with iron powder (143 mg, 2.56 mmol, 5 equiv.) and NH 4 Cl (219 mg, 4.10 mmol, 8 equiv.) was added. Then the mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. Water (80 mL) was added to the residue, and it was extracted with ethyl acetate (80 mL×3). The combined organic phase was washed with brine (100 mL×2) and anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (column: Phenomenex Gemini NX-C18 (75*30mm*3μm); mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B%: 18%-48%, 8 min). Compound 122 or 4-[2-amino-9-[(4-amino-2-fluoro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (20.14 mg, 54.73 μmol, 11% yield, 98.80% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.04(s, 1H), 8.97(d, J=5.1Hz, 1H), 8.87(dd, J=1.5, 5.1Hz, 1H), 8.22(s, 1H), 6.99(t, J =8.5Hz, 1H), 6.81(s, 2H), 6.34(s, 1H), 6.32(brd, J=1.2Hz, 1H), 5.48(s, 2H), 5.18(s, 2H). HRMS-TOF:361.1317.

[0513] Example 1.36: Preparation of 4-[2-amino-9-[(4-amino-2,6-difluoro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (Compound 126) TIFF0007681616000110.tif39158Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 110℃, 2 hours. (b) Fe, NH 4 Cl, THF / H 2 O, 80 °C, 0.5 hr.

[0514] Step 1: Preparation of 4-[2-amino-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile

[0515] To a solution of intermediate compound S13 or 6-chloro-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-2-amine (160 mg, 469.66 μmol, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (540 mg, 2.35 mmol, 5 equiv.) in dioxane (14 mL) and water (1.4 mL), 2 CO 3 (130 mg, 939.32 μmol, 2 equiv.) and Pd(dppf)Cl 2 (34 mg, 46.97 μmol, 0.1 equiv.) was added. The mixture was stirred at 110° C. for 2 hours. Water (30 mL) was added to the mixture, which was then extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® silica flash column, eluent of 0-42% ethyl acetate / petroleum ether gradient @ 40 mL / min). Compound 4-[2-amino-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (75 mg, 174.50 μmol, 37% yield, 95% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.02-9.00(m, 1H), 8.97(dd, J=0.6, 5.1Hz, 1H), 8.85(dd, J=1.6, 5.1Hz, 1H), 8.38(s, 1H), 8.10(d, J=7.5Hz, 2H), 6.79(s, 2H), 5.53(s, 2H). MS:m / z=409.1(M+1, ESI+)

[0516] Step 2: Preparation of 4-[2-amino-9-[(4-amino-2,6-difluoro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile

[0517] A solution of 4-[2-amino-9-[(2,6-difluoro-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (92 mg, 225.31 μmol, 1 equiv.) in ethanol (8 mL) and water (2 mL) was treated with iron powder (63 mg, 1.13 mmol, 5 equiv.) and NH 4 Cl (96 mg, 1.80 mmol, 8 equiv.) was added. The mixture was stirred at 80° C. for 0.5 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. Water (40 mL) was added to the residue, and it was extracted with ethyl acetate (30 mL×3). The combined organic layer was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250*25*10 μm; mobile phase: [heptane-EtOH (0.1% NH 3 H 2O)]; B%: 25%-65%, 15 min). Compound 126 or 4-[2-amino-9-[(4-amino-2,6-difluoro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (38 mg, 99.43 μmol, 44% yield, 97.67% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.03(dd, J=0.8, 1.6Hz, 1H), 8.97(dd, J=0.9, 5.1Hz, 1H), 8.86(dd, J=1.6, 5.1H z, 1H), 8.13(s, 1H), 6.79(s, 2H), 6.21(d, J=10.5Hz, 2H), 5.88(s, 2H), 5.18(s, 2H). HRMS-TOF:379.1231.

[0518] Example 1.37: Preparation of 4-[2-amino-9-[(2,6-difluorophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (Compound 134) TIFF0007681616000111.tif37150Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 110°C, 15 hr.

[0519] Intermediate compound S22 or 6-chloro-9-[(2,6-difluorophenyl)methyl]purin-2-amine (100 mg, 338.21 μmol, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (117 mg, 507.31 μmol, 1.5 equiv.), K 2 CO 3 (94 mg, 676.42 μmol, 2 equiv.) and Pd(dppf)Cl 2A mixture of (25 mg, 33.82 μmol, 0.1 equiv) was degassed and heated to 110° C. under nitrogen for 15 h. Water (20 mL) was added to the mixture and extracted with ethyl acetate (30 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (4 g SepaFlash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 30 mL / min) to give impure product. The impure product was purified by preparative HPLC (column: XtimateC18 150*40 mm*10 μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 30%-60%, 10 min). Compound 134 or 4-[2-amino-9-[(2,6-difluorophenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (18.9 mg, 50.98 μmol, 15% yield, 98.03% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.03(s, 1H), 8.98(dd, J=0.6, 5.1Hz, 1H), 8.86(dd, J=1.6, 5.1Hz, 1H), 8.2 9(s, 1H), 7.54-7.43(m, 1H), 7.17(t, J=8.1Hz, 2H), 6.80(s, 2H), 5.44(s, 2H). HRMS-TOF:364.1120.

[0520] Example 1.38: Preparation of 4-[2-amino-9-[(4-amino-3-methyl-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (Compound 130) TIFF0007681616000112.tif40155Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 110°C, 2 hours, MW. (b) Fe, NH 4 Cl, THF / H 2 O, 80 °C, 1 hr.

[0521] Step 1: Preparation of 4-[2-amino-9-[(3-methyl-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile

[0522] Intermediate compound S19 or 6-chloro-9-[(3-methyl-4-nitro-phenyl)methyl]purin-2-amine (100 mg, 313.76 μmol, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (144 mg, 627.51 μmol, 2 equiv.), Pd(dppf)Cl in dioxane (3 mL) and water (0.3 mL). 2 (23 mg, 31.38 μmol, 0.1 equiv.) and K 2 CO 3 The mixture of (87 mg, 627.51 μmol, 2 equiv.) was degassed and purged with nitrogen three times, then stirred under microwave irradiation at 110° C. for 2 h. The mixture was added with water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® silica flash column, eluent of 0-80% ethyl acetate / petroleum ether gradient @ 35 mL / min). The compound 4-[2-amino-9-[(3-methyl-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (104 mg, 242.26 μmol, 77% yield, 90% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.05(s, 1H), 8.99(d, J=5.1Hz, 1H), 8.89(dd, J=1.6, 5.1Hz, 1H), 8.44(s, 1H), 7.97(d, J= 8.4Hz, 1H), 7.41(s, 1H), 7.28(dd, J=1.4, 8.5Hz, 1H), 6.85(s, 2H), 5.45(s, 2H), 2.51(s, 3H). MS:m / z=387.1(M+1, ESI+)

[0523] Step 2: Preparation of 4-[2-amino-9-[(4-amino-3-methyl-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile

[0524] A solution of 4-[2-amino-9-[(3-methyl-4-nitro-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (200 mg, 517.64 μmol, 1 equiv.) in ethanol (6 mL) and water (2 mL) was treated with iron powder (145 mg, 2.59 mmol, 5 equiv.) and NH 4 Cl (221 mg, 4.14 mmol, 8 equiv) was added. The mixture was stirred at 80° C. for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. Water (40 mL) was added to the residue and extracted with ethyl acetate (30 mL×3). The combined organic layers were concentrated under reduced pressure to give a residue. The crude product was triturated with THF at 70° C. for 30 min. Compound 130 or 4-[2-amino-9-[(4-amino-3-methyl-phenyl)methyl]purin-6-yl]pyridine-2-carbonitrile (62 mg, 167.01 μmol, 32% yield, 96.73% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.04(s, 1H), 8.97(d, J=5.1Hz, 1H), 8.87(dd, J=1.5, 5.1Hz, 1H), 8.32(s, 1H), 6.99- 6.88(m, 2H), 6.85(s, 2H), 6.54(d, J=8.0Hz, 1H), 5.12(s, 2H), 4.87(s, 2H), 2.00(s, 3H). HRMS-TOF:357.1568.

[0525] Example 1.39: Preparation of 4-[2-amino-9-[[4-amino-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]pyridine-2-carbonitrile (Compound 136) TIFF0007681616000113.tif42155Reagents and conditions: (a) APhos-Pd-G3, K 3 PO 4 , DMAc, 60℃, 16 hours (b) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 1 hr.

[0526] Step 1: Preparation of 4-[2-amino-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]pyridine-2-carbonitrile

[0527] Intermediate compound S23 or 6-chloro-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-2-amine (50 mg, 134.16 μmol, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (34 mg, 147.58 μmol, 1.1 equiv.), K 3 PO 4 A mixture of (1.5 M in water, 90 μL, 1 equiv.) and APhos-Pd-G3 (8.52 mg, 13.42 μmol, 0.1 equiv.) was degassed and purged with nitrogen three times, after which the mixture was stirred at 60 °C under nitrogen atmosphere for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was analyzed by preparative TLC (SiO 2 , ethyl acetate / petroleum ether=1:1). The compound 4-[2-amino-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purine-6-yl]pyridine-2-carbonitrile (40 mg, 90.84 μmol, 68% yield) was obtained as a yellow oil. MS: m / z=441.1 (M+1, ESI+).

[0528] Step 2: Preparation of 4-[2-amino-9-[[4-amino-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]pyridine-2-carbonitrile A solution of 4-[2-amino-9-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]purin-6-yl]pyridine-2-carbonitrile (40 mg, 90.84 μmol, 1 equiv.) in ethanol (15 mL) and water (5 mL) was treated with iron powder (25 mg, 454.2 μmol, 5 equiv.) and NH 4Cl (39 mg, 726.72 μmol, 8 equiv.) was added. The mixture was stirred at 60° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-SiOH 250*50*10 μm; mobile phase: [hexane-EtOH (0.1% ammonium hydroxide)]; B%: 10%-50%, 15 min). Compound 136 or 4-[2-amino-9-[[4-amino-3-(trifluoromethyl)phenyl]methyl]purine-6-yl]pyridine-2-carbonitrile (8.9 mg, 20.71 μmol, 23% yield, 95.51% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.03(s, 1H), 8.97(d, J=5.1Hz, 1H), 8.87(dd, J=1.3, 5.1Hz, 1H), 8.38(s, 1H), 7.41(s, 1 H), 7.29(brd, J=8.4Hz, 1H), 6.84(s, 2H), 6.79(d, J=8.5Hz, 1H), 5.66(s, 2H), 5.20(s, 2H). HRMS-TOF:411.1305.

[0529] Example 1.40: Preparation of 3-(6-amino-1-(4-amino-3-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile (Compound 204)

[0530] 1.40.1. Preparation of 3-(6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile (intermediate compound S107) TIFF0007681616000114.tif33122Reagents and conditions: (a) Pd(PPh 3 ) 4 , Na 2 CO 3 , dioxane / H 2 O, 100°C, 16 hr.

[0531] 4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (500 mg, 1 equiv.), (3-cyanophenyl)boronic acid (519 mg, 1.2 equiv.), Pd(PPh 3 ) 4 (340 mg, 0.1 eq.) and Na 2 CO 3 A mixture of (625 mg, 2 equiv.) was degassed and purged with nitrogen three times, then the mixture was stirred at 100° C. under nitrogen atmosphere for 16 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (30 mL). The organic phase was separated, washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product 3-(6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile (500 mg, crude) was obtained as a yellow solid and used in the next step without further purification. MS: m / z=237.1 (M+1, ESI+).

[0532] 1.40.2. Preparation of 3-(6-amino-1-(4-amino-3-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile (Compound 204). TIFF0007681616000115.tif36148Reagents and conditions: (a) K 2 CO 3 , DMF, 80℃, 16 hours; (b) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 1 hr.

[0533] Step 1: Preparation of 3-[6-amino-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile

[0534] To a solution of 4-(chloromethyl)-2-methyl-1-nitrobenzene (500 mg, 1.27 equiv.) and intermediate compound S107 or 3-(6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile (500 mg, 1 equiv.) in DMF (10 mL), 2 CO 3(585mg, 2eq) was added. The mixture was stirred at 80°C for 16h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%, 10min). Compound 3-[6-amino-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile (200mg, 24% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.56-8.42(m, 3H), 8.10-8.06(m, 1H), 8.00-7.92(m, 1H), 7.86-7.76(m, 1H), 7.40-7.30(m, 1H), 7.24-7.08(m, 3H), 5.65-5.43(m, 2H), 2.49(s, 3H). MS: m / z=386.0 (M+1, ESI+).

[0535] Step 2: Preparation of 3-(6-amino-1-(4-amino-3-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile (Compound 204)

[0536] A solution of 3-[6-amino-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile (150 mg, 1 equiv.) in ethanol (12 mL) and water (4 mL) was treated with iron powder (108 mg, 1.95 mmol, 5 equiv.) and NH 4 Cl (166 mg, 8 equiv.) was added. The mixture was stirred at 60° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 23%-53%, 10 min). Compound 204 or 3-[6-amino-1-[(4-amino-3-methyl-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile (54.26 mg, 38% yield, 98.27% purity) was obtained as a white solid.1 H NMR (400 MHz, DMSO-d 6 )δ=8.54-8.49(m, 1H), 8.49-8.45(m, 1H), 8.37-8.31(m, 1H), 8.09-8.01(m, 1H), 7.84-7.70(m, 1H), 7.16-6.99(m, 2H) , 6.91-6.86(m, 1H), 6.86-6.80(m, 1H), 6.58-6.45(m, 1H), 5.33-5.14(m, 2H)), 4.98-4.57(m, 2H), 2.02-1.96(m, 3H).

[0537] Example 1.41: Preparation of 3-(6-amino-1-(4-amino-3-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile (Compound 206)

[0538] 1.41.1. Preparation of 4-chloro-1-(3-methyl-4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (intermediate compound S108) TIFF0007681616000116.tif42120Reagents and conditions: (a) K 2 CO 3 , DMAc, 80°C, 16 hours.

[0539] A solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (0.8 g, 1 equiv.) and 4-(chloromethyl)-2-methyl-1-nitrobenzene (720 mg, 0.8) in DMAc (50 mL) was 2 CO 3 (1.30 g, 2 eq.) was added. The mixture was stirred at 80° C. for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product 4-chloro-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (800 mg, crude) was obtained as a yellow solid and used in the next step without further purification. MS: m / z=354.9 (M+1, ESI+).

[0540] 1.41.2. Preparation of 3-(6-amino-1-(4-amino-3-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile (Compound 206) TIFF0007681616000117.tif39153Reagents and conditions: (a) Pd(PPh 3 ) 4 , K 2 CO 3 , dioxane / H 2 O, 100℃, 16 hours; (b) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 1 hr.

[0541] Step 1: Preparation of 3-(6-amino-1-(3-methyl-4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile

[0542] (3-cyano-2-fluoro-phenyl)boronic acid (434 mg, 1.2 equiv.), intermediate compound S108 or 4-chloro-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (700 mg, 1 equiv.), Pd(PPh 3 ) 4 (253 mg, 219.63 μmol, 0.1 equiv.) and Na 2 CO 3 A mixture of (465 mg, 2 equiv.) was degassed and purged with nitrogen three times, then the mixture was stirred at 110° C. under nitrogen atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g Sepa Flash® silica flash column, eluent of 0-80% ethyl acetate / petroleum ether gradient @ 40 mL / min). The compound 3-[6-amino-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-fluoro-benzonitrile (800 mg, 90% yield) was obtained as a yellow solid. MS: m / z=386.0 (M+1, ESI+).

[0543] Step 2: Preparation of 3-(6-amino-1-(4-amino-3-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile (Compound 206)

[0544] A solution of 3-[6-amino-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-fluoro-benzonitrile (200 mg, 1 equiv.) in water (4 mL) and ethanol (12 mL) was treated with iron powder (138 mg, 5 equiv.) and NH 4 Cl (212 mg, 8 equiv.) was added. The mixture was stirred at 60° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 16%-46%, 11 min) to give a compound with 89% purity after the first purification. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 18%-48%, 10 min). Compound 206 or 3-[6-amino-1-[(4-amino-3-methyl-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-fluoro-benzonitrile (111.35 mg, 59% yield, 97.78% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.21-8.10(m, 2H), 8.00-7.94(m, 1H), 7.66-7.52(m, 1H), 7.16-7.07(m, 2H), 6.92-6 .80(m, 2H), 6.56-6.46(m, 1H), 5.34-5.15(m, 2H), 4.93-4.67(m, 2H), 2.06-1.88(m, 3H).

[0545] Example 1.42: Preparation of 3-(6-amino-1-(4-amino-3-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile (Compound 210)

[0546] 1.42.1. Preparation of 4-chloro-1-(4-nitro-3-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Intermediate Compound S109) TIFF0007681616000118.tif41132Reagents and conditions: (a) K 2 CO 3 , DMAc, 80°C, 16 hours.

[0547] A solution of 4-(chloromethyl)-1-nitro-2-(trifluoromethyl)benzene (3.39 g, 1.2 equiv.) and 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (2 g, 1 equiv.) in DMF (20 mL) was diluted with K 2 CO 3 (3.26 g, 2 equiv.) was added. The mixture was stirred at 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure to remove DMF to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g Sepa Flash® silica flash column, 0-100% ethyl acetate / petroleum ether gradient @ 45 mL / min). The compound 4-chloro-1-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidin-6-amine (2 g, 45% yield) was obtained as a yellow solid. MS: m / z=373.3 (M+1, ESI+).

[0548] 1.42.2. Preparation of 3-(6-amino-1-(4-amino-3-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile (Compound 210) TIFF0007681616000119.tif42160Reagents and conditions: (a) Pd(PPh 3 ) 4 , K 2 CO 3 , dioxane / H 2 O, 100℃, 15 hours; (b) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 2 hr.

[0549] Step 1: Preparation of 3-(6-amino-1-(4-nitro-3-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile

[0550] (3-Cyanophenyl)boronic acid (236 mg, 1.5 equiv.), intermediate compound S109 or 4-chloro-1-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidin-6-amine (400 mg, 1 equiv.), Pd(PPh 3 ) 4 (124 mg, 0.1 equivalent), K 2 CO 3 A mixture of (296 mg, 2 equiv.) was degassed and purged with nitrogen three times, then the mixture was stirred at 100° C. under nitrogen atmosphere for 15 h. The reaction mixture was concentrated under reduced pressure to remove dioxane and water to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 35 mL / min). Compound 3-[6-amino-1-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile (300 mg, 63% yield) was obtained as a yellow oil. MS: m / z=440.1 (M+1, ESI+).

[0551] Step 2: Preparation of 3-(6-amino-1-(4-amino-3-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile (Compound 210)

[0552] A solution of 3-[6-amino-1-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile (290 mg, 1 equiv.) in water (5 mL) and ethanol (15 mL) was treated with iron powder (190 mg, 5 equiv.) and NH 4Cl (292 mg, 8 equiv.) was added. The mixture was stirred at 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove ethanol to give a residue. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 43%-63%, 10 min). Compound 210 or 3-[6-amino-1-[[4-amino-3-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile (59.98 mg, 21% yield, purity 99.14%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.52(s, 1H), 8.47(d, J=8.1Hz, 1H), 8.38(s, 1H), 8.06(d, J=7.7Hz, 1H), 7.79(t, J=7.8Hz, 1H), 7. 30(d, J=1.5Hz, 1H), 7.23-7.17(m, 1H), 7.10(s, 2H), 6.78(d, J=8.4Hz, 1H), 5.59(s, 2H), 5.30(s, 2H).

[0553] Example 1.43: Preparation of 3-(6-amino-1-(4-amino-3-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile (Compound 211) TIFF0007681616000120.tif42161Reagents and conditions: (a) Pd(PPh 3 ) 4 , K 2 CO 3 , dioxane / H 2 O, 100℃, 15 hours; (b) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 2 hr.

[0554] Step 1: Preparation of 3-(6-amino-1-(4-nitro-3-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile

[0555] A mixture of (3-cyano-2-fluoro-phenyl)boronic acid (265 mg, 1.5 equiv.), intermediate compound S109 or 4-chloro-1-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidin-6-amine (400 mg, 1 equiv.), Pd(PPh 3 ) 4 (124 mg, 0.1 equivalent), K 2 CO 3 A mixture of (296 mg, 2 equiv.) was degassed and purged with nitrogen three times, then the mixture was stirred at 100° C. under nitrogen atmosphere for 15 h. The reaction mixture was concentrated under reduced pressure to remove dioxane and water to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 35 mL / min). The compound 3-[6-amino-1-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-fluoro-benzonitrile (350 mg, 71% yield) was obtained as a yellow oil. MS: m / z=458.3 (M+1, ESI+).

[0556] Step 2: Preparation of 3-(6-amino-1-(4-amino-3-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile (Compound 211)

[0557] A solution of 3-[6-amino-1-[[4-nitro-3-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-fluoro-benzonitrile (300 mg, 1 equiv.) in ethanol (15 mL) and water (5 mL) was treated with iron powder (183 mg, 5 equiv.) and NH 4Cl (280 mg, 8 equivalents) was added. The mixture was stirred at 60 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol and a residue was obtained. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 43%-63%, 10 minutes). Compound 211 or 3-[6-amino-1-[[4-amino-3-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-fluoro-benzonitrile (41.58 mg, 15% yield, 98.23% purity) was obtained as a yellowish-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.20 - 8.11 (m, 2H), 8.00 (d, J = 3.5 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H), 7.23 - 7.17 (m, 1H), 7.15 (s, 2H), 6.78 (d, J = 8.4 Hz, 1H), 5.60 (s, 2H), 5.29 (s, 2H).

[0558] Example 1.44: Preparation of 3-(6-amino-1-(2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile (Compound 213) TIFF0007681616000121.tif40164Reagents and conditions: (a) K 2 CO 3 , DMAc, 80 °C, 16 hours; (b) Pd(PPh 3 ) 4 , K 2 CO 3 , dioxane / H 2 O, 80 °C, 16 hours.

[0559] Step 1: Preparation of 4-chloro-1-[(2,6-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (Intermediate Compound S110)

[0560] A solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (8 g, 47.18 mmol, 1 eq) and 2-(bromomethyl)-1,3-difluorobenzene (11.72 g, 56.61 mmol, 1.2 eq) in DMAc (100 mL) was added with K 2 CO 3 (13.04 g, 94.36 mmol, 2 eq). The mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO (registered trademark); 80 g Sepa Flash (registered trademark) silica flash column, eluent with 0 - 100% ethyl acetate / petroleum ether gradient @ 60 mL / min). Intermediate compound S110 or 4-chloro-1-[(2,6-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (4 g, 13.53 mmol, 29% yield) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.35 - 7.77 (m, 1H), 7.53 - 7.41 (m, 1H), 7.40 - 7.31 (m, 2H), 7.19 - 6.98 (m, 2H), 5.60 - 5.20 (m, 2H).

[0561] Step 2: Preparation of 3-(6-amino-1-(2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile (Compound 213)

[0562] (3-Cyano-2-fluoro-phenyl)boronic acid (251 mg, 1.5 eq), intermediate compound S110 or 4-chloro-1-[(2,6-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (300 mg, 1 eq), Pd(PPh 3 ) 4 (117 mg, 0.1 eq), K 2 CO 3(280 mg, 2 eq.) mixture was degassed and purged with nitrogen three times, then the mixture was stirred at 80° C. under nitrogen atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 45%-65%, 10 min). Compound 213 or 3-[6-amino-1-[(2,6-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-fluoro-benzonitrile (118.51 mg, 30% yield, 98.93% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.22-8.09(m, 2H), 7.95(d, J=3.5Hz, 1H), 7.60(t, J=7.8Hz, 1H), 7.52-7.39(m, 1H), 7.19(s, 2H), 7.13(t, J=8.0Hz, 2H), 5.45(s, 2H).

[0563] Example 1.45: Preparation of 3-(6-amino-1-(4-amino-2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile (Compound 209) TIFF0007681616000122.tif33160Reagents and conditions: (a) K 2 CO 3 , DMAc, 60°C, 16 hours; (b) Pd(PPh 3 ) 4 , K 2 CO 3 , dioxane / H 2 O, 80℃, 16 hours; (c) Fe, NH 4 Cl, EtOH / H 2 O, 80 °C, 3 hr.

[0564] Step 1: Preparation of 4-chloro-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (intermediate compound S111)

[0565] A solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (5.1 g, 1 equiv.) and 1-(bromomethyl)-2-fluoro-4-nitrobenzene (7 g, 1 equiv.) in DMF (20 mL) was diluted with K 2 CO 3 (8.3 g, 2 equiv.) was added. The mixture was stirred at 60° C. for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g Sepa Flash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 40 mL / min). Intermediate compound S111 or 4-chloro-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (5 g, 52% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.15-8.11(m, 1H), 8.08-8.06(m, 1H), 8.05-8.01(m, 1H), 7.47-7.38(m, 2H), 7.33(t, J=8.0Hz, 1H), 5.57(s, 2H). MS: m / z=323.3 (M+1, ESI+).

[0566] Step 2: Preparation of 3-(6-amino-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile

[0567] (3-cyanophenyl)boronic acid (341 mg, 1.5 equiv.), intermediate compound S111 or 4-chloro-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (500 mg, 1 equiv.), Pd(PPh 3 ) 4 (179 mg, 0.1 equivalent), K 2 CO 3(428 mg, 2 eq.) mixture was degassed and purged with nitrogen three times, then the mixture was stirred at 100° C. under nitrogen atmosphere for 16 h. The reaction mixture was concentrated under reduced pressure to remove dioxane to give a residue. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 45%-65%, 10 min). Compound 3-[6-amino-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile (200 mg, 33% yield, 99% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.55-8.51(m, 1H), 8.49-8.46(m, 1H), 8.31-8.26(m, 1H), 8.18-8.01(m, 4H), 7.38-7.28(m, 1H), 7.22-7.05(m, 2H), 5.62(s, 2H). MS: m / z=389.9 (M+1, ESI+).

[0568] Step 3: Preparation of 3-(6-amino-1-(4-amino-2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile (Compound 209)

[0569] A solution of 3-[6-amino-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile (200 mg, 513.69 μmol, 1 equiv.) in ethanol (15 mL) and water (5 mL) was treated with iron powder (143 mg, 5 equiv.) and NH 4Cl (219 mg, 8 equiv.) was added. The mixture was stirred at 80° C. for 3 h. The reaction mixture was concentrated under reduced pressure to remove ethanol and water to give a residue. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-50%, 10 min). Compound 209 or 3-[6-amino-1-[(4-amino-2-fluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile (36.42 mg, 19% yield, 97.66% purity) was obtained as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.51(s, 1H), 8.49-8.44(m, 1H), 8.35(s, 1H), 8.08-8.01(m, 1H), 7.79(t, J=7.8Hz, 1H), 7.07(s, 2H), 6.88(t, J=8.5Hz, 1H), 6.36-6.22(m, 2H), 5.40(s, 2H), 5.28(s, 2H).

[0570] Example 1.46: Preparation of 3-(6-amino-1-(4-amino-2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile (Compound 207) TIFF0007681616000123.tif59161 Reagents and conditions: (a1) NBS, AIBN, CCl 4 , 90℃, 15 hours; (a2)K 2 CO 3 , DMAc, 80°C, 3 hours; (b) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 110℃, 2 hours, MW; (c) Fe, NH 4 Cl, EtOH / H 2 O, 80 °C, 1 hr.

[0571] Step 1: Preparation of 4-chloro-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (intermediate compound S112)

[0572] To a solution of 1,3-difluoro-2-methyl-5-nitrobenzene (2 g, 11.55 mmol, 1 equiv.) in tetrachloromethane (50 mL) was added NBS (3.08 g, 17.33 mmol, 1.5 equiv.) and AIBN (190 mg, 1.16 mmol, 0.1 equiv.). The mixture was then stirred at 90° C. for 15 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was treated with DMAc (50 mL), 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (1.96 g, 11.55 mmol, 1 equiv.) and K 2 CO 3 (3.19 g, 23.11 mmol, 2 equiv.) was added. The mixture was then stirred at 80° C. for 3 h. Water (130 mL) and ethyl acetate (130 mL) were added to the mixture and the layers were separated. The aqueous was extracted with ethyl acetate (130 mL×2). The combined organic phase was washed with brine (150 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (40 g Sepa Flash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient @ 60 mL / min). Intermediate compound S112 or 4-chloro-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (1.5 g, 4.26 mmol, 37% yield, 96.7% purity) was obtained as a yellow solid.

[0573] Step 2: Preparation of 3-[6-amino-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile

[0574] Intermediate compound S112 or 4-chloro-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (500 mg, 1.47 mmol, 1 equiv.), (3-cyanophenyl)boronic acid (323 mg, 2.20 mmol, 1.5 equiv.), K 2 CO 3(405 mg, 2.94 mmol, 2 equiv) and Pd(dppf)Cl 2 (107 mg, 146.77 μmol, 0.1 equiv) were placed in a microwave tube in dioxane (6 mL) and water (2 mL). The sealed tube was heated at 110 °C for 2 h under microwave. Then, water (80 mL) and ethyl acetate (80 mL) were added to the mixture, and the layers were separated. The aqueous phase was extracted with ethyl acetate (80 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent 0 - 100% ethyl acetate / petroleum ether gradient @ 50 mL / min). Compound 3-[6-amino-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile (200 mg, 441.90 μmol, 30% yield, purity 90%) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.49 (d, J = 1.2 Hz, 1H), 8.47 - 8.41 (m, 1H), 8.35 (s, 1H), 8.16 - 8.07 (m, 2H), 8.06 (td, J = 1.3, 7.8 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.16 (s, 2H), 5.55 (s, 2H). MS: m / z = 408.0 (M+1, ESI+).

[0575] Step 3: Preparation of 3-[6-amino-1-[(4-amino-2,6-difluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile (Compound 207)

[0576] To a solution of 3-[6-amino-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile (200 mg, 491.00 μmol, 1 equiv) in ethanol (8 mL) and water (2 mL) were added iron powder (137 mg, 2.45 mmol, 5 equiv) and NH 4Cl (210 mg, 3.93 mmol, 8 equiv.) was added. The mixture was then stirred at 80° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuum. Then, water (30 mL) was added to the mixture, and then it was extracted with ethyl acetate (30 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250*70*10 μm; mobile phase: [hexane-EtOH (0.1% ammonium hydroxide)]; B%: 30%-70%, 15 min). Compound 207 or 3-[6-amino-1-[(4-amino-2,6-difluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]benzonitrile (62.95 mg, 163.33 μmol, 33% yield, 97.91% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.49(t, J=1.4Hz, 1H), 8.45(td, J=1.4, 7.9Hz, 1H), 8.29(s, 1H), 8.05(td, J=1.3, 7.7 Hz, 1H), 7.79(t, J=7.8Hz, 1H), 7.07(s, 2H), 6.30-6.06(m, 2H), 5.80(s, 2H), 5.25(s, 2H).

[0577] Example 1.47: Preparation of 3-(6-amino-1-(4-amino-2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile (Compound 203) TIFF0007681616000124.tif39160Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 110℃, 16 hours; (b) Fe, NH 4 Cl, EtOH / H 2 O, 80 °C, 3 hr.

[0578] Step 1: Preparation of 3-(6-amino-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile

[0579] A mixture of (3-cyano-2-fluoro-phenyl)boronic acid (383 mg, 2.33 mmol, 1.5 eq), intermediate compound S111 or 4-chloro-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (500 mg, 1 eq), Pd(PPh 3 ) 4 (179 mg, 0.1 eq), and K 2 CO 3 (428 mg, 2 eq) in dioxane (10 mL) and water (2 mL) was degassed and purged with nitrogen three times. Then the mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove dioxane, and a residue was obtained. The residue was purified by flash silica gel chromatography (ISCO (registered trademark); 12 g Sepa Flash (registered trademark) silica flash column, eluent with a 0 - 80% ethyl acetate / petroleum ether gradient @ 30 mL / min). Compound 3-[6-amino-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-fluoro-benzonitrile (300 mg, 48% yield) was obtained as a yellow solid. MS: m / z = 407.9 (M+1, ESI+).

[0580] Step 2: Preparation of 3-(6-amino-1-(4-amino-2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile (Compound 203)

[0581] To a solution of 3-[6-amino-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-fluoro-benzonitrile (209 mg, 1 eq) in ethanol (15 mL) and water (5 mL), iron powder (143 mg, 5 eq) and NH 4Cl (219 mg, 8 equiv.) was added. The mixture was stirred at 80° C. for 3 h. The reaction mixture was concentrated under reduced pressure to remove ethanol to give a residue. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 33%-53%, 10 min). After obtaining the desired compound with 80% purity, the residue was purified by a second preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 22%-52%, 7 min). Compound 203 or 3-[6-amino-1-[(4-amino-2-fluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-fluoro-benzonitrile (62.37 mg, 31% yield, 97.40% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.21-8.10(m, 2H), 7.98(d, J=3.7Hz, 1H), 7.61(t, J=7.8Hz, 1H), 7.14(s, 2H) ), 6.97-6.84(m, 1H), 6.32(s, 1H), 6.31-6.28(m, 1H), 5.42(s, 2H), 5.27(s, 2H).

[0582] Example 1.48: Preparation of 3-(6-amino-1-(4-amino-2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile (Compound 208) TIFF0007681616000125.tif41160Reagents and conditions: (a) Pd(dppf)Cl 4 , K 2 CO 3 , dioxane / H 2 O, 110℃, 15 hours. (b) Fe, NH 4 Cl, EtOH / H 2 O, 80 °C, 1 hr.

[0583] Step 1: Preparation of 3-[6-Amino-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-fluoro-benzonitrile

[0584] To a solution of intermediate compound S112 or 4-chloro-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (400 mg, 1.17 mmol, 1 equiv) in water (2 mL) and dioxane (8 mL) was added (3-cyano-2-fluoro-phenyl)boronic acid (300 mg, 1.82 mmol, 1.55 equiv), Pd(dppf)Cl 2 (86 mg, 117.41 μmol, 0.1 equiv) and K 2 CO 3 (325 mg, 2.35 mmol, 2 equiv). Next, the mixture was stirred at 110 °C for 15 h. Then, the mixture was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent: 20 - 100% ethyl acetate / petroleum ether gradient @ 50 mL / min). Compound 3-[6-Amino-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-fluoro-benzonitrile (140 mg, 322.25 μmol, 27% yield, 97.9% purity) was obtained as a yellow solid. 1 1H NMR (400 MHz, DMSO-d 6 ) δ = 8.20 - 8.12 (m, 2H), 8.12 - 8.05 (m, 2H), 7.99 (d, J = 3.6 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.22 (s, 2H), 5.54 (s, 2H). MS: m / z = 426.1 (M + 1, ESI+).

[0585] Step 2: Preparation of 3-(6-Amino-1-(4-amino-2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-fluorobenzonitrile (Compound 208)

[0586] A solution of 3-[6-amino-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-fluoro-benzonitrile (140 mg, 329.16 μmol, 1 equiv.) in ethanol (8 mL) and water (2 mL) was treated with iron powder (92 mg, 1.65 mmol, 5 equiv.) and NH 4 Cl (140 mg, 2.63 mmol, 8 equiv.) was added. The mixture was then stirred at 80° C. for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum. Water (50 mL) was added to the mixture, which was then extracted with ethyl acetate (30 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250*70*10 μm; mobile phase: [hexane-EtOH (0.1% NH 3 H 2 O)]; B%: 35%-75%, 15 min). Compound 208 or 3-[6-amino-1-[(4-amino-2,6-difluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-fluoro-benzonitrile (44.01 mg, 109.41 μmol, 33% yield, 98.28% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.14(dd, J=6.7, 7.7Hz, 2H), 7.93(d, J=3.6Hz, 1H), 7.60(t, J=7.8Hz, 1H), 7.13(s, 2H), 6.27-6.07(m, 2H), 5.80(s, 2H), 5.24(s, 2H).

[0587] Example 1.49: Preparation of 4-[6-amino-1-[(2,6-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (Compound 234) TIFF0007681616000126.tif36161Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 80°C, 16 hr.

[0588] Intermediate compound S110 or 4-chloro-1-[(2,6-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (300 mg, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (279 mg, 1.2 equiv.), K 2 CO 3 (279 mg, 2 equivalents), Pd(dppf)Cl 2 A mixture of (74 mg, 0.1 equiv.) was degassed and purged with nitrogen three times, then the mixture was stirred at 80° C. under nitrogen atmosphere for 16 h. The reaction mixture was concentrated under reduced pressure to remove dioxane to give a residue. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 38%-58%, 10 min). Compound 234 or 4-[6-amino-1-[(2,6-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (124.39 mg, 34% yield, 99.96% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.96(d, J=5.1Hz, 1H), 8.58(d, J=0.6Hz, 1H), 8.41-8.39(m, 1H), 8.39-8 .36(m, 1H), 7.51-7.41(m, 1H), 7.25(s, 2H), 7.17-7.08(m, 2H), 5.47(s, 2H).

[0589] Example 1.50: Preparation of 4-(6-amino-1-(4-amino-2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)picolinonitrile (Compound 226) TIFF0007681616000127.tif38160Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 80℃, 16 hours; (b) Fe, NH4 Cl, EtOH / H 2 O, 80 °C, 2 hr.

[0590] Step 1: Preparation of 4-[6-amino-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile

[0591] To a solution of intermediate compound S112 or 4-chloro-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (400 mg, 1.17 mmol, 1 equiv.) in dioxane (10 mL) and water (2 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (540 mg, 2.35 mmol, 2 equiv.), Pd(dppf)Cl 2 (86 mg, 117.41 μmol, 0.1 equiv.) and K 2 CO 3 (325 mg, 2.35 mmol, 2 equiv)) was added. The mixture was then stirred at 100° C. for 15 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (20 g Sepa Flash® silica flash column, eluent of 0-60% ethyl acetate / petroleum ether gradient @ 50 mL / min). Compound 4-[6-amino-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (300 mg, 625.68 μmol, 53% yield, 85% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.96(d, J=5.1Hz, 1H), 8.58(s, 1H), 8.43(s, 1H), 8.38(dd, J=1.7, 5.1Hz, 1H), 8.09(brd, J=7.1Hz, 2H), 7.28(brs, 2H), 5.56(s, 2H). MS: m / z=409.1 (M+1, ESI+).

[0592] Step 2: Preparation of 4-[6-amino-1-[(4-amino-2,6-difluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (compound 226) A mixture of 4-[6-amino-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (300 mg, 734.72 μmol, 1 equiv.) in water (3 mL) and ethanol (9 mL) was treated with iron powder (205 mg, 3.67 mmol, 5 equiv.) and NH 4 Cl (314 mg, 5.88 mmol, 8 equiv.) was added. The mixture was then stirred at 80° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuum. Water (30 mL) was added to the mixture, and it was extracted with ethyl acetate (30 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250*70*10 μm; mobile phase: [hexane-ethanol (0.1% NH3·H2O)]; B%: 30%-70%, 15 min). Compound 226 or 4-[6-amino-1-[(4-amino-2,6-difluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (70.80 mg, 178.73 μmol, 24% yield, 95.51% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.96(dd, J=0.8, 5.1Hz, 1H), 8.58(dd, J=0.8, 1.6Hz, 1H), 8.46-8.24(m, 2H), 7.19(s, 2H), 6.29-6.08(m, 2H), 5.80(s, 2H), 5.26(s, 2H).

[0593] Example 1.51: Preparation of 4-(6-amino-1-(4-amino-3-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)picolinonitrile (Compound 230) TIFF0007681616000128.tif36160Reagents and conditions: (a) Pd(dppf)Cl 2 , K2 CO 3 , dioxane / H 2 O, 110℃, 16 hours; (b) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 3 hr.

[0594] Step 1: Preparation of 4-(6-amino-1-(3-methyl-4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)picolinonitrile

[0595] Intermediate compound S108 or 4-chloro-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (500 mg, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (541 mg, 1.5 equiv.), K in dioxane (10 mL) and water (2 mL). 2 CO 3 (433 mg, 2 eq.), Pd(dppf)Cl 2 A mixture of (114 mg, 0.1 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 110° C. under atmospheric pressure for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 30 mL / min). Compound 4-[6-amino-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (500 mg, 82.49% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6)δ=8.99(dd, J=0.7, 5.1Hz, 1H), 8.56(s, 1H), 8.43(dd, J=1.7, 5.1Hz, 1H), 7.98-7.91 (m, 1H), 7.39-7.31(m, 1H), 7.30-7.07(m, 3H), 5.68-5.49(m, 2H), 2.49-2.47(m, 3H). MS: m / z=387.1 (M+1, ESI+).

[0596] Step 2: Preparation of 4-(6-amino-1-(4-amino-3-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)picolinonitrile (Compound 230)

[0597] A solution of 4-[6-amino-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (400 mg, 1 equiv.) in ethanol (15 mL) and water (5 mL) was diluted with iron powder (289 mg, 5 equiv.) and NH 4 Cl (443 mg, 8 equiv.) was added. The mixture was stirred at 60° C. for 3 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 15%-45%, 11.5 min). Compound 230 or 4-[6-amino-1-[(4-amino-3-methyl-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (41.4 mg, 7% yield, 95.38% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.97(dd, J=0.6, 5.1Hz, 1H), 8.60(d, J=0.9Hz, 1H), 8.44(s, 1H), 8.40(dd, J=1.7, 5.1Hz, 1H) , 7.17(s, 2H), 6.93-6.79(m, 2H), 6.52(d, J=8.1Hz, 1H), 5.24(s, 2H), 4.81(s, 2H), 1.99(s, 3H).

[0598] Example 1.52: Preparation of 6-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)picolinonitrile (Compound 215) TIFF0007681616000129.tif54161Reagents and conditions: (a) NaOMe, MeOH, 25°C, 0.5 hours; (b) Pd(OAc) 2 , K 2 CO 3 , Cy 3 P, dioxane, 120 °C, 16 h; (c) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 3 hr.

[0599] Step 1: Preparation of (6-cyano-2-pyridyl)sulfinyloxysodium (intermediate compound S113)

[0600] To a solution of sodium methoxide (212 mg, 1 eq.) in methanol (10 mL) was added methyl 3-[(6-cyano-2-pyridyl)sulfonyl]propanoate (1 g, 1 eq.). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove methanol to give a residue. The crude product of intermediate compound S113 or (6-cyano-2-pyridyl)sulfinyloxy sodium (1 g, crude) was obtained as a yellow solid and used in the next step without further purification. MS: m / z=167.0 (M+1, ESI+).

[0601] Step 2: Preparation of 6-[6-amino-1-[(4-nitrophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile

[0602] Intermediate compound S113 or 4-chloro-1-[(4-nitrophenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (500 mg, 1 equiv.), (6-cyano-2-pyridyl)sulfinyloxysodium (374 mg, 1.2 equiv.), palladium acetate (36 mg, 0.1 equiv.), Cy 3 P (92 mg, 0.2 equivalents), and K2 CO 3 A mixture of (453 mg, 2 equiv.) was degassed and purged with nitrogen three times, then the mixture was stirred at 120° C. under nitrogen atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® silica flash column, eluent of 70-100% ethyl acetate / petroleum ether gradient @ 35 mL / min). Compound 6-[6-amino-1-[(4-nitrophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (200 mg, 504.92 μmol, 31% yield, 94% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.66(dd, J=1.3, 8.0Hz, 1H), 8.50(s, 1H), 8.35-8.30(m, 1H), 8.28-8.24(m , 1H), 8.20(d, J=8.9Hz, 2H), 7.41(d, J=8.9Hz, 2H), 7.20(s, 2H), 5.64(s, 2H). MS: m / z=373.1 (M+1, ESI+).

[0603] Step 3: Preparation of 6-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)picolinonitrile (Compound 215)

[0604] A solution of 6-[6-amino-1-[(4-nitrophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (200 mg, 1 equiv.) in water (5 mL) and ethanol (15 mL) was treated with iron powder (150 mg, 5 equiv.) and NH 4Cl (230 mg, 8 equiv.) was added. The mixture was stirred at 60° C. for 3 h. The reaction mixture was concentrated under reduced pressure to remove ethanol and water to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 10%-40%, 11.5 min) to give the desired compound with 89% purity, and the residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250*50*10 μm; mobile phase: [hexane-EtOH (0.1%NH 3 H 2 O)]; B%: 20%-60%, 15min) to give the desired compound with 91% purity. The residue was then purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 16%-46%, 10min). Compound 215 or 6-[6-amino-1-[(4-aminophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (21.55mg, 11% yield, 98.25% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.65(d, J=7.6Hz, 1H), 8.39(s, 1H), 8.35-8.27(m, 1H), 8.26-8.22(m, 1H), 7.12( s, 2H), 6.94(brd, J=8.3Hz, 2H), 6.48(brd, J=8.3Hz, 2H), 5.25(s, 2H), 5.03(s, 2H).

[0605] Example 1.53: Preparation of 6-[6-amino-1-[(4-amino-2-fluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (Compound 219) TIFF0007681616000130.tif36160Reagents and conditions: (a) Pd(OAc) 2 , K 2 CO 3 , Cy 3 P, dioxane, 120°C, 16 hours; b)Fe, NH 4 Cl, THF / H 2 O, 80 °C, 4 hours.

[0606] Step 1: Preparation of 6-[6-amino-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile

[0607] A mixture of intermediate compound S113 or sodium (6-cyano-2-pyridyl)sulfinyloxide (495.01 mg, 2.60 mmol, 1.2 eq), intermediate compound S111 or 4-chloro-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (700 mg, 2.17 mmol, 1 eq), palladium acetate (48.70 mg, 216.93 μmol, 0.1 eq), Cy 3 P (121.67 mg, 433.86 μmol, 140.66 μL, 0.2 eq) and K 2 CO 3 (599.64 mg, 4.34 mmol, 2 eq) was degassed and purged three times with nitrogen, then the mixture was stirred at 120 °C for 16 hours under a nitrogen atmosphere. The mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent with a gradient of 10 - 50% ethyl acetate / petroleum ether @ 40 mL / min). The compound 6-[6-amino-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (220 mg, 503.88 μmol, 26% yield, 89.4% purity) was obtained as a yellow solid. 1 1H NMR (400 MHz, DMSO-d 6 ) δ = 8.66 (dd, J = 1.1, 7.9 Hz, 1H), 8.49 (s, 1H), 8.36 - 8.29 (m, 1H), 8.28 - 8.23 (m, 1H), 8.16 (dd, J = 2.3, 9.8 Hz, 1H), 8.04 (dd, J = 1.8, 8.6 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.22 (s, 2H), 5.64 (s, 2H).

[0608] Step 2: Preparation of 6-[6-amino-1-[(4-amino-2-fluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (compound 219)

[0609] A mixture of 6-[6-amino-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (200 mg, 512.39 μmol, 1 equiv.) in THF (10 mL) and water (2 mL) was treated with iron powder (143 mg, 2.56 mmol, 5 equiv.) and NH 4 Cl (219.27 mg, 4.10 mmol, 8 equiv.) was added. The mixture was then stirred at 80° C. for 4 h. The reaction mixture was filtered and the filtrate was diluted with 50 mL of saturated NaHCO 3 Aqueous solution was added and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250*70*10 μm; mobile phase: [hexane-EtOH (0.1% NH 3 H 2 O)]; B%: 35%-75%, 15 min). Compound 219 or 6-[6-amino-1-[(4-amino-2-fluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (56.69 mg, 151.63 μmol, 30% yield, 96.38% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.65(dd, J=1.2, 8.0Hz, 1H), 8.39(s, 1H), 8.34-8.29(m, 1H), 8.26-8.22(m, 1H), 7.13(s, 2H), 6.95-6.79(m, 1H), 6.31(dd, J=1.8, 5.4Hz, 1H), 6.28(s, 1H), 5.40(s, 2H), 5.29(s, 2H).

[0610] Example 1.54: Preparation of 6-[6-amino-1-[(4-amino-2,6-difluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (Compound 223) TIFF0007681616000131.tif38160Reagents and conditions: (a) Pd(OAc) 2 , K 2 CO 3 , Cy 3 P, dioxane, 120 °C, 16 h.( b ) Fe, NH 4 Cl, THF / H 2 O, 80 °C, 5 h.

[0611] Step 1: Preparation of 6-[6-amino-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile

[0612] The intermediate compound S113 or sodium 6-cyanopyridine-2-sulfinate (530 mg, 2.79 mmol, 2 eq) in dioxane (15 mL), the intermediate compound S112 or 4-chloro-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (470 mg, 1.38 mmol, 0.99 eq), palladium acetate (31 mg, 139.36 μmol, 0.1 eq), Cy 3 P (78 mg, 278.72 μmol, 0.2 eq) and K 2 CO 3(385 mg, 2.79 mmol, 2 equiv) was degassed and purged with nitrogen three times, after which the mixture was stirred at 120° C. under nitrogen atmosphere for 16 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (20 g Sepa Flash® silica flash column, eluent of 30-60% ethyl acetate / petroleum ether gradient @ 50 mL / min). Compound 6-[6-amino-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (180 mg, 290.95 μmol, 21% yield, 66% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.65(dd, J=1.1, 8.0Hz, 1H), 8.38(s, 1H), 8.35-8.33(m, 1H), 8.26-8.21(m, 1H), 8.12-8.06(m, 2H), 7.22(s, 2H), 5.57(s, 2H). MS: m / z=409.0 (M+1, ESI+).

[0613] Step 2: Preparation of 6-[6-amino-1-[(4-amino-2,6-difluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (compound 223)

[0614] A mixture of 6-[6-amino-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (180 mg, 290.95 μmol, 66% purity, 1 equiv.) in THF (10 mL) and water (3 mL) was treated with iron powder (81 mg, 1.45 mmol, 5 equiv.) and NH 4 Cl (124 mg, 2.33 mmol, 8 equiv.) was added. The mixture was then stirred at 80° C. for 5 h. The reaction mixture was filtered and the filtrate was treated with saturated NaHCO 3Aqueous solution (50 mL) was added and extracted with ethyl acetate (80 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250*70*10 μm; mobile phase: [hexane-EtOH (0.1% ammonium hydroxide)]; B%: 40%-80%, 10 min). Compound 223 or 6-[6-amino-1-[(4-amino-2,6-difluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (24.24 mg, 60.94 μmol, 21% yield, 95.11% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.65(dd, J=0.9, 8.0Hz, 1H), 8.35(s, 1H), 8.34-8.29(m, 1H), 8.27-8. 21(m, 1H), 7.13(s, 2H), 6.18(d, J=10.3Hz, 2H), 5.80(s, 2H), 5.27(s, 2H).

[0615] Example 1.55: Preparation of 6-(6-amino-1-(2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)picolinonitrile (Compound 231) TIFF0007681616000132.tif37160Reagents and conditions: (a) Pd(OAc) 2 , K 2 CO 3 , Cy 3 P, dioxane, 120°C, 10 h, MW.

[0616] (6-cyano-2-pyridyl)sulfinyloxysodium (231 mg, 1.2 equiv.), intermediate compound S110 or 4-chloro-1-[(2,6-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (300 mg, 1 equiv.), palladium acetate (23 mg, 0.1 equiv.), Cy 3 P (57 mg, 0.2 equiv.) and K 2 CO 3The mixture of [[ID=]] (280 mg, 2 eq) was degassed and purged three times with nitrogen. The mixture was then stirred at 120 °C for 10 h under microwave conditions. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 37%-67%, 11 min). Compound 231 or 6-[6-amino-1-[(2,6-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (70.52 mg, 18% yield, 95.65% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.65 (dd, J = 1.0, 8.0 Hz, 1H), 8.36 (s, 1H), 8.33 - 8.27 (m, 1H), 8.26 - 8.20 (m, 1H), 7.51 - 7.41 (m, 1H), 7.18 (s, 2H), 7.12 (t, J = 8.0 Hz, 2H), 5.48 (s, 2H).

[0617] Example 1.56: Preparation of 6-(6-amino-1-(4-amino-3-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)picolino-nitrile (Compound 227) TIFF0007681616000133.tif38160Reagents and conditions: (a) Pd(OAc) 2 , K 2 CO 3 , Cy 3 P, dioxane, 120 °C, 16 h. (b) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 2 h.

[0618] Step 1: Preparation of 6-[6-amino-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile

[0619] Intermediate compound S113 or (6-cyano-2-pyridyl)sulfinyloxy sodium (356 mg, 1.2 equiv.), intermediate compound S108 or 4-chloro-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (500 mg, 1 equiv.), palladium acetate (35 mg, 0.1 equiv.), Cy 3 P (88 mg, 0.2 equiv.) and K 2 CO 3 A mixture of (433 mg, 2 equiv.) was degassed and purged with nitrogen three times, then the mixture was stirred at 120° C. under nitrogen atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 24 g Sepa Flash® silica flash column, eluent of 50-80% ethyl acetate / petroleum ether gradient @ 35 mL / min). Compound 6-[6-amino-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (300 mg, 40% yield, 81% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.66(dd, J=1.1, 7.9Hz, 1H), 8.48(s, 1H), 8.37-8.29(m, 1H), 8.28-8.22(m, 1H) , 7.95(d, J=8.5Hz, 1H), 7.32(s, 1H), 7.24-7.14(m, 3H), 5.55(s, 2H), 2.47(s, 3H). MS: m / z=387.1 (M+1, ESI+).

[0620] Step 2: Preparation of 6-(6-amino-1-(4-amino-3-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)picolinonitrile (Compound 227)

[0621] A solution of 6-[6-amino-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (311 mg, 1 equiv.) in water (5 mL) and ethanol (15 mL) was diluted with iron powder (225 mg, 5 equiv.) and NH 4 Cl (344 mg, 8 equiv.) was added. The mixture was stirred at 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove ethanol and water to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 10%-40%, 11.5 min) to give the desired compound with 88% purity, and the residue was re-purified by preparative HPLC (column: Welch Ultimate XB-SiOH 250*50*10 μm; mobile phase: [hexane-EtOH (0.1%NH 3 H 2 O)]; B%: 15%-55%, 15 min) to give the desired compound with 90% purity. The residue was then purified by preparative HPLC (column: Welch Ultimate XB-SiOH 250*50*10 μm; mobile phase: [Hexane-EtOH (0.1% NH 3 H 2 O)]; B%: 15%-55%, 15 min), the desired compound was obtained with 91% purity. Finally, the residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 21%-51%, 10 min). Compound 227 or 6-[6-amino-1-[(4-amino-3-methyl-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-2-carbonitrile (30.69mg, 10% yield, 98.87% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6)δ=8.65(dd, J=1.1, 8.0Hz, 1H), 8.39(s, 1H), 8.34-8.27(m, 1H), 8.26-8.20(m, 1H), 7.11(s, 2H), 6.8 6(s, 1H), 6.82(dd, J=1.9, 8.1Hz, 1H), 6.52(d, J=8.0Hz, 1H), 5.24(s, 2H), 4.80(s, 2H), 1.99(s, 3H).

[0622] Example 1.57: Preparation of 2-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)isonicotinonitrile (Compound 216) TIFF0007681616000134.tif36161Reagents and conditions: (a) Pd(OAc) 2 , K 2 CO 3 , Cy 3 P, dioxane, 120°C, 16 hours. (b) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 2 hr.

[0623] Step 1: Preparation of 2-(6-amino-1-(4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)isonicotinonitrile

[0624] Sodium 4-cyanopyridine-2-sulfinate (298 mg, 1.2 equiv.), intermediate compound S3 or 4-chloro-1-[(4-nitrophenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (400 mg, 1 equiv.), palladium acetate (29 mg, 0.1 equiv.), Cy 3 P (73 mg, 0.2 equiv.), and K 2 CO 3A mixture of (362 mg, 2 equiv.) was degassed and purged with nitrogen three times, then the mixture was stirred under nitrogen atmosphere at 120° C. for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® silica flash column, eluent of 70-90% ethyl acetate / petroleum ether gradient @ 30 mL / min). Compound 2-[6-amino-1-[(4-nitrophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-4-carbonitrile (300 mg, 55% yield, 89% purity) was obtained as a yellow solid. MS: m / z=373.1 (M+1, ESI+).

[0625] Step 2: Preparation of 2-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)isonicotinonitrile (Compound 216)

[0626] A solution of 2-[6-amino-1-[(4-nitrophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-4-carbonitrile (300 mg, 1 equiv.) in water (5 mL) and ethanol (15 mL) was treated with iron powder (225 mg, 5 equiv.) and NH 4 Cl (345 mg, 8 equiv.) was added. The mixture was stirred at 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove ethanol and water to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (10 mM NH 4 HCO 3 The residue was then purified by a second preparative HPLC (column: Welch Ultimate XB-SiOH 250*50*10 μm; mobile phase: [hexane-EtOH (0.1%NH 3 H 2O)]; B%: 15%-55%, 15 min) to give the desired compound with 80% purity. Finally, the residue was purified by a third preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 17%-47%, 10 min). Compound 216 or 2-[6-amino-1-[(4-aminophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-4-carbonitrile (23.18mg, 8% yield, 95.02% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.54(d, J=2.1Hz, 1H), 9.22(d, J=2.0Hz, 1H), 8.92(t, J=2.1Hz, 1H), 8.45(s, 1H) ), 7.13(s, 2H), 6.96(d, J=8.4Hz, 2H), 6.63-6.37(m, 2H), 5.25(s, 2H), 5.04(s, 2H). HRMS-TOF:343.1408.

[0627] Example 1.58: Preparation of 2-(6-amino-1-(4-amino-2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)isonicotinonitrile (Compound 220) TIFF0007681616000135.tif36160 Reagents and conditions: (a) Pd(OAc) 2 , K 2 CO 3 , Cy 3 P, dioxane, 120°C, 16 hours. (b) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 1 hr

[0628] Step 1: Preparation of 2-(6-amino-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)isonicotinonitrile

[0629] Sodium 4-cyanopyridine-2-sulfinate (424 mg, 1.2 equiv.), intermediate compound S111 or 4-chloro-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (600 mg, 1 equiv.), palladium acetate (41 mg, 0.1 equiv.), Cy 3 P (104 mg, 0.2 equiv.) and K 2 CO 3 A mixture of (513 mg, 2 equiv.) was degassed and purged with nitrogen three times, then the mixture was stirred at 120° C. under nitrogen atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® silica flash column, eluent of 70-90% ethyl acetate / petroleum ether gradient @ 30 mL / min). Compound 2-[6-amino-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-4-carbonitrile (300 mg, 41% yield, 99% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.13-9.06(m, 1H), 8.68(dd, J=0.9, 1.5Hz, 1H), 8.55(s, 1H), 8.16(dd, J=2.3, 9.9Hz, 1H), 8.09( dd, J=1.6, 4.9Hz, 1H), 8.03(dd, J=2.1, 8.5Hz, 1H), 7.30(t, J=8.0Hz, 1H), 7.21(s, 2H), 5.63(s, 2H).

[0630] Step 2: Preparation of 2-(6-amino-1-(4-amino-2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)isonicotinonitrile (Compound 220)

[0631] A solution of 2-[6-amino-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-4-carbonitrile (300 mg, 1 equiv.) in water (5 mL) and ethanol (15 mL) was treated with iron powder (214 mg, 5 equiv.) and NH 4 Cl (328 mg, 8 equiv.) was added. The mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure to remove ethanol and water to give a residue. The residue was purified by preparative HPLC (Column: Welch Ultimate XB-CN 250*70*10 μm; Mobile phase: [Hexane-EtOH Column: Welch Ultimate XB-SiOH 250*50*10 μm; Mobile phase: [Hexane-EtOH (0.1% NH3·H2O)]; B%: 15%-55%, 15 min (0.1% NH 3 H 2 O)]; B%: 30%-70%, 15 min) to obtain the desired compound with 90% purity after preparative HPLC, and the residue was purified by a second preparative HPLC (column: Welch Ultimate XB-CN 250*70*10 μm; mobile phase: [Hexane-EtOH (0.1% aqueous ammonia)]; B%: 30%-70%, 15 min). Compound 220 or 2-[6-amino-1-[(4-amino-2-fluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-4-carbonitrile (33.67 mg, 89.81 μmol, purity 96.12%) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.08(dd, J=0.7, 5.0Hz, 1H), 8.68(d, J=1.3Hz, 1H), 8.46(s, 1H), 8.08(dd, J=1.6, 5.0Hz, 1H) , 7.13(s, 2H), 6.88(t, J=8.4Hz, 1H), 6.33-6.30(m, 1H), 6.29(s, 1H), 5.40(s, 2H), 5.29(s, 2H).

[0632] Example 1.59: Preparation of 2-[6-amino-1-[(4-amino-2,6-difluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-4-carbonitrile (Compound 224) TIFF0007681616000136.tif90118Reagents and conditions: (a) Fe, NH 4 Cl, EtOH / H 2 O, 80℃, 3 hours. (b)Pd(OAc) 2 , K 2 CO 3 , PCy3, dioxane, 120°C, 16 hours.

[0633] Step 1: Preparation of 1-(4-amino-2,6-difluorobenzyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (intermediate compound S114)

[0634] To a mixture of intermediate compound S112 or 4-chloro-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (700 mg, 1.38 mmol, 67% purity, 1 equiv.) in water (3 mL) and ethanol (10 mL) was added iron powder (385 mg, 6.88 mmol, 5 equiv.) and NH 4 Cl (590 mg, 11.01 mmol, 8 equiv.) was added. The mixture was then stirred at 80° C. for 3 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum. Water (30 mL) was added to the mixture and extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250*70*10 μm; mobile phase: [hexane-EtOH (0.1% NH 3 H 2 0)]; B%: 20%-60%, 15 min). Intermediate compound S114 or 1-(4-amino-2,6-difluorobenzyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (400 mg, 1.03 mmol, 75% yield, 88% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6)δ=7.92(s, 1H), 7.32(s, 2H), 6.25-6.09(m, 2H), 5.80(s, 2H), 5.18(s, 2H).

[0635] Step 2: Preparation of 2-[6-amino-1-[(4-amino-2,6-difluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-4-carbonitrile (compound 224)

[0636] (4-Cyano-2-pyridyl)sulfinyloxy sodium (550 mg, 2.89 mmol, 2.55 equiv.), intermediate compound S114 or 1-[(4-amino-2,6-difluoro-phenyl)methyl]-4-chloropyrazolo[3,4-d]pyrimidin-6-amine (400 mg, 1.13 mmol, 88% purity, 1 equiv.), palladium acetate (25 mg, 113.30 μmol, 0.1 equiv.), Cy in dioxane (10 mL). 3 P (63 mg, 226.59 μmol, 73.46 μL, 0.2 equiv.) and K 2 CO 3 (313 mg, 2.27 mmol, 2 equiv) was degassed and purged with nitrogen three times, after which the mixture was stirred at 120° C. under nitrogen atmosphere for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g Sepa Flash® silica flash column, eluent of 20-40% ethyl acetate / petroleum ether gradient @ 40 mL / min). Compound 224 or 2-[6-amino-1-[(4-amino-2,6-difluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-4-carbonitrile (70 mg, 181.87 μmol, 16% yield, 98.30% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.07(dd, J=0.8, 5.0Hz, 1H), 8.67(dd, J=0.9, 1.5Hz, 1H), 8.41(s, 1H), 8.06( dd, J=1.7, 5.0Hz, 1H), 7.11(s, 2H), 6.27-6.11(m, 2H), 5.79(s, 2H), 5.26(s, 2H).

[0637] Example 1.60: Preparation of 2-(6-amino-1-(2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)isonicotinonitrile (Compound 232) TIFF0007681616000137.tif38160Reagents and conditions: (a) Pd(OAc) 2 , K 2 CO 3 , Cy 3 P, dioxane, 120° C., 16 h.

[0638] (4-cyano-2-pyridyl)sulfinyloxysodium (232 mg, 1.2 equiv.), intermediate compound S110 or 4-chloro-1-[(2,6-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (300 mg, 1 equiv.), palladium acetate (23 mg, 0.1 equiv.), Cy3P (57 mg, 0.2 equiv.), and K in dioxane (5 mL). 2 CO 3 A mixture of (281 mg, 2 equiv.) was degassed and purged with nitrogen three times, then the mixture was stirred at 120° C. under nitrogen atmosphere for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 43%-63%, 10 min). Compound 232 or 2-[6-amino-1-[(2,6-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-4-carbonitrile (66.33 mg, 18% yield, 99.34% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.06(d, J=5.0Hz, 1H), 8.67(s, 1H), 8.44-8.38(m, 1H), 8.09-8.03(m, 1 H), 7.51-7.39(m, 1H), 7.22-7.15(m, 2H), 7.14-7.09(m, 2H), 5.47(s, 2H).

[0639] Example 1.61: 2-(6-amino-1-(4-amino-3-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)isonicotinonitrile (Compound 228) TIFF0007681616000138.tif36160Reagents and conditions: (a) Pd(OAc) 2 , K 2 CO 3 , Cy 3 P, dioxane, 120°C, 16 hours. (b) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 2 hr.

[0640] Step 1: Preparation of 2-(6-amino-1-(3-methyl-4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)isonicotinonitrile

[0641] (4-Cyano-2-pyridyl)sulfinyloxy sodium (215 mg, 1.2 equiv.), intermediate compound S108 or 4-chloro-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (300 mg, 1 equiv.), palladium acetate (21 mg, 0.1 equiv.), Cy 3 P (52 mg, 0.2 equiv.) and K 2 CO 3 (260 mg, 2 equiv.) mixture was degassed and purged with nitrogen three times, after which the mixture was stirred under nitrogen atmosphere at 120° C. for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 24 g Sepa Flash® silica flash column, eluent of 50-80% ethyl acetate / petroleum ether gradient @ 35 mL / min). Compound 2-[6-amino-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-4-carbonitrile (200 mg, 55% yield) was obtained as a yellow solid. MS: m / z=387.1 (M+1, ESI+).

[0642] Step 2: Preparation of 2-(6-amino-1-(4-amino-3-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)isonicotinonitrile (Compound 228)

[0643] A solution of 2-[6-amino-1-[(3-methyl-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-4-carbonitrile (200 mg, 1 equiv.) in ethanol (15 mL) and water (5 mL) was diluted with iron powder (145 mg, 5 equiv.) and NH 4 Cl (221 mg, 8 equiv.) was added. The mixture was stirred at 60° C. for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 20%-50%, 8 min) to give a compound with 80% purity after preparative HPLC, and the residue was purified by a second preparative HPLC (column: Shim-packC18 150*25*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 16%-46%, 10 min). Compound 228 or 2-[6-amino-1-[(4-amino-3-methyl-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-4-carbonitrile (19.65mg, 10% yield, 96.15% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.08(dd, J=0.8, 4.9Hz, 1H), 8.67(dd, J=0.9, 1.6Hz, 1H), 8.45(s, 1H), 8.07(dd, J=1.6, 5.0Hz, 1H), 7.10(s , 2H), 6.86(s, 1H), 6.82(dd, J=1.9, 8.1Hz, 1H), 6.51(d, J=8.0Hz, 1H), 5.23(s, 2H), 4.80(s, 2H), 1.98(s, 3H).

[0644] Example 1.62: Preparation of 5-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)nicotinonitrile (Compound 217) TIFF0007681616000139.tif36168Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 110℃, 16 hours; (b) Fe, NH 4 Cl, THF / H 2 O, 60 °C, 3 hr.

[0645] Step 1: Preparation of 5-(6-amino-1-(4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)nicotinonitrile

[0646] (5-cyano-3-pyridyl)boronic acid (583 mg, 1.5 equiv.), intermediate compound S3 or 4-chloro-1-[(4-nitrophenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (800 mg, 1 equiv.), K 2 CO 3 (726 mg, 2 equivalents), Pd(dppf)Cl 2 A mixture of (192 mg, 0.1 equiv.) was degassed and purged with nitrogen three times, then the mixture was stirred at 110° C. under nitrogen atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 24 g Sepa Flash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 30 mL / min). Compound 5-[6-amino-1-[(4-nitrophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-3-carbonitrile (800 mg, 82% yield) was obtained as a yellow solid. Solid. 1 H NMR (400 MHz, DMSO-d 6)δ=9.63-9.52(m, 1H), 9.37-9.31(m, 2H), 9.25-9.23(m, 1H), 9.15-9.12(m, 2H), 7.46-7.42(m, 2H), 5.65-5.60(m, 2H). MS: m / z=373.1 (M+1, ESI+).

[0647] Step 2: Preparation of 5-(6-amino-1-(4-aminobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)nicotinonitrile (Compound 217)

[0648] A solution of 5-[6-amino-1-[(4-nitrophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-3-carbonitrile (300 mg, 1 equiv.) in THF (15 mL) and water (5 mL) was treated with iron powder (224 mg, 5 equiv.) and NH 4 Cl (344 mg, 8 equiv.) was added. The mixture was stirred at 60° C. for 3 h. The reaction mixture was concentrated under reduced pressure to remove THF and water to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 10%-40%, 11.5 min). Compound 217 or 5-[6-amino-1-[(4-aminophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-3-carbonitrile (27.63 mg, 7% yield, 98.17% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.54(d, J=2.1Hz, 1H), 9.22(d, J=2.0Hz, 1H), 8.92(t, J=2.1Hz, 1H), 8.45(s, 1H) ), 7.13(s, 2H), 6.96(d, J=8.4Hz, 2H), 6.63-6.37(m, 2H), 5.25(s, 2H), 5.04(s, 2H).

[0649] Example 1.63: Preparation of 5-[6-amino-1-[(4-amino-2-fluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-3-carbonitrile (Compound 221) TIFF0007681616000140.tif33161Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 110℃, 16 hours; (b) Fe, NH 4 Cl, EtOH / H 2 O, 60 °C, 2 hr.

[0650] Step 1: Preparation of 5-(6-amino-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)nicotinonitrile

[0651] (5-cyano-3-pyridyl)boronic acid (343 mg, 1.5 equiv.), intermediate compound S111 or 4-chloro-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (500 mg, 1 equiv.), K 2 CO 3 (428 mg, 2 eq.), Pd(dppf)Cl 2 (113 mg, 0.1 equiv.) mixture was degassed and purged with nitrogen three times, after which the mixture was stirred under nitrogen atmosphere at 110° C. for 16 h. The reaction mixture was concentrated under reduced pressure to remove dioxane to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® silica flash column, eluent of 0-80% ethyl acetate / petroleum ether gradient @ 30 mL / min). Compound 5-[6-amino-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-3-carbonitrile (300 mg, 50% yield) was obtained as a yellow solid. MS: m / z=390.9 (M+1, ESI+).

[0652] Step 2: Preparation of 5-(6-amino-1-(4-amino-2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)nicotinonitrile (Compound 221)

[0653] A solution of 5-[6-amino-1-[(2-fluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-3-carbonitrile (300 mg, 1 equiv.) in ethanol (15 mL) and water (5 mL) was diluted with iron powder (214 mg, 5 equiv.) and NH 4 Cl (328 mg, 8 equiv.) was added. The mixture was stirred at 60° C. for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 13%-43%, 11.5 min). Compound 221 or 5-[6-amino-1-[(4-amino-2-fluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-3-carbonitrile (37.61 mg, 13% yield, 94.57% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=9.54(d, J=2.1Hz, 1H), 9.23(d, J=2.0Hz, 1H), 8.91(t, J=2.0Hz, 1H), 8.45(s, 1H), 7.14(s, 2H), 6.90(t, J=8.4Hz, 1H), 6.31(d, J=10.8Hz, 2H), 5.41(s, 2H), 5.29(s, 2H).

[0654] Example 1.64: Preparation of 5-[6-amino-1-[(4-amino-2,6-difluoro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-3-carbonitrile (Compound 225) TIFF0007681616000141.tif39160Reagents and conditions: (a) Pd(dppf)Cl 2 , K 2 CO 3 , dioxane / H 2 O, 100℃, 15 hours; (b) Fe, NH 4 Cl, EtOH / H 2 O, 80 °C, 2 hr.

[0655] Step 1: Preparation of 5-[6-amino-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]pyridine-3-carbonitrile

[0656] To a solution of intermediate compound S112 or 4-chloro-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (400 mg, 1.17 mmol, 1 equiv.) in dioxane (10 mL) and water (2 mL) was added (5-cyano-3-pyridyl)boronic acid (346 mg, 2.34 mmol, 2 equiv.), Pd(dppf)Cl 2 (86 mg, 117.00 μmol, 0.1 equiv.) and K 2 CO 3 (323 mg, 2.34 mmol, 2 equiv.) was added. The mixture was then stirred at 100° C. for 15 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (20 g Sepa Flash® silica flash column, eluent of 0-60% ethyl acetate / petroleum ether gradient @ 50 mL / min). Compound 5-[6-amino-1-[(2,6-difluoro-4-nitro-phenyl)methyl]pyrazolo[3,4-d...

Claims

1. A compound of formula (Ib) or a solvate, hydrate and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: (Ib) R is H, (C 1 -C 3 ) alkyl, or substituted (C 1 -C 3 ) alkyl; Y 1 Or Y 4 is an independent CR 10 and N, Y 1 Or Y 4 At least two of the following are independently CR 10 and R 10 are each independently H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 ) alkoxy, substituted (C 1 -C 8 ) Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, —CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 N.H. 2 , substituted sulfonamide, and thiol, with the proviso that Y 1 is not CH; R a and R b are each independently H, F, (C 1 -C 3 ) alkyl, and substituted (C 1 -C 3 ) alkyl, or R a and R b are attached to a ring and together with the carbon atoms to which they are attached form a cyclopropyl, or substituted cyclopropyl; A is phenyl, substituted phenyl, pyridyl, or substituted pyridyl.

2. i) A is phenyl or one, two or three R 20 phenyl substituted with R 20 are each independently (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 ) alkoxy, substituted (C 1 -C 8 ) Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, —CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 N.H. 2 , substituted sulfonamide, and thiol, or ii) A is pyridyl or one, two or three R 20 pyridyl substituted with R 20 are each independently (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 ) alkoxy, substituted (C 1 -C 8 ) Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, —CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 N.H. 2 13. The compound of claim 1, wherein the compound is selected from the group consisting of aryl, aryloxy ...

3. R a and R b 10. The compound of claim 1, wherein each is H, or a solvate, hydrate, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

4. 2. The compound of claim 1, wherein the compound of formula (Ib) is of formula (IIb): or a solvate, hydrate, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: (IIb) Here, R 1 (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 ) alkoxy, substituted (C 1 -C 8 ) Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, —CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 N.H. 2 , a substituted sulfonamide, and a thiol; R 2 Or R 9 are independently H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, substituted (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, substituted (C 2 -C 8 ) alkynyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 8 ) alkoxy, substituted (C 1 -C 8 ) Alkoxy, -CONH 2 , substituted amide, -NH 2 , substituted amino, —CO 2 H, cyano, halogen, hydroxyl, -NO 2 , -SO 3 H, -SO 2 N.H. 2 , substituted sulfonamide, and thiol.

5. R 1 NH 2 , F., C.H. 3 , and C.F. 3 is selected from R 2 Or R 9 are independently H, NH 2 , F., C.H. 3 , and C.F. 3 5. The compound according to claim 4, selected from: or a solvate, hydrate and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

6. 5. The compound of claim 4, wherein the compound of formula (IIb) is of formula (IIIb): or a solvate, hydrate, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: (IIIb) Here, R 21 and R 22 are independently H, (C 1 -C 8 ) alkyl, substituted (C 1 -C 8 ) alkyl, SO 2 R 30 , and C.O.R. 30 is selected from R 30 (C 1 -C 8 ) alkyl, or substituted (C 1 -C 8 ) alkyl.

7. R 21 and R 22 and each is H; or a solvate, hydrate, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

8. R 1 However, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 ) alkoxy, substituted (C 1 -C 5 ) selected from alkoxy, halogen, and hydroxyl; R 5 , R 6 , R 8 and R 9 However, independently, H, (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 ) alkoxy, substituted (C 1 -C 5 7. The compound of claim 6, wherein R is selected from the group consisting of alkoxy, halogen, and hydroxyl, or a solvate, hydrate, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

9. R 1 But F, CH 3 , and C.F. 3 is selected from R 5 , R 6 , R 8 and R 9 However, independently, H, F, CH 3 , and C.F. 3 and R 2 Or R 4 9. The compound of claim 8, wherein each is H, or a solvate, hydrate, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

10. R 2 Or R 4 are each H; R 1 (C 1 -C 5 ) alkyl, substituted (C 1 -C 5 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 5 ) alkoxy, substituted (C 1 -C 5 5. The compound of claim 4, wherein R is selected from the group consisting of alkoxy, halogen, and hydroxyl, or a solvate, hydrate, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

11. 2. The compound of claim 1, wherein the compound of formula (Ib) is selected from the following: or a solvate, hydrate, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a solvate, hydrate and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, optionally comprising a pharma- ceutically acceptable excipient.

13. 1. An in vitro method of inhibiting adenosine A2A and / or A1 receptors, comprising: A sample containing adenosine A2A and / or A1 receptors is contacted with an effective amount of a compound according to any one of claims 1-11, or a solvate, hydrate and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, to inhibit adenosine A2A and / or A1 receptors.

14. 1. An in vitro method of antagonizing adenosine A2A and / or A1 receptors, comprising: A cell containing adenosine A2A and / or A1 receptors is contacted with an effective amount of a compound according to any one of claims 1-11, or a solvate, hydrate, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, to antagonize the adenosine A2A and / or A1 receptors.

15. A pharmaceutical composition for treating cancer comprising as an active ingredient an A2A and / or A1 receptor antagonist compound according to any one of claims 1-11, or a solvate, hydrate and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

16. The pharmaceutical composition of claim 15, wherein the cancer is a solid tumor cancer.

17. 16. The pharmaceutical composition of claim 15, wherein the cancer is selected from lung cancer, breast cancer, prostate cancer, ovarian cancer, solenoma, cervical cancer, bladder cancer, head and neck cancer, renal cell carcinoma, esophageal cancer, pancreatic cancer, brain cancer, liver cancer, leukemia, lymphoma, melanoma, multiple myeloma, Ewing's sarcoma, osteosarcoma, colorectal tumor, bile duct cancer, choriocarcinoma, oral cancer, neuroblastoma, skin cancer, testicular cancer, stromal tumor, germ cell tumor, and thyroid cancer.

18. 16. The pharmaceutical composition of claim 15, which is administered in combination with an additional active agent.

19. 20. The pharmaceutical composition of claim 18, wherein the additional active agent is selected from an anti-angiogenic agent, an anti-inflammatory agent, an immune checkpoint inhibitor, a PARP inhibitor, a chemotherapeutic agent, and an immune anti-cancer agent.

20. 19. The pharmaceutical composition of claim 18, wherein the additional active agent is an immune checkpoint inhibitor selected from a CTLA-4 inhibitor, a PD-1 inhibitor, and a PD-L1 inhibitor.

21. 21. The pharmaceutical composition of claim 20, wherein the immune checkpoint inhibitor is an antibody or an antibody fragment.

22. A pharmaceutical composition for treating an inflammatory disease comprising an A2A and / or A1 receptor antagonist compound according to any one of claims 1-11, or a solvate, hydrate, and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

23. Use of an A2A and / or A1 receptor antagonist compound, or a solvate, hydrate and / or stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, according to any one of claims 1-11, in the manufacture of a pharmaceutical composition according to any one of claims 15-22.

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